INVITED COMMENTARIES
Early Mineral Metabolism in Very-Low-Birth-Weight Infants C. Pieltain and Jacques Rigo See ‘‘Early Postnatal Calcium and Phosphorus Metabolism in Preterm Infants’’ by Christmann et al on page 398.
A
voiding the development of hypophosphatemia during the first week of life could be a major issue for very-low-birthweight (VLBW) infants (1,2). Phosphate content is abundant in the cells because it represents the main anion in the intracellular space. It enters into the composition of the nucleic acids, the adenosine triphosphate, and the cell membrane (3,4). In addition to its role in bone mineralization, phosphorus (P) plays a major role in energy metabolism, acid-base status, and cellular growth, and P depletion could be associated with potential deleterious outcomes, such as nephrocalcinosis, insulin resistance (5), and nosocomial infection (6). Christmann et al (7) provide an illustration of the physiology of the mineral metabolism in preterm infants during parenteral and enteral nutrition (1,2). Calcium (Ca) and P supplies in parenteral and enteral routes are not metabolically equivalent. In parenteral nutrition, Ca and P are directly available for bone deposition as hydroxyapatite with a Ca/P molar ratio of 1.66. In addition, P is necessary for lean body mass accretion accounting for 0.33 mmol (10 mg) of P per gram of protein retention. In cases of relative P deficiency, available P is primarily oriented to the cellular metabolism, reducing bone mineralization or inducing bone resorption. Biochemical signs of P deficiency are the development of hypophosphatemia, hypophosphaturia, hypercalcemia, hypercalciuria, and an increase in the renal tubular reabsorption of P (TrP) > 95%. During the first week of life, Christmann et al (7) provided parenteral nutrition with a Ca/P molar ratio of 1.6 combined with human milk enriched from a starting intake of 50 mL/day onward. The combined use of a parenteral solution (PS) with a Ca/P molar ratio in the range of the bone deposition and unfortified human milk with a relative P deficiency could explain the development of the mineral metabolic disorder. Similar data were reported with the use of a PS with a Ca/P molar ratio of 2.0 and 1.2, respectively (3,6). Optimal P content in PS could be estimated on the basis of the Ca and the amino acid contents (1,3). An adequate Ca/P molar ratio would be close to 1.0 or below 1.0 in the case of high amino acid intake > 2.5/kg/day from the first day of life (1,4). Early P requirement is also increased in VLBW infants with intrauterine growth restriction (8).
Received and accepted November 12, 2013. From the University of Lie`ge, Department of Neonatology, CHU Lie`ge, CHR Citadelle, Lie`ge, Belgium. Address correspondence and reprint requests to Jacques Rigo, Department of Neonatology, CHR Citadelle, Blvd du XII de Ligne 1, 4000 Lie`ge, Belgium (e-mail: [email protected]). The authors report no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000250
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After the second week of life, infants were adequately fed enterally, with a minimal contribution of parenteral nutrition (7). P supplementation was still provided to more than 50% of the preterm infants during the third and fourth weeks. Mean total Ca and P intakes were approximately 3.5 mmol of Ca and 3.2 mmol g1 day1 of P with a Ca/P molar ratio of 1.1. This value below the recommended values for enteral nutrition (9) was associated with an increased urinary P excretion and a large reduction in the TrP below 80%, suggesting a relative P overload. During enteral nutrition, the optimal Ca/P molar ratio depends both on the Ca absorption rate and the protein retention, and is inversely related to the protein retention (1,2). The study by Christmann et al clearly demonstrates that urinary excretion of P and TrP are both sensitive markers in the evaluation of the relative P overload. The potential role of serum alkaline phosphatase (sAP) as a marker of bone disorder related to P deficiency was not fully addressed by Christmann et al (7). The mean sAP was within the normal range at birth. It increased rapidly, to reach a maximum value by day 7. This maximum level was significantly higher in the group receiving P supplementation. Unfortunately, the unsupplemented group was heterogeneous, with only 32 of 54 infants without any P supplementation during the first week of life. The sharp decrease in sAP from day 7 to week 3 could provide additional evidence of the value of sAP as a sensitive marker of P depletion and bone disorder in VLBW infants. Additional analysis of the relation between the minimum level of serum P concentration during the first week of life and the sAP at day 7 could provide additional evidence and should be developed in a future article.
REFERENCES 1. Pieltain C, de Halleux V, Senterre T, et al. Prematurity and bone health. World Rev Nutr Diet 2013;106:181–8. 2. Rigo J, Pieltain C, Viellevoye R, et al. Calcium and phosphorus homeostasis: pathophysiology. In: Buenocore G, et al, eds. Neonatology: A Practical Approach to Neonatal Diseases. Rome: Springer; 2012: 333–53. 3. Bonsante F, Iacobelli S, Latorre G, et al. Initial amino acid intake influences phosphorus and calcium homeostasis in preterm infants: it is time to change the composition of the early parenteral nutrition. PLoS ONE 2013;8:e722880. 4. Rigo J, Senterre T. Intrauterine-like growth rates can be achieved with premixed parenteral nutrition solution in preterm infants. J Nutr 2013; 143:2066S–70S. 5. Dreyfus L, Fisher C, Maucort-Boulch D, et al. Hypophosphoremie: un facteur de risque d’insulinotherapie chez les nouveau-ne´s de tre`s faible poids a` la naissance. Journ Franc Rech Neonatol Commun 2012: 117–8. 6. Moltu SJ, Strømmen K, Blakstad EW, et al. Enhanced feeding in very-low-birth-weight-infants may cause electrolyte disturbances and septicemia—a randomized, controlled trial. Clin Nutr 2013;32: 207–12. 7. Christmann V, de Grauw AM, Visser R, et al. Early postnatal calcium and phosphorus metabolism in preterm infants. J Pediatr Gastroenterol Nutr 2014;58:398–403. 8. Mizumoto H, Mikami M, Oda H, et al. Refeeding syndrome in a smallfor-dates micro-preemie receiving early parenteral nutrition. Pediatr Int 2012;54:715–7. 9. Agostoni C, Buonocore G, Carnielli VP, et al. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr 2010;50:85–91.
