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Purpose: Prompt treatment of sepsis and septic shock is critical as delays increase mortality risk. Various tools, such as electronic alerts, standardized order sets, and rapid response teams, are used to expedite sepsis bundled care, yet their individual effects on outcomes and antimicrobial timing are unclear. This study evaluated the impact of an Inpatient Code Sepsis protocol, featuring an overhead page and order set, on mortality in hospitalized patients with sepsis and septic shock. Methods: A retrospective cohort study was conducted at a 371-bed hospital from July 1, 2020, to July 31, 2023. Hospitalized adults (≥18 years) diagnosed with sepsis and septic shock before and after the Inpatient Code Sepsis protocol implementation were included. The primary outcome was 30-day all-cause mortality; secondary outcomes were hospital length of stay, 30-day readmission, and time to antibiotic administration. Patients were excluded if they were identified for sepsis without infection, had sepsis due to non-bacterial causes, lost to follow-up within 30 days of admission, received empiric antibiotics in an emergency department or outside hospital, or were missing antibiotic administration time. Results: A total of 138 patients were included in the analysis. Mortality within 30 days did not significantly differ preprotocol and postprotocol ( p = 0.381). However, a significant reduction in time to antibiotic administration was noted postimplementation ( p < 0.05). Hospital length of stay and 30-day readmission showed no significant changes. Conclusion: The Inpatient Code Sepsis protocol did not impact 30-day mortality but did improve the time to antibiotic administration., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Background: Reduction in sedation exposure is an important metric in intensive care unit (ICU) patients. However, challenges arose during the coronavirus disease-2019 (COVID-19) pandemic in adhering to this practice, driven by concerns on transmission and disease severity issues. Accordingly, diverse sedation approaches emerged, although the effect on mortality has not been studied thoroughly. Methods: Retrospective cohort study in the medical ICU of seven hospitals within a major Health System in Northeast Ohio. We included all adult patients admitted with COVID-19 requiring invasive mechanical ventilation (IMV) from March 2020 to December 2021. Results: Study included 2394 COVID-19 patients requiring IMV. Across waves, sample included 55-63% male subjects, with an average age of 61-68 years ( P  < 0.001), Acute Physiologic and Chronic Health Evaluation (APACHE)-III score 65.8-68.9 ( P  = 0.37), median IMV duration 8-10 days ( P  = 0.14), and median ICU duration 9.8-11.6 days ( P  = 0.084). Propofol remained the primary sedative (84-92%; P  = 0.089). Ketamine use increased from the first (9.7%) to fourth (19%) wave ( P  = 0.002). Midazolam use decreased from the first (27.4%) to third (9.4%) wave ( P  = 0.001). Dexmedetomidine use declined from 35% to 27-28% ( P  = 0.002) after the first wave. A multivariable regression analysis indicated clinical variables explained 34% of the variation in hospital mortality (R 2 ). Factors associated with higher mortality included age [aOR = 1.059 (95% CI 1.049-1.069); P  < 0.001], COVID-19 wave, especially fourth wave [aOR = 2.147, (95% CI 1.370-3.365); P  = 0.001], and higher number of vasopressors [aOR = 31.636, (95% CI 17.603-56.856); P  < 0.001]. Addition of sedative medications to a second model led to an increase in the R 2 by only 1.6% to 35.6% [aOR = 1 (95% CI 1-1); P  > 0.05] for propofol, ketamine, and midazolam. Dexmedetomidine demonstrated a decrease in the odds of mortality [aOR = 0.96 (95% CI 0.94-0.97); P  < 0.001]. Conclusion: Mortality in critical COVID-19 patients was mostly driven by illness severity, and the choice of sedation might have minimal impact when other factors are controlled., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Conventional prediction models fail to integrate the constantly evolving nature of critical illness. Alternative modelling approaches to study dynamic changes in critical illness progression are needed. We compare static risk prediction models to dynamic probabilistic models in early critical illness., Design: We developed models to simulate disease trajectories of critically ill COVID-19 patients across different disease states. Eighty per cent of cases were randomly assigned to a training and 20% of the cases were used as a validation cohort. Conventional risk prediction models were developed to analyse different disease states for critically ill patients for the first 7 days of intensive care unit (ICU) stay. Daily disease state transitions were modelled using a series of multivariable, multinomial logistic regression models. A probabilistic dynamic systems modelling approach was used to predict disease trajectory over the first 7 days of an ICU admission. Forecast accuracy was assessed and simulated patient clinical trajectories were developed through our algorithm., Setting and Participants: We retrospectively studied patients admitted to a Cleveland Clinic Healthcare System in Ohio, for the treatment of COVID-19 from March 2020 to December 2022., Results: 5241 patients were included in the analysis. For ICU days 2-7, the static (conventional) modelling approach, the accuracy of the models steadily decreased as a function of time, with area under the curve (AUC) for each health state below 0.8. But the dynamic forecasting approach improved its ability to predict as a function of time. AUC for the dynamic forecasting approach were all above 0.90 for ICU days 4-7 for all states., Conclusion: We demonstrated that modelling critical care outcomes as a dynamic system improved the forecasting accuracy of the disease state. Our model accurately identified different disease conditions and trajectories, with a <10% misclassification rate over the first week of critical illness., Competing Interests: Competing interests: No conflicts of interest or competing interests reported by any authors related to this work. Dr. Duggal is on the Advisory Board for ALung technologies, but that relationship has no impact on this work., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The immunomodulators tocilizumab and baricitinib improve outcomes in severely ill patients with coronavirus disease 2019 (COVID-19); however, comparative analyses of clinical outcomes related to these agents are lacking. A tocilizumab national shortage shifted treatment to baricitinib in critically ill patients, allowing for an outcome comparison in a similar population. The purpose of this study is to compare clinical outcomes in critically ill COVID-19 patients who received tocilizumab and those who received baricitinib., Design: Retrospective, observational cohort study using generalized estimating equation models, accounting for clustering by hospital and known confounders, to estimate the proportional odds of the ordinal World Health Organization Clinical Progression Scale (WHO-CPS) score at day 14, the primary outcome. Secondary outcomes included WHO-CPS score at day 7., Setting: Multiple hospitals within the Cleveland Clinic Health System., Patients: Adult patients admitted for COVID-19 between January 2021 and November 2021., Interventions: Receipt of tocilizumab, before its shortage, or baricitinib, during shortage., Measurements and Main Results: In total, 507 patients were included; 217 received tocilizumab and 290 received baricitinib. Over 96% of patients required ICU admission and 98% received concomitant dexamethasone. Tocilizumab recipients had higher (worse) baseline WHO-CPS scores. After adjustment, tocilizumab use was associated with higher odds of a worse day 14 WHO-CPS score compared with baricitinib (adjusted odds ratio [OR] 1.65 [95% confidence interval (CI) 1.10-2.48]). Similarly, after adjustment, tocilizumab use was associated with higher odds of a worse day 7 WHO-CPS score (adjusted OR 1.65 [95% CI 1.22-2.24])., Conclusions: Baricitinib use was associated with better WHO-CPS scores at day 14 and day 7 compared with tocilizumab in a cohort of critically ill patients with COVID-19. The odds of having a one unit increase in WHO-CPS score at day 14 was 71% higher with tocilizumab than baricitinib. No difference in mortality or adverse effects was noted., (© 2023 Pharmacotherapy Publications, Inc.)

Topic Importance: This review discusses the rationale for vasopressin use, summarizes the results of clinical trials evaluating vasopressin, and focuses on the timing of vasopressin initiation to provide clinicians guidance for optimal adjunctive vasopressin initiation in patients with septic shock., Review Findings: Patients with septic shock require vasoactive agents to restore adequate tissue perfusion. After norepinephrine, vasopressin is the suggested second-line adjunctive agent in patients with persistent inadequate mean arterial pressure. Vasopressin use in practice is heterogeneous likely because of inconsistent clinical trial findings, the lack of specific recommendations for when it should be used, and the high drug acquisition cost. Despite these limitations, vasopressin has demonstrated price inelastic demand, and its use in the United States has continued to increase. However, questions remain regarding optimal vasopressin use in patients with septic shock, particularly regarding patient selection and the timing of vasopressin initiation., Summary: Experimental studies evaluating the initiation timing of vasopressin in patients with septic shock are limited, and recent observational studies have revealed an association between vasopressin initiation at lower norepinephrine-equivalent doses or lower lactate concentrations and lower mortality., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: G. L. S. reports that she is a consultant for Wolters Kluwer. None declared (S. R. B.)., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Financial/Nonfinancial Disclosures None declared.

