Other bulletins in this series include:

Breast Surgery

Wednesday, 19 September 2018

Deresuscitation of Patients With Iatrogenic Fluid Overload Is Associated With Reduced Mortality in Critical Illness*

by Silversides, Jonathan A.; Fitzgerald, Emma; Manickavasagam, Uma S.; Lapinsky, Stephen E.; Nisenbaum, Rosane; Hemmings, Noel; Nutt, Christopher; Trinder, T. John; Pogson, David G.; Fan, Eddy; Ferguson, Andrew J.; McAuley, Daniel F.; Marshall, John C.; for the Role of Active Deresuscitation After Resuscitation (RADAR) Investigators  

Objectives: To characterize current practice in fluid administration and deresuscitation (removal of fluid using diuretics or renal replacement therapy), the relationship between fluid balance, deresuscitative measures, and outcomes and to identify risk factors for positive fluid balance in critical illness.
Design: Retrospective cohort study. Setting: Ten ICUs in the United Kingdom and Canada. Patients: Adults receiving invasive mechanical ventilation for a minimum of 24 hours. Interventions: None. Measurements and Main Results: Four-hundred patients were included. Positive cumulative fluid balance (fluid input greater than output) occurred in 87.3%: the largest contributions to fluid input were from medications and maintenance fluids rather than resuscitative IV fluids. In a multivariate logistic regression model, fluid balance on day 3 was an independent risk factor for 30-day mortality (odds ratio 1.26/L [95% CI, 1.07–1.46]), whereas negative fluid balance achieved in the context of deresuscitative measures was associated with lower mortality. Independent predictors of greater fluid balance included treatment in a Canadian site.
Conclusions: Fluid balance is a practice-dependent and potentially modifiable risk factor for adverse outcomes in critical illness. Negative fluid balance achieved with deresuscitation on day 3 of ICU stay is associated with improved patient outcomes. Minimization of day 3 fluid balance by limiting maintenance fluid intake and drug diluents, and using deresuscitative measures, represents a potentially beneficial therapeutic strategy which merits investigation in randomized trials.

Compliance With the National SEP-1 Quality Measure and Association With Sepsis Outcomes: A Multicenter Retrospective Cohort Study*

by Rhee, Chanu; Filbin, Michael R.; Massaro, Anthony F.; Bulger, Amy L.; McEachern, Donna; Tobin, Kathleen A.; Kitch, Barrett T.; Thurlo-Walsh, Bert; Kadar, Aran; Koffman, Alexandra; Pande, Anupam; Hamad, Yasir; Warren, David K.; Jones, Travis M.; O’Brien, Cara; Anderson, Deverick J.; Wang, Rui; Klompas, Michael; for the Centers for Disease Control and Prevention (CDC) Prevention Epicenters Program  

Objectives: Many septic patients receive care that fails the Centers for Medicare and Medicaid Services’ SEP-1 measure, but it is unclear whether this reflects meaningful lapses in care, differences in clinical characteristics, or excessive rigidity of the “all-or-nothing” measure. We compared outcomes in cases that passed versus failed SEP-1 during the first 2 years after the measure was implemented.
Design: Retrospective cohort study. Setting: Seven U.S. hospitals. Patients: Adult patients included in SEP-1 reporting between October 2015 and September 2017. Interventions: None.
Measurements and Main Results: Of 851 sepsis cases in the cohort, 281 (33%) passed SEP-1 and 570 (67%) failed. SEP-1 failures had higher rates of septic shock (20% vs 9%; p < 0.001), hospital-onset sepsis (11% vs 4%; p = 0.001), and vague presenting symptoms (46% vs 30%; p < 0.001). The most common reasons for failure were omission of 3- and 6-hour lactate measurements (228/570 failures, 40%). Only 86 of 570 failures (15.1%) had greater than 3-hour delays until broad-spectrum antibiotics. Cases that failed SEP-1 had higher in-hospital mortality rates (18.4% vs 11.0%; odds ratio, 1.82; 95% CI, 1.19–2.80; p = 0.006), but this association was no longer significant after adjusting for differences in clinical characteristics and severity of illness (adjusted odds ratio, 1.36; 95% CI, 0.85–2.18; p = 0.205). Delays of greater than 3 hours until antibiotics were significantly associated with death (adjusted odds ratio, 1.94; 95% CI, 1.04–3.62; p = 0.038), whereas failing SEP-1 for any other reason was not (adjusted odds ratio, 1.10; 95% CI, 0.70–1.72; p = 0.674).
Conclusions: Crude mortality rates were higher in sepsis cases that failed versus passed SEP-1, but there was no difference after adjusting for clinical characteristics and severity of illness. Delays in antibiotic administration were associated with higher mortality but only accounted for a small fraction of SEP-1 failures. SEP-1 may not clearly differentiate between high- and low-quality care, and detailed risk adjustment is necessary to properly interpret associations between SEP-1 compliance and mortality.

