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.

Antipsychotic Use for ICU Delirium and Associated Inflammatory Markers.

Purpose: We sought to evaluate critically ill patients with delirium to evaluate inflammatory cytokine production and delirium progression and the role of antipsychotics. Materials and Methods: Adult critically ill patients with confirmed delirium according to a positive CAM-ICU score were included and IL-6 and IL-8 levels were trended for 24 h in this single-center, prospective, observational cohort study. Results: A total of 23 patients were consented and had blood samples drawn for inclusion. There was no difference in IL-6 and IL-8 levels at baseline, 4 to 8 h, and 22 to 28 h after enrollment when comparing patients based on antipsychotic exposure. We identified 2 patient clusters based on age, APACHE III, need for mechanical ventilation, and concomitant infection. In cluster 1, 5 (33.3%) patients received antipsychotics versus 5 (62.5%) patients in cluster 2 (P = .18). Patients in cluster 1 had more co-inflammatory conditions (P < .0001), yet numerically lower baseline IL-6 (P = .18) and IL-8 levels (P = .80) compared to cluster 2. Patients in cluster 1 had a greater median number of delirium-free days compared to cluster 2 (17.0 vs 6.0 days; P = .05). Conclusions: In critically ill patients with delirium, IL-6 and IL-8 levels were variable and antipsychotics were not associated with improvements in delirium or inflammatory markers.

Evaluation of a protocol for rifaximin discontinuation in critically ill patients with liver disease receiving broad-spectrum antibiotic therapy.

BACKGROUND: Rifaximin is frequently administered to critically ill patients with liver disease and hepatic encephalopathy, but patients currently or recently treated with antibiotics were frequently excluded from studies of rifaximin efficacy. Due to overlapping spectrums of activity, combination therapy with broad-spectrum antibiotics and rifaximin may be unnecessary. A pharmacist-driven protocol was piloted to reduce potentially overlapping therapy in critically ill patients with liver disease. It was hypothesized that withholding rifaximin during broad-spectrum antibiotic therapy would be safe and reduce healthcare costs. AIM: To determine the clinical, safety, and financial impact of discontinuing rifaximin during broad-spectrum antibiotic therapy in critically ill liver patients. METHODS: This was a single-center, quasi-experimental, pre-post study based on a pilot pharmacist-driven protocol. Patients in the protocol group were prospectively identified via the medical intensive care unit (ICU) (MICU) protocol to have rifaximin withheld during broad-spectrum antibiotic treatment. These were compared to a historical cohort who received combination therapy with broad-spectrum antibiotics and rifaximin. All data were collected retrospectively. The primary outcome was days alive and free of delirium and coma (DAFD) to 14 d. Safety outcomes included MICU length of stay, 48-h change in vasopressor dose, and ICU mortality. Secondary outcomes characterized rifaximin cost savings and protocol adherence. Multivariable analysis was utilized to evaluate the association between group assignment and the primary outcome while controlling for potential confounding factors. RESULTS: Each group included 32 patients. The median number of delirium- and coma-free days was similar in the control and protocol groups [3 interquartile range (IQR 0, 8) vs 2 (IQR 0, 9.5), P = 0.93]. In multivariable analysis, group assignment was not associated with a reduced ratio of days alive and free of delirium or coma at 14 d. The protocol resulted in a reduced median duration of rifaximin use during broad-spectrum antibiotic therapy [6 d control (IQR 3, 9.5) vs 1 d protocol (IQR 0, 1); P < 0.001]. Rates of other secondary clinical and safety outcomes were similar including ICU mortality and 48-h change in vasopressor requirements. Overall adherence to the protocol was 91.4%. The median estimated total cost of rifaximin therapy per patient was reduced from $758.40 (IQR $379.20, $1200.80) to $126.40 (IQR $0, $126.40), P < 0.01. CONCLUSION: The novel pharmacist-driven protocol for rifaximin discontinuation was associated with significant cost savings and no differences in safety outcomes including DAFD.

Nonbronchoscopic Bronchoalveolar Lavage Improves Respiratory Culture Accuracy in Critically Ill Patients.

