Impact of withholding early parenteral nutrition completing enteral nutrition in pediatric critically ill patients (PEPaNIC trial): study protocol for a randomized controlled trial

The state-of-the-art nutrition used for critically ill children is essentially based on expert opinion, small studies with surrogate endpoints and extrapolations from adult studies or from studies in healthy children outside the ICU. It is widely accepted that in healthy children, nutrition not only serves to maintain body tissues but also allows growth, which is considered of particular importance during infancy and adolescence [1,2]. In hospitalized children, especially in the young, the current European and American guidelines for nutrition recommend early parenteral nutrition (PN) to prevent/correct malnutrition and to sustain appropriate growth when enteral nutrient (EN) supply is insufficient [3,4]. Observational studies suggest that about a quarter of children, most notably infants, admitted to pediatric intensive care units (PICUs) develop a pronounced caloric deficit [1]. The stores of energy, fat and protein in children are limited, leaving children to rely on muscle mass to provide necessary substrates for metabolism. The energy deficit observed with acute critical illness in children has been associated with adverse outcome [5]. Based hereon, it is current practice in PICUs to start PN in the acute phase of critical illness to supplement insufficient EN with the intention to avoid underfeeding [3,4]. However, overfeeding may also be harmful [6-9]. It is difficult to administer the correct amount of nutrition, avoiding overfeeding as well as underfeeding.

It is currently advised to assess energy expenditure considered to reflect energy requirements, through the use of indirect calorimetry during the course of critical illness and to use this technique for determining individualized targets to guide nutritional therapy [10]. However, a European survey conducted in 2004 showed that only 17% of the PICUs use this technique [11] and the technique itself has not been well standardized [12,13]. In the most critically ill, major caveats are present, such as respiratory support with more than 40% oxygen and the use of uncuffed tubes resulting in unpredictable measures. The use of standard equations to predict energy expenditure and/or requirements also carries the risk of overfeeding and underfeeding [14-16].

Experts worldwide agree that there are insufficient data to make evidence-based recommendations for the optimal target of caloric intake in critically ill children and for the optimal time after onset of critical illness by which this target should be reached. The lack of widely accepted caloric targets for critically ill children results in nutritional strategies that vary substantially across centers. The current European and American guidelines for nutrition in hospitalized children recommend PN to prevent or correct malnutrition and to sustain appropriate growth when EN supply is insufficient [10,17]. Most guidelines advise doing this early so that the recommended daily allowances for children are reached on day 2 or 3 after PICU admission. These recommendations are based on evidence from cohort studies without a control group, case series or expert opinion (Grade D level).

The ongoing controversy on optimal amount, composition and timing of administration of PN in critically ill children may in fact conceal the fact that there is no hard evidence for any use of PN in critically ill children. Supported by the results of a Cochrane systematic review, Joffe et al. concluded that randomized trials investigating the role of intravenous nutritional support during the first week of critical illness in children should be performed and should include a control arm in which no nutritional support is administered or hypocaloric goals (below basal metabolic rate) for nutritional support are used [18].

A recent randomized controlled trial (RCT) in critically ill adults [19] showed that the early provision of PN worsened rather than improved outcomes as compared with withholding PN and thus tolerating a substantial caloric deficit up to 1 week in ICU. Also, other studies did not show clinical benefit of early PN in adult ICU patients [20,21]. Hitherto, no well-designed RCT has been performed in critically ill children. The aim of the PEPaNIC trial (the acronym stands for Pediatric version of the effect of Early Parenteral Nutrition to complete insufficient enteral nutrition in ICU patients) is to investigate whether a strategy of withholding PN during the first 7 days in the PICU (late PN) provides clinical benefit over the current practice of early PN in critically ill children. We hypothesize that withholding PN for 1 week in the PICU reduces new infections and shortens the duration of PICU-stay.

This hypothesis is currently being tested in a multicenter superiority RCT performed in three large, tertiary referral PICUs (University Hospitals Leuven, Leuven, Belgium; Erasmus Medical Center, Sophia Children’s Hospital, Rotterdam, The Netherlands; Stollery Children’s Hospital, Edmonton, AB, Canada). The centers were invited to participate based on a self-declared routine use of early PN in the PICU. It was anticipated that this routine use of early PN differs among centers. This was considered to be an asset as it contributes to the external validity of the PEPaNIC trial.

The study protocol and (deferred) informed consent forms were approved by the institutional ethical review boards in Leuven, Belgium (ML8052 Amend-ID0005), Rotterdam, The Netherlands (NL38772.000.12) and Edmonton, AB, Canada (Pro00038098). Informed consent is given in writing by the parents or the legal guardians, confirmed by the child when older than 7 years, after providing all information orally in plain language and in writing. For planned admissions, informed consent is obtained prior to surgery/procedure. For unplanned admissions, informed consent is obtained within 24 hours after admission on the PICU (deferred informed consent as the nutritional therapy should be initiated from PICU admission onward).

Upon admission to the participating PICUs, all critically ill children are screened for nutritional risk and eligibility for inclusion in the PEPaNIC clinical study [22]. All non-eligible patients, identified by the local investigators, are logged.

