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Supplemental Digital Content is available in the text., OBJECTIVES: Critical care medicine is a natural environment for machine learning approaches to improve outcomes for critically ill patients as admissions to ICUs generate vast amounts of data. However, technical, legal, ethical, and privacy concerns have so far limited the critical care medicine community from making these data readily available. The Society of Critical Care Medicine and the European Society of Intensive Care Medicine have identified ICU patient data sharing as one of the priorities under their Joint Data Science Collaboration. To encourage ICUs worldwide to share their patient data responsibly, we now describe the development and release of Amsterdam University Medical Centers Database (AmsterdamUMCdb), the first freely available critical care database in full compliance with privacy laws from both the United States and Europe, as an example of the feasibility of sharing complex critical care data. SETTING: University hospital ICU. SUBJECTS: Data from ICU patients admitted between 2003 and 2016. INTERVENTIONS: We used a risk-based deidentification strategy to maintain data utility while preserving privacy. In addition, we implemented contractual and governance processes, and a communication strategy. Patient organizations, supporting hospitals, and experts on ethics and privacy audited these processes and the database. MEASUREMENTS AND MAIN RESULTS: AmsterdamUMCdb contains approximately 1 billion clinical data points from 23,106 admissions of 20,109 patients. The privacy audit concluded that reidentification is not reasonably likely, and AmsterdamUMCdb can therefore be considered as anonymous information, both in the context of the U.S. Health Insurance Portability and Accountability Act and the European General Data Protection Regulation. The ethics audit concluded that responsible data sharing imposes minimal burden, whereas the potential benefit is tremendous. CONCLUSIONS: Technical, legal, ethical, and privacy challenges related to responsible data sharing can be addressed using a multidisciplinary approach. A risk-based deidentification strategy, that complies with both U.S. and European privacy regulations, should be the preferred approach to releasing ICU patient data. This supports the shared Society of Critical Care Medicine and European Society of Intensive Care Medicine vision to improve critical care outcomes through scientific inquiry of vast and combined ICU datasets.

Supplemental Digital Content is available in the text., OBJECTIVES: To demonstrate the efficacy, safety, and pharmacokinetics of dexmedetomidine as a potential sedative for pediatric surgery patients in the ICU. DESIGN: Phase 3, multicenter, open-label study. SETTING: This study included 61 patients at 13 tertiary hospitals in Japan. PATIENTS: Pediatric patients (≥ 45 wk corrected gestational age to < 17 yr) undergoing intensive care treatment with mechanical ventilation requiring greater than 6 hours estimated duration of sedation following elective cardiac surgery. INTERVENTIONS: Dexmedetomidine was IV administered without a loading dose at age-specific dose regimens 0.2–1.4 (< 6 yr) and 0.2–1.0 µg/kg/hr (≥ 6 yr). The primary endpoint was the percentage of patients who did not require a rescue sedative (midazolam) infusion during mechanical ventilation or for the first 24 hours of a greater than 24 hours ventilation following the commencement of dexmedetomidine administration. MEASUREMENTS AND MAIN RESULTS: Overall, 47 of the 61 patients (77.0%) did not require rescue midazolam. Adverse events were reported in 53 patients (86.9%). Frequently observed adverse events were hypotension (47.5%), bradycardia (31.1%), and respiratory depression (26.2%). Most of these adverse events were mild, a few moderate, and none severe. Although serious adverse events occurred in four patients, including one cardiac tamponade resulting in the withdrawal of dexmedetomidine, none of the adverse events resulted in mortality or were directly related to dexmedetomidine. The plasma dexmedetomidine concentration generally reached the target concentration of 0.3–1.25 ng/mL at 1–2 hours prior to completion of administration or immediately prior to the commencement of tapering. CONCLUSIONS: The age-specific dose regimens of dexmedetomidine without an initial loading dose achieved an adequate sedation level during mechanical ventilation and caused no clinically significant adverse events in the intensive care pediatric patients. These effects were achieved within the therapeutic range of dexmedetomidine plasma concentration and were accompanied by minimal effects on hemodynamics and respiration.

Supplemental Digital Content is available in the text., OBJECTIVES: To 1) analyze the short-term biochemical improvements and clinical outcomes following treatment of children with post-severe acute respiratory syndrome coronavirus-2 inflammatory syndrome (multisystem inflammatory syndrome in children/pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus-2) admitted to U.K. PICUs and 2) collate current treatment guidance from U.K. PICUs. DESIGN: Multicenter observational study. SETTING: Twenty-one U.K. PICUs. PATIENTS: Children (< 18 yr) admitted to U.K. PICUs between April 1, 2020, and May 10, 2020, fulfilling the U.K. case definition of pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus-2. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Routinely collected, deidentified data were analyzed. Propensity score and linear mixed effects models were used to analyze the effect of steroids, IV immunoglobulin, and biologic agents on changes in C-reactive protein, platelet counts, and lymphocyte counts over the course of PICU stay. Treatment recommendations from U.K. clinical guidelines were analyzed. Over the 6-week study period, 59 of 78 children (76%) received IV immunoglobulin, 57 of 78 (73%) steroids, and 18 of 78 (24%) a biologic agent. We found no evidence of a difference in response in clinical markers of inflammation between patients with multisystem inflammatory syndrome in children/pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus-2 who were treated with IV immunoglobulin, steroids, or biologics, compared with those who were not. By the end of the study period, most patients had received immunomodulation. The 12 patients who did not receive any immunomodulators had similar decrease in inflammatory markers as those treated. Of the 14 guidelines analyzed, the use of IV immunoglobulin, steroids, and biologics was universally recommended. CONCLUSIONS: We were unable to identify any short-term benefit from any of the treatments, or treatment combinations, administered. Despite a lack of evidence, treatment guidelines for multisystem inflammatory syndrome in children/pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus-2 have become very similar in advising step-wise treatments. Retaining clinical equipoise regarding treatment will allow clinicians to enroll children in robust clinical trials to determine the optimal treatment for this novel important condition.

Supplemental Digital Content is available in the text., OBJECTIVES: Although early recognition of sepsis is vital to improving outcomes, the diagnosis may be missed or delayed in many patients. Acute kidney injury is one of the most common organ failures in patients with sepsis but may not be apparent on presentation. Novel biomarkers for acute kidney injury might improve organ failure recognition and facilitate earlier sepsis care. DESIGN: Retrospective, international, Sapphire study. SETTING: Academic Medical Center. PATIENTS: Adults admitted to the ICU without evidence of acute kidney injury at time of enrollment. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We stratified patients enrolled in the Sapphire study into three groups—those with a clinical diagnosis of sepsis (n = 216), those with infection without sepsis (n = 120), and those without infection (n = 387) at enrollment. We then examined 30-day mortality stratified by acute kidney injury within each group. Finally, we determined the operating characteristics for kidney stress markers (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) for prediction of acute kidney injury as a sepsis-defining organ failure in patients with infection without a clinical diagnosis of sepsis at enrollment. Combining all groups, 30-day mortality was 23% for patients who developed stage 2–3 acute kidney injury within the first 3 days compared with 14% without stage 2–3 acute kidney injury. However, this difference was greatest in the infection without sepsis group (34% vs 11%; odds ratio, 4.09; 95% CI, 1.53–11.12; p = 0.005). Using a (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) cutoff of 2.0 units, 14 patients (11.7%), in the infection/no sepsis group, tested positive of which 10 (71.4%) developed stage 2–3 acute kidney injury. The positive test result occurred a median of 19 hours (interquartile range, 0.8–34.0 hr) before acute kidney injury manifested by serum creatinine or urine output. Similar results were obtained using a cutoff of 1.0 for any stage of acute kidney injury. CONCLUSIONS: Use of the urinary (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) test could identify acute kidney injury in patients with infection, possibly helping to detect sepsis, nearly a day before acute kidney injury is apparent by clinical criteria.

