期刊题录 -- 2022 Critical Care

# 期刊题录 -- 2022 Critical Care

Atman 机器翻译，未校对

# Capnodynamic monitoring of lung volume and blood flow in response to increased positive end-expiratory pressure in moderate to severe COVID-19 pneumonia: an observational study

Abstract

BACKGROUND: The optimal level of positive end-expiratory pressure (PEEP) during mechanical ventilation for COVID-19 pneumonia remains debated and should ideally be guided by responses in both lung volume and perfusion. Capnodynamic monitoring allows both end-expiratory lung volume ([Formula: see text]) and effective pulmonary blood flow (EPBF) to be determined at the bedside with ongoing ventilation.

METHODS: Patients with COVID-19-related moderate to severe respiratory failure underwent capnodynamic monitoring of [Formula: see text] and EPBF during a step increase in PEEP by 50% above the baseline (PEEP(low) to PEEP(high)). The primary outcome was a > 20 mm Hg increase in arterial oxygen tension to inspired fraction of oxygen (P/F) ratio to define responders versus non-responders. Secondary outcomes included changes in physiological dead space and correlations with independently determined recruited lung volume and the recruitment-to-inflation ratio at an instantaneous, single breath decrease in PEEP. Mixed factor ANOVA for group mean differences and correlations by Pearson's correlation coefficient are reported including their 95% confidence intervals.

RESULTS: Of 27 patients studied, 15 responders increased the P/F ratio by 55 [24-86] mm Hg compared to 12 non-responders (p < 0.01) as PEEP(low) (11 ± 2.7 cm H(2)O) was increased to PEEP(high) (18 ± 3.0 cm H(2)O). The [Formula: see text] was 461 [82-839] ml less in responders at PEEP(low) (p = 0.02) but not statistically different between groups at PEEP(high). Responders increased both [Formula: see text] and EPBF at PEEP(high) (r = 0.56 [0.18-0.83], p = 0.03). In contrast, non-responders demonstrated a negative correlation (r = - 0.65 [- 0.12 to - 0.89], p = 0.02) with increased lung volume associated with decreased pulmonary perfusion. Decreased (- 0.06 [- 0.02 to - 0.09] %, p < 0.01) dead space was observed in responders. The change in [Formula: see text] correlated with both the recruited lung volume (r = 0.85 [0.69-0.93], p < 0.01) and the recruitment-to-inflation ratio (r = 0.87 [0.74-0.94], p < 0.01).

CONCLUSIONS: In mechanically ventilated patients with moderate to severe COVID-19 respiratory failure, improved oxygenation in response to increased PEEP was associated with increased end-expiratory lung volume and pulmonary perfusion. The change in end-expiratory lung volume was positively correlated with the lung volume recruited and the recruitment-to-inflation ratio. This study demonstrates the feasibility of capnodynamic monitoring to assess physiological responses to PEEP at the bedside to facilitate an individualised setting of PEEP.

# 在中至重度 COVID-19 肺炎中对呼气末正压增加应答的肺容量和血流量的二氧化碳动态监测：一项观察性研究

摘要

背景：COVID-19 肺炎机械通气期间呼气末正压 (PEEP) 的最佳水平仍有争议，理想情况下应通过肺容量和灌注的反应进行指导。二氧化碳监测仪允许在持续通气的情况下，在床边测定呼气末肺容量（[公式：见正文]）和有效肺血流量 (EPBF)。

方法：COVID-19 相关的中度至重度呼吸衰竭患者在 PEEP 较基线增加 50%（PEEP（低）至 PEEP（高））的过程中接受了二氧化碳动力学监测 [公式：见文本] 和 EPBF。主要结局是动脉血氧分压与吸入气中的氧气分数 (P/F) 比值增加 > 20 mmHg，以定义应答者与非应答者。次要结局包括生理死腔的变化以及与独立确定的肺复张体积和 PEEP 中单次呼吸瞬时减少时的肺复张 / 充气比的相关性。报告了组平均差异的混合因素 ANOVA 和 Pearson 相关系数的相关性，包括其 95% 置信区间。

结果：在研究的 27 例患者中，15 例应答者的 P/F 比增加了 55 [24-86] mm Hg，而 12 例无应答者 (P < 0.01)，因为 PEEP（低）(11±2.7 cm h2) O）增加至 PEEP（高）(18±3.0 cm h2) O）。PEEP（低）时应答者的 [公式：见文本] 少 461 [82-839] ml (p = 0.02)，但 PEEP（高）时组间无统计学差异。应答者增加了 [公式：见正文] 和 PEEP 时的 EPBF（高）(r = 0.56 [0.18-0.83]，p = 0.03)。相反，无应答者表现出与肺灌注减少相关的肺容量增加呈负相关（r =-0.65 [-0.12 至 - 0.89]，p = 0.02）。在反应者中观察到死腔减少（-0.06 [-0.02 至 - 0.09]%，p < 0.01）。[公式：见正文] 中的变化与肺容量 (r = 0.85 [0.69-0.93]，p < 0.01) 和肺通气比 (r = 0.87 [0.74-0.94]，p < 0.01) 相关。

结论：在中度至重度 COVID-19 呼吸衰竭的机械通气患者中，PEEP 增加导致的氧合改善与呼气末肺容量和肺灌注增加相关。呼气末肺容积的变化与肺容积招募和招募 - 充气比呈正相关。这项研究表明，二氧化碳监测仪在床边评估 PEEP 的生理反应，以促进 PEEP 个体化设置的可行性。

DOI: 10.1186/s13054-022-04110-0; No. 232

关键词：Humans; Oxygen; Positive-Pressure Respiration; *COVID-19; *Mechanical ventilation; *Respiratory Insufficiency; *Lung perfusion; *Lung volume; *Monitoring; *Positive end-expiratory pressure; Lung Volume Measurements; Tidal Volume/physiology

# Influence of temperature management at 33 °C versus normothermia on survival in patients with vasopressor support after out-of-hospital cardiac arrest: a post hoc analysis of the TTM-2 trial

Abstract

BACKGROUND: Targeted temperature management at 33 °C (TTM33) has been employed in effort to mitigate brain injury in unconscious survivors of out-of-hospital cardiac arrest (OHCA). Current guidelines recommend prevention of fever, not excluding TTM33. The main objective of this study was to investigate if TTM33 is associated with mortality in patients with vasopressor support on admission after OHCA.

METHODS: We performed a post hoc analysis of patients included in the TTM-2 trial, an international, multicenter trial, investigating outcomes in unconscious adult OHCA patients randomized to TTM33 versus normothermia. Patients were grouped according to level of circulatory support on admission: (1) no-vasopressor support, mean arterial blood pressure (MAP) ≥ 70 mmHg; (2) moderate-vasopressor support MAP < 70 mmHg or any dose of dopamine/dobutamine or noradrenaline/adrenaline dose ≤ 0.25 µg/kg/min; and (3) high-vasopressor support, noradrenaline/adrenaline dose > 0.25 µg/kg/min. Hazard ratios with TTM33 were calculated for all-cause 180-day mortality in these groups.

RESULTS: The TTM-2 trial enrolled 1900 patients. Data on primary outcome were available for 1850 patients, with 662, 896, and 292 patients in the, no-, moderate-, or high-vasopressor support groups, respectively. Hazard ratio for 180-day mortality was 1.04 [98.3% CI 0.78-1.39] in the no-, 1.22 [98.3% CI 0.97-1.53] in the moderate-, and 0.97 [98.3% CI 0.68-1.38] in the high-vasopressor support groups with regard to TTM33. Results were consistent in an imputed, adjusted sensitivity analysis.

CONCLUSIONS: In this exploratory analysis, temperature control at 33 °C after OHCA, compared to normothermia, was not associated with higher incidence of death in patients stratified according to vasopressor support on admission.

DOI: 10.1186/s13054-022-04107-9; No. 231

关键词：Humans; Adult; Vasoconstrictor Agents/therapeutic use; *Mortality; *Cardiopulmonary Resuscitation/methods; Epinephrine/therapeutic use; Norepinephrine/therapeutic use; Temperature; *Hypothermia, Induced/methods; *Shock; *Cardiac arrest; *Heart arrest; *Hypothermia induced; *Out-of-Hospital Cardiac Arrest/drug therapy; *Sudden

DOI: 10.1186/s13054-022-04106-w; No. 230

关键词：Humans; Intensive Care Units; Adult; Administration, Intravenous; *Sepsis/drug therapy; Vitamins/therapeutic use; *Ascorbic Acid/therapeutic use

DOI: 10.1186/s13054-022-04096-9; No. 229

关键词：Humans; Treatment Outcome; Double-Blind Method; Pilot Projects; Blood Loss, Surgical; *COVID-19; *Antifibrinolytic Agents; *Tranexamic Acid; Angiotensin I; Peptide Fragments

# Clustering identifies endotypes of traumatic brain injury in an intensive care cohort: a CENTER-TBI study

Abstract

BACKGROUND: While the Glasgow coma scale (GCS) is one of the strongest outcome predictors, the current classification of traumatic brain injury (TBI) as 'mild', 'moderate' or 'severe' based on this fails to capture enormous heterogeneity in pathophysiology and treatment response. We hypothesized that data-driven characterization of TBI could identify distinct endotypes and give mechanistic insights.

METHODS: We developed an unsupervised statistical clustering model based on a mixture of probabilistic graphs for presentation (< 24 h) demographic, clinical, physiological, laboratory and imaging data to identify subgroups of TBI patients admitted to the intensive care unit in the CENTER-TBI dataset (N = 1,728). A cluster similarity index was used for robust determination of optimal cluster number. Mutual information was used to quantify feature importance and for cluster interpretation.

RESULTS: Six stable endotypes were identified with distinct GCS and composite systemic metabolic stress profiles, distinguished by GCS, blood lactate, oxygen saturation, serum creatinine, glucose, base excess, pH, arterial partial pressure of carbon dioxide, and body temperature. Notably, a cluster with 'moderate' TBI (by traditional classification) and deranged metabolic profile, had a worse outcome than a cluster with 'severe' GCS and a normal metabolic profile. Addition of cluster labels significantly improved the prognostic precision of the IMPACT (International Mission for Prognosis and Analysis of Clinical trials in TBI) extended model, for prediction of both unfavourable outcome and mortality (both p < 0.001).

CONCLUSIONS: Six stable and clinically distinct TBI endotypes were identified by probabilistic unsupervised clustering. In addition to presenting neurology, a profile of biochemical derangement was found to be an important distinguishing feature that was both biologically plausible and associated with outcome. Our work motivates refining current TBI classifications with factors describing metabolic stress. Such data-driven clusters suggest TBI endotypes that merit investigation to identify bespoke treatment strategies to improve care.

DOI: 10.1186/s13054-022-04079-w; No. 228

关键词：Humans; Prognosis; Glasgow Coma Scale; Critical Care; *Critical care; *Intensive care unit; Cluster Analysis; *Traumatic brain injury; *Brain Injuries, Traumatic/therapy; *Endotypes; *Machine learning; *Unsupervised clustering

DOI: 10.1186/s13054-022-04093-y; No. 227

关键词：Humans; *Extracorporeal Membrane Oxygenation; *Azoles; *Extracorporeal membrane oxygenation; *Isavuconazole; *Pharmacokinetics; *Therapeutic drug monitoring; Nitriles; Pyridines/therapeutic use; Triazoles/pharmacokinetics/therapeutic use

DOI: 10.1186/s13054-022-04102-0; No. 226

关键词：Humans; *Oxygen; *Heart Arrest/complications/therapy; *Extracorporeal Membrane Oxygenation/methods; *Dual circulation; *Hyperoxemia; *Mixing zone; *Veno-arterial ECMO; Oxygen/therapeutic use; Shock, Cardiogenic

DOI: 10.1186/s13054-022-04086-x; No. 225

关键词：Humans; Critical Illness; Intensive Care Units; Cohort Studies; Retrospective Studies; *COVID-19; *Intensive care unit; Hospitals; *Epidemiology; *COVID-19/complications; *Mortality; *Acute kidney injury; *Acute Kidney Injury/diagnosis/epidemiology/etiology; *KDIGO; *Kidney replacement therapy; *Renal replacement therapy; *Serum creatinine; *Urine output; Belgium/epidemiology

DOI: 10.1186/s13054-022-04082-1; No. 224

关键词：Humans; Female; Male; Prospective Studies; Aged; Intensive Care Units; Cohort Studies; Respiration, Artificial; Pandemics; *COVID-19; *Intensive care unit; *COVID-19/therapy; *Respiratory Insufficiency/therapy; *Frailty; *Elderly; *Noninvasive ventilation; *Noninvasive Ventilation/adverse effects

# Long-term cognitive functioning is impaired in ICU-treated COVID-19 patients: a comprehensive controlled neuropsychological study

Abstract

BACKGROUND: Cognitive impairment has emerged as a common post-acute sequela of coronavirus disease 2019 (COVID-19). We hypothesised that cognitive impairment exists in patients after COVID-19 and that it is most severe in patients admitted to the intensive care unit (ICU).

METHODS: This prospective controlled cohort study of 213 participants performed at the Helsinki University Hospital and the University of Helsinki, Finland, comprised three groups of patients-ICU-treated (n = 72), ward-treated (n = 49), and home-isolated (n = 44)-with confirmed COVID-19 between March 13 and December 31, 2020, participating in a comprehensive neuropsychological evaluation six months after the acute phase. Our study included a control group with no history of COVID-19 (n = 48). Medical and demographic data were collected from electronic patient records and interviews carried out four months after the acute phase. Questionnaires filled six months after the acute phase provided information about change in cognitive functioning observed by a close informant, as well as the presence of self-reported depressive and post-traumatic symptoms.

RESULTS: The groups differed (effect size η(2)(p) = 0.065, p = 0.004) in the total cognitive score, calculated from neuropsychological measures in three domains (attention, executive functions, and memory). Both ICU-treated (p = 0.011) and ward-treated patients (p = 0.005) performed worse than home-isolated patients. Among those with more than 12 years of education, ICU-treated patients performed worse in the attention domain than ward-treated patients (p = 0.021) or non-COVID controls (p = 0.045); ICU-treated male patients, in particular, were impaired in executive functions (p = 0.037).

CONCLUSIONS: ICU-treated COVID-19 patients, compared to patients with less severe acute COVID-19 or non-COVID controls, showed more severe long-term cognitive impairment. Among those with more than 12 years of education, impairment existed particularly in the domains of attention and for men, of executive functions.

DOI: 10.1186/s13054-022-04092-z; No. 223

关键词：Humans; Male; Prospective Studies; Intensive Care Units; Cohort Studies; Cognition; *COVID-19; *Intensive care unit; *Cognitive Dysfunction/epidemiology/etiology; *Cognitive functioning; *Cognitive impairment; *Long-term outcome

DOI: 10.1186/s13054-022-04058-1; No. 222

关键词：Humans; *Positive-Pressure Respiration; *Respiratory Distress Syndrome

# Palliative care practice and moral distress during COVID-19 pandemic (PEOpLE-C19 study): a national, cross-sectional study in intensive care units in the Czech Republic

Abstract

BACKGROUND: Providing palliative care at the end of life (EOL) in intensive care units (ICUs) seems to be modified during the COVID-19 pandemic with potential burden of moral distress to health care providers (HCPs). We seek to assess the practice of EOL care during the COVID-19 pandemic in ICUs in the Czech Republic focusing on the level of moral distress and its possible modifiable factors.

METHODS: Between 16 June 2021 and 16 September 2021, a national, cross-sectional study in intensive care units (ICUs) in Czech Republic was performed. All physicians and nurses working in ICUs during the COVID-19 pandemic were included in the study. For questionnaire development ACADEMY and CHERRIES guide and checklist were used. A multivariate logistic regression model was used to analyse possible modifiable factors of moral distress.

RESULTS: In total, 313 HCPs (14.5% out of all HCPs who opened the questionnaire) fully completed the survey. Results showed that 51.8% (n = 162) of respondents were exposed to moral distress during the COVID-19 pandemic. 63.1% (n = 113) of nurses and 71.6% of (n = 96) physicians had experience with the perception of inappropriate care. If inappropriate care was perceived, a higher chance for the occurrence of moral distress for HCPs (OR, 1.854; CI, 1.057-3.252; p = 0.0312) was found. When patients died with dignity, the chance for moral distress was lower (OR, 0.235; CI, 0.128-0.430; p < 0.001). The three most often reported differences in palliative care practice during pandemic were health system congestion, personnel factors, and characteristics of COVID-19 infection.

CONCLUSIONS: HCPs working at ICUs experienced significant moral distress during the COVID-19 pandemic in the Czech Republic. The major sources were perceiving inappropriate care and dying of patients without dignity. Improvement of the decision-making process and communication at the end of life could lead to a better ethical and safety climate.

DOI: 10.1186/s13054-022-04066-1; No. 221

关键词：Humans; Intensive Care Units; Pandemics; Cross-Sectional Studies; *COVID-19; Surveys and Questionnaires; Stress, Psychological; Death; *Palliative Care; *COVID-19/epidemiology; Morals; Attitude of Health Personnel; *Ethical climate; *Inappropriate care; *Moral distress; *Palliative care; *Pandemic; *Survey; Czech Republic/epidemiology

# Feasibility and discriminatory value of tissue motion annular displacement in sepsis-induced cardiomyopathy: a single-center retrospective observational study

Abstract

BACKGROUND: There is no formal diagnostic criterion for sepsis-induced cardiomyopathy (SICM), but left ventricular ejection fraction (LVEF) < 50% was the most commonly used standard. Tissue motion annular displacement (TMAD) is a novel speckle tracking indicator to quickly assess LV longitudinal systolic function. This study aimed to evaluate the feasibility and discriminatory value of TMAD for predicting SICM, as well as prognostic value of TMAD for mortality.

METHODS: We conducted a single-center retrospective observational study in patients with sepsis or septic shock who underwent echocardiography examination within the first 24 h after admission. Basic clinical information and conventional echocardiographic data, including mitral annular plane systolic excursion (MAPSE), were collected. Based on speckle tracking echocardiography (STE), global longitudinal strain (GLS) and TMAD were, respectively, performed offline. The parameters acquisition rate, inter- and intra-observer reliability, time consumed for measurement were assessed for the feasibility analysis. Areas under the receiver operating characteristic curves (AUROC) values were calculated to assess the discriminatory value of TMAD/GLS/MAPSE for predicting SICM, defined as LVEF < 50%. Kaplan-Meier survival curve analysis was performed according to the cutoff values in predicting SICM. Cox proportional hazards model was performed to determine the risk factors for 28d and in-hospital mortality.

RESULTS: A total of 143 patients were enrolled in this study. Compared with LVEF, GLS or MAPSE, TMAD exhibited the highest parameter acquisition rate, intra- and inter-observer reliability. The mean time for offline analyses with TMAD was significantly shorter than that with LVEF or GLS (p < 0.05). According to the AUROC analysis, TMADMid presented an excellent discriminatory value for predicting SICM (AUROC > 0.9). Patients with lower TMADMid (< 9.75 mm) had significantly higher 28d and in-hospital mortality (both p < 0.05). The multivariate Cox proportional hazards model revealed that BMI and SOFA were the independent risk factors for 28d and in-hospital mortality in sepsis cases, but TMAD was not.

CONCLUSION: STE-based TMAD is a novel and feasible technology with promising discriminatory value for predicting SICM with LVEF < 50%.

DOI: 10.1186/s13054-022-04095-w; No. 220

关键词：Humans; Reproducibility of Results; Stroke Volume; Feasibility Studies; *Sepsis; *Sepsis/complications; *Mortality; Ventricular Function, Left; *Cardiomyopathies/complications; *Cardiomyopathy; *Speckle tracking echocardiography; *Tissue motion annular displacement

# Tidal volume challenge to predict preload responsiveness in patients with acute respiratory distress syndrome under prone position

Abstract

BACKGROUND: Prone position is frequently used in patients with acute respiratory distress syndrome (ARDS), especially during the Coronavirus disease 2019 pandemic. Our study investigated the ability of pulse pressure variation (PPV) and its changes during a tidal volume challenge (TVC) to assess preload responsiveness in ARDS patients under prone position.

METHODS: This was a prospective study conducted in a 25-bed intensive care unit at a university hospital. We included patients with ARDS under prone position, ventilated with 6 mL/kg tidal volume and monitored by a transpulmonary thermodilution device. We measured PPV and its changes during a TVC (ΔPPV TVC(6-8)) after increasing the tidal volume from 6 to 8 mL/kg for one minute. Changes in cardiac index (CI) during a Trendelenburg maneuver (ΔCI(TREND)) and during end-expiratory occlusion (EEO) at 8 mL/kg tidal volume (ΔCI EEO(8)) were recorded. Preload responsiveness was defined by both ΔCI(TREND) ≥ 8% and ΔCI EEO(8) ≥ 5%. Preload unresponsiveness was defined by both ΔCI(TREND) < 8% and ΔCI EEO(8) < 5%.

RESULTS: Eighty-four sets of measurements were analyzed in 58 patients. Before prone positioning, the ratio of partial pressure of arterial oxygen to fraction of inspired oxygen was 104 ± 27 mmHg. At the inclusion time, patients were under prone position for 11 (2-14) hours. Norepinephrine was administered in 83% of cases with a dose of 0.25 (0.15-0.42) µg/kg/min. The positive end-expiratory pressure was 14 (11-16) cmH(2)O. The driving pressure was 12 (10-17) cmH(2)O, and the respiratory system compliance was 32 (22-40) mL/cmH(2)O. Preload responsiveness was detected in 42 cases. An absolute change in PPV ≥ 3.5% during a TVC assessed preload responsiveness with an area under the receiver operating characteristics (AUROC) curve of 0.94 ± 0.03 (sensitivity: 98%, specificity: 86%) better than that of baseline PPV (0.85 ± 0.05; p = 0.047). In the 56 cases where baseline PPV was inconclusive (≥ 4% and < 11%), ΔPPV TVC(6-8) ≥ 3.5% still enabled to reliably assess preload responsiveness (AUROC: 0.91 ± 0.05, sensitivity: 97%, specificity: 81%; p < 0.01 vs. baseline PPV).

CONCLUSION: In patients with ARDS under low tidal volume ventilation during prone position, the changes in PPV during a TVC can reliably assess preload responsiveness without the need for cardiac output measurements.

# 潮气量挑战预测俯卧位急性呼吸窘迫综合征患者前负荷反应性

摘要

背景：仰卧位常用于急性呼吸窘迫综合征 (ARDS) 患者，尤其是在 2019 年冠状病毒病大流行期间。我们的研究探讨了脉压变化 (PPV) 及其在潮气量挑战 (TVC) 过程中的变化评估俯卧位 ARDS 患者前负荷反应性的能力。

方法：这是一项在大学医院的 25 张病床的重症监护室中进行的前瞻性研究。我们纳入了俯卧位 ARDS 患者，以 6 mL/kg 潮气量通气，并使用经肺热稀释装置监测。我们测量了潮气量从 6 mL/kg 增加至 8 mL/kg 1 分钟后 TVC 期间的 PPV 及其变化 (ΔPPV TVC (6-8))。记录了在特伦德伦伯格动作 (ΔCI (TREND)) 和以 8 mL/kg 潮气量呼气末阻断 (EEO)(ΔCI EEO (8)) 期间的心脏指数 (CI) 变化。前负荷反应性定义为 ΔCI (TREND)≥8% 和 ΔCI EEO (8)≥5%。将前负荷无应答定义为 ΔCI (TREND)< 8% 和 ΔCI EEO (8)< 5%。

结果：在 58 例患者中分析了 84 组测量值。在俯卧位前，动脉血氧分压与吸入气中的氧气分数的比值为 104±27 mmHg。入组时，患者处于俯卧位 11 (2-14) 小时。83% 的病例接受了去甲肾上腺素给药，剂量为 0.25 (0.15-0.42)µg/kg/min。呼气末正压为 14 (11-16) cmh2 O，驱动压力为 12 (10-17) cmh2 O，呼吸系统顺应性为 32 (22-40) mL/cmh2 O，42 例检测到前负荷反应性。TVC 期间 PPV 的绝对变化≥3.5% 评估了前负荷反应性，受试者工作特征 (AUROC) 曲线下面积为 0.94±0.03（灵敏度：98%，特异性：86%），优于基线 PPV (0.85±0.05；p = 0.047)。在基线 PPV 不确定（≥4% 和 < 11%）的 56 例病例中，ΔPPV TVC (6-8)≥3.5% 仍能够可靠地评估前负荷反应性（AUROC：0.91±0.05，灵敏度：97%，特异性：81%；与基线 PPV 相比 p < 0.01）。

结论：在俯卧位低潮气量通气 ARDS 患者中，TVC 期间 PPV 的变化可以可靠地评估前负荷反应性，而不需要心输出量测量。

DOI: 10.1186/s13054-022-04087-w; No. 219

关键词：Humans; Treatment Outcome; Prospective Studies; Pandemics; *ARDS; *Respiration, Artificial/methods; *End-expiratory occlusion test; *Fluid responsiveness; *Prone Position/physiology; *Pulse pressure variation; *Respiratory Distress Syndrome/physiopathology/therapy; *Tidal Volume/physiology; COVID-19/epidemiology

DOI: 10.1186/s13054-022-04094-x; No. 218

关键词：Humans; Intensive Care Units; Survivors; *Intensive care unit; *Critical Care; *Terminal Care; Family; *Patients; *Family; *Comfort; *Experiences; *Healthcare professionals; *Industry; *Perceptions; *Quality of health care

# Neurologic manifestations of COVID-19 in critically ill patients: results of the prospective multicenter registry PANDEMIC

Abstract

BACKGROUND: Neurologic manifestations are increasingly reported in patients with coronavirus disease 2019 (COVID-19). Yet, data on prevalence, predictors and relevance for outcome of neurological manifestations in patients requiring intensive care are scarce. We aimed to characterize prevalence, risk factors and impact on outcome of neurologic manifestations in critically ill COVID-19 patients.

METHODS: In the prospective, multicenter, observational registry study PANDEMIC (Pooled Analysis of Neurologic DisordErs Manifesting in Intensive care of COVID-19), we enrolled COVID-19 patients with neurologic manifestations admitted to 19 German intensive care units (ICU) between April 2020 and September 2021. We performed descriptive and explorative statistical analyses. Multivariable models were used to investigate factors associated with disorder categories and their underlying diagnoses as well as to identify predictors of outcome.

RESULTS: Of the 392 patients included in the analysis, 70.7% (277/392) were male and the mean age was 65.3 (SD ± 3.1) years. During the study period, a total of 2681 patients with COVID-19 were treated at the ICUs of 15 participating centers. New neurologic disorders were identified in 350 patients, reported by these centers, suggesting a prevalence of COVID-19-associated neurologic disorders of 12.7% among COVID-19 ICU patients. Encephalopathy (46.2%; 181/392), cerebrovascular (41.0%; 161/392) and neuromuscular disorders (20.4%; 80/392) were the most frequent categories identified. Out of 35 cerebrospinal fluid analyses with reverse transcriptase PCR for SARS-COV-2, only 3 were positive. In-hospital mortality was 36.0% (140/389), and functional outcome (mRS 3 to 5) of surviving patients was poor at hospital discharge in 70.9% (161/227). Intracerebral hemorrhage (OR 6.2, 95% CI 2.5-14.9, p < 0.001) and acute ischemic stroke (OR 3.9, 95% CI 1.9-8.2, p < 0.001) were the strongest predictors of poor outcome among the included patients.

CONCLUSIONS: Based on this well-characterized COVID-19 ICU cohort, that comprised 12.7% of all severe ill COVID-19 patients, neurologic manifestations increase mortality and morbidity. Since no reliable evidence of direct viral affection of the nervous system by COVID-19 could be found, these neurologic manifestations may for a great part be indirect para- or postinfectious sequelae of the infection or severe critical illness. Neurologic ICU complications should be actively searched for and treated.

# 危重患者中 COVID-19 的神经系统表现：前瞻性多中心登记研究 PANDEMIC 的结果

摘要

背景：2019 年，越来越多的冠状病毒病患者报告了神经系统表现 (COVID-19)。然而，在需要重症监护的患者中，关于患病率、预测因素和神经病学表现结局相关性的数据很少。我们旨在描述 COVID-19 重症患者神经系统表现的患病率、风险因素和对结局的影响。

方法：在前瞻性、多中心、观察性注册研究 PANDEMIC（COVID-19 重症监护中神经系统疾病表现的汇总分析）中，我们入选了 2020 年 4 月至 2021 年 9 月期间入住 19 家德国重症监护室 (ICU) 的具有神经系统表现的 COVID-19 患者。我们进行了描述性和探索性统计分析。多变量模型用于研究与疾病类别及其基础诊断相关的因素，并确定结局的预测因素。

结果：纳入分析的 392 例患者中，70.7%(277/392) 为男性，平均年龄为 65.3 (SD±3.1) 岁。研究期间，共 2681 例 COVID-19 患者在 15 家参与中心的 ICU 接受治疗。这些中心报告 350 例患者出现新的神经系统疾病，表明 COVID-19 ICU 患者中 COVID-19 相关神经系统疾病的患病率为 12.7%。脑病 (46.2%；181/392)、脑血管 (41.0%；161/392) 和神经肌肉疾病 (20.4%；80/392) 是最常见的分类。在使用逆转录酶 PCR 进行的 35 份 SARS-COV-2 脑脊液分析中，仅 3 份为阳性。住院死亡率为 36.0%(140/389)，70.9%(161/227) 的存活患者出院时功能结局 (mRS 3-5) 较差。在纳入的患者中，脑出血 (OR 6.2，95% CI 2.5-14.9，p < 0.001) 和急性缺血性卒中 (OR 3.9，95% CI 1.9-8.2，p < 0.001) 是结局不良的最强预测因子。

结论：根据这一良好描述的 COVID-19 ICU 队列（占所有 COVID-19 重症患者的 12.7%），神经病学表现增加了死亡率和发病率。由于没有可靠的证据表明神经系统受到 COVID-19 的直接病毒感染，这些神经系统表现在很大程度上可能是感染或严重危重症的间接感染后或感染后后遗症。应积极寻找并治疗神经系统 ICU 并发症。

DOI: 10.1186/s13054-022-04080-3; No. 217

关键词：Humans; Female; Male; Middle Aged; Prospective Studies; Aged; Intensive Care Units; Pandemics; Registries; *COVID-19; SARS-CoV-2; *Critically ill; *Intensive care; *Cerebral Hemorrhage/virology; *COVID-19/complications/epidemiology; *Ischemic Stroke/virology; *Nervous System Diseases/virology; *Neurologic manifestations; Critical Illness/epidemiology/therapy

DOI: 10.1186/s13054-022-04089-8; No. 216

关键词：Humans; Retrospective Studies; *Extracorporeal Membrane Oxygenation; *ECMO; *Extracorporeal membrane oxygenation; *Weaning failure; Shock, Cardiogenic/therapy

# External validation of a machine learning model to predict hemodynamic instability in intensive care unit

Abstract

BACKGROUND: Early prediction model of hemodynamic instability has the potential to improve the critical care, whereas limited external validation on the generalizability. We aimed to independently validate the Hemodynamic Stability Index (HSI), a multi-parameter machine learning model, in predicting hemodynamic instability in Asian patients.

METHOD: Hemodynamic instability was marked by using inotropic, vasopressor, significant fluid therapy, and/or blood transfusions. This retrospective study included among 15,967 ICU patients who aged 20 years or older (not included 20 years) and stayed in ICU for more than 6 h admitted to Taipei Veteran General Hospital (TPEVGH) between January 1, 2010, and March 31, 2020, of whom hemodynamic instability occurred in 3053 patients (prevalence = 19%). These patients in unstable group received at least one intervention during their ICU stays, and the HSI score of both stable and unstable group was calculated in every hour before intervention. The model performance was assessed using the area under the receiver operating characteristic curve (AUROC) and was compared to single indicators like systolic blood pressure (SBP) and shock index. The hemodynamic instability alarm was set by selecting optimal threshold with high sensitivity, acceptable specificity, and lead time before intervention was calculated to indicate when patients were firstly identified as high risk of hemodynamic instability.

RESULTS: The AUROC of HSI was 0.76 (95% CI, 0.75-0.77), which performed significantly better than shock Index (0.7; 95% CI, 0.69-0.71) and SBP (0.69; 95% CI, 0.68-0.70). By selecting 0.7 as a threshold, HSI predicted 72% of all 3053 patients who received hemodynamic interventions with 67% in specificity. Time-varying results also showed that HSI score significantly outperformed single indicators even up to 24 h before intervention. And 95% unstable patients can be identified more than 5 h in advance.

CONCLUSIONS: The HSI has acceptable discrimination but underestimates the risk of stable patients in predicting the onset of hemodynamic instability in an external cohort.

DOI: 10.1186/s13054-022-04088-9; No. 215

关键词：Humans; Retrospective Studies; Hemodynamics/physiology; ROC Curve; *Intensive Care Units; *Machine Learning; *Machine learning; *Clinical decision support; *Early prediction model; *External validation; *Hemodynamic Stability Index

DOI: 10.1186/s13054-022-04090-1; No. 213

关键词：Humans; Dysbiosis/microbiology; Liver/metabolism; Inflammation/metabolism; *Intestinal Mucosa/metabolism; *Sepsis/metabolism

DOI: 10.1186/s13054-022-04084-z; No. 214

关键词：Humans; Prospective Studies; Longitudinal Studies; Tidal Volume; *Respiratory Distress Syndrome/therapy; *Positive-Pressure Respiration/methods; *Positive end-expiratory pressure; *Acute respiratory distress syndrome; *Driving pressure; *Oxygenation

# Effects of PEEP on regional ventilation-perfusion mismatch in the acute respiratory distress syndrome

Abstract

PURPOSE: In the acute respiratory distress syndrome (ARDS), decreasing Ventilation-Perfusion [Formula: see text] mismatch might enhance lung protection. We investigated the regional effects of higher Positive End Expiratory Pressure (PEEP) on [Formula: see text] mismatch and their correlation with recruitability. We aimed to verify whether PEEP improves regional [Formula: see text] mismatch, and to study the underlying mechanisms.

METHODS: In fifteen patients with moderate and severe ARDS, two PEEP levels (5 and 15 cmH(2)O) were applied in random order. [Formula: see text] mismatch was assessed by Electrical Impedance Tomography at each PEEP. Percentage of ventilation and perfusion reaching different ranges of [Formula: see text] ratios were analyzed in 3 gravitational lung regions, leading to precise assessment of their distribution throughout different [Formula: see text] mismatch compartments. Recruitability between the two PEEP levels was measured by the recruitment-to-inflation ratio method.

RESULTS: In the non-dependent region, at higher PEEP, ventilation reaching the normal [Formula: see text] compartment (p = 0.018) increased, while it decreased in the high [Formula: see text] one (p = 0.023). In the middle region, at PEEP 15 cmH(2)O, ventilation and perfusion to the low [Formula: see text] compartment decreased (p = 0.006 and p = 0.011) and perfusion to normal [Formula: see text] increased (p = 0.003). In the dependent lung, the percentage of blood flowing through the non-ventilated compartment decreased (p = 0.041). Regional [Formula: see text] mismatch improvement was correlated to lung recruitability and changes in regional tidal volume.

CONCLUSIONS: In patients with ARDS, higher PEEP optimizes the distribution of both ventilation (in the non-dependent areas) and perfusion (in the middle and dependent lung). Bedside measure of recruitability is associated with improved [Formula: see text] mismatch.

DOI: 10.1186/s13054-022-04085-y; No. 211

关键词：Humans; Perfusion; *COVID-19; Lung; *Respiratory Distress Syndrome/therapy; Positive-Pressure Respiration/methods; *Acute lung injury; *Electrical impedance tomography; *Multiple inert gas elimination technique; *Recruitment-on-inflation ratio; Respiratory Physiological Phenomena

DOI: 10.1186/s13054-022-04070-5; No. 210

关键词：Humans; Prognosis; Child; Biomarkers; Multiple Organ Failure; *Sepsis; *Shock, Septic; *Biomarkers; *Endothelial dysfunction; *Multiple organ dysfunction syndrome; *Precision medicine; *Prognostic enrichment; *Sepsis/complications/diagnosis; *Septic shock; Intercellular Adhesion Molecule-1; Interleukin-8; Thrombomodulin

DOI: 10.1186/s13054-022-04033-w; No. 212

关键词：Humans; Prognosis; *COVID-19; SARS-CoV-2; Intubation, Intratracheal

# Disparities in adult critical care resources across Pakistan: findings from a national survey and assessment using a novel scoring system

Abstract

BACKGROUND: In response to the COVID-19 pandemic, concerted efforts were made by provincial and federal governments to invest in critical care infrastructure and medical equipment to bridge the gap of resource-limitation in intensive care units (ICUs) across Pakistan. An initial step in creating a plan toward strengthening Pakistan's baseline critical care capacity was to carry out a needs-assessment within the country to assess gaps and devise strategies for improving the quality of critical care facilities.

METHODS: To assess the baseline critical care capacity of Pakistan, we conducted a series of cross-sectional surveys of hospitals providing COVID-19 care across the country. These hospitals were pre-identified by the Health Services Academy (HSA), Pakistan. Surveys were administered via telephonic and on-site interviews and based on a unique checklist for assessing critical care units which was created from the Partners in Health 4S Framework, which is: Space, Staff, Stuff, and Systems. These components were scored, weighted equally, and then ranked into quartiles.

RESULTS: A total of 106 hospitals were surveyed, with the majority being in the public sector (71.7%) and in the metropolitan setting (56.6%). We found infrastructure, staffing, and systems lacking as only 19.8% of hospitals had negative pressure rooms and 44.4% had quarantine facilities for staff. Merely 36.8% of hospitals employed accredited intensivists and 54.8% of hospitals maintained an ideal nurse-to-patient ratio. 31.1% of hospitals did not have a staffing model, while 37.7% of hospitals did not have surge policies. On Chi-square analysis, statistically significant differences (p < 0.05) were noted between public and private sectors along with metropolitan versus rural settings in various elements. Almost all ranks showed significant disparity between public-private and metropolitan-rural settings, with private and metropolitan hospitals having a greater proportion in the 1st rank, while public and rural hospitals had a greater proportion in the lower ranks.

CONCLUSION: Pakistan has an underdeveloped critical care network with significant inequity between public-private and metropolitan-rural strata. We hope for future resource allocation and capacity development projects for critical care in order to reduce these disparities.

DOI: 10.1186/s13054-022-04046-5; No. 209

关键词：Humans; Adult; Critical Care; Cross-Sectional Studies; *COVID-19; *Pandemics; Pakistan

Abstract

BACKGROUND: During the COVID-19 pandemic, many more patients were turned prone than before, resulting in a considerable increase in workload. Whether extending duration of prone position may be beneficial has received little attention. We report here benefits and detriments of a strategy of extended prone positioning duration for COVID-19-related acute respiratory distress syndrome (ARDS).

METHODS: A eetrospective, monocentric, study was performed on intensive care unit patients with COVID-19-related ARDS who required tracheal intubation and who have been treated with at least one session of prone position of duration greater or equal to 24 h. When prone positioning sessions were initiated, patients were kept prone for a period that covered two nights. Data regarding the incidence of pressure injury and ventilation parameters were collected retrospectively on medical and nurse files of charts. The primary outcome was the occurrence of pressure injury of stage ≥ II during the ICU stay.

RESULTS: For the 81 patients included, the median duration of prone positioning sessions was 39 h [interquartile range (IQR) 34-42]. The cumulated incidence of stage ≥ II pressure injuries was 26% [95% CI 17-37] and 2.5% [95% CI 0.3-8.8] for stages III/IV pressure injuries. Patients were submitted to a median of 2 sessions [IQR 1-4] and for 213 (94%) prone positioning sessions, patients were turned over to supine position during daytime, i.e., between 9 AM and 6 PM. This increased duration was associated with additional increase in oxygenation after 16 h with the PaO(2)/FiO(2) ratio increasing from 150 mmHg [IQR 121-196] at H+ 16 to 162 mmHg [IQR 124-221] before being turned back to supine (p = 0.017).

CONCLUSION: In patients with extended duration of prone position up to 39 h, cumulative incidence for stage ≥ II pressure injuries was 26%, with 25%, 2.5%, and 0% for stage II, III, and IV, respectively. Oxygenation continued to increase significantly beyond the standard 16-h duration. Our results may have significant impact on intensive care unit staffing and patients' respiratory conditions.

DOI: 10.1186/s13054-022-04081-2; No. 208

关键词：Humans; Retrospective Studies; Pandemics; *COVID-19; Prone Position; Pulmonary Gas Exchange; *Respiratory Distress Syndrome/therapy; Respiration, Artificial/adverse effects; *Mechanical ventilation; Supine Position; *COVID-19-related ARDS; *Pressure injuries; *Prone positioning

# Development and validation of a multivariable prediction model of central venous catheter-tip colonization in a cohort of five randomized trials

Abstract

BACKGROUND: The majority of central venous catheters (CVC) removed in the ICU are not colonized, including when a catheter-related infection (CRI) is suspected. We developed and validated a predictive score to reduce unnecessary CVC removal.

METHODS: We conducted a retrospective cohort study from five multicenter randomized controlled trials with systematic catheter-tip culture of consecutive CVCs. Colonization was defined as growth of ≥10(3) colony-forming units per mL. Risk factors for colonization were identified in the training cohort (CATHEDIA and 3SITES trials; 3899 CVCs of which 575 (15%) were colonized) through multivariable analyses. After internal validation in 500 bootstrapped samples, the CVC-OUT score was computed by attaching points to the robust (> 50% of the bootstraps) risk factors. External validation was performed in the testing cohort (CLEAN, DRESSING2 and ELVIS trials; 6848 CVCs, of which 588 (9%) were colonized).

RESULTS: In the training cohort, obesity (1 point), diabetes (1 point), type of CVC (dialysis catheter, 1 point), anatomical insertion site (jugular, 4 points; femoral 5 points), rank of the catheter (second or subsequent, 1 point) and catheterization duration (≥ 5 days, 2 points) were significantly and independently associated with colonization . Area under the ROC curve (AUC) for the CVC-OUT score was 0.69, 95% confidence interval (CI) [0.67-0.72]. In the testing cohort, AUC for the CVC-OUT score was 0.60, 95% CI [0.58-0.62]. Among 1,469 CVCs removed for suspected CRI in the overall population, 1200 (82%) were not colonized. The negative predictive value (NPV) of a CVC-OUT score < 6 points was 94%, 95% CI [93%-95%].

CONCLUSION: The CVC-OUT score had a moderate ability to discriminate catheter-tip colonization, but the high NPV may contribute to reduce unnecessary CVCs removal. Preference of the subclavian site is the strongest and only modifiable risk factor that reduces the likelihood of catheter-tip colonization and consequently the risk of CRI.

DOI: 10.1186/s13054-022-04078-x; No. 205

关键词：Humans; Prospective Studies; Cohort Studies; Retrospective Studies; Randomized Controlled Trials as Topic; *Intensive care unit; *Catheterization, Central Venous/adverse effects; *Central Venous Catheters/adverse effects; Renal Dialysis; *Catheter-related infection; *Catheter-Related Infections/epidemiology/etiology; *Catheter-tip colonization; *Central Venous catheters; *Predictive score

# Comparison of diagnostic criteria for acute kidney injury in critically ill children: a multicenter cohort study

Abstract

BACKGROUND: Substantial interstudy heterogeneity exists in defining acute kidney injury (AKI) and baseline serum creatinine (SCr). This study assessed AKI incidence and its association with pediatric intensive care unit (PICU) mortality under different AKI and baseline SCr definitions to determine the preferable approach for diagnosing pediatric AKI.

METHODS: In this multicenter prospective observational cohort study, AKI was defined and staged according to the Kidney Disease: Improving Global Outcome (KDIGO), modified KDIGO, and pediatric reference change value optimized for AKI (pROCK) definitions. The baseline SCr was calculated based on the Schwartz formula or estimated as the upper normative value (NormsMax), admission SCr (AdmSCr) and modified AdmSCr. The impacts of different AKI definitions and baseline SCr estimation methods on AKI incidence, severity distribution and AKI outcome were evaluated.

RESULTS: Different AKI definitions and baseline SCr estimates led to differences in AKI incidence, from 6.8 to 25.7%; patients with AKI across all definitions had higher PICU mortality ranged from 19.0 to 35.4%. A higher AKI incidence (25.7%) but lower mortality (19.0%) was observed based on the Schwartz according to the KDIGO definition, which however was overcome by modified KDIGO (AKI incidence: 16.3%, PICU mortality: 26.1%). Furthermore, for the modified KDIGO, the consistencies of AKI stages between different baseline SCr estimation methods were all strong with the concordance rates > 90.0% and weighted kappa values > 0.8, and PICU mortality increased pursuant to staging based on the Schwartz. When the NormsMax was used, the KDIGO and modified KDIGO led to an identical AKI incidence (13.6%), but PICU mortality did not differ among AKI stages. For the pROCK, PICU mortality did not increase pursuant to staging and AKI stage 3 was not associated with mortality after adjustment for confounders.

CONCLUSIONS: The AKI incidence and staging vary depending on the definition and baseline SCr estimation method used. The modified KDIGO definition based on the Schwartz method leads AKI to be highly relevant to PICU mortality, suggesting that it may be the preferable approach for diagnosing AKI in critically ill children and provides promise for improving clinicians' ability to diagnose pediatric AKI.

DOI: 10.1186/s13054-022-04083-0; No. 207

关键词：Humans; Prospective Studies; Time Factors; Cohort Studies; Retrospective Studies; Child; Severity of Illness Index; Creatinine; *Acute kidney injury; *Serum creatinine; *Acute Kidney Injury/diagnosis/epidemiology; *Consensus definition; *Critical Illness/epidemiology; *Critically ill children

DOI: 10.1186/s13054-022-04062-5; No. 206

关键词：Animals; Mice; *Neutrophil; *COVID-19; SARS-CoV-2; *COVID-19/drug therapy; *Extracellular Traps/metabolism; *Innate immunity; *NETs; *Organ damage; Disulfiram/metabolism; Neutrophils/metabolism

# Intravenous IgM-enriched immunoglobulins in critical COVID-19: a multicentre propensity-weighted cohort study

Abstract

BACKGROUND: A profound inflammation-mediated lung injury with long-term acute respiratory distress and high mortality is one of the major complications of critical COVID-19. Immunoglobulin M (IgM)-enriched immunoglobulins seem especially capable of mitigating the inflicted inflammatory harm. However, the efficacy of intravenous IgM-enriched preparations in critically ill patients with COVID-19 is largely unclear.

METHODS: In this retrospective multicentric cohort study, 316 patients with laboratory-confirmed critical COVID-19 were treated in ten German and Austrian ICUs between May 2020 and April 2021. The primary outcome was 30-day mortality. Analysis was performed by Cox regression models. Covariate adjustment was performed by propensity score weighting using machine learning-based SuperLearner to overcome the selection bias due to missing randomization. In addition, a subgroup analysis focusing on different treatment regimens and patient characteristics was performed.

RESULTS: Of the 316 ICU patients, 146 received IgM-enriched immunoglobulins and 170 cases did not, which served as controls. There was no survival difference between the two groups in terms of mortality at 30 days in the overall cohort (HR(adj): 0.83; 95% CI: 0.55 to 1.25; p = 0.374). An improved 30-day survival in patients without mechanical ventilation at the time of the immunoglobulin treatment did not reach statistical significance (HR(adj): 0.23; 95% CI: 0.05 to 1.08; p = 0.063). Also, no statistically significant difference was observed in the subgroup when a daily dose of ≥ 15 g and a duration of ≥ 3 days of IgM-enriched immunoglobulins were applied (HR(adj): 0.65; 95% CI: 0.41 to 1.03; p = 0.068).

CONCLUSIONS: Although we cannot prove a statistically reliable effect of intravenous IgM-enriched immunoglobulins, the confidence intervals may suggest a clinically relevant effect in certain subgroups. Here, an early administration (i.e. in critically ill but not yet mechanically ventilated COVID-19 patients) and a dose of ≥ 15 g for at least 3 days may confer beneficial effects without concerning safety issues. However, these findings need to be validated in upcoming randomized clinical trials.

