Otoacoustic Emission Screens in Neonates Who Had Gentamicin
Otoacoustic Emission Screens in Neonates Who Had Gentamicin
Study Objective. To characterize the extent that serum gentamicin concentrations are associated with hearing loss indicated by otoacoustic emission (OAE) screen failure in critically ill neonates receiving gentamicin in accordance with a high-dose, extended-interval dosing protocol.
Design. Retrospective medical record review.
Setting. Two neonatal intensive care units in a pediatric tertiary care system.
Patients. Sequential sample of 528 critically ill neonates who were admitted between February 2003 and January 2008 and who received a gentamicin pharmacokinetic consultation during the first week of life and an OAE hearing screen before hospital discharge. Neonates were stratified into two groups: very low birth weight (VLBW[≤ 1500 g]) and non-VLBW(> 1500 g).
Measurements and Main Results. Gentamicin was dosed intravenously to achieve a target calculated gentamicin peak serum concentration (Cmax) of 7–10 μg/ml and a target trough serum concentration (Cmin) of less than 2 μg/ml. The dosage administered was 4 mg/kg/dose every 48 hours if the neonate's birth weight was less than 1250 g or if the neonate was receiving indomethacin. Otherwise, the dosing interval was every 24 hours. Initial OAE screen results were obtained from the medical records, and follow-up results were collected for neonates who failed the initial OAE screen. The overall rate of OAE screen failure was 13.1% (69/528 patients). The rate of OAE screen failure was 34.1% (29/85 patients) in the VLBW neonates, which was significantly higher than the failure rate in non-VLBW neonates (9.0% [40/443 patients], p=0.001). Multivariate analysis of non-VLBW neonates determined that each 1-μg/ml increase in gentamicin Cmax was associated with an increased risk of OAE screen failure (odds ratio [OR] 1.4, 95% confidence interval (CI) 1.1–1.7, p=0.003). Further, the non-VLBW neonate subpopulation had an increased rate of OAE screen failure if the gentamicin Cmax exceeded 10 μg/ml (OR 2.2, 95% CI 1.1–4.2, p=0.022) compared with neonates whose Cmax was 10 μg/ml or lower. No association between serum gentamicin concentration and OAE screen failure could be determined among the VLBW neonates.
Conclusion. Neonates weighing more than 1500 g at birth and whose gentamicin Cmax exceeded 10 μg/ml were at an increased risk for OAE screen failure. Monitoring and maintaining gentamicin Cmax at or below 10 μg/ml may minimize hearing impairment; however, further studies are necessary.
Gentamicin is an effective aminoglycoside antibiotic that has been used for decades for treating common bacteria found in critically ill newborns. Gentamicin pharmacokinetics are measured in this population to optimize gentamicin peak serum concentration (Cmax): bacterial minimum inhibitory concentration ratios for efficacy. The Cmax and gentamicin trough serum concentration (Cmin) are also adjusted to reduce the potential for toxicity. In neonates, a sustained gentamicin Cmin greater than 2 μg/ml and a sustained Cmax greater than 12 μg/ml are considered to be toxic. However, these definitions and clinical practice concerning the toxicity of gentamicin are extrapolated from adult literature.
In spite of the risk for toxicity, as well as the costs associated with monitoring serum concentrations, gentamicin is preferred over cefotaxime and ceftriaxone for coverage of suspected gram-negative infections in neonates. Extended-spectrum β-lactamase–producing gram-negative bacteria outbreaks in neonatal intensive care units (NICUs) have been reported in the literature. One study of ampicillin plus cefotaxime showed an increased risk of death compared with treatment with ampicillin and gentamicin during the first 3 days of life. The use of ceftriaxone in neonates increases the risk for bilirubin displacement from serum albumin and adverse cardio-pulmonary events.
Aminoglycoside-induced ototoxicity is due to destruction of cochlear hair cells through several possible mechanisms. Aminoglycosides may inhibit mitochondrial protein synthesis in genetically predisposed individuals. The drugs can also produce toxic free radicals in the inner ear of individuals without a genetic predisposition to toxicity. Another possible mechanism of ototoxicity is overstimulation of hair cells after high doses of aminoglycosides, causing excitotoxicity from excessive cellular calcium influx. This excitotoxicity may be a saturable effect due to slow clearance of aminoglycosides from the inner ear. According to this mechanism, extended-interval dosing regimens would allow for higher peak concentrations by allowing more time for clearance from the inner ear.
Data supporting and describing gentamicin-associated ototoxicity in neonates are lacking. Several studies investigating a correlation between aminoglycoside antibiotics and hearing loss in neonates have been published in the past 2 decades. However, the conclusions of those studies were confounded by small sample sizes and incomplete or absent descriptions of aminoglycoside dosing protocols and pharmacokinetic analyses.