Supplemental Digital Content is available in the text., Objectives: Amniotic fluid embolism is a rare disease that induces fatal coagulopathy; however, due to its rarity, it has not yet been examined in detail. The strict diagnostic criteria by Clark for amniotic fluid embolism include severe coagulopathy complicated by cardiopulmonary insufficiency, whereas the Japanese criteria also include postpartum hemorrhage or Disseminated Intravascular Coagulation in clinical practice. Amniotic fluid embolism cases with preceding consumptive coagulopathy may exist and are potential clinical targets for earlier assessments and interventions among amniotic fluid embolism cases fulfilling the Japanese, but not Clark criteria. The present study was performed to compare coagulopathy in the earlier stage between the amniotic fluid embolism patients diagnosed by Clark criteria (Clark group, n = 6), those by the Japanese criteria (Non-Clark group, n = 10), and peripartum controls and identify optimal clinical markers for earlier assessments of amniotic fluid embolism-related consumptive coagulopathy. Design: Retrospective case-control study. Setting: A single university-based center. Our amniotic fluid embolism registry program has accumulated clinical information and blood samples since 2003. Patients: Amniotic fluid embolism patients in the Clark and Non-Clark groups between 2009 and 2017 and peripartum controls. Interventions: None. Measurements and Main Results: Clinical information was collected on hemoglobin levels, platelet counts, and coagulation- and fibrinolysis-related variables. Fibrinolytic parameters were also measured and compared among the three groups before blood transfusion. Fibrinogen levels in all patients in the Clark group and most in the Non-Clark group decreased earlier than hemoglobin levels, which was consistent with the high hemoglobin/fibrinogen ratio and, thus, is a promising clinical marker for the earlier assessment of amniotic fluid embolism-related consumptive coagulopathy. Conclusions: Earlier evaluations of consumptive coagulopathy and hyperfibrinolysis using the hemoglobin/fibrinogen ratio following preemptive treatment may reduce the occurrence or prevent the aggravation of severe coagulopathy in amniotic fluid embolism patients.

Supplemental Digital Content is available in the text., OBJECTIVES: We aimed to assess the frequency of ICU-acquired bloodstream infections in coronavirus disease 2019 patients. DESIGN: Retrospective observational study. SETTING: The emergency expansion of an ICU from eight general beds to 30 coronavirus disease 2019 beds. PARTICIPANTS: Patients with coronavirus disease 2019 admitted to the ICU of Luigi Sacco Hospital (Milan, Italy) for greater than or equal to 48 hours between February 21, 2020, and April 30, 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The frequency of bloodstream infections per 1,000 days of ICU stay was calculated in 89 coronavirus disease 2019 patients, and the cumulative probability of bloodstream infection was estimated using death and ICU discharge as competing events. Sixty patients (67.4%) experienced at least one of the 93 recorded episodes of bloodstream infection, a frequency of 87 per 1,000 days of ICU stay (95% CI, 67–112).The patients who experienced a bloodstream infection had a higher Sequential Organ Failure Assessment score upon ICU admission (9.5; interquartile range, 8–12 vs 8, interquartile range, 5–10; p = 0.042), a longer median ICU stay (15 d; interquartile range, 11–23 vs 8, interquartile range, 5–12; p < 0.001), and more frequently required invasive mechanical ventilation (98.3% vs 82.8%; p = 0.013) than those who did not. The median time from ICU admission to the first bloodstream infection episode was 10 days. Gram-positive bacteria accounted for 74 episodes (79.6%), with Enterococcus species being the most prevalent (53 episodes, 55.8%). Thirty-two isolates (27.3%) showed multidrug resistance. CONCLUSIONS: Coronavirus disease 2019 seemed to increase the frequency of bloodstream infections (particularly Enterococcus-related bloodstream infection) after ICU admission. This may have been due to enteric involvement in patients with severe coronavirus disease 2019 and/or limitations in controlling the patient-to-patient transmission of infectious agents in extremely challenging circumstances.

Supplemental Digital Content is available in the text., Objectives: Recovery from coma might critically depend on the structural and functional integrity of frontoparietal networks. We aimed to measure this integrity in traumatic brain injury and anoxo-ischemic (cardiac arrest) coma patients by using an original multimodal MRI protocol. Design: Prospective cohort study. Setting: Three Intensive Critical Care Units affiliated to the University in Toulouse (France). Patients: We longitudinally recruited 43 coma patients (Glasgow Coma Scale at the admission < 8; 29 cardiac arrest and 14 traumatic brain injury) and 34 age-matched healthy volunteers. Exclusion criteria were disorders of consciousness lasting more than 30 days and focal brain damage within the explored brain regions. Patient assessments were conducted at least 2 days (5 ± 2 d) after complete withdrawal of sedation. All patients were followed up (Coma Recovery Scale-Revised) 3 months after acute brain injury. Interventions: None. Measurements and Main Results: Functional and structural MRI data were recorded, and the analysis was targeted on the posteromedial cortex, the medial prefrontal cortex, and the cingulum. Univariate analyses and machine learning techniques were used to assess diagnostic and predictive values. Coma patients displayed significantly lower medial prefrontal cortex–posteromedial cortex functional connectivity (area under the curve, 0.94; 95% CI, 0.93–0.95). Cardiac arrest patients showed specific structural disturbances within posteromedial cortex. Significant cingulum architectural disturbances were observed in traumatic brain injury patients. The machine learning medial prefrontal cortex–posteromedial cortex multimodal classifier had a significant predictive value (area under the curve, 0.96; 95% CI, 0.95–0.97), best combination of subregions that discriminates a binary outcome based on Coma Recovery Scale-Revised). Conclusions: This exploratory study suggests that frontoparietal functional disconnections are specifically observed in coma and their structural counterpart provides information about brain injury mechanisms. Multimodal MRI biomarkers of frontoparietal disconnection predict 3-month outcome in our sample. These findings suggest that fronto-parietal disconnection might be particularly relevant for coma outcome prediction and could inspire innovative precision medicine approaches.

