Post-operative pain control in patients on buprenorphine or methadone for opioid use disorder.

OBJECTIVE: This study aimed to determine whether there is a difference in pain scores and opioid consumption after elective surgery in patients maintained on methadone or buprenorphine for opioid use disorder (OUD). Additionally, we investigated the impact of continuing or discontinuing methadone or buprenorphine on post-operative pain outcomes. DESIGN: A single-center retrospective cohort study. SETTING: Tertiary care medical center. PATIENTS AND PARTICIPANTS: Adults aged 18 years or older with OUD maintained on buprenorphine or methadone who underwent elective surgery between January 1, 2017, and January 1, 2021. INTERVENTIONS: Patients were identified through electronic medical records, and demographic and clinical data were collected. MAIN OUTCOME MEASURES: The primary outcome was opioid consumption at 24 hours post-operatively, measured in milligram morphine equivalents. The secondary outcome was opioid consumption and pain scores up to 72 hours post-operatively, assessed using a numeric rating scale. RESULTS: This study included 366 patients (64 percent on buprenorphine and 36 percent on methadone). Opioid utilization significantly increased when buprenorphine was not administered post-operatively. Both groups exhibited comparable total opioid consumption during the post-operative period. In the buprenorphine cohort, pain scores differed significantly based on the receipt of medications for OUD post-operatively. CONCLUSIONS: This study reinforces existing evidence supporting the continuation of medications for opioid use disorder, specifically buprenorphine and methadone, during the perioperative period. Dissemination of guideline recommendations is essential to ensure optimal post-operative pain management for this patient population.

Buprenorphine in the Intensive Care Unit: Commentary on the Unanswered Questions.

The removal of the X-waiver in the Mainstreaming Addiction Treatment (MAT) Act of 2023 has substantial implications for buprenorphine prescribing as one of the options to treat opioid use disorder. The purpose of this commentary is to discuss the unanswered questions regarding buprenorphine in the intensive care unit (ICU) including how the passage of the MAT Act will affect ICU providers, which patients should receive buprenorphine, what is the most appropriate route of administration and dose of buprenorphine, what medications interact with buprenorphine, and how can transitions of care be optimized for these patients.

Delayed CCL23 response is associated with poor outcomes after cardiac arrest.

Chemokines, a family of chemotactic cytokines, mediate leukocyte migration to and entrance into inflamed tissue, contributing to the intensity of local inflammation. We performed an analysis of chemokine and immune cell responses to cardiac arrest (CA). Forty-two patients resuscitated from cardiac arrest were analyzed, and twenty-two patients who underwent coronary artery bypass grafting (CABG) surgery were enrolled. Quantitative antibody array, chemokines, and endotoxin quantification were performed using the patients blood. Analysis of CCL23 production in neutrophils obtained from CA patients and injected into immunodeficient mice after CA and cardiopulmonary resuscitation (CPR) were done using flow cytometry. The levels of CCL2, CCL4, and CCL23 are increased in CA patients. Temporal dynamics were different for each chemokine, with early increases in CCL2 and CCL4, followed by a delayed elevation in CCL23 at forty-eight hours after CA. A high level of CCL23 was associated with an increased number of neutrophils, neuron-specific enolase (NSE), worse cerebral performance category (CPC) score, and higher mortality. To investigate the role of neutrophil activation locally in injured brain tissue, we used a mouse model of CA/CPR. CCL23 production was increased in human neutrophils that infiltrated mouse brains compared to those in the peripheral circulation. It is known that an early intense inflammatory response (within hours) is associated with poor outcomes after CA. Our data indicate that late activation of neutrophils in brain tissue may also promote ongoing injury via the production of CCL23 and impair recovery after cardiac arrest.

A multicenter, randomized, doubleblind, placebo-controlled trial of amantadine to stimulate awakening in comatose patients resuscitated from cardiac arrest.

