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Pharmacokinetics Alterations in Critically Ill Pediatric Patients on Extracorporeal Membrane Oxygenation: A Systematic Review
Jan Hau Lee
Duke-NUS Medical School
Corresponding Author
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BACKGROUND
To identify alterations in pharmacokinetics in children on extracorporeal membrane oxygenation (ECMO), identify knowledge gaps and inform future clinical pharmacology studies.
METHODS
We systematically searched the following databases from earliest publication until November 2018: MEDLINE, CINAHL and EMBASE, using a controlled vocabulary and keywords related to: “ECMO”, and “pharmacokinetics”, “pharmacology”, “drug disposition”, “dosing” and “pediatrics”. Inclusion criteria were: study population aged <18 years, supported on ECMO for any indications, receiving any medications while on ECMO and reported pharmacokinetics data. Clearance and/or volume of distribution (Vd) values were extracted from the included studies.
RESULTS
41 studies (total patients=574) evaluating 23 drugs met the inclusion criteria. The most common drugs studied were anti-microbials (n=13), and anticonvulsants (n=3). 28 studies (68%) were conducted in children < 1 year of age. 33 studies (80%) were conducted without intra-study comparisons to non-ECMO controls. Increase in Vd attributable to ECMO was demonstrated for 9 (56%) drugs: cefotaxime, gentamicin, piperacillin/tazobactam, fluconazole, micafungin, levetiracetam, clonidine, midazolam and sildenafil (range: 23-345% increase relative to non-ECMO controls), which may suggest the need for higher initial dosing. Decreased Vd was reported for 2 drugs: acyclovir and ribavirin (50 and 69%, respectively). Decreased clearance was reported for gentamicin, ticarcillin/clavulanate, bumetanide and ranitidine (range: 26-95% decrease relative to non-ECMO controls). Increased clearance was reported for caspofungin, micafungin, clonidine, midazolam, morphine and sildenafil (range: 25-455% increase relative to non-ECMO controls).
CONCLUSIONS
There were substantial pharmacokinetic alterations in 70% of drugs studied in children on ECMO. However, studies evaluating pharmacokinetic changes of many drug classes, and those that allow direct comparisons between ECMO and non-ECMO patients, are still lacking. Systematic evaluation of pharmacokinetic alterations of drugs on ECMO that incorporate multi-drug opportunistic trials, physiologically based pharmacokinetic modeling, ex-vivo studies and other methods are necessary for definitive dose recommendations.
Keywords
ECMO, extracorporeal, pharmacokinetics, disposition, pediatrics, critically ill
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Research
Pharmacokinetics Alterations in Critically Ill Pediatric Patients on Extracorporeal Membrane Oxygenation: A Systematic Review
Jan Hau Lee
Duke-NUS Medical School
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 18 Dec, 2019
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Critical Care & Emergency Medicine
License:
This work is licensed under a CC BY 4.0 License. Read Full License
BACKGROUND
To identify alterations in pharmacokinetics in children on extracorporeal membrane oxygenation (ECMO), identify knowledge gaps and inform future clinical pharmacology studies.
METHODS
We systematically searched the following databases from earliest publication until November 2018: MEDLINE, CINAHL and EMBASE, using a controlled vocabulary and keywords related to: “ECMO”, and “pharmacokinetics”, “pharmacology”, “drug disposition”, “dosing” and “pediatrics”. Inclusion criteria were: study population aged <18 years, supported on ECMO for any indications, receiving any medications while on ECMO and reported pharmacokinetics data. Clearance and/or volume of distribution (Vd) values were extracted from the included studies.
RESULTS
41 studies (total patients=574) evaluating 23 drugs met the inclusion criteria. The most common drugs studied were anti-microbials (n=13), and anticonvulsants (n=3). 28 studies (68%) were conducted in children < 1 year of age. 33 studies (80%) were conducted without intra-study comparisons to non-ECMO controls. Increase in Vd attributable to ECMO was demonstrated for 9 (56%) drugs: cefotaxime, gentamicin, piperacillin/tazobactam, fluconazole, micafungin, levetiracetam, clonidine, midazolam and sildenafil (range: 23-345% increase relative to non-ECMO controls), which may suggest the need for higher initial dosing. Decreased Vd was reported for 2 drugs: acyclovir and ribavirin (50 and 69%, respectively). Decreased clearance was reported for gentamicin, ticarcillin/clavulanate, bumetanide and ranitidine (range: 26-95% decrease relative to non-ECMO controls). Increased clearance was reported for caspofungin, micafungin, clonidine, midazolam, morphine and sildenafil (range: 25-455% increase relative to non-ECMO controls).
CONCLUSIONS
There were substantial pharmacokinetic alterations in 70% of drugs studied in children on ECMO. However, studies evaluating pharmacokinetic changes of many drug classes, and those that allow direct comparisons between ECMO and non-ECMO patients, are still lacking. Systematic evaluation of pharmacokinetic alterations of drugs on ECMO that incorporate multi-drug opportunistic trials, physiologically based pharmacokinetic modeling, ex-vivo studies and other methods are necessary for definitive dose recommendations.
Figure 1