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.

Outcomes With Single-Site Dual-Lumen Versus Multisite Cannulation for Adults With COVID-19 Respiratory Failure Receiving Venovenous Extracorporeal Membrane Oxygenation.

OBJECTIVES: To determine whether multisite versus single-site dual-lumen (SSDL) cannulation is associated with outcomes for COVID-19 patients requiring venovenous extracorporeal membrane oxygenation (VV-ECMO). DESIGN: Retrospective analysis of the Extracorporeal Life Support Organization Registry. Propensity score matching (2:1 multisite vs SSDL) was used to control for confounders. PATIENTS: The matched cohort included 2,628 patients (1,752 multisite, 876 SSDL) from 170 centers. The mean ( sd ) age in the entire cohort was 48 (11) years, and 3,909 (71%) were male. Patients were supported with mechanical ventilation for a median (interquartile range) of 79 (113) hours before VV-ECMO support. INTERVENTIONS: None. MEASUREMENTS: The primary outcome was 90-day survival. Secondary outcomes included survival to hospital discharge, duration of ECMO support, days free of ECMO support at 90 days, and complication rates. MAIN RESULTS: There was no difference in 90-day survival (49.4 vs 48.9%, p = 0.66), survival to hospital discharge (49.8 vs 48.2%, p = 0.44), duration of ECMO support (17.9 vs 17.1 d, p = 0.82), or hospital length of stay after cannulation (28 vs 27.4 d, p = 0.37) between multisite and SSDL groups. More SSDL patients were extubated within 24 hours (4% vs 1.9%, p = 0.001). Multisite patients had higher ECMO flows at 24 hours (4.5 vs 4.1 L/min, p < 0.001) and more ECMO-free days at 90 days (3.1 vs 2.0 d, p = 0.02). SSDL patients had higher rates of pneumothorax (13.9% vs 11%, p = 0.03). Cannula site bleeding (6.4% vs 4.7%, p = 0.03), oxygenator failure (16.7 vs 13.4%, p = 0.03), and circuit clots (5.5% vs 3.4%, p = 0.02) were more frequent in multisite patients. CONCLUSIONS: In this retrospective study of COVID-19 patients requiring VV-ECMO, 90-day survival did not differ between patients treated with a multisite versus SSDL cannulation strategy and there were only modest differences in major complication rates. These findings do not support the superiority of either cannulation strategy in this setting.

Non-Lung Solid Organ Transplantation From SARS-CoV-2-Positive Donors to Uninfected Recipients.

BACKGROUND: There is a paucity of evidence on the risk of donor-recipient transmission of the SARS-CoV-2 in solid organ transplant recipients. Initial impressions suggest non-lung solid organs may be safely transplanted from SARS-CoV-2-positive donors without risk of viral transmission. METHODS: We reviewed clinical results of transplants in which SARS-CoV-2-negative recipients received non-lung solid organs from SARS-CoV-2-positive donors at a single transplant center. No prisoners were used in this study, and participants were neither coerced nor paid. The manuscript was created in compliance with the Helsinki Congress and the Declaration of Istanbul. RESULTS: Between June 2021 and January 2023, we transplanted 26 solid organs, including 13 kidneys, 8 livers, 3 hearts, and 1 simultaneous heart and kidney, from 23 SARS-CoV-2-positive donors into 25 SARS-CoV-2 negative recipients. Two of the recipients had a positive SARS-CoV-2 real-time polymerase chain reaction after transplantation, but otherwise, patients had no SARS-CoV-2-related complications, and all patients to date are alive with excellent allograft function. CONCLUSION: Transplantation of non-lung solid organs from SARS-CoV-2-positive donors into uninfected recipients can be safely performed without adverse effects from SARS-CoV-2.

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.

Review of heart transplantation from hepatitis C-positive donors.

