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.

Department of Clinical Sciences and Community Health Università degli Studi di Milano Milan Italy

Department of Development and Regeneration KU Leuven Leuven Belgium

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

Division of Neonatology Department of Pediatrics Erasmus MC Sophia Children's Hospital University Medical Center Rotterdam Rotterdam Netherlands

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico NICU Milan Italy

Intensive Care and Department of Pediatric Surgery Erasmus MC Sophia Children's Hospital Rotterdam Netherlands

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Bartlett RH, Gazzaniga AB, Jefferies MR, Huxtable RF, Haiduc N, Fong S. Extracorporeal membrane oxygenation (ECMO) cardiopulmonary support in infancy. ASAIO J. (1976) 22:80–92. PubMed

Bahrami KR, Van Meurs KP. ECMO for neonatal respiratory failure. Semin Perinatol. (2005) 29:15–23. 10.1053/j.semperi.2005.02.004 PubMed DOI

Slutsky AS, Ranieri VM. Ventilator-induced lung injury. N Engl J Med. (2013) 369:2126–36. 10.1056/NEJMra1208707 PubMed DOI

Buck ML. Pharmacokinetic changes during extracorporeal membrane oxygenation: implications for drug therapy of neonates. Clin Pharmacokinet. (2003) 42:403–17. 10.2165/00003088-200342050-00001 PubMed DOI

Lequier L. Extracorporeal life support in pediatric and neonatal critical care: a review. J Intensive Care Med. (2004) 19:243–58. 10.1177/0885066604267650 PubMed DOI

Blumenthal D, Brunton LL, Buxton IL, Parker KL. Goodman & Gilman's Manual of Pharmacology and Therapeutics. New York, NY: McGraw-Hill; (2008).

Katzung BG, Trevor AJ. Basic & Clinical Pharmacology. New York, NY: Lange Medical Books/McGraw-Hill; (2004).

Allegaert K, Simons SH, Tibboel D, Krekels EH, Knibbe CA, van den Anker JN. Non-maturational covariates for dynamic systems pharmacology models in neonates, infants, and children: filling the gaps beyond developmental pharmacology. Eur J Pharm Sci. (2017) 109: S27–31. 10.1016/j.ejps.2017.05.023 PubMed DOI

Allegaert K, van den Anker JN. Clinical pharmacology in neonates: small size, huge variability. Neonatology. (2014) 105:344–9. 10.1159/000360648 PubMed DOI PMC

Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology—drug disposition, action, and therapy in infants and children. N Engl J Med. (2003) 349:1157–67. 10.1056/NEJMra035092 PubMed DOI

van den Anker J, Reed MD, Allegaert K, Kearns GL. Developmental changes in pharmacokinetics and pharmacodynamics. J Clin Pharmacol. (2018) 58:S10–25. 10.1002/jcph.1284 PubMed DOI

Roberts JA, Kumar A, Lipman J. Right dose, right now: customized drug dosing in the critically ill. Crit Care Med. (2017) 45:331–6. 10.1097/CCM.0000000000002210 PubMed DOI

Shekar K, Roberts JA, Mcdonald CI, Fisquet S, Barnett AG, Mullany DV, et al. . Sequestration of drugs in the circuit may lead to therapeutic failure during extracorporeal membrane oxygenation. Crit Care. (2012) 16:R194. 10.1186/cc11679 PubMed DOI PMC

Shekar K, Roberts J, McDonald C, Ghassabian S, Anstey C, Wallis SC, et al. . Protein-bound drugs are prone to sequestration in the extracorporeal membrane oxygenation circuit: results from an ex vivo study. Crit Care. (2015) 19:164. 10.1186/s13054-015-0891-z PubMed DOI PMC

Wildschut ED, Ahsman MJ, Allegaert K, Mathot RA, Tibboel D. Determinants of drug absorption in different ECMO circuits. Intensive Care Med. (2010) 36:2109–16. 10.1007/s00134-010-2041-z PubMed DOI PMC

Bartelink IH, Rademaker CM, Schobben AF, van den Anker JN. Guidelines on paediatric dosing on the basis of developmental physiology and pharmacokinetic considerations. Clin Pharmacokinet. (2006) 45:1077–97. 10.2165/00003088-200645110-00003 PubMed DOI

Ehrnebo M, Agurell S, Jalling B, Boreus L. Age differences in drug binding by plasma proteins: studies on human foetuses, neonates and adults. Eur J Clin Pharmacol. (1971) 3:189–93. 10.1007/BF00565004 PubMed DOI

Friis-Hansen B. Water distribution in the foetus and newborn infant. Acta Pædiatrica. (1983) 72:7–11. 10.1111/j.1651-2227.1983.tb09852.x PubMed DOI

Allegaert K, Mian P, N van den Anker J. Developmental pharmacokinetics in neonates: maturational changes and beyond. Curr Pharm Design. (2017) 23:5769–78. 10.2174/1381612823666170926121124 PubMed DOI

Euteneuer JC, Kamatkar S, Fukuda T, Vinks AA, Akinbi HT. Suggestions for model-informed precision dosing to optimize neonatal drug therapy. J Clin Pharmacol. (2019) 59:168–76. 10.1002/jcph.1315 PubMed DOI PMC

Allegaert K, Cosaert K, van den Anker JN. Neonatal formulations: the need for a tailored, knowledge driven approach. Curr Pharm Design. (2015) 21:5674–79. 10.2174/1381612821666150901110207 PubMed DOI

Bone RC, Sibbald WJ, Sprung CL. The ACCP-SCCM consensus conference on sepsis and organ failure. Chest. (1992) 101:1481–4. 10.1378/chest.101.6.1481 PubMed DOI

Bodenham A, Shelly M, Park G. The altered pharmacokinetics and pharmacodynamics of drugs commonly used in critically ill patients. Clin Pharmacokinet. (1988) 14:347–73. 10.2165/00003088-198814060-00003 PubMed DOI

De Cock RF, Piana C, Krekels EH, Danhof M, Allegaert K, Knibbe CA. The role of population PK-PD modelling in paediatric clinical research. Eur J Clin Pharmacol. (2011) 67 (suppl. 1):5–16. 10.1007/s00228-009-0782-9 PubMed DOI PMC