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Invited Commentaries
JPGN
Expanded Neurologic Assessment in Pediatric Acute Liver Failure: An Important Initial Step Robert H. Squires
See ‘‘EEG Abnormalities Are Associated With Increased Risk of Transplant or Poor Outcome in Children With Acute Liver Failure’’ by Wainwright et al on page 449.
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he article by Wainwright et al (1) in this issue of the Journal of Pediatric Gastroenterology and Nutrition concludes that their work is an ‘‘initial step’’ in correlating neurologic findings with outcome in pediatric acute liver failure (PALF). Indeed it is, but emphasis must be placed on initial step. A retrospective analysis of a ‘‘clinical pathway’’ initiated in 2008 to assess and manage neurologic findings in PALF is presented, with 19 children analyzed. Clinical hepatic encephalopathy (HE) score, electroencephalogram (EEG), and radiographic imaging of the brain with computerized axial tomography and/or nuclear magnetic resonance imaging were used to assess neurologic function. Assessments were performed early in the hospital course, but the duration or management of the illness before the intensive care unit admission is not known. Administration of L-carnitine and maintenance of patient temperature at 30 years ago to support clinical trials in adults with cirrhosis and portal-systemic encephalopathy (PSE) included the PSE index (2) and West Haven criteria (WHC) (3). WHC were simpler and segregated into grades I to IV based on alterations of consciousness, intellectual function, and behavior. Although not developed to assess HE in acute liver failure (ALF), WHC were selected as the best tool to assess adults with ALF (4). Absent a pediatric specific tool to assess acute HE, WHC are generally used in older children. A pediatric modification of WHC was proposed by Whitington and Alonso for children 25 mmHg, with median ICP pressures in the high ICP group that ranged from 38 to 84 mmHg (8). Therefore, the clinically important elevation of ICP in PALF has yet to be clarified. Cerebral blood flow was not reported. For analytical purposes, death and S-LT were combined into a single outcome, but evidence suggests that the S-LT cohort is a combination of patients who would have lived with their native liver and died had LT not been available (9,10). Additional opportunities to better characterize neurologic features of PALF were not included in this study. Changes in clinical parameters over time may be useful to predict the outcome in liver failure (11). Continuous EEG patterns, which should include reactivity to painful or noxious stimuli (12), may help characterize dynamic features of HE in PALF and correlate them with clinical interventions. The assessment of biomarkers of inflammation, both intracerebral (13,14) and systemic (13,15), as well as brain injury (eg, S-100b, neuron-specific enolase) (16), may identify mechanistic and therapeutic targets. Monitoring optic nerve sheath diameter may be an adjunct or alternative method to assess increased ICP (17). A transcranial Doppler ultrasound to assess cerebral blood flow has been studied in children with sickle cell disease, traumatic brain injury, and stroke, but PALF was not mentioned in a review (18). As a retrospective analysis of a clinical pathway, this study was not, and could not, be hypothesis based. Rather, experienced investigators at a single site incorporated their individual and collective clinical expertise and biases into a management plan that served as their local standard of care. Such is the nature of much of clinical investigation, and it is often a necessary initial step to develop an evidence-based clinical practice. This study www.jpgn.org
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generated numerable hypotheses that should be formally tested, but to do this requires time commitment by and financial support for investigators to generate and implement a protocol, families willing to consent for their children to participate in clinical research, collaborative investigators willing to test hypotheses for which there is clinical equipoise, infrastructure support for data collection and analysis, and sufficient funding to support these efforts. The alignment of these and other factors is necessary to move beyond this initial step toward better neurologic assessment in PALF.
Invited Commentaries
Gastroesophageal Reflux Guidelines: The European Experience Marjorie McCracken
See ‘‘Noncompliance With NASPGHAN-ESPGHAN Practice Guidelines for GER in Europe: Is There a Point?’’ by Thaler on page 396, and ‘‘European Pediatricians’ Approach to Children With GER Symptoms: Survey of the Implementation of 2009 NASPGHAN-ESPGHAN Guidelines’’ by Quitadamo et al on page 505.
