Major Publications in the Critical Care Pharmacotherapy Literature: 2022.

OBJECTIVES: A number of trials related to critical care pharmacotherapy were published in 2022. We aimed to summarize the most influential publications related to the pharmacotherapeutic care of critically ill patients in 2022. DATA SOURCES: PubMed/Medical Literature Analysis and Retrieval System Online and the Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update. STUDY SELECTION: Randomized controlled trials, prospective studies, or systematic review/meta-analyses of adult critically ill patients assessing a pharmacotherapeutic intervention and reporting clinical endpoints published between January 1, 2022, and December 31, 2022, were included in this article. DATA EXTRACTION: Articles from a systematic search and the Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update were included and stratified into clinical domains based upon consistent themes. Consensus was obtained on the most influential publication within each clinical domain utilizing an a priori defined three-round modified Delphi process with the following considerations: 1) overall contribution to scientific knowledge and 2) novelty to the literature. DATA SYNTHESIS: The systematic search and Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update yielded a total of 704 articles, of which 660 were excluded. The remaining 44 articles were stratified into the following clinical domains: emergency/neurology, cardiovascular, gastroenterology/fluids/nutrition, hematology, infectious diseases/immunomodulation, and endocrine/metabolic. The final article selected from each clinical domain was summarized following a three-round modified Delphi process and included three randomized controlled trials and three systematic review/meta-analyses. Article topics summarized included dexmedetomidine versus other sedatives during mechanical ventilation, beta-blocker treatment in the critically ill, restriction of IV fluids in septic shock, venous thromboembolism prophylaxis in critically ill adults, duration of antibiotic therapy for Pseudomonas aeruginosa ventilator-associated pneumonia, and low-dose methylprednisolone treatment in severe community-acquired pneumonia. CONCLUSIONS: This concise review provides a perspective on articles published in 2022 that are relevant to the pharmacotherapeutic care of critically ill patients and their potential impact on clinical practice.

Outcomes of Extubated COVID and Non-COVID Patients Receiving Awake Venovenous Extracorporeal Membrane Oxygenation.

Cessation of continuous analgesia and sedation in patients with acute respiratory distress syndrome (ARDS) receiving venovenous (VV) extracorporeal membrane oxygenation (ECMO) facilitates early extubation, family, patient and provider engagement, and mobility. Outcomes associated with an awake ECMO strategy have not been well described in the literature. The purpose of this study was to evaluate outcomes in patients receiving this strategy. This was a retrospective review of ARDS patients receiving awake VV ECMO. The primary outcome was survival to hospital discharge. Secondary outcomes included days requiring ECMO, time from cannulation to extubation, complications, patients requiring tracheostomy, hospital and intensive care unit (ICU) length of stay (LOS), and discharge disposition. In a subgroup analysis, outcomes were compared between non-COVID and COVID ECMO patients. Sixty-two patients were included with a survival to hospital discharge of 85.5%. Days requiring ECMO was 33.0 (0.0-75.0) and cannulation to extubation was 6.0 (4.0-11.0). Three patients received a tracheostomy (4.8%). Bleeding and infection were reported in 80.6% and 82.3% of patients, respectively. Intensive care unit length of stay was 46.0 days (29.0-90.0) and hospital LOS was 51.0 days (32.0-91.0). Over half of the patients (51.6%) were discharged to an acute rehabilitation facility and 27.4% were discharged home. There was similar survival to hospital discharge between the COVID and non-COVID awake ECMO patients (85% in both groups, p = 1.000). This study highlights the impact of an awake ECMO approach on survival to hospital discharge. Future studies are needed to evaluate this approach as compared to current practice to determine if this should become the standard.

Under the Microscope: A Look Into the Role of Critical Care Pharmacists During the COVID-19 Pandemic.

Among disciplines, the COVID-19 pandemic has reinforced the importance of critical care pharmacists in assuming responsibility for managing medication therapy in direct patient care settings. Historically, pharmacists have been relied upon for prospective evaluation of drug therapy for appropriate indications, dosage, drug interactions, and drug allergies; monitoring patients' pharmacotherapeutic regimens for effectiveness and adverse effects; providing drug information to providers; and educating health professionals regarding drug therapies. Specific to COVID-19, pharmacists have been an integral member of the multidisciplinary rounding team, assisting with drug shortages and strategies for drug conservation; participating in emergencies, such as advanced cardiac life support (ACLS) and rapid sequence intubations; and creating as well as integrating evidence-based guidelines and pathways during the pandemic into clinical practice. The purpose of this article is to demonstrate the various roles of critical care pharmacists among the healthcare team in caring for critically ill COVID-19 patients.

