Brain injury as a risk factor for fever upon admission to the intensive care unit and association with in-hospital case fatality: a matched cohort study.

PURPOSE: To test the hypothesis that fever was more frequent in critically ill patients with brain injury when compared to nonneurological patients and to study its effect on in-hospital case fatality. METHODS: Retrospective matched cohort study utilizing a single-center prospectively compiled registry. Critically ill neurological patients ≥18 years and consecutively admitted to the intensive care unit (ICU) with acute ischemic stroke (AIS), intracerebral hemorrhage (ICH), and traumatic brain injury (TBI) were selected. Patients were matched by sex, age, and Acute Physiology and Chronic Health Evaluation II (APACHE-II) to a cohort of nonneurological patients. Fever was defined as any temperature ≥37.5°C within the first 24 hours upon admission to the ICU. The primary outcome measure was in-hospital case fatality. RESULTS: Mean age among neurological patients was 65.6 ± 15 years, 46% were men, and median APACHE-II was 15 (interquartile range 11-20). There were 18% AIS, 27% ICH, and 6% TBI. More neurological patients experienced fever than nonneurological patients (59% vs 47%, P = .007). The mean hospital length of stay was higher for nonneurological patients (18 ± 20 vs 14 ± 15 days, P = .007), and more neurological patients were dead at hospital discharge (29% vs 20%, P < .0001). After risk factor adjustment, diagnosis (neurological vs nonneurological), and the probability of being exposed to fever (propensity score), the following variables were associated with higher in-hospital case fatality: APACHE-II, neurological diagnosis, mean arterial pressure, cardiovascular and respiratory dysfunction in ICU, and fever (odds ratio 1.9, 95% confidence interval 1.04-3.6, P = .04). CONCLUSION: These data suggest that fever is a frequent occurrence after brain injury, and that it is independently associated with in-hospital case fatality.

The epidemiology of spontaneous fever and hypothermia on admission of brain injury patients to intensive care units: a multicenter cohort study.

OBJECTIVES: Fever and hypothermia (dysthermia) are associated with poor outcomes in patients with brain injuries. The authors sought to study the epidemiology of dysthermia on admission to the intensive care unit (ICU) and the effect on in-hospital case fatality in a mixed cohort of patients with brain injuries. METHODS: The authors conducted a multicenter retrospective cohort study in 94 ICUs in the United States. Critically ill patients with neurological injuries, including acute ischemic stroke (AIS), aneurysmal subarachnoid hemorrhage (aSAH), intracerebral hemorrhage (ICH), and traumatic brain injury (TBI), who were older than 17 years and consecutively admitted to the ICU from 2003 to 2008 were selected for analysis. RESULTS: In total, 13,587 patients were included in this study; AIS was diagnosed in 2973 patients (22%), ICH in 4192 (31%), aSAH in 2346 (17%), and TBI in 4076 (30%). On admission to the ICU, fever was more common among TBI and aSAH patients, and hypothermia was more common among ICH patients. In-hospital case fatality was more common among patients with hypothermia (OR 12.7, 95% CI 8.4-19.4) than among those with fever (OR 1.9, 95% CI 1.7-2.1). Compared with patients with ICH (OR 2.0, 95% CI 1.8-2.3), TBI (OR 1.5, 95% CI 1.3-1.8), and aSAH (OR 1.4, 95% CI 1.2-1.7), patients with AIS who developed fever had the highest risk of death (OR 3.1, 95% CI 2.5-3.7). Although all hypothermic patients had an increased mortality rate, this increase was not significantly different across subgroups. In a multivariable analysis, when adjusted for all other confounders, exposure to fever (adjusted OR 1.3, 95% CI 1.1-1.5) or hypothermia (adjusted OR 7.8, 95% CI 3.9-15.4) on admission to the ICU was found to be significantly associated with in-hospital case fatality. CONCLUSIONS: Fever is frequently encountered in the acute phase of brain injury, and a small proportion of patients with brain injuries may also develop spontaneous hypothermia. The effect of fever on mortality rates differed by neurological diagnosis. Both early spontaneous fever and hypothermia conferred a higher risk of in-hospital death after brain injury.

