Journal of Pediatric Surgery 50 (2015) 74–77
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Nutritional outcomes in survivors of congenital diaphragmatic hernia (CDH)—Factors associated with growth at one year☆,☆☆ Sigrid Bairdain a, Faraz A. Khan a, Jeremy Fisher a, David Zurakowski a,b, Katelyn Ariagno c, Ryan P. Cauley a, Jill Zalieckas a, Jay M. Wilson a, Tom Jaksic a, Nilesh M. Mehta b,d,⁎ a
Department of Pediatric Surgery, Boston Children's Hospital, and Harvard Medical School, Boston, MA, United States Department of Anesthesiology, Perioperative & Pain Medicine, Boston Children's Hospital, and Harvard Medical School, Boston, MA, United States Division of Gastroenterology and Nutrition, Boston Children's Hospital, and Harvard Medical School, Boston, MA, United States d Division of Critical Care Medicine, Boston Children's Hospital, and Harvard Medical School, Boston, MA, United States b c
a r t i c l e
i n f o
Article history: Received 26 September 2014 Accepted 6 October 2014 Key words: Nutrition Congenital diaphragmatic hernia Protein Growth Illness-related malnutrition
a b s t r a c t Background: Malnutrition is prevalent among congenital diaphragmatic hernia (CDH) survivors. We aimed to describe the nutritional status and factors that impact growth over the 12-months following discharge from the pediatric intensive care unit (PICU) in this cohort. Methods: CDH survivors, who were discharged from the PICU from 2000 to 2010 with follow-up of at least 12 months, were included. Nutritional intake, anthropometric, and clinical variables were recorded. Multivariable linear regression was used to determine factors associated with weight-for-age Z-scores (WAZ) at 12 months. Results: Data from 110 infants, 67% male, 50% patch repair, were analyzed. Median (IQR) WAZ for the cohort was −1.4 (−2.4 to −0.3) at PICU discharge and −0.4 (−1.3 to 0.2) at 12-months. The percentage of infants with significant malnutrition (WAZ b −2) decreased from 26% to 8.5% (p b 0.001). Patch repair (p = 0.009), protein intake b 2.3 g/kg/day (p = 0.014), and birth weight (BW) b 2.5 kg (p b 0.001) were associated with lower WAZ at 12-months. Conclusions: CDH survivors had a significantly improved nutritional status in the 12-months after PICU discharge. Patch repair, lower BW, and inadequate protein intake were significant predictors of lower WAZ at 12-months. A minimum protein intake in the PICU of 2.3 g/kg/day was essential to ensure optimal growth in this cohort. © 2015 Elsevier Inc. All rights reserved.
The provision of optimal and timely nutritional therapy is one of the key components of pediatric critical care. Suboptimal nutrient intake in mechanically ventilated children in the pediatric intensive care (PICU) is associated with significant morbidity and mortality [1]. The impact of suboptimal nutrient delivery may be particularly devastating in patient populations with pre-existing malnutrition and illness-related nutritional deterioration. Neonates with congenital diaphragmatic hernia (CDH) are at risk for poor nutrient intake and illness-related worsening of nutritional status during their PICU stay [2,3]. Furthermore, a subset of CDH infants has chronic malnutrition, with approximately 30% presenting with failure to thrive during the first year following discharge [4]. Cohort studies of CDH survivors may elucidate modifiable factors
☆ Podium presenter: Sigrid Bairdain, MD, MPH. ☆☆ Funding disclosure and conflicts of interest: No external funding was secured for this study. The authors have no financial relationships to disclose, as well as no other conflicts of interest to disclose. ⁎ Corresponding author at: Department of Anesthesia, Perioperative and Pain Medicine, Boston Children's Hospital, Division of Critical Care Medicine, Bader 634, 300 Longwood Avenue, Children's Hospital, Boston, MA 02115, United States. Tel.: +1 617 355 7327; fax: +1 617 730 0453. E-mail address: [email protected] (N.M. Mehta). http://dx.doi.org/10.1016/j.jpedsurg.2014.10.003 0022-3468/© 2015 Elsevier Inc. All rights reserved.
