Palliative Care Utilization in Patients Requiring Extracorporeal Membrane Oxygenation: An Observational Study.

Palliative care (PC) is a model of care centered around improving the quality of life for individuals with life-limiting illnesses. Few studies have examined its impact in patients on extracorporeal membrane oxygenation (ECMO). We aimed to describe demographics, clinical characteristics, and complications associated with PC consultation in adult patients requiring ECMO support. We analyzed data from an ECMO registry, including patients aged 18 years and older who have received either venoarterial (VA)- or venovenous (VV)-ECMO support between July 2016 and September 2021. We used analysis of variance and Fisher exact tests to identify factors associated with PC consultation. Of 256, 177 patients (69.1%) received VA-ECMO support and 79 (30.9%) received VV-ECMO support. Overall, 115 patients (44.9%) received PC consultation while on ECMO. Patients receiving PC consultation were more likely to be non-white (47% vs. 53%, p = 0.016), have an attending physician from a medical versus surgical specialty (65.3% vs. 39.6%), have VV-ECMO (77.2% vs. 30.5%, p < 0.001), and have longer ECMO duration (6.2 vs. 23.0, p < 0.001). Patients were seen by the PC team on an average of 7.6 times (range, 1-35), with those who died having significantly more visits (11.2 vs. 5.6, p < 0.001) despite the shorter hospital stay. The average time from cannulation to the first PC visit was 5.3 ± 5 days. Congestive heart failure in VA-ECMO, coronavirus disease 2019 infection in VV-ECMO, and non-white race and longer ECMO duration for all patients were associated with PC consultation. We found that despite the benefits of PC, it is underused in this population.

Extracorporeal membrane oxygenation in adults receiving haematopoietic cell transplantation: an international expert statement.

Combined advances in haematopoietic cell transplantation (HCT) and intensive care management have improved the survival of patients with haematological malignancies admitted to the intensive care unit. In cases of refractory respiratory failure or refractory cardiac failure, these advances have led to a renewed interest in advanced life support therapies, such as extracorporeal membrane oxygenation (ECMO), previously considered inappropriate for these patients due to their poor prognosis. Given the scarcity of evidence-based guidelines on the use of ECMO in patients receiving HCT and the need to provide equitable and sustainable access to ECMO, the European Society of Intensive Care Medicine, the Extracorporeal Life Support Organization, and the International ECMO Network aimed to develop an expert consensus statement on the use of ECMO in adult patients receiving HCT. A steering committee with expertise in ECMO and HCT searched the literature for relevant articles on ECMO, HCT, and immune effector cell therapy, and developed opinion statements through discussions following a Quaker-based consensus approach. An international panel of experts was convened to vote on these expert opinion statements following the Research and Development/University of California, Los Angeles Appropriateness Method. The Appraisal of Guidelines for Research and Evaluation statement was followed to prepare this Position Paper. 36 statements were drafted by the steering committee, 33 of which reached strong agreement after the first voting round. The remaining three statements were discussed by all members of the steering committee and expert panel, and rephrased before an additional round of voting. At the conclusion of the process, 33 statements received strong agreement and three weak agreement. This Position Paper could help to guide intensivists and haematologists during the difficult decision-making process regarding ECMO candidacy in adult patients receiving HCT. The statements could also serve as a basis for future research focused on ECMO selection criteria and bedside management.

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.

Incidence and Outcomes of Respiratory Failure after Nonmyeloablative Related Haploidentical Blood or Marrow Transplantation.