REFERENCES 1. Hussain E, Grimason M, Goldstein J, et al. EEG abnormalities are associated with increased risk of transplant or poor outcome in children with acute liver failure. J Pediatr Gastroenterol Nutr 2014; 58:449–56. 2. Conn HO, Leevy CM, Vlahcevic ZR, et al. Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial. Gastroenterology 1977;72: 573–83. 3. Atterbury CE, Maddrey WC, Conn HO. Neomycin-sorbitol and lactulose in the treatment of acute portal-systemic encephalopathy. A controlled, double-blind clinical trial. Am J Dig Dis 1978;23:398– 406. 4. Ferenci P, Lockwood A, Mullen K, et al. Hepatic encephalopathy: definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 2002;35:716–21. 5. Squires RH Jr, Shneider BL, Bucuvalas J, et al. Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group. J Pediatr 2006;148:652–8. 6. Whitington PF, Alonso EM. Fulminant hepatitis and acute liver failure. In: Kelly DA, ed. Paediatric Liver Disease. Oxford: Blackwell; 2003: 107–26. 7. Sutter R, Stevens RD, Kaplan PW. Clinical and imaging correlates of EEG patterns in hospitalized patients with encephalopathy. J Neurol 2013;260:1087–98. 8. Aggarwal S, Obrist W, Yonas H, et al. Cerebral hemodynamic and metabolic profiles in fulminant hepatic failure: relationship to outcome. Liver Transpl 2005;11:1353–60. 9. Azhar N, Ziraldo C, Barclay D, et al. Analysis of serum inflammatory mediators identifies unique dynamic networks associated with death and spontaneous survival in pediatric acute liver failure. PLoS One 2013; 8:e78202. 10. Sundaram V, Shneider BL, Dhawan A, et al. King’s College Hospital criteria for non-acetaminophen induced acute liver failure in an international cohort of children. J Pediatr 2013;162:319.e1– 23.e1. 11. Kumar R, Shalimar, Sharma H, et al. Prospective derivation and validation of early dynamic model for predicting outcome in patients with acute liver failure. Gut 2012;61:1068–75. 12. Thenayan EA, Savard M, Sharpe MD, et al. Electroencephalogram for prognosis after cardiac arrest. J Crit Care 2010;25:300–4. 13. Butterworth RF. Neuroinflammation in acute liver failure: mechanisms and novel therapeutic targets. Neurochem Int 2011;59: 830–6. 14. Wright G, Shawcross D, Olde Damink SW, et al. Brain cytokine flux in acute liver failure and its relationship with intracranial hypertension. Metab Brain Dis 2007;22:375–88. 15. Jalan R, Olde Damink SW, Hayes PC, et al. Pathogenesis of intracranial hypertension in acute liver failure: inflammation, ammonia and cerebral blood flow. J Hepatol 2004;41:613–20. 16. Strauss GI, Christiansen M, Moller K, et al. S-100b and neuron-specific enolase in patients with fulminant hepatic failure. Liver Transpl 2001; 7:964–70. 17. Kimberly HH, Shah S, Marill K, et al. Correlation of optic nerve sheath diameter with direct measurement of intracranial pressure. Acad Emerg Med 2008;15:201–4. 18. Verlhac S. Transcranial Doppler in children. Pediatr Radiol 2011;41 (suppl 1):S153–65.
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n this issue of the Journal of Pediatric Gastroenterology and Nutrition (JPGN), Quitadamo et al (1) reports on a survey performed in 2009 about the low compliance of guidelines by European pediatricians with the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN)/European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) guidelines for gastroesophageal reflux (GER) applied to children with symptoms of GER. In particular, the general pediatricians underused the recommended diagnostic tests, such as pH probe, impedance, and upper gastrointstinal (GI) endoscopy, and overused proton pump inhibitors. These problems are attributed to practitioners’ ignoring the recommended guidelines. The ignorance of the guidelines is certainly a part of the problem, but it is not the whole story. Lack of compliance with clinical practice guidelines may be widespread for 3 reasons: guidelines may not be well publicized, guidelines may change radically in a short period, and competing guidelines may exist (2). The first 2 refer to the 2009 NASPGHAN/ESPGHAN GER disease (GERD) guidelines (3), and the third one does not. These guidelines were published only in JPGN, a subspecialty publication. The NASPGHAN/ESPGHAN guidelines are in stark contrast to the American Academy of Pediatrics (AAP) clinical practice guidelines, which are widely publicized by the AAP in multiple venues including Pediatrics, AAP News, online, and in the lay press. The second problem is the change in clinical practice guidelines. Of course, when new science becomes available, clinical practice guidelines must change. The fact that the 2009 GER guidelines differ radically from the 2001 guidelines on the same subject, also published in JPGN (4), is, however, not immediately apparent upon casual reading of the 2 sets of guidelines. The 2009 guidelines make several recommendations that attempt to limit the overuse of proton pump inhibitors because of the studies documenting the lack of efficacy of these medications for infant crying (5,6); however, nowhere are the changes emphasized. For example, the 2001 guidelines state, ‘‘Empiric medical therapy. A trial of time limited medical therapy for GER is useful for determining if GER is Received August 22, 2013; accepted November 25, 2013. From the Good Samaritan Hospital, San Jose, CA. Address correspondence and reprint requests to Marjorie McCracken, MD, PhD, Good Samaritan Hospital, San Jose, CA (e-mail: margemccr@ gmail.com). The author reports no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000264
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Invited Commentaries causing a specific symptom’’ and ‘‘The infant with recurrent crying and irritability. . .expert opinion suggests two diagnostic and treatment strategies. Empiric treatment with either a sequential or simultaneous two-week trial of a hypoallergenic formula and acid suppression may be initiated.’’ In contrast, the 2009 recommendations state: ‘‘There is no evidence to support an empiric trial of acid suppression as a diagnostic test in infants and young children where symptoms suggestive of GERD are less specific,’’ and ‘‘Infants with unexplained crying and/or distressed behavior. . . there is no evidence to support empiric use of acid suppression for the treatment of irritable infants. . . a time limited trial of antisecretory therapy may be considered, but there is potential risk of adverse effects.’’ The consequences of these changes in the recommendations are huge. Instead of the simple treatment trial previously suggested, the invasive testing is recommended before the use of proton pump inhibitors in all but older children and teenagers. This is not emphasized in the 2009 guidelines. Instead, the differences are buried in the text. A pediatrician could be forgiven for not realizing how radical the differences truly are. Even when the guidelines are known, they may not be followed because they are perceived as impractical. That this problem applies to the 2009 GER guidelines is clearly demonstrated in the survey, which showed, ‘‘48% prescribed PPIs in children younger than 8–12 years with vomiting and heartburn without specific testing’’ and ‘‘9.7% use esophageal and gastric ultrasound to diagnose gastroesophageal reflux despite a specificity of only 11% for this test.’’ General pediatricians see many infants and children who are not seriously ill, but have complaints compatible with GERD. The empiric use of proton pump inhibitors undoubtedly reflects the doctors’ desire to help these patients without subjecting them to invasive testing not justified by their perceived relatively minor symptoms. This consideration probably also applies to the use of ultrasound as a diagnostic tool. In the United States, pediatricians frequently use upper GI series for the same purpose. There is also a problem of access. The recommended testing for GERD (pH probe, impedance, or upper GI endoscopy) can only be done by pediatric gastroenterologists. Minor symptoms do not warrant referral to a subspecialist, and in many areas subspecialty referral may be difficult because of lack of access and long wait times for appointments. Guidelines may not be followed because of patient and/or parental pressure for a solution to the problem. Parents want their children’s distress to be eliminated and frequently request medication. They are often understandably reluctant to subject their children to uncomfortable invasive testing unless such testing is clearly necessary. Finally, there is sometimes outright disagreement with clinical practice guidelines (2). That happens when there are competing guidelines (not the case here) or when guidelines are perceived as being influenced by conflicts of interest such as the authors receiving money from drug and/or device manufacturers or the sponsoring society being influenced by a desire to save money (2). It is not possible to tell from the survey whether European pediatricians disagree with our guidelines. The guidelines were, however, clearly generated ethically using good science, so they should not be perceived as having conflicts of interest. In summary, I believe the major barriers to general pediatricians’ implementation of the 2009 NASPGHAN/ESPGHAN clinical practice guidelines for GER are ignorance because of lack of publicity for the guidelines, and lack of clarity about guideline changes and the perceived impracticality of some of the recommendations. We may be able to alleviate these problems by widely publicizing our guidelines in multiple venues and, when changing the guidelines, emphasizing the major changes and the reasons for
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them upfront. Furthermore, the practicality of the guidelines should be a consideration when generating them.
REFERENCES 1. Quitadamo P, Papadopoulou A, Wenzl T, et al. European pediatricians’ approach to children with GER symptoms: survey of the implementation of 2009 NASPGHAN-ESPGHAN guidelines. J Pediatr Gastroenterol Nutr 2014;58:505–9. 2. Fletcher R, Clinical practice guidelines. www.uptodate.com. Accessed June 1, 2013. 3. Vandenplas Y, Rudolph C, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendation of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroenterol Nutr 2009;49:498–547. 4. Rudolph C, Mazur L, Liptak G, et al. Guidelines for the evaluation and treatment of gastroesophageal reflux in infants and children, recommendations of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr 2001;32(suppl 2):S1–31. 5. Orenstein SR, Hassel E, Furmaga-Jablonska W, et al. Multicenter, double-blind, placebo-controlled trial assessing efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease. J Pediatr 2009;154:514–20. 6. Moore DJ, Tao BS, Lines DR, et al. Double-blind placebo-controlled trial of omeprazole in irritable infants with gastroesophageal reflux. J Pediatr 2003;143:219–23.
Noncompliance With NASPGHANESPGHAN Practice Guidelines for GER in Europe: Is There a Point? M. Michael Thaler See ‘‘Gastroesophageal Reflux Guidelines: The European Experience’’ by McCracken on page 395, and ‘‘European Pediatricians’ Approach to Children With GER Symptoms: Survey of the Implementation of 2009 NASPGHAN-ESPGHAN Guidelines’’ by Quitadamo et al on page 505.
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n 2012, a survey of pediatricians from 11 European countries indicated that a vanishingly small handful (1.8%) of self-selected respondents applied the 2009 NASPGHAN-ESPGHAN clinical practice guidelines for GER. In the previous commentary, McCracken approaches the survey results from a practical perspective by postulating putative barriers to implementation: ignorance of the guidelines owing to inadequate publicity, lack of clarity as a Received November 22, 2013; accepted November 25, 2013. From the Division of Pediatric Gastroenterology, University of CaliforniaSan Francisco. Address correspondence and reprint requests to M. Michael Thaler, MD, Box 0136, University of California-San Francisco, San Francisco, CA 94143 (e-mail: [email protected]). The author reports no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000265
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result of rapid turnover in recommendations, impractical requirements, and parental resistance to recommended diagnostic procedures. McCracken understandably argues that once these obstacles are removed, compliance with the guidelines should improve. These are plausible explanations for the noncompliance, but they cannot be reliably tested. The authors themselves concede that ‘‘the analysis of the questionnaires does not allow us to comment on the reasons for the European pediatricians’ failure to comply with recommendations, and therefore does not suggest specific interventions.’’ Thus, the survey does not offer or suggest trustworthy answers for poor adherence to official guidelines. Nevertheless, the survey is worthy of publication as the results generate interesting and getatable questions. Most notable is the lack of comparative data from nonEuropean settings. Only when similar surveys are conducted in
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Invited Commentaries other contexts can we begin to ask what drives regional differences in diagnostic and therapeutic approaches to common yet vaguely characterized complaints such as ‘‘irritability.’’ For example, what if implementation of guidelines is no better in the United States than in Europe? What if compliance is higher in the United States, but not in Canada or vice versa? What do we find when Argentina is compared with Spain and Brazil compared with Portugal? I believe the answers to these questions are attainable and would shed light on the results of the European survey. With comparable data in hand, we may eventually hope to address larger issues that are beyond the scope of the present survey. These include the influence of traditional practice patterns and national health care systems, the threat of malpractice suits, and the application of the latest advances, on compliance with criterion standard clinical guidelines by pediatric practitioners.
