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PEDIATRICS Vol. 104 No. 3 September 1999, pp. 476-481
,
From the From the * Department of Pediatrics, China Medical
College Hospital, Taichung; and the Department of Pediatrics,
National Cheng Kung University Hospital, Tainan, Taiwan, Republic of
China.
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ABSTRACT |
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MaterialsMethods
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Objective. To assess the effects of early postnatal dexamethasone therapy on hematologic values in preterm infants.
Materials and Methods. We reviewed the hematologic data of 179 preterm infants who participated in a double-blind clinical trial of early postnatal dexamethasone therapy (<12 hours after birth) for the prevention of chronic lung disease. One group (86 infants) received saline and the other group (93 infants) received dexamethasone. Dexamethasone was given intravenously every 12 hours in tapering doses: 0.25 mg/kg on days 1 to 7, 0.12 mg/kg on days 8 to 14, 0.05 mg/kg on days 15 to 21, and 0.02 mg/kg on days 21 to 28. Blood samples were obtained on days 0, 3, 7, 10, 14, 21, and 28. None of the infants received prenatal steroid therapy.
Results. Multiple regression analysis revealed significant differences in the values versus time curves of the white blood cell, neutrophil, lymphocyte, basophil, and eosinophil counts between the two groups. The white blood cell count was significantly higher in the dexamethasone group on days 7 through 14, and this was associated with significantly higher numbers of segmented neutrophils and band forms and significantly lower numbers of lymphocytes and eosinophils. The hematocrit and platelet counts were similar in the two groups throughout most of the trial. Except for platelet count, steroid therapy did not alter the hematologic values for infants with bacteremia.
Conclusion. Dexamethasone affects white blood cell, segmented neutrophil, lymphocyte, basophil, and eosinophil counts in neonates. This should be taken into consideration when evaluating preterm infants who are receiving dexamethasone.early dexamethasone therapy; neonatal blood count; preterm infant; respiratory distress syndrome.
In several clinical trials, dexamethasone has been shown to
facilitate extubation of infants with chronic lung disease
(CLD)1-3 and to decrease the incidence of CLD among those
with respiratory distress syndrome (RDS), possibly by suppressing the
pulmonary inflammatory process in the early neonatal
period.1,4 However, dexamethasone is not without adverse
effects, including hypertension, hyperglycemia, and gastrointestinal
bleeding.5 Preterm infants are also at increased risk for
infection, thrombocytopenia, and anemia. Recognition of infection
depends on clinical acumen and supporting laboratory data, including
alterations in the number and morphology of neutrophils, number of
platelets, and hematocrit. Because the decision for antibiotic therapy
may be influenced by the blood cell count in neonates with suspected
infection, it is useful to appreciate the influence of
glucocorticosteroids on blood values.
Glucocorticoids have hematologic effects that have been shown to
stimulate erythropoiesis both in vivo6,7 and in
vitro.8 Dexamethasone has also been shown to increase leukocyte,9 neutrophil,9-11 and platelet
counts11 in preterm infants with CLD. Increases in
leukocyte and neutrophil counts,12 as well as a transient leukemoid reaction,13 have also been reported after antenatal administration of corticosteroids. However, little is known
about the effects of dexamethasone on hematologic parameters when
administered for extended periods beginning shortly after birth.
In our recent double blind clinical trial,1 262 preterm
infants with RDS were given either dexamethasone or placebo to study
the drug's effect in the prevention of CLD when given in tapering
doses beginning on the first day of life. The purpose of the present
study was to assess the effects of dexamethasone on the hematologic
profile in these patients.
Patients
The study group consisted of participants in a multicenter,
randomized, placebo-controlled trial on the effects of dexamethasone for the prevention of CLD in preterm infants with RDS. The study protocol was described in detail previously.1 Briefly, during a 30-month period, all infants from six hospitals in Taiwan (National Cheng Kung University Hospital, Chang Gung Children's Hospital, Mackay Memorial Hospital, China Medical College Hospital, Chung Shan Medical College Hospital, and Kuang Tien Hospital) were
eligible for the study. The selection criteria for infants were: 1)
birth weight in the range of 500 to 1999 g; 2) clinical and
radiologic features of severe RDS; and 3) requirement for mechanical
ventilation within 6 hours of birth. Infants with prenatal infection,
complex congenital anomalies, or fatal cardiopulmonary conditions
within 12 hours of birth were excluded. The study protocol was approved
by the Human Research and Ethics Committees of the participating
hospitals, and written informed consent was obtained from the parents
or legal guardians of all participants.