Shekar K, Roberts JA, Welch S, Buscher H, Rudham S, Burrows F, et al. . ASAP ECMO: antibiotic, sedative and analgesic pharmacokinetics during extracorporeal membrane oxygenation: a multi-centre study to optimise drug therapy during ECMO. BMC Anesthesiol. (2012) 12:29. 10.1186/1471-2253-12-29 PubMed DOI PMC

Di Nardo M, Wildschut ED. Drugs pharmacokinetics during veno-venous extracorporeal membrane oxygenation in pediatrics. J Thorac Dis. (2018) 10 (suppl. 5):S642–52. 10.21037/jtd.2017.11.02 PubMed DOI PMC

Boucher BA, Wood GC, Swanson JM. Pharmacokinetic changes in critical illness. Crit Care Clin. (2006) 22:255–71. 10.1016/j.ccc.2006.02.011 PubMed DOI

Carter BS, Haverkamp AD, Merenstein GB. The definition of acute perinatal asphyxia. Clin Perinatol. (1993) 20:287–304. 10.1016/S0095-5108(18)30394-4 PubMed DOI

Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E, et al. . Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. (2009) 361:1349–58. 10.1056/NEJMoa0900854 PubMed DOI

Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev. (2013) CD003311. 10.1002/14651858.CD003311.pub3 PubMed DOI PMC

Chhavi N, Zutshi K, Singh NK, Awasthi A, Goel A. Serum liver enzyme pattern in birth asphyxia associated liver injury. Pediatr Gastroenterol Hepatol Nutr. (2014) 17:162–9. 10.5223/pghn.2014.17.3.162 PubMed DOI PMC

Martin-Ancel A, Garcia-Alix A, Gaya F, Cabanas F, Burgueros M, Quero J. Multiple organ involvement in perinatal asphyxia. J Pediatr. (1995) 127:786–93. 10.1016/S0022-3476(95)70174-5 PubMed DOI

Shah P, Riphagen S, Beyene J, Perlman M. Multiorgan dysfunction in infants with post-asphyxial hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed. (2004) 89:F152–5. 10.1136/fn.89.2.F152 PubMed DOI PMC

ELSO Registry Report International Summary January 2019. Available online at: https://www.elso.org (accessed March 30, 2019).

Reiterer F, Resch E, Haim M, Maurer-Fellbaum U, Riccabona M, Zobel G, et al. . Neonatal extracorporeal membrane oxygenation due to respiratory failure: a single center experience over 28 years. Front Pediatr. (2018) 6:263. 10.3389/fped.2018.00263 PubMed DOI PMC

Cornell TT, Selewski DT, Alten JA, Askenazi D, Fitzgerald JC, Topjian A, et al. . Acute kidney injury after out of hospital pediatric cardiac arrest. Resuscitation. (2018) 131:63–8. 10.1016/j.resuscitation.2018.07.362 PubMed DOI PMC

Cristea S, Smits A, Kulo A, Knibbe CAJ, van Weissenbruch M, Krekels EHJ, et al. . Amikacin pharmacokinetics to optimize dosing in neonates with perinatal asphyxia treated with hypothermia. Antimicrob Agents Chemother. (2017) 61:e01282–17. 10.1128/AAC.01282-17 PubMed DOI PMC

Van Den Anker JN, Van Der Heijden BJ, Hop WC, Schoemaker RC, Broerse HM, Neijens HJ, et al. . The effect of asphyxia on the pharmacokinetics of ceftazidime in the term newborn. Pediatr Res. (1995) 38:808–11. 10.1203/00006450-199511000-00028 PubMed DOI

Bijleveld YA, de Haan TR, van der Lee HJ, Groenendaal F, Dijk PH, van Heijst A, et al. . Altered gentamicin pharmacokinetics in term neonates undergoing controlled hypothermia. Br J Clin Pharmacol. (2016) 81:1067–77. 10.1111/bcp.12883 PubMed DOI PMC

Bijleveld YA, Mathôt R, van der Lee JH, Groenendaal F, Dijk PH, van Heijst A, et al. . Population pharmacokinetics of amoxicillin in term neonates undergoing moderate hypothermia. Clin Pharmacol Therapeut. (2018) 103:458–67. 10.1002/cpt.748 PubMed DOI

Bijleveld YA, de Haan TR, van der Lee JH, Groenendaal F, Dijk PH, van Heijst A, et al. . Evaluation of a system-specific function to describe the pharmacokinetics of benzylpenicillin in term neonates undergoing moderate hypothermia. Antimicrob Agents Chemother. (2018) 62:e02311–17. 10.1128/AAC.02311-17 PubMed DOI PMC

Hinderling PH, Hartmann D. The pH dependency of the binding of drugs to plasma proteins in man. Therapeut Drug Monitor. (2005) 27:71–85. 10.1097/00007691-200502000-00014 PubMed DOI

van den Broek MP, Groenendaal F, Egberts AC, Rademaker CM. Effects of hypothermia on pharmacokinetics and pharmacodynamics: a systematic review of preclinical and clinical studies. Clin Pharmacokinet. (2010) 49:277–94. 10.2165/11319360-000000000-00000 PubMed DOI

Zanelli S, Buck M, Fairchild K. Physiologic and pharmacologic considerations for hypothermia therapy in neonates. J Perinatol. (2011) 31:377–86. 10.1038/jp.2010.146 PubMed DOI PMC

Zhou J, Poloyac SM. The effect of therapeutic hypothermia on drug metabolism and response: cellular mechanisms to organ function. Expert Opin Drug Metab Toxicol. (2011) 7:803–16. 10.1517/17425255.2011.574127 PubMed DOI PMC

Pokorna P, Wildschut ED, Vobruba V, van den Anker JN, Tibboel D. The impact of hypothermia on the pharmacokinetics of drugs used in neonates and young infants. Curr Pharmaceut Design. (2015) 21:5705–24. 10.2174/1381612821666150901110929 PubMed DOI