that are associated with optimal growth and assist in identifying best practices for this vulnerable patient population [5,6]. In a review of nutritional morbidity in CDH survivors at our institution from 1990 to 2000, 56% of the population was noted to be below the twenty-fifth percentile for weight during the first year of life [3]. We have since implemented a multidisciplinary, consensus-based, step-wise program for nutritional assessment, optimal nutrient delivery and nutritional follow-up after discharge in infants with CDH. In this current study that reviews our CDH cohort over the subsequent decade, we aimed to: 1) describe the nutritional status of survivors with CDH in terms of weight for age Z-scores (WAZ) at the time of PICU discharge, and during outpatient follow-up over 12 months; and, 2) to examine the independent risk factors associated with low WAZ at 12 months following discharge from the PICU. 1. Methods Following institutional review board approval, medical records of all CDH patients discharged from the PICU at Boston Children's Hospital from 2000 to 2010 were reviewed. Patients that died, lost to follow-up prior to 12-months, or who had multiple re-admissions were excluded. Growth parameters were recorded and WAZs were calculated (using
S. Bairdain et al. / Journal of Pediatric Surgery 50 (2015) 74–77
standardized World Health Organization reference data) at the following time points: (a) PICU discharge; (b) hospital discharge; (c) 3-months; (d) 6-months; and (e) 12-months after PICU discharge. Protein intake requirements were estimated utilizing the A.S.P.E.N. Clinical Guidelines for Critically Ill Children [7]. Patients with WAZ b −2.0 were defined as malnourished [8]. WAZ at 12 months was the primary outcome. A repeated, mixed-measured model ANOVA was used to compare median WAZ at each time point compared to baseline [9]. Univariate analysis was used to identify factors associated with WAZ at 12 months. Macronutrients associated with nutritional outcome were identified by the Youden J-index in receiver operating characteristic (ROC) curve analysis [10]. A multivariate linear regression model was used to determine the independent factors associated with low WAZ at 12 months [11]. Statistical analyses were performed using IBM/SPSS Statistics (version 19.0, SPSS Inc./IBM, Chicago, IL). At our institution, infants with CDH are admitted to the pediatric intensive care unit (PICU). A step-wise enteral nutrition advancement algorithm was incorporated after multidisciplinary consensus and based on literature review [12]. A multipronged approach to implement the algorithm, intensive educational efforts, discussion of nutritional strategy on daily rounds, and regular audits to assure adherence to the algorithm were undertaken to maximize the benefits of a uniform approach to nutrient delivery. A dedicated dietitian reviewed the nutritional status, prescribed macronutrient goals and provided support to bedside nurses. Detailed assessment of intake and nutritional status was incorporated as part of a multidisciplinary CDH follow-up clinic for infants discharged from the hospital. 2. Results A total of 201 infants with CDH patients were admitted to the PICU from 2000 to 2010. One hundred ten patients met the inclusion criteria. Patients were excluded from analysis because of in-hospital mortality (n = 39, 19%), death within 1 year (n = 1, 0.5%), or loss to follow-up (n = 51, 25%). Fifty-four patients (50%) received patch repair, 46% were classified as a C/D defect [13], and 25 (23%) patients required ECMO therapy. Inhaled nitric oxide (iNO) was prescribed in 31% of this cohort during PICU stay and oxygen supplementation was required in 34% of the cohort at PICU discharge. Sixty-two percent had medications for GER and 69% were on parenteral nutrition during their PICU stay. At the 3-month follow-up visit, 29 patients (27%) had gastrostomies, and 19 patients (18%) fundoplications (Table 1). Nutritional status (WAZ) and the proportion of patients with malnutrition (WAZ b −2.0) at each time period were recorded. The incidence of malnutrition was 26% at PICU discharge; 38% at hospital discharge; 32% at 3-month visit; 20% at 6-month visit; and, 8.5% at the 12-month visit. We recorded a significant decrease in the incidence of malnutrition from 26% at PICU discharge to 8.5% at the 12-month follow-up (p b 0.001). Median (IQR) WAZ at each time-point was: − 1.4 (− 2.4 to −0.3) at PICU discharge; −1.5 (−2.5 to −0.6) at hospital discharge; −1.4 (−2.5 to −0.5) at 3-month visit; −0.8 (−1.9 to 0.1, p b 0.002) at 6-month visit; and, −0.4 (−1.3 to 0.2, p b 0.001) at the 12-month visit (Fig. 1). WAZ at 6 months (p b 0.002) and 12-months (p b 0.001) visit were significantly higher than that at PICU discharge. Six candidate variables were found to be significantly associated with WAZ at 12 months by univariate analysis. Table 1 illustrates the demographic and clinical variables examined and the results of the univariate analysis. In addition to the variables identified by univariate analysis, we also included gender, nitric oxide therapy, gastroesophageal reflux therapy, fundoplication, gastrostomy, extracorporeal membrane oxygenator (ECMO) therapy, supplemental oxygen, parenteral nutrition, and energy content of formula in the multivariate modeling. Table 2 illustrates the multivariate predictive model for WAZ at 12 months. Patch repair (p = 0.009), protein intake during the PICU course of b 2.3 g/kg/day (p = 0.014), and birth weight b 2.5 kg (p b 0.001) were independent predictors of lower WAZ at 12 months.
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Table 1 Univariate analysis of factors associated with WAZ at 12 months follow-up. Variable Gender Male Female CDH defect size A or B C or D Gestational age, weeks b37 ≥37 Birth weight, kg b2.5 ≥2.5 ECMO Yes No Repair type Primary Patch Parenteral nutrition Yes No Pulmonary HTN at PICU discharge Yes No Oxygen at PICU discharge Yes No Diuretics at PICU discharge Yes No GERD therapy at PICU discharge Yes No Nitric oxide within PICU Yes No PICU Formula Content, kcal/oz. b34 ≥34 Protein intake during PICU stay, g/kg/d b2.3 ≥2.3 Gastrostomy, 3 month visit Yes No Fundoplication, 3 month visit Yes No
N (%)
WAZ (mean ± SD)
p Value 0.24
72 (67) 35 (33)
−0.61 ± 1.23 −0.32 ± 1.08
58 (54) 49 (46)
−0.44 ± 1.31 −0.60 ± 1.01
25 (23) 82 (77)
−1.10 ± 1.54 −0.34 ± 1.00
0.50
0.005⁎
0.004⁎ 16 (15) 91 (85)
−1.29 +/−1.70 −0.38 +/−1.02 0.80
25 (23) 82 (77)
−0.46 ± 1.05 −0.53 ± 1.23
53 (50) 54 (50)
−0.19 ± 1.12 −0.83 ± 1.17
75 (69) 32 (31)
−0.60 ± 1.17 −0.32 ± 1.22
58 (54) 49 (46)
−0.60 ± 1.07 −0.42 ± 1.31
36 (34) 71 (66)
−0.90 ± 1.45 −0.32 ± 0.98
58 (54) 49 (46)
−0.63 ± 1.17 −0.38 ± 1.20
63 (62) 39 (38)
−0.78 ± 1.24 −0.10 ± 0.93
33 (31) 74 (69)
−0.45 ± 0.97 −0.54 ± 1.27
74 (73) 29 (27)
−0.53 ± 1.26 −0.60 ± 0.94
60 (59) 41 (41)
−0.75 ± 1.18 −0.28 ± 1.14
29 (27) 78 (73)
−0.77 ± 1.36 −0.42 ± 1.11
19 (18) 88 (82)
−0.58 ± 1.14 −0.50 ± 1.20
0.005⁎
0.25
0.45
0.04⁎
0.30
0.002⁎
0.72
0.78
0.05⁎
0.17
0.80
PICU = pediatric intensive care unit; WAZ = weight-for-age Z-scores; Pulmonary HTN = pulmonary hypertension. ⁎ Statistically significant by Student t-test.
