Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Every 36-h gentamicin dosing in neonates with hypoxic–ischemic encephalopathy receiving hypothermia

Journal of Perinatology volume 33, pages 778–782 (2013)Cite this article

Subjects

Abstract

Objective:

To examine the impact of a change in the empiric gentamicin dose from 5 mg kg−1 every 24 h (Q24 h period) to 5 mg kg every 36 h (Q36 h period) on target drug concentration achievement in neonates with hypoxic ischemic encephalopathy (HIE) receiving therapeutic hypothermia.

Study Design:

Gentamicin drug concentrations in neonates with HIE receiving therapeutic hypothermia were examined during two time periods in a retrospective chart review. During the initial treatment period (November 2007 to March 2010; n=29), neonates received Q24 h period. During the second treatment period (January 2011 to May 2012; n=23), the dose was changed to Q36 h period. Cooling criteria and protocol remained the same between treatment periods. Gentamicin drug concentrations including achievement of target trough concentrations (<2 mg l−1) were compared between treatment periods. Individual Bayesian estimates of gentamicin clearance were also compared.

Result:

Neonates with an elevated trough concentration >2 mg l−1 decreased from 38 to 4% with implementation of a Q36-h dosing interval (P<0.007). The mean gentamicin trough concentration was 2.0±0.8 mg l−1 during the Q24 h period and 0.9±0.4 mg l−1 during the Q36 h period (P<0.001). Peak concentrations were minimally impacted (Q24 h 11.4±2.3 mg l−1 vs Q36 h 10.0±1.9 mg l−1; P=0.05). The change in gentamicin trough concentration could not be accounted for by differences in gentamicin clearance between treatment periods (P=0.9).

Conclusion:

A 5 mg kg−1 every 36-h gentamicin dosing strategy in neonates with HIE receiving therapeutic hypothermia improved achievement of target trough concentration <2 mg l−1, while still providing high peak concentration exposure.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. 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 (14): 1349–1358.

    Article  CAS  Google Scholar 

  2. Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005; 365 (9460): 663–670.

    Article  Google Scholar 

  3. Róka A, Vásárhelyi B, Bodrogi E, Machay T, Szabó M . Changes in laboratory parameters indicating cell necrosis and organ dysfunction in asphyxiated neonates on moderate systemic hypothermia. Acta Paediatr 2007; 96 (8): 1118–1121.

    Article  Google Scholar 

  4. 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 (2): F152–F155.

    Article  CAS  Google Scholar 

  5. Tarcan A, Tiker F, Güvenir H, Gürakan B . Hepatic involvement in perinatal asphyxia. J Matern Fetal Neonatal Med 2007; 20 (5): 407–410.

    Article  Google Scholar 

  6. Perlman JM, Wyllie J, Kattwinkel J, Atkins DL, Chameides L, Goldsmith JP et al. Part 11: Neonatal resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation 2010; 122 (16 Suppl 2): S516–S538.

    Article  Google Scholar 

  7. Zanelli S, Buck M, Fairchild K . Physiologic and pharmacologic considerations for hypothermia therapy in neonates. J Perinatol 2011; 31 (6): 377–386.

    Article  CAS  Google Scholar 

  8. Liu X, Borooah M, Stone J, Chakkarapani E, Thoresen M . Serum gentamicin concentrations in encephalopathic infants are not affected by therapeutic hypothermia. Pediatrics 2009; 124 (1): 310–315.

    Article  Google Scholar 

  9. Frymoyer A, Meng L, Bonifacio SL, Verotta D, Guglielmo BJ . Gentamicin pharmacokinetics and dosing in neonates with hypoxic ischemic encephalopathy receiving hypothermia. Pharmacotherapy, advance online publication, 1 April 2013 (e-pub ahead of print).

  10. Bonifacio SL, Glass HC, Vanderpluym J, Agrawal AT, Xu D, Barkovich AJ et al. Perinatal events and early magnetic resonance imaging in therapeutic hypothermia. J Pediatr 2011; 158 (3): 360–365.

