François Feihl

Early predictors of outcome in comatose survivors of ventricular fibrillation and non-ventricular fibrillation cardiac arrest treated with hypothermia: a prospective study.

Objectives:Current indications for therapeutic hypothermia (TH) are restricted to comatose patients with cardiac arrest (CA) due to ventricular fibrillation (VF) and without circulatory shock. Additional studies are needed to evaluate the benefit of this treatment in more heterogeneous groups of patients, including those with non-VF rhythms and/or shock and to identify early predictors of outcome in this setting. Design:Prospective study, from December 2004 to October 2006. Setting:32-bed medico-surgical intensive care unit, university hospital. Patients:Comatose patients with out-of-hospital CA. Interventions:TH to 33 ± 1°C (external cooling, 24 hrs) was administered to patients resuscitated from CA due to VF and non-VF (including asystole or pulseless electrical activity), independently from the presence of shock. Measurements and Main Results:We hypothesized that simple clinical criteria available on hospital admission (initial arrest rhythm, duration of CA, and presence of shock) might help to identify patients who eventually survive and might most benefit from TH. For this purpose, outcome was related to these predefined variables. Seventy-four patients (VF 38, non-VF 36) were included; 46% had circulatory shock. Median duration of CA (time from collapse to return of spontaneous circulation [ROSC]) was 25 mins. Overall survival was 39.2%. However, only 3.1% of patients with time to ROSC >25 mins survived, as compared to 65.7% with time to ROSC ≤25 mins. Using a logistic regression analysis, time from collapse to ROSC, but not initial arrest rhythm or presence of shock, independently predicted survival at hospital discharge. Conclusions:Time from collapse to ROSC is strongly associated with outcome following VF and non-VF cardiac arrest treated with therapeutic hypothermia and could therefore be helpful to identify patients who benefit most from active induced cooling.

Reproducibility of laser Doppler imaging of skin blood flow as a tool to assess endothelial function.

Endothelial dysfunction might be an important and early event in the pathogenesis of major cardiovascular diseases. Therefore, the evaluation of endothelial function in humans may be of great clinical relevance. Usual methods for that purpose are either invasive and/or technically demanding. In the dermal microcirculation, endothelial function may be assessed noninvasively from the laser Doppler measurement of increases in blood flow after either the transdermal application of acetylcholine by iontophoresis, or the release of transient arterial occlusion (reactive hyperemia). An endothelium-independent response may be provided by the iontophoresis of sodium nitroprusside. This approach is notable for technical simplicity, but of uncertain reproducibility. Sixteen young, healthy, nonsmoking males were examined in the fasting state. Changes in skin blood flow were measured with a laser Doppler imager during the iontophoresis of acetylcholine and sodium nitroprusside, as well as during reactive hyperemia, on two different days, at each of two different sites on the volar face of the forearm. Nonspecific effects related to the stimulation of terminal nerve fibers by the iontophoretic current were suppressed by prior surface anesthesia. The iontophoresis of acetylcholine and sodium nitroprusside induced a seven- to eightfold increase in dermal blood flow. The corresponding figure for peak reactive hyperemia was approximately fourfold. The mean coefficients of variation of responses recorded on different days, on the same site, in the same individual were <10% for iontophoresis of acetylcholine and for peak reactive hyperemia, and between 10 and 20% for iontophoresis of sodium nitroprusside. This day-to-day variation was significantly smaller than the site-to-site variation (p < 0.01 for all three responses). Endothelium-dependent and -independent responses of dermal blood flow evaluated with laser Doppler imaging are highly reproducible from day to day, at least in healthy nonsmoking young male subjects, and provided some simple precautions are observed, foremost among which is the strict standardization of the recording site. These observations may have implications for the testing of endothelial function in clinical studies.