Wildschut ED, de Wildt SN, Mathot RA, Reiss IK, Tibboel D, Van den Anker J. Effect of hypothermia and extracorporeal life support on drug disposition in neonates. Semin Fetal Neonatal Med. (2013) 18:23–7. 10.1016/j.siny.2012.10.002 PubMed DOI

Shellhaas RA, Ng CM, Dillon CH, Barks JD, Bhatt-Mehta V. Population pharmacokinetics of phenobarbital in infants with neonatal encephalopathy treated with therapeutic hypothermia. Pediatr Crit Care Med. (2013) 14:194–202. 10.1097/PCC.0b013e31825bbbc2 PubMed DOI PMC

van den Broek MP, Groenendaal F, Toet MC, van Straaten HL, van Hasselt JG, Huitema AD, et al. . Pharmacokinetics and clinical efficacy of phenobarbital in asphyxiated newborns treated with hypothermia: a thermopharmacological approach. Clin Pharmacokinet. (2012) 51:671–9. 10.1007/s40262-012-0004-y PubMed DOI

Völler S, Flint RB, Stolk LM, Degraeuwe PLJ, Simons SHP, Pokorna P, et al. . Model-based clinical dose optimization for phenobarbital in neonates: an illustration of the importance of data sharing and external validation. Eur J Pharmaceut Sci. (2017) 109S:S90–7. 10.1016/j.ejps.2017.05.026 PubMed DOI

Pokorná P, Posch L, Šíma M, Klement P, Slanar O, van den Anker J, et al. . Severity of asphyxia is a covariate of phenobarbital clearance in newborns undergoing hypothermia. J Maternal Fetal Neonatal Med. (2019) 32:2302–9. 10.1080/14767058.2018.1432039 PubMed DOI

Róka A, Melinda KT, Vásárhelyi B, Machay T, Azzopardi D, Szabó M. Elevated morphine concentrations in neonates treated with morphine and prolonged hypothermia for hypoxic ischemic encephalopathy. Pediatrics. (2008) 121:e844–9. 10.1542/peds.2007-1987 PubMed DOI

Smits A, Kulo A, van den Anker J, Allegaert K. The amikacin research program: a stepwise approach to validate dosing regimens in neonates. Expert Opin Drug Metab Toxicol. (2017) 13:157–66. 10.1080/17425255.2017.1234606 PubMed DOI

Filippi L, la Marca G, Cavallaro G, Fiorini P, Favelli F, Malvagia S, et al. . Phenobarbital for neonatal seizures in hypoxic ischemic encephalopathy: a pharmacokinetic study during whole body hypothermia. Epilepsia. (2011) 52:794–801. 10.1111/j.1528-1167.2011.02978.x PubMed DOI

Filippi L, la Marca G, Fiorini P, Poggi C, Cavallaro G, Malvagia S, et al. . Topiramate concentrations in neonates treated with prolonged whole body hypothermia for hypoxic ischemic encephalopathy. Epilepsia. (2009) 50:2355–61. 10.1111/j.1528-1167.2009.02302.x PubMed DOI

de Haan TR, Bijleveld YA, van der Lee JH, Groenendaal F, van den Broek MP, Rademaker CM, et al. . Pharmacokinetics and pharmacodynamics of medication in asphyxiated newborns during controlled hypothermia. The PharmaCool multicenter study. BMC Pediatr. (2012) 12:45. 10.1186/1471-2431-12-45 PubMed DOI PMC

Wynn JL. Defining neonatal sepsis. Curr Opin Pediatr. (2016) 28:135–40. 10.1097/MOP.0000000000000315 PubMed DOI PMC

Goldstein B, Giroir B, Randolph A, International Consensus Conference on Pediatric S . International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med. (2005) 6:2–8. 10.1097/01.PCC.0000149131.72248.E6 PubMed DOI

Bestati N, Leteurtre S, Duhamel A, Proulx F, Grandbastien B, Lacroix J, et al. . Differences in organ dysfunctions between neonates and older children: a prospective, observational, multicenter study. Crit Care. (2010) 14:R202. 10.1186/cc9323 PubMed DOI PMC

Renton KW. Regulation of drug metabolism and disposition during inflammation and infection. Expert Opin Drug Metab Toxicol. (2005) 1:629–40. 10.1517/17425255.1.4.629 PubMed DOI

Udy AA, Roberts JA, Lipman J. Implications of augmented renal clearance in critically ill patients. Nat Rev Nephrol. (2011) 7:539. 10.1038/nrneph.2011.92 PubMed DOI

Udy AA, Roberts JA, Boots RJ, Paterson DL, Lipman J. Augmented renal clearance. Clin Pharmacokinet. (2010) 49:1–16. 10.2165/11318140-000000000-00000 PubMed DOI

Hobbs AL, Shea KM, Roberts KM, Daley MJ. Implications of augmented renal clearance on drug dosing in critically ill patients: a focus on antibiotics. Pharmacotherapy. (2015) 35:1063–75. 10.1002/phar.1653 PubMed DOI

Dhont E, Van Der Heggen T, De Jaeger A, Walle JV, De Paepe P, De Cock PA. Augmented renal clearance in pediatric intensive care: are we undertreating our sickest patients? Pediatr Nephrol. (2018):1–15. 10.1007/s00467-018-4120-2 PubMed DOI

Avedissian SN, Bradley E, Zhang D, Bradley JS, Nazer LH, Tran TM, et al. . Augmented renal clearance using population-based pharmacokinetic modeling in critically ill pediatric patients. Pediatr Crit Care Med. (2017) 18:e388–94. 10.1097/PCC.0000000000001228 PubMed DOI

van den Anker JN, Knibbe CA, Tibboel D. Augmented renal clearance in critically III pediatric patients: does it impact the outcome of pharmacotherapy? Pediatr Crit Care Med. (2017) 18:901–2. 10.1097/PCC.0000000000001264 PubMed DOI

Vet NJ, de Hoog M, Tibboel D, de Wildt SN. The effect of inflammation on drug metabolism: a focus on pediatrics. Drug Discov Today. (2011) 16:435. 10.1016/j.drudis.2011.02.014 PubMed DOI

