Imipenem/relebactam pharmacokinetics in critically ill patients supported on extracorporeal membrane oxygenation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a life-saving modality but has the potential to alter the pharmacokinetics (PK) of antimicrobials. Imipenem/cilastatin/relebactam is an antibiotic with utility in treating certain multi-drug resistant Gram-negative infections. Herein, we describe the population pharmacokinetics of imipenem and relebactam in critically ill patients supported on ECMO. METHODS: Patients with infection supported on ECMO received 4-6 doses of imipenem/cilastatin/relebactam per current prescribing information based on estimated creatinine clearance. Blood samples were collected following the final dose of the antibiotic. Concentrations were determined via LC-MS/MS. Population PK models were fit with and without covariates using Pmetrics. Monte Carlo simulations of 1000 patients assessed joint PTA of fAUC0-24/MIC ≥ 8 for relebactam, and ≥40% fT > MIC for imipenem for each approved dosing regimen. RESULTS: Seven patients supported on ECMO were included in PK analyses. A two-compartment model with creatinine clearance as a covariate on clearance for both imipenem and relebactam fitted the data best. The mean ±â€Šstandard deviation parameters were: CL0, 15.21 ±â€Š6.52 L/h; Vc, 10.13 ±â€Š2.26 L; K12, 2.45 ±â€Š1.16 h-1 and K21, 1.76 ±â€Š0.49 h-1 for imipenem, and 6.95 ±â€Š1.34 L/h, 9.81 ±â€Š2.69 L, 2.43 ±â€Š1.13 h-1 and 1.52 ±â€Š0.67 h-1 for relebactam. Simulating each approved dose of imipenem/cilastatin/relebactam according to creatinine clearance yielded PTAs of ≥90% up to an MIC of 2 mg/L. CONCLUSIONS: Imipenem/cilastatin/relebactam dosed according to package insert in patients supported on ECMO is predicted to achieve exposures sufficient to treat susceptible Gram-negative isolates, including Pseudomonas aeruginosa.

Cefiderocol is Not Sequestered in an Ex Vivo Extracorporeal Membrane Oxygenation (ECMO) Circuit.

BACKGROUND AND OBJECTIVE: Extracorporeal membrane oxygenation (ECMO) is used in critically ill patients that require respiratory and/or cardiac support. Cefiderocol is a novel siderophore antibiotic that may require use in infected critically ill patients supported by ECMO. The objective of this study was to determine the loss of cefiderocol through an ex vivo adult ECMO circuit using a Quadrox-iD oxygenator. METHODS: A 3/8-inch, simulated, ex vivo closed-loop ECMO circuit was prepared with a Quadrox-iD adult oxygenator and primed with fresh whole blood. Cefiderocol was administered into the circuit to achieve a starting concentration of approximately 90 mg/L. Post-oxygenator blood samples were collected at 0, 0.25, 0.5, 1, 2, 4, 6, 12, and 24 h after the addition of the drug to determine the loss in the circuit. A glass control jar was prepared with the same blood matrix and maintained at the same temperature to determine drug degradation. The experiment was conducted in triplicate. The rate of cefiderocol loss in the ECMO circuit was compared with that in the control by one-way analysis of variance. RESULTS: At 0 h, the difference between the pre- and post-oxygenator concentrations was - 4 ± 4% (range 0 to - 7%). After 24 h, the cefiderocol percent reduction was similar between the ECMO circuit and control (50% ± 13 vs. 50% ± 9, p = 1.0). CONCLUSIONS: The degradation rate of cefiderocol did not differ significantly within the ECMO circuit and control, suggesting no loss due to sequestration or adsorption. Pharmacokinetic studies in patients supported by ECMO are warranted to determine final dosing recommendations.

Pharmacokinetics and Time above the MIC Exposure of Cefepime in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation (ECMO).

