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McKnite AM, Imburgia CE, Green DJ, Hunt JP, Hudson RE, Whelan AJ, Mathis CL, Kelley WE, Rower JE, Reilly CA, Watt KM. Clearance of Amlodipine, Fentanyl, Fluconazole, Methylprednisolone, and Midazolam by Continuous Renal Replacement Circuits. ASAIO J 2025:00002480-990000000-00680. [PMID: 40202156 DOI: 10.1097/mat.0000000000002422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/10/2025] Open
Abstract
Critically ill pediatric patients on continuous renal replacement therapy (CRRT) have high mortality rates ranging from 30% to 70%, due in part to altered drug exposure from drug-CRRT circuit interactions. Drug loss within CRRT circuits can occur through both clearance by the hemofilter and adsorption to circuit components. Although these interactions are known to exist, their impact on the pharmacokinetics of most drugs is unknown, resulting in limited drug dosing guidance and increased risk for suboptimal drug exposure. In this study, we administered amlodipine, fentanyl, fluconazole, methylprednisolone, and midazolam individually and in combination with ex vivo, closed-loop, blood-primed CRRT circuits to quantify drug-circuit interactions. Circuits were dosed to drug-specific therapeutic concentrations, and drug concentrations in both plasma and effluent were measured over time. For all drugs administered individually, variable extraction by the CRRT circuit was observed (mean plasma recovery 0.4-49%). For drugs coadministered into a circuit, significant decreases in extraction and increases in drug recovery (2.5-109%) were found, suggesting dosing adjustments may be needed. This study highlights the need for additional studies of drug coadministration within CRRT circuits to describe complex drug-circuit and drug-drug interactions to provide dosing guidance in pediatric CRRT patients.
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Affiliation(s)
- Autumn M McKnite
- From the Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah
| | - Carina E Imburgia
- Division of Clinical Pharmacology, Department of Pediatrics, University of Utah, Salt Lake City, Utah
| | - Danielle J Green
- Division of Clinical Pharmacology, Department of Pediatrics, University of Utah, Salt Lake City, Utah
- Division of Pediatric Critical Care, Department of Pediatrics, University of Utah, Salt Lake City, Utah
| | - J Porter Hunt
- Division of Clinical Pharmacology, Department of Pediatrics, University of Utah, Salt Lake City, Utah
| | - Rachel E Hudson
- Division of Clinical Pharmacology, Department of Pediatrics, University of Utah, Salt Lake City, Utah
| | - Aviva J Whelan
- Division of Clinical Pharmacology, Department of Pediatrics, University of Utah, Salt Lake City, Utah
- Division of Pediatric Critical Care, Department of Pediatrics, University of Utah, Salt Lake City, Utah
| | - Cheryl L Mathis
- Division of Clinical Pharmacology, Department of Pediatrics, University of Utah, Salt Lake City, Utah
| | - Walter E Kelley
- Biomedical Department, American Red Cross, Salt Lake City, Utah
- Department of Pathology, University of Arizona, Tucson, Arizona
| | - Joseph E Rower
- From the Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah
- Center for Human Toxicology, University of Utah, Salt Lake City, Utah
| | - Christopher A Reilly
- From the Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah
- Center for Human Toxicology, University of Utah, Salt Lake City, Utah
| | - Kevin M Watt
- Division of Clinical Pharmacology, Department of Pediatrics, University of Utah, Salt Lake City, Utah
- Division of Pediatric Critical Care, Department of Pediatrics, University of Utah, Salt Lake City, Utah
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2
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Szentgyorgyi L, Howitt SH, Iles-Smith H, Krishnamoorthy B. Sedation management and processed EEG-based solutions during venovenous extracorporeal membrane oxygenation: a narrative review of key challenges and potential benefits. J Artif Organs 2025:10.1007/s10047-025-01494-y. [PMID: 40056243 DOI: 10.1007/s10047-025-01494-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 01/29/2025] [Indexed: 03/10/2025]
Abstract
Extracorporeal membrane oxygenation (ECMO) is an established technique for managing severe cardiorespiratory failure. However, it is invasive and requires profound analgo-sedation during initiation and often throughout the therapy. Managing sedation in venovenous (VV) ECMO patients is particularly challenging due to the impact of ECMO circuits on pharmacokinetics and specific patient requirements. This can lead to unpredictable sedative effects and require multiple drugs at higher doses. Additionally, sedation is usually managed with traditional scoring methods, which are subjective and invalid during neuromuscular blockade. These uncertainties may impact outcomes. Recent clinical practice increasingly focuses on reducing sedation to enable earlier physiotherapy and mobilisation, particularly in patients awaiting transplants or receiving mechanical circulatory support. In this context, processed electroencephalogram-based (pEEG) sedation monitoring might be promising, having shown benefits in general anaesthesia and intensive care. However, the technology has limitations, and its benefits in ECMO practice have yet to be formally evaluated. This review provides insights into the challenges of ECMO sedation, including pharmacokinetics, unique ECMO requirements, and the implications of inadequate sedation scores. Finally, it includes a brief overview of the practicality and limitations of pEEG monitoring during VV-ECMO, highlighting a significant research gap.
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Affiliation(s)
- Lajos Szentgyorgyi
- School of Health and Society, University of Salford, Mary Seacole Building, Frederick Road Campus, Broad St, Frederick Road Campus, Salford, M6 6PU, UK.
- Manchester University NHS Foundation Trust, Cardiothoracic Critical Care Unit, Wythenshawe Hospital, Southmoor Road, Manchester, M23 9LT, UK.
| | - Samuel Henry Howitt
- School of Health and Society, University of Salford, Mary Seacole Building, Frederick Road Campus, Broad St, Frederick Road Campus, Salford, M6 6PU, UK
- Manchester University NHS Foundation Trust, Cardiothoracic Critical Care Unit, Wythenshawe Hospital, Southmoor Road, Manchester, M23 9LT, UK
- Division of Cardiovascular Sciences, University of Manchester, 46 Grafton Street, Manchester, M13 9NT, UK
| | - Heather Iles-Smith
- School of Health and Society, University of Salford, Mary Seacole Building, Frederick Road Campus, Broad St, Frederick Road Campus, Salford, M6 6PU, UK
- Centre for Clinical and Care Research, Northern Care Alliance NHS Foundation Trust, Stott Lane, Salford RoyalSalford, M6 8HD, UK
| | - Bhuvaneswari Krishnamoorthy
- School of Health and Society, University of Salford, Mary Seacole Building, Frederick Road Campus, Broad St, Frederick Road Campus, Salford, M6 6PU, UK.
- Manchester University NHS Foundation Trust, Cardiothoracic Critical Care Unit, Wythenshawe Hospital, Southmoor Road, Manchester, M23 9LT, UK.
- Division of Cardiovascular Sciences, University of Manchester, 46 Grafton Street, Manchester, M13 9NT, UK.
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Dabirzadeh A, Decary E, Fobisong CN, Wasserman SDF, Withington D. Systematic Review of Ex Vivo and In Vivo Pharmacokinetic Studies of Drugs Commonly Used During Extracorporeal Membrane Oxygenation. ASAIO J 2025; 71:1-10. [PMID: 39727272 DOI: 10.1097/mat.0000000000002326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2024] Open
Abstract
Extracorporeal membrane oxygenation (ECMO) is a lifesaving treatment for critically ill patients in cardiac or respiratory failure refractory to conventional treatment. Patients on an ECMO circuit (pump, oxygenator, tubing) require numerous medications including sedatives, analgesics, cardioactive medications, and anticonvulsants. Currently, there are few dosing guidelines to optimize pharmacotherapy in this situation. A systematic review was conducted to describe pharmacokinetics (PK) of medications commonly used during ECMO. MEDLINE, Embase, Cochrane, BIOSIS, PubMed, and Web of Science databases were searched. All articles presenting ex vivo, animal, and human data on the PK of the subject medications in the ECMO circuit were included. Three authors independently examined citation titles and abstracts. Four authors extracted relevant details from included studies into standardized data extraction forms. Methodological quality was assessed using the ClinPK guidelines and the Joanna Briggs Institute Checklist. Forty-four studies examining 30 medications were included, 26 ex vivo studies (mostly adult circuits) and 18 observational studies (mainly neonatal patients). Pharmacokinetics varied depending on the medication's characteristics, study type, and population. Study quality was variable, limiting the possibility of deriving hard dosing guidelines from this available literature. Further population PK studies are needed to adequately determine dosing guidelines in adults and children requiring ECMO.
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Affiliation(s)
- Anita Dabirzadeh
- From the Faculty of Medicine, McGill University, Montreal, Canada
- Department of Anesthesia and Perioperative Medicine, Western University, London, Canada
| | - Elizabeth Decary
- Department of Anesthesia, Université de Montréal, Montreal, Canada
| | | | | | - Davinia Withington
- Research Institute of the McGill University Health Centre, Montreal, Canada
- Division of Pediatric Anaesthesia, Department of Anaesthesia, McGill University Health Center, Montreal, Canada
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4
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Lyster H, Shekar K, Watt K, Reed A, Roberts JA, Abdul-Aziz MH. Antifungal Dosing in Critically Ill Patients on Extracorporeal Membrane Oxygenation. Clin Pharmacokinet 2023; 62:931-942. [PMID: 37300631 PMCID: PMC10338597 DOI: 10.1007/s40262-023-01264-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/07/2023] [Indexed: 06/12/2023]
Abstract
Extracorporeal membrane oxygenation (ECMO) is an established advanced life support system, providing temporary cardiac and/or respiratory support in critically ill patients. Fungal infections are associated with increased mortality in patients on ECMO. Antifungal drug dosing for critically ill patients is highly challenging because of altered pharmacokinetics (PK). PK changes during critical illness; in particular, the drug volume of distribution (Vd) and clearance can be exacerbated by ECMO. This article discusses the available literature to inform adequate dosing of antifungals in this patient population. The number of antifungal PK studies in critically ill patients on ECMO is growing; currently available literature consists of case reports and studies with small sample sizes providing inconsistent findings, with scant or no data for some antifungals. Current data are insufficient to provide definitive empirical drug dosing guidance and use of dosing strategies derived from critically patients not on ECMO is reasonable. However, due to high PK variability, therapeutic drug monitoring should be considered where available in critically ill patients receiving ECMO to prevent subtherapeutic or toxic antifungal exposures.
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Affiliation(s)
- Haifa Lyster
- Royal Brompton and Harefield Hospitals, Part of Guy's and St Thomas' NHS Foundation Trust, London, UK
- University of Portsmouth, Portsmouth, UK
| | - Kiran Shekar
- Adult Intensive Care Services and Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia
- Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
- Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
- Faculty of Health Sciences and Medicine, Bond University, Gold Coast, QLD, Australia
| | - Kevin Watt
- School of Pharmacy, University of Waterloo, 10 Victoria St S. Kitchener, Waterloo, ON, N2G 1C5, Canada
- Department of Paediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Anna Reed
- Royal Brompton and Harefield Hospitals, Part of Guy's and St Thomas' NHS Foundation Trust, London, UK
- Imperial College London, London, SW3 6NP, UK
| | - Jason A Roberts
- Faculty of Medicine, University of Queensland Centre for Clinical Research, The University of Queensland, Brisbane, Australia.
- Herston Infectious Diseases (HeIDI), Metro North Health, Brisbane, QLD, Australia.
- Department of Pharmacy, Royal Brisbane and Women's Hospital, Brisbane, Australia.
- Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, Australia.
- Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France.
| | - Mohd-Hafiz Abdul-Aziz
- Faculty of Medicine, University of Queensland Centre for Clinical Research, The University of Queensland, Brisbane, Australia
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Abidi E, El Nekidy WS, Atallah B, Al Zaman K, Ghisulal P, El Lababidi R, Manla Y, Ahmed I, Sadik Z, Taha A, Askalany M, Cherfan A, Helal M, Sultan S, Khan U, Kakar V, Mallat J. Sustaining Life versus Altering Life-Saving Drugs: Insights to Explain the Paradoxical Effect of Extracorporeal Membrane Oxygenation on Drugs. J Clin Med 2023; 12:3748. [PMID: 37297946 PMCID: PMC10253730 DOI: 10.3390/jcm12113748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 05/17/2023] [Accepted: 05/25/2023] [Indexed: 06/12/2023] Open
Abstract
There has been a substantial increase in the use of extracorporeal membrane oxygenation (ECMO) support in critically ill adults. Understanding the complex changes that could affect drugs' pharmacokinetics (PK) and pharmacodynamics (PD) is of suitable need. Therefore, critically ill patients on ECMO represent a challenging clinical situation to manage pharmacotherapy. Thus, clinicians' ability to predict PK and PD alterations within this complex clinical context is fundamental to ensure further optimal and, sometimes, individualized therapeutic plans that balance clinical outcomes with the minimum drug adverse events. Although ECMO remains an irreplaceable extracorporeal technology, and despite the resurgence in its use for respiratory and cardiac failures, especially in the era of the COVID-19 pandemic, scarce data exist on both its effect on the most commonly used drugs and their relative management to achieve the best therapeutic outcomes. The goal of this review is to provide key information about some evidence-based PK alterations of the drugs used in an ECMO setting and their monitoring.
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Affiliation(s)
- Emna Abidi
- Department of Pharmacy, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates; (E.A.)
| | - Wasim S. El Nekidy
- Department of Pharmacy, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates; (E.A.)
