Peripheral Administration of Norepinephrine: A Prospective Observational Study.

BACKGROUND: Historically, norepinephrine has been administered through a central venous catheter (CVC) because of concerns about the risk of ischemic tissue injury if extravasation from a peripheral IV catheter (PIVC) occurs. Recently, several reports have suggested that peripheral administration of norepinephrine may be safe. RESEARCH QUESTION: Can a protocol for peripheral norepinephrine administration safely reduce the number of days a CVC is in use and frequency of CVC placement? STUDY DESIGN AND METHODS: This was a prospective observational cohort study conducted in the medical ICU at a quaternary care academic medical center. A protocol for peripheral norepinephrine administration was developed and implemented in the medical ICU at the study site. The protocol was recommended for use in patients who met prespecified criteria, but was used at the treating clinician's discretion. All adult patients admitted to the medical ICU receiving norepinephrine through a PIVC from February 2019 through June 2021 were included. RESULTS: The primary outcome was the number of days of CVC use that were avoided per patient, and the secondary safety outcomes included the incidence of extravasation events. Six hundred thirty-five patients received peripherally administered norepinephrine. The median number of CVC days avoided per patient was 1 (interquartile range, 0-2 days per patient). Of the 603 patients who received norepinephrine peripherally as the first norepinephrine exposure, 311 patients (51.6%) never required CVC insertion. Extravasation of norepinephrine occurred in 35 patients (75.8 events/1,000 d of PIVC infusion [95% CI, 52.8-105.4 events/1,000 d of PIVC infusion]). Most extravasations caused no or minimal tissue injury. No patient required surgical intervention. INTERPRETATION: This study suggests that implementing a protocol for peripheral administration of norepinephrine safely can avoid 1 CVC day in the average patient, with 51.6% of patients not requiring CVC insertion. No patient experienced significant ischemic tissue injury with the protocol used. These data support performance of a randomized, prospective, multicenter study to characterize the net benefits of peripheral norepinephrine administration compared with norepinephrine administration through a CVC.

Evaluation of Response to High-Dose Intravenous Vitamin K Administration.

BACKGROUND: Essential to the coagulation pathway, vitamin K (phytonadione) is used to correct clotting factor deficiencies and for reversal of warfarin-induced bleeding. In practice, high-dose intravenous (IV) vitamin K is often used, despite limited evidence supporting repeated dosing. OBJECTIVE: This study sought to characterize differences in responders and nonresponders to high-dose vitamin K to guide dosing strategies. METHODS: This was a case-control study of hospitalized adults who received vitamin K 10 mg IV daily for 3 days. Cases were represented by patients who responded to the first dose of IV vitamin K and controls were nonresponders. The primary outcome was change in international normalized ratio (INR) over time with subsequent vitamin K doses. Secondary outcomes included factors associated with response to vitamin K and incidence of safety events. The Cleveland Clinic Institutional Review Board approved this study. RESULTS: There were 497 patients included, and 182 were responders. Most patients had underlying cirrhosis (91.5%). In responders, the INR decreased from 1.89 at baseline (95% CI = [1.74-2.04]) to 1.40 on day 3 (95% CI = [1.30-1.50]). In nonresponders, the INR decreased from 1.97 (95% CI = [1.83-2.13]) to 1.85 ([1.72-1.99]). Factors associated with response included lower body weight, absence of cirrhosis, and lower bilirubin. There was a low incidence of safety events observed. CONCLUSIONS: In this study of mainly patients with cirrhosis, the overall adjusted decrease in INR over 3 days was 0.3, which may have minimal clinical impact. Additional studies are needed to identify populations who may benefit from repeated daily doses of high-dose IV vitamin K.

Impact of Duration of N-Acetylcysteine in Non-Acetaminophen-Induced Acute Liver Failure.