High-dose, extended-interval dosing protocols result in increased peak concentrations compared with traditional dosing. Therefore, increased use of high-dose, extended-interval gentamicin dosing protocols may increase the risk of ototoxicity in neonates unless toxicity limits are identified. The use of high-dose, extended-interval dosing protocols in adults has not shown an increase in ototoxicity. However, the neonatal auditory system may not behave in the same way as the adult auditory system with regard to gentamicin toxicity. For example, the neonatal auditory system may be more sensitive and prone to damage. Excitotoxicity due to slow aminoglycoside clearance in the inner ear is based on animal data. Extrapolating that data to neonates may be inaccurate. Neonates may clear aminoglyco-sides faster or slower from the inner ear than do adults. Neonatal inner ear cells and neurons may not even be susceptible to excitotoxicity.
Otoacoustic emissions (OAEs) are sounds that originate as vibrations transmitted from the cochlea back to the middle ear. These emissions are a by-product of a cochlear function that amplifies sounds to aid the brain with discrimination of and sensitivity to external sound stimuli. Probes inserted into the neonate's ear canals emit click auditory stimuli at multiple frequencies to elicit production of otoacoustic emissions. The emissions are detected and recorded by the same ear canal probes. When used as the initial hearing screen in a universal newborn screening process, OAE is an effective method to improve detection of hearing loss and expedite the diagnosis and treatment of permanent childhood hearing impairment. When compared with auditory brain-stem response (ABR) and other screening methods as an initial screen for hearing loss detection, transient evoked OAE screening has equivalent sensitivity and specificity.
The positive predictive value of an OAE screen in the general neonatal population is estimated to be 6.7%. However, neonates in the NICU setting are at a 10–20 times higher risk for moderate-to-severe hearing loss. A two-step diagnostic process using OAE screen followed by ABR examination accurately detects hearing loss with up to 100% sensitivity and 99% specificity. A review of literature investigating universal newborn hearing screening published a decade ago calculated lower, but still high, rates of 84% sensitivity and 90% specificity. Diagnosis of permanent childhood hearing impairment before age 9 months has been shown to increase receptive and expressive language abilities of children in midchildhood.
The primary objective of this study was to characterize the extent that serum gentamicin concentrations are associated with hearing loss indicated by transient evoked OAE screen failure in critically ill neonates receiving gentamicin in accordance with a high-dose, extended-interval dosing protocol designed to achieve a gentamicin Cmax of 7–10 μg/ml and Cmin of less than 2 μg/ml. A secondary objective was to describe hearing loss and its association with other patient characteristics.
Abstract and Introduction
Abstract
Study Objective. To characterize the extent that serum gentamicin concentrations are associated with hearing loss indicated by otoacoustic emission (OAE) screen failure in critically ill neonates receiving gentamicin in accordance with a high-dose, extended-interval dosing protocol.
Design. Retrospective medical record review.
Setting. Two neonatal intensive care units in a pediatric tertiary care system.
Patients. Sequential sample of 528 critically ill neonates who were admitted between February 2003 and January 2008 and who received a gentamicin pharmacokinetic consultation during the first week of life and an OAE hearing screen before hospital discharge. Neonates were stratified into two groups: very low birth weight (VLBW[≤ 1500 g]) and non-VLBW(> 1500 g).
Measurements and Main Results. Gentamicin was dosed intravenously to achieve a target calculated gentamicin peak serum concentration (Cmax) of 7–10 μg/ml and a target trough serum concentration (Cmin) of less than 2 μg/ml. The dosage administered was 4 mg/kg/dose every 48 hours if the neonate's birth weight was less than 1250 g or if the neonate was receiving indomethacin. Otherwise, the dosing interval was every 24 hours. Initial OAE screen results were obtained from the medical records, and follow-up results were collected for neonates who failed the initial OAE screen. The overall rate of OAE screen failure was 13.1% (69/528 patients). The rate of OAE screen failure was 34.1% (29/85 patients) in the VLBW neonates, which was significantly higher than the failure rate in non-VLBW neonates (9.0% [40/443 patients], p=0.001). Multivariate analysis of non-VLBW neonates determined that each 1-μg/ml increase in gentamicin Cmax was associated with an increased risk of OAE screen failure (odds ratio [OR] 1.4, 95% confidence interval (CI) 1.1–1.7, p=0.003). Further, the non-VLBW neonate subpopulation had an increased rate of OAE screen failure if the gentamicin Cmax exceeded 10 μg/ml (OR 2.2, 95% CI 1.1–4.2, p=0.022) compared with neonates whose Cmax was 10 μg/ml or lower. No association between serum gentamicin concentration and OAE screen failure could be determined among the VLBW neonates.
Conclusion. Neonates weighing more than 1500 g at birth and whose gentamicin Cmax exceeded 10 μg/ml were at an increased risk for OAE screen failure. Monitoring and maintaining gentamicin Cmax at or below 10 μg/ml may minimize hearing impairment; however, further studies are necessary.
