What should be the recommended empirical gentamicin regimen for neonatal patients undergoing therapeutic hypothermia?

Comment by InpharmD Researcher

According to current guidance from the American Academy of Pediatrics (AAP), an empiric gentamicin regimen of 5 mg/kg/dose every 36 hours with therapeutic drug monitoring (TDM) is recommended for neonates with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia. Supporting pharmacokinetic evidence is relatively limited but generally consistent, demonstrating reduced gentamicin clearance and prolonged elimination during therapeutic hypothermia. Compared with 24-hour dosing, extending the dosing interval to 36 hours has been associated with lower trough concentrations while maintaining peak exposure. TDM remains important given variability in gentamicin clearance related to gestational age, renal function, and changes following rewarming.
Background

The 2026 clinical report from the American Academy of Pediatrics (AAP) recommends gentamicin 5 mg/kg/dose every 36 hours with therapeutic drug monitoring in neonates with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia. The report notes that therapeutic hypothermia and multiorgan dysfunction associated with HIE can alter drug disposition, with reduced clearance, longer half-lives, and increased drug exposures, particularly for renally eliminated medications. Specifically, gentamicin has decreased clearance and a prolonged half-life during therapeutic hypothermia, with delayed clearance supporting a 36-hour dosing interval. [1]

Reviews assessing gentamicin pharmacokinetics and dosing in neonates undergoing therapeutic hypothermia describe reduced gentamicin clearance and prolonged elimination compared with normothermic neonates, with reported reductions in clearance of approximately 25%–50%. Gentamicin regimens evaluated during therapeutic hypothermia have included 2.5 mg/kg every 12 hours, 4 mg/kg every 24 hours, and 4–5 mg/kg every 36 hours; extending the dosing interval from 24 to 36 hours increased the proportion of neonates with trough concentrations <2 mg/L from 62% to 96% without reducing the proportion achieving the targeted peak concentration. Therapeutic drug monitoring is recommended to guide subsequent dosing because of variability in gentamicin pharmacokinetics and to optimize the dosing interval. [2], [3]

A 2018 meta-analysis assessed the effect of therapeutic hypothermia on gentamicin pharmacokinetics and dosing in near-term and term neonates with HIE, including 8 observational studies and 277 patients. Gentamicin clearance was significantly lower with hypothermia compared with normothermia (mean difference −0.21 mL/kg/min; 95% confidence interval [CI] −0.31 to −0.12), while trough concentrations were numerically higher but did not differ significantly (mean difference 0.81 mg/L; 95% CI −0.07 to 1.69); gestational age, birthweight, and serum creatinine were identified as factors affecting clearance. Most included studies used gentamicin 4–5 mg/kg every 24 hours, although studies evaluating extended intervals found that 4–5 mg/kg every 36 hours achieved target concentrations, including simulations predicting trough concentrations <2 mg/L in >90% of neonates. Based on the reviewed pharmacokinetic and dosing data, the authors recommended a 36-hour gentamicin dosing interval for neonates with HIE undergoing therapeutic hypothermia. [4]

Background References: [1] Zanelli SA, Wusthoff CJ, Lucke AM, Kaufman DA; Committee on Fetus and Newborn ; Section on Neurology . Therapeutic Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy: Clinical Report. Pediatrics. 2026;157(2):e2025073627. doi:10.1542/peds.2025-073627
[2] Lutz IC, Allegaert K, de Hoon JN, Marynissen H. Pharmacokinetics during therapeutic hypothermia for neonatal hypoxic ischaemic encephalopathy: a literature review. BMJ Paediatr Open. 2020;4(1):e000685. Published 2020 Jun 15. doi:10.1136/bmjpo-2020-000685
[3] Hodiamont CJ, van den Broek AK, de Vroom SL, Prins JM, Mathôt RAA, van Hest RM. Clinical Pharmacokinetics of Gentamicin in Various Patient Populations and Consequences for Optimal Dosing for Gram-Negative Infections: An Updated Review. Clin Pharmacokinet. 2022;61(8):1075-1094. doi:10.1007/s40262-022-01143-0
[4] Choi DW, Park JH, Lee SY, An SH. Effect of hypothermia treatment on gentamicin pharmacokinetics in neonates with hypoxic-ischaemic encephalopathy: A systematic review and meta-analysis. J Clin Pharm Ther. 2018;43(4):484-492. doi:10.1111/jcpt.12711
Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What should be the recommended empirical gentamicin regimen for neonatal patients undergoing therapeutic hypothermia?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-3 for your response.

