Frédérique Schortgen

Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study

BACKGROUND Hydroxyethylstarch used for volume restoration in brain-dead kidney donors has been associated with impaired kidney function in the transplant recipients. We undertook a multicentre randomised study to assess the frequency of acute renal failure (ARF) in patients with severe sepsis or septic shock treated with hydroxyethylstarch or gelatin. METHODS Adults with severe sepsis or septic shock were enrolled prospectively in three intensive-care units in France. They were randomly assigned 6% hydroxyethylstarch (200 kDa, 0.60-0.66 substitution) or 3% fluid-modified gelatin. The primary endpoint was ARF (a two-fold increase in serum creatinine from baseline or need for renal replacement therapy). Analyses were by intention to treat. FINDINGS 129 patients were enrolled over 18 months. Severity of illness and serum creatinine (median 143 [IQR 88-203] vs 114 [91-175] micromol/L) were similar at baseline in the hydroxyethylstarch and gelatin groups. The frequencies of ARF (27/65 [42%] vs 15/64 [23%], p=0.028) and oliguria (35/62 [56%] vs 23/63 [37%], p=0.025) and the peak serum creatinine concentration (225 [130-339] vs 169 [106-273] micromol/L, p=0.04) were significantly higher in the hydroxyethylstarch group than in the gelatin group. In a multivariate analysis, risk factors for acute renal failure included mechanical ventilation (odds ratio 4.02 [95% CI 1.37-11.8], p=0.013) and use of hydroxyethylstarch (2.57 [1.13-5.83], p=0.026). INTERPRETATIONS The use of this preparation of hydroxyethylstarch as a plasma-volume expander is an independent risk factor for ARF in patients with severe sepsis or septic shock.

Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial

BACKGROUND Reduced duration of antibiotic treatment might contain the emergence of multidrug-resistant bacteria in intensive care units. We aimed to establish the effectiveness of an algorithm based on the biomarker procalcitonin to reduce antibiotic exposure in this setting. METHODS In this multicentre, prospective, parallel-group, open-label trial, we used an independent, computer-generated randomisation sequence to randomly assign patients in a 1:1 ratio to procalcitonin (n=311 patients) or control (n=319) groups; investigators were masked to assignment before, but not after, randomisation. For the procalcitonin group, antibiotics were started or stopped based on predefined cut-off ranges of procalcitonin concentrations; the control group received antibiotics according to present guidelines. Drug selection and the final decision to start or stop antibiotics were at the discretion of the physician. Patients were expected to stay in the intensive care unit for more than 3 days, had suspected bacterial infections, and were aged 18 years or older. Primary endpoints were mortality at days 28 and 60 (non-inferiority analysis), and number of days without antibiotics by day 28 (superiority analysis). Analyses were by intention to treat. The margin of non-inferiority was 10%. This trial is registered with ClinicalTrials.gov, number NCT00472667. FINDINGS Nine patients were excluded from the study; 307 patients in the procalcitonin group and 314 in the control group were included in analyses. Mortality of patients in the procalcitonin group seemed to be non-inferior to those in the control group at day 28 (21.2% [65/307] vs 20.4% [64/314]; absolute difference 0.8%, 90% CI -4.6 to 6.2) and day 60 (30.0% [92/307] vs 26.1% [82/314]; 3.8%, -2.1 to 9.7). Patients in the procalcitonin group had significantly more days without antibiotics than did those in the control group (14.3 days [SD 9.1] vs 11.6 days [SD 8.2]; absolute difference 2.7 days, 95% CI 1.4 to 4.1, p<0.0001). INTERPRETATION A procalcitonin-guided strategy to treat suspected bacterial infections in non-surgical patients in intensive care units could reduce antibiotic exposure and selective pressure with no apparent adverse outcomes. FUNDING Assistance Publique-Hôpitaux de Paris, France, and Brahms, Germany.

