Antihypertensive Medications Prior to Shock Onset Do Not Impact Initial Vasopressor Requirements in Patients With Shock.

Purpose: The effect of the use of antihypertensive agents in patients prior to the development of shock is unclear. The purpose of this study was to determine the impact of antihypertensive agents on vasopressor dose and duration in shock. Materials and Methods: This retrospective, single-center study included patients with shock who received at least one vasopressor for at least 24 hours after shock onset from January 1 to June 30, 2017. Patients taking an antihypertensive agent(s) were compared to those who were not. The primary outcome was the number of vasopressor-free hours at 72 hours. Secondary outcomes included maximum and cumulative vasopressor doses, intensive care unit length of stay, and 30-day mortality. Results: One hundred and sixty-eight patients were included and 99 (59%) were on antihypertensives. Distributive shock was the most common type of shock (75.5%) and more patients taking antihypertensives had hypertension, coronary artery disease, and dyslipidemia at baseline. There was no difference in the number of vasopressor-free hours at 72 hours between patients taking an antihypertensive medication(s) and the control group (2 hours vs 1 hour; P = .11). No difference was found between any of the secondary outcomes. Conclusion: Patients taking antihypertensive agents prior to shock onset did not require increased vasopressor doses or duration.

Impact of Pulmonary Embolism Response Team on Anticoagulation Prescribing Patterns in Patients With Acute Pulmonary Embolism.

INTRODUCTION: Anticoagulation remains the mainstay pharmacotherapy for acute pulmonary embolism (PE), but multiple treatment options exist. The Pulmonary Embolism Response Team (PERT) is a multidisciplinary group that evaluates patients, formulates evidence-based treatment plans, and mobilizes resources. The objective of this study was to characterize the anticoagulation prescribing patterns made by PERT and to determine the clinical impact of anticoagulant selection. MATERIALS AND METHODS: This was a retrospective analysis of patients evaluated by PERT from 2016 to 2018. Multivariable linear regression was conducted to determine predictors of length of stay (LOS). RESULTS: A total of 209 patients were evaluated by PERT and received anticoagulation on discharge. Of those, 47% received a non-vitamin K oral anticoagulant (NOAC), 29% received warfarin, and 23% received low-molecular-weight heparin. Patient preferences and comorbidities were the most common reasons for NOAC omission. Patients who received NOACs had a shorter median LOS than warfarin (6.1 [4.6-7.6] days vs 10.9 [8.4-13.4] days; P < .05). Selection of NOAC upon discharge was the only factor independently associated with reduced LOS (ß coefficient: -0.6; 95% CI: -1.01 to -0.18; P < .01). CONCLUSION: The most common recommendation made by PERT was to initiate a NOAC upon discharge, resulting in shorter hospital LOS compared to patients who received warfarin.

Pulmonary embolism response team implementation improves awareness and education among the house staff and faculty.

A subset of high-risk pulmonary embolism (PE) patients requires advanced therapy beyond anticoagulation. Significant variation in delivery of care has led institutions to standardize their approach by developing Pulmonary Embolism Response Team (PERT). We sought to assess the impact of PERT implementation on house staff and faculty education. After implementation of PERT, we employed a targeted educational intervention aimed to improve PERT awareness, familiarity with treatment options, role of echocardiogram and Doppler ultrasound, and knowledge of acute PE risk stratification tools. We conducted an anonymous survey among the house staff and faculty before and after intervention to assess the impact of PERT implementation on educational objectives among clinicians. Initial and follow up samples included 115 and 109 responses. The samples were well represented across the subspecialties and all levels of training, as well as junior and senior faculty. Following the educational campaign, awareness of the program increased (72.2-92.6%, p < 0.01). Proportion of clinicians with reported comfort level of managing PE increased (82.4-90.8%, p = 0.07). Proportion of clinicians with self-reported comfort with explaining all available treatment modalities to patients increased (49.1-67.9%, p = 0.005). Proportions of responders who correctly identified the role of echocardiography in risk stratification of patients with known PE increased (73.9-84.4%, p = 0.07). Accurate clinical risk stratification of acute PE increased (60.2-73.8%, p = 0.03). The implementation of a targeted educational program at a tertiary care center increased awareness of PERT among house staff and faculty and improved physician's accuracy of clinical risk stratification and comfort level with management of acute PE.

