Eric Mariotte

Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center.

Objective:To assess the efficacy and safety of rituximab in adults responding poorly to standard treatment for severe autoimmune thrombotic thrombocytopenic purpura. Design:Open-label prospective study. Outcomes in the survivors were compared to those of 53 historical survivors who were given therapeutic plasma exchange alone or with vincristine. Setting:Hospitals belonging to the Reference Network for Thrombotic Microangiopathies in France. Patients:Twenty-two adults with either no response or a disease exacerbation when treated with intensive therapeutic plasma exchange. Intervention:Add-on rituximab therapy, four infusions over 15 days. Measurements and Main Results:One patient died despite two rituximab infusions. In the rituximab-treated patients, the time to a durable remission was significantly shortened (p = .03), although the plasma volume required to achieve a durable remission was not significantly different compared to the controls. Platelet count recovery occurred within 35 days in all 21 survivors, compared to only 78% of the historical controls (p < .02). Of the rituximab-treated patients, none had a relapse within the first year but three relapsed later on. In patients treated with rituximab, a rapid and profound peripheral B-cell depletion was produced, lasting for 9 months and correlating with higher a disintegrin and metalloproteinase with thrombospondin-13 activity and lower anti-a disintegrin and metalloproteinase with thrombospondin-13 antibody titers. These differences were no longer significant after 12 months. No severe side effects occurred. Conclusions:Adults with severe thrombocytopenic purpura who responded poorly to therapeutic plasma exchange and who were treated with rituximab had shorter overall treatment duration and reduced 1-yr relapses than historical controls.

Survival in neutropenic patients with severe sepsis or septic shock.

Objective:To determine whether the survival gains achieved in critically ill cancer patients in recent years exist in the subset with neutropenia and severe sepsis or septic shock. Design:Retrospective 11-yr study (1998–2008). Setting:Medical intensive care unit in a teaching hospital. Patients:Four hundred twenty-eight intensive care unit patients with cancer, neutropenia, and severe sepsis or septic shock. The primary outcome was hospital mortality. Results:The main underlying diseases were acute leukemia (35.7%), lymphoma (31.7%), and solid tumors (16.5%). Two hundred thirty-seven (55.5%) patients had microbiologically documented infections, 141 (32.9%) clinically documented infections, and 50 (11.9%) fever of unknown origin. Acute noninfectious conditions were diagnosed in 175 of 428 (41%) patients, including 26 of 50 (52%) patients with fever of unknown origin, 66 of 141 (47%) patients with clinically documented infections, and 83 of 237 (35%) patients with microbiologically documented infections. Early indwelling catheter removal was performed routinely in the 107 (25%) patients without clinical evidence of a septic focus at intensive care unit admission. Early beta-lactam plus aminoglycoside therapy was used in 391 (91.3%) patients. Hospital mortality was 49.8%. Hospital mortality decreased from 58.7% (108 of 184) in 1998–2003 to 43% in 2004–2008 (105 of 244, p = .006). Multivariate analysis identified nine independent predictors of hospital mortality, of which six were associated with higher mortality (older age; need for vasopressors; neurologic, respiratory, or hepatic dysfunction; and acute noninfectious condition) and three with lower mortality (intensive care unit admission after 2003, combination antibiotic therapy including an aminoglycoside, and early indwelling catheter removal). Conclusion:In neutropenic patients with severe sepsis or septic shock, survival improved over time. Aminoglycoside use and early catheter removal in patients with undocumented sepsis may improve survival. Acute noninfectious conditions are associated with increased mortality, underlining the need for thorough and repeated clinical assessments.

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.

Outcomes of mechanically ventilated hematology patients with invasive pulmonary aspergillosis

BackgroundInvasive pulmonary aspergillosis (IPA) is a life-threatening infection documented in up to 15% of hematology patients who require intensive care for acute respiratory failure. We report outcomes in hematology patients given mechanical ventilation (MV) with IPA.MethodsRetrospective study of all hematology patients given MV with IPA between January 1998 and March 2011 at a single center. Predictors of 6-month survival or mortality were identified using multivariable analysis.ResultsWe studied 67 patients including 49 (73%) with neutropenia, 23 (34%) with long-term steroid therapy, and 14 (21%) with allogeneic bone marrow transplantation. Incidence of IPA in the ICU decreased between 1998 and 2011, and mortality in patients receiving mechanical ventilation did not change. IPA was confirmed in 6 patients by autopsy and was probable in 61 patients based on host factors, clinical and radiographic features, and either Aspergillus isolation (50 patients) or Aspergillus antigen detection alone (11 patients). Concomitant bacterial infections were documented in 24 (36%) patients. ICU and 6-month mortality rates were 67 and 82%, respectively. Mortality was stable throughout the study period. Concomitant bacterial infection was independently associated with higher mortality [HR, 2.1 (1.2–3.8)]. Mortality was lower in patients given voriconazole [OR, 0.5 (0.3–0.9)].ConclusionHospital mortality remains high in hematology patients requiring MV with IPA, particularly when concommittant infection occurred. The use of voriconazole improved survival.

