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2. Sondheimer JM, Asturias E, Cadnapaphornchai M. Infection and cholestasis in neonates with intestinal resection and long-term parenteral nutrition. J Pediatr Gastroenterol Nutr 1998;27:131-7. 3. Sondheimer JM, Cadnapaphornchai M, Sontag M, Zerbe GO. Predicting the duration of dependence on parenteral nutrition after neonatal intestinal resection. J Pediatr 1998;132:80-4. 4. Spencer AU, Kovacevich D, McKinney-Barnett M, Hair D, Canham J, Maksym C, Teitelbaum DH. Pediatric short-bowel syndrome: the cost of comprehensive care. Am J Clin Nutr 2008;88:1552-9. 5. Avitzur Y, Wang JY, de Silva NT, Burghardt KM, DeAngelis M, Grant D, et al. The impact of intestinal rehabilitation program and its innovative therapies on the outcome of intestine transplant candidates. J Pediatr Gastroenterol Nutr 2015. 6. Quiros-Tejeira RE, Ament ME, Reyen L, Herzog F, Merjanian M, Olivares-Serrano N, et al. Long-term parenteral nutritional support and intestinal adaptation in children with short bowel syndrome: a 25-year experience. J Pediatr 2004;145:157-63. 7. Squires RH, Duggan C, Teitelbaum DH, Wales PW, Balint J, Venick R, et al. Natural history of pediatric intestinal failure: initial report from the Pediatric Intestinal Failure Consortium. J Pediatr 2012;161:723-38.e2. 8. Abu-Elmagd KM, Kosmach-Park B, Costa G, Zenati M, Martin L, Koritsky DA, et al. Long-term survival, nutritional autonomy, and quality of life after intestinal and multivisceral transplantation. Ann of Surg 2012;256:494-508. 9. United Network of Organ Sharing 2015: UNOS.org. www.UNOS.org. Accessed March 24, 2015. 10. Beath S, Pironi L, Gabe S, Horslen S, Sudan D, Mazeriegos G, et al. Collaborative strategies to reduce mortality and morbidity in patients with chronic intestinal failure including those who are referred for small bowel transplantation. Transplantation 2008;85:1378-84. 11. Khan FA, Squires RH, Litman HJ, Balint J, Carter BA, Fisher JG, et al. Predictors of enteral autonomy in children with intestinal failure: a multicenter cohort study. J Pediatr 2015;167:29-34. 12. Kaplan J, Han L, Halgrimson W, Wang E, Fryer J. The impact of MELD/ PELD revisions on the mortality of liver-intestine transplantation candidates. Am J Transplant 2011;11:1896-904. 13. Raphael BP, Mitchell PD, Finkton D, Jiang H, Jansik T, Duggan C. Necrotizing enterocolitis and central line associated blood stream infection are predictors of the pace of growth in infants with short bowel syndrome. J Pediatr 2015;167:35-40. 14. de Meijer VE, Gura KM, Meisel JA, Le HD, Puder M. Parenteral fish oil as monotherapy for patients with parenteral nutrition-associated liver disease. Pediatr Surg Int 2009;25:123-4.
Vol. 167, No. 1 15. Fallon EM, Le HD, Puder M. Prevention of parenteral nutritionassociated liver disease: role of omega-3 fish oil. Curr Opin Organ Transplant 2010;15:334-40. 16. Nandivada P, Cowan E, Carlson SJ, Chang M, Gura KM, Puder M. Mechanisms for the effects of fish oil lipid emulsions in the management of parenteral nutrition-associated liver disease. Prostaglandins Leukot Essent Fatty Acids 2013;89:153-8. 17. Neu J. Preterm infant nutrition, gut bacteria, and necrotizing enterocolitis. Curr Opin Clin Nutr Metab Care 2015;18:285-8. 18. Chen AC, Chung MY, Chang JH, Lin HC. Pathogenesis implication for necrotizing enterocolitis prevention in preterm very-low-birth-weight infants. J Pediatr Gastroenterol Nutr 2014;58:7-11. 19. Patel RM, Kandefer S, Walsh MC, Bell EF, Carlo WA, Laptook AR, et al. Causes and timing of death in extremely premature infants from 2000 through 2011. N Engl J Med 2015;372:331-40. 20. Bechtold S, Simon D. Growth abnormalities in children and adolescents with juvenile idiopathic arthritis. Rheumatol Int 2014;34:1483-8. 21. Heuschkel R, Salvestrini C, Beattie RM, Hildebrand H, Walters T, Griffiths A. Guidelines for the management of growth failure in childhood inflammatory bowel disease. Inflamm Bowel Dis 2008;14:839-49. 22. Cole CR, Hansen NI, Higgins RD, Ziegler TR, Stoll BJ. Very low birth weight preterm infants with surgical short bowel syndrome: incidence, morbidity and mortality, and growth outcomes at 18 to 22 months. Pediatrics 2008;122:e573-82. 23. Cole CR, Frem JC, Schmotzer B, Gewirtz AT, Meddings JB, Gold BD, et al. The rate of bloodstream infection is high in infants with short bowel syndrome: relationship with small bowel bacterial overgrowth, enteral feeding, and inflammatory and immune responses. J Pediatr 2010;156:941-7.e1. 24. Kaufman SS, Loseke CA, Lupo JV, Young RJ, Murray ND, Pinch LW, et al. Influence of bacterial overgrowth and intestinal inflammation on duration of parenteral nutrition in children with short bowel syndrome. J Pediatr 1997;13:356-61. 25. Oliveira C, Nasr A, Brindle M, Wales PW. Ethanol locks to prevent catheter-related bloodstream infections in parenteral nutrition: a meta-analysis. Pediatrics 2012;129:318-29. 26. Stanger JD, Oliveira C, Blackmore C, Avitzur Y, Wales PW. The impact of multi-disciplinary intestinal rehabilitation programs on the outcome of pediatric patients with intestinal failure: a systematic review and metaanalysis. J Pediatr Surg 2013;48:983-92. 27. Jeppese PB, Pertkiewicz M, Messing B, Iyer K, Seidner DL, O’Keefe SJ, et al. Teduglutide reduces need for parenteral support among patients with short bowel syndrome with intestinal failure. Gastroenterology 2012;143:1473-81.e3.