3. Discussion We have described a quality improvement initiative at our institution where a multidisciplinary effort to standardize nutrition assessment and delivery was effective in improving nutritional status in infants with CDH. Over a decade after its implementation, we observed an overall improvement in WAZ during the first year after PICU discharge in this vulnerable cohort. By the 12-month visit, not only had the median WAZ increased significantly, but also the proportion of infants with malnutrition was significantly reduced. Birth weight (BW) and need for patch repair were strong predictors of lower WAZ at 12 months. Protein intake during the PICU stay was an important modifiable factor associated with WAZ at 12 months. Our results suggest that a minimum of 2.3 g/kg/day of protein intake during the initial hospitalization may be necessary for optimal growth and nutrition status in survivors of CDH.
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S. Bairdain et al. / Journal of Pediatric Surgery 50 (2015) 74–77 Table 2 Multivariate predictive model—WAZ at 12 months (stratified by birth weight) in relation to type of CDH repair and protein intake within PICU stay. Surgical and nutritional management factors
WAZ at 12 months (95% CI)
Repair type
Protein intake (g/kg/day)
Birth weight b2.5 kg
Birth Weight ≥2.5 kg
Patch Patch Primary Primary
b2.3 ≥2.3 b2.3 ≥2.3
−2.06 (−2.76, −1.37) −1.49 (−2.12, −0.86) −1.47 (−2.15, −0.80) −0.90 (−1.56, −0.23)
−0.98 (−1.36, −0.60) −0.40 (−0.81, 0.01) −0.39 (−0.73, −0.04) 0.20 (−0.26, 0.64)
WAZ = weight-for-age Z-scores; g/kg/day = grams per kilogram per day; CI = confidence interval.
Fig. 1. Box-and-whisker plots illustrating the median WAZ scores in congenital diaphragmatic hernia survivors. Footnote: Horizontal line represents the median value for WAZ, length of the box denotes the interquartile range, and whiskers represent the range.
Weight for age z-score (WAZ) was used as a marker of nutritional status in our study. Z-scores are now recommended by the WHO when describing anthropometric parameters within groups of subjects [14]. Z-scores describe nutritional status and growth more precisely than percentile curves. Nutritional rehabilitation and the ability to achieve catch-up growth are important outcomes and may predict long-term survival in infants and children with critical illness. For example, in infants undergoing cardiac surgery for congenital heart disease, the odds of late mortality were significantly related to a decrease in WAZ of ≥0.67 in the first 6 months after surgery [15]. In our current cohort of infants with CDH, WAZ scores improved significantly between discharge and 6-months, and again by 12-months. A similar trend toward “catch-up growth” in CDH survivors was previously reported from our institution over a decade ago. However, in that cohort, mean WAZ remained below − 2 at 12-months [3]. Thus, while both studies demonstrated the ability of growth to rebound after prolonged illness, this current cohort appeared to have much improved nutritional status at 12 months after discharge. The reasons for the improvement in nutritional outcomes are likely multifactorial. A number of advances in both inpatient and outpatient care, including the refinement of the multidisciplinary care approach, may have contributed. Of the factors during the PICU course that were evaluated in our study, univariate analysis revealed that low gestational age, BW, patch repair, low daily protein intake, as well as oxygen therapy and gastric acid suppression were significantly associated with lower WAZ at 12 months. In accordance with other studies, low BW strongly predicts low WAZ at 12 months [16]. Gastroesophageal reflux (GER) correlates with patch repair, and has been associated with nutritional morbidity in CDH infants [17–19]. The severity of GER in infants with CDH and its relationship to growth failure have prompted the practice of “prophylactic fundoplications” in this group [20]. Our study was not adequately powered to assess the effectiveness of gastrostomy or fundoplication on growth. The presence of oxygen therapy at PICU discharge was also associated with lower WAZ in our current cohort study. The association between the need for supplemental oxygen therapy and negative long-term nutritional and non-nutritional outcomes in CDH patients has been previously reported from our institution [21]. ECMO therapy and oxygen therapy at discharge were strong predictors of growth failure in CDH survivors [3]. The effectiveness of oxygen supplementation on growth needs to be further studied. The single modifiable factor associated with higher WAZ was the provision of protein above a threshold level during the PICU stay. Protein catabolism is the hallmark of the metabolic stress response and may result in loss of lean body mass with potential for short and long-
term morbidity. Adequate protein provision is essential for the preservation of skeletal muscle and may potentially improve outcomes in this group [22]. Though recent studies have attempted to establish the optimal requirements of protein for the critically ill patient, current recommendations are not uniform. We have previously shown that a minimum protein intake of 1.5 g/kg/day is required to achieve a positive nitrogen balance in critically-ill children; with up to 2.0 g/kg/day required for those on extracorporeal membrane oxygenator (ECMO) therapy [23]. Despite these benchmarks, many patients are prescribed or receive substantially less protein and thus may be a greater risk of catabolism and its attendant morbidity. In our multicenter study of mechanically-ventilated patients from over 30 centers, mean daily protein intake was less than 50% of the prescribed goal [1]. Newborn infants are at risk because of their relatively lower proportion of lean body mass and hence cannot afford further depletion of lean body mass from suboptimal nutrient intake [24]. Infants with CDH, in particular, are at risk of suboptimal nutrient delivery because of increased catabolism, fluid restriction, prolonged mechanical ventilation, and inappropriate caloric and protein provisions. Based on the results of the current study, strategies to optimize protein intake in infants with CDH may help improve long-term nutritional outcomes. No obvious deleterious effects of adequate protein prescription were observed in this cohort. A prospective study with careful monitoring of protein status that also incorporates long term clinical, body composition and cognitive outcomes may better define the ideal protein allotments for this at risk patient population. Despite the longitudinal nature, this study does have some limitations. It was retrospective and hence accurate energy intake on all patients was not readily available during the follow-up period. Although this is a relatively large cohort, the sample size from a single-center limits its power to examine more detailed statistical relationships. These results may not be generalizable to all centers because certain practices were site-specific. Furthermore, a significant number of patients were lost to follow-up during the 12 months (25%) probably because of a widespread referral base. Given the relative rarity of CDH, the findings of this investigation would be best confirmed with large multicenter study.
