- Email: [email protected]
Factors Associated with Permanent Hearing Impairment in Infants Treated with Therapeutic Hypothermia
Factors Associated with Permanent Hearing Impairment in Infants Treated with Therapeutic Hypothermia Elisa Smit, MRCPCH1,2, Xun Liu, PhD1, Hannah Gill, FRCP1, Hemmen Sabir, MD1, Sally Jary, MSc1,2, and Marianne Thoresen, MD, PhD1,2,3 Objective To define the incidence of hearing impairment, document plasma gentamicin concentrations, and identify factors associated with permanent hearing impairment in infants subjected to therapeutic hypothermia for moderate or severe neonatal encephalopathy. Study design Data were collected prospectively in a regional center providing therapeutic hypothermia. Cooled infants at $36 weeks gestation with moderate or severe neonatal encephalopathy were analyzed if a full dataset was available (n = 108), including clinical variables and gentamicin trough levels. Infants with hearing impairment were identified, and survivors were followed up with neurodevelopmental evaluation at age 18 months. Stepwise logistic regression identified factors associated with hearing impairment. Results Nine infants died, and among the survivors, 10.1% developed a permanent hearing impairment. The trough gentamicin level was above the recommended cutoff of 2 mg/L in 37% of the infants in the entire cohort and in 90% of the infants with hearing impairment. Logistic regression analysis identified high trough gentamicin level, low cord pH, and hypoglycemia (<46.8 mg/dL) in the first postnatal hour as significantly associated with hearing impairment. The need for inotropic support was close to significant (P = .055). Conclusion Hearing impairment was a common finding among cooled infants. Plasma gentamicin levels were commonly >2 mg/L. Based on these findings, we propose changes in gentamicin dosing interval and trough level monitoring to minimize the risk of potentially toxic levels in cooled newborns. (J Pediatr 2013;163:995-1000).
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nfants with neonatal encephalopathy are at risk for developing hearing impairment.1 Early detection of hearing impairment has greatly improved since the introduction of the Newborn Hearing Screening Program in England in March 2006. The program screens infants before age 44 postmenstrual weeks and ideally before hospital discharge. In 2011, 21 babies of 13 000 screened each week (0.16%) were diagnosed with permanent childhood hearing impairment.2 Therapeutic hypothermia has become standard care for infants with neonatal encephalopathy. Large randomized controlled trials of therapeutic hypothermia for neonatal encephalopathy found a 3.5%-7.8% rate of severe hearing impairment in cooled infants at the 18-month follow-up, compared with 5.4%-6.5% in infants maintained at normothermia.3 Our previous retrospective study of plasma gentamicin concentrations in both cooled and noncooled encephalopathic infants found similar trough levels in the 2 groups, but levels >2 mg/L in 36% of the cooled infants and 44% of the noncooled infants.4 The objective of the present study was to define the incidence of hearing impairment, document plasma gentamicin concentrations, and identify factors associated with permanent hearing impairment in infants who received therapeutic hypothermia for moderate to severe neonatal encephalopathy with follow-up for 18 months.
Methods This prospective study was carried out between December 2006 and March 2012 in a tertiary neonatal intensive care unit in Bristol, UK that treats both inborn and outborn infants. Eligible infants at $36 weeks gestation received therapeutic hypothermia for moderate or severe neonatal encephalopathy and met the original entry criteria for the CoolCap trial.5 The majority of infants underwent whole-body cooling to a rectal temperature of 33.5 C using a servo-controlled machine with a body wrap (Criticool; MTRE, Mennen Medical, Rehovot, Israel; n = 99) or a manually regulated cooling mattress (Tecotherm TS Med 200M; Inspiration Healthcare, Leicester, United Kingdom; n = 4). Five infants received seFrom the School of Clinical Sciences, University of 1
Bristol; 2Neonatal Intensive Care Unit, St Michael’s Hospital, University Hospitals Bristol, Bristol, United Kingdom; and 3Department of Physiology, University of Oslo, Oslo, Norway
AABR AOAE BSID-II MDI PDI
Automated auditory brainstem response Automated otoacoustic emissions Bayley Scales of Infant Development, Second Edition Mental Developmental Index Pyschomotor Developmental Index
Funded by Moulton Charitable Foundation, Sport Aiding Medical Research for Kids (SPARKS), and the University of Bristol Alumni Foundation. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.06.012
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lective head cooling with mild systemic hypothermia to a rectal temperature of 34.5 C using the Cool-Cap device (Olympic Cool-Cap System; Natus Medical, Seattle, Washington). With ethical permission from the local (University Hospitals Bristol) Research Ethics Committee (CH/ 2009/3091), anonymized data were collected from the medical records and stored in an electronic database between December 2006 and May 2012. Information collected included demographic data, Apgar scores, cord blood gas analysis results, serum glucose level in the first postnatal hour (with hypoglycemia defined as glucose <46.8 mg/dL [2.6 mmol/L]), any episodes of hypoglycemia after the first postnatal hour, concurrent ototoxic and nephrotoxic drugs, inotrope and anticonvulsant requirement, and first recorded gentamicin trough level with concurrent plasma creatinine value. Gentamicin was administered as a single dose of 4 mg/kg every 24 hours, with trough level routinely checked before administration of the third dose. In patients with low urine output (<2 mL/kg/hour) or elevated plasma creatinine (>100 mmol/L), trough level was checked before administration of the second dose. Levels exceeding 2 mg/L prompted the next dose to be withheld until the level dropped to within the normal range. All infants underwent a newborn hearing screen, which included automated otoacoustic emissions (AOAE) and automated auditory brainstem response (AABR) testing, before discharge to home. Our cooled infants are seen as outpatients until age 2 years. Infants are assessed at age 18-20 months by our senior physiotherapist using the Bayley Scales of Infant Development, Second Edition (BSID-II).6 BSID-II is a widely used quantitative method of assessment and uses aged-adjusted Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI) scores as summary measures. The population mean score is 100 with a standard deviation of 15. In children with hearing impairment, expressive language and sign language were used to assess the speech and language element if possible. BSID-II results were available for 72 infants. Twenty-seven infants had not yet reached age 18-20 months and so could not undergo BSID-II evaluation; however, all of these infants were reviewed at 3- to 6-month intervals in a dedicated neonatal follow-up clinic with assessment of development. SPSS 18.0 (IBM, Armonk, New York) was used for all statistical analyses. Continuous variables were described using mean SD or median (IQR) as applicable, and categorical data were described using proportions. Data from infants with hearing impairment and those with normal hearing outcome were compared using a 2-sample t-test to compare means or the (N 1) c2 test7 to compare proportions. The Mann-Whitney U test was used for nonparametric data. For each infant with hearing impairment, 2 infants without hearing impairment were matched for asphyxial severity based on cord pH, 10-minute Apgar score, and inotrope and anticonvulsant use, to ensure that any significant differences between the 2 groups were not likely related to more severe neonatal encephalopathy. 996
Vol. 163, No. 4 Stepwise binary logistic regression was performed on all surviving infants, with hearing impairment as the dependent variable and 10-minute Apgar score, cord pH, gentamicin trough level, glucose reading in first postnatal hour, any episode of hypoglycemia after the first postnatal hour, concurrent ototoxic and nephrotoxic drugs, use and number of anticonvulsants, and use and number of inotropes as the independent variables. A significance value of .05 was used when allowing independent factors to enter the regression, to identify potential relationships between hearing impairment and the independent variables.