Supplemental Digital Content is available in the text., Objectives: Pediatric acute respiratory distress syndrome is heterogeneous, with a paucity of risk stratification tools to assist with trial design. We aimed to develop and validate mortality prediction models for patients with pediatric acute respiratory distress syndrome. Design: Leveraging additional data collection from a preplanned ancillary study (Version 1) of the multinational Pediatric Acute Respiratory Distress syndrome Incidence and Epidemiology study, we identified predictors of mortality. Separate models were built for the entire Version 1 cohort, for the cohort excluding neurologic deaths, for intubated subjects, and for intubated subjects excluding neurologic deaths. Models were externally validated in a cohort of intubated pediatric acute respiratory distress syndrome patients from the Children’s Hospital of Philadelphia. Setting: The derivation cohort represented 100 centers worldwide; the validation cohort was from Children’s Hospital of Philadelphia. Patients: There were 624 and 640 subjects in the derivation and validation cohorts, respectively. Interventions: None. Measurements and Main Results: The model for the full cohort included immunocompromised status, Pediatric Logistic Organ Dysfunction 2 score, day 0 vasopressor-inotrope score and fluid balance, and Pao2/Fio2 6 hours after pediatric acute respiratory distress syndrome onset. This model had good discrimination (area under the receiver operating characteristic curve 0.82), calibration, and internal validation. Models excluding neurologic deaths, for intubated subjects, and for intubated subjects excluding neurologic deaths also demonstrated good discrimination (all area under the receiver operating characteristic curve ≥ 0.84) and calibration. In the validation cohort, models for intubated pediatric acute respiratory distress syndrome (including and excluding neurologic deaths) had excellent discrimination (both area under the receiver operating characteristic curve ≥ 0.85), but poor calibration. After revision, the model for all intubated subjects remained miscalibrated, whereas the model excluding neurologic deaths showed perfect calibration. Mortality models also stratified ventilator-free days at 28 days in both derivation and validation cohorts. Conclusions: We describe predictive models for mortality in pediatric acute respiratory distress syndrome using readily available variables from day 0 of pediatric acute respiratory distress syndrome which outperform severity of illness scores and which demonstrate utility for composite outcomes such as ventilator-free days. Models can assist with risk stratification for clinical trials.

OBJECTIVES: College of Intensive Care Medicine mandatory training in echocardiography requires a minimum 30 echocardiograms. Trainee echocardiography accuracy following mandatory training is unknown. Our objective was to determine the reliability of ICU trainee echocardiography after our yearlong College of Intensive Care Medicine accredited course. DESIGN: Single-center, prospective observational study. Trainee echocardiograms were compared to independent, blindedexpert echocardiograms, with a target of 37 matched scans per trainee. SUBJECTS: Trainees were eligible to participate on completion of our in-house, mandatory echocardiography training. SETTING: Epworth Richmond is in an Australian, private academic hospital with a critical care echocardiography teaching program. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Reliability was assessed on nine measurements. The primary outcome was agreement on left ventricular function; secondary outcomes included qualitative and quantitative assessments. Agreement was assessed using Cohen's kappa, Fleiss-Cohen weighted kappa, Lin's concordance correlation coefficient, or calculation of sensitivity and specificity as appropriate. Seven trainees performed a total of 270 matched scans. There was excellent agreement between experts and trainees for left ventricular function (Kappa, 0.86; 95% CI, 0.81-0.91). Secondary outcome measures (95% CI) were ventricular size ratio Kappa 0.76 (0.58-0.94), sensitivity 92.3% (64.0-99.8%), specificity 97.2% (94.9-99.1%), pericardial effusion Kappa 0.37 (0.13-0.60), sensitivity 33.3% (13.3-59.0%), specificity 97.6% (94.8-99.1%). Concordance coefficients (95% CI) for the remaining outcomes were left ventricular outflow tract velocity time integral 0.79 (0.74-0.84), left ventricular internal diameter in diastole 0.82 (0.78-0.86), left ventricular outflow tract diameter 0.61 (0.53-0.69), tricuspid annular plane systolic excursion 0.71 (0.64-0.78), tricuspid regurgitation maximum velocity 0.55 (0.44-0.65), and inferior vena cava diameter 0.60 (0.49-0.72). CONCLUSIONS: ICU trainees showed very high overall agreement with experts on left ventricular function and substantial agreement for most secondary outcomes. This is the first study to assess echocardiography accuracy in Australian ICU trainees.

Supplemental Digital Content is available in the text., Objectives: Sepsis-induced acute kidney injury is the dominant acute kidney injury etiology in critically ill patients and is often associated with a need for renal replacement therapy. The indication and timing of renal replacement therapy are controversially discussed. We hypothesized that the product of the G1-cell cycle arrest biomarkers tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 ([TIMP-2] × [IGFBP7]), and the soluble urokinase-type plasminogen activator receptor are of diagnostic value for the prediction of septic acute kidney injury courses requiring renal replacement therapy. Design: In this prospective study, critically ill patients were enrolled immediately after the fulfillment of Sepsis-3 criteria. Urinary [TIMP-2] × [IGFBP7] levels over time and serum soluble urokinase-type plasminogen activator receptor levels once at inclusion were measured. The primary endpoint was the development of septic acute kidney injury with the need for renal replacement therapy. Area under the receiver operating characteristic curves, de Long’s tests, and logistic regression models were calculated. Setting: Two ICUs at Heidelberg University Hospital between May 2017 and July 2018. Patients: One-hundred critically ill patients with positive Sepsis-3 criteria. Interventions: None. Measurement and Main Results: Nineteen patients required renal replacement therapy. Diagnostic performance of urinary [TIMP-2] × [IGFBP7] improved over time with the highest area under the receiver operating characteristic curve of 0.89 (95% CI, 0.80–0.98) 24 hours after study inclusion. Soluble urokinase-type plasminogen activator receptor levels at inclusion showed an area under the receiver operating characteristic curve of 0.83 (0.75–0.92). The best discrimination ability for the primary outcome measure was achieved for [TIMP-2] × [IGFBP7] at 24 hours after inclusion by applying a cutoff value of greater than or equal to 0.6 (ng/mL)2/1,000 (sensitivity 90.9, specificity 67.1). Soluble urokinase-type plasminogen activator receptor performed best by using a cutoff value of greater than or equal to 8.53 ng/mL (sensitivity 84.2, specificity 82.7). A combination of newly tested biomarkers with cystatin C resulted in a significantly improved diagnostic accuracy. Cystatin C in combination with [TIMP-2] × [IGFBP7] 24 hours outperformed all standard renal parameters (area under the receiver operating characteristic curve 0.93 [0.86–1.00]). Conclusions: [TIMP-2] × [IGFBP7] and soluble urokinase-type plasminogen activator receptor are promising biomarker candidates for the risk stratification of septic acute kidney injury patients with the need for renal replacement therapy.

Supplemental Digital Content is available in the text., Objectives: Decreased urine output and/or increased serum creatinine may herald the development of acute kidney injury or reflect normal physiology. In this secondary analysis of the Sapphire study, we examined biomarkers of cell cycle arrest in the settings of oliguria and/or azotemia to improve risk assessment when used with conventional indices in predicting severe acute kidney injury (Kidney Disease: Improving Global Outcomes 3 defined by the need for renal replacement therapy or changes in urine output, serum creatinine or both) or death. Design: Prospective, international, Sapphire study. Setting: Academic Medical Center. Patients: Patients without acute kidney injury Kidney Disease: Improving Global Outcomes stage 2 or 3. Interventions: None. Measurements and Main Results: The primary endpoint being development of severe acute kidney injury or death within 1 week. Secondary analysis examined the relationship between tissue inhibitor of metalloproteinases-2 ([TIMP-2]) and insulin growth factor binding protein 7 ([IGFBP7]) and 9-month death or dialysis conditioned on progression to stage 2–3 acute kidney injury within 1 week. Seventy-nine patients reached the primary endpoint and were more likely to be surgical, with higher nonrenal Acute Physiology and Chronic Health Evaluation III scores and more chronic kidney disease. Stage 1 urine output, serum creatinine, and urinary [TIMP-2]•[IGFBP7] greater than 2.0 were all predictive of progression to the primary endpoint independent from nonrenal Acute Physiology and Chronic Health Evaluation III score. Combinations of predictors increased the hazard ratios considerably (from 2.17 to 4.14 to 10.05, respectively). In the presence of acute kidney injury (stage 1), [TIMP-2]•[IGFBP7] greater than 2.0 leads to an increased risk of death or dialysis at 9 months even in the absence of progression of acute kidney injury (stage 2–3) within 7 days. Conclusions: Cell cycle arrest biomarkers, TIMP-2 and IGFBP7, improve risk stratification for severe outcomes in patients with stage 1 acute kidney injury by urine output, serum creatinine or both, with risk increasing with each acute kidney injury indicator. Longer term outcomes demonstrate that the associated risks of a [TIMP-2]•[IGFBP7] greater than 2.0 is equivalent to acute kidney injury progression even where no progression from stage 1 acute kidney injury is observed.