    Article  Google Scholar 

  11. Anderson BJ, Holford NHG . . Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol 2008; 48: 303–332.

    Article  CAS  Google Scholar 

  12. Shah PS . Hypothermia: a systematic review and meta-analysis of clinical trials. Semin Fetal Neonatal Med 2010; 15 (5): 238–246.

    Article  Google Scholar 

  13. Glass HC, Bonifacio SL, Peloquin S, Shimotake T, Sehring S, Sun Y et al. Neurocritical care for neonates. Neurocrit Care 2010; 12 (3): 421–429.

    Article  Google Scholar 

  14. Clark RH, Bloom BT, Spitzer AR, Gerstmann DR . Reported medication use in the neonatal intensive care unit: data from a large national data set. Pediatrics 2006; 117 (6): 1979–1987.

    Article  Google Scholar 

  15. Rao SC, Srinivasjois R, Hagan R, Ahmed M . One dose per day compared to multiple doses per day of gentamicin for treatment of suspected or proven sepsis in neonates. Cochrane Database Syst Rev 2011; 11, CD005091.

  16. Lacy MK, Nicolau DP, Nightingale CH, Quintiliani R . The pharmacodynamics of aminoglycosides. Clin Infect Dis 1998; 27 (1): 23–27.

    Article  CAS  Google Scholar 

  17. Gentamicin injection USP (package insert). APP Pharmaceuticals LLC: Schaumberg, IL, USA, 2008.

  18. Thomson AH, Way S, Bryson SM, McGovern EM, Kelman AW, Whiting B . Population pharmacokinetics of gentamicin in neonates. Dev Pharmacol Ther 1988; 11 (3): 173–179.

    Article  CAS  Google Scholar 

  19. Weber W, Kewitz G, Rost KL, Looby M, Nitz M, Harnisch L . Population kinetics of gentamicin in neonates. Eur J Clin Pharmacol 1993; 44 (Suppl 1): S23–S25.

    Article  Google Scholar 

  20. García B, Barcia E, Pérez F, Molina IT . Population pharmacokinetics of gentamicin in premature newborns. J Antimicrob Chemother 2006; 58 (2): 372–379.

    Article  Google Scholar 

  21. Nielsen EI, Sandström M, Honoré PH, Ewald U, Friberg LE . Developmental pharmacokinetics of gentamicin in preterm and term neonates: population modelling of a prospective study. Clin Pharmacokinet 2009; 48 (4): 253–263.

    Article  CAS  Google Scholar 

  22. Sarafidis K, Tsepkentzi E, Agakidou E, Diamanti E, Taparkou A, Soubasi V et al. Serum and urine acute kidney injury biomarkers in asphyxiated neonates. Pediatr Nephrol 2012; 27 (9): 1575–1582.

    Article  Google Scholar 

  23. Askenazi DJ, Ambalavanan N, Goldstein SL . Acute kidney injury in critically ill newborns: What do we know? What do we need to learn? Pediatr. Nephrology 2009; 24 (2): 265–274.

    Google Scholar 

  24. Askenazi DJ, Griffin R, McGwin G, Carlo W, Ambalavanan N . Acute kidney injury is independently associated with mortality in very low birthweight infants: a matched case–control analysis. Pediatr Nephrol 2009; 24 (5): 991–997.

    Article  Google Scholar 

  25. Krawczeski CD, Woo JG, Wang Y, Bennett MR, Ma Q, Devarajan P . Neutrophil gelatinase-associated lipocalin concentrations predict development of acute kidney injury in neonates and children after cardiopulmonary bypass. J Pediatr 2011; 158 (6): 1009–1015.

    Article  CAS  Google Scholar 

  26. Askenazi DJ, Montesanti A, Hunley H, Koralkar R, Pawar P, Shuaib F et al. Urine biomarkers predict acute kidney injury and mortality in very low birth weight infants. J Pediatr 2011; 159 (6): 907–912 e1.