- Cleveland Clinic Lerner, College of Medicine, Cleveland, OH 44195, USA
| | - Bassam Atallah
- Department of Pharmacy, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates; (E.A.)
- Cleveland Clinic Lerner, College of Medicine, Cleveland, OH 44195, USA
| | - Khaled Al Zaman
- Department of Pharmacy, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates; (E.A.)
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Praveen Ghisulal
- Critical Care Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates
| | - Rania El Lababidi
- Department of Pharmacy, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates; (E.A.)
| | - Yosef Manla
- Heart and Vascular Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates
| | - Ihab Ahmed
- Critical Care Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates
| | - Ziad Sadik
- Department of Pharmacy, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates; (E.A.)
| | - Ahmed Taha
- Critical Care Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates
| | - Mohamed Askalany
- Critical Care Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates
| | - Antoine Cherfan
- Department of Pharmacy, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates; (E.A.)
| | - Mohamed Helal
- Critical Care Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates
| | - Saad Sultan
- Department of Pharmacy, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates; (E.A.)
| | - Umar Khan
- Critical Care Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates
| | - Vivek Kakar
- Critical Care Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates
| | - Jihad Mallat
- Cleveland Clinic Lerner, College of Medicine, Cleveland, OH 44195, USA
- Critical Care Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates
- Faculty of Medicine, Normandy University, UNICAEN, ED 497 Caen, France
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6
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Shastri N. Pharmacology of Drugs and Their Kinetics and Dynamicity during Extracorporeal Life Support. JOURNAL OF CARDIAC CRITICAL CARE TSS 2023. [DOI: 10.25259/jccc_6_2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
ECMO/ECLS is now a days very common modality for saving patient life in ICU. ECMO is unphysiological circulation which hampers the multiorgan function. Direct impact by releasing of pro-inflammatory cytokinin leads to impact on the many organ homeostasis. The anaesthetist/intensivist must have enough knowledge of pKa/Pd and most importantly still we do not have ideal guidelines for drug dosing.
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Affiliation(s)
- Naman Shastri
- Chief Consultant, Cardiac Anesthesiologist and Intensivist, EPIC Hospital, Ahmedabad, Gujarat, India,
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7
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Roberts JA, Bellomo R, Cotta MO, Koch BCP, Lyster H, Ostermann M, Roger C, Shekar K, Watt K, Abdul-Aziz MH. Machines that help machines to help patients: optimising antimicrobial dosing in patients receiving extracorporeal membrane oxygenation and renal replacement therapy using dosing software. Intensive Care Med 2022; 48:1338-1351. [PMID: 35997793 PMCID: PMC9467945 DOI: 10.1007/s00134-022-06847-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 07/29/2022] [Indexed: 02/04/2023]
Abstract
Intensive care unit (ICU) patients with end-organ failure will require specialised machines or extracorporeal therapies to support the failing organs that would otherwise lead to death. ICU patients with severe acute kidney injury may require renal replacement therapy (RRT) to remove fluid and wastes from the body, and patients with severe cardiorespiratory failure will require extracorporeal membrane oxygenation (ECMO) to maintain adequate oxygen delivery whilst the underlying pathology is evaluated and managed. The presence of ECMO and RRT machines can further augment the existing pharmacokinetic (PK) alterations during critical illness. Significant changes in the apparent volume of distribution (Vd) and drug clearance (CL) for many important drugs have been reported during ECMO and RRT. Conventional antimicrobial dosing regimens rarely consider the impact of these changes and consequently, are unlikely to achieve effective antimicrobial exposures in critically ill patients receiving ECMO and/or RRT. Therefore, an in-depth understanding on potential PK changes during ECMO and/or RRT is required to inform antimicrobial dosing strategies in patients receiving ECMO and/or RRT. In this narrative review, we aim to discuss the potential impact of ECMO and RRT on the PK of antimicrobials and antimicrobial dosing requirements whilst receiving these extracorporeal therapies. The potential benefits of therapeutic drug monitoring (TDM) and dosing software to facilitate antimicrobial therapy for critically ill patients receiving ECMO and/or RRT are also reviewed and highlighted.
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Affiliation(s)
- Jason A. Roberts
- grid.1003.20000 0000 9320 7537Faculty of Medicine, University of Queensland Centre for Clinical Research (UQCCR), The University of Queensland, Brisbane, QLD 4029 Australia ,Herston Infectious Diseases (HeIDI), Metro North Health, Brisbane, QLD Australia ,grid.416100.20000 0001 0688 4634Department of Pharmacy and Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane, QLD Australia ,grid.121334.60000 0001 2097 0141Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France
| | - Rinaldo Bellomo
- grid.1008.90000 0001 2179 088XDepartment of Critical Care, The University of Melbourne, Melbourne, Australia ,grid.1002.30000 0004 1936 7857Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Australia ,grid.414094.c0000 0001 0162 7225Department of Intensive Care, Austin Hospital, Melbourne, Australia ,grid.416153.40000 0004 0624 1200Department of Intensive Care, Royal Melbourne Hospital, Melbourne, Australia
| | - Menino O. Cotta
- grid.1003.20000 0000 9320 7537Faculty of Medicine, University of Queensland Centre for Clinical Research (UQCCR), The University of Queensland, Brisbane, QLD 4029 Australia
| | - Birgit C. P. Koch
- grid.5645.2000000040459992XDepartment of Hospital Pharmacy, Erasmus University Medical Centre Rotterdam, Rotterdam, the Netherlands
| | - Haifa Lyster
- Pharmacy Department, Royal Brompton and Harefield Hospitals, London, SW3 6NP UK ,Cardiothoracic Transplant Unit, Royal Brompton and Harefield Hospitals, London, SW3 6NP UK
| | - Marlies Ostermann
- grid.425213.3Department of Critical Care, King’s College London, Guy’s and St Thomas Hospital, London, SE1 7EH UK
| | - Claire Roger
- Department of Anaesthesiology and Intensive Care, Pain and Emergency Medicine, Nîmes-Caremeau University Hospital, Place du Professeur Robert Debré, 30 029 Nîmes cedex 9, France ,grid.121334.60000 0001 2097 0141UR UM 103 IMAGINE, Faculty of Medicine, University of Montpellier, Nîmes, France
| | - Kiran Shekar
- grid.415184.d0000 0004 0614 0266Adult Intensive Care Services and Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD Australia ,grid.1003.20000 0000 9320 7537Faculty of Medicine, The University of Queensland, Brisbane, QLD Australia ,grid.1024.70000000089150953Faculty of Health, Queensland University of Technology, Brisbane, QLD Australia ,grid.1033.10000 0004 0405 3820Faculty of Health Sciences and Medicine, Bond University, Gold Coast, QLD Australia
| | - Kevin Watt
- grid.46078.3d0000 0000 8644 1405School of Pharmacy, University of Waterloo, 10 Victoria St S. Kitchener, Waterloo, ON N2G 1C5 Canada ,grid.223827.e0000 0001 2193 0096Department of Paediatrics, University of Utah School of Medicine, Salt Lake City, UT USA
| | - Mohd H. Abdul-Aziz
- grid.1003.20000 0000 9320 7537Faculty of Medicine, University of Queensland Centre for Clinical Research (UQCCR), The University of Queensland, Brisbane, QLD 4029 Australia
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8
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Kalaria SN, Kishk OA, Gopalakrishnan M, Bagdure DN. Evaluation of an ex-vivo neonatal extracorporeal membrane oxygenation circuit on antiepileptic drug sequestration. Perfusion 2021; 37:812-818. [PMID: 34192981 DOI: 10.1177/02676591211028183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Antiepileptic dosing information used to manage neonatal patients receiving extracorporeal membrane oxygenation (ECMO) is limited. The objective of this study is to quantify the extent of sequestration of various antiepileptic drugs using an ex-vivo neonatal ECMO circuit. Two neonatal closed-loop ECMO circuits were prepared using a Rotaflow centrifugal pump, custom polyvinylchloride tubing and a Quadrox-i Neonatal membrane oxygenator. After 5 minutes of circuit priming and stabilization with normal saline/albumin or expired human whole blood, single boluses of levetiracetam (200 mg), lacosamide (20 mg), and phenytoin (200 mg) were injected into the circuit. To account for spontaneous drug degradation, two polyvinylchloride beakers were filled with normal saline/albumin or expired human whole blood and equivalent antiepileptic drug doses were prepared. Simultaneous pharmacokinetic samples were collected from the control solution and the pre-centrifugal pump, pre-oxygenator, and post-oxygenator sampling ports from each circuit. Similar drug recovery profiles were observed among the three sampling sites investigated. Percent drug sequestration after a 24-hour circuit flow period was relatively similar between the two different circuits and ranged between 5.5%-13.2% for levetiracetam, 18.4%-22.3% for lacosamide, and 24.5%-30.2% for phenytoin. A comparison at 12 and 24 hours demonstrated similar percent drug sequestration across all three drugs in each circuit. Percent drug sequestrations for levetiracetam and lacosamide were less than 20% and for phenytoin were as high as 30% based on the sampling following single bolus dose administration into a neonatal ECMO circuit. Careful consideration of patient clinical status should be taken in consideration when optimizing antiepileptic therapy in neonates receiving ECMO.
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Affiliation(s)
- Shamir N Kalaria
- Center for Translational Medicine, School of Pharmacy, University of Maryland, Baltimore, MD, USA.,Department of Pharmacy Services, University of Maryland Medical Center, Baltimore, MD, USA
| | - Omayma A Kishk
- Department of Pharmacy Services, University of Maryland Medical Center, Baltimore, MD, USA
| | - Mathangi Gopalakrishnan
- Center for Translational Medicine, School of Pharmacy, University of Maryland, Baltimore, MD, USA
| | - Dayanand N Bagdure
- Department of Pediatrics, School of Medicine, University of Maryland, Baltimore, MD, USA
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9
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Zhang Y, Zeng Z, Zhang Q, Ou Q, Chen Z. [Effect of extracorporeal membrane oxygenation on pharmacokinetics of antimicrobial drugs: recent progress and recommendations]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2021; 41:793-800. [PMID: 34134970 DOI: 10.12122/j.issn.1673-4254.2021.05.23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Extracorporeal membrane oxygenation (ECMO) is an effective means to provide life support for patients with severe respiratory or heart failure. Existing studies have shown that ECMO may affect the metabolic process of some drugs by drug adsorption, increasing the apparent distribution volume and changing the clearance rate of the drugs. This review summarizes the recent progress in the studies of the effect of ECMO on the pharmacokinetics of antibacterial and antifungal drugs. For the antibacterial drugs, it is recommended that the dose of teicoplanin, imipenem, and linezolid should be increased during ECMO support, while the dose of azithromycin, ciprofloxacin, and tigecycline should not be modified for the time being. Currently studies on pharmacokinetic changes of antifungal drugs during ECMO support remain limited. Voriconazole can be absorbed substantially by ECMO due to its high lipophilicity, and higher doses are therefore recommended. The dose of micafungin also needs to be increased in children undergoing ECMO. However, current evidence concerning the dose of caspofungin and fluconazole are limited, and it is not clear whether the routine dose should be adjusted during ECMO support.
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Affiliation(s)
- Y Zhang
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Z Zeng
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Q Zhang
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Q Ou
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Z Chen
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
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10
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Malfertheiner MV, Broman LM, Vercaemst L, Belliato M, Aliberti A, Di Nardo M, Swol J, Barrett N, Pappalardo F, Bělohlávek J, Taccone FS, Millar JE, Crawford L, Lorusso R, Suen JY, Fraser JF. Ex vivo models for research in extracorporeal membrane oxygenation: a systematic review of the literature. Perfusion 2021; 35:38-49. [PMID: 32397884 DOI: 10.1177/0267659120907439] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
With ongoing progress of components of extracorporeal membrane oxygenation including improvements of oxygenators, pumps, and coating materials, extracorporeal membrane oxygenation became increasingly accepted in the clinical practice. A suitable testing in an adequate setup is essential for the development of new technical aspects. Relevant tests can be conducted in ex vivo models specifically designed to test certain aspects. Different setups have been used in the past for specific research questions. We conducted a systematic literature review of ex vivo models of extracorporeal membrane oxygenation components. MEDLINE and Embase were searched between January 1996 and October 2017. The inclusion criteria were ex vivo models including features of extracorporeal membrane oxygenation technology. The exclusion criteria were clinical studies, abstracts, studies in which the model of extracorporeal membrane oxygenation has been reported previously, and studies not reporting on extracorporeal membrane oxygenation components. A total of 50 studies reporting on different ex vivo extracorporeal membrane oxygenation models have been identified from the literature search. Models have been grouped according to the specific research question they were designed to test for. The groups are focused on oxygenator performance, pump performance, hemostasis, and pharmacokinetics. Pre-clinical testing including use of ex vivo models is an important step in the development and improvement of extracorporeal membrane oxygenation components and materials. Furthermore, ex vivo models offer valuable insights for clinicians to better understand the consequences of choice of components, setup, and management of an extracorporeal membrane oxygenation circuit in any given condition. There is a need to standardize the reporting of pre-clinical studies in this area and to develop best practice in their design.