OBJECTIVE: We hypothesized that the administration of amantadine would increase awakening of comatose patients resuscitated from cardiac arrest. METHODS: We performed a prospective, randomized, controlled pilot trial, randomizing subjects to amantadine 100 mg twice daily or placebo for up to 7 days. The study drug was administered between 72 and 120 hours after resuscitation and patients with absent N20 cortical responses, early cerebral edema, or ongoing malignant electroencephalography patterns were excluded. Our primary outcome was awakening, defined as following two-step commands, within 28 days of cardiac arrest. Secondary outcomes included length of stay, awakening, time to awakening, and neurologic outcome measured by Cerebral Performance Category at hospital discharge. We compared the proportion of subjects awakening and hospital survival using Fisher exact tests and time to awakening and hospital length of stay using Wilcoxon rank sum tests. RESULTS: After 2 years, we stopped the study due to slow enrollment and lapse of funding. We enrolled 14 subjects (12% of goal enrollment), seven in the amantadine group and seven in the placebo group. The proportion of patients who awakened within 28 days after cardiac arrest did not differ between amantadine (n=2, 28.6%) and placebo groups (n=3, 42.9%; P>0.99). There were no differences in secondary outcomes. Study medication was stopped in three subjects (21.4%). Adverse events included a recurrence of seizures (n=2; 14.3%), both of which occurred in the placebo group. CONCLUSION: We could not determine the effect of amantadine on awakening in comatose survivors of cardiac arrest due to small sample size.

Derivation and Validation of a New Equation for Estimating Free Valproate Concentration in Critically Ill Adult Patients.

IMPORTANCE: Protein binding of valproate varies among ICU patients, altering the biologically active free valproate concentration (VPAC). Free VPAC is measured at few laboratories and is often discordant with total VPAC. Existing equations to predict free VPAC are either not validated or are inaccurate in ICU patients. OBJECTIVES: We designed this study to derive and validate a novel equation to predict free VPAC using data from ICU patients and to compare its performance to published equations. DESIGN: Retrospective cohort study. SETTING: Two academic medical centers. PARTICIPANTS: Patients older than 18 years old with concomitant free and total VPACs measured in the ICU were included in the derivation cohort if admitted from 2014 to 2018, and the validation cohort if admitted from 2019 to 2022. MAIN OUTCOMES AND MEASURES: Multivariable linear regression was used to derive an equation to predict free VPAC. Modified Bland-Altman plots and the rate of therapeutic concordance between the measured and predicted free VPAC were compared. RESULTS: Demographics, median free and total VPACs, and valproate free fractions were similar among 115 patients in the derivation cohort and 147 patients in the validation cohort. The Bland-Altman plots showed the new equation performed better (bias, 0.3 [95% limits of agreement, -13.6 to 14.2]) than the Nasreddine (-9.2 [-26.5 to 8.2]), Kodama (-9.7 [-30.0 to 10.7]), Conde Giner (-7.9 [-24.9 to 9.1]), and Parent (-9.9 [-30.7 to 11.0]) equations, and similar to Doré (-2.0 [-16.0 to 11.9]). The Doré and new equations had the highest therapeutic concordance rate (73%). CONCLUSIONS AND RELEVANCE: For patients at risk of altered protein binding such as ICU patients, existing equations to predict free VPAC are discordant with measured free VPAC. A new equation had low bias but was imprecise. External validation should be performed to improve its precision and generalizability. Until then, monitoring free valproate is recommended during critical illness.

Medications for opioid use disorder prescribed at hospital discharge associated with decreased opioid agonist dispensing in patients with opioid use disorder requiring critical care: A retrospective study.