Prevention of Cerebral Palsy: Which Infants Will Benefit from Therapeutic Hypothermia?
C
term.1 Previous efforts to prevent CP related to perinatal an cerebral palsy (CP) be prevented? The answer depends on the etiology of CP. Although the causes of asphyxia in term infants, such as the use of continuous elecCP are largely related to early brain injury, both the tronic fetal monitoring, have not resulted in any decrease in nature of that injury and the later manifestations can differ the incidence of CP.2 This lack of progress may be attributed based on the gestational and postnatal ages at which the in part to the multiple etiologies of CP, with only a small perinjury occurs, as well as its source. centage related to perinatal asphyxia,3,4 but See related article, p 58 A number of clinical practices have been does not imply that there are no infants implemented in an effort to reduce the incidence of CP; howwho would benefit. Therapeutic hypothermia has been ever, many of these practices focus on preterm infants, even shown to decrease the incidence of death and though the majority of infants who develop CP are born at
CP RCT
Cerebral palsy Randomized controlled trial
The author declares no conflicts of interest. 0022-3476//$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2015.03.052
8
July 2015 neurodevelopmental disability, including CP, in infants with moderate to severe neonatal encephalopathy due to perinatal asphyxia.5 Current clinical recommendations have been modified from previous large randomized controlled trials (RCTs) to target those likely to benefit from therapeutic hypothermia.6-9 Those criteria from the Canadian Paediatric Society and the American Academy of Pediatrics include evidence of perinatal asphyxia (eg, Apgar score, need for resuscitation, presence of metabolic acidosis), as well as the presence of moderate to severe encephalopathy.10,11 In this issue of The Journal, Garfinkle et al12 evaluate the potential effectiveness of therapeutic hypothermia in preventing CP in patients born at term, using criteria for therapeutic hypothermia modified from the Canadian Paediatric Society with the additional consideration of a sentinel event. Although 1 in 4 patients with CP had previous evidence of neonatal encephalopathy, only 1 in 8 patients (64 total) met the criteria for receipt of therapeutic hypothermia. Using outcome data from a recent Cochrane systematic review5 suggesting a number needed to benefit of 8 (95% CI, 6-17), they estimate that had the 64 infants meeting therapeutic hypothermia criteria been treated, 8 cases of CP (out of a total of 543), or only 5%, could have been prevented. Although this may appear to be a small fraction of the infants with CP, their finding is consistent with the current consensus that most cases of CP are not related to perinatal asphyxia. For infants with encephalopathy due to other factors, such as metabolic disorders, meningitis, or neonatal stroke, additional therapeutic options are limited at present. Which infants will benefit from therapeutic hypothermia? In current practice, the presence of a sentinel event or shoulder dystocia is less commonly considered in the decision to perform hypothermia compared with evidence of perinatal asphyxia and neonatal encephalopathy, although the presence of such an event increases the clinical suspicion of perinatal asphyxia or neonatal encephalopathy. Indeed, Garfinkle et al12 report that the presence of shoulder dystocia was significantly more common in infants with moderate or severe encephalopathy who did not meet the criteria for hypothermia compared with those who did (12% vs 2%), owing in part to less severe systemic acidosis as assessed by cord pH. Although cord pH may not be as depressed as might be expected for the degree of encephalopathy in infants with neonatal encephalopathy following shoulder dystocia,13 the inclusion criteria in most of the large RCTs7-9 and in a Cochrane systematic review5 did not consider the presence of shoulder dystocia and sentinel events. In the National Institute of Child Health and Human Development trial,6 sentinel events (although not dystocia) were considered when the evidence for perinatal asphyxia was less clear, such as a pH of 7.01-7.15 on cord blood or early infant blood gas analysis. In contrast, infants with shoulder dystocia in Garfinkle et al had an average cord blood pH of 7.17, and as such would not have met the criteria for inclusion in the trial despite the presence of moderate to severe encephalopathy. When evaluating infants with perinatal asphyxia and neonatal encephalopathy, the application of clinical practice guidelines