DOI: 10.1186/s13054-022-04059-0; No. 204

关键词：Humans; Cohort Studies; Respiration, Artificial; Retrospective Studies; *COVID-19; *SARS-CoV-2; SARS-CoV-2; Critical Illness/therapy; *COVID-19/drug therapy; *Coronavirus disease; *Immunoglobulin M; *Immunoglobulins; Immunoglobulin M/therapeutic use; Immunoglobulins, Intravenous

# Extravascular lung water levels are associated with mortality: a systematic review and meta-analysis

Abstract

BACKGROUND: The prognostic value of extravascular lung water (EVLW) measured by transpulmonary thermodilution (TPTD) in critically ill patients is debated. We performed a systematic review and meta-analysis of studies assessing the effects of TPTD-estimated EVLW on mortality in critically ill patients.

METHODS: Cohort studies published in English from Embase, MEDLINE, and the Cochrane Database of Systematic Reviews from 1960 to 1 June 2021 were systematically searched. From eligible studies, the values of the odds ratio (OR) of EVLW as a risk factor for mortality, and the value of EVLW in survivors and non-survivors were extracted. Pooled OR were calculated from available studies. Mean differences and standard deviation of the EVLW between survivors and non-survivors were calculated. A random effects model was computed on the weighted mean differences across the two groups to estimate the pooled size effect. Subgroup analyses were performed to explore the possible sources of heterogeneity.

RESULTS: Of the 18 studies included (1296 patients), OR could be extracted from 11 studies including 905 patients (464 survivors vs. 441 non-survivors), and 17 studies reported EVLW values of survivors and non-survivors, including 1246 patients (680 survivors vs. 566 non-survivors). The pooled OR of EVLW for mortality from eleven studies was 1.69 (95% confidence interval (CI) [1.22; 2.34], p < 0.0015). EVLW was significantly lower in survivors than non-survivors, with a mean difference of -4.97 mL/kg (95% CI [-6.54; -3.41], p < 0.001). The results regarding OR and mean differences were consistent in subgroup analyses.

CONCLUSIONS: The value of EVLW measured by TPTD is associated with mortality in critically ill patients and is significantly higher in non-survivors than in survivors. This finding may also be interpreted as an indirect confirmation of the reliability of TPTD for estimating EVLW at the bedside. Nevertheless, our results should be considered cautiously due to the high risk of bias of many studies included in the meta-analysis and the low rating of certainty of evidence.

DOI: 10.1186/s13054-022-04061-6; No. 202

关键词：Humans; Prognosis; Reproducibility of Results; *Critically ill patients; *Critical Illness/mortality; *Extravascular Lung Water; *Hemodynamic monitoring; *Lung edema; *Transpulmonary thermodilution; Thermodilution/methods

# Composition and diversity analysis of the lung microbiome in patients with suspected ventilator-associated pneumonia

Abstract

BACKGROUND: Ventilator-associated pneumonia (VAP) is associated with high morbidity and health care costs, yet diagnosis remains a challenge. Analysis of airway microbiota by amplicon sequencing provides a possible solution, as pneumonia is characterised by a disruption of the microbiome. However, studies evaluating the diagnostic capabilities of microbiome analysis are limited, with a lack of alignment on possible biomarkers. Using bronchoalveolar lavage fluid (BALF) from ventilated adult patients suspected of VAP, we aimed to explore how key characteristics of the microbiome differ between patients with positive and negative BALF cultures and whether any differences could have a clinically relevant role.

METHODS: BALF from patients suspected of VAP was analysed using 16s rRNA sequencing in order to: (1) differentiate between patients with and without a positive culture; (2) determine if there was any association between microbiome diversity and local inflammatory response; and (3) correctly identify pathogens detected by conventional culture.

RESULTS: Thirty-seven of 90 ICU patients with suspected VAP had positive cultures. Patients with a positive culture had significant microbiome dysbiosis with reduced alpha diversity. However, gross compositional variance was not strongly associated with culture positivity (AUROCC range 0.66-0.71). Patients with a positive culture had a significantly higher relative abundance of pathogenic bacteria compared to those without [0.45 (IQR 0.10-0.84), 0.02 (IQR 0.004-0.09), respectively], and an increased interleukin (IL)-1β was associated with reduced species evenness (r(s) = - 0.33, p < 0.01) and increased pathogenic bacteria presence (r(s) = 0.28, p = 0.013). Untargeted 16s rRNA pathogen detection was limited by false positives, while the use of pathogen-specific relative abundance thresholds showed better diagnostic accuracy (AUROCC range 0.89-0.998).

CONCLUSION: Patients with positive BALF culture had increased dysbiosis and genus dominance. An increased caspase-1-dependent IL-1b expression was associated with a reduced species evenness and increased pathogenic bacterial presence, providing a possible causal link between microbiome dysbiosis and lung injury development in VAP. However, measures of diversity were an unreliable predictor of culture positivity and 16s sequencing used agnostically could not usefully identify pathogens; this could be overcome if pathogen-specific relative abundance thresholds are used.

# 疑似呼吸机相关性肺炎患者肺微生物组的组成和多样性分析

摘要

背景：呼吸机相关性肺炎 (VAP) 与高发病率和医疗保健费用相关，但诊断仍是一个挑战。通过扩增子测序分析气道菌群提供了一种可能的解决方案，因为肺炎的特征是破坏微生物组。然而，评估微生物组分析诊断能力的研究有限，缺乏可能的生物标志物的比对。使用疑似 VAP 的通气成人患者的支气管肺泡灌洗液 (BALF)，我们旨在探索 BALF 培养阳性和阴性患者之间微生物组关键特征的差异，以及任何差异是否可能具有临床相关作用。

方法：使用 16s rRNA 测序对疑似 VAP 患者的 BALF 进行分析，以便：(1) 区分有和无阳性培养物的患者；(2) 确定微生物组多样性与局部炎症反应之间是否存在任何关联；(3) 正确识别常规培养检出的病原体。

结果：90 例疑似 VAP 的 ICU 患者中 37 例培养阳性。培养阳性的患者存在显著的微生物组微生态失调，α 多样性降低。然而，总体组成差异与培养阳性无明显相关性（AUROCC 范围 0.66-0.71）。培养阳性患者的致病菌相对丰度显著高于无阳性患者 [分别为 0.45 (IQR 0.10-0.84)，0.02 (IQR 0.004-0.09)]，白细胞介素 (IL)-1β 升高与菌种均匀度降低相关（r (s)=-0.33，p < 0.01），致病菌增多 (r (s)= 0.28，p = 0.013)。非靶向 16s rRNA 病原体检测受到假阳性的限制，而使用病原体特异性相对丰度阈值显示出更好的诊断准确性（AUROCC 范围 0.89-0.998）。

结论：BALF 培养阳性的患者微生态失调增加，属优势。半胱天冬酶 - 1 依赖性 IL-1b 表达的增加与菌种均匀度的降低和致病菌的增加相关，提供了 VAP 中微生物组微生态失调和肺损伤发生之间可能的因果联系。然而，多样性的测量是培养阳性的一个不可靠的预测因素，不可思议地使用 16s 测序不能有效地识别病原体；如果使用病原体特异性相对丰度阈值，这可以克服。

DOI: 10.1186/s13054-022-04068-z; No. 203

关键词：Humans; Adult; *Microbiota; Dysbiosis; *Microbiome; RNA, Ribosomal, 16S/genetics; Bacteria; *Lung/microbiology; *Next-generation sequencing; *Pneumonia, Ventilator-Associated/diagnosis/microbiology; *Ventilator-associated pneumonia

# Paradoxical response to chest wall loading predicts a favorable mechanical response to reduction in tidal volume or PEEP

Abstract

BACKGROUND: Chest wall loading has been shown to paradoxically improve respiratory system compliance (C(RS)) in patients with moderate to severe acute respiratory distress syndrome (ARDS). The most likely, albeit unconfirmed, mechanism is relief of end-tidal overdistension in 'baby lungs' of low-capacity. The purpose of this study was to define how small changes of tidal volume (V(T)) and positive end-expiratory pressure (PEEP) affect C(RS) (and its associated airway pressures) in patients with ARDS who demonstrate a paradoxical response to chest wall loading. We hypothesized that small reductions of V(T) or PEEP would alleviate overdistension and favorably affect C(RS) and conversely, that small increases of V(T) or PEEP would worsen C(RS).

METHODS: Prospective, multi-center physiologic study of seventeen patients with moderate to severe ARDS who demonstrated paradoxical responses to chest wall loading. All patients received mechanical ventilation in volume control mode and were passively ventilated. Airway pressures were measured before and after decreasing/increasing V(T) by 1 ml/kg predicted body weight and decreasing/increasing PEEP by 2.5 cmH(2)O.

RESULTS: Decreasing either V(T) or PEEP improved C(RS) in all patients. Driving pressure (DP) decreased by a mean of 4.9 cmH(2)O (supine) and by 4.3 cmH(2)O (prone) after decreasing V(T), and by a mean of 2.9 cmH(2)O (supine) and 2.2 cmH(2)O (prone) after decreasing PEEP. C(RS) increased by a mean of 3.1 ml/cmH(2)O (supine) and by 2.5 ml/cmH(2)O (prone) after decreasing V(T.) C(RS) increased by a mean of 5.2 ml/cmH(2)O (supine) and 3.6 ml/cmH(2)O (prone) after decreasing PEEP (P < 0.01 for all). Small increments of either V(T) or PEEP worsened C(RS) in the majority of patients.

CONCLUSION: Patients with a paradoxical response to chest wall loading demonstrate uniform improvement in both DP and C(RS) following a reduction in either V(T) or PEEP, findings in keeping with prior evidence suggesting its presence is a sign of end-tidal overdistension. The presence of 'paradox' should prompt re-evaluation of modifiable determinants of end-tidal overdistension, including V(T), PEEP, and body position.

DOI: 10.1186/s13054-022-04073-2; No. 201

关键词：Humans; Prospective Studies; Positive-Pressure Respiration; Tidal Volume; *Respiratory Distress Syndrome/therapy; *Thoracic Wall

DOI: 10.1186/s13054-022-04077-y; No. 200

关键词：Humans; Critical Illness; Intensive Care Units; Critical Care; *COVID-19; *Intensive care unit; *Outcome; *Pandemics; *Architecture; *ICU design; *Neuroesthetics; *PICS; *PICS-F

# Dynamics of disease characteristics and clinical management of critically ill COVID-19 patients over the time course of the pandemic: an analysis of the prospective, international, multicentre RISC-19-ICU registry

Abstract

BACKGROUND: It remains elusive how the characteristics, the course of disease, the clinical management and the outcomes of critically ill COVID-19 patients admitted to intensive care units (ICU) worldwide have changed over the course of the pandemic.

METHODS: Prospective, observational registry constituted by 90 ICUs across 22 countries worldwide including patients with a laboratory-confirmed, critical presentation of COVID-19 requiring advanced organ support. Hierarchical, generalized linear mixed-effect models accounting for hospital and country variability were employed to analyse the continuous evolution of the studied variables over the pandemic.

RESULTS: Four thousand forty-one patients were included from March 2020 to September 2021. Over this period, the age of the admitted patients (62 [95% CI 60-63] years vs 64 [62-66] years, p < 0.001) and the severity of organ dysfunction at ICU admission decreased (Sequential Organ Failure Assessment 8.2 [7.6-9.0] vs 5.8 [5.3-6.4], p < 0.001) and increased, while more female patients (26 [23-29]% vs 41 [35-48]%, p < 0.001) were admitted. The time span between symptom onset and hospitalization as well as ICU admission became longer later in the pandemic (6.7 [6.2-7.2| days vs 9.7 [8.9-10.5] days, p < 0.001). The PaO(2)/FiO(2) at admission was lower (132 [123-141] mmHg vs 101 [91-113] mmHg, p < 0.001) but showed faster improvements over the initial 5 days of ICU stay in late 2021 compared to early 2020 (34 [20-48] mmHg vs 70 [41-100] mmHg, p = 0.05). The number of patients treated with steroids and tocilizumab increased, while the use of therapeutic anticoagulation presented an inverse U-shaped behaviour over the course of the pandemic. The proportion of patients treated with high-flow oxygen (5 [4-7]% vs 20 [14-29], p < 0.001) and non-invasive mechanical ventilation (14 [11-18]% vs 24 [17-33]%, p < 0.001) throughout the pandemic increased concomitant to a decrease in invasive mechanical ventilation (82 [76-86]% vs 74 [64-82]%, p < 0.001). The ICU mortality (23 [19-26]% vs 17 [12-25]%, p < 0.001) and length of stay (14 [13-16] days vs 11 [10-13] days, p < 0.001) decreased over 19 months of the pandemic.

CONCLUSION: Characteristics and disease course of critically ill COVID-19 patients have continuously evolved, concomitant to the clinical management, throughout the pandemic leading to a younger, less severely ill ICU population with distinctly different clinical, pulmonary and inflammatory presentations than at the onset of the pandemic.

# 大流行期间 COVID-19 危重患者的疾病特征和临床管理的动态：前瞻性、国际、多中心 RISC-19-ICU 登记研究分析

摘要

背景：全球范围内入住重症监护室 (ICU) 的 COVID-19 重症患者的特征、病程、临床管理和结局如何在大流行期间发生改变仍不明确。

方法：前瞻性、观察性登记研究，由全球 22 个国家的 90 间 ICU 组成，包括实验室证实有需要晚期器官支持的 COVID-19 关键表现的患者。采用考虑医院和国家变异性的分层、广义线性混合效应模型分析研究变量在大流行期间的连续演变。

结果：从 2020 年 3 月至 2021 年 9 月纳入 4,00041 例患者。在此期间，入院患者的年龄（62 [95% CI 60-63] 岁 vs 64 [62-66] 岁，p < 0.001）和 ICU 入院时器官功能障碍的严重程度降低（序贯器官衰竭评估 8.2 [7.6-9.0] vs 5.8 [5.3-6.4]，p < 0.001）并增加，而女性患者更多（26 [23-29]% vs 41 [35-48]%，p < 0.001）。在大流行期间，症状发作与住院以及入住 ICU 之间的时间跨度变得更长（6.7 [6.2-7.2 天 vs 9.7 [8.9-10.5] 天，p < 0.001）。入院时 PaO (2)/FiO (2) 较低 (132 [123-141] mmHg vs 101 [91-113] mmHg，p < 0.001)，但与 2020 年初相比，2021 年末在 ICU 住院的最初 5 天内改善更快 (34 [20-48] mmHg vs 70 [41-100] mmHg，p = 0.05)。在大流行期间，接受类固醇和托珠单抗治疗的患者数量增加，而抗凝治疗的使用呈现相反的 U 形行为。在大流行期间，接受高流量氧气 (5 [4-7]% vs 20 [14-29]，p < 0.001) 和无创机械通气 (14 [11-18]% vs 24 [17-33]%，p < 0.001) 治疗的患者比例随着有创机械通气减少而增加 (82 [76-86]% vs 74 [64-82]%，p < 0.001)。在大流行的 19 个月期间，ICU 死亡率 (23 [19-26]% vs 17 [12-25]%，p < 0.001) 和住院时间（14 [13-16] 天 vs 11 [10-13] 天，p < 0.001）降低。

结论：在大流行期间，伴随临床管理，COVID-19 重症患者的特征和病程不断演变，导致更年轻、病情不太严重的 ICU 人群，与大流行开始时的临床、肺部和炎症表现明显不同。

DOI: 10.1186/s13054-022-04065-2; No. 199

关键词：Humans; Female; Middle Aged; Prospective Studies; Intensive Care Units; Registries; *COVID-19; *Intensive care unit; *Pandemics; *COVID-19/therapy; *ARDS; *Pandemic; Critical Illness/epidemiology/therapy; *Disease dynamics

# Sepsis subphenotyping based on organ dysfunction trajectory

Abstract

BACKGROUND: Sepsis is a heterogeneous syndrome, and the identification of clinical subphenotypes is essential. Although organ dysfunction is a defining element of sepsis, subphenotypes of differential trajectory are not well studied. We sought to identify distinct Sequential Organ Failure Assessment (SOFA) score trajectory-based subphenotypes in sepsis.

METHODS: We created 72-h SOFA score trajectories in patients with sepsis from four diverse intensive care unit (ICU) cohorts. We then used dynamic time warping (DTW) to compute heterogeneous SOFA trajectory similarities and hierarchical agglomerative clustering (HAC) to identify trajectory-based subphenotypes. Patient characteristics were compared between subphenotypes and a random forest model was developed to predict subphenotype membership at 6 and 24 h after being admitted to the ICU. The model was tested on three validation cohorts. Sensitivity analyses were performed with alternative clustering methodologies.

RESULTS: A total of 4678, 3665, 12,282, and 4804 unique sepsis patients were included in development and three validation cohorts, respectively. Four subphenotypes were identified in the development cohort: Rapidly Worsening (n = 612, 13.1%), Delayed Worsening (n = 960, 20.5%), Rapidly Improving (n = 1932, 41.3%), and Delayed Improving (n = 1174, 25.1%). Baseline characteristics, including the pattern of organ dysfunction, varied between subphenotypes. Rapidly Worsening was defined by a higher comorbidity burden, acidosis, and visceral organ dysfunction. Rapidly Improving was defined by vasopressor use without acidosis. Outcomes differed across the subphenotypes, Rapidly Worsening had the highest in-hospital mortality (28.3%, P-value < 0.001), despite a lower SOFA (mean: 4.5) at ICU admission compared to Rapidly Improving (mortality:5.5%, mean SOFA: 5.5). An overall prediction accuracy of 0.78 (95% CI, [0.77, 0.8]) was obtained at 6 h after ICU admission, which increased to 0.87 (95% CI, [0.86, 0.88]) at 24 h. Similar subphenotypes were replicated in three validation cohorts. The majority of patients with sepsis have an improving phenotype with a lower mortality risk; however, they make up over 20% of all deaths due to their larger numbers.

CONCLUSIONS: Four novel, clinically-defined, trajectory-based sepsis subphenotypes were identified and validated. Identifying trajectory-based subphenotypes has immediate implications for the powering and predictive enrichment of clinical trials. Understanding the pathophysiology of these differential trajectories may reveal unanticipated therapeutic targets and identify more precise populations and endpoints for clinical trials.

# 基于器官功能障碍轨迹的败血症亚型

摘要

背景：脓毒症是一种异质性综合征，临床亚表型的识别至关重要。虽然器官功能障碍是败血症的定义要素，但差异轨迹的亚表型尚未充分研究。我们试图确定败血症中基于 mrs 的序贯器官衰竭评估 (SOFA) 评分亚表型。

方法：我们在 4 个不同的重症监护室 (ICU) 队列的败血症患者中创建了 72h SOFA 评分轨迹。然后，我们使用动态时间扭曲 (DTW) 计算异质性 SOFA 轨迹相似性，并使用分层聚类 (HAC) 来识别基于构型的亚表型。比较了亚表型之间的患者特征，并开发了随机森林模型，以预测入住 ICU 后 6h 和 24h 的亚表型成员。在 3 个验证队列中检验了模型。采用替代聚类方法进行敏感性分析。

结果：共有 4678、3665、12,282 和 4804 例独特败血症患者分别纳入开发队列和 3 个验证队列。在开发队列中确定了 4 个亚表型：快速恶化 (n = 612，13.1%)、延迟恶化 (n = 960，20.5%)、快速改善 (n = 1932，41.3%) 和延迟改善 (n = 1174，25.1%)。基线特征，包括器官功能障碍的模式，在亚表型之间有所不同。快速恶化定义为较高的合并症负担、酸中毒和内脏器官功能障碍。迅速改善定义为使用血管加压药而无酸中毒。结局在各亚表型之间存在差异，尽管与快速改善（死亡率：5.5%，平均 SOFA：5.5）相比，ICU 入院时的 SOFA（平均值：4.5）更低，但快速恶化的住院死亡率最高（28.3%，P 值 < 0.001）。在 ICU 入院后 6h 获得 0.78 (95% CI,[0.77,0.8]) 的总体预测准确性，24h 时增加至 0.87 (95% CI,[0.86,0.88])。在三个验证队列中重复相似的亚表型。大多数败血症患者的表型改善，死亡风险降低；然而，由于其数量较大，占所有死亡的 20% 以上。

结论：确定并验证了 4 种新的、临床定义的、膳食为基础的败血症亚表型。识别基于染色体的亚表型对临床试验的把握度和预测性富集具有直接影响。了解这些微分轨迹的病理生理学可能会揭示非预期的治疗靶点，并为临床试验确定更精确的人群和终点。

DOI: 10.1186/s13054-022-04071-4; No. 197

关键词：Humans; Intensive Care Units; Hospital Mortality; Hospitalization; *Sepsis; *Precision medicine; *Dynamic time warping; *Multiple Organ Failure; *Sequential Organ Failure Assessment (SOFA) score; *Subphenotype

# An updated HACOR score for predicting the failure of noninvasive ventilation: a multicenter prospective observational study

Abstract

BACKGROUND: Heart rate, acidosis, consciousness, oxygenation, and respiratory rate (HACOR) have been used to predict noninvasive ventilation (NIV) failure. However, the HACOR score fails to consider baseline data. Here, we aimed to update the HACOR score to take into account baseline data and test its predictive power for NIV failure primarily after 1-2 h of NIV.

METHODS: A multicenter prospective observational study was performed in 18 hospitals in China and Turkey. Patients who received NIV because of hypoxemic respiratory failure were enrolled. In Chongqing, China, 1451 patients were enrolled in the training cohort. Outside of Chongqing, another 728 patients were enrolled in the external validation cohort.

RESULTS: Before NIV, the presence of pneumonia, cardiogenic pulmonary edema, pulmonary ARDS, immunosuppression, or septic shock and the SOFA score were strongly associated with NIV failure. These six variables as baseline data were added to the original HACOR score. The AUCs for predicting NIV failure were 0.85 (95% CI 0.84-0.87) and 0.78 (0.75-0.81) tested with the updated HACOR score assessed after 1-2 h of NIV in the training and validation cohorts, respectively. A higher AUC was observed when it was tested with the updated HACOR score compared to the original HACOR score in the training cohort (0.85 vs. 0.80, 0.86 vs. 0.81, and 0.85 vs. 0.82 after 1-2, 12, and 24 h of NIV, respectively; all p values < 0.01). Similar results were found in the validation cohort (0.78 vs. 0.71, 0.79 vs. 0.74, and 0.81 vs. 0.76, respectively; all p values < 0.01). When 7, 10.5, and 14 points of the updated HACOR score were used as cutoff values, the probability of NIV failure was 25%, 50%, and 75%, respectively. Among patients with updated HACOR scores of ≤ 7, 7.5-10.5, 11-14, and > 14 after 1-2 h of NIV, the rate of NIV failure was 12.4%, 38.2%, 67.1%, and 83.7%, respectively.

CONCLUSIONS: The updated HACOR score has high predictive power for NIV failure in patients with hypoxemic respiratory failure. It can be used to help in decision-making when NIV is used.

DOI: 10.1186/s13054-022-04060-7; No. 196

关键词：Humans; Prospective Studies; Intensive Care Units; Treatment Failure; *Respiratory Insufficiency/etiology/therapy; *Noninvasive ventilation; *Acute respiratory failure; *Noninvasive Ventilation/methods; *Scoring system

DOI: 10.1186/s13054-022-04074-1; No. 198

关键词：Humans; Length of Stay; Adult; Survivors; *Critical care; Body Mass Index; *Critical Illness; *Mortality; *Obesity paradox; *Obesity, Morbid/complications; *Survivors

# Response to PEEP in COVID-19 ARDS patients with and without extracorporeal membrane oxygenation A multicenter case-control computed tomography study.

Abstract

BACKGROUND: PEEP selection in severe COVID-19 patients under extracorporeal membrane oxygenation (ECMO) is challenging as no study has assessed the alveolar recruitability in this setting. The aim of the study was to compare lung recruitability and the impact of PEEP on lung aeration in moderate and severe ARDS patients with or without ECMO, using computed tomography (CT).

METHODS: We conducted a two-center prospective observational case-control study in adult COVID-19-related patients who had an indication for CT within 72 h of ARDS onset in non-ECMO patients or within 72 h after ECMO onset. Ninety-nine patients were included, of whom 24 had severe ARDS under ECMO, 59 severe ARDS without ECMO and 16 moderate ARDS.

RESULTS: Non-inflated lung at PEEP 5 cmH(2)O was significantly greater in ECMO than in non-ECMO patients. Recruitment induced by increasing PEEP from 5 to 15 cmH(2)O was not significantly different between ECMO and non-ECMO patients, while PEEP-induced hyperinflation was significantly lower in the ECMO group and virtually nonexistent. The median [IQR] fraction of recruitable lung mass between PEEP 5 and 15 cmH(2)O was 6 [4-10]%. Total superimposed pressure at PEEP 5 cmH(2)O was significantly higher in ECMO patients and amounted to 12 [11-13] cmH(2)O. The hyperinflation-to-recruitment ratio (i.e., a trade-off index of the adverse effects and benefits of PEEP) was significantly lower in ECMO patients and was lower than one in 23 (96%) ECMO patients, 41 (69%) severe non-ECMO patients and 8 (50%) moderate ARDS patients. Compliance of the aerated lung at PEEP 5 cmH(2)O corrected for PEEP-induced recruitment (C(BABY LUNG)) was significantly lower in ECMO patients than in non-ECMO patients and was linearly related to the logarithm of the hyperinflation-to-recruitment ratio.

CONCLUSIONS: Lung recruitability of COVID-19 pneumonia is not significantly different between ECMO and non-ECMO patients, with substantial interindividual variations. The balance between hyperinflation and recruitment induced by PEEP increase from 5 to 15 cmH(2)O appears favorable in virtually all ECMO patients, while this PEEP level is required to counteract compressive forces leading to lung collapse. C(BABY LUNG) is significantly lower in ECMO patients, independently of lung recruitability.

# 有和无体外膜肺氧合的 COVID-19 ARDS 患者对 PEEP 的反应：一项多中心、病例对照计算机断层扫描研究。

摘要

背景：体外膜肺氧合 (ECMO) 条件下选择重度 COVID-19 患者的 PEEP 具有挑战性，因为尚无研究评估这种情况下的肺泡可恢复性。本研究的目的是采用计算机断层扫描 (CT)，在有或无 ECMO 的中度和重度 ARDS 患者中，比较肺复张力和 PEEP 对肺通气的影响。

方法：我们在成人 COVID-19 相关患者中进行了一项两中心前瞻性观察性病例对照研究，这些患者在非 ECMO 患者 ARDS 发作 72h 内或 72h 内有 CT 指征 ECMO 发作后 h。纳入 99 例患者，其中 24 例为 ECMO 下重度 ARDS，59 例为无 ECMO 下重度 ARDS，16 例为中度 ARDS。

结果：与非 ECMO 患者相比，ECMO 患者 PEEP 5cmh2 O 时的非充气肺显著更大。在 ECMO 和非 ECMO 患者之间，PEEP 从 5 增加到 15 cmh2 O 诱导的募集没有显著差异，而 PEEP 诱导的过度充气在 ECMO 组中显著较低，几乎不存在。PEEP 5-15 cmh2 O 之间可恢复肺质量的中位 [IQR] 分数为 6 [4-10]%。在 ECMO 患者中 PEEP 5cmh2 O 时的总叠加压显著较高，达 12 [11-13] cmh2 O。在 ECMO 患者中，过度充气与复张比率（即 PEEP 不良反应和获益的权衡指数）显著较低，低于 23 名 ECMO 患者中的 1 名 (96%)。41 例 (69%) 重度非 ECMO 患者和 8 例 (50%) 中度 ARDS 患者。与非 ECMO 患者相比，ECMO 患者 PEEP 5cmh2o (2) O 时通气肺对 PEEP 诱导肺复张 (C (BABY lung)) 的校正顺应性显著降低，且与过度充气 - 复张比率的对数呈线性相关。

结论：ECMO 和非 ECMO 患者中 COVID-19 肺炎的肺复张力无显著差异，存在显著的个体间差异。在几乎所有的 ECMO 患者中，PEEP 诱导的肺过度充气和肺复张之间的平衡从 5 增加到 15 cmh2o (2) O 似乎是有利的，而该 PEEP 水平需要抵消导致肺萎陷的压缩力。ECMO 患者的 C (BABY LUNG) 显著较低，与肺复张性无关。

DOI: 10.1186/s13054-022-04076-z; No. 195

关键词：Humans; Case-Control Studies; Adult; Tomography, X-Ray Computed; *COVID-19; *Extracorporeal Membrane Oxygenation; *ARDS; *ECMO; *Respiratory Distress Syndrome/diagnostic imaging/therapy; *COVID-19/complications/therapy; Positive-Pressure Respiration/methods; *Computed tomography; *PEEP

DOI: 10.1186/s13054-022-04072-3; No. 194

关键词：Humans; Respiration, Artificial; Respiration; *COVID-19; Prone Position; *ARDS; *Mechanical ventilation; *Prone position; Respiratory Function Tests

DOI: 10.1186/s13054-022-04069-y; No. 193

关键词：Humans; Perfusion; Prospective Studies; Respiration, Artificial; *COVID-19; Lung; Prone Position/physiology

# Key characteristics impacting survival of COVID-19 extracorporeal membrane oxygenation

Abstract

BACKGROUND: Severe COVID-19 induced acute respiratory distress syndrome (ARDS) often requires extracorporeal membrane oxygenation (ECMO). Recent German health insurance data revealed low ICU survival rates. Patient characteristics and experience of the ECMO center may determine intensive care unit (ICU) survival. The current study aimed to identify factors affecting ICU survival of COVID-19 ECMO patients.

METHODS: 673 COVID-19 ARDS ECMO patients treated in 26 centers between January 1st 2020 and March 22nd 2021 were included. Data on clinical characteristics, adjunct therapies, complications, and outcome were documented. Block wise logistic regression analysis was applied to identify variables associated with ICU-survival.

RESULTS: Most patients were between 50 and 70 years of age. PaO(2)/FiO(2) ratio prior to ECMO was 72 mmHg (IQR: 58-99). ICU survival was 31.4%. Survival was significantly lower during the 2nd wave of the COVID-19 pandemic. A subgroup of 284 (42%) patients fulfilling modified EOLIA criteria had a higher survival (38%) (p = 0.0014, OR 0.64 (CI 0.41-0.99)). Survival differed between low, intermediate, and high-volume centers with 20%, 30%, and 38%, respectively (p = 0.0024). Treatment in high volume centers resulted in an odds ratio of 0.55 (CI 0.28-1.02) compared to low volume centers. Additional factors associated with survival were younger age, shorter time between intubation and ECMO initiation, BMI > 35 (compared to < 25), absence of renal replacement therapy or major bleeding/thromboembolic events.

CONCLUSIONS: Structural and patient-related factors, including age, comorbidities and ECMO case volume, determined the survival of COVID-19 ECMO. These factors combined with a more liberal ECMO indication during the 2nd wave may explain the reasonably overall low survival rate. Careful selection of patients and treatment in high volume ECMO centers was associated with higher odds of ICU survival.

DOI: 10.1186/s13054-022-04053-6; No. 190

关键词：Humans; Survival Analysis; Intensive Care Units; Pandemics; *COVID-19; *COVID-19/therapy; *Respiratory Distress Syndrome/therapy; *Extracorporeal Membrane Oxygenation; *Intensive care; *Acute respiratory distress syndrome (ARDS); *Case-volume relationship; *Extracorporeal life support

DOI: 10.1186/s13054-022-04057-2; No. 191

关键词：Humans; Intensive Care Units; Pandemics; *COVID-19; Communication; *Intensive care; *Communication; *Family liaison service; *Hands-free communication device; *Role labels; *Videoconferencing

DOI: 10.1186/s13054-022-04067-0; No. 192

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# 更正：早期与延迟肠内营养在机械通气的循环性休克患者中的应用：一项国际多中心、实用临床试验的巢式队列分析

# Lung ultrasound response to awake prone positioning predicts the need for intubation in patients with COVID-19 induced acute hypoxemic respiratory failure: an observational study

Abstract

BACKGROUND: Awake prone positioning (APP) reduces the intubation rate in COVID-19 patients treated by high-flow nasal cannula (HFNC). However, the lung aeration response to APP has not been addressed. We aimed to explore the lung aeration response to APP by lung ultrasound (LUS).

METHODS: This two-center, prospective, observational study enrolled patients with COVID-19-induced acute hypoxemic respiratory failure treated by HFNC and APP. LUS score was recorded 5-10 min before, 1 h after APP, and 5-10 min after supine in the first APP session within the first three days. The primary outcome was LUS score changes in the first three days. Secondary outcomes included changes in SpO(2)/FiO(2) ratio, respiratory rate and ROX index (SpO(2)/FiO(2)/respiratory rate) related to APP, and the rate of treatment success (patients who avoided intubation).

RESULTS: Seventy-one patients were enrolled. LUS score decreased from 20 (interquartile range [IQR] 19-24) to 19 (18-21) (p < 0.001) after the first APP session, and to 19 (18-21) (p < 0.001) after three days. Compared to patients with treatment failure (n = 20, 28%), LUS score reduction after the first three days in patients with treatment success (n = 51) was greater (- 2.6 [95% confidence intervals - 3.1 to - 2.0] vs 0 [- 1.2 to 1.2], p = 0.001). A decrease in dorsal LUS score > 1 after the first APP session was associated with decreased risk for intubation (Relative risk 0.25 [0.09-0.69]). APP daily duration was correlated with LUS score reduction in patients with treatment success, especially in dorsal lung zones (r = - 0.76; p < 0.001).

CONCLUSIONS: In patients with acute hypoxemic respiratory failure due to COVID-19 and treated by HFNC, APP reduced LUS score. The reduction in dorsal LUS scores after APP was associated with treatment success. The longer duration on APP was correlated with greater lung aeration.

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DOI: 10.1186/s13054-022-04064-3; No. 189

关键词：Humans; Prospective Studies; *COVID-19; *Respiratory Insufficiency/etiology/therapy; Lung/diagnostic imaging; *COVID-19/complications/therapy; Intubation, Intratracheal/adverse effects; Prone Position/physiology; *Awake prone positioning; *High-flow nasal cannula; *Intubation; *Lung ultrasound; Wakefulness

DOI: 10.1186/s13054-022-04063-4; No. 188

关键词：Humans; Oxygen; Positive-Pressure Respiration; Respiration, Artificial; Algorithms; *Critical care; *Mechanical ventilation; *Airway Extubation; *Ventilator Weaning; *Extubation; *Respiratory mechanics; *Ventilator weaning

DOI: 10.1186/s13054-022-04056-3; No. 186

关键词：Hemodynamics; Humans; Fluid Therapy; Critical Illness/therapy; *Critically ill patients; *Shock, Septic; *Fluid responsiveness; *Fluid bolus; *Fluid challenge; *Fluids; *Hemodynamic Monitoring; Crystalloid Solutions/therapeutic use

DOI: 10.1186/s13054-022-04039-4; No. 187

关键词：Humans; Risk Assessment; *COVID-19; SARS-CoV-2; *Respiratory Distress Syndrome/therapy; *Extracorporeal Membrane Oxygenation

DOI: 10.1186/s13054-022-04052-7; No. 184

关键词：Humans; Hospitals; Hemorrhage/etiology/therapy; Resuscitation/methods; *Balloon Occlusion/methods; *Endovascular Procedures/methods; *Helicopter emergency medical services (HEMS); *Interventions; *Penetrating injuries; *Pre-hospital

# Driving pressure-guided ventilation decreases the mechanical power compared to predicted body weight-guided ventilation in the Acute Respiratory Distress Syndrome

Abstract

BACKGROUND: Whether targeting the driving pressure (∆P) when adjusting the tidal volume in mechanically ventilated patients with the acute respiratory distress syndrome (ARDS) may decrease the risk of ventilator-induced lung injury remains a matter of research. In this study, we assessed the effect of a ∆P-guided ventilation on the mechanical power.

METHODS: We prospectively included adult patients with moderate-to-severe ARDS. Positive end expiratory pressure was set by the attending physician and kept constant during the study. Tidal volume was first adjusted to target 6 ml/kg of predicted body weight (PBW-guided ventilation) and subsequently modified within a range from 4 to 10 ml/kg PBW to target a ∆P between 12 and 14 cm H(2)O. The respiratory rate was then re-adjusted within a range from 12 to 40 breaths/min until EtCO(2) returned to its baseline value (∆P-guided ventilation). Mechanical power was computed at each step.

RESULTS: Fifty-one patients were included between December 2019 and May 2021. ∆P-guided ventilation was feasible in all but one patient. The ∆P during PBW-guided ventilation was already within the target range of ∆P-guided ventilation in five (10%) patients, above in nine (18%) and below in 36 (72%). The change from PBW- to ∆P-guided ventilation was thus accompanied by an overall increase in tidal volume from 6.1 mL/kg PBW [5.9-6.2] to 7.7 ml/kg PBW [6.2-8.7], while respiratory rate was decreased from 29 breaths/min [26-32] to 21 breaths/min [16-28] (p < 0.001 for all comparisons). ∆P-guided ventilation was accompanied by a significant decrease in mechanical power from 31.5 J/min [28-35.7] to 28.8 J/min [24.6-32.6] (p < 0.001), representing a relative decrease of 7% [0-16]. With ∆P-guided ventilation, the PaO(2)/FiO(2) ratio increased and the ventilatory ratio decreased.

CONCLUSION: As compared to a conventional PBW-guided ventilation, a ∆P-guided ventilation strategy targeting a ∆P between 12 and 14 cm H(2)O required to change the tidal volume in 90% of the patients. Such ∆P-guided ventilation significantly reduced the mechanical power. Whether this physiological observation could be associated with clinical benefit should be assessed in clinical trials.

DOI: 10.1186/s13054-022-04054-5; No. 185

关键词：Humans; Adult; Positive-Pressure Respiration; Respiration, Artificial; Lung; Body Weight; *Respiratory Distress Syndrome/therapy; *Mechanical ventilation; Tidal Volume/physiology; *Acute respiratory distress syndrome; *Driving pressure; *Mechanical power; *Protective ventilation; *Tidal volume; *Ventilator-induced lung injury

# Effect of intravenous clarithromycin in patients with sepsis, respiratory and multiple organ dysfunction syndrome: a randomized clinical trial

Abstract

BACKGROUND: Clarithromycin may act as immune-regulating treatment in sepsis and acute respiratory dysfunction syndrome. However, clinical evidence remains inconclusive. We aimed to evaluate whether clarithromycin improves 28-day mortality among patients with sepsis, respiratory and multiple organ dysfunction syndrome.

METHODS: We conducted a multicenter, randomized, clinical trial in patients with sepsis. Participants with ratio of partial oxygen pressure to fraction of inspired oxygen less than 200 and more than 3 SOFA points from systems other than the respiratory function were enrolled between December 2017 and September 2019. Patients were randomized to receive 1 gr of clarithromycin or placebo intravenously once daily for 4 consecutive days. The primary endpoint was 28-day all-cause mortality. Secondary outcomes were 90-day mortality; sepsis response (defined as at least 25% decrease in SOFA score by day 7); sepsis recurrence; and differences in peripheral blood cell populations and leukocyte transcriptomics.

RESULTS: Fifty-five patients were allocated to each arm. By day 28, 27 (49.1%) patients in the clarithromycin and 25 (45.5%) in the placebo group died (risk difference 3.6% [95% confidence interval (CI) - 15.7 to 22.7]; P = 0.703, adjusted OR 1.03 [95%CI 0.35-3.06]; P = 0.959). There were no statistical differences in 90-day mortality and sepsis response. Clarithromycin was associated with lower incidence of sepsis recurrence (OR 0.21 [95%CI 0.06-0.68]; P = 0.012); significant increase in monocyte HLA-DR expression; expansion of non-classical monocytes; and upregulation of genes involved in cholesterol homeostasis. Serious and non-serious adverse events were equally distributed.

CONCLUSIONS: Clarithromycin did not reduce mortality among patients with sepsis with respiratory and multiple organ dysfunction. Clarithromycin was associated with lower sepsis recurrence, possibly through a mechanism of immune restoration. Clinical trial registration clinicaltrials.gov identifier NCT03345992 registered 17 November 2017; EudraCT 2017-001056-55.

DOI: 10.1186/s13054-022-04055-4; No. 183

关键词：Humans; Administration, Intravenous; *Sepsis; *Sepsis/complications; Oxygen/therapeutic use; *Cholesterol; *Clarithromycin; *Clarithromycin/pharmacology/therapeutic use; *Macrolides; *Multiple organ dysfunction; *Recurrence; Multiple Organ Failure/complications/drug therapy

DOI: 10.1186/s13054-022-04051-8; No. 182

关键词：Humans; *COVID-19; Lung; Body Mass Index; *Respiratory Distress Syndrome/therapy; Obesity/complications

# Safety and efficacy of the Seraph® 100 Microbind® Affinity Blood Filter to remove bacteria from the blood stream: results of the first in human study

Abstract

BACKGROUND: Bacterial burden as well as duration of bacteremia influence the outcome of patients with bloodstream infections. Promptly decreasing bacterial load in the blood by using extracorporeal devices in addition to anti-infective therapy has recently been explored. Preclinical studies with the Seraph® 100 Microbind® Affinity Blood Filter (Seraph® 100), which consists of heparin that is covalently bound to polymer beads, have demonstrated an effective binding of bacteria and viruses. Pathogens adhere to the heparin coated polymer beads in the adsorber as they would normally do to heparan sulfate on cell surfaces. Using this biomimetic principle, the Seraph® 100 could help to decrease bacterial burden in vivo.

METHODS: This first in human, prospective, multicenter, non-randomized interventional study included patients with blood culture positive bloodstream infection and the need for kidney replacement therapy as an adjunctive treatment for bloodstream infections. We performed a single four-hour hemoperfusion treatment with the Seraph® 100 in conjunction with a dialysis procedure. Post procedure follow up was 14 days.

RESULTS: Fifteen hemodialysis patients (3F/12 M, age 74.0 [68.0-78.5] years, dialysis vintage 28.0 [11.0-45.0] months) were enrolled. Seraph® 100 treatment started 66.4 [45.7-80.6] hours after the initial positive blood culture was drawn. During the treatment with the Seraph® 100 with a median blood flow of 285 [225-300] ml/min no device or treatment related adverse events were reported. Blood pressure and heart rate remained stable while peripheral oxygen saturation improved during the treatment from 98.0 [92.5-98.0] to 99.0 [98.0-99.5] %; p = 0.0184. Four patients still had positive blood culture at the start of Seraph® 100 treatment. In one patient blood cultures turned negative during treatment. The time to positivity (TTP) was increased between inflow and outflow blood cultures by 36 [- 7.2 to 96.3] minutes. However, overall TTP increase was not statistical significant.

CONCLUSIONS: Seraph® 100 treatment was well tolerated. Adding Seraph® 100 to antibiotics early in the course of bacteremia might result in a faster resolution of bloodstream infections, which has to be evaluated in further studies. TRAIL REGISTRATION: ClinicalTrials.gov Identifier: NCT02914132 , first posted September 26, 2016.

# Seraph®100 Microbind®Affinity 血液滤器去除血流中细菌的安全性和有效性：首次人体研究结果

摘要

背景：细菌负荷以及菌血症持续时间影响血液感染患者的结局。最近还探索了在抗感染治疗的同时使用体外装置来迅速降低血液中的细菌负荷。Seraph®100 Microbind®Affinity Blood Filter (Seraph®100) 的临床前研究已经证明，这种膜由共价结合到聚合物微球上的肝素组成，可以有效结合细菌和病毒。病原体粘附于吸附仪中肝素包被的聚合物珠，因为它们通常会吸附细胞表面的硫酸肝素。利用这种仿生原理，Seraph®100 有助于减少体内细菌负荷。

方法：这是首次人体、前瞻性、多中心、非随机干预性研究，纳入了血培养阳性血流感染且需要肾脏替代治疗作为血流感染辅助治疗的患者。我们采用 Seraph®100 进行了单次 4 小时血液灌流治疗联合透析操作。术后随访 14 天。

结果：入选了 15 例血液透析患者（3F/12 M，年龄 74.0 [68.0-78.5] 岁，透析时间 28.0 [11.0-45.0] 个月）。在首次血培养阳性后 66.4 [45.7-80.6] 小时开始 Seraph®100 治疗。在血流中值为 285 [225-300] ml/min 的 Seraph®100 治疗期间，未报告与装置或治疗相关的不良事件。治疗期间，血压和心率保持稳定，而外周血氧饱和度从 98.0 [92.5-98.0] 改善至 99.0 [98.0-99.5]%；p = 0.0184。4 例患者在开始 Seraph®100 治疗时血培养仍为阳性。治疗期间，1 例患者的血培养结果转为阴性。血液流入和流出培养物之间的至阳性时间 (TTP) 增加了 36 [-7.2 至 96.3] 分钟。但是，总体 TTP 增加无统计学显著性。

结论：Seraph®100 治疗耐受性良好。在菌血症早期抗生素治疗的基础上加用 Seraph®100，可能会使血液感染更快消退，这需要在进一步的研究中进行评价。TRAIL 注册：ClinicalTrials.gov 识别码：NCT02914132，2016 年 9 月 26 日首次发布。

DOI: 10.1186/s13054-022-04044-7; No. 181

关键词：Humans; Prospective Studies; Aged; Bacteria; *Bacteraemia; *Bacteremia/drug therapy; *Bloodstream infections; *Extracorporeal devices; *Haemodialysis; *Renal Dialysis; Heparin/pharmacology/therapeutic use; Polymers

# Andexanet alfa versus four-factor prothrombin complex concentrate for the reversal of apixaban- or rivaroxaban-associated intracranial hemorrhage: a propensity score-overlap weighted analysis

Abstract

BACKGROUND: Andexanet alfa is approved (FDA "accelerated approval"; EMA "conditional approval") as the first specific reversal agent for factor Xa (FXa) inhibitor-associated uncontrolled or life-threatening bleeding. Four-factor prothrombin complex concentrates (4F-PCC) are commonly used as an off-label, non-specific, factor replacement approach to manage FXa inhibitor-associated life-threatening bleeding. We evaluated the effectiveness and safety of andexanet alfa versus 4F-PCC for management of apixaban- or rivaroxaban-associated intracranial hemorrhage (ICH).

METHODS: This two-cohort comparison study included andexanet alfa patients enrolled at US hospitals from 4/2015 to 3/2020 in the prospective, single-arm ANNEXA-4 study and a synthetic control arm of 4F-PCC patients admitted within a US healthcare system from 12/2016 to 8/2020. Adults with radiographically confirmed ICH who took their last dose of apixaban or rivaroxaban < 24 h prior to the bleed were included. Patients with a Glasgow Coma Scale (GCS) score < 7, hematoma volume > 60 mL, or planned surgery within 12 h were excluded. Outcomes were hemostatic effectiveness from index to repeat scan, mortality within 30 days, and thrombotic events within five days. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated using propensity score-overlap weighted logistic regression.

RESULTS: The study included 107 andexanet alfa (96.6% low dose) and 95 4F-PCC patients (79.3% receiving a 25 unit/kg dose). After propensity score-overlap weighting, mean age was 79 years, GCS was 14, time from initial scan to reversal initiation was 2.3 h, and time from reversal to repeat scan was 12.2 h in both arms. Atrial fibrillation was present in 86% of patients. Most ICHs were single compartment (78%), trauma-related (61%), and involved the intracerebral and/or intraventricular space(s) (53%). ICH size was ≥ 10 mL in volume (intracerebral and/or ventricular) or ≥ 10 mm in thickness (subdural or subarachnoid) in 22% of patients and infratentorial in 15%. Andexanet alfa was associated with greater odds of achieving hemostatic effectiveness (85.8% vs. 68.1%; OR 2.73; 95% CI 1.16-6.42) and decreased odds of mortality (7.9% vs. 19.6%; OR 0.36; 95% CI 0.13-0.98) versus 4F-PCC. Two thrombotic events occurred with andexanet alfa and none with 4F-PCC.