4. Conclusion The nutritional status of CDH survivors at our institution improved significantly in the 12-months following PICU discharge. Lower BW and patch repair were significant independent predictors of lower WAZ at 12 months. Protein intake of at least 2.3 g/kg/day during their initial PICU course was a significant predictor of improved WAZ at 12 months. The provision of optimal protein at this level is thus a potentially important nutritional intervention in neonates with CDH. Its impact on body composition and functional outcomes in this population needs to be investigated.
S. Bairdain et al. / Journal of Pediatric Surgery 50 (2015) 74–77
Appendix A. Discussion Presented by Sigrid Bairdain, Boston, MA BRAD WARNER (St. Louis, MO): Congratulations. That is a beautiful study. I really think that the nutritional sort of support of our patients is really critical. I had a question though. In sepsis and other catabolic surgical states, there seems to be an obligatory protein catabolic effect that is not reversed with protein and not reversed with any type of really nutritional support. I think the best you can do is keep up with it. Are there other metabolic parameters that you think might be more important because it seems like no matter how much protein or how much nutritional support you provide there is an obligatory catabolic insult that you cannot reverse. SIGRID BAIRDAIN: Thank you for your question. I think that brings up one that point has been pervasive through this conference, as far as identifying which patients that we can actually improve. I think from my experience there have been three types of patients that I have seen: one, has acute inflammation during the ICU which you can reverse; two, patients that have fixed lesions that end up dying in the ICU; and three, the patients that end up transitioning from an acute inflammation to chronic inflammation. In hindsight I think we should have looked at markers better in the ICU to be able to determine which of those patients are the ones that are going to transition to the chronic inflammation over time. I think that is slightly shown by those patients who drop in between PICU and hospital discharge because they have less supportive care on the floor and those are probably the patients that we need to target better. AGOSTINO PIERRO (Toronto, ON): I enjoyed your paper. Thank you very much. One of the critical issues is the neurodevelopmental outcome. I wonder if you have any data on the head circumference because this is correlated with the brain growth. One of the major things of nutrition, particularly in the very rapid growth of the brain, is the initial stages in the neonatal period. Do you have any data on that? SIGRID BAIRDAIN: Great question. This was actually one of the initial parts of our study; however, given the retrospective component to the study itself, we had a hard time getting at every time point head circumference let alone just weights and heights and lengths. As part of our QI part to this study, we've educated both our ICU as well as our outpatient center to include head circumferences because that actually is the most important determinant of growth within the first year.
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References [1] Mehta NM, Bechard LJ, Cahill N, et al. Nutritional practices and their relationship to clinical outcomes in critically ill children—an international multicenter cohort study. Crit Care Med 2012;40:2204–11. [2] Peetsold MG, Heij HA, Kneepkens CM, et al. The long-term follow-up of patients with a congenital diaphragmatic hernia: a broad spectrum of morbidity. Pediatr Surg Int 2009;25:1–17. [3] Muratore CS, Utter S, Jaksic T, et al. Nutritional morbidity in survivors of congenital diaphragmatic hernia. J Pediatr Surg 2001;36:1171–6. [4] Bagolan P, Morini F. Long-term follow up of infants with congenital diaphragmatic hernia. Semin Pediatr Surg 2007;16:134–44. [5] Odibo AO, Najaf T, Vachharajani A, et al. Predictors of the need for extracorporeal membrane oxygenation and survival in congenital diaphragmatic hernia: a center's 10-year experience. Prenat Diagn 2010;30:518–21. [6] Kays DW, Islam S, Larson SD, et al. Long-term maturation of congenital diaphragmatic hernia treatment results: toward development of a severity-specific treatment algorithm. Ann Surg 2013;258:638–44 [discussion 644–635]. [7] Mehta NM, Compher C. A.s.p.e.N. Clinical guidelines: nutrition support of the critically ill child. JPEN J Parenter Enteral Nutr 2009;33:260–76. [8] de Onis M, Onyango AW. WHO child growth standards. Lancet 2008;371:204. [9] Vittinghoff E, Glidden DV, Shoboski SC, et al. Linear, logistic, survival and repeated measures model. New York: Springer; 2005. [10] Zhou XH, Obuchowski NA, McClish DK. Statistical methods in diagnostic medicine. New York: John Wiley & Sons; 2011. [11] Katz MH. Multivariable analysis: a practical guide for clinicians and public health researchers. New