EDITORIALS may need to include consideration of additional risk factors and emphasize the neurologic presentation. Criteria for cooling also include the presence of moderate to severe neonatal encephalopathy. In many of the large RCTs reported to date,6-8 infants with mild encephalopathy have been excluded from therapeutic hypothermia owing to their relatively favorable prognosis. Although 1 RCT did include some infants with mild encephalopathy,9 a recent statement from the American Academy of Pediatrics11 recommended that infants with mild encephalopathy be treated only in the context of clinical trials. However, given the improvements seen in outcomes after hypothermia for moderate to severe encephalopathy, in conjunction with the relatively benign safety profile, the practice of cooling infants with mild encephalopathy is becoming more widespread despite the absence of ongoing clinical trials. In a recent analysis of infants from the Vermont Oxford Network Neonatal Encephalopathy Registry, 43% would not have been eligible for therapeutic hypothermia according to the criteria used by the large RCTs.14 One of the more common reasons that these infants would have been ineligible for hypothermia was the presence of mild or no encephalopathy (40%). Ultimately, why not cool all infants with encephalopathiy, especially those who would be excluded from hypothermia because of milder encephalopathy or a less clear history of asphyxia? A retrospective study of infants with neonatal encephalopathy and acidemia treated with hypothermia demonstrated similar rates of death and disability in those meeting standard criteria for cooling and those not meeting cooling criteria for such reasons as gestational age 6 hours, and others,15 and the authors recommended considering cooling for these infants. Although it is tempting to broaden our reach to optimize outcomes, the risk should be fully evaluated when considering cooling in infants not strictly meeting the criteria. Further study is warranted for infants who do not strictly meet the criteria specified for hypothermia used in the large RCTs; however, some recommendations may be made even in the absence of data. Infants with moderate to severe encephalopathy should receive a complete evaluation and consideration for cooling even if they do not meet all of the criteria for perinatal asphyxia. This is especially true for those infants with a history of a sentinel event or another risk factor for perinatal asphyxia. Early evaluation includes screening for metabolic or congenital abnormalities that could account for the encephalopathy and possibly imaging to rule out perinatal stroke or traumatic etiology. If none of these are present, then cooling should be strongly considered. For infants with mild encephalopathy but a clear history of perinatal asphyxia and/or a sentinel event, electroencephalography should be obtained. When mild encephalopathy is confirmed, the risk:benefit for cooling is unclear. In the Cochrane systematic review of cooling for newborns with moderate to severe neonatal encephalopathy, a significant increase in thrombocytopenia (although not in thrombosis or hemorrhage) was seen in infants undergoing therapeutic hypothermia, as well as a nonsignificant but clinically 9
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important increase in the risk of persistent pulmonary hypertension.5 In comparison with the potential for preventing brain injury, these risks may seem small, but they must be considered (along with the need for intensive care and separation of the mother–infant dyad) in infants with mild encephalopathy who are less likely to benefit from cooling. There exists a tension between the need for further study and the need to provide immediate treatment to those infants most likely to benefit from this well-established therapy. The current criteria for therapeutic hypothermia represent our best estimate of the infants likely to benefit from this treatment. Broadening our reach in an attempt to optimize outcomes is tempting, but likely would result in unnecessary treatment of a large number of infants with less significant encephalopathy and acidosis. Alternatively, for the subset of infants in whom perinatal asphyxia is considered a contributing factor, therapeutic hypothermia remains our best means of prevention, and a full evaluation should be obtained even in infants not strictly meeting the criteria for this treatment. n Marie T. Berg, MD Division of Neonatal-Perinatal Medicine University of Vermont College of Medicine Burlington, Vermont Reprint requests: Marie T. Berg, MD, Division of Neonatal-Perinatal Medicine, University of Vermont Children’s Hospital, 111 Colchester Ave, Burlington, VT 05401. E-mail: [email protected]
References 1. Blair E, Watson L, Badawi N, Stanley FJ. Life expectancy among people with cerebral palsy in Western Australia. Dev Med Child Neurol 2001;43: 508-15. 2. Alfirevic Z, Devane D, Gyte GM. Continuous cardiotocography (CTG) as a form of electronic fetal monitoring (EFM) for fetal assessment during labour. Cochrane Database Syst Rev 2006;3:CD006066.