CONCLUSIONS: In this indirect comparison of patients with an apixaban- or rivaroxaban-associated ICH, andexanet alfa was associated with better hemostatic effectiveness and improved survival compared to 4F-PCC.

# Andexanet α 与四因素凝血酶原复合物浓缩制剂逆转阿哌沙班或利伐沙班相关的颅内出血：倾向评分重叠加权分析

摘要

背景：Andexanet α 获批（FDA “加速批准”；EMA “条件性批准”）作为 Xa 因子 (FXa) 抑制剂相关的未控制或危及生命的出血的首个特异性逆转剂。四因素凝血酶原复合物浓缩物 (4F-PCC) 通常用作标签外、非特异性因子替代方法，以管理 FXa 抑制剂相关危及生命的出血。我们评价了 andexanet α 对比 4F-PCC 治疗阿哌沙班或利伐沙班相关颅内出血 (ICH) 的有效性和安全性。

方法：这项双队列比较研究纳入了 2015 年 4 月至 2020 年 3 月在美国医院入组的 andexanet α 患者，参加了前瞻性、单组 ANNEXA-4 研究，并纳入了 2016 年 12 月至 2020 年 8 月在美国医疗保健系统住院的 4F-PCC 患者的合成对照组。纳入了伴有放射学证实的 ICH 且在出血前 <24h 接受阿哌沙班或利伐沙班末次给药的成人。排除 Glasgow 昏迷量表 (GCS) 评分 < 7 分、血肿量 > 60 mL 或 12 h 内计划手术的患者。结局为从指数到重复扫描的止血有效性、30 天内死亡率和 5 天内血栓形成事件。采用倾向得分重叠加权 logistic 回归计算 95% 置信区间 (CI) 的优势比 (OR)。

结果：研究包括 107 名 andexanet α（96.6% 低剂量）和 95 名 4F-PCC 患者（79.3% 接受 25 单位 /kg 剂量）。倾向评分重叠加权后，两组的平均年龄为 79 岁，GCS 为 14，从初始扫描到逆转开始的时间为 2.3h，从逆转到重复扫描的时间为 12.2h。86% 的患者存在房颤。大多数 ICH 为单室 (78%)、创伤相关 (61%)，并涉及脑内和 / 或心室内空间 (53%)。22% 的患者 ICH 体积≥10 mL（脑内和 / 或脑室）或厚度≥10 mm（硬膜下或蛛网膜下腔），15% 为幕下。Andexanet α 与 4F-PCC 相比，实现止血有效性的几率更大 (85.8% vs. 68.1%；OR 2.73；95% CI 1.16-6.42)，死亡率的几率下降 (7.9% vs. 19.6%；OR 0.36；95% CI 0.13-0.98)。andexanet α 组发生了 2 例血栓事件，4F-PCC 组未发生。

结论：在这项阿哌沙班或利伐沙班相关 ICH 患者的间接比较中，与 4F-PCC 相比，andexanet α 的止血效果更好，生存期改善。

DOI: 10.1186/s13054-022-04043-8; No. 180

关键词：Humans; Prospective Studies; Aged; Adult; Propensity Score; Retrospective Studies; Hemorrhage; Anticoagulants; *Thrombosis; Recombinant Proteins/therapeutic use; *Andexanet alfa; *Direct factor Xa inhibitor reversal; *Four-factor prothrombin complex concentrate; *Hemostatics; *Intracranial hemorrhage; Blood Coagulation Factors/pharmacology/therapeutic use; Factor Xa Inhibitors/adverse effects; Factor Xa/therapeutic use; Intracranial Hemorrhages/chemically induced/drug therapy; Pyrazoles; Pyridones; Rivaroxaban/adverse effects

# A dual-center cohort study on the association between early deep sedation and clinical outcomes in mechanically ventilated patients during the COVID-19 pandemic: The COVID-SED study

Abstract

BACKGROUND: Mechanically ventilated patients have experienced greater periods of prolonged deep sedation during the coronavirus disease (COVID-19) pandemic. Multiple studies from the pre-COVID era demonstrate that early deep sedation is associated with worse outcome. Despite this, there is a lack of data on sedation depth and its impact on outcome for mechanically ventilated patients during the COVID-19 pandemic. We sought to characterize the emergency department (ED) and intensive care unit (ICU) sedation practices during the COVID-19 pandemic, and to determine if early deep sedation was associated with worse clinical outcomes. STUDY DESIGN AND

METHODS: Dual-center, retrospective cohort study conducted over 6 months (March-August, 2020), involving consecutive, mechanically ventilated adults. All sedation-related data during the first 48 h were collected. Deep sedation was defined as Richmond Agitation-Sedation Scale of - 3 to - 5 or Riker Sedation-Agitation Scale of 1-3. To examine impact of early sedation depth on hospital mortality (primary outcome), we used a multivariable logistic regression model. Secondary outcomes included ventilator-, ICU-, and hospital-free days.

RESULTS: 391 patients were studied, and 283 (72.4%) experienced early deep sedation. Deeply sedated patients received higher cumulative doses of fentanyl, propofol, midazolam, and ketamine when compared to light sedation. Deep sedation patients experienced fewer ventilator-, ICU-, and hospital-free days, and greater mortality (30.4% versus 11.1%) when compared to light sedation (p < 0.01 for all). After adjusting for confounders, early deep sedation remained significantly associated with higher mortality (adjusted OR 3.44; 95% CI 1.65-7.17; p < 0.01). These results were stable in the subgroup of patients with COVID-19.

CONCLUSIONS: The management of sedation for mechanically ventilated patients in the ICU has changed during the COVID pandemic. Early deep sedation is common and independently associated with worse clinical outcomes. A protocol-driven approach to sedation, targeting light sedation as early as possible, should continue to remain the default approach.

DOI: 10.1186/s13054-022-04042-9; No. 179

关键词：Humans; Intensive Care Units; Adult; Cohort Studies; Retrospective Studies; Pandemics; *COVID-19; Hypnotics and Sedatives/therapeutic use; Respiration, Artificial/methods; *COVID; *Mechanical ventilation; *Deep sedation; *Deep Sedation/methods; *Emergency department

# Expert clinical pharmacological advice may make an antimicrobial TDM program for emerging candidates more clinically useful in tailoring therapy of critically ill patients

Abstract

BACKGROUND: Therapeutic drug monitoring (TDM) may represent an invaluable tool for optimizing antimicrobial therapy in septic patients, but extensive use is burdened by barriers. The aim of this study was to assess the impact of a newly established expert clinical pharmacological advice (ECPA) program in improving the clinical usefulness of an already existing TDM program for emerging candidates in tailoring antimicrobial therapy among critically ill patients.

METHODS: This retrospective observational study included an organizational phase (OP) and an assessment phase (AP). During the OP (January-June 2021), specific actions were organized by MD clinical pharmacologists together with bioanalytical experts, clinical engineers, and ICU clinicians. During the AP (July-December 2021), the impact of these actions in optimizing antimicrobial treatment of the critically ill patients was assessed. Four indicators of performance of the TDM-guided real-time ECPA program were identified [total TDM-guided ECPAs July-December 2021/total TDM results July-December 2020; total ECPA dosing adjustments/total delivered ECPAs both at first assessment and overall; and turnaround time (TAT) of ECPAs, defined as optimal (< 12 h), quasi-optimal (12-24 h), acceptable (24-48 h), suboptimal (> 48 h)].

RESULTS: The OP allowed to implement new organizational procedures, to create a dedicated pathway in the intranet system, to offer educational webinars on clinical pharmacology of antimicrobials, and to establish a multidisciplinary team at the morning bedside ICU meeting. In the AP, a total of 640 ECPAs were provided for optimizing 261 courses of antimicrobial therapy in 166 critically ill patients. ECPAs concerned mainly piperacillin-tazobactam (41.8%) and meropenem (24.9%), and also other antimicrobials had ≥ 10 ECPAs (ceftazidime, ciprofloxacin, fluconazole, ganciclovir, levofloxacin, and linezolid). Overall, the pre-post-increase in TDM activity was of 13.3-fold. TDM-guided dosing adjustments were recommended at first assessment in 61.7% of ECPAs (10.7% increases and 51.0% decreases), and overall in 45.0% of ECPAs (10.0% increases and 35.0% decreases). The overall median TAT was optimal (7.7 h) and that of each single agent was always optimal or quasi-optimal.

CONCLUSIONS: Multidisciplinary approach and timely expert interpretation of TDM results by MD Clinical Pharmacologists could represent cornerstones in improving the cost-effectiveness of an antimicrobial TDM program for emerging TDM candidates.

# 专家临床药理学建议可使新候选患者的抗微生物 TDM 项目在危重患者的个体化治疗中更具临床实用性

摘要

背景：治疗药物监测 (TDM) 可能是败血症患者优化抗微生物治疗的宝贵工具，但是广泛使用受到障碍的负担。本研究的目的是评估新建立的专家临床药理学建议 (ECPA) 项目对改善现有 TDM 项目的临床有效性的影响，该项目是为危重患者量身定制抗微生物治疗的新候选者。

方法：这项回顾性观察性研究包括一个组织阶段 (OP) 和一个评估阶段 (AP)。在 OP 期间（2021 年 1-6 月），MD 临床药理学家与生物分析专家、临床工程师和 ICU 临床医生一起组织了具体措施。在 AP 期间（2021 年 7 月至 12 月），评估了这些措施对重症患者优化抗生素治疗的影响。确定了 TDM - 引导的实时 ECPA 程序的 4 个绩效指标 [2021 年 7 月 - 12 月总 TDM - 引导的 ECPA/2020 年 7 月 - 12 月总 TDM 结果；首次评估和总体评估时的总 ECPA 剂量调整 / 总递送 ECPA；ECPA 的周转时间 (TAT)，定义为最佳 (< 12h)，准最佳 (12-24h)，可接受 (24-48h)，次优 (> 48h)]。

结果：OP 允许实施新的组织程序，在内部网络系统创建专用途径，提供抗菌药物临床药理学教育网络研讨会，并在早晨床边 ICU 会议上建立多学科团队。在 AP 中，为 166 例重症患者优化 261 个疗程的抗菌治疗，共计提供了 640 份 ECPA。ECPA 主要涉及哌拉西林 - 他唑巴坦 (41.8%) 和美罗培南 (24.9%)，其他抗菌药也有≥10 种 ECPA（头孢他啶、环丙沙星、氟康唑、更昔洛韦、左氧氟沙星和利奈唑胺）。总体而言，TDM 活性在给药前和给药后增加了 13.3 倍。首次评估时，61.7% 的 ECPA（增加 10.7%，降低 51.0%）和总体 45.0% 的 ECPA（增加 10.0%，降低 35.0%）推荐 TDM 指导的剂量调整。总体中位 TAT 为最佳 (7.7h)，每种单药的 TAT 始终为最佳或准最佳。

结论：多学科方法和 MD 临床药理学家对 TDM 结果的及时专家解释可成为提高新 TDM 候选者抗微生物 TDM 项目成本效益的基础。

DOI: 10.1186/s13054-022-04050-9; No. 178

关键词：Humans; Anti-Bacterial Agents; Critical Illness/therapy; *Critically ill patients; *Anti-Infective Agents/therapeutic use; *Dosing adjustments; *Drug Monitoring/methods; *Expert clinical pharmacological advice program; *General ICU; *Personalized antimicrobial therapy; *Transplant ICU; *Turnaround time; Meropenem

# The sit-to-stand test as a patient-centered functional outcome for critical care research: a pooled analysis of five international rehabilitation studies

Abstract

BACKGROUND: With ICU mortality rates decreasing, it is increasingly important to identify interventions to minimize functional impairments and improve outcomes for survivors. Simultaneously, we must identify robust patient-centered functional outcomes for our trials. Our objective was to investigate the clinimetric properties of a progression of three outcome measures, from strength to function.

METHODS: Adults (≥ 18 years) enrolled in five international ICU rehabilitation studies. Participants required ICU admission were mechanically ventilated and previously independent. Outcomes included two components of the Physical Function in ICU Test-scored (PFIT-s): knee extensor strength and assistance required to move from sit to stand (STS); the 30-s STS (30 s STS) test was the third outcome. We analyzed survivors at ICU and hospital discharge. We report participant demographics, baseline characteristics, and outcome data using descriptive statistics. Floor effects represented ≥ 15% of participants with minimum score and ceiling effects ≥ 15% with maximum score. We calculated the overall group difference score (hospital discharge score minus ICU discharge) for participants with paired assessments.

RESULTS: Of 451 participants, most were male (n = 278, 61.6%) with a median age between 60 and 66 years, a mean APACHE II score between 19 and 24, a median duration of mechanical ventilation between 4 and 8 days, ICU length of stay (LOS) between 7 and 11 days, and hospital LOS between 22 and 31 days. For knee extension, we observed a ceiling effect in 48.5% (160/330) of participants at ICU discharge and in 74.7% (115/154) at hospital discharge; the median [1st, 3rd quartile] PFIT-s difference score (n = 139) was 0 [0,1] (p < 0.05). For STS assistance, we observed a ceiling effect in 45.9% (150/327) at ICU discharge and in 77.5% (79/102) at hospital discharge; the median PFIT-s difference score (n = 87) was 1 [0, 2] (p < 0.05). For 30 s STS, we observed a floor effect in 15.0% (12/80) at ICU discharge but did not observe a floor or ceiling effect at hospital discharge. The median 30 s STS difference score (n = 54) was 3 [1, 6] (p < 0.05).

CONCLUSION: Among three progressive outcome measures evaluated in this study, the 30 s STS test appears to have the most favorable clinimetric properties to assess function at ICU and hospital discharge in moderate to severely ill participants.

# 坐立试验作为重症监护研究中以患者为中心的功能性结局：5 项国际康复研究的汇总分析

摘要

背景：随着 ICU 死亡率的降低，确定干预措施以尽量减少功能障碍并改善存活者的结局变得越来越重要。同时，我们必须为我们的试验确定稳健的以患者为中心的功能性结局。我们的目的是研究三种结局指标进展的临床特征，从强度到功能。

方法：入选 5 项国际 ICU 康复研究的成人（≥18 岁）。受试者需要入住 ICU 接受机械通气，以前是独立的。结果包括 ICU 测试评分的身体功能的两个部分 (PFIT-s)：膝伸肌力量和从坐立位转移到站立位所需的辅助 (STS)；30-s STS (30s STS) 测试是第三个结果。我们分析了 ICU 和出院时的存活者。我们使用描述性统计报告受试者的人口统计学、基线特征和结局数据。≥15% 的受试者的最低得分是地板效应，最高得分是天花板效应≥15%。我们通过配对评估计算了受试者的总体组间差异评分（出院评分减去 ICU 出院评分）。

结果：在 451 例参与者中，大多数为男性 (n = 278，61.6%)，中位年龄为 60-66 岁，平均 APACHE II 评分为 19-24，中位机械通气持续时间为 4-8 天，ICU 住院时间 (LOS) 为 7-11 天，住院 LOS 为 22-31 天。对于膝关节伸展，我们观察到 48.5%(160/330) 的参与者在 ICU 出院时和 74.7%(115/154) 的参与者在出院时存在上限效应；中位 [第 1、3 四分位数] PFIT-s 差异评分 (n = 139) 为 0 [0,1](p < 0.05)。对于 STS 辅助，我们观察到在离开 ICU 时 45.9%(150/327) 存在上限效应，在出院时 77.5%(79/102) 存在上限效应；中位 PFIT-s 差异评分 (n = 87) 为 1 [0，2](p < 0.05)。对于 30s 的 STS，我们在 ICU 出院时观察到 15.0%(12/80) 的地板效应，但在出院时未观察到地板或天花板效应。中位 30s STS 差异评分 (n = 54) 为 3 [1，6](p < 0.05)。

结论：在本研究评估的 3 个进行性结局指标中，30 sSTS 检测似乎具有最有利的临床特性来评估中至重度患者在 ICU 和出院时的功能。

DOI: 10.1186/s13054-022-04048-3; No. 175

关键词：Humans; Female; Male; Middle Aged; Aged; Length of Stay; Adult; Respiration, Artificial; Physical Therapy Modalities; *Intensive Care Units; *Critical Care; *Intensive care units; *Critical illness; Patient-Centered Care; *Exercise test; *Outcome assessment; *Physical outcome measures; *Rehabilitation; *Sit-to-stand test; Critical Illness/rehabilitation

DOI: 10.1186/s13054-022-04041-w; No. 174

关键词：Humans; Prospective Studies; Intensive Care Units; Adult; Quality of Life; *Sepsis; Respiration, Artificial/adverse effects; *Critical illness; *Critical Illness/epidemiology/therapy; *Intensive care; *Mechanical ventilation; *Disability; *Recovery; *Sepsis/complications/therapy

# Impact of dexamethasone on the incidence of ventilator-associated pneumonia in mechanically ventilated COVID-19 patients: a propensity-matched cohort study

Abstract

OBJECTIVE: To assess the impact of treatment with steroids on the incidence and outcome of ventilator-associated pneumonia (VAP) in mechanically ventilated COVID-19 patients. DESIGN: Propensity-matched retrospective cohort study from February 24 to December 31, 2020, in 4 dedicated COVID-19 Intensive Care Units (ICU) in Lombardy (Italy). PATIENTS: Adult consecutive mechanically ventilated COVID-19 patients were subdivided into two groups: (1) treated with low-dose corticosteroids (dexamethasone 6 mg/day intravenous for 10 days) (DEXA+); (2) not treated with corticosteroids (DEXA-). A propensity score matching procedure (1:1 ratio) identified patients' cohorts based on: age, weight, PEEP Level, PaO(2)/FiO(2) ratio, non-respiratory Sequential Organ Failure Assessment (SOFA) score, Charlson Comorbidity Index (CCI), C reactive protein plasma concentration at admission, sex and admission hospital (exact matching). INTERVENTION: Dexamethasone 6 mg/day intravenous for 10 days from hospital admission. MEASUREMENTS AND MAIN

RESULTS: Seven hundred and thirty-nine patients were included, and the propensity-score matching identified two groups of 158 subjects each. Eighty-nine (56%) DEXA+ versus 55 (34%) DEXA- patients developed a VAP (RR 1.61 (1.26-2.098), p = 0.0001), after similar time from hospitalization, ICU admission and intubation. DEXA+ patients had higher crude VAP incidence rate (49.58 (49.26-49.91) vs. 31.65 (31.38-31.91)VAP*1000/pd), (IRR 1.57 (1.55-1.58), p < 0.0001) and risk for VAP (HR 1.81 (1.31-2.50), p = 0.0003), with longer ICU LOS and invasive mechanical ventilation but similar mortality (RR 1.17 (0.85-1.63), p = 0.3332). VAPs were similarly due to G+ bacteria (mostly Staphylococcus aureus) and G- bacteria (mostly Enterobacterales). Forty-one (28%) VAPs were due to multi-drug resistant bacteria. VAP was associated with almost doubled ICU and hospital LOS and invasive mechanical ventilation, and increased mortality (RR 1.64 [1.02-2.65], p = 0.040) with no differences among patients' groups.

CONCLUSIONS: Critically ill COVID-19 patients are at high risk for VAP, frequently caused by multidrug-resistant bacteria, and the risk is increased by corticosteroid treatment.

# 在机械通气的 COVID-19 患者中地塞米松对呼吸机相关性肺炎发生率的影响：一项倾向性匹配的队列研究

摘要

目的：评估类固醇治疗对机械通气 COVID-19 患者的呼吸机相关性肺炎 (VAP) 的发生率和结局的影响。设计：2020 年 2 月 24 日至 12 月 31 日在意大利伦巴第的 4 个专门的 COVID-19 重症监护室 (ICU) 进行的倾向匹配回顾性队列研究。患者：成年连续机械通气 COVID-19 患者被细分为两组：(1) 接受低剂量皮质类固醇治疗（地塞米松 6 mg / 天静脉给药 10 天）(DEXA +)；(2) 未接受皮质类固醇治疗 (DEXA-)。倾向评分匹配程序（1:1 比率）基于以下因素确定患者队列：年龄、体重、PEEP 水平、PaO (2)/FiO (2) 比率、非呼吸系统序贯器官衰竭评估 (SOFA) 评分、Charlson 合并症指数 (CCI)、入院时 C 反应蛋白血浆浓度、性别和入院（精确匹配）。干预：入院后给予地塞米松 6 mg / 天，静脉注射，持续 10 天。测量和主要

结果：纳入 739 例患者，倾向评分匹配确定两组，每组 158 例受试者。与 55 名 (34%) DEXA + 患者相比，89 名 (56%) DEXA + 患者发生 VAP (RR 1.61 (1.26-2.098)，p = 0.0001)，发生 VAP 的时间与住院、入住 ICU 和插管的时间相似。DEXA + 患者的 VAP 粗发病率（49.58 (49.26-49.91) 比 31.65 (31.38-31.91) VAP*1000/pd）、(IRR 1.57 (1.55-1.58)，p < 0.0001) 和 VAP 风险 (HR 1.81 (1.31-2.50)，p = 0.0003) 更高，ICU LOS 和有创机械通气更长，但死亡率相似 (RR 1.17 (0.85-1.63)，p = 0.3332)。由于 G + 细菌（主要是金黄色葡萄球菌）和 G - 细菌（主要是肠杆菌），VAP 相似。41 例 (28%) VAP 由多重耐药菌所致。VAP 与 ICU 和医院 LOS 几乎翻倍以及侵入性机械通气以及死亡率增加相关 (RR 1.64 [1.02-2.65]，p = 0.040)，患者组间无差异。

结论：COVID-19 重症患者是 VAP 的高危患者，多由多重耐药菌引起，皮质类固醇治疗增加了 VAP 的风险。

DOI: 10.1186/s13054-022-04049-2; No. 176

关键词：Humans; Intensive Care Units; Adult; Cohort Studies; Retrospective Studies; Incidence; *COVID-19; *Critical care; *Intensive care unit; Respiration, Artificial/adverse effects; *Corticosteroids; Dexamethasone/therapeutic use; *Ventilator-associated pneumonia; *COVID-19/drug therapy/epidemiology; *Hospital-acquired infections; *Pneumonia, Ventilator-Associated/drug therapy/epidemiology/etiology

DOI: 10.1186/s13054-022-04045-6; No. 177

关键词：Humans; Hospital Mortality; *Sepsis; *Shock, Septic

DOI: 10.1186/s13054-022-04034-9; No. 171

关键词：Humans; Animals; Mice; *SARS-CoV-2; Angiotensin II; SARS-CoV-2; Lipopolysaccharides; *COVID-19/complications; *Respiratory Distress Syndrome; Recombinant Proteins/therapeutic use; *Acute lung injury; *ACE2; *Acute Lung Injury/prevention & control/virology; *Angiotensin II; *Angiotensin-Converting Enzyme 2/therapeutic use; *Spike RBD; Spike Glycoprotein, Coronavirus

# Early versus delayed enteral nutrition in mechanically ventilated patients with circulatory shock: a nested cohort analysis of an international multicenter, pragmatic clinical trial

Abstract

INTRODUCTION: Real-world evidence on the timing and efficacy of enteral nutrition (EN) practices in intensive care unit (ICU) patients with circulatory shock is limited. We hypothesized early EN (EEN), as compared to delayed EN (DEN), is associated with improved clinical outcomes in mechanically ventilated (MV) patients with circulatory shock.

METHODS: We analyzed a dataset from an international, multicenter, pragmatic randomized clinical trial (RCT) evaluating protein dose in ICU patients. Data were collected from ICU admission, and EEN was defined as initiating < 48 h from ICU admission and DEN > 48 h. We identified MV patients in circulatory shock to evaluate the association between the timing of EN initiation and clinical outcomes. The regression analysis model controlled for age, mNUTRIC score, APACHE II score, sepsis, and Site.

RESULTS: We included 626 patients, from 52 ICUs in 14 countries. Median age was 60 years [18-93], 55% had septic shock, 99% received norepinephrine alone, 91% received EN alone, and 50.3% were randomized to a usual protein dose. Forty-two percent of EEN patients had persistent organ dysfunction syndrome plus death at day 28, compared to 53% in the DEN group (p = 0.04). EEN was associated with more ICU-free days (9.3 ± 9.2 vs. 5.7 ± 7.9, p = 0.0002), more days alive and free of vasopressors (7.1 ± 3.1 vs. 6.3 ± 3.2, p = 0.007), and shorter duration of MV among survivors (9.8 ± 10.9 vs. 13.8 ± 14.5, p = 0.0002). This trend was no longer observed in the adjusted analysis. There were no differences in ICU/60-day mortality or feeding intolerance rates between groups.

CONCLUSION: In MV patients with circulatory shock, EEN, as compared to DEN, was associated with improved clinical outcomes, but no longer when adjusting for illness severity. RCTs comparing the efficacy of EEN to DEN in MV patients with circulatory shock are warranted.

DOI: 10.1186/s13054-022-04047-4; No. 173

关键词：Humans; Middle Aged; Prospective Studies; Intensive Care Units; Respiration, Artificial; Infant, Newborn; *Enteral nutrition; *Sepsis; *Enteral Nutrition; *Circulatory shock; *EFFORT; *ICU; *Vasopressors

DOI: 10.1186/s13054-022-03989-z; No. 172

关键词：Humans; Hospital Mortality; *Sepsis/mortality; *Shock, Septic/mortality

DOI: 10.1186/s13054-022-04032-x; No. 167

关键词：Humans; Male; Prognosis; Cohort Studies; ROC Curve; Biomarkers; *Sepsis; *Meta-analysis; *Mortality; *Sepsis/mortality; *AUC; *C-Reactive Protein/analysis; *Pentraxin-3; *Serum Amyloid P-Component/analysis

DOI: 10.1186/s13054-022-04031-y; No. 169

关键词：Humans; *Catheterization, Central Venous; Catheters, Indwelling; Axillary Vein

DOI: 10.1186/s13054-022-04038-5; No. 170

关键词：Humans; *COVID-19; *SARS-CoV-2; Critical Illness/therapy; Vaccination

DOI: 10.1186/s13054-022-04040-x; No. 168

关键词：Humans; *Leadership; *Burnout; *Burnout, Professional/psychology; *Mindfulness; *Organisational culture; *Resilience; *Resilience engineering; *Resilience, Psychological; *Well-being

DOI: 10.1186/s13054-022-04029-6; No. 163

关键词：Humans; Prospective Studies; Intensive Care Units; Length of Stay; *Shock, Septic; *Mechanical ventilation; Patient-Centered Care; Intubation, Intratracheal/adverse effects; *Septic shock; *Outcomes; *Tracheal intubation

DOI: 10.1186/s13054-022-04025-w; No. 164

关键词：Humans; Cytokines; Carrier Proteins; *Inflammasome; *Respiratory Distress Syndrome/drug therapy; *Acute respiratory distress syndrome; *Interleukin-18; *Personalised medicine; *Simvastatin; *Simvastatin/pharmacology/therapeutic use; Inflammasomes; Interleukin-18

DOI: 10.1186/s13054-022-04037-6; No. 165

关键词：Humans; Chronic Disease; Mass Screening; *Hypertension, Pulmonary/diagnosis/surgery; *Pulmonary Embolism/diagnosis/surgery; Endarterectomy/adverse effects; Pulmonary Artery

# An interventional quasi-experimental study to evaluate the impact of a rapid screening strategy in improving control of nosocomial extended-spectrum beta-lactamase-producing Enterobacterales and carbapenemase-producing organisms in critically ill patients

Abstract

INTRODUCTION: Rapid molecular tests could accelerate the control of extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-PE) and carbapenemase-producing organisms (CPO) in intensive care units (ICUs). OBJECTIVE AND

METHODS: This interventional 12-month cohort study compared a loop-mediated isothermal amplification (LAMP) assay performed directly on rectal swabs with culturing methods (control period, 6 months), during routine ICU screening. Contact precautions (CP) were implemented for CPO or non-E. coli ESBL-producing Enterobacterales (nEcESBL-PE) carriers. Using survival analysis, we compared the time intervals from admission to discontinuation of unnecessary preemptive CP among patients at-risk and the time intervals from screening to implementation of CP among newly identified carriers. We also compared diagnostic performances, and nEcESBL-PE/CPO acquisition rates. This study is registered, ISRCTN 23588440.

RESULTS: We included 1043 patients. During the intervention and control phases, 92/147 (62.6%) and 47/86 (54.7%) of patients at-risk screened at admission were candidates for early discontinuation of preemptive CP. The LAMP assay had a positive predictive value (PPV) of 44.0% and a negative predictive value (NPV) of 99.9% for CPO, and 55.6% PPV and 98.2% NPV for nEcESBL-PE. Due to result notification and interpretation challenges, the median time from admission to discontinuation of preemptive CP increased during the interventional period from 80.5 (95% CI 71.5-132.1) to 88.3 (95% CI 57.7-103.7) hours (p = 0.47). Due to the poor PPV, we had to stop using the LAMP assay to implement CP. No difference was observed regarding the incidence of nEcESBL-PE and CPO acquisition.

CONCLUSION: A rapid screening strategy with LAMP assays performed directly on rectal swabs had no benefit for infection control in a low-endemicity setting.

DOI: 10.1186/s13054-022-04027-8; No. 166

关键词：Humans; Cohort Studies; Critical Illness/therapy; *Infection control; beta-Lactamases; *ICU; *Clinical study; *Contact precautions; *Cross Infection/diagnosis/epidemiology/prevention & control; *Enterobacteriaceae Infections/diagnosis/prevention & control; *Molecular test; *Multiresistant Gram-negative bacteria; *Screening; *Surveillance; Bacterial Proteins

DOI: 10.1186/s13054-022-04028-7; No. 162

关键词：Humans; Middle Aged; Prospective Studies; Respiration, Artificial; *Critical care; *Intensive care unit; *Respiratory Distress Syndrome; *Dyspnea; *Dyspnea observation scale; *Respiratory Distress Observation Scale; *Spontaneous breathing trial; *Ventilator Weaning/methods; *Weaning from mechanical ventilation; Dyspnea/diagnosis/etiology

# Intermediate-risk pulmonary embolism: echocardiography predictors of clinical deterioration

Abstract

BACKGROUND: We determine the predictive value of transthoracic echocardiographic (TTE) metrics for clinical deterioration within 5 days in adults with intermediate-risk pulmonary embolism (PE).

METHODS: This was a prospective observational study of intermediate-risk PE patients. To determine associations of TTE and clinical predictors with clinical deterioration, we used univariable analysis, Youden's index for optimal thresholds, and multivariable analyses to report odds ratios (ORs) or area under the curve (AUC).

RESULTS: Of 306 intermediate-risk PE patients, 115 (37.6%) experienced clinical deterioration. PE patients who had clinical deterioration within 5 days had greater baseline right ventricle (RV) dilatation and worse systolic function than the group without clinical deterioration as indicated by the following: RV basal diameter 4.46 ± 0.77 versus 4.20 ± 0.77 cm; RV/LV basal width ratio 1.14 ± 0.29 versus 1.02 ± 0.24; tricuspid annular plane systolic excursion (TAPSE) 1.56 ± 0.55 versus 1.80 ± 0.52 cm; and RV systolic excursion velocity 10.40 ± 3.58 versus 12.1 ± 12.5 cm/s, respectively. Optimal thresholds for predicting clinical deterioration were: RV basal width 3.9 cm (OR 2.85 [1.64, 4.97]), RV-to-left ventricle (RV/LV) ratio 1.08 (OR 3.32 [2.07, 5.33]), TAPSE 1.98 cm (OR 3.3 [2.06, 5.3]), systolic excursion velocity 10.10 cm/s (OR 2.85 [1.75, 4.63]), and natriuretic peptide 190 pg/mL (OR 2.89 [1.81, 4.62]). Significant independent predictors were: transient hypotension 6.1 (2.2, 18.9), highest heart rate 1.02 (1.00, 1.03), highest respiratory rate 1.02 (1.00, 1.04), and RV/LV ratio 1.29 (1.14, 1.47). By logistic regression and random forest analyses, AUCs were 0.80 (0.73, 0.87) and 0.78 (0.70, 0.85), respectively.

CONCLUSIONS: Basal RV, RV/LV ratio, and RV systolic function measurements were significantly different between intermediate-risk PE patients grouped by subsequent clinical deterioration.

DOI: 10.1186/s13054-022-04030-z; No. 160

关键词：Humans; Adult; Echocardiography; *Prognosis; *Ventricular Dysfunction, Right/diagnostic imaging; Ventricular Function, Right; *Echocardiography; *Outcomes; *Clinical Deterioration; *Pulmonary embolism; *Pulmonary Embolism/diagnostic imaging; *Right ventricle; *Risk stratification

DOI: 10.1186/s13054-022-04035-8; No. 161

关键词：Humans; Female; Male; Middle Aged; Intensive Care Units; Retrospective Studies; Hospital Mortality; Hospitals; *Sepsis/complications; *Shock, Septic; *Septic shock; *Case volume; *Hospital mortality

DOI: 10.1186/s13054-022-04036-7; No. 159

关键词：Humans; Prospective Studies; Lung; *Quality of Life; *Phenotype; *Respiratory Distress Syndrome/therapy; *Quality of life; *Critical illness; *ARDS; Ventilators, Mechanical; *ICU; *Follow-up study; *Long-term outcomes

# Comparative incidence of early and late bloodstream and respiratory tract co-infection in patients admitted to ICU with COVID-19 pneumonia versus Influenza A or B pneumonia versus no viral pneumonia: wales multicentre ICU cohort study

Abstract

OBJECTIVE: The aim is to characterise early and late respiratory and bloodstream co-infection in patients admitted to intensive care units (ICUs) with SARS-CoV-2-related acute hypoxemic respiratory failure (AHRF) needing respiratory support in seven ICUs within Wales, during the first wave of the COVID-19 pandemic. We compare the rate of positivity of different secondary pathogens and their antimicrobial sensitivity in three different patient groups: patients admitted to ICU with COVID-19 pneumonia, Influenza A or B pneumonia, and patients without viral pneumonia.

DESIGN: Multicentre, retrospective, observational cohort study with rapid microbiology data from Public Health Wales, sharing of clinical and demographic data from seven participating ICUs. SETTING: Seven Welsh ICUs participated between 10 March and 31 July 2020. Clinical and demographic data for COVID-19 disease were shared by each participating centres, and microbiology data were extracted from a data repository within Public Health Wales. Comparative data were taken from a cohort of patients without viral pneumonia admitted to ICU during the same period as the COVID-19 cohort (referred to as no viral pneumonia or 'no viral' group), and to a retrospective non-matched cohort of consecutive patients with Influenza A or B admitted to ICUs from 20 November 2017. The comparative data for Influenza pneumonia and no viral pneumonia were taken from one of the seven participating ICUs. PARTICIPANTS: A total of 299 consecutive patients admitted to ICUs with COVID-19 pneumonia were compared with 173 and 48 patients admitted with no viral pneumonia or Influenza A or B pneumonia, respectively. MAIN OUTCOME MEASURES: Primary outcome was to calculate comparative incidence of early and late co-infection in patients admitted to ICU with COVID-19, Influenza A or B pneumonia and no viral pneumonia. Secondary outcome was to calculate the individual group of early and late co-infection rate on a per-patient and per-sample basis, with their antimicrobial susceptibility and thirdly to ascertain any statistical correlation between clinical and demographic variables with rate of acquiring co-infection following ICU admission.

RESULTS: A total of 299 adults (median age 57, M/F 2:1) were included in the COVID-19 ICU cohort. The incidence of respiratory and bloodstream co-infection was 40.5% and 15.1%, respectively. Staphylococcus aureus was the predominant bacterial pathogen within the first 48 h. Gram-negative organisms from Enterobacterales group were predominantly seen after 48 h in COVID-19 cohort. Comparative no viral pneumonia cohort had lower rates of respiratory tract infection and bloodstream infection. The influenza cohort had similar rates respiratory tract infection and bloodstream infection. Mortality in all three groups was similar, and no clinical or demographic variables were found to increase the rate of co-infection and ICU mortality.

CONCLUSIONS: Higher incidence of bacterial co-infection was found in COVID-19 cohort as compared to the no viral pneumonia cohort admitted to ICUs for respiratory support.

# 比较入住 ICU 的 COVID-19 肺炎患者与甲型或乙型流感肺炎患者相比无病毒性肺炎患者的早期和晚期血液和呼吸道合并感染的发生率：威尔士多中心 ICU 队列研究

摘要

目的：目的是描述在第一轮 COVID-19 大流行期间，威尔士 7 个 ICU 中，因 SARS-CoV-2 相关性急性低氧性呼吸衰竭 (AHRF) 而需要呼吸支持的重症监护室 (ICU) 患者的早期和晚期呼吸和血液混合感染。我们比较了 3 个不同患者组中不同次要病原体的阳性率及其抗菌敏感性：入住 ICU 的 COVID-19 肺炎患者、甲型流感或乙型肺炎患者和无病毒性肺炎患者。

设计：多中心、回顾性、观察性队列研究，快速微生物学数据来自威尔士公共卫生部，共享来自 7 个参与 ICU 的临床和人口统计学数据。设置：2020 年 3 月 10 日至 2020 年 7 月 31 日，7 间入住 Welsh ICU。每个参与中心共享 COVID-19 疾病的临床和人口统计学数据，微生物学数据提取自 Public Health Wales 的一个数据储存库。比较数据来自与 COVID-19 队列（称为无病毒性肺炎或 “无病毒性” 组）相同时期内入住 ICU 的无病毒性肺炎的患者队列和从 2017 年 11 月 20 日开始入住 ICU 的连续甲型或乙型流感患者的回顾性非匹配队列。从 7 个参与 ICU 中的 1 个获得了流行性感冒肺炎和无病毒性肺炎的比较数据。参与者：对 299 名连续入院的 COVID-19 肺炎患者与 173 名连续入院的无病毒性肺炎或甲型流感或乙型流感肺炎的患者进行比较。主要结局指标：主要结局是计算入住 ICU 时有 COVID-19、甲型或乙型流感肺炎和无病毒性肺炎患者的早期和晚期合并感染的比较发生率。次要结局是根据每位患者和每份样本计算早期和晚期混合感染率的个体组，以及它们的抗生素敏感性，第三是确定临床和人口统计学变量与 ICU 入院后获得性混合感染率之间的任何统计学相关性。

结果：COVID-19 ICU 队列共纳入 299 例成人（中位年龄 57 岁，男性 / 女性 2:1）。呼吸道和血液混合感染的发生率分别为 40.5% 和 15.1%。金黄色葡萄球菌是第一个 48h 内的主要细菌性病原体。在 COVID-19 队列中，48h 后主要观察到来自肠杆菌组的革兰氏阴性微生物。病毒性肺炎队列中呼吸道感染和血液感染的发生率较低。流感队列中呼吸道感染和血液感染的发生率相似。所有 3 组的死亡率相似，未发现临床或人口统计学变量增加共同感染率和 ICU 死亡率。

结论：COVID-19 队列的细菌合并感染发生率高于入住 ICU 进行呼吸支持的无病毒性肺炎队列。

DOI: 10.1186/s13054-022-04026-9; No. 158

关键词：Humans; Middle Aged; Intensive Care Units; Adult; Cohort Studies; Retrospective Studies; Pandemics; Incidence; *COVID-19; *SARS-CoV-2; SARS-CoV-2; *Sepsis; *COVID-19/epidemiology; *Pneumonia, Viral; *Antibiotic sensitivity; *Aspergillus; *Co-infection; *Coinfection/epidemiology; *Early; *Influenza A and B; *Influenza, Human/complications/epidemiology; *Late; *Respiratory Tract Infections; Wales/epidemiology

DOI: 10.1186/s13054-022-04023-y; No. 157

关键词：Humans; Cohort Studies; Respiration; *COVID-19; *Critical care; *COVID-19/therapy; *Respiratory Distress Syndrome/therapy; *ARDS; *Noninvasive Ventilation; *Cumulative fluid balance; *Liberation of ventilation; Water-Electrolyte Balance

DOI: 10.1186/s13054-022-04022-z; No. 156

关键词：Humans; Oxygen; Oxygen Inhalation Therapy; *Cannula; *Pulmonary Disease, Chronic Obstructive/therapy; Hypercapnia/therapy

DOI: 10.1186/s13054-022-04002-3; No. 155

关键词：Humans; Aged; Longitudinal Studies; Homeostasis; Severity of Illness Index; *Neutrophil; *COVID-19; Inflammation; SARS-CoV-2; *Community-Acquired Infections; *Angiogenic neutrophils; *Oxidative burst; *Pneumonia/pathology; *Vascular inflammation; Neutrophils/physiology

DOI: 10.1186/s13054-022-04021-0; No. 154

关键词：Humans; Perfusion; Prospective Studies; Tomography, X-Ray Computed; Prone Position; *Respiratory Distress Syndrome/therapy; *Mechanical ventilation; Electric Impedance; *Acute respiratory distress syndrome; *Electrical impedance tomography; *Prone positioning; *Lung; *Pulmonary perfusion; *Ventilation–perfusion matching

# Effect of abdominal weight training with and without cough machine assistance on lung function in the patients with prolonged mechanical ventilation: a randomized trial

Abstract

PURPOSE: The patients with prolonged mechanical ventilation (PMV) have the risk of ineffective coughing and infection due to diaphragm weakness. This study aimed to explore the effect of abdominal weight training (AWT) intervention with/without cough machine (CM) assistance on lung function, respiratory muscle strength and cough ability in these patients.

METHODS: Forty patients with PMV were randomly assigned to three groups: AWT group (n = 12), AWT + CM group (n = 14) and control group (n = 14). Change of maximum inspiratory pressure (MIP), Maximum expiratory pressure (MEP) and peak cough flow (PCF) between 1 day before and 2 weeks after the intervention were compared among these three groups.

RESULTS: MIP before and after intervention in AWT group (30.50 ± 11.73 vs. 36.00 ± 10.79; p < 0.05) and AWT + CM group (29.8 ± 12.14 vs. 36.14 ± 10.42; p < 0.05) compared with control group (28.43 ± 9.74 vs 26.71 ± 10.77; p > 0.05) was significantly improved. MEP before and after intervention in AWT group (30.58 ± 15.19 vs. 41.50 ± 18.33; p < 0.05) and AWT + CM group (27.29 ± 12.76 vs 42.43 ± 16.96; p < 0.05) compared with control group (28.86 ± 10.25 vs. 29.57 ± 14.21; p > 0.05) was significantly improved. PCF before and after intervention in AWT group in AWT group (105.83 ± 16.21 vs. 114.17 ± 15.20; p < 0.05) and AWT + CM group (108.57 ± 18.85 vs. 131.79 ± 38.96; p < 0.05) compared to control group (108.57 ± 19.96 vs. 109.86 ± 17.44; p > 0.05) showed significant improvements. AWT + CM group had significantly greater improvements than control group in MIP and peak cough flow than control group (13.71 ± 11.28 vs 19.64 ± 29.90, p < 0.05).

CONCLUSION: AWT can significantly improve lung function, respiratory muscle strength, and cough ability in the PMV patients. AWT + CM can further improve their expiratory muscle strength and cough ability.

DOI: 10.1186/s13054-022-04012-1; No. 153

关键词：Humans; Lung; *Respiration, Artificial; *Abdominal weight training; *Cough machine; *Cough/therapy; *Prolonged mechanical ventilation; *Weaning ventilator; Abdominal Muscles; Respiratory Muscles

# Effect of erythromycin on mortality and the host response in critically ill patients with sepsis: a target trial emulation

Abstract

BACKGROUND: Immunomodulatory therapies that improve the outcome of sepsis are not available. We sought to determine whether treatment of critically ill patients with sepsis with low-dose erythromycin-a macrolide antibiotic with broad immunomodulatory effects-decreased mortality and ameliorated underlying disease pathophysiology.

METHODS: We conducted a target trial emulation, comparing patients with sepsis admitted to two intensive care units (ICU) in the Netherlands for at least 72 h, who were either exposed or not exposed during this period to treatment with low-dose erythromycin (up to 600 mg per day, administered as a prokinetic agent) but no other macrolides. We used two common propensity score methods (matching and inverse probability of treatment weighting) to deal with confounding by indication and subsequently used Cox regression models to estimate the treatment effect on the primary outcome of mortality rate up to day 90. Secondary clinical outcomes included change in SOFA, duration of mechanical ventilation and the incidence of ICU-acquired infections. We used linear mixed models to assess differences in 15 host response biomarkers reflective of key pathophysiological processes from admission to day 4.

RESULTS: In total, 235 patients started low-dose erythromycin treatment, 470 patients served as controls. Treatment started at a median of 38 [IQR 25-52] hours after ICU admission for a median of 5 [IQR 3-8] total doses in the first course. Matching and weighting resulted in populations well balanced for proposed confounders. We found no differences between patients treated with low-dose erythromycin and control subjects in mortality rate up to day 90: matching HR 0.89 (95% CI 0.64-1.24), weighting HR 0.95 (95% CI 0.66-1.36). There were no differences in secondary clinical outcomes. The change in host response biomarker levels from admission to day 4 was similar between erythromycin-treated and control subjects.

CONCLUSION: In this target trial emulation in critically ill patients with sepsis, we could not demonstrate an effect of treatment with low-dose erythromycin on mortality, secondary clinical outcomes or host response biomarkers.

DOI: 10.1186/s13054-022-04016-x; No. 151

关键词：Humans; Intensive Care Units; Biomarkers; *Critical Illness/therapy; Clinical Trials as Topic; *Sepsis; *Mortality; *Critically ill; *Sepsis/drug therapy; *Macrolides; *Erythromycin; *Immunomodulation; *Propensity score; *Target trial; Erythromycin/pharmacology/therapeutic use

DOI: 10.1186/s13054-022-04024-x; No. 150

关键词：Humans; Heart; Vascular Resistance; *Models, Cardiovascular; Blood Pressure/physiology; *Fluid therapy; *Guyton; *Heart–lung interactions; *Mean systemic filling pressure; *Norepinephrine; *Veins; Cardiac Output/physiology

DOI: 10.1186/s13054-022-04014-z; No. 152

关键词：Humans; Intensive Care Units; Quality of Life; Survivors; *Critical care; *Family; *Rehabilitation; *Caregivers and mental health; *Caregivers/psychology; *Sleep Initiation and Maintenance Disorders/therapy; Depression/psychology; Social Support

# Evolving outcomes of extracorporeal membrane oxygenation during the first 2 years of the COVID-19 pandemic: a systematic review and meta-analysis

Abstract

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has been used extensively for coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome (ARDS). Reports early in the pandemic suggested that mortality in patients with COVID-19 receiving ECMO was comparable to non-COVID-19-related ARDS. However, subsequent reports suggested that mortality appeared to be increasing over time. Therefore, we conducted an updated systematic review and meta-analysis, to characterise changes in mortality over time and elucidate risk factors for poor outcomes.

METHODS: We conducted a meta-analysis (CRD42021271202), searching MEDLINE, Embase, Cochrane, and Scopus databases, from 1 December 2019 to 26 January 2022, for studies reporting on mortality among adults with COVID-19 receiving ECMO. We also captured hospital and intensive care unit lengths of stay, duration of mechanical ventilation and ECMO, as well as complications of ECMO. We conducted random-effects meta-analyses, assessed risk of bias of included studies using the Joanna Briggs Institute checklist and evaluated certainty of pooled estimates using GRADE methodology.

RESULTS: Of 4522 citations, we included 52 studies comprising 18,211 patients in the meta-analysis. The pooled mortality rate among patients with COVID-19 requiring ECMO was 48.8% (95% confidence interval 44.8-52.9%, high certainty). Mortality was higher among studies which enrolled patients later in the pandemic as opposed to earlier (1st half 2020: 41.2%, 2nd half 2020: 46.4%, 1st half 2021: 62.0%, 2nd half 2021: 46.5%, interaction p value = 0.0014). Predictors of increased mortality included age, the time of final patient enrolment from 1 January 2020, and the proportion of patients receiving corticosteroids, and reduced duration of ECMO run.

