3 0 6 Clinical and laboratory observations The Journal of Pediatrics February 1992

Phototherapy and the brain-stem auditory evoked response in neonatal hyperbilirubinemia

K. L. Tan, FRCPE, FRACP, B. A. Skurr, MAPSA, and Y. Y. Yip, MMed(Paediatr)

From the Departments of Neonatology and Otorhinotaryngology, National University Hospital, Republic of Singapore

The latencies of peak V and interpeaks I-V and III-V in the brain-stem auditory evoked response of infants with hyperbilirubinemia before phototherapy were significantly greater than those in a control group of infants. These values of the brain stem auditory-evoked response improved significantly during photother- apy and correlated significantly with the declining bilirubin levels. Improvement continued after phototherapy, despite a rebound of serum bilirubin concentra- tions. (J PEDIATR 1992;120:306-8)

Hyperbilirubinemia can result in abnormalities in the brain-stem auditory evoked response, l-4 but the changes are reversible with reduction of bilirubin levels by exchange transfusion. 24 Phototherapy is commonly used in the man- agement of hyperbilirubinemia, and we thought it impor- tant to ascertain whether reducing bilirubin levels by pho- totherapy can reverse changes in the BAER.

M E T H O D S

Otherwise healthy term infants (without infection or trauma/contusion/cephalhematoma) who had nonhe- molytic hyperbilirubinemia as previously defined 5,6 were

recruited for this study. All infants were progressing and feeding well. Phototherapy was begun only when bilirubin levels were >255 ~mol/L (15 mg/dl) and in those <48 hours of age when bilirubin levels exceeded 222 ~mol/L (13 mg/dl). A complete blood cell count was performed just before phototherapy was begun. Healthy term infants of comparable age with bilirubin levels <140 ~mol/L (8.2 mg/dl) were randomly selected to serve as control subjects. If subsequent jaundice > 140 #mol/L developed in a control infant, the data for that infant were excluded from the study. A slightly larger number of control infants were re- cruited to allow for this possibility. Informed consent was obtained from parents.

Phototherapy was provided by seven daylight fluorescent lamps (Philips TL 18W/54, Philips Electronic Instruments, Inc., Mahwah, N.J.) arranged in an arc approximately 35 cm above the infant. The infants, completely unclothed and

Submitted for publication May 29, 1991; accepted Aug. 2, 1991. Reprint requests: K. L. Tan, FRACP, Chief, Department of Neo- natotogy, National University Hospital, 5 Lower Kent Ridge Rd., Singapore 0511, Republic of Singapore. 9/24/32905

with eyes covered, were exposed to continuous phototherapy that was interrupted only for feeding and nursing. The ir- radiance was 350 #W/cm 2 in the 400to 480 nm range, 270 ~W/cm 2 in the 425 to 475 nm range, and 215 ~W/cm 2 in the 440 to 480 nm range. Measurements were made with the 11 A photometer/radiometer (United Detector Technology, Inc., Santa Monica, Calif.) as previously described. 5, 6 Fluid

intake was increased to offset the increased fluid loss dur- ing photoexposure.

Bilirubin determinations were performed on capillary blood obtained at 6- or 12-hour intervals; the lights were switched off and the infant was removed from the cot for

BAER Brain-stem auditory evoked response

blood sampling. The labeled capillary tubes were placed in a light-excluding box until the moment of determination. Phototherapy was continued until bilirubin levels had declined to <185 ~mol/L (11 mg/dl) on two consecutive determinations; the minimum exposure period was 24 hours.

The bilirubin level was determined under standard con- ditions by an American Optical bilirubinometer (American Optical Co., Southbridge, Mass.), which was checked reg- ularly against known standards. Paired random samples were checked to determine the reliability of the measure- ments; the direct-acting bilirubin was also determined in random samples and in infants not responding to photo- therapy as previously described, s, 6

The BAER test was performed on the infants undergo- ing phototherapy just before exposure, after 24 hours of ex- posure, at the termination of exposure, and 1 day later. The BAER test was also performed on the control infants on approximately the same days of life (i.e., third, fourth, fifth, and sixth days of life). The person performing the BAER

Volume 120 Clinical and laboratory observations 3 0 7 Number 2, Part 1

Table. Data from infants at start of study

Control group (mean • SE) p Study group (mean • SE)

