Abderrezak Bouchama

Cooling and hemodynamic management in heatstroke: practical recommendations

IntroductionAlthough rapid cooling and management of circulatory failure are crucial to the prevention of irreversible tissue damage and death in heatstroke, the evidence supporting the optimal cooling method and hemodynamic management has yet to be established.MethodsA systematic review of all clinical studies published in Medline (1966 to 2006), CINAHL (Cumulative Index to Nursing & Allied Health Literature) (1982 to 2006), and Cochrane Database was performed using the OVID interface without language restriction. Search terms included heatstroke, sunstroke, and heat stress disorders.ResultsFourteen articles reported populations subjected to cooling treatment for classic or exertional heatstroke and included data on cooling time, neurologic morbidity, or mortality. Five additional articles described invasive monitoring with central venous or pulmonary artery catheters. The four clinical trials and 15 observational studies covered a total of 556 patients. A careful analysis of the results obtained indicated that the cooling method based on conduction, namely immersion in iced water, was effective among young people, military personnel, and athletes with exertional heatstroke. There was no evidence to support the superiority of any one cooling technique in classic heatstroke. The effects of non-invasive, evaporative, or conductive-based cooling techniques, singly or combined, appeared to be comparable. No evidence of a specific endpoint temperature for safe cessation of cooling was found. The circulatory alterations in heatstroke were due mostly to a form of distributive shock associated with relative or absolute hypovolemia. Myocardial failure was found to be rare.ConclusionA systematic review of the literature failed to identify reliable clinical data on the optimum treatment of heatstroke. Nonetheless, the findings of this study could serve as a framework for preliminary recommendations in cooling and hemodynamic management of heatstroke until more evidence-based data are generated.

Concentrations of soluble tumor necrosis factor and interleukin-6 receptors in heatstroke and heatstress

OBJECTIVE Increased proinflammatory cytokine concentrations have been implicated in the pathogenesis of heatstroke. Soluble cytokine receptors can modulate circulating cytokine activities. We examined the possible role of soluble tumor necrosis factor receptors (sTNFR 60, sTNFR 80) and interleukin-6 receptor (sIL-6R) in heatstroke by determining their concentrations before and after cooling, as well as in heatstressed controls. DESIGN Prospective controlled study. SETTING Heatstroke Center, Makkah, Saudi Arabia (1993 pilgrimage). PATIENTS Twenty-five consecutive heatstroke patients before and after cooling, 14 heatstressed controls (HSC), and 13 normal controls (NC). MEASUREMENTS AND MAIN RESULTS Concentrations of sTNFR 60, sTNFR 80, and sIL-6R, as well as their ligands, were measured using commercially available enzyme-linked immunosorbent assay kits. Mean sTNFR 60 concentration was increased in heatstroke (p <.0001, vs. NC; p < .0001, vs. HSC) and in HSC (p = .004, vs. NC). Mean sTNFR 80 concentration was increased in heatstroke and decreased in HSC (p = .01, heatstroke vs. HSC). Mean sIL-6R concentration was decreased in heatstroke and increased in HSC (p = .04, heatstroke vs. NC; p = .001, heatstroke vs. HSC). IL-6 was undetectable in NC and mean IL-6 concentration was more increased in heatstroke than in HSC (p = .001). Rectal temperature and creatinine concentrations correlated significantly with sTNFR 60, sTNFR 80, sIL-6R, and IL-6 concentrations. After cooling, mean concentrations of sIL-6R and sTNFR 80 increased significantly, whereas the mean sTNFR 60 concentration did not change. Residual neurologic deficits were associated with higher precooling IL-6 (p = .002) and postcooling sTNFRs (p < .0001) concentrations. CONCLUSIONS Significant changes in cytokine receptor concentrations are associated with heatstress. In heatstroke, the changes are more pronounced, and for some cytokine receptors, the changes are in the opposite direction (compared with changes in heatstress). Concentrations of IL-6 and sTNFRs correlate with hyperthermia and outcome. Cooling did not normalize sTNFR concentrations, suggesting failure to control the inflammatory response.

Evidence for endothelial cell activation/injury in heatstroke.

