Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia.

While acute myeloid leukemia (AML) comprises many disparate genetic subtypes, one shared hallmark is the arrest of leukemic myeloblasts at an immature and self-renewing stage of development. Therapies that overcome differentiation arrest represent a powerful treatment strategy. We leveraged the observation that the majority of AML, despite their genetically heterogeneity, share in the expression of HoxA9, a gene normally downregulated during myeloid differentiation. Using a conditional HoxA9 model system, we performed a high-throughput phenotypic screen and defined compounds that overcame differentiation blockade. Target identification led to the unanticipated discovery that inhibition of the enzyme dihydroorotate dehydrogenase (DHODH) enables myeloid differentiation in human and mouse AML models. In vivo, DHODH inhibitors reduced leukemic cell burden, decreased levels of leukemia-initiating cells, and improved survival. These data demonstrate the role of DHODH as a metabolic regulator of differentiation and point to its inhibition as a strategy for overcoming differentiation blockade in AML.

Trends in the Utilization of Multiorgan Support Among Adults Undergoing High-risk Cardiac Surgery in the United States.

OBJECTIVES: To examine trends in the prevalence of multiorgan dysfunction (MODS), utilization of multi-organ support (MOS), and mortality among patients undergoing cardiac surgery with MODS who received MOS in the United States. DESIGN: Retrospective cohort study. SETTING: 183 hospitals in the Premier Healthcare Database. PARTICIPANTS: Adults ≥18 years old undergoing high-risk elective or non-elective cardiac surgery. INTERVENTIONS: none. MEASUREMENTS AND MAIN RESULTS: The exposure was time (consecutive calendar quarters) January 2008 and June 2018. We analyzed hospital data using day-stamped hospital billing codes and diagnosis and procedure codes to assess MODS prevalence, MOS utilization, and mortality. Among 129,102 elective and 136,190 non-elective high-risk cardiac surgical cases across 183 hospitals, 10,001 (7.7%) and 21,556 (15.8%) of patients developed MODS, respectively. Among patients who experienced MODS, 2,181 (22%) of elective and 5,425 (25%) of non-elective cardiac surgical cases utilized MOS. From 2008-2018, MODS increased in both high-risk elective and non-elective cardiac surgical cases. Similarly, MOS increased in both high-risk elective and non-elective cardiac surgical cases. As a component of MOS, mechanical circulatory support (MCS) increased over time. Over the study period, risk-adjusted mortality, in patients who developed MODS receiving MOS, increased in high-risk non-elective cardiac surgery and decreased in high-risk elective cardiac surgery, despite increasing MODS prevalence and MOS utilization (p<0.001). CONCLUSIONS: Among patients undergoing high-risk cardiac surgery in the United States, MODS prevalence and MOS utilization (including MCS) increased over time. Risk-adjusted mortality trends differed in elective and non-elective cardiac surgery. Further research is necessary to optimize outcomes among patients undergoing high-risk cardiac surgery.

Aldehyde dehydrogenase 3a2 protects AML cells from oxidative death and the synthetic lethality of ferroptosis inducers.

Metabolic alterations in cancer represent convergent effects of oncogenic mutations. We hypothesized that a metabolism-restricted genetic screen, comparing normal primary mouse hematopoietic cells and their malignant counterparts in an ex vivo system mimicking the bone marrow microenvironment, would define distinctive vulnerabilities in acute myeloid leukemia (AML). Leukemic cells, but not their normal myeloid counterparts, depended on the aldehyde dehydrogenase 3a2 (Aldh3a2) enzyme that oxidizes long-chain aliphatic aldehydes to prevent cellular oxidative damage. Aldehydes are by-products of increased oxidative phosphorylation and nucleotide synthesis in cancer and are generated from lipid peroxides underlying the non-caspase-dependent form of cell death, ferroptosis. Leukemic cell dependence on Aldh3a2 was seen across multiple mouse and human myeloid leukemias. Aldh3a2 inhibition was synthetically lethal with glutathione peroxidase-4 (GPX4) inhibition; GPX4 inhibition is a known trigger of ferroptosis that by itself minimally affects AML cells. Inhibiting Aldh3a2 provides a therapeutic opportunity and a unique synthetic lethality to exploit the distinctive metabolic state of malignant cells.

