Matty Koopmans

Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest

BACKGROUND Unconscious survivors of out-of-hospital cardiac arrest have a high risk of death or poor neurologic function. Therapeutic hypothermia is recommended by international guidelines, but the supporting evidence is limited, and the target temperature associated with the best outcome is unknown. Our objective was to compare two target temperatures, both intended to prevent fever. METHODS In an international trial, we randomly assigned 950 unconscious adults after out-of-hospital cardiac arrest of presumed cardiac cause to targeted temperature management at either 33°C or 36°C. The primary outcome was all-cause mortality through the end of the trial. Secondary outcomes included a composite of poor neurologic function or death at 180 days, as evaluated with the Cerebral Performance Category (CPC) scale and the modified Rankin scale. RESULTS In total, 939 patients were included in the primary analysis. At the end of the trial, 50% of the patients in the 33°C group (235 of 473 patients) had died, as compared with 48% of the patients in the 36°C group (225 of 466 patients) (hazard ratio with a temperature of 33°C, 1.06; 95% confidence interval [CI], 0.89 to 1.28; P=0.51). At the 180-day follow-up, 54% of the patients in the 33°C group had died or had poor neurologic function according to the CPC, as compared with 52% of patients in the 36°C group (risk ratio, 1.02; 95% CI, 0.88 to 1.16; P=0.78). In the analysis using the modified Rankin scale, the comparable rate was 52% in both groups (risk ratio, 1.01; 95% CI, 0.89 to 1.14; P=0.87). The results of analyses adjusted for known prognostic factors were similar. CONCLUSIONS In unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause, hypothermia at a targeted temperature of 33°C did not confer a benefit as compared with a targeted temperature of 36°C. (Funded by the Swedish Heart-Lung Foundation and others; TTM ClinicalTrials.gov number, NCT01020916.).

Citrate anticoagulation for continuous venovenous hemofiltration.

Objective:Continuous venovenous hemofiltration (CVVH) is applied in critically ill patients with acute renal failure for renal replacement. Heparins used to prevent circuit clotting may cause bleeding. Regional anticoagulation with citrate reduces bleeding, but has metabolic risks. The aim was to compare the safety and efficacy of the two. Design:Randomized, nonblinded, controlled single-center trial. Setting:General intensive care unit of a teaching hospital. Patients:Adult critically ill patients needing CVVH for acute renal failure and without an increased bleeding risk. Interventions:Regional anticoagulation with citrate or systemic anticoagulation with the low-molecular weight heparin nadroparin. Measurements and Main Results:End points were adverse events necessitating discontinuation of study anticoagulant, transfusion, metabolic and clinical outcomes, and circuit survival. Of the 215 randomized patients, 200 received CVVH per protocol (97 citrate and 103 nadroparin). Adverse events required discontinuation of citrate in two patients (accumulation and clotting) of nadroparin in 20 (bleeding and thrombocytopenia) (p < 0.001). Bleeding occurred in 6 vs. 16 patients (p = 0.08). The median number of red blood cell units transfused per CVVH day was 0.27 (interquartile range, 0.0–0.63) for citrate, 0.36 (interquartile range, 0–0.83) for nadroparin (p = 0.31). Citrate conferred less metabolic alkalosis (p = 0.001) and lower plasma calcium (p < 0.001). Circuit survival was similar. Three-month mortality on intention-to-treat was 48% (citrate) and 63% (nadroparin) (p = 0.03), per protocol 45% and 62% (p = 0.02). Citrate reduced mortality in surgical patients (p = 0.007), sepsis (p = 0.01), higher Sepsis-Related Organ Failure Assessment score (p = 0.006), and lower age (p = 0.009). Conclusions:The efficacy of citrate and nadroparin anticoagulation for CVVH was similar, however, citrate was safer. Unexpectedly, citrate reduced mortality. Less bleeding could only partly explain this benefit, less clotting could not. Post hoc citrate appeared particularly beneficial after surgery, in sepsis and severe multiple organ failure, suggesting interference with inflammation.

Effects of nitroglycerin on sublingual microcirculatory blood flow in patients with severe sepsis/septic shock after a strict resuscitation protocol: a double-blind randomized placebo controlled trial.