Varghese JM, Roberts JA, Lipman J. Antimicrobial pharmacokinetic and pharmacodynamic issues in the critically ill with severe sepsis and septic shock. Crit Care Clin. (2011) 27:19–34. 10.1016/j.ccc.2010.09.006 PubMed DOI

Shah S, Barton G, Fischer A. Pharmacokinetic considerations and dosing strategies of antibiotics in the critically ill patient. J Intensive Care Soc. (2015) 16:147–53. 10.1177/1751143714564816 PubMed DOI PMC

De Paepe P, Belpaire FM, Buylaert WA. Pharmacokinetic and pharmacodynamic considerations when treating patients with sepsis and septic shock. Clin Pharmacokinet. (2002) 41:1135–51. 10.2165/00003088-200241140-00002 PubMed DOI

Dagan O, Klein J, Gruenwald C, Bohn D, Barker G, Koren G. Preliminary studies of the effects of extracorporeal membrane oxygenator on the disposition of common pediatric drugs. Therapeut Drug Monitor. (1993) 15:263–66. 10.1097/00007691-199308000-00001 PubMed DOI

De Cock PA, Allegaert K, Linakis MW, Sherwin CM. Antibiotic dosing in pediatric critically Ill patients. In: Antibiotic Pharmacokinetic/Pharmacodynamic Considerations in the Critically Ill. Singapore: Springer; (2018). p. 239–63.

Wildschut ED, Ahsman MJ, Houmes RJ, Pokorna P, de Wildt SN, Mathot RA, et al. . Pharmacotherapy in neonatal and pediatric extracorporeal membrane oxygenation (ECMO). Curr Drug Metab. (2012) 13:767–77. 10.2174/138920012800840383 PubMed DOI

Rehder KJ, Turner DA, Bonadonna D, Walczak RJ, Rudder RJ, Cheifetz IM. Technological advances in extracorporeal membrane oxygenation for respiratory failure. Expert Rev Respir Med. (2012) 6:377–84. 10.1586/ers.12.31 PubMed DOI

ELSO Extracorporeal Life Support, The Red Book: The ELSO Red Book. 5th ed. Ann Arbor, MI: Extracorporeal Life Support Organization; (2017).

Poole SK, Poole CF. Separation methods for estimating octanol–water partition coefficients. J Chromatogr B. (2003) 797:3–19. 10.1016/j.jchromb.2003.08.032 PubMed DOI

Shekar K, Roberts JA, Barnett AG, Diab S, Wallis SC, Fung YL, et al. . Can physicochemical properties of antimicrobials be used to predict their pharmacokinetics during extracorporeal membrane oxygenation? Illustrative data from ovine models. Crit Care. (2015) 19:437. 10.1186/s13054-015-1151-y PubMed DOI PMC

Himebauch AS, Kilbaugh TJ, Zuppa AF. Pharmacotherapy during pediatric extracorporeal membrane oxygenation: a review. Expert Opin Drug Metab Toxicol. (2016) 12:1133–42. 10.1080/17425255.2016.1201066 PubMed DOI

Park J, Shin DA, Lee S, Cho YJ, Jheon S, Lee JC, et al. . Investigation of key circuit constituents affecting drug sequestration during extracorporeal membrane oxygenation treatment. ASAIO J. (2017) 63:293–8. 10.1097/MAT.0000000000000489 PubMed DOI

Bhatt-Mehta V, Annich G. Sedative clearance during extracorporeal membrane oxygenation. Perfusion. (2005) 20:309–15. 10.1191/0267659105pf827oa PubMed DOI

Wagner D, Pasko D, Phillips K, Waldvogel J, Annich G. In vitro clearance of dexmedetomidine in extracorporeal membrane oxygenation. Perfusion. (2013) 28:40–6. 10.1177/0267659112456894 PubMed DOI

Melchior RW, Sutton SW, Harris W, Dalton HJ. Evolution of membrane oxygenator technology for utilization during pediatric cardiopulmonary bypass. Pediatr Health Med Therapeut. (2016) 7:45. 10.2147/PHMT.S35070 PubMed DOI PMC

Rosen DA, Rosen KR, Silvasi DL. In vitro variability in fentanyl absorption by different membrane oxygenators. J Cardiothorac Anesth. (1990) 4:332–5. 10.1016/0888-6296(90)90041-D PubMed DOI

Raffaeli G, Allegaert K, Koch B, Cavallaro G, Mosca F, Tibboel D, et al. . In vitro adsorption of analgosedative drugs in new extracorporeal membrane oxygenation circuits. Pediatr Crit Care Med. (2018) 19:e251–8. 10.1097/PCC.0000000000001484 PubMed DOI

Preston TJ, Hodge AB, Riley JB, Leib-Sargel C, Nicol KK. In vitro drug adsorption and plasma free hemoglobin levels associated with hollow fiber oxygenators in the extracorporeal life support (ECLS) circuit. J Extra Corpor Technol. (2007) 39:234–7. PubMed PMC

Tron C, Leven C, Fillâtre P, Maillard N, Nesseler N, Tattevin P, et al. . Should we fear tubing adsorption of antibacterial drugs in extracorporeal membrane oxygenation? An answer for cephalosporins and carbapenems. Clin Exp Pharmacol Physiol. (2016) 43:281–3. 10.1111/1440-1681.12527 PubMed DOI

Leven C, Fillâtre P, Petitcollin A, Verdier MC, Laurent J, Nesseler N, et al. . ex vivo model to decipher the impact of extracorporeal membrane oxygenation on beta-lactam degradation kinetics. Therapeut Drug Monitor. (2017) 39:180–4. 10.1097/FTD.0000000000000369 PubMed DOI

Preston TJ, Ratliff TM, Gomez D, Olshove VE, Nicol KK, Sargel CL, et al. . Modified surface coatings and their effect on drug adsorption within the extracorporeal life support circuit. J Extra Corpor Technol. (2010) 42:199. PubMed PMC