397
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Early Mineral Metabolism in Very-Low-Birth-Weight Infants C. Pieltain and Jacques Rigo See ‘‘Early Postnatal Calcium and Phosphorus Metabolism in Preterm Infants’’ by Christmann et al on page 398.
A
voiding the development of hypophosphatemia during the first week of life could be a major issue for very-low-birthweight (VLBW) infants (1,2). Phosphate content is abundant in the cells because it represents the main anion in the intracellular space. It enters into the composition of the nucleic acids, the adenosine triphosphate, and the cell membrane (3,4). In addition to its role in bone mineralization, phosphorus (P) plays a major role in energy metabolism, acid-base status, and cellular growth, and P depletion could be associated with potential deleterious outcomes, such as nephrocalcinosis, insulin resistance (5), and nosocomial infection (6). Christmann et al (7) provide an illustration of the physiology of the mineral metabolism in preterm infants during parenteral and enteral nutrition (1,2). Calcium (Ca) and P supplies in parenteral and enteral routes are not metabolically equivalent. In parenteral nutrition, Ca and P are directly available for bone deposition as hydroxyapatite with a Ca/P molar ratio of 1.66. In addition, P is necessary for lean body mass accretion accounting for 0.33 mmol (10 mg) of P per gram of protein retention. In cases of relative P deficiency, available P is primarily oriented to the cellular metabolism, reducing bone mineralization or inducing bone resorption. Biochemical signs of P deficiency are the development of hypophosphatemia, hypophosphaturia, hypercalcemia, hypercalciuria, and an increase in the renal tubular reabsorption of P (TrP) > 95%. During the first week of life, Christmann et al (7) provided parenteral nutrition with a Ca/P molar ratio of 1.6 combined with human milk enriched from a starting intake of 50 mL/day onward. The combined use of a parenteral solution (PS) with a Ca/P molar ratio in the range of the bone deposition and unfortified human milk with a relative P deficiency could explain the development of the mineral metabolic disorder. Similar data were reported with the use of a PS with a Ca/P molar ratio of 2.0 and 1.2, respectively (3,6). Optimal P content in PS could be estimated on the basis of the Ca and the amino acid contents (1,3). An adequate Ca/P molar ratio would be close to 1.0 or below 1.0 in the case of high amino acid intake > 2.5/kg/day from the first day of life (1,4). Early P requirement is also increased in VLBW infants with intrauterine growth restriction (8).
Received and accepted November 12, 2013. From the University of Lie`ge, Department of Neonatology, CHU Lie`ge, CHR Citadelle, Lie`ge, Belgium. Address correspondence and reprint requests to Jacques Rigo, Department of Neonatology, CHR Citadelle, Blvd du XII de Ligne 1, 4000 Lie`ge, Belgium (e-mail: [email protected]). The authors report no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000250
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After the second week of life, infants were adequately fed enterally, with a minimal contribution of parenteral nutrition (7). P supplementation was still provided to more than 50% of the preterm infants during the third and fourth weeks. Mean total Ca and P intakes were approximately 3.5 mmol of Ca and 3.2 mmol g1 day1 of P with a Ca/P molar ratio of 1.1. This value below the recommended values for enteral nutrition (9) was associated with an increased urinary P excretion and a large reduction in the TrP below 80%, suggesting a relative P overload. During enteral nutrition, the optimal Ca/P molar ratio depends both on the Ca absorption rate and the protein retention, and is inversely related to the protein retention (1,2). The study by Christmann et al clearly demonstrates that urinary excretion of P and TrP are both sensitive markers in the evaluation of the relative P overload. The potential role of serum alkaline phosphatase (sAP) as a marker of bone disorder related to P deficiency was not fully addressed by Christmann et al (7). The mean sAP was within the normal range at birth. It increased rapidly, to reach a maximum value by day 7. This maximum level was significantly higher in the group receiving P supplementation. Unfortunately, the unsupplemented group was heterogeneous, with only 32 of 54 infants without any P supplementation during the first week of life. The sharp decrease in sAP from day 7 to week 3 could provide additional evidence of the value of sAP as a sensitive marker of P depletion and bone disorder in VLBW infants. Additional analysis of the relation between the minimum level of serum P concentration during the first week of life and the sAP at day 7 could provide additional evidence and should be developed in a future article.
REFERENCES 1. Pieltain C, de Halleux V, Senterre T, et al. Prematurity and bone health. World Rev Nutr Diet 2013;106:181–8. 2. Rigo J, Pieltain C, Viellevoye R, et al. Calcium and phosphorus homeostasis: pathophysiology. In: Buenocore G, et al, eds. Neonatology: A Practical Approach to Neonatal Diseases. Rome: Springer; 2012: 333–53. 3. Bonsante F, Iacobelli S, Latorre G, et al. Initial amino acid intake influences phosphorus and calcium homeostasis in preterm infants: it is time to change the composition of the early parenteral nutrition. PLoS ONE 2013;8:e722880. 4. Rigo J, Senterre T. Intrauterine-like growth rates can be achieved with premixed parenteral nutrition solution in preterm infants. J Nutr 2013; 143:2066S–70S. 5. Dreyfus L, Fisher C, Maucort-Boulch D, et al. Hypophosphoremie: un facteur de risque d’insulinotherapie chez les nouveau-ne´s de tre`s faible poids a` la naissance. Journ Franc Rech Neonatol Commun 2012: 117–8. 6. Moltu SJ, Strømmen K, Blakstad EW, et al. Enhanced feeding in very-low-birth-weight-infants may cause electrolyte disturbances and septicemia—a randomized, controlled trial. Clin Nutr 2013;32: 207–12. 7. Christmann V, de Grauw AM, Visser R, et al. Early postnatal calcium and phosphorus metabolism in preterm infants. J Pediatr Gastroenterol Nutr 2014;58:398–403. 8. Mizumoto H, Mikami M, Oda H, et al. Refeeding syndrome in a smallfor-dates micro-preemie receiving early parenteral nutrition. Pediatr Int 2012;54:715–7. 9. Agostoni C, Buonocore G, Carnielli VP, et al. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr 2010;50:85–91.
