ICU-level Care Research Articles

Development and validation of a predictive scoring model for complications following endoscopic endonasal skull base surgery.

The endoscopic endonasal approach (EEA) has evolved into an established technique in skull base surgery. The authors previously examined 1002 EEA procedures and reported factors associated with postoperative complications. Here they report the development and validation of a scoring model based on risk factors to better predict complications following EEA. The authors developed an optimized EEA scoring model for predicting postoperative complications as evidenced by the area under the receiver operating characteristic (AUROC) curve using their previously published data in addition to data collected from the subsequent 292 EEA procedures from years 2010-2020. The model was built systematically by evaluating the contributions that different variables had on the overall predictive ability of the model. The aim was to design a model containing as few variables as possible for practicality and to facilitate calculation and use at the bedside. The Clavien-Dindo grading system was used to classify complications into grades I-V based on the level of intervention that was required to manage the complication, with grades III-V considered to be higher-grade (i.e., those requiring reoperation or ICU-level care or death). The authors identified 1294 EEA operations performed between July 2010 and July 2020 that met their inclusion criteria. Higher-grade complications were identified following 135 EEA operations. The variables that were ultimately included in the model were age, BMI, operative time, meningioma, chordoma, expanded intradural approach, and nasoseptal flap use. The final model yielded an acceptable AUROC curve of 0.72 and predicted a stepwise increase in the rate of higher-grade complications as the score increased. A score of 0-2 (low) on the grading system was associated with an average complication rate of 5.1%. A score of 3-5 (medium) was associated with an average complication rate of 12.6%. A score of 6 or above (high) was associated with an average complication rate of 26%. This EEA complications scoring model accurately categorizes patients into low-, medium-, and high-risk groups with readily obtained variables. A high score in this complications model does not suggest that a patient is ineligible for surgery, but rather highlights the importance of thorough case selection, operating with caution, and appropriate preoperative counseling.

Longitudinal Assessment of Nasopharyngeal Biomarkers Post-COVID-19: Unveiling Persistent Markers and Severity Correlations.

SARS-CoV-19 infection provokes a variety of symptoms; most patients present mild/moderate symptoms, whereas a small proportion of patients progress to severe illness with multiorgan failure accompanied by metabolic disturbances requiring ICU-level care. Given the importance of the disease, researchers focused on identifying severity-associated biomarkers in infected patients as well as markers associated with patients suffering long-COVID. However, little is known about the presence of biomarkers that remain a few years after SARS-CoV-2 infection once the patients fully recover of the symptoms. In this study, we evaluated the presence of persistent biomarkers in the nasopharyngeal tract two years after SARS-Cov-2 infection in fully asymptomatic patients, taking into account the severity of their infection (mild/moderate and severe infections). In addition to the direct identification of several components of the Coronavirus Infection Pathway in those individuals that suffered severe infections, we describe herein 371 proteins and their associated canonical pathways that define the different adverse effects of SARS-CoV-2 infections. The persistence of these biomarkers for up to two years after infection, along with their ability to distinguish the severity of the infection endured, highlights the surprising presence of persistent nasopharyngeal exudate changes in fully recovered patients.

Importance of risk adjusting central line-associated bloodstream infection rates in children.

Central line-associated bloodstream infection (CLABSI) is one of the most prevalent pediatric healthcare-associated infections and is used to benchmark hospital performance. Pediatric patients have increased in acuity and complexity over time. Existing approaches to risk adjustment do not control for individual patient characteristics, which are strong predictors of CLABSI risk and vary over time. Our objective was to develop a risk adjustment model for CLABSI in hospitalized children and compare observed to expected rates over time. We conducted a prospective cohort study using electronic health record data at a quaternary Children's Hospital. We included hospitalized children with central catheters. Risk factors identified from published literature were considered for inclusion in multivariable modeling based on association with CLABSI risk in bivariable analysis and expert input. We calculated observed and expected (risk model-adjusted) annual CLABSI rates. Among 16,411 patients with 520,209 line days, 633 patients experienced 796 CLABSIs. The final model included age, behavioral health condition, non-English speaking, oncology service, port catheter type, catheter dwell time, lymphatic condition, total parenteral nutrition, and number of organ systems requiring ICU level care. For every organ system receiving ICU level care the odds ratio for CLABSI was 1.24 (95% CI 1.12-1.37). Although not statistically different, observed rates were lower than expected rates for later years. Failure to adjust for patient factors, particularly acuity and complexity of disease, may miss clinically significant differences in CLABSI rates, and may lead to inaccurate interpretation of the impact of quality improvement efforts.

Healthcare utilization disparities among children with high-risk neuroblastoma treated on Children's Oncology Group clinical trials.

Disparities in relapse and survival from high-risk neuroblastoma (HRNBL) persist among children from historically marginalized groups even in highly standardized clinical trial settings. Research in other cancers has identified differential treatment toxicity as one potential underlying mechanism. Whether racial and ethnic disparities in treatment-associated toxicity exist in HRNBL is poorly understood. This is a retrospective study utilizing a previously assembled merged cohort of children with HRNBL on Children's Oncology Group (COG) post-consolidation immunotherapy trials ANBL0032 and ANBL0931 at Pediatric Health Information System (PHIS) centers from 2005 to 2014. Race and ethnicity were categorized to reflect historically marginalized populations as Hispanic, non-Hispanic Black (NHB), non-Hispanic other (NHO), and non-Hispanic White (NHW). Associations between race-ethnicity and intensive care unit (ICU)-level care utilization as a proxy for treatment-associated toxicity were examined with log binomial regression and summarized as risk ratio (RR) and corresponding 95% confidence interval (CI). The analytic cohort included 370 children. Overall, 88 (23.8%) patients required ICU-level care for a median of 3.0days (interquartile range [IQR]: 1.0-6.5days). Hispanic children had nearly three times the risk of ICU-level care (RR 3.1, 95% CI: 2.1-4.5; fully adjusted RR [aRR] 2.5, 95% CI: 1.6-3.7) compared to NHW children and the highest percentage of children requiring cardiovascular-driven ICU-level care. Children of Hispanic ethnicity with HRNBL receiving clinical trial-delivered therapy were more likely to experience ICU-level care compared to NHW children. These data suggest that further investigation of treatment-related toxicity as a modifiable mechanism underlying outcome disparities is warranted.