Results Information for all 136 infants who received therapeutic hypothermia for neonatal encephalopathy, both included and excluded, is summarized in a flowchart in Figure 1. Complete data were available for 108 cooled infants, 10 of whom had significant sensorineural hearing impairment requiring amplification with a hearing aid (n = 8) or cochlear implant (n = 2). Nine infants died from severe neonatal encephalopathy. The prevalence of hearing impairment was 10.1% among the survivors. Results of the newborn hearing screen were available for all surviving infants and are summarized in Table I. Of the 10 infants with hearing impairment, 9 (90%) did not pass the newborn hearing screen. One infant had a clear response with both AOAE and AABR testing but was diagnosed with hearing impairment at age 12 months. In the group with a normal hearing outcome, 4 infants did not have a clear response on AOAE testing but had a normal AABR, and repeat AOAE testing was completely normal. Four infants did not undergo AABR testing, but all 4 had a normal
Figure 1. Flowchart of included and excluded infants. Smit et al
ORIGINAL ARTICLES
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Table I. Results of the initial newborn hearing screen Newborn hearing test result AOAE
AABR
+
+
+ Not done
+ Not done +
+, clear response;
Normal hearing outcome (n = 89)
Hearing impaired (n = 10)
80 0 4 4 1
1 9 0 0 0
, no clear response.
AOAE test in both ears, and 1 infant did not have an AOAE done but had a clear response on AABR testing. Cord blood pH, hypoglycemia during the first postnatal hour, need for inotropic support, requirement for $3 anticonvulsants, first gentamicin concentration, gentamicin trough level >2 mg/L, and MDI were significantly different in the infants with hearing impairment and those with normal hearing (Table II). Comparing the infants with hearing impairment with the 20 infants with normal hearing matched for asphyxial severity revealed significant differences in hypoglycemia during the first postnatal hour, requirement for $3 anticonvulsants, first gentamicin concentration, and gentamicin trough level >2 mg/L. Concurrent ototoxic and nephrotoxic drugs included furosemide, acyclovir, vancomycin, vecuronium infusion, and ranitidine. All infants received a morphine infusion during cooling, with a dosage range of 10-60 mg/kg/hour. Five infants with normal hearing required phototherapy for jaundice, compared with no infants in the hearing impaired group. Three infants had a confirmed infection with positive growth from blood culture or cerebrospinal
fluid culture, including 2 infants in the normal hearing group (group B Streptococcus, Pseudomonas) and 1 infant in the hearing impaired group (Serratia). Plasma gentamicin concentrations exceeded 2 mg/L in 37% of infants in the entire cohort and in 90% of infants in the hearing impaired group. The mean plasma gentamicin concentration was 2.66 0.65 mg/L in the hearing impaired group, compared with 1.65 1.16 mg/L in the normal hearing group. The relationship between gentamicin trough value and concurrent serum creatinine value is displayed in Figure 2. Gentamicin level was checked before administration of the third dose in 73 infants, before the second dose in 29 infants, and before the fourth dose in 6 infants. Mean MDI and PDI scores were 72 19 and 68 18, respectively, for the hearing impaired group (n = 9), compared with 88 21 and 80 18 for the normal hearing group (n = 63). Five of 9 children (56%) in the hearing impaired group had a PDI and/or MDI score of <70, compared with 18 of 63 (29%) in the normal hearing group, a statistically nonsignificant difference (P = .11). Stepwise logistic regression analysis revealed that the independent variables high trough gentamicin level (P = .010), low cord blood pH (P = .018), and early hypoglycemia (P = .014) were significantly associated with the dependent variable hearing impairment. The use and number of anticonvulsants (P = .783 and .628), use and number of inotropes (P = .055 and .834), hypoglycemia after the first postnatal hour (P = .474), concurrent ototoxic and nephrotoxic drugs (P = .843), and 10-minute Apgar score (P = .397) were not significantly associated, although the use of inotropes was close (P = .055).
Table II. Characteristics of the infants with hearing impairment, those with normal hearing, and those matched for asphyxial severity Hearing impairment (n = 10) Male sex, n (%) Birth weight, g, mean SD Gestational age, weeks, mean SD 10-minute Apgar score, median (IQR) Cord blood pH, mean SD Cord blood base excess, mEq/L, mean SD Hypoglycemia in first postnatal hour, n (%) Hypoglycemia after first postnatal hour, n (%) Concurrent ototoxic and nephrotoxic drugs, n (%) Need for inotropic support, n (%) Requiring $3 inotropes, n (%) Need for anticonvulsants, n (%) Requiring $3 anticonvulsants, n (%) First gentamicin concentration, mg/L, mean SD Concurrent creatinine, mmol/L, mean SD Gentamicin trough level > 2.0 mg/L, n (%) MDI, mean SD* PDI, mean SD*
4 (40) 3464 811 +5 38 1+4 4 (4-8) 6.88 0.12 20.5 2.12 7 (70) 4 (40) 6 (60) 10 (100) 4 (40) 8 (80) 5 (50) 2.66 0.65 103 39 9 (90) 72 19 68 18
Normal hearing (n = 89) 52 (58) 3405 576 39+4 1+5 7 (5-9) 7.03 0.18 14.65 7.26 11 (12) 15 (17) 29 (33) 58 (65) 18 (20) 66 (74) 12 (14) 1.68 1.18 82 31 26 (30) 88 21 80 18
Matched for asphyxial severity, normal hearing (n = 20)
P value, hearing impaired vs normal hearing
P value, hearing loss vs matched 20
10 (50) 3293 535 39+3 1+5 5 (3-6) 6.84 0.1 18.8 5.2 5 (25) 6 (30) 9 (45) 18 (90) 4 (20) 15 (75) 2 (10) 1.8 0.91 86 31 7 (35) 85 20 74 21
.30 .77 .131 .193 .009 .171 .0001 .08 .09 .03 .20 >.50 .004 .009 .051 .0001 .041 .055
>.50 .493 .365 .491 .445 .37 .02 >.50 .40 .54 .30 >.50 .02 .013 .213 .005 .119 .356
P values are given for infants with hearing impairment vs normal hearing and for infants with hearing impairment vs the 20 matched infants without hearing impairment. The 2-sample t-test or Mann-Whitney U test was used to compare continuous variables, and the (N 1) c2 test was used to compare proportions. *MDI and PDI results were available for 9 infants with hearing impairment, for 63 infants with normal hearing, and for 14 infants matched for asphyxial severity and normal hearing.