Significant scarcity of a donor pool exists for heart transplantation (HT) as the prevalence of patients with end-stage refractory heart failure is increasing exceptionally. With the discovery of effective direct-acting antiviral and favorable short-term outcomes following HT, the hearts from hepatitis C virus (HCV) patient are being utilized to increase the donor pool. Short-term outcomes with regards to graft function, coronary artery vasculopathy, and kidney and liver disease is comparable in HCV-negative recipients undergoing HT from HCV-positive donors compared to HCV-negative donors. A significant high incidence of donor-derived HCV transmission was observed with great success of achieving sustained viral response with the use of direct-acting antivirals. By accepting HCV-positive organs, the donor pool has expanded with younger donors, a shorter waitlist time, and a reduction in waitlist mortality. However, the long-term outcomes and impact of specific HCV genotypes remains to be seen. We reviewed the current literature on HT from HCV-positive donors.

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.

Outcomes by cannulation methods for venovenous extracorporeal membrane oxygenation during COVID-19: A multicenter retrospective study.

In a multicenter, retrospective analysis of 435 patients with refractory COVID-19 placed on V-V ECMO, cannulation by a single, dual-lumen catheter with directed outflow to the pulmonary artery was associated with lower inpatient mortality.

Application and outcomes of extracorporeal life support in emergency general surgery and trauma.

BACKGROUND: We analyzed the use of Extracorporeal Membranous Oxygenation (ECMO) in acute care surgery patients at our Level-1 trauma center. We hypothesized that this patient population has improved ECMO outcomes. METHODS: This was a retrospective analysis of emergency general surgery and trauma patients placed on ECMO between the periods of October 2013 and February 2020. There were 10 surgical and 12 trauma patients studied, who eventually required ECMO support. ECMO support and ECMO type/modality were analyzed with injury and survival prognostic scores examined. MAIN RESULTS: Overall, 16 of the 22 patients survived to hospital discharge, for a survival rate of 73%. Mean age was 34.18 years. Mean hospital length of stay was 23.4 days with mean days on ECMO equal to 7.5. The net negative fluid balance was 5.36 L. CONCLUSIONS: The survival of our ECMO cohort is notably higher than previously cited studies. Our group demonstrated decreased length of time on ECMO, decreased length of stay in the hospital, and similar rates of complications compared to prior reports. ECMO is a useful modality in acute care surgical patients and should be considered in these patient populations. Our focus on net negative fluid balance for ECMO patients demonstrates improved survival. ECMO should be considered early in surgical patients and early in advanced trauma life support.

Post Heart Transplantation Outcomes of Patients Supported on Biventricular Mechanical Support.

With the implementation of the new heart transplant (HT) allocation system, patients requiring biventricular support systems have the highest priority, a shorter waitlist time, and a higher frequency of HT. However, the short-term and long-term outcomes of such patients are often disputed. Hence, we examined the outcomes of these patients who underwent HT before change in allocation scheme. Additionally, we compared post-HT outcomes of extracorporeal membrane oxygenation (ECMO) with other nondischargeable biventricular (BiVAD) supported patients. We identified adult ECMO or BiVAD supported HT recipients between 2000 and 2018 in the Scientific Registry of Transplant Recipients database. We compared survival with the Kaplan-Meier method. Using overlap propensity score weighting, we constructed Cox proportional hazards regression models to determine the risk-adjusted influence of BiVAD versus ECMO on survival. Of the 730 patients HT recipients; 528 (72.3%) and 202 (27.7%) were bridged with BiVAD and ECMO, respectively. For BiVAD versus ECMO patients, the 30-day, 1-year, 3-year, and 5-year mortality rates were 8.0% versus 14.4%, 16.3% versus 21.3%, 22.4% versus 25.3%, and 26.3% versus 25.7%, respectively. Risk-adjusted post-HT survival of BiVAD and ECMO patients at 30-day (HR 1.24 [95% CI, 0.68-2.27]; P = 0.4863), 1-year (HR 1.29 [95% CI, 0.80-2.09]; P = 0.3009), 3-year (HR 1.27 [95% CI, 0.83-1.94]; P = 0.2801), and 5-year (HR 1.35, 95% CI, 0.90-2.05; P = 0.1501) were similar. Around three-fourth of the ECMO or BiVAD supported patients were alive at 5-years post-HT. The short-term and long-term post-HT survivals of groups were comparable.

