A Guide to Contrast-Enhanced Computed Tomography in Adult Patients Supported With Extracorporeal Membrane Oxygenation.

Veno-arterial extracorporeal membrane oxygenation (VA ECMO) fundamentally alters patient physiology and blood flow relevant to contrast delivery for computed tomography (CT) imaging. Here, we present a comprehensive guide to contrast-enhanced CT scanning in adult ECMO patients, addressing common questions related to contrast delivery via the ECMO circuit, and modifications to ECMO settings and scanning techniques, to avoid non-diagnostic CT scans. The approach is described in detail for patients supported on VA ECMO, with the return cannula sited in the femoral artery. Lesser modifications required for veno-venous ECMO (VV ECMO) are included in the supplemental material. Establishing a common understanding between the intensive care clinician, the CT radiographer, and the radiologist, concerning the patient's blood-flow-physiology, is the overarching goal. Our stepwise approach facilitates clear communication around modifications to the ECMO pump settings, contrast route and rate, as well as the scanning technique, for each individual scenario.

Population pharmacokinetics of fluconazole in critically ill patients receiving extracorporeal membrane oxygenation and continuous renal replacement therapy: an ASAP ECMO study.

This multicenter study describes the population pharmacokinetics (PK) of fluconazole in critically ill patients receiving concomitant extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) and includes an evaluation of different fluconazole dosing regimens for achievement of target exposure associated with maximal efficacy. Serial blood samples were obtained from critically ill patients on ECMO and CRRT receiving fluconazole. Total fluconazole concentrations were measured in plasma using a validated chromatographic assay. A population PK model was developed and Monte Carlo dosing simulations were performed using Pmetrics in R. The probability of target attainment (PTA) of various dosing regimens to achieve fluconazole area under the curve to minimal inhibitory concentration ratio (AUC0-24/MIC) >100 was estimated. Eight critically ill patients receiving concomitant ECMO and CRRT were included. A two-compartment model including total body weight as a covariate on clearance adequately described the data. The mean (±standard deviation, SD) clearance and volume of distribution were 2.87 ± 0.63 L/h and 15.90 ± 13.29 L, respectively. Dosing simulations showed that current guidelines (initial loading dose of 12 mg/kg then 6 mg/kg q24h) achieved >90% of PTA for a MIC up to 1 mg/L. None of the tested dosing regimens achieved 90% of PTA for MIC above 2 mg/L. Current fluconazole dosing regimen guidelines achieved >90% PTA only for Candida species with MIC <1 mg/L and thus should be only used for Candida-documented infections in critically ill patients receiving concomitant ECMO and CRRT. Total body weight should be considered for fluconazole dose.

The effect of restrictive versus liberal selection criteria on survival in ECPR: a retrospective analysis of a multi-regional dataset.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) is an established rescue therapy for both out-of-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA). However, there remains significant heterogeneity in populations and outcomes across different studies. The primary aim of this study was to compare commonly used selection criteria and their effect on survival and utilisation in an Australian ECPR cohort. METHODS: We performed a retrospective, observational study of three established ECPR centres in Australia, including cases from 1 January 2013 to 31 December 2020 to establish the baseline cohort. We applied five commonly used ECPR selection criteria, ranging from restrictive to liberal. RESULTS: The baseline cohort included 199 ECPR cases: 95 OHCA and 104 IHCA patients. Survival to hospital discharge was 20% for OHCA and 41.4% for IHCA. For OHCA patients, strictly applying the most restrictive criteria would have resulted in the highest survival rate 7/16 (43.8%) compared to the most liberal criteria 16/73 (21.9%). However, only 16/95 (16.8%) in our cohort strictly met the most restrictive criteria versus 73/95 (76.8%) with the most liberal criteria. Similarly, in IHCA, the most restrictive criteria would have resulted in a higher survival rate in eligible patients 10/15 (66.7%) compared to 27/59 (45.8%) with the most liberal criteria. With all criteria a large portion of survivors in IHCA would not have been eligible for ECMO if strictly applying criteria, 33/43 (77%) with restrictive and 16/43 (37%) with the most liberal criteria. CONCLUSIONS: Adherence to different selection criteria impacts both the ECPR survival rate and the total number of survivors. Commonly used selection criteria may be unsuitable to select IHCA ECPR patients.

