IntroductionBenzodiazepines and α2 adrenoceptor agonists exert opposing effects on innate immunity and mortality in animal models of infection. We hypothesized that sedation with dexmedetomidine (an α2 adrenoceptor agonist), as compared with lorazepam (a benzodiazepine), would provide greater improvements in clinical outcomes among septic patients than among non-septic patients.MethodsIn this a priori-determined subgroup analysis of septic vs non-septic patients from the MENDS double-blind randomized controlled trial, adult medical/surgical mechanically ventilated patients were randomized to receive dexmedetomidine-based or lorazepam-based sedation for up to 5 days. Delirium and other clinical outcomes were analyzed comparing sedation groups, adjusting for clinically relevant covariates as well as assessing interactions between sedation group and sepsis.ResultsOf the 103 patients randomized, 63 (31 dexmedetomidine; 32 lorazepam) were admitted with sepsis and 40 (21 dexmedetomidine; 19 lorazepam) without sepsis. Baseline characteristics were similar between treatment groups for both septic and non-septic patients. Compared with septic patients who received lorazepam, the dexmedetomidine septic patients had 3.2 more delirium/coma-free days (DCFD) on average (95% CI for difference, 1.1 to 4.9), 1.5 (-0.1, 2.8) more delirium-free days (DFD) and 6 (0.3, 11.1) more ventilator-free days (VFD). The beneficial effects of dexmedetomidine were more pronounced in septic patients than in non-septic patients for both DCFDs and VFDs (P-value for interaction = 0.09 and 0.02 respectively). Additionally, sedation with dexmedetomidine, compared with lorazepam, reduced the daily risk of delirium [OR, CI 0.3 (0.1, 0.7)] in both septic and non-septic patients (P-value for interaction = 0.94). Risk of dying at 28 days was reduced by 70% [hazard ratio 0.3 (0.1, 0.9)] in dexmedetomidine patients with sepsis as compared to the lorazepam patients; this reduction in death was not seen in non-septic patients (P-value for interaction = 0.11).ConclusionsIn this subgroup analysis, septic patients receiving dexmedetomidine had more days free of brain dysfunction and mechanical ventilation and were less likely to die than those that received a lorazepam-based sedation regimen. These results were more pronounced in septic patients than in non-septic patients. Prospective clinical studies and further preclinical mechanistic studies are needed to confirm these results.Trial RegistrationNCT00095251.

Venoarterial extracorporeal membrane oxygenation has emerged as a viable treatment for patients in cardiogenic shock with biventricular failure and pulmonary dysfunction. Advances in pump and oxygenator technology, cannulation strategies, patient selection and management, and durable mechanical circulatory support have contributed to expanded utilization of this technology. However, challenges remain that require investigation to improve outcomes.

Critically ill patients are frequently prescribed sedatives and analgesics to ensure patient safety, to relieve pain and anxiety, to reduce stress and oxygen consumption, and to prevent patient ventilator dysynchrony. Recent studies have revealed that these medications themselves contribute to worsening clinical outcomes. An evidence-based organizational approach referred to as the ABCDE bundle (Awakening and Breathing Coordination of daily sedation and ventilator removal trials; Choice of sedative or analgesic exposure; Delirium monitoring and management; and Early mobility and Exercise) is presented in this commentary.

IntroductionNon-intensive care unit (ICU) cohorts have shown an association between inflammatory disturbances and delirium, though these relationships have not been studied in critically ill patients. This study sought to investigate the relationship between two inflammatory biomarkers, procalcitonin and C-reactive protein (CRP), and duration of acute brain dysfunction in ventilated patients.MethodsPatients enrolled in the Maximizing Efficacy of Targeted Sedation and Reducing Neurological Dysfunction (MENDS) trial were assessed daily for delirium using the Confusion Assessment Method-ICU. Plasma levels of procalcitonin and CRP were obtained within 24 hours of enrollment. Proportional odds logistic regression was used to examine the association between procalcitonin and CRP separately with delirium/coma-free days, adjusting for age, acute physiology score (APS) of the Acute Physiology And Chronic Health Evaluation (APACHE) II, sedation group (dexmedetomidine vs. lorazepam), and sepsis. Secondary analyses examined the association of these markers with other organ dysfunctions and 28-day survival.ResultsEighty-seven patients were included in this analysis. The median age of the patients was 60 years with APACHE II scores of 28; 68% had sepsis within 48 hours of admission. Higher levels of procalcitonin were associated with fewer delirium/coma-free days [odds ratio (OR), 0.5; 95% confidence interval (CI), 0.3 to 1.0; P = 0.04], whereas higher CRP levels showed trends towards fewer delirium/coma-free days (OR, 0.6; 95% CI, 0.3 to 1.1; P = 0.08). Similar relationships were found regardless of the presence of sepsis. No associations were found between procalcitonin or CRP with 28-day survival (P = 0.40 and 0.16, respectively).ConclusionsIn our pilot study, high baseline inflammatory biomarkers predicted prolonged periods of acute brain dysfunction, implicating inflammation as an important mechanism in the pathophysiology of delirium and coma during critical illness, irrespective of whether patients had sepsis or not.

Critically ill patients are routinely provided analgesia and sedation to prevent pain and anxiety, permit invasive procedures, reduce stress and oxygen consumption, and improve synchrony with mechanical ventilation. Regional preferences, patient history, institutional bias, and individual patient and practitioner variability, however, create a wide discrepancy in the approach to sedation of critically ill patients. Untreated pain and agitation increase the sympathetic stress response, potentially leading to negative acute and long-term consequences. Oversedation, however, occurs commonly and is associated with worse clinical outcomes, including longer time on mechanical ventilation, prolonged stay in the intensive care unit, and increased brain dysfunction (delirium and coma). Modifying sedation delivery by incorporating analgesia and sedation protocols, targeted arousal goals, daily interruption of sedation, linked spontaneous awakening and breathing trials, and early mobilization of patients have all been associated with improvements in patient outcomes and should be incorporated into the clinical management of critically ill patients. To improve outcomes, including time on mechanical ventilation and development of acute brain dysfunction, conventional sedation paradigms should be altered by providing necessary analgesia, incorporating propofol or dexmedetomidine to reach arousal targets, and reducing benzodiazepine exposure.