Vol. 167, No. 1 3. McIntyre S, Blair E, Badawi N, Keogh J, Nelson KB. Antecedents of cerebral palsy and perinatal death in term and late preterm singletons. Obstet Gynecol 2013;122:869-77. 4. Ellenberg JH, Nelson KB. The association of cerebral palsy with birth asphyxia: a definitional quagmire. Dev Med Child Neurol 2013;55: 210-6. 5. Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2013;1:CD003311. 6. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005;353:1574-84. 7. Gluckman P, Wyatt J, Azzopardi D, Ballard R, Edwards A, Ferriero D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005; 365:663-70. 8. Azzopardi D, Strohm B, Edwards A, Dyet L, Halliday H, Juszczak E, et al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med 2009;361:1349-58. 9. Jacobs SE, Morley CJ, Inder TE, Stewart MJ, Smith KR, McNamara PJ, et al. Whole-body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial. Arch Pediatr Adolesc Med 2011;165:692-700. 10. Peliowski-Davidovich A. Hypothermia for newborns with hypoxic ischemic encephalopathy. Paediatr Child Health 2012;17:41-6. 11. Papile LA, Baley JE, Benitz W, Cummings J, Carlo WA, Eichenwald E, et al. Committee on Fetus and Newborn. Hypothermia and neonatal encephalopathy. Pediatrics 2014;133:1146-50. 12. Garfinkle J, Wintermark P, Shevell MI, Platt RW, Oskoui M. Cerebral palsy following neonatal encephalopathy: how much is preventable? J Pediatr 2015;167:58-63. 13. Leung TY, Stuart O, Sahota DS, Suen SS, Lau TK, Lao TT. Head-to-body delivery interval and risk of fetal acidosis and hypoxic ischaemic encephalopathy in shoulder dystocia: a retrospective review. BJOG 2011;118: 474-9. 14. Pfister RH, Bingham P, Edwards EM, Horbar JD, Kenny MJ, Inder T, et al. The Vermont Oxford Neonatal Encephalopathy Registry: rationale, methods, and initial results. BMC Pediatr 2012;12:84. 15. Smit E, Liu X, Jary S, Cowan F, Thoresen M. Cooling neonates who do not fulfil the standard cooling criteria: short- and long-term outcomes. Acta Paediatr 2015;104:138-45.
Erythropoiesis Stimulating Agents Demonstrate Safety and Show Promise as Neuroprotective Agents in Neonates
S
and decrease transfusions. Recent randomized, tudies published 27 years ago showed that erythroid multi-centered, placebo-controlled trials of erythropoiesis progenitor cells of preterm neonates were responsive stimulating agents (ESAs), such as Epo or longer acting darto recombinant erythropoietin (Epo).1 Many clinical bepoetin, administered to preterm infants also show a reductrials were subsequently performed worldwide, testing tion in blood donor exposure and a lower transfusion rate.2 whether administering Epo to preterm infants might be a safe and effective way to expand their red Along with the clinical trials aimed at See related article, p 52 cell mass and decrease their transfusion redecreasing or eliminating transfusions, aniquirements. Indeed, essentially all trials convincingly showed mal studies have shown that ESAs have neuroprotective that Epo can stimulate erythropoiesis in preterm and term infants, and has the capability to diminish donor exposure
Epo ESA ROP
Erythropoietin Erythropoiesis stimulating agent Retinopathy of prematurity
Supported by the National Institutes of Health (NIH; R01 HD059856, U01 NS077953 [to R.O.], U01 NS077953, R01HD073128, U01NS077953 [to S.J.], P01 HL046925, U01 NS077953 [to J.W.]), and Intermountain Healthcare Medical Foundation (to R.C.). J.W. is a paid consultant to HemoGenix. The other authors declare no conflicts of interest. 0022-3476//$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2015.03.054
10
www.jpeds.com
2. Sondheimer JM, Asturias E, Cadnapaphornchai M. Infection and cholestasis in neonates with intestinal resection and long-term parenteral nutrition. J Pediatr Gastroenterol Nutr 1998;27:131-7. 3. Sondheimer JM, Cadnapaphornchai M, Sontag M, Zerbe GO. Predicting the duration of dependence on parenteral nutrition after neonatal intestinal resection. J Pediatr 1998;132:80-4. 4. Spencer AU, Kovacevich D, McKinney-Barnett M, Hair D, Canham J, Maksym C, Teitelbaum DH. Pediatric short-bowel syndrome: the cost of comprehensive care. Am J Clin Nutr 2008;88:1552-9. 5. Avitzur Y, Wang JY, de Silva NT, Burghardt KM, DeAngelis M, Grant D, et al. The impact of intestinal rehabilitation program and its innovative therapies on the outcome of intestine transplant candidates. J Pediatr Gastroenterol Nutr 2015. 6. Quiros-Tejeira RE, Ament ME, Reyen L, Herzog F, Merjanian M, Olivares-Serrano N, et al. Long-term parenteral nutritional support and intestinal adaptation in children with short bowel syndrome: a 25-year experience. J Pediatr 2004;145:157-63. 