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

Retrospective chart review

N= 52
Objective To examine the impact of a change in the empiric gentamicin dose from 5 mg/kg every 24 h to 5 mg/kg every 36 h on target drug concentration achievement in neonates with hypoxic ischemic encephalopathy receiving therapeutic hypothermia
Study Groups

Q24 h period (n= 29)

Q36 h period (n= 23)
Inclusion Criteria Neonates with hypoxic ischemic encephalopathy receiving therapeutic hypothermia
Exclusion Criteria Neonates with incomplete gentamicin dose or drug concentration history, requiring extracorporeal membrane oxygenation, or with congenital heart disease or kidney disease
Methods

Retrospective chart review comparing gentamicin concentrations in neonates with HIE receiving whole-body therapeutic hypothermia (33.5°C) for rule-out sepsis before and after a change in empirical dosing from 5 mg/kg IV every 24 hours to every 36 hours. Trough concentrations were recommended after the second or third dose and obtained immediately before the next dose; peak concentrations, additionally monitored during the every-36-hour period, were obtained 30 minutes after completion of a 30-minute infusion.
Duration November 2007 to March 2010 (Q24 h period); January 2011 to May 2012 (Q36 h period)
Outcome Measures Achievement of target trough concentration <2 mg/L; peak concentration exposure
Baseline Characteristics   Q24 h period (n= 29) Q36 h period (n= 23)
Gestational age, weeks 39.3 ± 1.9 40.2 ± 1.1
Birthweight, kg 3.26 ± 0.58 3.45 ± 0.57

APGAR

5 min

10 min

 

3 ± 2

5 ± 2

 

4 ± 2

5 ± 2
Base deficit, mmol/L -20 ± 8 -15 ± 6
Serum creatinine, mg/dL 1.0 ± 0.3 1.0 ± 0.2
Death before discharge 6 (21%) 0 (0%)
Abbreviations: APGAR, Appearance, Pulse, Grimace, Activity, Respiration.
Results   Q24 h period (n= 29) Q36 h period (n= 23) p-value
Mean trough concentration, mg/L 2.0 ± 0.8 0.9 ± 0.4 <0.001
Elevated trough concentration >2 mg/L 11 (38%) 1 (4%) <0.007
Mean peak concentration, mg/L 11.4 ± 2.3 10.0 ± 1.9 0.05
Gentamicin clearance was similar between groups (1.15 ± 0.19 vs 1.17 ± 0.24 L/h/70 kg; p= 0.9).
Adverse Events Not specifically reported in the study
Study Author Conclusions

A 5 mg/kg every 36-h gentamicin dosing strategy in neonates with HIE receiving therapeutic hypothermia improved achievement of target trough concentration <2 mg/L, while still providing high peak concentration exposure.
Critique The study effectively demonstrated the benefits of a 36-hour dosing interval for gentamicin in achieving target trough concentrations in neonates with HIE. However, the retrospective design and small sample size may limit the generalizability of the findings. Additionally, the study did not directly evaluate clinical outcomes related to treatment effectiveness or toxicity.
Table 1 References:
[5] Frymoyer A, Lee S, Bonifacio SL, et al. Every 36-h gentamicin dosing in neonates with hypoxic-ischemic encephalopathy receiving hypothermia. J Perinatol. 2013;33(10):778-782. doi:10.1038/jp.2013.59
Gentamicin Pharmacokinetics and Dosing in Neonates with Hypoxic Ischemic Encephalopathy Receiving Hypothermia
Design