PHarmacist Avoidance or Reductions in Medical Costs in CRITically Ill Adults: PHARM-CRIT Study.

To comprehensively classify interventions performed by ICU clinical pharmacists and quantify cost avoidance generated through their accepted interventions. DESIGN: A multicenter, prospective, observational study was performed between August 2018 and January 2019. SETTING: Community hospitals and academic medical centers in the United States. PARTICIPANTS: ICU clinical pharmacists. INTERVENTIONS: Recommendations classified into one of 38 intervention categories (divided into six unique sections) associated with cost avoidance. MEASUREMENTS AND MAIN RESULTS: Two-hundred fifteen ICU pharmacists at 85 centers performed 55,926 interventions during 3,148 shifts that were accepted on 27,681 adult patient days and generated $23,404,089 of cost avoidance. The quantity of accepted interventions and cost avoidance generated in six established sections was adverse drug event prevention (5,777 interventions; $5,822,539 CA), resource utilization (12,630 interventions; $4,491,318), individualization of patient care (29,284 interventions; $9,680,036 cost avoidance), prophylaxis (1,639 interventions; $1,414,465 cost avoidance), hands-on care (1,828 interventions; $1,339,621 cost avoidance), and administrative/supportive tasks (4,768 interventions; $656,110 cost avoidance). Mean cost avoidance was $418 per intervention, $845 per patient day, and $7,435 per ICU pharmacist shift. The annualized cost avoidance from an ICU pharmacist is $1,784,302. The potential monetary cost avoidance to pharmacist salary ratio was between $3.3:1 and $9.6:1. CONCLUSIONS: Pharmacist involvement in the care of critically ill patients results in significant avoidance of healthcare costs, particularly in the areas of individualization of patient care, adverse drug event prevention, and resource utilization. The potential monetary cost avoidance to pharmacist salary ratio employing an ICU clinical pharmacist is between $3.3:1 and $9.6:1.

In-vitro and in-vivo comparisons of high versus low concentrations of inhaled epoprostenol to adult intubated patients.

BACKGROUND: Inhaled epoprostenol (iEPO) has been shown to reduce pulmonary artery pressure and improve oxygenation. iEPO is mainly delivered via a syringe pump with feed tubing connected to a vibrating mesh nebulizer with high or low formulation concentration delivery. METHODS: An in vitro study and a two-period retrospective case-control study were implemented. The in vitro study compared iEPO delivery via invasive ventilation at low concentrations of 7.5, and 15 mcg/mL and high concentration at 30 mcg/mL, to deliver the ordered dose of 30 and 50 ng/kg/min for three clinical scenarios with predicted body weight of 50, 70 and 90 kg. While in the clinical study, adult patients receiving iEPO via invasive ventilation to treat refractory hypoxemia, pulmonary hypertension, or right ventricular failure were included. 80 patients received low concentration iEPO at multiple concentrations (2.5, 7.5, and 15 mcg/mL, depending on the ordered dose) from 2015 to 2017, while 84 patients received high concentration iEPO at 30 mcg/mL from 2018 to 2019. RESULTS: In the in vitro study, there were no significant differences in aerosol deposition between high vs low concentrations of iEPO at a dose of 50 ng/kg/min. In the clinical study, age, gender, ethnicity, and indications for iEPO were similar between high and low concentration groups. After 30-120 min of iEPO administration, both delivery strategies significantly improved oxygenation in hypoxemic patients and reduced mean pulmonary arterial pressure (mPAP) for patients with pulmonary hypertension. However, no significant differences of the incremental changes were found between two delivery groups. Compared to low concentration, high concentration delivery group had better adherence to the iEPO weaning protocol (96% vs 71%, p < 0.001), fewer iEPO syringes utilized per patient (5 [3, 10] vs 12 [6, 22], p = 0.001), and shorter duration of invasive ventilation (6 [3, 12] vs 9 [5, 18] days, p = 0.028). Intensive care unit length of stay and mortality were similar between two groups. CONCLUSION: Compared to low concentration delivery of iEPO, high concentration iEPO via a vibrating mesh nebulizer maintained clinical benefits and increased clinician compliance with an iEPO weaning protocol, required less medication preparation time, and shortened duration of invasive ventilation.