This study determined the pharmacokinetics of cefepime in patients requiring extracorporeal membrane oxygenation (ECMO) support to guide dosage selection. Cefepime population pharmacokinetics where characterized in Pmetrics for R for six critically ill patients receiving ECMO. Simulation was employed to determine the fT>MIC and total trough concentration of varying regimens in each patient to evaluate ability to achieve optimal pharmacodynamic exposure and thresholds for cefepime-associated neurotoxicity. Of the six participants, two required continuous veno-venous hemodiafiltration (CVVHDF) while four had a CrCL between 92-199 ml/min. All patients received 2 g q8h as a 3h infusion. A two-compartment model fitted the data best with median (range) parameter estimates as follows: clearance, 5.99 (4.10-10.29) L/h; volume of central compartment, 10.08 (2.45-15.14) L; and intercompartment transfer constants (k12), 3.58 (2.01-4.99) h-1 and k21, 1.70 (1.00-2.88) h-1. The 2g q8h (3h infusion) regimen resulted in >70% fT>MIC in all patients up to an MIC of 16 µg/mL, whereas 2g q12h (0.5h) resulted in 5/6 patients achieving 70% ƒT>MIC at 8 µg/mL but only 1/6 at 16 µg/mL. Aggressive dosing regimens resulted in trough concentrations exceeding conservative neurotoxicity thresholds. No patient demonstrated signs or symptoms of neurotoxicity during treatment. For ECMO patients with normal to augmented renal clearance similar to those presented here, or those receiving CVVHDF, these data support dosing regimens of 2g q8h (3h infusions) to empirically target MICs up to 16 µg/mL. Larger studies are needed to determine how ECMO affects cefepime pharmacokinetics.

Extracorporeal Life Support Organization Guideline for Transport and Retrieval of Adult and Pediatric Patients with ECMO Support.

DISCLAIMER: This guideline for the preparation for and undertaking of transport and retrieval of patients on extracorporeal membrane oxygenation (ECMO) is intended for educational use to build the knowledge of physicians and other health professionals in assessing the conditions and managing the treatment of patients undergoing ECLS / ECMO and describe what are believed to be useful and safe practice for extracorporeal life support (ECLS, ECMO) but these are not necessarily consensus recommendations. The aim of clinical guidelines are to help clinicians to make informed decisions about their patients. However, adherence to a guideline does not guarantee a successful outcome. Ultimately, healthcare professionals must make their own treatment decisions about care on a case-by-case basis, after consultation with their patients, using their clinical judgement, knowledge and expertise. These guidelines do not take the place of physicians' and other health professionals' judgment in diagnosing and treatment of particular patients. These guidelines are not intended to and should not be interpreted as setting a standard of care or be deemed inclusive of all proper methods of care nor exclusive of other methods of care reasonably directed to obtaining the same results. The ultimate judgment must be made by the physician and other health professionals and the patient in light of all the circumstances presented by the individual patient, and the known variability and biological behavior of the clinical condition. These guidelines reflect the data at the time the guidelines were prepared; the results of subsequent studies or other information may cause revisions to the recommendations in these guidelines to be prudent to reflect new data, but ELSO is under no obligation to provide updates. In no event will ELSO be liable for any decision made or action taken in reliance upon the information provided through these guidelines.

Association Between Time-in-Therapeutic Tacrolimus Range and Early Rejection After Heart Transplant.

BACKGROUND: Historically, there is perceived pressure to achieve therapeutic levels of tacrolimus quickly after heart transplant (HT). We evaluated the association between time within therapeutic tacrolimus range and time to therapeutic trough and rejection in the 30 days following HT. METHODS: This is a single-center retrospective cohort study of consecutive adult HT patients receiving immunosuppression. Goal trough tacrolimus levels were 10-15 ng/ml. Surveillance endomyocardial biopsies were performed weekly for 4 weeks. Outcomes included the effect of time to and time-in-therapeutic tacrolimus range (Rosendaal method) on 30-day clinical rejection, 1R/1B, and 2R or higher histologic occurrences. RESULTS: We reviewed 67 HT patients (median age 58.8 yrs). For clinical rejection versus no-rejection groups, the median (25th, 75th percentile) time to therapeutic tacrolimus levels was 9.5 (8, 12.3) days versus 9.0 (7, 13) days (p=0.623). The median time-in-therapeutic tacrolimus range was 34.1% (23.2, 42.2) versus 36.2% (19.9, 51.2), respectively (p=0.512). Similarly, we observed no significant differences in time to and time-in-therapeutic tacrolimus range in patients who developed grade 1R/1B (p=0.650 and p=0.725) or grade 2R or higher histology (p=0.632 and p=0.933). CONCLUSIONS: Our small single-center analysis suggests that neither time to nor time in therapeutic tacrolimus range predicted acute rejection within 30 days of HT.