CONCLUSIONS: The mortality rate for patients receiving ECMO for COVID-19-related ARDS has increased as the pandemic has progressed. The reasons for this are likely multifactorial; however, as outcomes for these patients evolve, the decision to initiate ECMO should include the best contextual estimate of mortality at the time of ECMO initiation.

# COVID-19 大流行前 2 年期间体外膜肺氧合的演变结局：一项系统综述和荟萃分析

摘要

背景：体外膜肺氧合 (ECMO) 已广泛用于 2019 年冠状病毒病 (COVID-19) 相关的急性呼吸窘迫综合征 (ARDS)。大流行早期的报告表明，接受 ECMO 的 COVID-19 患者的死亡率与非 COVID-19 相关 ARDS 相当。然而，随后的报告表明死亡率似乎随时间而增加。因此，我们进行了一项更新的系统综述和荟萃分析，以表征死亡率随时间的变化，并阐明不良结局的风险因素。

方法：我们进行了一项荟萃分析 (CRD42021271202)，检索了 MEDLINE、Embase、Cochrane 和 Scopus 数据库，时间范围为 2019 年 12 月 2022 年 1 月 1 月 26 日，查找报告接受 ECMO 的 COVID-19 成人患者死亡率的研究。我们还采集了住院和重症监护病房的住院时间、机械通气和 ECMO 的持续时间以及 ECMO 的并发症。我们进行了随机效应荟萃分析，使用 Joanna Briggs Institute 自评量表评估了纳入研究的偏倚风险，并使用 GRADE 方法评估了合并估计值的确定性。

结果：在 4522 篇引文中，我们纳入了 52 项研究，包括荟萃分析中的 18,211 例患者。需要 ECMO 的 COVID-19 患者的汇总死亡率为 48.8%（95% 置信区间 44.8-52.9%，高度确定）。与早期研究相比，入组大流行较晚患者的研究死亡率更高（2020 年上半年：41.2%，2020 年下半年：46.4%，2021 年上半年：62.0%，2021 年下半年：46.5%，相互作用 p 值 = 0.0014）。死亡率升高的预测因素包括年龄、从 2020 年 1 月 1 日起最终患者入组的时间、接受皮质类固醇的患者比例和 ECMO 运行持续时间缩短。

结论：随着流感大流行的进展，因 COVID-19 相关 ARDS 而接受 ECMO 治疗的患者的死亡率增加。其原因可能是多因素的；但是，随着这些患者结局的变化，启动 ECMO 的决定应包括启动 ECMO 时死亡率的最佳背景估计。

DOI: 10.1186/s13054-022-04011-2; No. 147

关键词：Humans; Intensive Care Units; Adult; Pandemics; *Meta-analysis; *COVID-19/therapy; *Respiratory Distress Syndrome/therapy; *Mortality; *Extracorporeal Membrane Oxygenation/methods; *Extracorporeal membrane oxygenation; *Coronavirus disease 2019; *Severe acute respiratory syndrome coronavirus 2

# Long-term ketamine infusion-induced cholestatic liver injury in COVID-19-associated acute respiratory distress syndrome

Abstract

BACKGROUND: A higher-than-usual resistance to standard sedation regimens in COVID-19 patients suffering from acute respiratory distress syndrome (ARDS) has led to the frequent use of the second-line anaesthetic agent ketamine. Simultaneously, an increased incidence of cholangiopathies in mechanically ventilated patients receiving prolonged infusion of high-dose ketamine has been noted. Therefore, the objective of this study was to investigate a potential dose-response relationship between ketamine and bilirubin levels.

METHODS: Post hoc analysis of a prospective observational cohort of patients suffering from COVID-19-associated ARDS between March 2020 and August 2021. A time-varying, multivariable adjusted, cumulative weighted exposure mixed-effects model was employed to analyse the exposure-effect relationship between ketamine infusion and total bilirubin levels.

RESULTS: Two-hundred forty-three critically ill patients were included into the analysis. Ketamine was infused to 170 (70%) patients at a rate of 1.4 [0.9-2.0] mg/kg/h for 9 [4-18] days. The mixed-effects model revealed a positively correlated infusion duration-effect as well as dose-effect relationship between ketamine infusion and rising bilirubin levels (p < 0.0001). In comparison, long-term infusion of propofol and sufentanil, even at high doses, was not associated with increasing bilirubin levels (p = 0.421, p = 0.258). Patients having received ketamine infusion had a multivariable adjusted competing risk hazard of developing a cholestatic liver injury during their ICU stay of 3.2 [95% confidence interval, 1.3-7.8] (p = 0.01).

CONCLUSIONS: A causally plausible, dose-effect relationship between long-term infusion of ketamine and rising total bilirubin levels, as well as an augmented, ketamine-associated, hazard of cholestatic liver injury in critically ill COVID-19 patients could be shown. High-dose ketamine should be refrained from whenever possible for the long-term analgosedation of mechanically ventilated COVID-19 patients.

DOI: 10.1186/s13054-022-04019-8; No. 148

关键词：Humans; Critical Illness; Retrospective Studies; Liver; Hypnotics and Sedatives/adverse effects; Respiration, Artificial/adverse effects; *COVID-19/complications; *Chemical and drug-induced liver injury; *Cholangiopathy; *Cholangitis; *Cholestasis; *Hypnotics and sedatives; *Ketamine/adverse effects; *Propofol; *Respiratory Distress Syndrome/chemically induced; Bilirubin

DOI: 10.1186/s13054-022-03952-y; No. 149

关键词：Humans; Retrospective Studies; *COVID-19; *Extracorporeal Membrane Oxygenation; *ARDS; *ECMO; *Respiratory Distress Syndrome; *Influenza A Virus, H1N1 Subtype; *COVID-19 in 2021; *Difference of 11 years; *H1N1; *Impact upon mortality; *Influenza; *Influenza H1N1 in 2009; *Influenza, Human; *VV-ECMO

DOI: 10.1186/s13054-022-04017-w; No. 146

关键词：Humans; Retrospective Studies; Child; Infant, Newborn; *Extracorporeal Membrane Oxygenation; *Autonomic Nervous System Diseases/therapy; *Hypohidrosis/diagnosis/etiology; Flushing

DOI: 10.1186/s13054-022-04020-1; No. 145

关键词：Humans; Treatment Outcome; Retrospective Studies; Registries; Phenotype; *Sepsis; *Phenotype; *Sepsis/complications/drug therapy; *Coagulopathy; *Disseminated Intravascular Coagulation/drug therapy; *Prediction model; *Recombinant human thrombomodulin; Fibrinogen/therapeutic use; Internet; Recombinant Proteins/pharmacology/therapeutic use; Thrombomodulin/therapeutic use

# TTCOV19: timing of tracheotomy in SARS-CoV-2-infected patients: a multicentre, single-blinded, randomized, controlled trial

Abstract

BACKGROUND: Critically ill COVID-19 patients may develop acute respiratory distress syndrome and the need for respiratory support, including mechanical ventilation in the intensive care unit. Previous observational studies have suggested early tracheotomy to be advantageous. The aim of this parallel, multicentre, single-blinded, randomized controlled trial was to evaluate the optimal timing of tracheotomy.

METHODS: SARS-CoV-2-infected patients within the Region Västra Götaland of Sweden who needed intubation and mechanical respiratory support were included and randomly assigned to early tracheotomy (≤ 7 days after intubation) or late tracheotomy (≥ 10 days after intubation). The primary objective was to compare the total number of mechanical ventilation days between the groups.

RESULTS: One hundred fifty patients (mean age 65 years, 79% males) were included. Seventy-two patients were assigned to early tracheotomy, and 78 were assigned to late tracheotomy. One hundred two patients (68%) underwent tracheotomy of whom sixty-one underwent tracheotomy according to the protocol. The overall median number of days in mechanical ventilation was 18 (IQR 9; 28), but no significant difference was found between the two treatment regimens in the intention-to-treat analysis (between-group difference: - 1.5 days (95% CI - 5.7 to 2.8); p = 0.5). A significantly reduced number of mechanical ventilation days was found in the early tracheotomy group during the per-protocol analysis (between-group difference: - 8.0 days (95% CI - 13.8 to - 2.27); p = 0.0064). The overall correlation between the timing of tracheotomy and days of mechanical ventilation was significant (Spearman's correlation: 0.39, p < 0.0001). The total death rate during intensive care was 32.7%, but no significant differences were found between the groups regarding survival, complications or adverse events.

CONCLUSIONS: The potential superiority of early tracheotomy when compared to late tracheotomy in critically ill patients with COVID-19 was not confirmed by the present randomized controlled trial but is a strategy that should be considered in selected cases where the need for MV for more than 14 days cannot be ruled out.

DOI: 10.1186/s13054-022-04005-0; No. 142

关键词：Humans; Treatment Outcome; Female; Male; Aged; *COVID-19; *SARS-CoV-2; Respiration, Artificial/methods; *Intensive care; *Mechanical ventilation; Critical Illness/epidemiology/therapy; *Time factors; *Tracheotomy; Tracheotomy/methods

DOI: 10.1186/s13054-022-04018-9; No. 144

关键词：Humans; Ultrasonography; Respiratory System; *Extracorporeal Membrane Oxygenation; Drainage; *Pleural Effusion/diagnostic imaging/therapy

# Medical nutrition therapy and clinical outcomes in critically ill adults: a European multinational, prospective observational cohort study (EuroPN)

Abstract

BACKGROUND: Medical nutrition therapy may be associated with clinical outcomes in critically ill patients with prolonged intensive care unit (ICU) stay. We wanted to assess nutrition practices in European intensive care units (ICU) and their importance for clinical outcomes.

METHODS: Prospective multinational cohort study in patients staying in ICU ≥ 5 days with outcome recorded until day 90. Macronutrient intake from enteral and parenteral nutrition and non-nutritional sources during the first 15 days after ICU admission was compared with targets recommended by ESPEN guidelines. We modeled associations between three categories of daily calorie and protein intake (low: < 10 kcal/kg, < 0.8 g/kg; moderate: 10-20 kcal/kg, 0.8-1.2 g/kg, high: > 20 kcal/kg; > 1.2 g/kg) and the time-varying hazard rates of 90-day mortality or successful weaning from invasive mechanical ventilation (IMV).

RESULTS: A total of 1172 patients with median [Q1;Q3] APACHE II score of 18.5 [13.0;26.0] were included, and 24% died within 90 days. Median length of ICU stay was 10.0 [7.0;16.0] days, and 74% of patients could be weaned from invasive mechanical ventilation. Patients reached on average 83% [59;107] and 65% [41;91] of ESPEN calorie and protein recommended targets, respectively. Whereas specific reasons for ICU admission (especially respiratory diseases requiring IMV) were associated with higher intakes (estimate 2.43 [95% CI: 1.60;3.25] for calorie intake, 0.14 [0.09;0.20] for protein intake), a lack of nutrition on the preceding day was associated with lower calorie and protein intakes (- 2.74 [- 3.28; - 2.21] and - 0.12 [- 0.15; - 0.09], respectively). Compared to a lower intake, a daily moderate intake was associated with higher probability of successful weaning (for calories: maximum HR 4.59 [95% CI: 1.5;14.09] on day 12; for protein: maximum HR 2.60 [1.09;6.23] on day 12), and with a lower hazard of death (for calories only: minimum HR 0.15, [0.05;0.39] on day 19). There was no evidence that a high calorie or protein intake was associated with further outcome improvements.

CONCLUSIONS: Calorie intake was mainly provided according to the targets recommended by the active ESPEN guideline, but protein intake was lower. In patients staying in ICU ≥ 5 days, early moderate daily calorie and protein intakes were associated with improved clinical outcomes.

# 危重成人患者的医学营养治疗和临床结局：一项欧洲多国、前瞻性观察性队列研究 (EuroPN)

摘要

背景：医学营养治疗可能与延长重症监护室 (ICU) 住院时间的重症患者的临床结局相关。我们希望评估欧洲重症监护室 (ICU) 的营养实践及其对临床结局的重要性。

方法：在入住 ICU≥5 天的患者中进行的前瞻性多国家队列研究，记录结局至第 90 天。比较入住 ICU 后最初 15 天内从肠内和肠外营养和非营养来源摄入的大量营养素与 ESPEN 指南推荐的目标。我们对每日热量和蛋白质摄入量的 3 个类别（低：<10 kcal/kg，<0.8 g/kg；中：10-20 kcal/kg，0.8-1.2 g/kg，高：>20 kcal/kg；>1.2 g/kg）与 90 天死亡率或成功停用有创机械通气 (IMV) 的随时间变化的风险率之间的相关性进行了建模。

结果：共纳入 1172 例患者，中位 [Q1；Q3] APACHE II 评分为 18.5 [13.0；26.0]，24% 在 90 天内死亡。中位 ICU 住院时间为 10.0 [7.0；16.0] 天，74% 的患者可从有创机械通气中脱机。患者分别平均达到 83%[59；107] 和 65%[41；91] 的 ESPEN 热量和蛋白质推荐目标。入住 ICU 的具体原因（尤其是需要 IMV 的呼吸系统疾病）与较高的摄入量相关（卡路里摄入量估计值为 2.43 [95% CI：1.60；3.25]，蛋白质摄入量估计值为 0.14 [0.09；0.20]），前一天缺乏营养与较低的卡路里和蛋白质摄入量相关（-2.74 [-3.28；- 分别为 2.21] 和 - 0.12 [-0.15；-0.09]）。与较低的摄入量相比，每日中等摄入量与成功断奶的概率较高相关（卡路里：第 12 天最大 HR 4.59 [95% CI：1.5；14.09]；蛋白质：第 12 天最大 HR 2.60 [1.09；6.23]），死亡风险较低（仅卡路里：第 19 天最小 HR 0.15 [0.05；0.39]）。无证据表明高热量或蛋白质摄入与进一步结局改善相关。

结论：主要根据现行 ESPEN 指南推荐的目标提供热量摄入，但蛋白质摄入量较低。入住 ICU≥5 天的患者中，早期适度的每日热量和蛋白质摄入与临床结局改善相关。

DOI: 10.1186/s13054-022-03997-z; No. 143

关键词：Humans; Prospective Studies; Intensive Care Units; Adult; Cohort Studies; *Survival; *Critical Illness/therapy; *Critical illness; *Mechanical ventilation; Energy Intake; *Parenteral Nutrition; *Calorie; *Nutrition; *Protein; *Weaning

# Early short course of neuromuscular blocking agents in patients with COVID-19 ARDS: a propensity score analysis

Abstract

BACKGROUND: The role of neuromuscular blocking agents (NMBAs) in coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS) is not fully elucidated. Therefore, we aimed to investigate in COVID-19 patients with moderate-to-severe ARDS the impact of early use of NMBAs on 90-day mortality, through propensity score (PS) matching analysis.

METHODS: We analyzed a convenience sample of patients with COVID-19 and moderate-to-severe ARDS, admitted to 244 intensive care units within the COVID-19 Critical Care Consortium, from February 1, 2020, through October 31, 2021. Patients undergoing at least 2 days and up to 3 consecutive days of NMBAs (NMBA treatment), within 48 h from commencement of IMV were compared with subjects who did not receive NMBAs or only upon commencement of IMV (control). The primary objective in the PS-matched cohort was comparison between groups in 90-day in-hospital mortality, assessed through Cox proportional hazard modeling. Secondary objectives were comparisons in the numbers of ventilator-free days (VFD) between day 1 and day 28 and between day 1 and 90 through competing risk regression.

RESULTS: Data from 1953 patients were included. After propensity score matching, 210 cases from each group were well matched. In the PS-matched cohort, mean (± SD) age was 60.3 ± 13.2 years and 296 (70.5%) were male and the most common comorbidities were hypertension (56.9%), obesity (41.1%), and diabetes (30.0%). The unadjusted hazard ratio (HR) for death at 90 days in the NMBA treatment vs control group was 1.12 (95% CI 0.79, 1.59, p = 0.534). After adjustment for smoking habit and critical therapeutic covariates, the HR was 1.07 (95% CI 0.72, 1.61, p = 0.729). At 28 days, VFD were 16 (IQR 0-25) and 25 (IQR 7-26) in the NMBA treatment and control groups, respectively (sub-hazard ratio 0.82, 95% CI 0.67, 1.00, p = 0.055). At 90 days, VFD were 77 (IQR 0-87) and 87 (IQR 0-88) (sub-hazard ratio 0.86 (95% CI 0.69, 1.07; p = 0.177).

CONCLUSIONS: In patients with COVID-19 and moderate-to-severe ARDS, short course of NMBA treatment, applied early, did not significantly improve 90-day mortality and VFD. In the absence of definitive data from clinical trials, NMBAs should be indicated cautiously in this setting.

DOI: 10.1186/s13054-022-03983-5; No. 141

关键词：Humans; Female; Male; Middle Aged; Aged; Intensive Care Units; Propensity Score; Respiration, Artificial; *COVID-19; *SARS-CoV-2; *Intensive care unit; *COVID-19/drug therapy; *Mechanical ventilation; *Respiratory Distress Syndrome/drug therapy; *Neuromuscular blocking agent; *Neuromuscular Blocking Agents/therapeutic use

# Impact of prolonged requirement for insulin on 90-day mortality in critically ill patients without previous diabetic treatments: a post hoc analysis of the CONTROLING randomized control trial

Abstract

BACKGROUND: Stress hyperglycemia can persist during an intensive care unit (ICU) stay and result in prolonged requirement for insulin (PRI). The impact of PRI on ICU patient outcomes is not known. We evaluated the relationship between PRI and Day 90 mortality in ICU patients without previous diabetic treatments.

METHODS: This is a post hoc analysis of the CONTROLING trial, involving 12 French ICUs. Patients in the personalized glucose control arm with an ICU length of stay ≥ 5 days and who had never previously received diabetic treatments (oral drugs or insulin) were included. Personalized blood glucose targets were estimated on their preadmission usual glycemia as estimated by their glycated A1c hemoglobin (HbA1C). PRI was defined by insulin requirement. The relationship between PRI on Day 5 and 90-day mortality was assessed by Cox survival models with inverse probability of treatment weighting (IPTW). Glycemic control was defined as at least one blood glucose value below the blood glucose target value on Day 5.

RESULTS: A total of 476 patients were included, of whom 62.4% were male, with a median age of 66 (54-76) years. Median values for SAPS II and HbA1C were 50 (37.5-64) and 5.7 (5.4-6.1)%, respectively. PRI was observed in 364/476 (72.5%) patients on Day 5. 90-day mortality was 23.1% in the whole cohort, 25.3% in the PRI group and 16.1% in the non-PRI group (p < 0.01). IPTW analysis showed that PRI on Day 5 was not associated with Day 90 mortality ((IPTW)HR = 1.22; CI 95% 0.84-1.75; p = 0.29), whereas PRI without glycemic control was associated with an increased risk of death at Day 90 ((IPTW)HR = 3.34; CI 95% 1.26-8.83; p < 0.01).

CONCLUSION: In ICU patients without previous diabetic treatments, only PRI without glycemic control on Day 5 was associated with an increased risk of death. Additional studies are required to determine the factors contributing to these results.

DOI: 10.1186/s13054-022-04004-1; No. 138

关键词：Humans; Female; Male; Middle Aged; Aged; Intensive Care Units; Blood Glucose/metabolism; Randomized Controlled Trials as Topic; *Critical care; *Mortality; *Critical Illness/mortality/therapy; *Hyperglycemia/blood/drug therapy/mortality; *Insulin/administration & dosage; *Prolonged requirement for insulin; Glycated Hemoglobin A/metabolism

# Prevalence and prognostic value of preexisting sarcopenia in patients with mechanical ventilation: a systematic review and meta-analysis

Abstract

BACKGROUND: Sarcopenia is defined as age-related loss of muscle mass, strength, and/or function in the context of aging. Mechanical ventilation (MV) is one of the most frequently used critical care technologies in critically ill patients. The prevalence of preexisting sarcopenia and the clinical impact of its prognostic value on patients with MV are unclear. This review sought to identify the prevalence and prognostic value of preexisting sarcopenia on MV patient health outcomes.

METHODS: Relevant studies were identified by searching MEDLINE, Embase, and the Cochrane library and were searched for all articles published as of December 2021. The prevalence of sarcopenia was determined using the authors' definitions from the original studies. Comparisons were made between patients who did and did not have sarcopenia for prognostic outcomes, including mortality, the number of days of MV, the length of intensive care unit stay, and the length of hospital stay. Odds ratios (ORs) and weighted mean differences with 95% confidence intervals (CIs) were used for pooled analyses of the relationships between sarcopenia and prognostic outcomes.

RESULTS: The initial search identified 1333 studies, 17 of which met the eligibility criteria for the quantitative analysis, including 3582 patients. The pooled prevalence was 43.0% (95% CI 34.0-51.0%; I(2) = 96.7%). The pooled analyses showed that sarcopenia was related to increased mortality (OR 2.13; 95% CI 1.70, 2.67; I(2) = 45.0%), longer duration of MV (MD = 1.22; 95% CI 0.39, 2.05; I(2) = 97.0%), longer days of ICU stay (MD = 1.31; 95% CI 0.43, 2.19; I(2) = 97.0%), and hospital stay (MD 2.73; 95% CI 0.58, 4.88; I(2) = 98.0%) in patients with MV.

CONCLUSION: The prevalence of sarcopenia is relatively high in patients with MV, and it will have a negative impact on the prognosis of patients. However, further, large-scale, high-quality prospective cohort studies are required.

DOI: 10.1186/s13054-022-04015-y; No. 140

关键词：Humans; Prognosis; Prospective Studies; Intensive Care Units; Length of Stay; Prevalence; *Prognosis; *Mechanical ventilation; *Prevalence; *Respiration, Artificial/adverse effects; Critical Illness/epidemiology/therapy; *Sarcopenia; *Sarcopenia/diagnosis/epidemiology; *Systematic review

# Termination-of-resuscitation rule in the emergency department for patients with refractory out-of-hospital cardiac arrest: a nationwide, population-based observational study

Abstract

BACKGROUND: In Japan, emergency medical service (EMS) providers are prohibited from field termination-of-resuscitation (TOR) in out-of-hospital cardiac arrest (OHCA) patients. In 2013, we developed a TOR rule for emergency department physicians (Goto's TOR rule) immediately after hospital arrival. However, this rule is subject to flaws, and there is a need for revision owing to its relatively low specificity for predicting mortality compared with other TOR rules in the emergency department. Therefore, this study aimed to develop and validate a modified Goto's TOR rule by considering prehospital EMS cardiopulmonary resuscitation (CPR) duration.

METHODS: We analysed the records of 465,657 adult patients with OHCA from the All-Japan Utstein registry from 2016 to 2019 and divided them into two groups: development (n = 231,363) and validation (n = 234,294). The primary outcome measures were specificity, false-positive rate (FPR), and positive predictive value (PPV) of the revised TOR rule in the emergency department for predicting 1-month mortality.

RESULTS: Recursive partitioning analysis for the development group in predicting 1-month mortality revealed that a modified Goto's TOR rule could be defined if patients with OHCA met the following four criteria: (1) initial asystole, (2) unwitnessed arrest by any laypersons, (3) EMS-CPR duration > 20 min, and (4) no prehospital return of spontaneous circulation (ROSC). The specificity, FPR, and PPV of the rule for predicting 1-month mortality were 99.2% (95% confidence interval [CI], 99.0-99.4%), 0.8% (0.6-1.0%), and 99.8% (99.8-99.9%), respectively. The proportion of patients who fulfilled the rule and the area under the receiver operating curve (AUC) was 27.5% (95% CI 27.3-27.7%) and 0.904 (0.902-0.905), respectively. In the validation group, the specificity, FPR, PPV, proportion of patients who met the rule, and AUC were 99.1% (95% CI 98.9-99.2%), 0.9% (0.8-1.1%), 99.8% (99.8-99.8%), 27.8% (27.6-28.0%), and 0.889 (0.887-0.891), respectively.

CONCLUSION: The modified Goto's TOR rule (which includes the following four criteria: initial asystole, unwitnessed arrest, EMS-CPR duration > 20 min, and no prehospital ROSC) with a > 99% predictor of 1-month mortality is a reliable tool for physicians treating refractory OHCAs immediately after hospital arrival.

# 难治性院外心脏骤停患者在急诊科的复苏终止规则：一项基于全国人群的观察性研究

摘要

背景：在日本，紧急医疗服务 (EMS) 提供者禁止在院外心脏骤停 (OHCA) 患者中进行现场复苏终止 (TOR)。2013 年，我们在医院到达后立即为急诊科医生制定了 TOR 规则（Goto 的 TOR 规则）。但是，该规则存在缺陷，与急诊科的其他 TOR 规则相比，其预测死亡率的特异性相对较低，因此需要进行修订。因此，本研究旨在通过考虑院前 EMS 心肺复苏 (CPR) 持续时间来开发和验证改良 Goto 的 TOR 规则。

方法：我们分析了 2016 年至 2019 年来自全日本 Utstein 登记研究的 465,657 例成人 OHCA 患者的记录，并将其分为两组：开发 (n = 231,363) 和验证 (n = 234,294)。主要结局指标为急诊科预测 1 个月死亡率的修订 TOR 规则的特异性、假阳性率 (FPR) 和阳性预测值 (PPV)。

结果：对开发组预测 1 个月死亡率的递归分区分析显示，如果 OHCA 患者符合以下四个标准，可以定义改良的 Goto TOR 规则：(1) 初始心搏停止，(2) 任何非专业人员无目击者的心脏骤停，(3) EMS-CPR 持续时间 > 20 min，(4) 院前无自主循环恢复 (ROSC)。预测 1 个月死亡率的规则的特异性、FPR 和 PPV 分别为 99.2%（95% 置信区间 [CI]，99.0-99.4%）、0.8%(0.6-1.0%) 和 99.8%(99.8-99.9%)。符合规则的患者比例和受试者工作曲线下面积 (AUC) 分别为 27.5%(95% CI 27.3-27.7%) 和 0.904 (0.902-0.905)。验证组特异性、FPR、PPV、符合规则的患者比例、AUC 分别为 99.1%(95% CI 98.9-99.2%)、0.9%(0.8-1.1%)、99.8%(99.8-99.8%)、27.8%(27.6-28.0%)、0.889 (0.887-0.891)。

结论：改良 Goto TOR 规则（包括以下四个标准：初始心搏停止、无目击者的心搏停止、EMS-CPR 持续时间 > 20 min 和无院前 ROSC）预测 1 个月死亡率 > 99% 是医生在医院到达后立即治疗难治性 OHCA 的可靠工具。

DOI: 10.1186/s13054-022-03999-x; No. 137

关键词：Humans; Adult; Emergency Service, Hospital; Registries; *Outcome; *Epidemiology; *Cardiopulmonary Resuscitation; *Out-of-Hospital Cardiac Arrest/therapy; *Emergency Medical Services; Resuscitation Orders; *Emergency department; *Cardiopulmonary resuscitation; *Out-of-hospital cardiac arrest; *Termination-of-resuscitation rule; Decision Support Techniques

DOI: 10.1186/s13054-022-03992-4; No. 139

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DOI: 10.1186/s13054-022-04007-y; No. 131

关键词：Humans; Prognosis; Haptoglobins; *Shock, Septic/complications

# Hospital-onset sepsis and community-onset sepsis in critical care units in Japan: a retrospective cohort study based on a Japanese administrative claims database

Abstract

BACKGROUND: Hospital- and community-onset sepsis are significant sepsis subgroups. Japanese data comparing these subgroups are limited. This study aimed to describe the epidemiology of hospital- and community-onset sepsis in critical care units in Japan.

METHODS: We performed a retrospective cohort study using the Japanese Diagnosis and Procedure Combination database. Adult patients admitted to critical care units with sepsis from April 2010 to March 2020 were included. Sepsis cases were identified based on ICD-10 codes for infectious diseases, procedure codes for blood culture tests, and medication codes for antimicrobials. Patients' characteristics, in-hospital mortality, and resource utilization were assessed. The in-hospital mortality between groups was compared using the Poisson regression generalized linear mixed-effect model.

RESULTS: Of 516,124 patients, 52,183 (10.1%) had hospital-onset sepsis and 463,940 (89.9%) had community-onset sepsis. Hospital-onset sepsis was characterized by younger age, infrequent emergency hospitalization, frequent surgery under general anesthesia, and frequent organ support upon critical care unit admission compared to community-onset sepsis. In-hospital mortality was higher for hospital-onset than for community-onset sepsis (35.5% versus 19.2%; unadjusted mean difference, 16.3% [95% confidence interval (CI) 15.9-16.7]; adjusted mean difference, 15.6% [95% CI 14.9-16.2]). Mean hospital length of stay was longer for hospital-onset than for community-onset sepsis (47 days versus 30 days; unadjusted mean difference, 17 days [95% CI 16-17]; adjusted mean difference, 13 days [95% CI 12-14]).

CONCLUSION: Patients with hospital-onset sepsis admitted to critical care units in Japan had a poorer prognosis and more resource utilization including organ support rate, number of days with critical care unit surcharge codes, and hospital length of stay than those with community-onset sepsis.

DOI: 10.1186/s13054-022-04013-0; No. 136

关键词：Humans; Length of Stay; Adult; Critical Care; Retrospective Studies; Hospital Mortality; *Intensive Care Units; *Intensive care unit; *Sepsis; Hospitals; *Mortality; *Hospital length of stay; *Organ support therapy; *Resource utilization; Japan/epidemiology

# Clinical and biochemical endpoints and predictors of response to plasma exchange in septic shock: results from a randomized controlled trial

Abstract

BACKGROUND: Recently, a randomized controlled trial (RCT) demonstrated rapid but individually variable hemodynamic improvement with therapeutic plasma exchange (TPE) in patients with septic shock. Prediction of clinical efficacy in specific sepsis treatments is fundamental for individualized sepsis therapy.

METHODS: In the original RCT, patients with septic shock of < 24 h duration and norepinephrine (NE) requirement ≥ 0.4 μg/kg/min received standard of care (SOC) or SOC + one single TPE. Here, we report all clinical and biological endpoints of this study. Multivariate mixed-effects modeling of NE reduction was performed to investigate characteristics that could be associated with clinical response to TPE.

RESULTS: A continuous effect of TPE on the reduction in NE doses over the initial 24 h was observed (SOC group: estimated NE dose reduction of 0.005 µg/kg/min per hour; TPE group: 0.018 µg/kg/min per hour, p = 0.004). Similarly, under TPE, serum lactate levels, continuously decreased over the initial 24 h in the TPE group, whereas lactate levels increased under SOC (p = 0.001). A reduction in biomarkers and disease mediators (such as PCT (p = 0.037), vWF:Ag (p < 0.001), Angpt-2 (p = 0.009), sTie-2 (p = 0.005)) along with a repletion of exhausted protective factors (such as AT-III (p = 0.026), Protein C (p = 0.012), ADAMTS-13 (p = 0.008)) could be observed in the TPE but not in the SOC group. In a multivariate mixed effects model, increasing baseline lactate levels led to greater NE dose reduction effects with TPE as opposed to SOC (p = 0.004).

CONCLUSIONS: Adjunctive TPE is associated with the removal of injurious mediators and repletion of consumed protective factors altogether leading to preserved hemodynamic stabilization in refractory septic shock. We identified that baseline lactate concentration as a potential response predictor might guide future designing of large RCTs that will further evaluate TPE with regard to hard endpoints.

DOI: 10.1186/s13054-022-04003-2; No. 134

关键词：Humans; *Sepsis; *Sepsis/therapy; Norepinephrine/therapeutic use; *Shock, Septic/therapy; *Precision medicine; *Blood purification; *Endothelium; *Extracorporeal treatment [; *Fresh frozen plasma; *Personalized medicine; *Plasmapheresis; *Shock/therapy; Lactates; Plasma Exchange/methods

DOI: 10.1186/s13054-022-04009-w; No. 135

关键词：Humans; Animals; *Sepsis; Adsorption; *Shock, Septic; *Hemoperfusion/methods; Polymyxin B

# Impact of critical illness and withholding of early parenteral nutrition in the pediatric intensive care unit on long-term physical performance of children: a 4-year follow-up of the PEPaNIC randomized controlled trial

Abstract

BACKGROUND: Many critically ill children face long-term developmental impairments. The PEPaNIC trial attributed part of the problems at the level of neurocognitive and emotional/behavioral development to early use of parenteral nutrition (early-PN) in the PICU, as compared with withholding it for 1 week (late-PN). Insight in long-term daily life physical functional capacity after critical illness is limited. Also, whether timing of initiating PN affects long-term physical function of these children remained unknown.

METHODS: This preplanned follow-up study of the multicenter PEPaNIC randomized controlled trial subjected 521 former critically ill children (253 early-PN, 268 late-PN) to quantitative physical function tests 4 years after PICU admission in Leuven or Rotterdam, in comparison with 346 age- and sex-matched healthy children. Tests included handgrip strength measurement, timed up-and-go test, 6-min walk test, and evaluation of everyday overall physical activity with an accelerometer. We compared these functional measures for the former critically ill and healthy children and for former critically ill children randomized to late-PN versus early-PN, with multivariable linear or logistic regression analyses adjusting for risk factors.

RESULTS: As compared with healthy children, former critically ill children showed less handgrip strength (p < 0.0001), completed the timed up-and-go test more slowly (p < 0.0001), walked a shorter distance in 6 min (p < 0.0001) during which they experienced a larger drop in peripheral oxygen saturation (p ≤ 0.026), showed a lower energy expenditure (p ≤ 0.024), performed more light and less moderate physical activity (p ≤ 0.047), and walked fewer steps per day (p = 0.0074). Late-PN as compared with early-PN did not significantly affect these outcomes.

CONCLUSIONS: Four years after PICU admission, former critically ill children showed worse physical performance as compared with healthy children, without impact of timing of supplemental PN in the PICU. This study provides further support for de-implementing the early use of PN in the PICU.

DOI: 10.1186/s13054-022-04010-3; No. 133

关键词：Humans; Time Factors; Child; Follow-Up Studies; *Critical Illness/therapy; Intensive Care Units, Pediatric; *Critical illness; *Children; *Hand Strength; *Long term; *Physical function; *PICU; *Strength; Parenteral Nutrition/adverse effects; Physical Functional Performance

DOI: 10.1186/s13054-022-04008-x; No. 132

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# 更正：急诊期间的治疗和临床过程对重症监护患者严重程度评分和预测死亡风险的影响

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DOI: 10.1186/s13054-022-03998-y; No. 129

关键词：Humans; Middle Aged; Aged; Adult; Cohort Studies; Aged, 80 and over; Young Adult; Adolescent; Retrospective Studies; *Extracorporeal Membrane Oxygenation; *Cardiopulmonary Resuscitation; *Out-of-Hospital Cardiac Arrest/therapy; *Out-of-hospital cardiac arrest; Japan/epidemiology; *Complication; *Extracorporeal cardiopulmonary resuscitation; *Neurological outcome; *Real-world data; *Survival rate

# Diagnostic concordance between BioFire® FilmArray® Pneumonia Panel and culture in patients with COVID-19 pneumonia admitted to intensive care units: the experience of the third wave in eight hospitals in Colombia

Abstract

BACKGROUND: The detection of coinfections is important to initiate appropriate antimicrobial therapy. Molecular diagnostic testing identifies pathogens at a greater rate than conventional microbiology. We assessed both bacterial coinfections identified via culture or the BioFire® FilmArray® Pneumonia Panel (FA-PNEU) in patients infected with SARS-CoV-2 in the ICU and the concordance between these techniques.

METHODS: This was a prospective study of patients with SARS-CoV-2 who were hospitalized for no more than 48 h and on mechanical ventilation for no longer than 24 h in 8 ICUs in Medellín, Colombia. We studied mini-bronchoalveolar lavage or endotracheal aspirate samples processed via conventional culture and the FA-PNEU. Coinfection was defined as the identification of a respiratory pathogen using the FA-PNEU or cultures. Serum samples of leukocytes, C-reactive protein, and procalcitonin were taken on the first day of intubation. We analyzed the empirical antibiotics and the changes in antibiotic management according to the results of the FA-PNEUM and cultures.

RESULTS: Of 110 patients whose samples underwent both methods, FA-PNEU- and culture-positive samples comprised 24.54% versus 17.27%, respectively. Eighteen samples were positive in both techniques, 82 were negative, 1 was culture-positive with a negative FA-PNEU result, and 9 were FA-PNEU-positive with negative culture. The two bacteria most frequently detected by the FA-PNEU were Staphylococcus aureus (37.5%) and Streptococcus agalactiae (20%), and those detected by culture were Staphylococcus aureus (34.78%) and Klebsiella pneumoniae (26.08%). The overall concordance was 90.1%, and when stratified by microorganism, it was between 92.7 and 100%. The positive predictive value (PPV) was between 50 and 100% and were lower for Enterobacter cloacae and Staphylococcus aureus. The negative predictive value (NPV) was high (between 99.1 and 100%); MecA/C/MREJ had a specificity of 94.55% and an NPV of 100%. The inflammatory response tests showed no significant differences between patients whose samples were positive and negative for both techniques. Sixty-one patients (55.45%) received at least one dose of empirical antibiotics.

CONCLUSIONS: The overall concordance was 90.1%, and it was between 92.7% and 100% when stratified by microorganisms. The positive predictive value was between 50 and 100%, with a very high NPV.

# BioFire®FilmArray® 肺炎检测试剂盒与培养对入住重症监护室的 COVID-19 肺炎患者的诊断一致性：哥伦比亚 8 家医院第三次波的经验

摘要

背景：共感染的检测对启动适当的抗菌治疗很重要。分子诊断检测比常规微生物学识别病原体的速度更快。我们评估了通过培养或 BioFire®FilmArray® 肺炎试剂盒 (FA-PNEU) 鉴定的 ICU 中 SARS-CoV-2 感染患者的细菌双重感染以及这些技术之间的一致性。

方法：这是一项前瞻性研究，在哥伦比亚 Medellín 的 8 个 ICU 中，SARS-CoV-2 患者住院不超过 48h，机械通气不超过 24h。我们研究了通过常规培养和 FA-PNEU 处理的微量支气管肺泡灌洗或气管内抽吸样本。共感染定义为使用 FA-PNEU 或培养物鉴定出呼吸道病原体。在插管的第一天采集了白细胞、C 反应蛋白和降钙素原的血清样本。我们根据 FA-PNEUM 和培养结果分析了经验性抗生素和抗生素管理的变化。

结果：110 例同时使用两种方法的患者中，FA-PNEU - 和培养阳性样本分别占 24.54% 和 17.27%。两种技术均为阳性的 18 份样本，82 份为阴性，1 份培养阳性伴阴性 FA-PNEU 结果，9 份 FA-PNEU 阳性伴阴性培养。FA-PNEU 最常检出的两种细菌是金黄色葡萄球菌 (37.5%) 和无乳链球菌 (20%)，培养检出的细菌是金黄色葡萄球菌 (34.78%) 和肺炎克雷伯菌 (26.08%)。总体一致性为 90.1%，按微生物分层时，其在 92.7 和 100% 之间。阳性预测值 (PPV) 在 50-100% 之间，阴沟肠杆菌和金黄色葡萄球菌更低。阴性预测值 (NPV) 较高（在 99.1 和 100% 之间）；MecA/C/MREJ 的特异性为 94.55%，NPV 为 100%。炎症反应试验显示，两种技术阳性和阴性样本患者之间无显著差异。61 例患者 (55.45%) 至少接受 1 剂经验性抗生素治疗。

结论：总体一致性为 90.1%，按微生物分层时在 92.7% 和 100% 之间。阳性预测值介于 50-100% 之间，NPV 非常高。

DOI: 10.1186/s13054-022-04006-z; No. 130

关键词：Humans; Prospective Studies; Intensive Care Units; *COVID-19; SARS-CoV-2; Anti-Bacterial Agents/therapeutic use; Bacteria; Hospitals; *Pneumonia/drug therapy; *Intensive care units; *Bacterial coinfection; *Bacterial pneumonia; *Coinfection; *COVID-19/diagnosis; *FilmArray; Colombia; Multiplex Polymerase Chain Reaction/methods

# Lung response to prone positioning in mechanically-ventilated patients with COVID-19

Abstract

BACKGROUND: Prone positioning improves survival in moderate-to-severe acute respiratory distress syndrome (ARDS) unrelated to the novel coronavirus disease (COVID-19). This benefit is probably mediated by a decrease in alveolar collapse and hyperinflation and a more homogeneous distribution of lung aeration, with fewer harms from mechanical ventilation. In this preliminary physiological study we aimed to verify whether prone positioning causes analogue changes in lung aeration in COVID-19. A positive result would support prone positioning even in this other population.

METHODS: Fifteen mechanically-ventilated patients with COVID-19 underwent a lung computed tomography in the supine and prone position with a constant positive end-expiratory pressure (PEEP) within three days of endotracheal intubation. Using quantitative analysis, we measured the volume of the non-aerated, poorly-aerated, well-aerated, and over-aerated compartments and the gas-to-tissue ratio of the ten vertical levels of the lung. In addition, we expressed the heterogeneity of lung aeration with the standardized median absolute deviation of the ten vertical gas-to-tissue ratios, with lower values indicating less heterogeneity.

RESULTS: By the time of the study, PEEP was 12 (10-14) cmH(2)O and the PaO(2):FiO(2) 107 (84-173) mmHg in the supine position. With prone positioning, the volume of the non-aerated compartment decreased by 82 (26-147) ml, of the poorly-aerated compartment increased by 82 (53-174) ml, of the normally-aerated compartment did not significantly change, and of the over-aerated compartment decreased by 28 (11-186) ml. In eight (53%) patients, the volume of the over-aerated compartment decreased more than the volume of the non-aerated compartment. The gas-to-tissue ratio of the ten vertical levels of the lung decreased by 0.34 (0.25-0.49) ml/g per level in the supine position and by 0.03 (- 0.11 to 0.14) ml/g in the prone position (p < 0.001). The standardized median absolute deviation of the gas-to-tissue ratios of those ten levels decreased in all patients, from 0.55 (0.50-0.71) to 0.20 (0.14-0.27) (p < 0.001).

CONCLUSIONS: In fifteen patients with COVID-19, prone positioning decreased alveolar collapse, hyperinflation, and homogenized lung aeration. A similar response has been observed in other ARDS, where prone positioning improves outcome. Therefore, our data provide a pathophysiological rationale to support prone positioning even in COVID-19.

# COVID-19 机械通气患者俯卧位的肺反应

摘要

背景：俯卧位改善与新型冠状病毒病 (COVID-19) 无关的中重度急性呼吸窘迫综合征 (ARDS) 的生存率。这种获益很可能是由肺泡萎缩和过度充气的减少以及肺通气更均匀的分布介导，机械通气的危害更少。在这项初步的生理学研究中，我们旨在验证俯卧位是否会导致 COVID-19 中肺通气的模拟变化。阳性结果将支持倾向定位，即使在其他人群中。

方法：15 例接受机械通气的 COVID-19 患者在气管插管后 3 天内以仰卧位和俯卧位接受了肺计算机断层扫描，并保持呼气末正压 (PEEP) 恒定。使用定量分析，我们测量了不通气、通气不良、通气良好和过度通气隔室的体积以及肺 10 个垂直水平的气体 - 组织比。此外，我们用 10 个垂直气体 - 组织比的标准化中位绝对偏差表示肺通气的异质性，较低值表示异质性较小。

结果：研究时，仰卧位 PEEP 为 12 (10-14) cmh2 O，pao2：fio2 为 107 (84-173) mmHg。俯卧位时，不通气隔室的容积减少了 82 (26-147) ml，通气不良隔室的容积增加了 82 (53-174) ml，正常通气隔室的容积没有显著变化，过度通气隔室的容积减少了 28 (11-186) ml。在 8 例 (53%) 患者中，过度充气隔室的容积下降大于非充气隔室的容积。仰卧位时，肺的 10 个垂直水平的气体 - 组织比下降 0.34 (0.25-0.49) ml/g，俯卧位时下降 0.03（-0.11 至 0.14）ml/g (p < 0.001)。这 10 个水平的气体 - 组织比的标准化中位绝对偏差在所有患者中均下降，从 0.55 (0.50-0.71) 下降至 0.20 (0.14-0.27)(p < 0.001)。

结论：在 15 例 COVID-19 患者中，俯卧位减少了肺泡塌陷、过度充气和均质化肺通气。在其他 ARDS 患者中观察到了类似的反应，俯卧位改善了结局。因此，我们的数据提供了病理生理学依据，支持即使在 COVID-19 中的俯卧位。

DOI: 10.1186/s13054-022-03996-0; No. 127

关键词：Humans; Respiration, Artificial; *Hypoxia; *COVID-19/therapy; *Respiratory Distress Syndrome/therapy; *Pneumonia; *Mechanical ventilation; Lung/diagnostic imaging; *Acute respiratory distress syndrome; *Prone positioning; Prone Position/physiology; *Coronavirus disease 2019

# Machine learning derivation of four computable 24-h pediatric sepsis phenotypes to facilitate enrollment in early personalized anti-inflammatory clinical trials

Abstract

BACKGROUND: Thrombotic microangiopathy-induced thrombocytopenia-associated multiple organ failure and hyperinflammatory macrophage activation syndrome are important causes of late pediatric sepsis mortality that are often missed or have delayed diagnosis. The National Institutes of General Medical Science sepsis research working group recommendations call for application of new research approaches in extant clinical data sets to improve efficiency of early trials of new sepsis therapies. Our objective is to apply machine learning approaches to derive computable 24-h sepsis phenotypes to facilitate personalized enrollment in early anti-inflammatory trials targeting these conditions.

METHODS: We applied consensus, k-means clustering analysis to our extant PHENOtyping sepsis-induced Multiple organ failure Study (PHENOMS) dataset of 404 children. 24-hour computable phenotypes are derived using 25 available bedside variables including C-reactive protein and ferritin.

RESULTS: Four computable phenotypes (PedSep-A, B, C, and D) are derived. Compared to all other phenotypes, PedSep-A patients (n = 135; 2% mortality) were younger and previously healthy, with the lowest C-reactive protein and ferritin levels, the highest lymphocyte and platelet counts, highest heart rate, and lowest creatinine (p < 0.05); PedSep-B patients (n = 102; 12% mortality) were most likely to be intubated and had the lowest Glasgow Coma Scale Score (p < 0.05); PedSep-C patients (n = 110; mortality 10%) had the highest temperature and Glasgow Coma Scale Score, least pulmonary failure, and lowest lymphocyte counts (p < 0.05); and PedSep-D patients (n = 56, 34% mortality) had the highest creatinine and number of organ failures, including renal, hepatic, and hematologic organ failure, with the lowest platelet counts (p < 0.05). PedSep-D had the highest likelihood of developing thrombocytopenia-associated multiple organ failure (Adj OR 47.51 95% CI [18.83-136.83], p < 0.0001) and macrophage activation syndrome (Adj OR 38.63 95% CI [13.26-137.75], p < 0.0001).

CONCLUSIONS: Four computable phenotypes are derived, with PedSep-D being optimal for enrollment in early personalized anti-inflammatory trials targeting thrombocytopenia-associated multiple organ failure and macrophage activation syndrome in pediatric sepsis. A computer tool for identification of individual patient membership ( www.pedsepsis.pitt.edu ) is provided. Reproducibility will be assessed at completion of two ongoing pediatric sepsis studies.