OBJECTIVES We treated the hypothesis that heatstroke is associated with endothelial cell activation/injury and examined the possibility that the markers of endothelial cell activation/injury may be associated with its severity and complications such as disseminated intravascular coagulation, lung injury, and renal dysfunction. DESIGN Prospective analyses. SETTING Heatstroke Center in Makkah, Saudi Arabia. PATIENTS Twenty-two adult patients with heatstroke. INTERVENTIONS The plasma concentration of endothelin, circulating intercellular adhesion molecule-1 (ICAM-1), and von Willebrand factor-antigen values were measured, respectively, by radioimmunoassay, enzyme-linked immunosorbent assay, and rocket electroimmunoassay, in heatstroke patients on admission (precooling) and after complete cooling (postcooling), and in ten normal control patients. MEASUREMENTS AND MAIN RESULTS Precooling heatstroke patients (rectal temperature 40.9 +/- 1.1 [SD] degrees C) had increased circulating concentrations of endothelin, c-ICAM-1, and von Willebrand factor-antigen in 100%, 80%, and 77% of patients to 126.4 +/- 11.2 pmol/L, 523.1 +/- 154.4 ng/mL, and 3.85 +/- 2.3 U/mL, respectively (control values: 13.7 +/- 4.2 pmol/L [p < .001]; 247.4 +/- 68.2 ng/ml [p < .001]; and < 1.5 U/mL, respectively). There was a significant (r2 = .68, p < .01) correlation between circulating ICAM-1 and endothelin concentrations. Plasma endothelin concentration correlated negatively with temperature (r2 = .35, p < .05). Mean endothelin concentration was similar in patients with or without renal dysfunction, and mean von Willebrand factor-antigen concentration was similar in patients with or without lung injury or disseminated intravascular coagulation. There were no significant correlations between circulating ICAM-1, endothelin, or von Willebrand factor-antigen concentration and the Simplified Acute Physiology core. After cooling, mean circulating ICAM-1 and endothelin concentrations decreased significantly to 400 +/- 109 ng/mL and 93 +/- 38.5 pmol/L, respectively, whereas the mean von Willebrand factor-antigen concentration increased to 5.55 +/- 2.18 U/mL (p > .05). CONCLUSIONS Our findings of increased circulating concentrations of circulating ICAM-1, endothelin, and von Willebrand factor-antigen are consistent with the hypothesis that heatstroke is associated with endothelial cell activation/injury. Whether the endothelial cell activation/injury is implicated in the pathophysiology of this disorder merits further studies.

Clinical characteristics, sepsis interventions and outcomes in the obese patients with septic shock: an international multicenter cohort study

See related commentary by Dickerson, http://ccforum.com/content/17/3/154IntroductionData are sparse as to whether obesity influences the risk of death in critically ill patients with septic shock. We sought to examine the possible impact of obesity, as assessed by body mass index (BMI), on hospital mortality in septic shock patients.MethodsWe performed a nested cohort study within a retrospective database of patients with septic shock conducted in 28 medical centers in Canada, United States and Saudi Arabia between 1996 and 2008. Patients were classified according to the World Health Organization criteria for BMI. Multivariate logistic regression analysis was performed to evaluate the association between obesity and hospital mortality.ResultsOf the 8,670 patients with septic shock, 2,882 (33.2%) had height and weight data recorded at ICU admission and constituted the study group. Obese patients were more likely to have skin and soft tissue infections and less likely to have pneumonia with predominantly Gram-positive microorganisms. Crystalloid and colloid resuscitation fluids in the first six hours were given at significantly lower volumes per kg in the obese and very obese patients compared to underweight and normal weight patients (for crystalloids: 55.0 ± 40.1 ml/kg for underweight, 43.2 ± 33.4 for normal BMI, 37.1 ± 30.8 for obese and 27.7 ± 22.0 for very obese). Antimicrobial doses per kg were also different among BMI groups. Crude analysis showed that obese and very obese patients had lower hospital mortality compared to normal weight patients (odds ratio (OR) 0.80, 95% confidence interval (CI) 0.66 to 0.97 for obese and OR 0.61, 95% CI 0.44 to 0.85 for very obese patients). After adjusting for baseline characteristics and sepsis interventions, the association became non-significant (OR 0.80, 95% CI 0.62 to 1.02 for obese and OR 0.69, 95% CI 0.45 to 1.04 for very obese).ConclusionsThe obesity paradox (lower mortality in the obese) documented in other populations is also observed in septic shock. This may be related in part to differences in patient characteristics. However, the true paradox may lie in the variations in the sepsis interventions, such as the administration of resuscitation fluids and antimicrobial therapy. Considering the obesity epidemic and its impact on critical care, further studies are warranted to examine whether a weight-based approach to common therapeutic interventions in septic shock influences outcome.