Supplemental Digital Content is available in the text., Objectives: Continuous renal replacement therapy becomes available utilization for pediatric critically ill, but the impact of mortality rate in severe sepsis remains no consistent conclusion. The aim of the study is to assess the effect of continuous renal replacement therapy in pediatric patients with severe sepsis and the impact this therapy may have on their mortality. Design: Propensity score-matched cohort study analyzing data prospectively collected by the PICUs over 2 years (2016–2018). Setting: Four PICUs of tertiary university children’s hospital in China. Patients: The consecutive patients with severe sepsis admitted to study PICUs were enrolled from July 2016 to June 2018. Interventions: The patients were divided into the continuous renal replacement therapy group and the conventional (noncontinuous renal replacement therapy) group. Measurements and Main Results: A total of 324 patients with severe sepsis were enrolled. The hospital mortality rate was 35.6% (64/180) in the continuous renal replacement therapy group and 47.9% (69/144) in the noncontinuous renal replacement therapy group. After propensity score adjustment, the hospital mortality rate was 21.3% (29/136) in the continuous renal replacement therapy group and 32.4% (44/136) in the noncontinuous renal replacement therapy group. In subgroup analysis, the relative risk of dying was 0.447 (95% CI, 0.208–0.961) only in patients complicated by acute respiratory distress syndrome (p = 0.037), but not in patients with shock, acute kidney injury, acute liver dysfunction, encephalopathy, and fluid overload greater than 10%. The mean duration of continuous renal replacement therapy was 45 hours (26–83 hr) with an ultrafiltration rate of 50 mL/kg/hr. The level of interleukin-6 was decreased, and the percent of natural killer cells (%) was improved in the continuous renal replacement therapy group compared with the noncontinuous renal replacement therapy group. Furthermore, continuous renal replacement therapy was an independently significant risk factor for hospital mortality in pediatric patients with severe sepsis, and the interval between continuous renal replacement therapy initiation and PICU admission was an independent risk factor for hospital mortality in patients receiving continuous renal replacement therapy. Conclusions: Continuous renal replacement therapy with an ultrafiltration rate of 50 mL/kg/hr decreases hospital mortality rate in pediatric severe sepsis, especially in patients with acute respiratory distress syndrome.

Supplemental Digital Content is available in the text., Objectives: To investigate whether XueBiJing injection improves clinical outcomes in critically ill patients with severe community-acquired pneumonia. Design: Prospective, randomized, controlled study. Setting: Thirty-three hospitals in China. Patients: A total of 710 adults 18–75 years old with severe community-acquired pneumonia. Interventions: Participants in the XueBiJing group received XueBiJing, 100 mL, q12 hours, and the control group received a visually indistinguishable placebo. Measurements and Main Results: The primary outcome was 8-day improvement in the pneumonia severity index risk rating. Secondary outcomes were 28-day mortality rate, duration of mechanical ventilation and total duration of ICU stay. Improvement in the pneumonia severity index risk rating, from a previously defined endpoint, occurred in 203 (60.78%) participants receiving XueBiJing and in 158 (46.33%) participants receiving placebo (between-group difference [95% CI], 14.4% [6.9–21.8%]; p < 0.001). Fifty-three (15.87%) XueBiJing recipients and 84 (24.63%) placebo recipients (8.8% [2.4–15.2%]; p = 0.006) died within 28 days. XueBiJing administration also decreased the mechanical ventilation time and the total ICU stay duration. The median mechanical ventilation time was 11.0 versus 16.5 days for the XueBiJing and placebo groups, respectively (p = 0.012). The total duration of ICU stay was 12 days for XueBiJing recipients versus 16 days for placebo recipients (p = 0.004). A total of 256 patients experienced adverse events (119 [35.63%] vs 137 [40.18%] in the XueBiJing and placebo groups, respectively [p = 0.235]). Conclusions: In critically ill patients with severe community-acquired pneumonia, XueBiJing injection led to a statistically significant improvement in the primary endpoint of the pneumonia severity index as well a significant improvement in the secondary clinical outcomes of mortality, duration of mechanical ventilation and duration of ICU stay.

Supplemental Digital Content is available in the text., Objectives: To compare methods to adjust for confounding by disease severity during multicenter intervention studies in ICU, when different disease severity measures are collected across centers. Design: In silico simulation study using national registry data. Setting: Twenty mixed ICUs in The Netherlands. Subjects: Fifty-five–thousand six-hundred fifty-five ICU admissions between January 1, 2011, and January 1, 2016. Interventions: None. Measurements and Main Results: To mimic an intervention study with confounding, a fictitious treatment variable was simulated whose effect on the outcome was confounded by Acute Physiology and Chronic Health Evaluation IV predicted mortality (a common measure for disease severity). Diverse, realistic scenarios were investigated where the availability of disease severity measures (i.e., Acute Physiology and Chronic Health Evaluation IV, Acute Physiology and Chronic Health Evaluation II, and Simplified Acute Physiology Score II scores) varied across centers. For each scenario, eight different methods to adjust for confounding were used to obtain an estimate of the (fictitious) treatment effect. These were compared in terms of relative (%) and absolute (odds ratio) bias to a reference scenario where the treatment effect was estimated following correction for the Acute Physiology and Chronic Health Evaluation IV scores from all centers. Complete neglect of differences in disease severity measures across centers resulted in bias ranging from 10.2% to 173.6% across scenarios, and no commonly used methodology—such as two-stage modeling or score standardization—was able to effectively eliminate bias. In scenarios where some of the included centers had (only) Acute Physiology and Chronic Health Evaluation II or Simplified Acute Physiology Score II available (and not Acute Physiology and Chronic Health Evaluation IV), either restriction of the analysis to Acute Physiology and Chronic Health Evaluation IV centers alone or multiple imputation of Acute Physiology and Chronic Health Evaluation IV scores resulted in the least amount of relative bias (0.0% and 5.1% for Acute Physiology and Chronic Health Evaluation II, respectively, and 0.0% and 4.6% for Simplified Acute Physiology Score II, respectively). In scenarios where some centers used Acute Physiology and Chronic Health Evaluation II, regression calibration yielded low relative bias too (relative bias, 12.4%); this was not true if these same centers only had Simplified Acute Physiology Score II available (relative bias, 54.8%). Conclusions: When different disease severity measures are available across centers, the performance of various methods to control for confounding by disease severity may show important differences. When planning multicenter studies, researchers should make contingency plans to limit the use of or properly incorporate different disease measures across centers in the statistical analysis.