Importance: Ritonavir-boosted nirmatrelvir and molnupiravir are currently used in the US and in other countries to treat nonhospitalized patients who have mild-to-moderate COVID-19 and who are at high risk for progression to severe disease. The associations of these 2 oral antiviral drugs with hospitalization and death resulting from infection with new SARS-CoV-2 Omicron subvariants, particularly BQ.1.1 and XBB.1.5, are unknown., Objective: To assess the association of nirmatrelvir or molnupiravir use with the risks of hospitalization and death among patients infected with new Omicron subvariants., Design, Setting, and Participants: This was a cohort study of patients who received a diagnosis of COVID-19 at Cleveland Clinic from April 1, 2022, to February 20, 2023 (during which the Omicron variant evolved from BA.2 to BA.4/BA.5, then to BQ.1/BQ.1.1, and finally to XBB/XBB.1.5) and who were at high risk of progressing to severe disease, with follow-up through 90 days after diagnosis. The final date for follow-up data collection was February 27, 2023., Exposures: Treatment with ritonavir-boosted nirmatrelvir or molnupiravir., Main Outcomes and Measures: The primary outcome was time to death. The secondary outcome was time to either hospitalization or death. The association of either nirmatrelvir or molnupiravir use with each outcome was measured by the hazard ratio (HR) adjusted for demographic factors, socioeconomic status, date of COVID-19 diagnosis, coexisting medical conditions, COVID-19 vaccination status, and previous SARS-CoV-2 infection., Results: There were 68 867 patients (29 386 [42.7%] aged ≥65 years; 26 755 [38.9%] male patients; 51 452 [74.7%] non-Hispanic White patients). Thirty of 22 594 patients treated with nirmatrelvir, 27 of 5311 patients treated with molnupiravir, and 588 of 40 962 patients who received no treatment died within 90 days of Omicron infection. The adjusted HRs of death were 0.16 (95% CI, 0.11-0.23) for nirmatrelvir and 0.23 (95% CI, 0.16-0.34) for molnupiravir. The adjusted HRs of hospitalization or death were 0.63 (95% CI, 0.59-0.68) for nirmatrelvir and 0.59 (95% CI, 0.53-0.66) for molnupiravir. The associations of both drugs with both outcomes were observed across subgroups defined by age, race and ethnicity, date of COVID-19 diagnosis, vaccination status, previous infection status, and coexisting conditions., Conclusions and Relevance: These findings suggest that the use of either nirmatrelvir or molnupiravir is associated with reductions in mortality and hospitalization in patients infected with Omicron, regardless of age, race and ethnicity, virus strain, vaccination status, previous infection status, or coexisting conditions. Both drugs can, therefore, be used to treat nonhospitalized patients who are at high risk of progressing to severe COVID-19.

Purpose: Vasopressin, used as a catecholamine adjunct, is a vasoconstrictor that may be detrimental in some hemodynamic profiles, particularly left ventricular (LV) systolic dysfunction. This study tested the hypothesis that echocardiographic parameters differ between patients with a hemodynamic response after vasopressin initiation and those without a response., Methods: This retrospective, single-center, cross-sectional study included adults with septic shock receiving catecholamines and vasopressin with an echocardiogram performed after shock onset but before vasopressin initiation. Patients were grouped by hemodynamic response, defined as decreased catecholamine dosage with mean arterial pressure ≥ 65 mmHg six hours after vasopressin initiation, with echocardiographic parameters compared. LV systolic dysfunction was defined as LV ejection fraction (LVEF) <45%., Results: Of 129 included patients, 72 (56%) were hemodynamic responders. Hemodynamic responders, versus non-responders, had higher LVEF (61% [55%,68%] vs. 55% [40%,65%]; p = 0.02) and less-frequent LV systolic dysfunction (absolute difference  -16%; 95% CI -30%,-2%). Higher LVEF was associated with higher odds of hemodynamic response (for each LVEF 10%, response OR 1.32; 95% CI 1.04-1.68). Patients with LV systolic dysfunction, versus without LV systolic dysfunction, had higher mortality risk (HR(t) = e [0.81-0.1*t] ; at t = 0, HR 2.24; 95% CI 1.08-4.64)., Conclusions: Pre-drug echocardiographic profiles differed in hemodynamic responders after vasopressin initiation versus non-responders., Competing Interests: Declaration of Competing Interest PC disclosed he received consulting and speaking fees from Philips. All other authors have disclosed that they do not have any conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The use of stress dose corticosteroids, specifically, hydrocortisone, in septic shock is heterogeneous, and current clinical trials yield conflicting results. Regardless, they are still recommended by guidelines for vasopressor-dependent septic shock. Objectives: This study sought to characterize current practice of hydrocortisone use in patients with septic shock and secondarily to compare clinical outcomes of those who received hydrocortisone to those who did not. Methods: This single center, retrospective cohort study evaluated patients with septic shock admitted to a tertiary care center between 2012 and 2017. Patients receiving hydrocortisone for at least two doses were compared to those without. Results: 3411 septic shock patients were included; 1593 (47%) received hydrocortisone and 1818 (53%) did not. Patients who received hydrocortisone had higher lactate (4.0 vs 3.4 mmol/L; P < .01) and Acute Physiology and Chronic Health Evaluation (APACHE) III scores (104.1 vs 91.0; P < .01). Vasopressor duration was 1.7 days longer in the hydrocortisone group ( P < .01), and the hydrocortisone group had higher hospital mortality (52% vs 38%; P < .01). A propensity score-matched population was conducted in patients with APACHE scores >100: vasopressor duration was longer in those who received hydrocortisone (3.9 vs 2.0 days; P < .01), and hospital mortality was higher (59.3% vs 53.1%; P = .036); however, after multivariable adjustment, no association between receipt of hydrocortisone and hospital mortality was detected (OR 1.2 [95% CI .9-1.6]). Conclusions: Patients who received hydrocortisone were more severely ill than those that did not, making retrospective evaluation of this question challenging. These results highlight the wide variability and heterogeneity in hydrocortisone use in clinical practice.