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Affiliation(s)
| | - Lars Mikael Broman
- ECMO Centre Karolinska, Department of Pediatric Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden
| | - Leen Vercaemst
- Perfusion Department, University Hospital Gasthuisberg, Louvain, Belgium
| | - Mirko Belliato
- U.O.C. Anestesia e Rianimazione 1, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Anna Aliberti
- U.O.C. Anestesia e Rianimazione 1, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Matteo Di Nardo
- Pediatric Intensive Care Unit, Children's Hospital Bambino Gesù, IRCCS, Rome, Italy
| | - Justyna Swol
- Department of Pulmonology, Intensive Care Medicine, Paracelsus Medical University, Nuremberg, Germany
| | - Nicholas Barrett
- Department of Critical Care, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Federico Pappalardo
- Department of Cardiothoracic Anesthesia and Intensive Care, San Raffaele Hospital, Milan, Italy
| | - Jan Bělohlávek
- Second Department of Medicine, Cardiovascular Medicine, General University Hospital in Prague, First Faculty of Medicine, Charles University in Prague, Praha, Czech Republic
| | - Fabio Silvio Taccone
- Department of Intensive Care, Hôpital Erasme, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | | | - Lachlan Crawford
- Critical Care Research Group, Prince Charles Hospital, Brisbane, QLD, Australia
| | - Roberto Lorusso
- Cardio-Thoracic Surgery Department, Heart & Vascular Centre, Maastricht University Medical Hospital (MUMC), Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands
| | - Jacky Y Suen
- Critical Care Research Group, Prince Charles Hospital, Brisbane, QLD, Australia
| | - John F Fraser
- Critical Care Research Group, Prince Charles Hospital, Brisbane, QLD, Australia
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11
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Bakdach D, Akkari A, Gazwi K, Deloso F, Tan D, Ibrahim A, Abdussalam A, Hassan I. Propofol Safety in Anticoagulated and Nonanticoagulated Patients During Extracorporeal Membrane Oxygenation. ASAIO J 2021; 67:201-207. [PMID: 32639256 PMCID: PMC7326318 DOI: 10.1097/mat.0000000000001207] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Sedation management during extracorporeal membrane oxygenation(ECMO) is a common challenge encountered by treating intensivists. Data about the safety of propofol use during ECMO has been contradictory. We aimed to investigate associated risks of propofol use on oxygenator lifespan and to explore the effect of propofol use on oxygenator membranes when therapeutic anticoagulation was omitted. Adult respiratory ECMO patients who received propofol were retrospectively compared with those who did not, and outcomes were assessed by means of duration of oxygenator functionality before requiring an exchange, and number of exchanges during propofol use and/or ECMO support. Out of the 63patients included in the analysis, 46%received propofol during ECMO as part of sedation regimen. The use of propofol was not found to be associated with an increased incidence of oxygenator failure when compared with cohorts who did not receive propofol (21% propofol arm vs. 6% control, p = 0.13). When analyzed for anticoagulation omission effects, propofol did not increase the risk of oxygenator failure (p = 0.63). The only predictor that statistically predicted the risk of oxygenator failure was development of heparin-induced thrombocytopenia (HIT) during ECMO. The results of this study further support the previously reported safety of propofol utilization during respiratory ECMO even in the absence of anticoagulation.
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Affiliation(s)
- Dana Bakdach
- From the Department of Pharmacy, Medical Intensive Care Unit, Hamad Medical Corporation, Doha, Qatar
| | - Abdelrauof Akkari
- Department of Medicine, Medical Intensive Care Unit, Hamad Medical Corporation, Doha, Qatar
| | - Khaled Gazwi
- Department of Medicine, Medical Intensive Care Unit, Hamad Medical Corporation, Doha, Qatar
| | - Ferdinand Deloso
- Department of Nursing, Intensive Care Unit, Hamad Medical Corporation, Doha, Qatar
| | - Darwin Tan
- Department of Nursing, Intensive Care Unit, Hamad Medical Corporation, Doha, Qatar
| | - Abdulsalam Ibrahim
- Department of Medicine, Medical Intensive Care Unit, Hamad Medical Corporation, Doha, Qatar
| | - Ahmad Abdussalam
- Department of Medicine, Medical Intensive Care Unit, Hamad Medical Corporation, Doha, Qatar
| | - Ibrahim Hassan
- Department of Medicine, Medical Intensive Care Unit, Hamad Medical Corporation, Doha, Qatar
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12
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Grasselli G, Giani M, Scaravilli V, Fumagalli B, Mariani C, Redaelli S, Lucchini A, Zanella A, Patroniti N, Pesenti A, Foti G. Volatile Sedation for Acute Respiratory Distress Syndrome Patients on Venovenous Extracorporeal Membrane Oxygenation and Ultraprotective Ventilation. Crit Care Explor 2021; 3:e0310. [PMID: 33458679 PMCID: PMC7803679 DOI: 10.1097/cce.0000000000000310] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Supplemental Digital Content is available in the text. Patients on extracorporeal support for severe acute respiratory distress syndrome may require a prolonged period of deep sedation. In these patients, volatile sedation may represent a valid alternative to IV drugs. The aim of our study was to describe the feasibility of volatile sedation in a large cohort of acute respiratory distress syndrome patients undergoing venovenous extracorporeal membrane oxygenation and ultraprotective ventilation.
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Affiliation(s)
- Giacomo Grasselli
- Dipartimento di Fisiopatologia Medico Chirurgica e dei Trapianti, Università degli Studi di Milano, Milan, Italy.,Dipartimento di Anestesia-Rianimazione e Emergenza Urgenza, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Marco Giani
- Dipartimento di Medicina e Chirurgia, Università degli Studi di Milano-Bicocca, Monza, Italy.,Dipartimento di Emergenza-Urgenza, ASST Monza, Monza, Italy
| | - Vittorio Scaravilli
- Dipartimento di Fisiopatologia Medico Chirurgica e dei Trapianti, Università degli Studi di Milano, Milan, Italy.,Dipartimento di Anestesia-Rianimazione e Emergenza Urgenza, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Benedetta Fumagalli
- Dipartimento di Medicina e Chirurgia, Università degli Studi di Milano-Bicocca, Monza, Italy
| | - Carminia Mariani
- Dipartimento di Medicina e Chirurgia, Università degli Studi di Milano-Bicocca, Monza, Italy
| | - Sara Redaelli
- Dipartimento di Emergenza-Urgenza, ASST Monza, Monza, Italy
| | | | - Alberto Zanella
- Dipartimento di Fisiopatologia Medico Chirurgica e dei Trapianti, Università degli Studi di Milano, Milan, Italy.,Dipartimento di Anestesia-Rianimazione e Emergenza Urgenza, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Nicolò Patroniti
- Dipartimento di Scienze Chirurgiche e Diagnostiche Integrate, Università di Genova, Genova, Italy.,Dipartimento di Anestesia e Terapia Intensiva, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Antonio Pesenti
- Dipartimento di Fisiopatologia Medico Chirurgica e dei Trapianti, Università degli Studi di Milano, Milan, Italy.,Dipartimento di Anestesia-Rianimazione e Emergenza Urgenza, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Giuseppe Foti
- Dipartimento di Medicina e Chirurgia, Università degli Studi di Milano-Bicocca, Monza, Italy.,Dipartimento di Emergenza-Urgenza, ASST Monza, Monza, Italy
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13
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Zimmerman KO, Dallefeld SH, Hornik CP, Watt KM. Sedative and Analgesic Pharmacokinetics During Pediatric ECMO. J Pediatr Pharmacol Ther 2020; 25:675-688. [PMID: 33214778 PMCID: PMC7671016 DOI: 10.5863/1551-6776-25.8.675] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/10/2020] [Indexed: 11/11/2022]
Abstract
Sedatives and analgesics are often administered to critically ill children supported by extracorporeal membrane oxygenation (ECMO) to facilitate comfort and to decrease risks of life-threatening complications. Optimization of sedative and analgesic dosing is necessary to achieve desired therapeutic benefits and must consider interactions between the circuit and patient that may affect drug metabolism, clearance, and impact on target organs. This paper reviews existing in vitro and pediatric in vivo literature concerning the effects of the ECMO circuit on sedative and analgesic disposition and offers dosing guidance for the management of critically ill children receiving these drugs.
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Affiliation(s)
- Kanecia O Zimmerman
- Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC (KOZ, CPH)
- Division of Pediatric Critical Care Medicine, Department of Pediatrics, Duke Children's Hospital, Durham, NC (KOZ, CPH)
| | - Samantha H Dallefeld
- Pediatric Critical Care Medicine, Dell Children's Medical Center of Central Texas, Austin, TX (SHD)
| | - Christoph P Hornik
- Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC (KOZ, CPH)
- Division of Pediatric Critical Care Medicine, Department of Pediatrics, Duke Children's Hospital, Durham, NC (KOZ, CPH)
| | - Kevin M Watt
- Division of Clinical Pharmacology, University of Utah School of Medicine, Salt Lake City, UT (KMW)
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14
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Influence of the ECMO circuit on the concentration of nutritional supplements. Sci Rep 2020; 10:19275. [PMID: 33159150 PMCID: PMC7648645 DOI: 10.1038/s41598-020-76299-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 10/19/2020] [Indexed: 11/17/2022] Open
Abstract
Circulating compounds such as drugs and nutritional components might adhere to the oxygenator fibers and tubing during ECMO support. This study evaluated the amount of nutritional supplements adsorbed to the ECMO circuit under controlled ex vivo conditions. Six identical ECMO circuits were primed with fresh human whole blood and maintained under physiological conditions at 36 °C for 24 h. A dose of nutritional supplement calculated for a 70 kg patient was added. 150 mL volume was drawn from the priming bag for control samples and kept under similar conditions. Blood samples were obtained at predetermined time points and analyzed for concentrations of vitamins, minerals, lipids, and proteins. Data were analyzed using mixed models with robust standard errors. No significant differences were found between the ECMO circuits and the controls for any of the measured variables: cobalamin, folate, vitamin A, glucose, minerals, HDL cholesterol, LDL cholesterol, total cholesterol, triglycerides or total proteins. There was an initial decrease and then an increase in the concentration of cobalamin and folate. Vitamin A concentrations decreased in both groups over time. There was a decrease in concentration of glucose and an increased concentration of lactate dehydrogenase over time in both groups. There were no significant alterations in the concentrations of nutritional supplements in an ex vivo ECMO circuit compared to control samples. The time span of this study was limited, thus, clinical studies over a longer period of time are needed.
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15
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Dallefeld SH, Sherwin J, Zimmerman KO, Watt KM. Dexmedetomidine extraction by the extracorporeal membrane oxygenation circuit: results from an in vitro study. Perfusion 2020; 35:209-216. [PMID: 31431126 PMCID: PMC7275646 DOI: 10.1177/0267659119868062] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Dexmedetomidine is a sedative administered to minimize distress and decrease the risk of life threatening complications in children supported with extracorporeal membrane oxygenation. The extracorporeal membrane oxygenation circuit can extract drug and decrease drug exposure, placing the patient at risk of therapeutic failure. OBJECTIVE To determine the extraction of dexmedetomidine by the extracorporeal membrane oxygenation circuit. MATERIALS AND METHODS Dexmedetomidine was studied in three closed-loop circuit configurations to isolate the impact of the oxygenator, hemofilter, and tubing on circuit extraction. Each circuit was primed with human blood according to standard practice for Duke Children's Hospital, and flow was set to 1 L/min. Dexmedetomidine was dosed to achieve a therapeutic concentration of ~600 pg/mL. Dexmedetomidine was added to a separate tube of blood to serve as a control and evaluate for natural drug degradation. Serial blood samples were collected over 24 hours and concentrations were quantified with a validated assay. Drug recovery was calculated at each time point. RESULTS Dexmedetomidine was highly extracted by the oxygenator evidenced by a mean recovery of 62-67% at 4 hours and 23-34% at 24 hours in circuits with an oxygenator in-line. In contrast, mean recovery with the oxygenator removed was 96% at 4 hours and 93% at 24 hours. Dexmedetomidine was stable over time with a mean recovery in the control samples of 102% at 24 hours. CONCLUSION These results suggest dexmedetomidine is extracted by the oxygenator in the extracorporeal membrane oxygenation circuit which may result in decreased drug exposure in vivo.