PHarmacist Avoidance or Reductions in Medical Costs in Patients Presenting the EMergency Department: PHARM-EM Study.

To comprehensively classify interventions performed by emergency medicine clinical pharmacists and quantify cost avoidance generated through their accepted interventions. DESIGN: A multicenter, prospective, observational study was performed between August 2018 and January 2019. SETTING: Community and academic hospitals in the United States. PARTICIPANTS: Emergency medicine clinical pharmacists. INTERVENTIONS: Recommendations classified into one of 38 intervention categories associated with cost avoidance. MEASUREMENTS AND MAIN RESULTS: Eighty-eight emergency medicine pharmacists at 49 centers performed 13,984 interventions during 917 shifts that were accepted on 8,602 patients and generated $7,531,862 of cost avoidance. The quantity of accepted interventions and cost avoidance generated in six established categories were as follows: adverse drug event prevention (1,631 interventions; $2,225,049 cost avoidance), resource utilization (628; $310,582), individualization of patient care (6,122; $1,787,170), prophylaxis (24; $22,804), hands-on care (3,533; $2,836,811), and administrative/supportive tasks (2,046; $342,881). Mean cost avoidance was $538.61 per intervention, $875.60 per patient, and $8,213.59 per emergency medicine pharmacist shift. The annualized cost avoidance from an emergency medicine pharmacist was $1,971,262. The monetary cost avoidance to pharmacist salary ratio was between $1.4:1 and $10.6:1. CONCLUSIONS: Pharmacist involvement in the care of patients presenting to the emergency department results in significant avoidance of healthcare costs, particularly in the areas of hands-on care and adverse drug event prevention. The potential monetary benefit-to-cost ratio for emergency medicine pharmacists is between $1.4:1 and $10.6:1.

Bisphosphonate Versus Bisphosphonate and Calcitonin for the Treatment of Moderate to Severe Hypercalcemia of Malignancy.

BACKGROUND: Historically, intravenous (IV) bisphosphonates with calcitonin are the treatment of choice for hypercalcemia of malignancy. However, evidence is lacking. OBJECTIVE: The objective of this study was to compare the use of bisphosphonate versus bisphosphonate with calcitonin for moderate to severe hypercalcemia of malignancy. METHODS: This was a retrospective study evaluating patients who received bisphosphonate and/or calcitonin for treatment of moderate to severe hypercalcemia of malignancy. Patients received usual care plus either (1) bisphosphonate or (2) bisphosphonate with calcitonin. The primary outcome was change in corrected serum calcium concentrations 48 hours after treatment. Secondary outcomes included corrected calcium levels, incidence of normocalcemia and hypocalcemia, time to normocalcemia, hospital length of stay, and cost avoidance. RESULTS: The 48-hour decrease in corrected calcium was less in the bisphosphonate group than in the combination group (2.4 [1.6-3.4] vs 3.9 [3.5-5.3]; P < 0.001). However, initial calcium levels in the combination group were higher than in the bisphosphonate group, and calcium levels at 24, 48, and 72 hours were similar. Secondary outcomes did not differ. Average cost avoidance with bisphosphonate monotherapy was $11 248 per patient and $291 448 per year. CONCLUSIONS AND RELEVANCE: In the treatment of moderate to severe hypercalcemia of malignancy, IV bisphosphonate in combination with calcitonin resulted in a higher difference in corrected calcium levels at 48 hours compared with bisphosphonate therapy alone. However, corrected calcium levels in the first 72 hours, time to normocalcemia, and clinical outcomes were similar. The addition of calcitonin increases cost without substantial clinical benefit, and providers may consider avoiding calcitonin.

The Clinical Impact of Flow Titration on Epoprostenol Delivery via High Flow Nasal Cannula for ICU Patients with Pulmonary Hypertension or Right Ventricular Dysfunction: A Retrospective Cohort Comparison Study.