Length of Stay, Readmission Rates, and Mortality Are Similar Between Hospitalized Individuals With Sickle Cell Disease With and Without COVID-19.

Background We sought to clarify the impact of COVID-19 on clinical outcomes in sickle cell disease patients, given their baseline hypercoagulable state in combination with COVID-19-related coagulopathies and other complications. Methods Retrospective chart review of two groups of sickle cell disease patients hospitalized between March 2020 to December 2021: Group 1 did not have COVID-19 (n = 95) and Group 2 did (n = 73). Results Groups 1 and 2 were similar in terms of age, race, sex, comorbid illnesses, genotype, hydroxyurea use, and opioid use. Group 1 and 2 patients had a mean hospital length of stay of 7.05 and 7.64 days, respectively (p = 0.981). ICU-level care was required for six (6.3%) Group 1 patients and four (5.5%) Group 2 patients (p = 1.000). Readmissions within 30 days occurred for 25 (26.3%) Group 1 patients, and 18 (24.7%) Group 2 patients (p = 0.807). Death occurred for one (1.05%) Group 1 patient and one (1.4%) Group 2 patient (p = 1.000). There were no significant differences in commonly ordered initial laboratory values (total bilirubin, hemoglobin, hematocrit, creatinine, lactate dehydrogenase, and D-dimer) between Group 1 and Group 2 patients. Conclusions We observed no significant differences in clinical outcomes among sickle cell disease patients hospitalized due to COVID-19 compared to those without COVID-19.

Surgical stabilization of rib fractures in the geriatric trauma population is associated with equivalent outcomes to a younger cohort: A propensity matched analysis

BackgroundSurgical stabilization of rib fractures (SSRF) improves outcomes in chest wall trauma. Geriatric patients are particularly vulnerable to poor outcomes; yet, this population is often excluded from SSRF studies. Further delineating patient outcomes by age is necessary to optimize care for the aging trauma population. MethodsA retrospective cohort study was conducted examining outcomes among patients aged 40+ for whom an SSRF consult was placed between 2017 and 2022 at a level 1 trauma center. Patients were categorized into geriatric (65+) and adult (40–64), as well as 80 years and older (80+) and 79 and younger (40–79). Patient outcomes were assessed comparing non-operative and operative management of chest wall trauma. Propensity matched analysis was performed to evaluate mortality differences between adult and geriatric patients who did and did not undergo SSRF. ResultsA total of 543 patients had an SSRF consult. Of these, 227 were 65+, and 73 were 80+. A total of 129 patients underwent SSRF (24 %). The percentage of patients undergoing SSRF did not vary between 40 and 64 and 65+ (23.7 % and 23.6 %, respectively, p = 0.97) or 40–79 and 80+ (24.0 vs 21.9, p = 0.69). Patients undergoing SSRF had higher chest injury burden and were more likely to require mechanical ventilation and ICU level care on admission. Overall, in-hospital mortality rate was 4.6 %. Among patients who underwent SSRF, mortality rate did not significantly differ between 65+ and 40–64 (7.8% vs 2.7 %, p = 0.18) or 80+ and 40–79 (6.3% vs 4.6 %, p = 0.77). This remained true in propensity matched analysis. ConclusionGeriatric and octogenarian patients with rib fractures underwent SSRF at similar rates and achieved equivalent outcomes to their younger counterparts. SSRF did not differentially affect mortality outcomes based on age group in propensity matched analysis. SSRF is safe for geriatric patients including octogenarians.

Household income and health-related quality of life in children receiving treatment for acute myeloid leukemia: Potential impact of selection bias in health equity research.

Examine the influence of household income on health-related quality of life (HRQOL) among children with newly diagnosed acute myeloid leukemia (AML). Secondary analysis of data prospectively collected from pediatric patients receiving treatment for AML at 14 hospitals across the United States. Household income was self-reported on a demographic survey. The examined mediators included the acuity of presentation and treatment toxicity. Caregiver proxy reported assessment of patient HRQOL from the Peds QL 4.0 survey. Children with AML (n = 131) and caregivers were prospectively enrolled to complete PedsQL assessments. HRQOL scores were better for patients in the lowest versus highest income category (mean ± SD: 76.0 ± 14 household income <$25,000 vs. 59.9 ± 17 income ≥$75,000; adjusted mean difference: 11.2, 95% CI: 2.2-20.2). Seven percent of enrolled patients presented with high acuity (ICU-level care in the first 72 h), and 16% had high toxicity (any ICU-level care); there were no identifiable differences by income, refuting mediating roles in the association between income and HRQOL. Enrolled patients were less likely to be Black/African American (9.9% vs. 22.2%), more likely to be privately insured (50.4% vs. 40.7%), and more likely to have been treated on a clinical trial (26.7% vs. 18.5%) compared to eligible unenrolled patients not enrolled. Evaluations of potential selection bias on the association between income and HRQOL suggested differences in HRQOL may be smaller than observed or even in the opposing direction. While primary analyses suggested lower household income was associated with superior HRQOL, differential participation may have biased these results. Future studies should partner with patients/families to identify strategies for equitable participation in clinical research.