ECMO PAL: using deep neural networks for survival prediction in venoarterial extracorporeal membrane oxygenation.

PURPOSE: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is a complex and high-risk life support modality used in severe cardiorespiratory failure. ECMO survival scores are used clinically for patient prognostication and outcomes risk adjustment. This study aims to create the first artificial intelligence (AI)-driven ECMO survival score to predict in-hospital mortality based on a large international patient cohort. METHODS: A deep neural network, ECMO Predictive Algorithm (ECMO PAL) was trained on a retrospective cohort of 18,167 patients from the international Extracorporeal Life Support Organisation (ELSO) registry (2017-2020), and performance was measured using fivefold cross-validation. External validation was performed on all adult registry patients from 2021 (N = 5015) and compared against existing prognostication scores: SAVE, Modified SAVE, and ECMO ACCEPTS for predicting in-hospital mortality. RESULTS: Mean age was 56.8 ± 15.1 years, with 66.7% of patients being male and 50.2% having a pre-ECMO cardiac arrest. Cross-validation demonstrated an inhospital mortality sensitivity and precision of 82.1 ± 0.2% and 77.6 ± 0.2%, respectively. Validation accuracy was only 2.8% lower than training accuracy, reducing from 75.5% to 72.7% [99% confidence interval (CI) 71.1-74.3%]. ECMO PAL accuracy outperformed the ECMO ACCEPTS (54.7%), SAVE (61.1%), and Modified SAVE (62%) scores. CONCLUSIONS: ECMO PAL is the first AI-powered ECMO survival score trained and validated on large international patient cohorts. ECMO PAL demonstrated high generalisability across ECMO regions and outperformed existing, widely used scores. Beyond ECMO, this study highlights how large international registry data can be leveraged for AI prognostication for complex critical care therapies.

The Hematological Effects of Extracorporeal Membrane Oxygenator Exchange.

Membrane oxygenator failure during venovenous (V-V) extracorporeal membrane oxygenation (ECMO) can lead to life-threatening hypoxia, high replacement costs, and may be associated with a hyperfibrinolytic state and bleeding. The current understanding of the underlying mechanisms that drive this is limited. The primary aim of this study therefore is to investigate the hematological changes that occur before and after membrane oxygenator and circuit exchanges (ECMO circuit exchange) in patients with severe respiratory failure managed on V-V ECMO. We analyzed 100 consecutive V-V ECMO patients using linear mixed-effects modeling to evaluate hematological markers in the 72 hours before and 72 hours after ECMO circuit exchange. A total of 44 ECMO circuit exchanges occurred in 31 of 100 patients. The greatest change from baseline to peak were seen in plasma-free hemoglobin (42-fold increase p < 0.01) and the D-dimer:fibrinogen ratio (1.6-fold increase p = 0.03). Bilirubin, carboxyhemoglobin, D-dimer, fibrinogen, and platelets also showed statistically significant changes ( p < 0.01), whereas lactate dehydrogenase did not ( p = 0.93). Progressively deranged hematological markers normalize more than 72 hours after ECMO circuit exchange, with an associated reduction in membrane oxygenator resistance. This supports the biologic plausibility that ECMO circuit exchange may prevent further complications such as hyperfibrinolysis, membrane failure, and clinical bleeding.

Modified indirect calorimetry for patients on venoarterial extracorporeal membrane oxygenation: a pilot feasibility study.

