Angiotensin II and Vasopressin for Vasodilatory Shock: A Critical Appraisal of Catecholamine-Sparing Strategies

© The Author(s) 2020. Vasodilatory shock is a serious medical condition that increases the morbidity and mortality of perioperative and critically ill patients. Norepinephrine is an established first-line therapy for this condition, but at high doses, it may lead to diminishing returns. Oftentimes, secondary noncatecholamine agents are required in those whose hypotension persists. Angiotensin II and vasopressin are both noncatecholamine agents available for the treatment of hypotension in vasodilatory shock. They have distinct modes of action and unique pharmacologic properties when compared to norepinephrine. Angiotensin II and vasopressin have shown promise in certain subsets of the population, such as those with acute kidney injury, high Acute Physiology and Chronic Health Evaluation II scores, or those receiving cardiac surgery. Any benefit from these drugs must be weighed against the risks, as overall mortality has not been shown to decrease mortality in the general population. The aims of this narrative review are to provide insight into the historical use of noncatecholamine vasopressors and to compare and contrast their unique modes of action, physiologic rationale for administration, efficacy, and safety profiles

Multicenter Retrospective Review of Ketamine Use in Pediatric Intensive Care Units (Ketamine-PICU Study)

Objective. Describe continuous infusion (CI) ketamine practices in pediatric intensive care units (PICUs) and evaluate its effect on pain/sedation scores, exposure to analgesics/sedatives, and adverse effects (AEs). Methods. Multicenter, retrospective, observational study in children <18 years who received CI ketamine between 2014 and 2017. Time spent in goal pain/sedation score range and daily cumulative doses of analgesics/sedatives were compared from the 24 hours (H) prior to CI ketamine to the first 24H and 25−48H of the CI. Adverse effects were collected over the first 7 days of CI ketamine. Results. Twenty-four patients from 4 PICUs were included; median (IQR) age 7 (1-13.25) years, 54% female (n = 13), 92% intubated (n = 22), 25% on CI vasopressors (n = 6), and 33% on CI paralytics (n = 8). Ketamine indications were analgesia/sedation (n = 21, 87.5%) and status epilepticus (n = 3, 12.5%). Median starting dose was 0.5 (0.48–0.70) mg/kg/hr and continued for a median of 2.4 (1.3–4.4) days. There was a significant difference in mean proportion of time spent within goal pain score range (24H prior: 74% ± 14%, 0–24H: 85% ± 10%, and 25−48H: 72% ± 20%; p=0.014). A significant reduction in median morphine milligram equivalents (MME) was seen (24H prior: 58 (8–195) mg vs. 0–24H: 4 (0–69) mg and p=0.01), but this was not sustained (25−48H: 24 (2–246) mg and p=0.29). Common AEs were tachycardia (63%), hypotension (54%), secretions/suctioning (29%), and emergence reactions (13%). Conclusions. Ketamine CI improved time in goal pain score range and significantly reduced MME, but this was not sustained. Larger prospective studies are needed in the pediatric population