York: Cambridge University Press; 2011. [12] Hamilton S, McAleer D, Ariagno K, et al. A stepwise enteral nutrition algorithm for critically ill children helps achieve nutrient delivery goals. Pediatr Crit Care Med 2014;15(17):583–9. [13] Lally KP, Lasky RE, Lally PA, et al. Standardized reporting for congenital diaphragmatic hernia—an international consensus. J Pediatr Surg 2013;48:2408–15. [14] Mehta NM, Corkins MR, Lyman B, et al. Defining pediatric malnutrition: a paradigm shift toward etiology-related definitions. JPEN J Parenter Enteral Nutr 2013;37:460–81. [15] Eskedal LT, Hagemo PS, Seem E, et al. Impaired weight gain predicts risk of late death after surgery for congenital heart defects. Arch Dis Child 2008;93:495–501. [16] Landmann E, Reiss I, Misselwitz B, et al. Ponderal index for discrimination between symmetric and asymmetric growth restriction: percentiles for neonates from 30 weeks to 43 weeks of gestation. J Matern Fetal Neonatal Med 2006;19:157–60. [17] Koot VC, Bergmeijer JH, Bos AP, et al. Incidence and management of gastroesophageal reflux after repair of congenital diaphragmatic hernia. J Pediatr Surg 1993;28:48–52. [18] Kieffer J, Sapin E, Berg A, et al. Gastroesophageal reflux after repair of congenital diaphragmatic hernia. J Pediatr Surg 1995;30:1330–3. [19] Fasching G, Huber A, Uray E, et al. Gastroesophageal reflux and diaphragmatic motility after repair of congenital diaphragmatic hernia. Eur J Pediatr Surg 2000;10:360–4. [20] Dariel A, Roze JC, Piloquet H, et al. Impact of prophylactic fundoplication on survival without growth disorder in left congenital diaphragmatic hernia requiring a patch repair. J Pediatr 2010;157:688–90 [690 e681]. [21] Cauley RP, Stoffan A, Potanos K, et al. Pulmonary support on day 30 as a predictor of morbidity and mortality in congenital diaphragmatic hernia. J Pediatr Surg 2013;48: 1183–9. [22] Agus MS, Javid PJ, Piper HG, et al. The effect of insulin infusion upon protein metabolism in neonates on extracorporeal life support. Ann Surg 2006;244:536–44. [23] Bechard LJ, Parrott JS. Mehta NM: Systematic review of the influence of energy and protein intake on protein balance in critically ill children. Pediatr 2012;161(2): 333–339.e1. http://dx.doi.org/10.1016/j.jpeds.2012.01.046 [Epub 2012 Mar 7]. [24] Hulst JM, van Goudoever JB, Zimmermann LJ, et al. The effect of cumulative energy and protein deficiency on anthropometric parameters in a pediatric ICU population. Clin Nutr 2004;23:1381–9.
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Nutritional outcomes in survivors of congenital diaphragmatic hernia (CDH)—Factors associated with growth at one year☆,☆☆ Sigrid Bairdain a, Faraz A. Khan a, Jeremy Fisher a, David Zurakowski a,b, Katelyn Ariagno c, Ryan P. Cauley a, Jill Zalieckas a, Jay M. Wilson a, Tom Jaksic a, Nilesh M. Mehta b,d,⁎ a
Department of Pediatric Surgery, Boston Children's Hospital, and Harvard Medical School, Boston, MA, United States Department of Anesthesiology, Perioperative & Pain Medicine, Boston Children's Hospital, and Harvard Medical School, Boston, MA, United States Division of Gastroenterology and Nutrition, Boston Children's Hospital, and Harvard Medical School, Boston, MA, United States d Division of Critical Care Medicine, Boston Children's Hospital, and Harvard Medical School, Boston, MA, United States b c
a r t i c l e
i n f o
Article history: Received 26 September 2014 Accepted 6 October 2014 Key words: Nutrition Congenital diaphragmatic hernia Protein Growth Illness-related malnutrition
a b s t r a c t Background: Malnutrition is prevalent among congenital diaphragmatic hernia (CDH) survivors. We aimed to describe the nutritional status and factors that impact growth over the 12-months following discharge from the pediatric intensive care unit (PICU) in this cohort. Methods: CDH survivors, who were discharged from the PICU from 2000 to 2010 with follow-up of at least 12 months, were included. Nutritional intake, anthropometric, and clinical variables were recorded. Multivariable linear regression was used to determine factors associated with weight-for-age Z-scores (WAZ) at 12 months. Results: Data from 110 infants, 67% male, 50% patch repair, were analyzed. Median (IQR) WAZ for the cohort was −1.4 (−2.4 to −0.3) at PICU discharge and −0.4 (−1.3 to 0.2) at 12-months. The percentage of infants with significant malnutrition (WAZ b −2) decreased from 26% to 8.5% (p b 0.001). Patch repair (p = 0.009), protein intake b 2.3 g/kg/day (p = 0.014), and birth weight (BW) b 2.5 kg (p b 0.001) were associated with lower WAZ at 12-months. Conclusions: CDH survivors had a significantly improved nutritional status in the 12-months after PICU discharge. Patch repair, lower BW, and inadequate protein intake were significant predictors of lower WAZ at 12-months. A minimum protein intake in the PICU of 2.3 g/kg/day was essential to ensure optimal growth in this cohort. © 2015 Elsevier Inc. All rights reserved.