INTRODUCTION: Buprenorphine is highly effective for the treatment of opioid use disorder (OUD), and, in recent years, the rates of patients maintained on buprenorphine requiring critical care have been steadily increasing. Currently, no unified guidance exists for buprenorphine management during critical illness. Likewise, we do not know if patients maintained on buprenorphine for OUD are prescribed medications for OUD (MOUD) following hospital discharge or if buprenorphine management influences mu opioid agonist dispensing. METHODS: In our cohort of adults over the age of 18 with OUD, receiving buprenorphine formulations in the 3 months preceding their ICU admission, we sought to investigate the relationship between receipt of MOUD and non-MOUD opioid prescribing up to 12 months following hospital discharge. This was a single-center, retrospective cohort study approved by the MaineHealth institutional review board. The study analyzed differences in prescription rates between discharge and subsequent time points using chi square or Fisher's exact test, as appropriate. We performed analyses using SPSS Statistical Software version 28 (IBM SPSS Inc., Armonk, NY) with significance set at p < 0.05. RESULTS: We identified a statistically significant increase in MOUD prescribing 3 months posthospital discharge in patients who received MOUD at time of discharge (87.9 % vs 40 % p = 0.002.) The study found a significant increase in nonbuprenorphine opioid prescribing in patients who did not receive an MOUD prescription at time of discharge (24.2 % vs 70 % p = 0.007). This trend persisted at the 6-month and 12-month time points; however, it did not reach statistical significance. Additionally, the study identified a significant reduction in the incidence of non-MOUD opioid dispensing in patients prescribed MOUD at each time point measured (p = 0.007, p < 0.001. p < 0.001 and p = 0.008 at discharge, 3, 6, and 12 months, respectively). CONCLUSIONS: These findings support continuing buprenorphine dispensing following hospital discharge.

Decreased circulating CD73 and adenosine deaminase are associated with disease severity in hospitalized patients with COVID-19.

OBJECTIVE: SARS-CoV-2 infection has been shown to result in increased circulating levels of adenosine triphosphate and adenosine diphosphate and decreased levels of adenosine, which has important anti-inflammatory activity. The goal of this pilot project was to assess the levels of soluble CD73 and soluble Adenosine Deaminase (ADA) in hospitalized patients with COVID-19 and determine if levels of these molecules are associated with disease severity. METHODS: Plasma from 28 PCR-confirmed hospitalized COVID-19 patients who had varied disease severity based on WHO classification (6 mild/moderate, 10 severe, 12 critical) had concentrations of both soluble CD73 and ADA determined by ELISA. These concentrations were compared to healthy control plasma that is commercially available and was biobanked prior to the start of the pandemic. Additionally, outcomes such as WHO ordinal scale for disease severity, ICU admission, needed for invasive ventilation, hospital length of stay, and development of thrombosis during admission were used as markers of disease severity. RESULTS: Our results show that both CD73 and ADA are decreased during SARS-CoV-2 infection. The level of circulating CD73 is directly correlated to the severity of the disease defined by the need for ICU admission, invasive ventilation, and hospital length of stay. Low level of CD73 is also associated with clinical thrombosis, a severe complication of SARS-CoV-2 infection. CONCLUSION: Our study indicates that adenosine metabolism is down-regulated in patients with COVID-19 and associated with severe infection. Further large-scale studies are warranted to investigate the role of the adenosinergic anti-inflammatory CD73/ADA axis in protection against COVID-19.

Buprenorphine Continuation During Critical Illness Associated With Decreased Inpatient Opioid Use in Individuals Maintained on Buprenorphine for Opioid Use Disorder in a Retrospective Study.