Background: Delay to first antibiotic dose in patients with sepsis has been associated with increased mortality. Second dose antibiotic delay has also been linked to worsened patient outcomes. Optimal methods to decrease second dose delay are currently unclear. The primary objective of this study was to evaluate the association between updating an emergency department (ED) sepsis order set design from one-time doses to scheduled antibiotic frequencies and delay to administration of second piperacillin-tazobactam dose., Methods: This retrospective cohort study was conducted at eleven hospitals in a large, integrated health system and included adult patients treated in the ED with at least one dose of piperacillin-tazobactam ordered through an ED sepsis order set over a two year period. Patients were excluded if they received less than two doses of piperacillin-tazobactam. Midway through the study period, the enterprise-wide ED sepsis order set was updated to include scheduled antibiotic frequencies. Two patient cohorts receiving piperacillin-tazobactam were compared: those in the year before the order set update and those in the year post-update. The primary outcome was major delay, defined as an administration delay >25% of the recommended dosing interval, which was evaluated with multivariable logistic regression and interrupted time series analysis., Results: 3219 patients were included: 1222 in the pre-update group and 1997 in the post-update group. The proportion of patients who experienced major second dose delay was significantly lower in the post-update group (32.7% vs 25.6%, p < 0.01; adjusted OR 0.64, 95% CI 0.52 to 0.78). No between-group difference was detected in the slope of monthly major delay frequency, but there was a significant level change (post-update change -10%, 95% CI -17.9% to -1.9%)., Conclusions: Including scheduled antibiotic frequencies in ED sepsis order sets is a pragmatic mechanism to decrease delays in second antibiotic doses., Competing Interests: Declaration of Competing Interest SRB is supported by a grant from the National Institutes of Health, National Institute of General Medical Sciences [grant number K08GM147806]. The funding sources had no role in study design; data collection, analysis, or interpretation; writing the report; or the decision to submit the report for publication. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. The remaining authors have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: In septic shock, vasopressors aim to improve tissue perfusion and prevent persistent organ dysfunction, a characteristic of chronic critical illness (CCI). Adjunctive vasopressin is often used to decrease catecholamine dosage, but the association of vasopressin response with subsequent patient outcomes is unclear. We hypothesized vasopressin response is associated with favorable clinical trajectory., Methods: We included patients with septic shock receiving vasopressin as a catecholamine adjunct in this retrospective cohort study. We defined vasopressin response as a lowering of the catecholamine dose required to maintain mean arterial pressure ≥65 mm Hg, 6 h after vasopressin initiation. Clinical trajectories were adjudicated as early death (ED; death before day 14), CCI (ICU stay ≥14 days with persistent organ dysfunction), or rapid recovery (RR; not meeting ED or CCI criteria). Trajectories were placed on an ordinal scale with ED the worst outcome, CCI next, and RR the best outcome. The association of vasopressin response with clinical trajectory was assessed with multivariable ordinal logistic regression., Results: In total 938 patients were included; 426 (45.4%) were vasopressin responders. The most frequent trajectory was ED (49.8%), 29.7% developed CCI, and 20.5% had rapid recovery. In survivors to ICU day 14 (those without ED), 59.2% had CCI and 40.8% experienced RR. Compared with vasopressin non-responders, vasopressin responders less frequently experienced ED (42.5% vs. 55.9%) and more frequently experienced RR (24.6% vs. 17.0%; P  < 0.01). After controlling for confounders, vasopressin response was independently associated with higher odds of developing a better clinical trajectory (OR 1.63; 95% CI 1.26-2.10). Medical patients most frequently developed ED and survivors more commonly developed CCI than RR; surgical patients developed the three trajectories with similar frequency ( P  < 0.01)., Conclusions: Vasopressin responsive status was associated with improved clinical trajectory in septic shock patients. Early vasopressin response is a potential novel prognostic marker for short-term clinical trajectory.

Background: Vancomycin pharmacokinetics are altered in the critically ill and are further distorted by renal replacement therapy. Limited literature is available evaluating vancomycin dosing in continuous veno-venous hemodialysis (CVVHD)., Objective: The goal of this analysis was to identify factors that affect vancomycin trough concentration in patients on CVVHD and to determine an appropriate dosing strategy., Methods: This was a single-center, retrospective cohort study of adult inpatients admitted to the Cleveland Clinic from May 2016-December 2017. Patients in the intensive care unit who received ≥ 2 doses of vancomycin during CVVHD were included. Patients with interruptions of CVVHD inappropriately timed troughs, a change in dialysate rate, and those who received different vancomycin dosages were excluded. Multivariable linear regression including age, sex, weight, Sequential Organ Failure Assessment score, albumin, 24-hour urine output (UOP), dialysate rate, filter type, and vancomycin dose was run to determine predictors of vancomycin concentration., Results: A total of 160 patients were included. The median vancomycin dose was 12.6 mg/kg with a trough of 24.6 mcg/mL. Weight, 24-hour UOP, vancomycin dose (mg/kg), and dialysate rate (mL/kg/h) were all determined to be independent predictors of vancomycin trough level. Patients who received <10 mg/kg doses of vancomycin (N=18) achieved a median trough of 21.5 mcg/mL, with 83% being therapuetic. In patients who received >10 mg/kg (N=142), the median trough was 25.5 mcg/mL, with 47% being therapeutic., Conclusion and Relevance: Vancomycin dose, dialysate rate, UOP, and weight are independently associated with vancomycin trough concentration. In CVVHD patients, vancomycin dosed at 10 mg/kg every 24 hours may be an appropriate recommendation.

Objectives: Despite the established role of the critical care pharmacist on the ICU multiprofessional team, critical care pharmacist workloads are likely not optimized in the ICU. Medication regimen complexity (as measured by the Medication Regimen Complexity-ICU [MRC-ICU] scoring tool) has been proposed as a potential metric to optimize critical care pharmacist workload but has lacked robust external validation. The purpose of this study was to test the hypothesis that MRC-ICU is related to both patient outcomes and pharmacist interventions in a diverse ICU population., Design: This was a multicenter, observational cohort study., Setting: Twenty-eight ICUs in the United States., Patients: Adult ICU patients., Interventions: Critical care pharmacist interventions (quantity and type) on the medication regimens of critically ill patients over a 4-week period were prospectively captured. MRC-ICU and patient outcomes (i.e., mortality and length of stay [LOS]) were recorded retrospectively., Measurements and Main Results: A total of 3,908 patients at 28 centers were included. Following analysis of variance, MRC-ICU was significantly associated with mortality (odds ratio, 1.09; 95% CI, 1.08-1.11; p < 0.01), ICU LOS (β coefficient, 0.41; 95% CI, 00.37-0.45; p < 0.01), total pharmacist interventions (β coefficient, 0.07; 95% CI, 0.04-0.09; p < 0.01), and a composite intensity score of pharmacist interventions (β coefficient, 0.19; 95% CI, 0.11-0.28; p < 0.01). In multivariable regression analysis, increased patient: pharmacist ratio (indicating more patients per clinician) was significantly associated with increased ICU LOS (β coefficient, 0.02; 0.00-0.04; p = 0.02) and reduced quantity (β coefficient, -0.03; 95% CI, -0.04 to -0.02; p < 0.01) and intensity of interventions (β coefficient, -0.05; 95% CI, -0.09 to -0.01)., Conclusions: Increased medication regimen complexity, defined by the MRC-ICU, is associated with increased mortality, LOS, intervention quantity, and intervention intensity. Further, these results suggest that increased pharmacist workload is associated with decreased care provided and worsened patient outcomes, which warrants further exploration into staffing models and patient outcomes., Competing Interests: Dr. Newsome has received research funding through the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Numbers UL1TR002378 and KL2TR002381. Dr. Rech’s institution received funding from Spero Pharmaceuticals; she received funding from Harm Reduction Therapeutics. Dr. DePriest received funding from Baxter. Dr. Flannery’s institution received funding from the National Institute of Diabetes and Digestive and Kidney Diseases, the American Society of Nephrology, and La Jolla Pharmaceutical Company. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: At outset of the coronavirus disease 2019 (COVID-19) pandemic, the significance of bacterial and fungal coinfections in individuals with COVID-19 was unknown. Initial reports indicated that the prevalence of coinfection in the general population was low, but there was uncertainty regarding the risk of coinfection in critically ill patients., Methods: Nine hundred critically ill adult patients with COVID-19 infection were enrolled in this observational case-control study. Patients with a coinfection (case) and patients without a coinfection (control) were compared using univariate and multivariable analyses. A subgroup analysis was performed on patients with coinfection, dividing them into early (infection within 7 days) and late (infection after 7 days) infection groups., Results: Two hundred and thirty-three patients (25.9%) had a bacterial or fungal coinfection. Vasopressor use (P<0.001) and severity of illness (higher Acute Physiology and Chronic Health Evaluation III score, P=0.009) were risk factors for the development of a coinfection. Patients with coinfection had higher mortality and length of stay. Vasopressor and corticosteroid use and central line and foley catheter placement were risk factors for late infection (>7 days). There were high rates of drug-resistant infections., Conclusions: Critically ill patients with COVID-19 are at risk for both community-acquired and hospital-acquired infections throughout their hospitalization for COVID-19. It is important to consider the development of a coinfection in clinically worsening critically ill patients with COVID-19 and consider the likelihood of drug-resistance when choosing an empiric regimen.

Septic shock remains a health care concern associated with significant morbidity and mortality. The Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock recommend early fluid resuscitation and antimicrobials. Beyond initial management, the guidelines do not provide clear recommendations on appropriate time to initiate vasoactive therapies and corticosteroids in patients who develop shock. This review summarizes the literature regarding time of initiation of these interventions. Clinical data regarding time of initiation of these therapies in relation to shock onset, sequence of treatments with regard to each other, and clinical markers evaluated to guide initiation are summarized. Early-high vasopressor initiation within first 6 h of shock onset is associated with lower mortality. Following norepinephrine initiation, the exact dose and timing of escalation to adjunctive vasopressor agents are not well elucidated in the literature. However, recent data indicate that timing may be an important factor in initiating vasopressors and adjunctive therapies, such as corticosteroids. Norepinephrine-equivalent dose and lactate concentration can aid in determining when to initiate vasopressin and angiotensin II in patients with septic shock. Future guidelines with clear recommendations on the time of initiation of septic shock therapies are warranted., (© 2022. The Author(s).)