(1) Background: inhaled epoprostenol (iEPO) delivered via high-flow nasal cannula (HFNC) has been reported to be effective for pulmonary hypertension and right ventricular dysfunction. In vitro studies have identified HFNC gas flow as a key factor in trans-nasal aerosol delivery efficiency; however, little evidence is available on the clinical impact of flow titration on trans-nasal aerosol delivery. At our institution, iEPO via HFNC was initiated in 2015 and the concept of flow titration during iEPO via HFNC has been gradually accepted and carried out by clinicians in the recent years. (2) Methods: a retrospective review of the electronic medical records for all adult patients who received iEPO via HFNC in a tertiary teaching hospital. Pre- and post- iEPO responses were reported for patients whose HFNC flow was titrated or maintained constant during iEPO delivery. Positive response to iEPO was defined as the reduction of mean pulmonary arterial pressure (mPAP) > 10% for pulmonary hypertension patients or the improvement of oxygenation [pulse oximetry (SpO2)/fraction of inhaled oxygen (FIO2)] > 20%. The number of responders to iEPO was compared between groups with titrated vs constant flow. (3) Results: 51 patients who used iEPO to treat pulmonary hypertension and/or right ventricular dysfunction were reviewed. Following iEPO administration via HFNC, mPAP decreased (43.6 ± 11.7 vs. 36.3 ± 9.7 mmHg, p < 0.001). Among the 51 patients, 24 had concomitant refractory hypoxemia, their oxygenation (SpO2/FIO2) improved after iEPO delivery (127.8 ± 45.7 vs. 157.6 ± 62.2, p < 0.001). During iEPO initiation, gas flow was titrated in 25 patients and the remaining 26 patients used constant flow. The percentage of patients in the flow titration group who met the criteria for a positive response was higher compared to the group with constant flow (85.7% vs. 50%, p = 0.035). Pre- vs post-iEPO responses were significant in the flow titration group included improvement in cardiac output (p = 0.050), cardiac index (p = 0.021) and FIO2 reduction (p = 0.016). These improvements in hemodynamics and FIO2 were not observed in the constant flow group. (4) Conclusion: in patients with pulmonary hypertension and/or right ventricular dysfunction, trans-nasal iEPO decreased pulmonary arterial pressure. It also improved oxygenation in patients with combined refractory hypoxemia. These improvements were more evident in patients whose gas flow was titrated during iEPO initiation than those patients using constant flow.

A Case of Linezolid Induced Toxicity.

Adverse effects of linezolid are typically limited to diarrhea, nausea, and headache when shorter durations are used; however, as extended durations of linezolid therapy are increasingly more common, additional monitoring parameters should be considered in these patients. We describe a unique case of hypoglycemia, lactic acidosis, and pancreatitis related to an extended duration of linezolid therapy. A 52-year-old woman presented with altered mental status, abdominal pain, and hypotension following six weeks of linezolid and ertapenem therapy. Laboratory data revealed an initial blood glucose of 40 mg/dL and metabolic acidosis secondary to lactic acidosis. Finally, her abdominal pain on admission was likely related to an enlarged pancreas noted on computed tomography of her abdomen. Due to suspected linezolid toxicity, the patient received two intermittent hemodialysis sessions to remove linezolid and correct the metabolic acidosis. Given limited data on long-term monitoring of patients receiving extended durations of linezolid therapy, we suggest periodic monitoring of lactate, arterial blood gas, and blood glucose. If patients present with this triad of symptoms secondary to linezolid therapy, adverse effects should be treated with dextrose and intravenous thiamine while reserving hemodialysis for those with metabolic acidosis refractory to thiamine.

Predictive value of scoring tools in determining heparin-induced thrombocytopenia in patients on extracorporeal membrane oxygenation.

