Advertisement

Pediatric Drugs

, Volume 17, Issue 1, pp 43–53 | Cite as

Ethics of Drug Research in the Pediatric Intensive Care Unit

  • Niina Kleiber
  • Krista Tromp
  • Miriam G. Mooij
  • Suzanne van de Vathorst
  • Dick Tibboel
  • Saskia N. de WildtEmail author
Review Article
Part of the following topical collections:
  1. Ethics of Pediatric Drug Research

Abstract

Critical illness and treatment modalities change pharmacokinetics and pharmacodynamics of medications used in critically ill children, in addition to age-related changes in drug disposition and effect. Hence, to ensure effective and safe drug therapy, research in this population is urgently needed. However, conducting research in the vulnerable population of the pediatric intensive care unit (PICU) presents with ethical challenges. This article addresses the main ethical issues specific to drug research in these critically ill children and proposes several solutions. The extraordinary environment of the PICU raises specific challenges to the design and conduct of research. The need for proxy consent of parents (or legal guardians) and the stress-inducing physical environment may threaten informed consent. The informed consent process is challenging because emergency research reduces or even eliminates the time to seek consent. Moreover, parental anxiety may impede adequate understanding and generate misconceptions. Alternative forms of consent have been developed taking into account the unpredictable reality of the acute critical care environment. As with any research in children, the burden and risk should be minimized. Recent developments in sample collection and analysis as well as pharmacokinetic analysis should be considered in the design of studies. Despite the difficulties inherent to drug research in critically ill children, methods are available to conduct ethically sound research resulting in relevant and generalizable data. This should motivate the PICU community to commit to drug research to ultimately provide the right drug at the right dose for every individual child.

Keywords

Pediatric Intensive Care Unit Drug Research Informed Consent Process Pediatric Intensive Care Unit Admission Proxy Consent 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

This research is supported by grants from The Netherlands Organization for Health Research and Development (113203203, 113202007 and 90700304); however, no financial support was received specifically for the writing of the manuscript.

N. Kleiber, K. Tromp, M. G. Mooij, S. van de Vathorst, D. Tibboel and S. N. de Wildt declare no relevant conflicts of interest.

Ko Hagoort is thanked for editing the manuscript.