Objectives: To determine the association of catecholamine dose, lactate concentration, and timing from shock onset at vasopressin initiation with in-hospital mortality., Design: Retrospective, observational study using segmented and multivariable logistic regression to evaluate the associations of catecholamine dose, lactate concentration, and timing from shock onset at vasopressin initiation with in-hospital mortality., Setting: Multiple hospitals within the Cleveland Clinic Health System., Patients: Adult patients who met criteria for septic shock based on the U.S. Centers for Disease Control and Prevention Adult Sepsis Event definition., Interventions: All patients received continuous infusion vasopressin as an adjunct to catecholamine vasopressors., Measurements and Main Results: In total, 1,610 patients were included with a mean Acute Physiology and Chronic Health Evaluation III 109.0 ± 35.1 and Sequential Organ Failure Assessment 14.0 ± 3.5; 41% of patients survived the hospital admission. At the time of vasopressin initiation, patients had median (interquartile range) lactate concentration 3.9 mmol/L (2.3-7.2 mmol/L), norepinephrine-equivalent dose 25 µg/min (18-40 µg/min), and 5.3 hours (2.1-12.2 hr) elapsed since shock onset. The odds of in-hospital mortality increased 20.7% for every 10 µg/min increase in norepinephrine-equivalent dose up to 60 µg/min at the time of vasopressin initiation (adjusted odds ratio, 1.21 [95% CI, 1.09-1.34]), but no association was detected when the norepinephrine-equivalent dose exceeded 60 µg/min (adjusted odds ratio, 0.96 [95% CI, 0.84-1.10]). There was a significant interaction between timing of vasopressin initiation and lactate concentration (p = 0.02) for the association with in-hospital mortality. A linear association between increasing in-hospital mortality was detected for increasing lactate concentration at the time of vasopressin initiation, but no association was detected for time elapsed from shock onset., Conclusions: Higher norepinephrine-equivalent dose at vasopressin initiation and higher lactate concentration at vasopressin initiation were each associated higher in-hospital mortality in patients with septic shock who received vasopressin., Competing Interests: Dr. Bauer reports that he is a consultant for Wolters Kluwer, and he received funding from Wolters Kluwer. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objectives: Vasopressin is suggested as an adjunct to norepinephrine in patients with septic shock. However, after vasopressin was rebranded in November 2014, its cost exponentially increased. Utilization patterns of vasopressin after its rebranding are unclear. The objective of this study was to determine if there is an association between the rebranding of vasopressin in November 2014 and its utilization in vasopressor-dependent patients with severe sepsis or septic shock., Design: Retrospective, multicenter, database study between January 2010 and March 2017., Setting: Premier Healthcare Database hospitals., Patients: Adult patients admitted to an ICU with severe sepsis or septic shock, who received at least one vasoactive agent for two or more calendar days were included., Interventions: The proportion of patients who received vasopressin and vasopressin cost was assessed before and after rebranding, and evaluated with segmented regression., Measurements and Main Results: Among 294,733 patients (mean age, 66 ± 15 yr), 27.8% received vasopressin, and ICU mortality was 26.5%. The proportion of patients receiving vasopressin was higher after rebranding (31.2% postrebranding vs 25.8% prerebranding). Before vasopressin rebranding, the quarterly proportion of patients who received vasopressin had an increasing slope (prerebranding slope 0.41% [95% CI, 0.35-0.46%]), with no difference in slope detected after vasopressin rebranding (postrebranding slope, 0.47% [95% CI, 0.29-0.64%]). After vasopressin rebranding, mean vasopressin cost per patient was higher ($527 ± 1,130 vs $77 ± 160), and the quarterly slope of vasopressin cost was higher (change in slope $77.18 [95% CI, $75.73-78.61]). Total vasopressin billed cost postrebranding continually increased by ~$294,276 per quarter from less than $500,000 in Q4 2014 to over $3,000,000 in Q1 2017., Conclusions: After vasopressin rebranding, utilization continued to increase quarterly despite a significant increase in vasopressin cost. Vasopressin appeared to have price inelastic demand in septic shock., Competing Interests: Dr. Bauer reports he is a consultant for Wolters Kluwer. Dr. Reynolds has a research contract with Bristol, Myers, and Squibb administered through the University of Colorado and serves as the Deputy Editor at Circulation: Cardiovascular Quality and Outcomes Journal. Dr. Kiser’s institution received funding from seed grant funding from the Department of Clinical Pharmacy at the University of Colorado Skaggs School of Pharmacy, and the Colorado Clinical and Translational Science Award grant UL1 TR002535 from the National Center for Advancing Translational Sciences/National Institutes of Health. Dr. Ho’s institution received funding from Bristol-Myers Squibb through the University of Colorado; he received funding from Circulation: Cardiovascular Quality and Outcomes (Deputy Editor); he received research grants from Veterans Affairs and the National Heart, Lung, and Blood Institute and the University of Colorado School of Medicine; and he disclosed government work. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objectives: Vasopressin is reported to retain vasoconstrictive activity in the setting of acidemia, but preclinical models are inconsistent and studies have not evaluated the clinical effectiveness of vasopressin based on arterial pH. This study sought to determine the association between arterial pH and blood pressure after vasopressin initiation in septic shock., Design: This retrospective, multicenter, observational cohort study evaluated the association of arterial pH at the time of vasopressin initiation with hemodynamic response to vasopressin and change in catecholamine dose after vasopressin initiation. Hemodynamic response was defined as a catecholamine dose decrease with mean arterial pressure greater than or equal to 65 mm Hg at 6 hours after vasopressin initiation., Setting: Patients from eight hospitals in a health system were evaluated., Patients: Patients with septic shock initiated on vasopressin as a catecholamine adjunct between January 2012 and November 2017 were screened for inclusion., Interventions: None., Measurements and Main Results: A total of 1,350 patients were included. At the time of vasopressin initiation patients were severely ill with arterial pH 7.28 ± 0.13, Sequential Organ Failure Assessment 14.1 ± 3.5, lactate 5.6 ± 4.6 mmol/L, and norepinephrine-equivalent catecholamine dose 32.3 ± 25.4 µg/min. After adjusting for lactate and Sequential Organ Failure Assessment with multivariable logistic regression, lower arterial pH was independently associated with lower odds of hemodynamic response to vasopressin (for each 0.1 unit arterial pH was below 7.40, response odds ratio 0.79; 95% CI, 0.72-0.87). For each 0.1 unit the pH was below 7.40 at vasopressin initiation, the norepinephrine-equivalent catecholamine dose increased by 1.5 µg/min (95% CI, 0.5-2.5 µg/min) at 1 hour, and increased by 2.5 µg/min (95% CI, 1.4-3.5 µg/min) at 6 hours after vasopressin initiation., Conclusions: Compared with higher arterial pH, patients with septic shock and low arterial pH had lower odds of vasopressin response and higher catecholamine doses after vasopressin initiation. Similar to other vasopressors, the clinical effectiveness of vasopressin appears to be impaired in the setting of acidemia., Competing Interests: Dr. Bauer reports receiving consultancy fees from Wolters Kluwer and is supported by a grant from the Cleveland Clinic Department of Pharmacy. Dr. Vachharajani is supported by a grant from the National Institutes of Health (grant number R01AA028763). The remaining authors have disclosed that they do not have any conflicts of interest., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Arginine vasopressin (AVP) is suggested as an adjunct to norepinephrine in patients with septic shock. Guidelines recommend an AVP dosage up to 0.03 units/min, but 0.04 units/min is commonly used in practice based on initial studies. This study was designed to compare the incidence of hemodynamic response between initial fixed-dosage AVP 0.03 units/min and AVP 0.04 units/min., Methods: This retrospective, multi-hospital health system, cohort study included adult patients with septic shock receiving AVP as an adjunct to catecholamine vasopressors. Patients were excluded if they received an initial dosage other than 0.03 units/min or 0.04 units/min, or AVP was titrated within the first 6 hours of therapy. The primary outcome was hemodynamic response, defined as a mean arterial pressure ≥65 mm Hg and a decrease in catecholamine dosage at 6 hours after AVP initiation. Inverse probability of treatment weighting (IPTW) based on the propensity score for initial AVP dosage receipt was utilized to estimate adjusted exposure effects., Results: Of the 1536 patients included in the observed data, there was a nearly even split between initial AVP dosage of 0.03 units/min (n = 842 [54.8%]) and 0.04 units/min (n = 694 [45.2%]). Observed patients receiving AVP 0.03 units/min were more frequently treated at the main campus academic medical center (96.3% vs. 52.2%, p < 0.01) and in a medical intensive care unit (87.4% vs. 39.8%, p < 0.01). The IPTW analysis included 1379 patients with achievement of baseline covariate balance. There was no evidence for a difference between groups in the incidence of hemodynamic response (0.03 units/min 50.0% vs. 0.04 units/min 53.1%, adjusted relative risk 1.06 [95% CI 0.94, 1.20])., Conclusions: Initial AVP dosing varied by hospital and unit type. Although commonly used, an initial AVP dosage of 0.04 units/min was not associated with a higher incidence of early hemodynamic response to AVP in patients with septic shock.