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Figure 2. Gentamicin trough levels (before the second, third, or fourth dose, first recorded) on the y-axis with concurrent plasma creatinine values on the x-axis for all infants studied (n = 108). A plasma gentamicin level >2 mg/L (orange line), considered potentially toxic, was seen in 37% of infants. Plasma creatinine value was correlated with gentamicin trough level (Pearson’s correlation, r = 0.593).
Discussion We found a high incidence of permanent hearing impairment (10.1%) among survivors in our cohort of cooled infants with moderate to severe neonatal encephalopathy compared with previously published rates of 3.5%7.8%.5,8,9 This discrepancy may reflect improved early detection after introduction of the universal newborn hearing screen, or may be related to the fact that more children have survived. Mortality in our center during the study period was low (12.5%) compared with published data from randomized trials of infants undergoing therapeutic hypothermia, in which mortality among cooled infants ranged from 19% to 33%.5,8,9 Infants recruited into those randomized trials were treated for infection according to local antibiotic practices, which would have involved gentamicin in some proportion of these infants. Mencher and Mencher10 studied 56 severely asphyxiated noncooled infants and identified the combination of hypoxic-ischemic encephalopathy with seizures, associated organ damage, and intrauterine growth restriction as a risk factor for sensorineural hearing impairment. We identified 1 factor—low cord blood pH—as related to the severity of illness, but also found low early blood glucose level and high trough gentamicin level to be associated with hearing impairment. None of the infants in our hearing impaired group had intrauterine growth restriction; birth weight ranged from the 9th percentile to the 99.6th percentile. 998
Vol. 163, No. 4 None of our hearing impaired infants had a family history of hearing impairment, and none was diagnosed with an underlying metabolic or genetic condition. In our logistic regression analysis, the use of inotropes had a P value of .055. This is a clinically important result, because hypotension may be a marker of associated cardiac organ damage. Gentamicin in combination with beta-lactam antibiotics is a common first-line antibiotic regimen in neonates with suspected sepsis or at high risk for infection from invasive catheter use. This drug combination provides synergistic activity against gram-positive and gram-negative bacteria with low resistance rates. The use of gentamicin in neonates has long been controversial because of the drug’s narrow therapeutic window and potential nephrotoxic and ototoxic effects, and thus close monitoring of plasma trough levels is important.11,12 Neonates, especially critically ill neonates, have a low glomerular filtration rate, leading to slower gentamicin clearance.13 Gentamicin is excreted almost exclusively by the kidneys, and its pharmacokinetics is linked to glomerular filtration rate.14 In our previous study,4 we found that impaired renal function was strongly associated with high gentamicin trough levels, and that cooling did not affect the clearance of gentamicin. Despite those findings, 37% of our current cohort of cooled infants had a trough level above the recommended cutoff of 2 mg/L. This result is likely related to renal impairment associated with the severity of neonatal encephalopathy, as reflected by concurrent high creatinine values. A dosing interval of 24 hours does not appear to suit all infants undergoing cooling for neonatal encephalopathy and leads to a high proportion of potentially toxic trough levels. Thus, revising our gentamicin regimen and trough level monitoring in infants with neonatal encephalopathy is appropriate. Based on our findings, we propose administering the initial gentamicin dose of 4 mg/kg and proceeding to the subsequent dose when the trough level drops below 2 mg/L in cooled infants with neonatal encephalopathy. For roughly two-third of the infants, this means that they will remain on a 24-hourly dosing regimen, but for the others, this means delaying the second dose until the trough level drops below 2 mg/L after a 36-hour or even a 48-hour interval. Initial hypoglycemia has been identified as a risk factor for perinatal brain injury in the context of fetal acidemia, defined as an umbilical arterial pH <7.00.15 Current evidence suggests that neurodevelopmental outcome is worse when neonatal encephalopathy is associated with hypoglycemia,16,17 and our findings indicate that early hypoglycemia is a risk factor for hearing impairment in infants with neonatal encephalopathy. Thus, early monitoring of blood glucose levels and immediate treatment in case of hypoglycemia remain paramount. Early hypoglycemia reflects exhausted energy stores after prolonged labor and/or resuscitation. The incidence of any episodes of hypoglycemia occurring after the first postnatal hour was higher in the hearing impaired group, but the difference was not statistically significant, and this variable was not a significant factor in our logistic regression analysis. Smit et al
October 2013 The development of hearing impairment in infants with neonatal encephalopathy may be linked to the extent and location of brain damage. A magnetic resonance imaging study of gray matter injury in newborns with hypoxicischemic encephalopathy kept normothermic found that 6% of survivors had neurosensorial hearing impairment,18 but did not identify a clear relationship between hearing impairment and imaging findings. The effect of cooling on hearing impairment has been studied in animal models and humans. In a gerbil model of ischemia-reperfusion of the cochlea, hypothermia (rectal temperature 32 C) during the insult prevented inner ear damage and subsequent hearing impairment compared with animals maintained at normothermia.19 The effect of local hypothermia on idiopathic sudden sensorineural hearing impairment has been studied in adults.20 Cooling the head and neck for 48 hours using a water pillow at 15 C decreased tympanic membrane temperature by 1.4 C and was associated with significantly improved recovery rates of hearing impairment by 6 months after the onset of idiopathic hearing impairment. A study of children undergoing cardiac bypass surgery identified subtle cochlear dysfunction (ie, a statistically significant reduction in amplitude levels at high frequencies) during the postoperative period in children subjected to deep hypothermia (28-32 C) during extracorporeal circulation compared with those subjected to only mild hypothermia (33-37 C).21 Other studies have shown a possible association betweeen deep hypothermia and cochlear cell injury22 and have identified a possible protective role of mild hypothermia on the cochlea during cardiac bypass surgery in children.23 Translating this research to newborn infants receiving therapeutic hypothermia is difficult, but it can be speculated that moderate hypothermia in infants with neonatal encephalopathy may have a protective role on the cochlea and subsequent hearing outcome. Caution is urged when further refining therapeutic hypothermia using deeper or longer cooling, given that some of the aforementioned findings suggest a potential harmful effect on the cochlea when using lower temperatures. A limitation of the present study is the fact that MDI assesses both language elements and cognition, and the 2 are difficult to distinguish using the BSID-II. In children with hearing impairment, the language component could be affected by hearing loss. One of the hearing impaired children had an incomplete MDI score, because his cochlear implants had been fitted only recently and had not yet been activated. In some of the other children, we relied on their use of sign language to assess the language and cognitive component. In summary, this study demonstrates that hearing impairment is a common finding in survivors of moderate to severe neonatal encephalopathy, a finding that stresses the importance of a newborn hearing screening program in this particular patient group. Our findings also underscore the importance of careful gentamicin drug level monitoring and early identification and treatment of hypoglycemia,