The provision of optimal and timely nutritional therapy is one of the key components of pediatric critical care. Suboptimal nutrient intake in mechanically ventilated children in the pediatric intensive care (PICU) is associated with significant morbidity and mortality [1]. The impact of suboptimal nutrient delivery may be particularly devastating in patient populations with pre-existing malnutrition and illness-related nutritional deterioration. Neonates with congenital diaphragmatic hernia (CDH) are at risk for poor nutrient intake and illness-related worsening of nutritional status during their PICU stay [2,3]. Furthermore, a subset of CDH infants has chronic malnutrition, with approximately 30% presenting with failure to thrive during the first year following discharge [4]. Cohort studies of CDH survivors may elucidate modifiable factors
☆ Podium presenter: Sigrid Bairdain, MD, MPH. ☆☆ Funding disclosure and conflicts of interest: No external funding was secured for this study. The authors have no financial relationships to disclose, as well as no other conflicts of interest to disclose. ⁎ Corresponding author at: Department of Anesthesia, Perioperative and Pain Medicine, Boston Children's Hospital, Division of Critical Care Medicine, Bader 634, 300 Longwood Avenue, Children's Hospital, Boston, MA 02115, United States. Tel.: +1 617 355 7327; fax: +1 617 730 0453. E-mail address: [email protected] (N.M. Mehta). http://dx.doi.org/10.1016/j.jpedsurg.2014.10.003 0022-3468/© 2015 Elsevier Inc. All rights reserved.
that are associated with optimal growth and assist in identifying best practices for this vulnerable patient population [5,6]. In a review of nutritional morbidity in CDH survivors at our institution from 1990 to 2000, 56% of the population was noted to be below the twenty-fifth percentile for weight during the first year of life [3]. We have since implemented a multidisciplinary, consensus-based, step-wise program for nutritional assessment, optimal nutrient delivery and nutritional follow-up after discharge in infants with CDH. In this current study that reviews our CDH cohort over the subsequent decade, we aimed to: 1) describe the nutritional status of survivors with CDH in terms of weight for age Z-scores (WAZ) at the time of PICU discharge, and during outpatient follow-up over 12 months; and, 2) to examine the independent risk factors associated with low WAZ at 12 months following discharge from the PICU. 1. Methods Following institutional review board approval, medical records of all CDH patients discharged from the PICU at Boston Children's Hospital from 2000 to 2010 were reviewed. Patients that died, lost to follow-up prior to 12-months, or who had multiple re-admissions were excluded. Growth parameters were recorded and WAZs were calculated (using
S. Bairdain et al. / Journal of Pediatric Surgery 50 (2015) 74–77
standardized World Health Organization reference data) at the following time points: (a) PICU discharge; (b) hospital discharge; (c) 3-months; (d) 6-months; and (e) 12-months after PICU discharge. Protein intake requirements were estimated utilizing the A.S.P.E.N. Clinical Guidelines for Critically Ill Children [7]. Patients with WAZ b −2.0 were defined as malnourished [8]. WAZ at 12 months was the primary outcome. A repeated, mixed-measured model ANOVA was used to compare median WAZ at each time point compared to baseline [9]. Univariate analysis was used to identify factors associated with WAZ at 12 months. Macronutrients associated with nutritional outcome were identified by the Youden J-index in receiver operating characteristic (ROC) curve analysis [10]. A multivariate linear regression model was used to determine the independent factors associated with low WAZ at 12 months [11]. Statistical analyses were performed using IBM/SPSS Statistics (version 19.0, SPSS Inc./IBM, Chicago, IL). At our institution, infants with CDH are admitted to the pediatric intensive care unit (PICU). A step-wise enteral nutrition advancement algorithm was incorporated after multidisciplinary consensus and based on literature review [12]. A multipronged approach to implement the algorithm, intensive educational efforts, discussion of nutritional strategy on daily rounds, and regular audits to assure adherence to the algorithm were undertaken to maximize the benefits of a uniform approach to nutrient delivery. A dedicated dietitian reviewed the nutritional status, prescribed macronutrient goals and provided support to bedside nurses. Detailed assessment of intake and nutritional status was incorporated as part of a multidisciplinary CDH follow-up clinic for infants discharged from the hospital. 2. Results A total of 201 infants with CDH patients were admitted to the PICU from 2000 to 2010. One hundred ten patients met the inclusion criteria. Patients were excluded from analysis because of in-hospital mortality (n = 39, 19%), death within 1 year (n = 1, 0.5%), or loss to follow-up (n = 51, 25%). Fifty-four patients (50%) received patch repair, 46% were classified as a C/D defect [13], and 25 (23%) patients required ECMO therapy. Inhaled nitric oxide (iNO) was prescribed in 31% of this cohort during PICU stay and oxygen supplementation was required in 34% of the cohort at PICU discharge. Sixty-two percent had medications for GER and 69% were on parenteral nutrition during their PICU stay. At the 3-month follow-up visit, 29 patients (27%) had gastrostomies, and 19 patients (18%) fundoplications (Table 1). Nutritional status (WAZ) and the proportion of patients with malnutrition (WAZ b −2.0) at each time period were recorded. The incidence of malnutrition was 26% at PICU discharge; 38% at hospital discharge; 32% at 3-month visit; 20% at 6-month visit; and, 8.5% at the 12-month visit. We recorded a significant decrease in the incidence of malnutrition from 26% at PICU discharge to 8.5% at the 12-month follow-up (p b 0.001). Median (IQR) WAZ at each time-point was: − 1.4 (− 2.4 to −0.3) at PICU discharge; −1.5 (−2.5 to −0.6) at hospital discharge; −1.4 (−2.5 to −0.5) at 3-month visit; −0.8 (−1.9 to 0.1, p b 0.002) at 6-month visit; and, −0.4 (−1.3 to 0.2, p b 0.001) at the 12-month visit (Fig. 1). WAZ at 6 months (p b 0.002) and 12-months (p b 0.001) visit were significantly higher than that at PICU discharge. Six candidate variables were found to be significantly associated with WAZ at 12 months by univariate analysis. Table 1 illustrates the demographic and clinical variables examined and the results of the univariate analysis. In addition to the variables identified by univariate analysis, we also included gender, nitric oxide therapy, gastroesophageal reflux therapy, fundoplication, gastrostomy, extracorporeal membrane oxygenator (ECMO) therapy, supplemental oxygen, parenteral nutrition, and energy content of formula in the multivariate modeling. Table 2 illustrates the multivariate predictive model for WAZ at 12 months. Patch repair (p = 0.009), protein intake during the PICU course of b 2.3 g/kg/day (p = 0.014), and birth weight b 2.5 kg (p b 0.001) were independent predictors of lower WAZ at 12 months.