Translational Sepsis Research: Spanning the Divide

by Lewis, Anthony J.; Lee, Janet S.; Rosengart, Matthew R.  

Objective: Our knowledge of the molecular mechanisms of sepsis has attained exponential growth. Yet, the pillars of its care remain antibiotics, fluid resuscitation, and physiologic support of failing organ systems. The inability to bring biologic breakthroughs to the bedside is not for lack of effort. Over 60 clinical trials of novel therapies, each heavily supported by the momentum of biologic data suggesting clinical utility, have been conducted and have failed to identify benefit. This mass of “negative” clinical data abut an equally towering mound of knowledge of sepsis biology, which collectively have led investigators to ask, “what happened?”

Data Sources: Review of published scientific literature via MEDLINE searches using key terms related to the article topics. Study Selection: Original articles, review articles, and systematic reviews were considered. Data Extraction: Articles were selected for inclusion based upon author consensus.
Data Synthesis: Here, we present a synthetic review of some of the challenges in translating experimental animal models of sepsis to the bedside. We commence with the concept that the heterogeneity in the kinetics of the sepsis response serves as an important, often underappreciated but surmountable, source of translational impedance. Upon this groundwork, we discuss distinctions between animal experimentation and clinical trial design in the elements for hypothesis testing: cohort selection, power and sample size, randomization and blinding, and timing of intervention. From this concept, we develop a contextual framework for advancing the paradigm of animal-based investigations to facilitate science that transitions from molecule to medicine.
Conclusions: A persistent divide exists between the laboratory and clinical research arenas, which may be addressable via systematic targeting of identified translational gaps.

Diabetes and Glucose Dysregulation and Transition to Delirium in ICU Patients

van Keulen, Kris; Knol, Wilma; Belitser, Svetlana V.; van der Linden, Paul D.; Heerdink, Eibert R.; Egberts, Toine C. G.; Slooter, Arjen J. C.

Objectives: To investigate whether diabetes and glucose dysregulation (hyperglycemia and/or hypoglycemia) are associated with ICU delirium.

Design: Prospective cohort study. Setting: Thirty-two–bed mixed intensive care in a tertiary care center. Patients: Critically ill patients admitted to the ICU with transitions of mental status from awake and nondelirious to delirious or remaining awake and nondelirious on the next day. Patients admitted because of a neurologic illness were excluded. Interventions: None.

Measurements and Main Results: The study population consisted of 2,745 patients with 1,720 transitions from awake and nondelirious to delirious and 11,421 nontransitions remaining awake and nondelirious. Generalized mixed effects models with logit link function were performed to study the association between diabetes mellitus, glucose dysregulation, and delirium, adjusting for potential confounders. Diabetes was not associated with delirium (odds ratio adjusted, 0.93; 95% CI, 0.73–1.18). In all patients, the occurrence of hyperglycemia (odds ratio adjusted, 1.35; 95% CI, 1.15–1.59) and the occurrence of both hyperglycemia and hypoglycemia on the same day (odds ratio adjusted, 1.65; 95% CI, 1.12–2.28) compared with normoglycemia were associated with transition to delirium. Hypoglycemia was not associated with transition to delirium (odds ratio adjusted, 1.86; 95% CI, 0.73–3.71). In patients without diabetes, the occurrence of hyperglycemia (odds ratio adjusted, 1.41; 95% CI, 1.16–1.68) and the occurrence of both hyperglycemia and hypoglycemia on the same day (odds ratio adjusted, 1.87; 95% CI, 1.07–2.89) were associated with transition to delirium. In patients with diabetes, glucose dysregulation was not associated with ICU delirium.