ORIGINAL ARTICLES both of which have been identified as risk factors for hearing impairment. n Submitted for publication Mar 7, 2013; last revision received May 15, 2013; accepted Jun 11, 2013. Reprint requests: Marianne Thoresen, MD, PhD, Department of Neonatal Neuroscience, St Michael’s Hospital, Child Health Level D, Southwell St, Bristol, BS2 8EG, UK. E-mail: [email protected]
References 1. Morzaria S, Westerberg BD, Kozak FK. Systematic review of the etiology of bilateral sensorineural hearing loss in children. Int J Pediatr Otorhinolaryngol 2004;68:1193-8. 2. Annual report of the NHS Newborn Hearing Screening Programme, April 2010 to March 2011. Available from: http://hearing.screening. nhs.uk/publications. Accessed November 29, 2012. 3. Edwards AD, Brocklehurst P, Gunn AJ, Halliday H, Juszczak E, Levene M, et al. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ 2010;340: c363. 4. Liu X, Borooah M, Stone J, Chakkarapani E, Thoresen M. Serum gentamicin concentrations in encephalopathic infants are not affected by therapeutic hypothermia. Pediatrics 2009;124:310-5. 5. 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;365:663-70. 6. Bayley N. Bayley Scales of Infant Development. Second Edition. San Antonio (TX): The Psychological Corporation; 1993. 7. Campbell I. Chi-squared and Fisher-Irwin tests of two-by-two tables with small sample recommendations. Stat Med 2007;26:3661-75. 8. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005;353:1574-84. 9. 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;361:1349-58. 10. Mencher LS, Mencher GT. Neonatal asphyxia, definitive markers and hearing loss. Audiology 1999;38:291-5. 11. Touw DJ, Westerman EM, Sprij AJ. Therapeutic drug monitoring of aminoglycosides in neonates. Clin Pharmacokinet 2009;48:71-88. 12. McCracken GH Jr, Threlkeld N, Thomas ML. Intravenous administration of kanamycin and gentamicin in newborn infants. Pediatrics 1977;60:463-6. 13. Nielsen EI, Sandstrom M, Honore PH, Ewald U, Friberg LE. Developmental pharmacokinetics of gentamicin in preterm and term neonates: population modelling of a prospective study. Clin Pharmacokinet 2009;48:253-63. 14. McCracken GH Jr, Chrane DF, Thomas ML. Pharmacologic evaluation of gentamicin in newborn infants. J Infect Dis 1971;124(Suppl): S214-23. 15. Salhab WA, Wyckoff MH, Laptook AR, Perlman JM. Initial hypoglycemia and neonatal brain injury in term infants with severe fetal acidemia. Pediatrics 2004;114:361-6. 16. Tam EW, Haeusslein LA, Bonifacio SL, Glass HC, Rogers EE, Jeremy RJ, et al. Hypoglycemia is associated with increased risk for brain injury and adverse neurodevelopmental outcome in neonates at risk for encephalopathy. J Pediatr 2012;161:88-93. 17. Nadeem M, Murray DM, Boylan GB, Dempsey EM, Ryan CA. Early blood glucose profile and neurodevelopmental outcome at two years in neonatal hypoxic-ischaemic encephalopathy. BMC Pediatr 2011; 11:10.
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18. Martinez-Biarge M, Diez-Sebastian J, Rutherford MA, Cowan FM. Outcomes after central grey matter injury in term perinatal hypoxic-ischaemic encephalopathy. Early Hum Dev 2010;86:675-82. 19. Watanabe F, Koga K, Hakuba N, Gyo K. Hypothermia prevents hearing loss and progressive hair cell loss after transient cochlear ischemia in gerbils. Neuroscience 2001;102:639-45. 20. Hato N, Hyodo J, Takeda S, Takagi D, Okada M, Hakuba N, et al. Local hypothermia in the treatment of idiopathic sudden sensorineural hearing loss. Auris Nasus Larynx 2010;37:626-30.
Vol. 163, No. 4 21. El Ganzoury MM, Kamel TB, Khalil LH, Seliem AM. Cochlear dysfunction in children following cardiac bypass surgery. ISRN Pediatr 2012; 2012:375038. 22. Veuillet E, Gartner M, Champsaur G, Neidecker J, Collet L. Effects of hypothermia on cochlear micromechanical properties in humans. J Neurol Sci 1997;145:69-76. 23. Namyslowski G, Morawski K, Urban I, Lisowska G, Skalski J. Influence of hypothermia and extracorporeal circulation on transiently evoked otoacoustic emission (TEOAE) in children operated on for various heart defects (I). Otolaryngol Polska 2003;57:263-9 (in Polish).
50 Years Ago in THE JOURNAL OF PEDIATRICS Polyarteritis Nodosa in Infancy Roberts FB, Fetterman GH. J Pediatr 1963;63:519-29
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oberts and Fetterman reported 2 cases of fatal vasculitis of medium-sized arteries in the first year of life and added 18 cases from the literature from as early as the 1940s. Most cases were in infants during the first 6 months of life. Sixteen infants died, most suddenly. The authors termed the disease “infantile polyarteritis nodosa.” In an extensive clinical and pathologic descriptive study, they found common clinical and pathological features. The infants presented with prolonged fever (80%), transient polymorphic rash (75%), transient conjunctivitis (50%), heart failure (35%), central nervous system involvement (30%), and, less commonly, pancreatitis and extremity gangrene. Common laboratory features were leukocytosis, pyuria, and left ventricular hypertrophy and ischemic changes on electrocardiography. Remarkably, all 18 infants who died exhibited coronary artery changes (vs 58% in cases of adult polyarteritis nodosa), mainly aneurysms. Seven infants (35%) had infarcts of other viscera, mainly the kidney and spleen. The median duration of disease was 27 days, much shorter than that of idiopathic adult polyarteritis nodosa. Ineffective treatment with acetylsalicytic acid and corticosteroids was reported only in the 2 cases described by the authors. Today it is clear that the vast majority of these cases were actually descriptions of Kawasaki disease, preceding the original descriptions by Dr Kawasaki in Japanese by 4 years and in English by 11 years.1 Interestingly, none of the cases in this study were reported by Japanese authors. Kawasaki disease occurring in the first year of life is more severe, with a higher prevalence of coronary artery involvement (including in treated infants) and widespread vasculitis, compared with the disease in older children.2 The presentation is often atypical, not fulfilling classic diagnostic criteria. Indeed, in this study, only a minority of the children had lymphadenopathy and oral mucous membrane changes, and none had extremity swelling. Modern therapy with intravenous immunoglobulin and, in refractory cases, with corticosteroids and biological therapy has markedly improved the prognosis of this disease, with mortality during acute disease now <1%. Philip J. Hashkes, MD, MSc Pediatric Rheumatology Unit Shaare Zedek Medical Center Jerusalem, Israel http://dx.doi.org/10.1016/j.jpeds.2013.03.065
References 1. Kawasaki T. Pediatric acute mucocutaneous lymph node syndrome: clinical observation of 50 cases [in Japanese]. Jpn J Allergy 1967;16:178-222. 2. Rosenfeld EA, Corydon KE, Shulman ST. Kawasaki disease in infants less than one year of age. J Pediatr 1995;126:524-9.
