- Open Access
Impact of a computer-assisted decision support system (CDSS) on nutrition management in critically ill hematology patients: the NUTCHOCO study (nutritional care in hematology oncologic patients and critical outcome)
© The Author(s) 2019
- Received: 13 January 2019
- Accepted: 27 April 2019
- Published: 7 May 2019
Mortality of critically ill hematology (HM) patients has improved over time. Thus, those patients require an extensive diagnostic workup and the optimal use of available treatments. There are no data regarding nutrition strategy for critically ill HM patients, while nutritional support is crucial for both HM and critically ill patients. We hypothesized that the implementation of a computer-assisted decision support system (CDSS), designed to supervise a nutritional intervention by a multidisciplinary team, would be able to increase guidelines adherence and outcomes.
In this before/after study, 275 critically ill hematology patients admitted to the ICU over 5-year period were included. Energy and protein intakes were delivered using standard protocol in the 147 patients (53%) of the ‘before group’ and using a CDSS in order to reach every day predefined caloric and protein targets accordingly to the catabolic or anabolic status in the 128 patients (47%) of the ‘after group.’ Using a Poisson regression, we showed that the use of CDSS allowed to reach a relative increase in the rate of days in compliance with caloric (1.57; 95% confidence interval (CI), [1.17–2.10], p = 0.0025) and protein targets (3.86 [2.21–6.73], p < 0.0001) in the ‘after group’ by more than 50% as compared with the ‘before group.’ Interestingly, compliance rates were low and only reached 30% after intervention. Hospital mortality, ICU-acquired infection, and hospital, and ICU length of stay were similar in the two groups of patients. Importantly, exploratory analysis showed that hospital mortality was lower in the ‘after group’ for neutropenic and severely ill patients.
For critically ill hematology patients, the use of a nutritional CDSS allowed to increase the days in compliance with caloric and protein targets as compared with no CDSS use. In this context, overall hospital mortality was not affected.
HM patients increasingly require admission to the intensive care unit (ICU) for life-threatening events related to the malignancy and/or treatments [1, 2]. The prognosis of HM patients has improved considerably over time, in fact mortality in HM patients septic shock has fallen by 30% , while in patients receiving invasive mechanical ventilation (IMV) improvement has resulted in a sharp drop in mortality, from nearly 90% to about 40% . Thus, critically ill HM patients require an extensive diagnostic workup  and the optimal use of available treatments . Nutritional support is crucial in critically ill patients. Guidelines recommend early enteral feeding supplying 25 kcal/kg per day during the acute phase of critical illness [7, 8] with however a low level of evidence. For HM patients treated with myeloablative conditioning for allogeneic stem cell transplantation, early nutritional intervention has proven a benefit on outcome and mortality outside the ICU . There are no data regarding nutrition strategy for HM patients during ICU stay. As most of ICU therapies, nutritional support has become more complex requiring tight supervision and monitoring. Thus, computer-assisted decision support systems (CDSSs), designed to implement rational care strategies based on guidelines and pathways, have been developed and studied over the past several years . For this study, we hypothesized that implementation of a CDSS, designed to actively supervise a nutritional intervention by a multidisciplinary team, would be able to increase guidelines adherence and outcomes.
This retrospective ‘before/after’ cohort study was conducted over two time periods within 5 years totaling 3501 patient days in the ICU for 275 patients. The pre-interventional period (‘before period’) took place from November 2009 to March 2011, the post-interventional period (‘after period’) from November 2011 to November 2014. We compared two chronological cohorts: the ‘before group’ with unmonitored nutritional care and the ‘after group’ with updated nutritional care (computer assisted, guideline updated, immunonutrient supplemented). Patients and most of clinico-biological data were retrospectively identified and analyzed using our prospective ICU database included in our ICU information system (MetaVision®, iMDsoft, Tel Aviv, Israel). Following the ‘before period,’ a CDSS module was locally designed and added to our ICU information system as a tool to provide clinicians with essential guideline-based information concerning nutritional support in the ICU and hematology patients [7, 11–13]. Details concerning the implementation of the nutrition protocols during the 2 periods are provided in the Additional file 1. The study was approved by the Paoli-Calmettes Institute institutional review board which waived the need for informed consent.