Multicenter Retrospective Review of Ketamine Use in the ICU

IMPORTANCE: The response of ICU patients to continuously infused ketamine when it is used for analgesia and/or sedation remains poorly established. OBJECTIVES: To describe continuous infusion (CI) ketamine use in critically ill patients, including indications, dose and duration, adverse effects, patient outcomes, time in goal pain/sedation score range, exposure to analgesics/sedatives, and delirium. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, retrospective, observational study from twenty-five diverse institutions in the United States. Patients receiving CI ketamine between January 2014 and December 2017. MAIN OUTCOMES AND MEASURES: Chart review evaluating institutional and patient demographics, ketamine indication, dose, administration, and adverse effects. Pain/sedation scores, cumulative doses of sedatives and analgesics, and delirium screenings in the 24 hours prior to ketamine were compared with those at 0–24 hours and 25–48 hours after. RESULTS: A total of 390 patients were included (median age, 54.5 yr; interquartile range, 39–65 yr; 61% males). Primary ICU types were medical (35.3%), surgical (23.3%), and trauma (17.7%). Most common indications were analgesia/sedation (n = 357, 91.5%). Starting doses were 0.2 mg/kg/hr (0.1–0.5 mg/kg/hr) and continued for 1.6 days (0.6–2.9 d). Hemodynamics in the first 4 hours after ketamine were variable (hypertension 24.0%, hypotension 23.5%, tachycardia 19.5%, bradycardia 2.3%); other adverse effects were minimal. Compared with 24 hours prior, there was a significant increase in proportion of time spent within goal pain score after ketamine initiation (24 hr prior: 68.9% [66.7–72.6%], 0–24 hr: 78.6% [74.3–82.5%], 25–48 hr: 80.3% [74.6–84.3%]; p \u3c 0.001) and time spent within goal sedation score (24 hr prior: 57.1% [52.5–60.0%], 0–24 hr: 64.1% [60.7–67.2%], 25–48 hr: 68.9% [65.5–79.5%]; p \u3c 0.001). There was also a significant reduction in IV morphine (mg) equivalents (24 hr prior: 120 [25–400], 0–24 hr: 118 [10–363], 25–48 hr: 80 [5–328]; p \u3c 0.005), midazolam (mg) equivalents (24 hr prior: 11 [4–67], 0–24 hr: 6 [0–68], 25–48 hr: 3 [0–57]; p \u3c 0.001), propofol (mg) (24 hr prior: 942 [223–4,018], 0–24 hr: 160 [0–2,776], 25–48 hr: 0 [0–1,859]; p \u3c 0.001), and dexmedetomidine (µg) (24 hr prior: 1,025 [276–1,925], 0–24 hr: 285 [0–1,283], 25–48 hr: 0 [0–826]; p \u3c 0.001). There was no difference in proportion of time spent positive for delirium (24 hr prior: 43.0% [17.0–47.0%], 0–24 hr: 39.5% [27.0–43.8%], 25–48 hr: 0% [0–43.7%]; p = 0.233). Limitations to these data include lack of a comparator group, potential for confounders and selection bias, and varying pain and sedation practices that may have changed since completion of the study. CONCLUSIONS AND RELEVANCE: There is variability in the use of CI ketamine. Hemodynamic instability was the most common adverse effect. In the 48 hours after ketamine initiation compared with the 24 hours prior, proportion of time spent in goal pain/sedation score range increased and exposure to other analgesics/sedatives decreased

Causes, Consequences, and Treatments of Sleep and Circadian Disruption in the ICU: An Official American Thoracic Society Research Statement.

Background: Sleep and circadian disruption (SCD) is common and severe in the ICU. On the basis of rigorous evidence in non-ICU populations and emerging evidence in ICU populations, SCD is likely to have a profound negative impact on patient outcomes. Thus, it is urgent that we establish research priorities to advance understanding of ICU SCD. Methods: We convened a multidisciplinary group with relevant expertise to participate in an American Thoracic Society Workshop. Workshop objectives included identifying ICU SCD subtopics of interest, key knowledge gaps, and research priorities. Members attended remote sessions from March to November 2021. Recorded presentations were prepared and viewed by members before Workshop sessions. Workshop discussion focused on key gaps and related research priorities. The priorities listed herein were selected on the basis of rank as established by a series of anonymous surveys. Results: We identified the following research priorities: establish an ICU SCD definition, further develop rigorous and feasible ICU SCD measures, test associations between ICU SCD domains and outcomes, promote the inclusion of mechanistic and patient-centered outcomes within large clinical studies, leverage implementation science strategies to maximize intervention fidelity and sustainability, and collaborate among investigators to harmonize methods and promote multisite investigation. Conclusions: ICU SCD is a complex and compelling potential target for improving ICU outcomes. Given the influence on all other research priorities, further development of rigorous, feasible ICU SCD measurement is a key next step in advancing the field

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)

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 \u3c 0.01), ICU LOS (β coefficient, 0.41; 95% CI, 00.37-0.45; p \u3c 0.01), total pharmacist interventions (β coefficient, 0.07; 95% CI, 0.04-0.09; p \u3c 0.01), and a composite intensity score of pharmacist interventions (β coefficient, 0.19; 95% CI, 0.11-0.28; p \u3c 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 \u3c 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

