Comment
Not another steroid trial: early low-dose hydrocortisone in preterm infants to poor enrolment. The DART study5 did not show an effect on mortality or bronchopulmonary dysplasia. However, because of their short-term potency, steroids are still widely prescribed (ironically, often following the DART protocol) in neonatal intensive care units (NICUs) around the world for in-extremis rescue of late respiratory failure and severe lung disease.6 Given that prevention is better than a palliative approach, and that delaying use of steroids for too long might negate their beneficial effects on the lungs, the quest is therefore to determine the lowest efficient dose of anti-inflammatory steroid needed, and the optimum timing to reduce pulmonary morbidity in the NICU, without causing collateral damage to the developing organs. Second, Baud and colleagues chose the less frequently used—but appealing—method of prophylactic administration of low-dose hydrocortisone. Extensive work by Watterberg and colleagues7 provided a strong rationale for using this more physiological strategy by showing evidence of early adrenal insufficiency, increased lung inflammation, and patent ductus arteriosus in premature infants who subsequently developed bronchopulmonary dysplasia. Unfortunately, this randomised clinical trial8 did not have the power to make a conclusion about the usefulness of hydrocortisone to prevent bronchopulmonary dysplasia, because it
www.thelancet.com Published online February 22, 2016 http://dx.doi.org/10.1016/S0140-6736(16)00503-1
Published Online February 22, 2016 http://dx.doi.org/10.1016/ S0140-6736(16)00503-1 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(16)00202-6
Mark Thomas/Science Photo Library
In The Lancet, Baud and colleagues1 address a very important (and recurrent) topic in neonatology—the use of steroids to reduce the incidence of bronchopulmonary dysplasia in very preterm infants. This large multicentre double-blind randomised controlled trial shows that a large proportion of infants born at 24–27 weeks of gestation who were randomly assigned to receive low dose hydrocortisone (153 [60%] of 255) during their first 10 postnatal days survived to 36 weeks post conceptual age without bronchopulmonary dysplasia, compared with infants who received placebo (136 [51%] of 266). The beneficial effect of hydrocortisone was more pronounced in infant girls (74 [65%] of 114 girls vs 67 [53%] of 127 girls in the placebo group). Importantly, hydrocortisone was not associated with an increase in adverse events, including gastrointestinal perforation, a complication feared by neonatologists when steroids are used in combination with non-steroidal antiinflammatory drugs (NSAIDs) to close the ductus. Baud and colleagues’ study bridges an important gap in neonatal medicine, and the investigators should be commended on several counts. First, their trial was courageously designed at a time when neonatologists refrained from using steroids for any lung disease. Several studies in preterm infants, almost exclusively with dexamethasone, have attempted to reduce lung inflammation and ultimately bronchopulmonary dysplasia using many different protocols of different timing, duration, and doses. The resulting accumulation of published data—beyond offering meta-analysts a lot to digest— overall shows that dexamethasone very effectively decreases ventilator requirements, and probably also lung inflammation (at least in the short term), but that with early use, such as in the first week of life, higher doses and longer treatments are deleterious for the developing brain, and probably also for the growing lungs.2 This worrisome neurodevelopmental effect on the lungs resulted in a near complete halt to the use of steroids in preterm infants.3,4 It was in this context that the important DART study,5 which looked at low-dose and delayed dexamethasone to help extubation, had to be stopped prematurely owing
1
Comment
was prematurely terminated as a result of intestinal perforation when hydrocortisone was associated with NSAID use to close the ductus.8 Third, considering the complexity of the problem, Baud and colleagues should also be praised for their extremely well designed study protocol with strict, precise, and even restrictive recruitment criteria (NSAID use in infants was not allowed on their first day of life), which has allowed them convincingly to address the relevance of early low-dose hydrocortisone in the prevention of bronchopulmonary dysplasia. The hydrocortisone dose used in this study (1 mg per day for 7 days followed by 0·5 mg per day for 3 days) is indeed a very low dose, but has previously been deemed to be physiologically relevant.8 The cumulative dose (the total amount of hydrocortisone the infants will have received over the 10 days of the treatment protocol) is the lowest systemic dose tested in neonates so far. The present study is, therefore, not another steroid trial, but should be regarded as a supplementation therapy trial because this low dose of hydrocortisone is not pharmacological, but rather brings back or maintains the infants’ cortisol concentrations within a normal range. Another important finding was the