Eugene W. Ely

Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis.

ObjectiveTo assess the effects of drotrecogin alfa (activated) therapy, a recombinant human activated protein C, across clinically relevant subpopulations in a randomized, phase 3, placebo-controlled study of patients with severe sepsis (recombinant human activated protein C worldwide evaluation in severe sepsis [PROWESS]). DesignUnivariate and multivariable analysis of prospectively defined subgroups from the PROWESS study. SettingA total of 164 medical centers in 11 countries. PatientsA total of 1,690 patients with severe sepsis. Measurements and Main ResultsWe report observed 28-day mortality rates for drotrecogin alfa (activated) and placebo patients for subgroups prospectively defined by demographic data, surgical status, type and site of infection, and clinical and biochemical measures of disease severity. We performed subgroup analyses to explore the consistency of the mortality benefit observed in the overall population and performed tests for both quantitative and qualitative interactions. To examine the magnitude of the treatment benefit with drotrecogin alfa (activated) across the underlying predicted risk of mortality spectrum, we used stepwise logistic regression on PROWESS placebo patients to generate a predicted risk of mortality model that simultaneously included many clinical and biochemical markers of mortality risk. Because drotrecogin alfa (activated) has anticoagulant properties, we also present analyses of bleeding and thrombotic events. Actual mortality rates were lower with drotrecogin alfa (activated) compared with placebo for nearly all prospectively defined subgroups. Both univariate and multivariable regression analyses showed a consistent relative risk reduction in 28-day mortality rates for drotrecogin alfa (activated). Larger absolute risk reductions were found with drotrecogin alfa (activated) in patients with a higher baseline predicted risk of mortality, and actual mortality rates were lower with drotrecogin alfa (activated) in all subgroups defined by disease severity measures where a ≥20% placebo mortality was observed. Although discriminatory power was limited by few observed events, the increased absolute risk of experiencing a serious bleeding event with treatment did not seem to vary according to the baseline predicted risk of mortality. ConclusionsThe administration of drotrecogin alfa (activated) to patients with severe sepsis was associated with a significant survival benefit that tended to increase with higher baseline likelihood of death. Current data suggest that the increased risk of bleeding does not vary according to likelihood of death.

Activated protein C for severe sepsis.

To the Editor: In this issue of the Journal, Warren et al.1 and Siegel2 offer their views on the approval of drotrecogin alfa (activated), or recombinant human activated protein C, for the treatmen...

Inappropriate Medications in Elderly ICU Survivors: Where to Intervene?

Elderly patients are often prescribed potentially inappropriate medications (PIMs) during their hospital stay which are still present at discharge.1 It is, however, unknown where these PIMs are initiated (i.e., pre-hospital, pre-ICU ward, ICU, post-ICU ward) and if they are stopped or continued across care transitions within the hospital. Furthermore, it is unclear if these PIMs are actually inappropriate medications (AIMs), given the patients’ underlying medical condition. We evaluated medication appropriateness in a cohort of critically ill elderly patients, assessing the number and types of PIMs and AIMs at hospital discharge and determining their source of initiation.

Pediatric delirium: monitoring and management in the pediatric intensive care unit.

This review article updates the pediatric medical community on the current literature regarding diagnosis and treatment of delirium in critically ill children. This information will be of value to pediatricians, intensivists, and anesthesiologists in developing delirium monitoring and management protocols in their pediatric critical care units.

Cognitive Impairment after Critical Illness: Etiologies, Risk Factors, and Future Directions

Mortality rates have declined substantially among critically ill populations in recent years, resulting in increasing numbers of individuals with significant physical, cognitive, and psychiatric morbidities due to the effects of their illness. A consensus has begun to develop regarding the nature of the difficulties experienced by intensive care unit (ICU) survivors, including physical, cognitive, and psychiatric decrements. This article focuses primarily on wide-ranging aspects of cognition and discusses potential mechanisms, risk factors, and recovery and rehabilitation of post-ICU cognitive impairment.

Burst suppression on processed electroencephalography as a predictor of postcoma delirium in mechanically ventilated ICU patients.