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Affiliation(s)
- Samantha H Dallefeld
- Department of Pediatrics, Duke Clinical Research Institute, Duke University, Durham, NC, USA
- Pediatric Intensive Care Unit, Dell Children’s Medical Center of Central Texas, Austin, TX, USA
| | - Jennifer Sherwin
- Department of Pediatrics, Duke Clinical Research Institute, Duke University, Durham, NC, USA
| | - Kanecia O Zimmerman
- Department of Pediatrics, Duke Clinical Research Institute, Duke University, Durham, NC, USA
| | - Kevin M Watt
- Department of Pediatrics, Duke Clinical Research Institute, Duke University, Durham, NC, USA
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16
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Abstract
OBJECTIVES To determine the oxygenator impact on alterations of ceftolozane/tazobactam in a contemporary neonatal/pediatric (1/4-inch) and adolescent/adult (3/8-inch) extracorporeal membrane oxygenation circuit including the Quadrox-i oxygenator (Maquet, Wayne, NJ). DESIGN A 1/4-inch and 3/8-inch, simulated closed-loop extracorporeal membrane oxygenation circuits were prepared with a Quadrox-i pediatric and Quadrox-i adult oxygenator and blood primed. Additionally, 1/4-inch and 3/8-inch circuits were also prepared without an oxygenator in series. A one-time dose of ceftolozane/tazobactam was administered into the circuits and serial preoxygenator and postoxygenator concentrations were obtained at 5 minutes, 1, 2, 3, 4, 5, 6, and 24-hour time points. Ceftolozane/tazobactam was also maintained in a glass vial and samples were taken from the vial at the same time periods for control purposes to assess for spontaneous drug degradation SETTING:: A free-standing extracorporeal membrane oxygenation circuit. PATIENTS None. INTERVENTIONS Single-dose administration of ceftolozane/tazobactam into closed-loop extracorporeal membrane oxygenation circuits prepared with and without an oxygenator in series with serial preoxygenator, postoxygenator, and reference samples obtained for concentration determination over a 24-hour study period. MEASUREMENTS AND MAIN RESULTS For the 1/4-inch circuit, there was approximately 92% ceftolozane and 22-25% tazobactam loss with the oxygenator in series and 19-30% ceftolozane and 31-34% tazobactam loss without an oxygenator in series at 24 hours. For the 3/8-inch circuit, there was approximately 85% ceftolozane and 29% tazobactam loss with the oxygenator in series and 25-27% ceftolozane and 23-26% tazobactam loss without an oxygenator in series at 24 hours. The reference ceftolozane and tazobactam concentrations remained relatively constant during the entire study period demonstrating the drug loss in each size of the extracorporeal membrane oxygenation circuit with or without an oxygenator was not a result of spontaneous drug degradation. CONCLUSIONS This ex vivo investigation demonstrated substantial ceftolozane loss within an extracorporeal membrane oxygenation circuit with an oxygenator in series with both sizes of the Quadrox-i oxygenator at 24 hours and significant ceftolozane loss in the absence of an oxygenator. Tazobactam loss was similar regardless of the presence of an oxygenator. Further evaluations with multiple dose in vitro and in vivo investigations are needed before specific drug dosing recommendations can be made for clinical application with extracorporeal membrane oxygenation.
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17
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Raffaeli G, Cavallaro G, Allegaert K, Koch BCP, Mosca F, Tibboel D, Wildschut ED. Sequestration of Voriconazole and Vancomycin Into Contemporary Extracorporeal Membrane Oxygenation Circuits: An in vitro Study. Front Pediatr 2020; 8:468. [PMID: 32974242 PMCID: PMC7481439 DOI: 10.3389/fped.2020.00468] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 07/03/2020] [Indexed: 12/29/2022] Open
Abstract
Background: Bacterial and fungal infections are common and often contribute to death in patients undergoing extracorporeal membrane oxygenation (ECMO). Drug disposition is altered during ECMO, and adsorption in the circuit is an established causative factor. Vancomycin and voriconazole are widely used, despite the lack of evidence-based prescription guidelines. Objective: The objective of this study was to determine the extraction of voriconazole and vancomycin by the Xenios/Novalung ECMO circuits. Methods: We have set up nine closed-loop ECMO circuits, consisting of four different iLAActivve ® kits for neonatal, pediatric, and adult support: three iLA-ActivveMiniLung ® petite kits, two iLA-ActivveMiniLung ® kits, two iLA-ActivveiLA ® kits, and two iLA-Activve X-lung ® kits. The circuits were primed with whole blood and maintained at physiologic conditions for 24 h. Voriconazole and vancomycin were injected as a single-bolus age-related dose into the circuits. Pre-membrane (P2) blood samples were obtained at baseline and after drug injection at 2, 10, 30, 180, 360 min, and 24 h. A control sample at 2 min was collected for spontaneous drug degradation testing at 24 h. Results: Seventy-two samples were analyzed in triplicate. The mean percentage of drug recovery at 24 h was 20% for voriconazole and 62% for vancomycin. Conclusions: The extraction of voriconazole and vancomycin by contemporary ECMO circuits is clinically relevant across all age-related circuit sizes and may result in reduced drug exposure in vivo.
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Affiliation(s)
- Genny Raffaeli
- Intensive Care and Department of Pediatric Surgery Erasmus MC-Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, Netherlands.,Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.,Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, NICU, Milan, Italy
| | - Giacomo Cavallaro
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, NICU, Milan, Italy
| | - Karel Allegaert
- Department of Development and Regeneration and Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.,Hospital Pharmacy, Erasmus MC, Rotterdam, Netherlands
| | | | - Fabio Mosca
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.,Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, NICU, Milan, Italy
| | - Dick Tibboel
- Intensive Care and Department of Pediatric Surgery Erasmus MC-Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Enno D Wildschut
- Intensive Care and Department of Pediatric Surgery Erasmus MC-Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, Netherlands
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18
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Sieg A, Pandya K, Winstead R, Evans R. Overview of Pharmacological Considerations in Extracorporeal Membrane Oxygenation. Crit Care Nurse 2019; 39:29-43. [PMID: 30936129 DOI: 10.4037/ccn2019236] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
Extracorporeal membrane oxygenation has become more widely used in recent years. Although this technology has proven to be lifesaving, it is not devoid of complications contributing to significant morbidity and mortality. Nurses who care for patients receiving extracorporeal membrane oxygenation should further their understanding of changes in medication profiles due to complex interactions with the extracorporeal membrane oxygenation circuitry. The aim of this comprehensive review is to give nurses a better understanding of analgesic, sedative, anti-infective, and anticoagulation medications that are frequently used to treat patients receiving extracorporeal membrane oxygenation.
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Affiliation(s)
- Adam Sieg
- Adam Sieg is an assistant professor in the Department of Pharmacy Practice and Science at the University of Kentucky College of Pharmacy, Lexington, Kentucky, and a clinical pharmacist specialist in advanced heart failure and heart transplant/mechanical circulatory support. .,Komal Pandya is a cardiothoracic surgery clinical pharmacist with the University of Kentucky Medical Center in Lexington, Kentucky, and adjunct assistant professor in the Department of Pharmacy Practice and Science at the University of Kentucky College of Pharmacy. .,Ryan Winstead is a clinical transplant specialist at Virginia Commonwealth University Health, Richmond, Virginia. .,Rickey Evans is an assistant professor in the Department of Clinical Pharmacy and Outcomes Sciences at the University of South Carolina College of Pharmacy and clinical pharmacy specialist in critical care at Palmetto Health Richland in Columbia, South Carolina.
| | - Komal Pandya
- Adam Sieg is an assistant professor in the Department of Pharmacy Practice and Science at the University of Kentucky College of Pharmacy, Lexington, Kentucky, and a clinical pharmacist specialist in advanced heart failure and heart transplant/mechanical circulatory support.,Komal Pandya is a cardiothoracic surgery clinical pharmacist with the University of Kentucky Medical Center in Lexington, Kentucky, and adjunct assistant professor in the Department of Pharmacy Practice and Science at the University of Kentucky College of Pharmacy.,Ryan Winstead is a clinical transplant specialist at Virginia Commonwealth University Health, Richmond, Virginia.,Rickey Evans is an assistant professor in the Department of Clinical Pharmacy and Outcomes Sciences at the University of South Carolina College of Pharmacy and clinical pharmacy specialist in critical care at Palmetto Health Richland in Columbia, South Carolina
| | - Ryan Winstead
- Adam Sieg is an assistant professor in the Department of Pharmacy Practice and Science at the University of Kentucky College of Pharmacy, Lexington, Kentucky, and a clinical pharmacist specialist in advanced heart failure and heart transplant/mechanical circulatory support.,Komal Pandya is a cardiothoracic surgery clinical pharmacist with the University of Kentucky Medical Center in Lexington, Kentucky, and adjunct assistant professor in the Department of Pharmacy Practice and Science at the University of Kentucky College of Pharmacy.,Ryan Winstead is a clinical transplant specialist at Virginia Commonwealth University Health, Richmond, Virginia.,Rickey Evans is an assistant professor in the Department of Clinical Pharmacy and Outcomes Sciences at the University of South Carolina College of Pharmacy and clinical pharmacy specialist in critical care at Palmetto Health Richland in Columbia, South Carolina
| | - Rickey Evans
- Adam Sieg is an assistant professor in the Department of Pharmacy Practice and Science at the University of Kentucky College of Pharmacy, Lexington, Kentucky, and a clinical pharmacist specialist in advanced heart failure and heart transplant/mechanical circulatory support.,Komal Pandya is a cardiothoracic surgery clinical pharmacist with the University of Kentucky Medical Center in Lexington, Kentucky, and adjunct assistant professor in the Department of Pharmacy Practice and Science at the University of Kentucky College of Pharmacy.,Ryan Winstead is a clinical transplant specialist at Virginia Commonwealth University Health, Richmond, Virginia.,Rickey Evans is an assistant professor in the Department of Clinical Pharmacy and Outcomes Sciences at the University of South Carolina College of Pharmacy and clinical pharmacy specialist in critical care at Palmetto Health Richland in Columbia, South Carolina
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19
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20
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Valencia E, Nasr VG. Updates in Pediatric Extracorporeal Membrane Oxygenation. J Cardiothorac Vasc Anesth 2019; 34:1309-1323. [PMID: 31607521 DOI: 10.1053/j.jvca.2019.09.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Revised: 08/30/2019] [Accepted: 09/05/2019] [Indexed: 01/28/2023]
Abstract
Extracorporeal membrane oxygenation is an increasingly used mode of life support for patients with cardiac and/or respiratory failure refractory to conventional therapy. This review provides a synopsis of the evolution of extracorporeal life support in neonates, infants, and children and offers a framework for areas in need of research. Specific aspects addressed are the changing epidemiology; technologic advancements in extracorporeal membrane oxygenation circuitry; the current status and future direction of anticoagulation management; sedative and analgesic strategies; and outcomes, with special attention to the lessons learned from neonatal survivors.
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Affiliation(s)
- Eleonore Valencia
- Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA
| | - Viviane G Nasr
- Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA.
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21
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Raffaeli G, Pokorna P, Allegaert K, Mosca F, Cavallaro G, Wildschut ED, Tibboel D. Drug Disposition and Pharmacotherapy in Neonatal ECMO: From Fragmented Data to Integrated Knowledge. Front Pediatr 2019; 7:360. [PMID: 31552205 PMCID: PMC6733981 DOI: 10.3389/fped.2019.00360] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 08/16/2019] [Indexed: 12/27/2022] Open
Abstract
Extracorporeal membrane oxygenation (ECMO) is a lifesaving support technology for potentially reversible neonatal cardiac and/or respiratory failure. As the survival and the overall outcome of patients rely on the treatment and reversal of the underlying disease, effective and preferentially evidence-based pharmacotherapy is crucial to target recovery. Currently limited data exist to support the clinicians in their every-day intensive care prescribing practice with the contemporary ECMO technology. Indeed, drug dosing to optimize pharmacotherapy during neonatal ECMO is a major challenge. The impact of the maturational changes of the organ function on both pharmacokinetics (PK) and pharmacodynamics (PD) has been widely established over the last decades. Next to the developmental pharmacology, additional non-maturational factors have been recognized as key-determinants of PK/PD variability. The dynamically changing state of critical illness during the ECMO course impairs the achievement of optimal drug exposure, as a result of single or multi-organ failure, capillary leak, altered protein binding, and sometimes a hyperdynamic state, with a variable effect on both the volume of distribution (Vd) and the clearance (Cl) of drugs. Extracorporeal membrane oxygenation introduces further PK/PD perturbation due to drug sequestration and hemodilution, thus increasing the Vd and clearance (sequestration). Drug disposition depends on the characteristics of the compounds (hydrophilic vs. lipophilic, protein binding), patients (age, comorbidities, surgery, co-medications, genetic variations), and circuits (roller vs. centrifugal-based systems; silicone vs. hollow-fiber oxygenators; renal replacement therapy). Based on the potential combination of the above-mentioned drug PK/PD determinants, an integrated approach in clinical drug prescription is pivotal to limit the risks of over- and under-dosing. The understanding of the dose-exposure-response relationship in critically-ill neonates on ECMO will enable the optimization of dosing strategies to ensure safety and efficacy for the individual patient. Next to in vitro and clinical PK data collection, physiologically-based pharmacokinetic modeling (PBPK) are emerging as alternative approaches to provide bedside dosing guidance. This article provides an overview of the available evidence in the field of neonatal pharmacology during ECMO. We will identify the main determinants of altered PK and PD, elaborate on evidence-based recommendations on pharmacotherapy and highlight areas for further research.