Diagnosis and management of bone cement implantation syndrome: case report and brief review.

Bone cement implantation syndrome (BCIS) is a rare but potentially fatal intraoperative complication that occurs in patients undergoing cemented orthopedic surgeries. Lack of a robust definition of the syndrome due to rarity of the condition has probably contributed to under reporting of cases. We report a case of a 72-year-old woman hospitalized for an elective orthopedic procedure with a postoperative course complicated by BCIS requiring supportive care in the intensive care unit setting.

Hydralazine-induced pulmonary-renal syndrome: a case report.

Drug-induced lupus erythematosus differs in its manifestation from drug-induced vasculitis. The former is associated with characteristic symptoms that improve following discontinuation, whereas the latter is predominantly an antineutrophil cytoplasmic antibody (ANCA) positive small vessel vasculitis involving the kidneys, skin, and lungs. We present a case of advanced disease in an elderly Caucasian woman requiring corticosteroids, and immunosuppressive therapy, who was on hydralazine for >2 years.

Valsartan-induced angioedema in a patient on angiotensin-converting enzyme inhibitor for years: case report and literature review.

Angioedema is a rare but life-threatening adverse effect of administration of angiotensin-converting enzyme inhibitors (ACEIs) administration. It has been classically associated with ACEIs, although angioedema has also been reported with angiotensin receptor blockers (ARBs). Angioedema is a deep swelling of tissues just below the skin and mucous membranes, characterized by non-pitting asymmetric swelling that is usually non-pruritic. ARBs may cause an increase in plasma angiotensin II levels, which may lead to a negative feedback inhibition of ACE activity, predisposing to angioedema development. We report a case of valsartan-induced angioedema that occurred in a patient who was on ACEIs for years, with no incidence of angioedema.

TAKEDA-143242 increased survival via reduced cytokines in porcine peritonitis.

TAKEDA-143242 (TAK-242) is a small molecule shown to inhibit lipopolysaccharide-induced intracellular signaling and inflammation. In vitro studies demonstrated that TAK-242 can prevent release of TNF-α, IL-1ß, and IL-6 from activated macrophages of several species, including pigs. This study tested the hypothesis that TAK-242 would protect pigs from lethal gram-negative peritonitis via an anti-cytokine mechanism. A validated model of porcine gram-negative peritonitis, which employs chronically inplantated cardiac transducers and aortic and pulmonary artery catheters, was used. Pigs were pretreated with TAK-242 or its vehicle via a blinding procedure prior to intraperitoneal implantation of an LD(90) dose of E. coli 0111:B4 in a fibrin clot. Ten pigs were treated with TAK-242 and nine with its vehicle. All ten TAK-242 treated pigs survived, while three of the nine vehicle treated pigs survived (P = 0.01 χ(2) test). Pulmonary artery pressure increased markedly in vehicle pigs, and this elevation was significantly (two-way ANOVA) obviated in TAK-242 treated group. Circulating levels of cytokines in vehicle treated pigs showed increased expression (3930 ± 1770 at 1 h, 1007 ± 400 TNF-α at 2 h; 719 ± 308 of IL-1ß at 2-6 h; 33000 ± 1000 of IL-6 at 2-4 h [pg/mL, mean ± SEM]). Peak circulating levels of these cytokines were significantly reduced by pretreatment with TAK-242 (<25 pg/mL TNF-α ; <100 pg/mL IL-1ß; 0-1700 pg/mL IL-6, peak values). This study found that pretreatment with TAK-242 yielded significantly positive survival benefit in a lethal sepsis model that was associated with improved cardiovascular status and suppressed cytokine release.

Targeted temperature management in critical care: a report and recommendations from five professional societies.