References

  1. 1.
    Council for International Organizations of Medical Sciences (CIOMS). International Ethical Guidelines for Biomedical Research Involving Human Subjects. Geneva 2002.Google Scholar
  2. 2.
    Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10. Washington: US Government Printing Office; 1949. p. 181–2.Google Scholar
  3. 3.
    The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Washington: US Government Printing Office; 1978.Google Scholar
  4. 4.
    Declaration of Helsinki. Ethical principles for medical research involving human subjects (8th revision; original: 1964), 2013.Google Scholar
  5. 5.
    Bos W, Tromp K, Tibboel D, Pinxten W. Ethical aspects of clinical research with minors. Eur J Pediatr. 2013;172(7):859–66. doi: 10.1007/s00431-012-1856-8.PubMedCrossRefGoogle Scholar
  6. 6.
    Shirkey H. Therapeutic orphans. J Pediatr. 1968;72(1):119–20.PubMedCrossRefGoogle Scholar
  7. 7.
    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 Eng J Med. 2003;349(12):1157–67. doi: 10.1056/NEJMra035092.CrossRefGoogle Scholar
  8. 8.
    Shann F, Chiletti R. Neonatal herpes virus infection: duration of extracorporeal support and the dose of acyclovir. Pediatr Crit Care Med. 2011;12(5):605–6. doi: 10.1097/PCC.0b013e3182191780 (author reply).PubMedCrossRefGoogle Scholar
  9. 9.
    Prodhan P, Okhuysen-Cawley R, Imamura M. Central extracorporeal membrane oxygenation for refractory pediatric septic shock. Pediatr Crit Care Med. 2011;12(5):606–7. doi: 10.1097/PCC.0b013e31821917cc (author reply).PubMedCrossRefGoogle Scholar
  10. 10.
    Conroy S. Association between licence status and medication errors. Arch Dis Child. 2011;96(3):305–6. doi: 10.1136/adc.2010.191940.PubMedCrossRefGoogle Scholar
  11. 11.
    Turner S, Gill A, Nunn T, Hewitt B, Choonara I. Use of “off-label” and unlicensed drugs in paediatric intensive care unit. Lancet. 1996;347(9000):549–50. doi: 10.1016/S0140-6736(96)91182-4.PubMedCrossRefGoogle Scholar
  12. 12.
    Sutherland JM. Fatal cardiovascular collapse of infants receiving large amounts of chloramphenicol. AMA J Dis Child. 1959;97(6):761–7. doi: 10.1001/archpedi.1959.02070010763001.PubMedGoogle Scholar
  13. 13.
    Johnson TN. The development of drug metabolising enzymes and their influence on the susceptibility to adverse drug reactions in children. Toxicology. 2003;192(1):37–48. doi: 10.1016/S0300-483X(03)00249-X.PubMedCrossRefGoogle Scholar
  14. 14.
    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(9–10):435–42. doi: 10.1016/j.drudis.2011.02.014.PubMedCrossRefGoogle Scholar
  15. 15.
    Daschner M. Drug dosage in children with reduced renal function. Pediatr Nephrol. 2005;20(12):1675–86. doi: 10.1007/s00467-005-1922-9.PubMedCrossRefGoogle Scholar
  16. 16.
    Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol. 2008;64(12):1147–61. doi: 10.1007/s00228-008-0553-z.PubMedCrossRefGoogle Scholar
  17. 17.
    Verbeeck RK, Musuamba FT. Pharmacokinetics and dosage adjustment in patients with renal dysfunction. Eur J Clin Pharmacol. 2009;65(8):757–73. doi: 10.1007/s00228-009-0678-8.PubMedCrossRefGoogle Scholar
  18. 18.
    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(6):767–77. doi: 10.2174/138920012800840383.PubMedCrossRefGoogle Scholar
  19. 19.
    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(5):277–94. doi: 10.2165/11319360-000000000-00000.PubMedCrossRefGoogle Scholar
  20. 20.
    Schetz M. Drug dosing in continuous renal replacement therapy: general rules. Curr Opin Crit Care. 2007;13(6):645–51. doi: 10.1097/MCC.0b013e3282f0a3d3.PubMedCrossRefGoogle Scholar
  21. 21.
    Best Pharmaceuticals for Children Act, US Public Law 107–109, 2002.Google Scholar
  22. 22.