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Affiliation(s)
- Genny Raffaeli
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, NICU, Milan, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Pavla Pokorna
- Department of Pediatrics—ICU, General University Hospital, 1st Faculty of Medicine Charles University, Prague, Czechia
- Department of Pharmacology, General University Hospital, 1st Faculty of Medicine Charles University, Prague, Czechia
- Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, Netherlands
| | - Karel Allegaert
- Division of Neonatology, Department of Pediatrics, Erasmus MC Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, Netherlands
- Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Fabio Mosca
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, NICU, Milan, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Giacomo Cavallaro
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, NICU, Milan, Italy
| | - Enno D. Wildschut
- Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, Netherlands
| | - Dick Tibboel
- Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, Netherlands
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Cies JJ, Moore WS, Giliam N, Low T, Enache A, Chopra A. Oxygenator Impact on Ceftaroline in Extracorporeal Membrane Oxygenation Circuits. Pediatr Crit Care Med 2018; 19:1077-1082. [PMID: 30048366 DOI: 10.1097/pcc.0000000000001693] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
OBJECTIVES To determine the oxygenator impact on alterations of ceftaroline in a contemporary neonatal/pediatric (1/4-inch) and adolescent/adult (3/8-inch) extracorporeal membrane oxygenation circuit including the Quadrox-i oxygenator (Maquet, Wayne, NJ). DESIGN Quarter-inch and 3/8-inch, simulated closed-loop extracorporeal membrane oxygenation circuits were prepared with a Quadrox-i pediatric and Quadrox-i adult oxygenator and blood primed. Additionally, 1/4-inch and 3/8-inch circuits were also prepared without an oxygenator in series. An one-time dose of ceftaroline was administered into the circuits, and serial pre- and postoxygenator concentrations were obtained at 5 minutes, 1-, 2-, 3-, 4-, 5-, 6-, and 24-hour time points. Ceftaroline was also maintained in a glass vial, and samples were taken from the vial at the same time periods for control purposes to assess for spontaneous drug degradation. SETTING A free-standing extracorporeal membrane oxygenation circuit. PATIENTS None. INTERVENTION Single dose administration of ceftaroline into closed-loop extracorporeal membrane oxygenation circuits prepared with and without an oxygenator in series with serial preoxygenator, postoxygenator, and reference samples obtained for concentration determination over a 24-hour study period. MEASUREMENTS AND MAIN RESULTS For the 1/4-inch circuit with an oxygenator, there was 79.8% drug loss preoxygenator and 82.5% drug loss postoxygenator at 24 hours. There was a statistically significant difference (p < 0.01) in the amount of ceftaroline remaining at 24 hours when compared with each prior time point for the 1/4-inch circuit. For the 1/4-inch circuit without an oxygenator, there was no significant drug loss at any study time point. For the 3/8-inch circuit with an oxygenator, there was 76.2% drug loss preoxygenator and 77.6% drug loss postoxygenator at 24 hours. There was a statistically significant difference (p < 0.01) in the amount of ceftaroline remaining at 24 hours when compared with each prior time point for the 3/8-inch circuit. For the 3/8-inch circuit without an oxygenator, there was no significant drug loss at any study time point. The reference ceftaroline concentrations remained relatively constant during the entire study period demonstrating the ceftaroline loss in each size of the extracorporeal membrane oxygenation circuit with or without an oxygenator was not a result of spontaneous drug degradation and primarily the result of the oxygenator. CONCLUSIONS This ex vivo investigation demonstrated significant ceftaroline loss within an extracorporeal membrane oxygenation circuit with an oxygenator in series with both sizes of the Quadrox-i oxygenator at 24 hours. Therapeutic concentrations of ceftaroline in the setting of extracorporeal membrane oxygenation may not be achieved with current U.S. Food and Drug Administration-recommended doses, and further evaluation is needed before specific drug dosing recommendations can be made for clinical application with extracorporeal membrane oxygenation.
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Affiliation(s)
- Jeffrey J Cies
- The Center for Pediatric Pharmacotherapy LLC, Pottstown, PA
- St. Christopher's Hospital for Children, Philadelphia, PA
- Drexel University College of Medicine, Philadelphia, PA
| | - Wayne S Moore
- The Center for Pediatric Pharmacotherapy LLC, Pottstown, PA
| | - Nadji Giliam
- St. Christopher's Hospital for Children, Philadelphia, PA
| | - Tracy Low
- St. Christopher's Hospital for Children, Philadelphia, PA
| | | | - Arun Chopra
- The Center for Pediatric Pharmacotherapy LLC, Pottstown, PA
- NYU Langone Medical Center, New York, NY
- NYU School of Medicine, New York, NY
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23
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Cies JJ, Moore WS, Giliam N, Low T, Enache A, Chopra A. Impact of ex-vivo extracorporeal membrane oxygenation circuitry on daptomycin. Perfusion 2018; 33:624-629. [DOI: 10.1177/0267659118781761] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background: The objective was to determine the alterations of daptomycin (DAP) in a contemporary neonatal/pediatric (1/4-inch) and adolescent/adult (3/8-inch) extracorporeal membrane oxygenation (ECMO) circuit including the Quadrox-i® oxygenator. Methods: Quarter-inch and 3/8-inch, simulated, closed-loop, ECMO circuits were prepared with a Quadrox-i pediatric and Quadrox-i adult oxygenator and blood primed. A one-time dose of DAP was administered into the circuit and serial pre- and post-oxygenator concentrations were obtained at 0-5 minutes and 1, 2, 3, 4, 5, 6 and 24-hour time points. DAP was also maintained in a glass vial and samples were taken from the vial at the same time periods for control purposes to assess for spontaneous drug degradation Results: For both the 1/4-inch and 3/8-inch circuits, there was no significant DAP loss at 24 hours. Additionally, the reference DAP concentrations remained relatively constant during the entire 24-hour study period. Conclusion: This ex-vivo investigation demonstrated no significant DAP loss within an ECMO circuit with both sizes of the Quadrox-i oxygenator at 24 hours. Therapeutic concentrations of DAP in the setting of ECMO may be anticipated with current recommended doses, depending on the amount of extracorporeal volume needed for circuit maintenance in comparison to the patient’s apparent volume of distribution. Additional studies with a larger sample size are needed to confirm these findings.
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Affiliation(s)
- Jeffrey J. Cies
- The Center for Pediatric Pharmacotherapy LLC, Pottstown, PA, USA
- St. Christopher’s Hospital for Children, Philadelphia, PA, USA
- Drexel University College of Medicine, Philadelphia, PA, USA
| | - Wayne S. Moore
- The Center for Pediatric Pharmacotherapy LLC, Pottstown, PA, USA
| | - Nadji Giliam
- St. Christopher’s Hospital for Children, Philadelphia, PA, USA
| | - Tracy Low
- St. Christopher’s Hospital for Children, Philadelphia, PA, USA
| | - Adela Enache
- Atlantic Diagnostic Laboratories, Bensalem, PA, USA
| | - Arun Chopra
- The Center for Pediatric Pharmacotherapy LLC, Pottstown, PA, USA
- NYU Langone Medical Center, New York, NY, USA
- NYU School of Medicine, New York, NY, USA
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24
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Inhalative sedation with small tidal volumes under venovenous ECMO. J Artif Organs 2018; 21:201-205. [DOI: 10.1007/s10047-018-1030-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Accepted: 01/28/2018] [Indexed: 12/11/2022]
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25
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Cheng V, Abdul-Aziz MH, Roberts JA, Shekar K. Optimising drug dosing in patients receiving extracorporeal membrane oxygenation. J Thorac Dis 2018; 10:S629-S641. [PMID: 29732181 DOI: 10.21037/jtd.2017.09.154] [Citation(s) in RCA: 103] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Optimal pharmacological management during extracorporeal membrane oxygenation (ECMO) involves more than administering drugs to reverse underlying disease. ECMO is a complex therapy that should be administered in a goal-directed manner to achieve therapeutic endpoints that allow reversal of disease and ECMO wean, minimisation of complications (treatment of complications when they do occur), early interruption of sedation and rehabilitation, maximising patient comfort and minimising risks of delirium. ECMO can alter both the pharmacokinetics (PK) and pharmacodynamics (PD) of administered drugs and our understanding of these alterations is still evolving. Based on available data it appears that modern ECMO circuitry probably has a less significant impact on PK when compared with critical illness itself. However, these findings need further confirmation in clinical population PK studies and such studies are underway. The altered PD associated with ECMO is less understood and more research is indicated. Until robust dosing guidelines become available, clinicians will have to rely on the principles of drug dosing in critically ill and known PK alterations induced by ECMO itself. This article summarises the PK alterations and makes preliminary recommendations on possible dosing approaches.
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Affiliation(s)
- Vesa Cheng
- Faculty of Medicine, The University of Queensland, UQ Centre for Clinical Research, Brisbane, Australia
| | - Mohd-Hafiz Abdul-Aziz
- Faculty of Medicine, The University of Queensland, UQ Centre for Clinical Research, Brisbane, Australia.,School of Pharmacy, International Islamic University Malaysia, Kuantan, Malaysia
| | - Jason A Roberts
- Faculty of Medicine, The University of Queensland, UQ Centre for Clinical Research, Brisbane, Australia.,Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, Australia.,Department of Pharmacy, Royal Brisbane and Women's Hospital, Brisbane, Australia.,Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, Australia
| | - Kiran Shekar
- Adult Intensive Care Services, the Prince Charles Hospital, Chermside, Australia.,Critical Care Research Group, Centre of Research Excellence for Advanced Cardio-respiratory Therapies Improving OrgaN Support (ACTIONS) and the University of Queensland, Brisbane, Australia
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26
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Abstract
The need for extracorporeal membrane oxygenation (ECMO) therapy is a marker of disease severity for which multiple medications are required. The therapy causes physiologic changes that impact drug pharmacokinetics. These changes can lead to exposure-driven decreases in efficacy or increased incidence of side effects. The pharmacokinetic changes are drug specific and largely undefined for most drugs. We review available drug dosing data and provide guidance for use in the ECMO patient population.
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Sedation Management in Children Supported on Extracorporeal Membrane Oxygenation for Acute Respiratory Failure. Crit Care Med 2017; 45:e1001-e1010. [PMID: 28614197 DOI: 10.1097/ccm.0000000000002540] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES To describe sedation management in children supported on extracorporeal membrane oxygenation for acute respiratory failure. DESIGN Secondary analysis of prospectively collected data from a multicenter randomized trial of sedation (Randomized Evaluation of Sedation Titration for Respiratory Failure). SETTING Twenty-one U.S. PICUs. PATIENTS One thousand two hundred fifty-five children, 2 weeks to 17 years old, with moderate/severe pediatric acute respiratory distress syndrome. INTERVENTIONS Sedation managed per usual care or Randomized Evaluation of Sedation Titration for Respiratory Failure protocol. MEASUREMENTS AND MAIN RESULTS Sixty-one Randomized Evaluation of Sedation Titration for Respiratory Failure patients (5%) with moderate/severe pediatric acute respiratory distress syndrome were supported on extracorporeal membrane oxygenation, including 29 managed per Randomized Evaluation of Sedation Titration for Respiratory Failure protocol. Most extracorporeal membrane oxygenation patients received neuromuscular blockade (46%) or were heavily sedated with State Behavioral Scale scores -3/-2 (34%) by extracorporeal membrane oxygenation day 3. Median opioid and benzodiazepine doses on the day of cannulation, 0.15 mg/kg/hr (3.7 mg/kg/d) and 0.11 mg/kg/hr (2.8 mg/kg/d), increased by 36% and 58%, respectively, by extracorporeal membrane oxygenation day 3. In the 41 patients successfully decannulated prior to study discharge, patients were receiving 0.40 mg/kg/hr opioids (9.7 mg/kg/d) and 0.39 mg/kg/hr benzodiazepines (9.4 mg/kg/d) at decannulation, an increase from cannulation of 108% and 192%, respectively (both p < 0.001). Extracorporeal membrane oxygenation patients experienced more clinically significant iatrogenic withdrawal than moderate/severe pediatric acute respiratory distress syndrome patients managed without extracorporeal membrane oxygenation support (p < 0.001). Compared to extracorporeal membrane oxygenation patients managed per Randomized Evaluation of Sedation Titration for Respiratory Failure protocol, usual care extracorporeal membrane oxygenation patients received more opioids during the study period (mean cumulative dose of 183.0 vs 89.8 mg/kg; p = 0.02), over 6.5 greater exposure days (p = 0.002) with no differences in wakefulness or agitation. CONCLUSIONS In children, the initiation of extracorporeal membrane oxygenation support is associated with deep sedation, substantial sedative exposure, and increased frequency of iatrogenic withdrawal syndrome. A standardized, goal-directed, nurse-driven sedation protocol may help mitigate these effects.
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28
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Hahn J, Choi JH, Chang MJ. Pharmacokinetic changes of antibiotic, antiviral, antituberculosis and antifungal agents during extracorporeal membrane oxygenation in critically ill adult patients. J Clin Pharm Ther 2017; 42:661-671. [PMID: 28948652 DOI: 10.1111/jcpt.12636] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2017] [Accepted: 09/07/2017] [Indexed: 12/24/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE Extracorporeal membrane oxygenation (ECMO) is a life-saving system used for critically ill patients with cardiac and/or respiratory failure. The pharmacokinetics (PK) of drugs can change in patients undergoing ECMO, which can result in therapeutic failure or drug toxicity requiring further management of drug complications. In this review, we discussed changes in the PK of antibiotic, antiviral, antituberculosis and antifungal agents administered to adult patients on ECMO. These drugs are crucial for managing infections, which commonly occur during ECMO. METHODS A literature search was conducted using the PubMed and EMBASE databases with the following keywords: "extracorporeal membrane oxygenation OR extracorporeal membrane oxygenations OR ECMO" and "PK OR pharmacokinetics OR pharmacokinetic*" and "anti infective* OR antibiotic* OR antiviral* OR antituberculosis OR antifungal*." RESULTS AND DISCUSSION Generally, the volume of distribution (Vd) increases and drug clearance (CL) and elimination decrease during ECMO. Highly significant changes in drug PK can occur by interactions with the ECMO device itself, drug characteristics, pathological changes and patient characteristics. This may affect the blood concentrations of drugs, which influence the success of therapy. The PK of vancomycin, piperacillin-tazobactam, meropenem, azithromycin, amikacin and caspofungin did not change significantly in adult patients receiving ECMO. However, there were significant changes in the PK of imipenem, oseltamivir, rifampicin and voriconazole. The trough concentrations of imipenem were highly variable; oseltamivir had a decreased CL and increased Vd, and rifampicin concentrations were below therapeutic levels, even when a higher-than-standard dose was used in patients treated with ECMO. Additionally, voriconazole exhibited high mean peak concentrations during ECMO. WHAT IS NEW AND CONCLUSION The impact of ECMO on PK varies among drugs in adult patients, and there is no consistent correlation between the effects observed in adult and infant studies. This review suggested that doses of imipenem, oseltamivir, rifampicin and voriconazole should be adjusted and therapeutic drug monitoring is needed when ECMO is used in adult patients. In the future, large PK trials in adults on ECMO are needed to provide optimal dosing guidelines. A PK/PD modelling approach will be useful for determining the precise impact of ECMO and other factors that contribute to PK changes for each drug. Finally, it is important to develop dosing guidelines based on PK/PD modelling studies that can be used in clinical practice.