Supplemental Digital Content is available in the text., OBJECTIVES: Mannitol and hypertonic saline are used to treat raised intracerebral pressure in patients with traumatic brain injury, but their possible effects on kidney function and mortality are unknown. DESIGN: A post hoc analysis of the erythropoietin trial in traumatic brain injury (ClinicalTrials.gov NCT00987454) including daily data on mannitol and hypertonic saline use. SETTING: Twenty-nine university-affiliated teaching hospitals in seven countries. PATIENTS: A total of 568 patients treated in the ICU for 48 hours without acute kidney injury of whom 43 (7%) received mannitol and 170 (29%) hypertonic saline. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We categorized acute kidney injury stage according to the Kidney Disease Improving Global Outcome classification and defined acute kidney injury as any Kidney Disease Improving Global Outcome stage-based changes from the admission creatinine. We tested associations between early (first 2 d) mannitol and hypertonic saline and time to acute kidney injury up to ICU discharge and death up to 180 days with Cox regression analysis. Subsequently, acute kidney injury developed more often in patients receiving mannitol (35% vs 10%; p < 0.001) and hypertonic saline (23% vs 10%; p < 0.001). On competing risk analysis including factors associated with acute kidney injury, mannitol (hazard ratio, 2.3; 95% CI, 1.2–4.3; p = 0.01), but not hypertonic saline (hazard ratio, 1.6; 95% CI, 0.9–2.8; p = 0.08), was independently associated with time to acute kidney injury. In a Cox model for predicting time to death, both the use of mannitol (hazard ratio, 2.1; 95% CI, 1.1–4.1; p = 0.03) and hypertonic saline (hazard ratio, 1.8; 95% CI, 1.02–3.2; p = 0.04) were associated with time to death. CONCLUSIONS: In this post hoc analysis of a randomized controlled trial, the early use of mannitol, but not hypertonic saline, was independently associated with an increase in acute kidney injury. Our findings suggest the need to further evaluate the use and choice of osmotherapy in traumatic brain injury.

Supplemental Digital Content is available in the text., OBJECTIVES: Many trials investigate potential effects of treatments for coronavirus disease 2019. To provide sufficient information for all involveddecision-makers (clinicians, public health authorities, and drug regulatory agencies), a multiplicity of endpoints must be considered. The objectives are to provide hands-on statistical guidelines for harmonizing heterogeneous endpoints in coronavirus disease 2019 clinical trials. DESIGN: Randomized controlled trials for patients infected with coronavirus disease 2019. SETTING: General methods that apply to any randomized controlled trial for patients infected with coronavirus disease 2019. PATIENTS: Coronavirus disease 2019 positive individuals. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We develop a multistate model that is based on hospitalization, mechanical ventilation, death, and discharge. These events are both categories of the ordinal endpoint recommended by the World Health Organization and also within the core outcome set of the Core Outcome Measures in Effectiveness Trials initiative for coronavirus disease 2019 trials. To support our choice of states in the multistate model, we also perform a brief review of registered coronavirus disease 2019 clinical trials. Based on the multistate model, we give recommendation for compact, informative illustration of time-dynamic treatment effects and explorative statistical analysis. A majority of coronavirus disease 2019 clinical trials collect information on mechanical ventilation, hospitalization, and death. Using reconstructed and real data of coronavirus disease 2019 trials, we show how a stacked probability plot provides a detailed understanding of treatment effects on the patients’ course of hospital stay. It contributes to harmonizing multiple endpoints and differing lengths of follow-up both within and between trials. CONCLUSIONS: All ongoing clinical trials should include a stacked probability plot in their statistical analysis plan as descriptive analysis. While primary analysis should be on an early endpoint with appropriate capability to be a surrogate (parameter), our multistate model provides additional detailed descriptive information and links results within and between coronavirus disease 2019 trials.

Supplemental Digital Content is available in the text., Objectives: The disease caused by severe acute respiratory syndrome coronavirus 2, known as coronavirus disease 2019, has resulted in a global pandemic. Reports are emerging of a new severe hyperinflammatory syndrome related to coronavirus disease 2019 in children and adolescents. The Centers for Disease Control and Prevention has designated this disease multisystem inflammatory syndrome in children. Our objective was to develop a clinical inpatient protocol for the evaluation, management, and follow-up of patients with this syndrome. Data Sources: The protocol was developed by a multidisciplinary team based on relevant literature related to coronavirus disease 2019, multisystem inflammatory syndrome in children, and related inflammatory syndromes, as well as our experience caring for children with multisystem inflammatory syndrome in children. Data were obtained on patients with multisystem inflammatory syndrome in children at our institution from the pre-protocol and post-protocol periods. Data Synthesis: Our protocol was developed in order to identify cases of multisystem inflammatory syndrome in children with high sensitivity, stratify risk to guide treatment, recognize co-infectious or co-inflammatory processes, mitigate coronary artery abnormalities, and manage hyperinflammatory shock. Key elements of evaluation include case identification using broad clinical characteristics and comprehensive laboratory and imaging investigations. Treatment centers around glucocorticoids and IV immunoglobulin with biologic immunomodulators as adjuncts. Multidisciplinary follow-up after discharge is indicated to manage continued outpatient therapy and evaluate for disease sequelae. In nearly 2 months, we admitted 54 patients with multisystem inflammatory syndrome in children, all of whom survived without the need for invasive ventilatory or mechanical circulatory support. After institution of this protocol, patients received earlier treatment and had shorter lengths of hospital stay. Conclusions: This report provides guidance to clinicians on evaluation, management, and follow-up of patients with a novel hyperinflammatory syndrome related to coronavirus disease 2019 known as multisystem inflammatory syndrome in children. It is based on the relevant literature and our experience. Instituting such a protocol during a global pandemic is feasible and is associated with patients receiving treatment and returning home more quickly.

Supplemental Digital Content is available in the text., Objectives: Extracorporeal membrane oxygenation provides short-term cardiopulmonary life support, but is associated with peripheral innate inflammation, disruptions in cerebral autoregulation, and acquired brain injury. We tested the hypothesis that extracorporeal membrane oxygenation also induces CNS-directed adaptive immune responses which may exacerbate extracorporeal membrane oxygenation-associated brain injury. Design: A single center prospective observational study. Setting: Pediatric and cardiac ICUs at a single tertiary care, academic center. Patients: Twenty pediatric extracorporeal membrane oxygenation patients (0–14 yr; 13 females, 7 males) and five nonextracorporeal membrane oxygenation Pediatric Logistic Organ Dysfunction score matched patients Interventions: None. Measurements and Main Results: Venous blood samples were collected from the extracorporeal membrane oxygenation circuit at day 1 (10–23 hr), day 3, and day 7 of extracorporeal membrane oxygenation. Flow cytometry quantified circulating innate and adaptive immune cells, and CNS-directed autoreactivity was detected using an in vitro recall response assay. Disruption of cerebral autoregulation was determined using continuous bedside near-infrared spectroscopy and acquired brain injury confirmed by MRI. Extracorporeal membrane oxygenation patients with acquired brain injury (n = 9) presented with a 10-fold increase in interleukin-8 over extracorporeal membrane oxygenation patients without brain injury (p < 0.01). Furthermore, brain injury within extracorporeal membrane oxygenation patients potentiated an inflammatory phenotype in adaptive immune cells and selective autoreactivity to brain peptides in circulating B cell and cytotoxic T cell populations. Correlation analysis revealed a significant relationship between adaptive immune responses of extracorporeal membrane oxygenation patients with acquired brain injury and loss of cerebral autoregulation. Conclusions: We show that pediatric extracorporeal membrane oxygenation patients with acquired brain injury exhibit an induction of pro-inflammatory cell signaling, a robust activation of adaptive immune cells, and CNS-targeting adaptive immune responses. As these patients experience developmental delays for years after extracorporeal membrane oxygenation, it is critical to identify and characterize adaptive immune cell mechanisms that target the developing CNS.