Silvetti S, Koster A, Pappalardo F. Do we need heparin coating for extracorporeal membrane oxygenation? New concepts and controversial positions about coating surfaces of extracorporeal circuits. Artif Organs. (2015) 39:176–9. 10.1111/aor.12335 PubMed DOI

Myers GJ, Voorhees C, Eke B, Johnstone R. The effect of Diprivan (propofol) on phosphorylcholine surfaces during cardiopulmonary bypass—an In vitro investigation. Perfusion. (2009) 24:349–55. 10.1177/0267659109353819 PubMed DOI

Peters JW, Anderson BJ, Simons SH, Uges DR, Tibboel D. Morphine metabolite pharmacokinetics during venoarterial extra corporeal membrane oxygenation in neonates. Clin Pharmacokinet. (2006) 45:705–14. 10.2165/00003088-200645070-00005 PubMed DOI

Mehta NM, Halwick DR, Dodson BL, Thompson JE, Arnold JH. Potential drug sequestration during extracorporeal membrane oxygenation: results from an ex vivo experiment. Intensive Care Med. (2007) 33:1018–24. 10.1007/s00134-007-0606-2 PubMed DOI

Mulla H, Lawson G, von Anrep C, Burke MD, Upton DU, Firmin RK, et al. . In vitro evaluation of sedative drug losses during extracorporeal membrane oxygenation. Perfusion. (2000) 15:21–26. 10.1177/026765910001500104 PubMed DOI

Shekar K, Fraser JF, Smith MT, Roberts JA. Pharmacokinetic changes in patients receiving extracorporeal membrane oxygenation. J Crit Care. (2012) 27:741.e749-18. 10.1016/j.jcrc.2012.02.013 PubMed DOI

Pea F. Plasma pharmacokinetics of antimicrobial agents in critically ill patients. Curr Clin Pharmacol. (2013) 8:5–12. 10.2174/157488413804810585 PubMed DOI

Brink A. Hypoalbuminaemia and altered protein binding. In: Antibiotic Pharmacokinetic/Pharmacodynamic Considerations in the Critically III. Springer; (2018). p. 73–99.

Koch-Weser J, Sellers EM. Binding of drugs to serum albumin. N Engl J Med. (1976) 294:311–6. 10.1056/NEJM197602052940605 PubMed DOI

Kozik DJ, Tweddell JS. Characterizing the inflammatory response to cardiopulmonary bypass in children. Ann Thorac Surg. (2006) 81:S2347–54. 10.1016/j.athoracsur.2006.02.073 PubMed DOI

McILwain RB, Timpa JG, Kurundkar AR, Holt DW, Kelly DR, Hartman YE, et al. . Plasma concentrations of inflammatory cytokines rise rapidly during ECMO-related SIRS due to the release of preformed stores in the intestine. Lab Invest. (2010) 90:128–39. 10.1038/labinvest.2009.119 PubMed DOI PMC

Millar JE, Fanning JP, McDonald CI, McAuley DF, Fraser JF. The inflammatory response to extracorporeal membrane oxygenation (ECMO): a review of the pathophysiology. Crit Care. (2016) 20:387. 10.1186/s13054-016-1570-4 PubMed DOI PMC

Raffaeli G, Ghirardello S, Passera S, Mosca F, Cavallaro G. Oxidative stress and neonatal respiratory extracorporeal membrane oxygenation. Front Physiol. (2018) 9:1739. 10.3389/fphys.2018.01739 PubMed DOI PMC

Peek GJ, Firmin RK. The inflammatory and coagulative response to prolonged extracorporeal membrane oxygenation. ASAIO J. (1999) 45:250–63. 10.1097/00002480-199907000-00003 PubMed DOI

Shekar K, Roberts JA, Ghassabian S, Mullany DV, Wallis SC, Smith MT, et al. . Altered antibiotic pharmacokinetics during extracorporeal membrane oxygenation: cause for concern? J Antimicrob Chemother. (2013) 68:726–27. 10.1093/jac/dks435 PubMed DOI

Many M, Soroff H, Birtwell W, Giron F, Wise H, Deterling RA. The physiologic role of pulsatile and nonpulsatile blood flow: II. Effects on renal function. Arch Surg. (1967) 95:762–7. 10.1001/archsurg.1967.01330170070009 PubMed DOI

Arnold JH, Truog RD, Orav EJ, Scavone JM, Hershenson MB. Tolerance and dependence in neonates sedated with fentanyl during extracorporeal membrane oxygenation. Anesthesiology. (1990) 73:1136–40. 10.1097/00000542-199012000-00011 PubMed DOI

Mulla H, Lawson G, Woodland E, Peek GJ, Killer H, Firmin RK, et al. Effects of neonatal extracorporeal membrane oxygenation circuits on drug disposition. Curr Therapeut Res. (2000) 61:838–48. 10.1016/S0011-393X(00)90010-9 DOI

Leuschen MP, Willett LD, Hoie EB, Bolam DL, Bussey ME, Goodrich PD, et al. . Plasma fentanyl levels in infants undergoing extracorporeal membrane oxygenation. J Thorac Cardiovasc Surg. (1993) 105:885–91. PubMed

Mulla H, McCormack P, Lawson G, Firmin RK, Upton DR. Pharmacokinetics of midazolam in neonates undergoing extracorporeal membrane oxygenation. Anesthesiology. (2003) 99:275–82. 10.1097/00000542-200308000-00008 PubMed DOI

Mulla H, Lawson G, Peek GJ, Firmin R, Upton DR. Plasma concentrations of midazolam in neonates receiving extracorporeal membrane oxygenation. ASAIO J. (2003) 49:41–47. 10.1097/00002480-200301000-00007 PubMed DOI

Nasr VG, Meserve J, Pereira LM, Faraoni D, Brediger S, Goobie S, et al. . Sedative and analgesic drug sequestration after a single bolus injection in an ex vivo extracorporeal membrane oxygenation infant circuit. ASAIO J. (2019) 65:187–91. 10.1097/MAT.0000000000000793 PubMed DOI

Suresh S, Anand K. Opioid tolerance in neonates: a state-of-the-art review. Pediatr Anesth. (2001) 11:511–21. 10.1046/j.1460-9592.2001.00764.x PubMed DOI