BACKGROUND/OBJECTIVES: Traditional indirect calorimetry is unable to capture complete gas exchange in patients receiving venoarterial extracorporeal membrane oxygenation (VA ECMO). We aimed to determine the feasibility of using a modified indirect calorimetry protocol in patients receiving VA ECMO, report measured energy expenditure (EE) and compare EE to control critically ill patients. SUBJECTS/METHODS: Mechanically ventilated adult patients receiving VA ECMO were included. EE was measured within 72 h of VA ECMO commencement (timepoint one [T1]) and on approximately day seven of Intensive Care Unit (ICU) admission (timepoint two [T2]). Traditional indirect calorimetry via the ventilator was combined with calculations of oxygen consumption and carbon dioxide production derived from pre- and post-ECMO membrane blood gas analyses. Completion of ≥60% EE measurements was deemed feasible. Measured EE was compared between T1 and T2 and to control patients not receiving VA ECMO. Data is presented as n(%) and median[interquartile range (IQR)]. RESULTS: Twenty-one patients were recruited; 16(76%) male, aged 55[42-64] years. The protocol was feasible to complete at T1 (14(67%)) but not at T2 (7(33%)) due to predominantly ECMO decannulation, extubation or death. EE was 1454[1213-1860] at T1 and 1657[1570-2074] kcal/d at T2 (P = 0.043). In patients receiving VA ECMO versus controls, EE was 1577[1434-1801] versus 2092[1609-2272] kcal/d, respectively (P = 0.056). CONCLUSION: Modified indirect calorimetry is feasible early in admission to ICU but is not possible in all patients receiving VA ECMO, especially later in admission. EE increases during the first week of ICU admission but may be lower than EE in control critically ill patients.

Antimicrobial Exposures in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation.

Rationale: Data suggest that altered antimicrobial concentrations are likely during extracorporeal membrane oxygenation (ECMO). Objectives: The primary aim of this analysis was to describe the pharmacokinetics (PKs) of antimicrobials in critically ill adult patients receiving ECMO. Our secondary aim was to determine whether current antimicrobial dosing regimens achieve effective and safe exposure. Methods: This study was a prospective, open-labeled, PK study in six ICUs in Australia, New Zealand, South Korea, and Switzerland. Serial blood samples were collected over a single dosing interval during ECMO for 11 antimicrobials. PK parameters were estimated using noncompartmental methods. Adequacy of antimicrobial dosing regimens were evaluated using predefined concentration exposures associated with maximal clinical outcomes and minimal toxicity risks. Measurements and Main Results: We included 993 blood samples from 85 patients. The mean age was 44.7 ± 14.4 years, and 61.2% were male. Thirty-eight patients (44.7%) were receiving renal replacement therapy during the first PK sampling. Large variations (coefficient of variation of ⩾30%) in antimicrobial concentrations were seen leading to more than fivefold variations in all PK parameters across all study antimicrobials. Overall, 70 (56.5%) concentration profiles achieved the predefined target concentration and exposure range. Target attainment rates were not significantly different between modes of ECMO and renal replacement therapy. Poor target attainment was observed across the most frequently used antimicrobials for ECMO recipients, including for oseltamivir (33.3%), piperacillin (44.4%), and vancomycin (27.3%). Conclusions: Antimicrobial PKs were highly variable in critically ill patients receiving ECMO, leading to poor target attainment rates. Clinical trial registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612000559819).

Survival and left ventricular dysfunction post lung transplantation for pulmonary arterial hypertension.