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Affiliation(s)
- J Hahn
- Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, Korea
| | - J H Choi
- Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, Korea
| | - M J Chang
- Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, Korea.,Department of Pharmaceutical Medicine and Regulatory Science, College of Medicine and Pharmacy, Yonsei University, Incheon, Korea
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29
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Abstract
Extracorporeal membrane oxygenation (ECMO) or extracorporeal life support (ECLS) is a form of heart lung bypass that is used to support neonates, pediatrics, and adult patients with cardiorespiratory failure for days or weeks till organ recovery or transplantation. Venoarterial (VA) and venovenous (VV) ECLS are the most common modes of support. ECLS circuit components and monitoring have been evolving over the last 40 years. The technology is safer, simpler, and more durable with fewer complications. The use of neonatal respiratory ECLS use has been declining over the last two decades, while adult respiratory ECLS is growing especially since the H1N1 influenza pandemic in 2009. This review provides an overview of ECLS evolution over the last four decades, its use in neonatal, pediatric and adults, description of basic principles, circuit components, complications, and outcomes as well as a quick look into the future.
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30
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Dzierba AL, Abrams D, Brodie D. Medicating patients during extracorporeal membrane oxygenation: the evidence is building. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2017; 21:66. [PMID: 28320466 PMCID: PMC5359850 DOI: 10.1186/s13054-017-1644-y] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2017. Other selected articles can be found online at http://ccforum.com/series/annualupdate2017 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901 .
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Affiliation(s)
- Amy L Dzierba
- Columbia University Medical Center, Department of Pharmacy, NewYork-Presbyterian Hospital, New York, NY, 10032, USA.
| | - Darryl Abrams
- Division of Pulmonary, Columbia University College of Physicians and Surgeons, Allergy and Critical Care, 622 West 168th Street, New York, NY, 10032, USA
| | - Daniel Brodie
- Division of Pulmonary, Columbia University College of Physicians and Surgeons, Allergy and Critical Care, 622 West 168th Street, New York, NY, 10032, USA
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31
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Ha MA, Sieg AC. Evaluation of Altered Drug Pharmacokinetics in Critically Ill Adults Receiving Extracorporeal Membrane Oxygenation. Pharmacotherapy 2017; 37:221-235. [DOI: 10.1002/phar.1882] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Michael A. Ha
- Surgical Intensive Care Unit; UMass Memorial Medical Center; Worcester Massachusetts
| | - Adam C. Sieg
- Heart Transplant/MCS; Gill Heart Institute; University of Kentucky; Lexington Kentucky
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32
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Burcham PK, Rozycki AJ, Abel EE. Considerations for analgosedation and antithrombotic management during extracorporeal life support. ANNALS OF TRANSLATIONAL MEDICINE 2017; 5:69. [PMID: 28275614 PMCID: PMC5337214 DOI: 10.21037/atm.2016.11.45] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Accepted: 10/17/2016] [Indexed: 11/08/2023]
Abstract
Despite the immense growth in extracorporeal life support (ECLS) technology and experience, opportunity remains to better characterize the pharmacotherapeutic considerations during ECLS. Analgosedation can be particularly challenging in the ECLS population due to in drug-circuit interactions that may lead to decreased systemic concentrations and pharmacodynamic effect. ECLS also requires the use of antithrombotic agents to mitigate the prothrombotic state created by the artificial surface in the ECLS circuit. There are a number of coagulation monitoring tests available. However, optimal monitoring and management in ECLS has not been established. Heparin continues to be the anticoagulant of choice for most ECLS centers, however, there is growing interest in the use of parenteral direct thrombin inhibitors (DTI) in this population. Advances in understanding pharmacotherapeutic management have not kept up with the technological advances in this population. More investigation is warranted to gain a greater understanding of the pharmacotherapeutic implications, facilitate standardized evidence-based practices, and improve patient centered outcomes.
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Affiliation(s)
- Pamela K Burcham
- Department of Pharmacy, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, USA
| | - Alan J Rozycki
- Department of Pharmacy, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, USA
| | - Erik E Abel
- Department of Pharmacy, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, USA
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33
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Anton-Martin P, Modem V, Taylor D, Potter D, Darnell-Bowens C. A retrospective study of sedation and analgesic requirements of pediatric patients on extracorporeal membrane oxygenation (ECMO) from a single-center experience. Perfusion 2016; 32:183-191. [PMID: 27729502 DOI: 10.1177/0267659116670483] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
INTRODUCTION The purpose of this study is to describe the sedative and analgesic requirements identifying factors associated with medication escalation in neonates and children supported on ECMO. METHOD Observational retrospective cohort study in a tertiary pediatric intensive care unit from June 2009 to June 2013. RESULTS One hundred and sixty patients were included in the study. Fentanyl and midazolam were the first line agents used while on ECMO. Higher opiate requirements were associated with younger age (p=0.01), thoracic cannulation (p=0.002), the use of dexmedetomidine (p=0.007) and prolonged use of muscle relaxants (p=0.03). Higher benzodiazepine requirements were associated with younger age (p=0.01), respiratory failure (p=0.02) and the use of second line agents (p=0.002). One third of the patients required second line agents as adjuvants for comfort without a decrease in opiate and/or benzodiazepine requirements. CONCLUSIONS Providing comfort to subpopulations of pediatric ECMO patients seems to be more challenging. The use of second line agents did not improve comfort in our cohort. Prospective studies are required to optimize analgesia and sedation management in children on ECMO.
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Affiliation(s)
- Pilar Anton-Martin
- 1 Department of Pediatrics, Critical Care Division, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Vinai Modem
- 2 Department of Pediatrics, Critical Care Division, University of Texas Health Science Center at Houston, Texas, USA
| | - Donna Taylor
- 3 Department of Respiratory Therapy, Children's Health Dallas, Dallas, Texas, USA
| | - Donald Potter
- 3 Department of Respiratory Therapy, Children's Health Dallas, Dallas, Texas, USA
| | - Cindy Darnell-Bowens
- 1 Department of Pediatrics, Critical Care Division, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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34
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DeGrado JR, Hohlfelder B, Ritchie BM, Anger KE, Reardon DP, Weinhouse GL. Evaluation of sedatives, analgesics, and neuromuscular blocking agents in adults receiving extracorporeal membrane oxygenation. J Crit Care 2016; 37:1-6. [PMID: 27610584 DOI: 10.1016/j.jcrc.2016.07.020] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Revised: 07/09/2016] [Accepted: 07/27/2016] [Indexed: 10/21/2022]
Abstract
PURPOSE The objective of this study was to evaluate the use of sedative, analgesic, and neuromuscular blocking agents (NMBAs) in patients undergoing extracorporeal membrane oxygenation (ECMO) support. MATERIALS AND METHODS This was a 2-year, prospective, observational study of adult intensive care unit patients on ECMO support for more than 48hours. RESULTS We analyzed 32 patients, including 15 receiving VA (venoarterial) ECMO and 17 VV (venovenous) ECMO. The median daily dose of benzodiazepines (midazolam equivalents) was 24mg, and the median daily dose of opioids (fentanyl equivalents) was 3875 μg. There was a moderate negative correlation between the day of ECMO and the median daily benzodiazepine dose (r=-0.5515) and a very weak negative correlation for the median daily opioid dose (r=-0.0053). On average, patients were sedated to Richmond Agitation Sedation Scale scores between 0 and -1. Continuous infusions of opioids, benzodiazepines, propofol, dexmedetomidine, and NMBAs were administered on 404 (85.1%), 199 (41.9%), 95 (20%), 32 (6.7%), and 60 (12.6%) ECMO days, respectively. Patients in the VA arm received a continuous infusion opioid (96.4% vs 81.6% days; P<.001) and benzodiazepine (58.2% vs 37.0% days; P<.001) more frequently. CONCLUSIONS Patients received relatively low doses of sedatives and analgesics while at a light level of sedation on average. Patients rarely required neuromuscular blockade.
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Affiliation(s)
- Jeremy R DeGrado
- Department of Pharmacy, Brigham and Women's Hospital, Boston, MA.
| | | | | | - Kevin E Anger
- Department of Pharmacy, Brigham and Women's Hospital, Boston, MA
| | - David P Reardon
- Department of Pharmacy, Yale-New Haven Hospital, New Haven, CT
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35
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Himebauch AS, Kilbaugh TJ, Zuppa AF. Pharmacotherapy during pediatric extracorporeal membrane oxygenation: a review. Expert Opin Drug Metab Toxicol 2016; 12:1133-42. [PMID: 27322360 DOI: 10.1080/17425255.2016.1201066] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Pediatric critical illness and associated alterations in organ function can change drug pharmacokinetics (PK). Extracorporeal membrane oxygenation (ECMO), a life-saving therapy for severe cardiac and/or respiratory failure, causes additional PK alterations that affect drug disposition. AREAS COVERED The purposes of this review are to discuss the PK changes that occur during ECMO, the associated therapeutic implications, and to review PK literature relevant to pediatric ECMO. We discuss various classes of drugs commonly used for pediatric patients on ECMO, including sedatives, analgesics, antimicrobials and cardiovascular drugs. Finally, we discuss future areas of research and recommend strategies for future pediatric ECMO pharmacologic investigations. EXPERT OPINION Clinicians caring for pediatric patients treated with ECMO must have an understanding of PK alterations that could lead to either therapeutic failures or increased drug toxicity during this life-saving therapy. Limited data currently exist for optimal drug dosing in pediatric populations who are treated with ECMO. While there are clear challenges to conducting and analyzing data associated with clinical pharmacokinetic-pharmacodynamic studies of children on ECMO, we present techniques to address these challenges. Improved understanding of the physiology and drug disposition during ECMO combined with PK-PD modeling will allow for more adaptable and individualized dosing schemes.
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Affiliation(s)
- Adam S Himebauch
- a Department of Anesthesiology and Critical Care Medicine, Perelman School of Medicine , University of Pennsylvania, The Children's Hospital of Philadelphia , Philadelphia , PA , USA.,b Center for Clinical Pharmacology , The Children's Hospital of Philadelphia , Philadelphia , PA , USA
| | - Todd J Kilbaugh
- a Department of Anesthesiology and Critical Care Medicine, Perelman School of Medicine , University of Pennsylvania, The Children's Hospital of Philadelphia , Philadelphia , PA , USA
| | - Athena F Zuppa
- a Department of Anesthesiology and Critical Care Medicine, Perelman School of Medicine , University of Pennsylvania, The Children's Hospital of Philadelphia , Philadelphia , PA , USA.,b Center for Clinical Pharmacology , The Children's Hospital of Philadelphia , Philadelphia , PA , USA
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36
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Nigoghossian CD, Dzierba AL, Etheridge J, Roberts R, Muir J, Brodie D, Schumaker G, Bacchetta M, Ruthazer R, Devlin JW. Effect of Extracorporeal Membrane Oxygenation Use on Sedative Requirements in Patients with Severe Acute Respiratory Distress Syndrome. Pharmacotherapy 2016; 36:607-16. [DOI: 10.1002/phar.1760] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
| | - Amy L. Dzierba
- Department of Pharmacy; NewYork-Presbyterian Hospital; New York New York
| | - Joshua Etheridge
- School of Pharmacy; Northeastern University; Boston Massachusetts
| | - Russel Roberts
- Department of Pharmacy; Tufts Medical Center; Boston Massachusetts
| | - Justin Muir
- Department of Pharmacy; NewYork-Presbyterian Hospital; New York New York
| | - Daniel Brodie
- Division of Pulmonary and Critical Care Medicine; Columbia College of Physicians and Surgeons; New York New York
| | - Greg Schumaker
- Division of Pulmonary; Critical Care Medicine and Sleep Medicine; Tufts Medical Center; Boston Massachusetts
| | - Matthew Bacchetta
- Division of Pulmonary and Critical Care Medicine; Columbia College of Physicians and Surgeons; New York New York
| | - Robin Ruthazer
- Biostatistical Research Center; Tufts Medical Center; Boston Massachusetts
| | - John W. Devlin
- School of Pharmacy; Northeastern University; Boston Massachusetts
- Division of Pulmonary; Critical Care Medicine and Sleep Medicine; Tufts Medical Center; Boston Massachusetts
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37
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Vet NJ, Kleiber N, Ista E, de Hoog M, de Wildt SN. Sedation in Critically Ill Children with Respiratory Failure. Front Pediatr 2016; 4:89. [PMID: 27606309 PMCID: PMC4995367 DOI: 10.3389/fped.2016.00089] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2016] [Accepted: 08/09/2016] [Indexed: 01/08/2023] Open
Abstract
This article discusses the rationale of sedation in respiratory failure, sedation goals, how to assess the need for sedation as well as effectiveness of interventions in critically ill children, with validated observational sedation scales. The drugs and non-pharmacological approaches used for optimal sedation in ventilated children are reviewed, and specifically the rationale for drug selection, including short- and long-term efficacy and safety aspects of the selected drugs. The specific pharmacokinetic and pharmacodynamic aspects of sedative drugs in the critically ill child and consequences for dosing are presented. Furthermore, we discuss different sedation strategies and their adverse events, such as iatrogenic withdrawal syndrome and delirium. These principles can guide clinicians in the choice of sedative drugs in pediatric respiratory failure.