Respiratory failure is a devastating complication of allogenic blood or marrow transplantation (BMT). Prior data suggest that respiratory failure occurs in 20% of BMT recipients and acute respiratory distress syndrome (ARDS) occurs in 15%. Nonmyeloablative (NMA) haploidentical BMT allows donor pool expansion and may decrease complications. Incidence, outcomes, and risk factors for respiratory failure after NMA haploidentical BMT are unknown. This study aimed to determine the incidence of respiratory failure after NMA haploidentical BMT and explore outcomes and risk factors for respiratory failure. In this single-center, retrospective study of all patients age >18 years undergoing NMA haploidentical BMT between 2004 and 2016, the primary outcome was respiratory failure, marked by the use of high-flow nasal cannula oxygen, noninvasive ventilation (NIV), or invasive mechanical ventilation (IMV) within 2 years after BMT. Respiratory failure incidence is reported as incidence rate ratio (IRR) with 95% confidence interval (CI). Unadjusted and multivariable Cox proportional hazards models with adjustment for a priori identified patient-level characteristics were used. Results are presented as hazard ratio (HR) with 95% CI. A total of 520 patients underwent NMA haploidentical BMT, of whom 82 (15.8%) developed respiratory failure (IRR, 0.114/person-year) at a median of 0.34 year (interquartile range, 0.06 to 0.75 year) after BMT. Older age (HR, 1.04; 95% CI, 1.02 to 1.07), transplantation for myelodysplastic syndrome (MDS) (HR, 1.99; 95% CI, 1.07 to 3.72), and parent donor (HR, 3.49; 95% CI, 1.32 to 9.26) were associated with an increased risk of respiratory failure, whereas higher pretransplantation lung diffusion capacity of carbon monoxide (DLCO; % of predicted) was associated with lower risk (HR, 0.98; 95% CI, 0.77 to 0.99). Sixty-one patients (11.7%) required IMV, and 30 were successfully extubated. Only 37 patients (7%) had ARDS. Of the 82 patients with respiratory failure, 43 (52.4%) died during index hospitalization and 61 (77.2%) died by 2 years post-transplantation. Only 40 (49%) had nonrelapse mortality. The incidence of respiratory failure and ARDS after NMA haploidentical BMT is modest at 15% by 2 years post-transplantation. Despite successful extubation in >50% of patients, respiratory failure, regardless of cause, is associated with a high rate of death by 2 years from both relapse and nonrelapse causes. Age, BMT for MDS, parental donor, and pretransplantation DLCO are risk factors for respiratory failure.

Variation in Early Management Practices in Moderate-to-Severe ARDS in the United States: The Severe ARDS: Generating Evidence Study.

BACKGROUND: Although specific interventions previously demonstrated benefit in patients with ARDS, use of these interventions is inconsistent, and patient mortality remains high. The impact of variability in center management practices on ARDS mortality rates remains unknown. RESEARCH QUESTION: What is the impact of treatment variability on mortality in patients with moderate to severe ARDS in the United States? STUDY DESIGN AND METHODS: We conducted a multicenter, observational cohort study of mechanically ventilated adults with ARDS and Pao2 to Fio2 ratio of ≤ 150 with positive end-expiratory pressure of ≥ 5 cm H2O, who were admitted to 29 US centers between October 1, 2016, and April 30, 2017. The primary outcome was 28-day in-hospital mortality. Center variation in ventilator management, adjunctive therapy use, and mortality also were assessed. RESULTS: A total of 2,466 patients were enrolled. Median baseline Pao2 to Fio2 ratio was 105 (interquartile range, 78.0-129.0). In-hospital 28-day mortality was 40.7%. Initial adherence to lung protective ventilation (LPV; tidal volume, ≤ 6.5 mL/kg predicted body weight; plateau pressure, or when unavailable, peak inspiratory pressure, ≤ 30 mm H2O) was 31.4% and varied between centers (0%-65%), as did rates of adjunctive therapy use (27.1%-96.4%), methods used (neuromuscular blockade, prone positioning, systemic steroids, pulmonary vasodilators, and extracorporeal support), and mortality (16.7%-73.3%). Center standardized mortality ratios (SMRs), calculated using baseline patient-level characteristics to derive expected mortality rate, ranged from 0.33 to 1.98. Of the treatment-level factors explored, only center adherence to early LPV was correlated with SMR. INTERPRETATION: Substantial center-to-center variability exists in ARDS management, suggesting that further opportunities for improving ARDS outcomes exist. Early adherence to LPV was associated with lower center mortality and may be a surrogate for overall quality of care processes. Future collaboration is needed to identify additional treatment-level factors influencing center-level outcomes. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03021824; URL: www.clinicaltrials.gov.

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.

Critical Care Management of Toxicities Associated With Targeted Agents and Immunotherapies for Cancer.