Objectives: Historically, patients with a hematologic malignancy have one of the highest mortality rates among cancer patients admitted to the ICU. Therefore, physicians are often reluctant to admit these patients to the ICU. The aim of our study was to examine the survival of patients who have a hematologic malignancy and multiple organ failure admitted to the ICU. Design: This retrospective cohort study, part of the HEMA-ICU study group, was designed to study the survival of patients with a hematologic malignancy and organ failure after admission to the ICU. Patients were followed for at least 1 year. Setting: Five university hospitals in the Netherlands. Patients: One-thousand ninety-seven patients with a hematologic malignancy who were admitted at the ICU. Interventions: None. Measurements and Main Results: Primary outcome was 1-year survival. Organ failure was categorized as acute kidney injury, respiratory failure, hepatic failure, and hemodynamic failure; multiple organ failure was defined as failure of two or more organs. The World Health Organization performance score measured 3 months after discharge from the ICU was used as a measure of functional outcome. The 1-year survival rate among these patients was 38%. Multiple organ failure was inversely associated with long-term survival, and an absence of respiratory failure was the strongest predictor of 1-year survival. The survival rate among patients with 2, 3, and 4 failing organs was 27%, 22%, and 8%, respectively. Among all surviving patients for which World Health Organization scores were available, 39% had a World Health Organization performance score of 0-1 3 months after ICU discharge. Functional outcome was not associated with the number of failing organs. Conclusions: Our results suggest that multiple organ failure should not be used as a criterion for excluding a patient with a hematologic malignancy from admission to the ICU.

Supplemental Digital Content is available in the text., Objectives: Time-averaged intracranial pressure-to-blood pressure Fisher-transformed Pearson correlation (PRx) is used to assess cerebral autoregulation and derive optimal cerebral perfusion pressure. Empirically, impaired cerebral autoregulation is considered present when PRx is positive; greater difference between time series median cerebral perfusion pressure and optimal cerebral perfusion pressure (ΔCPP) is associated with worse outcomes. Our aims are to better understand: 1) the potential strategies for targeting optimal cerebral perfusion pressure; 2) the relationship between cerebral autoregulation and PRx; and 3) the determinants of greater ΔCPP. Design: Mechanistic simulation using a lumped compartmental model of blood pressure, intracranial pressure, cerebral autoregulation, cerebral blood volume, Paco2, and cerebral blood flow. Setting: University critical care integrative modeling and precision physiology research group. Subjects: None, in silico studies. Interventions: Simulations in blood pressure, intracranial pressure, Paco2, and impairment of cerebral autoregulation, with examination of “output” cerebral perfusion pressure versus PRx-plots, optimal cerebral perfusion pressure, and ΔCPP. Measurements and Main Results: In regard to targeting optimal cerebral perfusion pressure, a shift in mean blood pressure or mean intracranial pressure with no change in mean blood pressure, with intact cerebral autoregulation, impacts optimal cerebral perfusion pressure. Second, a positive PRx occurs even with intact cerebral autoregulation. In relation to ΔCPP, for a given input blood pressure profile, with constant intracranial pressure, altering the degree of impairment in cerebral autoregulation or the level of Paco2 maintains differences to within ±5 mm Hg. Change in intracranial pressure due to either an intermittently prolonged pattern of raised intracranial pressure or terminal escalation shows ΔCPP greater than 10 mm Hg and less than –10 mm Hg, respectively. Conclusions: These mechanistic simulations provide insight into the empiric basis of optimal cerebral perfusion pressure and the significance of PRx and ΔCPP. PRx and optimal cerebral perfusion pressure deviations do not directly reflect changes in cerebral autoregulation but are, in general, related to the presence of complex states involving well-described clinical progressions with raised intracranial pressure.

Supplemental Digital Content is available in the text., Objective: To assess the performance of the Pediatric Index of Mortality 3 score in a population of children admitted to PICUs in Argentina. Design: Prospective, national, multicenter study. Setting: Forty-nine PICUs located in Argentina belonging to public and private institutions. Patients: All children between 1 month and 16 years old admitted to the participating PICUs between May 15, 2016, and February 15, 2017. Interventions: None. Measurement and Main Results: A total of 6,602 patients were enrolled in the study. The observed mortality was 8% (531/6,602), whereas mortality predicted by Pediatric Index of Mortality 3 was 6.16% (407 deaths). The standardized mortality rate was 1.3 (95% CI, 1.20–1.42). The area under the receiver operating characteristic curve was 0.83 (95% CI, 0.82–0.85). The Hosmer-Lemeshow test showed that the difference between the mortality observed and the mortality predicted by Pediatric Index of Mortality 3 was statistically significant (χ2, 135.63; p < 0.001). Conclusions: The Pediatric Index of Mortality 3 score adequately discriminated patients who died from those who survived in our population. However, the observed mortality was higher than predicted by the score. The use of an updated instrument such as Pediatric Index of Mortality 3 will allow an actual comparison between pediatric intensive care provided in the country and care provided internationally. This might also allow future planning of pediatric intensive care services in Argentina.

Supplemental Digital Content is available in the text., Objectives: To describe the characteristics, circumstances, change over time, resource use, and outcomes of patients admitted to ICUs in Australia and New Zealand for the purposes of “palliative care of a dying patient” or “potential organ donation,” and compare with actively managed ICU patients. Design: A retrospective study of data from the Australian and New Zealand Intensive Care Society Adult Patient Database and a nested cohort analysis of a single center. Setting: One hundred seventy-seven ICUs in Australia and New Zealand and a nested analysis of one university-affiliated hospital ICU in Melbourne, VIC, Australia. Patients: Three thousand seven hundred “palliative care of a dying patient” and 1,115 “potential organ donation” patients from 2007 to 2016. The nested cohort included 192 patients. Interventions: No interventions. Data extracted included patient demographics, diagnoses, length of stay, circumstances, and outcome of admission. Measurements and Main Results: ICU admissions for “palliative care of a dying patient” and “potential organ donation” increased from 179 in 2007 to 551 in 2016 and from 44 in 2007 to 174 in 2016 in each respective group, though only the “potential organ donation” cohort showed an increase in proportion of total ICU admissions. Lengths of stay in ICU were a mean of 33.8 hours (median, 17.5; interquartile range, 6.4–38.8) and 44.7 hours (26.6; 16.0–44.6), respectively, compared with 74.2 hours (41.5; 21.7–77.0) in actively managed patients. Hospital mortality was 86.6% and 95.9%, respectively. In the nested cohort of 192 patients, facilitating family discussions about goals of treatment and organ donation represented the most common reason for ICU admission. Conclusions: Patients admitted to ICU to manage end-of-life care represent a small proportion of overall ICU admissions, with an increasing proportion of “potential organ donation” admissions. They have shorter ICU lengths of stay than actively managed patients, suggesting resource use for these patients is not disproportionate.