Prognostic contributions of the underlying inflammatory disease and acute organ dysfunction in critically ill patients with systemic rheumatic diseases

BACKGROUND Knowledge about the clinical features, outcomes and predictors of short-term mortality in critically ill patients with systemic rheumatic disease (SRD) requires further characterization. METHODS Single center retrospective observational cohort study of 149 critically ill patients with SRD followed in a French medical intensive care unit over a 20-year period. Multivariate logistic regression was used to identify predictors of day-30 mortality. RESULTS Most patients (63%) had systemic lupus erythematosus, rheumatoid arthritis, or systemic sclerosis. The critical illness usually developed late after the diagnosis of SRD (median time to ICU admission 82 months, IQR [9-175] in the 127 patients with a previous diagnosis of SRD). Two-thirds of patients were taking immunosuppressive drugs to treat their SRD. Reasons for ICU admission were infection (47%), SRD exacerbation (48%), and iatrogenic complications (11%); the most common organ failure was acute renal failure. Thirty-day mortality was 16%. Predictors of 30-day mortality were the LODS score on day 1 (OR 1.3 (1.06-1.48)), bacterial pneumonia (OR 3.8 (1.03-14.25)), need for vasoactive drugs (OR 7.1 (1.83-27.68)), SRD exacerbation (OR 4.3 (1.15-16.53)), and dermatomyositis (OR 9.2 (1.05-80.78)) as the underlying disease. Year of ICU admission was not significantly associated with 30-day survival. CONCLUSION Patients with SRD are mostly admitted in the ICU with infection or SRD exacerbation, and can be treated with immunosuppressive therapy and life-sustaining interventions with acceptable 30-day mortality. Death is associated with both the severity of the acute medical condition and the characteristics of the underlying SRD.

Coagulation Disorders and Bleedings in Critically Ill Patients With Hemophagocytic Lymphohistiocytosis.

AbstractReactive hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition related to a cytokine storm leading to multiorgan dysfunction. A better understanding of coagulation disorders, frequently reported in HLH patients, may improve outcomes.Critically ill HLH patients managed in a multidisciplinary national reference center were retrospectively included. Relationships between coagulation disorders, severe bleedings, and outcomes were assessed.One hundred and seventeen patients fulfilled the HLH 2004 criteria. The most common HLH etiology was hematologic conditions (73%), followed by infectious diseases (20%), systemic rheumatic diseases (5%), and undetermined HLH etiology (3%). All patients exerted thrombocytopenia. Coagulation disorders were diagnosed in 79 (68%) patients (61 had hypofibrinogenemia < 1.5 g/L, 51 had prothrombin time [PT] < 50%). The worst median value throughout ICU stay was 52% (38–65) for PT with a factor V level of 35% (27–43), 1.59 (1.30–2.09) for the activated partial thromboplastin time (APTT) ratio, and 2.33 g/L (1.13–3.86) for the fibrinogen level. Disseminated intravascular coagulation (DIC) was found in 50% of patients. Coagulation disorders were more frequent in immunocompromised patients, those with histological/cytological feature of hemophagocytosis, those with the highest ferritin concentrations, and in patients with HLH not related to infection. These patients were more prone to receive mechanical ventilation, vasopressors, or renal replacement therapy. Twenty-six (22%) patients presented severe bleeding complications, including 5 patients dying from hemorrhagic shock. Strikingly, the only coagulation parameter significantly associated with severe bleeding was low fibrinogen with a cutoff value of 2 g/L (P = 0.03). Overall, 33 (28%) patients died in the ICU and hospital mortality was 44%. Coagulation disorders were associated with higher mortality, especially fibrinogen < 2 g/L (P = 0.04) and PT value (P = 0.03). The occurrence of bleeding complications was not associated with higher risk of hospital death. Risk factors associated with mortality by multivariate analysis were fibrinogen level < 2 g/L (OR 2.42 [1.08–5.41]), SOFA score > 6 (OR 3.04 [1.32–6.98]), and age > 46 years (OR 2.26 [1.02–5.04]).Up to two-third of critically ill HLH patients present with coagulation disorders. Hypofibrinogenemia or DIC was found in half of the patients and low PT in 40%. These patients require more life support and have a higher mortality rate. Fibrinogen <2 g/L is associated with the occurrence of severe bleeding and mortality.

Metastatic cancer-related thrombotic microangiopathies: a cohort study

Thrombotic microangiopathies (TMAs) in patients with metastatic cancer are poorly characterized. We recorded 17 patients who had TMAs associated with disseminated solid cancer in our intensive care unit over an 11-year period. We compared them with a group of 20 patients with proven idiopathic thrombotic thrombocytopenic purpura hospitalized during the same period. We aimed to specify the clinical and biological features of cancer-related TMAs (CR-TMAs). CR-TMAs can either be inaugural of the underlying cancer or reflect worsening course. Clues to the presence of CR-TMA include respiratory symptoms, bone pain, myelemia or higher platelet count than in thrombotic thrombocytopenic purpura. In this context, bone marrow aspiration is a fast and gainful investigation to avoid plasmatherapy and immunosuppressive drugs. Indeed, this severe and poor-prognosis disease requires prompt diagnosis and rapid initiation of specific chemotherapy.

