Nicolas de Prost

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.).

Ventilator-induced lung injury: historical perspectives and clinical implications

Mechanical ventilation can produce lung physiological and morphological alterations termed ventilator-induced lung injury (VILI). Early experimental studies demonstrated that the main determinant of VILI is lung end-inspiratory volume. The clinical relevance of these experimental findings received resounding confirmation with the results of the acute respiratory distress syndrome (ARDS) Network study, which showed a 22% reduction in mortality in patients with the acute respiratory distress syndrome through a simple reduction in tidal volume. In contrast, the clinical relevance of low lung volume injury remains debated and the application of high positive end-expiratory pressure levels can contribute to lung overdistension and thus be deleterious. The significance of inflammatory alterations observed during VILI is debated and has not translated into clinical application. This review examines seminal experimental studies that led to our current understanding of VILI and contributed to the current recommendations in the respiratory support of ARDS patients.

Bacteremia in Stevens-Johnson syndrome and toxic epidermal necrolysis: epidemiology, risk factors, and predictive value of skin cultures.

Toxic epidermal necrolysis (TEN) is a rare drug-related life-threatening acute condition. Sepsis is the main cause of mortality. Skin colonization on top of impaired barrier function promotes bloodstream infections (BSI). We conducted this study to describe the epidemiology, identify early predictors of BSI, and assess the predictive value for bacteremia of routine skin surface cultures. We retrospectively analyzed the charts of all patients with Stevens-Johnson syndrome (SJS) and TEN hospitalized over an 11-year period. Blood cultures and skin isolates were recovered from the microbiology laboratory database. Early predictors of BSI were identified using a Cox model. Sensitivity, specificity, and negative and positive predictive values of skin cultures for the etiology of BSI were assessed. The study included 179 patients, classified as having SJS (n = 54; 30.2%), SJS/TEN overlap (n = 59; 33.0%), and TEN (n = 66; 36.9%). Forty-eight episodes of BSI occurred, yielding a rate of 15.5/1000 patient days. Inhospital mortality was 13.4% (24/179). Overall, 70 pathogens were recovered, mainly Staphylococcus aureus (n = 23/70; 32.8%), Pseudomonas aeruginosa (n = 15/70; 21.4%), and Enterobacteriaceae organisms (n = 17/70; 24.3%). Variables associated with BSI in multivariate analysis included age >40 years (hazard ratio [HR], 2.5; 95% confidence interval [CI], 1.35-4.63), white blood cell count >10,000/mm3 (HR, 1.9; 95% CI, 0.96-3.61), and percentage of detached body surface area ≥30% (HR, 2.5; 95% CI, 1.13-5.47). Skin cultures had an excellent negative predictive value for bacteremia due to S aureus (especially methicillin-resistant strains) and P aeruginosa, but not for those due to Enterobacteriaceae organisms. In contrast, the positive predictive value was low for all pathogens studied. To our knowledge, this is the largest study describing the epidemiology and risk factors of BSI in patients with SJS/TEN. The body surface area involved is the main predictor of BSI. Excellent negative predictive values of skin cultures for S aureus and P aeruginosa bacteremia should help clinicians consider targeted empirical antibiotic choices when appropriate. Abbreviations: BSI = bloodstream infection, CI = confidence interval, HR = hazard ratio, ICU = intensive care unit, IQR = interquartile range, IVIG = intravenous immunoglobulin, LOD score = Logistic Organ Dysfunction score, NPV = negative predictive value, OR = odds ratio, SAPS II = Simplified Acute Physiology Score II, SJS = Stevens-Johnson syndrome, TEN = toxic epidermal necrolysis.

Diffuse alveolar hemorrhage in immunocompetent patients: Etiologies and prognosis revisited

BACKGROUND Diffuse alveolar hemorrhage (DAH) represents a diagnostic challenge of acute respiratory failure. Prompt identification of the underlying cause of DAH and initiation of appropriate treatment are required in order to prevent acute respiratory failure and irreversible loss of renal function. More than 100 causes of DAH have been reported. However, the relative frequency and the differential presentation of those causes have been poorly documented, as well as their respective prognosis. METHODS We retrospectively reviewed the charts of 112 consecutive patients hospitalized for DAH in a tertiary referral center over a 30-year period. RESULTS Twenty-four causes of DAH were classified into four etiologic groups: immune (n = 39), congestive heart failure (CHF; n = 33), miscellaneous (n = 26), and idiopathic DAH (n = 14). Based on this classification, clinical and laboratory features of DAH differed on hospital admission. Patients with immune DAH had more frequent pulmonary-renal syndrome (p < 0.001), extra-pulmonary symptoms (p < 0.01), and lower blood hemoglobin level than others (p < 0.001). Patients with CHF-related DAH were older and received more anticoagulant treatments than others (p < 0.05). Those with miscellaneous causes of DAH exhibited a shorter prodromal phase (p < 0.001) and had more frequent hemoptysis >200 mL (p < 0.05). Patients with idiopathic DAH had more bronchoalveolar lavage siderophages (p < 0.01). In-hospital mortality was 24.1%, ranging from 7.1% in patients with idiopathic DAH to 36.4% in those with CHF. CONCLUSIONS Arbitrary classification of DAH in four etiologic groups gives the opportunity to underline distinct presentations and outcomes of various causes of DAH.