    European Parliament and the Council of the European Union. Regulation (EC) No. 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No. 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No. 726/2004. Off J Eur Union. 2006;49(L 378):1–19.Google Scholar
  23. 23.
    Benjamin DK Jr, Smith PB, Murphy MD, Roberts R, Mathis L, Avant D, et al. Peer-reviewed publication of clinical trials completed for pediatric exclusivity. JAMA. 2006;296(10):1266–73. doi: 10.1001/jama.296.10.1266.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Wimmer S, Rascher W, McCarthy S, Neubert A. The eu paediatric regulation: still a large discrepancy between therapeutic needs and approved paediatric investigation plans. Paediatr Drugs. 2014. doi: 10.1007/s40272-014-0082-4.
  25. 25.
    Davies EH, Ollivier CM, Saint Raymond A. Paediatric investigation plans for pain: painfully slow! Eur J Clin Pharmacol. 2010;66(11):1091–7. doi: 10.1007/s00228-010-0886-2.PubMedCrossRefGoogle Scholar
  26. 26.
    Kimland E, Odlind V. Off-label drug use in pediatric patients. Clin Pharmacol Ther. 2012;91(5):796–801. doi: 10.1038/clpt.2012.26.PubMedCrossRefGoogle Scholar
  27. 27.
    Yang CP, Veltri MA, Anton B, Yaster M, Berkowitz ID. Food and Drug Administration approval for medications used in the pediatric intensive care unit: a continuing conundrum. Pediatr Crit Care Med. 2011;12(5):e195–9. doi: 10.1097/PCC.0b013e3181fe25b9.PubMedCrossRefGoogle Scholar
  28. 28.
    Doherty DR, Pascuet E, Ni A, Stewart P, Splinter W, Vaillancourt R. Off-label drug use in pediatric anesthesia and intensive care according to official and pediatric reference formularies. Can J Anaesth. 2010;57(12):1078–88. doi: 10.1007/s12630-010-9395-0.PubMedCrossRefGoogle Scholar
  29. 29.
    Ceelie I, van der Starre C, Tibboel D, Stol K, Koren G, de Wildt SN. Evaluation of drug formularies for pediatric intensive care. Pediatr Crit Care Med. 2011;12(1):e14–9. doi: 10.1097/PCC.0b013e3181d90228.PubMedCrossRefGoogle Scholar
  30. 30.
    Morris AD, Zaritsky AL, LeFever G. Evaluation of ethical conflicts associated with randomized, controlled trials in critically ill children. Crit Care Med. 2000;28(4):1152–6. doi: 10.1097/00003246-199801001-00173.PubMedCrossRefGoogle Scholar
  31. 31.
    Duffett M, Choong K, Hartling L, Menon K, Thabane L, Cook DJ. Randomized controlled trials in pediatric critical care: a scoping review. Crit Care. 2013;17(5):R256. doi: 10.1186/cc13083.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Sharkey K, Savulescu J, Aranda S, Schofield P. Clinician gate-keeping in clinical research is not ethically defensible: an analysis. J Med Ethics. 2010;36(6):363–6. doi: 10.1136/jme.2009.031716.PubMedCrossRefGoogle Scholar
  33. 33.
    Menon K, Ward R, Canadian Critical Care Trials Group. A study of consent for participation in a non-therapeutic study in the pediatric intensive care population. J Med Ethics. 2014;40(2):123–6. doi: 10.1136/medethics-2012-101075.PubMedCrossRefGoogle Scholar
  34. 34.
    Harron K, Lee T, Ball T, Mok Q, Gamble C, Macrae D, et al. Making co-enrolment feasible for randomised controlled trials in paediatric intensive care. PloS One. 2012;7(8):e41791. doi: 10.1371/journal.pone.0041791.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Duffett M, Choong K, Foster J, Cheng J, Meade MO, Menon K, et al. Clonidine in the sedation of mechanically ventilated children: a pilot randomized trial. J Crit Care. 2014;29(5):758–63. doi: 10.1016/j.jcrc.2014.05.029.PubMedCrossRefGoogle Scholar
  36. 36.
    Rabe H. The need for noninvasive biomarkers for drug safety in neonatal circulation. Biomarkers Med. 2010;4(5):771–6. doi: 10.2217/bmm.10.88.CrossRefGoogle Scholar
  37. 37.
