Forecasting disease trajectories in critical illness: comparison of probabilistic dynamic systems to static models to predict patient status in the intensive care unit.

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.

Impact of Sedation Practices on Mortality in COVID-19-Associated Adult Respiratory Distress Syndrome Patients: A Multicenter Retrospective Descriptive Study.

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 (R2). 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 R2 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.

Baricitinib versus tocilizumab in critically ill COVID-19 patients: A retrospective cohort study.

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.

Nirmatrelvir or Molnupiravir Use and Severe Outcomes From Omicron Infections.

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.

Adjunctive Vasopressors in Patients with Septic Shock: Protocol for a Systematic Review and Meta-Analysis.

Background: Over one-third of patients with septic shock have adjunctive vasopressors added to first-line vasopressors. However, no randomized trial has detected improved mortality with adjunctive vasopressors. Published systematic reviews and meta-analysis have sought to inform the use of adjunctive vasopressors, yet each published review has limitations that hinder its interpretation. This review aims to overcome the limitations of previous reviews by systematically synthesizing the direct evidence for adjunctive vasopressor therapy use in adult patients with septic shock. Methods: We will conduct a systematic review and meta-analysis of randomized controlled trials evaluating adjunctive vasopressors (vasopressin analogues, angiotensin II, hydroxocobalamin, methylene blue, and catecholamine analogues) in adult patients with septic shock. Relevant studies will be identified through comprehensive searches of MEDLINE, Embase, CENTRAL, and reference lists of previous systematic reviews. Only randomized trials comparing adjunctive vasopressors (>75% of subjects on vasopressors at enrollment) to standard care vasopressors in adults with septic shock (>75% of subjects having septic shock) will be included. Titles and abstracts will be screened, full-text articles assessed for eligibility, and data extracted from included studies. Outcomes of interest include short-term mortality, intermediate-term mortality, kidney replacement therapy, digital/peripheral ischemia, and venous thromboembolism. Pairwise meta-analysis using a random-effects model will be utilized to estimate the risk ratio for the outcomes. Risk of bias will be adjudicated with the Cochrane Risk of Bias 2 tool, and GRADE will be used to rate the certainty of the body of evidence. Discussion: Although adjunctive vasopressors are commonly used in patients with septic shock their effect on patient-important outcomes is unclear. This study is planned to use rigorous systematic review methodology, including strict adhere to established guidelines, in order to overcome limitations of previously-published reviews and inform clinical practice and treatment guidelines for the use of adjunctive vasopressors in adults with septic shock. Systematic review registration: PROSPERO CRD4202327984.

Optimizing Vasopressin Use and Initiation Timing in Septic Shock: A Narrative Review.

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.

Echocardiographic profiles and hemodynamic response after vasopressin initiation in septic shock: A cross-sectional study.

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.

Association between emergency department sepsis order set design and delay to second dose piperacillin-tazobactam administration.

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.

Clinical Utilization of Stress Dose Hydrocortisone in Adult Patients With Septic Shock: A Retrospective Observational Study at a Large Academic Medical Center.

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.

Vasopressin Response and Clinical Trajectory in Septic Shock Patients.

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.

Risk factors associated with development of coinfection in critically Ill patients with COVID-19.

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.

Timing of vasoactive agents and corticosteroid initiation in septic shock.

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.

Impact of Pharmacists to Improve Patient Care in the Critically Ill: A Large Multicenter Analysis Using Meaningful Metrics With the Medication Regimen Complexity-ICU (MRC-ICU) Score.

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 (ß coefficient, 0.41; 95% CI, 00.37-0.45; p < 0.01), total pharmacist interventions (ß coefficient, 0.07; 95% CI, 0.04-0.09; p < 0.01), and a composite intensity score of pharmacist interventions (ß 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 (ß coefficient, 0.02; 0.00-0.04; p = 0.02) and reduced quantity (ß coefficient, -0.03; 95% CI, -0.04 to -0.02; p < 0.01) and intensity of interventions (ß 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.

Determinants of Vancomycin Trough Concentration in Patients Receiving Continuous Veno-Venous Hemodialysis.

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.

Association of Arterial pH With Hemodynamic Response to Vasopressin in Patients With Septic Shock: An Observational Cohort Study.

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.