Objectives:Many patients, due to a combination of illness and sedatives, spend a considerable amount of time in a comatose state that can include time in burst suppression. We sought to determine if burst suppression measured by processed electroencephalography during coma in sedative-exposed patients is a predictor of post-coma delirium during critical illness. Design:Observational convenience sample cohort. Setting:Medical and surgical ICUs in a tertiary care medical center. Patients:Cohort of 124 mechanically ventilated ICU patients. Interventions:None. Measurements and Main Results:Depth of sedation was monitored twice daily using the Richmond Agitation-Sedation Scale and continuously monitored by processed electroencephalography. When noncomatose, patients were assessed for delirium twice daily using Confusion Assessment Method for the ICU. Multiple logistic regression and Cox proportional hazards regression were used to assess associations between time in burst suppression and both prevalence and time to resolution of delirium, respectively, adjusting for time in deep sedation and a principal component score consisting of Acute Physiology and Chronic Health Evaluation II score and cumulative doses of sedatives while comatose. Of the 124 patients enrolled and monitored, 55 patients either never had coma or never emerged from coma, yielding 69 patients for whom we performed these analyses; 42 of these 69 (61%) had post-coma delirium. Most patients had burst suppression during coma, although often short-lived (median [interquartile range] time in burst suppression, 6.4 [1–58] min). After adjusting for covariates, even this short time in burst suppression independently predicted a higher prevalence of post-coma delirium (odds ratio, 4.16; 95% CI, 1.27–13.62; p = 0.02) and a lower likelihood (delayed) resolution of delirium (hazard ratio, 0.78; 95% CI, 0.53–0.98; p = 0.04). Conclusions:Time in burst suppression during coma, as measured by processed electroencephalography, was an independent predictor of prevalence and time to resolution of postcoma/post–deep sedation delirium. These findings of this single-center investigation support lighter sedation strategies.

Insulin-like growth factor-1 and delirium in critically ill mechanically ventilated patients: a preliminary investigation.

BACKGROUND Delirium occurs frequently in the intensive care unit (ICU), but its pathophysiology is still unclear. Low levels of insulin-like growth factor 1 (IGF-1), a hormone with neuroprotective properties, have been associated with delirium in some non-ICU studies, but this relationship has not been examined in the ICU. We sought to test the hypothesis that low IGF-1 concentrations are associated with delirium during critical illness. METHODS Mechanically ventilated medical ICU patients were prospectively enrolled, and blood was collected after enrollment for measurement of IGF-1 using radioimmunometric assay. Delirium and coma were identified daily using the Confusion Assessment Method for the ICU and the Richmond Agitation-Sedation Scale, respectively. The association between IGF-1 and delirium was evaluated with logistic regression. In addition, the association between IGF-1 and duration of normal mental state, measured as days alive without delirium or coma, was assessed using multiple linear regression. RESULTS Among 110 patients, the median age was 65 years (IQR, 52-75) and APACHE II was 27 (IQR, 22 -32). IGF-1 levels were not a risk factor for delirium on the day after IGF-1 measurement (p = 0.97), at which time 65% of the assessable patients were delirious. No significant association was found between IGF-1 levels and duration of normal mental state (p = 0.23). CONCLUSIONS This pilot study, the first to investigate IGF-1 and delirium in critically ill patients, found no association between IGF-1 and delirium. Future studies including serial measurements of IGF-1 and IGF-1 binding proteins are needed to determine whether this hormone has a role in delirium during critical illness.

Cognitive and Physical Rehabilitation of ICU Survivors: results of the RETURN randomized, controlled pilot investigation

Background:Millions of patients who survive medical and surgical general intensive care unit care every year experience newly acquired long-term cognitive impairment and profound physical and functional disabilities. To overcome the current reality in which patients receive inadequate rehabilitation, we devised a multifaceted, in-home, telerehabilitation program implemented using social workers and psychology technicians with the goal of improving cognitive and functional outcomes. Methods:This was a single-site, feasibility, pilot, randomized trial of 21 general medical/surgical intensive care unit survivors (8 controls and 13 intervention patients) with either cognitive or functional impairment at hospital discharge. After discharge, study controls received usual care (sporadic rehabilitation), whereas intervention patients received a combination of in-home cognitive, physical, and functional rehabilitation over a 3-month period via a social worker or master’s level psychology technician utilizing telemedicine to allow specialized multidisciplinary treatment. Interventions over 12 wks included six in-person visits for cognitive rehabilitation and six televisits for physical/functional rehabilitation. Outcomes were measured at the completion of the rehabilitation program (i.e., at 3 months), with cognitive functioning as the primary outcome. Analyses were conducted using linear regression to examine differences in 3-month outcomes between treatment groups while adjusting for baseline scores. Results:Patients tolerated the program with only one adverse event reported. At baseline both groups were well-matched. At 3-month follow-up, intervention group patients demonstrated significantly improved cognitive executive functioning on the widely used and well-normed Tower test (for planning and strategic thinking) vs. controls (median [interquartile range], 13.0 [11.5–14.0] vs. 7.5 [4.0–8.5]; adjusted p < .01). Intervention group patients also reported better performance (i.e., lower score) on one of the most frequently used measures of functional status (Functional Activities Questionnaire at 3 months vs. controls, 1.0 [0.0 –3.0] vs. 8.0 [6.0–11.8], adjusted p = .04). Conclusions:A multicomponent rehabilitation program for intensive care unit survivors combining cognitive, physical, and functional training appears feasible and possibly effective in improving cognitive performance and functional outcomes in just 3 months. Future investigations with a larger sample size should be conducted to build on this pilot feasibility program and to confirm these results, as well as to elucidate the elements of rehabilitation contributing most to improved outcomes.