7. Squires RH, Duggan C, Teitelbaum DH, Wales PW, Balint J, Venick R, et al. Natural history of pediatric intestinal failure: initial report from the Pediatric Intestinal Failure Consortium. J Pediatr 2012;161:723-38.e2. 8. Abu-Elmagd KM, Kosmach-Park B, Costa G, Zenati M, Martin L, Koritsky DA, et al. Long-term survival, nutritional autonomy, and quality of life after intestinal and multivisceral transplantation. Ann of Surg 2012;256:494-508. 9. United Network of Organ Sharing 2015: UNOS.org. www.UNOS.org. Accessed March 24, 2015. 10. Beath S, Pironi L, Gabe S, Horslen S, Sudan D, Mazeriegos G, et al. Collaborative strategies to reduce mortality and morbidity in patients with chronic intestinal failure including those who are referred for small bowel transplantation. Transplantation 2008;85:1378-84. 11. Khan FA, Squires RH, Litman HJ, Balint J, Carter BA, Fisher JG, et al. Predictors of enteral autonomy in children with intestinal failure: a multicenter cohort study. J Pediatr 2015;167:29-34. 12. Kaplan J, Han L, Halgrimson W, Wang E, Fryer J. The impact of MELD/ PELD revisions on the mortality of liver-intestine transplantation candidates. Am J Transplant 2011;11:1896-904. 13. Raphael BP, Mitchell PD, Finkton D, Jiang H, Jansik T, Duggan C. Necrotizing enterocolitis and central line associated blood stream infection are predictors of the pace of growth in infants with short bowel syndrome. J Pediatr 2015;167:35-40. 14. de Meijer VE, Gura KM, Meisel JA, Le HD, Puder M. Parenteral fish oil as monotherapy for patients with parenteral nutrition-associated liver disease. Pediatr Surg Int 2009;25:123-4.
Vol. 167, No. 1 15. Fallon EM, Le HD, Puder M. Prevention of parenteral nutritionassociated liver disease: role of omega-3 fish oil. Curr Opin Organ Transplant 2010;15:334-40. 16. Nandivada P, Cowan E, Carlson SJ, Chang M, Gura KM, Puder M. Mechanisms for the effects of fish oil lipid emulsions in the management of parenteral nutrition-associated liver disease. Prostaglandins Leukot Essent Fatty Acids 2013;89:153-8. 17. Neu J. Preterm infant nutrition, gut bacteria, and necrotizing enterocolitis. Curr Opin Clin Nutr Metab Care 2015;18:285-8. 18. Chen AC, Chung MY, Chang JH, Lin HC. Pathogenesis implication for necrotizing enterocolitis prevention in preterm very-low-birth-weight infants. J Pediatr Gastroenterol Nutr 2014;58:7-11. 19. Patel RM, Kandefer S, Walsh MC, Bell EF, Carlo WA, Laptook AR, et al. Causes and timing of death in extremely premature infants from 2000 through 2011. N Engl J Med 2015;372:331-40. 20. Bechtold S, Simon D. Growth abnormalities in children and adolescents with juvenile idiopathic arthritis. Rheumatol Int 2014;34:1483-8. 21. Heuschkel R, Salvestrini C, Beattie RM, Hildebrand H, Walters T, Griffiths A. Guidelines for the management of growth failure in childhood inflammatory bowel disease. Inflamm Bowel Dis 2008;14:839-49. 22. Cole CR, Hansen NI, Higgins RD, Ziegler TR, Stoll BJ. Very low birth weight preterm infants with surgical short bowel syndrome: incidence, morbidity and mortality, and growth outcomes at 18 to 22 months. Pediatrics 2008;122:e573-82. 23. Cole CR, Frem JC, Schmotzer B, Gewirtz AT, Meddings JB, Gold BD, et al. The rate of bloodstream infection is high in infants with short bowel syndrome: relationship with small bowel bacterial overgrowth, enteral feeding, and inflammatory and immune responses. J Pediatr 2010;156:941-7.e1. 24. Kaufman SS, Loseke CA, Lupo JV, Young RJ, Murray ND, Pinch LW, et al. Influence of bacterial overgrowth and intestinal inflammation on duration of parenteral nutrition in children with short bowel syndrome. J Pediatr 1997;13:356-61. 25. Oliveira C, Nasr A, Brindle M, Wales PW. Ethanol locks to prevent catheter-related bloodstream infections in parenteral nutrition: a meta-analysis. Pediatrics 2012;129:318-29. 26. Stanger JD, Oliveira C, Blackmore C, Avitzur Y, Wales PW. The impact of multi-disciplinary intestinal rehabilitation programs on the outcome of pediatric patients with intestinal failure: a systematic review and metaanalysis. J Pediatr Surg 2013;48:983-92. 27. Jeppese PB, Pertkiewicz M, Messing B, Iyer K, Seidner DL, O’Keefe SJ, et al. Teduglutide reduces need for parenteral support among patients with short bowel syndrome with intestinal failure. Gastroenterology 2012;143:1473-81.e3.
Prevention of Cerebral Palsy: Which Infants Will Benefit from Therapeutic Hypothermia?
C