# 机器学习推导出 4 个可计算的 24h 儿科脓毒症表型，以促进早期个体化抗炎临床试验的入组

摘要

背景：血栓性微血管病引起的血小板减少相关多器官功能衰竭和高炎性巨噬细胞活化综合征是儿科脓毒症晚期死亡的重要原因，常被漏诊或延误诊断。美国国立综合医学研究院败血症研究工作组建议，在现有临床数据集中应用新的研究方法，以提高败血症新疗法早期试验的效率。我们的目的是应用机器学习方法得出可计算的 24h 脓毒症表型，以促进靶向这些疾病的早期抗炎试验的个性化入组。

方法：我们对 404 名儿童现有的 PHENOtyping 脓毒症诱导的多器官衰竭研究 (PHENOMS) 数据集应用共识、k-means 聚类分析。24 小时可计算的表型是使用 25 个可用的床旁变量得出的，包括 C - 反应蛋白和铁蛋白。

结果：得出 4 个可计算表型（PedSep-A、B、C 和 D）。与所有其他表型相比，PedSep-A 患者（n = 135；死亡率 2%）更年轻且既往健康，C 反应蛋白和铁蛋白水平最低，淋巴细胞和血小板计数最高，心率最高，肌酐最低 (p < 0.05)；PedSep-B 患者（n = 102；12% 死亡率）最有可能插管，且格拉斯哥昏迷量表评分最低 (p < 0.05)；PedSep-C 患者（n = 110；死亡率 10%）体温和格拉斯哥昏迷量表评分最高，肺衰竭最少，淋巴细胞计数最低 (p < 0.05)；PedSep-D 患者（n = 56，34% 死亡率）的肌酐和器官衰竭数量最高，包括肾脏、肝脏和血液学器官衰竭，血小板计数最低 (p < 0.05)。PedSep-D 发生血小板减少相关多器官功能衰竭 (Adj OR 47.51 95% CI [18.83-136.83]，p < 0.0001) 和巨噬细胞活化综合征 (Adj OR 38.63 95% CI [13.26-137.75]，p < 0.0001) 的可能性最高。

结论：得出 4 个可计算的表型，PedSep-D 是靶向血小板减少相关多器官功能衰竭和巨噬细胞活化综合征儿科脓毒症早期个体化抗炎试验的最佳入组患者。识别个体患者成员的计算机工具（www.pedsepsis.pitt.edu）。完成两项正在进行的儿科败血症研究时，将对重现性进行评估。

DOI: 10.1186/s13054-022-03977-3; No. 128

关键词：Humans; Child; Reproducibility of Results; Phenotype; Clinical Trials as Topic; *Sepsis; Anti-Inflammatory Agents; Multiple Organ Failure/etiology; Organ Dysfunction Scores; *Thrombocytopenia; Creatinine; Machine Learning; *Hyperferritinemic sepsis; *Immunoparalysis-associated multiple organ failure; *Macrophage activation syndrome; *Macrophage Activation Syndrome/complications; *Multiple organ failure; *Sequential multiple organ failure; *Severe sepsis; *Thrombocytopenia-associated multiple organ failure; C-Reactive Protein; Ferritins

Abstract

Survival has been considered the cornerstone for clinical outcome evaluation in critically ill patients admitted to intensive care unit (ICU). There is evidence that ICU survivors commonly show impairments in long-term outcomes such as quality of life (QoL) considering them as the most relevant ones. In the last years, the concept of patient-important outcomes has been introduced and increasingly reported in peer-reviewed publications. In the present systematic review, we evaluated how many randomized controlled trials (RCTs) were conducted on critically ill patients and reporting a benefit on survival reported also data on QoL. All RCTs investigating nonsurgical interventions that significantly reduced mortality in critically ill patients were searched on MEDLINE/PubMed, Scopus and Embase from inception until August 2021. In a second stage, for all the included studies, the outcome QoL was investigated. The primary outcome was to evaluate how many RCTs analyzing interventions reducing mortality reported also data on QoL. The secondary endpoint was to investigate if QoL resulted improved, worsened or not modified. Data on QoL were reported as evaluated outcome in 7 of the 239 studies (2.9%). The tools to evaluate QoL and QoL time points were heterogeneous. Four interventions showed a significant impact on QoL: Two interventions improved survival and QoL (pravastatin in subarachnoid hemorrhage, dexmedetomidine in elderly patients after noncardiac surgery), while two interventions reduced mortality but negatively influenced QoL (caloric restriction in patients with refeeding syndrome and systematic ICU admission in elderly patients). In conclusion, only a minority of RCTs in which an intervention demonstrated to affect mortality in critically ill patients reported also data on QoL. Future research in critical care should include patient-important outcomes like QoL besides mortality. Data on this topic should be collected in conformity with PROs statement and core outcome sets to guarantee quality and comparability of results.

DOI: 10.1186/s13054-022-03993-3; No. 126

关键词：Humans; Aged; Intensive Care Units; Critical Care; *Critical Illness/therapy; *Critical care; Hospitalization; *Quality of Life; *Mortality; *Quality of life; *Critical illness; *Long-term outcomes; *Patient-important outcomes

DOI: 10.1186/s13054-022-04001-4; No. 125

关键词：Humans; Norepinephrine; *Shock, Septic/drug therapy; Vasopressins/therapeutic use; Vasoconstrictor Agents/pharmacology/therapeutic use

# Early intubation and decreased in-hospital mortality in patients with coronavirus disease 2019

Abstract

BACKGROUND: Some academic organizations recommended that physicians intubate patients with COVID-19 with a relatively lower threshold of oxygen usage particularly in the early phase of pandemic. We aimed to elucidate whether early intubation is associated with decreased in-hospital mortality among patients with novel coronavirus disease 2019 (COVID-19) who required intubation.

METHODS: A multicenter, retrospective, observational study was conducted at 66 hospitals in Japan where patients with moderate-to-severe COVID-19 were treated between January and September 2020. Patients who were diagnosed as COVID-19 with a positive reverse-transcription polymerase chain reaction test and intubated during admission were included. Early intubation was defined as intubation conducted in the setting of ≤ 6 L/min of oxygen usage. In-hospital mortality was compared between patients with early and non-early intubation. Inverse probability weighting analyses with propensity scores were performed to adjust patient demographics, comorbidities, hemodynamic status on admission and time at intubation, medications before intubation, severity of COVID-19, and institution characteristics. Subgroup analyses were conducted on the basis of age, severity of hypoxemia at intubation, and days from admission to intubation.

RESULTS: Among 412 patients eligible for the study, 110 underwent early intubation. In-hospital mortality was lower in patients with early intubation than those with non-early intubation (18 [16.4%] vs. 88 [29.1%]; odds ratio, 0.48 [95% confidence interval 0.27-0.84]; p = 0.009, and adjusted odds ratio, 0.28 [95% confidence interval 0.19-0.42]; p < 0.001). The beneficial effects of early intubation were observed regardless of age and severity of hypoxemia at time of intubation; however, early intubation was associated with lower in-hospital mortality only among patients who were intubated later than 2 days after admission.

CONCLUSIONS: Early intubation in the setting of ≤ 6 L/min of oxygen usage was associated with decreased in-hospital mortality among patients with COVID-19 who required intubation.

DOI: 10.1186/s13054-022-03995-1; No. 124

关键词：Humans; Oxygen; Retrospective Studies; Hospital Mortality; *COVID-19; Hypoxia; SARS-CoV-2; *Critical care; *Oxygen; Intubation, Intratracheal; *Coronavirus infection; *Pulmonary function; *Respiratory failure; *Timing of intubation

DOI: 10.1186/s13054-022-04000-5; No. 123

关键词：Humans; Energy Metabolism; *Critical Illness/therapy; *Energy Intake; Blood Coagulation Tests; Calorimetry, Indirect; Nutritional Requirements

# Comparison of the predictive ability of clinical frailty scale and hospital frailty risk score to determine long-term survival in critically ill patients: a multicentre retrospective cohort study

Abstract

BACKGROUND: The Clinical Frailty Scale (CFS) is the most commonly used frailty measure in intensive care unit (ICU) patients. The hospital frailty risk score (HFRS) was recently proposed for the quantification of frailty. We aimed to compare the HFRS with the CFS in critically ill patients in predicting long-term survival up to one year following ICU admission.

METHODS: In this retrospective multicentre cohort study from 16 public ICUs in the state of Victoria, Australia between 1st January 2017 and 30th June 2018, ICU admission episodes listed in the Australian and New Zealand Intensive Care Society Adult Patient Database registry with a documented CFS, which had been linked with the Victorian Admitted Episode Dataset and the Victorian Death Index were examined. The HFRS was calculated for each patient using the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes that represented pre-existing conditions at the time of index hospital admission. Descriptive methods, Cox proportional hazards and area under the receiver operating characteristic (AUROC) were used to investigate the association between each frailty score and long-term survival up to 1 year, after adjusting for confounders including sex and baseline severity of illness on admission to ICU (Australia New Zealand risk-of-death, ANZROD).

RESULTS: 7001 ICU patients with both frailty measures were analysed. The overall median (IQR) age was 63.7 (49.1-74.0) years; 59.5% (n = 4166) were male; the median (IQR) APACHE II score 14 (10-20). Almost half (46.7%, n = 3266) were mechanically ventilated. The hospital mortality was 9.5% (n = 642) and 1-year mortality was 14.4% (n = 1005). HFRS correlated weakly with CFS (Spearman's rho 0.13 (95% CI 0.10-0.15) and had a poor agreement (kappa = 0.12, 95% CI 0.10-0.15). Both frailty measures predicted 1-year survival after adjusting for confounders, CFS (HR 1.26, 95% CI 1.21-1.31) and HFRS (HR 1.08, 95% CI 1.02-1.15). The CFS had better discrimination of 1-year mortality than HFRS (AUROC 0.66 vs 0.63 p < 0.0001).

CONCLUSION: Both HFRS and CFS independently predicted up to 1-year survival following an ICU admission with moderate discrimination. The CFS was a better predictor of 1-year survival than the HFRS.

# 比较临床虚弱量表与医院虚弱风险评分对确定危重患者长期生存的预测能力：一项多中心回顾性队列研究

摘要

背景：临床衰弱量表 (CFS) 是重症监护室 (ICU) 患者最常用的衰弱测量指标。最近提出采用医院虚弱风险评分 (HFRS) 对虚弱进行量化。我们旨在比较危重患者 HFRS 与 CFS 在预测入住 ICU 后 1 年内的长期生存率。

方法：在本项回顾性多中心队列研究中，研究于 2017 年 1 月 1 日至 2018 年 6 月 30 日在澳大利亚维多利亚州的 16 家公立 ICU 中，记录了 CFS 的澳大利亚和新西兰重症监护协会成人患者数据库登记研究的 ICU 入院发作，检查了与维多利亚州入院事件数据集和维多利亚州死亡指数相关的数据。使用疾病和有关健康问题的国际统计分类第 10 次修订版 (ICD-10) 代码计算每例患者的 HFRS，这些代码代表在索引入院时的既存疾病。采用描述性方法、Cox 比例风险和受试者工作特征曲线下面积 (AUROC)，在校正混杂因素（包括性别和入住 ICU 时的基线疾病严重程度）后，研究每个虚弱评分与长达 1 年的长期生存之间的相关性（澳大利亚、新西兰、ANZROD）。

结果：分析了 7001 例具有两种虚弱指标的 ICU 患者。总体中位 (IQR) 年龄为 63.7 (49.1-74.0) 岁；59.5%(n = 4166) 为男性；中位 (IQR) APACHE II 评分为 14 (10-20)。几乎一半 (46.7%，n = 3266) 为机械通气。住院死亡率为 9.5%(n = 642)，1 年死亡率为 14.4%(n = 1005)。HFRS 与 CFS 弱相关（Spearman rho 0.13 (95% CI 0.10-0.15)，一致性较差 (kappa = 0.12，95% CI 0.10-0.15)。在校正混杂因素 CFS (HR 1.26，95% CI 1.21-1.31) 和 HFRS (HR 1.08，95% CI 1.02-1.15) 后，两种虚弱指标均可预测 1 年生存率。CFS 对 1 年死亡率的区分能力优于 HFRS (AUROC 0.66 vs 0.63 p < 0.0001)。

结论：HFRS 和 CFS 均可在中度区分度的情况下独立预测入住 ICU 后 1 年的生存率。CFS 是比 HFRS 更好的 1 年生存率预测指标。

DOI: 10.1186/s13054-022-03987-1; No. 121

关键词：Humans; Female; Male; Middle Aged; Prospective Studies; Aged; Critical Illness; Adult; Cohort Studies; Risk Factors; Retrospective Studies; Hospitals; *Frailty; *Fatigue Syndrome, Chronic; *Long-term outcomes; *1-year survival; *CFS; *Clinical frailty scale; *Hemorrhagic Fever with Renal Syndrome; *HFRS; *Hospital frailty risk score; Victoria

# Sequential use of midazolam and dexmedetomidine for long-term sedation may reduce weaning time in selected critically ill, mechanically ventilated patients: a randomized controlled study

Abstract

BACKGROUND: Current sedatives have different side effects in long-term sedation. The sequential use of midazolam and dexmedetomidine for prolonged sedation may have distinct advantages. We aimed to evaluate the efficacy and safety of the sequential use of midazolam and either dexmedetomidine or propofol, and the use of midazolam alone in selected critically ill, mechanically ventilated patients.

METHODS: This single-center, randomized controlled study was conducted in medical and surgical ICUs in a tertiary, academic medical center. Patients enrolled in this study were critically ill, mechanically ventilated adult patients receiving midazolam, with anticipated mechanical ventilation for ≥ 72 h. They passed the spontaneous breathing trial (SBT) safety screen, underwent a 30-min-SBT without indication for extubation and continued to require sedation. Patients were randomized into group M-D (midazolam was switched to dexmedetomidine), group M-P (midazolam was switched to propofol), and group M (sedation with midazolam alone), and sedatives were titrated to achieve the targeted sedation range (RASS - 2 to 0).

RESULTS: Total 252 patients were enrolled. Patients in group M-D had an earlier recovery, faster extubation, and more percentage of time at the target sedation level than those in group M-P and group M (all P < 0.001). They also experienced less weaning time (25.0 h vs. 49.0 h; HR1.47, 95% CI 1.05 to 2.06; P = 0.025), and a lower incidence of delirium (19.5% vs. 43.8%, P = 0.002) than patients in group M. Recovery (P < 0.001), extubation (P < 0.001), and weaning time (P = 0.048) in group M-P were shorter than in group M, while the acquisition cost of sedative drug was more expensive than other groups (both P < 0.001). There was no significant difference in adverse events among these groups (all P > 0.05).

CONCLUSIONS: The sequential use of midazolam and dexmedetomidine was an effective and safe sedation strategy for long-term sedation and could provide clinically relevant benefits for selected critically ill, mechanically ventilated patients.

DOI: 10.1186/s13054-022-03967-5; No. 122

关键词：Humans; Adult; Respiration, Artificial; Critical Illness/therapy; *Dexmedetomidine/adverse effects; *Critically ill; *Mechanical ventilation; *Propofol/adverse effects; *Propofol; *Dexmedetomidine; *Midazolam; *Sequential sedation; Hypnotics and Sedatives/pharmacology/therapeutic use; Midazolam/adverse effects

DOI: 10.1186/s13054-022-03994-2; No. 120

关键词：Humans; Prospective Studies; Time Factors; Adult; Japan; Registries; *Cardiopulmonary Resuscitation; *Out-of-Hospital Cardiac Arrest; *Emergency Medical Services; *Cardiopulmonary resuscitation; *Out-of-hospital cardiac arrest; *Cardiopulmonary resuscitation duration; *Neurological outcomes

DOI: 10.1186/s13054-022-03990-6; No. 119

关键词：Humans; Female; Male; Middle Aged; Adult; Retrospective Studies; Magnetic Resonance Imaging; Brain/diagnostic imaging; *Neuroimaging; Feasibility Studies; *Safety; *ECMO; *Extracorporeal Membrane Oxygenation/methods; *Bedside; *Brain; *Portable MRI

Abstract

BACKGROUND: Whether prone position (PP) improves clinical outcomes in COVID-19 pneumonia treated with noninvasive ventilation (NIV) is unknown. We evaluated the effect of early PP on 28-day NIV failure, intubation and death in noninvasively ventilated patients with moderate-to-severe acute hypoxemic respiratory failure due to COVID-19 pneumonia and explored physiological mechanisms underlying treatment response.

METHODS: In this controlled non-randomized trial, 81 consecutive prospectively enrolled patients with COVID-19 pneumonia and moderate-to-severe (paO2/FiO2 ratio < 200) acute hypoxemic respiratory failure treated with early PP + NIV during Dec 2020-May 2021were compared with 162 consecutive patients with COVID-19 pneumonia matched for age, mortality risk, severity of illness and paO2/FiO2 ratio at admission, treated with conventional (supine) NIV during Apr 2020-Dec 2020 at HUMANITAS Gradenigo Subintensive Care Unit, after propensity score adjustment for multiple baseline and treatment-related variables to limit confounding. Lung ultrasonography (LUS) was performed at baseline and at day 5. Ventilatory parameters, physiological dead space indices (DSIs) and circulating inflammatory and procoagulative biomarkers were monitored during the initial 7 days.

RESULTS: In the intention-to-treat analysis. NIV failure occurred in 14 (17%) of PP patients versus 70 (43%) of controls [HR = 0.32, 95% CI 0.21-0.50; p < 0.0001]; intubation in 8 (11%) of PP patients versus 44 (30%) of controls [HR = 0.31, 95% CI 0.18-0.55; p = 0.0012], death in 10 (12%) of PP patients versus 59 (36%) of controls [HR = 0.27, 95% CI 0.17-0.44; p < 0.0001]. The effect remained significant within different categories of severity of hypoxemia (paO2/FiO2 < 100 or paO2/FiO2 100-199 at admission). Adverse events were rare and evenly distributed. Compared with controls, PP therapy was associated with improved oxygenation and DSIs, reduced global LUS severity indices largely through enhanced reaeration of dorso-lateral lung regions, and an earlier decline in inflammatory markers and D-dimer. In multivariate analysis, day 1 CO2 response outperformed O2 response as a predictor of LUS changes, NIV failure, intubation and death.

CONCLUSION: Early prolonged PP is safe and is associated with lower NIV failure, intubation and death rates in noninvasively ventilated patients with COVID-19-related moderate-to-severe hypoxemic respiratory failure. Early dead space reduction and reaeration of dorso-lateral lung regions predicted clinical outcomes in our study population.

# SARS-CoV-2 相关中重度低氧性呼吸衰竭无创通气患者的早期延长俯卧位：PRO-NIV 研究中的临床结局和治疗应答机制

摘要

背景：在接受无创通气 (NIV) 治疗的 COVID-19 肺炎中，俯卧位 (PP) 是否能改善临床结局尚不清楚。我们评估了早期 PP 对无创通气的 COVID-19 肺炎所致中重度急性低氧血症性呼吸衰竭患者 28 天 NIV 衰竭、插管和死亡的影响，并探讨了潜在治疗反应的生理机制。

方法：在这项对照的非随机试验中，在 2020 年 12 月至 2021 年 5 月期间，81 例连续前瞻性入组的 COVID-19 肺炎和中度至重度（paO2/FiO2 比值 <200）急性低氧性呼吸衰竭患者接受早期 PP + NIV 治疗，与 162 例连续的年龄、死亡风险、在对多个基线和治疗相关变量进行倾向评分校正以限制混杂因素后，2020 年 4 月 2020 日至 2020 年 12 月在 HUMANITAS Gradenigo 亚重症监护室采用常规（仰卧位）NIV 治疗的入院时疾病严重程度和 paO2/FiO2 比值。在基线和第 5 天进行肺部超声检查 (LUS)。在最初 7 天内监测通气参数、生理死腔指数 (DSI) 以及循环炎症和促凝生物标志物。

结果：意向治疗分析。14 例 (17%) PP 患者与 70 例 (43%) 对照患者发生了 NIV 失败 [HR = 0.32，95% CI 0.21-0.50；p < 0.0001]；8 例 (11%) PP 患者与 44 例 (30%) 对照患者发生了插管 [HR = 0.31，95% CI 0.18-0.55；p = 0.0012]；10 例 (12%) PP 患者与 59 例 (36%) 对照患者发生了死亡 [HR = 0.27，95% CI 0.17-0.44；p < 0.0001]。在低氧血症严重程度的不同类别中，该效应仍然显著（入院时 paO2/FiO2 < 100 或 paO2/FiO2 100-199）。不良事件罕见且均匀分布。与对照组相比，PP 治疗改善了氧合和 DSIs，主要通过增强肺背侧区域再通气降低了整体 LUS 严重程度指数，并且炎症标志物和 D - 二聚体更早下降。在多变量分析中，作为 LUS 变化、NIV 失败、插管和死亡的预测因子，第 1 天 CO2 反应优于 O2 反应。

结论：在 COVID-19 相关的中重度低氧血性呼吸衰竭无创通气患者中，早期延长 PP 是安全的，并且与较低的 NIV 衰竭、插管和死亡率相关。在我们的研究人群中，早期死腔减少和背外侧肺区域再通气可预测临床结局。

DOI: 10.1186/s13054-022-03937-x; No. 118

关键词：Humans; Prospective Studies; Respiration, Artificial; SARS-CoV-2; Prone Position; *Respiratory Distress Syndrome; *Respiratory Insufficiency/etiology/therapy; *COVID-19/complications/therapy; *Noninvasive ventilation; *Noninvasive Ventilation/adverse effects; *Lung ultrasound; *Corrected minute ventilation; *Dead space; *Ventilatory ratio

DOI: 10.1186/s13054-022-03991-5; No. 117

关键词：Humans; Anti-Bacterial Agents/therapeutic use; Vancomycin/therapeutic use; *Vancomycin; Adsorption; *Continuous Renal Replacement Therapy; *AN69ST membrane; *Doses; *Hemodiafiltration; *PAES membrane

DOI: 10.1186/s13054-022-03988-0; No. 116

关键词：Humans; Female; Male; *Acute Kidney Injury/etiology/therapy; *Azotemia/pathology; Fibrosis; Kidney/pathology; Social Planning

DOI: 10.1186/s13054-022-03972-8; No. 114

关键词：Humans; Prospective Studies; Intensive Care Units; Survivors; *Quality of Life; *Sepsis; *Sepsis/complications/epidemiology; *Biomarkers; *Prognostic enrichment; *Personalized medicine; *Latent profile analysis; *Mixture modeling; *Post-intensive care syndrome (PICS); Latent Class Analysis

DOI: 10.1186/s13054-022-03985-3; No. 113

关键词：Humans; Prospective Studies; Echocardiography; *Catheterization, Central Venous/methods; Echocardiography, Transesophageal; *Bubble test; *Cardiac surgery patients; *Central venous catheterization; *Central Venous Catheters; *Chest radiography; *CVC misplacements; *Internal jugular vein cannulation; Ultrasonography, Interventional/methods

DOI: 10.1186/s13054-022-03982-6; No. 115

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DOI: 10.1186/s13054-022-03984-4; No. 111

关键词：Humans; *Safety; Volunteers; *Conflict; *Crisis; *Disaster; *Disaster Planning; *Humanitarian; *Relief Work; *Volunteerism; Altruism

# The effect of treatment and clinical course during Emergency Department stay on severity scoring and predicted mortality risk in Intensive Care patients

Abstract

BACKGROUND: Treatment and the clinical course during Emergency Department (ED) stay before Intensive Care Unit (ICU) admission may affect predicted mortality risk calculated by the Acute Physiology and Chronic Health Evaluation (APACHE)-IV, causing lead-time bias. As a result, comparing standardized mortality ratios (SMRs) among hospitals may be difficult if they differ in the location where initial stabilization takes place. The aim of this study was to assess to what extent predicted mortality risk would be affected if the APACHE-IV score was recalculated with the initial physiological variables from the ED. Secondly, to evaluate whether ED Length of Stay (LOS) was associated with a change (delta) in these APACHE-IV scores.

METHODS: An observational multicenter cohort study including ICU patients admitted from the ED. Data from two Dutch quality registries were linked: the Netherlands Emergency department Evaluation Database (NEED) and the National Intensive Care Evaluation (NICE) registry. The ICU APACHE-IV, predicted mortality, and SMR based on data of the first 24 h of ICU admission were compared with an ED APACHE-IV model, using the most deviating physiological variables from the ED or ICU.

RESULTS: A total of 1398 patients were included. The predicted mortality from the ICU APACHE-IV (median 0.10; IQR 0.03-0.30) was significantly lower compared to the ED APACHE-IV model (median 0.13; 0.04-0.36; p < 0.01). The SMR changed from 0.63 (95%CI 0.54-0.72) to 0.55 (95%CI 0.47-0.63) based on ED APACHE-IV. Predicted mortality risk changed more than 5% in 321 (23.2%) patients by using the ED APACHE-IV. ED LOS > 3.9 h was associated with a slight increase in delta APACHE-IV of 1.6 (95% CI 0.4-2.8) compared to ED LOS < 1.7 h.

CONCLUSION: Predicted mortality risks and SMRs calculated by the APACHE IV scores are not directly comparable in patients admitted from the ED if hospitals differ in their policy to stabilize patients in the ED before ICU admission. Future research should focus on developing models to adjust for these differences.

DOI: 10.1186/s13054-022-03986-2; No. 112

关键词：Humans; APACHE; Length of Stay; Cohort Studies; Emergency Service, Hospital; Retrospective Studies; Hospital Mortality; *Intensive Care Units; *Critical Care; *Intensive care; *Benchmarking; *APACHE III; *Data quality; *Medical registries

# Transcranial Doppler as a screening test to exclude intracranial hypertension in brain-injured patients: the IMPRESSIT-2 prospective multicenter international study

Abstract

BACKGROUND: Alternative noninvasive methods capable of excluding intracranial hypertension through use of transcranial Doppler (ICPtcd) in situations where invasive methods cannot be used or are not available would be useful during the management of acutely brain-injured patients. The objective of this study was to determine whether ICPtcd can be considered a reliable screening test compared to the reference standard method, invasive ICP monitoring (ICPi), in excluding the presence of intracranial hypertension.

METHODS: This was a prospective, international, multicenter, unblinded, diagnostic accuracy study comparing the index test (ICPtcd) with a reference standard (ICPi), defined as the best available method for establishing the presence or absence of the condition of interest (i.e., intracranial hypertension). Acute brain-injured patients pertaining to one of four categories: traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH) or ischemic stroke (IS) requiring ICPi monitoring, were enrolled in 16 international intensive care units. ICPi measurements (reference test) were compared to simultaneous ICPtcd measurements (index test) at three different timepoints: before, immediately after and 2 to 3 h following ICPi catheter insertion. Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) were calculated at three different ICPi thresholds (> 20, > 22 and > 25 mmHg) to assess ICPtcd as a bedside real-practice screening method. A receiver operating characteristic (ROC) curve analysis with the area under the curve (AUC) was used to evaluate the discriminative accuracy and predictive capability of ICPtcd.

RESULTS: Two hundred and sixty-two patients were recruited for final analysis. Intracranial hypertension (> 22 mmHg) occurred in 87 patients (33.2%). The total number of paired comparisons between ICPtcd and ICPi was 687. The NPV was elevated (ICP > 20 mmHg = 91.3%, > 22 mmHg = 95.6%, > 25 mmHg = 98.6%), indicating high discriminant accuracy of ICPtcd in excluding intracranial hypertension. Concordance correlation between ICPtcd and ICPi was 33.3% (95% CI 25.6-40.5%), and Bland-Altman showed a mean bias of -3.3 mmHg. The optimal ICPtcd threshold for ruling out intracranial hypertension was 20.5 mmHg, corresponding to a sensitivity of 70% (95% CI 40.7-92.6%) and a specificity of 72% (95% CI 51.9-94.0%) with an AUC of 76% (95% CI 65.6-85.5%). CONCLUSIONS AND RELEVANCE: ICPtcd has a high NPV in ruling out intracranial hypertension and may be useful to clinicians in situations where invasive methods cannot be used or not available.

# 经颅多普勒作为排除脑损伤患者颅内高压的筛选试验：IMPRESSIT-2 前瞻性多中心国际研究

摘要

背景：在无法使用或无法获得侵入性方法的情况下，能够通过使用经颅多普勒 (ICPtcd) 排除颅内高压的替代非侵入性方法将有助于急性脑损伤患者的治疗。本研究的目的是确定与参考标准方法有创 ICP 监测 (ICPi) 相比，在排除颅内高压存在时，ICPtcd 是否可视为可靠的筛选试验。

方法：这是一项前瞻性、国际、多中心、非盲、诊断准确性研究，比较索引试验 (ICPtcd) 与参考标准 (ICPi)，定义为确定是否存在关注疾病（即颅内高压）的最佳可用方法。在 16 个国际重症监护室中入组了属于以下四个类别之一的急性脑损伤患者：创伤性脑损伤 (TBI)、蛛网膜下腔出血 (SAH)、需要 ICPi 监测的脑出血 (ICH) 或缺血性卒中 (IS)。在 3 个不同的时间点比较 ICPi 测量值（参考试验）与同时 ICPtcd 测量值（指数试验）：ICPi 导管插入之前、之后即刻和之后 2-3h。在 3 种不同的 ICPi 阈值（> 20、> 22 和 > 25 mmHg）下计算敏感性、特异性、阳性 (PPV) 和阴性预测值 (NPV)，以评估 ICPtcd 作为床旁实践筛查方法。使用受试者工作特征 (ROC) 曲线分析和曲线下面积 (AUC) 评价 ICPtcd 的鉴别准确性和预测能力。

结果：招募了 262 例患者进行最终分析。87 例患者 (33.2%) 发生颅内高压 (> 22 mmHg)。ICPtcd 和 ICPi 之间的配对比较总数为 687。NPV 升高（ICP > 20 mmHg = 91.3%，> 22 mmHg = 95.6%，> 25 mmHg = 98。6%），表明 ICPtcd 排除颅内高压的判别准确性高。ICPtcd 和 ICPi 之间的一致性相关性为 33.3%(95% CI 25.6-40.5%)，Bland-Altman 显示平均偏倚为 - 3.3 mmHg。排除颅内高压的最佳 ICPtcd 阈值为 20.5 mmHg，对应的敏感性为 70%(95% CI 40.7-92.6%)，特异性为 72%(95% CI 51.9-94.0%)，AUC 为 76%(95% CI 65.6-85.5%)。结论和相关性：ICPtcd 在排除颅内高压症方面具有较高的 NPV，在无法使用或无法获得侵入性方法的情况下可能对临床医生有用。

DOI: 10.1186/s13054-022-03978-2; No. 110

关键词：Humans; Prospective Studies; Brain; Intracranial Pressure; *Brain injury; *Intracranial hypertension; *Intracranial Hypertension/diagnosis/etiology; *Intracranial pressure; *Noninvasive monitoring; Ultrasonography, Doppler, Transcranial/methods

# High-flow nasal cannula versus conventional oxygen therapy in acute COPD exacerbation with mild hypercapnia: a multicenter randomized controlled trial

Abstract

BACKGROUND: High-flow nasal cannula (HFNC) can improve ventilatory function in patients with acute COPD exacerbation. However, its effect on clinical outcomes remains uncertain.

METHODS: This randomized controlled trial was conducted from July 2017 to December 2020 in 16 tertiary hospitals in China. Patients with acute COPD exacerbation with mild hypercapnia (pH ≥ 7.35 and arterial partial pressure of carbon dioxide > 45 mmHg) were randomly assigned to either HFNC or conventional oxygen therapy. The primary outcome was the proportion of patients who met the criteria for intubation during hospitalization. Secondary outcomes included treatment failure (intolerance and need for non-invasive or invasive ventilation), length of hospital stay, hospital cost, mortality, and readmission at day 90.

RESULTS: Among 337 randomized patients (median age, 70.0 years; 280 men [83.1%]; median pH 7.399; arterial partial pressure of carbon dioxide 51 mmHg), 330 completed the trial. 4/158 patients on HFNC and 1/172 patient on conventional oxygen therapy met the criteria for intubation (P = 0.198). Patients progressed to NPPV in both groups were comparable (15 [9.5%] in the HFNC group vs. 22 [12.8%] in the conventional oxygen therapy group; P = 0.343). Compared with conventional oxygen therapy, HFNC yielded a significantly longer median length of hospital stay (9.0 [interquartile range, 7.0-13.0] vs. 8.0 [interquartile range, 7.0-11.0] days) and a higher median hospital cost (approximately $2298 [interquartile range, $1613-$3782] vs. $2005 [interquartile range, $1439-$2968]). There were no significant differences in other secondary outcomes between groups.

CONCLUSIONS: In this multi-center randomized controlled study, HFNC compared to conventional oxygen therapy did not reduce need for intubation among acute COPD exacerbation patients with mild hypercapnia. The future studies should focus on patients with acute COPD exacerbation with respiratory acidosis (pH < 7.35). However, because the primary outcome rate was well below expected, the study was underpowered to show a meaningful difference between the two treatment groups.

DOI: 10.1186/s13054-022-03973-7; No. 109

关键词：Humans; Female; Male; Aged; Oxygen; Oxygen Inhalation Therapy; *Hypercapnia; *Respiratory Insufficiency/therapy; *Noninvasive Ventilation; Cannula; Carbon Dioxide; *High-flow nasal cannula; Hypercapnia/therapy; *Chronic obstructive; *Pulmonary disease; *Pulmonary Disease, Chronic Obstructive; *Respiratory insufficiency; *Respiratory support

# Serum IL-17 levels are higher in critically ill patients with AKI and associated with worse outcomes

Abstract

BACKGROUND: Interleukin-17 (IL-17) antagonism in rats reduces the severity and progression of AKI. IL-17-producing circulating T helper-17 (TH17) cells is increased in critically ill patients with AKI indicating that this pathway is also activated in humans. We aim to compare serum IL-17A levels in critically ill patients with versus without AKI and to examine their relationship with mortality and major adverse kidney events (MAKE).

METHODS: Multicenter, prospective study of ICU patients with AKI stage 2 or 3 and without AKI. Samples were collected at 24-48 h after AKI diagnosis or ICU admission (in those without AKI) [timepoint 1, T1] and 5-7 days later [timepoint 2, T2]. MAKE was defined as the composite of death, dependence on kidney replacement therapy or a reduction in eGFR of ≥ 30% from baseline up to 90 days following hospital discharge.

RESULTS: A total of 299 patients were evaluated. Patients in the highest IL-17A tertile (versus lower tertiles) at T1 had higher acuity of illness and comorbidity scores. Patients with AKI had higher levels of IL-17A than those without AKI: T1 1918.6 fg/ml (692.0-5860.9) versus 623.1 fg/ml (331.7-1503.4), p < 0.001; T2 2167.7 fg/ml (839.9-4618.9) versus 1193.5 fg/ml (523.8-2198.7), p = 0.006. Every onefold higher serum IL-17A at T1 was independently associated with increased risk of hospital mortality (aOR 1.35, 95% CI: 1.06-1.73) and MAKE (aOR 1.26, 95% CI: 1.02-1.55). The highest tertile of IL-17A (vs. the lowest tertile) was also independently associated with higher risk of MAKE (aOR 3.03, 95% CI: 1.34-6.87). There was no effect modification of these associations by AKI status. IL-17A levels remained significantly elevated at T2 in patients that died or developed MAKE.

CONCLUSIONS: Serum IL-17A levels measured by the time of AKI diagnosis or ICU admission were differentially elevated in critically ill patients with AKI when compared to those without AKI and were independently associated with hospital mortality and MAKE.

DOI: 10.1186/s13054-022-03976-4; No. 107

关键词：Humans; Female; Male; Prospective Studies; Intensive Care Units; Animals; Rats; Critical Illness/therapy; *Critical care; *Mortality; *Acute Kidney Injury/therapy; *Acute kidney injury; *IL-17; *Interleukin-17; *Major adverse kidney events

DOI: 10.1186/s13054-022-03970-w; No. 108

关键词：Humans; Adult; Pandemics; Cross-Over Studies; *COVID-19/therapy; *Respiratory Insufficiency/etiology/therapy; Cannula; Oxygen Inhalation Therapy/methods; Hypoxia/etiology/therapy; Oxygen/therapeutic use; *Acute respiratory failure; *Automatic oxygen titration; *Closed-loop oxygen control; *High flow nasal cannula; *High-flow nasal oxygen; *Nasal high-flow

# Derivation and performance of an end-of-life practice score aimed at interpreting worldwide treatment-limiting decisions in the critically ill

Abstract

BACKGROUND: Limitations of life-sustaining interventions in intensive care units (ICUs) exhibit substantial changes over time, and large, contemporary variation across world regions. We sought to determine whether a weighted end-of-life practice score can explain a large, contemporary, worldwide variation in limitation decisions.

METHODS: The 2015-2016 (Ethicus-2) vs. 1999-2000 (Ethicus-1) comparison study was a two-period, prospective observational study assessing the frequency of limitation decisions in 4952 patients from 22 European ICUs. The worldwide Ethicus-2 study was a single-period prospective observational study assessing the frequency of limitation decisions in 12,200 patients from 199 ICUs situated in 8 world regions. Binary end-of-life practice variable data (1 = presence; 0 = absence) were collected post hoc (comparison study, 22/22 ICUs, n = 4592; worldwide study, 186/199 ICUs, n = 11,574) for family meetings, daily deliberation for appropriate level of care, end-of-life discussions during weekly meetings, written triggers for limitations, written ICU end-of-life guidelines and protocols, palliative care and ethics consultations, ICU-staff taking communication or bioethics courses, and national end-of-life guidelines and legislation. Regarding the comparison study, generalized estimating equations (GEE) analysis was used to determine associations between the 12 end-of-life practice variables and treatment limitations. The weighted end-of-life practice score was then calculated using GEE-derived coefficients of the end-of-life practice variables. Subsequently, the weighted end-of-life practice score was validated in GEE analysis using the worldwide study dataset.

RESULTS: In comparison study GEE analyses, end-of-life discussions during weekly meetings [odds ratio (OR) 0.55, 95% confidence interval (CI) 0.30-0.99], end-of-life guidelines [OR 0.52, (0.31-0.87)] and protocols [OR 15.08, (3.88-58.59)], palliative care consultations [OR 2.63, (1.23-5.60)] and end-of-life legislation [OR 3.24, 1.60-6.55)] were significantly associated with limitation decisions (all P < 0.05). In worldwide GEE analyses, the weighted end-of-life practice score was significantly associated with limitation decisions [OR 1.12 (1.03-1.22); P = 0.008].

CONCLUSIONS: Comparison study-derived, weighted end-of-life practice score partly explained the worldwide study's variation in treatment limitations. The most important components of the weighted end-of-life practice score were ICU end-of-life protocols, palliative care consultations, and country end-of-life legislation.

# 旨在解释危重患者中全球治疗限制性决策的临终实践评分的推导和性能

摘要

背景：随着时间的推移，重症监护室 (ICU) 中维持生命的干预措施的局限性出现了实质性的变化，并且在世界范围内存在巨大的当代差异。我们试图确定加权临终实践评分是否能够解释限制决策中的巨大、当代、全球差异。

方法：2015-2016 年 (Ethicus-2) 与 1999-2000 年 (Ethicus-1) 的比较研究是一项两阶段、前瞻性观察性研究，评估了来自 22 个欧洲 ICU 的 4952 例患者的限制决定的频率。全球 Ethicus-2 研究是一项单阶段前瞻性观察性研究，在 8 个世界地区 199 个 ICU 的 12200 例患者中评估了限制决策的频率。对家庭会议、适当护理水平的日常审议、每周会议期间的临终讨论、限制的书面触发因素进行事后分析（比较研究，22/22 ICU，n = 4592；全球研究，186/199 ICU，n = 11,574），收集二元临终实践变量数据（1 = 有；0 = 无），书面 ICU 临终指南和方案，姑息治疗和伦理咨询，ICU - 工作人员参加沟通或生物伦理学课程，以及国家临终指南和立法。关于比较研究，使用广义估计方程 (GEE) 分析确定 12 项临终实践变量和治疗局限性之间的相关性。然后使用 GEE 衍生的临终实践变量系数计算加权的临终实践评分。随后，在 GEE 分析中使用全球研究数据集验证了加权临终实践评分。

结果：在比较研究 GEE 分析中，在每周会议 [比值比 (OR) 0.55，95% 置信区间 (CI) 0.30-0.99]、临终指南 [OR 0.52，(0.31-0.87)] 和方案 [OR 15.08，(3.88-58.59)]、姑息治疗咨询 [OR 2.63，(1.23-5.60)] 和临终立法 [OR 3.24，1.60-6.55）] 与限制决定显著相关（所有 P < 0.05）。在全球 GEE 分析中，加权临终实践评分与限制决策显著相关 [OR 1.12 (1.03-1.22)；P = 0.008]。

结论：比较研究得出的加权临终实践评分部分解释了全球研究治疗局限性的变化。加权临终实践评分的最重要组分为 ICU 临终方案、姑息治疗咨询和国家临终立法。

DOI: 10.1186/s13054-022-03971-9; No. 106

关键词：Humans; Intensive Care Units; Palliative Care; *Critical Illness/therapy; *Intensive care unit; Death; *Palliative care; *End-of-life care; *End-of-life practice score; *Life-sustaining therapy; *Medical ethics; *ROC analysis; *Terminal Care/methods

# Gut bacteriobiota and mycobiota are both associated with Day-28 mortality among critically ill patients

Abstract

INTRODUCTION: Gut microbiota is associated with host characteristics such as age, sex, immune condition or frailty and is thought to be a key player in numerous human diseases. Nevertheless, its association with outcome in critically ill patients has been poorly investigated. The aim of this study is to assess the association between gut microbiota composition and Day-28 mortality in critically ill patients.

METHODS: Rectal swab at admission of every patient admitted to intensive care unit (ICU) between October and November 2019 was frozen at - 80 °C. DNA extraction was performed thanks to QIAamp(®) PowerFecal(®) Pro DNA kit (QIAgen(®)). V3-V4 regions of 16SRNA and ITS2 coding genes were amplified by PCR. Sequencing (2x250 bp paired-end) was performed on MiSeq sequencer (Illumina(®)). DADA2 pipeline on R software was used for bioinformatics analyses. Risk factors for Day-28 mortality were investigated by logistic regression.

RESULTS: Fifty-seven patients were consecutively admitted to ICU of whom 13/57 (23%) deceased and 44/57 (77%) survived. Bacteriobiota α-diversity was lower among non-survivors than survivors (Shannon and Simpson index respectively, p < 0.001 and p = 0.001) as was mycobiota α-diversity (respectively p = 0.03 and p = 0.03). Both gut bacteriobiota and mycobiota Shannon index were independently associated with Day-28 mortality in multivariate analysis (respectively OR: 0.19, 97.5 CI [0.04-0.60], p < 0.01 and OR: 0.29, 97.5 CI [0.09-0.75], p = 0.02). Bacteriobiota β-diversity was significantly different between survivors and non-survivors (p = 0.05) but not mycobiota β-diversity (p = 0.57). Non-survivors had a higher abundance of Staphylococcus haemolyticus, Clostridiales sp. , Campylobacter ureolyticus, Akkermansia sp. , Malassezia sympodialis, Malassezia dermatis and Saccharomyces cerevisiae, whereas survivors had a higher abundance of Collinsella aerofaciens, Blautia sp. , Streptococcus sp. , Faecalibacterium prausnitzii and Bifidobacterium sp.

CONCLUSION: The gut bacteriobiota and mycobiota α diversities are independently associated with Day-28 mortality in critically ill patients. The causal nature of this interference and, if so, the underlying mechanisms should be further investigated to assess if gut microbiota modulation could be a future therapeutic approach.

# 肠道细菌生物门和霉菌生物门均与重症患者第 28 天死亡率相关

摘要

引言：肠道菌群与宿主特征有关，如年龄、性别、免疫状况或虚弱，被认为是许多人类疾病的关键因素。然而，尚未充分研究其与重症患者结局的相关性。本研究旨在评估重症患者肠道菌群组成与第 28 天死亡率之间的相关性。

方法：2019 年 10 月至 11 月期间入住重症监护室 (ICU) 的每例患者入院时的直肠拭子在 - 80 ℃下冷冻。借助 QIAamp (®) PowerFecal (®) Pro DNA 试剂盒 (QIAgen (®)) 进行 DNA 提取。PCR 扩增 16SRNA 和 ITS2 编码基因的 V3-V4 区。使用 MiSeq 测序仪 (Illumina (®)) 进行测序（2 x 250 bp 配对末端）。使用 R 软件上的 DADA2 pipeline 进行生物信息学分析。通过 logistic 回归研究第 28 天死亡率的风险因素。

结果：57 例患者连续进入 ICU，其中 13/57 (23%) 例死亡，44/57 (77%) 例存活。非存活者的细菌生物多样性 α 低于存活者（分别为 Shannon 和 Simpson 指数，p < 0.001 和 p = 0.001），真菌生物多样性 α 也是如此（分别为 p = 0.03 和 p = 0.03）。在多变量分析中，肠道菌生物门和菌生物门 Shannon 指数均与第 28 天死亡率独立相关（分别为 OR：0.19，97.5 CI [0.04-0.60]，p < 0.01 和 OR：0.29，97.5 CI [0.09-0.75]，p = 0.02）。存活者和非存活者之间的细菌生物多样性 β- 多样性存在显著差异 (p = 0.05)，但不存在细菌生物多样性 β- 多样性 (p = 0.57)。非存活者的溶血葡萄球菌、梭状芽孢杆菌的丰度更高。、解脲弯曲杆菌、Akkermansia sp. 共生马拉色菌、皮炎马拉色菌和酿酒酵母，而存活者的产气 Collinsella aerofaciens,Blautia sp. 丰度较高。链球菌。Faecalibacterium prausnitzii 和 Bifidobacterium sp.

结论：危重患者肠道细菌生物型和霉菌生物型 α 多样性与 Day-28 死亡率独立相关。这种干扰的因果性质，如果是，应进一步研究潜在机制，以评估肠道菌群调节是否可作为未来的治疗方法。

DOI: 10.1186/s13054-022-03980-8; No. 105

关键词：Humans; Survivors; *Gastrointestinal Microbiome; *Intensive care unit; *Microbiota; *Critical Illness; *Mycobiota; DNA

# ICU bereaved surrogates' comorbid psychological-distress states and their associations with prolonged grief disorder

Abstract

BACKGROUND/OBJECTIVE: Bereaved ICU family surrogates' psychological distress, e.g., anxiety, depression, and post-traumatic stress disorder (PTSD), is usually examined independently, despite the well-recognized comorbidity of these symptoms. Furthermore, the few studies exploring impact of psychological distress on development of prolonged grief disorder (PGD) did not consider the dynamic impact of symptom evolution. We identified surrogates' distinct patterns/states of comorbid psychological distress and their evolution over the first 3 months of bereavement and evaluated their associations with PGD at 6-month postloss.

METHODS: A longitudinal observational study was conducted on 319 bereaved surrogates. Symptoms of anxiety, depression, PTSD, and PGD were measured by the anxiety and depression subscales of the Hospital Anxiety and Depression Scale, Impact of Event Scale-Revised scale, and the PGD-13, respectively. Distinct psychological-distress states and their evolution were examined by latent transition analysis. Association between psychological-distress states and PGD symptoms was examined by logistic regression.

RESULTS: Three distinct comorbid psychological-distress states (prevalence) were initially identified: no distress (56.3%), severe-depressive/borderline-anxiety distress (30.5%), and severe-anxiety/depressive/PTSD distress (13.3%). Except for those in the stable no-distress state, surrogates tended to regress to states of less psychological distress at the subsequent assessment. The proportion of participants in each psychological-distress state changed to no distress (76.8%), severe-depressive/borderline-anxiety distress (18.6%), and severe-anxiety/depressive/PTSD distress (4.6%) at 3-month postloss. Surrogates in the severe-depressive/borderline-anxiety distress and severe-anxiety/depressive/PTSD-distress state at 3-month postloss were more likely to develop PGD at 6-month postloss (OR [95%] = 14.58 [1.48, 143.54] and 104.50 [10.45, 1044.66], respectively).

CONCLUSIONS: A minority of family surrogates of ICU decedents suffered comorbid severe-depressive/borderline-anxiety distress and severe-anxiety/depressive/PTSD symptoms during early bereavement, but they were more likely to progress into PGD at 6-month postloss.