PURPOSE: Bilateral lung transplantation for end-stage pulmonary arterial hypertension (PAH) is traditionally associated with higher early post-transplant mortality when compared with other indications. Changes in perioperative management, including the growing use of perioperative extracorporeal membrane oxygenation (ECMO) and an increased awareness of postoperative left ventricular dysfunction (LVD), have resulted in outcomes that are uncertain. MATERIALS AND METHODS: We conducted a single-center, retrospective observational study at a lung transplantation center in Melbourne, Australia, from 2006 to 2019. ECMO use was categorized as preoperative, prophylactic, or rescue. Postoperative LVD was defined as a reduction in left ventricular function on echocardiography or using strict clinical criteria. RESULTS: 50 patients underwent lung transplantation for PAH. 12-month survival was 48/50 (96%). ECMO was used in 26 (52%) patients, and the use of prophylactic VA-ECMO increased over the study period. Postoperative LVD was diagnosed in 21 (42%) patients. 12-month survival and left ventricular function was no different between LVD and non-LVD groups. CONCLUSIONS: This study showed that high survival rates can be achieved following lung transplantation for PAH. We found that ECMO utilization was common, and indications have changed over time. LVD was common but did not impact 12-month survival.

Population pharmacokinetics of ciprofloxacin in critically ill patients receiving extracorporeal membrane oxygenation (an ASAP ECMO study).

INTRODUCTION: This study aimed to describe the pharmacokinetics (PK) of ciprofloxacin in critically ill patients receiving ECMO and recommend a dosing regimen that provides adequate drug exposure. METHODS: Serial blood samples were taken from ECMO patients receiving ciprofloxacin. Total ciprofloxacin concentrations were measured by chromatographic assay and analysed using a population PK approach with Pmetrics®. Dosing simulations were performed to ascertain the probability of target attainment (PTA) represented by the area under the curve to minimum inhibitory concentration ratio (AUC0-24/MIC) ≥ 125. RESULTS: Eight patients were enrolled, of which three received concurrent continuous venovenous haemodiafiltration (CVVHDF). Ciprofloxacin was best described in a two-compartment model with total body weight and creatinine clearance (CrCL) included as significant predictors of PK. Patients not requiring renal replacement therapy generated a mean clearance of 11.08 L/h while patients receiving CVVHDF had a mean clearance of 1.51 L/h. Central and peripheral volume of distribution was 77.31 L and 90.71 L, respectively. ECMO variables were not found to be significant predictors of ciprofloxacin PK. Dosing simulations reported that a 400 mg 8 -hly regimen achieved > 72% PTA in all simulated patients with CrCL of 30 mL/min, 50 mL/min and 100 mL/min and total body weights of 60 kg and 100 kg at a MIC of 0.5 mg/L. CONCLUSION: Our study reports that established dosing recommendations for critically ill patients not on ECMO provides sufficient drug exposure for maximal ciprofloxacin activity for ECMO patients. In line with non-ECMO critically ill adult PK studies, higher doses and therapeutic drug monitoring may be required for critically ill adult patients on ECMO.

Population Pharmacokinetics of Vancomycin in Critically Ill Adult Patients Receiving Extracorporeal Membrane Oxygenation (an ASAP ECMO Study).

Our study aimed to describe the population pharmacokinetics (PK) of vancomycin in critically ill patients receiving extracorporeal membrane oxygenation (ECMO), including those receiving concomitant renal replacement therapy (RRT). Dosing simulations were used to recommend maximally effective and safe dosing regimens. Serial vancomycin plasma concentrations were measured and analyzed using a population PK approach on Pmetrics. The final model was used to identify dosing regimens that achieved target exposures of area under the curve (AUC0-24) of 400-700 mg · h/liter at steady state. Twenty-two patients were enrolled, of which 11 patients received concomitant RRT. In the non-RRT patients, the median creatinine clearance (CrCL) was 75 ml/min and the mean daily dose of vancomycin was 25.5 mg/kg. Vancomycin was well described in a two-compartment model with CrCL, the presence of RRT, and total body weight found as significant predictors of clearance and central volume of distribution (Vc). The mean vancomycin renal clearance and Vc were 3.20 liters/h and 29.7 liters respectively, while the clearance for patients on RRT was 0.15 liters/h. ECMO variables did not improve the final covariate model. We found that recommended dosing regimens for critically ill adult patients not on ECMO can be safely and effectively used in those on ECMO. Loading doses of at least 25 mg/kg followed by maintenance doses of 12.5-20 mg/kg every 12 h are associated with a 97-98% probability of efficacy and 11-12% probability of toxicity, in patients with normal renal function. Therapeutic drug monitoring along with reductions in dosing are warranted for patients with renal impairment and those with concomitant RRT. (This study is registered with the Australian New Zealand Clinical Trials Registry [ANZCTR] under number ACTRN12612000559819.).