term.1 Previous efforts to prevent CP related to perinatal an cerebral palsy (CP) be prevented? The answer depends on the etiology of CP. Although the causes of asphyxia in term infants, such as the use of continuous elecCP are largely related to early brain injury, both the tronic fetal monitoring, have not resulted in any decrease in nature of that injury and the later manifestations can differ the incidence of CP.2 This lack of progress may be attributed based on the gestational and postnatal ages at which the in part to the multiple etiologies of CP, with only a small perinjury occurs, as well as its source. centage related to perinatal asphyxia,3,4 but See related article, p 58 A number of clinical practices have been does not imply that there are no infants implemented in an effort to reduce the incidence of CP; howwho would benefit. Therapeutic hypothermia has been ever, many of these practices focus on preterm infants, even shown to decrease the incidence of death and though the majority of infants who develop CP are born at
CP RCT
Cerebral palsy Randomized controlled trial
The author declares no conflicts of interest. 0022-3476//$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2015.03.052
8
July 2015 neurodevelopmental disability, including CP, in infants with moderate to severe neonatal encephalopathy due to perinatal asphyxia.5 Current clinical recommendations have been modified from previous large randomized controlled trials (RCTs) to target those likely to benefit from therapeutic hypothermia.6-9 Those criteria from the Canadian Paediatric Society and the American Academy of Pediatrics include evidence of perinatal asphyxia (eg, Apgar score, need for resuscitation, presence of metabolic acidosis), as well as the presence of moderate to severe encephalopathy.10,11 In this issue of The Journal, Garfinkle et al12 evaluate the potential effectiveness of therapeutic hypothermia in preventing CP in patients born at term, using criteria for therapeutic hypothermia modified from the Canadian Paediatric Society with the additional consideration of a sentinel event. Although 1 in 4 patients with CP had previous evidence of neonatal encephalopathy, only 1 in 8 patients (64 total) met the criteria for receipt of therapeutic hypothermia. Using outcome data from a recent Cochrane systematic review5 suggesting a number needed to benefit of 8 (95% CI, 6-17), they estimate that had the 64 infants meeting therapeutic hypothermia criteria been treated, 8 cases of CP (out of a total of 543), or only 5%, could have been prevented. Although this may appear to be a small fraction of the infants with CP, their finding is consistent with the current consensus that most cases of CP are not related to perinatal asphyxia. For infants with encephalopathy due to other factors, such as metabolic disorders, meningitis, or neonatal stroke, additional therapeutic options are limited at present. Which infants will benefit from therapeutic hypothermia? In current practice, the presence of a sentinel event or shoulder dystocia is less commonly considered in the decision to perform hypothermia compared with evidence of perinatal asphyxia and neonatal encephalopathy, although the presence of such an event increases the clinical suspicion of perinatal asphyxia or neonatal encephalopathy. Indeed, Garfinkle et al12 report that the presence of shoulder dystocia was significantly more common in infants with moderate or severe encephalopathy who did not meet the criteria for hypothermia compared with those who did (12% vs 2%), owing in part to less severe systemic acidosis as assessed by cord pH. Although cord pH may not be as depressed as might be expected for the degree of encephalopathy in infants with neonatal encephalopathy following shoulder dystocia,13 the inclusion criteria in most of the large RCTs7-9 and in a Cochrane systematic review5 did not consider the presence of shoulder dystocia and sentinel events. In the National Institute of Child Health and Human Development trial,6 sentinel events (although not dystocia) were considered when the evidence for perinatal asphyxia was less clear, such as a pH of 7.01-7.15 on cord blood or early infant blood gas analysis. In contrast, infants with shoulder dystocia in Garfinkle et al had an average cord blood pH of 7.17, and as such would not have met the criteria for inclusion in the trial despite the presence of moderate to severe encephalopathy. When evaluating infants with perinatal asphyxia and neonatal encephalopathy, the application of clinical practice guidelines