    Vet NJ, Ista E, de Wildt SN, van Dijk M, Tibboel D, de Hoog M. Optimal sedation in pediatric intensive care patients: a systematic review. Intensive Care Med. 2013;39(9):1524–34. doi: 10.1007/s00134-013-2971-3.PubMedCrossRefGoogle Scholar
  38. 38.
    de Graaf J, van Lingen RA, Valkenburg AJ, Weisglas-Kuperus N, Groot Jebbink L, Wijnberg-Williams B, et al. Does neonatal morphine use affect neuropsychological outcomes at 8 to 9 years of age? Pain. 2013;154(3):449–58. doi: 10.1016/j.pain.2012.12.006.PubMedCrossRefGoogle Scholar
  39. 39.
    Holubkov R, Dean JM, Berger J, Anand KJ, Carcillo J, Meert K, et al. Is “rescue” therapy ethical in randomized controlled trials? Pediatr Crit Care Med. 2009;10(4):431–8. doi: 10.1097/PCC.0b013e318198bd13.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    European Parliament and the Council of the Europan Union. Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC. Off J Eur Union. 2014;57(L 158):1–76.Google Scholar
  41. 41.
    Protections for children involved as subjects in research (45 CFR Part 46, Subpart D), 2009.Google Scholar
  42. 42.
    Kent G. Shared understandings for informed consent: the relevance of psychological research on the provision of information. Soc Sci Med. 1996;43(10):1517–23. doi: 10.1016/0277-9536(96)00173-6.PubMedCrossRefGoogle Scholar
  43. 43.
    Cuttini M. Proxy informed consent in pediatric research: a review. Early Hum Dev. 2000;60(2):89–100. doi: 10.1016/S0378-3782(00)00106-7.PubMedCrossRefGoogle Scholar
  44. 44.
    Balluffi A, Kassam-Adams N, Kazak A, Tucker M, Dominguez T, Helfaer M. Traumatic stress in parents of children admitted to the pediatric intensive care unit. Pediatr Crit Care Med. 2004;5(6):547–53. doi: 10.1097/01.PCC.0000137354.19807.44.PubMedCrossRefGoogle Scholar
  45. 45.
    Rees G, Gledhill J, Garralda ME, Nadel S. Psychiatric outcome following paediatric intensive care unit (PICU) admission: a cohort study. Intensive Care Med. 2004;30(8):1607–14. doi: 10.1007/s00134-004-2310-9.PubMedCrossRefGoogle Scholar
  46. 46.
    Woolfall K, Frith L, Gamble C, Young B. How experience makes a difference: practitioners’ views on the use of deferred consent in paediatric and neonatal emergency care trials. BMC Med Ethics. 2013;14:45. doi: 10.1186/1472-6939-14-45.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Menon K, Ward RE, Gaboury I, Thomas M, Joffe A, Burns K, et al. Factors affecting consent in pediatric critical care research. Intensive Care Med. 2012;38(1):153–9. doi: 10.1007/s00134-011-2412-0.PubMedCrossRefGoogle Scholar
  48. 48.
    Thomas M, Menon K. Consenting to pediatric critical care research: understanding the perspective of parents. Dynamics. 2013;24(3):18–24.PubMedGoogle Scholar
  49. 49.
    Hulst JM, Peters JW, van den Bos A, Joosten KF, van Goudoever JB, Zimmermann LJ, et al. Illness severity and parental permission for clinical research in a pediatric ICU population. Intensive Care Med. 2005;31(6):880–4. doi: 10.1007/s00134-005-2647-8.PubMedCrossRefGoogle Scholar
  50. 50.
    Flanagan BM, Philpott S, Strosberg MA. Protecting participants of clinical trials conducted in the intensive care unit. J Intensive Care Med. 2011;26(4):237–49. doi: 10.1177/0885066610390867.PubMedCrossRefGoogle Scholar
  51. 51.
    Needle JS, O’Riordan M, Smith PG. Parental anxiety and medical comprehension within 24 hrs of a child’s admission to the pediatric intensive care unit*. Pediatr Crit Care Med. 2009;10(6):668–74. doi: 10.1097/PCC.0b013e3181a706c9 (quiz 74).PubMedCrossRefGoogle Scholar
  52. 52.
    Ballard HO, Shook LA, Desai NS, Anand KJ. Neonatal research and the validity of informed consent obtained in the perinatal period. J Perinatol. 2004;24(7):409–15. doi: 10.1038/sj.jp.7211142.PubMedCrossRefGoogle Scholar
  53. 53.