Is nitric oxide overproduction the target of choice for the management of septic shock

Sepsis is a heterogeneous class of syndromes caused by a systemic inflammatory response to infection. Septic shock, a severe form of sepsis, is associated with the development of progressive damage in multiple organs, and is a leading cause of patient mortality in intensive care units. Despite important advances in understanding its pathophysiology, therapy remains largely symptomatic and supportive. A decade ago, the overproduction of nitric oxide (NO) had been discovered as a potentially important event in this condition. As a result, great hopes arose that the pharmacological inhibition of NO synthesis could be developed into an efficient, mechanism-based therapeutic approach. Since then, an extraordinary effort by the scientific community has brought a deeper insight regarding the feasibility of this goal. Here we present in summary form the present state of knowledge of the biological chemistry and physiology of NO. We then proceed to a systematic review of experimental and clinical data, indicating an up-regulation of NO production in septic shock; information on the role of NO in septic shock, as provided by experiments in transgenic mice that lack the ability to up-regulate NO production; effects of pharmacological inhibitors of NO production in various experimental models of septic shock; and relevant clinical experience. The accrued evidence suggests that the contribution of NO to the pathophysiology of septic shock is highly heterogeneous and, therefore, difficult to target therapeutically without appropriate monitoring tools, which do not exist at present.

Hypertension and microvascular remodelling

In the present review, microvascular remodelling refers to alterations in the structure of resistance vessels contributing to elevated systemic vascular resistance in hypertension. We start with some historical aspects, underscoring the importance of Folkows contribution made half a century ago. We then move to some basic concepts on the biomechanics of blood vessels, and explicit the definitions proposed by Mulvany for specific forms of remodelling, especially inward eutrophic and inward hypertrophic. The available evidence for the existence of remodelled resistance vessels in hypertension comes next, with relatively more weight given to human, in comparison with animal data. Mechanisms are discussed. The impact of antihypertensive drug treatment on remodelling is described, again with emphasis on human data. Some details are given on the three studies to date which point to remodelling of subcutaneous resistance arteries as an independent predictor of cardiovascular risk in hypertensive patients. We terminate by considering the potential role of remodelling in the pathogenesis of end-organ damage and in the perpetuation of hypertension.

Nonselective versus Selective Inhibition of Inducible Nitric Oxide Synthase in Experimental Endotoxic Shock

The effects of two nitric oxide synthase (NOS) inhibitors with different isoform selectivity were compared in a murine model of endotoxemia. Mice challenged with 70 mg/kg intraperitoneal (ip) lipopolysaccharide (LPS) were treated 6 h after LPS with either NG-gamma-L-arginine methyl ester (L-NAME, nonselective NOS inhibitor, 10-60 mg/kg), L-canavanine (selective inhibitor of inducible NOS, 50-300 mg/kg), or saline (0.2 mL) given ip. In a subset of mice, plasma concentrations of nitrate (NO breakdown product), lipase (pancreas injury), lactate dehydrogenase, and transaminases (liver injury) were measured 16 h after LPS. Although both inhibitors reduced plasma nitrate, they produced contrasting effects on survival and organ injury. L-NAME enhanced liver damage and tended to accelerate the time of death, while L-canavanine significantly reduced mortality and had no deleterious effects in terms of organ damage. These results indicate that nonselective NOS inhibitors are detrimental in endotoxic shock and support the potential usefulness of selective inducible NOS inhibitors in this setting.

Brain hypoxia is associated with short-term outcome after severe traumatic brain injury independently of intracranial hypertension and low cerebral perfusion pressure.