OBJECTIVES: Studies of the use of IV N-acetylcysteine in the management of non-acetaminophen-induced acute liver failure have evaluated various dosing regimens. The only randomized trial studying this application described a 72-hour regimen. However, observational studies have reported extended duration until normalization of international normalized ratio. This study seeks to compare differences in patient outcomes based on IV N-acetylcysteine duration. DESIGN: Retrospective cohort study. SETTING: Medical ICU at a large quaternary care academic medical institution and liver transplant center. PATIENTS: Adult patients admitted to the medical ICU who received IV N-acetylcysteine for the treatment of non-acetaminophen-induced acute liver failure. INTERVENTIONS: Patients were divided into cohorts based on duration; standard duration of IV N-acetylcysteine was considered 72 hours, whereas extended duration was defined as continuation beyond 72 hours. MEASUREMENTS AND MAIN RESULTS: The primary outcome was time to normalization of international normalized ratio to less than 1.3 or less than 1.5; secondary outcomes included all-cause mortality and transplant-free survival at 3 weeks. In total, 53 patients were included: 40 in the standard duration cohort and 13 in the extended duration. There were no major differences in baseline characteristics. There was no significant difference in time to international normalized ratio normalization between cohorts. Transplant-free survival was higher with extended duration (76.9% extended vs 41.4% standard; p = 0.03). All-cause mortality at 3 weeks was numerically lower in the extended duration group (0% extended vs 24.1% standard; p = 0.08). CONCLUSIONS: Patients with non-acetaminophen-induced acute liver failure who received extended duration N-acetylcysteine were found to have significantly higher transplant-free survival than patients who received standard duration, although there was no significant difference in time to normalization of international normalized ratio or overall survival. Prospective, randomized, multicenter study is warranted to identify subpopulations of patients with non-acetaminophen-induced acute liver failure who could benefit from extended treatment duration as a bridge to transplant or spontaneous recovery.

Sedation, Analgesia, and Paralysis in COVID-19 Patients in the Setting of Drug Shortages.

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.

Comparison of Single-Dose and Extended-Duration Empiric Aminoglycoside Combination Therapy in Patients With Septic Shock.

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.

Advancing Infectious Diseases Diagnostic Testing and Applications to Antimicrobial Therapy in the ICU.

Treatment of suspected infections in critically ill patients requires the timely initiation of appropriate antimicrobials and rapid de-escalation of unnecessary broad-spectrum coverage. New advances in rapid diagnostic tests can now offer earlier detection of pathogen and potential resistance mechanisms within hours of initial culture growth. These technologies, combined with pharmacist antimicrobial stewardship efforts, may result in shorten time to adequate coverage or earlier de-escalation of unnecessary broad spectrum antimicrobials, which could improve patient outcomes and lower overall treatment cost. Furthermore, de-escalation of antimicrobials may lead to decreased emergence of resistant organisms and adverse events associated with antimicrobials. Clinical pharmacists should be aware of new rapid diagnostic tests, including their application, clinical evidence, and limitations, in order to implement the most appropriate clinical treatment strategy when patients have positive cultures. This review will focus on commercially available rapid diagnostic tests for infections that are routinely encountered by critically ill patients, including gram-positive and gram-negative bacterial blood stream infections, Candida, and Clostridioides difficile.

Predictors of response to fixed-dose vasopressin in adult patients with septic shock.

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.

Compliance with Procalcitonin Algorithm Antibiotic Recommendations for Patients in Medical Intensive Care Unit.

STUDY OBJECTIVES: To describe compliance with antibiotic recommendations based on a previously published procalcitonin (PCT)-guided algorithm in clinical practice, to compare PCT algorithm compliance rates between PCT assays ordered in the antibiotic initiation setting (PCT concentration measured less than 24 hours after antibiotic initiation or before antibiotic initiation) with those in the antibiotic continuation setting (PCT concentration measured 24 hours or more after antibiotic initiation), and to evaluate patient- and PCT-related factors independently associated with algorithm compliance in patients in the medical intensive care unit (MICU). DESIGN: Single-center retrospective cohort study. SETTING: Large MICU in a tertiary care academic medical center. PATIENTS: A total of 527 adults admitted to the MICU unit over a 2-year period (November 1, 2011-October 31, 2013) who had a total of 957 PCT assays performed. PCT assays whose results were determined in the MICU were allocated retrospectively to either the initiation setting cohort or the continuation setting cohort based on timing of the PCT assay. MEASUREMENTS AND MAIN RESULTS: Each PCT assay was treated as a separate episode. Antibiotic regimens were compared between the 24-hour periods before and after the results of each PCT assay and evaluated against an algorithm to determine compliance. Clinical, laboratory, PCT-related, and microbiologic variables were assessed during the 24-hour period after the PCT assay results to determine their influence on PCT algorithm compliance. A larger proportion of PCT episodes occurred in the initiation setting (540 [56.4%]) than in the continuation setting (417 [43.5%]). Overall, compliance with PCT algorithm recommendations was low (48.5%) and not significantly different between the initiation setting and the continuation setting (49.1% vs 47.7%, p=0.678). No patient-related or PCT-related factors were independently associated with PCT algorithm compliance on multivariable logistic regression. CONCLUSION: Compliance with PCT algorithm antibiotic recommendations in both the initiation and continuation settings was lower than that reported in published randomized studies. No factors were independently associated with PCT algorithm compliance. Institutions using PCT assays to guide antibiotic use should assess compliance with algorithm antibiotic recommendations. Inclusion of a formalized antimicrobial stewardship program along with a PCT-guided algorithm is highly recommended.