Severe COVID-19 illness is associated with intense inflammation, leading to high rates of thrombotic complications that increase morbidity and mortality. Markedly elevated levels of D-dimer with normal fibrinogen levels are the hallmark laboratory findings of severe COVID-19-associated coagulopathy. Prophylaxis against venous thromboembolism is paramount for all hospitalized patients with COVID-19, with more aggressive prophylaxis and screening recommended for critically ill patients with D-dimer levels above 3.0 μg/mL. Point-of-care ultrasonography is the imaging method of choice for patients at high risk, as it entails minimal risk of exposing providers to the virus., (Copyright © 2020 The Cleveland Clinic Foundation. All Rights Reserved.)

Background: IV pushes of phenylephrine may be used for patients with septic shock with the intent of rapidly achieving mean arterial pressure (MAP) goals. However, the clinical effectiveness and safety of this approach are unclear., Research Question: In patients with septic shock, is administration of a phenylephrine push before norepinephrine initiation associated with a higher incidence of hemodynamic stability?, Methods: This retrospective, multicenter cohort study included adult patients with septic shock initiated on norepinephrine. Propensity scores for initial phenylephrine push receipt were generated, and patients receiving an initial phenylephrine push were propensity score-matched 1:2 to those not receiving an initial phenylephrine push. The primary outcome was achievement of hemodynamic stability (defined as maintaining MAP of ≥ 65 mm Hg for at least 6 h without an increase in continuous infusion vasoactive agent dosage) within 3 and 12 h of norepinephrine initiation., Results: Of 1,317 included patients, 181 received an initial phenylephrine push; 141 phenylephrine push patients were matched to 282 patients not receiving a phenylephrine push. More patients who received a phenylephrine push achieved hemodynamic stability at hour 3 than those who did not receive a phenylephrine push (28.4% vs 18.8%; risk difference, 10%; 95% CI, 0.9%-18%). Phenylephrine push receipt was associated independently with hemodynamic stability within 3 h (adjusted OR, 1.8; 95% CI, 1.09-2.97), but not at 12 h (adjusted OR, 1.42; 95% CI, 0.93-2.16). Phenylephrine push receipt was associated independently with higher ICU mortality (adjusted OR, 1.88; 95% CI, 1.1-3.21)., Interpretation: Phenylephrine pushes were associated with a higher incidence of early, but not sustained, hemodynamic stability and were associated independently with higher ICU mortality. Caution is warranted when clinicians are considering the use of phenylephrine pushes in patients with septic shock., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Introduction: Clinical studies evaluating the use of hydrocortisone in patients with septic shock are heterogeneous in design with conflicting results. The appropriate time in which to initiate hydrocortisone after shock onset is unknown. This study sought to compare clinical outcomes including vasopressor duration and mortality in patients with septic shock who received hydrocortisone based on timing of initiation after shock onset., Methods: Retrospective cohort study of patients between 2011 and 2017 admitted to 10 medical, surgical, and neurosciences intensive care units (ICUs) at a large, tertiary care academic medical center. Adult patients with vasopressor-dependent septic shock who received hydrocortisone were included. Patients were divided into five timing cohorts based on time after shock onset: 0-6, 6-12, 12-24, 24-48, or >48 h. The primary outcome was days alive and free from vasopressors., Results: One thousand four hundred seventy patients were included: 567 (38.6%) received hydrocortisone between 0 and 6 h, 231 (15.7%) 6 and 12 h, 260 (17.7%) 12 and 24 h, 195 (13.3%) 24 and 48 h, and 217 (14.8%) >48 h after shock onset. Patients who received hydrocortisone earlier were sicker at baseline with higher APACHE III scores, lactate concentrations, and norepinephrine requirements. On univariate analysis, days alive and free from vasopressors did not significantly differ amongst the timing groups (median 3.3 days for 0-6 h; 1.9 for 6-12 h; 1.9 for 12-24 h; 0 for 24-48 h; 0 for >48 h; P = 0.39); similarly, ICU mortality did not differ. On multivariable linear regression, timing of hydrocortisone was independently associated with more days alive and free from vasopressors when comparing initiation within 0 to 6 h with >48 h (beta-coefficient 2.8 days [95% CI 0.8-4.7]), 6-12 h with >48 h (2.5 days [95% CI 0.2-4.7]), and 12-24 h with >48 h (2.3 days [95% CI 0.2-4.5]). On multivariable logistic regression, timing of hydrocortisone was associated with reduced ICU mortality when comparing receipt within 0 to 6 h of shock onset to >48 h after shock onset (OR 0.6, 95% CI 0.4-0.8)., Conclusions: In patients in whom hydrocortisone is prescribed for vasopressor-dependent septic shock, timing is crucial and hydrocortisone should be started within the first 12 h after shock onset., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by the Shock Society.)

The rapid spread of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to a global pandemic. The 2019 coronavirus disease (COVID-19) presents with a spectrum of symptoms ranging from mild to critical illness requiring intensive care unit (ICU) admission. Acute respiratory distress syndrome is a major complication in patients with severe COVID-19 disease. Currently, there are no recognized pharmacological therapies for COVID-19. However, a large number of COVID-19 patients require respiratory support, with a high percentage requiring invasive ventilation. The rapid spread of the infection has led to a surge in the rate of hospitalizations and ICU admissions, which created a challenge to public health, research, and medical communities. The high demand for several therapies, including sedatives, analgesics, and paralytics, that are often utilized in the care of COVID-19 patients requiring mechanical ventilation, has created pressure on the supply chain resulting in shortages in these critical medications. This has led clinicians to develop conservation strategies and explore alternative therapies for sedation, analgesia, and paralysis in COVID-19 patients. Several of these alternative approaches have demonstrated acceptable levels of sedation, analgesia, and paralysis in different settings but they are not commonly used in the ICU. Additionally, they have unique pharmaceutical properties, limitations, and adverse effects. This narrative review summarizes the literature on alternative drug therapies for the management of sedation, analgesia, and paralysis in COVID-19 patients. Also, this document serves as a resource for clinicians in current and future respiratory illness pandemics in the setting of drug shortages.