    Mason SA, Allmark PJ. Obtaining informed consent to neonatal randomised controlled trials: interviews with parents and clinicians in the Euricon study. Lancet. 2000;356(9247):2045–51. doi: 10.1016/S0140-6736(00)03401-2.PubMedCrossRefGoogle Scholar
  54. 54.
    Chappuy H, Baruchel A, Leverger G, Oudot C, Brethon B, Haouy S, et al. Parental comprehension and satisfaction in informed consent in paediatric clinical trials: a prospective study on childhood leukaemia. Arch Dis Child. 2010;95(10):800–4. doi: 10.1136/adc.2009.180695.PubMedCrossRefGoogle Scholar
  55. 55.
    Tait AR, Voepel-Lewis T, Malviya S. Do they understand? (part I): parental consent for children participating in clinical anesthesia and surgery research. Anesthesiology. 2003;98(3):603–8. doi: 10.1097/00000542-200303000-00005.PubMedCrossRefGoogle Scholar
  56. 56.
    Raymond TT, Carroll TG, Sales G, Morris MC. Effectiveness of the informed consent process for a pediatric resuscitation trial. Pediatrics. 2010;125(4):e866–75. doi: 10.1542/peds.2009-2427.PubMedCrossRefGoogle Scholar
  57. 57.
    US Department of Health and Human Services. Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors: Exception from Informed Consent Requirements for Emergency Research (updated 2013). March 2011.Google Scholar
  58. 58.
    Koogler T. Legal and ethical policies regarding research involving critically ill children. Virtual Mentor. 2012;14(10):797–800. doi: 10.1001/virtualmentor.2012.14.10.pfor1-1210.PubMedCrossRefGoogle Scholar
  59. 59.
    Gamble C, Nadel S, Snape D, McKay A, Hickey H, Williamson P, et al. What parents of children who have received emergency care think about deferring consent in randomised trials of emergency treatments: postal survey. PloS One. 2012;7(5):e35982. doi: 10.1371/journal.pone.0035982.PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Woolfall K, Young B, Frith L, Appleton R, Iyer A, Messahel S, et al. Doing challenging research studies in a patient-centred way: a qualitative study to inform a randomised controlled trial in the paediatric emergency care setting. BMJ Open. 2014;4(5):e005045. doi: 10.1136/bmjopen-2014-005045.PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Eltorki M, Uleryk E, Freedman SB. Waiver of informed consent in pediatric resuscitation research: a systematic review. Acad Emerg Med. 2013;20(8):822–34. doi: 10.1111/acem.12180.PubMedCrossRefGoogle Scholar
  62. 62.
    Duffett M, Burns KE, Kho ME, Lauzier F, Meade MO, Arnold DM, et al. Consent in critical care trials: a survey of Canadian research ethics boards and critical care researchers. J Crit Care. 2011;26(5):533 e11–22. doi: 10.1016/j.jcrc.2010.12.009.CrossRefGoogle Scholar
  63. 63.
    Jansen TC, Bakker J, Kompanje EJ. Inability to obtain deferred consent due to early death in emergency research: effect on validity of clinical trial results. Intensive Care Med. 2010;36(11):1962–5. doi: 10.1007/s00134-010-1988-0.PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Jansen TC, Kompanje EJ, Druml C, Menon DK, Wiedermann CJ, Bakker J. Deferred consent in emergency intensive care research: what if the patient dies early? Use the data or not? Intensive Care Med. 2007;33(5):894–900. doi: 10.1007/s00134-007-0580-8.PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Maitland K, Molyneux S, Boga M, Kiguli S, Lang T. Use of deferred consent for severely ill children in a multi-centre phase III trial. Trials. 2011;12:90. doi: 10.1186/1745-6215-12-90.PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Simons SH, van Dijk M, van Lingen RA, Roofthooft D, Duivenvoorden HJ, Jongeneel N, et al. Routine morphine infusion in preterm newborns who received ventilatory support: a randomized controlled trial. JAMA. 2003;290(18):2419–27. doi: 10.1001/jama.290.18.2419.PubMedCrossRefGoogle Scholar
