Daniel W. Johnson

Lessons learned: critical care management of patients with Ebola in the United States.

Objective:This report will describe the preparations for and the provision of care of two patients with Ebola virus disease in the biocontainment unit at the University of Nebraska Medical Center. Data Sources:Patient medical records. Study Selection:Not applicable. Data Extraction:Not applicable. Data Synthesis:Not applicable. Conclusions:Safe and effective care of patients with Ebola virus disease requires significant communication and planning. Adherence to a predetermined isolation protocol is essential, including proper donning and doffing of personal protective equipment. Location of the patient care area and the logistics of laboratory testing, diagnostic imaging, and the removal of waste must be considered. Patients with Ebola virus disease are often dehydrated and need adequate vascular access for fluid resuscitation, nutrition, and phlebotomy for laboratory sampling. Advanced planning for acute life-threatening events and code status must be considered. Intensivist scheduling should account for the significant amount of time required for the care of patients with Ebola virus disease. With appropriate precautions and resources, designated hospitals in the United States can safely provide care for patients with Ebola virus disease.

Critical Care for Multiple Organ Failure Secondary to Ebola Virus Disease in the United States.

Objective:This report describes three patients with Ebola virus disease who were treated in the United States and developed for severe critical illness and multiple organ failure secondary to Ebola virus infection. The patients received mechanical ventilation, renal replacement therapy, invasive monitoring, vasopressor support, and investigational therapies for Ebola virus disease. Data Sources:Patient medical records from three tertiary care centers (Emory University Hospital, University of Nebraska Medical Center, and Texas Health Presbyterian Dallas Hospital). Study Selection:Not applicable. Data Extraction:Not applicable. Data Synthesis:Not applicable. Conclusion:In the severe form, patients with Ebola virus disease may require life-sustaining therapy, including mechanical ventilation and renal replacement therapy. In conjunction with other reported cases, this series suggests that respiratory and renal failure may occur in severe Ebola virus disease, especially in patients burdened with high viral loads. Ebola virus disease complicated by multiple organ failure can be survivable with the application of advanced life support measures. This collective, multicenter experience is presented with the hope that it may inform future treatment of patients with Ebola virus disease requiring critical care treatment.

Early Goal-directed Therapy for Sepsis: A Novel Solution for Discordant Survival Outcomes in Clinical Trials

Objectives: Early goal-directed therapy has shown discordant survival outcomes in sepsis studies. We aim to find the reasons for this discordance. Design: Random-effects and Bayesian hierarchical analyses. Setting: Studies that evaluated early goal-directed therapy. Subjects: Patients with severe sepsis and/or septic shock. Interventions: Early goal-directed therapy. Measurements and Main Results: A total of 19,998 patients were included in the main analysis: 31 observational (n = 15,656) and six randomized (n = 4,342) studies. The analysis from 37 studies showed that early goal-directed therapy was associated with a 23% reduction in the risk of death: relative risk = 0.77 (95% CI, 0.71–0.83); p value of less than 0.0001. Mortality reduction was seen with observational studies: relative risk = 0.73 (0.67–0.80); p value of less than 0.0001 but not with randomized studies: relative risk = 0.92 (0.78–1.07); p = 0.268. Meta-regression analysis showed lower risk of death in observational compared with randomized studies: relative risk = 0.81 (0.68–0.95); p = 0.01. Differences in age, country, hospital location, era, systolic pressure, mean arterial pressure, lactate, bundle compliance, amount of fluid administered, and hemodynamic goal achievements were not associated with survival differences between studies. Factors associated with mortality differences between early goal-directed therapy and control included Acute Physiology and Chronic Health Evaluation II (relative risk = 1.05 [1.02–1.09]; p = 0.003), Sequential Organ Failure Assessment (relative risk = 1.09 [1.00–1.18]; p = 0.04), presence of shock (relative risk = 1.007 [1.002–1.013]; p = 0.006), time-to-first antibiotic (relative risk = 1.22 [1.09–1.36]; p = 0.0006), antibiotic administration within 6 hours (relative risk = 0.20 [0.09–0.45]; p = 0.0001), 4 hours (relative risk = 0.16 [0.06–0.39]; p = 0.0001), and 3 hours (relative risk = 0.09 [0.03–0.27]; p < 0.0001). The only factors that explained mortality differences between randomized and observational studies were time-to-first antibiotic (R 2 = 87%), antibiotic administration within 6 hours (R 2 = 94%), 4 hours (R 2 = 99%), 3 hours (R 2 = 99%), and appropriate antibiotic use (R 2 = 96%). Conclusions: Survival discordance was not associated with differences in early goal-directed therapy bundle compliance or hemodynamic goal achievement. Our results suggest that it was associated with faster and more appropriate antibiotic co-intervention in the early goal-directed therapy arm compared with controls in the observational studies but not in the randomized trials. Early goal-directed therapy was associated with increased mortality in patients with high-disease severity.

Is Interleukin-1 Receptor Blockade Ready for Prime Time in Patients With Severe Sepsis and Macrophage Activation Syndrome?