Influence of Colistin Dose on Global Cure in Patients with Bacteremia Due to Carbapenem-Resistant Gram-Negative Bacilli.

The increasing prevalence of multidrug-resistant (MDR) nosocomial infections accounts for increased morbidity and mortality of such infections. Infections with MDR Gram-negative isolates are frequently treated with colistin. Based on recent pharmacokinetic studies, current colistin dosing regimens may result in a prolonged time to therapeutic concentrations, leading to suboptimal and delayed effective treatment. In addition, studies have demonstrated an association between an increased colistin dose and improved clinical outcomes. However, the specific dose at which these outcomes are observed is unknown and warrants further investigation. This retrospective study utilized classification and regression tree (CART) analysis to determine the dose of colistin most predictive of global cure at day 7 of therapy. Patients were assigned to high- and low-dose cohorts based on the CART-established breakpoint. The secondary outcomes included microbiologic outcomes, clinical cure, global cure, lengths of intensive care unit (ICU) and hospital stays, and 7- and 28-day mortalities. Additionally, safety outcomes focused on the incidence of nephrotoxicity associated with high-dose colistin therapy. The CART-established breakpoint for high-dose colistin was determined to be >4.4 mg/kg of body weight/day, based on ideal body weight. This study evaluated 127 patients; 45 (35%) received high-dose colistin, and 82 (65%) received low-dose colistin. High-dose colistin was associated with day 7 global cure (40% versus 19.5%; P = 0.013) in bivariate and multivariate analyses (odds ratio [OR] = 3.40; 95% confidence interval [CI], 1.37 to 8.45; P = 0.008). High-dose colistin therapy was also associated with day 7 clinical cure, microbiologic success, and mortality but not with the development of acute kidney injury. We concluded that high-dose colistin (>4.4 mg/kg/day) is independently associated with day 7 global cure.

Noninferiority of Inhaled Epoprostenol to Inhaled Nitric Oxide for the Treatment of ARDS.

BACKGROUND: Inhaled nitric oxide and inhaled epoprostenol have been evaluated for the management of hypoxemia in acute respiratory distress syndrome, with clinical trials demonstrating comparable improvements in oxygenation. However, these trials have several limitations, making it difficult to draw definitive conclusions regarding clinical outcomes. OBJECTIVE: The aim of this study was to evaluate the noninferiority and safety of inhaled epoprostenol compared with inhaled nitric oxide in mechanically ventilated acute respiratory distress syndrome (ARDS) patients with a primary outcome of ventilator-free days from day 1 to day 28. METHODS: This was a retrospective, noninterventional, propensity-matched, noninferiority cohort study. Propensity score for receipt of inhaled nitric oxide was developed and patients were matched accordingly using a prespecified algorithm. Secondary objectives included evaluating day 28 intensive care unit-free days, changes in PaO2/FiO2 ratio after inhalation therapy initiation, and hospital mortality. Safety endpoints assessed included hypotension, methemoglobinemia, renal dysfunction, rebound hypoxemia, significant bleeding, and thrombocytopenia. RESULTS: Ninety-four patients were included, with 47 patients in each group. Patients were well-matched with similar baseline characteristics, except patients in inhaled nitric oxide group had lower PaO2/FiO2 ratio. Management of ARDS was similar between groups. Mean difference in ventilator-free days between inhaled epoprostenol and inhaled nitric oxide was 2.16 days (95% confidence interval = -0.61 to 4.9), with lower limit of 95% confidence interval greater than the prespecified margin, hence satisfying noninferiority. There were no differences in any secondary or safety outcomes. CONCLUSIONS: Inhaled epoprostenol was noninferior to inhaled nitric oxide with regard to ventilator-free days from day 1 to day 28 in ARDS patients.