  67. 67.
    van Dijk M, Bouwmeester NJ, Duivenvoorden HJ, Koot HM, Tibboel D, Passchier J, et al. Efficacy of continuous versus intermittent morphine administration after major surgery in 0–3-year-old infants; a double-blind randomized controlled trial. Pain. 2002;98(3):305–13. doi: 10.1016/S0304-3959(02)00031-3.PubMedCrossRefGoogle Scholar
  68. 68.
    Knibbe CA, Krekels EH, van den Anker JN, DeJongh J, Santen GW, van Dijk M, et al. Morphine glucuronidation in preterm neonates, infants and children younger than 3 years. Clin Pharmacokinet. 2009;48(6):371–85. doi: 10.2165/00003088-200948060-00003.PubMedCrossRefGoogle Scholar
  69. 69.
    Krekels EH, Tibboel D, de Wildt SN, Ceelie I, Dahan A, van Dijk M, et al. Evidence-based morphine dosing for postoperative neonates and infants. Clin Pharmacokinet. 2014. doi: 10.1007/s40262-014-0135-4.
  70. 70.
    Ahsman MJ, Tibboel D, Mathot RA, de Wildt SN. Sample collection, biobanking, and analysis. Handb Exp Pharmacol. 2011;205:203–17. doi: 10.1007/978-3-642-20195-0_10.PubMedCrossRefGoogle Scholar
  71. 71.
    Autmizguine J, Benjamin DK, Smith PB, Sampson M, Ovetchkine P, Cohen-Wolkowiez M, et al. Pharmacokinetic studies in infants using minimal-risk study designs. Curr Clin Pharmacol. 2014.Google Scholar
  72. 72.
    Howie SR. Blood sample volumes in child health research: review of safe limits. Bull World Health Organ. 2011;89(1):46–53. doi: 10.2471/BLT.10.080010.PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    Vogeser M, Seger C. A decade of HPLC-MS/MS in the routine clinical laboratory—goals for further developments. Clin Biochem. 2008;41(9):649–62. doi: 10.1016/j.clinbiochem.2008.02.017.PubMedCrossRefGoogle Scholar
  74. 74.
    Jebrail MJ, Bartsch MS, Patel KD. Digital microfluidics: a versatile tool for applications in chemistry, biology and medicine. Lab Chip. 2012;12(14):2452–63. doi: 10.1039/c2lc40318h.PubMedCrossRefGoogle Scholar
  75. 75.
    Wootton RC, Demello AJ. Microfluidics: analog-to-digital drug screening. Nature. 2012;483(7387):43–4. doi: 10.1038/483043a.PubMedCrossRefGoogle Scholar
  76. 76.
    Lafreniere NM, Shih SC, Abu-Rabie P, Jebrail MJ, Spooner N, Wheeler AR. Multiplexed extraction and quantitative analysis of pharmaceuticals from DBS samples using digital microfluidics. Bioanalysis. 2014;6(3):307–18. doi: 10.4155/bio.13.311.PubMedCrossRefGoogle Scholar
  77. 77.
    Li CG, Lee CY, Lee K, Jung H. An optimized hollow microneedle for minimally invasive blood extraction. Biomed Microdevices. 2013;15(1):17–25. doi: 10.1007/s10544-012-9683-2.PubMedCrossRefGoogle Scholar
  78. 78.
    Lehmann S, Delaby C, Vialaret J, Ducos J, Hirtz C. Current and future use of “dried blood spot” analyses in clinical chemistry. Clin Chem Lab Med. 2013;51(10):1897–909. doi: 10.1515/cclm-2013-0228.PubMedCrossRefGoogle Scholar
  79. 79.
    Cohen-Wolkowiez M, Watt KM, Zhou C, Bloom BT, Poindexter B, Castro L, et al. Developmental pharmacokinetics of piperacillin and tazobactam using plasma and dried blood spots from infants. Antimicrob Agents Chemother. 2014;58(5):2856–65. doi: 10.1128/AAC.02139-13.PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    Spooner N, Lad R, Barfield M. Dried blood spots as a sample collection technique for the determination of pharmacokinetics in clinical studies: considerations for the validation of a quantitative bioanalytical method. Anal Chem. 2009;81(4):1557–63. doi: 10.1021/ac8022839.PubMedCrossRefGoogle Scholar
  81. 81.
    de Boer T, Wieling J, Meulman E, Reuvers M, Renkema G, den Daas I, et al. Application of dried blood spot sampling combined with LC–MS/MS for genotyping and phenotyping of CYP450 enzymes in healthy volunteers. Biomed Chromatogr BMC. 2011;25(10):1112–23. doi: 10.1002/bmc.1580.CrossRefGoogle Scholar