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nfants with neonatal encephalopathy are at risk for developing hearing impairment.1 Early detection of hearing impairment has greatly improved since the introduction of the Newborn Hearing Screening Program in England in March 2006. The program screens infants before age 44 postmenstrual weeks and ideally before hospital discharge. In 2011, 21 babies of 13 000 screened each week (0.16%) were diagnosed with permanent childhood hearing impairment.2 Therapeutic hypothermia has become standard care for infants with neonatal encephalopathy. Large randomized controlled trials of therapeutic hypothermia for neonatal encephalopathy found a 3.5%-7.8% rate of severe hearing impairment in cooled infants at the 18-month follow-up, compared with 5.4%-6.5% in infants maintained at normothermia.3 Our previous retrospective study of plasma gentamicin concentrations in both cooled and noncooled encephalopathic infants found similar trough levels in the 2 groups, but levels >2 mg/L in 36% of the cooled infants and 44% of the noncooled infants.4 The objective of the present study was to define the incidence of hearing impairment, document plasma gentamicin concentrations, and identify factors associated with permanent hearing impairment in infants who received therapeutic hypothermia for moderate to severe neonatal encephalopathy with follow-up for 18 months.
Methods This prospective study was carried out between December 2006 and March 2012 in a tertiary neonatal intensive care unit in Bristol, UK that treats both inborn and outborn infants. Eligible infants at $36 weeks gestation received therapeutic hypothermia for moderate or severe neonatal encephalopathy and met the original entry criteria for the CoolCap trial.5 The majority of infants underwent whole-body cooling to a rectal temperature of 33.5 C using a servo-controlled machine with a body wrap (Criticool; MTRE, Mennen Medical, Rehovot, Israel; n = 99) or a manually regulated cooling mattress (Tecotherm TS Med 200M; Inspiration Healthcare, Leicester, United Kingdom; n = 4). Five infants received seFrom the School of Clinical Sciences, University of 1
Bristol; 2Neonatal Intensive Care Unit, St Michael’s Hospital, University Hospitals Bristol, Bristol, United Kingdom; and 3Department of Physiology, University of Oslo, Oslo, Norway
AABR AOAE BSID-II MDI PDI
Automated auditory brainstem response Automated otoacoustic emissions Bayley Scales of Infant Development, Second Edition Mental Developmental Index Pyschomotor Developmental Index
Funded by Moulton Charitable Foundation, Sport Aiding Medical Research for Kids (SPARKS), and the University of Bristol Alumni Foundation. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.06.012
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lective head cooling with mild systemic hypothermia to a rectal temperature of 34.5 C using the Cool-Cap device (Olympic Cool-Cap System; Natus Medical, Seattle, Washington). With ethical permission from the local (University Hospitals Bristol) Research Ethics Committee (CH/ 2009/3091), anonymized data were collected from the medical records and stored in an electronic database between December 2006 and May 2012. Information collected included demographic data, Apgar scores, cord blood gas analysis results, serum glucose level in the first postnatal hour (with hypoglycemia defined as glucose <46.8 mg/dL [2.6 mmol/L]), any episodes of hypoglycemia after the first postnatal hour, concurrent ototoxic and nephrotoxic drugs, inotrope and anticonvulsant requirement, and first recorded gentamicin trough level with concurrent plasma creatinine value. Gentamicin was administered as a single dose of 4 mg/kg every 24 hours, with trough level routinely checked before administration of the third dose. In patients with low urine output (<2 mL/kg/hour) or elevated plasma creatinine (>100 mmol/L), trough level was checked before administration of the second dose. Levels exceeding 2 mg/L prompted the next dose to be withheld until the level dropped to within the normal range. All infants underwent a newborn hearing screen, which included automated otoacoustic emissions (AOAE) and automated auditory brainstem response (AABR) testing, before discharge to home. Our cooled infants are seen as outpatients until age 2 years. Infants are assessed at age 18-20 months by our senior physiotherapist using the Bayley Scales of Infant Development, Second Edition (BSID-II).6 BSID-II is a widely used quantitative method of assessment and uses aged-adjusted Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI) scores as summary measures. The population mean score is 100 with a standard deviation of 15. In children with hearing impairment, expressive language and sign language were used to assess the speech and language element if possible. BSID-II results were available for 72 infants. Twenty-seven infants had not yet reached age 18-20 months and so could not undergo BSID-II evaluation; however, all of these infants were reviewed at 3- to 6-month intervals in a dedicated neonatal follow-up clinic with assessment of development. SPSS 18.0 (IBM, Armonk, New York) was used for all statistical analyses. Continuous variables were described using mean SD or median (IQR) as applicable, and categorical data were described using proportions. Data from infants with hearing impairment and those with normal hearing outcome were compared using a 2-sample t-test to compare means or the (N 1) c2 test7 to compare proportions. The Mann-Whitney U test was used for nonparametric data. For each infant with hearing impairment, 2 infants without hearing impairment were matched for asphyxial severity based on cord pH, 10-minute Apgar score, and inotrope and anticonvulsant use, to ensure that any significant differences between the 2 groups were not likely related to more severe neonatal encephalopathy. 996
Vol. 163, No. 4 Stepwise binary logistic regression was performed on all surviving infants, with hearing impairment as the dependent variable and 10-minute Apgar score, cord pH, gentamicin trough level, glucose reading in first postnatal hour, any episode of hypoglycemia after the first postnatal hour, concurrent ototoxic and nephrotoxic drugs, use and number of anticonvulsants, and use and number of inotropes as the independent variables. A significance value of .05 was used when allowing independent factors to enter the regression, to identify potential relationships between hearing impairment and the independent variables.