Is Everyone Beating Around the Bush?: A Qualitative Study Examining the Status of Shared Decision-Making Between Veterans Affairs Providers and Surgical Patients in the ICU.

We sought to determine if and how providers use elements of shared decision-making (SDM) in the care of surgical patients in the intensive care unit (ICU). SDM is the gold standard for decision-making in the ICU. However, it is unknown if this communication style is used in caring for critically ill surgical patients. Qualitative interviews were conducted with providers who provide ICU-level care to surgical patients in Veterans Affairs hospitals. Interviews were designed to examine end-of-life care among veterans who have undergone surgery and require ICU-level care. Forty-eight providers across 14 Veterans Affairs hospitals were interviewed. These participants were diverse with respect to age, race, and sex. Participant dialogue was deductively mapped into 8 established SDM components: describing treatment options; determining roles in the decision-making process; fostering partnerships; health care professional preferences; learning about the patient; patient preferences; supporting the decision-making process; and tailoring the information. Within these components, participants shared preferred tools and tactics used to satisfy a given SDM component. Participants also noted numerous barriers to achieving SDM among surgical patients. Providers use elements of SDM when caring for critically ill surgical patients. Additionally, this work identifies facilitators that can be leveraged and barriers that can be addressed to facilitate better communication and decision-making through SDM. These findings are of value for future interventions that seek to enhance SDM among surgical patients both in the ICU and in other settings.

Aligning patient values and code status: Choice of Diction's Effect (CODE) study.

Decisions regarding resuscitation after cardiac arrest are critical from ethical, patient satisfaction, outcome, and healthcare cost standpoints. Physician-reported discussion barriers include topic discomfort, fear of time commitment, and difficulty articulating end-of-life concepts. The influence of language used in these discussions has not been tested. This study explored whether utilizing the alternate term "allow (a) natural death" changed code status decisions in hospitalized patients versus "do not resuscitate" (DNR). All patients age 65 and over admitted to a general medicine hospital teaching service were screened (English-speaking, not ICU-level care, no active psychiatric illness, no substance misuse, no active DNR). Participants were randomized to resuscitation discussions with either DNR or "allow natural death" as the "no code" phrasing. Outcomes included patient resuscitation decision, satisfaction with and duration of the conversation, and decision correlation with illness severity and predicted resuscitation success. 102 participants were randomized to the "allow natural death" (N = 49) or DNR (N = 53) arms. The overall "no code" rate for our sample of hospitalized general medicine inpatients age >65 was 16.7%, with 13% in the DNR and 20.4% in the "allow natural death" arms (p = 0.35). Discussion length was similar in the DNR and "allow natural death" arms (3.9 + 3.2 vs. 4.9 + 3.9 minutes), and not significantly different (p = 0.53). Over 90% of participants were highly satisfied with their code status decision, without difference between arms (p = 0.49). Participants' code status discussions did not differ in "no code" rate between "allow natural death" and DNR arms but were short in length and had high patient satisfaction. Previously reported code status discussion barriers were not encountered. It is appropriate to screen code status in all hospitalized patients regardless of phrasing used.

Association Between High Sensitivity Troponin Levels Following Pediatric Orthotopic Heart Transplantation and Intensive Care Unit Resource Utilization.

The utility of troponin levels, including high sensitivity troponin T (hs-TnT), after orthotopic heart transplant (OHT) is controversial. Conflicting data exist regarding its use as a marker of acute rejection. Few studies have examined possible associations of hs-TnT levels immediately after OHT with metrics of intensive care unit (ICU) resource utilization or risk of acute rejection. We performed a retrospective cohort chart review including all OHT recipients < 20years of age at our center between June 2019 and December 2022. Patients were divided into two groups based on supra- or sub-median initial hs-TnT levels (median 3462.5ng/L). Primary outcome was days requiring ICU-level care, secondary outcomes included days intubated, days requiring positive pressure ventilation (PPV), days on inotropic medications, actual ICU length of stay, Vasoactive Inotrope Scores (VIS) on postoperative days (POD) 0 through 7, and acute rejection at 30days and one year after OHT. Patients with higher hs-TnT required ICU level care for longer [13.5 (10-17.5) vs. 9.5 (8-12) days, p = 0.01] and spent more days intubated [6 (4-7) vs. 3 (3-5) days, p < 0.001], on PPV [9 (6-15) vs. 6 (5-8.5) days, p = 0.02], and on inotropes [11 (9-14) vs. 8 (7-11) days, p = 0.025]. VIS was only different between groups on POD7 [5 (3-7) vs. 3 (0-5), p = 0.04]. There was no difference in rejection between the groups. Higher hs-TnT immediately following pediatric OHT may predict higher ICU resource utilization, despite no difference in VIS, although it does not predict acute rejection in the first year after OHT.