Racial and Ethnic Differences in the Prevalence of Do-Not-Resuscitate Orders among Older Adults with Severe Traumatic Brain Injury.

BACKGROUND: Older adults suffering from traumatic brain injury (TBI) are subject to higher injury burden and mortality. Do Not Resuscitate (DNR) orders are used to provide care aligned with patient wishes, but they may not be equitably distributed across racial/ethnic groups. We examined racial/ethnic differences in the prevalence of DNR orders at hospital admission in older patients with severe TBI. METHODS: We conducted a retrospective cohort study using the National Trauma Databank (NTDB) between 2007 to 2016. We examined patients ≥ 65 years with severe TBI. For our primary aim, the exposure was race/ethnicity and outcome was the presence of a documented DNR at hospital admission. We conducted an exploratory analysis of hospital outcomes including hospital mortality, discharge to hospice, and healthcare utilization (intracranial pressure monitor placement, hospital LOS, and duration of mechanical ventilation). RESULTS: Compared to White patients, Black patients (OR 0.48, 95% CI 0.35-0.64), Hispanic patients (OR 0.54, 95% CI 0.40-0.70), and Asian patients (OR 0.63, 95% CI 0.44-0.90) had decreased odds of having a DNR order at hospital admission. Patients with DNRs had increased odds of hospital mortality (OR 2.16, 95% CI 1.94-2.42), discharge to hospice (OR 2.08, 95% CI 1.75-2.46), shorter hospital LOS (-2.07 days, 95% CI -3.07 to -1.08) and duration of mechanical ventilation (-1.09 days, 95% CI -1.52 to -0.67). There was no significant difference in the utilization of ICP monitoring (OR 0.94, 95% CI 0.78-1.12). CONCLUSIONS: We found significant racial and ethnic differences in the utilization of DNR orders among older patients with severe TBI. Additionally. DNR orders at hospital admission were associated with increased in-hospital mortality, increased hospice utilization, and decreased healthcare utilization. Future studies should examine mechanisms underlying race-based differences in DNR utilization.

Exploring Factors Associated With Morbidity and Mortality in Patients With Do-Not-Resuscitate Orders: A National Surgical Quality Improvement Program Database Analysis Within Surgical Groups.

BACKGROUND: Anesthesiologists caring for patients with do-not-resuscitate (DNR) orders may have ethical concerns because of their resuscitative wishes and may have clinical concerns because of their known increased risk of morbidity/mortality. Patient heterogeneity and/or emphasis on mortality outcomes make previous studies among patients with DNR orders difficult to interpret. We sought to explore factors associated with morbidity and mortality among patients with DNR orders, which were stratified by surgical subgroups. METHODS: Exploratory retrospective cohort study in adult patients undergoing prespecified colorectal, vascular, and orthopedic surgeries was performed using the American College of Surgeons National Surgical Quality Improvement Program Participant Use File data from 2010 to 2013. Among patients with preoperative DNR orders (ie, active DNR order written in the patient's chart before surgery), factors associated with 30-day mortality, increased length of stay, and inpatient death were determined via penalized regression. Unadjusted and adjusted estimates for selected variables are presented. RESULTS: After selection as above, 211,420 patients underwent prespecified procedures, and of those, 2755 (1.3%) had pre-existing DNR orders and met above selection to address morbidity/mortality aims. By specialty, of these patients with a preoperative DNR, 1149 underwent colorectal, 870 vascular, and 736 orthopedic surgery. Across groups, 36.2% were male and had a mean age 79.9 years (range 21-90). The 30-day mortality was 15.4%-27.2% and median length of stay was 6-12 days. Death at discharge was 7.0%, 13.1%, and 23.0% in orthopedics, vascular, and colorectal patients with a DNR, respectively. The strongest factors associated with increased odds of 30-day mortality were preoperative septic shock in colorectal patients, preoperative ascites in vascular patients, and any requirement of mechanical ventilation at admission in orthopedic patients. CONCLUSIONS: In patients with DNR orders undergoing common surgical procedures, the association of characteristics with morbidity and mortality varies in both direction and magnitude. The DNR order itself should not be the defining measure of risk.