Microvascular Injury, Thrombosis, Inflammation, and Apoptosis in the Pathogenesis of Heatstroke: A Study in Baboon Model

Objective—Severe heatstroke is a leading cause of morbidity and mortality during heat waves. The pathogenesis of tissue injury, organ failure, and death in heatstroke is not well understood. Methods and Result—We investigated the pathways of heatstroke-induced tissue injury and cell death in anesthetized baboons (Papio hamadyras) subjected to environmental heat stress until core temperature attained 42.5°C (moderate heatstroke; n=3) or onset of severe heatstroke (n=4) signaled by a fall in systolic blood pressure to <90 mm Hg and rise in core temperature to 43.1±0.1°C. Three sham-heated animals served as controls. Light and electron microscopy revealed widespread hemorrhage and thrombosis, transmural migration of leukocytes, and microvascular endothelium injury in severe heatstroke. Immunohistology and ultrastructural analysis demonstrated increased staining of endothelial von Willebrand factor (vWF), tissue factor (TF), and endothelial leukocyte-platelet interaction. Extensive apoptosis was noted in spleen, gut, and lung, and in hematopoeitic cells populating these organs. Double-labeling studies colocalized active caspase-3 and TF with apoptotic cells. Findings in sham-heated animals were unremarkable. Conclusion—These data suggested that microvascular injury, thrombosis, inflammation, and apoptosis may play an important role in the pathogenesis of heatstroke injury.

Middle East Respiratory Syndrome

The Middle East respiratory syndrome is caused by a coronavirus that was first identified in Saudi Arabia in 2012. Periodic outbreaks continue to occur in the Middle East and elsewhere. This report provides the latest information on MERS.

Open Lung Biopsy Provides a Higher and More Specific Diagnostic Yield Compared to Broncho-Alveolar Lavage in Immunocompromised Patients

In order to examine the feasibility and safety of undertaking a larger prospective study to compare the diagnostic yield from concurrent open lung biopsy (OLB) and bronchoalveolar lavage (BAL) in febrile neutropenic patients with pulmonary infiltrates and the impact of such knowledge on clinical outcome, a pilot exploratory study was performed. 13 immunocompromised patients (mainly with haematological malignancy or bone marrow transplantation recipients) were investigated. At least one diagnostic finding in 12 of 13 patients was provided by OLB compared to 4 of 13 patients by BAL. BAL provided 7 specific diagnoses (pneumocystis 1, fungal infection 3, bacterial pneumonia 1, pulmonary haemorrhage 2) whilst OLB provided 12 specific diagnosis (CMV 2, pneumocystis 3, fungal infection 1, bacterial pneumonia 1, pulmonary haemorrhage 4, pulmonary embolism 1). Five patients with nonspecific interstitial/alveolar inflammation were diagnosed only by OLB. The concordance that the exact same specific diagnoses present in the OLB were found in the BAL was zero. There were 2 minor complications (1 wound infection by OLB, 1 moderate haemorrhage by BAL). Mortality at 28 days was 8 of 13 patients which in no case was related to either procedure. We suggest that OLB is a safe procedure in such patients, provides superior and more complete diagnostic information compared to BAL and a larger controlled study to investigate the impact of early OLB on the outcome of these patients appears to be justified.

Toll-like receptor 4 and high-mobility group box 1 are critical mediators of tissue injury and survival in a mouse model for heatstroke.