The number of patients maintained on buprenorphine is steadily increasing. To date, no study has reported buprenorphine management practices for these patients during critical illness, nor its relationship with supplemental full-agonist opioid administration during their hospital stay. In this single-center retrospective study, we have explored the incidence of buprenorphine continuation during critical illness among patients receiving buprenorphine for the treatment of opioid use disorder. Additionally, we investigated the relationship between nonbuprenorphine opioid exposure and buprenorphine administration during the intensive care unit (ICU) and post-ICU phases of care. Our study included adults maintained on buprenorphine for opioid use disorder admitted to the ICU between December 1, 2014, and May 31, 2019. Nonbuprenorphine, full agonist opioid doses were converted to fentanyl equivalents (FEs). Fifty-one (44%) patients received buprenorphine during the ICU phase of care, with an average dose of 8 (8-12) mg/day. During the post-ICU phase of care, 68 (62%) received buprenorphine, with an average dose of 10 (7-14) mg/day. Lack of mechanical ventilation and acetaminophen use were also associated with buprenorphine use. Full agonist opioid use was more frequent on days when buprenorphine was not given (odds ratio [OR], 6.2 [95% CI, 2.3-16.4]; P < .001). Additionally, the average cumulative dose of opioids given on nonbuprenorphine administration days was significantly higher both in the ICU (OR, 1803 [95% CI, 1271-2553] vs OR, 327 [95% CI, 152-708] FEs/day; P < 0.001) and after ICU discharge (OR, 1476 [95% CI, 962-2265] vs OR, 238 [95% CI, 150-377] FEs/day; P < .001). Given these findings, buprenorphine continuation during critical illness should be considered, as it is associated with significantly decreased full agonist opioid use.

Vasopressin-Induced Hyponatremia in Patients With Aneurysmal Subarachnoid Hemorrhage: A Case Series and Literature Review.

Objective: Vasopressin may be administered to treat vasospasm following aneurysmal subarachnoid hemorrhage (aSAH). The objectives of this study were to describe five cases of suspected vasopressin-induced hyponatremia after aSAH and to review the literature. Design: Single-center, observational case series of intensive care unit (ICU) patients. Settings: Ten-bed neurological ICU at Maine Medical Center in Portland, Maine. Patients: Convenience sample of patients with aSAH treated with a vasopressin for symptomatic, radiologically confirmed vasospasm. Results: A total of five patients were included in the case series with a median age of 57 (51, 65) years and all were women. The median Glasgow coma scale score was 15 (11, 15) on admission, and the Hunt and Hess scale score was 3, (3, 4). All patients were treated with endovascular coiling of their aneurysm. Vasopressin was administered to treat symptomatic, radiographically confirmed vasospasm on median post-bleed day (PBD) 10 (10, 15) at a fixed-dose of .03 units/min. Serum sodium at baseline was 140 (140, 144) mEq/L and decreased to 129 (126, 129) mEq/L within 26 (17, 83) hours of vasopressin initiation for a median change of -16 (-10, -16) mEq/L. Serum sodium returned to baseline within 18 (14, 22) hours of stopping the infusion. Conclusions: Vasopressin use in vasospasm after aSAH may be associated with clinically significant hyponatremia within 24 hours of starting the infusion. Hyponatremia appears to resolve within 24 hours of stopping the infusion. Additional study in a larger sample size is needed to determine if a causal relationship exist.

The number of circulating CD26 expressing cells is decreased in critical COVID-19 illness.

We evaluated the number of CD26 expressing cells in peripheral blood of patients with COVID-19 within 72 h of admission and on day 4 and day 7 after enrollment. The majority of CD26 expressing cells were presented by CD3+ CD4+ lymphocytes. A low number of CD26 expressing cells were found to be associated with critical-severity COVID-19 disease. Conversely, increasing numbers of CD26 expressing T cells over the first week of standard treatment was associated with good outcomes. Clinically, the number of circulating CD26 cells might be a marker of recovery or the therapeutic efficacy of anti-COVID-19 treatment. New therapies aimed at preserving and increasing the level of CD26 expressing T cells may prove useful in the treatment of COVID-19 disease.

Publication rate and impact stratified by gender among pharmacists designated Fellow in the American College of Critical Care Medicine.

