title: Effect of sepsis and systemic inflammatory response syndrome on neonatal hearing screening outcomes following gentamicin exposure.
abstract: OBJECTIVE
  Hearing loss in neonatal intensive care unit (NICU) graduates range from 2% to 15% compared to 0.3% in full-term births, and the etiology of this discrepancy remains unknown. The majority of NICU admissions receive potentially ototoxic aminoglycoside therapy, such as gentamicin, for presumed sepsis. Endotoxemia and inflammation are associated with increased cochlear uptake of aminoglycosides and potentiated ototoxicity in mice. We tested the hypothesis that sepsis or systemic inflammatory response syndrome (SIRS) and intravenous gentamicin exposure increases the risk of hearing loss in NICU admissions.
  
  
  METHODS
  The Institutional Review Board at Oregon Health & Science University (OHSU) approved this study design. Two hundred and eight infants met initial criteria, and written, informed consent were obtained from parents or guardians of 103 subjects ultimately enrolled in this study. Prospective data from 91 of the enrolled subjects at OHSU Doernbecher Children's Hospital Neonatal Care Center were processed. Distortion product otoacoustic emissions (DPOAEs; f2 frequency range: 2063-10,031 Hz) were obtained prior to discharge to assess auditory performance. To pass the DPOAE screen, normal responses in >6 of 10 frequencies in both ears were required; otherwise the subject was considered a "referral" for a diagnostic hearing evaluation after discharge. Cumulative dosing data and diagnosis of neonatal sepsis or SIRS were obtained from OHSU's electronic health record system, and the data processed to obtain risk ratios.
  
  
  RESULTS
  Using these DPOAE screening criteria, 36 (39.5%) subjects would be referred. Seventy-four (81%) subjects had intravenous gentamicin exposure. Twenty (22%) had ≥4 days of gentamicin, and 71 (78%) had <4 days. The risk ratio (RR) of referral with ≥4 days of gentamicin was 1.92 (p=0.01). Eighteen subjects had sepsis or met neonatal SIRS criteria, 9 of whom had ≥5 days of gentamicin and a DPOAE referral risk ratio of 2.12 (p=0.02) compared to all other subjects. Combining subjects with either vancomycin or furosemide overlap with gentamicin treatment yielded an almost significant risk ratio (RR=1.77, p=0.05) compared to the rest of the cohort.
  
  
  CONCLUSIONS
  We report an increased risk of referral with DPOAE screening for those receiving ≥4 days of intravenous gentamicin administration that may contribute to the greater prevalence of hearing loss in NICU graduates. We propose an expanded prospective study to gather a larger cohort of subjects, identifying those with sepsis or neonatal SIRS, to increase the statistical power of this study design. Subsequent studies also need to obtain follow-up diagnostic audiological data to verify whether the outcomes of DPOAE screening, in addition to the standard AABR screen, is a reliable predictor of permanent hearing loss following gentamicin exposure in the NICU.
authors.affiliation: Oregon Hearing Research Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA. Electronic address: crossca@ohsu.edu.
authors.forename: Campbell P
authors.initials: CP
authors.lastname: Cross
authors.affiliation: Otolaryngology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Selena
authors.initials: S
authors.lastname: Liao
authors.affiliation: Oregon Hearing Research Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Oregon Health & Science University, MD/PhD Program, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Zachary D
authors.initials: ZD
authors.lastname: Urdang
authors.affiliation: Department of Public Health & Preventive Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Mail Code CB 669, Portland, OR 97239, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Srikanth
authors.affiliation: Oregon Hearing Research Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Portland Veterans Administration, National Center for Rehabilitative Auditory Research (NCRAR), 3710 SW US Veterans Hospital Road, Portland, OR 97239, USA.
authors.forename: Angela C
authors.initials: AC
authors.lastname: Garinis
authors.affiliation: Oregon Hearing Research Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Otolaryngology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Portland Veterans Administration, National Center for Rehabilitative Auditory Research (NCRAR), 3710 SW US Veterans Hospital Road, Portland, OR 97239, USA. Electronic address: steygerp@ohsu.edu.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Steyger
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D015331:Cohort Studies; D005260:Female; D005839:Gentamicins / Q000627:therapeutic use*; D034381:Hearing Loss / Q000175:diagnosis* / Q000209:etiology; D006320:Hearing Tests; D006801:Humans; D007231:Infant, Newborn; D015931:Intensive Care, Neonatal; D008297:Male; D015997:Neonatal Screening; D009922:Oregon; D017084:Otoacoustic Emissions, Spontaneous / Q000502:physiology; D011446:Prospective Studies; D018805:Sepsis / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy*; D018746:Systemic Inflammatory Response Syndrome / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy*
chemical_list: D000900:Anti-Bacterial Agents; D005839:Gentamicins
keywords: Aminoglycosides; DPOAE; Gentamicin; Ototoxicity; SIRS; Sepsis