OBJECTIVES: To describe the most common serious adverse effects and organ toxicities associated with emerging therapies for cancer that may necessitate admission to the ICU. DATA SOURCES AND STUDY SELECTION: PubMed and Medline search of relevant articles in English on the management of adverse effects of immunotherapy for cancer. DATA EXTRACTION AND DATA SYNTHESIS: Targeted therapies including tyrosine kinase inhibitors, monoclonal antibodies, checkpoint inhibitors, and immune effector cell therapy have improved the outcome and quality of life of patients with cancer. However, severe and life-threatening side effects can occur. These toxicities include infusion or hypersensitivity reactions, cytokine release syndrome, pulmonary, cardiac, renal, hepatic, and neurologic toxicities, hemophagocytic lymphohistiocytosis, opportunistic infections, and endocrinopathies. Cytokine release syndrome is the most common serious toxicity after administration of monoclonal antibodies and immune effector cell therapies. Most of the adverse events from immunotherapy results from an exaggerated T-cell response directed against normal tissue, resulting in the generation of high levels of proinflammatory cytokines. Toxicities from targeted therapies are usually secondary to "on target toxicities." Management is largely supportive and may include discontinuation of the specific agent, corticosteroids, and other immune suppressing agents for severe (grade 3 or 4) immune-related adverse events like neurotoxicity and pneumonitis. CONCLUSIONS: The complexity of toxicities associated with modern targeted and immunotherapeutic agents for cancer require a multidisciplinary approach among ICU staff, oncologists, and organ specialists and adoption of standardized treatment protocols to ensure the best possible patient outcomes.

Management of the Critically Ill Adult Chimeric Antigen Receptor-T Cell Therapy Patient: A Critical Care Perspective.

OBJECTIVES: Chimeric antigen receptor T-cell therapy, a type of immune effector therapy for cancer, has demonstrated encouraging results in clinical trials for the treatment of patients with refractory hematologic malignancies. Nevertheless, there are toxicities specific to these treatments that, if not recognized and treated appropriately, can lead to multiple organ failure and death. This article is a comprehensive review of the available literature and provides, from a critical care perspective, recommendations by experienced intensivists in the care of critically ill adult chimeric antigen receptor T-cell patients. DATA SOURCES: PubMed and Medline search of articles published from 2006 to date. STUDY SELECTION: Clinical studies, reviews, or guidelines were selected and reviewed by the authors. DATA EXTRACTION: Not available. DATA SYNTHESIS: Not available. CONCLUSIONS: Until modifications in chimeric antigen receptor T-cell therapy decrease their toxicities, the intensivist will play a leading role in the management of critically ill chimeric antigen receptor T-cell patients. As this novel immunotherapeutic approach becomes widely available, all critical care clinicians need to be familiar with the recognition and management of complications associated with this treatment.

Imatinib Is Protective Against Ischemia-Reperfusion Injury in an Ex Vivo Rabbit Model of Lung Injury.

BACKGROUND: Ischemia-reperfusion injury is characterized by an increase in oxidative stress and leads to significant morbidity and death. The tyrosine kinase c-Abl is activated by oxidative stress and mediates processes that affect endothelial barrier function. We hypothesized treatment with the c-Abl inhibitor imatinib would be protective against ischemia-reperfusion injury in our ex vivo rabbit model. METHODS: Heart-lung blocs were harvested from rabbits and stored in cold in Perfadex (Vitrolife, Englewood, CO) for 18 hours. Blocs were reperfused for 2 hours in an ex vivo circuit with donor rabbit blood alone (untreated group, n = 7) or donor rabbit blood and 4 mg imatinib (treatment group, n = 10). Serial clinical variables measured every 15 minutes (arterial oxygen and carbon dioxide tension and mean pulmonary artery pressures) and biochemistry of tissue samples before and after reperfusion were assessed. RESULTS: Compared with untreated lungs, imatinib treatment improved physiologic parameters, including oxygen, carbon dioxide, and pulmonary artery pressures. Imatinib-treated lungs had less vascular barrier dysfunction as quantified by wet-to-dry weight ratios and bronchoalveolar lavage protein concentrations. Treated lungs showed less inflammation as measured by bronchoalveolar lavage myeloperoxidase assay, less mitochondrial reactive oxygen species production, and increased antioxidant catalase levels. Finally, imatinib protected lungs from DNA damage and p53 upregulation. CONCLUSIONS: Imatinib treatment significantly improved the physiologic performance of reperfused lungs and biochemical indicators associated with reperfusion injury in this ex vivo model. Further study is necessary to elucidate the mechanism of tyrosine kinase inhibition in lungs exposed to ischemia and reperfusion.

Red blood cell transfusion triggers in acute leukemia: a randomized pilot study.