UNIQUE MONOCYTE EXPRESSION SIGNATURE IN A STXBP2 MUTATION CAUSING INFANTILE ONSET VEO-IBD AND HLH

Abstract Mutations in syntaxin-binding-protein-2 (STXBP2) can result in NK cell dysfunction leading to a hyperinflammatory state including familial HLH and infantile onset inflammatory bowel disease (IBD). While the function of STXBP2 in NK cells and cytotoxic T cells has been well described, it is highly expressed in monocytes with unclear relevance. We report the case of an infant who presented with severe infantile onset diarrhea with an identified pathogenic mutation in STXBP2. We sought to utilize scRNA-Seq to study the impact of STXBP2 deficiency on monocyte transcription, with the goal of generating insight into the pathogenesis of disease. METHODS: Trio whole exome sequencing was performed. PBMCs were collected from the described patient (case), and two control groups: 3 patients with VEO-IBD, and 3 age matched healthy controls. Single cell RNA-Seq was performed using the 10x platform and data analysis was done using Seurat in R. RESULTS: A male infant presented at 1 week of age with diarrhea and metabolic acidosis. Endoscopic evaluation at 4 weeks of age showed histologic findings of colitis and marked epithelial cell changes, including cell rounding. WES identified a homozygous pathogenic mutation in STXBP2. Due to significant risk of HLH, he underwent evaluation for stem cell transplant. However, in the interim he developed severe HLH requiring ICU level care. He recovered following aggressive treatment and underwent HSCT at 4 months of age and retransplant for graft failure at 11 months of age. He is currently in endoscopic remission off therapy. We analyzed PBMCs from the case patient using single cell RNA-Seq, as compared to patients with VEO-IBD and age-matched controls. STXBP2 expression was most enriched in monocyte populations and reduced in the case patient compared to controls. 231 and 187 genes were differentially expressed in the case monocytes as compared to both controls. The case patient had a paucity of non-classical monocytes. Within the classical monocytes, differentially expressed genes showed enrichment of host defense, cytokine processes, and apoptotic processes. Within the intermediate monocytes, differentially expressed genes showed enrichment of chemotaxis pathways, antigen presentation and T cell activation processes. CONCLUSIONS: Mutations in STXBP2 are a life-threatening cause of fHLH and infantile onset IBD. We report a case of infantile onset IBD due to a homozygous mutation in STXBP2 with resolution of disease post HSCT. Transcriptional analysis of PBMCs from this patient reveals a paucity of non-classical monocytes in the peripheral blood, and differential regulation of genes implicated in host defenses, antigen presentation, chemotaxis and apoptosis. These results may suggest the role of monocyte function in pathogenesis of STXBP2 and in other forms of IBD.

Demographics, medication use, and admission characteristics of patients hospitalized with diabetes in Ontario, Canada: A retrospective cohort study.

In Canada, one in seven adults has diabetes (i.e., 2.3 million) and the lifetime risk of developing diabetes is approximately 30% by age 65. Although 30% of patients admitted to the hospital have diabetes, data from inpatient hospitalizations for patients with diabetes are lacking, both in Canada and globally. To validate International Classification of Diseases 10th edition Canadian version (ICD-10-CA) codes for the identification of patients with diabetes, to create a multicenter database of patients with diabetes hospitalized under internal medicine in Ontario, and to determine their baseline characteristics, medication use, and admission characteristics. We created a database of people who had diabetes and were hospitalized between 2010 and 2020 at 8 hospitals in Ontario that were part of the General Medicine Inpatient Initiative (GEMINI) hospital data-sharing network. Patients who had diabetes were identified using chart review, based upon either (i) a previous physician diagnosis of diabetes, (ii) a recorded hemoglobin A1c ≥ 6.5% or (iii) outpatient prescription of a diabetes medication preceding the hospitalization. The test characteristics of ICD-10-CA codes for diabetes were evaluated. We compared baseline demographics, medication use and hospitalization details among patients with and without diabetes. For hospitalization details, we collected information on the admission diagnosis, comorbidity index, length of stay, receipt of ICU-level care, and inpatient mortality. There were 384,588 admissions within the total study cohort, of which 118,987 (30.9%) had an ICD-10-CA diagnosis code of diabetes (E10.x, E11.x, E13.x, E14.x). The sensitivity and specificity of ICD-10-CA diagnostic codes was 95.9% and 98.8%, respectively. Most patients with an ICD-10-CA code for diabetes had a code for type 2 diabetes (93.9%) and a code for type 1 diabetes was rare (6.1%). The mean age was 66.4 years for patients without diabetes and 71.3 years for those with an ICD-10-CA diagnosis code for diabetes. Patients with diabetes had a higher prevalence of hypertension (64% vs. 37.9%), coronary artery disease (28.7% vs. 15.3%), heart failure (24.5% vs. 12.1%) and renal failure (33.8% vs. 17.3%) in comparison to those without diabetes. The most prevalent diabetes medications received in hospital were metformin (43%), DPP4 inhibitors (22.7%) and sulfonylureas (18.8%). The most common reason for admission among patients with diabetes was heart failure (9.0%), and among patients without diabetes was pneumonia (7.8%). Median length of stay was longer for patients with diabetes (5.5 vs. 4.5 days) and in-hospital mortality was similar between groups (6.8% with diabetes vs. 6.5% without diabetes). Diabetes is one of the most prevalent chronic medical conditions, affecting roughly one third of all patients hospitalized on an internal medicine ward and is associated with other comorbidities and longer hospital stays. ICD-10-CA codes were highly accurate in identifying patients with diabetes. The development of an inpatient cohort will allow for further study of in-hospital practices and outcomes among patients with diabetes.