Left ventricular assist device implantation improves glycaemic control: a systematic review and meta-analysis.

AIMS: Heart failure (HF) and diabetes mellitus (DM) often coexist and have bidirectional association. Advanced HF is associated with worsened glycaemic control. This meta-analysis investigated the effects of left ventricular assist device (LVAD) implantation on markers of DM control. METHODS AND RESULTS: We performed a systematic search of MEDLINE and Cochrane through October 2017 to identify studies evaluating advanced HF patients who had received an LVAD and reported markers of glycaemic control. The primary outcome was glycosylated haemoglobin A1c (HbA1c), and the secondary outcomes included fasting glucose, daily insulin requirements, and body mass index (BMI). Outcomes were pooled using a Hartung-Knapp random-effects model producing a mean difference (MD) and 95% confidence interval (CI). Thirteen studies, including 820 participants, were included. HbA1c was 1.23% lower following LVAD implantation (95% CI -1.49 to -0.98). Greater HbA1c reductions were seen with higher pre-LVAD values. Similarly, fasting plasma glucose (-24.4 mg/dL, 95% CI -33.4 to -15.5), daily insulin requirements (-18.8 units, 95% CI -28.8 to -8.7), and serum creatinine levels (MD -0.20, 95% CI -0.35 to -0.06) were significantly lower than pre-LVAD levels. We saw no difference in BMI (MD 0.09, 95% CI -1.24 to 1.42). CONCLUSIONS: LVAD implantation was associated with significant improvement in HbA1c, fasting plasma glucose, and daily insulin need in advanced HF patients.

Cardiopulmonary Resuscitation in Adults and Children With Mechanical Circulatory Support: A Scientific Statement From the American Heart Association.

Cardiac arrest in patients on mechanical support is a new phenomenon brought about by the increased use of this therapy in patients with end-stage heart failure. This American Heart Association scientific statement highlights the recognition and treatment of cardiovascular collapse or cardiopulmonary arrest in an adult or pediatric patient who has a ventricular assist device or total artificial heart. Specific, expert consensus recommendations are provided for the role of external chest compressions in such patients.

Systematic Review of Phosphodiesterase-5 Inhibitor Use in Right Ventricular Failure Following Left Ventricular Assist Device Implantation.

Our aim was to identify relevant literature supporting the use of phosphodiesterase-5 (PDE5) inhibitors in patients with persistent pulmonary hypertension with signs of postprocedural right ventricular (RV) dysfunction following left ventricular assist device (LVAD) implantation. We searched MEDLINE, SCOPUS, and Web of Science from inception through November 27, 2014 for citations evaluating patients with end-stage heart failure necessitating LVAD, continuous and pulsatile, who received a PDE5 inhibitor to prevent RV failure. Outcomes of interest included changes in mean pulmonary artery pressure, pulmonary vascular resistance, central venous pressure, cardiac index, and mean arterial pressure. Results are presented qualitatively. Four citations (n = 83 patients) were included. These included a single case report, two retrospective case series, and a prospective open-label study with a historical control. All four studies utilized the PDE5 inhibitor sildenafil with various doses for up to 3 months. Sildenafil routinely reduced mean pulmonary artery pressures as soon as 90 min after administration. Reductions in pulmonary vascular resistance were also seen shortly after the procedure and maintained through 12-15 weeks. While one study saw improvements in postoperative central venous pressures, another did not. Evidence supporting PDE5 inhibitor use to attenuate RV failure in patients requiring an LVAD is weak.

The Association Between Baseline Left Atrial Volume Index and All-Cause Mortality in Patients with Heart Failure: A Meta-Analysis.