Geospatial Variations and Neighborhood Deprivation in Drug-Related Admissions and Overdoses.

Drug overdoses are a national and global epidemic. However, while overdoses are inextricably linked to social, demographic, and geographical determinants, geospatial patterns of drug-related admissions and overdoses at the neighborhood level remain poorly studied. The objective of this paper is to investigate spatial distributions of patients admitted for drug-related admissions and overdoses from a large, urban, tertiary care center using electronic health record data. Additionally, these spatial distributions were adjusted for a validated socioeconomic index called the Area Deprivation Index (ADI). We showed spatial heterogeneity in patients admitted for opioid, amphetamine, and psychostimulant-related diagnoses and overdoses. While ADI was associated with drug-related admissions, it did not correct for spatial variations and could not account alone for this spatial heterogeneity.

Bleeding After Musculoskeletal Surgery in Hospitals That Switched From Hydroxyethyl Starch to Albumin Following a Food and Drug Administration Warning.

BACKGROUND: While US Food and Drug Administration (FDA) black box warnings are common, their impact on perioperative outcomes is unclear. Hydroxyethyl starch (HES) is associated with increased bleeding and kidney injury in patients with sepsis, leading to an FDA black box warning in 2013. Among patients undergoing musculoskeletal surgery in a subset of hospitals where colloid use changed from HES to albumin following the FDA warning, we examined the rate of major perioperative bleeding post- versus pre-FDA warning. METHODS: The authors of this article used a retrospective, quasi-experimental, repeated cross-sectional, interrupted time series study of patients undergoing musculoskeletal surgery in hospitals within the Premier Healthcare Database, in the year before and year after the 2013 FDA black box warning. We examined patients in 23 "switcher" hospitals (where the percentage of colloid recipients receiving HES exceeded 50% before the FDA warning and decreased by at least 25% in absolute terms after the FDA warning) and patients in 279 "nonswitcher" hospitals. Among patients having surgery in "switcher" and "nonswitcher" hospitals, we determined monthly rates of major perioperative bleeding during the 12 months after the FDA warning, compared to 12 months before the FDA warning. Among patients who received surgery in "switcher" hospitals, we conducted a propensity-weighted segmented regression analysis assessing differences-in-differences (DID), using patients in "nonswitcher" hospitals as a control group. RESULTS: Among 3078 patients treated at "switcher" hospitals (1892 patients treated pre-FDA warning versus 1186 patients treated post-FDA warning), demographic and clinical characteristics were well-balanced. Two hundred fifty-one (13.3%) received albumin pre-FDA warning, and 900 (75.9%) received albumin post-FDA warning. Among patients undergoing surgery in "switcher" hospitals during the pre-FDA warning period, 282 of 1892 (14.9%) experienced major bleeding during the hospitalization, compared to 149 of 1186 (12.6%) following the warning. In segmented regression, the adjusted ratio of slopes for major perioperative bleeding post- versus pre-FDA warning was 0.98 (95% confidence interval [CI], 0.93-1.04). In the DID estimate using "nonswitcher" hospitals as a control group, the ratio of ratios was 0.93 (95% CI, 0.46-1.86), indicating no significant difference. CONCLUSIONS: We identified a subset of hospitals where colloid use for musculoskeletal surgery changed following a 2013 FDA black box warning regarding HES use in sepsis. Among patients undergoing musculoskeletal surgery at these "switcher" hospitals, there was no significant decrease in the rate of major perioperative bleeding following the warning, possibly due to incomplete practice change. Evaluation of the impact of systemic changes in health care may contribute to the understanding of patient outcomes in perioperative medicine.

Effects of Tourniquets in the Development of Pain States: a Novel Clinical Pilot Study and Review of Utilization of Tissue Oximetry to Measure Neural Ischemia.