Right Ventricular Outflow Doppler Predicts Low Cardiac Index in Intermediate Risk Pulmonary Embolism.

Intermediate-risk pulmonary embolism (PE) has variable outcomes. Current risk stratification models lack the positive predictive value to identify patients at highest risk of PE-related mortality. We identified intermediate-risk PE patients who underwent catheter-based interventions and right heart catheterization (RHC) and identified those with low cardiac index (CI < 2.2 L/min/m2). We utilized regression models to identify echocardiographic predictors of low CI and Kaplan Meier curve to evaluate PE-related mortality when stratified by the echocardiographic predictor. Of 174 intermediate-risk PE patients, 41 underwent RHC. Within this cohort, 46.3% had low CI. Univariable linear regression identified right ventricular outflow tract velocity time integral (RVOT VTI), right/left ventricular ratio, S prime, inferior vena cava diameter, and pulmonary artery systolic pressure as potential predictors of low CI. Multivariable linear regression identified RVOT VTI as significant predictor of low CI (ß coefficient 0.124, 95% confidence interval [CI]: 0.01-0.24, P = .034). Right ventricular outflow tract velocity time integral <9.5 cm was associated with increased PE-related mortality, P = .002. A substantial proportion of intermediate-risk PE patients referred for catheter-based interventions had low CI despite normotension. Right ventricular outflow tract velocity time integral was a significant predictor of low CI. Low RVOT VTI was associated with increased PE-related mortality.

Recent evidence for pharmacological treatment of idiopathic pulmonary fibrosis.

OBJECTIVE: To describe emerging evidence for the pharmacological treatment of idiopathic pulmonary fibrosis (IPF). DATA SOURCES: A search of PubMed (1966 to July 2014) was performed using the terms idiopathic pulmonary fibrosis and treatment. STUDY SELECTION AND DATA EXTRACTION: Review of articles was restricted to articles in English and relating to placebo-controlled or comparative clinical trial data of recent significance. Evidence statements from the most recent international guidelines and some historical trial data were also included for context. DATA SYNTHESIS: Numerous treatment options have been evaluated for IPF. Therapies evaluated in large trials have either resulted in increased mortality (anticoagulation, triple-therapy with N-acetylcysteine [NAC], azathioprine, and prednisone) or demonstrated a lack of efficacy (endothelin receptor antagonists, single-agent NAC). Pirfenidone, a novel antifibrotic and anti-inflammatory agent, has demonstrated efficacy in several recent analyses and is the only approved medication for the treatment of IPF in more than 30 countries outside of the United States, with resubmission to the Food and Drug Administration (FDA) recently made. Nintedanib, a tyrosine kinase inhibitor, has demonstrated encouraging results in phase III studies and has also recently been submitted for FDA approval. CONCLUSIONS: Limited options have existed for the treatment of IPF. New evidence suggests that safe and efficacious treatment options for IPF are on the horizon in the form of pirfenidone and nintedanib, although both agents await FDA decisions.

Tolerability and safety of enteral nutrition in critically ill patients receiving intravenous vasopressor therapy.