Conclusions: Diabetes mellitus was not associated with the development of ICU delirium. For hypoglycemia, only a nonsignificant odds ratio for ICU delirium could be noted. Hyperglycemia and the occurrence of hyperglycemia and hypoglycemia on the same day were associated with ICU delirium but only in patients without diabetes. Our study supports the institution of measures to prevent glucose dysregulation in nondiabetic ICU patients and contributes to the understanding of the determinants of delirium.

Acute Neurologic Complications During Extracorporeal Membrane Oxygenation: A Systematic Review

by Sutter, Raoul; Tisljar, Kai; Marsch, Stephan  

Objectives: We determine the frequency, risk factors, and mortality of neurologic complications in adults on extracorporeal membrane oxygenation and propose an algorithm for preventive strategies. Data Sources: PubMed, Embase, and Cochrane databases. Study Selection: Screening was performed using predefined search terms to identify cohort studies reporting neurologic complications in adults during extracorporeal membrane oxygenation from 1990 to 2017. Data Extraction: The final reference list was generated on the basis of relevance to the discussed topics. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation classification of evidence scheme. Data Synthesis: In 44 studies, the median frequency of acute neurologic complications is 13% (1–78%; 5% intracranial hemorrhages, 5% ischemic strokes, 2% seizures). Neurologic complications are reported more frequently with venoarterial extracorporeal membrane oxygenation compared with venovenous extracorporeal membrane oxygenation (14 vs eight studies) with a median proportion of complications of 15% (6–33%; 95% CI, 8–19) for venoarterial extracorporeal membrane oxygenation. Median in-hospital mortality is higher with neurologic complications (83%; interquartile range, 54–100% vs 42%; interquartile range, 24–55% without neurologic complications; p < 0.001). Median mortality is 96% for hemorrhages, 84% for ischemic strokes 84%, and 40% for seizures. Risk factors are age, preextracorporeal membrane oxygenation cardiac arrest, hypoglycemia, and administration of inotropes. Hemorrhages are associated with female gender, duration of ventilation and extracorporeal membrane oxygenation, decreased serum fibrinogen, heparin, serum creatinine greater than 2.6 mg/dL, hemodialysis, and thrombocytopenia. Increased odds for ischemic stroke is seen with a preextracorporeal membrane oxygenation serum lactate greater than 10 mmol/L. No studies report daily coagulation monitoring and neurologic assessments, and quality of evidence was low to very low. Conclusions: Neurologic complications are reported frequently and with high occurrence rate, especially with venoarterial extracorporeal membrane oxygenation, and associated with high mortality calling for daily weaning from sedation and neuromuscular blockers for neurologic assessment and coagulation monitoring. The low quality of evidence indicates the need for higher quality studies in this context.

Benzodiazepines and Development of Delirium in Critically Ill Children: Estimating the Causal Effect*

by Mody, Kalgi; Kaur, Savneet; Mauer, Elizabeth A.; Gerber, Linda M.; Greenwald, Bruce M.; Silver, Gabrielle; Traube, Chani  
Objectives: Benzodiazepine use may be associated with delirium in critically ill children. However, benzodiazepines remain the first-line sedative choice in PICUs. Objectives were to determine the temporal relationship between administration of benzodiazepines and delirium development, control for time-varying covariates such as mechanical ventilation and opiates, and evaluate the association between dosage of benzodiazepines and subsequent delirium.