Electroconvulsive therapy for catatonia in anti-NMDA receptor encephalitis: A case series

BackgroundAnti-NMDAR encephalitis is the most common cause of immune-mediated catatonia. Case seriesThree females presented with neuropsychiatric symptoms and were empirically treated with first-line immunotherapy and ovarian teratoma resection for suspected autoimmune encephalitis, preceding diagnostic confirmation via NMDAR antibody positivity. They required escalating large doses of benzodiazepines for refractory malignant catatonia resulting in ICU level care. ECT treatments were initiated, and patients were gradually noted to have clinical improvement as was measured by the Bush-Francis Catatonia Rating Scale. ConclusionsClinicians should recognize catatonia among patients with suspected anti-NMDAR encephalitis and consider the early implementation of ECT into treatment algorithms.

Patients hospitalized for Acute Decompensated Heart Failure with Diabetes Mellitus affected by Non-Alcoholic Fatty Liver Disease have Greater Risk of Mortality and Worse Clinical Outcomes

BackgroundDiabetes mellitus (DM) and Heart Failure (HF) are global diseases affecting millions worldwide. Non-Alcoholic Fatty Liver Disease (NAFLD) is a condition that predisposes to adverse outcomes. There is limited scientific evidence of clinical outcomes of NAFLD in patients with DM who were hospitalized for Acute Decompensated Heart Failure (ADHF). Hence, we sought to investigate this population. MethodsWe queried NIS between 2017-2020 for adult patients who were hospitalized with ADHF&DM and had NAFLD. The primary outcome was inpatient mortality. The secondary outcomes were cardiogenic shock, cardiac arrest, gastrointestinal bleeding (GIB), invasive mechanical ventilation, length of stay (LOS) and total hospital charge. Multivariable logistic and Poisson regression analyses were used to estimate clinical outcomes. P-value < 0.05 was significant. ResultsThere were 4,148,725 hospitalizations with ADHF&DM and 183,885 (4.4%) had NAFLD. NAFLD and non-NAFLD cohorts were with mean age of 67.8 vs. 70.5 yrs; males 56.6% vs 53%; Caucasians 63.7% vs 62.7%; systolic HF 58.4% vs 54.3%; diastolic HF 61% vs 64.8; STEMI 2.9% vs 1.3%, HTN 1.8% vs 2.2%; pulmonary hypertension (PH) 22.7% vs 19.3%; AF 44.6% vs 42.7%; AKI 57.9% vs 41.3%; DKA 1.8% vs 0.7%; obesity 68.6% vs 65.4%; anemia 24.6% vs 21.4%; history of MI 12.6% vs 16.2%; stroke 2.1% vs 1.5%, COPD 33.2% vs 37.1, respectively. NAFLD cohort had significantly higher mortality and worse clinical outcomes (Table 1). ConclusionADHF&DM cohort demonstrated significantly higher mortality, worse clinical outcomes, and resource utilization. They were younger, predominantly Caucasian males, with more frequent systolic HF, STEMI, PH, AF, AKI, DKA, obesity, stroke, and anemia. NAFLD is associated with cardiac and renal impairment, complications during hospitalization and the need for ICU-level care. Awareness of NALFD and its early identification is important to improve health outcomes. Further research is necessary to describe long-term outcomes in this population.

Iron and erythropoietin to heal and recover after intensive care (ITHRIVE): A pilot randomised clinical trial

ObjectiveTo determine the feasibility of a pivotal randomised clinical trial of intravenous (IV) iron and erythropoietin in adult survivors of critical illness with anaemia requiring treatment in the intensive care unit. DesignAn investigator-initiated, parallel group, placebo-controlled, randomised feasibility trial. SettingA tertiary intensive care unit (ICU) in Perth, Western Australia. ParticipantsAdults with anaemia (haemoglobin <100 g/L), requiring ICU-level care for more than 48 h, and likely to be ready for ICU discharge within 24 h. InterventionsA single dose of IV ferric carboxymaltose and Epoetin alfa (active group) or an equal volume of 0.9% saline (placebo group). Main outcome measuresStudy feasibility was considered met if the pilot achieved a recruitment rate of ≥2 participants per site per month, ≥90% of participants received their allocated study treatment, and≥ 90% of participants were followed up for the proposed pivotal trial primary outcome - days alive and at home to day 90 (DAH90). ResultsThe 40-participant planned sample size included twenty in each group and was enrolled between 1/9/2021 and 2/3/2022. Participants spent a median of 3.4 days (interquartile range 2.8–5.1) in the ICU prior to enrolment and had a mean baseline haemoglobin of 83.7 g/L (standard deviation 6.7). The recruitment rate was 6.7 participants per month [95% confidence interval (CI) 4.8–9.0], DAH90 follow-up was 100% (95% CI 91.2%–100%), and 39 (97.5%, 95% CI 86.8%–99.9%) participants received the allocated study intervention. No serious adverse events were reported. ConclusionThe iron and erythropoietin to heal and recover after intensive care (ITHRIVE) pilot demonstrated feasibility based on predefined participant recruitment, study drug administration, and follow-up thresholds.

Establishing Costs for Commercial Chimeric Antigen Receptor T-Cell (Tisagenlecleucel; Kymriah) in Children and Young Adult B-Cell Acute Lymphoblastic Leukemia; A Merged Analysis from the Prwcc and PHIS

