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Brief Reports Indian Pediatrics 2002; 39:945-951 |
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As per the National Neonatal Perinatal Database (NNPD) report of 1995, 5% of all neonates in India develop significant jaundice with total serum bilirubin (TSB) >15mg/dL(1). The problem is exaggerated in small and preterm babies. Between 1995-1998, 77.5% of babies with birth weight 1000-1499 grams born at PGIMER and, surviving for more than 2 days, developed significant jaundice requiring phototherapy, while exchange transfusion (ET) was needed in 38.2% of them(unpublished observation). Exchange transfusion however carries significant morbidity and mortality apart-from the risks associated with exposure to blood products. Hence, a form of prophylactic therapy, which would prevent the rise of TSB to dangerous levels, would be a better option in very low birth weight (VLBW) babies. Phototherapy as well as phenobarbitone have been evaluated as prophylactic agents for neonatal jaundice. Both the modalities are effective in decreasing the peak TSB level(2,3). But phototherapy causes increased insensible water loss, increased incidence of patent ductus arteriosus and temperature instability especially in small babies(4-6). Besides, phototherapy units are difficult and costly to maintain. Hence, phenobarbitone, which is cheaper and simpler to administer, appears to be a more attractive prophylactic agent. Most of the studies with prophylactic phenobarbitone were done when use of phototherapy was not common(2,7-11). Only one study has been done exclusively in the VLBW babies(12). There is no study reported on this issue from our country. We planned this study to evaluate the effect of prophylactic postnatal phenobarbitone on neonatal jaundice (need for phototherapy and exchange transfusion) in babies with birth weight 1000-1499 grams. Patients and Methods This study was carried out from December 1998 to October 1999 on babies born at Nehru Hospital, PGIMER with birth weight 1000-1499 grams. Following babies were excluded: (i) those born to mothers receiving phenobarbitone in the antenatal period (within 2 weeks of delivery), (ii) those born to mothers with evidence of chorioamnionitis (fever, foul smelling liquor, and total leukocyte count >18000 per cu mm), (iii) Rh hemolytic disease, (iv) major congenital malformations, (v) those who received phenobarbitone for neonatal seizure. The babies fulfilling the eligibility criteria were randomized into 3 Groups according to computer generated random number list: Group I -Babies were given 10mg/kg loading dose of phenobarbitone on day 1 followed by maintenance 5mg/kg/day from day 2 to day 5, Group II - Babies were given Phenobarbitone in the maintenance dose of 5mg/kg/day from day 1 to day 5. Phenobarbitone was given as an intravenous infusion at a rate not exceeding 1 mg/kg/min. The first dose was given within 6 hrs of the birth and Group III babies acted as controls. The TSB was measured twice a day (12 hourly) for 7 days by dual wavelength direct spectrophotometer method using spun capillary tube samples (Wako Bilirubin Tester, Model: SE-101DII). Babies were investigated for the cause of jaundice (blood grouping of mother and baby, direct coomb’s test, glucose 6 phosphate dehydrogenase level) and evidence of hemolysis (reticulocyte count > 5%). Babies were monitored hourly for their vital signs and records of daily fluid intake, enteral feeding pattern, stool frequency, daily weight were kept as per our routine monitoring protocol of neonatal intensive care unit. Ultrasound head was done on Day 1, Day 3, and Day 7 for the detection of intraventricular-periventricular hemorrhage. Treatment of jaundice was as per standard unit protocol, i.e. phototherapy was started when the TSB (in mg/dL) was above 0.5 % of the birth weight (in grams) and ET was done when TSB (in mg/dL) was above 1% of the birth weight (in grams)(13). The Institute ethics committee approved the study, and informed parental consent was taken before inclusion into the study. Statistical analysis: The Chi-square test was used to see the effect of the phenobarbitone on categorical variables. Fisher-exact test was applied where numbers were very small. The difference of mean values for various parameters among the different Groups was determined by using analysis of variance (ANOVA). Statistical tests were performed using ‘Epi-info version-6’ computer software. Results During the study period, 50 babies each were enrolled in the three Groups. The baseline characteristics of the 3 Groups were similar except for a higher number of male babies in the Group I and higher proportion of small for gestational age babies in Group I and II. There was no difference in the occurrence of other disease states, which could affect TSB levels between the 3 Groups (Table 1). Survival rates till 7 days of age were 84%, 82% and 82% in Group I, Group II and Group III respectively. The daily fluid intake as well as the average fluid intake over the first week was similar in the 3 Groups. The enteral feed intake, stool frequency and weight loss were also not different between the 3 Groups (Table II). There was no significant difference in the causes of jaundice between the 3 Groups. 35(70%), 32(64%) and 43(86%) babies in Group I, II and III respectively developed significant jaundice. At 12 hours of age, the TSB was similar in the 3 Groups but subsequently it was significantly higher in Group III as compared to Group I and II (Fig. 1). There was no significant difference in the TSB between Group I and II. The difference in mean TSB between Group III and Group II or I became progressively more with increasing age. At 72 hours of life, TSB in Group III was 1.78 mg/dL and 1.67 mg/dL higher than Group I and Group II respectively. This difference increased to 3.39 mg/dL and 2.98 mg/dL compared with Group I and Group II respectively at 168 hours (Fig. 1). The peak values were significantly lower in Group I and II compared to controls (Table II). Peak Bilirubin Birth weight Index (BBI), which is considered a better way of representing TSB in VLBW babies, was also significantly lower in Group I and II. There was no difference in the timing of peak TSB between Groups I and II (Table II). The need for phototherapy was higher in Group III as compared to Group I, but the difference failed to reach statistical significance. The mean duration of phototherapy was significantly less in Group I as compared to Group II or III. Exchange transfusion was done in 4(8%), 7(14%) and 16(32%) babies in Group I, II and III respectively. The total number of ET done were 5, 9, and 21 in these babies respectively. The need for ET was significantly lower in Group I as compared to Group III. The need was also lower in Group I compared to Group II though the difference did not reach statistical significance. Similarly, comparing Group II and III, the need for exchange transfusion in Group II was lower than Group III without reaching statistical significance (Table III). In other words, only 4.2 babies needed to be treated by 10mg/kg of phenobarbitone followed by 5mg/kg/day for 5 days (Group I) to prevent one baby from ET as compared to control Group (Group III). The differences were more marked when the total numbers of exchange transfusions required in each Group were compared. Only 3.1 babies needed to be treated by 10mg/kg of phenobarbitone followed by 5mg/kg/day for 5 days (Group I) to prevent one ET as compared to control Group (Group III). Since there were less number of small for date babies in the Group III, we performed a subgroup analysis in these babies. There was no difference in the requirement of exchange transfusion and the duration of phototherapy among three groups of babies. When the analysis was performed after excluding SGA babies, the requirement of exchange transfusion and phototherapy was less in the group I as compared to group III. There were no significant side effects due to phenobarbitone administration. Two babies had apnea: one each in Group I and Group II, which may be attributed to blood culture positive sepsis that occurred in both of them, on the day of apnea. Drowsiness was not observed in the babies, who received phenobarbitone. Table I__Baseline Characteristics of the Study Groups
* P value: Group 1 vs. Group II = 0.01, Group 1 vs. Group III = 0.03 + P value: Group 1 vs. Group III = 0.03 Discussion The availability of effective phototherapy has significantly decreased the need for exchange transfusion in the developed countries. Among seven hospitals of National Institute of Child Health and Human Development (NICHD) Neonatal Intensive Care Network of United States of America, incidence of exchange transfusion for neonatal jaundice in VLBW babies was only 4% (14). In India, although the incidence of prematurity is high and their survival is increasing, maintenance of effective phototherapy system is costly and difficult. Hence, prophylactic phenobarbitone seems a cheap alternative. It has been shown that phenobarbitone is effective in lowering serum bilirubin levels(7-11). In our study, exchange transfusion was required in 8%,14% and 32% of babies in Group I, Group II and Group III respectively. Epstein et al.(15) evaluated the effect of postnatal phenobarbitone 10 mg/kg followed by 2.5mg/kg twice daily for 5 days in 280 ventilated babies (128 cases, 118 controls) with birth weight <1750 grams. They found TSB of >10 mg/dL in 7% of treated babies against 13.6% of control Group and 1.6% babies required exchange transfusion in the treatment Group and 3.5% in the control Group. We also observed decreased phototherapy requirements in phenobarbitone treated babies. Valdivieso et al.(12) also observed similar results in their study on phenobarbitone treated babies (5.5 days vs 7.5 days). In the study by Epstein et al.(15) using 10 mg/kg loading dose, the mean duration of phototherapy was 5.7 days in the phenobarbitone Group and 6.3 days in control Group. Table II__Mean ± SD of Bilirubin Values, Fluid Intake and Weight in Study Subjects
* P value = Group 1 vs. Group III - 0.00002, Group II vs. Group III = 0.00002. + P value = Group 1 vs. Group III = 0.0066, Group II vs. Grtoup III = 0.010 ** BBI - Bilirubin Birth-weight Index = TSB (mg/dL)/birth weight (g) It seems from these studies that the amount of loading dose may be important. Valdivieso et al.(12) who used a loading dose of 20mg/kg showed the most marked decrease in the duration of phototherapy. Wallin et al.(16) evaluated the pharmacokinetics of pheno-barbitone given as 5 mg/kg/day for 7 days in preterm babies. Increment in plasma drug level occurred throughout the period of administration and steady state was not achieved even at 7 days. The peak level of phenobarbitone in plasma always occurred later than that of bilirubin. They suggested that dosage regimens should be so constructed that the drug may exert its maximal effect very early after birth. There are few limitations in our study. This is not a placebo-controlled study and thus blinding was not done. This might have created some bias in the management of the jaundice although clinicians managing the babies were not influenced. We also did not measure the irradiance of phototherapy units, so we cannot make comments about the quality of phototherapy received by different groups, however there was no selection bias for a particular phototherapy unit for specific babies. Table III__Effect of Phenobarbitone on Need for Phototherapy and Exchange Transfusion
PT = phototherapy, ET - exchange transfusion. In summary, phenobarbitone in the dose of 10mg/kg given within 6 hours of life followed by 5mg/kg/day for 5 days by intravenous route significantly decreased the need for exchange transfusion and duration of phototherapy in babies with birth weight of 1000-1499 grams. The amount of phenobarbitone given as first dose within 6 hours of life seems to be the crucial factor in the action of phenobarbitone. Further studies are warranted to evaluate the role of much larger loading dose or a single large loading dose in the prevention of significant neonatal jaundice in VLBW babies. Contributors: RK carried out this study as his dissertation for DM (Neonatology) course. AN was the chief guide and co-ordinated the study and will act as the guarantor for this paper. PK and GG were co-guides and helped in manuscript preparation and laboratory investigations respectively. Funding: None Competing interests: None stated.
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