Objectives:Microcirculatory alterations have been associated with morbidity and mortality in human sepsis. Such alterations occur despite pressure-guided resuscitation. Earlier data suggested that impaired microcirculatory blood flow could be corrected with intravenous nitroglycerin in these patients. We tested this concept after fulfillment of preset systemic hemodynamic resuscitation end points in the early phase of sepsis. Design:Prospective, single center, randomized, placebo-controlled, double-blind clinical trial. Setting:Closed-format 22-bed mixed intensive care unit in a tertiary teaching hospital. Patients:Patients ≥18 yrs with sepsis, according to international criteria, and at least one early sign of organ dysfunction, as the principal reason for intensive care unit admission, were eligible for enrollment. Interventions:Patients were randomly assigned to receive nitroglycerin (n = 35) or placebo (n = 35) after fulfillment of protocol-driven resuscitation end points. This trial is registered with ClinicalTrials.gov as NCT00493415. Measurements and Main Results:Primary outcome was sublingual microcirculatory blood flow of small vessels, as assessed by side-stream dark field imaging. After protocolized resuscitation, we observed recruitment of sublingual microcirculation in both groups, as indicated by a significant improvement in the microcirculatory flow index after 24 hrs, in comparison to baseline. However, no difference in the sublingual microvascular flow index was observed between groups. The median microvascular flow index in sublingual small-sized vessels was 2.71 (1.85-3) in the nitroglycerin group and 2.71 (1.27-3), p = .80, in the placebo group. In medium-sized vessels, the respective values were 3 (2.75-3) vs. 2.86 (2.19-3), p = .21, and in large-sized vessels, 3 (3-3) vs. 3 (2.89-3), p = .06. In-hospital mortality, as a secondary outcome, was 34.3% in the nitroglycerin group and 14.2% in the placebo group, p = .09. Conclusions:In the context of a strict resuscitation protocol, based upon fulfillment of systemic hemodynamic end points in patients with early-phase severe sepsis or septic shock, we conclude that intravenous nitroglycerin does not promote sublingual microcirculatory blood flow.

Bayesian estimation of hepatitis E virus seroprevalence for populations with different exposure levels to swine in The Netherlands.

Hepatitis E virus (HEV) is ubiquitous in pigs worldwide and may be zoonotic. Previous HEV seroprevalence estimates for groups of people working with swine were higher than for control groups. However, discordance among results of anti-HEV assays means that true seroprevalence estimates, i.e. seroprevalence due to previous exposure to HEV, depends on choice of seroassay. We tested blood samples from three subpopulations (49 swine veterinarians, 153 non-swine veterinarians and 644 randomly selected individuals from the general population) with one IgM and two IgG ELISAs, and subsets with IgG and/or IgM Western blots. A Bayesian stochastical model was used to combine results of all assays. The model accounted for imperfection of each assay by estimating sensitivity and specificity, and accounted for dependence between serological assays. As expected, discordance among assay results occurred. Applying the model yielded seroprevalence estimates of approximately 11% for swine veterinarians,approximately 6% for non-swine veterinarians and approximately 2% for the general population. By combining the results of five serological assays in a Bayesian stochastical model we confirmed that exposure to swine or their environment was associated with elevated HEV seroprevalence.

A one-year intensified study of outbreaks of gastroenteritis in The Netherlands

In 2002, in The Netherlands a national study of gastroenteritis outbreaks was performed. Epidemiological information was collected by the Public Health Services (PHS) and the Food Inspection Services (FIS) using standardized questionnaires. Stool samples were collected for diagnostic testing. For foodborne outbreaks, food samples were taken. In total, 281 gastroenteritis outbreaks were included, mainly from nursing homes and homes for the elderly (57%), restaurants (11%), hospitals (9%) and day-care centres (7%). Direct person-to-person spread was the predominant transmission route in all settings (overall 78%), except for restaurant outbreaks where food was suspected in almost 90% (overall in 21% of outbreaks). The most common pathogen was norovirus (54%), followed by Salmonella spp. (4%), rotavirus group A (2%), Campylobacter spp. (1%) and only incidentally others. In conclusion, most outbreaks were reported from health and residential institutions, with norovirus as the dominant agent. Control should aim at reducing person-to-person spread. In foodborne outbreaks norovirus was common, due to contamination of food by food handlers. Salmonella, as the second foodborne pathogen, was mainly associated with raw shell eggs. These results stress the continuous need for food safety education, complementary to governmental regulation.