BACKGROUND: Enlargement of the left atrium is a marker of mortality in the general population. Left atrial volume index (LAVI) has long been proposed as a measure of prognosis in patients with heart failure (HF). The aim of this meta-analysis was to assess the utility of using baseline LAVI as an independent predictor of all-cause mortality in patients with HF. METHODS: A search of Medline and Embase bibliographic databases was performed to identify studies meeting the following inclusion criteria: 1) studies evaluating a cohort of patients with HF (both reduced and preserved ejection fraction); 2) studies conducting multivariate analysis or patient matching to determine the relationship between baseline LAVI measured by echocardiography and all-cause mortality; and 3) studies reporting data on the relationship between baseline LAVI (per difference in mL/m2) and all-cause mortality. Adjusted hazard ratios depicting the association between baseline LAVI and all-cause mortality were pooled using traditional random-effects meta-analysis. RESULTS: 1,188 publications were reviewed from which four studies were included in the present meta-analysis. We found each 10 mL/m2 increase in baseline LAVI was associated with a 22% increased adjusted hazard of all-cause mortality (95% confidence interval, 13% to 31%, I2 = 14%). CONCLUSION: Baseline LAVI is an important independent predictor of all-cause mortality in patients with heart failure and should be reported routinely in these patients undergoing echocardiography.

Extracorporeal Membrane Oxygenation as a Bridge to Surgery for Infective Endocarditis Complicated by Aorto-Atrial Fistula and Cardiopulmonary Collapse.

The timing of surgery for active infective endocarditis is challenging when patients exhibit mechanical dysfunction and hemodynamic compromise. Extracorporeal membrane oxygenation has been described in treating sepsis but not, insofar as we know, in treating the acute mechanical sequelae that arise from infective endocarditis. We report perhaps the first case that shows the usefulness of extracorporeal membrane oxygenation as a bridge to definitive treatment in a 35-year-old man who had infective endocarditis followed by aorto-atrial fistula and cardiopulmonary collapse.

A Survey of Knowledge and Perspectives of Ventricular Assist Device Therapy: Evaluating the Timing of Advanced Heart Failure Referral.

BACKGROUND: While advancements in ventricular assist device (VAD) therapy have improved survival and quality of life for select patients with advanced heart failure (HF), variations in provider knowledge and opinions may ultimately serve as barriers to therapy. METHODS AND RESULTS: A 12-item survey assessing experience, knowledge, and perspectives of VAD therapy was sent to 106 practicing cardiologists at three neighboring institutions. We received 34 responses for a total response rate of 32.1%. The majority of respondents elected to refer patients with refractory disease for VAD therapy, while only 29.4% elected to refer when standard medical therapy is withdrawn due to hypotension. CONCLUSIONS: While providers are well-informed on the fundamentals of advanced therapy, identifying patients with advanced HF who may benefit from referral remains an educational challenge. An automated referral program that identifies patients with advanced HF based on validated clinical parameters could increase appropriately timed referrals to HF specialists to further improve survival and quality of life outcomes with advanced therapy.

Reduction of Cardiac Arrests: The Experience of a Novel Service Centric Medical Emergency Team.

OBJECTIVE: To determine whether a novel, service-centric, medical emergency team (MET) model can impact cardiac arrest (CA) rates. METHODS: A retrospective pre- vs. postintervention analysis was performed on patients ≥ 18 years who had a CA between 2007 and 2012. A service centric MET model was initially implemented on the inpatient cardiology service and expanded hospital wide during 2008-2009, maturing to 10 teams in 2010. Service centric is defined as a medical or surgical service-specific MET team based on the location of the patient. RESULTS: The rate of CA (per 1,000 hospital days) in the year 2007 prior to the initiation of MET was compared to rates during program maturation (2008/2009) and after full maturation to 10 teams (2010-2012). A total of 1,140,233 hospital-care days were analyzed between 2007 and 2012, with 745 CAs recorded (0.65 events per 1,000 hospital days). The overall CA rate was higher prior to MET initiation (0.84 in 2007) compared to postinitiation (0.59 in 2008/09) and maturation to 10 teams (0.64 in 2010-12) (P < 0.003 for both pre- vs postcomparisons). No differences in CA rates were detected between either post-MET initiation time frames (P = 0.342). Similar trends in CA rates were observed in the intensive care unit (ICU) (3.96 vs 2.14 vs 2.68 per 1,000 hospital days in 2007, 2008/2009, and 2010-2012 respectively, with P < 0.001 for both pre- vs postcomparisons). CONCLUSIONS: A service-centric MET program was associated with a reduction in the rate of CAs both hospital wide and in the ICU. These observations maybe explained by the earlier intervention in care of unstable patients by an expanded group of caregivers.