OBJECTIVES: Mechanical ventilation can cause ventilator-induced brain injury via afferent vagal signaling and hippocampal neurotransmitter imbalances. The triggering mechanisms for vagal signaling during mechanical ventilation are unknown. The objective of this study was to assess whether pulmonary transient receptor potential vanilloid type-4 (TRPV4) mechanoreceptors and vagal afferent purinergic receptors (P2X) act as triggers of ventilator-induced brain injury. DESIGN: Controlled, human in vitro and ex vivo studies, as well as murine in vivo laboratory studies. SETTING: Research laboratory. SUBJECTS: Wild-type, TRPV4-deficient C57BL/6J mice, 8-10 weeks old. Human postmortem lung tissue and human lung epithelial cell line BEAS-2B. INTERVENTION: Mice subjected to mechanical ventilation were studied using functional MRI to assess hippocampal activity. The effects of lidocaine (a nonselective ion-channel inhibitor), P2X-purinoceptor antagonist (iso-PPADS), or genetic TRPV4 deficiency on hippocampal dopamine-dependent pro-apoptotic signaling were studied in mechanically ventilated mice. Human lung epithelial cells (BEAS-2B) were used to study the effects of mechanical stretch on TRPV4 and P2X expression and activation. TRPV4 levels were measured in postmortem lung tissue from ventilated and nonventilated patients. MEASUREMENTS AND MAIN RESULTS: Hippocampus functional MRI analysis revealed considerable changes in response to the increase in tidal volume during mechanical ventilation. Intratracheal lidocaine, iso-PPADS, and TRPV4 genetic deficiency protected mice against ventilationinduced hippocampal pro-apoptotic signaling. Mechanical stretch in both, BEAS-2B cells and ventilated wild-type mice, resulted in TRPV4 activation and reduced Trpv4 and P2x expression. Intratracheal replenishment of adenosine triphosphate in Trpv4 mice abrogated the protective effect of TRPV4 deficiency. Autopsy lung tissue from ventilated patients showed decreased lung TRPV4 levels compared with nonventilated patients. CONCLUSIONS: TRPV4 mechanosensors and purinergic receptors are involved in the mechanisms of ventilator-induced brain injury. Inhibition of this neural signaling, either using nonspecific or specific inhibitors targeting the TRPV4/adenosine triphosphate/P2X signaling axis, may represent a novel strategy to prevent or treat ventilator-induced brain injury.

Supplemental Digital Content is available in the text., Objectives: Managing hemoptysis in chronic thromboembolic pulmonary hypertension can be challenging due to the difficulties in maintaining coagulation homeostasis in affected patients. In this study, we evaluated the efficacy and safety of bronchial artery embolization in treating hemoptysis in chronic thromboembolic pulmonary hypertension patients. Design: Pilot, prospective cohort study. Setting: A large respiratory medical institute. Patients: From January 1, 2012, to December 31, 2017, hospitalized chronic thromboembolic pulmonary hypertension patients were eligible for inclusion. Patients with pulmonary hypertension caused by other conditions, or who failed to participate in the follow-up were excluded. Interventions: Hemoptysis in chronic thromboembolic pulmonary hypertension patients was treated with or without bronchial artery embolization based on whether the bleeding could be stopped with medication alone and patient willingness for bronchial artery embolization treatment. Measurements and Main Results: A total of 328 patients diagnosed with chronic thromboembolic pulmonary hypertension were consecutively collected, 317 patients were completed the follow-up. There were 15 chronic thromboembolic pulmonary hypertension patients with hemoptysis in total, and the occurrence rate of hemoptysis in chronic thromboembolic pulmonary hypertension patients was 4.7%. Among the hemoptysis chronic thromboembolic pulmonary hypertension patients, 10 (67%) underwent bronchial artery embolization, and five (33%) were treated with medication only. The median follow-up period for hemoptysis patients was 7.6 months. In patients underwent bronchial artery embolization treatment, oxygenation index and right heart function showed no significant difference between pre bronchial artery embolization and post bronchial artery embolization. Hemoptysis relapse (20% vs 80%; p = 0.025) and hemoptysis-related mortality (0% vs 40%; p = 0.032) were significantly lower, whereas the overall survival (90% vs 40%; p = 0.040) was higher in patients treated with bronchial artery embolization than in patients treated without bronchial artery embolization. Conclusions: Bronchial artery embolization procedure demonstrated effectiveness and safety to treat hemoptysis in chronic thromboembolic pulmonary hypertension patients at our center, but further controlled studies are needed before it can be considered as an effective therapy for these patients.

Supplemental Digital Content is available in the text., Objectives: To determine the relationship between theophylline trough levels and urine output in critically ill children administered aminophylline as adjunctive diuretic therapy. Design: Retrospective cohort study. Setting: The PICU of a tertiary care children’s hospital. Patients: A mixed population of medical/surgical including postoperative cardiothoracic surgery patients less than 18 years old. Interventions: Electronic medical records of all PICU patients admitted from July 2010 to June 2015 were reviewed, and patients who received aminophylline as diuretic therapy were identified. Measurements and Main Results: Patient cohort data including demographics, daily aminophylline, furosemide and chlorothiazide dosing, theophylline trough levels, fluid intake, urine output and total fluid balance, blood urea nitrogen, and creatinine levels were abstracted. Multivariate analysis based on a generalized estimating equations approach demonstrated that aminophylline administration, when analyzed as a categorical variable, was associated with an increase in urine output and decreased fluid balance. However, aminophylline dosing, when analyzed as a continuous variable, was associated with neither an increase in urine output nor decreased fluid balance. Theophylline trough levels were not correlated with urine output at 24 hours (p = 0.78) and were negatively correlated with urine output at 48 hours (r2 = 0.078; p < 0.005). Conclusions: Aminophylline administration provided a measure of increased diuresis, regardless of dosage, and theophylline trough levels. Therefore, achieving a prescribed therapeutic trough level may not be necessary for full diuretic effect. Because, as opposed to the diuretic effect, the side effect profile of aminophylline is dose-dependent, low maintenance dosing may optimize the balance between providing adjunctive diuretic effect while minimizing the risk of toxicity.

Supplemental Digital Content is available in the text., Objective: To assess temporal trends in 1-year healthcare costs and outcome of intensive care for traumatic brain injury in Finland. Design: Retrospective observational cohort study. Setting: Multicenter study including four tertiary ICUs. Patients: Three thousand fifty-one adult patients (≥ 18 yr) with significant traumatic brain injury treated in a tertiary ICU during 2003–2013. Intervention: None. Measurements and Main Results : Total 1-year healthcare costs included the index hospitalization costs, rehabilitation unit costs, and social security reimbursements. All costs are reported as 2013 U.S. dollars ($). Outcomes were 1-year mortality and permanent disability. Multivariate regression models, adjusting for case-mix, were used to assess temporal trends in costs and outcome in predefined Glasgow Coma Scale (3–8, 9–12, and 13–15) and age (18–40, 41–64, and ≥ 65 yr) subgroups. Overall 1-year survival was 76% (n = 2,304), and of 1-year survivors, 37% (n = 850) were permanently disabled. Mean unadjusted 1-year healthcare cost was $39,809 (95% CI, $38,144–$41,473) per patient. Adjusted healthcare costs decreased only in the Glasgow Coma Scale 13–15 and 65 years and older subgroups, due to lower rehabilitation costs. Adjusted 1-year mortality did not change in any subgroup (p < 0.05 for all subgroups). Adjusted risk of permanent disability decreased significantly in all subgroups (p < 0.05). Conclusion: During the last decade, healthcare costs of ICU-admitted traumatic brain injury patients have remained largely the same in Finland. No change in mortality was noted, but the risk for permanent disability decreased significantly. Thus, our results suggest that cost-effectiveness of traumatic brain injury care has improved during the past decade in Finland.