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Affiliation(s)
- Nienke J Vet
- Intensive Care, Erasmus MC - Sophia Children's Hospital, Rotterdam, Netherlands; Department of Pediatrics, Erasmus MC - Sophia Children's Hospital, Rotterdam, Netherlands
| | - Niina Kleiber
- Intensive Care, Erasmus MC - Sophia Children's Hospital, Rotterdam, Netherlands; Department of Pediatric Surgery, Erasmus MC - Sophia Children's Hospital, Rotterdam, Netherlands; Department of Pediatrics, CHU Sainte-Justine, Montreal, QC, Canada
| | - Erwin Ista
- Intensive Care, Erasmus MC - Sophia Children's Hospital, Rotterdam, Netherlands; Department of Pediatrics, Erasmus MC - Sophia Children's Hospital, Rotterdam, Netherlands
| | - Matthijs de Hoog
- Intensive Care, Erasmus MC - Sophia Children's Hospital, Rotterdam, Netherlands; Department of Pediatrics, Erasmus MC - Sophia Children's Hospital, Rotterdam, Netherlands
| | - Saskia N de Wildt
- Intensive Care, Erasmus MC - Sophia Children's Hospital, Rotterdam, Netherlands; Department of Pediatric Surgery, Erasmus MC - Sophia Children's Hospital, Rotterdam, Netherlands; Department of Pharmacology and Toxicology, Radboud University, Nijmegen, Netherlands
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Erstad BL. Designing drug regimens for special intensive care unit populations. World J Crit Care Med 2015; 4:139-151. [PMID: 25938029 PMCID: PMC4411565 DOI: 10.5492/wjccm.v4.i2.139] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Revised: 09/06/2014] [Accepted: 02/09/2015] [Indexed: 02/06/2023] Open
Abstract
This review is intended to help clinicians design drug regimens for special populations of critically ill patients with extremes of body size, habitus and composition that make drug choice or dosing particularly challenging due to the lack of high-level evidence on which to make well-informed clinical decisions. The data sources included a literature search of MEDLINE and EMBASE with reviews of reference lists of retrieved articles. Abstracts of original research investigations and review papers were reviewed for their relevance to drug choice or dosing in the following special critically ill populations: patients with more severe forms of bodyweight or height, patients with amputations or missing limbs, pregnant patients, and patients undergoing extracorporeal membrane oxygenation or plasma exchange. Relevant papers were retrieved and evaluated, and their associated reference lists were reviewed for citations that may have been missed through the electronic search strategy. Relevant original research investigations and review papers that could be used to formulate general principles for drug choice or dosing in special populations of critically ill patients were extracted. Randomized studies with clinically relevant endpoints were not available for performing quantitative analyses. Critically ill patients with changes in body size, habitus and composition require special consideration when designing medication regimens, but there is a paucity of literature on which to make drug-specific, high-level evidence-based recommendations. Based on the evidence that is available, general recommendations are provided for drug choice or dosing in special critically ill populations.
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Shekar K, Roberts JA, Mcdonald CI, Ghassabian S, Anstey C, Wallis SC, Mullany DV, Fung YL, Fraser JF. Protein-bound drugs are prone to sequestration in the extracorporeal membrane oxygenation circuit: results from an ex vivo study. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2015; 19:164. [PMID: 25888449 PMCID: PMC4407324 DOI: 10.1186/s13054-015-0891-z] [Citation(s) in RCA: 177] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Accepted: 03/19/2015] [Indexed: 11/10/2022]
Abstract
Introduction Vital drugs may be degraded or sequestered in extracorporeal membrane oxygenation (ECMO) circuits, with lipophilic drugs considered to be particularly vulnerable. However, the circuit effects on protein-bound drugs have not been fully elucidated. The aim of this experimental study was to investigate the influence of plasma protein binding on drug disposition in ex vivo ECMO circuits. Methods Four identical ECMO circuits comprising centrifugal pumps and polymethylpentene oxygenators and were used. The circuits were primed with crystalloid, albumin and fresh human whole blood and maintained at a physiological pH and temperature for 24 hours. After baseline sampling, known quantities of study drugs (ceftriaxone, ciprofloxacin, linezolid, fluconazole, caspofungin and thiopentone) were injected into the circuit to achieve therapeutic concentrations. Equivalent doses of these drugs were also injected into four polypropylene jars containing fresh human whole blood for drug stability testing. Serial blood samples were collected from the controls and the ECMO circuits over 24 hours, and the concentrations of the study drugs were quantified using validated chromatographic assays. A regression model was constructed to examine the relationship between circuit drug recovery as the dependent variable and protein binding and partition coefficient (a measure of lipophilicity) as explanatory variables. Results Four hundred eighty samples were analysed. There was no significant loss of any study drugs in the controls over 24 hours. The average drug recoveries from the ECMO circuits at 24 hours were as follows: ciprofloxacin 96%, linezolid 91%, fluconazole 91%, ceftriaxone 80%, caspofungin 56% and thiopentone 12%. There was a significant reduction of ceftriaxone (P = 0.01), caspofungin (P = 0.01) and thiopentone (P = 0.008) concentrations in the ECMO circuit at 24 hours. Both protein binding and partition coefficient were highly significant, with the model possessing a high coefficient of determination (R2 = 0.88, P <0.001). Conclusions Recovery of the highly protein-bound drugs ceftriaxone, caspofungin and thiopentone was significantly lower in the ECMO circuits at 24 hours. For drugs with similar lipophilicity, the extent of protein binding may determine circuit drug loss. Future clinical population pharmacokinetic studies should initially be focused on drugs with greater lipophilicity and protein binding, and therapeutic drug monitoring should be strongly considered with the use of such drugs.
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Affiliation(s)
- Kiran Shekar
- Critical Care Research Group, Adult Intensive Care Services, The Prince Charles Hospital and The University of Queensland, Rode Road, Chermside, 4032, Australia.
| | - Jason A Roberts
- Burns Trauma and Critical Care Research Centre, The University of Queensland, Herston, Queensland, Chermside, 4029, Australia.
| | - Charles I Mcdonald
- Critical Care Research Group, Adult Intensive Care Services, The Prince Charles Hospital and The University of Queensland, Rode Road, Chermside, 4032, Australia.
| | - Sussan Ghassabian
- Centre for Integrated Preclinical Drug Development, The University of Queensland, Herston, Queensland, 4029, Australia.
| | - Chris Anstey
- Department of Critical Care Medicine, Nambour General Hospital, Nambour, 4560, Queensland, Australia.
| | - Steven C Wallis
- Burns Trauma and Critical Care Research Centre, The University of Queensland, Herston, Queensland, Chermside, 4029, Australia.
| | - Daniel V Mullany
- Critical Care Research Group, Adult Intensive Care Services, The Prince Charles Hospital and The University of Queensland, Rode Road, Chermside, 4032, Australia.
| | - Yoke L Fung
- Inflammation and Healing Research Cluster, School of Health and Sport Sciences, Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Sippy Downs, 4556, Australia.
| | - John F Fraser
- Critical Care Research Group, Adult Intensive Care Services, The Prince Charles Hospital and The University of Queensland, Rode Road, Chermside, 4032, Australia.
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Harthan AA, Buckley KW, Heger ML, Fortuna RS, Mays K. Medication adsorption into contemporary extracorporeal membrane oxygenator circuits. J Pediatr Pharmacol Ther 2015; 19:288-95. [PMID: 25762874 DOI: 10.5863/1551-6776-19.4.288] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
OBJECTIVE This study was conducted to evaluate the amount of medication adsorbed into extracorporeal membrane oxygenation (ECMO) circuits with a polymethylpentane membrane oxygenator and heparin-coated polyvinyl chloride tubing. METHODS An ECMO circuit with the aforementioned components was set up ex vivo and primed with expired blood. Midazolam, lorazepam, morphine, and fentanyl were administered to the circuit. Fifteen minutes after medication administration, 60 mL of blood were removed and stored in a 60-mL syringe to serve as a control. Medication levels were drawn from the ECMO circuit (test) and control syringe (control) 15 minutes, 24 hours, and 48 hours after the medications were administered. ECMO circuit medication levels were compared to their corresponding syringe control medication levels. Descriptive statistics were used to determine the percentage of medication remaining in the blood and compare it to the control value. RESULTS Except for morphine, there was a large decline in medication levels over the 48-hour period. Compared to control values, 17.2% of midazolam, 41.3% of lorazepam, 32.6% of fentanyl, and 102% of morphine remained in the ECMO circuit. CONCLUSION Despite the use of newer components in ECMO circuits, a large quantity of medication is adsorbed into the ECMO circuit. Midazolam, lorazepam, and fentanyl all showed reductions in medication levels greater than 50%. Morphine may have advantages for patients on ECMO, as its concentration does not appear to be affected.
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Affiliation(s)
- Aaron A Harthan
- Pharmacy Department, Children's Hospital of Illinois, Peoria, Illinois
| | - Klayton W Buckley
- Perfusion Department, Children's Hospital of Illinois, Peoria, Illinois
| | - Margaret L Heger
- Pharmacy Department, Children's Hospital of Illinois, Peoria, Illinois
| | - Randall S Fortuna
- Department of Cardiothoracic Surgery, Children's Hospital of Illinois, Peoria, Illinois
| | - Kyle Mays
- Pharmacy Department, Children's Hospital of Illinois, Peoria, Illinois
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Donadello K, Antonucci E, Cristallini S, Roberts JA, Beumier M, Scolletta S, Jacobs F, Rondelet B, de Backer D, Vincent JL, Taccone FS. β-Lactam pharmacokinetics during extracorporeal membrane oxygenation therapy: A case-control study. Int J Antimicrob Agents 2014; 45:278-82. [PMID: 25542059 DOI: 10.1016/j.ijantimicag.2014.11.005] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Accepted: 11/03/2014] [Indexed: 11/19/2022]
Abstract
Most adult patients receiving extracorporeal membrane oxygenation (ECMO) require antibiotic therapy, however the pharmacokinetics of β-lactams have not been well studied in these conditions. In this study, data from all patients receiving ECMO support and meropenem (MEM) or piperacillin/tazobactam (TZP) were reviewed. Drug concentrations were measured 2h after the start of a 30-min infusion and just before the subsequent dose. Therapeutic drug monitoring (TDM) results in ECMO patients were matched with those in non-ECMO patients for (i) drug regimen, (ii) renal function, (iii) total body weight, (iv) severity of organ dysfunction and (v) age. Drug concentrations were considered adequate if they remained 4-8× the clinical MIC breakpoint for Pseudomonas aeruginosa for 50% (TZP) or 40% (MEM) of the dosing interval. A total of 41 TDM results (27 MEM; 14 TZP) were obtained in 26 ECMO patients, with 41 matched controls. There were no significant differences in serum concentrations or pharmacokinetic parameters between ECMO and non-ECMO patients, including Vd [0.38 (0.27-0.68) vs. 0.46 (0.33-0.79)L/kg; P=0.37], half-life [2.6 (1.8-4.4) vs. 2.9 (1.7-3.7)h; P=0.96] and clearance [132 (66-200) vs. 141 (93-197)mL/min; P=0.52]. The proportion of insufficient (13/41 vs. 12/41), adequate (15/41 vs. 19/41) and excessive (13/41 vs. 10/41) drug concentrations was similar in ECMO and non-ECMO patients. Achievement of target concentrations of these β-lactams was poor in ECMO and non-ECMO patients. The influence of ECMO on MEM and TZP pharmacokinetics does not appear to be significant.
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Affiliation(s)
- Katia Donadello
- Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070 Brussels, Belgium
| | - Elio Antonucci
- Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070 Brussels, Belgium
| | - Stefano Cristallini
- Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070 Brussels, Belgium
| | - Jason A Roberts
- Burns, Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, QLD, Australia; Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia
| | - Marjorie Beumier
- Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070 Brussels, Belgium
| | - Sabino Scolletta
- Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070 Brussels, Belgium
| | - Frédérique Jacobs
- Department of Infectious Diseases, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070 Brussels, Belgium
| | - Benoit Rondelet
- Department of Thoracic Surgery, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070 Brussels, Belgium
| | - Daniel de Backer
- Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070 Brussels, Belgium
| | - Jean-Louis Vincent
- Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070 Brussels, Belgium
| | - Fabio Silvio Taccone
- Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070 Brussels, Belgium.
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Abstract
As a standard of care for preterm/term newborns effective pain management may improve their clinical and neurodevelopmental outcomes. Neonatal pain is assessed using context-specific, validated, and objective pain methods, despite the limitations of currently available tools. Therapeutic approaches reducing invasive procedures and using pharmacologic, behavioral, or environmental measures are used to manage neonatal pain. Nonpharmacologic approaches like kangaroo care, facilitated tucking, non-nutritive sucking, sucrose, and others can be used for procedural pain or adjunctive therapy. Local/topical anesthetics, opioids, NSAIDs/acetaminophen and other sedative/anesthetic agents can be incorporated into NICU protocols for managing moderate/severe pain or distress in all newborns.