There are currently no scoring tools validated for use in predicting heparin-induced thrombocytopenia in patients receiving extracorporeal membrane oxygenation. This study aims to determine the predictive value of the Warkentin 4T score, Lilo-Le Louet score, and the heparin-induced thrombocytopenia expert probability score in detecting heparin-induced thrombocytopenia in patients on extracorporeal membrane oxygenation. This was a single center, retrospective, observational cohort study of patients at Rush University Medical Center. Heparin-induced thrombocytopenia-positive patients were defined as those with an optical density greater than or equal to 0.4, consistent with a positive anti-platelet 4 heparin antibody. Out of 39 patients on extracorporeal membrane oxygenation with suspected heparin-induced thrombocytopenia, six (15.4%) were found to be anti-platelet 4-positive. A heparin-induced thrombocytopenia diagnosis was confirmed by serotonin-release assay in two patients (5.1%). The 4T, heparin-induced thrombocytopenia expert probability, and Lilo-Le Louet scoring tools all demonstrated a low positive predictive value (21.4%, 16.7%, and 6.7%, respectively), with the 4T and heparin-induced thrombocytopenia expert probability scores demonstrating the highest specificity (66.7% and 84.8%, respectively) and lowest sensitivity (50% and 16.7%, respectively). The Lilo-Le Louet score had high sensitivity (100%) and low specificity (12.5%) in post-cardiopulmonary bypass patients. Based on the findings of this study, all three scoring tools have limited utility for predicting heparin-induced thrombocytopenia in patients on extracorporeal membrane oxygenation.

Treatment of pulmonary blastomycosis with high-dose liposomal amphotericin B in a patient receiving extracorporeal membrane oxygenation.

Blastomycosis-associated acute respiratory distress syndrome (ARDS) has a rare incidence. We report the case of a 29-year-old man with blastomycosis-associated ARDS receiving extracorporeal membrane oxygenation and managed with high-dose liposomal amphotericin B. This case illustrates the importance of timely diagnosis of pulmonary blastomycosis and appropriate dosing of antifungal therapy.

Scoping Review of Interventions Associated with Cost Avoidance Able to Be Performed in the Intensive Care Unit and Emergency Department.

A framework for evaluating pharmacists' impact on cost avoidance in the intensive care unit (ICU) and emergency department (ED) has not been established. This scoping review was registered (CRD42018091217) and conducted to identify, aggregate, and qualitatively describe the highest quality evidence for cost avoidance generated by clinical pharmacists on interventions performed in an ICU or ED. Searches were conducted in PubMed, Scopus, CINAHL, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews from inception until April 2018. The level of evidence (LOE) for each specific category of intervention was evaluated according to the Grading of Recommendations, Assessment, Development and Evaluation evidence-to-decision framework. The risks of bias for articles were evaluated using Newcastle Ottawa and Cochrane Collaboration tools. The values from all interventions were inflated to 2018 U.S. dollars using the consumer price index for medical care. Of the 464 articles initially identified, 371 were excluded and 93 were included. After reviewing references from the articles included, an additional 71 articles were also reviewed. The 38 cost intervention categories were supported by varying LOEs: IA (0 categories), IB (1 category), IIA (4 categories), IIB (0 categories), III (27 categories), and IV (6 categories), and articles mostly displayed low to moderate risks of bias. Pharmacists generate cost avoidance through a variety of interventions in critically and emergently ill patients. The quality of evidence supporting specific cost avoidance values is generally low. Quantification of and factors associated with the cost avoidance generated from pharmacists caring for these patients are of paramount importance.

Prolonged use of eptifibatide as a bridge to maintain drug-eluting stent patency in a patient receiving extracorporeal membrane oxygenation.

BACKGROUND: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) has been used as a bridge to cardiac recovery in patients following a major cardiac event. There is a lack of literature surrounding prolonged use of eptifibatide and optimal dosing during ECMO. This case report describes our experience with extended durations and standard dosing of eptifibatide in the setting of ECMO. CASE: A 40-year-old male with a history of Marfan's syndrome, aortic root and ascending aortic aneurysm status post a modified Bentall with a St. Jude mechanical aortic valve conduit and hemi-Cabrol with a Dacron graft to the left main coronary artery presented with exertional chest pain and was found to have an anastomotic narrowing to the left main which occluded while awaiting surgical revision. A rescue percutaneous coronary intervention at the anastomotic site was performed. Due to hemodynamic instability, he was placed on femoral VA-ECMO. The patient was started on anticoagulation for the ECMO circuit and eptifibatide to maintain stent patency. The patient experienced several bleeding episodes for which he received supportive care, endoscopic intervention and left gastric artery embolization. Eptifibatide was maintained at standard dosing and the heparin infusion was withheld. A coronary angiogram revealed no thrombus within the Cabrol graft a patent stent previously placed at the site of the distal graft-coronary anastomosis. The patient was decannulated from ECMO and underwent coronary artery bypass grafting and division of the hemi-Cabrol graft. CONCLUSION: While eptifibatide was effective in maintaining stent patency, our patient experienced several bleeding episodes during ECMO. Thus, the risks and benefits of concurrent antiplatelet and anticoagulant therapy must be appropriately weighed in this patient population. Additionally, as the need for dual antiplatelet therapy due to coronary stent implantation is increasing, further studies are needed to validate optimal dosing of eptifibatide in patients at a high risk of bleeding during ECMO.