Design: Retrospective observational study. Setting: Academic tertiary care PICU. Patients: All consecutive admissions from January 2015 to June 2015. Interventions: Retrospective assessment of benzodiazepine exposure in a population that had been prospectively screened for delirium.

Measurements and Main Results: All subjects were prospectively screened for delirium throughout their stay, using the Cornell Assessment for Pediatric Delirium, with daily cognitive status assigned as follows: delirium, coma, or normal. Multivariable mixed effects modeling determined predictors of delirium overall, followed by subgroup analysis to assess effect of benzodiazepines on subsequent development of delirium. Marginal structural modeling was used to create a pseudorandomized sample and control for time-dependent variables, obtaining an unbiased estimate of the relationship between benzodiazepines and next day delirium. The cumulative daily dosage of benzodiazepines was calculated to test for a dose-response relationship. Benzodiazepines were strongly associated with transition from normal cognitive status to delirium, more than quadrupling delirium rates (odds ratio, 4.4; CI, 1.7–11.1; p < 0.002). Marginal structural modeling demonstrated odds ratio 3.3 (CI, 1.4–7.8), after controlling for time-dependent confounding of cognitive status, mechanical ventilation, and opiates. With every one log increase in benzodiazepine dosage administered, there was a 43% increase in risk for delirium development.

Conclusions: Benzodiazepines are an independent and modifiable risk factor for development of delirium in critically ill children, even after carefully controlling for time-dependent covariates, with a dose-response effect. This temporal relationship suggests causality between benzodiazepine exposure and pediatric delirium and supports limiting the use of benzodiazepines in critically ill children.

Prevention of Nosocomial Infections in Critically Ill Patients With Lactoferrin: A Randomized, Double-Blind, Placebo-Controlled Study

by Muscedere, John; Maslove, David M.; Boyd, J. Gordon; O’Callaghan, Nicole; Sibley, Stephanie; Reynolds, Steven; Albert, Martin; Hall, Richard; Jiang, Xuran; Day, Andrew G.; Jones, Gwyneth; Lamontagne, Francois  

Objective: To obtain preliminary evidence for the efficacy of lactoferrin as a preventative measure for nosocomial infections and inform the conduct of a definitive study. 

Design: Phase 2, multicenter, randomized, double-blind, placebo-controlled study. Setting: Medical-surgical ICUs. Patients: Adult, critically ill patients receiving invasive mechanical ventilation. Interventions: Randomized, eligible, consenting patients expected to require invasive mechanical ventilation more than 48 hours received lactoferrin both enterally and via an oral swab or a placebo of sterile water for up to 28 days. 

Measurements and Main Results: Of the 214 patients who were randomized, 212 received at least one dose of the intervention and were analyzed (107 lactoferrin and 105 placebo). Protocol adherence was 87.5%. Patients receiving lactoferrin were older (mean [SD], 66.3 [13.5] vs 62.5 [16.2] yr), had a higher Acute Physiology and Chronic Health Evaluation II score (26.8 [7.8] vs 23.5 [7.9]), and need for vasopressors (79% vs 70%). Antibiotic-free days (17.3 [9.0] vs 18.5 [7.1]; p = 0.91) and nosocomial infections (0.3 [0.7] vs 0.4 [0.6] per patient; p = 0.48) did not differ between lactoferrin and placebo groups, respectively. Clinical outcomes for lactoferrin versus placebo were as follows: ICU length of stay (14.5 [18.0] vs 15.0 [37.3] d; p = 0.82), hospital length of stay (25.0 [25.9] vs 28.1 [44.6] d; p = 0.57), hospital mortality (41.1% vs 30.5%; p = 0.11), and 90-day mortality (44.9% vs 32.4%; p = 0.06). Biomarker levels did not differ between the groups. 

Conclusions: Lactoferrin did not improve the primary outcome of antibiotic-free days, nor any of the secondary outcomes. Our data do not support the conduct of a larger phase 3 trial.