    Article  CAS  Google Scholar 

  27. Koren G, Barker C, Bohn D, Kent G, Biggar WD . Influence of hypothermia on the pharmacokinetics of gentamicin and theophylline in piglets. Crit Care Med 1985; 13 (10): 844–847.

    Article  CAS  Google Scholar 

  28. Satas S, Hoem NO, Melby K, Porter H, Lindgren CG, Whitelaw A et al. Influence of mild hypothermia after hypoxia–ischemia on the pharmacokinetics of gentamicin in newborn pigs. Biol Neonate 2000; 77 (1): 50–57.

    Article  CAS  Google Scholar 

  29. Shellhaas RA, Ng CM, Dillon CH, Barks JDE, Bhatt-Mehta V . Population pharmacokinetics of phenobarbital in infants with neonatal encephalopathy treated with therapeutic hypothermia. Pediatr Crit Care Med 2012; 14 (2): 194–202.

    Article  Google Scholar 

  30. Van den Broek MPH, Groenendaal F, Toet MC, Van Straaten HLM, Van Hasselt JGC, Huitema ADR et al. Pharmacokinetics and clinical efficacy of phenobarbital in asphyxiated newborns treated with hypothermia: a thermopharmacological approach. Clin Pharmacokinet 2012; 51 (10): 671–679.

    Article  CAS  Google Scholar 

  31. Gal P, Toback J, Erkan NV, Boer HR . The influence of asphyxia on phenobarbital dosing requirements in neonates. Dev Pharmacol Ther 1984; 7 (3): 145–152.

    Article  CAS  Google Scholar 

  32. Rastogi A, Agarwal G, Pyati S, Pildes RS . Comparison of two gentamicin dosing schedules in very low birth weight infants. Pediatr Infect Dis J 2002; 21 (3): 234–240.

    Article  Google Scholar 

  33. Touw DJ, Westerman EM, Sprij AJ . Therapeutic drug monitoring of aminoglycosides in neonates. Clin Pharmacokinet 2009; 48 (2): 71–88.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Susan Peloquin, RN, MS, Clinical Coordinator of the UCSF Neuro-Intensive Care Nursery and members of the UCSF Neuro-Intensive Care Nursery leadership and nursing teams for helping support this project. AF received support, in part, by the National Institutes of Health Grant R01 AI50587. DV received support, in part, by National Institutes of Health Grant R01 AI50587, GM26696. SLB received support by the National Center for Advancing Translational Sciences and National Institutes of Health through UCSF-CTSI Grant KL2TR000143.

Author contributions

AF wrote the first draft of the manuscript and NO honorarium, grant or other form of payment was given to anyone to produce the manuscript. Each author listed on the manuscript has seen and approved the submission of this version of the manuscript and takes full responsibility for the manuscript. Each author clearly meets authorship criteria as described at http://www.icmje.org.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Stanford University, San Francisco, CA, USA

    A Frymoyer

  2. Department of Clinical Pharmacy, University of California, San Francisco, San Francisco, CA, USA

    S Lee, S S Lucas & B J Guglielmo

  3. Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA

    S L Bonifacio & Y Sun

  4. Department of Pharmacy, Stanford Hospital and Clinics, San Francisco, CA, USA

    L Meng

  5. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA

    D Verotta

Authors
  1. A Frymoyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S L Bonifacio
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S S Lucas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B J Guglielmo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Y Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D Verotta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Frymoyer.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Previously presented: (1) data from the Q24 h period were used for a published population pharmacokinetic analysis and formed the basis for the every 36-h gentamicin dose change under study; (2) Preliminary findings of this work, in part, will be presented as abstract and poster for the Pediatric Academic Societies Annual Meeting, Washington, DC, 4–7 May 2013.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Frymoyer, A., Lee, S., Bonifacio, S. et al. Every 36-h gentamicin dosing in neonates with hypoxic–ischemic encephalopathy receiving hypothermia. J Perinatol 33, 778–782 (2013). https://doi.org/10.1038/jp.2013.59

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/jp.2013.59

Keywords

This article is cited by

Search

Advanced search

Quick links