BACKGROUND: There are approximately 352,000 pharmacists practicing in the United States, with most (59%) being female. Editorial board membership and publications with a female as the first author in selected pharmacy journals has increased in the past 2 decades. This study determined whether these positive trends are also occurring in critical care pharmacy. OBJECTIVE: To report publication rate and publication impact stratified by male and female gender among pharmacists designated Fellow of Critical Care Medicine (FCCM). METHODS: Pharmacists designated FCCM from inception through the 2020 convocation year were identified in January 2021 using a list provided by the Society of Critical Care Medicine. Pharmacists were excluded if they were designated Master of Critical Care Medicine, did not have an active pharmacist license, or did not have data in the Scopus database. Data were collected in February 2021 including year of first publication, total number of publications, citations, and Hirsch index (h-index). RESULTS: A total of 134 pharmacists were evaluable, including 76 males (57%) and 58 females (43%). Males had an earlier first publication year than females (2005 vs. 2010; P < 0.001). Males have produced a higher number of publications per individual pharmacist (29 vs. 13; P = 0.002) and a similar number of publications per year (2 vs. 1; P = 0.05). When comparing publication impact, males generated more citations (384 vs. 139; P = 0.001) and had a higher h-index (10 vs. 6, P < 0.001). These trends persisted when data from only the past 5 years were used. CONCLUSION: There is statistically significant gender disparity in publication rate and impact. However, this disparity seems to be decreasing with time as the rate of females designated FCCM is increasing. This is consistent with an overall increase in the proportion of pharmacists who are female and deserves further exploration.

Community consultation for Exception from Informed consent (EFIC) before and during the COVID-19 pandemic.

Aim: Describe community consultation and surrogate consent rates for two Exception From Informed Consent (EFIC) trials for out-of-hospital cardiac arrest (OOHCA) - before and during the COVID-19 pandemic. Methods: The PEARL study (2016-2018) randomized OOHCA patients without ST-elevation to early cardiac catheterization or not. Community consultation included flyers, radio announcements, newspaper advertisements, mailings, and in-person surveys at basketball games and ED waiting rooms. The PROTECT trial (2021-present) randomizes OOHCA survivors to prophylactic ceftriaxone or placebo; the community consultation plan during the pandemic included city council presentations, social media posts, outpatient flyers, but no in-person encounters. Demographics for PROTECT community consultation were compared to PEARL and INTCAR registry data, with p-value < 0.05 considered significant. Results: PEARL surveyed 1,362 adults, including 64 % ≥60 years old, 96 % high school graduates or beyond; research acceptance rate was 92 % for the community and 76 % for personal level. PROTECT initially obtained 221 surveys from electronic media - including fewer males (28 % vs 72 %,p < 0.001) and those > 60 years old (14 % vs 53 %;p < 0.001) compared to INTCAR. These differences prompted a revised community consultation plan, targeting 79 adult in-patients with cardiac disease which better matched PEARL and INTCAR data: the majority were ≥ 60 years old (66 %) and male (54 %). Both PEARL and PROTECT enrolled more patients using surrogate consent vs EFIC (57 %, 61 %), including 71 % as remote electronic consents during PROTECT. Conclusions: Community consultation for EFIC studies changed with the COVID-19 pandemic, resulting in different demographic patterns. We describe effective adaptations to community consultation and surrogate consent during the pandemic.

Opioid Prescribing Patterns Before, During, and After Critical Illness: An Observational Study.