Population pharmacokinetics of cefepime in critically ill patients receiving extracorporeal membrane oxygenation (an ASAP ECMO study).

OBJECTIVES: This study aimed to describe the population pharmacokinetics (PK) of cefepime during extracorporeal membrane oxygenation (ECMO) and through dosing simulations, identify a maximally effective and safe dosing strategy. METHODS: Serial cefepime plasma concentrations were measured in patients on ECMO, and data were analysed using a population PK approach with Pmetrics®. Dosing simulations were used to identify the optimal dosing strategy that achieved target trough concentrations (Cmin) of 8-20 mg/L. Six patients were enrolled, of which one was receiving renal replacement therapy. Cefepime was best described in a two-compartment model, with total body weight and creatinine clearance (CrCL) as significant predictors of PK parameters. The mean clearance and central volume of distribution were 2.42 L/h and 15.09 L, respectively. RESULTS: Based on simulations, patients with CrCL of 120 mL/min receiving 1 g 8-hourly dosing achieved a 40-44% probability of efficacy (Cmin > 8 mg/L) and 1-6% toxicity (Cmin > 20 mg/L). Patients with CrCL 30 mL/min and 65 mL/min receiving 1 g 12-hourly dosing achieved an 84-92% and 46-53% probability of efficacy and 8-44% and 1-8% probability of toxicity, respectively. Simulations demonstrated a lower probability of efficacy and higher probability of toxicity with decreasing patient weight. CONCLUSION: This study reported reduced cefepime clearance in patients receiving ECMO, resulting in an increased risk of cefepime toxicity. To avoid drug accumulation, modified dosing regimens should be used in critically ill patients on ECMO. Clinicians should adopt therapeutic drug monitoring when treating less susceptible organisms and in patients with reduced renal clearance on ECMO.

The impact of selection criteria and study design on reported survival outcomes in extracorporeal oxygenation cardiopulmonary resuscitation (ECPR): a systematic review and meta-analysis.

BACKGROUND: The use of extracorporeal membrane oxygenation (ECMO) during cardiac arrest (ECPR) has increased exponentially. However, reported outcomes vary considerably due to differing study designs and selection criteria. This review assessed the impact of pre-defined selection criteria on ECPR survival. METHODS: Systematic review applying PRISMA guidelines. We searched Medline, Embase, and Evidence-Based Medicine Reviews for RCTs and observational studies published from January 2000 to June 2021. Adult patients (> 12 years) receiving ECPR were included. Two investigators reviewed and extracted data on study design, number and type of inclusion criteria. Study quality was assessed using the Newcastle-Ottawa Scale (NOS). Outcomes included overall and neurologically favourable survival. Meta-analysis and meta-regression were performed. RESULTS: 67 studies were included: 14 prospective and 53 retrospective. No RCTs were identified at time of search. The number of inclusion criteria to select ECPR patients (p = 0.292) and study design (p = 0.962) was not associated with higher favourable neurological survival. However, amongst prospective studies, increased number of inclusion criteria was associated with improved outcomes in both OHCA and IHCA cohorts. (ß = 0.12, p = 0.026) and arrest to ECMO flow time was predictive of survival. (ß = -0.023, p < 0.001). CONCLUSIONS: Prospective studies showed number of selection criteria and, in particular, arrest to ECMO time were associated with significant improved survival. Well-designed prospective studies assessing the relative importance of criteria as well as larger efficacy studies are required to ensure appropriate application of what is a costly intervention.