Impact of combination antimicrobial therapy on mortality risk for critically ill patients with carbapenem-resistant bacteremia.

There are limited treatment options for carbapenem-resistant Gram-negative infections. Currently, there are suggestions in the literature that combination therapy should be used, which frequently includes antibiotics to which the causative pathogen demonstrates in vitro resistance. This case-control study evaluated risk factors associated with all-cause mortality rates for critically ill patients with carbapenem-resistant Gram-negative bacteremia. Adult patients who were admitted to an intensive care unit with sepsis and a blood culture positive for Gram-negative bacteria resistant to a carbapenem were included. Patients with polymicrobial, recurrent, or breakthrough infections were excluded. Included patients were classified as survivors (controls) or nonsurvivors (cases) at 30 days after the positive blood culture. Of 302 patients screened, 168 patients were included, of whom 90 patients died (53.6% [cases]) and 78 survived (46.4% [controls]) at 30 days. More survivors received appropriate antibiotics (antibiotics with in vitro activity) than did nonsurvivors (93.6% versus 53.3%; P < 0.01). Combination therapy, defined as multiple appropriate agents given for 48 h or more, was more common among survivors than nonsurvivors (32.1% versus 7.8%; P < 0.01); however, there was no difference in multiple-agent use when in vitro activity was not considered (including combinations with carbapenems) (87.2% versus 80%; P = 0.21). After adjustment for baseline factors with multivariable logistic regression, combination therapy was independently associated with decreased risk of death (odds ratio, 0.19 [95% confidence interval, 0.06 to 0.56]; P < 0.01). These data suggest that combination therapy with multiple agents with in vitro activity is associated with improved survival rates for critically ill patients with carbapenem-resistant Gram-negative bacteremia. However, that association is lost if in vitro activity is not considered.

Comparison of oral vancomycin capsule and solution for treatment of initial episode of severe Clostridium difficile Infection.

OBJECTIVE: Vancomycin is recommended as a first-line therapy for severe Clostridium difficile infection (CDI). Due to the high cost of commercially available vancomycin capsules, hospitals frequently compound oral solution despite a lack of data comparing outcomes. This study was conducted to determine treatment outcome differences based on oral vancomycin formulation. METHODS: Medical charts of 76 patients with an initial episode of severe CDI receiving oral vancomycin as a commercially available capsule or a compounded oral solution for at least 72 hours were retrospectively reviewed. The primary objective was to compare the time to clinical cure of CDI. RESULTS: Baseline characteristics between groups were similar except for the median lactate, which was higher in compounded oral solution group (1.5 vs 0.6 mmol/L, P < .001). There was no difference in clinical cure at day 10 (64% solution vs 59% capsules, P = .664). Median time to clinical cure was 8 days for solution and 7 for capsules (P = .597). After adjustment, the hazard ratio of time to clinical cure for solution compared to capsules was 1.15 (P = .69). No significant differences in mortality, recurrence, or complications were noted. CONCLUSION: Formulation of oral vancomycin did not impact treatment outcomes in this retrospective study.

Effect of vancomycin dose on treatment outcomes in severe Clostridium difficile infection.

Current guidelines recommend vancomycin 125 mg four times daily for the treatment of severe Clostridium difficile infection (CDI). However, the optimal dose of vancomycin has not been elucidated. This study was conducted to evaluate outcome differences in patients with severe CDI treated with either low-dose (≤500 mg daily) or high-dose (>500 mg daily) oral vancomycin. The medical records of 78 patients with severe CDI were evaluated retrospectively. The primary outcome was time to clinical cure of CDI, defined as the first day of resolution of diarrhoea for ≥48 h without development of a complication. Other endpoints included cure rates, complication rates and recurrence rates. Overall, 48 patients (61.5%) achieved clinical cure at Day 10 after treatment initiation. The cure rates in the high-dose and low-dose vancomycin groups were 60% and 64%, respectively (P = 0.76). Using a multivariate Cox proportional hazards model adjusting for baseline discrepancies, vancomycin dose was not independently associated with clinical cure. No difference in time to cure, complication rates or mortality was observed between the groups. There was a trend towards lower rates of recurrence associated with higher doses of oral vancomycin (12% vs. 1.9%; P = 0.09). In conclusion, these data suggest that there is no difference in treatment outcomes between high-dose and low-dose vancomycin for the treatment of severe CDI. The potential difference in recurrence rates between the groups warrants further investigation.