  82. 82.
    Hollegaard MV, Grauholm J, Nielsen R, Grove J, Mandrup S, Hougaard DM. Archived neonatal dried blood spot samples can be used for accurate whole genome and exome-targeted next-generation sequencing. Mol Genet Metab. 2013;110(1–2):65–72. doi: 10.1016/j.ymgme.2013.06.004.PubMedCrossRefGoogle Scholar
  83. 83.
    Hollegaard MV, Grauholm J, Norgaard-Pedersen B, Hougaard DM. DNA methylome profiling using neonatal dried blood spot samples: a proof-of-principle study. Mol Genet Metab. 2013;108(4):225–31. doi: 10.1016/j.ymgme.2013.01.016.PubMedCrossRefGoogle Scholar
  84. 84.
    Admiraal R, van Kesteren C, Boelens JJ, Bredius RG, Tibboel D, Knibbe CA. Towards evidence-based dosing regimens in children on the basis of population pharmacokinetic pharmacodynamic modelling. Arch Dis Child. 2014;99(3):267–72. doi: 10.1136/archdischild-2013-303721.PubMedCrossRefGoogle Scholar
  85. 85.
    Marsot A, Boulamery A, Bruguerolle B, Simon N. Population pharmacokinetic analysis during the first 2 years of life: an overview. Clin Pharmacokinet. 2012;51(12):787–98. doi: 10.1007/s40262-012-0015-8.PubMedCrossRefGoogle Scholar
  86. 86.
    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. doi: 10.1007/s00228-009-0782-9.PubMedCentralPubMedCrossRefGoogle Scholar
  87. 87.
    Ahsman MJ, Wildschut ED, Tibboel D, Mathot RA. Pharmacokinetics of cefotaxime and desacetylcefotaxime in infants during extracorporeal membrane oxygenation. Antimicrob Agents Chemother. 2010;54(5):1734–41. doi: 10.1128/AAC.01696-09.PubMedCentralPubMedCrossRefGoogle Scholar
  88. 88.
    Vuong LT, Blood AB, Vogel JS, Anderson ME, Goldstein B. Applications of accelerator MS in pediatric drug evaluation. Bioanalysis. 2012;4(15):1871–82. doi: 10.4155/bio.12.173.PubMedCrossRefGoogle Scholar
  89. 89.
    European Medicines Agency. ICH guideline M3(R2) on non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals. 2009.Google Scholar
  90. 90.
    US Department of Health and Human Services. Guidance for industry, investigators and reviewers: exploratory IND studies. 2006.Google Scholar
  91. 91.
    Salehpour M, Possnert G, Bryhni H. Subattomole sensitivity in biological accelerator mass spectrometry. Anal Chem. 2008;80(10):3515–21. doi: 10.1021/ac800174j.PubMedCrossRefGoogle Scholar
  92. 92.
    Vet NJ, de Wildt SN, Verlaat CW, Knibbe CA, Mooij MG, Hop WC, et al. Daily interruption of sedation in critically ill children: study protocol for a randomized controlled trial. Trials. 2014;15:55. doi: 10.1186/1745-6215-15-55.PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Carroll TG, Dimas VV, Raymond TT. Vasopressin rescue for in-pediatric intensive care unit cardiopulmonary arrest refractory to initial epinephrine dosing: a prospective feasibility pilot trial. Pediatr Crit Care Med. 2012;13(3):265–72. doi: 10.1097/PCC.0b013e31822f1569.PubMedCrossRefGoogle Scholar
  94. 94.
    Mooij MG, van Duijn E, Knibbe CA, Windhorst AD, Hendrikse NH, Vaes WH, et al. Pediatric microdose study of [C]Paracetamol to study drug metabolism using accelerated mass spectrometry: proof of concept. Clin Pharmacokinet. 2014. doi: 10.1007/s40262-014-0176-8.

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Niina Kleiber
    • 1
  • Krista Tromp
    • 2
  • Miriam G. Mooij
    • 1
  • Suzanne van de Vathorst
    • 2
  • Dick Tibboel
    • 1
  • Saskia N. de Wildt
    • 1
    Email author
  1. 1.Intensive Care and Department of Pediatric SurgeryErasmus MC–Sophia Children’s HospitalRotterdamThe Netherlands
  2. 2.Department of Medical Ethics and Philosophy of MedicineErasmus MCRotterdamThe Netherlands

Personalised recommendations