Julien Mayaux

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.).

Outcomes of Critically Ill Patients With Hematologic Malignancies: Prospective Multicenter Data From France and Belgium—A Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique Study

PURPOSE Patients with hematologic malignancies are increasingly admitted to the intensive care unit (ICU) when life-threatening events occur. We sought to report outcomes and prognostic factors in these patients. PATIENTS AND METHODS Ours was a prospective, multicenter cohort study of critically ill patients with hematologic malignancies. Health-related quality of life (HRQOL) and disease status were collected after 3 to 6 months. Results Of the 1,011 patients, 38.2% had newly diagnosed malignancies, 23.1% were in remission, and 24.9% had received hematopoietic stem-cell transplantations (HSCT, including 145 allogeneic). ICU admission was mostly required for acute respiratory failure (62.5%) and/or shock (42.3%). On day1, 733 patients (72.5%) received life-supporting interventions. Hospital, day-90, and 1-year survival rates were 60.7%, 52.5%, and 43.3%, respectively. By multivariate analysis, cancer remission and time to ICU admission less than 24 hours were associated with better hospital survival. Poor performance status, Charlson comorbidity index, allogeneic HSCT, organ dysfunction score, cardiac arrest, acute respiratory failure, malignant organ infiltration, and invasive aspergillosis were associated with higher hospital mortality. Mechanical ventilation (47.9% of patients), vasoactive drugs (51.2%), and dialysis (25.9%) were associated with mortality rates of 60.5%, 57.5%, and 59.2%, respectively. On day 90, 80% of survivors had no HRQOL alterations (physical and mental health similar to that of the overall cancer population). After 6 months, 80% of survivors had no change in treatment intensity compared with similar patients not admitted to the ICU, and 80% were in remission. CONCLUSION Critically ill patients with hematologic malignancies have good survival, disease control, and post-ICU HRQOL. Earlier ICU admission is associated with better survival.

Effect of Noninvasive Ventilation vs Oxygen Therapy on Mortality Among Immunocompromised Patients With Acute Respiratory Failure: A Randomized Clinical Trial

IMPORTANCE Noninvasive ventilation has been recommended to decrease mortality among immunocompromised patients with hypoxemic acute respiratory failure. However, its effectiveness for this indication remains unclear. OBJECTIVE To determine whether early noninvasive ventilation improved survival in immunocompromised patients with nonhypercapnic acute hypoxemic respiratory failure. DESIGN, SETTING, AND PARTICIPANTS Multicenter randomized trial conducted among 374 critically ill immunocompromised patients, of whom 317 (84.7%) were receiving treatment for hematologic malignancies or solid tumors, at 28 intensive care units (ICUs) in France and Belgium between August 12, 2013, and January 2, 2015. INTERVENTIONS Patients were randomly assigned to early noninvasive ventilation (n = 191) or oxygen therapy alone (n = 183). MAIN OUTCOMES AND MEASURES The primary outcome was day-28 mortality. Secondary outcomes were intubation, Sequential Organ Failure Assessment score on day 3, ICU-acquired infections, duration of mechanical ventilation, and ICU length of stay. RESULTS At randomization, median oxygen flow was 9 L/min (interquartile range, 5-15) in the noninvasive ventilation group and 9 L/min (interquartile range, 6-15) in the oxygen group. All patients in the noninvasive ventilation group received the first noninvasive ventilation session immediately after randomization. On day 28 after randomization, 46 deaths (24.1%) had occurred in the noninvasive ventilation group vs 50 (27.3%) in the oxygen group (absolute difference, -3.2 [95% CI, -12.1 to 5.6]; P = .47). Oxygenation failure occurred in 155 patients overall (41.4%), 73 (38.2%) in the noninvasive ventilation group and 82 (44.8%) in the oxygen group (absolute difference, -6.6 [95% CI, -16.6 to 3.4]; P = .20). There were no significant differences in ICU-acquired infections, duration of mechanical ventilation, or lengths of ICU or hospital stays. CONCLUSIONS AND RELEVANCE Among immunocompromised patients admitted to the ICU with hypoxemic acute respiratory failure, early noninvasive ventilation compared with oxygen therapy alone did not reduce 28-day mortality. However, study power was limited. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01915719.

Postartesunate delayed hemolysis is a predictable event related to the lifesaving effect of artemisinins.

Patients with severe malaria treated with artesunate sometimes experience a delayed hemolytic episode. Artesunate (AS) induces pitting, a splenic process whereby dead parasites are expelled from their host erythrocytes. These once-infected erythrocytes then return to the circulation. We analyzed hematologic parameters in 123 travelers treated with AS for severe malaria. Among 60 nontransfused patients observed for more than 8 days, 13 (22%) had delayed hemolysis. The peak concentration of circulating once-infected erythrocytes was measured during the first week in 21 patients and was significantly higher in 9 patients with delayed hemolysis than in 12 with other patterns of anemia (0.30 vs 0.07; P = .0001). The threshold of 180 million once-infected erythrocytes per liter discriminated patients with delayed hemolysis with 89% sensitivity and 83% specificity. Once-infected erythrocyte morphology analyzed by using ImageStream in 4 patients showed an 8.9% reduction in their projected area, an alteration likely contributing to their shorter lifespan. Delayed clearance of infected erythrocytes spared by pitting during AS treatment is an original mechanism of hemolytic anemia. Our findings consolidate a disease framework for posttreatment anemia in malaria in which delayed hemolysis is a new entity. The early concentration of once-infected erythrocytes is a solid candidate marker to predict post-AS delayed hemolysis.