PURPOSE OF REVIEW: Approximately 20% of patients undergoing surgery develop persistent lower extremity pain following total knee arthroplasty. Animal studies have confirmed that prolonged tourniquet time increases the risk of endoneural ischemia and can mediate or modulate the development of chronic pain. The use of Near InfraRed Spectroscopy (NIRS) adjacent to nerve tissue, previously described as ONG has been shown to detect early neural compromise and has demonstrated clinical utility in carpal tunnel diagnosis. RECENT FINDINGS: In this pilot study, we recruited 10 healthy adult volunteers to undergo oxyneurography (ONG) and sensory nerve conduction testing (sNCT). We performed testing on the upper and lower extremities in each individual. The tourniquet was applied followed by measurements of sNCT and ONG as described. We observed a significant drop in the mean ONG index at 3 and 5 min following tourniquet inflation in upper and lower extremities. Similar to raw ONG values, there was significant variability in sNCT measurements, which in general increased from baseline with tourniquet inflation. In the upper extremity, there was a significant increase in sNCT with tourniquet inflation, while in the lower extremity, there was a trend towards significance. The use of ONG can be supported as a diagnostic tool to detect nerve ischemia and to potentially reduce the incidence of tourniquet-mediated or -modulated neural ischemia and reduce the development of chronic post-tourniquet pain.

Use of Early Ketamine Sedation and Association With Clinical and Cost Outcomes Among Mechanically Ventilated Patients With COVID-19: A Retrospective Cohort Study.

OBJECTIVES: To describe the utilization of early ketamine use among patients mechanically ventilated for COVID-19, and examine associations with in-hospital mortality and other clinical outcomes. DESIGN: Retrospective cohort study. SETTING: Six hundred ten hospitals contributing data to the Premier Healthcare Database between April 2020 and June 2021. PATIENTS: Adults with COVID-19 and greater than or equal to 2 consecutive days of mechanical ventilation within 5 days of hospitalization. INTERVENTION: The exposures were early ketamine use initiated within 2 days of intubation and continued for greater than 1 day. MEASUREMENTS: Primary was hospital mortality. Secondary outcomes included length of stay (LOS) in the hospital and ICUs, ventilator days, vasopressor days, renal replacement therapy (RRT), and total hospital cost. The propensity score matching analysis was used to adjust for confounders. MAIN RESULTS: Among 42,954 patients, 1,423 (3.3%) were exposed to early ketamine use. After propensity score matching including 1,390 patients in each group, recipients of ketamine infusions were associated with higher hospital mortality (52.5% vs. 45.9%, risk ratio: 1.14, [1.06-1.23]), longer median ICU stay (13 vs. 12 d, mean ratio [MR]: 1.15 [1.08-1.23]), and longer ventilator days (12 vs. 11 d, MR: 1.19 [1.12-1.27]). There were no associations for hospital LOS (17 [10-27] vs. 17 [9-28], MR: 1.05 [0.99-1.12]), vasopressor days (4 vs. 4, MR: 1.04 [0.95-1.14]), and RRT (22.9% vs. 21.7%, RR: 1.05 [0.92-1.21]). Total hospital cost was higher (median $72,481 vs. $65,584, MR: 1.11 [1.05-1.19]). CONCLUSIONS: In a diverse sample of U.S. hospitals, about one in 30 patients mechanically ventilated with COVID-19 received ketamine infusions. Early ketamine may have an association with higher hospital mortality, increased total cost, ICU stay, and ventilator days, but no associations for hospital LOS, vasopressor days, and RRT. However, confounding by the severity of illness might occur due to higher extracorporeal membrane oxygenation and RRT use in the ketamine group. Further randomized trials are needed to better understand the role of ketamine infusions in the management of critically ill patients.

Resilience, Survival and Functional Independence in Older Adults Facing Critical Illness.