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Hites M, Dell'Anna AM, Scolletta S, Taccone FS. The challenges of multiple organ dysfunction syndrome and extra-corporeal circuits for drug delivery in critically ill patients. Adv Drug Deliv Rev 2014; 77:12-21. [PMID: 24842474 DOI: 10.1016/j.addr.2014.05.007] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 04/01/2014] [Accepted: 05/07/2014] [Indexed: 12/25/2022]
Abstract
The multiple organ dysfunction syndrome (MODS) is characterized by more than one organ system failing, especially during critical illness. MODS is the leading cause of morbidity and mortality in current ICU practice; moreover, multiple organ dysfunction, especially liver and kidneys, may significantly affect the pharmacokinetics (PKs) of different drugs that are currently administered in critically ill patients. These PK alterations may either result in insufficient drug concentrations to achieve the desired effects or in blood and tissue accumulation, with the development of serious adverse events. The use of extra-corporeal circuits, such as extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT), may further contribute to PKs changes in this patients' population. In this review, we have described the main PK changes occurring in all these conditions and how drug concentrations may potentially be affected. The lack of prospective studies on large cohorts of patients makes impossible any specific recommendation on drug regimen adjustment in ICU patients. Nevertheless, the clinicians should be aware of these abnormalities in order to better understand some unexpected therapeutic issues occurring in such patients.
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Affiliation(s)
- Maya Hites
- Department of Infectious Diseases, Hopital Erasme - Université Libre de Bruxelles, Route de Lennik, 808, 1070 Brussels Belgium
| | - Antonio Maria Dell'Anna
- Department of Intensive Care, Hopital Erasme - Université Libre de Bruxelles, Route de Lennik, 808, 1070 Brussels Belgium
| | - Sabino Scolletta
- Department of Anesthesia and Intensive Care, University of Siena, Viale Bracci 1, 53100 Siena, Italy
| | - Fabio Silvio Taccone
- Department of Intensive Care, Hopital Erasme - Université Libre de Bruxelles, Route de Lennik, 808, 1070 Brussels Belgium.
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Gillogly A, Kilbourn C, Waldvogel J, Martin J, Annich G, Wagner D. In vitro clearance of intravenous acetaminophen in extracorporeal membrane oxygenation. Perfusion 2012. [PMID: 23201817 DOI: 10.1177/0267659112467825] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Extracorporeal membrane oxygenation (ECMO) is a life support system used as a bridge to transplantation in critically ill patients who suffer from acute respiratory or cardiac failure with resultant hypoxemia and tissue hypoxia. This is not amendable to conventional support intervention. Previous studies have shown significant drug losses in the components of an ECMO circuit, leading to decreased plasma drug levels. An in vitro study was conducted to determine: (1) changes in intravenous acetaminophen levels over time and (2) changes in concentration observed between different sites of the ECMO circuit. A single bolus dose of intravenous (IV) acetaminophen was injected into a standard blood-primed ECMO circuit. Plasma drug concentrations in the circuit were then measured at specific time points at three different locations to determine concentrations of the drug at time 0, 15, 30, 60, 240 and 360 minutes. The three samples were drawn pre- and post-membrane oxygenator and the polyvinyl chloride (PVC) tubing. A second bolus dose was administered 24 hours after the first in order to compare "new" and "old" circuits. This entire process was repeated a total of three times. The results show that acetaminophen concentrations do not change significantly over time, with consistent levels seen in both new and old circuits (N=9). Average old circuit concentrations were approximately two times greater than the average new circuit concentrations after the circuit was re-dosed at 24 hours. Drug sequestration in the circuit was not significant in any of the three sites measured. It appears that, while acetaminophen levels remain relatively constant over a six hour period, dosing adjustments may be required for use in a circuit beyond the initial 24 hour period, depending on physiologic clearance of the drug. Assuming a six-hour dosing interval, levels should remain constant.
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Affiliation(s)
- A Gillogly
- College of Pharmacy, University of Michigan, Ann Arbor, MI, USA
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Shekar K, Roberts JA, Mcdonald CI, Fisquet S, Barnett AG, Mullany DV, Ghassabian S, Wallis SC, Fung YL, Smith MT, Fraser JF. Sequestration of drugs in the circuit may lead to therapeutic failure during extracorporeal membrane oxygenation. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2012; 16:R194. [PMID: 23068416 PMCID: PMC3682296 DOI: 10.1186/cc11679] [Citation(s) in RCA: 207] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2012] [Accepted: 09/18/2012] [Indexed: 01/19/2023]
Abstract
Introduction Extracorporeal membrane oxygenation (ECMO) is a supportive therapy, with its success dependent on effective drug therapy that reverses the pathology and/or normalizes physiology. However, the circuit that sustains life can also sequester life-saving drugs, thereby compromising the role of ECMO as a temporary support device. This ex vivo study was designed to determine the degree of sequestration of commonly used antibiotics, sedatives and analgesics in ECMO circuits. Methods Four identical ECMO circuits were set up as per the standard protocol for adult patients on ECMO. The circuits were primed with crystalloid and albumin, followed by fresh human whole blood, and were maintained at a physiological pH and temperature for 24 hours. After baseline sampling, fentanyl, morphine, midazolam, meropenem and vancomycin were injected into the circuit at therapeutic concentrations. Equivalent doses of these drugs were also injected into four polyvinylchloride jars containing fresh human whole blood for drug stability testing. Serial blood samples were collected from the ECMO circuits and the controls over 24 hours and the concentrations of the study drugs were quantified using validated assays. Results Four hundred samples were analyzed. All study drugs, except meropenem, were chemically stable. The average drug recoveries from the ECMO circuits and the controls at 24 hours relative to baseline, respectively, were fentanyl 3% and 82%, morphine 103% and 97%, midazolam 13% and 100%, meropenem 20% and 42%, vancomycin 90% and 99%. There was a significant loss of fentanyl (p = 0.0005), midazolam (p = 0.01) and meropenem (p = 0.006) in the ECMO circuit at 24 hours. There was no significant circuit loss of vancomycin at 24 hours (p = 0.26). Conclusions Sequestration of drugs in the circuit has implications on both the choice and dosing of some drugs prescribed during ECMO. Sequestration of lipophilic drugs such as fentanyl and midazolam appears significant and may in part explain the increased dosing requirements of these drugs during ECMO. Meropenem sequestration is also problematic and these data support a more frequent administration during ECMO.
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Shekar K, Roberts JA, Mullany DV, Corley A, Fisquet S, Bull TN, Barnett AG, Fraser JF. Increased sedation requirements in patients receiving extracorporeal membrane oxygenation for respiratory and cardiorespiratory failure. Anaesth Intensive Care 2012; 40:648-55. [PMID: 22813493 DOI: 10.1177/0310057x1204000411] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Critically ill patients receiving extracorporeal membrane oxygenation (ECMO) are often noted to have increased sedation requirements. However, data related to sedation in this complex group of patients is limited. The aim of our study was to characterise the sedation requirements in adult patients receiving ECMO for cardiorespiratory failure. A retrospective chart review was performed to collect sedation data for 30 consecutive patients who received venovenous or venoarterial ECMO between April 2009 and March 2011. To test for a difference in doses over time we used a regression model. The dose of midazolam received on ECMO support increased by an average of 18 mg per day (95% confidence interval 8, 29 mg, P=0.001), while the dose of morphine increased by 29 mg per day (95% confidence interval 4, 53 mg, P=0.021) The venovenous group received a daily midazolam dose that was 157 mg higher than the venoarterial group (95% confidence interval 53, 261 mg, P=0.005). We did not observe any significant increase in fentanyl doses over time (95% confidence interval 1269, 4337 µg, P=0.94). There is a significant increase in dose requirement for morphine and midazolam during ECMO. Patients on venovenous ECMO received higher sedative doses as compared to patients on venoarterial ECMO. Future research should focus on mechanisms behind these changes and also identify drugs that are most suitable for sedation during ECMO.
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Affiliation(s)
- K Shekar
- Critical Care Research Group, Adult Intensive Care Unit, The Prince Charles Hospital, Brisbane, Queensland, Australia.
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Wagner D, Pasko D, Phillips K, Waldvogel J, Annich G. In vitro clearance of dexmedetomidine in extracorporeal membrane oxygenation. Perfusion 2012; 28:40-6. [DOI: 10.1177/0267659112456894] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Dexmedetomidine (DMET) is a useful agent for sedation, both alone and in combination with other agents, in critically ill patients, including those on extracorporeal membrane oxygenation (ECMO) therapy. The drug is a clonidine-like derivative with an 8-fold greater specificity for the alpha 2-receptor while maintaining respiratory and cardiovascular stability. An in vitro ECMO circuit was used to study the effects of both “new” and “old” membrane oxygenators on the clearance of dexmedetomidine over the course of 24 hours. Once primed, the circuit was dosed with 840 μg of dexmedetomidine for a final concentration of 0.9 μg/ml. Serial samples, both pre- and post-oxygenator, were taken at 5, 60, 360, and 1440 minutes. Concentrations of the drug were expressed as a percentage of the original concentration remaining at each time point, both for new and old circuits. The new circuits were run at a standard flow for 24 hours, after which time the circuit was considered old and re-dosed with dexmedetomidine and the trial repeated. Results show that dexmedetomidine losses occur early in the circuits and then continue to decline. Initial losses in the first hour were 11+-65% and 59-73% pre- and post-oxygenator in the new circuit and 36-50% and 42-72% in the old circuit. The clearance of the drug through the membrane oxygenator exhibits no statistical difference between pre and post or new and old circuits. Dexmedetomidine can be expected to exhibit concentration changes during ECMO therapy. This effect appears to be more related to adsorption to the polyvinyl chloride (PVC) tubing rather than the membrane oxygenator. Dosage adjustments during dexmedetomidine administration during ECMO therapy may be warranted in order to maintain adequate serum concentrations and, hence, the desired degree of sedation.*(Lack of equilibrium)
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Affiliation(s)
- D Wagner
- Pharmacy/Anesthesiology, University of Michigan Hospitals and Health Systems, Ann Arbor, MI, USA
| | - D Pasko
- C&W Administration, University of Michigan Hospitals and Health Centers, Ann Arbor, MI, USA
| | - K Phillips
- Geriatric Research Education and Clinical Center, VA Ann Arbor Healthcare System, Ann Arbor, MI, USA
| | - J Waldvogel
- Extracorporeal Life Support, University of Michigan Hospitals and Health Centers, Ann Arbor, MI, USA
| | - G Annich
- Pediatric Critical Care Medicine, University of Michigan Hospitals and Health Centers, Ann Arbor, MI, USA
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Shekar K, Fraser JF, Smith MT, Roberts JA. Pharmacokinetic changes in patients receiving extracorporeal membrane oxygenation. J Crit Care 2012; 27:741.e9-18. [PMID: 22520488 DOI: 10.1016/j.jcrc.2012.02.013] [Citation(s) in RCA: 207] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2011] [Revised: 02/13/2012] [Accepted: 02/20/2012] [Indexed: 10/28/2022]
Abstract
Extracorporeal membrane oxygenation (ECMO) is a form of prolonged cardiopulmonary bypass used to temporarily sustain cardiac and/or respiratory function in critically ill patients. Extracorporeal membrane oxygenation further complicates the management of critically ill patients who already have profound physiologic derangements with consequent altered pharmacokinetics. The purpose of this study is to identify and critically review the published literature describing pharmacokinetics in the presence of ECMO. This review revealed a dearth of data describing pharmacokinetics during ECMO in critically ill adults, with most of the available data originating in neonates. Of concern, the present data indicate substantial variability and a lack of predictability in drug behavior in the presence of ECMO. The most common mechanisms by which ECMO affects pharmacokinetics are sequestration in the circuit, increased volume of distribution, and decreased drug elimination. While lipophilic drugs and highly protein-bound drugs (eg, voriconazole and fentanyl) are significantly sequestered in the circuit, hydrophilic drugs (eg, β-lactam antibiotics, glycopeptides) are significantly affected by hemodilution and other pathophysiologic changes that occur during ECMO. Although the published literature is insufficient to make any meaningful recommendations for adjusting therapy for drug dosing, this review systematically describes the available data enabling clinicians to make conclusions based on available data. Furthermore, this review serves to highlight the need for well-designed and conducted clinical and laboratory-based studies to provide the data from which robust dosing guidance can be developed to improve clinical outcomes in this most unwell cohort of patients.
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Affiliation(s)
- Kiran Shekar
- Critical Care Research Group, The Prince Charles Hospital and The University of Queensland, Brisbane, Australia.
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Abstract
Painful procedures in the neonatal intensive care unit are common, undertreated, and lead to adverse consequences. A stepwise approach to treatment should include pain recognition, assessment, and treatment, starting with nonpharmacologic and progressing to pharmacologic methods for increasing pain. The most common nonpharmacologic techniques include nonnutritive sucking with and without sucrose, kangaroo care, swaddling, and massage therapy. Drugs used to treat neonatal pain include the opiates, benzodiazepines, barbiturates, ketamine, propofol, acetaminophen, and local and topical anesthetics. The indications, advantages, and disadvantages of the commonly used analgesic drugs are discussed. Guidance and references for drugs and dosing for specific neonatal procedures are provided.
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Affiliation(s)
- R. Whit Hall
- Division of Neonatology, University of Arkansas for Medical Sciences, Slot 512B, 4301 West Markham, Little Rock, AR 72205, USA,
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