Wildschut ED, Hanekamp MN, Vet NJ, Houmes RJ, Ahsman MJ, Mathot RA, et al. . Feasibility of sedation and analgesia interruption following cannulation in neonates on extracorporeal membrane oxygenation. Intensive Care Med. (2010) 36:1587–91. 10.1007/s00134-010-1931-4 PubMed DOI PMC

DeBerry BB, Lynch JE, Chernin JM, Zwischenberger JB, Chung DH. A survey for pain and sedation medications in pediatric patients during extracorporeal membrane oxygenation. Perfusion. (2005) 20:139–43. 10.1191/0267659105pf801oa PubMed DOI

Gillogly A, Kilbourn C, Waldvogel J, Martin J, Annich G, Wagner D. In vitro clearance of intravenous acetaminophen in extracorporeal membrane oxygenation. Perfusion. (2013) 28:141–5. 10.1177/0267659112467825 PubMed DOI

Kleiber N, Mathôt RA, Ahsman MJ, Wildschut ED, Tibboel D, Wildt SN. Population pharmacokinetics of intravenous clonidine for sedation during paediatric extracorporeal membrane oxygenation and continuous venovenous hemofiltration. Br J Clin Pharmacol. (2017) 83:1227–39. 10.1111/bcp.13235 PubMed DOI PMC

Cies JJ, Moore WS, Giliam N, Low T, Enache A, Chopra A. Impact of ex vivo extracorporeal membrane oxygenation circuitry on daptomycin. Perfusion. (2018) 33:624–9. 10.1177/0267659118781761 PubMed DOI

Ahsman MJ, Hanekamp M, Wildschut ED, Tibboel D, Mathot RA. Population pharmacokinetics of midazolam and its metabolites during venoarterial extracorporeal membrane oxygenation in neonates. Clin Pharmacokinet. (2010) 49:407–19. 10.2165/11319970-000000000-00000 PubMed DOI

Taketomo C, Hodding J, Kraus D. Pediatric Dosage Handbook. Hudson, OH: Lexi-Comp. Inc; (2010).

Dagan O, Klein J, Bohn D, Koren G. Effects of extracorporeal membrane oxygenation on morphine pharmacokinetics in infants. Crit Care Med. (1994) 22:1099–101. 10.1097/00003246-199407000-00008 PubMed DOI

Ziesenitz VC, Vaughns JD, Koch G, Mikus G, van den Anker JN. Pharmacokinetics of fentanyl and its derivatives in children: a comprehensive review. Clin Pharmacokinet. (2018) 57:125–49. 10.1007/s40262-017-0569-6 PubMed DOI PMC

Ahsman MJ, Wildschut ED, Tibboel D, Mathot RA. Pharmacokinetics of cefotaxime and desacetylcefotaxime in infants during extracorporeal membrane oxygenation. Antimicrob Agents Chemother. (2010) 54:1734–41. 10.1128/AAC.01696-09 PubMed DOI PMC

Cies JJ, Moore WS, Conley SB, Dickerman MJ, Small C, Carella D, et al. . Pharmacokinetics of continuous infusion meropenem with concurrent extracorporeal life support and continuous renal replacement therapy: a case report. J Pediatr Pharmacol Therapeut. (2016) 21:92–97. 10.5863/1551-6776-21.1.92 PubMed DOI PMC

Cies JJ, Moore WS, Nichols K, Knoderer CA, Carella DM, Chopra A. Population pharmacokinetics and pharmacodynamic target attainment of vancomycin in neonates on extracorporeal life support. Pediatr Crit Care Med. (2017) 18:977–85. 10.1097/PCC.0000000000001250 PubMed DOI

An SH, Lee EM, Kim JY, sun Gwak H. Vancomycin pharmacokinetics in critically ill neonates receiving extracorporeal membrane oxygenation. Eur J Hosp Pharm. (2019). 10.1136/ejhpharm-2018-001720. [Epub ahead of print]. PubMed DOI PMC

Moffett BS, Morris J, Galati M, Munoz F, Arikan AA. Population pharmacokinetics of vancomycin in pediatric extracorporeal membrane oxygenation. Pediatr Crit Care Med. (2018) 19:973–80. 10.1097/PCC.0000000000001682 PubMed DOI

Munzenberger PJ, Massoud N. Pharmacokinetics of gentamicin in neonatal patients supported with extracorporeal membrane oxygenation. ASAIO Trans. (1991) 37:16–18. 10.1097/00002480-199101000-00006 PubMed DOI

Moffett BS, Morris J, Galati M, Munoz FM, Arikan AA. Population pharmacokinetic analysis of gentamicin in pediatric extracorporeal membrane oxygenation. Therapeut Drug Monitor. (2018) 40:581–8. 10.1097/FTD.0000000000000547 PubMed DOI

Southgate WM, DiPiro JT, Robertson AF. Pharmacokinetics of gentamicin in neonates on extracorporeal membrane oxygenation. Antimicrob Agents Chemother. (1989) 33:817–9. 10.1128/AAC.33.6.817 PubMed DOI PMC

Bhatt-Mehta V, Johnson CE, Schumacher RE. Gentamicin pharmacokinetics in term neonates receiving extracorporeal membrane oxygenation. Pharmacotherapy. (1992) 12:28–32. PubMed

Kamal MA, Acosta EP, Kimberlin DW, Gibiansky L, Jester P, Niranjan V, et al. . The posology of oseltamivir in infants with influenza infection using a population pharmacokinetic approach. Clin Pharmacol Therapeut. (2014) 96:380–9. 10.1038/clpt.2014.120 PubMed DOI

Wildschut ED, De Hoog M, Ahsman MJ, Tibboel D, Osterhaus AD, Fraaij PL. Plasma concentrations of oseltamivir and oseltamivir carboxylate in critically ill children on extracorporeal membrane oxygenation support. PLoS ONE. (2010) 5:e10938. 10.1371/journal.pone.0010938 PubMed DOI PMC