393
Copyright 2014 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
Invited Commentaries
JPGN
Expanded Neurologic Assessment in Pediatric Acute Liver Failure: An Important Initial Step Robert H. Squires
See ‘‘EEG Abnormalities Are Associated With Increased Risk of Transplant or Poor Outcome in Children With Acute Liver Failure’’ by Wainwright et al on page 449.
T
he article by Wainwright et al (1) in this issue of the Journal of Pediatric Gastroenterology and Nutrition concludes that their work is an ‘‘initial step’’ in correlating neurologic findings with outcome in pediatric acute liver failure (PALF). Indeed it is, but emphasis must be placed on initial step. A retrospective analysis of a ‘‘clinical pathway’’ initiated in 2008 to assess and manage neurologic findings in PALF is presented, with 19 children analyzed. Clinical hepatic encephalopathy (HE) score, electroencephalogram (EEG), and radiographic imaging of the brain with computerized axial tomography and/or nuclear magnetic resonance imaging were used to assess neurologic function. Assessments were performed early in the hospital course, but the duration or management of the illness before the intensive care unit admission is not known. Administration of L-carnitine and maintenance of patient temperature at 30 years ago to support clinical trials in adults with cirrhosis and portal-systemic encephalopathy (PSE) included the PSE index (2) and West Haven criteria (WHC) (3). WHC were simpler and segregated into grades I to IV based on alterations of consciousness, intellectual function, and behavior. Although not developed to assess HE in acute liver failure (ALF), WHC were selected as the best tool to assess adults with ALF (4). Absent a pediatric specific tool to assess acute HE, WHC are generally used in older children. A pediatric modification of WHC was proposed by Whitington and Alonso for children 25 mmHg, with median ICP pressures in the high ICP group that ranged from 38 to 84 mmHg (8). Therefore, the clinically important elevation of ICP in PALF has yet to be clarified. Cerebral blood flow was not reported. For analytical purposes, death and S-LT were combined into a single outcome, but evidence suggests that the S-LT cohort is a combination of patients who would have lived with their native liver and died had LT not been available (9,10). Additional opportunities to better characterize neurologic features of PALF were not included in this study. Changes in clinical parameters over time may be useful to predict the outcome in liver failure (11). Continuous EEG patterns, which should include reactivity to painful or noxious stimuli (12), may help characterize dynamic features of HE in PALF and correlate them with clinical interventions. The assessment of biomarkers of inflammation, both intracerebral (13,14) and systemic (13,15), as well as brain injury (eg, S-100b, neuron-specific enolase) (16), may identify mechanistic and therapeutic targets. Monitoring optic nerve sheath diameter may be an adjunct or alternative method to assess increased ICP (17). A transcranial Doppler ultrasound to assess cerebral blood flow has been studied in children with sickle cell disease, traumatic brain injury, and stroke, but PALF was not mentioned in a review (18). As a retrospective analysis of a clinical pathway, this study was not, and could not, be hypothesis based. Rather, experienced investigators at a single site incorporated their individual and collective clinical expertise and biases into a management plan that served as their local standard of care. Such is the nature of much of clinical investigation, and it is often a necessary initial step to develop an evidence-based clinical practice. This study www.jpgn.org
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generated numerable hypotheses that should be formally tested, but to do this requires time commitment by and financial support for investigators to generate and implement a protocol, families willing to consent for their children to participate in clinical research, collaborative investigators willing to test hypotheses for which there is clinical equipoise, infrastructure support for data collection and analysis, and sufficient funding to support these efforts. The alignment of these and other factors is necessary to move beyond this initial step toward better neurologic assessment in PALF.
Invited Commentaries
Gastroesophageal Reflux Guidelines: The European Experience Marjorie McCracken
See ‘‘Noncompliance With NASPGHAN-ESPGHAN Practice Guidelines for GER in Europe: Is There a Point?’’ by Thaler on page 396, and ‘‘European Pediatricians’ Approach to Children With GER Symptoms: Survey of the Implementation of 2009 NASPGHAN-ESPGHAN Guidelines’’ by Quitadamo et al on page 505.
