F van Bel

Short- and long-term effects of neonatal glucocorticoid therapy: is hydrocortisone an alternative to dexamethasone?

Aim: To compare short‐term effects and neurodevelopmental outcome of neonatal glucocorticoid therapy between two centres. Methods: A retrospective study was performed in two centres using a tapering course of either 5 to 1 mgkg−1 hydrocortisone (HC; 22 d) or 0.5 to 0.1 mg kg−1 dexamethasone (DEX; 21 d). In both centres glucocorticoid‐treated infants and control patients were matched for gestational age, birthweight, severity of infant respiratory distress syndrome and periventricular‐intraventricular haemorrhage. The following short‐term glucocorticoid‐induced effects were investigated in 25 HC‐treated and 25 control patients in centre A, and in 23 DEX‐treated and 23 control patients in centre B: oxygen dependency (inspiratory oxygen fraction), arterial pressure, blood glucose and urea concentrations, weight gain and head circumference before, during and after therapy (in treated infants), or at an interval comparable to treated infants (in control infants). Neurological outcome, psychomotor development and school performance at 5–7 y of age was evaluated in all groups. Results: HC and DEX were equally potent in reducing oxygen dependency. Mean arterial pressure as well as blood glucose and urea concentrations were significantly increased during DEX, but not during HC treatment. Weight gain stopped during DEX therapy, but not during HC. Head circumference in both treatment groups was decreased after therapy compared with controls. Neonatally DEX ‐treated children needed special school education significantly more often (p < 0.01) than controls at 5–7 y of age. No differences between neonatally HC‐treated children and controls on neurodevelopmental outcome were found at 5–7 y of age.

Neonatal Dexamethasone Treatment Increases Susceptibility to Experimental Autoimmune Disease in Adult Rats

Major concern has emerged about the possible long term adverse effects of glucocorticoid treatment, which is frequently used for the prevention of chronic lung disease in preterm infants. Here we show that neonatal glucocorticoid treatment of rats increases the severity (p ≤ 0.01) and incidence (p ≤ 0.01) of the inflammatory autoimmune disease experimental autoimmune encephalomyelitis in adult life. In search of possible mechanisms responsible for the increased susceptibility to experimental autoimmune encephalomyelitis, we investigated the reactivity of the hypothalamo-pituitary-adrenal axis and of immune cells in adult rats after neonatal glucocorticoid treatment. We observed that neonatal glucocorticoid treatment reduces the corticosterone response after an LPS challenge in adult rats (p ≤ 0.001). Interestingly, LPS-stimulated macrophages of glucocorticoid-treated rats produce less TNF-α and IL-1β in adult life than control rats (p < 0.05). In addition, splenocytes obtained from adult rats express increased mRNA levels of the proinflammatory cytokines IFN-γ (p < 0.01) and TNF-β (p < 0.05) after neonatal glucocorticoid treatment. Apparently, neonatal glucocorticoid treatment has permanent programming effects on endocrine as well as immune functioning in adult life. In view of the frequent clinical application of glucocorticoids to preterm infants, our data demonstrate that neonatal glucocorticoid treatment may be a risk factor for the development of (auto)immune disease in man.

Early postnatal allopurinol does not improve short term outcome after severe birth asphyxia

Objective: To investigate whether postnatal allopurinol would reduce free radical induced reperfusion/reoxygenation injury of the brain in severely asphyxiated neonates. Method: In an interim analysis of a randomised, double blind, placebo controlled study, 32 severely asphyxiated infants were given allopurinol or a vehicle within four hours of birth. Results: The analysis showed an unaltered (high) mortality and morbidity in the infants treated with allopurinol. Conclusion: Allopurinol treatment started postnatally was too late to reduce the early reperfusion induced free radical surge. Allopurinol administration to the fetus with (imminent) hypoxia via the mother during labour may be more effective in reducing free radical induced post-asphyxial brain damage.