Initiation Strategies for Renal-Replacement Therapy in the Intensive Care Unit

BACKGROUND The timing of renal-replacement therapy in critically ill patients who have acute kidney injury but no potentially life-threatening complication directly related to renal failure is a subject of debate. METHODS In this multicenter randomized trial, we assigned patients with severe acute kidney injury (Kidney Disease: Improving Global Outcomes [KDIGO] classification, stage 3 [stages range from 1 to 3, with higher stages indicating more severe kidney injury]) who required mechanical ventilation, catecholamine infusion, or both and did not have a potentially life-threatening complication directly related to renal failure to either an early or a delayed strategy of renal-replacement therapy. With the early strategy, renal-replacement therapy was started immediately after randomization. With the delayed strategy, renal-replacement therapy was initiated if at least one of the following criteria was met: severe hyperkalemia, metabolic acidosis, pulmonary edema, blood urea nitrogen level higher than 112 mg per deciliter, or oliguria for more than 72 hours after randomization. The primary outcome was overall survival at day 60. RESULTS A total of 620 patients underwent randomization. The Kaplan-Meier estimates of mortality at day 60 did not differ significantly between the early and delayed strategies; 150 deaths occurred among 311 patients in the early-strategy group (48.5%; 95% confidence interval [CI], 42.6 to 53.8), and 153 deaths occurred among 308 patients in the delayed-strategy group (49.7%, 95% CI, 43.8 to 55.0; P=0.79). A total of 151 patients (49%) in the delayed-strategy group did not receive renal-replacement therapy. The rate of catheter-related bloodstream infections was higher in the early-strategy group than in the delayed-strategy group (10% vs. 5%, P=0.03). Diuresis, a marker of improved kidney function, occurred earlier in the delayed-strategy group (P<0.001). CONCLUSIONS In a trial involving critically ill patients with severe acute kidney injury, we found no significant difference with regard to mortality between an early and a delayed strategy for the initiation of renal-replacement therapy. A delayed strategy averted the need for renal-replacement therapy in an appreciable number of patients. (Funded by the French Ministry of Health; ClinicalTrials.gov number, NCT01932190.).

The risk associated with hyperoncotic colloids in patients with shock

ObjectiveCrystalloids, artificial and natural colloids have been opposed as representing different strategies for shock resuscitation, but it may be relevant to distinguish fluids based on their oncotic characteristics. This study assessed the risk of renal adverse events in patients with shock resuscitated using hypooncotic colloids, artificial hyperoncotic colloids, hyperoncotic albumin or crystalloids, according to physician’s choice.Participants and settingInternational prospective cohort study including 1,013 ICU patients needing fluid resuscitation for shock. Patients suffering from cirrhosis or receiving plasma were excluded.Measurements and resultsInfluence of different types of colloids and crystalloids on the occurrence of renal events (twofold increase in creatinine or need for dialysis) and mortality was assessed using multivariate analyses and propensity score. Statistical adjustment was based on severity at the time of resuscitation, risks factor for renal failure, and on variables influencing physicians’ preferences regarding fluids. A renal event occurred in 17% of patients. After adjustment on potential confounding factors and on propensity score for the use of hyperoncotic colloids, the use of artificial hyperoncotic colloids [OR: 2.48 (1.24–4.97)] and hyperoncotic albumin [OR: 5.99 (2.75–13.08)] was significantly associated with occurrence of renal event. Overall ICU mortality was 27.1%. The use of hyperoncotic albumin was associated with an increased risk of ICU death [OR: 2.79 (1.42–5.47)].ConclusionsThis study suggests that harmful effects on renal function and outcome of hyperoncotic colloids may exist. Although an improper usage of these compounds and confounding factors cannot be ruled out, their use should be regarded with caution, especially because suitable alternatives exist.

Outcomes of extubation failure in medical intensive care unit patients

Objective:Extubation failure is associated with a poor prognosis, but the respective roles for reintubation per se and underlying disease severity remain unclear. Our objectives were to evaluate the impact of failed extubation, whether planned or unplanned, on patient outcomes and to identify a patient subset at risk for extubation failure. Design:Prospective 1-yr observational study with daily data collection. Setting:Thirteen-bed medical intensive care unit in a teaching hospital. Patients:Consecutive patients requiring invasive mechanical ventilation were screened and followed until discharge or death. Interventions:None. Measurements and Main Results:Of 168 planned extubations in 340 patients, 26 (15%) failed. Of these 26 patients, seven (27%) had pneumonia and 13 (50%) died after reintubation. Compared with successfully extubated patients, the patients with failed extubation were not significantly different regarding disease severity, mechanical ventilation duration, or blood gas values. Age and underlying diseases were the only factors associated with extubation failure, and extubation failure occurred in 34% of patients >65 yrs with chronic cardiac or respiratory disease compared with only 9% of other patients (p < .01). Unplanned extubation occurred in 9% of patients, and inadequate endotracheal tube position was a risk factor. Failure of both planned and unplanned extubation was specifically associated with significant rapid worsening of daily organ dysfunction scores. Conclusions:Patients >65 yrs with underlying chronic cardiac or respiratory disease are at high risk for extubation failure and subsequent pneumonia and death. Contrasting with successful extubation, failed planned or unplanned extubation was followed by marked clinical deterioration, suggesting a direct and specific effect of extubation failure and reintubation on patient outcomes.