REFERENCES 1. Hussain E, Grimason M, Goldstein J, et al. EEG abnormalities are associated with increased risk of transplant or poor outcome in children with acute liver failure. J Pediatr Gastroenterol Nutr 2014; 58:449–56. 2. Conn HO, Leevy CM, Vlahcevic ZR, et al. Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial. Gastroenterology 1977;72: 573–83. 3. Atterbury CE, Maddrey WC, Conn HO. Neomycin-sorbitol and lactulose in the treatment of acute portal-systemic encephalopathy. A controlled, double-blind clinical trial. Am J Dig Dis 1978;23:398– 406. 4. Ferenci P, Lockwood A, Mullen K, et al. Hepatic encephalopathy: definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 2002;35:716–21. 5. Squires RH Jr, Shneider BL, Bucuvalas J, et al. Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group. J Pediatr 2006;148:652–8. 6. Whitington PF, Alonso EM. Fulminant hepatitis and acute liver failure. In: Kelly DA, ed. Paediatric Liver Disease. Oxford: Blackwell; 2003: 107–26. 7. Sutter R, Stevens RD, Kaplan PW. Clinical and imaging correlates of EEG patterns in hospitalized patients with encephalopathy. J Neurol 2013;260:1087–98. 8. Aggarwal S, Obrist W, Yonas H, et al. Cerebral hemodynamic and metabolic profiles in fulminant hepatic failure: relationship to outcome. Liver Transpl 2005;11:1353–60. 9. Azhar N, Ziraldo C, Barclay D, et al. Analysis of serum inflammatory mediators identifies unique dynamic networks associated with death and spontaneous survival in pediatric acute liver failure. PLoS One 2013; 8:e78202. 10. Sundaram V, Shneider BL, Dhawan A, et al. King’s College Hospital criteria for non-acetaminophen induced acute liver failure in an international cohort of children. J Pediatr 2013;162:319.e1– 23.e1. 11. Kumar R, Shalimar, Sharma H, et al. Prospective derivation and validation of early dynamic model for predicting outcome in patients with acute liver failure. Gut 2012;61:1068–75. 12. Thenayan EA, Savard M, Sharpe MD, et al. Electroencephalogram for prognosis after cardiac arrest. J Crit Care 2010;25:300–4. 13. Butterworth RF. Neuroinflammation in acute liver failure: mechanisms and novel therapeutic targets. Neurochem Int 2011;59: 830–6. 14. Wright G, Shawcross D, Olde Damink SW, et al. Brain cytokine flux in acute liver failure and its relationship with intracranial hypertension. Metab Brain Dis 2007;22:375–88. 15. Jalan R, Olde Damink SW, Hayes PC, et al. Pathogenesis of intracranial hypertension in acute liver failure: inflammation, ammonia and cerebral blood flow. J Hepatol 2004;41:613–20. 16. Strauss GI, Christiansen M, Moller K, et al. S-100b and neuron-specific enolase in patients with fulminant hepatic failure. Liver Transpl 2001; 7:964–70. 17. Kimberly HH, Shah S, Marill K, et al. Correlation of optic nerve sheath diameter with direct measurement of intracranial pressure. Acad Emerg Med 2008;15:201–4. 18. Verlhac S. Transcranial Doppler in children. Pediatr Radiol 2011;41 (suppl 1):S153–65.
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n this issue of the Journal of Pediatric Gastroenterology and Nutrition (JPGN), Quitadamo et al (1) reports on a survey performed in 2009 about the low compliance of guidelines by European pediatricians with the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN)/European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) guidelines for gastroesophageal reflux (GER) applied to children with symptoms of GER. In particular, the general pediatricians underused the recommended diagnostic tests, such as pH probe, impedance, and upper gastrointstinal (GI) endoscopy, and overused proton pump inhibitors. These problems are attributed to practitioners’ ignoring the recommended guidelines. The ignorance of the guidelines is certainly a part of the problem, but it is not the whole story. Lack of compliance with clinical practice guidelines may be widespread for 3 reasons: guidelines may not be well publicized, guidelines may change radically in a short period, and competing guidelines may exist (2). The first 2 refer to the 2009 NASPGHAN/ESPGHAN GER disease (GERD) guidelines (3), and the third one does not. These guidelines were published only in JPGN, a subspecialty publication. The NASPGHAN/ESPGHAN guidelines are in stark contrast to the American Academy of Pediatrics (AAP) clinical practice guidelines, which are widely publicized by the AAP in multiple venues including Pediatrics, AAP News, online, and in the lay press. The second problem is the change in clinical practice guidelines. Of course, when new science becomes available, clinical practice guidelines must change. The fact that the 2009 GER guidelines differ radically from the 2001 guidelines on the same subject, also published in JPGN (4), is, however, not immediately apparent upon casual reading of the 2 sets of guidelines. The 2009 guidelines make several recommendations that attempt to limit the overuse of proton pump inhibitors because of the studies documenting the lack of efficacy of these medications for infant crying (5,6); however, nowhere are the changes emphasized. For example, the 2001 guidelines state, ‘‘Empiric medical therapy. A trial of time limited medical therapy for GER is useful for determining if GER is Received August 22, 2013; accepted November 25, 2013. From the Good Samaritan Hospital, San Jose, CA. Address correspondence and reprint requests to Marjorie McCracken, MD, PhD, Good Samaritan Hospital, San Jose, CA (e-mail: margemccr@ gmail.com). The author reports no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000264
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Invited Commentaries causing a specific symptom’’ and ‘‘The infant with recurrent crying and irritability. . .expert opinion suggests two diagnostic and treatment strategies. Empiric treatment with either a sequential or simultaneous two-week trial of a hypoallergenic formula and acid suppression may be initiated.’’ In contrast, the 2009 recommendations state: ‘‘There is no evidence to support an empiric trial of acid suppression as a diagnostic test in infants and young children where symptoms suggestive of GERD are less specific,’’ and ‘‘Infants with unexplained crying and/or distressed behavior. . . there is no evidence to support empiric use of acid suppression for the treatment of irritable infants. . . a time limited trial of antisecretory therapy may be considered, but there is potential risk of adverse effects.’’ The consequences of these changes in the recommendations are huge. Instead of the simple treatment trial previously suggested, the invasive testing is recommended before the use of proton pump inhibitors in all but older children and teenagers. This is not emphasized in the 2009 guidelines. Instead, the differences are buried in the text. A pediatrician could be forgiven for not realizing how radical the differences truly are. Even when the guidelines are known, they may not be followed because they are perceived as impractical. That this problem applies to the 2009 GER guidelines is clearly demonstrated in the survey, which showed, ‘‘48% prescribed PPIs in children younger than 8–12 years with vomiting and heartburn without specific testing’’ and ‘‘9.7% use esophageal and gastric ultrasound to diagnose gastroesophageal reflux despite a specificity of only 11% for this test.’’ General pediatricians see many infants and children who are not seriously ill, but have complaints compatible with GERD. The empiric use of proton pump inhibitors undoubtedly reflects the doctors’ desire to help these patients without subjecting them to invasive testing not justified by their perceived relatively minor symptoms. This consideration probably also applies to the use of ultrasound as a diagnostic tool. In the United States, pediatricians frequently use upper GI series for the same purpose. There is also a problem of access. The recommended testing for GERD (pH probe, impedance, or upper GI endoscopy) can only be done by pediatric gastroenterologists. Minor symptoms do not warrant referral to a subspecialist, and in many areas subspecialty referral may be difficult because of lack of access and long wait times for appointments. Guidelines may not be followed because of patient and/or parental pressure for a solution to the problem. Parents want their children’s distress to be eliminated and frequently request medication. They are often understandably reluctant to subject their children to uncomfortable invasive testing unless such testing is clearly necessary. Finally, there is sometimes outright disagreement with clinical practice guidelines (2). That happens when there are competing guidelines (not the case here) or when guidelines are perceived as being influenced by conflicts of interest such as the authors receiving money from drug and/or device manufacturers or the sponsoring society being influenced by a desire to save money (2). It is not possible to tell from the survey whether European pediatricians disagree with our guidelines. The guidelines were, however, clearly generated ethically using good science, so they should not be perceived as having conflicts of interest. In summary, I believe the major barriers to general pediatricians’ implementation of the 2009 NASPGHAN/ESPGHAN clinical practice guidelines for GER are ignorance because of lack of publicity for the guidelines, and lack of clarity about guideline changes and the perceived impracticality of some of the recommendations. We may be able to alleviate these problems by widely publicizing our guidelines in multiple venues and, when changing the guidelines, emphasizing the major changes and the reasons for
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them upfront. Furthermore, the practicality of the guidelines should be a consideration when generating them.
REFERENCES 1. Quitadamo P, Papadopoulou A, Wenzl T, et al. European pediatricians’ approach to children with GER symptoms: survey of the implementation of 2009 NASPGHAN-ESPGHAN guidelines. J Pediatr Gastroenterol Nutr 2014;58:505–9. 2. Fletcher R, Clinical practice guidelines. www.uptodate.com. Accessed June 1, 2013. 3. Vandenplas Y, Rudolph C, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendation of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroenterol Nutr 2009;49:498–547. 4. Rudolph C, Mazur L, Liptak G, et al. Guidelines for the evaluation and treatment of gastroesophageal reflux in infants and children, recommendations of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr 2001;32(suppl 2):S1–31. 5. Orenstein SR, Hassel E, Furmaga-Jablonska W, et al. Multicenter, double-blind, placebo-controlled trial assessing efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease. J Pediatr 2009;154:514–20. 6. Moore DJ, Tao BS, Lines DR, et al. Double-blind placebo-controlled trial of omeprazole in irritable infants with gastroesophageal reflux. J Pediatr 2003;143:219–23.
Noncompliance With NASPGHANESPGHAN Practice Guidelines for GER in Europe: Is There a Point? M. Michael Thaler See ‘‘Gastroesophageal Reflux Guidelines: The European Experience’’ by McCracken on page 395, and ‘‘European Pediatricians’ Approach to Children With GER Symptoms: Survey of the Implementation of 2009 NASPGHAN-ESPGHAN Guidelines’’ by Quitadamo et al on page 505.
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n 2012, a survey of pediatricians from 11 European countries indicated that a vanishingly small handful (1.8%) of self-selected respondents applied the 2009 NASPGHAN-ESPGHAN clinical practice guidelines for GER. In the previous commentary, McCracken approaches the survey results from a practical perspective by postulating putative barriers to implementation: ignorance of the guidelines owing to inadequate publicity, lack of clarity as a Received November 22, 2013; accepted November 25, 2013. From the Division of Pediatric Gastroenterology, University of CaliforniaSan Francisco. Address correspondence and reprint requests to M. Michael Thaler, MD, Box 0136, University of California-San Francisco, San Francisco, CA 94143 (e-mail: [email protected]). The author reports no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000265
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result of rapid turnover in recommendations, impractical requirements, and parental resistance to recommended diagnostic procedures. McCracken understandably argues that once these obstacles are removed, compliance with the guidelines should improve. These are plausible explanations for the noncompliance, but they cannot be reliably tested. The authors themselves concede that ‘‘the analysis of the questionnaires does not allow us to comment on the reasons for the European pediatricians’ failure to comply with recommendations, and therefore does not suggest specific interventions.’’ Thus, the survey does not offer or suggest trustworthy answers for poor adherence to official guidelines. Nevertheless, the survey is worthy of publication as the results generate interesting and getatable questions. Most notable is the lack of comparative data from nonEuropean settings. Only when similar surveys are conducted in
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Invited Commentaries other contexts can we begin to ask what drives regional differences in diagnostic and therapeutic approaches to common yet vaguely characterized complaints such as ‘‘irritability.’’ For example, what if implementation of guidelines is no better in the United States than in Europe? What if compliance is higher in the United States, but not in Canada or vice versa? What do we find when Argentina is compared with Spain and Brazil compared with Portugal? I believe the answers to these questions are attainable and would shed light on the results of the European survey. With comparable data in hand, we may eventually hope to address larger issues that are beyond the scope of the present survey. These include the influence of traditional practice patterns and national health care systems, the threat of malpractice suits, and the application of the latest advances, on compliance with criterion standard clinical guidelines by pediatric practitioners.
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