BACKGROUND: Older adults surviving critical illness often experience new or worsening functional impairments. Modifiable positive psychological constructs, like resilience, may mitigate post-intensive care morbidity. RESEARCH QUESTION: Is pre-ICU resilience associated with: (1) post-ICU survival; (2) the drop in post-ICU functional independence; and (3) a lesser decline of independence before versus after the ICU? STUDY DESIGN AND METHODS: We performed a retrospective cohort study using Medicare-linked Health and Retirement Study surveys from 2006-2018. We included Older adults ≥65 years admitted to an ICU. We calculated resilience before ICU admission. The resilience measure was defined from the Simplified Resilience Score which was previously adapted and validated for the Health and Retirement Study. Resilience was scored using the leave-behind survey normalized to 0 (lowest resilience) to 12 (highest resilience) point scale. Outcomes were survival and probability of functional independence. We modeled survival using Gompertz models and independence using joint survival models adjusting for sociodemographic and clinical variables. We estimated average marginal effects to determine independence probabilities. RESULTS: Across 3,409 patients ≥65 years old admitted to ICUs, pre-existing frailty (30.5%) and cognitive impairment (24.3%) were common. Most patients were previously independent (82.7%). Mechanical ventilation occurred in 14.8% and sepsis in 43.2%. Highest versus lowest resilience had lower risk of post-ICU mortality (aHR 0.81 95% CI [0.70, 0.94]). Higher resilience was associated with greater likelihood in post-ICU independence (estimated probability of independence 5 years post-ICU in highest-to-lowest resilience: 0.53 CI 95% [0.33, 0.74], 0.47 [0.26, 0.68], 0.49 [0.28, 0.70], 0.36 [0.17, 0.55] p<0.01). Resilience was not associated with a difference in the drop of independence across resilience groups, nor a difference in declines of independence post-ICU. INTERPRETATION: ICU survivors with higher resilience had increased rates of survival and functional independence, though the slope of functional decline did not differ by resilience group pre- to post-ICU.

Measuring Implicit Bias in ICU Notes Using Word-Embedding Neural Network Models.

BACKGROUND: Language in nonmedical data sets is known to transmit human-like biases when used in natural language processing (NLP) algorithms that can reinforce disparities. It is unclear if NLP algorithms of medical notes could lead to similar transmissions of biases. RESEARCH QUESTION: Can we identify implicit bias in clinical notes, and are biases stable across time and geography? STUDY DESIGN AND METHODS: To determine whether different racial and ethnic descriptors are similar contextually to stigmatizing language in ICU notes and whether these relationships are stable across time and geography, we identified notes on critically ill adults admitted to the University of California, San Francisco (UCSF), from 2012 through 2022 and to Beth Israel Deaconess Hospital (BIDMC) from 2001 through 2012. Because word meaning is derived largely from context, we trained unsupervised word-embedding algorithms to measure the similarity (cosine similarity) quantitatively of the context between a racial or ethnic descriptor (eg, African-American) and a stigmatizing target word (eg, nonco-operative) or group of words (violence, passivity, noncompliance, nonadherence). RESULTS: In UCSF notes, Black descriptors were less likely to be similar contextually to violent words compared with White descriptors. Contrastingly, in BIDMC notes, Black descriptors were more likely to be similar contextually to violent words compared with White descriptors. The UCSF data set also showed that Black descriptors were more similar contextually to passivity and noncompliance words compared with Latinx descriptors. INTERPRETATION: Implicit bias is identifiable in ICU notes. Racial and ethnic group descriptors carry different contextual relationships to stigmatizing words, depending on when and where notes were written. Because NLP models seem able to transmit implicit bias from training data, use of NLP algorithms in clinical prediction could reinforce disparities. Active debiasing strategies may be necessary to achieve algorithmic fairness when using language models in clinical research.

Negativity and Positivity in the ICU: Exploratory Development of Automated Sentiment Capture in the Electronic Health Record.

OBJECTIVES: To develop proof-of-concept algorithms using alternative approaches to capture provider sentiment in ICU notes. DESIGN: Retrospective observational cohort study. SETTING: The Multiparameter Intelligent Monitoring of Intensive Care III (MIMIC-III) and the University of California, San Francisco (UCSF) deidentified notes databases. PATIENTS: Adult (≥18 yr old) patients admitted to the ICU. MEASUREMENTS AND MAIN RESULTS: We developed two sentiment models: 1) a keywords-based approach using a consensus-based clinical sentiment lexicon comprised of 72 positive and 103 negative phrases, including negations and 2) a Decoding-enhanced Bidirectional Encoder Representations from Transformers with disentangled attention-v3-based deep learning model (keywords-independent) trained on clinical sentiment labels. We applied the models to 198,944 notes across 52,997 ICU admissions in the MIMIC-III database. Analyses were replicated on an external sample of patients admitted to a UCSF ICU from 2018 to 2019. We also labeled sentiment in 1,493 note fragments and compared the predictive accuracy of our tools to three popular sentiment classifiers. Clinical sentiment terms were found in 99% of patient visits across 88% of notes. Our two sentiment tools were substantially more predictive (Spearman correlations of 0.62-0.84, p values < 0.00001) of labeled sentiment compared with general language algorithms (0.28-0.46). CONCLUSION: Our exploratory healthcare-specific sentiment models can more accurately detect positivity and negativity in clinical notes compared with general sentiment tools not designed for clinical usage.