OBJECTIVE: Representatives of five international critical care societies convened topic specialists and a nonexpert jury to review, assess, and report on studies of targeted temperature management and to provide clinical recommendations. DATA SOURCES: Questions were allocated to experts who reviewed their areas, made formal presentations, and responded to questions. Jurors also performed independent searches. Sources used for consensus derived exclusively from peer-reviewed reports of human and animal studies. STUDY SELECTION: Question-specific studies were selected from literature searches; jurors independently determined the relevance of each study included in the synthesis. CONCLUSIONS AND RECOMMENDATIONS: 1) The jury opines that the term "targeted temperature management" replace "therapeutic hypothermia." 2) The jury opines that descriptors (e.g., "mild") be replaced with explicit targeted temperature management profiles. 3) The jury opines that each report of a targeted temperature management trial enumerate the physiologic effects anticipated by the investigators and actually observed and/or measured in subjects in each arm of the trial as a strategy for increasing knowledge of the dose/duration/response characteristics of temperature management. This enumeration should be kept separate from the body of the report, be organized by body systems, and be made without assertions about the impact of any specific effect on the clinical outcome. 4) The jury STRONGLY RECOMMENDS targeted temperature management to a target of 32°C-34°C as the preferred treatment (vs. unstructured temperature management) of out-of-hospital adult cardiac arrest victims with a first registered electrocardiography rhythm of ventricular fibrillation or pulseless ventricular tachycardia and still unconscious after restoration of spontaneous circulation (strong recommendation, moderate quality of evidence). 5) The jury WEAKLY RECOMMENDS the use of targeted temperature management to 33°C-35.5°C (vs. less structured management) in the treatment of term newborns who sustained asphyxia and exhibit acidosis and/or encephalopathy (weak recommendation, moderate quality of evidence).

Ventricular dilation is associated with improved cardiovascular performance and survival in sepsis.

OBJECTIVES: Myocardial dysfunction in sepsis may be associated with changes in left ventricular (LV) size. The goal of this study was to evaluate the impact of myocardial dysfunction and changes in LV diameter on hemodynamics and survival in a murine model of sepsis. METHODS: C57Bl/6 mice (N = 30) were used. Septic mice (n = 24) had cecal ligation and puncture (CLP) followed by fluid and antibiotic resuscitation and control mice (n = 6) received sham ligation. Echocardiography with a 30-mHz probe was performed at baseline and at frequent predefined time points after CLP. Stroke volume (SV), cardiac output (CO), LV internal diameter in diastole (LVIDd), and fractional shortening (FS) were measured. LV dilation was prospectively defined as an increase in LVIDd ≥ 5% from baseline values. Septic animals were classified as dilators or nondilators. RESULTS: Among septic animals, 37% were dilators and 63% were nondilators. After CLP, SV and CO decreased early in both groups. With resuscitation, SV and CO improved to a greater extent in dilators than nondilators (for SV, 46.0 ± 8.2 vs 36.1 ± 12.7 µL at 24 h, P = .05; for CO, 20.4 ± 4.8 vs 14.8 ± 6.7 mL/min, P = .04). Survival at 72 h was significantly improved in dilators compared with nondilators (88% vs 40%, P = .01). CONCLUSIONS: In a clinically relevant murine model of sepsis, animals with LV dilation had better cardiovascular performance and increased survival. Our results suggest that LV dilation is associated with improved SV and CO, a pattern resulting in greatly improved survival. These studies highlight the importance of diastolic function in septic shock.

Animal models of sepsis.

In this review, we start with a general discussion of relevant factors that can determine the validity of a sepsis animal model. We briefly review some of the currently used animal models of sepsis (small animal models and large animal models). We discuss the clinical relevance of animal models in sepsis research today and address potential reasons for the apparent underperformance of animal models in predicting therapeutic success of novel drugs in clinical trials.

Cardiac dysfunction in severe sepsis and septic shock.

