Cefepime pharmacokinetics in adult extracorporeal membrane oxygenation patients.

BACKGROUND: The impact of extracorporeal membrane oxygenation (ECMO) on the pharmacokinetics/dynamics (PK/PD) of beta-lactam antibiotics have not been well studied in general, but cefepime specifically has the least amount of data. We aimed to investigate whether ECMO alters the PK of cefepime in adult intensive care unit (ICU) patients. METHODS: This single-center, retrospective case-control study evaluated cefepime therapeutic drug monitoring (TDM) results from ECMO patients that were matched 1:1 with TDM results in non-ECMO patients for drug regimen and renal function. The primary outcome was the difference in PK/PD of cefepime in ECMO compared with non-ECMO ICU patients. Secondary outcomes included hospital length of stay, treatment failure, superinfection, bacterial resistance, and survival to discharge. RESULTS: Eighty-two patients were included with 44 matched cefepime concentrations in each group. ECMO patients had higher free maximum concentrations (fCmax) (p = 0.003), lower free minimum concentration (fCmin)/1x minimum inhibitory concentration (MIC) ratios (p = 0.040), and lower attainment of free Cmin/4x MIC (p = 0.010). There were no differences between the groups for free Cmin, time above 1xMIC or 4x MIC, and pharmacokinetic parameters (ke, half-life, and Vd). Of those who survived to discharge, hospital length of stay was longer in the ECMO group (p < 0.001). Patients on ECMO were more likely to experience treatment failure (p = 0.036). The incidence of bacterial resistance, superinfection, or survival were similar among the groups. CONCLUSION: These data suggest that more aggressive empiric dosing may be warranted in patients on ECMO. Therapeutic drug monitoring and future prospective studies would provide more evidence to guide decision making regarding dose adjustments.

Utility of the 4Ts score in excluding heparin-induced thrombocytopenia in lung transplant recipients.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic complication following heparin exposure. Data is limited on the incidence of HIT and validity of 4Ts score in the solid organ transplant population. This retrospective observational cohort included patients who underwent lung transplant between August 2015 and June 2018 and had a clinical suspicion of HIT with heparin-PF4 testing. The 4Ts score was correlated with the heparin-PF4 antibody and serotonin release assay (SRA) results, with positive SRA considered confirmed HIT. Of 146 patients evaluated, the overall incidence of HIT was low (2(1%)). Fifty-one patients had heparin-PF4 testing and were included in the cohort; 5 (10%) had positive heparin-PF4 and 1 (2%) had confirmed HIT. The median 4Ts score was 3 (3-4). Thirty (59%), 17 (33%), and 4 (8%) patients had low, intermediate, and high risk, respectively. The intermediate/high risk group compared to the low risk group had a higher use of alternative non-heparin anticoagulation [13 (62%) vs 7 (23%); p = 0.0086)] and a higher incidence of thrombosis [13 (62%) vs 1 (3%); p < 0.0001]. No patient with a low 4Ts score had confirmed HIT, supporting the utility of low 4Ts score to exclude HIT diagnosis in lung transplant recipients.

SSRI/SNRI Therapy is Associated With a Higher Risk of Gastrointestinal Bleeding in LVAD Patients.

BACKGROUND: Gastrointestinal bleeding (GIB) is common in left ventricular assist device (LVAD) patients. Serotonin release from platelets promotes platelet aggregation, and selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI) therapy inhibits the transporter responsible for re-uptake. METHODS: We reviewed the records of LVAD (HeartMateII™, Abbott Medical, Lake Bluff, IL, USA and Heartware™, Medtronic, Minneapolis, MN, USA) patients at the Medical University of South Carolina and Johns Hopkins Hospital between January 2009 and January 2016. After exclusions, 248 patients were included for analysis. After univariate analysis, logistic regression multivariate analysis was performed to adjust for any demographic, cardiovascular, and laboratory data variables found to be associated with GI bleeding post-LVAD. RESULTS: Gastrointestinal bleeding occurred in 85 patients (35%) with 55% of GIBs due to arteriovenous malformations (AVMs). Of the total cohort, 105 patients received an SSRI or SNRI during LVAD support. Forty-four (44) SSRI/SNRI (41.9%) and 41 non-SSRI/SNRI (28.7%) patients had a GIB (RR 1.46, p = 0.03). Twenty-six (26) (24.8%) of the SSRI/SNRI patients had a GIB due to AVMs versus 21 (14.7%) of the non-SSRI/SNRI patients (RR 1.69, p = 0.05). In fully-adjusted multivariate regression analysis, SSRI/SNRI therapy was independently associated with GIB (OR 1.78, p = 0.045). For GIB, the number needed to harm (NNH) was 7.6. CONCLUSION: In conclusion, SSRI/SNRI therapy is independently associated with an increased risk of GIB in LVAD patients.

Effect of Angiotensin II Inhibitors on Gastrointestinal Bleeding in Patients With Left Ventricular Assist Devices.

BACKGROUND: Angiotensin II receptor activation may result in angiogenesis, and ultimately arteriovenous malformations (AVM), through transforming growth factor (TGF)-ß and angiopoietin-2 pathway activation. OBJECTIVES: The goal of this study was to determine whether angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) were associated with lower risk of major gastrointestinal bleeds (GIB) and AVM-related GIBs in continuous-flow left ventricular assist device (CF-LVAD) patients. METHODS: The authors reviewed HeartMate II CF-LVAD recipients between January 2009 and July 2016. Major GIBs were endoscopically confirmed requiring ≥2 U of packed red blood cells or resulting in death. ACE inhibitor/ARB dose was abstracted from medical records. ACE inhibitor/ARB exposure status was landmarked at 30 days post-operatively to avoid immortal time bias. Fine and Gray hazard models assessed the impact of ACE inhibitor/ARB therapy on major GIB and AVM-related GIB, whereas standard Cox regression assessed the impact on mortality, adjusting for baseline variables. RESULTS: One-hundred and eleven patients were included with a mean 2.1 ± 1.4 years follow-up. Patients who received an ACE inhibitor/ARB within 30 days post-operatively had a 57% reduction in the risk of major GIB (adjusted hazard ratio [aHR]: 0.43; 95% confidence interval [CI]: 0.19 to 0.97; p = 0.042) and a 63% reduction in the risk of AVM-related GIB (aHR: 0.37; 95% CI: 0.16 to 0.84; p = 0.017). When the mean daily post-operative lisinopril-equivalent ACE inhibitor/ARB dose was >5 mg, the risk of major GIB decreased in a dose-threshold manner (aHR: 0.28; 95% CI: 0.09 to 0.85; p = 0.025). CONCLUSIONS: ACE inhibitor/ARB therapy is associated with a protective effect of developing GIBs in CF-LVAD patients, with a dose threshold of >5 mg of daily lisinopril equivalence, possibly due to prevention of AVM formation.