significant reduction in the numbers of patent ductus arteriosus that required ligation in the hydrocortisone-treated group. This is consistent with Watterberg’s findings7 and suggests that the use of NSAIDs for this indication might be unnecessary, and could be substantially reduced. The mechanism is unclear but might include decreased sensitivity of the ductus to prostaglandin E2-mediated vasodilation.9 We also speculate that the patent ductus is more likely to be ignored if the infant is no longer receiving ventilator support. The clinical approach of the participating NICUs to the most premature infants (24–25 weeks), in whom the incidence of bronchopulmonary dysplasia is the highest, should be noted because it was probably different from that of the group of infants born at 26–27 weeks. Indeed, the rate of birth by elective caesarean at 24–25 weeks was around 50% lower than for infants born at 26–27 weeks; this could be related to a prior decision of providing active resuscitation, or not, for these very premature infants. Therefore, whether infants born at 24–25 weeks in the study are representative of all infants born at 24–25 weeks in other parts of the world is uncertain. 2
Neonatology has gone from one extreme to another with regard to the use of oxygen,10 vitamin E,11 and now steroids as treatment options.12 Baud and colleagues’ study brings sound physiological rationale (not solely epidemiological association) to the forefront to support clinical trial designs that attempt to determine the optimum management of neonates. Although this trial brings hope and enthusiasm to neonatologists and their patients, long-term outcomes must be assessed carefully and followed up (as is planned for this study), especially in terms of neurodevelopment and brain growth, as well as lung growth and function. Our community must also ensure that funding agencies commit to supporting crucial follow-up studies for neonatal trials so that history does not repeat itself. *Anne Monique Nuyt, Bernard Thébaud Department of Pediatrics, Sainte-Justine University Hospital Research Center, Faculty of Medicine, Université de Montréal, Montreal H3T 1C5, QC, Canada (AMN); and Department of Pediatrics, Ottawa Hospital Research Institute, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada (BT) [email protected] We declare no competing interests. 1
2
3
4
5
6 7
8
9
10 11 12
Baud O, Maury L, Lebail F, et al. Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial. Lancet 2016; published online Feb 22. http://dx.doi.org/10.1016/ S0140-6736(16)00202-6. Doyle LW, Ehrenkranz RA, Halliday HL. Early (
Not another steroid trial: early low-dose hydrocortisone in preterm infants to poor enrolment. The DART study5 did not show an effect on mortality or bronchopulmonary dysplasia. However, because of their short-term potency, steroids are still widely prescribed (ironically, often following the DART protocol) in neonatal intensive care units (NICUs) around the world for in-extremis rescue of late respiratory failure and severe lung disease.6 Given that prevention is better than a palliative approach, and that delaying use of steroids for too long might negate their beneficial effects on the lungs, the quest is therefore to determine the lowest efficient dose of anti-inflammatory steroid needed, and the optimum timing to reduce pulmonary morbidity in the NICU, without causing collateral damage to the developing organs. Second, Baud and colleagues chose the less frequently used—but appealing—method of prophylactic administration of low-dose hydrocortisone. Extensive work by Watterberg and colleagues7 provided a strong rationale for using this more physiological strategy by showing evidence of early adrenal insufficiency, increased lung inflammation, and patent ductus arteriosus in premature infants who subsequently developed bronchopulmonary dysplasia. Unfortunately, this randomised clinical trial8 did not have the power to make a conclusion about the usefulness of hydrocortisone to prevent bronchopulmonary dysplasia, because it
www.thelancet.com Published online February 22, 2016 http://dx.doi.org/10.1016/S0140-6736(16)00503-1
Published Online February 22, 2016 http://dx.doi.org/10.1016/ S0140-6736(16)00503-1 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(16)00202-6
Mark Thomas/Science Photo Library
In The Lancet, Baud and colleagues1 address a very important (and recurrent) topic in neonatology—the use of steroids to reduce the incidence of bronchopulmonary dysplasia in very preterm infants. This large multicentre double-blind randomised controlled trial shows that a large proportion of infants born at 24–27 weeks of gestation who were randomly assigned to receive low dose hydrocortisone (153 [60%] of 255) during their first 10 postnatal days survived to 36 weeks post conceptual age without bronchopulmonary dysplasia, compared with infants who received placebo (136 [51%] of 266). The beneficial effect of hydrocortisone was more pronounced in infant girls (74 [65%] of 114 girls vs 67 [53%] of 127 girls in the placebo group). Importantly, hydrocortisone was not associated with an increase in adverse events, including gastrointestinal perforation, a complication