BACKGROUND: Enteral nutrition (EN) is recommended within the first 24-48 hours following admission to an intensive care unit (ICU) once resuscitation and hemodynamic stability have been achieved; however, hemodynamic stability is not well defined. OBJECTIVE: To evaluate the tolerability and safety of EN in critically ill patients receiving intravenous (IV) vasopressor therapy. METHODS: A retrospective medical record review was conducted in an urban academic medical center and included adult ICU patients from 2011 who received concomitant EN and IV vasopressor therapy for ≥1 hour. EN tolerance was defined as an absence of gastric residuals ≥300 mL, emesis, positive finding on abdominal imaging, and evidence of bowel ischemia/perforation. RESULTS: Two hundred fifty-nine patients received 346 episodes of concomitant EN and IV vasopressor therapy. Overall EN tolerability was 74.9%. Adverse events included rising serum lactate (30.6%), elevated gastric residuals (14.5%), emesis (9.0%), positive finding on kidney/ureter/bladder radiograph (4.3%), and bowel ischemia/perforation (0.9%). An inverse relationship was found between maximum norepinephrine equivalent dose and EN tolerability (12.5 mcg/min for patients who tolerated EN vs 19.4 mcg/min, P = .0009). This relationship remained statistically significant after controlling for other variables (P = .019). Patients who tolerated EN were less likely to have received dopamine (63.8% vs 77.6%, P = .018) or vasopressin (58.9% vs 77.9%, P = .0027). These patients received concomitant therapy for less time and received more nutrition. CONCLUSIONS: Most patients receiving IV vasopressor therapy tolerate EN. Tolerability was related to the maximum cumulative vasopressor dose and may be related to the specific vasopressor administered.

Contemporary Anticoagulation Reversal Focus on Direct Thrombin Inhibitors and Factor Xa Inhibitors.

Several oral direct thrombin inhibitors (DTIs) and factor Xa (FXa) inhibitors have recent Food and Drug Administration approval or are under investigation in late-stage clinical trials for the prevention and treatment of thromboembolic events. Rapid reversal of anticoagulation is typically recommended in patients with severe or life-threatening bleeding and in patients requiring surgery or invasive procedures. However, no antidote exists for DTIs or FXa inhibitors though replacement of coagulation factors using clotting factor concentrates is routinely considered in some clinical scenarios. Clotting factor concentrates available in the United States include prothrombin complex concentrate, activated prothrombin complex concentrate, and recombinant factor VII, activated. Coagulation tests to confirm adequate reversal of anticoagulation should be considered and commonly include activated partial thromboplastin time and thrombin time (TT) for DTIs, and chromogenic FXa assay and TT for FXa inhibitors. Monitoring of coagulation tests should continue for 1 to 2 days after achievement of hemostasis, since the duration of the clotting factor concentrate may be shorter than the oral anticoagulant, especially in patients with organ dysfunction. Utilization of decision-support tools and use of standardized reversal protocols are recommended to prevent errors in prescribing and dispensing for clotting factor concentrates.

Ipilimumab: a novel treatment for metastatic melanoma.

OBJECTIVE: To review the mechanism of action, pharmacokinetics, efficacy, safety, drug interactions, dosing, and economic considerations of ipilimumab. DATA SOURCES: A literature search using MEDLINE (1966-November 2010) was performed using the terms ipilimumab, metastatic melanoma, MDX-010, and MDX-101. Additional data were obtained from meeting abstracts, bibliographies, and media releases. STUDY SELECTION AND DATA EXTRACTION: English-language articles identified from the data sources were reviewed. Selected studies evaluated the pharmacology, pharmacokinetics, efficacy, and safety of ipilimumab for the treatment of metastatic melanoma. DATA SYNTHESIS: The incidence of melanoma in the US is increasing faster than any other type of cancer in men and more than any other type of cancer, except lung cancer, in women. For patients with metastatic melanoma, systemic therapies are limited by low response rates, short durations of response, and a 5-year survival rate <10%. Ipilimumab, a novel CTLA-4 inhibitor, is under investigation for the treatment of metastatic melanoma. Results of a randomized, controlled Phase 3 trial showed a first-ever overall survival benefit for patients with previously treated metastatic melanoma who received ipilimumab compared with the controls. The majority of adverse events reported with ipilimumab administration are considered to be low-grade immune-related events involving the skin and intestine and can be managed medically. Nonetheless, 10-17% of patients have immune-related adverse events of grade 3 or higher severity, with 2-3% of these events resulting in death. CONCLUSIONS: Ipilimumab is a novel CTLA-4 inhibitor that has been evaluated for the treatment of metastatic melanoma. On March 25, 2011, the Food and Drug Administration approved ipilimumab, making it the first agent indicated for unresectable or metastatic melanoma in more than a decade.

Clinical and economic value of screening for Kras mutations as predictors of response to epidermal growth factor receptor inhibitors.