Furosemide does not improve renal recovery after hemofiltration for acute renal failure in critically ill patients: a double blind randomized controlled trial.

Objective:To study the potential beneficial role of furosemide in resolving renal failure after hemofiltration in mechanically ventilated critically ill patients. Design:Single-center randomized, double blind, placebo-controlled study. Setting:A 13-bed mixed intensive care unit (ICU) in a teaching hospital. Patients:Patients who had been treated with continuous venovenous hemofiltration were included. Interventions:After the end of continuous venovenous hemofiltration, the urine of the first 4 hours was collected for measuring creatinine clearance. Patients were subsequently randomized for furosemide (0.5 mg/kg/hr) or placebo by continuous infusion. To prevent hypovolemia, the rate of fluid infusion was adapted every hour and was set as the urinary production of the previous hour. Measurements and Main Results:End points were renal recovery (creatinine clearance more than 30 mL/min or stable serum creatinine without renal replacement therapy) in the ICU and in the hospital. Seventy-two patients were included and 71 were eligible for the analysis. The 36 furosemide-treated patients had a significantly increased urinary volume compared with the 35 placebo-treated patients (median 247 mL/hr (interquartile range [IQR] 774 mL/hr) vs. 117 mL/hr (IQR 158 mL/hr), p = 0.003) and greater sodium excretion (median 73 mmol/L (IQR 48) vs. 37 (IQR 48) mmol/L, p = 0.001). In the furosemide group 25 patients and in the placebo group 27 patients showed recovery of renal function at ICU discharge (p = 0.46). Two patients of the furosemide group needed long-term dialysis dependency (p = 0.23). Conclusion:Furosemide by continuous infusion in the recovery phase of hemofiltration-dependent acute kidney failure did increase urinary volume and sodium excretion but did not lead to a shorter duration of renal failure or more frequent renal recovery.

International study on microcirculatory shock occurrence in acutely ill patients

Objectives:Microcirculatory alterations are associated with adverse outcome in subsets of critically ill patients. The prevalence and significance of microcirculatory alterations in the general ICU population are unknown. We studied the prevalence of microcirculatory alterations in a heterogeneous ICU population and its predictive value in an integrative model of macro- and microcirculatory variables. Design:Multicenter observational point prevalence study. Setting:The Microcirculatory Shock Occurrence in Acutely ill Patients study was conducted in 36 ICUs worldwide. Patients:A heterogeneous ICU population consisting of 501 patients. Interventions:None. Measurements and Main Results:Demographic, hemodynamic, and laboratory data were collected in all ICU patients who were 18 years old or older. Sublingual Sidestream Dark Field imaging was performed to determine the prevalence of an abnormal capillary microvascular flow index (< 2.6) and its additional value in predicting hospital mortality. In 501 patients with a median Acute Physiology and Chronic Health Evaluation II score of 15 (10–21), a Sequential Organ Failure Assessment score of 5 (2–8), and a hospital mortality of 28.4%, 17% exhibited an abnormal capillary microvascular flow index. Tachycardia (heart rate > 90 beats/min) (odds ratio, 2.71; 95% CI, 1.67–4.39; p < 0.001), mean arterial pressure (odds ratio, 0.979; 95% CI, 0.963–0.996; p = 0.013), vasopressor use (odds ratio, 1.84; 95% CI, 1.11–3.07; p = 0.019), and lactate level more than 1.5 mEq/L (odds ratio, 2.15; 95% CI, 1.28–3.62; p = 0.004) were independent risk factors for hospital mortality, but not abnormal microvascular flow index. In reference to microvascular flow index, a significant interaction was observed with tachycardia. In patients with tachycardia, the presence of an abnormal microvascular flow index was an independent, additive predictor for in-hospital mortality (odds ratio, 3.24; 95% CI, 1.30–8.06; p = 0.011). This was not true for nontachycardic patients nor for the total group of patients. Conclusions:In a heterogeneous ICU population, an abnormal microvascular flow index was present in 17% of patients. This was not associated with mortality. However, in patients with tachycardia, an abnormal microvascular flow index was independently associated with an increased risk of hospital death.