Protocol
After a 2- to 4-hour period of initial stabilization, infants
were randomly assigned to receive a 28-day course of either 0.9%
saline placebo or dexamethasone sodium phosphate. For infants who
received dexamethasone, the following dosage was given intravenously every 12 hours: days 1 to 7, 0.25 mg/kg/dose; days 8 to 14, 0.12 mg/kg/dose; days 15 to 21, 0.05 mg/kg/dose; and days 22 to 28, 0.02 mg/kg/dose. The first dose was administered within 12 hours of birth in
all cases. In the control group, saline was given according to the same
time schedule.
A protocol for the treatment of RDS was followed by all participants.
The protocol emphasized the criteria of initiation of and weaning from
mechanical ventilation. During the study, all infants were maintained
at appropriate blood gases and acid-base balance. Total fluid intake
was adjusted to 80 mL/kg/d in the first postnatal day and increased
daily to 150 mL/kg/d by day 5 and onward. Because of the possible risk
of infection associated with steroid therapy, all infants were given
ampicillin and gentamicin for 7 days. Subsequently antibiotic use was
the decision of the attending physician. Blood culture was obtained for
any infant suspected to have sepsis.
Hematologic Analysis
All blood samples were obtained from the umbilical artery
catheter during the first postnatal week and subsequently from a peripheral vein. The white blood cell (WBC) count, hematocrit, and
platelet count were determined using standard laboratory techniques, using the Symex NE 8000 automated hematology analyzer (Symex, Kobe,
Japan) or Coulter S plus (Coulter, Hialeah, FL) profile. The absolute
segmented neutrophil, band form, eosinophil, and basophil counts were
calculated based on the differential count. Blood samples were
collected on days 0 (before the first 12 hours of life, for baseline
data) and as possible on days 3, 7, 10, 14, 21, and 28 for analyses of
hematologic parameters. Transfusion with red blood cells and platelets
was given as necessary, depending on the clinical course, and was
determined by the individual attending physician. None of the patients
received transfusions with WBCs during the study. Four infants in the
control group and 3 in the dexamethasone group required platelet
transfusions because of severe thrombocytopenia
(<20 000/mm3) during the study period.
Statistical Analysis
Data are presented as the mean plus/minus standard deviation.
Differences in the mean values between groups on individual days were
assessed using the two-tailed Student's t test for paired data. The overall differences between the two groups for each variable
were analyzed with multiple regression using general estimating
equations. All analyses were performed using SPSS for Windows
statistical software (SPSS Inc, Chicago, IL). A P value of
<.05 was considered statistically significant.
Of the 262 infants who were included in the initial double-blind
study, 83 infants (44 in the control group and 39 in the dexamethasone
group) were excluded from this analyses because of prenatal steroid
therapy. The final number of infants included for data analysis was 179 (86 in the control group and 93 in the dexamethasone group). The
demographic data are summarized in Table
1. The perinatal characteristics of the
two groups were similar with respect to birth weight, gestational age,
age (hours) at the start of study, sex, and Apgar scores at 1 and 5 minutes. The first dose of dexamethasone in the treatment group was
given at 7.6 ± 4.8 hours of age.
TABLE 1
MATERIALS AND METHODS
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RESULTS
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Clinical Characteristics in the Perinatal Period
Initial Hospital Course
The initial hospital course showed that infants in the dexamethasone group had significantly (P < .05) lower incidence of CLD than infants in the placebo group judged at 28-postnatal days (15 out of 93 vs 38 out of 86). There was no difference between the groups in mortality (25 out of 86 vs 62 out of 93). The immediate but transient side effects observed in the dexamethasone group were: increase in blood glucose and blood pressure, cardiac hypertrophy, hyperparathyroidism, and a transient delay in the rate of growth, similar to the overall group previously reported.1
Comparison of the Hematologic Data Between the Groups
The total WBC count in the dexamethasone group increased significantly beginning on day 3, and began to taper off again after day 14. This trend was not noted in the control group (Fig 1). By day 28, the mean WBC count of the dexamethasone group had dropped significantly lower than that of the control group. This was probably a result of a significantly lower lymphocyte count in the dexamethasone-treated infants. Although the WBC count was significantly (P < .05) higher in the dexamethasone group only on days 7, 10, and 14, the overall shape of the curves were significantly different in the two groups (Fig 1).
