Transient adrenal suppression during early dexamethasone therapy

Indian J Pediatr 1991; 58 : 115-118 Transient Adrenal Suppression During Early Dexamethasone Therapy Gopal Srinivasan, Martin Anyebuno, C.IL Kannan, Rosita S. Pildes and Tsu F. Yeh Divisions of Neonatology and Endocrinology, Cook County Hospital and University of Illinois, and University of Health Sciences/The Chicago Medical School, Chicago, U.S.A. mg/kg/day on days 4--6; 0.25 mg/kg/day on days 7-9 and 0.1 mg/kg/day on days 1012. Daily dexamethasone or placebo (saline) was given in two doses, every 12 hours. Serial assay of plasma concentration of dexamethasone and cortisol were performed using radioimmunoassay just before the study and at 30 hours (day 2), 102 hours (day 4), 174 hours (day 7) and 246 hours (day 10) after starting the study. All the samples collected during the study were stored at -20~ until the time of the assay and done in one batch. The cross reactivity of the assay with dexamethasone was 0.53% and the sensitivity of the assay was 0.2 pg/dl. During the first half of the clinical trial infants were observed for evidence of adrenal suppression which included blood pressure, BUN, serum glucose and electrolytes. No evidence of adrenal suppression was noted. During the second half of the study, serum samples for cortisol were also drawn one week after completion of therapy and were analysed soon after collection. Serum cortisols < 10 pg/dl were considered as low values for study purposes. ACTH stimulation test was done in the infants with values < 10 pg/dl using cortrosyn 12.5 units intravenously;, samples for High doses of glucocorticoids have been used in the immediate neonatal period to reduce the severity or respiratory distress syndrome) Side effects have been noted but little is known about endogenous pituitary-adrenal function following high doses of steroids during the first two weeks of postnatal life. This study was performed as part of a randomized double blind dexamo ethasone/placebo therapy in preterm infants with severe respiratory distress syndrome. MATERIAL AND METHODS Preterm infants who weighed between 700-2000 g and required assisted ventilation for respiratory distress syndrome were included in the study between June-November 1988. The study was approved by Federal Food and Drug Administration (IND 31545) and by the Scientific and Lay Committees of Cook County Hospital. After informed consent, the infants were randomly assigned to control (placebo)/treatment (Dexamethasone) group based on a double blind design. The dose of dexamethasone was 1 mg/kg/day on days 1-3; 0.5 Reprint requests : Dr. G. Srinivasan, Division of Neonatology, 700 South Wood Street, Chicago, IL 60612, (312) 633-6455, U.S.A. 115 116 THE INDIANJOURNALOF PEDIATRICS cortisol and glucose were drawn prior to, 30 minutes, and 60 minutes after stimulation..A rise in serum cortisol > 21.6/tg/dl a n d / o r increase of < 10 /~g/dl from baseline values was considered an adequate response. 2 Data were analyzed using student "t" test, and ANOVA. Log transformation was used prior to ANOVA if the standard deviation was not independent of the mean. Vol. 58, No. 1 9~I (26) 80 70 Placabo [z~ Dexamethasone 60 50 l Mean SO J NO of Infants ] = p<001 "~ 40~.~. 30 ~ (281 0~ 20~ 15- (16) (23) T 10- RESULTS There were no significant differences (Table 1) between the group prior to entry into the study. Pre study-cortisol values (Figure 1) showed marked variability but were not significantly different between the groups (40.0 _+ 40.0 vs 36~4 _+ 50.3 ttg/dl). Serum cortisol values were significantly lower (p < 0.01) in the treatment group on day 2, days 4, day 7, and day 10. One week post study, samples were available in 11 control and 16 dexamTABLE1. Clinical and Perinatal Characteristics Placebo (29) Dexamethasone (28) Birth weight (gm) 1273 -+ 322* 1318 + 359 Gest. age (weeks) 30.1 -+ 2.1 30.8 _+2.7 16/13 13/15 8 7 VD 18 14 C/S 11 14 Sex (M/F) PROM (> 24 hr) Type of delivery Age at time of starting study (hr) 8.7 + 3.1" *Mean _+S.D. 8.5 + 3.1 q Re- Study Day 2 Day 4 Day 7 Day 10 PostStudy Fig. 1. Serum cortisol values of placebo and dexamethasone groups during and after study period. ethasone treated infants; cortisol values were not significantly different between the two groups (4.7 + 3 vs 9.3 -+ 7.9/tg/dl). Eight infants had serum cortisol levels > 10/tg/dl and were not given ACTH stimulation tests; 19 infants had values of < 10 /tg/dl and 17 of these were studied with ACTH stimulation (9 control, 8 dexamethasone). One infant in the control group with serum eortisol < 10/tg/dl was suspected of having necrotizing enterocolitis and was not studied. One infant in dexamethasone group was restarted on dexamethasone because of bronchopulmonary dysplasia. Thus, 9 control and 8 treated infants were studied. Baseline values (9.2 + 12.7 vs 6.5 -4-- 5.1 pg/dl), post stimulation values at 30 minutes (25.8 _+ 9.0 vs 22.8 _+ 8 pg/dl) and 60 minutes (32.9 _+ 13.1 vs 28.3 _ 8.2/~g/dl) were not significantly different between placebo and treatment groups (Figure 2). Plasma glucose was monitored during the study period. Pre-study and post-study SRINIVASAN ET AL : TRANSIENT ADRENAL SUPPRESSION ACTH Stimulation Test 50 Placebo ~ C30examethasone Mean• ( ) No. of Infant -~ 