Coexistence and Impact of Limb Muscle and Diaphragm Weakness at Time of Liberation from Mechanical Ventilation in Medical Intensive Care Unit Patients

Rationale: Intensive care unit (ICU)‐ and mechanical ventilation (MV)‐acquired limb muscle and diaphragm dysfunction may both be associated with longer length of stay and worse outcome. Whether they are two aspects of the same entity or have a different prevalence and prognostic impact remains unclear. Objectives: To quantify the prevalence and coexistence of these two forms of ICU‐acquired weakness and their impact on outcome. Methods: In patients undergoing a first spontaneous breathing trial after at least 24 hours of MV, diaphragm dysfunction was evaluated using twitch tracheal pressure in response to bilateral anterior magnetic phrenic nerve stimulation (a pressure <11 cm H2O defined dysfunction) and ultrasonography (thickening fraction [TFdi] and excursion). Limb muscle weakness was defined as a Medical Research Council (MRC) score less than 48. Measurements and Main Results: Seventy‐six patients were assessed at their first spontaneous breathing trial: 63% had diaphragm dysfunction, 34% had limb muscle weakness, and 21% had both. There was a significant but weak correlation between MRC score and twitch pressure (&rgr; = 0.26; P = 0.03) and TFdi (&rgr; = 0.28; P = 0.01), respectively. Low twitch pressure (odds ratio, 0.60; 95% confidence interval, 0.45‐0.79; P < 0.001) and TFdi (odds ratio, 0.84; 95% confidence interval, 0.76‐0.92; P < 0.001) were independently associated with weaning failure, but the MRC score was not. Diaphragm dysfunction was associated with higher ICU and hospital mortality, and limb muscle weakness was associated with longer duration of MV and hospital stay. Conclusions: Diaphragm dysfunction is twice as frequent as limb muscle weakness and has a direct negative impact on weaning outcome. The two types of muscle weakness have only limited overlap.

Neurally adjusted ventilatory assist improves patient–ventilator interaction during postextubation prophylactic noninvasive ventilation*

Objectives:To compare the respective impact of pressure support ventilation and naturally adjusted ventilatory assist, with and without a noninvasive mechanical ventilation algorithm, on patient–ventilator interaction. Design:Prospective 2-month study. Setting:Adult critical care unit in a tertiary university hospital. Patients:Seventeen patients receiving a prophylactic postextubation noninvasive mechanical ventilation. Interventions:Patients were randomly mechanically ventilated for 10 mins with: pressure support ventilation without a noninvasive mechanical ventilation algorithm (PSV-NIV–), pressure support ventilation with a noninvasive mechanical ventilation algorithm (PSV-NIV+), neurally adjusted ventilatory assist without a noninvasive mechanical ventilation algorithm (NAVA-NIV–), and neurally adjusted ventilatory assist with a noninvasive mechanical ventilation algorithm (NAVA-NIV+). Measurements and Main Results:Breathing pattern descriptors, diaphragm electrical activity, leak volume, inspiratory trigger delay, inspiratory time in excess, and the five main asynchronies were quantified. Asynchrony index and asynchrony index influenced by leaks were computed. Peak inspiratory pressure and diaphragm electrical activity were similar for each of the four experimental conditions. For both pressure support ventilation and neurally adjusted ventilatory assist, the noninvasive mechanical ventilation algorithm significantly reduced the level of leakage (p < .01). Inspiratory trigger delay was not affected by the noninvasive mechanical ventilation algorithm but was shorter in neurally adjusted ventilatory assist than in pressure support ventilation (p < .01). Inspiratory time in excess was shorter in neurally adjusted ventilatory assist and PSV-NIV+ than in PSV-NIV– (p < .05). Asynchrony index was not affected by the noninvasive mechanical ventilation algorithm but was significantly lower in neurally adjusted ventilatory assist than in pressure support ventilation (p < .05). Asynchrony index influenced by leaks was insignificant with neurally adjusted ventilatory assist and significantly lower than in pressure support ventilation (p < .05). There was more double triggering with neurally adjusted ventilatory assist. Conclusions:Both neurally adjusted ventilatory assist and a noninvasive mechanical ventilation algorithm improve patient–ventilator synchrony in different manners. NAVA-NIV+ offers the best compromise between a good patient–ventilator synchrony and a low level of leaks. Clinical studies are required to assess the potential clinical benefit of neurally adjusted ventilatory assist in patients receiving noninvasive mechanical ventilation. Trial Registration:Clinicaltrials.gov Identifier NCT01280760.

Outcomes in critically ill cancer patients with septic shock of pulmonary origin.