BACKGROUND Brain hypoxia (BH) can aggravate outcome after severe traumatic brain injury (TBI). Whether BH or reduced brain oxygen (Pbto2) is an independent outcome predictor or a marker of disease severity is not fully elucidated. OBJECTIVE To analyze the relationship between Pbto2, intracranial pressure (ICP), and cerebral perfusion pressure (CPP) and to examine whether BH correlates with worse outcome independently of ICP and CPP. METHODS We studied 103 patients monitored with ICP and Pbto2 for > 24 hours. Durations of BH (Pbto2 < 15 mm Hg), ICP > 20 mm Hg, and CPP < 60 mm Hg were calculated with linear interpolation, and their associations with outcome within 30 days were analyzed. RESULTS Duration of BH was longer in patients with unfavorable (Glasgow Outcome Scale score, 1-3) than in those with favorable (Glasgow Outcome Scale, 4-5) outcome (8.3 ± 15.9 vs 1.7 ± 3.7 hours; P < .01). In patients with intracranial hypertension, those with BH had fewer favorable outcomes (46%) than those without (81%; P < .01); similarly, patients with low CPP and BH were less likely to have favorable outcome than those with low CPP but normal Pbto2 (39% vs 83%; P < .01). After ICP, CPP, age, Glasgow Coma Scale score, Marshall computed tomography grade, and Acute Physiology and Chronic Health Evaluation II score were controlled for, BH was independently associated with poor prognosis (adjusted odds ratio for favorable outcome, 0.89 per hour of BH; 95% confidence interval, 0.79-0.99; P = .04). CONCLUSION Brain hypoxia is associated with poor short-term outcome after severe traumatic brain injury independently of elevated ICP, low CPP, and injury severity. Pbto2 may be an important therapeutic target after severe traumatic brain injury. ABBREVIATIONS AOR: adjusted odds ratio APACHE II: Acute Physiology and Chronic Health Evaluation II CI: confidence interval CPP: cerebral perfusion pressure GCS: Glasgow Coma Scale ICP: intracranial pressure IQR: interquartile range MAP: mean arterial pressure TBI: traumatic brain injury

Body temperature regulation and outcome after cardiac arrest and therapeutic hypothermia

OBJECTIVE Therapeutic temperature modulation is recommended after cardiac arrest (CA). However, body temperature (BT) regulation has not been extensively studied in this setting. We investigated BT variation in CA patients treated with therapeutic hypothermia (TH) and analyzed its impact on outcome. METHODS A prospective cohort of comatose CA patients treated with TH (32-34°C, 24h) at the medical/surgical intensive care unit of the Lausanne University Hospital was studied. Spontaneous BT was recorded on hospital admission. The following variables were measured during and after TH: time to target temperature (TTT=time from hospital admission to induced BT target <34°C), cooling rate (spontaneous BT-induced BT target/TTT) and time of passive rewarming to normothermia. Associations of spontaneous and induced BT with in-hospital mortality were examined. RESULTS A total of 177 patients (median age 61 years; median time to ROSC 25 min) were studied. Non-survivors (N=90, 51%) had lower spontaneous admission BT than survivors (median 34.5 [interquartile range 33.7-35.9]°C vs. 35.1 [34.4-35.8]°C, p=0.04). Accordingly, time to target temperature was shorter among non-survivors (200 [25-363]min vs. 270 [158-375]min, p=0.03); however, when adjusting for admission BT, cooling rates were comparable between the two outcome groups (0.4 [0.2-0.5]°C/h vs. 0.3 [0.2-0.4]°C/h, p=0.65). Longer duration of passive rewarming (600 [464-744]min vs. 479 [360-600]min, p<0.001) was associated with mortality. CONCLUSIONS Lower spontaneous admission BT and longer time of passive rewarming were associated with in-hospital mortality after CA and TH. Impaired thermoregulation may be an important physiologic determinant of post-resuscitation disease and CA prognosis. When assessing the benefit of early cooling on outcome, future trials should adjust for patient admission temperature and use the cooling rate rather than the time to target temperature.

Increased blood glucose variability during therapeutic hypothermia and outcome after cardiac arrest.