Impact of the implementation of a sepsis protocol for the management of fluid-refractory septic shock: A single-center, before-and-after study.

BACKGROUND: Evidence-based guidelines have been published for the acute management of severe sepsis and septic shock. Key goals of institution-driven protocols include timely fluid resuscitation and antibiotic selection, as well as source control. OBJECTIVE: This study assessed the impact of a sepsis protocol on the timeliness of antibiotic administration, the adequacy of fluid resuscitation, and 28-day mortality in patients with fluid-refractory septic shock. METHODS: This was a single-center, before-and-after study (18 months before July 2007 and 18 months after) with prospective data collection evaluating the outcomes of a sepsis protocol in adult patients with fluid-refractory septic shock. All patients received a fluid challenge and antibiotics; those who did not were excluded from this analysis. Preprotocol findings led to the development of the sepsis protocol, which emphasized fluid resuscitation, timely administration of antibiotic therapy, and collection of specimens for culture at the onset of septic shock. In the pre- and postprotocol phases of the study, data were collected prospectively and analyzed for demographic characteristics; Acute Physiology and Chronic Health Evaluation (APACHE) II score; appropriateness of fluid resuscitation; antibiotic use; number of vasopressor, ventilator, and intensive care unit (ICU) days; and 28-day mortality. Outcomes were measured prospectively at any time during the patient's hospital admission. The primary end points were the time to administration of antimicrobial therapy and the appropriateness of fluid resuscitation before and after implementation of the sepsis protocol. RESULTS: A total of 118 patients were included in the analysis: 64 and 54 in the pre- and postprotocol groups, respectively. Patients in the preprotocol group were primarily women (53% [34/64]) and had a mean (SD) age of 61 (15.5) years and a mean APACHE II score of 28 (6.0). Patients in the postprotocol group were primarily men (54% [29/54]) and had a mean age of 52 (18.0) years and a mean APACHE II score of 27 (6.4). Implementation of the sepsis protocol resulted in a greater percentage of patients receiving timely antibiotic therapy (ie, within 4.5 hours of refractory shock; 85% [46/54] vs 56% [36/64]; P = 0.001) and adequate fluid resuscitation (72% [39/54] vs 31% [20/64]; P < 0.001) compared with the preprotocol group. Post hoc analysis found significant decreases in the number of vasopressor days (mean [SD], 3.8 [2.7] to 1.4 [1.5]; P < 0.001), ventilator days (9.1 [12.2] to 2.7 [4.0]; P < 0.001), and ICU days (12.3 [12.6] to 4.9 [3.9]; P < 0.001) in the postprotocol group. In-hospital mortality was not significantly different between the groups (survival 46% [28/61] before vs 54% [33/61] after the protocol). Multivariate analysis for predictors of in-hospital mortality identified an interval between shock and empiric antibiotic administration of >4.5 hours (odds ratio [OR] = 5.54; 95% CI, 1.91-16.07; P < 0.002), vasopressor duration in days (OR = 1.27; 95% CI, 1.01-1.59; P = 0.037), APACHE II score (OR = 1.14; 95% CI, 1.05-1.24; P = 0.003), and type of infection (community vs nosocomial, OR = 0.18; 95% CI, 0.05-0.61; P = 0.006) as significant predictors. The 28-day mortality decreased from 61% (39/64) to 33% (18/54) after implementation of the protocol (P = 0.004). CONCLUSION: Implementation of a sepsis protocol emphasizing early administration of antibiotic therapy and adequate fluid resuscitation was associated with improved clinical outcomes and lower 28-day mortality in patients with fluid-refractory septic shock at this institution.