Trends in Palliative Care Consultations in Critically Ill Patient Populations, 2013-2019.

CONTEXT: Critically ill patients have important palliative care (PC) needs in the intensive care unit (ICU), but specialty PC is often underutilized. OBJECTIVE: To evaluate changes in utilization and reasons for PC consultation over time. METHODS: Data from a national multi-site network of inpatient PC visits were used to identify patients age ≥18 years admitted to an ICU between 2013 and 2019. Year of ICU admission was the exposure. Primary diagnosis and reason for referral were identified by standardized process measures within the dataset at the time of referral. Trends in primary diagnosis and reason for referral were modeled as a function of year of ICU admission. RESULTS: Across 39,515 ICU patients seen by a PC team, overall numbers of consultations from the ICU increased each year. Referrals for patients with cancer decreased from 17.6% (95% CI 13.7%-21.5%) to 14.3% (95% CI 13.2%-14.7%) and for patients with cardiovascular disease increased from 16.8% in (95% CI 16.8%-16.9%) to 18.8% (95% CI 18.8%-18.9%). Reasons for referrals were primarily for goals of care and advance care planning and increased from 74.0% (95% CI 70.0%-78.0%) in 2013 to 80.0% (95% CI 79.4%-80.0%) in 2019 (P < 0.0001 for all trends). CONCLUSION: PC referrals in ICU patients with cancer are decreasing, while those for cardiovascular disease are increasing. Reasons for referrals in the ICU are commonly for goals of care; other reasons, like pain control are uncommon. Early goals of care conversations and further training in advance care planning should be emphasized in the ICU setting.

Utilization and Delivery of Specialty Palliative Care in the ICU: Insights from the Palliative Care Quality Network.

CONTEXT: Palliative care (PC) benefits critically ill patients but remains underutilized. Important to developing interventions to overcome barriers to PC in the ICU and address PC needs of ICU patients is to understand how, when, and for which patients PC is provided in the ICU. OBJECTIVES: Compare characteristics of specialty PC consultations in the ICU to those on medical-surgical wards. METHODS: Retrospective analysis of national Palliative Care Quality Network data for hospitalized patients receiving specialty PC consultation January 1, 2013 to December 31, 2019 in ICU or medical-surgical setting. 98 inpatient PC teams in 16 states contributed data. Measures and outcomes included patient characteristics, consultation features, process metrics and patient outcomes. Mixed effects multivariable logistic regression was used to compare ICU and medical-surgical units. RESULTS: Of 102,597 patients 63,082 were in medical-surgical units and 39,515 ICU. ICU patients were younger and more likely to have non-cancer diagnoses (all P < 0.001). While fewer ICU patients were able to report symptoms, most patients in both groups reported improved symptoms. ICU patients were more likely to have consultation requests for GOC, comfort care, and withdrawal of interventions and less likely for pain and/or symptoms (OR-all P < 0.001). ICU patients were less often discharged alive. CONCLUSION: ICU patients receiving PC consultation are more likely to have non-cancer diagnoses and less likely able to communicate. Although symptom management and GOC are standard parts of ICU care, specialty PC in the ICU is often engaged for these issues and results in improved symptoms, suggesting routine interventions and consultation targeting these needs could improve care.

Trends in Geriatric Conditions Among Older Adults Admitted to US ICUs Between 1998 and 2015.