Acute Respiratory Failure in Patients With Toxic Epidermal Necrolysis: Clinical Features and Factors Associated With Mechanical Ventilation

Objectives:Stevens-Johnson syndrome and toxic epidermal necrolysis are severe adverse cutaneous drug reactions characterized by widespread skin and mucous membrane detachments, including bronchial mucosa, which may be associated with respiratory failure requiring mechanical ventilation. The presentation and outcome of patients requiring mechanical ventilation and the characteristics of bronchial epithelial lesions among ventilated patients are reported. Predictors of mechanical ventilation available on hospital admission were identified using univariate and multivariate logistic regressions. Design:Retrospective cohort study. Setting:Medical ICU and dermatology department of a tertiary care hospital, which hosts the French national referral center for toxic epidermal necrolysis. Patients:Patients admitted for Stevens-Johnson syndrome/toxic epidermal necrolysis over a 14-year period were included. Interventions:None. Measurements and Main Results:Of the 221 patients included in the study, 56 patients (25.3%) required mechanical ventilation. None of the patients received noninvasive ventilation. Patients requiring mechanical ventilation had a larger baseline detached body surface area, higher Logistic Organ Dysfunction score, and Simplified Acute Physiology Score II, and they presented more often with shock, pulmonary infiltrates, and renal dysfunction (p < 0.0001 for all comparisons). Among patients receiving mechanical ventilation, 57% of the patients died; those having bronchial epithelial lesions (22 of 56) required intubation earlier than others (1 [1–4] vs 4 [1–6] d after hospital admission; p = 0.027). Variables associated with mechanical ventilation in multivariate analysis included serum bicarbonates less than 20 mM (odds ratio, 4.9 [95% CI, 1.1–22.7]; p = 0.041), serum urea greater than 10 mM (odds ratio, 7.0 [95% CI, 2.2–22.8]; p < 0.001), a detached body surface area between 10% and 29% (odds ratio, 3.7 [95% CI, 1.0–13.8]; p = 0.048) or greater than or equal to 30% (odds ratio, 19.7 [95% CI, 4.4–87.4]; p < 0.0001), WBCs more than 12,000/mm3 (odds ratio, 11.6 [95% CI, 2.8–48.1]; p < 0.001), blood hemoglobin less than 8 g/dL (odds ratio, 8.1 [95% CI, 1.2–55.2]; p = 0.032), and more extensive pulmonary infiltrates (odds ratio, 9.7 [95% CI, 3.6–25.9]; p < 0.0001). Conclusions:Mechanical ventilation is required in one of four Stevens-Johnson syndrome/toxic epidermal necrolysis patients and is associated with a poor outcome. Prompt identification of Stevens-Johnson syndrome/toxic epidermal necrolysis patients at higher risk of intubation could help guide their early management, particularly for those having bronchial epithelial lesions.

Glucose transport in the lung and its role in liquid movement

Glucose concentration in the liquid present in the alveolar/airway lumen is the consequence of the balance between removal by lung epithelial cells and entry from the plasma or lung interstitium through the paracellular pathway. Glucose removal is mediated by active, Na(+) -dependent, cotransport and results in transepithelial Na(+) transport and liquid absorption in animals with significant rates of luminal glucose uptake and when luminal glucose concentration is high enough. Cotransport kinetics predicted a low luminal glucose concentration at the steady state, and foetal lung fluid and adult alveolar epithelial lining fluid glucose concentrations were indeed found lower than plasma. When luminal glucose concentration is low, the glucose-dependent part of transepithelial Na(+) transport is abated and alveolar liquid clearance reduced. A means to refuel this mechanism of liquid absorption would be to increase glucose entry in alveolar spaces through an increase in paracellular permeability. This hypothesis was modelled, and experimental data were found to acceptably agree with predictions.

Comparison of two strategies for initiating renal replacement therapy in the intensive care unit: study protocol for a randomized controlled trial (AKIKI).