Aims of the study
By the use of CDDS, our primary objective was to demonstrate a significant increase in the number of days in compliance with calories target, defined as days on which caloric delivery fitted the target of 25 kcal/kg/day ± 15% during the aggression period, or 35 kcal/kg/day ± 15% during stable recovering periods, and in the number of days in compliance with protein target, defined as days on which protein delivery fitted a target of 1.5 g/kg/day ± 15%. Secondary clinical objectives were to assess the impact of the use of the CDSS on morbidity (ICU and hospital lengths of stay, duration of IMV, antimicrobial, renal replacement, and vasopressors treatments) and hospital survival for the overall patients, exploratory analysis was also realized for hematopoietic stem cell transplant (HSCT) recipients, neutropenic and severe patients defined as SAPS II > 56 on ICU admission [14–16]. Nutritional secondary objectives were to assess the impact of the use of the CDSS on cumulative days of enteral, parenteral, and total caloric and protein cumulative balance on day 3, day 5, and day of ICU discharge.
Targets and nutrition protocols
Protocols were based on ESPEN guidelines [7, 11–13] that were locally adapted and validated by the ICU staff. During the study periods, the energy target recommendation was 25 kcal/kg/day and 35 kcal/kg/day during acute illness and recovery period, respectively. Patients were categorized as in acute phase or recovery phase at the clinician’s opinion and corresponded to any of the following situations: ongoing vasopressor treatment, renal replacement therapy (RRT), IMV, sepsis, shock, etc. Recovery period was defined as stable clinical state which could include prolonged (> 48 h) stable ventilation periods. Ideal body weight was used for calculations in case of BMI > 30 kg/m2 . Protein recommendations were set at 1.5 g/kg/day. Enteral nutrition (EN) was used whenever possible, combined feeding when EN did not cover the prescribed target, and parenteral nutrition (PN) when EN was not feasible. Compliance with guidelines was evaluated for each patient each day of the ICU stay according to the recommended energy and protein targets. Intravenous energy was received from PN, as well as from non-nutritional energy sources (calculated by the CDSS which considered glucose, gluco-saline, or drug infusion, and fat from propofol). Daily protein delivery was also retrieved from the CDSS on days with artificial nutrition. Feeding routes were defined as PN, EN, combined (EN and PN), and oral. Since our CDSS was designed to only assist the EN and PN prescriptions, oral intake was not taken into account for the primary endpoints of the overall population. In addition, oral alimentation is commonly difficult to realize in severe hematology patients (ARF, septic shock, mucositis, HSCT recipient), thus we assume the oral intakes to be negligible in those situations.
Feeding products are described in Additional file 2.
Our medical institution is a tertiary care reference center for cancer patients. Patients admitted to the ICU benefit from a daily close collaboration between their referring hematologists and ICU-appointed intensivists. All consecutive patients suffering from a hematologic neoplasia were included at 48 h of ICU. Pregnant women, minors, patients admitted for, or switched within the first 48 h to palliative ICU care, patients discharged alive within the first 48 h were not included. Reasons for ICU admission were recorded based on the main symptoms at ICU admission. Acute respiratory failure was defined as oxygen saturation less than 90% or PaO2 less than 60 mmHg on room air combined with severe dyspnoea at rest with an inability to speak in sentences or a respiratory rate greater than 30 breaths per minute or clinical signs of respiratory distress . Shock was defined as previously reported . Mild malnutrition was defined as total weight loss > 5% and ≤ 10% usual body weight over the last 6 months and severe malnutrition as weight loss > 10%. Life-supporting interventions, anti-infectious agents, prophylactic treatments, urate oxidase use, and diagnostic procedures were administered at the discretion of the attending intensivists, who followed best clinical practice and guidelines. Chemotherapy, corticosteroids, hematopoietic growth factors, immunosuppressive drugs, and other cancer-related treatments were prescribed by the hematologist in charge of each patient in accordance with institutional guidelines. Etiologic diagnoses were made by consensus by the intensivists, hematologists, and consultants, according to recent definitions .
Clinical and biological data
Characteristics of the population
Before group (n = 147)
After group (n = 128)
Weight at ICU admission (kg)
Weight at ICU discharge (kg)
Weight loss at ICU discharge (kg)
No or Mild malnutrition
Oral alimentation at ICU discharge
Severe patients (SAPSII > 56)
Main cause for ICU admission
ICU length of stay (days)
Hospital length of stay (days)
Individual data collected prior to ICU were summarized using counts (frequencies) for qualitative variables and medians [25th–75th percentiles] or means [standard deviations (SD)] for quantitative variables. The primary objective was to compare the number of days in compliance with calories target between the study cohorts enrolled prior and after initiation of CDSS intervention, respectively. Analysis of the primary endpoint was performed using Poisson regression including terms for cohort (after vs. prior CDSS) and length of ICU stay as an offset term to account for individual duration of exposure. A multivariate regression was then performed to confirm the results, by adding as covariates neutropenic, severe and allogeneic SCT statuses. Estimate of intensity rate ratio (IRR) derived from Poisson regression was used to assess the difference in the number of days in compliance between the two cohorts. Correction for over dispersion in variance estimation was used to derive robust 95% confidence intervals for IRR. Similar analyses were performed for the number of protein compliant days, treatment days IMV, vasopressors, RRT, and antibiotics. Exploratory similar analyses of the number of caloric and protein compliant days were also performed in neutropenic, severe and allogeneic HSCT patients, respectively; in order to account for multiple comparisons, a Bonferroni correction was applied to these analyses and the level of significance was set to 0.05/6 = 0.008. In each cohort, cumulative incidences of death during ICU stay were estimated using the Prentice’s method by considering patient alive at ICU discharge as a competing risk and compared using Gray’s tests. Other secondary endpoints were compared across the two groups of patients by using Chi-square or Fisher’s exact tests for qualitative variables, and Wilcoxon rank-sum tests for quantitative variables.