Fever control using external cooling in septic shock: a randomized controlled trial.

RATIONALE Fever control may improve vascular tone and decrease oxygen consumption, but fever may contribute to combat infection. OBJECTIVES To determine whether fever control by external cooling diminishes vasopressor requirements in septic shock. METHODS In a multicenter randomized controlled trial, febrile patients with septic shock requiring vasopressors, mechanical ventilation, and sedation were allocated to external cooling (n = 101) to achieve normothermia (36.5-37°C) for 48 hours or no external cooling (n = 99). Vasopressors were tapered to maintain the same blood pressure target in the two groups. The primary endpoint was the number of patients with a 50% decrease in baseline vasopressor dose after 48 hours. MEASUREMENTS AND MAIN RESULTS Body temperature was significantly lower in the cooling group after 2 hours of treatment (36.8 ± 0.7 vs. 38.4 ± 1.1°C; P < 0.01). A 50% vasopressor dose decrease was significantly more common with external cooling from 12 hours of treatment (54 vs. 20%; absolute difference, 34%; 95% confidence interval [95% CI], -46 to -21; P < 0.001) but not at 48 hours (72 vs. 61%; absolute difference, 11%; 95% CI, -23 to 2). Shock reversal during the intensive care unit stay was significantly more common with cooling (86 vs. 73%; absolute difference, 13%; 95% CI, 2 to 25; P = 0.021). Day-14 mortality was significantly lower in the cooling group (19 vs. 34%; absolute difference, -16%; 95% CI, -28 to -4; P = 0.013). CONCLUSIONS In this study, fever control using external cooling was safe and decreased vasopressor requirements and early mortality in septic shock.

Preferred plasma volume expanders for critically ill patients: results of an international survey

ObjectiveCriteria for plasma volume expander selection in critically ill patients remain controversial. This study evaluated preferences of intensivists regarding plasma volume expanders.DesignInternational survey using a 75-item questionnaire.Participants and settingAll members of the European and French Societies of Intensive Care Medicine (n=2,415 in 1,610 adult ICUs in Europe and elsewhere) were invited to participate, and 577 (24%) working in 515 ICUs (32%) returned completed questionnaires.ResultsAmong respondents, 17% used crystalloids alone as their first-choice strategy, 18% colloids alone, and 65% both. Colloids alone were often chosen in patients with cirrhosis (42%), coagulation disorders (42%), or adult respiratory distress syndrome (39%); and crystalloids in patients with dehydration (85%), drug overdose (59%), or acute renal failure (49%). First-line plasma expanders were as follows: isotonic crystalloids (81%), starches (55%), gelatins (35%), albumin (7%), plasma (6%), dextrans (4%), and hypertonic crystalloids (2%). Colloids alone were used more frequently in the United Kingdom (40%), starches in Germany (81%) and The Netherlands (66%), and gelatins in the United Kingdom (68%). The main factors behind preferences for first-line plasma volume expanders were time to volume loss correction, duration of effect, adverse events, and cost.ConclusionsColloids are widely used as first-line treatment, usually in combination with crystalloids. Starches are the most widely used colloids in Europe, where albumin use is declining. However, strategies vary widely across clinical situations and countries.