BACKGROUND: Older adults are increasingly admitted to the ICU, and those with disabilities, dementia, frailty, and multimorbidity are vulnerable to adverse outcomes. Little is known about how pre-existing geriatric conditions have changed over time. RESEARCH QUESTION: How have changes in disability, dementia, frailty, and multimorbidity in older adults admitted to the ICU changed from 1998 through 2015? STUDY DESIGN AND METHODS: Medicare-linked Health and Retirement Survey (HRS) data identifying patients 65 years of age and older admitted to an ICU between 1998 and 2015. ICU admission was the unit of analysis. Year of ICU admission was the exposure. Disability, dementia, frailty, and multimorbidity were identified based on responses to HRS surveys before ICU admission. Disability represented the need for assistance with ≥ 1 activity of daily living. Dementia used cognitive and functional measures. Frailty included deficits in ≥ 2 domains (physical, nutritive, cognitive, or sensory function). Multimorbidity represented ≥ 3 self-reported chronic diseases. Time trends in geriatric conditions were modeled as a function of year of ICU admission and were adjusted for age, sex, race or ethnicity, and proxy interview status. RESULTS: Across 6,084 ICU patients, age at admission increased from 77.6 years (95% CI, 76.7-78.4 years) in 1998 to 78.7 years (95% CI, 77.5-79.8 years) in 2015 (P < .001 for trend). The adjusted proportion of ICU admissions with pre-existing disability rose from 15.5% (95% CI, 12.1%-18.8%) in 1998 to 24.0% (95% CI, 18.5%-29.6%) in 2015 (P = .001). Rates of dementia did not change significantly (P = .21). Frailty increased from 36.6% (95% CI, 30.9%-42.3%) in 1998 to 45.0% (95% CI, 39.7%-50.2%) in 2015 (P = .04); multimorbidity rose from 54.4% (95% CI, 49.2%-59.7%) in 1998 to 71.8% (95% CI, 66.3%-77.2%) in 2015 (P < .001). INTERPRETATION: Rates of pre-existing disability, frailty, and multimorbidity in older adults admitted to ICUs increased over time. Geriatric principles need to be deeply integrated into the ICU setting.

Monotherapy with methotrexate for primary central nervous lymphoma has single agent activity in the absence of radiotherapy: a single institution cohort.

We have retrospectively reviewed toxicities and response of a cohort of primary central nervous system lymphoma (PCNSL) patients treated with high dose parenteral methotrexate (MTX) monotherapy without whole brain radiation. From The Massachusetts General Hospital (MGH) Cancer Registry, active since 1946, we selected all immunocompetent patients with histologic and/or radiographic PCNSL diagnosed between 1980 and 2007. We identified the recipients of MTX with leucovorin rescue as sole therapy. No patient received radiation therapy (XRT). We analyzed this cohort for toxicity, response and patterns of recurrence. The cohort of 121 patients received on average 11 cycles of intravenous MTX at a median dose of 8 g/m(2). Median interval between cycles was 10 days. After 3 months of therapy, the overall response rate was 85% (58% CR, 27% PR). The overall survival (OS) for the cohort was 7 years and progression-free survival (PFS) was 3.14 years. A trend toward a higher PFS was seen in patients who continued to receive MTX (3.48 years) every three months as compared to patients who ceased MTX after one year (2.86 years). Of 68 patients who achieved initial CR, there were 40 recurrences. Twenty-six of the 40 were re-induced with MTX as above; Sixty-nine percent again achieved CR. Eighty-one treatment-related toxicities occurred in 1316 MTX cycles. These toxicities included MRI white matter changes (N = 8) and lead to MTX cessation in 16 patients. High-dose MTX monotherapy of PCNSL is well-tolerated and provides PFS of >3 years and OS >7 years.

Intrapulmonary Activated Factor VII for Hemoptysis Complicating Pulmonary Thromboendarterectomy.

Massive hemoptysis represents a life-threatening disorder that has numerous different causes. The development of recombinant factor concentrates has allowed for novel treatments in this emergency setting. This report describes a patient with chronic thromboembolic pulmonary hypertension who underwent pulmonary thromboendarterectomy. The postoperative course was complicated by massive hemoptysis resulting in severe hypoxemia that required extracorporeal membrane oxygenation and multiple daily blood transfusions. After failure of conservative and interventional approaches, recombinant factor VII was administered by bronchial isolation. After treatment, the patient's hemoptysis dramatically resolved, with eventual hospital discharge and excellent function at follow-up. This case presents the use of intrapulmonary activated factor VII to control massive hemoptysis.