Purpose: To compare patient outcomes based on management of arginine vasopressin (AVP) during the recovery phase of septic shock (abrupt vs. tapering discontinuation)., Patients and Methods: Multicenter, retrospective cohort study of patients receiving AVP with concomitant norepinephrine for septic shock. Primary outcome measure was time to intensive care unit (ICU) discharge (from decision to titrate or stop AVP). Secondary outcomes included ICU and hospital mortality, and incidence of hypotension., Results: A total of 958 (73%) abrupt discontinuation and 360 (27%) down-titration patients were included. Patient characteristics and septic shock treatment courses were similar between groups. Median time to ICU discharge was similar between abrupt discontinuation (7.9 days, 95% CI 7.2-8.7 days) and tapered patients (7.3 days, 95% CI 6.3-9.3 days, P = 0.60). After controlling for baseline discrepancies, down-titration was not an independent predictor of time to ICU discharge (HR = 0.99, 95% CI: 0.85-1.15, P = 0.91). There was no difference in ICU mortality (21.8% vs. 18.0%, P = 0.13) or hospital mortality (28.9% vs. 31.1%, P = 0.44). Although incidence of hypotension was similar (39.7% vs. 41.7%, P = 0.53), patients in the down-titration group more frequently required an escalation of AVP dose (5.7% vs. 11.1%, P < 0.001). Median AVP duration was shorter in the abrupt discontinuation group (1.4 days [IQR: 0.6-2.6 days] vs. 1.8 days [IQR: 1.1-3.2 days], P < 0.001)., Conclusions: A difference in time to ICU discharge was not detected between abrupt AVP discontinuation and down-titration in patients recovering from septic shock. In patients recovering from septic shock, abrupt discontinuation of AVP appears to be safe and may lead to shortened AVP duration., Competing Interests: The other authors report no conflicts of interest., (Copyright © 2020 by the Shock Society.)

The primary objective was to evaluate ICU mortality at 28 days in patients with severe hypoxemic respiratory failure due to coronavirus disease 2019 infection who received tocilizumab. The secondary objectives were to evaluate ICU-, hospital-, mechanical ventilation-, and vasopressor-free days at day 28 and development of secondary infections., Design: Retrospective, observational, multicenter, cohort study between March 15, 2020, and May 31, 2020. Using propensity score matching based on ICU admission source, C-reactive protein, Sequential Organ Failure Assessment score, vasopressor use, age, race, weight, and mechanical ventilation, patients who received tocilizumab were matched to patients who did not receive tocilizumab., Setting: Ten hospitals within the Cleveland Clinic Enterprise., Patients: Adult patients admitted to a medical, surgical, neurosciences, or mixed ICU with severe acute respiratory syndrome coronavirus 2 infection., Interventions: None., Measurements and Main Results: Four-hundred forty-four patients were included: 342 patients (77%) did not receive tocilizumab and 102 patients (23%) received tocilizumab. Of those, 82 patients in each arm were matched. Before matching, patients who received tocilizumab had higher Sequential Organ Failure Assessment scores (6.1 ± 3.4 vs 4.7 ± 3.6), higher C-reactive protein (21.0 ± 10.2 vs 13.7 ± 9.6 mg/dL), higher frequency of intubation, vasopressor requirement, and paralytics. After matching, characteristics were more balanced and over 85% of patients required mechanical ventilation. ICU mortality was lower in tocilizumab group (23.2% vs 37.8%; risk difference, -15%; 95% CI, -29% to -1%), with more ICU-, hospital-, and vasoactive-free days at day 28 compared with those who did not receive tocilizumab. There was no difference in mechanical ventilation-free days at day 28 or development of secondary infections., Conclusions: Tocilizumab use was associated with a significant decrease in ICU mortality in critically ill coronavirus disease 2019 patients with severe hypoxemic respiratory failure. Future randomized controlled trials limited to tocilizumab administration in critically ill coronavirus disease 2019 patients, with severe hypoxemic respiratory failure, are needed to support these findings., Competing Interests: Dr. Vachharajani is the principal investigator for a grant (National Institutes of Health R01 GM99807). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Drugs targeting RNA respiratory viruses have resulted in few effective therapies, highlighting challenges for antivirals to treat COVID-19. Several antivirals are being investigated for symptomatic COVID-19 but no definitive data support their clinical use. Remdesivir appears to result in favorable outcomes with shortened time to recovery and a modest decrease in mortality for hospitalized patients in compassionate use series and some randomized controlled trials. Currently, remdesivir is available only from the US government via an emergency use authorization process. A randomized controlled trial of lopinavir/ritonavir demonstrated no apparent clinical or virologic benefit and drug-drug interactions and side effects further limit its utility. Antivirals to treat influenza (oseltamivir) have limited activity against SARS-CoV-2, but favipiravir and umifenovir, two influenza antivirals available internationally, may have distinct viral targets and require further investigation. Antivirals with evidence of clinical activity must be studied as treatment and prophylaxis for those at high risk for severe COVID-19., (Copyright © 2020 The Cleveland Clinic Foundation. All Rights Reserved.)

Interleukin 6 (IL-6) took center stage as a therapeutic target, given its role in the cytokine storm phase of COVID-19. While IL-6 inhibitors have been widely used to treat a variety of immune-mediated disease states, they have not been used often in the intensive care setting, and new data question their efficacy. This brief review provides practical information on their administration and safety., (Copyright © 2020 The Cleveland Clinic Foundation. All Rights Reserved.)

Severe COVID-19 illness is associated with intense inflammation, leading to high rates of thrombotic complications that increase morbidity and mortality. Markedly elevated levels of D-dimer with normal fibrinogen levels are the hallmark laboratory findings of severe COVID-19- associated coagulopathy. Prophylaxis against venous thromboembolism is paramount for all hospitalized patients, with more aggressive prophylaxis and screening recommended for patients with D-dimer levels above 3.0 μg/mL. Point-of-care ultrasonography is the imaging method of choice for patients at high risk, as it entails minimal risk of exposing providers to the virus., (Copyright © 2020 The Cleveland Clinic Foundation. All Rights Reserved.)

Background: Vasopressin decreases vasopressor requirements in patients with septic shock. However, the optimal norepinephrine dose for initiation or cessation of vasopressin is unclear. Objective: Analyze monthly intensive care unit (ICU) mortality rates 1 year preimplementation and postimplementation of a guideline suggesting a norepinephrine dose of 50 µg/min or more for initiation of vasopressin and early cessation of vasopressin. Methods: This retrospective quasi-experimental study included adult patients with septic shock admitted to the medical ICU of a tertiary care medical center over 2 years. Time periods were evaluated with interrupted time series analysis. Results: A total of 1148 patients were included: 573 patients preguideline and 575 patients postguideline. Group characteristics were well balanced at baseline, except patients postguideline had higher sequential organ failure assessment scores. Postguideline, fewer patients were initiated on vasopressin (305 [53.2%] vs 217 [37.7%], absolute difference -15.5% [95% CI -21.2% to -9.8%]), and the norepinephrine dose at vasopressin initiation was higher (median 25 [interquartile range 18, 40] µg/min vs 40 [22, 52] µg/min; median difference 15 [95% CI 11 to 19] µg/min; P < 0.01). After guideline implementation, there was no evidence for a difference in ICU mortality rate slope (slope change 0.07% [95% CI -0.8% to 1.0%] per month; P 0.87), but the vasoactive cost level decreased by US$183 (95% CI -US$327 to -US$39) per patient immediately after implementation. Conclusion and Relevance: Implementation of a guideline suggesting a high norepinephrine dose threshold for vasopressin initiation and early vasopressin cessation in patients with septic shock appears to be safe and may decrease vasoactive costs.