Critically ill children, newborn to 17 years (inclusive or exclusive depending on the local definition of a pediatric patient) old, with a STRONGkids (Nutritional risk score) score of 2 points or more and who are likely to stay in the PICU for more than 24 hours, are eligible for inclusion [22].

Patients fulfilling one or more of the following criteria are excluded:

At baseline, data on demographic (age, gender, race/ethnicity, (pre-)admission bodyweight and height) and clinical characteristics of the patients are obtained. For all patients, severity of illness scores are calculated such as the PEdiatric Logistic Organ Dysfunction PELOD score and, for cardiac surgery patients, the Risk-Adjustment in Congenital Heart Surgery or RACHS score. The Pediatric RISk of Mortality (PRISM) score cannot be used for this study as the nutritional management is expected to affect the highest blood glucose concentration during the first 24 hours. In addition, co-morbidities prior to admission are noted. These comprise, among others, the presence of a genetic syndrome, gestational age at birth, presence/history of cancer, diabetes mellitus, kidney failure and infection upon admission.

In Leuven, patients in both study groups receive continuous insulin infusion to target blood glucose levels of 50 to 80 mg/dl when aged < 1 year and 70 to 100 mg/dl when aged ≥ 1 year. Blood glucose and potassium are monitored systematically every 1 to 4 hours on the blood gas analyzer (ABL Radiometer, Copenhagen, Denmark) using undiluted arterial blood samples drawn via a VAMP® system (Edwards Lifescience Pontbeekstraat 4 1702 Groot-Bijgaarden), Edwards Lifescience Pontbeekstraat 4 1702 Groot-Bijgaarden [24] and insulin infusion is adjusted when needed.

In Rotterdam, patients in all age groups receive continuous insulin infusion using a step-wise nurse-driven glucose control protocol to target blood glucose levels of 72 to 145 mg/dl, except for patients with traumatic brain injury for whom the target is set at 108 to 145 mg/dl [25]. Blood glucose and potassium are monitored systematically every 1 to 3 hours on the blood gas analyzer (ABL 625; Radiometer, Copenhagen, Denmark) using arterial or capillary blood samples.

In Edmonton, patients in all age groups receive continuous insulin infusion at the discretion of the attending physician when blood glucose levels exceed 180 mg/dl. The attending physician sets the lower target range limit.

Other medical treatments are not described by the study protocol. Patients are weaned from the ventilator and from hemodynamic support according to standardized guidelines used in each participating PICU. End-of-life decisions, when further intensive care is considered to be futile, are taken in consensus by senior PICU physicians and the referring specialist.

Patients who are readmitted to the PICU after a participation in PEPaNIC are not eligible for reinclusion. Patients who are readmitted to the PICU within 48 hours of discharge and who are still within the 7 days’ time window of the initial randomization receive the nutrition strategy they were randomly assigned to during the initial PICU admission. Patients readmitted more than 48 hours after PICU discharge will be fed at the discretion of the attending physician (standard care).

All systemically applied medications received by the patients during the stay in PICU are registered. Every day the quantities of kilocalories, carbohydrates, lipids and proteins delivered by either PN or EN are calculated and entered into the electronic Case Record Form (eCRF). The need for and the number of days of mechanical ventilatory support, of mechanical and pharmacological hemodynamic support, of renal replacement therapies, days on antibiotics and days requiring a central line are recorded. Blood, urine, buccal mucosal swabs and hair samples are taken upon PICU admission and during PICU-stay. Such samples are appropriately handled (collected on ice when required) and immediately stored (at room temperature or at −20°C/−80°C as appropriate) for future measurements. Analyses on blood and urine for the primary clinical analyses include routine chemistry, hematology, and markers of inflammation. Further metabolic, endocrine, inflammatory and (epi)genetic measurements on stored samples in the context of mechanistic analyses are planned. For mechanistic and exploratory studies, ultrasound evaluation of the skeletal muscle, in combination with muscle strength measurements will be performed in a subset of patients [28-30]. Quality of life on admission and after 4 to 6 months is recorded through a validated, semi-structured questionnaire, filled out by the parents, which is repeated at 2 and 4 years after enrollment in the PEPaNIC trial.

Data are collected electronically in an anonymized eCRF, unambiguously linked to the source file. Data are manually transferred and checked for accuracy into the eCRF by the clinical research assistants’ team on a daily basis. Extensive range and consistency checks are performed by the study monitor. All original records, such as consent forms, eCRFs and relevant correspondence, will be archived at the participating centers, according to the local regulations. Vital status at 90 days (and at later follow-up times) will be recorded for all patients, by the National Death Registries. When this information is not available, vital status will be checked through the hospital information system or the regional network of pediatricians and general practitioners.

All data are stored anonymously. Investigators involved in the trial do not have direct access to the database. In addition, the study monitor has logged the use of the database. After the trial, the study monitor will store all data in a secured file that is only accessible by the study monitor himself.