Results Information for all 136 infants who received therapeutic hypothermia for neonatal encephalopathy, both included and excluded, is summarized in a flowchart in Figure 1. Complete data were available for 108 cooled infants, 10 of whom had significant sensorineural hearing impairment requiring amplification with a hearing aid (n = 8) or cochlear implant (n = 2). Nine infants died from severe neonatal encephalopathy. The prevalence of hearing impairment was 10.1% among the survivors. Results of the newborn hearing screen were available for all surviving infants and are summarized in Table I. Of the 10 infants with hearing impairment, 9 (90%) did not pass the newborn hearing screen. One infant had a clear response with both AOAE and AABR testing but was diagnosed with hearing impairment at age 12 months. In the group with a normal hearing outcome, 4 infants did not have a clear response on AOAE testing but had a normal AABR, and repeat AOAE testing was completely normal. Four infants did not undergo AABR testing, but all 4 had a normal
Figure 1. Flowchart of included and excluded infants. Smit et al
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Table I. Results of the initial newborn hearing screen Newborn hearing test result AOAE
AABR
+
+
+ Not done
+ Not done +
+, clear response;
Normal hearing outcome (n = 89)
Hearing impaired (n = 10)
80 0 4 4 1
1 9 0 0 0
, no clear response.
AOAE test in both ears, and 1 infant did not have an AOAE done but had a clear response on AABR testing. Cord blood pH, hypoglycemia during the first postnatal hour, need for inotropic support, requirement for $3 anticonvulsants, first gentamicin concentration, gentamicin trough level >2 mg/L, and MDI were significantly different in the infants with hearing impairment and those with normal hearing (Table II). Comparing the infants with hearing impairment with the 20 infants with normal hearing matched for asphyxial severity revealed significant differences in hypoglycemia during the first postnatal hour, requirement for $3 anticonvulsants, first gentamicin concentration, and gentamicin trough level >2 mg/L. Concurrent ototoxic and nephrotoxic drugs included furosemide, acyclovir, vancomycin, vecuronium infusion, and ranitidine. All infants received a morphine infusion during cooling, with a dosage range of 10-60 mg/kg/hour. Five infants with normal hearing required phototherapy for jaundice, compared with no infants in the hearing impaired group. Three infants had a confirmed infection with positive growth from blood culture or cerebrospinal
fluid culture, including 2 infants in the normal hearing group (group B Streptococcus, Pseudomonas) and 1 infant in the hearing impaired group (Serratia). Plasma gentamicin concentrations exceeded 2 mg/L in 37% of infants in the entire cohort and in 90% of infants in the hearing impaired group. The mean plasma gentamicin concentration was 2.66 0.65 mg/L in the hearing impaired group, compared with 1.65 1.16 mg/L in the normal hearing group. The relationship between gentamicin trough value and concurrent serum creatinine value is displayed in Figure 2. Gentamicin level was checked before administration of the third dose in 73 infants, before the second dose in 29 infants, and before the fourth dose in 6 infants. Mean MDI and PDI scores were 72 19 and 68 18, respectively, for the hearing impaired group (n = 9), compared with 88 21 and 80 18 for the normal hearing group (n = 63). Five of 9 children (56%) in the hearing impaired group had a PDI and/or MDI score of <70, compared with 18 of 63 (29%) in the normal hearing group, a statistically nonsignificant difference (P = .11). Stepwise logistic regression analysis revealed that the independent variables high trough gentamicin level (P = .010), low cord blood pH (P = .018), and early hypoglycemia (P = .014) were significantly associated with the dependent variable hearing impairment. The use and number of anticonvulsants (P = .783 and .628), use and number of inotropes (P = .055 and .834), hypoglycemia after the first postnatal hour (P = .474), concurrent ototoxic and nephrotoxic drugs (P = .843), and 10-minute Apgar score (P = .397) were not significantly associated, although the use of inotropes was close (P = .055).
Table II. Characteristics of the infants with hearing impairment, those with normal hearing, and those matched for asphyxial severity Hearing impairment (n = 10) Male sex, n (%) Birth weight, g, mean SD Gestational age, weeks, mean SD 10-minute Apgar score, median (IQR) Cord blood pH, mean SD Cord blood base excess, mEq/L, mean SD Hypoglycemia in first postnatal hour, n (%) Hypoglycemia after first postnatal hour, n (%) Concurrent ototoxic and nephrotoxic drugs, n (%) Need for inotropic support, n (%) Requiring $3 inotropes, n (%) Need for anticonvulsants, n (%) Requiring $3 anticonvulsants, n (%) First gentamicin concentration, mg/L, mean SD Concurrent creatinine, mmol/L, mean SD Gentamicin trough level > 2.0 mg/L, n (%) MDI, mean SD* PDI, mean SD*
4 (40) 3464 811 +5 38 1+4 4 (4-8) 6.88 0.12 20.5 2.12 7 (70) 4 (40) 6 (60) 10 (100) 4 (40) 8 (80) 5 (50) 2.66 0.65 103 39 9 (90) 72 19 68 18
Normal hearing (n = 89) 52 (58) 3405 576 39+4 1+5 7 (5-9) 7.03 0.18 14.65 7.26 11 (12) 15 (17) 29 (33) 58 (65) 18 (20) 66 (74) 12 (14) 1.68 1.18 82 31 26 (30) 88 21 80 18
Matched for asphyxial severity, normal hearing (n = 20)
P value, hearing impaired vs normal hearing
P value, hearing loss vs matched 20
10 (50) 3293 535 39+3 1+5 5 (3-6) 6.84 0.1 18.8 5.2 5 (25) 6 (30) 9 (45) 18 (90) 4 (20) 15 (75) 2 (10) 1.8 0.91 86 31 7 (35) 85 20 74 21
.30 .77 .131 .193 .009 .171 .0001 .08 .09 .03 .20 >.50 .004 .009 .051 .0001 .041 .055
>.50 .493 .365 .491 .445 .37 .02 >.50 .40 .54 .30 >.50 .02 .013 .213 .005 .119 .356
P values are given for infants with hearing impairment vs normal hearing and for infants with hearing impairment vs the 20 matched infants without hearing impairment. The 2-sample t-test or Mann-Whitney U test was used to compare continuous variables, and the (N 1) c2 test was used to compare proportions. *MDI and PDI results were available for 9 infants with hearing impairment, for 63 infants with normal hearing, and for 14 infants matched for asphyxial severity and normal hearing.
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Figure 2. Gentamicin trough levels (before the second, third, or fourth dose, first recorded) on the y-axis with concurrent plasma creatinine values on the x-axis for all infants studied (n = 108). A plasma gentamicin level >2 mg/L (orange line), considered potentially toxic, was seen in 37% of infants. Plasma creatinine value was correlated with gentamicin trough level (Pearson’s correlation, r = 0.593).
