Critically Ill Patients Treated for Chimeric Antigen Receptor-Related Toxicity: A Multicenter Study.

OBJECTIVES: To report the epidemiology, treatments, and outcomes of adult patients admitted to the ICU after cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. DESIGN: Retrospective cohort study. SETTING: Nine centers across the U.S. part of the chimeric antigen receptor-ICU initiative. PATIENTS: Adult patients treated with chimeric antigen receptor T-cell therapy who required ICU admission between November 2017 and May 2019. INTERVENTIONS: Demographics, toxicities, specific interventions, and outcomes were collected. RESULTS: One-hundred five patients treated with axicabtagene ciloleucel required ICU admission for cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome during the study period. At the time of ICU admission, the majority of patients had grade 3-4 toxicities (66.7%); 15.2% had grade 3-4 cytokine release syndrome and 64% grade 3-4 immune effector cell-associated neurotoxicity syndrome. During ICU stay, cytokine release syndrome was observed in 77.1% patients and immune effector cell-associated neurotoxicity syndrome in 84.8% of patients; 61.9% patients experienced both toxicities. Seventy-nine percent of patients developed greater than or equal to grade 3 toxicities during ICU stay, however, need for vasopressors (18.1%), mechanical ventilation (10.5%), and dialysis (2.9%) was uncommon. Immune Effector Cell-Associated Encephalopathy score less than 3 (69.7%), seizures (20.2%), status epilepticus (5.7%), motor deficits (12.4%), and cerebral edema (7.9%) were more prevalent. ICU mortality was 8.6%, with only three deaths related to cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Median overall survival time was 10.4 months (95% CI, 6.64-not available mo). Toxicity grade or organ support had no impact on overall survival; higher cumulative corticosteroid doses were associated to decreased overall and progression-free survival. CONCLUSIONS: This is the first study to describe a multicenter cohort of patients requiring ICU admission with cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome after chimeric antigen receptor T-cell therapy. Despite severe toxicities, organ support and in-hospital mortality were low in this patient population.

Iatrogenic Toxicities in the Intensive Care Unit.

Drug-induced iatrogenic toxicities are common in critically ill patients and have been associated with increased morbidity and mortality. Early recognition and management of iatrogenic toxicities is essential; however, the diagnosis is usually complicated by the underlying critical illness, comorbidities, and administration of multiple medications. This article reviews several types of iatrogenic toxicities associated with medications that are commonly used in critically ill patients. The mechanism of the iatrogenic toxicities, clinical presentation, and diagnosis, as well as management are discussed.

Effect of hydrocortisone versus methylprednisolone on clinical outcomes in oncology patients with septic shock.

BACKGROUND: Corticosteroids are used as adjunctive treatment of critical illness-related corticosteroid insufficiency in patients with septic shock. This study aims to compare the impact of hydrocortisone versus methylprednisolone on duration of septic shock in critically ill oncology patients. METHODS: Single-center, retrospective cohort study of adult patients receiving hydrocortisone ≥200 mg/day or methylprednisolone ≥40 mg/day with septic shock. The primary outcome was time to shock reversal defined as time to systolic blood pressure ≥90 mmHg without vasopressors for ≥24 h. RESULTS: Eighty-eight patients were included, 49 patients received hydrocortisone and 39 patients received methylprednisolone. Solid tumor malignancy was more common in the hydrocortisone group, while hematological malignancy was more common in the methylprednisolone group (p = 0.009). Time to shock reversal was similar between hydrocortisone and methylprednisolone groups (72.4 versus 70.4 h; p = 0.825). Intensive care unit mortality occurred in 51.02% versus 53.85% of patients in hydrocortisone versus methylprednisolone, respectively (p = 0.792). Patients who received methylprednisolone had higher rates of mechanical ventilation (89.74% versus 55.1%, p < 0.001) and longer intensive care unit and hospital lengths of stay (4.2 versus 11.4 days and 14.3 versus 25.7 days; p < 0.001) compared to hydrocortisone. No differences were seen in incidence of steroid-related adverse effects between groups. CONCLUSIONS: In oncology patients with septic shock, the use of hydrocortisone versus methylprednisolone does not appear to affect time to shock reversal.

Variation in Fluid and Vasopressor Use in Shock With and Without Physiologic Assessment: A Multicenter Observational Study.