OBJECTIVES: The association between opioid therapy during critical illness and persistent opioid use after discharge is understudied relative to ICU opioid exposure and modifiable risk factors. Our objectives were to compare persistent opioid use after discharge among patients with and without chronic opioid use prior to admission (OPTA) and identify risk factors associated with persistent use. DESIGN: Retrospective cohort study. SETTING: Medical, trauma/surgical, or neurologic ICU at an academic hospital. PARTICIPANTS: Adult patients surviving hospital admission. INTERVENTIONS: Opioid use during the ICU and post-ICU stays. MEASUREMENTS AND MAIN RESULTS: The primary outcome was persistent opioid use accounting for greater than 70% of days 4-6 months after discharge. Among 2,975 included patients, 257 (8.6%) were classified as OPTA, and 305 (10.2%) persistently filled opioid prescriptions, including 186/257 (72%) OPTA and 119/2,718 (4.4%) with no chronic opioid fills prior to admission. Among all patients, OPTA was strongly associated with persistent opioid use (odds ratio, 57.2 [95% CI, 41.4-80.0]). Multivariable logistic regression revealed that male sex, surgical procedure, and ICU opioid-free days were associated with reduced persistent opioid use for OPTA patients. Age and ICU opioid-free days were associated with reduced persistent opioid use for non-OPTA patients. Total ICU opioid dose and dose per day of ICU exposure were not associated with persistent use for either group. CONCLUSIONS: In this mixed cohort of ICU patients, 10.2% persistently filled opioid prescriptions 4-6 months after discharge. Although ICU opioid doses were not associated with persistent use, duration of ICU opioid administration is a modifiable risk factor that may reduce persistent opioid use after critical illness.

Ceftriaxone to PRevent pneumOnia and inflammaTion aftEr Cardiac arresT (PROTECT): study protocol for a randomized, placebo-controlled trial.

BACKGROUND: Pneumonia is the most common infection after out-of-hospital cardiac arrest (OHCA) occurring in up to 65% of patients who remain comatose after return of spontaneous circulation. Preventing infection after OHCA may (1) reduce exposure to broad-spectrum antibiotics, (2) prevent hemodynamic derangements due to local and systemic inflammation, and (3) prevent infection-associated morbidity and mortality. METHODS: The ceftriaxone to PRevent pneumOnia and inflammaTion aftEr Cardiac arrest (PROTECT) trial is a randomized, placebo-controlled, single-center, quadruple-blind (patient, treatment team, research team, outcome assessors), non-commercial, superiority trial to be conducted at Maine Medical Center in Portland, Maine, USA. Ceftriaxone 2 g intravenously every 12 h for 3 days will be compared with matching placebo. The primary efficacy outcome is incidence of early-onset pneumonia occurring < 4 days after mechanical ventilation initiation. Concurrently, T cell-mediated inflammation bacterial resistomes will be examined. Safety outcomes include incidence of type-one immediate-type hypersensitivity reactions, gallbladder injury, and Clostridioides difficile-associated diarrhea. The trial will enroll 120 subjects over approximately 3 to 4 years. DISCUSSION: The PROTECT trial is novel in its (1) inclusion of OHCA survivors regardless of initial heart rhythm, (2) use of a low-risk antibiotic available in the USA that has not previously been tested after OHCA, (3) inclusion of anti-inflammatory effects of ceftriaxone as a novel mechanism for improved clinical outcomes, and (4) complete metagenomic assessment of bacterial resistomes pre- and post-ceftriaxone prophylaxis. The long-term goal is to develop a definitive phase III trial powered for mortality or functional outcome. TRIAL REGISTRATION: ClinicalTrials.gov NCT04999592 . Registered on August 10, 2021.

Perceptions Regarding the SARS-CoV-2 Pandemic's Impact on Neurocritical Care Delivery: Results From a Global Survey.