DOI: 10.1186/s13054-022-03981-7; No. 102

关键词：Humans; Intensive Care Units; Comorbidity; *Anxiety; *Bereavement; *Psychological Distress; Depression/psychology; *End-of-life care; *Depression; *ICU care; *Post-traumatic stress disorder; *Prolonged grief disorder; *Psychological distress; *Stress Disorders, Post-Traumatic/complications/epidemiology/psychology; Grief; Prolonged Grief Disorder

DOI: 10.1186/s13054-022-03979-1; No. 104

关键词：Humans; Infusions, Intravenous; Postoperative Period; Inflammation; *Pharmacokinetics; *Albumin; *C-reactive protein; *Half-life; *Plasma Volume; *Serum Albumin/metabolism/therapeutic use

DOI: 10.1186/s13054-022-03968-4; No. 103

关键词：Humans; Retrospective Studies; Fluid Therapy; Hospital Mortality; *Sepsis; *Mortality; *Shock, Septic; *Septic shock; *Fluid balance; *Fluid resuscitation; *Hematocrit; *Vascular leak

DOI: 10.1186/s13054-022-03954-w; No. 95

关键词：Humans; Prognosis; Critical Care; Retrospective Studies; Algorithms; *Outcome; *Hypothermia, Induced; *Cardiac arrest; *Guideline algorithm; *Heart Arrest/complications/diagnosis/therapy; *Out-of-Hospital Cardiac Arrest/diagnosis/therapy; *Prognostic accuracy

# Auxora vs placebo for the treatment of patients with severe COVID-19 pneumonia: a randomized-controlled clinical trial.

Abstract

BACKGROUND: Calcium release-activated calcium (CRAC) channel inhibitors block proinflammatory cytokine release, preserve endothelial integrity and may effectively treat patients with severe COVID-19 pneumonia.

METHODS: CARDEA was a phase 2, randomized, double-blind, placebo-controlled trial evaluating the addition of Auxora, a CRAC channel inhibitor, to corticosteroids and standard of care in adults with severe COVID-19 pneumonia. Eligible patients were adults with ≥ 1 symptom consistent with COVID-19 infection, a diagnosis of COVID-19 confirmed by laboratory testing using polymerase chain reaction or other assay, and pneumonia documented by chest imaging. Patients were also required to be receiving oxygen therapy using either a high flow or low flow nasal cannula at the time of enrolment and have at the time of enrollment a baseline imputed PaO(2)/FiO(2) ratio > 75 and ≤ 300. The PaO(2)/FiO(2) was imputed from a SpO(2)/FiO(2) determine by pulse oximetry using a non-linear equation. Patients could not be receiving either non-invasive or invasive mechanical ventilation at the time of enrolment. The primary endpoint was time to recovery through Day 60, with secondary endpoints of all-cause mortality at Day 60 and Day 30. Due to declining rates of COVID-19 hospitalizations and utilization of standard of care medications prohibited by regulatory guidance, the trial was stopped early.

RESULTS: The pre-specified efficacy set consisted of the 261 patients with a baseline imputed PaO(2)/FiO(2)≤ 200 with 130 and 131 in the Auxora and placebo groups, respectively. Time to recovery was 7 vs. 10 days (P = 0.0979) for patients who received Auxora vs. placebo, respectively. The all-cause mortality rate at Day 60 was 13.8% with Auxora vs. 20.6% with placebo (P = 0.1449); Day 30 all-cause mortality was 7.7% and 17.6%, respectively (P = 0.0165). Similar trends were noted in all randomized patients, patients on high flow nasal cannula at baseline or those with a baseline imputed PaO(2)/FiO(2) ≤ 100. Serious adverse events (SAEs) were less frequent in patients treated with Auxora vs. placebo and occurred in 34 patients (24.1%) receiving Auxora and 49 (35.0%) receiving placebo (P = 0.0616). The most common SAEs were respiratory failure, acute respiratory distress syndrome, and pneumonia.

CONCLUSIONS: Auxora was safe and well tolerated with strong signals in both time to recovery and all-cause mortality through Day 60 in patients with severe COVID-19 pneumonia. Further studies of Auxora in patients with severe COVID-19 pneumonia are warranted.

# Auxora 对比安慰剂治疗重度 COVID-19 肺炎患者：一项随机对照临床试验。

摘要

背景：钙释放激活钙 (CRAC) 通道抑制剂阻滞促炎性细胞因子释放，保留内皮完整性，可有效治疗重症 COVID-19 肺炎患者。

方法：CARDEA 是一项 2 期、随机、双盲、安慰剂对照试验，在重度 COVID-19 肺炎成人患者中评价在皮质类固醇和标准治疗中添加 CRAC 通道抑制剂 Auxora。符合条件的患者是具有≥1 种符合 COVID-19 感染的症状、经聚合酶链反应实验室检查或其他试验证实诊断为 COVID-19 和胸部影像学证实的肺炎的成人患者。在入组时还要求患者使用高流量或低流量鼻插管接受氧疗，并且在入组时基线插补 PaO (2)/FiO (2) 比值 > 75 且≤300。PaO (2)/FiO (2) 通过脉搏血氧仪使用非线性方程测定的 SpO (2)/FiO (2) 进行插补。入组时，患者不能接受无创或有创机械通气。主要终点为至恢复时间至第 60 天，次要终点为第 60 天和第 30 天的全因死亡率。由于 COVID-19 住院率下降和使用监管指南禁止的标准治疗药物，试验提前终止。

结果：预先规定的疗效集包括 261 名基线插补 PaO (2)/FiO (2)≤200 的患者，Auxora 和安慰剂组分别为 130 和 131 名。接受 Auxora 和安慰剂的患者至痊愈的时间分别为 7 天和 10 天 (P = 0.0979)。Auxora 组和安慰剂组第 60 天的全因死亡率分别为 13.8% 和 20.6%(P = 0.1449)；第 30 天的全因死亡率分别为 7.7% 和 17.6%(P = 0.0165)。在所有随机化患者、基线时接受高流量鼻插管或基线插补 PaO (2)/FiO (2)≤100 的患者中观察到相似的趋势。Auxora 治疗患者的严重不良事件 (SAE) 发生率低于安慰剂治疗患者，Auxora 治疗组有 34 例患者 (24.1%) 发生 SAE，安慰剂组有 49 例患者 (35.0%) 发生 SAE (P = 0.0616)。最常见的 SAE 是呼吸衰竭、急性呼吸窘迫综合征和肺炎。

结论：在重度 COVID-19 肺炎患者中，Auxora 是安全的，耐受性良好，至恢复时间和至第 60 天的全因死亡率均有很强的信号。有必要在重度 COVID-19 肺炎患者中进行 Auxora 的进一步研究。

DOI: 10.1186/s13054-022-03964-8; No. 101

关键词：Humans; Treatment Outcome; Adult; Respiration, Artificial; SARS-CoV-2; *COVID-19/drug therapy; *Respiratory Distress Syndrome; *Benzamides/therapeutic use; *Calcium Release Activated Calcium Channels/antagonists & inhibitors; *Pyrazines/therapeutic use

# EXpert consensus On Diaphragm UltraSonography in the critically ill (EXODUS): a Delphi consensus statement on the measurement of diaphragm ultrasound-derived parameters in a critical care setting

Abstract

BACKGROUND: Diaphragm ultrasonography is rapidly evolving in both critical care and research. Nevertheless, methodologically robust guidelines on its methodology and acquiring expertise do not, or only partially, exist. Therefore, we set out to provide consensus-based statements towards a universal measurement protocol for diaphragm ultrasonography and establish key areas for research.

METHODS: To formulate a robust expert consensus statement, between November 2020 and May 2021, a two-round, anonymous and online survey-based Delphi study among experts in the field was performed. Based on the literature review, the following domains were chosen: "Anatomy and physiology", "Transducer Settings", "Ventilator Impact", "Learning and expertise", "Daily practice" and "Future directions". Agreement of ≥ 68% (≥ 10 panelists) was needed to reach consensus on a question.

RESULTS: Of 18 panelists invited, 14 agreed to participate in the survey. After two rounds, the survey included 117 questions of which 42 questions were designed to collect arguments and opinions and 75 questions aimed at reaching consensus. Of these, 46 (61%) consensus was reached. In both rounds, the response rate was 100%. Among others, there was agreement on measuring thickness between the pleura and peritoneum, using > 10% decrease in thickness as cut-off for atrophy and using 40 examinations as minimum training to use diaphragm ultrasonography in clinical practice. In addition, key areas for research were established.

CONCLUSION: This expert consensus statement presents the first set of consensus-based statements on diaphragm ultrasonography methodology. They serve to ensure high-quality and homogenous measurements in daily clinical practice and in research. In addition, important gaps in current knowledge and thereby key areas for research are established.

DOI: 10.1186/s13054-022-03975-5; No. 99

关键词：Humans; Critical Care; Ultrasonography; *Critical Illness/therapy; *Consensus; *Delphi; *Diaphragm; *Diaphragm/diagnostic imaging; *Ultrasound; Delphi Technique

DOI: 10.1186/s13054-022-03953-x; No. 100

关键词：Humans; Biomarkers/metabolism; *Sepsis/diagnosis; *Lithostathine

# Association between timing of speech and language therapy initiation and outcomes among post-extubation dysphagia patients: a multicenter retrospective cohort study

Abstract

BACKGROUND: Post-extubation dysphagia (PED) is recognized as a common complication in the intensive care unit (ICU). Speech and language therapy (SLT) can potentially help improve PED; however, the impact of the timing of SLT initiation on persistent PED has not been well investigated. This study aimed to examine the timing of SLT initiation and its effect on patient outcomes after extubation in the ICU.

METHODS: We conducted this multicenter, retrospective, cohort study, collecting data from eight ICUs in Japan. Patients aged ≥ 20 years with orotracheal intubation and mechanical ventilation for longer than 48 h, and those who received SLT due to PED, defined as patients with modified water swallowing test scores of 3 or lower, were included. The primary outcome was dysphagia at hospital discharge, defined as functional oral intake scale score < 5 or death after extubation. Secondary outcomes included dysphagia or death at the seventh, 14th, or 28th day after extubation, aspiration pneumonia, and in-hospital mortality. Associations between the timing of SLT initiation and outcomes were determined using multivariable logistic regression.

RESULTS: A total of 272 patients were included. Of them, 82 (30.1%) patients exhibited dysphagia or death at hospital discharge, and their time spans from extubation to SLT initiation were 1.0 days. The primary outcome revealed that every day of delay in SLT initiation post-extubation was associated with dysphagia or death at hospital discharge (adjusted odds ratio (AOR), 1.09; 95% CI, 1.02-1.18). Similarly, secondary outcomes showed associations between this per day delay in SLT initiation and dysphagia or death at the seventh day (AOR, 1.28; 95% CI, 1.05-1.55), 14th day (AOR, 1.34; 95% CI, 1.13-1.58), or 28th day (AOR, 1.21; 95% CI, 1.07-1.36) after extubation and occurrence of aspiration pneumonia (AOR, 1.09; 95% CI, 1.02-1.17), while per day delay in post-extubation SLT initiation did not affect in-hospital mortality (AOR, 1.04; 95% CI, 0.97-1.12).

CONCLUSIONS: Delayed initiation of SLT in PED patients was associated with persistent dysphagia or death. Early initiation of SLT may prevent this complication post-extubation. A randomized controlled study is needed to validate these results.

DOI: 10.1186/s13054-022-03974-6; No. 98

关键词：Humans; Intensive Care Units; Cohort Studies; Retrospective Studies; *Intensive care; Airway Extubation/adverse effects; *Aspiration pneumonia; *Deglutition Disorders/epidemiology/etiology/therapy; *Dysphagia; *Pneumonia, Aspiration/complications; *Post-extubation dysphagia; *Speech and language therapy; Language Therapy; Speech

# Amniotic fluid embolism rescued by venoarterial extracorporeal membrane oxygenation

Abstract

BACKGROUND: Amniotic fluid embolism (AFE) is a rare but often catastrophic complication of pregnancy that leads to cardiopulmonary dysfunction and severe disseminated intravascular coagulopathy (DIC). Although few case reports have reported successful use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) with AFE, concerns can be raised about the increased bleeding risks with that device.

METHODS: This study included patients with AFE rescued by VA-ECMO hospitalized in two high ECMO volume centers between August 2008 and February 2021. Clinical characteristics, critical care management, in-intensive care unit (ICU) complications, and hospital outcomes were collected. ICU survivors were assessed for health-related quality of life (HRQL) in May 2021.

RESULTS: During that 13-year study period, VA-ECMO was initiated in 54 parturient women in two high ECMO volume centers. Among that population, 10 patients with AFE [median (range) age 33 (24-40), SAPS II at 69 (56-81)] who fulfilled our diagnosis criteria were treated with VA-ECMO. Pregnancy evolved for 36 (30-41) weeks. Seven patients had a cardiac arrest before ECMO and two were cannulated under cardiopulmonary resuscitation. Pre-ECMO hemodynamic was severely impaired with an inotrope score at 370 (55-1530) μg/kg/min, a severe left ventricular ejection fraction measured at 14 (0-40)%, and lactate at 12 (2-30) mmol/L. 70% of these patients were alive at hospital discharge despite an extreme pre-ECMO severity and massive blood product transfusion. However, HRQL was lower than age-matched controls and still profoundly impaired in the role-physical, bodily pain, and general health components after a median of 44 months follow-up.

CONCLUSION: In this rare per-delivery complication, our results support the use of VA-ECMO despite intense DIC and ongoing bleeding. Future studies should focus on customized, patient-centered, rehabilitation programs that could lead to improved HRQL in this population.

DOI: 10.1186/s13054-022-03969-3; No. 96

关键词：Humans; Female; Adult; Retrospective Studies; Child, Preschool; Pregnancy; Quality of Life; Stroke Volume; *Extracorporeal Membrane Oxygenation/methods; Ventricular Function, Left; *Extracorporeal membrane oxygenation; Shock, Cardiogenic/therapy; *Outcomes; *Amniotic fluid embolism; *Cardiogenic shock; *Disseminated intravascular coagulopathy; *Embolism, Amniotic Fluid/therapy; Dacarbazine

DOI: 10.1186/s13054-022-03959-5; No. 97

关键词：Humans; Middle Aged; Adult; Cohort Studies; Retrospective Studies; Hospital Mortality; *COVID-19; Poland/epidemiology; *Respiratory Distress Syndrome/therapy; *Extracorporeal Membrane Oxygenation; *Mortality; *Intensive care; *ECMO; *COVID-19/complications/therapy; Lactic Acid; *Outcomes

DOI: 10.1186/s13054-022-03958-6; No. 94

关键词：Humans; Prospective Studies; Aged; Intensive Care Units; Critical Care; Outcome Assessment, Health Care; *COVID-19; *Quality of Life; *Quality of life; Patient Discharge; Aftercare; *Autonomy

# The necessity of a loading dose when prescribing intravenous colistin in critically ill patients with CRGNB-associated pneumonia: a multi-center observational study

Abstract

BACKGROUND: The importance or necessity of a loading dose when prescribing intravenous colistin has not been well established in clinical practice, and approximate one-third to half of patients with carbapenem-resistant gram-negative bacteria (CRGNB) infection did not receive the administration of a loading dose. The aim of this study is to investigate the efficacy and risk of acute kidney injury when prescribing intravenous colistin for critically ill patients with nosocomial pneumonia caused by CRGNB.

METHODS: This was a multicenter, retrospective study that recruited ICU-admitted patients who had CRGNB-associated nosocomial pneumonia and were treated with intravenous colistin. Then, we classified the patients into colistin loading dose (N = 85) and nonloading dose groups (N = 127). After propensity-score matching for important covariates, we compared the mortality rate, clinical outcome and microbiological eradication rates between the groups (N = 67).

RESULTS: The loading group had higher percentages of patients with favorable clinical outcomes (55.2% and 35.8%, p = 0.037) and microbiological eradication rates (50% and 27.3%, p = 0.042) at day 14 than the nonloading group. The mortality rates at days 7, 14 and 28 and overall in-hospital mortality were not different between the two groups, but the Kaplan-Meier analysis showed that the loading group had a longer survival time than the nonloading group. Furthermore, the loading group had a shorter length of hospital stay than the nonloading group (52 and 60, p = 0.037). Regarding nephrotoxicity, there was no significant difference in the risk of developing acute kidney injury between the groups.

CONCLUSIONS: The administration of a loading dose is recommended when prescribing intravenous colistin for critically ill patients with nosocomial pneumonia caused by CRGNB.

DOI: 10.1186/s13054-022-03947-9; No. 91

关键词：Humans; Gram-Negative Bacteria; Retrospective Studies; Critical Illness/therapy; Anti-Bacterial Agents/therapeutic use; *Carbapenem resistant; *Colistin; *Colistin/adverse effects; *Loading dose; *Nephrotoxicity; *Nosocomial pneumonia; *Pneumonia, Bacterial/drug therapy; Carbapenems/therapeutic use

# Continuous renal replacement therapy versus intermittent hemodialysis as first modality for renal replacement therapy in severe acute kidney injury: a secondary analysis of AKIKI and IDEAL-ICU studies

Abstract

BACKGROUND: Intermittent hemodialysis (IHD) and continuous renal replacement therapy (CRRT) are the two main RRT modalities in patients with severe acute kidney injury (AKI). Meta-analyses conducted more than 10 years ago did not show survival difference between these two modalities. As the quality of RRT delivery has improved since then, we aimed to reassess whether the choice of IHD or CRRT as first modality affects survival of patients with severe AKI.

METHODS: This is a secondary analysis of two multicenter randomized controlled trials (AKIKI and IDEAL-ICU) that compared an early RRT initiation strategy with a delayed one. We included patients allocated to the early strategy in order to emulate a trial where patients would have been randomized to receive either IHD or CRRT within twelve hours after the documentation of severe AKI. We determined each patient's modality group as the first RRT modality they received. The primary outcome was 60-day overall survival. We used two propensity score methods to balance the differences in baseline characteristics between groups and the primary analysis relied on inverse probability of treatment weighting.

RESULTS: A total of 543 patients were included. Continuous RRT was the first modality in 269 patients and IHD in 274. Patients receiving CRRT had higher cardiovascular and total-SOFA scores. Inverse probability weighting allowed to adequately balance groups on all predefined confounders. The weighted Kaplan-Meier death rate at day 60 was 54·4% in the CRRT group and 46·5% in the IHD group (weighted HR 1·26, 95% CI 1·01-1·60). In a complementary analysis of less severely ill patients (SOFA score: 3-10), receiving IHD was associated with better day 60 survival compared to CRRT (weighted HR 1.82, 95% CI 1·01-3·28; p < 0.01). We found no evidence of a survival difference between the two RRT modalities in more severe patients.

CONCLUSION: Compared to IHD, CRRT as first modality seemed to convey no benefit in terms of survival or of kidney recovery and might even have been associated with less favorable outcome in patients with lesser severity of disease. A prospective randomized non-inferiority trial should be implemented to solve the persistent conundrum of the optimal RRT technique.

DOI: 10.1186/s13054-022-03955-9; No. 93

关键词：Humans; Prospective Studies; Intensive Care Units; *Critical care; *Acute Kidney Injury/therapy; *Continuous Renal Replacement Therapy; *Acute kidney injury; *Renal replacement therapy; Renal Dialysis/methods; Renal Replacement Therapy/methods

# Predictors of response to intra-arterial vasodilatory therapy of non-occlusive mesenteric ischemia in patients with severe shock: results from a prospective observational study

Abstract

BACKGROUND: Non-occlusive mesenteric ischemia (NOMI) is a life-threatening condition occurring in patients with shock and is characterized by vasoconstriction of the mesenteric arteries leading to intestinal ischemia and multi-organ failure. Although minimal invasive local intra-arterial infusion of vasodilators into the mesenteric circulation has been suggested as a therapeutic option in NOMI, current knowledge is based on retrospective case series and it remains unclear which patients might benefit. Here, we prospectively analyzed predictors of response to intra-arterial therapy in patients with NOMI.

METHODS: This is a prospective single-center observational study to analyze improvement of ischemia (indicated by reduction of blood lactate > 2 mmol/l from baseline after 24 h, primary endpoint) and 28-day mortality (key secondary endpoint) in patients with NOMI undergoing intra-arterial vasodilatory therapy. Predictors of response to therapy concerning primary and key secondary endpoint were identified using a) clinical parameters as well as b) data from 2D-perfusion angiography and c) experimental biomarkers of intestinal injury.

RESULTS: A total of 42 patients were included into this study. At inclusion patients had severe shock, indicated by high doses of norepinephrine (NE) (median (interquartile range (IQR)) 0.37 (0.21-0.60) μg/kg/min), elevated lactate concentrations (9.2 (5.2-13) mmol/l) and multi-organ failure. Patients showed a continuous reduction of lactate following intra-arterial prostaglandin infusion (baseline: (9.2 (5.2-13) mmol/l vs. 24 h: 4.4 (2.5-9.1) mmol/l, p < 0.001) with 22 patients (52.4%) reaching a lactate reduction > 2 mmol/l at 24 h following intervention. Initial higher lactate concentrations and lower NE doses at baseline were independent predictors of an improvement of ischemia. 28-day mortality was 59% in patients with a reduction of lactate > 2 mmol/l 24 h after inclusion, while it was 85% in all other patients (hazard ratio 0.409; 95% CI, 0.14-0.631, p = 0.005).

CONCLUSIONS: A reduction of lactate concentrations was observed following implementation of intra-arterial therapy, and lactate reduction was associated with better survival. Our findings concerning outcome predictors in NOMI patients undergoing intra-arterial prostaglandin therapy might help designing a randomized controlled trial to further investigate this therapeutic approach.

# 重度休克患者对非闭塞性肠系膜缺血的动脉内血管扩张治疗反应的预测因素：一项前瞻性观察性研究的结果

摘要

背景：非闭塞性肠系膜缺血 (NOMI) 是发生在休克患者中的一种危及生命的疾病，其特征是肠系膜动脉血管收缩，导致肠缺血和多器官衰竭。尽管已表明微创局部动脉内输注血管扩张剂至肠系膜循环是 NOMI 的一种治疗选择，但目前的知识是基于回顾性病例系列研究，仍不清楚哪些患者可能获益。在此，我们前瞻性分析了 NOMI 患者动脉内治疗反应的预测因素。

方法：这是一项前瞻性单中心观察性研究，旨在分析接受动脉内血管扩张治疗的 NOMI 患者的缺血改善（表现为 24h 后血乳酸较基线降低 > 2 mmol/L，主要终点）和 28 天死亡率（关键次要终点）。使用 a）临床参数以及 b）来自 2D 灌注血管造影术的数据和 c）肠损伤的实验生物标志物来识别主要和关键次要终点相关治疗应答的预测因子。

结果：本研究共纳入 42 例患者。入选时，患者出现重度休克，表现为高剂量去甲肾上腺素 (NE)（中位数（四分位距 (IQR)）0.37 (0.21-0.60)μg/kg/min）、乳酸盐浓度升高 (9.2 (5.2-13) mmol/l) 和多器官衰竭。动脉内前列腺素输注结束后，患者的乳酸盐水平持续下降（基线：9.2 (5.2-13) mmol/l vs. 24 h：4.4 (2.5-9.1) mmol/l，p<0.001），干预结束后 24h，22 名患者 (52.4%) 的乳酸盐水平下降幅度 > 2 mmol/L。基线时初始较高的乳酸盐浓度和较低的 NE 剂量是缺血改善的独立预测因素。入选后 24h 乳酸盐降低 > 2 mmol/L 的患者中 28 天死亡率为 59%，而所有其他患者中为 85%（风险比 0.409；95% CI，0.14-0.631，p = 0.005）。

结论：动脉内治疗后观察到乳酸盐浓度降低，乳酸盐降低与更好的生存率相关。我们关于接受动脉内前列腺素治疗的 NOMI 患者结局预测因子的结果可能有助于设计一项随机对照试验，以进一步研究这种治疗方法。

DOI: 10.1186/s13054-022-03962-w; No. 92

关键词：Humans; Prospective Studies; Retrospective Studies; Vasodilation; *Sepsis; *Intestinal failure; *Shock; *Mesenteric Ischemia/drug therapy; *Non-occlusive mesenteric ischemia; *Shock/drug therapy

DOI: 10.1186/s13054-022-03966-6; No. 89

关键词：Humans; Prognosis; Time Factors; Intensive Care Units; *COVID-19; Intubation, Intratracheal; *Mechanical ventilation; *Acute respiratory distress syndrome; *COVID 19; *High flow nasal oxygen therapy; *Steroid

# Dopamine use and its consequences in the intensive care unit: a cohort study utilizing the Japanese Intensive care PAtient Database

Abstract

BACKGROUND: Dopamine is used to treat patients with shock in intensive care units (ICU) throughout the world, despite recent evidence against its use. The aim of this study was to identify the latest practice of dopamine use in Japan and also to explore the consequences of dopamine use in a large Asian population.

METHODS: The Japanese Intensive Care PAtient Database (JIPAD), the largest intensive care database in Japan, was utilized. Inclusion criteria included: 1) age 18 years or older, 2) admitted to the ICU for reasons other than procedures, 3) ICU length of stay of 24 h or more, and 4) treatment with either dopamine or noradrenaline within 24 h of admission. The primary outcome was in-hospital mortality. Multivariable regression analysis was performed, followed by a propensity score-matched analysis.

RESULTS: Of the 132,354 case records, 14,594 records from 56 facilities were included in this analysis. Dopamine was administered to 4,653 patients and noradrenaline to 11,844. There was no statistically significant difference in facility characteristics between frequent dopamine users (N = 28) and infrequent users (N = 28). Patients receiving dopamine had more cardiovascular diagnosis codes (70% vs. 42%; p < 0.01), more post-elective surgery status (60% vs. 31%), and lower APACHE III scores compared to patients given noradrenaline alone (70.7 vs. 83.0; p < 0.01). Multivariable analysis showed an odds ratio for in-hospital mortality of 0.86 [95% CI: 0.71-1.04] in the dopamine ≤ 5 μg/kg/min group, 1.46 [95% CI: 1.18-1.82] in the 5-15 μg/kg/min group, and 3.30 [95% CI: 1.19-9.19] in the > 15 μg/kg/min group. In a 1:1 propensity score matching for dopamine use as a vasopressor (570 pairs), both in-hospital mortality and ICU mortality were significantly higher in the dopamine group compared to no dopamine group (22.5% vs. 17.4%, p = 0.038; 13.3% vs. 8.8%, p = 0.018), as well as ICU length of stay (mean 9.3 days vs. 7.4 days, p = 0.004).

CONCLUSION: Dopamine is still widely used in Japan. The results of this study suggest detrimental effects of dopamine use specifically at a high dose.

DOI: 10.1186/s13054-022-03960-y; No. 90

关键词：Humans; Cohort Studies; Critical Care; Adolescent; *Intensive Care Units; *Critical care; *Intensive care unit; Japan/epidemiology; *Cardiovascular; *Catecholamine; *Dopamine; *Dopamine/therapeutic use; *Low-dose dopamine

# Pain and sedation management and monitoring in pediatric intensive care units across Europe: an ESPNIC survey

Abstract

BACKGROUND: Management and monitoring of pain and sedation to reduce discomfort as well as side effects, such as over- and under-sedation, withdrawal syndrome and delirium, is an integral part of pediatric intensive care practice. However, the current state of management and monitoring of analgosedation across European pediatric intensive care units (PICUs) remains unknown. The aim of this survey was to describe current practices across European PICUs regarding the management and monitoring of pain and sedation.

METHODS: An online survey was distributed among 357 European PICUs assessing demographic features, drug choices and dosing, as well as usage of instruments for monitoring pain and sedation. We also compared low- and high-volume PICUs practices. Responses were collected from January to April 2021.

RESULTS: A total of 215 (60% response rate) PICUs from 27 European countries responded. Seventy-one percent of PICUs stated to use protocols for analgosedation management, more frequently in high-volume PICUs (77% vs 63%, p = 0.028). First-choice drug combination was an opioid with a benzodiazepine, namely fentanyl (51%) and midazolam (71%) being the preferred drugs. The starting doses differed between PICUs from 0.1 to 5 mcg/kg/h for fentanyl, and 0.01 to 0.5 mg/kg/h for midazolam. Daily assessment and documentation for pain (81%) and sedation (87%) was reported by most of the PICUs, using the preferred validated FLACC scale (54%) and the COMFORT Behavioural scale (48%), respectively. Both analgesia and sedation were mainly monitored by nurses (92% and 84%, respectively). Eighty-six percent of the responding PICUs stated to use neuromuscular blocking agents in some scenarios. Monitoring of paralysed patients was preferably done by observation of vital signs with electronic devices support.

CONCLUSIONS: This survey provides an overview of current analgosedation practices among European PICUs. Drugs of choice, dosing and assessment strategies were shown to differ widely. Further research and development of evidence-based guidelines for optimal drug dosing and analgosedation assessment are needed.

DOI: 10.1186/s13054-022-03957-7; No. 88

关键词：Humans; Child; Europe; *Critical care; Surveys and Questionnaires; Pain; *Intensive Care Units, Pediatric; *Monitoring; *Analgesia; *Analgesia/methods; *Pediatric intensive care unit; *Sedation

DOI: 10.1186/s13054-022-03965-7; No. 87

关键词：Humans; *Sepsis; *Shock, Septic/drug therapy; *Nutrition Therapy; Ascorbic Acid/pharmacology/therapeutic use

DOI: 10.1186/s13054-022-03961-x; No. 85

关键词：Humans; *Intensive Care Units; *Ventilators, Mechanical

DOI: 10.1186/s13054-022-03963-9; No. 86

关键词：Humans; *Extracorporeal Membrane Oxygenation; Hematologic Tests; Hemoglobins/therapeutic use; Magnetic Phenomena

# Effects of different positive end-expiratory pressure titration strategies during prone positioning in patients with acute respiratory distress syndrome: a prospective interventional study

Abstract

BACKGROUND: Prone positioning in combination with the application of low tidal volume and adequate positive end-expiratory pressure (PEEP) improves survival in patients with moderate to severe acute respiratory distress syndrome (ARDS). However, the effects of PEEP on end-expiratory transpulmonary pressure (Ptp(exp)) during prone positioning require clarification. For this purpose, the effects of three different PEEP titration strategies on Ptp(exp), respiratory mechanics, mechanical power, gas exchange, and hemodynamics were evaluated comparing supine and prone positioning.

METHODS: In forty consecutive patients with moderate to severe ARDS protective ventilation with PEEP titrated according to three different titration strategies was evaluated during supine and prone positioning: (A) ARDS Network recommendations (PEEP(ARDSNetwork)), (B) the lowest static elastance of the respiratory system (PEEP(Estat,RS)), and (C) targeting a positive Ptp(exp) (PEEP(Ptpexp)). The primary endpoint was to analyze whether Ptp(exp) differed significantly according to PEEP titration strategy during supine and prone positioning.

RESULTS: Ptp(exp) increased progressively with prone positioning compared with supine positioning as well as with PEEP(Estat,RS) and PEEP(Ptpexp) compared with PEEP(ARDSNetwork) (positioning effect p < 0.001, PEEP strategy effect p < 0.001). PEEP was lower during prone positioning with PEEP(Estat,RS) and PEEP(Ptpexp) (positioning effect p < 0.001, PEEP strategy effect p < 0.001). During supine positioning, mechanical power increased progressively with PEEP(Estat,RS) and PEEP(Ptpexp) compared with PEEP(ARDSNetwork), and prone positioning attenuated this effect (positioning effect p < 0.001, PEEP strategy effect p < 0.001). Prone compared with supine positioning significantly improved oxygenation (positioning effect p < 0.001, PEEP strategy effect p < 0.001) while hemodynamics remained stable in both positions.

CONCLUSIONS: Prone positioning increased transpulmonary pressures while improving oxygenation and hemodynamics in patients with moderate to severe ARDS when PEEP was titrated according to the ARDS Network lower PEEP table. This PEEP titration strategy minimized parameters associated with ventilator-induced lung injury induction, such as transpulmonary driving pressure and mechanical power. We propose that a lower PEEP strategy (PEEP(ARDSNetwork)) in combination with prone positioning may be part of a lung protective ventilation strategy in patients with moderate to severe ARDS.

# 急性呼吸窘迫综合征患者俯卧位时不同呼气末正压滴定策略的前瞻性干预研究

摘要

背景：俯卧位联合应用低潮气量和足够的呼气末正压通气 (PEEP) 改善了中重度急性呼吸窘迫综合征 (ARDS) 患者的生存率。然而，需要澄清俯卧位时 PEEP 对呼气末跨肺压 (Ptp (exp)) 的影响。为此，通过比较仰卧位和俯卧位，评估了三种不同 PEEP 滴定策略对 Ptp (exp)、呼吸力学、机械功率、气体交换和血流动力学的影响。

方法：在连续 40 例中度至重度 ARDS 患者中，在仰卧位和俯卧位时，评估根据三种不同滴定策略滴定 PEEP 的保护性通气：(A) ARDS 网络推荐 (PEEP (ARDSNetwork))，(B) 呼吸系统的最低静态弹性 (PEEP (Estat，RS))，和 (C) 靶向阳性 Ptp (exp)(PEEP (Ptpexp))。主要终点是分析仰卧位和俯卧位时，根据 PEEP 滴定策略，Ptp (exp) 是否有显著差异。

结果：采用俯卧位时 Ptp (exp) 较仰卧位时逐渐增加，采用 PEEP (Estat，RS) 和 PEEP (Ptpexp) 时较 PEEP (ARDSNetwork) 时也逐渐增加（定位效应 p < 0.001，PEEP 策略效应 p < 0.001）。采用 PEEP (Estat，RS) 和 PEEP (Ptpexp) 时，俯卧位时 PEEP 较低（定位效应 p < 0.001，PEEP 策略效应 p < 0.001）。仰卧位时，与 PEEP (ARDSNetwork) 相比，PEEP (Estat，RS) 和 PEEP (Ptpexp) 的机械功率逐渐增加，俯卧位减弱了这种效应（定位效应 p < 0.001，PEEP 策略效应 p < 0.001）。与仰卧位相比，仰卧位显著改善了氧合（定位效应 p < 0.001，PEEP 策略效应 p < 0.001），而两种体位的血液动力学均保持稳定。

结论：根据 ARDS 网络下限 PEEP 表进行 PEEP 滴定时，俯卧位增加中至重度 ARDS 患者的跨肺压，同时改善氧合和血流动力学。这种 PEEP 滴定策略可最大限度地减少与呼吸机诱导的肺损伤诱导相关的参数，如跨肺驱动压力和机械功率。我们提出，较低的 PEEP 策略 (PEEP (ARDSNetwork)) 结合俯卧位可能是中重度 ARDS 患者肺保护通气策略的一部分。

DOI: 10.1186/s13054-022-03956-8; No. 82

关键词：Humans; Prospective Studies; Tidal Volume; Prone Position; *Respiratory Distress Syndrome/therapy; *Positive-Pressure Respiration; *Prone position; *Positive end-expiratory pressure; *Acute respiratory distress syndrome; *Respiratory mechanics; *Ventilator-induced lung injury; *Lung protective ventilation; *Transpulmonary pressure

DOI: 10.1186/s13054-022-03950-0; No. 84

关键词：Humans; *COVID-19; Prone Position; Cannula; *COVID-19/complications/therapy; *Awake prone positioning; *Intubation; Wakefulness; *Acute hypoxemic respiratory failure; *Respiratory Insufficiency/complications/therapy

DOI: 10.1186/s13054-022-03945-x; No. 83

关键词：Humans; Male; *COVID-19; SARS-CoV-2; *Respiratory Distress Syndrome/therapy; *ECMO; *Extracorporeal Membrane Oxygenation/adverse effects; *Respiratory Insufficiency/etiology/therapy; *COVID-19/complications/therapy; *Autopsy; *Bleeding events; *Intracranial bleeding; *Registry; Intracranial Hemorrhages/complications/epidemiology

DOI: 10.1186/s13054-022-03915-3; No. 75

关键词：Humans; Critical Care; *Artificial Intelligence; *Emergency Medicine

DOI: 10.1186/s13054-022-03916-2; No. 79

关键词：Humans; Intensive Care Units; Critical Care; *Artificial Intelligence; *Emergency Medicine

DOI: 10.1186/s13054-022-03913-5; No. 81

关键词：Humans; Critical Care; Biomarkers; *Brain Injuries; *Heart Arrest; *Emergency Medicine

DOI: 10.1186/s13054-022-03917-1; No. 77

关键词：Humans; Critical Care; *Sepsis/therapy; *Emergency Medicine

DOI: 10.1186/s13054-022-03914-4; No. 78

关键词：Humans; *Critical Care; *Emergency Medicine

DOI: 10.1186/s13054-022-03909-1; No. 74

关键词：Humans; Critical Care; *Critical Illness/therapy; Immunomodulation; *Emergency Medicine; Tetracyclines

DOI: 10.1186/s13054-022-03912-6; No. 73

关键词：Humans; *Critical Care; *Emergency Medicine

DOI: 10.1186/s13054-022-03910-8; No. 62

关键词：Humans; Critical Care; *Continuous Renal Replacement Therapy; *Emergency Medicine

DOI: 10.1186/s13054-022-03911-7; No. 76

关键词：Humans; Critical Care; Vasoconstrictor Agents/pharmacology/therapeutic use; *Shock/drug therapy; *Hypotension

DOI: 10.1186/s13054-022-03908-2; No. 80

关键词：Humans; Critical Care; Immunity; *Critical Illness; Mitochondria; *Emergency Medicine

Abstract

BACKGROUND: Delaying time to prone positioning (PP) may be associated with higher mortality in acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19). We evaluated the use and the impact of early PP on clinical outcomes in intubated patients hospitalized in intensive care units (ICUs) for COVID-19.

METHODS: All intubated patients with ARDS due to COVID-19 were involved in a secondary analysis from a prospective multicenter cohort study of COVID-ICU network including 149 ICUs across France, Belgium and Switzerland. Patients were followed-up until Day-90. The primary outcome was survival at Day-60. Analysis used a Cox proportional hazard model including a propensity score.

RESULTS: Among 2137 intubated patients, 1504 (70.4%) were placed in PP during their ICU stay and 491 (23%) during the first 24 h following ICU admission. One hundred and eighty-one patients (36.9%) of the early PP group had a PaO(2)/FiO(2) ratio > 150 mmHg when prone positioning was initiated. Among non-early PP group patients, 1013 (47.4%) patients had finally been placed in PP within a median delay of 3 days after ICU admission. Day-60 mortality in non-early PP group was 34.2% versus 39.3% in the early PP group (p = 0.038). Day-28 and Day-90 mortality as well as the need for adjunctive therapies was more important in patients with early PP. After propensity score adjustment, no significant difference in survival at Day-60 was found between the two study groups (HR 1.34 [0.96-1.68], p = 0.09 and HR 1.19 [0.998-1.412], p = 0.053 in complete case analysis or in multiple imputation analysis, respectively).

CONCLUSIONS: In a large multicentric international cohort of intubated ICU patients with ARDS due to COVID-19, PP has been used frequently as a main treatment. In this study, our data failed to show a survival benefit associated with early PP started within 24 h after ICU admission compared to PP after day-1 for all COVID-19 patients requiring invasive mechanical ventilation regardless of their severity.

DOI: 10.1186/s13054-022-03949-7; No. 71

关键词：Humans; Prospective Studies; Intensive Care Units; Cohort Studies; Propensity Score; *COVID-19; *Intensive care unit; Prone Position; *COVID-19/therapy; *Respiratory Distress Syndrome/therapy; *Mortality; *Prone position; *Acute respiratory distress syndrome; *Intubation

# Nasal pressure swings as the measure of inspiratory effort in spontaneously breathing patients with de novo acute respiratory failure

Abstract

BACKGROUND: Excessive inspiratory effort could translate into self-inflicted lung injury, thus worsening clinical outcomes of spontaneously breathing patients with acute respiratory failure (ARF). Although esophageal manometry is a reliable method to estimate the magnitude of inspiratory effort, procedural issues significantly limit its use in daily clinical practice. The aim of this study is to describe the correlation between esophageal pressure swings (ΔP(es)) and nasal (ΔP(nos)) as a potential measure of inspiratory effort in spontaneously breathing patients with de novo ARF.

METHODS: From January 1, 2021, to September 1, 2021, 61 consecutive patients with ARF (83.6% related to COVID-19) admitted to the Respiratory Intensive Care Unit (RICU) of the University Hospital of Modena (Italy) and candidate to escalation of non-invasive respiratory support (NRS) were enrolled. Clinical features and tidal changes in esophageal and nasal pressure were recorded on admission and 24 h after starting NRS. Correlation between ΔP(es) and ΔP(nos) served as primary outcome. The effect of ΔP(nos) measurements on respiratory rate and ΔP(es) was also assessed.

RESULTS: ΔP(es) and ΔP(nos) were strongly correlated at admission (R(2) = 0.88, p < 0.001) and 24 h apart (R(2) = 0.94, p < 0.001). The nasal plug insertion and the mouth closure required for ΔP(nos) measurement did not result in significant change of respiratory rate and ΔP(es). The correlation between measures at 24 h remained significant even after splitting the study population according to the type of NRS (high-flow nasal cannulas [R(2) = 0.79, p < 0.001] or non-invasive ventilation [R(2) = 0.95, p < 0.001]).

CONCLUSIONS: In a cohort of patients with ARF, nasal pressure swings did not alter respiratory mechanics in the short term and were highly correlated with esophageal pressure swings during spontaneous tidal breathing. ΔP(nos) might warrant further investigation as a measure of inspiratory effort in patients with ARF.

DOI: 10.1186/s13054-022-03938-w; No. 70

关键词：Humans; *COVID-19; Respiration, Artificial/methods; *Respiratory Distress Syndrome; *Respiratory Insufficiency/therapy; *Noninvasive Ventilation; *Acute respiratory failure; *Endotracheal intubation; *Esophageal pressure swings; *Inspiratory effort; *Nasal pressure swings; *Non-invasive Mechanical ventilation; *Respiratory monitoring; *Self-inflicted lung injury

DOI: 10.1186/s13054-022-03940-2; No. 69

关键词：Humans; Wound Healing; *Acquired bleeding; *Blood Coagulation Disorders/etiology; *Factor XIII; *Factor XIII deficiency; *Factor XIII Deficiency/complications/diagnosis/drug therapy; *Surgery; *Wound healing; Factor XIII/metabolism/therapeutic use; Hemorrhage/drug therapy

Abstract

BACKGROUND: Secondary nosocomial infections, which are commonly caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) and vancomycin-resistant Enterococcus faecium (VRE), often develop in septic patients. This study aimed to identify the origin of secondary systemic pathogens and reveal the underlying mechanism of infection.

METHODS: In this prospective, observational case-control study, a total of 34 septic patients, 33 non-septic intensive care unit (ICU) patients and 10 healthy individuals serving as controls were enrolled. Three hundred and twelve fecal samples were collected and subjected to 16S rRNA gene amplicon sequencing. Metagenome sequencing was performed to identify the homology between dominant CRKP or VRE in the intestine and pathogens isolated from secondary infectious sites. C57/BL mice were established as pseudo germ-free animal model by pretreatment with broad-spectrum antibiotics for two weeks.

RESULTS: The abundance and diversity of the gut microbiota in septic patients was drastically decreased one week after ICU admission, potentially leading to the enrichment of antibiotic-resistant bacteria, such as CRKP. Furthermore, secondary bloodstream and abdominal infections caused by CRKP or VRE in septic patients occurred after intestinal colonization with the predominant bacterial species. Genomic analysis showed that bacteria isolated from secondary infection had high homology with the corresponding predominant intestinal opportunistic pathogens. In addition, animal model experiments validated the hypothesis that the administration of antibiotics caused the enrichment of CRKP and VRE among the intestinal microbiota, increasing the likelihood of permeation of other tissues and potentially causing subsequent systemic infection in pseudo germ-free mice.

CONCLUSION: Our study indicated that the pathogens causing secondary infection in septic patients might originate from the intestinal colonization of pathogens following broad-spectrum antibiotic treatment.

DOI: 10.1186/s13054-022-03943-z; No. 68

关键词：Humans; Prospective Studies; Case-Control Studies; Animals; Mice; RNA, Ribosomal, 16S/genetics; *Gut microbiota; *Sepsis; Genotype; *Bacterial translocation; *Sepsis/drug therapy; *Coinfection; *Secondary nosocomial infection

DOI: 10.1186/s13054-022-03932-2; No. 67

关键词：Humans; Hospital Mortality; *Sepsis/mortality; *Shock, Septic/mortality

DOI: 10.1186/s13054-022-03944-y; No. 66

关键词：Humans; Feasibility Studies; Prone Position; *Extracorporeal Membrane Oxygenation; Patient Positioning; Shock, Cardiogenic

DOI: 10.1186/s13054-022-03936-y; No. 64

关键词：Humans; Intensive Care Units; *Time-to-Treatment; *Acute kidney injury; *Renal replacement therapy; *Personalized medicine; *Acute Kidney Injury/etiology; *Heterogeneity of treatment effect; Kidney; Renal Replacement Therapy/adverse effects

DOI: 10.1186/s13054-022-03951-z; No. 65

关键词：Humans; *Critical Care

# Digital PCR applications for the diagnosis and management of infection in critical care medicine

Abstract

Infection (either community acquired or nosocomial) is a major cause of morbidity and mortality in critical care medicine. Sepsis is present in up to 30% of all ICU patients. A large fraction of sepsis cases is driven by severe community acquired pneumonia (sCAP), which incidence has dramatically increased during COVID-19 pandemics. A frequent complication of ICU patients is ventilator associated pneumonia (VAP), which affects 10-25% of all ventilated patients, and bloodstream infections (BSIs), affecting about 10% of patients. Management of these severe infections poses several challenges, including early diagnosis, severity stratification, prognosis assessment or treatment guidance. Digital PCR (dPCR) is a next-generation PCR method that offers a number of technical advantages to face these challenges: it is less affected than real time PCR by the presence of PCR inhibitors leading to higher sensitivity. In addition, dPCR offers high reproducibility, and provides absolute quantification without the need for a standard curve. In this article we reviewed the existing evidence on the applications of dPCR to the management of infection in critical care medicine. We included thirty-two articles involving critically ill patients. Twenty-three articles focused on the amplification of microbial genes: (1) four articles approached bacterial identification in blood or plasma; (2) one article used dPCR for fungal identification in blood; (3) another article focused on bacterial and fungal identification in other clinical samples; (4) three articles used dPCR for viral identification; (5) twelve articles quantified microbial burden by dPCR to assess severity, prognosis and treatment guidance; (6) two articles used dPCR to determine microbial ecology in ICU patients. The remaining nine articles used dPCR to profile host responses to infection, two of them for severity stratification in sepsis, four focused to improve diagnosis of this disease, one for detecting sCAP, one for detecting VAP, and finally one aimed to predict progression of COVID-19. This review evidences the potential of dPCR as a useful tool that could contribute to improve the detection and clinical management of infection in critical care medicine.

DOI: 10.1186/s13054-022-03948-8; No. 63

关键词：Humans; Critical Care; Reproducibility of Results; *Critically ill patients; *COVID-19/diagnosis; *Digital PCR; *Host response; *Infection diagnosis; *Prognosis and treatment guidance; Real-Time Polymerase Chain Reaction/methods

DOI: 10.1186/s13054-022-03946-w; No. 61

关键词：Humans; Randomized Controlled Trials as Topic; *Shock, Septic/drug therapy; Vitamins; *Ascorbic Acid/administration & dosage

# Ischemic injury of the upper gastrointestinal tract after out-of-hospital cardiac arrest: a prospective, multicenter study

Abstract

BACKGROUND: The consequences of cardiac arrest (CA) on the gastro-intestinal tract are poorly understood. We measured the incidence of ischemic injury in the upper gastro-intestinal tract after Out-of-hospital CA (OHCA) and determined the risk factors for and consequences of gastrointestinal ischemic injury according to its severity.