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Table 1 Univariate analysis of factors associated with WAZ at 12 months follow-up. Variable Gender Male Female CDH defect size A or B C or D Gestational age, weeks b37 ≥37 Birth weight, kg b2.5 ≥2.5 ECMO Yes No Repair type Primary Patch Parenteral nutrition Yes No Pulmonary HTN at PICU discharge Yes No Oxygen at PICU discharge Yes No Diuretics at PICU discharge Yes No GERD therapy at PICU discharge Yes No Nitric oxide within PICU Yes No PICU Formula Content, kcal/oz. b34 ≥34 Protein intake during PICU stay, g/kg/d b2.3 ≥2.3 Gastrostomy, 3 month visit Yes No Fundoplication, 3 month visit Yes No
N (%)
WAZ (mean ± SD)
p Value 0.24
72 (67) 35 (33)
−0.61 ± 1.23 −0.32 ± 1.08
58 (54) 49 (46)
−0.44 ± 1.31 −0.60 ± 1.01
25 (23) 82 (77)
−1.10 ± 1.54 −0.34 ± 1.00
0.50
0.005⁎
0.004⁎ 16 (15) 91 (85)
−1.29 +/−1.70 −0.38 +/−1.02 0.80
25 (23) 82 (77)
−0.46 ± 1.05 −0.53 ± 1.23
53 (50) 54 (50)
−0.19 ± 1.12 −0.83 ± 1.17
75 (69) 32 (31)
−0.60 ± 1.17 −0.32 ± 1.22
58 (54) 49 (46)
−0.60 ± 1.07 −0.42 ± 1.31
36 (34) 71 (66)
−0.90 ± 1.45 −0.32 ± 0.98
58 (54) 49 (46)
−0.63 ± 1.17 −0.38 ± 1.20
63 (62) 39 (38)
−0.78 ± 1.24 −0.10 ± 0.93
33 (31) 74 (69)
−0.45 ± 0.97 −0.54 ± 1.27
74 (73) 29 (27)
−0.53 ± 1.26 −0.60 ± 0.94
60 (59) 41 (41)
−0.75 ± 1.18 −0.28 ± 1.14
29 (27) 78 (73)
−0.77 ± 1.36 −0.42 ± 1.11
19 (18) 88 (82)
−0.58 ± 1.14 −0.50 ± 1.20
0.005⁎
0.25
0.45
0.04⁎
0.30
0.002⁎
0.72
0.78
0.05⁎
0.17
0.80
PICU = pediatric intensive care unit; WAZ = weight-for-age Z-scores; Pulmonary HTN = pulmonary hypertension. ⁎ Statistically significant by Student t-test.
3. Discussion We have described a quality improvement initiative at our institution where a multidisciplinary effort to standardize nutrition assessment and delivery was effective in improving nutritional status in infants with CDH. Over a decade after its implementation, we observed an overall improvement in WAZ during the first year after PICU discharge in this vulnerable cohort. By the 12-month visit, not only had the median WAZ increased significantly, but also the proportion of infants with malnutrition was significantly reduced. Birth weight (BW) and need for patch repair were strong predictors of lower WAZ at 12 months. Protein intake during the PICU stay was an important modifiable factor associated with WAZ at 12 months. Our results suggest that a minimum of 2.3 g/kg/day of protein intake during the initial hospitalization may be necessary for optimal growth and nutrition status in survivors of CDH.
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S. Bairdain et al. / Journal of Pediatric Surgery 50 (2015) 74–77 Table 2 Multivariate predictive model—WAZ at 12 months (stratified by birth weight) in relation to type of CDH repair and protein intake within PICU stay. Surgical and nutritional management factors
WAZ at 12 months (95% CI)
Repair type
Protein intake (g/kg/day)
Birth weight b2.5 kg
Birth Weight ≥2.5 kg
Patch Patch Primary Primary
b2.3 ≥2.3 b2.3 ≥2.3
−2.06 (−2.76, −1.37) −1.49 (−2.12, −0.86) −1.47 (−2.15, −0.80) −0.90 (−1.56, −0.23)
−0.98 (−1.36, −0.60) −0.40 (−0.81, 0.01) −0.39 (−0.73, −0.04) 0.20 (−0.26, 0.64)
WAZ = weight-for-age Z-scores; g/kg/day = grams per kilogram per day; CI = confidence interval.
Fig. 1. Box-and-whisker plots illustrating the median WAZ scores in congenital diaphragmatic hernia survivors. Footnote: Horizontal line represents the median value for WAZ, length of the box denotes the interquartile range, and whiskers represent the range.