Background: Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable efficacy in children and young adult (CAYA) B-cell acute lymphoblastic leukemia (B-ALL). Nonetheless, this therapy is highly personalized, technically complex, and costly to manufacture. The USA FDA approved the first CAR T cell therapy (Kymriah) in Aug 2017, for relapsed/refractory CAYA B-ALL. The list price of Kymriah is $475,000, not accounting for costs related to delivery of care, inpatient hospitalization, toxicity management or follow-up. A half-decade of clinical experience has amassed since commercialization, yet financial analyses remain sparse. Here, we conduct the first study to understand costs for commercial CAR in CAYA B-ALL. Methods: Ten centers participating in both the Pediatric Real-world CAR Consortium (PRWCC) and Pediatric Health Information System (PHIS; Children's Hospital Association, Lenexa, KS) were eligible for study (08/2017-03/2020). Clinical data from the PRWCC database was merged with PHIS using age, diagnosis, center and lymphodepletion dates. Utilizing center and year specific charge-to-cost ratio, PHIS provided data for inpatient admission associated costs, but not outpatient care. For patients that were infused outpatient and subsequently admitted, only inpatient cost was available and analyzed for the first 60 days post-infusion. For patients that were infused inpatient, cost was calculated from the first day of admission for lymphodepletion or Kymriah infusion to 60 days post-infusion. The 60-day follow up was chosen as most of the clinical activity and toxicities occur within the 60 days post-infusion. Each patient was assigned a cost of $475,000 for Kymriah (list price). For the subset of patients who underwent allogeneic hematopoietic cell transplantation (alloHCT) following Kymriah, the median inpatient cost was assessed for 1-year post-alloHCT. Cost data was analyzed as medians and ranges. Univariable and multivariable logistic regression models were used to identify factors associated with the higher median cost associated with inpatient admissions. Results: 109 Kymriah-recipients were included. Patient characteristics are listed in Table 1. The incidence of grade 1-2 and ≥3 CRS was 42% and 23%, respectively, and grade 1-2 and ≥3 ICANS was 17% and 6%, respectively. Relapse/refractory disease at day 30 and 60 post-Kymriah infusion was 11% and 16%, respectively. AlloHCT was performed in 17 (16%) patients. Median time to alloHCT from Kymriah infusion was 148 days (36-354). The median number of admissions was 1 (0-5) and median length of all hospitalization was 18 days (0-69), 99% patients required inpatient admission. Thirty-six patients (33%) required intensive care unit (ICU) admission with a median ICU stay of 5 days (1-24). The median total cost (Kymriah + inpatient cost) per patient was $615,845 ($475,000-1,578,321). Breakdown of median total cost (excluding Kymriah) was: room/board $33,676 ($0-454,256), pharmacy $65,854 ($0-515,132), laboratory/pathology cost $10,496 ($0-201,900) and other cost $8,204 ($0-573,163). One-year median cost associated with inpatient admissions for alloHCT was $556,712 ($105,670-1,919,275), combined median cost associated with Kymriah + alloHCT was $1,263,316 ($696,768-2,404,447). Factors associated with higher inpatient cost were public insurance ($96,287, p=0.002); inpatient Kymriah infusion ($395,182, p&amp;lt;0.001); CRS grade≥3 ($342,176, p&amp;lt;0.001); ICANS grade ≥3 ($354,013, p=0.010); ICU stay ($346,737 p&amp;lt;0.001). Multivariable analysis demonstrated that only inpatient infusion of Kymriah significantly associated with higher cost (Table 2). Conclusion: In this cost analysis across CAYA receiving Kymriah, we describe the total inpatient treatment-associated cost, with inpatient infusion emerging as a main driver of cost. With increased clinical experience, outpatient infusions and early interventions to avoid high-grade toxicity and ICU-level care have become more common and potentially more cost-effective. Our data justifies efforts to deliver Kymriah in the outpatient setting, when safe and feasible, and to provide support systems to facilitate this. Additionally, Kymriah drug cost accounts for the bulk (73%) of the overall median cost, highlighting that efforts to lower drug costs may permit enhanced access globally.

Toxicity Profile of Brexucabtagene Autoleucel (brexu-cel; CD19-directed CAR T-cell therapy) in Adult Patients (pts) with Relapsed/Refractory (R/R) B-Cell Acute Lymphoblastic Leukemia (B-ALL): Results from a Multicenter Real-World Outcomes Study