METHODS: Prospective, non-controlled, multicenter study in nine ICUs in France and Belgium conducted from November 1, 2014 to November 30, 2018. Included patients underwent an esophago-gastro-duodenoscopy 2 to 4 d after OHCA if still intubated and the presence of ischemic lesions of the upper gastro-intestinal tract was determined by a gastroenterologist. Lesions were a priori defined as severe if there was ulceration or necrosis and moderate if there was mucosal edema or erythema. We compared clinical and cardiac arrest characteristics of three groups of patients (no, moderate, and severe lesions) and identified variables associated with gastrointestinal ischemic injury using multivariate regression analysis. We also compared the outcomes (organ failure during ICU stay and neurological status at hospital discharge) of the three groups of patients.

RESULTS: Among the 214 patients included in the analysis, 121 (57%, 95% CI 50-63%) had an upper gastrointestinal ischemic lesion, most frequently on the fundus. Ischemic lesions were severe in 55/121 (45%) patients. In multivariate regression, higher adrenaline dose during cardiopulmonary resuscitation (OR 1.25 per mg (1.08-1.46)) was independently associated with increased odds of severe upper gastrointestinal ischemic lesions; previous proton pump inhibitor use (OR 0.40 (0.14-1.00)) and serum bicarbonate on day 1 (OR 0.89 (0.81-0.97)) were associated with lower odds of ischemic lesions. Patients with severe lesions had a higher SOFA score during the ICU stay and worse neurological outcome at hospital discharge.

CONCLUSIONS: More than half of the patients successfully resuscitated from OHCA had upper gastrointestinal tract ischemic injury. Presence of ischemic lesions was independently associated with the amount of adrenaline used during resuscitation. Patients with severe lesions had higher organ failure scores during the ICU stay and a worse prognosis.

DOI: 10.1186/s13054-022-03939-9; No. 59

关键词：Humans; Prospective Studies; Intensive Care Units; *Gut; *Cardiac arrest; *Cardiopulmonary Resuscitation/adverse effects; *Gastrointestinal tract; *Gastroscopy; *Ischemia/reperfusion; *Mesenteric ischemia; *Organ failure; *Out-of-Hospital Cardiac Arrest/complications/epidemiology; *Upper Gastrointestinal Tract

DOI: 10.1186/s13054-022-03941-1; No. 60

关键词：Humans; United States; *COVID-19; *Obesity; *COVID-19/complications/drug therapy; Decision Making; *Baricitinib; *Dexamethasone; *Dosing; *Remdesivir; *Sarilumab; *Tocilizumab; *Tofacitinib; Obesity/complications/drug therapy

# Target temperature management following cardiac arrest: a systematic review and Bayesian meta-analysis

Abstract

BACKGROUND: Temperature control with target temperature management (TTM) after cardiac arrest has been endorsed by expert societies and adopted in international clinical practice guidelines but recent evidence challenges the use of hypothermic TTM.

METHODS: Systematic review and Bayesian meta-analysis of clinical trials on adult survivors from cardiac arrest undergoing TTM for at least 12 h comparing TTM versus no TTM or with a separation > 2 °C between intervention and control groups using the PubMed/MEDLINE, EMBASE, CENTRAL databases from inception to 1 September 2021 (PROSPERO CRD42021248140). All randomised and quasi-randomised controlled trials were considered. The risk ratio and 95% confidence interval for death (primary outcome) and unfavourable neurological recovery (secondary outcome) were captured using the original study definitions censored up to 180 days after cardiac arrest. Bias was assessed using the updated Cochrane risk-of-bias for randomised trials tool and certainty of evidence assessed using the Grading of Recommendation Assessment, Development and Evaluation methodology. A hierarchical robust Bayesian model-averaged meta-analysis was performed using both minimally informative and data-driven priors and reported by mean risk ratio (RR) and its 95% credible interval (95% CrI).

RESULTS: In seven studies (three low bias, three intermediate bias, one high bias, very low to low certainty) recruiting 3792 patients the RR by TTM 32-34 °C was 0.95 [95% CrI 0.78-1.09] for death and RR 0.93 [95% CrI 0.84-1.02] for unfavourable neurological outcome. The posterior probability for no benefit (RR ≥ 1) by TTM 32-34 °C was 24% for death and 12% for unfavourable neurological outcome. The posterior probabilities for favourable treatment effects of TTM 32-34 °C were the highest for an absolute risk reduction of 2-4% for death (28-53% chance) and unfavourable neurological outcome (63-78% chance). Excluding four studies without active avoidance of fever in the control arm reduced the probability to achieve an absolute risk reduction > 2% for death or unfavourable neurological outcome to ≤ 50%.

CONCLUSIONS: The posterior probability distributions did not support the use of TTM at 32-34 °C compared to 36 °C also including active control of fever to reduce the risk of death and unfavourable neurological outcome at 90-180 days. Any likely benefit of hypothermic TTM is smaller than targeted in RCTs to date.

DOI: 10.1186/s13054-022-03935-z; No. 58

关键词：Humans; Adult; Bayes Theorem; Body Temperature; *Cardiac arrest; *Bayesian statistics; *Heart Arrest/physiopathology/therapy; *Target temperature management

DOI: 10.1186/s13054-022-03942-0; No. 57

关键词：Humans; Female; Resuscitation; *Aortic occlusion; *Balloon Occlusion; *Postpartum haemorrhage; *Postpartum Hemorrhage/therapy; *PPH; *REBOA; *Shock, Hemorrhagic; Aorta/surgery

# Accuracy of heparin-binding protein for the diagnosis of nosocomial meningitis and ventriculitis

Abstract

BACKGROUND: The sensitive and accurate diagnosis of nosocomial meningitis and ventriculitis is still a critical problem. This study was designed to explore the diagnostic value of cerebrospinal fluid heparin-binding protein (HBP) in nosocomial meningitis and ventriculitis in comparison with procalcitonin and lactate.

METHODS: In this observational study, 323 suspected patients were enrolled, of which 42 participants were excluded because they could not be accurately grouped, 131 subjects who were eventually diagnosed with nosocomial meningitis or ventriculitis and 150 patients in whom infection was ultimately ruled out were included in the final analysis. The main results are expressed as medians (interquartile ranges). The Chi-squared test was used to compare the baseline characteristics. The Mann-Whitney U-test was used for group and subgroup analyses. The area under the receiver operating characteristic curve was calculated to describe the diagnostic accuracy of the biomarkers. Spearman's partial correlation was used to analyze associations between the biomarkers. Statistical significance was set when p value < 0.05.

RESULTS: HBP achieved the largest area under the receiver operating characteristic curve, which was 0.99 (95% confidence interval 0.98-1.00) compared with 0.98 (95% confidence interval 0.96-0.99) for lactate and 0.69 (95% confidence interval 0.62-0.75) for procalcitonin. With a cutoff level at 23 ng/mL, HBP achieved a sensitivity of 97%, a specificity of 95%, a positive predictive value of 93% and a negative predictive value of 98%. The levels of HBP presented no significant discrepancy between patients who received previous empiric anti-infective therapy and those who did not (p > 0.05). Higher concentrations of HBP were present in patients with positive microbiological findings (p < 0.05). Levels of HBP positively correlated with polymorphonuclear cell count (Spearman's rho = 0.68, p < 0.01), white blood cell count (Spearman's rho = 0.57, p < 0.01) and lactate (Spearman's rho = 0.34, p < 0.01).

CONCLUSIONS: Cerebrospinal fluid heparin-binding protein is a reliable auxiliary diagnostic marker that is preferable over lactate and procalcitonin in identifying nosocomial meningitis and ventriculitis, and it also contributes to solving the diagnostic difficulties caused by empiric antibiotherapy.

DOI: 10.1186/s13054-022-03929-x; No. 56

关键词：Humans; Prospective Studies; ROC Curve; Biomarkers; Carrier Proteins; *Antimicrobial Cationic Peptides; *Cerebral Ventriculitis/diagnosis; *Cerebrospinal fluid; *Cross Infection/diagnosis; *Heparin-binding protein; *Lactate; *Meningitis, Bacterial/cerebrospinal fluid/diagnosis; *Procalcitonin; Blood Proteins; Membrane Proteins

# Limitations of the ARDS criteria during high-flow oxygen or non-invasive ventilation: evidence from critically ill COVID-19 patients

Abstract

BACKGROUND: The ratio of partial pressure of arterial oxygen to inspired oxygen fraction (PaO(2)/F(I)O(2)) during invasive mechanical ventilation (MV) is used as criteria to grade the severity of respiratory failure in acute respiratory distress syndrome (ARDS). During the SARS-CoV2 pandemic, the use of PaO(2)/F(I)O(2) ratio has been increasingly used in non-invasive respiratory support such as high-flow nasal cannula (HFNC) and non-invasive ventilation (NIV). The grading of hypoxemia in non-invasively ventilated patients is uncertain. The main hypothesis, investigated in this study, was that the PaO(2)/F(I)O(2) ratio does not change when switching between MV, NIV and HFNC.

METHODS: We investigated respiratory function in critically ill patients with COVID-19 included in a single-center prospective observational study of patients admitted to the intensive care unit (ICU) at Uppsala University Hospital in Sweden. In a steady state condition, the PaO(2)/F(I)O(2) ratio was recorded before and after any change between two of the studied respiratory support techniques (i.e., HFNC, NIV and MV).

RESULTS: A total of 148 patients were included in the present analysis. We find that any change in respiratory support from or to HFNC caused a significant change in PaO(2)/F(I)O(2) ratio. Changes in respiratory support between NIV and MV did not show consistent change in PaO(2)/F(I)O(2) ratio. In patients classified as mild to moderate ARDS during MV, the change from HFNC to MV showed a variable increase in PaO(2)/F(I)O(2) ratio ranging between 52 and 140 mmHg (median of 127 mmHg). This made prediction of ARDS severity during MV from the apparent ARDS grade during HFNC impossible.

CONCLUSIONS: HFNC is associated with lower PaO(2)/F(I)O(2) ratio than either NIV or MV in the same patient, while NIV and MV provided similar PaO(2)/F(I)O(2) and thus ARDS grade by Berlin definition. The large variation of PaO(2)/F(I)O(2) ratio indicates that great caution should be used when estimating ARDS grade as a measure of pulmonary damage during HFNC.

DOI: 10.1186/s13054-022-03933-1; No. 55

关键词：Humans; Oxygen; Respiration, Artificial; Oxygen Inhalation Therapy; SARS-CoV-2; Critical Illness/therapy; *COVID-19/therapy; *Respiratory Distress Syndrome/therapy; *Respiratory Insufficiency/therapy; *Mechanical ventilation; Cannula; *Acute respiratory distress syndrome; *Noninvasive Ventilation/methods; *High-flow oxygen; *Non-invasive ventilation; RNA, Viral

DOI: 10.1186/s13054-022-03934-0; No. 54

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DOI: 10.1186/s13054-022-03922-4; No. 52

关键词：Humans; Acute Disease; *Acute pancreatitis; *Acute compartment syndrome; *Intra-abdominal hypertension; *Intra-Abdominal Hypertension/complications; *Neostigmine; *Pancreatitis/complications/drug therapy; Neostigmine/pharmacology/therapeutic use

# Distribution of delirium motor subtypes in the intensive care unit: a systematic scoping review

Abstract

BACKGROUND: Delirium is the most common cerebral dysfunction in the intensive care unit (ICU) and can be subdivided into a hypoactive, hyperactive, or mixed motor subtype based on the clinical manifestation. The aim of this review was to describe the distribution, pharmacological interventions, and outcomes of delirium motor subtypes in ICU patients.

METHODS: This systematic scoping review was performed according to the PRISMA-ScR and Cochrane guidelines. We performed a systematic search in six major databases to identify relevant studies. A meta-regression analysis was performed where pooled estimates with 95% confidence intervals were computed by a random effect model.

RESULTS: We included 131 studies comprising 13,902 delirious patients. There was a large between-study heterogeneity among studies, including differences in study design, setting, population, and outcome reporting. Hypoactive delirium was the most prevalent delirium motor subtype (50.3% [95% CI 46.0-54.7]), followed by mixed delirium (27.7% [95% CI 24.1-31.3]) and hyperactive delirium (22.7% [95% CI 19.0-26.5]). When comparing the delirium motor subtypes, patients with mixed delirium experienced the longest delirium duration, ICU and hospital length of stay, the highest ICU and hospital mortality, and more frequently received administration of specific agents (antipsychotics, α2-agonists, benzodiazepines, and propofol) during ICU stay. In studies with high average age for delirious patients (> 65 years), patients were more likely to experience hypoactive delirium.

CONCLUSIONS: Hypoactive delirium was the most prevalent motor subtype in critically ill patients. Mixed delirium had the worst outcomes in terms of delirium duration, length of stay, and mortality, and received more pharmacological interventions compared to other delirium motor subtypes. Few studies contributed to secondary outcomes; hence, these results should be interpreted with care. The large between-study heterogeneity suggests that a more standardized methodology in delirium research is warranted.

DOI: 10.1186/s13054-022-03931-3; No. 53

关键词：Humans; Aged; Critical Illness; Intensive Care Units; Critical Care; *Critically ill; *Delirium; *Intensive care; *Delirium motor subtype; *Delirium/epidemiology; Psychomotor Agitation

# Adverse effects of delayed antimicrobial treatment and surgical source control in adults with sepsis: results of a planned secondary analysis of a cluster-randomized controlled trial

Abstract

BACKGROUND: Timely antimicrobial treatment and source control are strongly recommended by sepsis guidelines, however, their impact on clinical outcomes is uncertain.

METHODS: We performed a planned secondary analysis of a cluster-randomized trial conducted from July 2011 to May 2015 including forty German hospitals. All adult patients with sepsis treated in the participating ICUs were included. Primary exposures were timing of antimicrobial therapy and delay of surgical source control during the first 48 h after sepsis onset. Primary endpoint was 28-day mortality. Mixed models were used to investigate the effects of timing while adjusting for confounders. The linearity of the effect was investigated by fractional polynomials and by categorizing of timing.

RESULTS: Analyses were based on 4792 patients receiving antimicrobial treatment and 1595 patients undergoing surgical source control. Fractional polynomial analysis identified a linear effect of timing of antimicrobials on 28-day mortality, which increased by 0.42% per hour delay (OR with 95% CI 1.019 [1.01, 1.028], p ≤ 0.001). This effect was significant in patients with and without shock (OR = 1.018 [1.008, 1.029] and 1.026 [1.01, 1.043], respectively). Using a categorized timing variable, there were no significant differences comparing treatment within 1 h versus 1-3 h, or 1 h versus 3-6 h. Delays of more than 6 h significantly increased mortality (OR = 1.41 [1.17, 1.69]). Delay in antimicrobials also increased risk of progression from severe sepsis to septic shock (OR per hour: 1.051 [1.022, 1.081], p ≤ 0.001). Time to surgical source control was significantly associated with decreased odds of successful source control (OR = 0.982 [0.971, 0.994], p = 0.003) and increased odds of death (OR = 1.011 [1.001, 1.021]; p = 0.03) in unadjusted analysis, but not when adjusted for confounders (OR = 0.991 [0.978, 1.005] and OR = 1.008 [0.997, 1.02], respectively). Only, among patients with septic shock delay of source control was significantly related to risk-of death (adjusted OR = 1.013 [1.001, 1.026], p = 0.04).

CONCLUSIONS: Our findings suggest that management of sepsis is time critical both for antimicrobial therapy and source control. Also patients, who are not yet in septic shock, profit from early anti-infective treatment since it can prevent further deterioration.

# 脓毒症成人患者延迟抗菌治疗和手术源控制的不良反应：一项集群随机对照试验的计划次要分析结果

摘要

背景：脓毒症指南强烈建议及时进行抗菌治疗和来源控制，然而，其对临床结局的影响尚不确定。

方法：我们对 2011 年 7 月至 2015 年 5 月进行的包括 40 家德国医院的集群随机试验进行了计划的二次分析。纳入所有在参与 ICU 接受治疗的脓毒症成人患者。主要暴露是抗菌治疗的时间和败血症发生后的前 48h 内手术源控制的延迟。主要终点为 28 天死亡率。混合模型用于研究时间效应，同时调整混杂因素。通过分数多项式和时间分类研究了效应的线性。

结果：分析基于 4792 名接受抗菌治疗的患者和 1595 名接受手术源控制的患者。分数多项式分析确定了抗菌剂使用时间对 28 天死亡率的线性效应，每小时延迟增加 0.42%（OR 的 95% CI 为 1.019 [1.01，1.028]，p≤0.001）。在有和无休克的患者中该效应显著（OR 分别为 1.018 [1.008，1.029] 和 1.026 [1.01，1.043]）。使用分类的时间变量，比较 1h 内与 1-3h 或 1h 与 3-6h 的治疗，没有显著差异。延迟超过 6h 显著增加死亡率 (or = 1.41 [1.17，1.69])。抗菌剂延迟也增加了从重度败血症进展为感染性休克的风险（每小时 OR：1.051 [1.022，1.081]，p≤0.001）。在未校正的分析中，至手术源控制的时间与成功源控制的几率下降 (OR = 0.982 [0.971，0.994]，p = 0.003) 和死亡的几率增加 (OR = 1.011 [1.001，1.021]；p = 0.03) 显著相关，但当校正混杂因素时（OR = 0.991 [0.978，1.005] 和 OR = 1.008 [0.997,1.02]）。仅在脓毒性休克患者中，来源控制延迟与死亡风险显著相关（调整后 OR = 1.013 [1.001，1.026]，p = 0.04）。

结论：我们的研究结果表明，败血症的管理对于抗菌治疗和来源控制都是至关重要的。此外，还未处于感染性休克的患者可从早期抗感染治疗中获益，因为早期抗感染治疗可防止病情进一步恶化。

DOI: 10.1186/s13054-022-03901-9; No. 51

关键词：Humans; Intensive Care Units; Adult; Hospital Mortality; Anti-Bacterial Agents/therapeutic use; *Infection control; *Sepsis; *Shock, Septic/drug therapy; *Anti-Infective Agents/therapeutic use; *Anti-biotic agents; *Patient care bundles; *Surgical source control; *Time-to-treatment

# The role of cell-free hemoglobin and haptoglobin in acute kidney injury in critically ill adults with ARDS and therapy with VV ECMO

Abstract

BACKGROUND: Increased plasma concentrations of circulating cell-free hemoglobin (CFH) are supposed to contribute to the multifactorial etiology of acute kidney injury (AKI) in critically ill patients while the CFH-scavenger haptoglobin might play a protective role. We evaluated the association of CFH and haptoglobin with AKI in patients with an acute respiratory distress syndrome (ARDS) requiring therapy with VV ECMO.

METHODS: Patients with CFH and haptoglobin measurements before initiation of ECMO therapy were identified from a cohort of 1044 ARDS patients and grouped into three CFH concentration groups using a risk stratification. The primary objective was to assess the association of CFH and haptoglobin with KDIGO stage 3 AKI. Further objectives included the identification of a target haptoglobin concentration to protect from CFH-associated AKI. MEASUREMENTS AND MAIN

RESULTS: Two hundred seventy-three patients fulfilled the inclusion criteria. Of those, 154 patients (56.4%) had AKI at ECMO initiation. The incidence of AKI increased stepwise with increasing concentrations of CFH reaching a plateau at 15 mg/dl. Compared to patients with low [< 5 mg/dl] CFH concentrations, patients with moderate [5-14 mg/dl] and high [≥ 15 mg/dl] CFH concentrations had a three- and five-fold increased risk for AKI (adjusted odds ratio [OR] moderate vs. low, 2.69 [95% CI, 1.25-5.95], P = 0.012; and OR high vs. low, 5.47 [2.00-15.9], P = 0.001). Among patients with increased CFH concentrations, haptoglobin plasma levels were lower in patients with AKI compared to patients without AKI. A haptoglobin concentration greater than 2.7 g/l in the moderate and 2.4 g/l in the high CFH group was identified as clinical cutoff value to protect from CFH-associated AKI (sensitivity 89.5% [95% CI, 83-96] and 90.2% [80-97], respectively).

CONCLUSIONS: In critically ill patients with ARDS requiring therapy with VV ECMO, an increased plasma concentration of CFH was identified as independent risk factor for AKI. Among patients with increased CFH concentrations, higher plasma haptoglobin concentrations might protect from CFH-associated AKI and should be subject of future research.

DOI: 10.1186/s13054-022-03894-5; No. 50

关键词：Humans; Adult; Retrospective Studies; Hemoglobins; Critical Illness/therapy; Haptoglobins; *Respiratory Distress Syndrome/therapy; *Extracorporeal Membrane Oxygenation; *ARDS; *Acute kidney injury; *Acute Kidney Injury/etiology; *Cell-free hemoglobin; *Haptoglobin

DOI: 10.1186/s13054-022-03928-y; No. 49

关键词：Humans; *Outcome; Hemorrhage/etiology/therapy; *Blood Coagulation Disorders/etiology; *Haemorrhage; *Platelet count; *Platelet transfusion; *Thrombocytopenia/etiology/therapy; *Trauma; Platelet Transfusion/adverse effects; Trauma Centers

Abstract

BACKGROUND: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced acute respiratory distress syndrome (ARDS) causes high mortality. Umbilical cord-derived mesenchymal stromal cells (UC-MSCs) have potentially relevant immune-modulatory properties, whose place in ARDS treatment is not established. This phase 2b trial was undertaken to assess the efficacy of UC-MSCs in patients with SARS-CoV-2-induced ARDS.

METHODS: This multicentre, double-blind, randomized, placebo-controlled trial (STROMA-CoV-2) recruited adults (≥ 18 years) with SARS-CoV-2-induced early (< 96 h) mild-to-severe ARDS in 10 French centres. Patients were randomly assigned to receive three intravenous infusions of 10(6) UC-MSCs/kg or placebo (0.9% NaCl) over 5 days after recruitment. For the modified intention-to-treat population, the primary endpoint was the partial pressure of oxygen to fractional inspired oxygen (PaO(2)/FiO(2))-ratio change between baseline (day (D) 0) and D7.

RESULTS: Among the 107 patients screened for eligibility from April 6, 2020, to October 29, 2020, 45 were enrolled, randomized and analyzed. PaO(2)/FiO(2) changes between D0 and D7 did not differ significantly between the UC-MSCs and placebo groups (medians [IQR] 54.3 [- 15.5 to 93.3] vs 25.3 [- 33.3 to 104.6], respectively; ANCOVA estimated treatment effect 7.4, 95% CI - 44.7 to 59.7; P = 0.77). Six (28.6%) of the 21 UC-MSCs recipients and six of 24 (25%) placebo-group patients experienced serious adverse events, none of which were related to UC-MSCs treatment.

CONCLUSIONS: D0-to-D7 PaO(2)/FiO(2) changes for intravenous UC-MSCs-versus placebo-treated adults with SARS-CoV-2-induced ARDS did not differ significantly. Repeated UC-MSCs infusions were not associated with any serious adverse events during treatment or thereafter (until D28). Larger trials enrolling patients earlier during the course of their ARDS are needed to further assess UC-MSCs efficacy in this context.

DOI: 10.1186/s13054-022-03930-4; No. 48

关键词：Humans; Treatment Outcome; Double-Blind Method; *COVID-19; SARS-CoV-2; *Mesenchymal Stem Cells; *Respiratory Distress Syndrome/therapy; *Acute respiratory distress syndrome; *Good-manufacturing practice; *Severe acute respiratory syndrome coronavirus-2; *Umbilical cord-derived mesenchymal stromal cells

DOI: 10.1186/s13054-022-03924-2; No. 47

关键词：Respiration, Artificial; Animals; Swine; *Respiratory Distress Syndrome; *Lung Injury; Positive-Pressure Respiration/methods; *Lung deflation; *Pulmonary Edema/etiology; *Pulmonary oedema; *Pulmonary vascular resistance

# Actively implementing an evidence-based feeding guideline for critically ill patients (NEED): a multicenter, cluster-randomized, controlled trial

Abstract

BACKGROUND: Previous cluster-randomized controlled trials evaluating the impact of implementing evidence-based guidelines for nutrition therapy in critical illness do not consistently demonstrate patient benefits. A large-scale, sufficiently powered study is therefore warranted to ascertain the effects of guideline implementation on patient-centered outcomes.

METHODS: We conducted a multicenter, cluster-randomized, parallel-controlled trial in intensive care units (ICUs) across China. We developed an evidence-based feeding guideline. ICUs randomly allocated to the guideline group formed a local "intervention team", which actively implemented the guideline using standardized educational materials, a graphical feeding protocol, and live online education outreach meetings conducted by members of the study management committee. ICUs assigned to the control group remained unaware of the guideline content. All ICUs enrolled patients who were expected to stay in the ICU longer than seven days. The primary outcome was all-cause mortality within 28 days of enrollment.

RESULTS: Forty-eight ICUs were randomized to the guideline group and 49 to the control group. From March 2018 to July 2019, the guideline ICUs enrolled 1399 patients, and the control ICUs enrolled 1373 patients. Implementation of the guideline resulted in significantly earlier EN initiation (1.20 vs. 1.55 mean days to initiation of EN; difference - 0.40 [95% CI - 0.71 to - 0.09]; P = 0.01) and delayed PN initiation (1.29 vs. 0.80 mean days to start of PN; difference 1.06 [95% CI 0.44 to 1.67]; P = 0.001). There was no significant difference in 28-day mortality (14.2% vs. 15.2%; difference - 1.6% [95% CI - 4.3% to 1.2%]; P = 0.42) between groups.

CONCLUSIONS: In this large-scale, multicenter trial, active implementation of an evidence-based feeding guideline reduced the time to commencement of EN and overall PN use but did not translate to a reduction in mortality from critical illness.

DOI: 10.1186/s13054-022-03921-5; No. 46

关键词：Humans; Time Factors; Intensive Care Units; *Critical Illness/therapy; *Intensive care unit; China; *Nutritional Support; *Cluster-randomized trial; *Evidence-based guideline; *Nutrition therapy

DOI: 10.1186/s13054-022-03926-0; No. 45

关键词：Humans; *COVID-19; SARS-CoV-2; *Airway Extubation; Ventilator Weaning; Muscle Strength/physiology

DOI: 10.1186/s13054-022-03925-1; No. 44

关键词：Humans; Hospitals; *Pandemics; *Critical Care; Intubation, Intratracheal; Bed Occupancy

DOI: 10.1186/s13054-022-03920-6; No. 42

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DOI: 10.1186/s13054-022-03899-0; No. 43

关键词：Humans; Prospective Studies; Emergency Service, Hospital; Hospital Mortality; *Sepsis; *Sepsis/therapy; *Shock, Septic/therapy; *Septic shock; *Off-hour effect; *Surviving Sepsis Campaign; Guideline Adherence

DOI: 10.1186/s13054-022-03886-5; No. 41

关键词：Humans; SARS-CoV-2; *COVID-19/drug therapy; Dexamethasone/adverse effects; *Respiratory Distress Syndrome/chemically induced; *Dexamethasone; *COVID ARDS; *High occurrence; *PCP

DOI: 10.1186/s13054-022-03923-3; No. 39

关键词：Humans; Survival Analysis; Retrospective Studies; Prone Position; *Respiratory Distress Syndrome/therapy; *Extracorporeal Membrane Oxygenation

DOI: 10.1186/s13054-022-03904-6; No. 40

关键词：Humans; Length of Stay; Pandemics; *COVID-19; SARS-CoV-2; *Intensive care unit; *Meta-analysis; *Respiration, Artificial; *Tracheostomy; *Respiratory failure; *COVID-19/surgery; *Invasive mechanical ventilation

DOI: 10.1186/s13054-022-03905-5; No. 37

关键词：Humans; Intensive Care Units; Retrospective Studies; Oxygen Inhalation Therapy; *COVID-19; SARS-CoV-2; *COVID-19/therapy; Intubation, Intratracheal; *Intensive care; *Respiratory Insufficiency/therapy; *Noninvasive Ventilation; Cannula; *Acute hypoxemic respiratory failure; *Non-invasive oxygenation; Spain

# Detection of cerebral hypoperfusion with a dynamic hyperoxia test using brain oxygenation pressure monitoring

Abstract

INTRODUCTION: Brain multimodal monitoring including intracranial pressure (ICP) and brain tissue oxygen pressure (PbtO(2)) is more accurate than ICP alone in detecting cerebral hypoperfusion after traumatic brain injury (TBI). No data are available for the predictive role of a dynamic hyperoxia test in brain-injured patients from diverse etiology. AIM: To examine the accuracy of ICP, PbtO(2) and the oxygen ratio (OxR) in detecting regional cerebral hypoperfusion, assessed using perfusion cerebral computed tomography (CTP) in patients with acute brain injury.

METHODS: Single-center study including patients with TBI, subarachnoid hemorrhage (SAH) and intracranial hemorrhage (ICH) undergoing cerebral blood flow (CBF) measurements using CTP, concomitantly to ICP and PbtO(2) monitoring. Before CTP, FiO(2) was increased directly from baseline to 100% for a period of 20 min under stable conditions to test the PbtO(2) catheter, as a standard of care. Cerebral monitoring data were recorded and samples were taken, allowing the measurement of arterial oxygen pressure (PaO(2)) and PbtO(2) at FiO(2) 100% as well as calculation of OxR (= ΔPbtO(2)/ΔPaO(2)). Regional CBF (rCBF) was measured using CTP in the tissue area around intracranial monitoring by an independent radiologist, who was blind to the PbtO(2) values. The accuracy of different monitoring tools to predict cerebral hypoperfusion (i.e., CBF < 35 mL/100 g × min) was assessed using area under the receiver-operating characteristic curves (AUCs).

RESULTS: Eighty-seven CTPs were performed in 53 patients (median age 52 [41-63] years-TBI, n = 17; SAH, n = 29; ICH, n = 7). Cerebral hypoperfusion was observed in 56 (64%) CTPs: ICP, PbtO(2) and OxR were significantly different between CTP with and without hypoperfusion. Also, rCBF was correlated with ICP (r = - 0.27; p = 0.01), PbtO(2) (r = 0.36; p < 0.01) and OxR (r = 0.57; p < 0.01). Compared with ICP alone (AUC = 0.65 [95% CI, 0.53-0.76]), monitoring ICP + PbO(2) (AUC = 0.78 [0.68-0.87]) or ICP + PbtO(2) + OxR (AUC = 0.80 (0.70-0.91) was significantly more accurate in predicting cerebral hypoperfusion. The accuracy was not significantly different among different etiologies of brain injury.

CONCLUSIONS: The combination of ICP and PbtO(2) monitoring provides a better detection of cerebral hypoperfusion than ICP alone in patients with acute brain injury. The use of dynamic hyperoxia test could not significantly increase the diagnostic accuracy.

# 脑氧合压力监测动态高氧试验检测脑低灌注

摘要

引言：包括颅内压 (ICP) 和脑组织氧分压 (PbtO (2)) 的脑多模式监测比单独使用 ICP 更准确地检测创伤性脑损伤 (TBI) 后的脑低灌注。尚无数据表明动态高氧试验对不同病因的脑损伤患者的预测作用。目的：利用灌注脑计算机断层扫描 (CTP) 评估急性脑损伤患者 ICP、PbtO (2) 和氧比 (OxR) 检测局部脑灌注不足的准确性。

方法：单中心研究，纳入 TBI、蛛网膜下腔出血 (SAH) 和颅内出血 (ICH) 患者，使用 CTP 测量脑血流量 (CBF)，同时进行 ICP 和 PbtO (2) 监测。在 CTP 前，FiO (2) 在稳定条件下直接从基线增加到 100% 持续 20 min，以测试 PbtO (2) 导管，作为标准治疗。记录脑监测数据并采样，允许在 FiO (2) 100% 时测量动脉血氧分压 (PaO (2)) 和 PbtO (2)，并计算 OxR (= ΔPbtO (2)/ΔPaO (2))。局部脑血流量 (rCBF) 由独立的放射科医生使用 CTP 在颅内监测周围的组织区域进行测量，该医生不知道 PbtO (2) 值。使用受试者工作特征曲线下面积 (AUC) 评估不同监测工具预测脑灌注不足（即，CBF < 35 mL/100 g×min）的准确性。

结果：53 例患者进行了 87 次 CTP（中位年龄 52 [41-63] 岁 - TBI，n = 17；SAH，n = 29；ICH，n = 7）。在 56 例 (64%) CTP 中观察到脑灌注不足：ICP、PbtO (2) 和 OxR 在 CTP 伴和不伴灌注不足之间有显著差异。此外，rCBF 与 ICP (r =-0.27；p = 0.01)、PbtO (2)(r = 0.36；p < 0.01) 和 OxR (r = 0.57；p < 0.01) 相关。与单纯 ICP (AUC = 0.65 [95% CI，0.53-0.76]) 相比，监测 ICP + PbO (2)(AUC = 0.78 [0.68-0.87]) 或 ICP + PbtO (2)+ OxR（AUC = 0.80 (0.70-0.91) 预测脑低灌注更准确。不同病因脑损伤的准确性无显著差异。

结论：在急性脑损伤患者中，ICP 与 PbtO (2) 联合监测比 ICP 单独监测提供了更好的脑低灌注检测。动态高氧试验不能显著提高诊断的准确性。

DOI: 10.1186/s13054-022-03918-0; No. 35

关键词：Humans; Middle Aged; Cerebrovascular Circulation; Intracranial Pressure; Oxygen; *Hyperoxia; Brain/diagnostic imaging; *Brain injury; *Brain Injuries, Traumatic/diagnostic imaging; *Hypoperfusion; *Multimodal monitoring; *Oxygen test

# Multidimensional analysis of the host response reveals prognostic and pathogen-driven immune subtypes among adults with sepsis in Uganda

Abstract

BACKGROUND: The global burden of sepsis is concentrated in sub-Saharan Africa, where severe infections disproportionately affect young, HIV-infected adults and high-burden pathogens are unique. In this context, poor understanding of sepsis immunopathology represents a crucial barrier to development of locally-effective treatment strategies. We sought to determine inter-individual immunologic heterogeneity among adults hospitalized with sepsis in a sub-Saharan African setting, and characterize associations between immune subtypes, infecting pathogens, and clinical outcomes.

METHODS: Among a prospective observational cohort of 288 adults hospitalized with suspected sepsis in Uganda, we applied machine learning methods to 14 soluble host immune mediators, reflective of key domains of sepsis immunopathology (innate and adaptive immune activation, endothelial dysfunction, fibrinolysis), to identify immune subtypes in randomly-split discovery (N = 201) and internal validation (N = 87) sub-cohorts. In parallel, we applied similar methods to whole-blood RNA-sequencing data from a consecutive subset of patients (N = 128) to identify transcriptional subtypes, which we characterized using biological pathway and immune cell-type deconvolution analyses.

RESULTS: Unsupervised clustering consistently identified two immune subtypes defined by differential activation of pro-inflammatory innate and adaptive immune pathways, with transcriptional evidence of concomitant CD56(-)/CD16( +) NK-cell expansion, T-cell exhaustion, and oxidative-stress and hypoxia-induced metabolic and cell-cycle reprogramming in the hyperinflammatory subtype. Immune subtypes defined by greater pro-inflammatory immune activation, T-cell exhaustion, and metabolic reprogramming were consistently associated with a high-prevalence of severe and often disseminated HIV-associated tuberculosis, as well as more extensive organ dysfunction, worse functional outcomes, and higher 30-day mortality.

CONCLUSIONS: Our results highlight unique host- and pathogen-driven features of sepsis immunopathology in sub-Saharan Africa, including the importance of severe HIV-associated tuberculosis, and reinforce the need to develop more biologically-informed treatment strategies in the region, particularly those incorporating immunomodulation.

DOI: 10.1186/s13054-022-03907-3; No. 36

关键词：Humans; Prognosis; *Sepsis; *Biomarkers; *Africa; *High-throughput nucleotide sequencing; *HIV Infections; *Tuberculosis; *Uganda; Uganda/epidemiology

# Extracorporeal membrane oxygenation for COVID-19 and influenza H1N1 associated acute respiratory distress syndrome: a multicenter retrospective cohort study

Abstract

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has become an established rescue therapy for severe acute respiratory distress syndrome (ARDS) in several etiologies including influenza A H1N1 pneumonia. The benefit of receiving ECMO in coronavirus disease 2019 (COVID-19) is still uncertain. The aim of this analysis was to compare the outcome of patients who received veno-venous ECMO for COVID-19 and Influenza A H1N1 associated ARDS.

METHODS: This was a multicenter retrospective cohort study including adults with ARDS, receiving ECMO for COVID-19 and influenza A H1N1 pneumonia between 2009 and 2021 in seven Italian ICU. The primary outcome was any-cause mortality at 60 days after ECMO initiation. We used a multivariable Cox model to estimate the difference in mortality accounting for patients' characteristics and treatment factors before ECMO was started. Secondary outcomes were mortality at 90 days, ICU and hospital length of stay and ECMO associated complications.

RESULTS: Data from 308 patients with COVID-19 (N = 146) and H1N1 (N = 162) associated ARDS who had received ECMO support were included. The estimated cumulative mortality at 60 days after initiating ECMO was higher in COVID-19 (46%) than H1N1 (27%) patients (hazard ratio 1.76, 95% CI 1.17-2.46). When adjusting for confounders, specifically age and hospital length of stay before ECMO support, the hazard ratio decreased to 1.39, 95% CI 0.78-2.47. ICU and hospital length of stay, duration of ECMO and invasive mechanical ventilation and ECMO-associated hemorrhagic complications were higher in COVID-19 than H1N1 patients.

CONCLUSION: In patients with ARDS who received ECMO, the observed unadjusted 60-day mortality was higher in cases of COVID-19 than H1N1 pneumonia. This difference in mortality was not significant after multivariable adjustment; older age and longer hospital length of stay before ECMO emerged as important covariates that could explain the observed difference.

DOI: 10.1186/s13054-022-03906-4; No. 34

关键词：Humans; Aged; Adult; Retrospective Studies; *COVID-19; SARS-CoV-2; *Respiratory Distress Syndrome/therapy; *Extracorporeal Membrane Oxygenation; *ARDS; *ECMO; *Influenza A Virus, H1N1 Subtype; *H1N1; *Influenza; *Influenza, Human/complications/therapy

# Endotheliopathy is associated with slower liberation from mechanical ventilation: a cohort study

Abstract

BACKGROUND: Endotheliopathy is suggested as pivotal pathophysiology of sepsis and trauma-associated organ failure, but its role in acute respiratory failure is not yet determined. We investigated if endotheliopathy biomarkers at ICU admission are associated with illness severity and clinical outcomes in patients with acute respiratory failure requiring mechanical ventilation.

METHODS: We conducted a prospective single-center cohort study including 459 mechanically ventilated adults at ICU admission. Plasma levels of three endotheliopathy biomarkers were measured at ICU admission: Syndecan-1, soluble Thrombomodulin (sTM), and Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1). The primary outcome was the rate of liberation from mechanical ventilation, which is presented together with the rate of the competing risk of death while still on mechanical ventilation. Secondary outcomes were PaO(2)/FiO(2)-ratios on admission and on last measurement in patients dying within five days, and 30-day all-cause mortality. The primary outcome and 30-day all-cause mortality were analyzed using Cox regression, controlled for gender, age, chronic obstructive pulmonary disease, septic shock, heart failure, PaO(2)/FiO(2)-ratio at admission, respiratory infection, acute kidney injury, and bilirubin. PaO(2)/FiO(2)-ratios were analyzed using linear regression, controlled for age, chronic obstructive pulmonary disease, respiratory infection, and shock.

RESULTS: Patients with high sTM were liberated from mechanical ventilation at a lower rate (adjusted hazard ratio (HR) 0.71, for an increase from the 25th to the 75th percentile, 95% confidence interval (CI) 0.54-0.93, p = 0.01). Patients with high PECAM-1 were liberated from mechanical ventilation at a lower rate, but only during the first 5 days (adjusted HR 0.72, for an increase from the 25th to the 75th percentile, 95% CI 0.58-0.9, p < 0.01). High levels of Syndecan-1 and PECAM-1 were associated with a higher rate of death while still on mechanical ventilation. sTM and PECAM-1 were negatively associated with PaO(2)/FiO(2)-ratio at ICU admission and no biomarker was associated with last measured PaO(2)/FiO(2)-ratio. High levels of all biomarkers were associated with higher 30-day all-cause mortality.

CONCLUSION: In acute respiratory failure, endotheliopathy biomarkers are associated with lower rates of liberation from mechanical ventilation, hypoxemia at ICU admission, and 30-day all-cause mortality.

# 内皮病变与机械通气减慢有关：一项队列研究

摘要

背景：内皮病变被认为是败血症和创伤相关器官衰竭的关键病理生理学，但其在急性呼吸衰竭中的作用尚未确定。我们研究了在需要机械通气的急性呼吸衰竭患者中，入住 ICU 时的内皮病变生物标志物是否与疾病严重程度和临床结局相关。

方法：我们进行了一项前瞻性单中心队列研究，包括 459 例入住 ICU 时机械通气的成人。在入住 ICU 时测量三种内皮病变生物标志物的血浆水平：Syndecan-1、可溶性血栓调节蛋白 (sTM) 和血小板内皮细胞粘附分子 - 1 (PECAM-1)。主要结局是脱离机械通气的比率，与仍接受机械通气时竞争死亡风险的比率一起列出。次要结局为入院时 PaO (2)/FiO (2) 比值、5 天内死亡患者最后一次测量值和 30 天全因死亡率。主要结局和 30 天全因死亡率采用 Cox 回归进行分析，控制性别、年龄、慢性阻塞性肺疾病、感染性休克、心力衰竭、入院时 PaO (2)/FiO (2) 比值、呼吸道感染、急性肾损伤和胆红素。采用线性回归分析 PaO (2)/FiO (2) 比值，控制年龄、慢性阻塞性肺疾病、呼吸道感染和休克。

结果：高 sTM 患者脱离机械通气的比率较低（调整后的风险比 (HR) 为 0.71，从第 25 百分位数增加至第 75 百分位数，95% 置信区间 (CI) 为 0.54-0.93，p = 0.01）。高 PECAM-1 患者以较低的速率从机械通气中解放出来，但仅在前 5 天（校正 HR 0.72，从第 25 百分位数增加至第 75 百分位数，95% CI 0.58-0.9，p < 0.01）。高水平的 Syndecan-1 和 PECAM-1 与仍在接受机械通气时的高死亡率相关。sTM 和 PECAM-1 与入住 ICU 时的 PaO (2)/FiO (2) 比值呈负相关，没有生物标志物与最后一次测量的 PaO (2)/FiO (2) 比值相关。所有生物标志物的高水平与 30 天全因死亡率较高相关。

结论：在急性呼吸衰竭中，内皮病生物标志物与较低的机械通气释放率、ICU 入院时的低氧血症和 30 天全因死亡率相关。

DOI: 10.1186/s13054-021-03877-y; No. 33

关键词：Humans; Prospective Studies; Intensive Care Units; Cohort Studies; Proportional Hazards Models; *Respiration, Artificial; *Respiratory Distress Syndrome; *Endothelium; *Observational study; *Platelet Endothelial Cell Adhesion Molecule-1; *Respiratory insufficiency/physiopathology; *Syndecan-1; *Thrombomodulin; *Vascular

# Timing of inspiratory muscle activity detected from airway pressure and flow during pressure support ventilation: the waveform method

Abstract

BACKGROUND: Whether respiratory efforts and their timing can be reliably detected during pressure support ventilation using standard ventilator waveforms is unclear. This would give the opportunity to assess and improve patient-ventilator interaction without the need of special equipment.

METHODS: In 16 patients under invasive pressure support ventilation, flow and pressure waveforms were obtained from proximal sensors and analyzed by three trained physicians and one resident to assess patient's spontaneous activity. A systematic method (the waveform method) based on explicit rules was adopted. Esophageal pressure tracings were analyzed independently and used as reference. Breaths were classified as assisted or auto-triggered, double-triggered or ineffective. For assisted breaths, trigger delay, early and late cycling (minor asynchronies) were diagnosed. The percentage of breaths with major asynchronies (asynchrony index) and total asynchrony time were computed.

RESULTS: Out of 4426 analyzed breaths, 94.1% (70.4-99.4) were assisted, 0.0% (0.0-0.2) auto-triggered and 5.8% (0.4-29.6) ineffective. Asynchrony index was 5.9% (0.6-29.6). Total asynchrony time represented 22.4% (16.3-30.1) of recording time and was mainly due to minor asynchronies. Applying the waveform method resulted in an inter-operator agreement of 0.99 (0.98-0.99); 99.5% of efforts were detected on waveforms and agreement with the reference in detecting major asynchronies was 0.99 (0.98-0.99). Timing of respiratory efforts was accurately detected on waveforms: AUC for trigger delay, cycling delay and early cycling was 0.865 (0.853-0.876), 0.903 (0.892-0.914) and 0.983 (0.970-0.991), respectively.

CONCLUSIONS: Ventilator waveforms can be used alone to reliably assess patient's spontaneous activity and patient-ventilator interaction provided that a systematic method is adopted.

DOI: 10.1186/s13054-022-03895-4; No. 32

关键词：Humans; Respiration, Artificial; Respiration; *Positive-Pressure Respiration; *Ventilators, Mechanical; *Asynchronies; *Patient–ventilator interaction; *Pressure support ventilation; *Respiratory effort; *Spontaneous respiratory activity; *Ventilator waveforms; Muscles

DOI: 10.1186/s13054-022-03902-8; No. 30

关键词：Humans; Critical Care; Risk Factors; *COVID-19; SARS-CoV-2; Adrenal Cortex Hormones/adverse effects; *Dexamethasone; *CAPA; *Corticosteroid; *Pulmonary aspergillosis; *Pulmonary Aspergillosis

# Immune effects of PI3K/Akt/HIF-1α-regulated glycolysis in polymorphonuclear neutrophils during sepsis

Abstract

BACKGROUND: Effective removal of pathogenic bacteria is key to improving the prognosis of sepsis. Polymorphonuclear neutrophils (PMNs) are the most important components of innate cellular immunity and play vital roles in clearing pathogenic bacteria. However, the metabolic characteristics and immunomodulatory pathways of PMNs during sepsis have not been investigated. In the present study, we explored the immune metabolism characteristics of PMNs and the mechanism by which neutrophilic glycolysis is regulated during sepsis.

METHODS: Metabolomics analysis was performed on PMNs isolated from 14 septic patients, 26 patients with acute appendicitis, and 19 healthy volunteers. Transcriptome analysis was performed on the PMNs isolated from the healthy volunteers and the patients with sepsis to assess glycolysis and investigate its mechanism. Lipopolysaccharide (LPS) was used to stimulate the neutrophils isolated from the healthy volunteers at different time intervals to build an LPS-tolerant model. Chemotaxis, phagocytosis, lactate production, oxygen consumption rate (OCR), and extracellular acidification rate (ECAR) were evaluated.

RESULTS: Transcriptomics showed significant changes in glycolysis and the mTOR/HIF-1α signaling pathway during sepsis. Metabolomics revealed that the Warburg effect was significantly altered in the patients with sepsis. We discovered that glycolysis regulated PMNs' chemotaxis and phagocytosis functions during sepsis. Lactate dehydrogenase A (LDHA) downregulation was a key factor in the inhibition of glycolysis in PMNs. This study confirmed that the PI3K/Akt-HIF-1α pathway was involved in the LDHA expression level and also influenced PMNs' chemotaxis and phagocytosis functions.

CONCLUSIONS: The inhibition of glycolysis contributed to neutrophil immunosuppression during sepsis and might be controlled by PI3K/Akt-HIF-1α pathway-mediated LDHA downregulation. Our study provides a scientific theoretical basis for the management and treatment of patients with sepsis and promotes to identify therapeutic target for the improvement of immune function in sepsis.