A total of 252 patients was initially planned in this study (126 in each cohort). This sample size was determined using Cook’s formula to a detect a 50% increase in the primary endpoint using CDSS (IRR = 1.5) with 95% power and 5% error risk, assuming equal period of accrual in each cohort; an expected length of stay in ICU of 7 days, an intensity rate of 0.40 in the first cohort and a default value for over dispersion parameter (ϕ = 1).
All statistical analyses were performed using the Statistical Analysis System (SAS), version 9.3 (SAS Institute Inc, Cary, NC, USA).
Clinical parameters (Table 1)
Two hundred seventy-five patients were included in the present study, 147 (53%) in the ‘before group’ and 128 (47%) in the ‘after group.’ Clinical characteristics of patients are presented in Table 1. Briefly, age was 59 years [49–67] and SAPSII score was 47 [37–59]. Main comorbidities were cardiovascular disease for 34% (n = 93) of subjects, respiratory 29% (n = 79), hepatic 5% (n = 13), renal 6% (n = 16), neurological 7% (n = 19), and diabetes mellitus 10% (n = 28). Regarding hematological malignancy, 113 (41%) patients presented with acute leukemia, 90 (33%) with lymphoma and 41 (15%) with chronic leukemia. At ICU admission, 100 (36%) patients were neutropenic, 70 (25%) and 57 (21%) patients benefited from allogeneic and autologous HSCT, respectively. One hundred six (38%) patients presented with ARF and 83 (30%) with shock. During ICU stay, 131 (48%) patients required IMV, 155 (56%) vasopressors and 67 (24%) RRT. Hospital mortality was 46% (n = 126).
Number of days reaching caloric and protein targets during ICU stay
Intensity rate ratio
Number of days in ICU days within target
Number of days in days within target
n = 147
n = 128
n = 43
n = 57
n = 41
n = 40
n = 32
n = 38
Outcomes during ICU stay
‘Before group’ (n = 147)
‘After group’ (n = 128)
Intensity rate ratio [CI 95%]
Days with IMV
Days with vasopressors
Days with dialysis
Days with antibiotics
Number of antibiotics used during ICU stay
Urinary tract infection
We report herein, in this before/after study, on 275 critically ill hematology patients admitted to the ICU over 5-year period. Energy and protein intakes were delivered using standard protocol in the 147 patients (53%) of the ‘before group’ and using a CDSS in order to reach every day predefined caloric and protein targets accordingly to the catabolic or anabolic status in the 128 patients (47%) of the ‘after group.’ We showed that the use of CDSS allows to relatively increase the rate of days in compliance with caloric and protein targets in the ‘after group’ by more than 50% as compared with the ‘before group.’ Interestingly, compliance rates were low and only reached 30% after intervention. Hospital mortality, ICU-acquired infection, and hospital and ICU length of stay were similar in the two groups of patients. Exploratory analysis showed that hospital mortality was lower in the ‘after group’ for neutropenic and severely ill patients.
There is growing evidence that protein intake might also affect outcomes [30, 31]; however, the best protein intake in critically ill patients is still unknown. Recent recommendations on protein intake for critically ill patients are only based on studies with a low level of evidence . In the present study, we showed that the use of CDSS was associated with both a significant increase in protein delivery and decrease in protein deficit during ICU stay. Thus, mean daily protein intake after intervention was about 56 g/day (Additional file 1: Table S1) and similar to that recently described by Nicolo et al. . As for energy intake, 47% (‘after group’) and 52% (‘before group’) of the total protein deficit was reached during the first 5 days of ICU admission (Additional file 1: Table S1) underlining once again the potent crucial role of early PN for those patients. Intensivists usually focus on caloric rather than protein goals, and the parenteral nutrition products we used have compositions that could not provide 1.5 g of protein/kg/day without overfeeding. Thus, prescribers needed to tradeoff between high calories or high proteins. Glutamine, added to total PN, could be a key to higher protein delivery without a caloric overshoot . During the ‘after period,’ glutamine was available in our institution and thus integrated in the CDSS and could have allowed us to better reach our protein targets.