The molecular mechanisms that initiate the inflammatory response in heatstroke and their relation with tissue injury and lethality are not fully elucidated. We examined whether endogenous ligands released by damaged/stressed cells such as high-mobility group box 1 (HMGB1) signaling through Toll-like receptor 4 (TLR4) may play a pathogenic role in heatstroke. Mutant TLR4-defective (C3H/HeJ) and wild type (C3H/HeOuJ) mice were subjected to heat stress in an environmental chamber pre-warmed at 43.5°C until their core temperature reached 42.7°C, which was taken as the onset of heatstroke. The animals were then allowed to recover passively at ambient temperature. A sham-heated group served as a control. Mutant mice displayed more histological liver damage and higher mortality compared with wild type mice (73% vs. 27%, respectively, P<0.001). Compared to wild type mice, mutant mice exhibited earlier plasma release of markers of systemic inflammation such as HMGB1 (206±105 vs. 63±21 ng/ml; P = 0.0018 and 209±100 vs. 46±32 ng/ml; P<0.0001), IL-6 (144±40 vs. 46±20 pg/ml; P<0.001 and 184±21 vs. 84±54 pg/ml; P = 0.04), and IL-1β (27±4 vs. 1.7±2.3 pg/ml; P<0.0001 at 1 hour). Both strains of mice displayed early release of HMGB1 into the circulation upstream of IL-1β and IL-6 responses which remained elevated up to 24 h. Specific inhibition of HMGB1 activity with DNA-binding A Box (600 µg/mouse) protected the mutant mice against the lethal effect of heat stress (60% A Box vs. 18% GST protein, P = 0.04). These findings suggest a protective role for the TLR4 in the host response to severe heat stress. They also suggest that HMGB1 is an early mediator of inflammation, tissue injury and lethality in heatstroke in the presence of defective TLR4 signaling.

Feasibility of Using Convalescent Plasma Immunotherapy for MERS-CoV Infection, Saudi Arabia.

Efficacy testing will be challenging because of the small pool of donors with sufficiently high antibody titers.

Tissue factor/factor VIIa pathway mediates coagulation activation in induced-heat stroke in the baboon.

Objective:Excessive activation of coagulation, which can culminate in overt disseminated intravascular coagulation, is a prominent feature of heat stroke. However, neither the mechanism that initiates the coagulation activation nor its pathogenic role is known. We examined whether the tissue factor/factor VIIa complex initiates the coagulation activation in heat stroke and, if so, whether upstream inhibition of coagulation activation through its neutralization may minimize cellular injury and organ dysfunction. We also examined whether coagulation inhibition influences heat stroke-induced fibrinolytic and inflammatory responses. Design:Randomized controlled study. Setting:Comparative Medicine Department, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. Subjects:Baboons (Papio Hamadryas). Interventions:Twelve anesthetized baboons assigned randomly to recombinant nematode anticoagulant protein c2, a powerful inhibitor of tissue factor/factor VIIa-dependent coagulation (n = 6), or a control group (n = 6) were heat-stressed in a prewarmed neonatal incubator at 44–47°C until systolic blood pressure fell <90 mm Hg, signaling the onset of severe heat stroke. Recombinant nematode anticoagulant protein c2 was administered as a single intravenous dose of 30 &mgr;g/kg body weight at onset of heat stroke. The control group received an equivalent volume of sterile saline intravenously. Measurements and Main Results:Heat stroke was associated with coagulation activation and fibrin formation as evidenced by the increased plasma thrombin–antithrombin complexes, endogenous thrombin potential, and D-dimer levels. Recombinant nematode anticoagulant protein c2 induced significant inhibition of thrombin generation and fibrin formation. Inhibition of coagulation in recombinant nematode anticoagulant protein c2-treated animals did not influence either fibrinolysis (assessed by tissue plasminogen activator, plasmin-&agr;2-antiplasmin complexes, and plasminogen activator inhibitor) or the release of pro- and anti-inflammatory cytokines. No difference in markers of cell injury and organ dysfunction was observed between recombinant nematode anticoagulant protein c2-treated and control groups. Conclusions:Tissue factor/factor VIIa-dependent pathway initiates coagulation activation in induced-heat stroke in the baboon without an effect on fibrinolysis and inflammation. The findings suggest also that coagulation activation is not a prerequisite of cell injury and organ dysfunction. (Crit Care Med 2012; 40:–1236)