PURPOSE OF REVIEW: Severe sepsis and septic shock are among the most important causes of morbidity and mortality in patients admitted to the intensive care unit. The purpose of this review is to review current understanding of sepsis-induced cardiac dysfunction and discuss pertinent findings regarding its clinical presentation, underlying mechanisms of disease, and therapy. RECENT FINDINGS: Cardiac dysfunction in sepsis is characterized by decreased contractility, impaired ventricular response to fluid therapy, and in some patients ventricular dilatation. Current data support a complex underlying physiopathology with a host of potential pathways leading to myocardial depression. Circulating factors such as cytokines (TNF-alpha, IL-1beta), lysozyme c, endothelin-1 have direct inhibitory actions on myocyte contractility. Nitric oxide has a complex role in sepsis-induced cardiac dysfunction. Current data suggest a combination of deleterious and positive effects on the myocardium determined by the specific type of nitric oxide expressed. Recent studies have shown that mitochondrial dysfunction and apoptosis also play a role in the development of sepsis-induced cardiac dysfunction. Current treatment for sepsis-induced cardiac dysfunction is based on appropriate treatment for the infectious focus (antibiotics and source control) and hemodynamic support (fluids, vasopressors, and inotropes). SUMMARY: Cardiac dysfunction is common in patients with severe sepsis and septic shock. Current understanding of the underlying mechanisms responsible is rapidly evolving and future novel therapeutic targets may be soon available. Present therapy for sepsis-induced cardiac dysfunction is based on treatment of underlying sepsis with antibiotics and hemodynamic support.

Fluid resuscitation influences cardiovascular performance and mortality in a murine model of sepsis.

RATIONALE: Current murine models of sepsis do not account for the effects of aggressive fluid resuscitation on hemodynamics and mortality. OBJECTIVES: Evaluate the impact of fluid resuscitation regimens on cardiovascular performance and survival in a murine model of sepsis. METHODS: Mice (n = 90) were made septic by cecal ligation and puncture (CLP), and received antibiotics plus Low, Intermediate, or High fluid resuscitation regimens. Stroke volume (SV), cardiac output (CO), and fractional shortening (FS) were measured by echocardiography at predefined time points. MEASUREMENTS AND MAIN RESULTS: Baseline echocardiographic measurements were similar in all groups. After CLP, SV and CO decreased early in all groups; High: 57.2 +/- 9.2 to 23.9 +/- 7.2 microL, and 26.8 +/- 4.9 to 13.1 +/- 5.8 ml/min; Intermediate: 52.1 +/- 7.0 to 21.5 +/- 6.6 microL, and 24.9 +/- 4.1 to 11.9 +/- 3.9 ml/min; Low: 54.0 +/- 7.0 to 20.3 +/- 5.6 microL, and 25.8 +/- 4.0 to 11.3 +/- 3.9 ml/min (P < 0.05 for all vs. baseline). With resuscitation there was a dose-dependent improvement in SV and CO (P < 0.05). At 24 h SV and CO were 44.0 +/- 13.8 microL and 20.7 +/- 8.5 ml/min in the High group, 39.8 +/- 12.3 microL and 16.7 +/- 6.5 ml/min in the Intermediate group, and 30.1 +/- 12.4 microL and 14.0 +/- 7.2 ml/min in the Low group. Survival was improved in the High fluid group (75%) compared to the Intermediate (58%) and the Low (35%) resuscitation groups (P < 0.05). CONCLUSIONS: In this model, as in human sepsis, the intensity of fluid resuscitation modulates hemodynamic response and mortality. Incorporation of early and aggressive fluid resuscitation can significantly enhances the clinical relevance of murine models of sepsis.

Hemodynamic optimization of sepsis-induced tissue hypoperfusion.