40 ) ~ to Stimulation 30 'min 60 min Post-Stimulation Fig. 2. Serum cortisol levels in placebo and control groups before and after ACTH stimulation test. glucose values were not significantly different between placebo and treatment groups (101 -+ 24 mg/dl vs 83 _+ 25 mg/dl; 101 -+ 28 mg/dl vs 102 + 24 mg/dl). The treatment group has significantly higher glucose values during the entire study period by ANOVA (p < 0.01). Four infants in treatment group and one infant in control group had two or more episodes of hyperglycemia during the study period. Serum electrolytes were not significantly different between the groups. DISCUSSION Cortisol values in the first hours after birth are high in stressed premature infants but by the second day, cortisol values fall and remain significantly lower than baseline values. Baseline serum cortisol values in our study were higher than those reported by Reynolds in preterm infants with "fatal Hyaline Membrane Disease"; values on days 4 and 7 in placebo group were similar to the previous study? The marked variation in eortisol values is similar to previous studies in large preterm infants during first 72 hours of life and older 117 newborns. 3,4z Neonates who were given dexamethasone had significantly lower values of cortisol than the controls during the time dexamethasone was administered indicating suppression of adrenal function; one week after discontinution of dexamethasone, however, basal cortisol values were not significantly different from those in the control infants. Moreover, ACTH stimulation showed adequate and similar responses in both groups of infants. Thus, adrenal suppression appears to be transient with rapid recovery within one week following cessation of therapy; this is similar to previous reports in the post neonatal period. 2~6 Side effects of dexamethasone were also demonstrated by the significantly higher glucose values in treated infants during the period of study. Other side effects including weight loss, hypertension, sepsis and renal problems have also been reported. 7,s In summary, adrenal suppression occurs during dexamethasone administration but is transient and may not be of clinical significance. However, coupled with other potential side effects, therapeutic intervention with dexamethasone requires assessment of the potential risk-benefits ratio in each individual patient. REFERENCES 1. Baden M, Bauer CR, Colic E, Klein G, Taeuch HW Jr, Stern L. A controlled trial of hydrocortisone therapy in infants with respiratory distress syndrome. Pediatrics 1972; 50 : 526-534. 2. Arnold J'D, Leslie GI, Williams G, Rack P. Silink M. Adrenocortical responsiveness in neonates weaned from the ventilator with dexamethasone. Aust Pediatr ] 1987; 23 : 227-229. 3. Reynolds JW. Serum total corticoid and cortisol levels in premature infants with 118 THE INDIANJOURNALOF PEDIATRICS respiratory distress syndrome. J Pediatr 1973; 51 : 884-890. 4. Noguchi A, Reynolds J. Serum cortisol and dehydroepiandrosterone sulfate responses to ardrenocorticotropin stimulation in premature infants. Pediatr Res 1978; 12 : 1057-1061. 5. Wilson DM, Baldwin RB, Ariango RL. A randomized, placebo-controlled trial of effects of dexamethasone on hypothalamic-pituitary-adrenal axis in preterm infants. J Pediatr 1988; 113 : 764-768. VoL58, No. 1 6. Thomas S, Murphy JF, Dyas M, Hughes IA. Response to ACTH in the newborn. Arch Dis Child 1986; 61 : 57-60. 7. Taeusch HW. Glucocorticoid prophylaxis for respiratory distress syndrome. A review of potential toxicity. J Pediatr 1975; 87 : 617-623. 8. Yeh TF, Torte JA, Rastogi A, Anyebuno MA, Pildes RS. Early postnatal demamethasone therapy in premature infants with severe respiratory distress syndrome : Double blind controlled study. (in press). GLOBAL PROGRESS IN DIARRHEAL DISEASES - 5 IMPROVED ORS Even though ORS is an effective treatment of dehydration caused by acute diarrhea, it does not diminish the amount or duration of diarrhea, which is what most caretakers desire. For this reason an improved ORS that has this effect has been the object of extensive research. In one approach glucose is replaced by a starch-based cereal powder, such a cooked rice powder; in the second approach chemically defined ingredients are either used in place of glucose (e.g. maltodextrin) or added to the formulation (e.g. alanine, gluamine). The theoretical advantage of using a starch-like material with a polymeric structure is that, during its digestion, glucose is released slowly and promotes sodium absorption without increasing the osmolarity of ORS. The use of amino acids is based on evidence that they also can enhance water and electrolyte absorption by mechanisms distinct from the mode of actions of glucose. Research results to date have suggested that the use of cereals in place of glucose in the current ORS formulation is the most effective alternative, rice being the cereal that has been most widely studied. These have shown that the addition of glycine or glycylglycine to ORS has no beneficial effect. One study however, conducted in adult cholera patients, showed that stool output during the first 24 hours of treatment was reduced by 40% in those given ORS containing L-alanine. Abstracted from : Cleason M and Merson MH. Pediatr h~fDis 1990; 9 : 345-355.