Severe Imported Falciparum Malaria: A Cohort Study in 400 Critically Ill Adults

Background Large studies on severe imported malaria in non-endemic industrialized countries are lacking. We sought to describe the clinical spectrum of severe imported malaria in French adults and to identify risk factors for mortality at admission to the intensive care unit. Methodology and Principal Findings Retrospective review of severe Plasmodium falciparum malaria episodes according to the 2000 World Health Organization definition and requiring admission to the intensive care unit. Data were collected from medical charts using standardised case-report forms, in 45 French intensive care units in 2000–2006. Risk factors for in-hospital mortality were identified by univariate and multivariate analyses. Data from 400 adults admitted to the intensive care unit were analysed, representing the largest series of severe imported malaria to date. Median age was 45 years; 60% of patients were white, 96% acquired the disease in sub-Saharan Africa, and 65% had not taken antimalarial chemoprophylaxis. Curative quinine treatment was used in 97% of patients. Intensive care unit mortality was 10.5% (42 deaths). By multivariate analysis, three variables at intensive care unit admission were independently associated with hospital death: older age (per 10-year increment, odds ratio [OR], 1.72; 95% confidence interval [95%CI], 1.28–2.32; P = 0.0004), Glasgow Coma Scale score (per 1-point decrease, OR, 1.32; 95%CI, 1.20–1.45; P<0.0001), and higher parasitemia (per 5% increment, OR, 1.41; 95%CI, 1.22–1.62; P<0.0001). Conclusions and Significance In a large population of adults treated in a non-endemic industrialized country, severe malaria still carried a high mortality rate. Our data, including predictors of death, can probably be generalized to other non-endemic countries where high-quality healthcare is available.

Characteristics and outcomes of HIV-infected patients in the ICU: impact of the highly active antiretroviral treatment era

ObjectiveTo examine whether the introduction of highly active antiretroviral therapy (HAART) has changed the rate of admission, the clinical spectrum, and the mortality of HIV-infected ICU patients.DesignObservational study.SettingInfectious diseases ICU in a teaching hospital, Paris, France.PatientsAll HIV-infected patients admitted during a pre-HAART era (1995–1996; n=189) and a HAART era (1998–2000; n=236).InterventionsNone.Measurements and resultsAt the HAART era, 79% of patients had derived no or little benefit from the availability of HAART at ICU admission: 44% had no history of antiretroviral (ARV) medications and 35% had failed to respond to ARV. As compared with the pre-HAART era, the rate of hospitalized HIV-infected patients requiring the ICU stay increased (HAART, 5.9% vs pre-HAART, 4.4%; p=0.004). The admission was more likely to occur through the emergency room (45 vs 29%, p=0.0004), and the patients to be foreigners (38.1 vs 28.6%; p=0.04). After adjustment for significant prognostic covariates (AIDS-related tumors at admission, CD4 count <50/mm3, poor functional status (Knaus score C or D), SAPSII, and need for mechanical ventilation), ICU survival was unchanged (adjusted OR=0.613, 95% CI=0.312–1.206), but 3-month survival was significantly improved (adjusted OR=0.57; 95% CI=0.32–0.99; p=0.045).ConclusionThe number of HIV-infected patients admitted to the ICU remained high in the HAART era. Underutilization of HAART and limited access to health care are possible explanations. The ICU mortality has remained unchanged, but 3-month mortality has decreased.

Diagnostic performance of fractional excretion of urea in the evaluation of critically ill patients with acute kidney injury: a multicenter cohort study

IntroductionSeveral factors, including diuretic use and sepsis, interfere with the fractional excretion of sodium, which is used to distinguish transient from persistent acute kidney injury (AKI). These factors do not affect the fractional excretion of urea (FeUrea). However, there are conflicting data on the diagnostic accuracy of FeUrea.MethodsWe conducted an observational, prospective, multicenter study at three ICUs in university hospitals. Unselected patients, except those with obstructive AKI, were admitted to the participating ICUs during a six-month period. Transient AKI was defined as AKI caused by renal hypoperfusion and reversal within three days. The results are reported as medians (interquartile ranges).ResultsA total of 203 patients were included. According to our definitions, 67 had no AKI, 54 had transient AKI and 82 had persistent AKI. FeUrea was 39% (28 to 40) in the no-AKI group, 41% (29 to 54) in the transient AKI group and 32% (22 to 51) in the persistent AKI group (P = 0.12). FeUrea was of little help in distinguishing transient AKI from persistent AKI, with the area under the receiver operating characteristic curve being 0.59 (95% confidence interval, 0.49 to 0.70; P = 0.06). Sensitivity was 63% and specificity was 54% with a cutoff of 35%. In the subgroup of patients receiving diuretics, the results were similar.ConclusionsFeUrea may be of little help in distinguishing transient AKI from persistent AKI in critically ill patients, including those receiving diuretic therapy. Additional studies are needed to evaluate alternative markers or strategies to differentiate transient from persistent AKI.