Background: Empiric combination antimicrobial therapy is often used in patients with decompensating septic shock. However, the optimal duration of combination therapy is unknown., Study Question: The goal of this study was to compare the clinical effects of a single dose of an aminoglycoside to an extended duration of aminoglycosides for combination therapy in patients with septic shock without renal dysfunction., Study Design: Retrospective, single-center evaluation of patients with septic shock who received empiric combination therapy with an aminoglycoside., Measures and Outcomes: Two patient cohorts were evaluated: those who received a single dose of an aminoglycoside and those who received more than 1 dose of an aminoglycoside. The primary outcome was shock-free days at day 14. Secondary outcomes included mortality, length of stay, clinical cure, and nephrotoxicity. A post hoc subgroup analysis including only patients who received more than 2 doses of an aminoglycoside compared with a single dose was conducted., Results: One hundred fifty-one patients were included in this evaluation, 94 in the single-dose aminoglycoside group and 57 in the extended duration group. There was no difference in shock-free days at day 14 between patients who received a single dose of an aminoglycoside or those who received an extended duration (12.0 vs. 11.6 days; P = 0.56). There were no differences in mortality, length of stay, clinical cure rates, or rates of nephrotoxicity between groups (28% for single dose vs. 26% for extended duration; P = 0.86). No differences in outcomes were detected when evaluating patients who received more than 2 doses of an aminoglycoside compared with a single dose., Conclusions: Patients with septic shock and normal renal function who received a single dose of an aminoglycoside for combination antimicrobial therapy had no differences detected in shock duration or nephrotoxicity development compared with those who received an extended duration of aminoglycoside combination therapy., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Positive hemodynamic response to vasopressin after 6 hours of infusion was independently associated with lower mortality in a previous retrospective study of patients with septic shock. However, factors previously associated with higher plasma vasopressin concentration were not associated with response, and the relationship between plasma vasopressin concentration and hemodynamic response has not been evaluated., Objectives: This cross-sectional study compared plasma vasopressin concentrations in hemodynamic responders and nonresponders to vasopressin in patients with septic shock to evaluate plasma vasopressin concentration as a therapeutic target for hemodynamic response to vasopressin., Methods: Adult patients with septic shock were included if they were treated with fixed-dose vasopressin as an adjunct to catecholamines for at least 3 hours. Patients were assigned to groups based on vasopressin response., Results: Ten hemodynamic responders to vasopressin and eight nonresponders were included. Blood samples for plasma vasopressin concentration were collected 3-6 hours after vasopressin initiation. Baseline characteristics were similar between groups. No difference was detected in plasma vasopressin concentrations between hemodynamic responders and nonresponders (median 88.6 pg/ml [interquartile range (IQR) 84.4-107.5 pg/ml] vs 89.9 pg/ml [IQR 67.5-157.4 pg/ml], p=0.79, respectively). We also did not detect a difference between groups after correcting for vasopressin dose; median vasopressin plasma concentration per 0.01 units/minute of vasopressin infusion for responders was 25.9 pg/ml (IQR 21.8-31.8 pg/ml) versus 29.5 pg/ml (IQR 23.0-57.5 pg/ml, p=0.48) for nonresponders. No difference in clinical outcomes was detected between groups. The findings were robust to multiple sensitivity analyses., Conclusions: This study does not support the use of plasma vasopressin concentrations as a therapeutic target to predict hemodynamic response to exogenous vasopressin in septic shock., (© 2019 Pharmacotherapy Publications, Inc.)

Purpose: The specific norepinephrine dose at which epinephrine should be added in septic shock is unclear. This study sought to determine the norepinephrine-equivalent dose at epinephrine initiation that correlated with hemodynamic stability., Methods: Septic shock patients receiving both norepinephrine and epinephrine were included in this study. Classification and regression tree analysis was conducted to determine breakpoints in norepinephrine-equivalent dose predicting hemodynamic stability, with two cohorts identified. The primary outcome was hemodynamic stability, and secondary outcomes were shock-free survival, time to achieve hemodynamic stability, and change in SOFA score., Results: Optimal dose group was identified as initiating epinephrine when norepinephrine-equivalent dose was between 37 and 133 μg/min. A total of 138 and 61 patients were classified in optimal and non-optimal dose groups, respectively. Baseline characteristics were similar between groups except vasopressin use was more frequent in the optimal dose group. More patients in optimal dose group versus non-optimal dose group achieved hemodynamic stability (40 [29%] vs. 9 [14.8%]), absolute risk difference 14.2% [95% CI 2.5-25.9%]; p = .03). On multivariable analysis, initiating epinephrine within the optimal norepinephrine-equivalent dose range was independently associated with higher odds of hemodynamic response (OR 3.06 [95% CI 1.2-7.6]; p = .02). No differences were observed in other secondary outcomes., Conclusions: Initiation of epinephrine when patients were receiving norepinephrine-equivalent doses of 37-133 μg/min was associated with a higher rate of hemodynamic stability., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: The impact of vasopressin and norepinephrine discontinuation order in the recovery phase of septic shock remains controversial. This systematic review and patient-level meta-analysis were performed to determine the impact of vasopressin and norepinephrine discontinuation order on clinically significant outcomes in the recovery phase of septic shock., Methods: Cumulative Index to Nursing and Allied Health Literature, Embase, PubMed, and ClinicalTrials.gov were searched from inception through November 2018 for studies comparing outcomes after the discontinuation of vasopressin or norepinephrine in septic shock. Individual patient-level data were obtained from included studies and combined using a two-stage meta-analysis., Results: Six studies of low or moderate risk of bias with 957 patients were included. Clinically significant hypotension occurred more frequently when vasopressin was discontinued first compared to norepinephrine (60.7% versus 43.3%, respectively). First discontinuation of norepinephrine compared to vasopressin had lower pooled odds of developing clinically significant hypotension (odds ratio [OR] 0.22, 95% confidence interval [CI] 0.07-0.68, I 2 87%). No differences were detected in short-term mortality (OR 1.12, 95% CI 0.67-1.86, I 2 45%), intensive care unit length of stay (mean difference 0.15 day, 95% CI -1.58 to 1.88, I 2 21%), or hospital length of stay (mean difference 1.65 days, 95% CI -0.47 to 3.76, I 2 0%)., Conclusions: Discontinuation of norepinephrine prior to vasopressin during the recovery phase of septic shock resulted in less clinically significant hypotension but no difference in mortality or lengths of stay. Larger, prospective studies evaluating the impact of relative vasopressin deficiency and norepinephrine and vasopressin discontinuation order and timing on patient-centered outcomes are needed., (© 2019 Pharmacotherapy Publications, Inc.)

Septic shock is a life-threatening disorder associated with high mortality rates requiring rapid identification and intervention. Vasoactive agents are often required to maintain goal hemodynamics and preserve tissue perfusion. However, guidance regarding the proper administration of adjunct agents for the management of septic shock is limited in patients who are refractory to norepinephrine. This review summarizes vasopressor agents and describes the nuanced application of these agents in patients with septic shock, specifically focusing on clinical scenarios with limited guidance including patients who are nonresponsive to first-line agents and individuals with mixed shock states, tachyarrhythmias, obesity, valvular abnormalities, or other comorbid conditions., (© 2019 Pharmacotherapy Publications, Inc.)

Introduction: The effect of patient weight and body mass index (BMI) on hemodynamic response to vasoactive medications is not fully understood. In titratable vasopressors, this effect is less likely a concern due to the ability to titrate dose to response; however, with the use of fixed-dose vasopressin, patient weight and BMI may impact response., Methods: This was a single-center, retrospective cohort of patients who received fixed-dose vasopressin for septic shock for at least 6 h with concomitant catecholamines in the medical, surgical, or neurosciences intensive care unit (ICU) at a tertiary care center. The association of weight- and BMI-adjusted vasopressin dose with change in catecholamine dose and change in mean arterial pressure (MAP) were evaluated using Spearman's correlation. Patients were further stratified by World Health Organization BMI categories to evaluate secondary outcomes., Results: There were 938 patients included with a median weight of 86.3 (70.6-106.6) kg and BMI of 29.5 (24.9-36.2) kg/m. There was no correlation between weight-adjusted vasopressin dose and change in catecholamine dose (r = -0.05, P = 0.13) or change in MAP (r = 0.04, P = 0.31) 2 h after initiation of vasopressin. Similarly, no correlation was found when evaluating change in catecholamine dose or MAP at 6 and 12 h after vasopressin initiation (all P values >0.05). Comparable findings were observed when evaluating correlations between BMI-adjusted vasopressin dose with change in MAP and catecholamine dose at all time points (all P values >0.05). BMI groupings were balanced with 238 patients (25.4%) having a BMI less than 25, 254 patients (27.1%) having BMI 25 to 30, 182 patients (19.4%) having BMI 30 to 35, and 264 patients (28.1%) having BMI more than 35. The median duration of mechanical ventilation and ICU free days were 3.99 (1.50-5.07) and 0 (0-1.6) days, respectively, with no differences observed when stratified by BMI (P = 0.59 and P = 0.83, respectively). In-hospital mortality was 64.8% and there was no difference among BMI groups (P = 0.35)., Conclusions: In this large cohort of septic shock patients, adjusting vasopressin dose for weight and BMI did not impact changes in catecholamine doses or MAP. Duration of mechanical ventilation, ICU free days, and mortality after vasopressin initiation were not affected by BMI.