OBJECTIVES: To characterize the association between the use of physiologic assessment (central venous pressure, pulmonary artery occlusion pressure, stroke volume variation, pulse pressure variation, passive leg raise test, and critical care ultrasound) with fluid and vasopressor administration 24 hours after shock onset and with in-hospital mortality. DESIGN: Multicenter prospective cohort study between September 2017 and February 2018. SETTINGS: Thirty-four hospitals in the United States and Jordan. PATIENTS: Consecutive adult patients requiring admission to the ICU with systolic blood pressure less than or equal to 90 mm Hg, mean arterial blood pressure less than or equal to 65 mm Hg, or need for vasopressor. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Of 1,639 patients enrolled, 39% had physiologic assessments. Use of physiologic assessment was not associated with cumulative fluid administered within 24 hours of shock onset, after accounting for baseline characteristics, etiology and location of shock, ICU types, Acute Physiology and Chronic Health Evaluation III, and hospital (beta coefficient, 0.04; 95% CI, -0.07 to 0.15). In multivariate analysis, the use of physiologic assessment was associated with a higher likelihood of vasopressor use (adjusted odds ratio, 1.98; 95% CI, 1.45-2.71) and higher 24-hour cumulative vasopressor dosing as norepinephrine equivalent (beta coefficient, 0.37; 95% CI, 0.19-0.55). The use of vasopressor was associated with increased odds of in-hospital mortality (adjusted odds ratio, 1.88; 95% CI, 1.27-2.78). In-hospital mortality was not associated with the use of physiologic assessment (adjusted odds ratio, 0.86; 95% CI, 0.63-1.18). CONCLUSIONS: The use of physiologic assessment in the 24 hours after shock onset is associated with increased use of vasopressor but not with fluid administration.

The chimeric antigen receptor-intensive care unit (CAR-ICU) initiative: Surveying intensive care unit practices in the management of CAR T-cell associated toxicities.

PURPOSE: A task force of experts from 11 United States (US) centers, sought to describe practices for managing chimeric antigen receptor (CAR) T-cell toxicity in the intensive care unit (ICU). MATERIALS AND METHODS: Between June-July 2019, a survey was electronically distributed to 11 centers. The survey addressed: CAR products, toxicities, targeted treatments, management practices and interventions in the ICU. RESULTS: Most centers (82%) had experience with commercial and non-FDA approved CAR products. Criteria for ICU admission varied between centers for patients with Cytokine Release Syndrome (CRS) but were similar for Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS). Practices for vasopressor support, neurotoxicity and electroencephalogram monitoring, use of prophylactic anti-epileptic drugs and tocilizumab were comparable. In contrast, fluid resuscitation, respiratory support, methods of surveillance and management of cerebral edema, use of corticosteroid and other anti-cytokine therapies varied between centers. CONCLUSIONS: This survey identified areas of investigation that could improve outcomes in CAR T-cell recipients such as fluid and vasopressor selection in CRS, management of respiratory failure, and less common complications such as hemophagocytic lymphohistiocytosis, infections and stroke. The variability in specific treatments for CAR T-cell toxicities, needs to be considered when designing future outcome studies of critically ill CAR T-cell patients.

Carbapenem versus Cefepime or Piperacillin-Tazobactam for Empiric Treatment of Bacteremia Due to Extended-Spectrum-ß-Lactamase-Producing Escherichia coli in Patients with Hematologic Malignancy.

Infections with extended-spectrum-ß-lactamase (ESBL)-producing Escherichia coli are common in patients with hematologic malignancy. The utility of cefepime and piperacillin-tazobactam as empiric therapy for ESBL-producing E. coli bacteremia in patients with hematologic malignancy is largely unknown. We conducted a single-center, retrospective cohort review of 103 adult inpatients with leukemia and/or hematopoietic stem cell transplant (HCT) recipients with monomicrobial ESBL-producing E. coli bacteremia. No association between increased 14-day mortality and empiric treatment with cefepime (8%) or piperacillin-tazobactam (0%) relative to that with carbapenems (19%) was observed (P = 0.19 and P = 0.04, respectively). This observation was consistent in multivariate Cox proportional hazards models adjusted for confounding and an inverse probability of treatment-weighted (IPTW) Cox proportional hazards model. Both fever and persistent bacteremia were more common in patients treated empirically with cefepime or piperacillin-tazobactam. Empiric treatment with cefepime or piperacillin-tazobactam did not result in increased mortality relative to that with treatment with carbapenems in patients with hematologic malignancy and ESBL-producing E. coli bacteremia, although most patients were changed to carbapenems early in treatment. However, due to prolonged fever and persistent bacteremia, their role may be limited in this patient population.