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The dexamethasone group showed higher band counts than the control group on days 0 to 28, with significantly higher counts on days 7 and 14 (Fig 2). The difference in the overall response patterns of the two groups, however, was not significant (Fig 2).
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The segmented neutrophil count increased markedly in the dexamethasone group and was significantly higher than that of the control group on days 3, 7, 10, 14, and 21 (Fig 3). The neutrophil count returned to near baseline values on day 28. Again, the shape of the curves differed significantly between the two groups (Fig 3).
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The absolute lymphocyte count was comparable between the groups from day 0 to day 14. In both groups, the lymphocyte count dropped on day 3, and recovered slightly from days 7 to 14. The lymphocyte count in the dexamethasone group dropped again and became significantly lower than the control group on days 21 to 28 (Fig 4).
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Both groups had a comparable basophil count on day 0. In the dexamethasone group the basophil count dropped dramatically and had become significantly lower than that of the control group on days 7 and 14. The counts were similar in the two groups at the end of the treatment period. In general, the pattern of changes differed significantly between the two groups.
Although the total eosinophil count did not differ significantly between the two groups on most days, the dexamethasone group tended to have lower values throughout the trial. Multiple regression analysis detected a significant difference in the shapes of the curves.
The platelet count tended to be higher in the dexamethasone group throughout the trial; this difference was significant on days 3 and 21 (Fig 5). The overall shape of the curves, however, was similar in the two groups. The hematocrit was similar in the dexamethasone and control groups throughout most of the trial.
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Comparison of Hematologic Data Between the Groups in Infants Without Bacteremia
Bacteremia was seen in 13 infants in the dexamethasone group and in 8 infants in the control group. Bacteremia may affect the cell count values, we therefore excluded these 21 infants with bacteremia from analysis. Significant differences between the groups were again seen in neutrophil, lymphocyte, and eosinophil count. Infants in the dexamethasone group had a significantly higher neutrophil count (P < .05), and a lower lymphocyte (P < .01) and eosinophil (P < .01) count starting from day 3 through day 21. By day 28, there was no difference between the groups. Platelet count was comparable between the groups.
Comparison of Hematologic Data Between Bacteremia and Nonbacteremia Infants Within the Group
In the control group, there was a significantly (P < .05) lower eosinophil count and lower platelet count on days 10, 28, and days 10, 14, and 21, respectively, in the bacteremia infants than in the nonbacteremia infants. In the dexamethasone group, infants with bacteremia also had a significantly (P < .05) lower eosinophil count on days 3 and 10 than infants without bacteremia. However, the low platelet count that was usually seen in infants with bacteremia in the control group was not noted in the dexamethasone group.
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DISCUSSION |
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This is the first study to assess the effects of dexamethasone on hematologic values in preterm infants who received dexamethasone therapy shortly after birth and for an extended period of time. Our findings indicate that dexamethasone influences several hematologic parameters in preterm infants. Premature infants treated with tapering doses of dexamethasone experienced a rise in leukocyte counts in the first 14 days of life, with much of the increase attributed to an increase in the number of segmented neutrophils. A subsequent decrease in lymphocyte count was also observed with dexamethasone therapy.
Hydrocortisone is known to decrease bone marrow granulocyte reserve distribution of cells to the marginal and circulating granulocyte pools.14,15 In vitro studies have shown that neutrophil colonies increase in number when hydrocortisone is added to cultures. Dexamethasone has also been shown to cause neutrophilia in vivo by blocking egress of granulocytes from the vascular system, and by inducing release of granulocytes from the bone marrow. This was reflected in our study by the significantly higher segmented neutrophil counts in the dexamethasone group on days 3, 7, 10, 14, and 21. Dexamethasone is also known to delay apoptosis of neutrophils,16 and this might also have contributed to the higher levels of segmented neutrophils in the treatment group. Bourchier and Weston11 found that a 21-day tapering dose regimen of dexamethasone in ventilator-dependent preterm infants led to an increase in total and immature neutrophil numbers, although the immature:total ratio did not change. In our study, the treatment group had significantly higher numbers of band forms on days 7 and 14. However, they also had higher values at baseline. The clinical significance of this finding is not known. De Winter and Van Bel10 found no such difference after a single treatment with dexamethasone.