Population Pharmacokinetics of Piperacillin and Tazobactam in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation: an ASAP ECMO Study.

Our study aimed to describe the population pharmacokinetics (PK) of piperacillin and tazobactam in patients on extracorporeal membrane oxygenation (ECMO), with and without renal replacement therapy (RRT). We also aimed to use dosing simulations to identify the optimal dosing strategy for these patient groups. Serial piperacillin and tazobactam plasma concentrations were measured with data analyzed using a population PK approach that included staged testing of patient and treatment covariates. Dosing simulations were conducted to identify the optimal dosing strategy that achieved piperacillin target exposures of 50% and 100% fraction of time free drug concentration is above MIC (%fT>MIC) and toxic exposures of greater than 360 mg/liter. The tazobactam target of percentage of time free concentrations of >2 mg/liter was also assessed. Twenty-seven patients were enrolled, of which 14 patients were receiving concurrent RRT. Piperacillin and tazobactam were both adequately described by two-compartment models, with body mass index, creatinine clearance, and RRT as significant predictors of PK. There were no substantial differences between observed PK parameters and published parameters from non-ECMO patients. Based on dosing simulations, a 4.5-g every 6 hours regimen administered over 4 hours achieves high probabilities of efficacy at a piperacillin MIC of 16 mg/liter while exposing patients to a <3% probability of toxic concentrations. In patients receiving ECMO and RRT, a frequency reduction to every 12 hours dosing lowers the probability of toxic concentrations, although this remains at 7 to 9%. In ECMO patients, piperacillin and tazobactam should be dosed in line with standard recommendations for the critically ill.

Association Between Arterial Carbon Dioxide Tension and Clinical Outcomes in Venoarterial Extracorporeal Membrane Oxygenation.

OBJECTIVES: The manipulation of arterial carbon dioxide tension is associated with differential mortality and neurologic injury in intensive care and cardiac arrest patients; however, few studies have investigated this relationship in patients on venoarterial extracorporeal membrane oxygenation. We investigated the association between the initial arterial carbon dioxide tension and change over 24 hours on mortality and neurologic injury in patients undergoing venoarterial extracorporeal membrane oxygenation for cardiac arrest and refractory cardiogenic shock. DESIGN: Retrospective cohort analysis of adult patients recorded in the international Extracorporeal Life Support Organization Registry. SETTING: Data reported to the Extracorporeal Life Support Organization from all international extracorporeal membrane oxygenation centers during 2003-2016. PATIENTS: Adult patients (≥ 18 yr old) supported with venoarterial extracorporeal membrane oxygenation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 7,168 patients had sufficient data for analysis at the initiation of venoarterial extracorporeal membrane oxygenation, 4,918 of these patients had arterial carbon dioxide tension data available at 24 hours on support. The overall in-hospital mortality rate was 59.9%. A U-shaped relationship between arterial carbon dioxide tension tension at extracorporeal membrane oxygenation initiation and in-hospital mortality was observed. Increased mortality was observed with a arterial carbon dioxide tension less than 30 mm Hg (odds ratio, 1.26; 95% CI, 1.08-1.47; p = 0.003) and greater than 60 mm Hg (odds ratio, 1.28; 95% CI, 1.10-1.50; p = 0.002). Large reductions (> 20 mm Hg) in arterial carbon dioxide tension over 24 hours were associated with important neurologic complications: intracranial hemorrhage, ischemic stroke, and/or brain death, as a composite outcome (odds ratio, 1.63; 95% CI, 1.03-2.59; p = 0.04), independent of the initial arterial carbon dioxide tension. CONCLUSIONS: Initial arterial carbon dioxide tension tension was independently associated with mortality in this cohort of venoarterial extracorporeal membrane oxygenation patients. Reductions in arterial carbon dioxide tension (> 20 mm Hg) from the initiation of extracorporeal membrane oxygenation were associated with neurologic complications. Further prospective studies testing these associations are warranted.