Watt KM, Benjamin DK, Cheifetz IM, Moorthy G, Wade KC, Smith PB, et al. . Pharmacokinetics and safety of fluconazole in young infants supported with extracorporeal membrane oxygenation. Pediatr Infect Dis J. (2012) 31:1042–7. 10.1097/INF.0b013e31825d3091 PubMed DOI PMC

Sherwin J, Heath T, Watt K. Pharmacokinetics and dosing of anti-infective drugs in patients on extracorporeal membrane oxygenation: a review of the current literature. Clin Therapeut. (2016) 38:1976–94. 10.1016/j.clinthera.2016.07.169 PubMed DOI PMC

Geiduschek JM, Lynn AM, Bratton SL, Sanders JC, Levy FH, Haberkern CM, et al. . Morphine pharmacokinetics during continuous infusion of morphine sulfate for infants receiving extracorporeal membrane oxygenation. Crit Care Med. (1997) 25:360–4. 10.1097/00003246-199702000-00027 PubMed DOI

Bauer TM, Ritz R, Haberthür C, Ha HR, Hunkeler W, Sleight AJ, et al. . Prolonged sedation due to accumulation of conjugated metabolites of midazolam. Lancet. (1995) 346:145–7. 10.1016/S0140-6736(95)91209-6 PubMed DOI

Koren G, Crean P, Klein J, Goresky G, Villamater J, MacLeod S. Sequestration of fentanyl by the cardiopulmonary bypass (CPBP). Eur J Clin Pharmacol. (1984) 27:51–56. 10.1007/BF02395206 PubMed DOI

Franck LS, Vilardi J, Durand D, Powers R. Opioid withdrawal in neonates after continuous infusions of morphine or fentanyl during extracorporeal membrane oxygenation. Am J Crit Care. (1998) 7:364. PubMed

Kam P, Cardone D. Propofol infusion syndrome. Anaesthesia. (2007) 62:690–701. 10.1111/j.1365-2044.2007.05055.x PubMed DOI

Bizzarro MJ, Conrad SA, Kaufman DA, Rycus P. Infections acquired during extracorporeal membrane oxygenation in neonates, children, and adults*. Pediatr Crit Care Med. (2011) 12:277–81. 10.1097/PCC.0b013e3181e28894 PubMed DOI

Pokorná P, Šíma M, Vobruba V, Tibboel D, Slanar O. Phenobarbital pharmacokinetics in neonates and infants during extracorporeal membrane oxygenation. Perfusion. (2018) 33 (suppl. 1):80–6. 10.1177/0267659118766444 PubMed DOI

Niimi KS, Fanning JJ. Initial experience with recombinant antithrombin to treat antithrombin deficiency in patients on extracorporeal membrane oxygenation. J Extra Corpor Technol. (2014) 46:84–90. PubMed PMC

Ahsman MJ, Witjes BC, Wildschut ED, Sluiter I, Vulto AG, Tibboel D, et al. . Sildenafil exposure in neonates with pulmonary hypertension after administration via a nasogastric tube. Arch Dis Child Fetal Neonatal Ed. (2010) 95:F109–14. 10.1136/adc.2009.168336 PubMed DOI

Kendrick JG, Macready JJ, Kissoon N. Amiodarone treatment of junctional ectopic tachycardia in a neonate receiving extracorporeal membrane oxygenation. Ann Pharmacother. (2006) 40:1872–5. 10.1345/aph.1H148 PubMed DOI

Peters JW, Anderson BJ, Simons SH, Uges DR, Tibboel D. Morphine pharmacokinetics during venoarterial extracorporeal membrane oxygenation in neonates. Intensive Care Med. (2005) 31:257–63. 10.1007/s00134-004-2545-5 PubMed DOI

Mulla H, Nabi F, Nichani S, Lawson G, Firmin R, Upton DR. Population pharmacokinetics of theophylline during paediatric extracorporeal membrane oxygenation. Br J Clin Pharmacol. (2003) 55:23–31. 10.1046/j.1365-2125.2003.01735.x PubMed DOI PMC

Wells TG, Heulitt MJ, Taylor BJ, Fasules JW, Kearns GL. Pharmacokinetics and pharmacodynamics of ranitidine in neonates treated with extracorporeal membrane oxygenation. J Clin Pharmacol. (1998) 38:402–7. 10.1002/j.1552-4604.1998.tb04443.x PubMed DOI

Aebi C, Headrick CL, McCracken GH, Jr, Lindsay CA. Intravenous ribavirin therapy in a neonate with disseminated adenovirus infection undergoing extracorporeal membrane oxygenation: pharmacokinetics and clearance by hemofiltration. J Pediatr. (1997) 130:612–5. 10.1016/S0022-3476(97)70246-4 PubMed DOI

Wells TG, Fasules JW, Taylor BJ, Kearns GL. Pharmacokinetics and pharmacodynamics of bumetanide in neonates treated with extracorporeal membrane oxygenation. J Pediatr. (1992) 121:974–80. 10.1016/S0022-3476(05)80355-5 PubMed DOI

Pokorná P, Šíma M, Vobruba V, Bašková M, Posch L, Slanar O. Sufentanil pharmacokinetics in a full-term neonate treated with extracorporeal membrane oxygenation: a case report. Perfusion. 2019:0267659118824011 10.1177/0267659118824011 PubMed DOI

Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, et al. . DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. (2008) 36 (suppl. 1):D901–6. 10.1093/nar/gkm958 PubMed DOI PMC

Wyatt RG, Okamoto GA, Feigin RD. Stability of antibiotics in parenteral solutions. Pediatrics. (1972) 49:22–29. PubMed

Cies JJ, Moore WS, Dickerman MJ, Small C, Carella D, Chopra A, et al. . Pharmacokinetics of continuous-infusion meropenem in a pediatric patient receiving extracorporeal life support. Pharmacotherapy. (2014) 34:e175–9. 10.1002/phar.1476 PubMed DOI

Tripathi N, Cotten CM, Smith PB. Antibiotic use and misuse in the neonatal intensive care unit. Clin Perinatol. (2012) 39:61–68. 10.1016/j.clp.2011.12.003 PubMed DOI PMC