Human-to-human transmission of avian influenza A/H7N7, The Netherlands, 2003.

An outbreak of highly pathogenic avian influenza A virus subtype H7N7 began in poultry farms in the Netherlands in 2003. Virus infection was detected by RT-PCR in 86 poultry workers and three household contacts of PCR-positive poultry workers, mainly associated with conjunctivitis. To determine the magnitude of and risk factors for human-to-human transmission of influenza A/H7N7 in the Netherlands, a retrospective cohort study among household members of infected poultry workers was undertaken. In total, 33 (58.9%) of 56 (among 62) participants who provided blood samples had positive H7 serology, using single convalescent serum samples obtained at least 3 weeks after onset of symptoms of the index case. Eight household members (12.9%) reported symptoms (conjunctivitis and/or ILI), of which four of five (80.0%) tested seropositive. On univariate analysis, significant risk factors for seropositivity included having at least two toilets, a pet bird, and using cloth handkerchiefs. It was not possible to obtain a stable model for binomial regression for the outcome of A/H7N7 infection. Further seroprevalence studies among contacts of asymptomatic H7 cases should be conducted.

Severe abnormalities in microvascular perfused vessel density are associated to organ dysfunctions and mortality and can be predicted by hyperlactatemia and norepinephrine requirements in septic shock patients

PURPOSE The aims of this study are to determine the general relationship of perfused vessel density (PVD) to mortality and organ dysfunctions and to explore if patients in the lowest quartile of distribution for this parameter present a higher risk of bad outcome and to identify systemic hemodynamic and perfusion variables that enhances the probability of finding a severe underlying microvascular dysfunction. MATERIALS AND METHODS This is a retrospective multicenter study including 122 septic shock patients participating in 7 prospective clinical trials on which at least 1 sublingual microcirculatory assessment was performed during early resuscitation. RESULTS Perfused vessel density was significantly related to organ dysfunctions and mortality, but this effect was largely explained by patients in the lowest quartile of distribution for PVD (P = .037 [odds ratio {OR}, 8.7; 95% confidence interval {CI}, 1.14-66.78] for mortality). Hyperlactatemia (P < .026 [OR, 1.23; 95% CI, 1.03-1.47]) and high norepinephrine requirements (P < .019 [OR, 7.04; 95% CI, 1.38-35.89]) increased the odds of finding a severe microvascular dysfunction. CONCLUSIONS Perfused vessel density is significantly related to organ dysfunctions and mortality in septic shock patients, particularly in patients exhibiting more severe abnormalities as represented by the lowest quartile of distribution for this parameter. The presence of hyperlactatemia and high norepinephrine requirements increases the odds of finding a severe underlying microvascular dysfunction during a sublingual microcirculatory assessment.

Molecular Characterizations of Human and Animal Group A Rotaviruses in The Netherlands

ABSTRACT To gain more insight into interspecies transmission of rotavirus group A, human and animal fecal samples were collected between 1997 and 2001 in The Netherlands. A total of 110 human stool samples were successfully P and G genotyped by reverse transcriptase PCR. All strains belonged to the main human rotavirus genotypes G1 to G4, G9, [P4], [P6], [P8], and [P9]. [P8]G1 was predominant, and 5.5% belonged to the G9 genotype. Eleven percent of all P[8] genotypes could be genotyped only by a recently published modified primer. Rotavirus-positive fecal samples from 28 calf herds were genotyped by DNA sequencing. Genotypes G6 and G10 predominated; G6 and G10 were detected in 22 (78.6%) and 16 (57.1%) of the rotavirus-positive calf herds, respectively. In 12 (42.9%) calf herds, we found mixed infections. Genotype G8 was not found. Genotype G6 bovine rotaviruses were divided into three clusters: UK-like, VMRI-29-like, and Hun4-like. DNA sequencing of a part of the VP7 gene was shown to be useful as a quick determination of uncommon or novel strains of which the genotyping cannot be done by genotyping PCR. Of equine strains, both VP4 and VP7 genes could be used for genotyping: two [P12]G3 and four [P12]G14 equine rotaviruses were determined. We did not find indications for rotavirus interspecies transmissions, although the recently published human G6-Hun4 is genetically related to our G6 bovine isolates. All bovine, porcine, and equine rotaviruses were within genotypes previously reported for these animal species.