The fall in lymphocyte numbers that usually occurs 61 to 120 hours after birth17 seemed to be accentuated in the treatment group. However, the lymphocyte count remained comparable between the group throughout most of the trial until day 21 to day 28 when the treated group had a significantly lower lymphocyte count. This finding is somewhat consistent with Schwarze and Bartmann's study,18 which reported a suppression of the lymphocyte proliferative response in whole blood cultures of neonates after treatment with dexamethasone at therapeutic doses. They thus proposed that dexamethasone treatment may compromise the immune system of preterm neonates. Kavelaars et al19 noted that the immune system of the newborn is more sensitive to dexamethasone inhibition of T-cell proliferation than is the adult immune system, and proposed that this increased sensitivity to glucocorticosteroids may compensate for the low levels of circulating glucocorticosteroids early in life. The basophil count also tended to be lower in the treatment group, and the overall difference was significant. The clinical significance of this is not known.
The eosinophil count tended to be higher in the control group throughout the trial. This finding is consistent with that of De Winter and Van Bel,10 who found that the eosinophil count decreased in both term and preterm infants who received a single dose of dexamethasone from 6 to 28 days postnatally.10 There are several possible mechanisms to account for this effect. First, corticosteroids have been shown to inhibit the formation of eosinophil colonies, dose-dependently, both in cultures of peripheral blood and in bone marrow.20 In addition, corticosteroids may exert a direct eosinopenic effect.21
We found that dexamethasone had no apparent effect on the hematocrit, which seems to conflict with reports that corticosteroids stimulate erythropoiesis.7,8 Unfortunately, our results may be difficult to interpret because infants with transfusions were not excluded from the analysis. The decision for transfusion was based on the clinical course of the patient. Because dexamethasone may improve cardiopulmonary function, it is possible that patients in the treatment group received fewer transfusions than those in the control group, and that the hematocrit values are thus artificially high.22,23
Dexamethasone did not seem to have a marked effect on the platelet count in our study, although the platelet counts were higher in the treatment group toward the end of the trial. This is not completely consistent with the findings of previous reports.22,23 Bourchier and Weston11 reported an increase in platelet count after dexamethasone. They suggested that, because dexamethasone decreases the inflammatory response, an increased platelet count could result from a reduction of the platelet consumption caused by the inflammatory response that occurs in the interstitium of the lungs of infants with CLD. Steroids may also increase production of thrombocytes.24 The increase in platelet count after steroid therapy may mask the thrombocytopenia in infants with bacteremia.
Hematologic values are often used to assess sepsis in neonates, and an understanding of the influence of corticosteroids on these parameters is thus essential. Our study suggests that, except for platelet count, this influence is probably very little. However, because of the small number of infants with bacteremia in our study, a definite conclusion could not be made. Bourchier and Weston11 found that the expected fall in total neutrophil and platelet counts and the rise in immature neutrophil counts seen in neonatal sepsis still occur in infants treated with dexamethasone. They reported that the hematologic response to sepsis was not altered by dexamethasone.10 De Winter and Van Bel10 pointed out that, although the rise in WBC count after dexamethasone may suggest infection, the increase in the number of band forms normally seen in neonatal infections did not occur after dexamethasone in their patients. It is difficult to compare our results with those of De Winter and Van Bel,10 however, because their patients received only a single dose of dexamethasone (1 mg) before extubation. Our findings indicate that careful attention is needed when interpreting the hematologic values of preterm infants treated with dexamethasone.
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CONCLUSION |
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In summary, our findings show that dexamethasone can significantly influence hematologic values in preterm infants with RDS who receive treatment soon after birth. Although our study did not seek to determine the diagnostic significance of these influences, the potential alterations in blood values should be taken into consideration when evaluating preterm infants treated with dexamethasone.
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ACKNOWLEDGMENTS |
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This study was supported in part by Grants DOH 82-HR-C17, DOH 83-HR-217, and DOH-HR-84-217, from the National Health Research Institute and the Department of Health, Taiwan, ROC. We would also like to thank all doctors and nurses in the neonatal intensive care units of the participating hospitals for their cooperation and contributions to this project.
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FOOTNOTES |
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Received for publication Oct 5, 1998; accepted Jan 21, 1999.
Reprint requests to (T.F.Y.) Department of Pediatrics, National Cheng Kung University Hospital, 138 Sheng Li Rd, Tainan, Taiwan, ROC. E-mail: em72010{at}email.ncku.edu.tw
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ABBREVIATIONS |
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CLD, chronic lung disease; RDS, respiratory distress syndrome; WBC, white blood cell.
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REFERENCES |
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a possible physiological regulator of human granulopoiesis.
Scand J Haematol.
1983;
31:31-38 [Medline]
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