•Cefepime PK in 6 critically ill patients supported by ECMO is described•In normal or augmented renal function, 2g q8h (3h infusion) achieves ≥70% fT>MIC up to 16 µg/mL•None of the patients ...experienced cefepime associated neurotoxicity at this dosage•TDM may be useful to balance therapeutic exposure while preventing toxicity
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 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.
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.
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 ± standard deviation parameters were: CL0, 15.21 ± 6.52 L/h; Vc, 10.13 ± 2.26 L; K12, 2.45 ± 1.16 h-1 and K21, 1.76 ± 0.49 h-1 for imipenem, and 6.95 ± 1.34 L/h, 9.81 ± 2.69 L, 2.43 ± 1.13 h-1 and 1.52 ± 0.67 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.
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.
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.
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.
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.
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.
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.
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.
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).
Our small single-center analysis suggests that neither time to nor time in therapeutic tacrolimus range predicted acute rejection within 30 days of HT.
Is Entresto good for the brain? Patel, Nirav; Gluck, Jason
World journal of cardiology,
07/2017, Volume:
9, Issue:
7
Journal Article
Open access
The main stay pharmacotherapy for heart failure(HF) is targeted towards rennin-angiotensin-aldosterone(RAAS) and neprilysin pathways(NP). Both therapeutic strategies decreases morbidity and mortality ...but also carry considerable adverse effects. This review of the literature highlights the new generation of HF drug, sacubitril-valsartan(SV), trade name Entresto(researched as LCZ696, Novartis) which simultaneously blocks RAAS and NP. This dual action of angiotensin receptors blocker and neprilysin inhibitor(NPi) has improved HF prognosis and it is an evolution in the management of HF. Although the initial follow-up of patients treated with SV has yielded promising results, there are concerns regarding potential side effects especially an increase in the risk of Alzheimer’s disease(AD) and young onset of AD. NPi interferes with the breakdown and clearing of beta-amyloid peptides, the plaques seen in AD, raising concern for AD in SV patients. On the other hand, hypertension and cardiovascular diseases are established risk factors for AD which can be decreased by SV therapy. It is therefore essential that SV treated patients are followed up over an extended period of time to detect any adverse cognitive changes.
Right and left heart catheterization corroborated constriction demonstrating equalization of diastolic pressures, prominent y-descent, 'dip and plateau pattern', respiratory discordance between LV ...and RV systolic pressures and decreased cardiac index.
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