Objective:Hypothermia impairs blood glucose homeostasis and insulin sensitivity. However, the impact of therapeutic hypothermia on blood glucose levels and insulin requirements is unknown. We analyzed blood glucose variability during therapeutic hypothermia in patients with coma after cardiac arrest and examined its impact on outcome. Design:Prospective observational study. Setting:Two university hospital medical/surgical intensive care units. Patients:Comatose cardiac arrest patients treated with therapeutic hypothermia (33°C, 24 hrs). Interventions:Insulin therapy (blood glucose target 6–8 mmol/L [110–150 mg/dL]), according to a written algorithm, with nurse-driven adjustment of insulin dose. Measurements and Main Results:Two-hundred and twenty patients (median age 61 yrs, median time to return of spontaneous circulation 20 min) were studied. Two time periods, comparable in duration, were categorized: therapeutic hypothermia (stable maintenance phase) and normothermia (after rewarming). Blood glucose variability was defined as the difference between maximum and minimum blood glucose concentration during each time period. Mean blood glucose (8.3 ± 2.3 vs. 7.1 ± 1.3 mmol/L), blood glucose variability (5.7 ± 3.9 vs. 3.7 ± 3.6 mmol/L), and insulin dose (2 ± 2 vs. 1 ± 1 U/h) were higher during therapeutic hypothermia compared to normothermia (all p < .001). Higher mean blood glucose (7.9 ± 1.8 mmol/L in survivors vs. 8.7 ± 2.6 mmol/L in nonsurvivors, p = .02) and increased blood glucose variability (4.9 ± 3.5 vs. 6.5 ± 4.1 mmol/L, p = .003) during therapeutic hypothermia were associated with mortality. After adjusting for time to return of spontaneous circulation, initial arrest rhythm, and cardiac arrest etiology, increased blood glucose variability during therapeutic hypothermia, but not mean blood glucose level, was an independent predictor of inhospital mortality (odds ratio for death 1.10 [confidence interval 1.02–1.19], p = .016). Conclusions:Mild therapeutic hypothermia is associated with higher blood glucose levels, increased blood glucose variability, and greater insulin requirements compared to the postrewarming normothermic phase. Increased blood glucose variability during therapeutic hypothermia is a predictor of inhospital mortality after cardiac arrest, independent of injury severity and mean blood glucose levels.

Cardiac arrest: prognostic factors and outcome at one year.

This study was designed to determine by multivariate statistical methods the influence of 38 variables on outcome after cardiopulmonary resuscitation (CPR) and to assess neuropsychological status in long-term survivors. The charts of 181 consecutive patients resuscitated in a 1,100-bed University Hospital over a 2-year period were analyzed retrospectively. Of the 181 resuscitated patients, 23 (13%) could be discharged. Outcome was significantly affected by the following variables: presence of shock or renal failure before cardiac arrest (CA) (odds ratio = 10.6; 95% confidence interval = 1.3-85.8 and odds ratio = 13.8; 95% confidence interval = 1.7-109.2, respectively), administration of epinephrine (odds ratio = 11.2; 95% confidence interval = 3.2-39.2) or prolonged CPR (> 15 min) (odds ratio = 4.9; 95% confidence interval = 1.7-13.7). By contrast, when CA occurred in uncomplicated acute myocardial infarction a significantly better prognosis could be demonstrated (odds ratio = 0.2; 95% confidence interval = 0.0-0.6). The 10 long-term survivors investigated lead an independent life and all returned to former occupation. The most common complaint was moderate memory disturbance (five patients). The conclusion is that this study confirms the critical influence of cellular anoxia on prognosis and allows the improved delineation of the situations in which cardiopulmonary resuscitation appears to be hopeless or likely to be successful. The follow up in a small number of survivors has shown a good quality of life and minor neuropsychological sequellae.

Cutting Edge: IL-1α Is a Crucial Danger Signal Triggering Acute Myocardial Inflammation during Myocardial Infarction

Myocardial infarction (MI) induces a sterile inflammatory response that contributes to adverse cardiac remodeling. The initiating mechanisms of this response remain incompletely defined. We found that necrotic cardiomyocytes released a heat-labile proinflammatory signal activating MAPKs and NF-κB in cardiac fibroblasts, with secondary production of cytokines. This response was abolished in Myd88−/− fibroblasts but was unaffected in nlrp3-deficient fibroblasts. Despite MyD88 dependency, the response was TLR independent, as explored in TLR reporter cells, pointing to a contribution of the IL-1 pathway. Indeed, necrotic cardiomyocytes released IL-1α, but not IL-1β, and the immune activation of cardiac fibroblasts was abrogated by an IL-1R antagonist and an IL-1α–blocking Ab. Moreover, immune responses triggered by necrotic Il1a−/− cardiomyocytes were markedly reduced. In vivo, mice exposed to MI released IL-1α in the plasma, and postischemic inflammation was attenuated in Il1a−/− mice. Thus, our findings identify IL-1α as a crucial early danger signal triggering post-MI inflammation.