ABSTRACT Increased therapeutic intensity has translated into better survival at a price of infectious and toxic life-threatening complications, chiefly affecting the lungs. Yet, no study specifically evaluated outcomes in cancer patients admitted to the intensive care unit (ICU) for septic shock of pulmonary origin. This is a multicenter cohort study of cancer patients admitted to the ICU for septic shock and pneumonia between 1998 and 2008. Independent determinants of hospital mortality were assessed using a multivariate logistic regression model. Prognostic impact of persistence or acquisition of organ failures was evaluated by survival conditional probabilities. During the 10-year study period, 218 patients were included. Hematologic malignancy (mostly non–Hodgkin lymphoma and acute leukemia) affected 84%, and solid tumors (mostly lung cancer) affected 16% of patients. Chemotherapy was recently administered in 89% of patients, and 24.5% of patients were recipients of hematopoietic stem cell transplantation (35 autologous, 18 allogeneic). At the time of ICU admission, 60% of patients were in partial or complete remission. All patients received vasopressors; invasive mechanical ventilation (MV) was needed in 78.4% and dialysis in 30% of patients. Intensive care unit and hospital mortality rates were 56.4% and 62.4%, respectively. Independent risk factors for hospital mortality were age older than 60 years, time between first symptoms and ICU admission, use of invasive MV, need for invasive MV after use of noninvasive ventilation, and coma. Analysis of survival probability showed that there was no temporal threshold after which persistence or gain of organ dysfunction indicated no hope for survival. Survival in cancer patients with septic shock from pulmonary origin is substantial, even when organ dysfunctions are not rapidly reversible. Delayed ICU management is an independent predictor of death. Studies assessing survival benefits from early ICU management are warranted.

Clinical Features and Outcomes in Patients With Disseminated Toxoplasmosis Admitted to Intensive Care: A Multicenter Study

BACKGROUND Characteristics and outcomes of adult patients with disseminated toxoplasmosis admitted to the intensive care unit (ICU) have rarely been described. METHODS We performed a retrospective study on consecutive adult patients with disseminated toxoplasmosis who were admitted from January 2002 through December 2012 to the ICUs of 14 university-affiliated hospitals in France. Disseminated toxoplasmosis was defined as microbiological or histological evidence of disease affecting >1 organ in immunosuppressed patients. Isolated cases of cerebral toxoplasmosis were excluded. Clinical data on admission and risk factors for 60-day mortality were collected. RESULTS Thirty-eight patients were identified during the study period. Twenty-two (58%) had received an allogeneic hematopoietic stem cell transplant (median, 61 [interquartile range {IQR}, 43-175] days before ICU admission), 4 (10%) were solid organ transplant recipients, and 10 (27%) were infected with human immunodeficiency virus (median CD4 cell count, 14 [IQR, 6-33] cells/µL). The main indications for ICU admission were acute respiratory failure (89%) and shock (53%). The 60-day mortality rate was 82%. Allogeneic hematopoietic stem cell transplant (hazard ratio [HR] = 2.28; 95% confidence interval [CI], 1.05-5.35; P = .04) and systolic cardiac dysfunction (HR = 3.54; 95% CI, 1.60-8.10; P < .01) within 48 hours of ICU admission were associated with mortality. CONCLUSIONS Severe disseminated toxoplasmosis leading to ICU admission has a poor prognosis. Recipients of allogeneic hematopoietic stem cell transplant appear to have the highest risk of mortality. We identified systolic cardiac dysfunction as a major determinant of outcome. Strategies aimed at preventing this fatal opportunistic infection may improve outcomes.

Clinical assessment for identifying causes of acute respiratory failure in cancer patients

In cancer patients with acute respiratory failure (ARF), early adequate therapy is associated with better outcomes. We investigated the performance of the DIRECT approach, which uses criteria available at the bedside at admission to the intensive care unit (ICU), to identify causes of ARF in cancer patients. This cohort study included cancer patients with ARF of determined aetiology. Associations of aetiological groups with the selected criteria were evaluated using correspondence analysis. 424 cancer patients were included: 201 (47%) with bacterial pneumonia, 131 (31%) with opportunistic infections and 92 (22%) with noninfectious disorders. Mechanical ventilation (both invasive and noninvasive) was needed in 328 (77%) patients, treatment for shock in 217 (51%) patients and dialysis in 82 (19%) patients. 142 (34%) patients died in the ICU. Correspondence plots showed that bacterial pneumonia was associated with neutropenia, solid tumour, multiple myeloma, <3 days since symptom onset, shock, unilateral crackles and unilateral radiographic pattern. Opportunistic infections were associated with steroids, lymphoproliferative disorders and haematopoietic stem-cell transplantation, whereas noninfectious disorders were associated with acute leukaemia The selected criteria are strongly associated with causes of ARF in cancer patients and could be used to develop an algorithm for selecting first-line diagnostic investigations and empirical treatments.

Delayed-Onset Hemolytic Anemia in Patients with Travel-Associated Severe Malaria Treated with Artesunate, France, 2011–2013

Hemolysis occurred in a low proportion of patients and did not increase transfusion requirements.