Introduction: In October 2021, the FDA approved brexu-cel for the treatment of adults ≥ 18 years old with R/R B-ALL. Following this approval, a consortium of cancer centers was formed across the US to investigate outcomes following commercial brexu-cel use for adults with R/R B-ALL. One area of interest is the toxicity profile of brexu-cel when given in the real-world context, including the respective incidences and severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS). Methods: Eligible pts included adults ≥ 18 years old who received commercial brexu-cel starting in October 2021 onward at a participating center in the US (N = 25). Retrospective patient data were collected across participating institutions, with the most recent data lock occurring on June 30, 2023. Criteria from the ASTCT were used to grade CRS and ICANS severity. Statistical methods included the use of medians and simple ratios for descriptive outcomes; univariate logistic regression models were used to assess the association of various factors with the probability of CRS and ICANS, and Cox regression was used to examine the association of each with the hazards of mortality and failure for event-free survival (EFS; earliest of progression, relapse, or death). Results: Key demographics and toxicities are described in Tables 1 and 2 (respectively). Of the 152 pts infused with brexu-cel, 82% (N = 125) developed CRS and 56% (N = 85) developed ICANS. CRS and ICANS did NOT develop in 12% (N = 19). Twenty percent of all pts (N = 31) required ICU-level care for management of CAR-related toxicities, with a median LOS in ICU of 4 days (range 1-79). In univariate models, grade 3+ ICANS was most likely to occur in pts with active disease (≥ 5% marrow blasts and/or EMD) at the time of apheresis (OR 2.63, 1.28-5.38, p = 0.008); a numerical increase for grade 3+ CRS (OR 2.35, 0.69-8, p = 0.17) was seen in pts with active disease at apheresis. Therapies received for these CAR-related toxicities included steroids, tocilizumab (toci), and anakinra (Table 2). Among pts who received steroids (N = 94), 37% (N = 34) achieved a sufficient response to the first steroid trial and did not require subsequent therapies; otherwise, toxicities improved with the first steroid course but later worsened in 16% (N = 15); the first trial of steroids was not effective but improved when further steroids were given in 31% (N = 29); there were no responses to any doses of steroids in 10% (N = 9). In pts receiving toci (N = 103), 31% (N = 32) achieved a sufficient response to the first dose and did not require any further therapy; toxicities improved with the first dose but later worsened in 31% (N = 32); the first dose was ineffective but improvement was seen with subsequent doses in 21% (N = 22); 9% (N = 9) did not respond at all to toci. The rate of death within day +28 was 6% (N = 9), and the respective causes were typically multifactorial: CRS was implicated in 3 cases, ICANS in 3, infection in 5, disease relapse/progression in 2, and HLH in 1 case. In total, uncontrolled ICANS was implicated in the death of 6 pts (between day +9 to day +106). HLH was reported in 6 pts: in most cases, this was a biochemical diagnosis, and it either overlapped with concurrent CRS or infection or occurred following CRS/ICANS. The most common infections between day 0 and day +28 included bacteremia in 8% of pts (N = 12), fungal infections in 4% (N = 6), pneumonia in 3% (N = 5), and CMV infections in 3% (N = 4). The fungal infections included 4 instances of invasive sinopulmonary infections (2 due to aspergillus; 2 due to mucormycosis) and 2 cases of candidemia. With both CRS and ICANS treated as a time-varying covariate, the development of grade 3+ CRS was associated with a higher hazard of death (HR 2.38, 1.00-5.66, p = 0.05); grade 3+ ICANS was not associated with a demonstrably higher risk of death (HR 1.11, 0.60-2.05, p = 0.74). The HR of EFS failure for Grade 3+ CRS was 1.81 (0.87-3.79, p = 0.12) and for grade 3+ ICANS HR = 0.93 (0.56-1.53, p = 0.77). Conclusions: In this real-world study of toxicities from brexu-cel use for adults with R/R B-ALL, we observed CRS and ICANS in the majority of pts, and no new safety signals were observed. Rates of severe CRS and ICANS were more common with active disease. Interestingly, though CRS-related mortality was rare, grade 3+ CRS was associated with a higher risk of death. Efforts to identify mechanisms and mitigable risk factors for these toxicities are warranted.

Association of Age with Acuity and Severity of Illness at Initial Presentation in Children, Adolescents, and Young Adults with Leukemia

Background: Adolescent and Young Adult (AYA) patients, historically defined by the National Cancer Institute as patients between 15-39 years, diagnosed with cancer are at risk for increased mortality compared with younger patients. Age 10 has been an alternate threshold for higher risk of treatment failure in leukemia. Acuity of illness - as defined by intensive care unit (ICU) level resource use at admission - in children with acute myeloid leukemia (AML) was shown in prior data from the Pediatric Health Information System to mediate excess mortality in Black patients (Winestone et al, Am J Hematol., 2017). This study aims to evaluate the acuity and severity of illness in patients presenting with new diagnoses of leukemia and evaluate whether AYAs have a higher acuity and severity of illness compared to younger patients. Methods: We performed a retrospective analysis of 771 patients aged 1-21 years with initial presentation of newly diagnosed leukemia at Children's Healthcare of Atlanta (CHOA) between 2010-2018. Exclusion criteria included those who received any treatment at another facility or those for whom information about the first 72 hours following presentation to the hospital was not available. High acuity of illness was defined (yes/no) as any ICU admission or ICU-level resource use - regardless of physical location in the hospital - by organ system (cardiovascular, respiratory, renal, hematologic, and neurologic) on manual chart review. High severity of illness was defined as initial white blood cell (WBC) count ≥ 50,000 cells/microliter or central nervous system (CNS) disease. Both acuity and severity were assessed during the first 72 hours following the point of diagnosis. Multivariable logistic regression was used to examine the association of age at diagnosis with acuity or severity of illness, controlling for sex, race/ethnicity, insurance status, and type of leukemia. Results: Among 536 patients with complete data to date, the median age was 6 years (interquartile range 3-12 years, 65.5% aged 1-9 years, 34.5% aged 10-21 years), 53.4% were male, 45.7% were Non-Hispanic White, and 65.7% had private insurance. Diagnoses included B-cell acute lymphoblastic leukemia (ALL) (70.5%), AML (16.4%), T-cell ALL (9.3%), and other leukemias (3.7%) (juvenile myelomonocytic, chronic myeloid, and Burkitt's). High acuity of illness was seen in 24.2% of patients and was more likely in older patients (10-21 years, 33.5% versus 1-9 years, 19.4%, p &amp;lt;0.01). Figure 1 illustrates involved organ systems by age group. High severity of illness was seen in 31.3% of cases, and although not significant, was also more likely in older patients (10-21 years, 32.5% versus 1-9 years, 27.9%, p=0.06). In multivariable analysis, compared to patients aged 1-9 years, patients aged 10-21 years had an increased odds of high acuity of illness [odds ratio (OR) 1.69, 95% confidence interval (CI 1.09-2.63)]. Patients with T-ALL also had an increased odds of high acuity of illness [OR 3.40 (CI 1.76-6.54); referent B-ALL]. The odds of high severity of illness did not differ by age [10-21 years OR 1.23 (CI 0.81-1.86)], but was significantly higher by Non-Hispanic Black race [OR 1.83 (CI 1.14-2.94); referent Non-Hispanic White] and type of leukemia [T-ALL OR 3.90 (CI 2.03-7.48); other leukemia OR 3.26 (CI 1.28-8.32); referent B-ALL] (Table 1). Discussion and Conclusions: AYA patients had an increased likelihood of high acuity of illness requiring ICU-level care at presentation, indicating a risk for disparities of outcomes from the point of initial presentation. Future directions will examine the association of acuity of illness with mortality in this cohort, as well as the role of race/ethnicity on severity of illness and mortality. This research will ultimately help inform strategies toward narrowing age disparities in outcomes of AYA leukemia.