Evaluating early administration of the hydroxymethylglutaryl-CoA reductase inhibitor simvastatin in the prevention and treatment of delirium in critically ill ventilated patients (MoDUS trial): study protocol for a randomized controlled trial

BackgroundThe incidence of delirium in ventilated patients is estimated at up to 82%, and it is associated with longer intensive care and hospital stays, and long-term cognitive impairment and mortality. The pathophysiology of delirium has been linked with inflammation and neuronal apoptosis. Simvastatin has pleiotropic properties; it penetrates the brain and, as well as reducing cholesterol, reduces inflammation when used at clinically relevant doses over the short term. This is a single centre randomised, controlled trial which aims to test the hypothesis that treatment with simvastatin will modify delirium incidence and outcomes.Methods/DesignThe ongoing study will include 142 adults admitted to the Watford General Hospital Intensive Care Unit who require mechanical ventilation in the first 72 hours of admission. The primary outcome is the number of delirium- and coma-free days in the first 14 days. Secondary outcomes include incidence of delirium, delirium- and coma-free days in the first 28 days, days in delirium and in coma at 14 and 28 days, number of ventilator-free days at 28 days, length of critical care and hospital stay, mortality, cognitive decline and healthcare resource use. Informed consent will be taken from patient’s consultee before randomisation to receive either simvastatin (80 mg) or placebo once daily. Daily data will be recorded until day 28 after randomisation or until discharge from the ICU if sooner. Surviving patients will be followed up on at six months from discharge. Plasma and urine samples will be taken to investigate the biological effect of simvastatin on systemic markers of inflammation, as related to the number of delirium- and coma-free days, and the potential of cholinesterase activity and beta-amyloid as predictors of the risk of delirium and long-term cognitive impairment.DiscussionThis trial will test the efficacy of simvastatin on reducing delirium in the critically ill. If patients receiving the statin show a reduced number of days in delirium compared with the placebo group, the inflammatory theory implicated in the pathogenesis of delirium will be strengthened.Trial registrationThe trial was registered with the International Standard Randomised Controlled Trial Registry (ISRCTN89079989) on 26 March 2013.

Adapting the ABCDEF Bundle to Meet the Needs of Patients Requiring Prolonged Mechanical Ventilation in the Long-Term Acute Care Hospital Setting: Historical Perspectives and Practical Implications.

When robust clinical trials are lacking, clinicians are often forced to extrapolate safe and effective evidence-based interventions from one patient care setting to another. This article is about such an extrapolation from the intensive care unit (ICU) to the long-term acute care hospital (LTACH) setting. Chronic critical illness is an emerging, disabling, costly, and yet relatively silent epidemic that is central to both of these settings. The number of chronically critically ill patients requiring prolonged mechanical ventilation is expected to reach unprecedented levels over the next decade. Despite the prevalence, numerous distressing symptoms, and exceptionally poor outcomes associated with chronic critical illness, to date there is very limited scientific evidence available to guide the care and management of this exceptionally vulnerable population, particularly in LTACHs. Recent studies conducted in the traditional ICU setting suggest interprofessional, multicomponent strategies aimed at effectively assessing, preventing, and managing pain, agitation, delirium, and weakness, such as the ABCDEF bundle, may play an important role in the recovery of the chronically critically ill. This article reviews what is known about the chronically critically ill, provide readers with some important historical perspectives on the ABCDEF bundle, and address some controversies and practical implications of adopting the ABCDEF bundle into the everyday care of patients requiring prolonged mechanical ventilation in the LTACH setting. We believe developing new and better ways of addressing both the science and organizational aspects of managing the common and distressing symptoms associated with chronic critical illness and prolonged mechanical ventilation will ultimately improve the quality of life for the many patients and families admitted to LTACHs annually.