ECMO after cardiac surgery: a single center study on survival and optimizing outcomes.

BACKGROUND: The study purpose is to examine survival prognostic and extracorporeal membrane oxygenation (ECMO) application outcomes at our tertiary care center. METHODS: This is a retrospective analysis, January 2014 to September 2019. We analyzed 60 patients who underwent cardiac surgery and required peri-operative ECMO. All inpatients with demographic and intervention data was examined. 52 patients (86.6%) had refractory cardiogenic shock, 7 patients (11.6%) had pulmonary insufficiency, and 1 patient (1.6%) had hemorrhagic shock, all patients required either venous-arterial (VA) (n = 53, 88.3%), venous-venous (VV) (n = 5, 8.3%) or venous-arterial-venous (VAV) (n = 2, 3.3%) ECMO for hemodynamic support. ECMO parameters were analyzed and common postoperative complications were examined in the setting of survival with comorbidities. RESULTS: In-hospital mortality was 60.7% (n = 37). Patients who survived were younger (52 ± 3.3 vs 66 ± 1.5, p < 0.001) with longer hospital stays (35 ± 4.0 vs 20 ± 1.5, p < 0.03). Survivors required fewer blood products (13 ± 2.3 vs 25 ± 2.3, p = 0.02) with a net negative fluid balance (- 3.5 ± 1.6 vs 3.4 ± 1.6, p = 0.01). Cardiac re-operations worsened survival. CONCLUSION: ECMO is a viable rescue strategy for cardiac surgery patients with a 40% survival to discharge rate. Careful attention to volume management and blood transfusion are important markers for potential survival.

Clinical outcomes of older adults listed for heart transplantation in the United States.

OBJECTIVE: To examine if older age (>70 years) should be a relative contraindication for heart transplantation, we evaluated the characteristics and outcomes of patients with age ≥70 years listed for heart transplantation; and whether post-transplantation survival was inferior to younger counterparts. DESIGN: Retrospective cohort analysis. SETTING: The scientific registry of transplant recipients (SRTR). PARTICIPANTS: Adults (≥18 years) listed for heart transplantation in the SRTR between 2000 and 2018. INTERVENTIONS: Heart transplantation. MEASUREMENTS: Characteristics and outcomes were compared for adults ≥70 years and <70 years. We evaluated waitlist mortality and post-transplant 1-year and 5-year survivals. RESULTS: The study included 57,285 patients (age range 18-79 years) listed for heart transplantation; 1203 (2.1%) age ≥70 years. Of these, 37,135 patients underwent heart transplantation; 806 (2.2%) were age ≥70 years. Yearly listing of those age ≥70 years has consistently increased from 2.5% (n = 30) in 2000 to 11% (n = 132) in 2017 (p < 0.01). As compared with the age <70 years group, those ≥70 years had a similar risk of death while waiting (sub-hazard ratio [SHR] 0.86, 95% confidence interval [HR] 0.68-1.08; p = 0.19) but were more likely to be transplanted (SHR 1.36, 95% CI 1.26-1.48; p < 0.01). Among the older patients, the overall post-transplant 1- and 5-year mortality rate was 10.4% and 19.2%, respectively. Older recipients had lower unadjusted survival compared with younger recipients (log-rank p = 0.03). However, after adjustment for relevant covariates, there was no significant difference in 5-year mortality between both groups (HR 1.06, 95% CI 0.91-1.254; p = 0.43). CONCLUSIONS: Post-transplant survival up to 5 years among patients of age ≥70 years was similar to that of younger recipients. Older patients who received heart transplantation appear to have lower risk features but receive hearts from higher risk donors. Chronologic age alone should not constitute a contraindication for heart transplantation, although careful patient selection criteria should be applied.