BACKGROUND: Red blood cell (RBC) transfusion thresholds have yet to be examined in large randomized trials in hematologic malignancies. This pilot study in acute leukemia uses a restrictive compared to a liberal transfusion strategy. STUDY DESIGN AND METHODS: A randomized (2:1) study was conducted of restrictive (LOW) hemoglobin (Hb) trigger (7 g/dL) compared to higher (HIGH) Hb trigger (8 g/dL). The primary outcome was feasibility of conducting a larger trial. The four requirements for success required that more than 50% of the eligible patients could be consented, more than 75% of the patients randomized to the LOW arm tolerated the transfusion trigger, fewer than 15% of patients crossed over from the LOW arm to the HIGH arm, and no indication for the need to pause the study for safety concerns. Secondary outcomes included fatigue, bleeding, and RBCs and platelets transfused. RESULTS: Ninety patients were consented and randomly assigned to LOW to HIGH. The four criteria for the primary objective of feasibility were met. When the number of units transfused was compared, adjusting for baseline Hb, the LOW arm was transfused on average 8.0 (95% confidence interval [CI], 6.9-9.1) units/patient while the HIGH arm received 11.7 (95% CI, 10.1-13.2) units (p = 0.0003). There was no significant difference in bleeding events or neutropenic fevers between study arms. CONCLUSION: This study establishes feasibility for trial of Hb thresholds in leukemia through demonstration of success in all primary outcome metrics and a favorable safety profile. This population requires further study to evaluate the equivalence of liberal and restrictive transfusion thresholds in this unique clinical setting.

A curious case of acute respiratory distress syndrome.

Gestational acute respiratory distress syndrome (ARDS) is a complicated problem with the potential to gravely harm both mother and fetus. This case report describes a young woman in her second trimester of pregnancy who developed progressive respiratory failure in the setting of newly diagnosed influenza, diffuse alveolar hemorrhage and lymphangioleiomyomatosis. The patient's condition was refractory to conventional interventions and required extracorporeal membrane oxygenation (ECMO) support. Her course was further complicated by preeclampsia requiring preterm delivery with cesarean section while on ECMO. Through novel therapies and a multidisciplinary approach to care, both the patient and her child would overcome these unique and challenging conditions and survive.

Postoperative Critical Care of the Adult Cardiac Surgical Patient: Part II: Procedure-Specific Considerations, Management of Complications, and Quality Improvement.

OBJECTIVES: The armamentarium of cardiac surgery continues to expand, and the cardiac intensivist must be familiar with a broad spectrum of procedures and their specific management concerns. In the conclusion of this two-part review, we will review procedure-specific concerns after cardiac surgery and the management of common complications. We also discuss performance improvement and outcome assurance. DATA SOURCE AND SYNTHESIS: Narrative review of relative English language peer-reviewed medical literature. CONCLUSIONS: Knowledge of procedure-specific sequelae informs anticipation and prevention of many complications after cardiac surgery. Most complications after cardiac surgery fall into a limited number of categories. Familiarity with common complications combined with a structured approach to management facilitates response to even the most complicated postoperative situations. Standardized care and constant self-examination are essential for programmatic improvement and consistent high-quality care.

Postoperative Critical Care of the Adult Cardiac Surgical Patient. Part I: Routine Postoperative Care.

OBJECTIVES: Cardiac surgery, including coronary artery bypass, cardiac valve, and aortic procedures, is among the most common surgical procedures performed in the United States. Successful outcomes after cardiac surgery depend on optimum postoperative critical care. The cardiac intensivist must have a comprehensive understanding of cardiopulmonary physiology and the sequelae of cardiopulmonary bypass. In this concise review, targeted at intensivists and surgeons, we discuss the routine management of the postoperative cardiac surgical patient. DATA SOURCE AND SYNTHESIS: Narrative review of relevant English-language peer-reviewed medical literature. CONCLUSIONS: Critical care of the cardiac surgical patient is a complex and dynamic endeavor. Adequate fluid resuscitation, appropriate inotropic support, attention to rewarming, and ventilator management are key components. Patient safety is enhanced by experienced personnel, a structured handover between the operating room and ICU teams, and appropriate transfusion strategies.

Protein kinase G increases antioxidant function in lung microvascular endothelial cells by inhibiting the c-Abl tyrosine kinase.