Alterations in adult rat heart after neonatal dexamethasone therapy

Glucocorticoid treatment in preterm babies to prevent chronic lung disease causes myocardial hypertrophy and increased myocardial protein content. Although these changes are thought to be transient, there is evidence that dexamethasone (DEX) induces permanent myocardial abnormalities as well. We investigated whether a therapeutic course of neonatal DEX in rat pups produces anatomic and biochemical alterations in rat hearts during adult life. Twenty-four rat pups were treated with DEX on d 1, 2, and 3 (0.5, 0.3, and 0.1 μg/g) of life, with doses proportional to those used in preterm babies. Twenty-four control pups were treated with saline. At d 7, wk 8, or wk 45 (n = 8 per group) rats were killed. The anatomic parameters measured were body weight (Bw, in grams), heart (myocardial) weight (Hw, in milligrams), and the Hw:Bw ratio. Myocardial total protein (Prot) and DNA content were determined, and the Prot:DNA ratio was calculated. Histopathology and morphometry were performed on 45-wk-old rat hearts. In DEX-treated rat pups, at d 7, Bw and Hw were lower and the Hw:Bw ratio was increased. DNA content was lower, Prot higher, and Prot:DNA ratio was increased. In 8-wk-old rats Bw, Hw, DNA content, Prot content or Prot:DNA ratio did not differ between groups, but the Prot:DNA ratio still tended to be higher in DEX-treated rats. In 45-wk-old rats Hw and Hw:Bw ratio were significantly lower and Prot:DNA ratio higher in DEX-treated rats. Histopathologic analysis showed larger cardiomyocyte volume, length, and width, indicating hypertrophy, and increased collagen, indicating early degeneration of individual myocytes. In conclusion, neonatal DEX treatment in rat pups causes a permanent decrease in heart weight, as well as hypertrophy and early degeneration of cardiomyocytes during adulthood.

The End-Systolic Pressure-Volume Relationship in the Newborn Lamb: Effects of Loading and Inotropic Interventions

ABSTRACT: Indices of global systolic performance of the newborn left ventricle exceed those of the adult, despite isolated tissue studies showing immature contractile mechanisms. To evaluate contractility in situ, we investigated the end-systolic pressure-volume relationship (ESPVR) by the conductance technique in nine newborn lambs. After percutaneous placement of catheters, we generated ESPVR by inferior vena cava occlusion, aortic occlusion, and volume infusion in two control states, during three levels of dobutamine infusion, and after propranolol. We performed linear and nonlinear regression analyses of the end-systolic points and derived the slope (Ees) and volume at 14 kPa pressure. We found that reliable ESPVR could be obtained in almost all inferior vena cava and aortic occlusions (50 of 51 in each), but in only 18 of 27 volume infusions. Overall, linear regressions adequately defined the ESPVR (75 of 102 were not statistically different than nonlinear regressions; of those different, the mean linear R2 was 0.934 ± 0.048). By multiple regression analysis, neither Ees nor volume at 14 kPa significantly changed with dobutamine, but both changed after propranolol (23% less than control and 54% greater, respectively), supporting previous studies showing a limited contractile reserve in the newborn secondary to high resting β-adrenergic tone. Neither Ees nor volume at 14 kPa was different between control states. However, Ees was 25% less steep when generated by inferior vena cava than by aortic occlusion. We conclude that the ESPVR can be generated reliably and reproducibly in the newborn lamb and is relatively linear and sensitive to changes in contractility, but that it is also sensitive to the technique of load intervention.

Effect of the "InSurE" Procedure on Cerebral Oxygenation and Electrical Brain Activity of the Preterm Infant.

Background: In preterm infants with respiratory distress syndrome (RDS) nasal continuous positive airway pressure (nCPAP) with the “InSurE” procedure (intubation, surfactant, extubation) is increasingly used. However, its effect on cerebral oxygenation and brain function is not known. Objective: To evaluate the effects of the “InSurE” procedure in infants with RDS on regional cerebral oxygen saturation (rScO2) and relative cerebral fractional tissue oxygen extraction (cFTOE) using near infrared spectroscopy and on electrical brain activity using amplitude-integrated electroencephalography (aEEG). Methods: Sixteen infants with RDS, treated with the “InSurE” procedure, and 16 matched controls with nCPAP, were monitored for mean arterial blood pressure (MABP), arterial oxygen saturation (SaO2), rScO2, cFTOE and aEEG. Ten-minute periods were selected and averaged at 120 and 20 minutes before, during the procedure and at 30 minutes, 1, 2, 6, 12 and 24 h after the start of the “InSurE” procedure. aEEG was analysed by quantitative and qualitative (Burdjalov score) methods. Results: MABP was not different between groups on all time points. rScO2 and cFTOE were comparable between groups, but there was a trend towards lower rScO2 and higher cFTOE 30 minutes after opioid administration in the “InSurE” infants compared with controls (62% (SD 11) vs 68% (SD 10) and 0.30 (SD 0.10 ) vs 0.28 (SD 0.11), respectively). aEEG amplitudes and Burdjalov scores were significantly lower in “InSurE” infants from 30 minutes after opioid administration up to 24 h after the start of the procedure (p<0.05). Conclusion: In the present study, the “InSurE” procedure did not induce perturbation of cerebral oxygen delivery and extraction, whereas electrical brain activity decreased for a prolonged period of time.