Discussion We found a high incidence of permanent hearing impairment (10.1%) among survivors in our cohort of cooled infants with moderate to severe neonatal encephalopathy compared with previously published rates of 3.5%7.8%.5,8,9 This discrepancy may reflect improved early detection after introduction of the universal newborn hearing screen, or may be related to the fact that more children have survived. Mortality in our center during the study period was low (12.5%) compared with published data from randomized trials of infants undergoing therapeutic hypothermia, in which mortality among cooled infants ranged from 19% to 33%.5,8,9 Infants recruited into those randomized trials were treated for infection according to local antibiotic practices, which would have involved gentamicin in some proportion of these infants. Mencher and Mencher10 studied 56 severely asphyxiated noncooled infants and identified the combination of hypoxic-ischemic encephalopathy with seizures, associated organ damage, and intrauterine growth restriction as a risk factor for sensorineural hearing impairment. We identified 1 factor—low cord blood pH—as related to the severity of illness, but also found low early blood glucose level and high trough gentamicin level to be associated with hearing impairment. None of the infants in our hearing impaired group had intrauterine growth restriction; birth weight ranged from the 9th percentile to the 99.6th percentile. 998
Vol. 163, No. 4 None of our hearing impaired infants had a family history of hearing impairment, and none was diagnosed with an underlying metabolic or genetic condition. In our logistic regression analysis, the use of inotropes had a P value of .055. This is a clinically important result, because hypotension may be a marker of associated cardiac organ damage. Gentamicin in combination with beta-lactam antibiotics is a common first-line antibiotic regimen in neonates with suspected sepsis or at high risk for infection from invasive catheter use. This drug combination provides synergistic activity against gram-positive and gram-negative bacteria with low resistance rates. The use of gentamicin in neonates has long been controversial because of the drug’s narrow therapeutic window and potential nephrotoxic and ototoxic effects, and thus close monitoring of plasma trough levels is important.11,12 Neonates, especially critically ill neonates, have a low glomerular filtration rate, leading to slower gentamicin clearance.13 Gentamicin is excreted almost exclusively by the kidneys, and its pharmacokinetics is linked to glomerular filtration rate.14 In our previous study,4 we found that impaired renal function was strongly associated with high gentamicin trough levels, and that cooling did not affect the clearance of gentamicin. Despite those findings, 37% of our current cohort of cooled infants had a trough level above the recommended cutoff of 2 mg/L. This result is likely related to renal impairment associated with the severity of neonatal encephalopathy, as reflected by concurrent high creatinine values. A dosing interval of 24 hours does not appear to suit all infants undergoing cooling for neonatal encephalopathy and leads to a high proportion of potentially toxic trough levels. Thus, revising our gentamicin regimen and trough level monitoring in infants with neonatal encephalopathy is appropriate. Based on our findings, we propose administering the initial gentamicin dose of 4 mg/kg and proceeding to the subsequent dose when the trough level drops below 2 mg/L in cooled infants with neonatal encephalopathy. For roughly two-third of the infants, this means that they will remain on a 24-hourly dosing regimen, but for the others, this means delaying the second dose until the trough level drops below 2 mg/L after a 36-hour or even a 48-hour interval. Initial hypoglycemia has been identified as a risk factor for perinatal brain injury in the context of fetal acidemia, defined as an umbilical arterial pH <7.00.15 Current evidence suggests that neurodevelopmental outcome is worse when neonatal encephalopathy is associated with hypoglycemia,16,17 and our findings indicate that early hypoglycemia is a risk factor for hearing impairment in infants with neonatal encephalopathy. Thus, early monitoring of blood glucose levels and immediate treatment in case of hypoglycemia remain paramount. Early hypoglycemia reflects exhausted energy stores after prolonged labor and/or resuscitation. The incidence of any episodes of hypoglycemia occurring after the first postnatal hour was higher in the hearing impaired group, but the difference was not statistically significant, and this variable was not a significant factor in our logistic regression analysis. Smit et al
October 2013 The development of hearing impairment in infants with neonatal encephalopathy may be linked to the extent and location of brain damage. A magnetic resonance imaging study of gray matter injury in newborns with hypoxicischemic encephalopathy kept normothermic found that 6% of survivors had neurosensorial hearing impairment,18 but did not identify a clear relationship between hearing impairment and imaging findings. The effect of cooling on hearing impairment has been studied in animal models and humans. In a gerbil model of ischemia-reperfusion of the cochlea, hypothermia (rectal temperature 32 C) during the insult prevented inner ear damage and subsequent hearing impairment compared with animals maintained at normothermia.19 The effect of local hypothermia on idiopathic sudden sensorineural hearing impairment has been studied in adults.20 Cooling the head and neck for 48 hours using a water pillow at 15 C decreased tympanic membrane temperature by 1.4 C and was associated with significantly improved recovery rates of hearing impairment by 6 months after the onset of idiopathic hearing impairment. A study of children undergoing cardiac bypass surgery identified subtle cochlear dysfunction (ie, a statistically significant reduction in amplitude levels at high frequencies) during the postoperative period in children subjected to deep hypothermia (28-32 C) during extracorporeal circulation compared with those subjected to only mild hypothermia (33-37 C).21 Other studies have shown a possible association betweeen deep hypothermia and cochlear cell injury22 and have identified a possible protective role of mild hypothermia on the cochlea during cardiac bypass surgery in children.23 Translating this research to newborn infants receiving therapeutic hypothermia is difficult, but it can be speculated that moderate hypothermia in infants with neonatal encephalopathy may have a protective role on the cochlea and subsequent hearing outcome. Caution is urged when further refining therapeutic hypothermia using deeper or longer cooling, given that some of the aforementioned findings suggest a potential harmful effect on the cochlea when using lower temperatures. A limitation of the present study is the fact that MDI assesses both language elements and cognition, and the 2 are difficult to distinguish using the BSID-II. In children with hearing impairment, the language component could be affected by hearing loss. One of the hearing impaired children had an incomplete MDI score, because his cochlear implants had been fitted only recently and had not yet been activated. In some of the other children, we relied on their use of sign language to assess the language and cognitive component. In summary, this study demonstrates that hearing impairment is a common finding in survivors of moderate to severe neonatal encephalopathy, a finding that stresses the importance of a newborn hearing screening program in this particular patient group. Our findings also underscore the importance of careful gentamicin drug level monitoring and early identification and treatment of hypoglycemia,