Sepsis is associated with cardiovascular changes that may lead to development of tissue hypoperfusion. Early recognition of sepsis and tissue hypoperfusion is critical to implement appropriate hemodynamic support and prevent irreversible organ damage. End points for resuscitation need to be defined and invasive hemodynamic monitoring is usually required. Targets for hemodynamic optimization should include intravascular volume, blood pressure, and cardiac output. Therapeutic interventions aimed at optimizing hemodynamics in patients with sepsis include aggressive fluid resuscitation, the use of vasopressor agents, inotropic agents and in selected cases transfusions of blood products. This review will cover the most important aspects of hemodynamic optimization for treatment of sepsis induced tissue-hypoperfusion.

Inclusion criteria for clinical trials in sepsis: did the American College of Chest Physicians/Society of Critical Care Medicine consensus conference definitions of sepsis have an impact?

BACKGROUND: Over the last 25 years, a growing number of clinical trials have evaluated novel sepsis therapies. To promote uniformity in inclusion criteria for patient enrollment, the American College of Chest Physicians and Society of Critical Care Medicine first published consensus conference definitions for sepsis in 1992. STUDY OBJECTIVES: To characterize (1) the utilization of specific criteria for patient enrollment in sepsis clinical trials and (2) the impact that the consensus conference definitions have had on these criteria. DESIGN: We used MEDLINE to identify clinical trials in sepsis from 1976 to 2001. Clinical trials published after the consensus conference (ACC; from 1993 to 2001) were compared with trials published before the consensus conference (BCC; from 1976 to 1992). RESULTS: We identified 176 clinical trials (ACC, 119 trials; BCC, 57 trials). Clinical trials published ACC were more likely to utilize or reference a previously published standard for inclusion criteria (65% vs 11%, respectively; p < 0.001). The consensus conference definitions were the standards used in 69% of these trials. The utilization of specified values for WBC count, temperature (T), heart rate (HR), and respiratory rate (RR) was significantly increased in the ACC group compared to the BCC group, as follows: WBC count, 62% vs 26%, respectively (p < 0.001); T, 89% vs 56%, respectively (p < 0.001); HR, 77% vs 26%, respectively (p < 0.001); and RR, respectively 76% vs 28% (p < 0.001). ACC, clinical trials were less likely to require blood culture positivity (4 of 119 trials [3%] vs 9 of 57 trials [16%], respectively; p < 0.006) and were more likely to incorporate markers of acute organ dysfunction (81 of 119 trials [68%] vs 28 of 57 trials [49%], respectively; p < 0.03) in the inclusion criteria. CONCLUSIONS: (1) Since 1992 there has been a significant increase in the utilization of predefined sepsis criteria for patient enrollment in clinical trials, and this increase can be attributed to the existence of consensus conference definitions. (2) Compared to inclusion criteria BCC, inclusion criteria ACC were less reliant on blood culture positivity and were more likely to incorporate markers of organ dysfunction.

Practice parameters for hemodynamic support of sepsis in adult patients: 2004 update.

OBJECTIVE: To provide the American College of Critical Care Medicine with updated guidelines for hemodynamic support of adult patients with sepsis. DATA SOURCE: Publications relevant to hemodynamic support of septic patients were obtained from the medical literature, supplemented by the expertise and experience of members of an international task force convened from the membership of the Society of Critical Care Medicine. STUDY SELECTION: Both human studies and relevant animal studies were considered. DATA SYNTHESIS: The experts articles reviewed the literature and classified the strength of evidence of human studies according to study design and scientific value. Recommendations were drafted and graded levels based on an evidence-based rating system described in the text. The recommendations were debated, and the task force chairman modified the document until <10% of the experts disagreed with the recommendations. CONCLUSIONS: An organized approach to the hemodynamic support of sepsis was formulated. The fundamental principle is that clinicians using hemodynamic therapies should define specific goals and end points, titrate therapies to those end points, and evaluate the results of their interventions on an ongoing basis by monitoring a combination of variables of global and regional perfusion. Using this approach, specific recommendations for fluid resuscitation, vasopressor therapy, and inotropic therapy of septic in adult patients were promulgated.