No. (M/F) 31 (15/16) 30 (14/16) Birth weight 3238 + 94 NS 3025 _+ 94 Gestation 38.80 _+ 0.35 NS 38.50 _+ 0.31 Age 3.10 + 0.01 NS 3.25 • 0.02 Serum bilirubin (/zmol/L) 119.50 _+ 8.96 <0.00l 258.00 • 5.26 BAER

Latencies (msec) I 1.77 • 0.03 NS 1.75 _+ 0.02 III 4.54 • 0.04 NS 4.56 • 0.04 V 6.75 _+ 0.03 <0.02 7.00 • 0.08

Interpeak latencies (msec) l-III 2.77 _+ 0.04 NS 2.80 + 0.04 III-V 2.25 + 0.04 <0.05 2.44 + 0.08 I-V 5.00 _+ 0.04 <0.05 5.25 • 0.09

NS, Not significant.

test had no knowledge of the status of the infants. The

BAER was recorded in a quiet room beside the nursery, with

the infant in a quiet state or asleep; the Cadwell model

Quantum 84 evoked-response unit (Cadwell Laboratories,

Kennewick, Wash.) was used. Montage placement included

an active electrode on the ipsilateral mastoid, the ground

electrode on the midfrontal area, and the reference elec-

trode on the vertex. Electrode impedance was kept to less

than 5000 ohms. Responses were recorded monoaurally in

the right ear to a 70 dB stimulus with an alternating click

stimulus, generated by a 100 msec square-wave pulse

administered through the headphones with an average of

2000 clicks. At least two replicate recordings were made at

each test. The latencies, interpeak latencies, and amplitude

were measured.

The results were analyzed by means of the Student t test

(paired and unpaired) and Pearson product-moment corre-

lation coefficient.

R E S U L T S

Thirty infants with hyperbilirubinemia and 31 control

infants were studied (Table); two infants in the study group

and two in the control group were less than 48 hours of age

at the start of the study. All the infants remained healthy

and well and had no complications during the study period.

The level of direct-acting bilirubin did not exceed 15

#mol/L (0.9 mg/dl) in any of the samples studied There

were initially 36 control infants, but five later had higher

bilirubin levels and were excluded from the study.

As shown in the Table, the BAER in the infants exposed

to phototherapy had significantly prolonged latency V

( t = 2.394; p < 0 . 0 2 ) and interpeak latencies III-V

(t = 2.032;p < 0.05) and 1-V (t = 2.351;p < 0.05), with no

significant differences from control infants in latencies I and

III (unpaired Student t test). As the bilirubin levels declined

in response to phototherapy, concomitant improvement oc-

curred in these BAER values (Figure); the difference

between values in the control group and study group

narrowed but remained significant at 24 hours of exposure,

at which time the bilirubin levels were still significantly dif-

ferent. However, the differences in the latencies were no

longer significant at the end of exposure; the bilirubin val-

ues had declined markedly but were still significantly higher

than those of the control group, improvement in the BAER

continued, the values becoming comparable to those of the

control group 1 day after cessation of exposure, despite

some rebound of bilirubin values. This lag period precluded

the evaluation of the threshold bilirubin concentration ca-

pable of causing changes in the BAER.

In the phototherapy group there was a significant differ-

ence between the preexposure and postexposure values of

latency V (t -- 7.664; p < 0.001) and interpeak latency I-V

(t -- 9.539;p < 0.001); this was also the case with interpeak

latency III-V (t = 5.276; p < 0.001; paired Student t test).

The correlation between the bilirubin levels and the BAER

values during phototherapy was highly significant: r = 0.967

and p < 0.001 for latency V; r -- 0.999 and p < 0.001 for

interpeak latency I-V; and r = 0.963 and p < 0.001 for in-

terpeak latency III-V. The amplitude measurements proved

too unreliable for meaningful comparison.

D I S C U S S I O N

This study demonstrates significant prolongation of the

central conduction time with hyperbilirubinemia, as has

been previously reported 2-4, latency V and interpeak laten-

cies III-V and I-V in the group with hyperbilirubinemia

were significantly longer than those in the control group.

These differences gradually decreased as the bilirubin lev-

els of the experimental group declined during phototherapy.