ORIGINAL ARTICLES both of which have been identified as risk factors for hearing impairment. n Submitted for publication Mar 7, 2013; last revision received May 15, 2013; accepted Jun 11, 2013. Reprint requests: Marianne Thoresen, MD, PhD, Department of Neonatal Neuroscience, St Michael’s Hospital, Child Health Level D, Southwell St, Bristol, BS2 8EG, UK. E-mail: [email protected]
References 1. Morzaria S, Westerberg BD, Kozak FK. Systematic review of the etiology of bilateral sensorineural hearing loss in children. Int J Pediatr Otorhinolaryngol 2004;68:1193-8. 2. Annual report of the NHS Newborn Hearing Screening Programme, April 2010 to March 2011. Available from: http://hearing.screening. nhs.uk/publications. Accessed November 29, 2012. 3. Edwards AD, Brocklehurst P, Gunn AJ, Halliday H, Juszczak E, Levene M, et al. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ 2010;340: c363. 4. Liu X, Borooah M, Stone J, Chakkarapani E, Thoresen M. Serum gentamicin concentrations in encephalopathic infants are not affected by therapeutic hypothermia. Pediatrics 2009;124:310-5. 5. 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;365:663-70. 6. Bayley N. Bayley Scales of Infant Development. Second Edition. San Antonio (TX): The Psychological Corporation; 1993. 7. Campbell I. Chi-squared and Fisher-Irwin tests of two-by-two tables with small sample recommendations. Stat Med 2007;26:3661-75. 8. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005;353:1574-84. 9. 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;361:1349-58. 10. Mencher LS, Mencher GT. Neonatal asphyxia, definitive markers and hearing loss. Audiology 1999;38:291-5. 11. Touw DJ, Westerman EM, Sprij AJ. Therapeutic drug monitoring of aminoglycosides in neonates. Clin Pharmacokinet 2009;48:71-88. 12. McCracken GH Jr, Threlkeld N, Thomas ML. Intravenous administration of kanamycin and gentamicin in newborn infants. Pediatrics 1977;60:463-6. 13. Nielsen EI, Sandstrom M, Honore PH, Ewald U, Friberg LE. Developmental pharmacokinetics of gentamicin in preterm and term neonates: population modelling of a prospective study. Clin Pharmacokinet 2009;48:253-63. 14. McCracken GH Jr, Chrane DF, Thomas ML. Pharmacologic evaluation of gentamicin in newborn infants. J Infect Dis 1971;124(Suppl): S214-23. 15. Salhab WA, Wyckoff MH, Laptook AR, Perlman JM. Initial hypoglycemia and neonatal brain injury in term infants with severe fetal acidemia. Pediatrics 2004;114:361-6. 16. Tam EW, Haeusslein LA, Bonifacio SL, Glass HC, Rogers EE, Jeremy RJ, et al. Hypoglycemia is associated with increased risk for brain injury and adverse neurodevelopmental outcome in neonates at risk for encephalopathy. J Pediatr 2012;161:88-93. 17. Nadeem M, Murray DM, Boylan GB, Dempsey EM, Ryan CA. Early blood glucose profile and neurodevelopmental outcome at two years in neonatal hypoxic-ischaemic encephalopathy. BMC Pediatr 2011; 11:10.
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18. Martinez-Biarge M, Diez-Sebastian J, Rutherford MA, Cowan FM. Outcomes after central grey matter injury in term perinatal hypoxic-ischaemic encephalopathy. Early Hum Dev 2010;86:675-82. 19. Watanabe F, Koga K, Hakuba N, Gyo K. Hypothermia prevents hearing loss and progressive hair cell loss after transient cochlear ischemia in gerbils. Neuroscience 2001;102:639-45. 20. Hato N, Hyodo J, Takeda S, Takagi D, Okada M, Hakuba N, et al. Local hypothermia in the treatment of idiopathic sudden sensorineural hearing loss. Auris Nasus Larynx 2010;37:626-30.
Vol. 163, No. 4 21. El Ganzoury MM, Kamel TB, Khalil LH, Seliem AM. Cochlear dysfunction in children following cardiac bypass surgery. ISRN Pediatr 2012; 2012:375038. 22. Veuillet E, Gartner M, Champsaur G, Neidecker J, Collet L. Effects of hypothermia on cochlear micromechanical properties in humans. J Neurol Sci 1997;145:69-76. 23. Namyslowski G, Morawski K, Urban I, Lisowska G, Skalski J. Influence of hypothermia and extracorporeal circulation on transiently evoked otoacoustic emission (TEOAE) in children operated on for various heart defects (I). Otolaryngol Polska 2003;57:263-9 (in Polish).
50 Years Ago in THE JOURNAL OF PEDIATRICS Polyarteritis Nodosa in Infancy Roberts FB, Fetterman GH. J Pediatr 1963;63:519-29
R
oberts and Fetterman reported 2 cases of fatal vasculitis of medium-sized arteries in the first year of life and added 18 cases from the literature from as early as the 1940s. Most cases were in infants during the first 6 months of life. Sixteen infants died, most suddenly. The authors termed the disease “infantile polyarteritis nodosa.” In an extensive clinical and pathologic descriptive study, they found common clinical and pathological features. The infants presented with prolonged fever (80%), transient polymorphic rash (75%), transient conjunctivitis (50%), heart failure (35%), central nervous system involvement (30%), and, less commonly, pancreatitis and extremity gangrene. Common laboratory features were leukocytosis, pyuria, and left ventricular hypertrophy and ischemic changes on electrocardiography. Remarkably, all 18 infants who died exhibited coronary artery changes (vs 58% in cases of adult polyarteritis nodosa), mainly aneurysms. Seven infants (35%) had infarcts of other viscera, mainly the kidney and spleen. The median duration of disease was 27 days, much shorter than that of idiopathic adult polyarteritis nodosa. Ineffective treatment with acetylsalicytic acid and corticosteroids was reported only in the 2 cases described by the authors. Today it is clear that the vast majority of these cases were actually descriptions of Kawasaki disease, preceding the original descriptions by Dr Kawasaki in Japanese by 4 years and in English by 11 years.1 Interestingly, none of the cases in this study were reported by Japanese authors. Kawasaki disease occurring in the first year of life is more severe, with a higher prevalence of coronary artery involvement (including in treated infants) and widespread vasculitis, compared with the disease in older children.2 The presentation is often atypical, not fulfilling classic diagnostic criteria. Indeed, in this study, only a minority of the children had lymphadenopathy and oral mucous membrane changes, and none had extremity swelling. Modern therapy with intravenous immunoglobulin and, in refractory cases, with corticosteroids and biological therapy has markedly improved the prognosis of this disease, with mortality during acute disease now <1%. Philip J. Hashkes, MD, MSc Pediatric Rheumatology Unit Shaare Zedek Medical Center Jerusalem, Israel http://dx.doi.org/10.1016/j.jpeds.2013.03.065
References 1. Kawasaki T. Pediatric acute mucocutaneous lymph node syndrome: clinical observation of 50 cases [in Japanese]. Jpn J Allergy 1967;16:178-222. 2. Rosenfeld EA, Corydon KE, Shulman ST. Kawasaki disease in infants less than one year of age. J Pediatr 1995;126:524-9.
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