Hoie EB, Swigart SA, Leuschen MP, Willett LD, Bolam DL, Goodrich PD, et al. . Vancomycin pharmacokinetics in infants undergoing extracorporeal membrane oxygenation. Clin Pharm. (1990) 9:711–5. PubMed

Amaker RD, DiPiro JT, Bhatia J. Pharmacokinetics of vancomycin in critically ill infants undergoing extracorporeal membrane oxygenation. Antimicrob Agents Chemother. (1996) 40:1139–42. 10.1128/AAC.40.5.1139 PubMed DOI PMC

Buck ML. Vancomycin pharmacokinetics in neonates receiving extracorporeal membrane oxygenation. Pharmacotherapy. (1998) 18:1082–6. PubMed

Mulla H, Pooboni S. Population pharmacokinetics of vancomycin in patients receiving extracorporeal membrane oxygenation. Br J Clin Pharmacol. (2005) 60:265–75. 10.1111/j.1365-2125.2005.02432.x PubMed DOI PMC

Gwee A, Cranswick N, McMullan B, Perkins E, Bolisetty S, Gardiner K, et al. . Continuous versus intermittent vancomycin infusions in infants: a randomized controlled trial. Pediatrics. (2019) 143:e20182179. 10.1542/peds.2018-2179 PubMed DOI

Wi J, Noh H, Min KL, Yang S, Jin BH, Hahn J, et al. . Population pharmacokinetics and dose optimization of teicoplanin during venoarterial extracorporeal membrane oxygenation. Antimicrob Agents Chemother. (2017) 61:e01015–17. 10.1128/AAC.01015-17 PubMed DOI PMC

Karadag-Oncel E, Ceyhan M. Oseltamivir in neonates, infants and young children: a focus on clinical pharmacology. Infect Disord Drug Targets. (2013) 13:15–24. 10.2174/18715265112129990004 PubMed DOI

Food and Drug Administration Tamiflu (oseltamivir phosphate) Information. Available online at: https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/tamiflu-oseltamivir-phosphate-information (accessed May 2, 2019).

Eyler RF, Heung M, Pleva M, Sowinski KM, Park PK, Napolitano LM, et al. Pharmacokinetics of oseltamivir and oseltamivir carboxylate in critically ill patients receiving continuous venovenous hemodialysis and/or extracorporeal membrane oxygenation. Pharmacotherapy. (2012) 32:1061–9. 10.1002/phar.1151 PubMed DOI

Lemaitre F, Luyt CE, Roullet-Renoleau F, Nieszkowska A, Zahr N, Corvol E, et al. . Impact of extracorporeal membrane oxygenation and continuous venovenous hemodiafiltration on the pharmacokinetics of oseltamivir carboxylate in critically ill patients with pandemic (H1N1) influenza. Therapeut Drug Monitor. (2012) 34:171–5. 10.1097/FTD.0b013e318248672c PubMed DOI

Zeilmaker GA, Pokorna P, Mian P, Wildschut ED, Knibbe CAJ, Krekels EHJ, et al. . Pharmacokinetic considerations for pediatric patients receiving analgesia in the intensive care unit; targeting postoperative, ECMO and hypothermia patients. Expert Opin Drug Metab Oxicol. (2018) 14:417–28. 10.1080/17425255.2018.1461836 PubMed DOI

Smits A, De Cock P, Vermeulen A, Allegaert K. Physiologically based pharmacokinetic (PBPK) modeling and simulation in neonatal drug development: how clinicians can contribute. Expert Opin Drug Metab Toxicol. (2019) 15:25–34. 10.1080/17425255.2019.1558205 PubMed DOI

Watt KM, Cohen-Wolkowiez M, Barrett JS, Sevestre M, Zhao P, Brouwer KLR, et al. . Physiologically based pharmacokinetic approach to determine dosing on extracorporeal life support: fluconazole in children on ECMO. CPT. (2018) 7:629–37. 10.1002/psp4.12338 PubMed DOI PMC

Michelet R, Bocxlaer JV, Vermeulen A. PBPK in preterm and term neonates: a review. Curr Pharm Design. (2017) 23:5943–54. 10.2174/1381612823666171009143840 PubMed DOI

Yellepeddi V, Rower J, Liu X, Kumar S, Rashid J, Sherwin CM. State-of-the-art review on physiologically based pharmacokinetic modeling in pediatric drug development. Clin Pharmacokinet. (2018) 58:1–13. 10.1007/s40262-018-0677-y PubMed DOI

Anderson BJ, Merry AF. Data sharing for pharmacokinetic studies. Pediatr Anesth. (2009) 19:1005–10. 10.1111/j.1460-9592.2009.03051.x PubMed DOI

Rasool MF, Khalil F, Läer S. A Physiologically based pharmacokinetic drug–disease model to predict carvedilol exposure in adult and paediatric heart failure patients by incorporating pathophysiological changes in hepatic and renal blood flows. Clin Pharmacokinet. (2015) 54:943–62. 10.1007/s40262-015-0253-7 PubMed DOI PMC

T'jollyn H, Vermeulen A, Van Bocxlaer J, Colin P. A physiologically based pharmacokinetic perspective on the clinical utility of albumin-based dose adjustments in critically ill patients. Clin Pharmacokinet. (2018) 57:59–69. 10.1007/s40262-017-0549-x PubMed DOI

Coppini R, Simons SH, Mugelli A, Allegaert K. Clinical research in neonates and infants: challenges and perspectives. Pharmacol Res. (2016) 108:80–7. 10.1016/j.phrs.2016.04.025 PubMed DOI

Maharaj AR, Gonzalez D, Cohen-Wolkowiez M, Hornik CP, Edginton AN. Improving pediatric protein binding estimates: an evaluation of α1-acid glycoprotein maturation in healthy and infected subjects. Clin Pharmacokinet. (2018) 57:577–89. 10.1007/s40262-017-0576-7 PubMed DOI PMC

Current knowledge, challenges and innovations in developmental pharmacology: A combined conect4children Expert Group and European Society for Developmental, Perinatal and Paediatric Pharmacology White Paper