feared by neonatologists when steroids are used in combination with non-steroidal antiinflammatory drugs (NSAIDs) to close the ductus. Baud and colleagues’ study bridges an important gap in neonatal medicine, and the investigators should be commended on several counts. First, their trial was courageously designed at a time when neonatologists refrained from using steroids for any lung disease. Several studies in preterm infants, almost exclusively with dexamethasone, have attempted to reduce lung inflammation and ultimately bronchopulmonary dysplasia using many different protocols of different timing, duration, and doses. The resulting accumulation of published data—beyond offering meta-analysts a lot to digest— overall shows that dexamethasone very effectively decreases ventilator requirements, and probably also lung inflammation (at least in the short term), but that with early use, such as in the first week of life, higher doses and longer treatments are deleterious for the developing brain, and probably also for the growing lungs.2 This worrisome neurodevelopmental effect on the lungs resulted in a near complete halt to the use of steroids in preterm infants.3,4 It was in this context that the important DART study,5 which looked at low-dose and delayed dexamethasone to help extubation, had to be stopped prematurely owing
1
Comment
was prematurely terminated as a result of intestinal perforation when hydrocortisone was associated with NSAID use to close the ductus.8 Third, considering the complexity of the problem, Baud and colleagues should also be praised for their extremely well designed study protocol with strict, precise, and even restrictive recruitment criteria (NSAID use in infants was not allowed on their first day of life), which has allowed them convincingly to address the relevance of early low-dose hydrocortisone in the prevention of bronchopulmonary dysplasia. The hydrocortisone dose used in this study (1 mg per day for 7 days followed by 0·5 mg per day for 3 days) is indeed a very low dose, but has previously been deemed to be physiologically relevant.8 The cumulative dose (the total amount of hydrocortisone the infants will have received over the 10 days of the treatment protocol) is the lowest systemic dose tested in neonates so far. The present study is, therefore, not another steroid trial, but should be regarded as a supplementation therapy trial because this low dose of hydrocortisone is not pharmacological, but rather brings back or maintains the infants’ cortisol concentrations within a normal range. Another important finding was the significant reduction in the numbers of patent ductus arteriosus that required ligation in the hydrocortisone-treated group. This is consistent with Watterberg’s findings7 and suggests that the use of NSAIDs for this indication might be unnecessary, and could be substantially reduced. The mechanism is unclear but might include decreased sensitivity of the ductus to prostaglandin E2-mediated vasodilation.9 We also speculate that the patent ductus is more likely to be ignored if the infant is no longer receiving ventilator support. The clinical approach of the participating NICUs to the most premature infants (24–25 weeks), in whom the incidence of bronchopulmonary dysplasia is the highest, should be noted because it was probably different from that of the group of infants born at 26–27 weeks. Indeed, the rate of birth by elective caesarean at 24–25 weeks was around 50% lower than for infants born at 26–27 weeks; this could be related to a prior decision of providing active resuscitation, or not, for these very premature infants. Therefore, whether infants born at 24–25 weeks in the study are representative of all infants born at 24–25 weeks in other parts of the world is uncertain. 2
Neonatology has gone from one extreme to another with regard to the use of oxygen,10 vitamin E,11 and now steroids as treatment options.12 Baud and colleagues’ study brings sound physiological rationale (not solely epidemiological association) to the forefront to support clinical trial designs that attempt to determine the optimum management of neonates. Although this trial brings hope and enthusiasm to neonatologists and their patients, long-term outcomes must be assessed carefully and followed up (as is planned for this study), especially in terms of neurodevelopment and brain growth, as well as lung growth and function. Our community must also ensure that funding agencies commit to supporting crucial follow-up studies for neonatal trials so that history does not repeat itself. *Anne Monique Nuyt, Bernard Thébaud Department of Pediatrics, Sainte-Justine University Hospital Research Center, Faculty of Medicine, Université de Montréal, Montreal H3T 1C5, QC, Canada (AMN); and Department of Pediatrics, Ottawa Hospital Research Institute, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada (BT) [email protected] We declare no competing interests. 1
2
3
4
5
6 7
8
9
10 11 12
Baud O, Maury L, Lebail F, et al. Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial. Lancet 2016; published online Feb 22. http://dx.doi.org/10.1016/ S0140-6736(16)00202-6. Doyle LW, Ehrenkranz RA, Halliday HL. Early (