Weight for age z-score (WAZ) was used as a marker of nutritional status in our study. Z-scores are now recommended by the WHO when describing anthropometric parameters within groups of subjects [14]. Z-scores describe nutritional status and growth more precisely than percentile curves. Nutritional rehabilitation and the ability to achieve catch-up growth are important outcomes and may predict long-term survival in infants and children with critical illness. For example, in infants undergoing cardiac surgery for congenital heart disease, the odds of late mortality were significantly related to a decrease in WAZ of ≥0.67 in the first 6 months after surgery [15]. In our current cohort of infants with CDH, WAZ scores improved significantly between discharge and 6-months, and again by 12-months. A similar trend toward “catch-up growth” in CDH survivors was previously reported from our institution over a decade ago. However, in that cohort, mean WAZ remained below − 2 at 12-months [3]. Thus, while both studies demonstrated the ability of growth to rebound after prolonged illness, this current cohort appeared to have much improved nutritional status at 12 months after discharge. The reasons for the improvement in nutritional outcomes are likely multifactorial. A number of advances in both inpatient and outpatient care, including the refinement of the multidisciplinary care approach, may have contributed. Of the factors during the PICU course that were evaluated in our study, univariate analysis revealed that low gestational age, BW, patch repair, low daily protein intake, as well as oxygen therapy and gastric acid suppression were significantly associated with lower WAZ at 12 months. In accordance with other studies, low BW strongly predicts low WAZ at 12 months [16]. Gastroesophageal reflux (GER) correlates with patch repair, and has been associated with nutritional morbidity in CDH infants [17–19]. The severity of GER in infants with CDH and its relationship to growth failure have prompted the practice of “prophylactic fundoplications” in this group [20]. Our study was not adequately powered to assess the effectiveness of gastrostomy or fundoplication on growth. The presence of oxygen therapy at PICU discharge was also associated with lower WAZ in our current cohort study. The association between the need for supplemental oxygen therapy and negative long-term nutritional and non-nutritional outcomes in CDH patients has been previously reported from our institution [21]. ECMO therapy and oxygen therapy at discharge were strong predictors of growth failure in CDH survivors [3]. The effectiveness of oxygen supplementation on growth needs to be further studied. The single modifiable factor associated with higher WAZ was the provision of protein above a threshold level during the PICU stay. Protein catabolism is the hallmark of the metabolic stress response and may result in loss of lean body mass with potential for short and long-
term morbidity. Adequate protein provision is essential for the preservation of skeletal muscle and may potentially improve outcomes in this group [22]. Though recent studies have attempted to establish the optimal requirements of protein for the critically ill patient, current recommendations are not uniform. We have previously shown that a minimum protein intake of 1.5 g/kg/day is required to achieve a positive nitrogen balance in critically-ill children; with up to 2.0 g/kg/day required for those on extracorporeal membrane oxygenator (ECMO) therapy [23]. Despite these benchmarks, many patients are prescribed or receive substantially less protein and thus may be a greater risk of catabolism and its attendant morbidity. In our multicenter study of mechanically-ventilated patients from over 30 centers, mean daily protein intake was less than 50% of the prescribed goal [1]. Newborn infants are at risk because of their relatively lower proportion of lean body mass and hence cannot afford further depletion of lean body mass from suboptimal nutrient intake [24]. Infants with CDH, in particular, are at risk of suboptimal nutrient delivery because of increased catabolism, fluid restriction, prolonged mechanical ventilation, and inappropriate caloric and protein provisions. Based on the results of the current study, strategies to optimize protein intake in infants with CDH may help improve long-term nutritional outcomes. No obvious deleterious effects of adequate protein prescription were observed in this cohort. A prospective study with careful monitoring of protein status that also incorporates long term clinical, body composition and cognitive outcomes may better define the ideal protein allotments for this at risk patient population. Despite the longitudinal nature, this study does have some limitations. It was retrospective and hence accurate energy intake on all patients was not readily available during the follow-up period. Although this is a relatively large cohort, the sample size from a single-center limits its power to examine more detailed statistical relationships. These results may not be generalizable to all centers because certain practices were site-specific. Furthermore, a significant number of patients were lost to follow-up during the 12 months (25%) probably because of a widespread referral base. Given the relative rarity of CDH, the findings of this investigation would be best confirmed with large multicenter study.
4. Conclusion The nutritional status of CDH survivors at our institution improved significantly in the 12-months following PICU discharge. Lower BW and patch repair were significant independent predictors of lower WAZ at 12 months. Protein intake of at least 2.3 g/kg/day during their initial PICU course was a significant predictor of improved WAZ at 12 months. The provision of optimal protein at this level is thus a potentially important nutritional intervention in neonates with CDH. Its impact on body composition and functional outcomes in this population needs to be investigated.
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Appendix A. Discussion Presented by Sigrid Bairdain, Boston, MA BRAD WARNER (St. Louis, MO): Congratulations. That is a beautiful study. I really think that the nutritional sort of support of our patients is really critical. I had a question though. In sepsis and other catabolic surgical states, there seems to be an obligatory protein catabolic effect that is not reversed with protein and not reversed with any type of really nutritional support. I think the best you can do is keep up with it. Are there other metabolic parameters that you think might be more important because it seems like no matter how much protein or how much nutritional support you provide there is an obligatory catabolic insult that you cannot reverse. SIGRID BAIRDAIN: Thank you for your question. I think that brings up one that point has been pervasive through this conference, as far as identifying which patients that we can actually improve. I think from my experience there have been three types of patients that I have seen: one, has acute inflammation during the ICU which you can reverse; two, patients that have fixed lesions that end up dying in the ICU; and three, the patients that end up transitioning from an acute inflammation to chronic inflammation. In hindsight I think we should have looked at markers better in the ICU to be able to determine which of those patients are the ones that are going to transition to the chronic inflammation over time. I think that is slightly shown by those patients who drop in between PICU and hospital discharge because they have less supportive care on the floor and those are probably the patients that we need to target better. AGOSTINO PIERRO (Toronto, ON): I enjoyed your paper. Thank you very much. One of the critical issues is the neurodevelopmental outcome. I wonder if you have any data on the head circumference because this is correlated with the brain growth. One of the major things of nutrition, particularly in the very rapid growth of the brain, is the initial stages in the neonatal period. Do you have any data on that? SIGRID BAIRDAIN: Great question. This was actually one of the initial parts of our study; however, given the retrospective component to the study itself, we had a hard time getting at every time point head circumference let alone just weights and heights and lengths. As part of our QI part to this study, we've educated both our ICU as well as our outpatient center to include head circumferences because that actually is the most important determinant of growth within the first year.
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