Improvement in latency V and interpeak latencies III-V and

3 0 8 Clinical and laboratory observations The Journal of Pediatrics February 1992

300-

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m 1 0 0 ,

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i . . . . . . . . . i . . . . . . . . . ; . . . . . . . . . i i i I

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D A Y S

Figure. Effect of phototherapy on bilirubin levels and BAER. Start of study is referred to as 0 on the x-axis. As bilirubin levels declined during phototherapy, improvements in BAER occurred.

I-V continued after phototherapy until values comparable

to those in the control group were observed 1 day later; this

occurred despite a slight bilirubin rebound with signifi-

cantly higher bilirubin levels in the study group. This

observation suggests that reversal to normal values in the

BAER requires an additional period of 24 hours. The low-

est bilirubin concentration likely to cause these changes in

the BAER could not be reliably determined because of this

lag period; from this study it appears that a bilirubin con-

centration of 160 # m o l / L does not affect the brain stem.

Full recovery of the B A E R after exchange transfusion 4

seemed to require a longer period, but inasmuch as postex-

change bilirubin values were not fully provided in that re-

port, the correlation with bilirubin levels could not be

determined. However, a marked rebound after exchange can usually be expected6; obvious improvement still oc-

curred in such a situation.

A previous study I demonstrated prolongation of latencies

of waves III and IV-V, as well of as latencies of interpeaks

I-III and I-V. The bilirubin levels were only moderately

raised and usually were not associated with the latency of

wave I, which seems to be affected only by severe hyperbi-

lirubinemia.7, 8 However, in another study in which severe

hyperbilirubinemia occurred, 4 latencies I and V were

affected but interpeak latency I-V was not. Our study dem-

onstrated prolongation of latency V and interpeak latencies

I I I -V and I-V with no effect on I and III. The bilirubin lev-

els in our subjects may not have been sufficiently high to af-

fect wave I, but this would not explain the apparently nor-

mal latency of wave i i i and interpeak I-III. There seem to

be differences in the findings of the various studies, but all

demonstrate an aberration in the BAER, with prolongation

of the central conduction time. We conclude that photo-

therapy is effective not only in reducing serum bilirubin

values but also in reversing the effects of bilirubin on the

BAER.

We thank the doctors, nurses, and other ward personnel for their cooperation and assistance, K. H. Yeoh, chief of the Department of Otorhinolaryngology, for his encouragement, and the chief ex- ecutive officer of the National University Hospital for permission to undertake this study.

R E F E R E N C E S

1. Vohr BR, Lester B, Rapisardi G, O'Dea C, et al. Abnormal brain-stem function (brain-stem auditory evoked response) correlates with acoustic cry features in term infants with hy- perbilirubinemia. J PEDIATR 1989;115:303-8.

2. Perlman M, Fainmesser P, Sohmer H, Tamaris H, Wax Y, Pevsmer B. Auditory brainstem evoked responses in hyperbi- lirubinemia. Pediatrics 1983;72:658-64.

3. Wennberg RP, Ahlfors CE, Bickers R, McMurty CA, Shetter JL. Abnormal auditory brain-stem response in a newborn in- fant with hyperbilirubinemia: improvement with exchange transfusion. J PEOIATR 1982;100:624-6.

4. Nakamura H, Takada S, Shimabuku R, Matsuo M, Matsuo T, Negishi H. Auditory nerve and brainstem responses in newborns with hyperbilirubinemia. Pediatrics 1985;75:703-8.

5. Tan KL. Comparison of the effectiveness of "single direction" and "double direction" phototherapy for neonatal jaundice. Pediatrics 1975;56:550-3.

6. Tan KL. Comparison of the effectiveness of phototherapy and exchange transfusion in the management of nonhemolytic neonatal hyperbilirubinemia. J PEDIATR 1975;87:609-12.

7. Chisin R, Perlman M, Sohmer H. Cochlear and brainstem re- sponses in hearing loss following neonatal hyperbilirubinemia. Ann Otol Rhinol Laryngol 1979;89:352-7.

8. Kaga K, Kitazume E, Dodama K. Auditory brainstem re- sponses of kernicterus infants. Int J Pediatr Otorhinolaryngol 1979;1:255-64.