Critical Care Medicine www.ccmjournal.org 443 Patients with severe sepsis or septic shock have a hospital mortality rate greater than 20% even with adherence to evidence-based sepsis bundles (1). Despite worldwide efforts to reduce its devastating impact, sepsis continues to be a leading cause of death in all ICUs. Ever since the discovery of the prominent role of cytokines in normal and exaggerated immune responses, researchers have worked to determine how manipulation of cytokines and their receptors might reduce patient harm in sepsis and other inflammatory disorders (2). Of note, the very same cytokine can have both proand antiinflammatory properties, which varies according the location of expression and timing. Although hyperinflammation in sepsis may cause significant harm, inflammatory cytokines represent only a part of an incredibly complex molecular interplay within the immune system. In addition, sepsis-induced coagulation disturbances (3) and apoptosis of both immunerelated cells (e.g., lymphocytes, dendritic cells, and NK cells) and cells related to specific organs (e.g., epithelial cells [acute respiratory distress syndrome ], endothelial cells [capillary leak], myocytes [cardiac dysfunction]) (4, 5) may be as or more relevant to survival outcomes than cytokines’ modulation. Several trials have attempted to show improved sepsis outcomes from specific cytokine blockade but have, as of yet, been unsuccessful. Early investigations suggested that the damaging effects of sepsis arose solely from excessive inflammation. More recent studies suggest that the lethality of sepsis may be due to both the hyperinflammatory state typical of early sepsis and the impaired immune state more commonly seen later in disease (4). Furthermore, this concept of bimodal immunological reaction is not necessarily applicable to all patients with sepsis because recent evidence suggests that both hyperand hypoinflammatory responses may ensue concomitantly during septic shock (6). This “feast or famine” ambiguous nature of the immune response in sepsis helps to explain the great difficulty researchers have had in creating effective therapeutics beyond the traditional measures of source control, antimicrobials, and restoration of hemodynamics. In this issue of Critical Care Medicine, Dr. Shakoory et al (7) report the results of a re-analysis of data from a 1997 phaseIII randomized trial of recombinant interleukin-1 receptor antagonist (rIL-1ra) versus placebo in patient with sepsis (8). Although we recognize a need for a paradigm shift with regard to future sepsis research (9, 10), investigators must also make optimal use of the plethora of sepsis trial data collected over the previous 20 years. Shakoory et al (7) noted that interleukin-1 receptor antagonist has shown potential efficacy in macrophage activation syndrome (MAS)—a fulminant cytokine storm associated with pancytopenia, hemophagocytosis, liver dysfunction, and central nervous system dysfunction; therefore, based on the clinical and cytokine pattern similarity between severe sepsis and MAS, they hypothesized that this drug might improve outcomes in patients with sepsis who exhibit the cardinal features of MAS: hepatobiliary dysfunction (HBD) and disseminated intravascular coagulation (DIC). Shakoory et al (7) re-analyzed the data from the phase III randomized clinical trial from Opal et al (8), which compared rIL-1ra against placebo in patients with severe sepsis in 91 centers from 11 countries. A total of 763 patients completed the study and 43 met the HBD/DIC criteria (patients whose clinical presentation met the definitions of both HBD and DIC), whereas 720 met the non-HBD/DIC criteria (patients who did not have both HBD and DIC). The observed randomization ratio of rIL-1ra to placebo was 2:1. The baseline characteristics of this post hoc subgroup analysis showed significant imbalances in several variables: age, acute kidney injury, shock, and predicted death risk score (Table 2 of [7]). Although the 28-day mortality was not different Copyright

Con: cardiac anesthesiologists should not be the intensivists of the operating room

ANESTHESIOLOGISTS can be challenged when caring for patients who are critically ill before surgery and by those who develop critical illness during a surgical procedure. The care of critically ill patients can be fundamentally different from the routine care rendered in the operating room. In the setting of a major intraoperative crisis such as cardiac arrest, massive unexpected hemorrhage, or hypoxemia refractory to aggressive therapies, the skill set of the operating room team can be pushed to the limit. Operating room crises require rapid, coordinated management in a stressful, time-critical setting, and successful resuscitation depends largely on clinicians’ retained knowledge and skill. Failure to adhere to critical steps in the management of such crises is common and may be hazardous to patients. A high-fidelity simulation study of ventricular fibrillation cardiac arrests in the operating room revealed that 61% of anesthesiologists demonstrated “major deviations” from advanced cardiac life support protocols. 1 The availability of specialized teams and resources for support during management of crisis situations is essential and is the focus of ongoing investigations. 2,3 Physicians with expertise in the care of critically ill patients and who regularly manage acute crisis situations must be available to provide consultation in the operating room when the need arises. With formal training and daily experience in managing critically ill patients, the fellowship-trained critical care anesthesiologist is the obvious choice to fulfill this role. Unfortunately, the specialty of critical care medicine is facing a staffing crisis. 4–6 The growing shortage of intensivists and its implications for hospitalized Americans is well documented and remains an ongoing concern for hospitals, clinicians, and the federal government. 6 The mismatch between intensivist