DOI: 10.1186/s13054-022-03893-6; No. 29

关键词：Humans; Signal Transduction; *Neutrophil; *Sepsis; *Metabolomics; *Glycolysis; *Immune; *Neutrophils/metabolism; Glycolysis; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism; Phosphatidylinositol 3-Kinases/metabolism; Proto-Oncogene Proteins c-akt/metabolism

# Effects of positive end-expiratory pressure on lung ultrasound patterns and their correlation with intracranial pressure in mechanically ventilated brain injured patients

Abstract

BACKGROUND: The effects of positive end-expiratory pressure (PEEP) on lung ultrasound (LUS) patterns, and their relationship with intracranial pressure (ICP) in brain injured patients have not been completely clarified. The primary aim of this study was to assess the effect of two levels of PEEP (5 and 15 cmH(2)O) on global (LUStot) and regional (anterior, lateral, and posterior areas) LUS scores and their correlation with changes of invasive ICP. Secondary aims included: the evaluation of the effect of PEEP on respiratory mechanics, arterial partial pressure of carbon dioxide (PaCO(2)) and hemodynamics; the correlation between changes in ICP and LUS as well as respiratory parameters; the identification of factors at baseline as potential predictors of ICP response to higher PEEP.

METHODS: Prospective, observational study including adult mechanically ventilated patients with acute brain injury requiring invasive ICP. Total and regional LUS scores, ICP, respiratory mechanics, and arterial blood gases values were analyzed at PEEP 5 and 15 cmH(2)O.

RESULTS: Thirty patients were included; 19 of them (63.3%) were male, with median age of 65 years [interquartile range (IQR) = 66.7-76.0]. PEEP from 5 to 15 cmH(2)O reduced LUS score in the posterior regions (LUSp, median value from 7 [5-8] to 4.5 [3.7-6], p = 0.002). Changes in ICP were significantly correlated with changes in LUStot (rho = 0.631, p = 0.0002), LUSp (rho = 0.663, p < 0.0001), respiratory system compliance (rho = - 0.599, p < 0.0001), mean arterial pressure (rho = - 0.833, p < 0.0001) and PaCO(2) (rho = 0.819, p < 0.0001). Baseline LUStot score predicted the increase of ICP with PEEP.

CONCLUSIONS: LUS-together with the evaluation of respiratory and clinical variables-can assist the clinicians in the bedside assessment and prediction of the effect of PEEP on ICP in patients with acute brain injury.

DOI: 10.1186/s13054-022-03903-7; No. 31

关键词：Humans; Male; Prospective Studies; Aged; Adult; Brain; Positive-Pressure Respiration; Lung; *Respiration, Artificial; *Mechanical ventilation; Respiratory Mechanics; *Intracranial Pressure; *Lung ultrasound; *Intracranial pressure; *Brain injured patients; *Positive end expiratory pressure

DOI: 10.1186/s13054-022-03897-2; No. 28

关键词：Humans; Oxygen Inhalation Therapy; *COVID-19; SARS-CoV-2; Prone Position; *Respiratory Insufficiency/therapy; Cannula

DOI: 10.1186/s13054-022-03898-1; No. 27

关键词：Humans; Tomography; *Intensive care unit; *Sepsis; *Outcome; *Computed tomography; *Fasciitis, Necrotizing; *Necrotizing soft-tissue infection; *Soft Tissue Infections

# Intravenous vitamin C administration to patients with septic shock: a pilot randomised controlled trial

Abstract

BACKGROUND: Intravenous vitamin C administration in septic shock may have a sparing effect on vasopressor requirements, and vitamin C's enzyme cofactor functions provide a mechanistic rationale. Our study aimed to determine the effect of intravenous vitamin C administration on vasopressor requirements and other outcomes in patients with septic shock.

METHODS: This was a double-blind, randomised placebo-controlled trial in 40 patients with septic shock who were randomised (1:1) to receive intravenous vitamin C (at a dose of 25 mg/kg of body weight every 6 h) or placebo (intravenous 5% dextrose) for up to 96 h, or until death or discharge. The primary outcome was intravenous vasopressor requirements (dose and duration), and secondary outcomes included Sequential Organ Failure Assessment (SOFA) scores, intensive care unit (ICU) and hospital length of stay, and mortality. In addition, blood samples were collected to determine vitamin C kinetics and inflammatory marker concentrations.

RESULTS: Median plasma vitamin C concentrations were deficient at baseline (9.2 [4.4, 12] µmol/L) and increased to 408 (227, 560) µmol/L following 72 h of intervention. The mean duration of intravenous vasopressor infusion in the vitamin C group was 48 (95% CI 35-62) hours and in the placebo group was 54 (95% CI 41-62) hours (p = 0.52). The dose of vasopressor delivered over time was comparable between the two groups, as were SOFA scores (p > 0.05). The median ICU length of stay in the intervention group was 3.8 (2.2, 9.8) days versus 7.1 (3.1, 20) days in the placebo group (p = 0.12). The median hospital length of stay for the vitamin C group was 18 (11, 35) days versus 22 (10, 52) days for the placebo group (p = 0.65). Mortality was comparable between the two groups (p > 0.05). Of the inflammatory markers, neutrophil counts were elevated in the vitamin C group relative to placebo by 72 h (p = 0.01). C-reactive protein and myeloperoxidase concentrations were elevated at baseline, however, the two groups were comparable over time (p > 0.05).

CONCLUSIONS: Our pilot study indicated that intravenous vitamin C did not provide significant decreases in the mean dose or duration of vasopressor infusion. Further research that takes into account the potential impact of intervention timing, dose and duration, and location of trial, may provide more definitive evidence.

# 在感染性休克患者中静脉给予维生素 C：一项初步随机对照试验

摘要

背景：在脓毒性休克中静脉给予维生素 C 可能对血管加压素的需求具有保护作用，维生素 C 的酶辅因子功能提供了机制依据。我们的研究旨在确定静脉注射维生素 C 对感染性休克患者血管加压素需求和其他结局的影响。

方法：这是一项在 40 例感染性休克患者中进行的双盲、随机、安慰剂对照试验，患者随机 (1:1) 接受静脉维生素 C（剂量为 25 mg/kg 体重，每 6h 一次）或安慰剂（静脉给予 5% 葡萄糖）最长 96h，或直至死亡或出院。主要结局是静脉内升压药需求（剂量和持续时间），次要结局包括序贯器官衰竭评估 (SOFA) 评分、重症监护室 (ICU) 和住院时间以及死亡率。此外，采集血样以测定维生素 C 动力学和炎症标志物浓度。

结果：基线时中位血浆维生素 C 浓度不足 (9.2 [4.4，12]µmol/L)，干预 72h 后增加至 408 (227，560)µmol/L。维生素 C 组静脉输注血管加压药的平均持续时间为 48 (95% CI 35-62) 小时，安慰剂组为 54 (95% CI 41-62) 小时 (p = 0.52)。随着时间推移，两组之间的血管加压素给药剂量相当，SOFA 评分也是如此 (p > 0.05)。干预组的中位 ICU 住院时间为 3.8 (2.2，9.8) 天，安慰剂组为 7.1 (3.1，20) 天 (p = 0.12)。维生素 C 组的中位住院时间为 18 (11，35) 天，安慰剂组为 22 (10，52) 天 (p = 0.65)。两组的死亡率相当 (p > 0.05)。到 72h 时，维生素 C 组的炎症标志物中性粒细胞计数相对于安慰剂组升高 (p = 0.01)。基线时 C 反应蛋白和髓过氧化物酶浓度升高，但是两组随时间的变化相当 (p > 0.05)。

结论：我们的初探性研究表明，静脉输注维生素 C 并未导致血管加压药的平均剂量或持续时间显著降低。考虑干预时间、剂量和持续时间以及试验地点的潜在影响的进一步研究可能提供更明确的证据。

DOI: 10.1186/s13054-022-03900-w; No. 26

关键词：Humans; Double-Blind Method; Pilot Projects; *Sepsis; *Shock, Septic/drug therapy; Ascorbic Acid/therapeutic use; Organ Dysfunction Scores; Vitamins; *Septic shock; *ICU length of stay; *Noradrenaline; *Vasopressor; *Vitamin C

DOI: 10.1186/s13054-022-03891-8; No. 25

关键词：Humans; Perfusion; Resuscitation; Microcirculation; *Sepsis; *Shock, Septic/drug therapy; Ascorbic Acid/pharmacology/therapeutic use; *Vitamin C; *Microvascular function; *Mottling; *Tissue perfusion

# Association between hospital and ICU structural factors and patient outcomes in China: a secondary analysis of the National Clinical Improvement System Data in 2019

Abstract

BACKGROUND: Hospital and ICU structural factors are key factors affecting the quality of care as well as ICU patient outcomes. However, the data from China are scarce. This study was designed to investigate how differences in patient outcomes are associated with differences in hospital and ICU structure variables in China throughout 2019.

METHODS: This was a multicenter observational study. Data from a total of 2820 hospitals were collected using the National Clinical Improvement System Data that reports ICU information in China. Data collection consisted of a) information on the hospital and ICU structural factors, including the hospital type, number of beds, staffing, among others, and b) ICU patient outcomes, including the mortality rate as well as the incidence of ventilator-associated pneumonia (VAP), catheter-related bloodstream infections (CRBSIs), and catheter-associated urinary tract infections (CAUTIs). Generalized linear mixed models were used to analyse the association between hospital and ICU structural factors and patient outcomes.

RESULTS: The median ICU patient mortality was 8.02% (3.78%, 14.35%), and the incidences of VAP, CRBSI, and CAUTI were 5.58 (1.55, 11.67) per 1000 ventilator days, 0.63 (0, 2.01) per 1000 catheter days, and 1.42 (0.37, 3.40) per 1000 catheter days, respectively. Mortality was significantly lower in public hospitals (β = - 0.018 (- 0.031, - 0.005), p = 0.006), hospitals with an ICU-to-hospital bed percentage of more than 2% (β = - 0.027 (- 0.034, -0.019), p < 0.001) and higher in hospitals with a bed-to-nurse ratio of more than 0.5:1 (β = 0.009 (0.001, 0.017), p = 0.027). The incidence of VAP was lower in public hospitals (β = - 0.036 (- 0.054, - 0.018), p < 0.001). The incidence of CRBSIs was lower in public hospitals (β = - 0.008 (- 0.014, - 0.002), p = 0.011) and higher in secondary hospitals (β = 0.005 (0.001, 0.009), p = 0.010), while the incidence of CAUTIs was higher in secondary hospitals (β = 0.010 (0.002, 0.018), p = 0.015).

CONCLUSION: This study highlights the association between specific ICU structural factors and patient outcomes. Modifying structural factors is a potential opportunity that could improve patient outcomes in ICUs.

DOI: 10.1186/s13054-022-03892-7; No. 24

关键词：Humans; Intensive Care Units; Hospitals; *Pneumonia, Ventilator-Associated/epidemiology; Ventilators, Mechanical; *Catheter-Related Infections/epidemiology; *China; *Critical care medicine; *Cross Infection/epidemiology; *ICUs; *Patient outcome; *Staffing; *Structure factors

# Omega-6 sparing effects of parenteral lipid emulsions-an updated systematic review and meta-analysis on clinical outcomes in critically ill patients

Abstract

BACKGROUND: Parenteral lipid emulsions in critical care are traditionally based on soybean oil (SO) and rich in pro-inflammatory omega-6 fatty acids (FAs). Parenteral nutrition (PN) strategies with the aim of reducing omega-6 FAs may potentially decrease the morbidity and mortality in critically ill patients.

METHODS: A systematic search of MEDLINE, EMBASE, CINAHL and CENTRAL was conducted to identify all randomized controlled trials in critically ill patients published from inception to June 2021, which investigated clinical omega-6 sparing effects. Two independent reviewers extracted bias risk, treatment details, patient characteristics and clinical outcomes. Random effect meta-analysis was performed.

RESULTS: 1054 studies were identified in our electronic search, 136 trials were assessed for eligibility and 26 trials with 1733 critically ill patients were included. The median methodologic score was 9 out of 14 points (95% confidence interval [CI] 7, 10). Omega-6 FA sparing PN in comparison with traditional lipid emulsions did not decrease overall mortality (20 studies; risk ratio [RR] 0.91; 95% CI 0.76, 1.10; p = 0.34) but hospital length of stay was substantially reduced (6 studies; weighted mean difference [WMD] - 6.88; 95% CI - 11.27, - 2.49; p = 0.002). Among the different lipid emulsions, fish oil (FO) containing PN reduced the length of intensive care (8 studies; WMD - 3.53; 95% CI - 6.16, - 0.90; p = 0.009) and rate of infectious complications (4 studies; RR 0.65; 95% CI 0.44, 0.95; p = 0.03). When FO was administered as a stand-alone medication outside PN, potential mortality benefits were observed compared to standard care.

CONCLUSION: Overall, these findings highlight distinctive omega-6 sparing effects attributed to PN. Among the different lipid emulsions, FO in combination with PN or as a stand-alone treatment may have the greatest clinical impact.

DOI: 10.1186/s13054-022-03896-3; No. 23

关键词：Humans; *Critical Illness/therapy; *Critical illness; *Parenteral Nutrition; *Fish oil; *Immunonutrition; *Omega-3 fatty acid; *Omega-6 fatty acid; *Parenteral nutrition; Emulsions; Fish Oils/therapeutic use

# 蛋白 C 作为成人脓毒症生物标志物的预后效用：系统综述和荟萃分析

摘要

背景：脓毒症是宿主对感染的应答失调，引发异常促凝和促炎性宿主反应。早期疾病干预的局限性突出了对有效诊断和预后生物标志物的需求。蛋白 C 作为抗凝和抗炎分子的作用使其成为败血症生物标志物研究的一个有吸引力的靶标。这项荟萃分析旨在评估蛋白 C (PC) 作为成人脓毒症生物标志物的诊断和预后价值。

方法：我们检索了 MEDLINE、PubMed、EMBASE、CINAHL 和 Cochrane Library 数据库，时间范围从建库至 2021 年 9 月 12 日。我们纳入了以下前瞻性观察性研究：(1) 伴有败血症或疑似败血症的成年患者 (> 17)；(2) 研究入院 24h 后测量 PC 水平；(3) 检查 PC 作为诊断或预后生物标志物的目标。两位作者使用预后研究质量 (QUIPS) 和诊断研究质量评估 - 2 (QUADAS-2) 工具筛选文章并进行偏倚风险 (RoB) 评估。如果数据充足，则进行荟萃分析，估计患者人群之间的标准化平均差异 (SMD)。

结果：纳入 12 项研究，综合 8 项进行荟萃分析。汇总分析表明，PC 水平降低的证据具有中等确定性，败血症存活者低于非存活者（6 项研究，741 例患者，SMD = 0.52，95% CI 0.24-0.81，p = 0.0003，I (2)= 55%），无弥散性血管内凝血 (DIC) 的败血症患者中，PC 水平下降幅度低于 DIC 患者的证据确定性较低（3 项研究，644 例患者，SMD = 0.97，95% CI 0.62-1.32，p < 0.00001，I (2)= 67%）。由于研究间对照人群的异质性，PC 不能作为一种诊断工具进行评价。结论与相关性：我们的综述证实，与非存活者和患有败血症但非弥散性血管内凝血 (DIC) 的患者相比，败血症存活者的 PC 水平显著升高。我们的评估受到了纳入研究中高 RoB 以及作为败血症生物标志物的 PC 的敏感性和特异性的较差报告的限制。未来的研究需要确定 PC 的敏感性和特异性，以确定其作为早期败血症识别生物标志物的临床意义。试验注册 PROSPERO 注册号：CRD42021229786。研究方案发表在 BMJ Open 上。

DOI: 10.1186/s13054-022-03887-4; No. 22

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# 更正：患者离开 ICU 前的生命体征昼夜节律：常规记录生理数据的回顾性观察分析

# The prognostic utility of protein C as a biomarker for adult sepsis: a systematic review and meta-analysis

Abstract

BACKGROUND: Sepsis, the dysregulated host response to infection, triggers abnormal pro-coagulant and pro-inflammatory host responses. Limitations in early disease intervention highlight the need for effective diagnostic and prognostic biomarkers. Protein C's role as an anticoagulant and anti-inflammatory molecule makes it an appealing target for sepsis biomarker studies. This meta-analysis aims to assess the diagnostic and prognostic value of protein C (PC) as a biomarker for adult sepsis.

METHODS: We searched MEDLINE, PubMed, EMBASE, CINAHL and Cochrane Library from database inception to September 12, 2021. We included prospective observational studies of (1) adult patients (> 17) with sepsis or suspicion of sepsis that; (2) measured PC levels with 24 h of study admission with; and (3) the goal of examining PC as a diagnostic or prognostic biomarker. Two authors screened articles and conducted risk of bias (RoB) assessment, using the Quality in Prognosis Studies (QUIPS) and the Quality Assessment in Diagnostic Studies-2 (QUADAS-2) tools. If sufficient data were available, meta-analysis was conducted to estimate the standardized mean difference (SMD) between patient populations.

RESULTS: Twelve studies were included, and 8 were synthesized for meta-analysis. Pooled analysis demonstrated moderate certainty of evidence that PC levels were less reduced in sepsis survivors compared to non-survivors (6 studies, 741 patients, SMD = 0.52, 95% CI 0.24-0.81, p = 0.0003, I(2) = 55%), and low certainty of evidence that PC levels were less reduced in septic patients without disseminated intravascular coagulation (DIC) compared to those with DIC (3 studies, 644 patients, SMD = 0.97, 95% CI 0.62-1.32, p < 0.00001, I(2) = 67%). PC could not be evaluated as a diagnostic tool due to heterogeneous control populations between studies. CONCLUSION AND RELEVANCE: Our review demonstrates that PC levels were significantly higher in sepsis survivors compared to non-survivors and patients with sepsis but not disseminated intravascular coagulation (DIC). Our evaluation is limited by high RoB in included studies and poor reporting of the sensitivity and specificity of PC as a sepsis biomarker. Future studies are needed to determine the sensitivity and specificity of PC to identify its clinical significance as a biomarker for early sepsis recognition. Trial Registration PROSPERO registration number: CRD42021229786. The study protocol was published in BMJ Open.

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DOI: 10.1186/s13054-022-03889-2; No. 21

关键词：Humans; Prognosis; Adult; Biomarkers; Observational Studies as Topic; *Sepsis; *Disseminated Intravascular Coagulation; *Sepsis/diagnosis; *Systematic review; *Biomarker; *Diagnostic; *Prognostic; *Protein C; Protein C

# Value of variation of end-tidal carbon dioxide for predicting fluid responsiveness during the passive leg raising test in patients with mechanical ventilation: a systematic review and meta-analysis

Abstract

BACKGROUND: The ability of end-tidal carbon dioxide (ΔEtCO2) for predicting fluid responsiveness has been extensively studied with conflicting results. This meta-analysis aimed to explore the value of ΔEtCO2 for predicting fluid responsiveness during the passive leg raising (PLR) test in patients with mechanical ventilation.

METHODS: PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched up to November 2021. The diagnostic odds ratio (DOR), sensitivity, and specificity were calculated. The summary receiver operating characteristic curve was estimated, and the area under the curve (AUROC) was calculated. Q test and I(2) statistics were used for study heterogeneity and publication bias was assessed by Deeks' funnel plot asymmetry test. We performed meta-regression analysis for heterogeneity exploration and sensitivity analysis for the publication bias.

RESULTS: Overall, six studies including 298 patients were included in this review, of whom 149 (50%) were fluid responsive. The cutoff values of ΔEtCO2 in four studies was 5%, one was 5.8% and the other one was an absolute increase 2 mmHg. Heterogeneity between studies was assessed with an overall Q = 4.098, I(2) = 51%, and P = 0.064. The pooled sensitivity and specificity for the overall population were 0.79 (95% CI 0.72-0.85) and 0.90 (95% CI 0.77-0.96), respectively. The DOR was 35 (95% CI 12-107). The pooled AUROC was 0.81 (95% CI 0.77-0.84). On meta-regression analysis, the number of patients was sources of heterogeneity. The sensitivity analysis showed that the pooled DOR ranged from 21 to 140 and the pooled AUC ranged from 0.92 to 0.96 when one study was omitted.

CONCLUSIONS: Though the limited number of studies included and study heterogeneity, our meta-analysis confirmed that the ΔEtCO2 performed moderately in predicting fluid responsiveness during the PLR test in patients with mechanical ventilation.

DOI: 10.1186/s13054-022-03890-9; No. 20

关键词：Humans; Fluid Therapy; Sensitivity and Specificity; *Meta-analysis; *Respiration, Artificial; *Mechanical ventilation; *Fluid responsiveness; *Carbon Dioxide; *End-tidal carbon dioxide; Leg

# Time-to-antibiotics and clinical outcomes in patients with sepsis and septic shock: a prospective nationwide multicenter cohort study

Abstract

BACKGROUND: Timely administration of antibiotics is one of the most important interventions in reducing mortality in sepsis. However, administering antibiotics within a strict time threshold in all patients suspected with sepsis will require huge amount of effort and resources and may increase the risk of unintentional exposure to broad-spectrum antibiotics in patients without infection with its consequences. Thus, controversy still exists on whether clinicians should target different time-to-antibiotics thresholds for patients with sepsis versus septic shock.

METHODS: This study analyzed prospectively collected data from an ongoing multicenter cohort of patients with sepsis identified in the emergency department. Adjusted odds ratios (ORs) were compared for in-hospital mortality of patients who had received antibiotics within 1 h to that of those who did not. Spline regression models were used to assess the association of time-to-antibiotics as continuous variables and increasing risk of in-hospital mortality. The differences in the association between time-to-antibiotics and in-hospital mortality were assessed according to the presence of septic shock.

RESULTS: Overall, 3035 patients were included in the analysis. Among them, 601 (19.8%) presented with septic shock, and 774 (25.5%) died. The adjusted OR for in-hospital mortality of patients whose time-to-antibiotics was within 1 h was 0.78 (95% confidence interval [CI] 0.61-0.99; p = 0.046). The adjusted OR for in-hospital mortality was 0.66 (95% CI 0.44-0.99; p = 0.049) and statistically significant in patients with septic shock, whereas it was 0.85 (95% CI 0.64-1.15; p = 0.300) in patients with sepsis but without shock. Among patients who received antibiotics within 3 h, those with septic shock showed 35% (p = 0.042) increased risk of mortality for every 1-h delay in antibiotics, but no such trend was observed in patients without shock.

CONCLUSION: Timely administration of antibiotics improved outcomes in patients with septic shock; however, the association between early antibiotic administration and outcome was not as clear in patients with sepsis without shock.

DOI: 10.1186/s13054-021-03883-0; No. 19

关键词：Humans; Prospective Studies; Cohort Studies; Emergency Service, Hospital; Retrospective Studies; Hospital Mortality; Anti-Bacterial Agents/therapeutic use; *Sepsis; *Mortality; *Sepsis/drug therapy; *Shock, Septic/drug therapy; *Septic shock; *Hour-1 bundle; *Time-to-antibiotics

DOI: 10.1186/s13054-021-03882-1; No. 18

关键词：Humans; Male; Prospective Studies; Aged; Respiration, Artificial; *COVID-19; SARS-CoV-2; *Critically ill patients; *Critical Illness; Intubation, Intratracheal; *ARDS; *Early intubation; *Pulmonary sequelae; *Respiratory management

DOI: 10.1186/s13054-021-03880-3; No. 17

关键词：Humans; Cohort Studies; *COVID-19; *Extracorporeal Membrane Oxygenation; *Respiratory Distress Syndrome; *Extracorporeal membrane oxygenation; *Patient selection

# Protein intake and outcome of critically ill patients: analysis of a large international database using piece-wise exponential additive mixed models

Abstract

BACKGROUND: Proteins are an essential part of medical nutrition therapy in critically ill patients. Guidelines almost universally recommend a high protein intake without robust evidence supporting its use.

METHODS: Using a large international database, we modelled associations between the hazard rate of in-hospital death and live hospital discharge (competing risks) and three categories of protein intake (low: < 0.8 g/kg per day, standard: 0.8-1.2 g/kg per day, high: > 1.2 g/kg per day) during the first 11 days after ICU admission (acute phase). Time-varying cause-specific hazard ratios (HR) were calculated from piece-wise exponential additive mixed models. We used the estimated model to compare five different hypothetical protein diets (an exclusively low protein diet, a standard protein diet administered early (day 1 to 4) or late (day 5 to 11) after ICU admission, and an early or late high protein diet).

RESULTS: Of 21,100 critically ill patients in the database, 16,489 fulfilled inclusion criteria for the analysis. By day 60, 11,360 (68.9%) patients had been discharged from hospital, 4,192 patients (25.4%) had died in hospital, and 937 patients (5.7%) were still hospitalized. Median daily low protein intake was 0.49 g/kg [IQR 0.27-0.66], standard intake 0.99 g/kg [IQR 0.89- 1.09], and high intake 1.41 g/kg [IQR 1.29-1.60]. In comparison with an exclusively low protein diet, a late standard protein diet was associated with a lower hazard of in-hospital death: minimum 0.75 (95% CI 0.64, 0.87), and a higher hazard of live hospital discharge: maximum HR 1.98 (95% CI 1.72, 2.28). Results on hospital discharge, however, were qualitatively changed by a sensitivity analysis. There was no evidence that an early standard or a high protein intake during the acute phase was associated with a further improvement of outcome.

CONCLUSIONS: Provision of a standard protein intake during the late acute phase may improve outcome compared to an exclusively low protein diet. In unselected critically ill patients, clinical outcome may not be improved by a high protein intake during the acute phase. Study registration ID number ISRCTN17829198.

DOI: 10.1186/s13054-021-03870-5; No. 7

关键词：Humans; Intensive Care Units; *Survival; Hospital Mortality; *Critical care; *Critical Illness; Databases, Factual; *Nutrition; *Nutrition Therapy; *Protein supply

# Hyperoxemia in postsurgical sepsis/septic shock patients is associated with reduced mortality

Abstract

BACKGROUND: Despite growing interest in treatment strategies that limit oxygen exposure in ICU patients, no studies have compared conservative oxygen with standard oxygen in postsurgical patients with sepsis/septic shock, although there are indications that it may improve outcomes. It has been proven that high partial pressure of oxygen in arterial blood (PaO(2)) reduces the rate of surgical-wound infections and mortality in patients under major surgery. The aim of this study is to examine whether PaO(2) is associated with risk of death in adult patients with sepsis/septic shock after major surgery.

METHODS: We performed a secondary analysis of a prospective observational study in 454 patients who underwent major surgery admitted into a single ICU. Patients were stratified in two groups whether they had hyperoxemia, defined as PaO(2) > 100 mmHg (n = 216), or PaO(2) ≤ 100 mmHg (n = 238) at the day of sepsis/septic shock onset according to SEPSIS-3 criteria maintained during 48 h. Primary end-point was 90-day mortality after diagnosis of sepsis. Secondary endpoints were ICU length of stay and time to extubation.

RESULTS: In patients with PaO(2) ≤ 100 mmHg, we found prolonged mechanical ventilation (2 [8] vs. 1 [4] days, p < 0.001), higher ICU stay (8 [13] vs. 5 [9] days, p < 0.001), higher organ dysfunction as assessed by SOFA score (9 [3] vs. 7 [5], p < 0.001), higher prevalence of septic shock (200/238, 84.0% vs 145/216) 67.1%, p < 0.001), and higher 90-day mortality (37.0% [88] vs. 25.5% [55], p = 0.008). Hyperoxemia was associated with higher probability of 90-day survival in a multivariate analysis (OR 0.61, 95%CI: 0.39-0.95, p = 0.029), independent of age, chronic renal failure, procalcitonin levels, and APACHE II score > 19. These findings were confirmed when patients with severe hypoxemia at the time of study inclusion were excluded.

CONCLUSIONS: Oxygenation with a PaO(2) above 100 mmHg was independently associated with lower 90-day mortality, shorter ICU stay and intubation time in critically ill postsurgical sepsis/septic shock patients. Our findings open a new venue for designing clinical trials to evaluate the boundaries of PaO(2) in postsurgical patients with severe infections.

DOI: 10.1186/s13054-021-03875-0; No. 4

关键词：Humans; Prognosis; Prospective Studies; Intensive Care Units; Adult; *Sepsis; *Outcome; *Shock, Septic; *Hyperoxemia; *Infection; *Septic Shock; *Surgical patients; Procalcitonin

DOI: 10.1186/s13054-021-03837-6; No. 15

关键词：Humans; *Ceftolozane/tazobactam, meropenem; *Cephalosporins/therapeutic use; *Confounders; *CRRT; *Ventilator hospital-acquired bacterial pneumonia; Meropenem/pharmacology/therapeutic use; Tazobactam/pharmacology/therapeutic use

Abstract

BACKGROUND: In patients with COVID-19-related acute respiratory failure (ARF), awake prone positioning (AW-PP) reduces the need for intubation in patients treated with high-flow nasal oxygen (HFNO). However, the effects of different exposure times on clinical outcomes remain unclear. We evaluated the effect of AW-PP on the risk of endotracheal intubation and in-hospital mortality in patients with COVID-19-related ARF treated with HFNO and analyzed the effects of different exposure times to AW-PP.

METHODS: This multicenter prospective cohort study in six ICUs of 6 centers in Argentine consecutively included patients > 18 years of age with confirmed COVID-19-related ARF requiring HFNO from June 2020 to January 2021. In the primary analysis, the main exposure was awake prone positioning for at least 6 h/day, compared to non-prone positioning (NON-PP). In the sensitivity analysis, exposure was based on the number of hours receiving AW-PP. Inverse probability weighting-propensity score (IPW-PS) was used to adjust the conditional probability of treatment assignment. The primary outcome was endotracheal intubation (ETI); and the secondary outcome was hospital mortality.

RESULTS: During the study period, 580 patients were screened and 335 were included; 187 (56%) tolerated AW-PP for [median (p25-75)] 12 (9-16) h/day and 148 (44%) served as controls. The IPW-propensity analysis showed standardized differences < 0.1 in all the variables assessed. After adjusting for other confounders, the OR (95% CI) for ETI in the AW-PP group was 0.36 (0.2-0.7), with a progressive reduction in OR as the exposure to AW-PP increased. The adjusted OR (95% CI) for hospital mortality in the AW-PP group ≥ 6 h/day was 0.47 (0.19-1.31). The exposure to prone positioning ≥ 8 h/d resulted in a further reduction in OR [0.37 (0.17-0.8)].

CONCLUSION: In the study population, AW-PP for ≥ 6 h/day reduced the risk of endotracheal intubation, and exposure ≥ 8 h/d reduced the risk of hospital mortality.

DOI: 10.1186/s13054-021-03881-2; No. 16

关键词：Humans; Treatment Outcome; Prospective Studies; Time Factors; Administration, Intranasal; *COVID-19; Prone Position; *COVID-19/complications; *Mortality; *Prone position; *Oxygen Inhalation Therapy/methods; Oxygen/administration & dosage; *Acute respiratory failure; Wakefulness; *Endotracheal intubation; *Awake; *Respiratory Insufficiency/therapy/virology

DOI: 10.1186/s13054-021-03862-5; No. 14

关键词：Humans; Systemic Inflammatory Response Syndrome; Biomarkers; *Sepsis; *Shock, Septic; *Sepsis/diagnosis; *Septic shock; *Biomarker; *Sepsis-associated encephalopathy; *Systemic inflammatory response; Leukocytosis

# Association between unmet medication needs after hospital discharge and readmission or death among acute respiratory failure survivors: the addressing post-intensive care syndrome (APICS-01) multicenter prospective cohort study

Abstract

INTRODUCTION: Survivors of acute respiratory failure (ARF) commonly experience long-lasting physical, cognitive, and/or mental health impairments. Unmet medication needs occurring immediately after hospital discharge may have an important effect on subsequent recovery.

METHODS AND ANALYSIS: In this multicenter prospective cohort study, we enrolled ARF survivors who were discharged directly home from their acute care hospitalization. The primary exposure was unmet medication needs. The primary outcome was hospital readmission or death within 3 months after discharge. We performed a propensity score analysis, using inverse probability weighting for the primary exposure, to evaluate the exposure-outcome association, with an a priori sample size of 200 ARF survivors.

RESULTS: We enrolled 200 ARF survivors, of whom 107 (53%) were female and 77 (39%) were people of color. Median (IQR) age was 55 (43-66) years, APACHE II score 20 (15-26) points, and hospital length of stay 14 (9-21) days. Of the 200 participants, 195 (98%) were in the analytic cohort. One hundred fourteen (57%) patients had at least one unmet medication need; the proportion of medication needs that were unmet was 6% (0-15%). Fifty-six (29%) patients were readmitted or died by 3 months; 10 (5%) died within 3 months. Unmet needs were not associated (risk ratio 1.25; 95% CI 0.75-2.1) with hospital readmission or death, although a higher proportion of unmet needs may have been associated with increased hospital readmission (risk ratio 1.7; 95% CI 0.96-3.1) and decreased mortality (risk ratio 0.13; 95% CI 0.02-0.99). DISCUSSION: Unmet medication needs are common among survivors of acute respiratory failure shortly after discharge home. The association of unmet medication needs with 3-month readmission and mortality is complex and requires additional investigation to inform clinical trials of interventions to reduce unmet medication needs. Study registration number: NCT03738774 . The study was prospectively registered before enrollment of the first patient.

DOI: 10.1186/s13054-021-03848-3; No. 6

关键词：Humans; Female; Middle Aged; Prospective Studies; Aged; Critical Illness; Patient Readmission; Cohort Studies; Survivors; Hospitals; *Patient Discharge; *Respiratory Insufficiency; *Acute respiratory failure; *Long-term outcomes; *Discharge planning; *Health services research

DOI: 10.1186/s13054-021-03878-x; No. 13

关键词：Humans; Female; Middle Aged; Prospective Studies; Critical Illness; Intensive Care Units; Biomarkers; *Acute Kidney Injury; Kidney/physiology; *Acute kidney injury; *Galectin 3; *Galectin-3; *Major Adverse Kidney Event; *Renal biomarker

DOI: 10.1186/s13054-021-03879-w; No. 8

关键词：Humans; Prospective Studies; Retrospective Studies; Prone Position; *Respiratory Distress Syndrome/therapy; *Extracorporeal Membrane Oxygenation; *Mortality; Patient Positioning; *Extracorporeal membrane oxygenation; *Acute respiratory distress syndrome; *Prone positioning; *Pooled data analysis; Data Analysis

DOI: 10.1186/s13054-021-03884-z; No. 10

关键词：Humans; Prospective Studies; Critical Illness; Intensive Care Units; Adult; *COVID-19; *Infection control; Nasopharynx/virology; COVID-19 Nucleic Acid Testing; *COVID-19/therapy/virology; *RT-PCR; *SARS-CoV-2/isolation & purification; *Viral culture

# Invasive pulmonary aspergillosis among intubated patients with SARS-CoV-2 or influenza pneumonia: a European multicenter comparative cohort study

Abstract

BACKGROUND: Recent multicenter studies identified COVID-19 as a risk factor for invasive pulmonary aspergillosis (IPA). However, no large multicenter study has compared the incidence of IPA between COVID-19 and influenza patients. OBJECTIVES: To determine the incidence of putative IPA in critically ill SARS-CoV-2 patients, compared with influenza patients.

METHODS: This study was a planned ancillary analysis of the coVAPid multicenter retrospective European cohort. Consecutive adult patients requiring invasive mechanical ventilation for > 48 h for SARS-CoV-2 pneumonia or influenza pneumonia were included. The 28-day cumulative incidence of putative IPA, based on Blot definition, was the primary outcome. IPA incidence was estimated using the Kalbfleisch and Prentice method, considering extubation (dead or alive) within 28 days as competing event.

RESULTS: A total of 1047 patients were included (566 in the SARS-CoV-2 group and 481 in the influenza group). The incidence of putative IPA was lower in SARS-CoV-2 pneumonia group (14, 2.5%) than in influenza pneumonia group (29, 6%), adjusted cause-specific hazard ratio (cHR) 3.29 (95% CI 1.53-7.02, p = 0.0006). When putative IPA and Aspergillus respiratory tract colonization were combined, the incidence was also significantly lower in the SARS-CoV-2 group, as compared to influenza group (4.1% vs. 10.2%), adjusted cHR 3.21 (95% CI 1.88-5.46, p < 0.0001). In the whole study population, putative IPA was associated with significant increase in 28-day mortality rate, and length of ICU stay, compared with colonized patients, or those with no IPA or Aspergillus colonization.

CONCLUSIONS: Overall, the incidence of putative IPA was low. Its incidence was significantly lower in patients with SARS-CoV-2 pneumonia than in those with influenza pneumonia. Clinical trial registration The study was registered at ClinicalTrials.gov, number NCT04359693 .

DOI: 10.1186/s13054-021-03874-1; No. 11

关键词：Humans; Adult; Retrospective Studies; Incidence; *COVID-19; SARS-CoV-2; *Intensive care unit; *Mechanical ventilation; Europe/epidemiology; *COVID-19/epidemiology/therapy; *Intubation; *Influenza, Human/epidemiology/therapy; *Invasive pulmonary aspergillosis; *Invasive Pulmonary Aspergillosis/epidemiology; *Severe influenza

DOI: 10.1186/s13054-021-03873-2; No. 9

关键词：Humans; Treatment Outcome; Pilot Projects; Biomarkers; *COVID-19/drug therapy; *Corticosteroids; *Coronavirus disease 2019; *C-reactive protein; *Steroids/administration & dosage

DOI: 10.1186/s13054-021-03876-z; No. 12

关键词：Humans; Positive-Pressure Respiration; SARS-CoV-2; *COVID-19/complications; *Mechanical ventilation; *Acute respiratory distress syndrome; *Respiratory mechanics; *Lung/physiopathology; *Recruitability; *Recruitment maneuver; *Respiratory Distress Syndrome/therapy/virology

# Vitamin C for ≥ 5 days is associated with decreased hospital mortality in sepsis subgroups: a nationwide cohort study

Abstract

BACKGROUND: Previous randomized trials of vitamin C, hydrocortisone, and thiamine on sepsis were limited by short-term vitamin C administration, heterogeneous populations, and the failure to evaluate each component's effect. The purpose of this study was to determine whether vitamin C alone for ≥ 5 days or in combination with corticosteroids and/or thiamine was associated with decreased mortality across the sepsis population and subpopulation.

METHODS: Nationwide population-based study conducted using the Korean National Health Insurance Service database. A total of 384,282 adult patients with sepsis who were admitted to the intensive care unit were enrolled from January 2017 to December 2019. The primary outcome was hospital mortality, while the key secondary outcome was 90-day mortality.

RESULTS: The mean [standard deviation] age was 69.0 [15.4] years; 57% were male; and 36,327 (9%) and 347,955 did and did not receive vitamin C, respectively. After propensity score matching, each group involved 36,327 patients. The hospital mortality was lower by - 0.9% in the treatment group (17.1% vs 18.0%; 95% confidence interval, - 1.3 to - 0.5%; p < 0.001), a significant but extremely small difference. However, mortality decreased greater in patients who received vitamin C for ≥ 5 days (vs 1-2 or 3-4 days) (15.8% vs 18.8% vs 18.3%; p < 0.001). Further, vitamin C was associated with a lower hospital mortality in patients with older age, multiple comorbidities, pneumonia, genitourinary infection, septic shock, and mechanical ventilation. Consistent findings were found for 90-day mortality. Moreover, vitamin C alone or in combination with thiamine was significantly associated with decreased hospital mortality.

CONCLUSIONS: Intravenous vitamin C of ≥ 5 days was significantly associated with decreased hospital and 90-day mortality in sepsis patients. Vitamin C combined with corticosteroids and/or thiamine in specific sepsis subgroups warrants further study.

DOI: 10.1186/s13054-021-03872-3; No. 3

关键词：Humans; Drug Therapy, Combination; Male; Aged; Adult; Cohort Studies; Adolescent; Hospital Mortality; *Sepsis; *Steroids; *Mortality; *Sepsis/drug therapy; *Shock, Septic/drug therapy; Ascorbic Acid/therapeutic use; Thiamine/therapeutic use; *Septic shock; *Ascorbic acid; *Thiamine

# Mechanical power in pediatric acute respiratory distress syndrome: a PARDIE study

Abstract

BACKGROUND: Mechanical power is a composite variable for energy transmitted to the respiratory system over time that may better capture risk for ventilator-induced lung injury than individual ventilator management components. We sought to evaluate if mechanical ventilation management with a high mechanical power is associated with fewer ventilator-free days (VFD) in children with pediatric acute respiratory distress syndrome (PARDS).

METHODS: Retrospective analysis of a prospective observational international cohort study.

RESULTS: There were 306 children from 55 pediatric intensive care units included. High mechanical power was associated with younger age, higher oxygenation index, a comorbid condition of bronchopulmonary dysplasia, higher tidal volume, higher delta pressure (peak inspiratory pressure-positive end-expiratory pressure), and higher respiratory rate. Higher mechanical power was associated with fewer 28-day VFD after controlling for confounding variables (per 0.1 J·min(-1)·Kg(-1) Subdistribution Hazard Ratio (SHR) 0.93 (0.87, 0.98), p = 0.013). Higher mechanical power was not associated with higher intensive care unit mortality in multivariable analysis in the entire cohort (per 0.1 J·min(-1)·Kg(-1) OR 1.12 [0.94, 1.32], p = 0.20). But was associated with higher mortality when excluding children who died due to neurologic reasons (per 0.1 J·min(-1)·Kg(-1) OR 1.22 [1.01, 1.46], p = 0.036). In subgroup analyses by age, the association between higher mechanical power and fewer 28-day VFD remained only in children < 2-years-old (per 0.1 J·min(-1)·Kg(-1) SHR 0.89 (0.82, 0.96), p = 0.005). Younger children were managed with lower tidal volume, higher delta pressure, higher respiratory rate, lower positive end-expiratory pressure, and higher PCO(2) than older children. No individual ventilator management component mediated the effect of mechanical power on 28-day VFD.

CONCLUSIONS: Higher mechanical power is associated with fewer 28-day VFDs in children with PARDS. This association is strongest in children < 2-years-old in whom there are notable differences in mechanical ventilation management. While further validation is needed, these data highlight that ventilator management is associated with outcome in children with PARDS, and there may be subgroups of children with higher potential benefit from strategies to improve lung-protective ventilation. TAKE HOME MESSAGE: Higher mechanical power is associated with fewer 28-day ventilator-free days in children with pediatric acute respiratory distress syndrome. This association is strongest in children <2-years-old in whom there are notable differences in mechanical ventilation management.

# 机械通气在急性呼吸窘迫综合征患儿中的应用：一项 PARDIE 研究

摘要

背景：机械动力是随时间推移传递至呼吸系统的能量的复合变量，与单独的呼吸机管理组件相比，可能更好地捕获呼吸机诱导肺损伤的风险。我们试图评估在急性呼吸窘迫综合征 (PARDS) 患儿中，高机械功率的机械通气管理是否与较少的无呼吸机天数 (VFD) 相关。

方法：前瞻性观察性国际队列研究的回顾性分析。

结果：共有 306 名儿童来自 55 个儿科重症监护室。高机械功率与年龄较小、氧合指数较高、合并存在支气管肺发育不良、潮气量较高、δ 压（吸气峰压 - 呼气末正压）较高和呼吸率较高相关。在控制混杂变量（每 0.1 J・min (-1)・Kg (-1) 子分布风险比 (SHR) 0.93 (0.87，0.98)，p = 0.013）后，较高的机械功率与较少的 28 天 VFD 相关。在整个队列的多变量分析中（每 0.1 J・min (-1)・Kg (-1) OR 1.12 [0.94，1.32]，p = 0.20），较高的机械功率与较高的重症监护室死亡率无关。但当排除因神经系统原因死亡的儿童时，死亡率更高（每 0.1 J・min (-1)・Kg (-1) 或 1.22 [1.01，1.46]，p = 0.036）。在按年龄进行的亚组分析中，较高的机械功率与较少的 28 天 VFD 之间的相关性仅在 < 2 岁的儿童中存在（每 0.1 J・min (-1)・Kg (-1) SHR 0.89 (0.82，0.96)，p = 0.005）。较年幼儿童的潮气量较年长儿童更低，δ 压更高，呼吸频率更高，呼气末正压更低，PCO (2) 更高。没有单独的呼吸机管理组件介导机械功率对 28 天 VFD 的影响。

结论：在 PARDS 儿童中，较高的机械功率与较少的 28 天 VFD 相关。这种相关性在机械通气管理存在显著差异的 2 岁以下儿童中最强。尽管需要进一步验证，但这些数据强调，呼吸机管理与 PARDS 儿童的结局相关，并且可能有亚组儿童从改善肺保护通气的策略中获得更高的潜在获益。家庭消息：较高的机械功率与儿科急性呼吸窘迫综合征患儿较少的 28 天无呼吸机治疗天数相关。这种相关性在机械通气管理存在显著差异的 2 岁以下儿童中最强。

DOI: 10.1186/s13054-021-03853-6; No. 2

关键词：Humans; Adult; Cohort Studies; Adolescent; Retrospective Studies; Child; Infant, Newborn; Child, Preschool; *Critical care; Respiration, Artificial/adverse effects; Intensive Care Units, Pediatric; *Respiratory Distress Syndrome; *Pediatrics; *Ventilator-induced lung injury; *Mechanical; *Ventilators

DOI: 10.1186/s13054-021-03867-0; No. 5

关键词：Humans; *Gastrointestinal Microbiome; Dysbiosis; Gastrointestinal Tract; *Analgesics, Opioid/adverse effects

# Sildenafil for treating patients with COVID-19 and perfusion mismatch: a pilot randomized trial

Abstract

BACKGROUND: SARS-CoV-2 seems to affect the regulation of pulmonary perfusion. Hypoperfusion in areas of well-aerated lung parenchyma results in a ventilation-perfusion mismatch that can be characterized using subtraction computed tomography angiography (sCTA). This study aims to evaluate the efficacy of oral sildenafil in treating COVID-19 inpatients showing perfusion abnormalities in sCTA.

METHODS: Triple-blinded, randomized, placebo-controlled trial was conducted in Chile in a tertiary-care hospital able to provide on-site sCTA scans and ventilatory support when needed between August 2020 and March 2021. In total, 82 eligible adults were admitted to the ED with RT-PCR-confirmed or highly probable SARS-COV-2 infection and sCTA performed within 24 h of admission showing perfusion abnormalities in areas of well-aerated lung parenchyma; 42 were excluded and 40 participants were enrolled and randomized (1:1 ratio) once hospitalized. The active intervention group received sildenafil (25 mg orally three times a day for seven days), and the control group received identical placebo capsules in the same way. Primary outcomes were differences in oxygenation parameters measured daily during follow-up (PaO(2)/FiO(2) ratio and A-a gradient). Secondary outcomes included admission to the ICU, requirement of non-invasive ventilation, invasive mechanical ventilation (IMV), and mortality rates. Analysis was performed on an intention-to-treat basis.

RESULTS: Totally, 40 participants were enrolled (20 in the placebo group and 20 in the sildenafil group); 33 [82.5%] were male; and median age was 57 [IQR 41-68] years. No significant differences in mean PaO(2)/FiO(2) ratios and A-a gradients were found between groups (repeated-measures ANOVA p = 0.67 and p = 0.69). IMV was required in 4 patients who received placebo and none in the sildenafil arm (logrank p = 0.04). Patients in the sildenafil arm showed a significantly shorter median length of hospital stay than the placebo group (9 IQR 7-12 days vs. 12 IQR 9-21 days, p = 0.04).

CONCLUSIONS: No statistically significant differences were found in the oxygenation parameters. Sildenafil treatment could have a potential therapeutic role regarding the need for IMV in COVID-19 patients with specific perfusion patterns in sCTA. A large-scale study is needed to confirm these results.

DOI: 10.1186/s13054-021-03885-y; No. 1

关键词：Humans; Treatment Outcome; Female; Male; Middle Aged; Aged; Adult; Pilot Projects; *COVID-19; *Intensive care unit; Administration, Oral; *Mechanical ventilation; *Blood gas analysis; *COVID-19/drug therapy/physiopathology; *Length of stay; *Sildenafil; *Sildenafil Citrate/administration & dosage; *Subtraction CT angiography; *Vasodilator Agents/administration & dosage; *Ventilation–perfusion ratio; Ventilation-Perfusion Ratio

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上次更新: 2022/08/11, 23:04:56

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