The sponsor (KU Leuven) provides direct access to the eCRF, the source data and the study master file for monitoring, for review by the independent ethics committee and regulatory inspection. The sponsor established an independent data safety monitoring board (DSMB). The sponsor appointed one monitor. The monitor verifies that the trial is performed in accordance to the protocol as described in the European Medicine Agency’s ‘Note for guidance on good clinical practice CPMP/ICH/135/95.’ as well as the Declaration of Helsinki. Monitoring is performed and reported according to the sponsor’s standard operating procedures. The clinical research team guarantees a daily follow-up of patient screening and inclusion, availability of requested clinical data in the clinical patient files and protocol compliance. Non-compliance to the protocol and other questions or problems are reported to the study monitor and discussed with the principal investigators and trial steering committee. SAEs are reported to the study sponsor and, if needed, to the local ethics committee. The study monitor regularly provides the sponsor and the DSMB with reports on inclusions and SAEs. Regular meetings are organized with principal investigators and clinical research teams to discuss the daily progression of the PEPaNIC trial.

The protocol has been instructed in each hospital to all clinical medical and nursing staff through frequent teaching sessions and clinical feedback rounds. The protocol decision support is integrated into the PICU PDMS in Leuven and Rotterdam, facilitating the prescription of the exact amounts of PN and EN according to protocol and clinical evolution.

In order to achieve adequate participant enrollment to reach target sample size, regular meetings and site visits take place every 3 months together with the Rotterdam team and via teleconferences with the Edmonton team.

Regular data auditing is done by the administrative trial team, the DSMB and by the central independent audit procedure in place at the University Hospital of Leuven in compliance with the European Trials Directives.

One Consolidated Standards of Reporting Trials (CONSORT) diagram will be reported.

Protocol compliance will be documented by comparing the actual amounts of PN and EN during the intervention window and this will be reported as absolute numbers of calories and weight units.

For the primary and secondary endpoints taking place during PICU-stay all data will be available. In case of request for discontinuation of the study intervention by patients, parents or legal guardians, this will be respected, but all data will be analyzed. In case of consent withdrawal, the parents will be asked whether the data can be used for analysis. In case this would not be allowed, all data of that patient will be removed from the database, and this will be reported in the CONSORT diagram. At all time, the intention-to-treat principle will be respected and reported. No data imputation will be undertaken for any of the primary or secondary outcomes.

Variables will be summarized as frequencies and percentages, means and standard errors of the means, or medians and interquartile ranges, as appropriate.

Results will be analyzed with the use of chi-square testing, Student’s t-test or non-parametric testing (Wilcoxon rank-sum test, Van der Waerden test or Median test), as appropriate. Kaplan-Meier plots will be used to document time-to-event effects, and the time-to-event effect size will be estimated with the use of Cox proportional-hazard analysis. All time-to-event analyses will also be performed on data censored at 90 days. As death is a competing risk for duration of care outcomes, non-survivors will be censored beyond the longest duration of such care required for survivors [19]. All outcomes will be analyzed both with and without adjustment for baseline risk factors, including the diagnostic and age groups, severity of illness, severity of nutritional risk and center. The latter is considered necessary to account for the differences among centers in nutrition given to the control group and the variation in blood glucose control targets. For these analyses, P-values will be considered significant when at or below 0.05 without correction for multiple comparisons. To assess whether any eventual impact of the intervention on the primary endpoints is affected by the baseline risk factor subgroups, interaction P-values will be calculated (logistic regression or Cox proportional hazard analysis) with a threshold for significance of interaction set at a P-value of < 0.1. All analyses will be conducted on an intention-to-treat basis.

In the design phase of the PEPaNIC trial, and based on the previous adult EPaNIC trial results, the sample size (N = 1,440, 720 patients per arm) was determined in order to detect a reduction in the incidence of new infections during PICU-stay from 20 to 15% (Absolute Risk Reduction 5%), with at least 80% 1-tailed power and at least 70% 2-tailed power and at an alpha error of 5%. With this sample size, the trial can also detect a major safety issue, such as a doubling of the PICU mortality rate from 4% (the baseline mortality in the Leuven center) to 8% with a statistical power of 89% in a 2-sided test with an alpha error of 5%. This sample size will also allow to detect a reduction in mean duration of stay in PICU of 1 day with at least 90% power (2-tailed) and 95% certainty.

Two interim analyses of the safety endpoints (except 90-day mortality) only were planned (after inclusion of 480 upon specific request of the DSMB, and after inclusion of 50% of the study population). It was a priori decided to determine the actual incidence of new infections during PICU-stay in the 3 centers, as this was not known exactly for each of the participating centers prior to trial initiation. In order to allow statistical repowering and to judge the necessity of inclusion of more trial sites, the assessment of incidence of new infections during PICU-stay in the control group took place after inclusion of 750 patients. Based on this actual incidence of new PICU infections in the control group, the hypothesized absolute risk reduction of 5% and an alpha error rate of 5%, the sample size of 1,440 patients (720 patients in each arm) was found sufficiently large to yield a statistical power of 77% 2-sided and of 85% 1-sided. As these interim analyses did not assess any of the efficacy endpoints, no adjustments of the P-values are needed.

KU Leuven Research and Development, Waaistraat 6 bus 5105, B-3000 Leuven, Belgium.