Oxidant injury contributes to acute lung injury (ALI). We previously reported that activation of protein kinase GI (PKGI) posttranscriptionally increased the key antioxidant enzymes catalase and glutathione peroxidase 1 (Gpx-1) and attenuated oxidant-induced cytotoxicity in mouse lung microvascular endothelial cells (MLMVEC). The present studies tested the hypothesis that the antioxidant effect of PKGI is mediated via inhibition of the c-Abl tyrosine kinase. We found that activation of PKGI with the cGMP analog 8pCPT-cGMP inhibited c-Abl activity and decreased c-Abl expression in wild-type but not PKGI(-/-) MLMVEC. Treatment of wild-type MLMVEC with atrial natriuretic peptide also inhibited c-Abl activation. Moreover, treatment of MLMVEC with the c-Abl inhibitor imatinib increased catalase and GPx-1 protein in a posttranscriptional fashion. In imatinib-treated MLMVEC, there was no additional effect of 8pCPT-cGMP on catalase or GPx-1. The imatinib-induced increase in antioxidant proteins was associated with an increase in extracellular H2O2 scavenging by MLMVEC, attenuation of oxidant-induced endothelial barrier dysfunction, and prevention of oxidant-induced endothelial cell death. Finally, in the isolated perfused lung, imatinib prevented oxidant-induced endothelial toxicity. We conclude that cGMP, through activation of PKGI, inhibits c-Abl, leading to increased key antioxidant enzymes and resistance to lung endothelial oxidant injury. Inhibition of c-Abl by active PKGI may be the downstream mechanism underlying PKGI-mediated antioxidant signaling. Tyrosine kinase inhibitors may represent a novel therapeutic approach in oxidant-induced ALI.

CD36 and Fyn kinase mediate malaria-induced lung endothelial barrier dysfunction in mice infected with Plasmodium berghei.

Severe malaria can trigger acute lung injury characterized by pulmonary edema resulting from increased endothelial permeability. However, the mechanism through which lung fluid conductance is altered during malaria remains unclear. To define the role that the scavenger receptor CD36 may play in mediating this response, C57BL/6J (WT) and CD36-/- mice were infected with P. berghei ANKA and monitored for changes in pulmonary endothelial barrier function employing an isolated perfused lung system. WT lungs demonstrated a >10-fold increase in two measures of paracellular fluid conductance and a decrease in the albumin reflection coefficient (σalb) compared to control lungs indicating a loss of barrier function. In contrast, malaria-infected CD36-/- mice had near normal fluid conductance but a similar reduction in σalb. In WT mice, lung sequestered iRBCs demonstrated production of reactive oxygen species (ROS). To determine whether knockout of CD36 could protect against ROS-induced endothelial barrier dysfunction, mouse lung microvascular endothelial monolayers (MLMVEC) from WT and CD36-/- mice were exposed to H2O2. Unlike WT monolayers, which showed dose-dependent decreases in transendothelial electrical resistance (TER) from H2O2 indicating loss of barrier function, CD36-/- MLMVEC demonstrated dose-dependent increases in TER. The differences between responses in WT and CD36-/- endothelial cells correlated with important differences in the intracellular compartmentalization of the CD36-associated Fyn kinase. Malaria infection increased total lung Fyn levels in CD36-/- lungs compared to WT, but this increase was due to elevated production of the inactive form of Fyn further suggesting a dysregulation of Fyn-mediated signaling. The importance of Fyn in CD36-dependent endothelial signaling was confirmed using in vitro Fyn knockdown as well as Fyn-/- mice, which were also protected from H2O2- and malaria-induced lung endothelial leak, respectively. Our results demonstrate that CD36 and Fyn kinase are critical mediators of the increased lung endothelial fluid conductance caused by malaria infection.

Lung injury and acute respiratory distress syndrome after cardiac surgery.

As many as 20% of patients undergoing cardiac surgery will have acute respiratory distress syndrome during the perioperative period, with a mortality as high as 80%. If patients at risk can be identified, preventative measures can be taken and may improve outcomes. Care for patients with acute respiratory distress syndrome is supportive, with low tidal volume ventilation being the mainstay of therapy. Careful fluid management, minimization of blood product transfusion, appropriate nutrition, and early physical rehabilitation may improve outcomes. In cases of refractory hypoxemia, rescue therapies such as recruitment maneuvers, high-frequency oscillatory ventilation, and extracorporeal membrane oxygenation may preserve life.