Purpose of Review: There are limited vasoactive options to utilize for patients presenting with vasodilatory shock. This review discusses vasoactive agents in vasodilatory, specifically, septic shock and focuses on angiotensin II as a novel, noncatecholamine agent and describes its efficacy, safety, and role in the armamentarium of vasoactive agents utilized in this patient population., Recent Findings: The Angiotensin II for the Treatment of High-Output Shock 3 study evaluated angiotensin II use in patients with high-output, vasodilatory shock and demonstrated reduced background catecholamine doses and improved ability to achieve blood pressure goals associated with the use of angiotensin II. A subsequent analysis showed that patients with a higher severity of illness and relative deficiency of intrinsic angiotensin II and who received angiotensin II had improved mortality rates. In addition, a systematic review showed infrequent adverse reactions with angiotensin II demonstrating its safety for use in patients with vasodilatory shock., Summary: With the approval and release of angiotensin II, a new vasoactive agent is now available to utilize in these patients. Overall, the treatment for vasodilatory shock should not be a one-size fits all approach and should be individualized to each patient. A multimodal approach, integrating angiotensin II as a noncatecholamine option should be considered for patients presenting with this disease state.

Circulatory shock is a medical emergency that requires rapid intervention to optimize patient outcomes. Although catecholamine vasopressors are considered life-sustaining therapy, they are associated with adverse reactions, and vasopressin and angiotensin II may be used to minimize these adverse effects. However, vasopressin and angiotensin II are also associated with adverse reactions that must be known to the clinician to mitigate risk for patients. This review focuses on the known adverse drug effects of vasopressin and angiotensin II while offering potential solutions to minimize harm with these agents. Future directions with vasoactive medication safety including optimization of the electronic medical record, clinical decision support, prediction analytics, and precision medicine for patients with circulatory shock are also discussed., (© 2018 Pharmacotherapy Publications, Inc.)

Background: Vasopressin is often utilized for hemodynamic support in patients with septic shock. However, the most appropriate patient to initiate therapy in is unknown. This study was conducted to determine factors associated with hemodynamic response to fixed-dose vasopressin in patients with septic shock., Methods: Single-center, retrospective cohort of patients receiving fixed-dose vasopressin for septic shock for at least 6 h with concomitant catecholamines in the medical, surgical, or neurosciences intensive care unit (ICU) at a tertiary care center. Patients were classified as responders or non-responders to fixed-dose vasopressin. Response was defined as a decrease in catecholamine dose requirements and achievement of mean arterial pressure ≥ 65 mmHg at 6 h after initiation of vasopressin., Results: A total of 938 patients were included: 426 responders (45%), 512 non-responders (55%). Responders had lower rates of in-hospital (57 vs. 72%; P < 0.001) and ICU mortality (50 vs. 68%; P < 0.001), and increased ICU-free days at day 14 and hospital-free days at day 28 (2.3 ± 3.8 vs. 1.6 ± 3.3; P < 0.001 and 4.2 ± 7.2 vs. 2.8 ± 6.0; P < 0.001, respectively). On multivariable analysis, non-medical ICU location was associated with increased response odds (OR 1.70; P = 0.0049) and lactate at vasopressin initiation was associated with decreased response odds (OR 0.93; P = 0.0003). Factors not associated with response included APACHE III score, SOFA score, corticosteroid use, and catecholamine dose., Conclusion: In this evaluation, 45% responded to the addition of vasopressin with improved outcomes compared to non-responders. The only factors found to be associated with vasopressin response were ICU location and lactate concentration.

Study Objectives: Patients with septic shock often require vasoactive agents for hemodynamic support; however, the optimal approach to discontinuing these agents once patients reach the recovery phase is currently unknown. The objective of this evaluation was to compare the incidence of hypotension within 24 hours based on the discontinuation order of norepinephrine (NE) and vasopressin (AVP) in patients in the recovery phase of septic shock., Design: Retrospective cohort study., Setting: The medical, surgical, and neurosciences intensive care units (ICUs) at a large tertiary care academic medical center., Patients: A total of 585 adults in the recovery phase of septic shock who received fixed-dose AVP for at least 6 hours as an adjunct to NE between September 2011 and August 2015 were included. Of these patients, 155 had AVP discontinued first, and 430 had NE discontinued first., Measurements and Main Results: Hypotension was evaluated during the 24-hour period after discontinuation of the first vasoactive agent and was defined as mean arterial pressure less than 60 mm Hg with one or more of the following interventions: increased remaining vasoactive agent dose by 25%, reinstitution of the discontinued agent, or administration of at least 1 L of fluid bolus. Time to hypotension was evaluated with survival analysis, and risk of hypotension was evaluated with multivariable Cox proportional hazards regression. No significant difference between groups was noted in the incidence of hypotension within 24 hours (55% in the AVP discontinued first group vs 50% in the NE discontinued first group, p=0.28) or ICU mortality (45.2% vs 40.0%, p=0.26). After adjustment for baseline factors with multivariable Cox proportional hazards regression, having AVP discontinued first was independently associated with an increased risk of hypotension with a time-varying effect that decreased over time (HR(t) = e [1.16-0.08*t] , p<0.001)., Conclusion: In patients recovering from septic shock treated with concomitant AVP and NE, no significant difference was noted in the incidence of hypotension based on discontinuation order of these agents., (© 2018 Pharmacotherapy Publications, Inc.)

Objectives: Limited data support how to safely and effectively treat refractory pain and agitation in neonates and infants. Gabapentin has been used in this patient population and has shown promising results, yet there is still a paucity of data about its clinical efficacy. There is a need for a larger evaluation to determine its effectiveness. This study describes one institution's experience with gabapentin for the treatment of refractory pain and agitation in the neonatal intensive care unit (NICU)., Methods: This was a retrospective, observational evaluation of patients who received gabapentin in the level IV NICU at the Cleveland Clinic Children's Hospital. Changes in neonatal pain, agitation, and sedation scale (N-PASS) scores and analgesic and sedative medication requirements were analyzed, as were gabapentin dose requirements and adverse reactions., Results: Between January 2012 and November 2015, 22 patients received gabapentin and were included in this study. The average gabapentin starting dose was 10.2 mg/kg/day, with maximum doses up to 25.5 mg/kg/day. The median N-PASS score at gabapentin therapy initiation was 3.1 and after gabapentin initiation the last N-PASS score documented was 0 in all but 5 patients. Gabapentin use reduced the need for analgesic or sedative medications. The drug was well tolerated, and only 1 patient experienced an adverse reaction to gabapentin (i.e., nystagmus)., Conclusions: Gabapentin was well tolerated and associated with decreases in pain scores. It's use resulted in decreased requirements for analgesic and sedative medications. Gabapentin therapy appears to be an effective option for neonates and infants with refractory pain and agitation., Competing Interests: Disclosure The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. Dr. Sacha had full access to all data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis.

Therapeutic enoxaparin is commonly used over heparin because of its favorable pharmacokinetic profile and ease of administration. Monitoring of the anticoagulant response, if necessary, is done with anti-factor Xa levels. Currently, it is suggested that monitoring may be beneficial in patients who are overweight and those with renal dysfunction. This study aimed to characterize the use of enoxaparin at a large-academic medical center in patients >150 kg, <45 kg and in those with renal dysfunction, and to describe the rate of anti-factor Xa monitoring in these patients. There were 273 patients included in the study: n = 96 for <45 kg arm, n = 111 for >150 kg arm and n = 66 for renal dysfunction arm. Less than 30 % of patients in each arm had low molecular weight heparin anti-factor Xa levels drawn. Of these only half were drawn as peak levels (4 h post dose). Overall rates of anti-factor Xa monitoring was low. It was found that obese patients achieved therapeutic anticoagulation with lower than recommended doses; underweight patients were often subtherapeutic on the recommended doses; and patients with renal dysfunction tended to have therapeutic to subtherapeutic anti-factor Xa levels. Ultimately, this evaluation showed that enoxaparin has unpredictable pharmacokinetics in these three high-risk patient populations and anti-factor Xa monitoring may be necessary to ensure therapeutic levels and appropriate dosing.

Competing Interests: The authors have no conflicts of interest to declare.