Abstract 15794: Incidence &amp; Complications of Myocarditis in US Active-Duty Service Members Hospitalized With COVID-19 Infection

Introduction: Cardiovascular complications of coronavirus disease 2019 (COVID-19) infection, including myocarditis, have been widely reported. Research question/hypothesis: What was the incidence and clinical implications of viral myocarditis resulting from COVID-19 infection in hospitalized United States active-duty service members (US ADSM)? Goal/aims: Report the incidence of complications in US ADSM who suffered COVID-19 associated myocarditis. Methods: This retrospective observational cohort study from the Joint Trauma Service COVID-19 Registry included 399,284 US ADSM who contracted COVID-19 infection. Our team independently reviewed records of hospitalized US ADSM who were determined to have COVID-19 associated myocarditis. Results: Among the 399,284 US ADSM who contracted COVID-19, 1,629 (0.4%) required hospitalization and 18 (1.1%) met criteria for myocarditis. The most common presenting symptoms were chest pain (72%) and dyspnea (67%). Half of the patients required ICU level care of which 44% required inotropes or vasopressors, and one patient required mechanical circulatory support. Eight (44%) patients had clinical findings consistent with acute heart failure and two (11%) patients suffered intermittent advanced heart block that did not require permanent pacing. No patients died in the hospital. In the patients who had a left ventricular ejection fraction of less than 50% during their illness, 75% had full recovery of their left ventricular systolic function during follow up imaging. Conclusions: While myocarditis was an uncommon complication in US ADSM hospitalized for COVID-19, its clinical course was not benign.

A-123 Increased Rate of Recurrent Hemolysis Is Associated With COVID-19 Infection and Propofol Administration in the Intensive Care Unit (ICU)

Abstract Background Hemolysis is a pre-analytic issue that challenges clinical laboratories. When a specimen with significant hemolysis is obtained in our laboratory, tests where the hemolysis threshold is exceeded are not reported and blood is recollected. Unfortunately, in a subset of patients, the recollected specimen is also hemolyzed (termed “recurrent hemolysis”). In these cases, the second recollection utilizes special collection and handling protocols (i.e., hand-carried to lab, plasma collection, etc.) to mitigate preventable causes of hemolysis. Lipemia is also a known contributor to specimen hemolysis. Mayo Clinic Rochester experienced an increased rate of hemolysis as well as recurrent hemolysis during the height of the COVID-19 pandemic (January 2022). The objective of this study was to investigate the increased rate of recurrent hemolysis and compare to a rate prior to the COVID-19 pandemic (January 2019). Methods Retrospective data analysis was performed for January 2019 (negative control) and January 2022. The number of Mayo Clinic Rochester hospital admissions, admitting diagnosis, medications administered, and number of test collections performed were obtained using reporting functionality in our Electronic Health Record (EHR), Epic. The Laboratory Information System, SoftLab, was utilized to obtain recollection rates due to hemolysis. Data were normalized to total patient admissions for the specified period to account for inter-year variability. R/R Studio was utilized to analyze and visualize the data. Pearson’s Chi-squared test for independence was performed on categorical variables (significance defined as P &amp;lt; 0.05). Results A 28% decrease in hospital admissions (n = 3958:Jan-22 vs n = 5517:Jan-19) and a 23% decrease in total specimens collected on hospitalized patients (n = 40 557:Jan-22 vs n = 52 373:Jan-19) was observed between Jan-19 to Jan-22. However, the laboratory observed a 6% increase in hemolyzed specimens (n = 256:Jan-22 vs n = 241:Jan-19). Recurrent hemolysis occurred in 24% (n = 62/256) of Jan-22 and 17% (n = 43/241) of Jan-19 hemolyzed specimens and required special handling protocols. COVID positive patients comprised 48% (n = 30/62) of those requiring special handling protocols in Jan-22. Further examination revealed 34% (n = 21/62) of Jan-22 and 12% (n = 5/43) of Jan-19 cases of recurrent hemolysis were due to lipemia (P &amp;lt; 0.01). Chart review highlighted a potential source of lipemia from the administration of propofol, a lipophilic sedative emulsion. Of those COVID positive cases with recurrent hemolysis due to lipemia (n = 15/30), 93% (n = 14/15) were receiving propofol at the time of collection (P &amp;lt; 0.001). Conclusion We observed increased rates of specimen hemolysis during the COVID-19 pandemic. While most hemolysis resolves upon specimen recollection, patients with recurrently hemolyzed specimens often require special specimen collection and handling protocols to mitigate hemolysis. Approximately half of the recurrent hemolysis cases in Jan 2022 were COVID-19 positive patients. Lipemia-induced hemolysis was also more frequent in this patient population presumably due to the administration of propofol, a lipophilic emulsion sedative commonly used for COVID positive patients requiring sedation and ICU-level care. It is critical to understand the variety of factors which may contribute to recurrent hemolysis, as intervening with specialized collection and handling protocols to reduce observed pre-analytical hemolysis is required to provide accurate and timely laboratory results.