Introduction
Gentamicin is an effective aminoglycoside antibiotic that has been used for decades for treating common bacteria found in critically ill newborns. Gentamicin pharmacokinetics are measured in this population to optimize gentamicin peak serum concentration (Cmax): bacterial minimum inhibitory concentration ratios for efficacy. The Cmax and gentamicin trough serum concentration (Cmin) are also adjusted to reduce the potential for toxicity. In neonates, a sustained gentamicin Cmin greater than 2 μg/ml and a sustained Cmax greater than 12 μg/ml are considered to be toxic. However, these definitions and clinical practice concerning the toxicity of gentamicin are extrapolated from adult literature.
In spite of the risk for toxicity, as well as the costs associated with monitoring serum concentrations, gentamicin is preferred over cefotaxime and ceftriaxone for coverage of suspected gram-negative infections in neonates. Extended-spectrum β-lactamase–producing gram-negative bacteria outbreaks in neonatal intensive care units (NICUs) have been reported in the literature. One study of ampicillin plus cefotaxime showed an increased risk of death compared with treatment with ampicillin and gentamicin during the first 3 days of life. The use of ceftriaxone in neonates increases the risk for bilirubin displacement from serum albumin and adverse cardio-pulmonary events.
Aminoglycoside-induced ototoxicity is due to destruction of cochlear hair cells through several possible mechanisms. Aminoglycosides may inhibit mitochondrial protein synthesis in genetically predisposed individuals. The drugs can also produce toxic free radicals in the inner ear of individuals without a genetic predisposition to toxicity. Another possible mechanism of ototoxicity is overstimulation of hair cells after high doses of aminoglycosides, causing excitotoxicity from excessive cellular calcium influx. This excitotoxicity may be a saturable effect due to slow clearance of aminoglycosides from the inner ear. According to this mechanism, extended-interval dosing regimens would allow for higher peak concentrations by allowing more time for clearance from the inner ear.
Data supporting and describing gentamicin-associated ototoxicity in neonates are lacking. Several studies investigating a correlation between aminoglycoside antibiotics and hearing loss in neonates have been published in the past 2 decades. However, the conclusions of those studies were confounded by small sample sizes and incomplete or absent descriptions of aminoglycoside dosing protocols and pharmacokinetic analyses.
High-dose, extended-interval dosing protocols result in increased peak concentrations compared with traditional dosing. Therefore, increased use of high-dose, extended-interval gentamicin dosing protocols may increase the risk of ototoxicity in neonates unless toxicity limits are identified. The use of high-dose, extended-interval dosing protocols in adults has not shown an increase in ototoxicity. However, the neonatal auditory system may not behave in the same way as the adult auditory system with regard to gentamicin toxicity. For example, the neonatal auditory system may be more sensitive and prone to damage. Excitotoxicity due to slow aminoglycoside clearance in the inner ear is based on animal data. Extrapolating that data to neonates may be inaccurate. Neonates may clear aminoglyco-sides faster or slower from the inner ear than do adults. Neonatal inner ear cells and neurons may not even be susceptible to excitotoxicity.
Otoacoustic emissions (OAEs) are sounds that originate as vibrations transmitted from the cochlea back to the middle ear. These emissions are a by-product of a cochlear function that amplifies sounds to aid the brain with discrimination of and sensitivity to external sound stimuli. Probes inserted into the neonate's ear canals emit click auditory stimuli at multiple frequencies to elicit production of otoacoustic emissions. The emissions are detected and recorded by the same ear canal probes. When used as the initial hearing screen in a universal newborn screening process, OAE is an effective method to improve detection of hearing loss and expedite the diagnosis and treatment of permanent childhood hearing impairment. When compared with auditory brain-stem response (ABR) and other screening methods as an initial screen for hearing loss detection, transient evoked OAE screening has equivalent sensitivity and specificity.
The positive predictive value of an OAE screen in the general neonatal population is estimated to be 6.7%. However, neonates in the NICU setting are at a 10–20 times higher risk for moderate-to-severe hearing loss. A two-step diagnostic process using OAE screen followed by ABR examination accurately detects hearing loss with up to 100% sensitivity and 99% specificity. A review of literature investigating universal newborn hearing screening published a decade ago calculated lower, but still high, rates of 84% sensitivity and 90% specificity. Diagnosis of permanent childhood hearing impairment before age 9 months has been shown to increase receptive and expressive language abilities of children in midchildhood.
The primary objective of this study was to characterize the extent that serum gentamicin concentrations are associated with hearing loss indicated by transient evoked OAE screen failure in critically ill neonates receiving gentamicin in accordance with a high-dose, extended-interval dosing protocol designed to achieve a gentamicin Cmax of 7–10 μg/ml and Cmin of less than 2 μg/ml. A secondary objective was to describe hearing loss and its association with other patient characteristics.
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