Population pharmacokinetic study using retrospective medical record data

N= 29
Objective To evaluate the pharmacokinetics of gentamicin in neonates with hypoxic ischemic encephalopathy (HIE) receiving hypothermia and to identify an empiric gentamicin dosing strategy in this population that optimizes achievement of target peak and trough concentrations
Study Groups All patients (N= 29)
Inclusion Criteria Full-term neonates diagnosed with HIE treated with hypothermia who received gentamicin and underwent therapeutic drug monitoring
Exclusion Criteria Gentamicin drug levels or a complete gentamicin dosing history not available, extracorporeal membrane oxygenation required during the gentamicin course, or congenital heart disease or kidney disease diagnosed
Methods Patient demographics, gentamicin dosing, and concentration data were retrospectively collected over a 2-year period. The recommended regimen was gentamicin 5 mg/kg IV every 24 hours, administered over 30 minutes, with TDM at the third or fourth dose when therapy continued beyond 48 hours; target peak and trough concentrations were >6 mg/L and <2 mg/L, respectively. A population pharmacokinetic model was developed, and Monte Carlo simulations of 5,000 hypothetical neonates evaluated doses of 3–5 mg/kg every 24, 36, or 48 hours for achievement of target peak and trough concentrations.
Duration November 2007–March 2010
Outcome Measures Achievement of target peak (> 6 mg/L) and trough (< 2 mg/L) gentamicin concentrations; influence of birthweight and serum creatinine on gentamicin clearance
Baseline Characteristics   All patients (N= 29)
Gestational age, wks (IQR) 40.0 (37.6–40.7)
Birthweight, kg (IQR) 3.32 (2.97–3.50)
Female 18 (62%)
Apgar 5 min (IQR) 3 (1–4)
Apgar 10 min (IQR) 5 (3–6)
First arterial or capillary pH (IQR) 7.0 (6.9–7.1)
Base deficit, mmol/L (IQR) -19 (-15 to -27)
Serum creatinine on PNA day 1, mg/dl (IQR) 0.9 (0.8–1.2)
Assisted ventilation 24 (83%)
Seizures 16 (55%)
Dopamine 18 (62%)
Death before discharge 6 (21%)
Abbreviations: IQR, interquartile range; PNA, postnatal age.
Results   Peak Trough
24-hr interval, 5 mg/kg (IQR) 11.8 (8.5-15.7) 2.3 (1.0-4.5)
36-hr interval, 5 mg/kg (IQR) 10.5 (7.8-13.5) 0.9 (0.3-2.0)
48-hr interval, 5 mg/kg (IQR) 10.0 (7.3-12.8) 0.4 (0.1-1.0)

A total of 29 neonates were included in the population pharmacokinetic analysis, with 25 receiving an empiric gentamicin regimen of 5 mg/kg every 24 hours. The median initial trough concentration was 1.8 mg/L (IQR, 1.4–2.6), with 38% (11/29) having a trough ≥2 mg/L; all measured initial peak concentrations were ≥6 mg/L.

Birthweight and serum creatinine significantly influenced gentamicin clearance, with higher serum creatinine associated with lower clearance.

Monte Carlo simulations found that q24h dosing did not reliably achieve trough concentrations <2 mg/L at any evaluated dose, whereas >90% of simulated neonates achieved trough concentrations <2 mg/L with 3–5 mg/kg every 36 or 48 hours; doses of 4.5–5 mg/kg achieved first-dose peak concentrations >6 mg/L in >90%.

With 5 mg/kg every 36 hours, achievement of target trough concentrations declined with increasing serum creatinine and fell below 80% at serum creatinine ≥1.3 mg/dL.
Adverse Events Not specifically reported in the study
Study Author Conclusions Gentamicin clearance is decreased in neonates with HIE treated with hypothermia compared with previous reports in nonasphyxiated normothermic full-term neonates. A prolonged 36-hour dosing interval will be needed to achieve target gentamicin trough concentrations in this population. Further prospective evaluation of this dosing recommendation is needed.
Critique This study directly evaluated empiric gentamicin dosing in neonates with HIE receiving therapeutic hypothermia and identified 4–5 mg/kg every 36 hours as a simulated regimen associated with target peak and trough achievement in >90% of neonates. However, the pharmacokinetic model was derived from a small, single-center retrospective cohort of 29 neonates, most of whom actually received 5 mg/kg every 24 hours; the every-36-hour regimen was evaluated through Monte Carlo simulation rather than administered to this study population. The authors noted that prospective evaluation of the dosing recommendation was needed.
Table 2 References:
[6] Frymoyer A, Meng L, Bonifacio SL, Verotta D, Guglielmo BJ. Gentamicin pharmacokinetics and dosing in neonates with hypoxic ischemic encephalopathy receiving hypothermia. Pharmacotherapy. 2013 Jul;33(7):718-26. doi:10.1002/phar.1263
Altered gentamicin pharmacokinetics in term neonates undergoing controlled hypothermia
Design