Objectives To review the characteristics of and to identify the reasons for severe maternal admissions to the ICU. Design This was an analytical, observational, open, and retrospective study. Setting In our ICU. Patients A total of 487 severe maternal cases were reviewed during the 8-year study period of January 2009 to December 2016. Intervention None. Measurements and main results A total of 487 severe maternal cases (12.6%) among the 3,867 patients admitted to ICU were reviewed. Of these, 361 patients were admitted for obstetric reasons, mainly pregnancy-induced hypertension (58.7%) and postpartum hemorrhage (36.8%). The remaining 126 patients were admitted for nonobstetric reasons, including cardiac-related disease (31.0%), immune-related disease (24.6%), and sepsis (20.6%). A total of 249 patients experienced combined comorbidities: the most common was a scarred uterus (100 patients; 40.2%), followed by endocrine-related disease (25.3%), immune-related disease (21.3%), and cardiac-related disease (18.1%). Central venous insertion (90.6%) was the most common intervention, followed by arterial catheter insertion (33.7%), mechanical ventilation (11.7%), blood purification (5.7%), and invasive hemodynamic monitoring (3.7%). Nine patients died during the study period, of which the death of four could have been avoided. Conclusions The number of severe maternal cases has increased annually in our ICU. Although obstetric causes remained the most common reason for admission, the nonobstetric causes and basic complications were too complex, dangerous, and beyond the reach of the obstetrician with regard to monitoring and treatment. We call for a multidisciplinary team mainly composed of ICU staff to improve severe maternal outcomes.

Objectives: Mortality prediction scores have been used for a long time in ICUs; however, numerous studies have shown that they over-predict mortality in the obstetric population. With sepsis remaining a major cause of obstetric mortality, we aimed to look at five mortality prediction scores (one obstetric-based and four general) in the septic obstetric population and compare them to a nonobstetric septic control group. Subject and Design: Women in the age group of 16–50 years with an admission diagnosis or suspicion of sepsis were included. In a multicenter obstetric population (n = 797), these included all pregnant and postpartum patients up to 6 weeks postpartum. An age- and gender-matched control nonobstetric population was drawn from a single-center general critical care population (n = 2,461). Sepsis in Obstetric Score, Acute Physiology and Chronic Health Evaluation II, Simplified Acute Physiology Score II, Sequential Organ Failure Assessment, and Multiple Organ Dysfunction Scores were all applied to patients meeting inclusion criteria in both cohorts, and their area under the receiver-operator characteristic curves was calculated to find the most accurate predictor. Measurements and Main Results: A total of 146 septic patients were found for the obstetric cohort and 299 patients for the nonobstetric control cohort. The Sepsis in Obstetric Score, Acute Physiology and Chronic Health Evaluation II, Simplified Acute Physiology Score II, Sequential Organ Failure Assessment, and Multiple Organ Dysfunction Scores gave area under the receiver-operator characteristic curves of 0.67, 0.68, 0.72, 0.79, and 0.84 in the obstetric cohort, respectively, and 0.64, 0.72, 0.61, 0.78, and 0.74 in the nonobstetric cohort, respectively. The Sepsis in Obstetric Score performed similarly to all the other scores with the exception of the Multiple Organ Dysfunction Score, which was significantly better (p < 0.05). Conclusion: The Sepsis in Obstetric Score, designed specifically for sepsis in obstetric populations, was not better than general severity of illness scoring systems. Furthermore, the Sepsis in Obstetric Score performance was no different in an obstetric sepsis population compared to a nonobstetric sepsis population. The Multiple Organ Dysfunction Score is a simple organ-based score, and this result supports the use of organ-based outcome predictors in ICU even in an obstetric sepsis population.

Supplemental Digital Content is available in the text., Objectives: Aneurysmal subarachnoid hemorrhage often leads to death and poor clinical outcome. Injury occurring during the first 72 hours is termed “early brain injury,” with disruption of the nitric oxide pathway playing an important pathophysiologic role in its development. Quantitative electroencephalographic variables, such as α/δ frequency ratio, are surrogate markers of cerebral ischemia. This study assessed the quantitative electroencephalographic response to a cerebral nitric oxide donor (intravenous sodium nitrite) to explore whether this correlates with the eventual development of delayed cerebral ischemia. Design: Unblinded pilot study testing response to drug intervention. Setting: Neuroscience ICU, John Radcliffe Hospital, Oxford, United Kingdom. Patients: Fourteen World Federation of Neurosurgeons grades 3, 4, and 5 patients (mean age, 52.8 yr [range, 41–69 yr]; 11 women). Interventions: IV sodium nitrite (10 μg/kg/min) for 1 hour. Measurements and Main Results: Continuous electroencephalographic recording for 2 hours. The alpha/delta frequency ratio was measured before and during IV sodium nitrite infusion. Seven of 14 patients developed delayed cerebral ischemia. There was a +30% to +118% (range) increase in the alpha/delta frequency ratio in patients who did not develop delayed cerebral ischemia (p < 0.0001) but an overall decrease in the alpha/delta frequency ratio in those patients who did develop delayed cerebral ischemia (range, +11% to –31%) (p = 0.006, multivariate analysis accounting for major confounds). Conclusions: Administration of sodium nitrite after severe subarachnoid hemorrhage differentially influences quantitative electroencephalographic variables depending on the patient’s susceptibility to development of delayed cerebral ischemia. With further validation in a larger sample size, this response may be developed as a tool for risk stratification after aneurysmal subarachnoid hemorrhage.

Supplemental Digital Content is available in the text., Objectives: To characterize glucocorticoid receptor expression in peripheral WBCs of critically ill children using flow cytometry. Design: Prospective observational cohort. Setting: A university-affiliated, tertiary PICU. Patients: Fifty-two critically ill children. Interventions: Samples collected for measurement of glucocorticoid receptor expression and parallel cortisol levels. Measurements and Main Results: Subjects with cardiovascular failure had significantly lower glucocorticoid receptor expression both in CD4 lymphocytes (mean fluorescence intensity, 522 [354–787] vs 830 [511–1,219]; p = 0.036) and CD8 lymphocytes (mean fluorescence intensity, 686 [350–835] vs 946 [558–1,511]; p = 0.019) compared with subjects without cardiovascular failure. Subjects in the upper 50th percentile of Pediatric Risk of Mortality III scores and organ failure also had significantly lower glucocorticoid receptor expression in CD4 and CD8 lymphocytes. There was no linear correlation between cortisol concentrations and glucocorticoid receptor expression. Conclusions: Our study suggests that patients with shock and increased severity of illness have lower glucocorticoid receptor expression in CD4 and CD8 lymphocytes. Glucocorticoid receptor expression does not correlate well with cortisol levels. Future studies could focus on studying glucocorticoid receptor expression variability and isoform distribution in the pediatric critically ill population as well as on different strategies to optimize glucocorticoid response.