Thrombotic thrombocytopenic purpura: from diagnosis to therapy.

Purpose of reviewThrombotic thrombocytopenic purpura (TTP) is a rare but challenging disease for intensive care specialists. Patients with acute TTP frequently require admission to the intensive care unit because of organ dysfunctions due to the disease or because of the risk of sudden aggravation at the onset of the disease. This review aims at describing recent evolutions in the diagnosis and for the management of TTP for the use of intensive care specialists. Recent findingsThe use of A Disintegrin and Metalloprotease with ThromboSpondin type 1 repeats (ADAMTS13) activity along with clinico-biological features to define TTP by most researchers’ teams has led to easier interpretation of the literature. The main issues in TTP treatment in 2015 remain the indication and timing of introduction of anti-CD20 antibody rituximab for the treatment of inaugural TTP and the preemptive use of rituximab in asymptomatic patients with decreasing ADAMTS13 activity. SummaryThe classification of thrombotic microangiopathies has evolved from a clinical to a pathophysiological definition. TTP is characterized by a severe ADAMTS13 deficiency that can be documented in vitro, along with anti-ADAMTS13 antibodies in most adult cases. Plasmapheresis and immunosuppressive therapy with steroids remain the standard of care for acute inaugural TTP. Anti-CD20 monoclonal antibody rituximab is safe and indicated in relapsing and/or refractory TTP. Its indication in inaugural TTP remains to be evaluated but is nevertheless recommended by experts. Novel therapies for TTP are still in preclinical phases.

Vasculitic emergencies in the intensive care unit: a special focus on cryoglobulinemic vasculitis

Vasculitis is characterized by the infiltration of vessel walls by inflammatory leukocytes with reactive damage and subsequent loss of vessel integrity. The clinical course of systemic vasculitis may be punctuated by acute life-threatening manifestations that require intensive care unit (ICU) admission. Furthermore, the diagnosis may be established in the ICU after admission for a severe inaugural symptom, mostly acute respiratory failure. Among the systemic vasculitides, cryoglobulinemic vasculitis (CV) has been rarely studied in an ICU setting. Severe CV-related complications may involve the kidneys, lungs, heart, gut, and/or central nervous system. The diagnosis of CV in the ICU may be delayed or completely unrecognized. A high level of suspicion is critical to obtain a timely and accurate diagnosis and to initiate appropriate treatment. We describe severe acute manifestations of CV based on six selected patients admitted to our ICU. That all six patients survived suggests the benefit of prompt ICU admission of patients with severe CV.

Early-onset status epilepticus in patients with acute encephalitis.

AbstractStatus epilepticus (SE) is a common complication of acute encephalitis, but its determinants and prognostic value in this setting are not known.Risk factors for early-onset SE (within 48 hours of intensive care unit [ICU] admission) in consecutive adult patients with all-cause encephalitis admitted to the medical ICU of a university hospital (1991–2013) were evaluated by multivariate logistic regression analysis. To examine the prognostic value of SE, patients were classified into 3 groups: no SE, nonrefractory SE (NRSE), and refractory SE (RSE). Poor neurologic outcome was defined by a modified Rankin score of 4 to 6.Among the 290 patients, 58 (20%, 95% CI: 15%–25%) developed early-onset SE, comprising 44 patients with NRSE and 14 patients with RSE. Coma (adjusted odds ratio [OR]: 3.1, 95% CI: 1.5–6.3), cortical lesions on neuroimaging (adjusted OR: 3.7, 95% CI: 1.8–7.8), and nonneurologic organ failure(s) (adjusted OR: 13.6, 95% CI: 4.9–37.7) were found to be independent risk factors for SE. By contrast, a bacterial etiology had a protective effect (adjusted OR: 0.3, 95% CI: 0.1–0.7). Age, body temperature, and blood sodium levels were not independently associated with SE. Poor neurologic outcomes were observed at day 90 in respectively 23% (95% CI: 17%–28%), 23% (95% CI: 10%–35%), and 71% (95% CI: 48%–95%) of no SE, NRSE, and RSE patients (P < 0.01). After adjusting for confounders, RSE, but not NRSE, remained independently associated with 90-day mortality (adjusted OR: 6.0, 95% CI: 1.5–23.3).Coma, cortical involvement on neuroimaging, and nonneurologic organ failure(s) are independent risk factors for SE in patients with acute encephalitis. Conversely, a bacterial etiology is associated with a lower risk of SE.These findings may help identify patients who may benefit from prophylactic antiepileptic drugs.