BACKGROUND: The SARS-CoV-2 (COVID-19) pandemic has impacted many facets of critical care delivery. METHODS: An electronic survey was distributed to explore the pandemic's perceived impact on neurocritical care delivery between June 2020 and March 2021. Variables were stratified by World Bank country income level, presence of a dedicated neurocritical care unit (NCCU) and experiencing a COVID-19 patient surge. RESULTS: Respondents from 253 hospitals (78.3% response rate) from 47 countries (45.5% low/middle income countries; 54.5% with a dedicated NCCU; 78.6% experienced a first surge) participated in the study. Independent of country income level, NCCU and surge status, participants reported reductions in NCCU admissions (67%), critical care drug shortages (69%), reduction in ancillary services (43%) and routine diagnostic testing (61%), and temporary cancellation of didactic teaching (44%) and clinical/basic science research (70%). Respondents from low/middle income countries were more likely to report lack of surge preparedness (odds ratio [OR], 3.2; 95% confidence interval [CI], 1.8-5.8) and struggling to return to prepandemic standards of care (OR, 12.2; 95% CI, 4.4-34) compared with respondents from high-income countries. Respondents experiencing a surge were more likely to report conversion of NCCUs and general-mixed intensive care units (ICUs) to a COVID-ICU (OR 3.7; 95% CI, 1.9-7.3), conversion of non-ICU beds to ICU beds (OR, 3.4; 95% CI, 1.8-6.5), and deviations in critical care and pharmaceutical practices (OR, 4.2; 95% CI 2.1-8.2). Respondents from hospitals with a dedicated NCCU were less likely to report conversion to a COVID-ICU (OR, 0.5; 95% CI, 0.3-0.9) or conversion of non-ICU to ICU beds (OR, 0.5; 95% CI, 0.3-0.9). CONCLUSION: This study reports the perceived impact of the COVID-19 pandemic on global neurocritical care delivery, and highlights shortcomings of health care infrastructures and the importance of pandemic preparedness.

Evaluation of Free Valproate Concentration in Critically Ill Patients.

Protein binding of valproate is variable in ICU patients, and the total valproate concentration does not predict the free valproate concentration, even when correcting for albumin. We sought to quantify valproate free concentration among ICU patients, identify risk factors associated with an increasing free valproate concentration, and evaluate the association between free valproate concentration with potential adverse drug effect. DESIGN: Retrospective multicenter cohort study. SETTING: Two academic medical centers. PATIENTS: Patients greater than or equal to 18 years of age with concomitant free and total valproate concentrations collected in the ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two-hundred fifty-six patients were included in the study, with a median age of 56 years (42-70) and 65% of patients were male. The median total valproate concentration was 53 µg/mL (38-70 µg/mL), the free valproate concentration was 12 µg/mL (7-20 µg/mL), and the free fraction was 23.6% (17.0-33.9%). Therapeutic discordance between the free and total valproate concentration occurred in 70% of patients. On multivariable analysis, increased free valproate concentration was associated with higher total valproate concentration (per 5 µg/mL increase, increase 1.72 µg/mL, 95% CI, 1.48-1.96) and lower serum albumin (per 1 g/dL decrease, increase 4.60 µg/mL, 95% CI, 2.71-6.49). There was no association between free valproate concentration and adverse effects. CONCLUSIONS: The valproate total and free concentration was discordant in the majority of patients (70%). Increased valproate free concentration was associated with hypoalbuminemia and total valproate concentration. Clinical decisions based on total valproate concentration may be incorrect for many ICU patients. Prospective, controlled studies are needed to confirm these findings and their clinical relevance.

DEspRhigh neutrophils are associated with critical illness in COVID-19.

SARS-CoV-2 infection results in a spectrum of outcomes from no symptoms to widely varying degrees of illness to death. A better understanding of the immune response to SARS-CoV-2 infection and subsequent, often excessive, inflammation may inform treatment decisions and reveal opportunities for therapy. We studied immune cell subpopulations and their associations with clinical parameters in a cohort of 26 patients with COVID-19. Following informed consent, we collected blood samples from hospitalized patients with COVID-19 within 72 h of admission. Flow cytometry was used to analyze white blood cell subpopulations. Plasma levels of cytokines and chemokines were measured using ELISA. Neutrophils undergoing neutrophil extracellular traps (NET) formation were evaluated in blood smears. We examined the immunophenotype of patients with COVID-19 in comparison to that of SARS-CoV-2 negative controls. A novel subset of pro-inflammatory neutrophils expressing a high level of dual endothelin-1 and VEGF signal peptide-activated receptor (DEspR) at the cell surface was found to be associated with elevated circulating CCL23, increased NETosis, and critical-severity COVID-19 illness. The potential to target this subpopulation of neutrophils to reduce secondary tissue damage caused by SARS-CoV-2 infection warrants further investigation.