PURPOSE: The clinical and economic value of screening for Kras mutations as predictors of response to cetuximab and panitumumab are reviewed. SUMMARY: Epidermal growth factor receptor (EGFR) inhibitors cetuximab and panitumumab are agents currently used in the treatment of metastatic colorectal cancer. Cetuximab is approved in combination with irinotecan for second-line therapy or as a single agent in the third-line setting, and panitumumab is approved as a single agent for third-line therapy. Historically, response rates to EGFR inhibitors have been low; therefore, predictors of response or lack of response have been highly sought after. Mutations in the Kras oncogene, which encodes for the RAS protein located downstream from EGFR, have been associated with poor response to EGFR inhibitor therapy. Numerous studies have confirmed a Kras mutation frequency in approximately 40% of all metastatic colorectal cancers, as well as an associated lack of response to EGFR inhibitor therapy. Screening for Kras mutations before selecting a therapy may be clinically beneficial by avoiding the cost and toxicity of ineffective therapy. A simple breakeven analysis using a group of 100 hypothetical patients with metastatic colorectal cancer revealed that cost savings will be achieved if screening can be conducted for less than $3460 per patient, regardless of which EGFR inhibitor is used. CONCLUSION: Mutations in the Kras oncogene are associated with a poor response to EGFR inhibitor therapy in metastatic colorectal cancer. Implementing routine Kras screening and limiting the use of EGFR inhibitors to patients with wild-type (not mutated) Kras may have the potential for cost savings.

The effect of carbapenem antibiotics on plasma concentrations of valproic acid.

OBJECTIVE: To critically evaluate the mechanisms of the interaction between valproic acid and carbapenem antibiotics. DATA SOURCES: A PubMed search (January 1971-June 2009) was performed to identify literature on the interaction between valproic acid and carbapenem antibiotics. Additional references were identified through review of bibliographies of identified articles. STUDY SELECTION AND DATA EXTRACTION: Data on the mechanisms of the interaction between valproic acid and carbapenem antibiotics were extracted from identified references that were published in English. DATA SYNTHESIS: Valproic acid plasma concentrations fall markedly during concomitant administration with carbapenem antibiotics due to a combination of absorption, distribution, and metabolism mechanisms. Carbapenems appear to inhibit the intestinal transporter of valproic acid, thereby reducing absorption of orally administered valproic acid. In vivo experiments in rats demonstrate a 57% reduction in absorption of orally administered valproic acid in the presence of imipenem. Follow-up studies in Caco-2 cells suggest that the inhibition probably occurs at the basolateral membrane. In addition, enterohepatic recycling of valproic acid may be diminished due to carbapenem activity against gut flora producing beta-glucuronidase. When rabbits and rats were given intravenous valproic acid-glucuronide, the glucuronide metabolite of valproic acid, 50-90% of the conversion back into valproic acid was inhibited in the presence of a carbapenem. An increase in erythrocyte distribution of valproic acid has also been observed in the presence of carbapenems. After intravenous administration of a carbapenem and valproic acid, valproic acid plasma concentrations fell in the presence of a carbapenem, yet whole blood concentrations of valproic acid did not change significantly. Follow-up studies suggest that the mechanism of this distribution shift is that multidrug resistance proteins on adenosine triphosphate-binding cassette transporters on erythrocyte membranes are inhibited by carbapenems. Thus, valproic acid is not effluxed out of the erythrocytes. Finally, carbapenems may enhance glucuronidation of valproic acid by increasing UDP-glucuronic acid levels. In rats, UDP-glucuronic acid levels increased by 1.7-fold in the presence of panipenem, which was proportionate to the increase in valproic acid-glucuronide formation. CONCLUSIONS: Published data demonstrate a serious and complex interaction between valproic acid and carbapenem antibiotics. Coadministration should be avoided, but if no other antibiotic therapies exist, it is imperative to monitor valproic acid concentrations more frequently. Clinicians should anticipate higher doses of valproic acid to maintain therapeutic serum concentrations during coadministration and subsequent dose reductions upon discontinuation of the carbapenem antibiotic.