EDITORIALS may need to include consideration of additional risk factors and emphasize the neurologic presentation. Criteria for cooling also include the presence of moderate to severe neonatal encephalopathy. In many of the large RCTs reported to date,6-8 infants with mild encephalopathy have been excluded from therapeutic hypothermia owing to their relatively favorable prognosis. Although 1 RCT did include some infants with mild encephalopathy,9 a recent statement from the American Academy of Pediatrics11 recommended that infants with mild encephalopathy be treated only in the context of clinical trials. However, given the improvements seen in outcomes after hypothermia for moderate to severe encephalopathy, in conjunction with the relatively benign safety profile, the practice of cooling infants with mild encephalopathy is becoming more widespread despite the absence of ongoing clinical trials. In a recent analysis of infants from the Vermont Oxford Network Neonatal Encephalopathy Registry, 43% would not have been eligible for therapeutic hypothermia according to the criteria used by the large RCTs.14 One of the more common reasons that these infants would have been ineligible for hypothermia was the presence of mild or no encephalopathy (40%). Ultimately, why not cool all infants with encephalopathiy, especially those who would be excluded from hypothermia because of milder encephalopathy or a less clear history of asphyxia? A retrospective study of infants with neonatal encephalopathy and acidemia treated with hypothermia demonstrated similar rates of death and disability in those meeting standard criteria for cooling and those not meeting cooling criteria for such reasons as gestational age 6 hours, and others,15 and the authors recommended considering cooling for these infants. Although it is tempting to broaden our reach to optimize outcomes, the risk should be fully evaluated when considering cooling in infants not strictly meeting the criteria. Further study is warranted for infants who do not strictly meet the criteria specified for hypothermia used in the large RCTs; however, some recommendations may be made even in the absence of data. Infants with moderate to severe encephalopathy should receive a complete evaluation and consideration for cooling even if they do not meet all of the criteria for perinatal asphyxia. This is especially true for those infants with a history of a sentinel event or another risk factor for perinatal asphyxia. Early evaluation includes screening for metabolic or congenital abnormalities that could account for the encephalopathy and possibly imaging to rule out perinatal stroke or traumatic etiology. If none of these are present, then cooling should be strongly considered. For infants with mild encephalopathy but a clear history of perinatal asphyxia and/or a sentinel event, electroencephalography should be obtained. When mild encephalopathy is confirmed, the risk:benefit for cooling is unclear. In the Cochrane systematic review of cooling for newborns with moderate to severe neonatal encephalopathy, a significant increase in thrombocytopenia (although not in thrombosis or hemorrhage) was seen in infants undergoing therapeutic hypothermia, as well as a nonsignificant but clinically 9
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important increase in the risk of persistent pulmonary hypertension.5 In comparison with the potential for preventing brain injury, these risks may seem small, but they must be considered (along with the need for intensive care and separation of the mother–infant dyad) in infants with mild encephalopathy who are less likely to benefit from cooling. There exists a tension between the need for further study and the need to provide immediate treatment to those infants most likely to benefit from this well-established therapy. The current criteria for therapeutic hypothermia represent our best estimate of the infants likely to benefit from this treatment. Broadening our reach in an attempt to optimize outcomes is tempting, but likely would result in unnecessary treatment of a large number of infants with less significant encephalopathy and acidosis. Alternatively, for the subset of infants in whom perinatal asphyxia is considered a contributing factor, therapeutic hypothermia remains our best means of prevention, and a full evaluation should be obtained even in infants not strictly meeting the criteria for this treatment. n Marie T. Berg, MD Division of Neonatal-Perinatal Medicine University of Vermont College of Medicine Burlington, Vermont Reprint requests: Marie T. Berg, MD, Division of Neonatal-Perinatal Medicine, University of Vermont Children’s Hospital, 111 Colchester Ave, Burlington, VT 05401. E-mail: [email protected]
References 1. Blair E, Watson L, Badawi N, Stanley FJ. Life expectancy among people with cerebral palsy in Western Australia. Dev Med Child Neurol 2001;43: 508-15. 2. Alfirevic Z, Devane D, Gyte GM. Continuous cardiotocography (CTG) as a form of electronic fetal monitoring (EFM) for fetal assessment during labour. Cochrane Database Syst Rev 2006;3:CD006066.