BackgroundThere is currently no validated strategy for the timing of renal replacement therapy (RRT) for acute kidney injury (AKI) in the intensive care unit (ICU) when short-term life-threatening metabolic abnormalities are absent. No adequately powered prospective randomized study has addressed this issue to date. As a result, significant practice heterogeneity exists and may expose patients to either unnecessary hazardous procedures or undue delay in RRT.Methods/designThis is a multicenter, prospective, randomized, open-label parallel-group clinical trial that compares the effect of two RRT initiation strategies on overall survival of critically ill patients receiving intravenous catecholamines or invasive mechanical ventilation and presenting with AKI classification stage 3 (KDIGO 2012). In the ‘early’ strategy, RRT is initiated immediately. In the ‘delayed’ strategy, clinical and metabolic conditions are closely monitored and RRT is initiated only when one or more events (severity criteria) occur, including: oliguria or anuria for more than 72 hours after randomization, serum urea concentration >40 mmol/l, serum potassium concentration >6 mmol/l, serum potassium concentration >5.5 mmol/l persisting despite medical treatment, arterial blood pH <7.15 in a context of pure metabolic acidosis (PaCO2 < 35 mmHg) or in a context of mixed acidosis with a PaCO2 ≥ 50 mmHg without possibility of increasing alveolar ventilation, acute pulmonary edema due to fluid overload despite diuretic therapy leading to severe hypoxemia requiring oxygen flow rate >5 l/min to maintain SpO2 > 95% or FiO2 > 50% under invasive or noninvasive mechanical ventilation.The primary outcome measure is overall survival, measured from randomization (D0) until death, regardless of the cause. The minimum follow-up duration for each patient will be 60 days. Two interim analyses are planned, blinded to group allocation. It is expected that there will be 620 subjects in all.DiscussionThe AKIKI study will be one of the very few large randomized controlled trials evaluating mortality according to the timing of RRT in critically ill patients with AKI classification stage 3 (KDIGO 2012). Results should help clinicians decide when to initiate RRT.Trial registrationClinicalTrials.gov NCT01932190.

Unrevealing culture-negative severe sepsis.

Sepsis involves a wide array of sources and microorganisms, only a fraction of which are microbiologically documented. Culture-negative sepsis poses special diagnostic challenges to both clinicians and microbiologists and further questions the validity of sepsis definitions.

Fluorine-18 fluorodeoxyglucose with positron emission tomography revealed bone marrow involvement in sarcoidosis patients with anaemia.

Background: Anaemia occurs in 13–28% of sarcoidosis patients. It is associated with bone marrow infiltration by epitheliod granulomas in about 50% of cases, but its pathophysiology remains unclear. Objectives: It was the aim of this study to describe a series of sarcoidosis patients with and without anaemia who underwent metabolic imaging with fluorine-18 fluorodeoxyglucose with positron emission tomography (18F-FDG PET). Methods: The files of 3 sarcoidosis patients who exhibited anaemia and underwent metabolic imaging with 18F-FDG PET were reviewed in comparison with those of all sarcoidosis patients (n = 7) who underwent 18F-FDG PET during the same period of time. Results: In the 3 cases, symptomatic anaemia was associated with bone marrow sarcoidosis as attested by 18F-FDG PET and confirmed by bone marrow biopsy. This observation is strengthened by the lack of bone marrow hypermetabolism by PET scan in the 7 control patients. Corticosteroids dramatically improved anaemia in 2 cases which correlated with a dramatic decrease in bone marrow glucose uptake. In contrast, there was a moderate increase in haemoglobin level in the third case and no change in metabolic imaging. Conclusion: Whole-body 18F-FDG PET imaging should be considered in sarcoidosis patients with symptomatic anaemia. It can noninvasively suggest bone marrow involvement, indicate sarcoidosis treatment and monitor its efficiency.

Blood cocaine and metabolite pharmacokinetics after cardiac arrest in a body-packer case

Introduction: Cocaine body packing, the internal concealment of cocaine for transportation between countries, may expose to life-threatening intoxications. No data is currently available on the pharmacokinetics of cocaine and its metabolites when a packet rupture occurs in a body packer. Case report: We report the first pharmacokinetic data associated with a severe cocaine intoxication in a body packer, resulting in cardiac arrest. Massive concentrations of cocaine (observed maximal concentration: 1.66 mg/L, 1 hour after the cardiac arrest) were measured in plasma up to about 15 hours, suggesting a prolonged absorption due to a slow-release in the gastrointestinal tract despite surgical extraction of the packets. Apparent cocaine elimination half-life was 7.6 hours. Conclusion: A prolonged apparent cocaine elimination half-life has been observed. Further pharmacokinetic studies are needed to understand better the pathophysiology of acute cocaine intoxication in body packers.