Acute Effects of Indomethacin on Cerebral Hemodynamics and Oxygenation

Although an indomethacin-induced decrease of brain perfusion in preterm infants has been well established, the acute effects of this vasoactive drug on cerebral hemodynamics and oxygenation are not well documented. Using near infrared spectroscopy we monitored in 6 very preterm infants changes in cerebral blood volume (delta CBV) and cytochrome oxidase concentration (delta Cytaa3), used as relative measures of changes in brain perfusion and as an indicator for cellular oxygenation of brain tissue, during and up to 1 h after indomethacin infusion. delta CBV showed a quick blood-pressure-related increase as compared to baseline (preindomethacin values) during indomethacin infusion (averaged maximal increase 13%), followed by a sharp decrease below baseline values (averaged maximal decrease 24%). There was a sustained recovery to baseline during the registration period. delta Cytaa3 showed a small, early increase in 4 of 6 babies, followed by a substantial decrease below baseline in 5 babies. delta Cytaa3 showed only a partial recovery in those 5 babies during the study period. We conclude that a therapeutic dose of indomethacin may cause substantial swings in brain perfusion and a marked and rather longstanding decrease in Cytaa3, suggesting a decrease in cellular oxygenation of brain tissue. Awareness of these effects may be important in sick preterm babies during periods of pulmonary and cardiac instability.

Cerebral blood flow velocity pattern in healthy and asphyxiated newborns: a controlled study.

In a controlled study serial determinations of cerebral blood flow velocity using Doppler ultrasound and repeated real-time ultrasonographic- or computerized axial tomographic studies of the brain were performed in 17 (nearly) full-term newborns who experienced perinatal asphyxia and in 17 healthy matched controls during the first week of life. A higher cerebral blood flow velocity was found during the first 4 days of life, indicating a lower cerebrovascular resistance in the asphyxiated infants compared to the control infants. These haemodynamic changes coincided with cerebral oedema and neurological abnormalities. It is speculated that the changes in the cerebral circulation in asphyxiated infants are at least partly caused by cerebral oedema-induced increase of intracranial pressure due to severe perinatal asphyxia. Serial Doppler ultrasound investigations of the brain may be a useful non-invasive method for early detection and follow-up of the consequences of severe perinatal asphyxia.

Lung maturation in small for gestational age fetuses from pregnancies complicated by placental insufficiency or maternal hypertension

BACKGROUND Clinical studies suggest that respiratory outcome of infants born preterm may be influenced by placental insufficiency and hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. If so, one could expect to see differences in lung maturation indices (lecithin/sphingomyelin (L/S) ratio and lamellar body count (LBC)) in the amniotic fluid. The present study investigates lung maturation indices of preterm small for gestational age (SGA) fetuses with or without abnormal Doppler ultrasound examination and with or without maternal hypertension/HELLP syndrome. STUDY DESIGN Retrospective cohort study of 76 neonates born in our center between 1997 and 2003 with gestational age (GA) <34 weeks, birth weight <p10 for GA and available results from amniocentesis. All analyses were corrected for potential confounders. RESULTS The L/S ratio was significantly higher in the abnormal Doppler group as compared to the normal Doppler group (p=0.02). The L/S ratio was significantly lower in hypertensive pregnancies as compared to normotensive pregnancies (p=0.02). Subdivision of the maternal hypertension group showed a significantly lower L/S ratio in the HELLP syndrome group as compared to the normotension group (p=0.04). CONCLUSION The L/S ratio of SGA fetuses is significantly higher in cases with presumed placental insufficiency and significantly lower when pregnancies are complicated by HELLP syndrome. These observations are in line with the hypothesis that placental insufficiency accelerates lung maturation and with recent reports of poorer respiratory outcome in infants from mothers with HELLP syndrome.

Postnatal hydrocortisone treatment for chronic lung disease in the preterm newborn and long-term neurodevelopmental follow-up.

The benefits versus the risks of postnatal administration of steroids in preterm-born infants are still debatable. This review examines the literature on postnatal hydrocortisone treatment for chronic lung disease (CLD) in preterm-born infants with a particular focus on the effects of such treatment on long-term neurodevelopmental outcomes. Quantitative published evidence does not point to a clear advantage of treatment with hydrocortisone over dexamethasone with regard to the impact on long-term neurological outcomes. However, in the absence of a randomised comparison, a consensus may soon have to be reached on the basis of the best available evidence whether hydrocortisone should replace dexamethasone in the treatment of CLD.