Air Medical Transport of Patients Diagnosed With Confirmed Coronavirus Disease 2019 Infection Undergoing Extracorporeal Membrane Oxygenation: A Case Review and Lessons Learned.

The coronavirus disease 2019 pandemic disrupted health care delivery in every respect, including critical care resources and the transport of patients requiring extracorporeal membrane oxygenation. Innovative solutions allowing for safe helicopter air transport of these critical patients is needed because extracorporeal membrane oxygenation resources are only available in specialty centers. We present a case demonstrating the interfacility collaboration of care for a patient with coronavirus disease 2019 infection and the lessons learned from the air transport. Careful planning, coordination, communication, and teamwork contributed to the safe transport of this patient and several others subsequently.

Incidental COVID-19 in a heart-kidney transplant recipient with malnutrition and recurrent infections: Implications for the SARS-CoV-2 immune response.

The clinical course and outcomes of immunocompromised patients, such as transplant recipients, with COVID-19 remain unclear. It has been postulated that a substantial portion of the disease burden seems to be mediated by the host immune activation to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Herein, we present a simultaneous heart-kidney transplant (SHKT) recipient who was hospitalized for the management of respiratory failure from volume overload complicated by failure to thrive, multiple opportunistic infections, and open non-healing wounds in the setting of worsening renal dysfunction weeks prior to the first case of SARS-CoV-2 being detected in the state of Connecticut. After his third endotracheal intubation, routine nucleic acid testing (NAT) for SARS-CoV-2, in anticipation of a planned tracheostomy, was positive. His hemodynamics, respiratory status, and ventilator requirements remained stable without any worsening for 4 weeks until he had a negative NAT test. It is possible that the immunocompromised status of our patient may have prevented significant immune activation leading up to clinically significant cytokine storm that could have resulted in acute respiratory distress syndrome and multisystem organ failure.

ICD shocks in LVAD patients are not associated with increased subsequent mortality risk.

BACKGROUND: Implantable cardioverter-defibrillator (ICD) shocks are associated with increased mortality risk in heart failure patients. Whether ICD shocks are associated with mortality in continuous flow LVAD (CF-LVAD) patients is unknown. We studied the relationship of ICD shocks and ventricular arrhythmias (VAs) to morbidity and mortality in CF-LVAD-supported patients in our institution. METHODS: Single-center, retrospective study of prospectively collected ICD and LVAD databases. We analyzed data on VA which received ICD therapy in patients who underwent CF-LVAD implantation at Hartford Hospital between 2008 and 2018. RESULTS: A total of 157 patients were studied. During a median follow-up of 10 months (interquartile range 5-20 months), 48 patients (30.6%) experienced post-LVAD sustained VA. Thirty patients (19.1%) had appropriate shocks for VA and 5 patients (3.1%) had inappropriate shocks. Shocks for any arrhythmia were not associated with an increased risk of death (OR 0.836, 95% CI 0.224-3.115, p = 0.789). Neither post-LVAD VA nor the rate of VA was associated with an increased mortality risk (OR 0.662 [0.329-1.334], p = 0.248; OR 1.001 [0.989-1.014], p = 0.817, respectively). Cox multivariate regression analysis revealed pre-LVAD VA as a significant predictor of VA post LVAD implantation (OR 3.284 [1.584-6.808], p = 0.001). Symptoms with VA occurred in 22 (45.8%) patients, ranging from palpitations to near syncope/syncope. None of the variables including the rate of VA was associated with death or symptoms. CONCLUSIONS: VAs are common in CF-LVAD patients and occur with higher frequency in those with pre-LVAD VA and frequently cause symptoms. Neither VA nor ICD shocks are associated with mortality risk.

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.