Vol. 167, No. 1 3. McIntyre S, Blair E, Badawi N, Keogh J, Nelson KB. Antecedents of cerebral palsy and perinatal death in term and late preterm singletons. Obstet Gynecol 2013;122:869-77. 4. Ellenberg JH, Nelson KB. The association of cerebral palsy with birth asphyxia: a definitional quagmire. Dev Med Child Neurol 2013;55: 210-6. 5. Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2013;1:CD003311. 6. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005;353:1574-84. 7. Gluckman P, Wyatt J, Azzopardi D, Ballard R, Edwards A, Ferriero D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005; 365:663-70. 8. Azzopardi D, Strohm B, Edwards A, Dyet L, Halliday H, Juszczak E, et al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med 2009;361:1349-58. 9. Jacobs SE, Morley CJ, Inder TE, Stewart MJ, Smith KR, McNamara PJ, et al. Whole-body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial. Arch Pediatr Adolesc Med 2011;165:692-700. 10. Peliowski-Davidovich A. Hypothermia for newborns with hypoxic ischemic encephalopathy. Paediatr Child Health 2012;17:41-6. 11. Papile LA, Baley JE, Benitz W, Cummings J, Carlo WA, Eichenwald E, et al. Committee on Fetus and Newborn. Hypothermia and neonatal encephalopathy. Pediatrics 2014;133:1146-50. 12. Garfinkle J, Wintermark P, Shevell MI, Platt RW, Oskoui M. Cerebral palsy following neonatal encephalopathy: how much is preventable? J Pediatr 2015;167:58-63. 13. Leung TY, Stuart O, Sahota DS, Suen SS, Lau TK, Lao TT. Head-to-body delivery interval and risk of fetal acidosis and hypoxic ischaemic encephalopathy in shoulder dystocia: a retrospective review. BJOG 2011;118: 474-9. 14. Pfister RH, Bingham P, Edwards EM, Horbar JD, Kenny MJ, Inder T, et al. The Vermont Oxford Neonatal Encephalopathy Registry: rationale, methods, and initial results. BMC Pediatr 2012;12:84. 15. Smit E, Liu X, Jary S, Cowan F, Thoresen M. Cooling neonates who do not fulfil the standard cooling criteria: short- and long-term outcomes. Acta Paediatr 2015;104:138-45.
Erythropoiesis Stimulating Agents Demonstrate Safety and Show Promise as Neuroprotective Agents in Neonates
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and decrease transfusions. Recent randomized, tudies published 27 years ago showed that erythroid multi-centered, placebo-controlled trials of erythropoiesis progenitor cells of preterm neonates were responsive stimulating agents (ESAs), such as Epo or longer acting darto recombinant erythropoietin (Epo).1 Many clinical bepoetin, administered to preterm infants also show a reductrials were subsequently performed worldwide, testing tion in blood donor exposure and a lower transfusion rate.2 whether administering Epo to preterm infants might be a safe and effective way to expand their red Along with the clinical trials aimed at See related article, p 52 cell mass and decrease their transfusion redecreasing or eliminating transfusions, aniquirements. Indeed, essentially all trials convincingly showed mal studies have shown that ESAs have neuroprotective that Epo can stimulate erythropoiesis in preterm and term infants, and has the capability to diminish donor exposure
Epo ESA ROP
Erythropoietin Erythropoiesis stimulating agent Retinopathy of prematurity
Supported by the National Institutes of Health (NIH; R01 HD059856, U01 NS077953 [to R.O.], U01 NS077953, R01HD073128, U01NS077953 [to S.J.], P01 HL046925, U01 NS077953 [to J.W.]), and Intermountain Healthcare Medical Foundation (to R.C.). J.W. is a paid consultant to HemoGenix. The other authors declare no conflicts of interest. 0022-3476//$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2015.03.054
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