OBJECTIVES: Diagnosis of pneumonia is challenging in critically ill, intubated patients due to limited diagnostic modalities. Endotracheal aspirate (EA) cultures are standard of care in many ICUs; however, frequent EA contamination leads to unnecessary antibiotic use. Nonbronchoscopic bronchoalveolar lavage (NBBL) obtains sterile, alveolar cultures, avoiding contamination. However, paired NBBL and EA sampling in the setting of a lack of gold standard for airway culture is a novel approach to improve culture accuracy and limit antibiotic use in the critically ill patients. DESIGN: We designed a pilot study to test respiratory culture accuracy between EA and NBBL. Adult, intubated patients with suspected pneumonia received concurrent EA and NBBL cultures by registered respiratory therapists. Respiratory culture microbiology, cell counts, and antibiotic prescribing practices were examined. SETTING: We performed a prospective pilot study at the Cleveland Clinic Main Campus Medical ICU in Cleveland, Ohio for 22 months from May 2021 through March 2023. PATIENTS OR SUBJECTS: Three hundred forty mechanically ventilated patients with suspected pneumonia were screened. Two hundred fifty-seven patients were excluded for severe hypoxia (Fio2 ≥ 80% or positive end-expiratory pressure ≥ 12 cm H2O), coagulopathy, platelets less than 50,000, hemodynamic instability as determined by the treating team, and COVID-19 infection to prevent aerosolization of the virus. INTERVENTIONS: All 83 eligible patients were enrolled and underwent concurrent EA and NBBL. MEASUREMENTS AND MAIN RESULTS: More EA cultures (42.17%) were positive than concurrent NBBL cultures (26.51%, p = 0.049), indicating EA contamination. The odds of EA contamination increased by eight-fold 24 hours after intubation. EA was also more likely to be contaminated with oral flora when compared with NBBL cultures. There was a trend toward decreased antibiotic use in patients with positive EA cultures if paired with a negative NBBL culture. Alveolar immune cell populations were recovered from NBBL samples, indicating successful alveolar sampling. There were no major complications from NBBL. CONCLUSIONS: NBBL is more accurate than EA for respiratory cultures in critically ill, intubated patients. NBBL provides a safe and effective technique to sample the alveolar space for both clinical and research purposes.

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.

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.

Effect of Phenylephrine Push Before Continuous Infusion Norepinephrine in Patients With Septic Shock.

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

Corticosteroids for Septic Shock: Another Chapter in the Saga.

The use of corticosteroids in the management of septic shock has been a highly debated topic for quite some time. Corticosteroids have the ability to combat hyperinflammatory and exaggerated vasodilatory responses, as well as to sensitize adrenergic receptors to decrease the duration of shock. While helpful clinically, this has not translated to consistent mortality benefits. Conflicting results from 2 landmark trials published in 2002 and 2008 have led to varying clinical practices, and a clearly defined role of corticosteroids in septic shock is lacking. A decade later, an influx of new data derived from 2 more large trials continues to echo diverging viewpoints regarding patient mortality. In combination with fluctuating study designs (eg, adjunctive therapies and shock management) and patient populations (eg, illness severity), generalized conclusions are still difficult to draw. Despite these challenges, this review critically analyzes recently published data in the context of historical debate to provide an updated comment on the role of corticosteroids in septic shock. In summary, hydrocortisone therapy is likely to demonstrate maximal benefit when initiated on patients with septic shock and organ failure refractory to vasopressor therapy and should be used judiciously in other settings as it comes without a demonstrated benefit in mortality and increased potential for adverse effects.

Vasopressin Plasma Concentrations Are Not Associated with Hemodynamic Response to Exogenous Vasopressin for Septic Shock.

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

Effectiveness of venous thromboembolism prophylaxis in patients with liver disease.

BACKGROUND: Patients with liver disease are concomitantly at increased risk of venous thromboembolism (VTE) and bleeding events due to changes in the balance of pro- and anti-hemostatic substances. As such, recommendations for the use of pharmacological VTE prophylaxis are lacking. Recent studies have found no difference in rates of VTE in those receiving and not receiving pharmacological VTE prophylaxis, though most studies have been small. Thus, our study sought to establish if pharmacological VTE prophylaxis is effective and safe in patients with liver disease. AIM: To determine if there is net clinical benefit to providing pharmacological VTE prophylaxis to cirrhotic patients. METHODS: In this retrospective study, 1806 patients were propensity matched to assess if pharmacological VTE prophylaxis is effective and safe in patients with cirrhosis. Patients were divided and evaluated based on receipt of pharmacological VTE prophylaxis. RESULTS: The composite primary outcome of VTE or major bleeding was more common in the no prophylaxis group than the prophylaxis group (8.7% vs 5.1%, P = 0.002), though this outcome was driven by higher rates of major bleeding (6.9% vs 2.9%, P < 0.001) rather than VTE (1.9% vs 2.2%, P = 0.62). There was no difference in length of stay or in-hospital mortality between groups. Pharmacological VTE prophylaxis was independently associated with lower rates of major bleeding (OR = 0.42, 95%CI: 0.25-0.68, P = 0.0005), but was not protective against VTE on multivariable analysis. CONCLUSION: Pharmacological VTE prophylaxis was not associated with a significant reduction in the rate of VTE in patients with liver disease, though no increase in major bleeding events was observed.