Prospective observational cohort study

N= 47
Objective To evaluate and describe the population pharmacokinetics of gentamicin in term neonates undergoing controlled hypothermia after hypoxic-ischaemic encephalopathy due to perinatal asphyxia
Study Groups All patients (N= 47)
Inclusion Criteria Term newborns (>37 weeks gestational age) fulfilling the criteria of perinatal asphyxia, cooled within 6 hours after birth to a core body temperature of 33.5°C for 72 hours, and rewarmed to normothermia (36.5°C) over 8 hours
Exclusion Criteria Presence of congenital hepatic or renal pathology, no central venous or arterial line for non-invasive blood sampling, or no parental informed consent
Methods

Gentamicin was prescribed at 4 mg/kg once daily with dose adjustments based on TDM. Population pharmacokinetic modeling was performed using gentamicin concentration data collected during hypothermia and after return to normothermia. Monte Carlo simulations evaluated gentamicin 4 or 5 mg/kg every 24, 36, or 48 hours, using trough concentrations <1 mg/L and peak concentrations of 8–10 mg/L as reference values to select the dosing regimen.
Duration November 2010 to October 2014
Outcome Measures Description of the pharmacokinetic properties of gentamicin; evaluation of the most optimal dosing regimen based on simulations
Baseline Characteristics   All patients (N= 47)
GA, weeks (IQR) 40 (36-42)
BW, g (IQR) 3400 (2090-5070)
Male 27 (58.7%)
PNA, days 4.7 (2.3-5.2)
SCr, μmol/l 49 (26-114)
ASAT, U/l 58 (19-9179)
ALAT, U/l 23 (3-2631)
MOF 19 (40.4%)
Inotropic medication 30 (63.8%)
Thompson score 9 (3-19)

Abbreviations: ALAT, alanine aminotransferase; ASAT, aspartate aminotransferase; BW, birth weight; GA, gestational age; IQR, interquartile range; MOF, multi-organ failure; PNA, postnatal age; SCr, serum creatinine.

Most patients received approximately 4 mg/kg every 24 hours (33/47; 70%), while 8 (17%) received approximately 4 mg/kg every 36 hours, 3 (6%) received 4 mg/kg every 48 hours, and the remaining 3 received approximately 5 mg/kg every 36 or 48 hours.
Results

Gentamicin clearance was unchanged during the first 4 study days and increased by 29% after study day 5 (>96 hours postnatal age), when normothermia had been reached; gestational age significantly influenced clearance. In simulations, among neonates at 36, 38, and 40 weeks’ gestation, 5 mg/kg every 36 hours produced median trough concentrations of 0.7, 0.6, and 0.4 mg/L and median peak concentrations of 9.5, 9.5, and 9.2 mg/L, respectively.

In comparison, 5 mg/kg every 24 hours produced higher median trough concentrations of 1.6, 1.4, and 1.0 mg/L, while 5 mg/kg every 48 hours produced lower trough concentrations of 0.4, 0.3, and 0.2 mg/L. Based on the simulations, the authors selected 5 mg/kg every 36 hours for neonates at 36–40 weeks’ gestation and 5 mg/kg every 24 hours at 42 weeks as regimens providing the specified peak and trough concentrations.
Adverse Events Not specifically reported in the study
Study Author Conclusions The study describes the pharmacokinetics of gentamicin in neonates undergoing controlled hypothermia, showing a 29% higher clearance in the normothermic phase compared to the hypothermic and rewarming phases. The authors recommend an empiric dose of 5 mg/kg every 36 hours or every 24 hours for patients with gestational age 36–40 weeks and 42 weeks, respectively.
Critique

The study provides valuable prospective data on the pharmacokinetics of gentamicin in neonates undergoing controlled hypothermia, addressing a gap in existing literature. However, the study's findings are limited by the lack of a control group due to ethical considerations, and the variability in gentamicin dosing regimens prior to study inclusion may affect the generalizability of the results.
Table 3 References:
[7] Bijleveld YA, de Haan TR, van der Lee HJ, et al. Altered gentamicin pharmacokinetics in term neonates undergoing controlled hypothermia. Br J Clin Pharmacol. 2016;81(6):1067-1077. doi:10.1111/bcp.12883