Variation in Fluid and Vasopressor Use in Shock With and Without Physiologic Assessment: A Multicenter Observational Study

ObjectivesTo characterize the association between the use of physiologic assessment (central venous pressure, pulmonary artery occlusion pressure, stroke volume variation, pulse pressure variation, passive leg raise test, and critical care ultrasound) with fluid and vasopressor administration 24 hours after shock onset and with in-hospital mortality.DesignMulticenter prospective cohort study between September 2017 and February 2018.SettingsThirty-four hospitals in the United States and Jordan.PatientsConsecutive adult patients requiring admission to the ICU with systolic blood pressure less than or equal to 90 mm Hg, mean arterial blood pressure less than or equal to 65 mm Hg, or need for vasopressor.InterventionsNone.Measurement and main resultsOf 1,639 patients enrolled, 39% had physiologic assessments. Use of physiologic assessment was not associated with cumulative fluid administered within 24 hours of shock onset, after accounting for baseline characteristics, etiology and location of shock, ICU types, Acute Physiology and Chronic Health Evaluation III, and hospital (beta coefficient, 0.04; 95% CI, -0.07 to 0.15). In multivariate analysis, the use of physiologic assessment was associated with a higher likelihood of vasopressor use (adjusted odds ratio, 1.98; 95% CI, 1.45-2.71) and higher 24-hour cumulative vasopressor dosing as norepinephrine equivalent (beta coefficient, 0.37; 95% CI, 0.19-0.55). The use of vasopressor was associated with increased odds of in-hospital mortality (adjusted odds ratio, 1.88; 95% CI, 1.27-2.78). In-hospital mortality was not associated with the use of physiologic assessment (adjusted odds ratio, 0.86; 95% CI, 0.63-1.18).ConclusionsThe use of physiologic assessment in the 24 hours after shock onset is associated with increased use of vasopressor but not with fluid administration

Evaluation of Vasopressor Exposure and Mortality in Patients With Septic Shock*

OBJECTIVES: The objectives of this study were to: 1) determine the association between vasopressor dosing intensity during the first 6 hours and first 24 hours after the onset of septic shock and 30-day in-hospital mortality; 2) determine whether the effect of vasopressor dosing intensity varies by fluid resuscitation volume; and 3) determine whether the effect of vasopressor dosing intensity varies by dosing titration pattern. DESIGN: Multicenter prospective cohort study between September 2017 and February 2018. Vasopressor dosing intensity was defined as the total vasopressor dose infused across all vasopressors in norepinephrine equivalents. SETTING: Thirty-three hospital sites in the United States (n = 32) and Jordan (n = 1). PATIENTS: Consecutive adults requiring admission to the ICU with septic shock treated with greater than or equal to 1 vasopressor within 24 hours of shock onset. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Out of 1,639 patients screened, 616 were included. Norepinephrine (93%) was the most common vasopressor. Patients received a median of 3,400 mL (interquartile range, 1,851-5,338 mL) during the 24 hours after shock diagnosis. The median vasopressor dosing intensity during the first 24 hours of shock onset was 8.5 μg/min norepinephrine equivalents (3.4-18.1 μg/min norepinephrine equivalents). In the first 6 hours, increasing vasopressor dosing intensity was associated with increased odds ratio of 30-day in-hospital mortality, with the strength of association dependent on concomitant fluid administration. Over the entire 24 hour period, every 10 μg/min increase in vasopressor dosing intensity was associated with an increased risk of 30-day mortality (adjusted odds ratio, 1.33; 95% CI, 1.16-1.53), and this association did not vary with the amount of fluid administration. Compared to an early high/late low vasopressor dosing strategy, an early low/late high or sustained high vasopressor dosing strategy was associated with higher mortality. CONCLUSIONS: Increasing vasopressor dosing intensity during the first 24 hours after septic shock was associated with increased mortality. This association varied with the amount of early fluid administration and the timing of vasopressor titration