The hospital mortality was about 46% consistent with recent results . For the overall population, CDSS use did not translate into a mortality benefit. Because mortality was a secondary objective, our sample was not powered to show significant mortality difference. However, exploratory analysis showed a significant effect on hospital outcome after CDSS use for the neutropenic and severe patients but not for HSCT recipients. Interestingly, SAPSII score was similar at ICU admission between ‘before group’ and ‘after group’ for neutropenic and severe patients. These results should be interpreted cautiously nevertheless they reinforce the hypothesis of a beneficial effect on outcome of using CDSS. After intervention, we described in severe patients, a significant increase in days within protein target, while this effect was not retrieved for calories target. Taken together, these results suggest that protein intake in critically ill hematology patients might be a crucial step of ICU management. Indeed, it has been recently shown in critically ill patients that if the basal amount of protein is provided, restricted calories intake did not impact on outcome . Recent data have also shown in patients who remained in the ICU ≥ 4 days and achieved at least 80% of prescribed protein intake a lower mortality than those achieving < 80% of prescribed. In this situation, percentage of prescribed energy intake was not associated with outcomes . Whether reciprocal relationships exist between calorie and protein intakes exist in severe hematology patients remains to be determined.
Our study presents several limitations. First, the distinction between the acute phase and the recovery period was based on the clinician’s choice. Because there is no consensus on the definitions of acute phase and recovery phase, the retrospective analysis of the clinician’s evaluation might have led to significant variability from one patient to another. Such variability might have influenced the results. Second, due to the retrospective nature of the study, we were unable to collect the causes of non-use of enteral nutrition among the 14 patients who did not benefit. However, the causes of failure of enteral nutrition are detailed Fig. 2. Third, we did not plan to collect cases of refeeding syndrome; however, in our daily practice. these cases are rare, whereas the ICU admission of severely malnourished patients was relatively frequent (22%).
In conclusion, we showed that the use of CDSS allows to increase relatively the rate of days in compliance with caloric and protein targets by more than 50%. Interestingly, compliance rates were low and only reached 30% after intervention. Hospital mortality, ICU-acquired infection and lengths of stay were similar in the two groups.
The study was partly funded by limited grant from Fresenius Kabi, France.
DM and FE contributed to the design of the work and were involved in the acquisition, analysis, and interpretation of data, and drafted the manuscript; CZ and JMB contributed to the acquisition and analysis of data and drafted the manuscript; LCC and AS contributed to the acquisition of data and revision of the manuscript; MB and GF contributed to the analysis of data and revision of the manuscript; LS, JMD, and MF contributed to the analysis of data and drafted the manuscript; AH contributed to the conception and design of the work and was involved in interpretation of data and revision of the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
The study was approved by the Paoli-Calmettes Institute Institutional Review Board, and since there was no interference with patients’ management, signed informed consent was waived.
Consent for publication
All authors declare no competing interests. Fresenius Kabi was not involved in any aspect of the design or conduct of the study, the data analysis, or the manuscript preparation and presentation.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
- Azoulay E, Mokart D, Pene F, Lambert J, Kouatchet A, Mayaux J, et al. Outcomes of critically ill patients with hematologic malignancies: prospective multicenter data from France and Belgium—a groupe de recherche respiratoire en reanimation onco-hematologique study. J Clin Oncol. 2013;31:2810–8.View ArticleGoogle Scholar
- Tavares M, Lemiale V, Mokart D, Pene F, Lengline E, Kouatchet A, et al. Determinants of 1-year survival in critically ill acute leukemia patients: a GRRR-OH study. Leuk Lymphoma. 2018;59:1323–31.View ArticleGoogle Scholar
- Zuber B, Tran TC, Aegerter P, Grimaldi D, Charpentier J, Guidet B, et al. Impact of case volume on survival of septic shock in patients with malignancies. Crit Care Med. 2012;40:55–62.View ArticleGoogle Scholar
- Azoulay E, Pickkers P, Soares M, Perner A, Rello J, Bauer PR, et al. Acute hypoxemic respiratory failure in immunocompromised patients: the Efraim multinational prospective cohort study. Intensive Care Med. 2017;43:1808–19.View ArticleGoogle Scholar
- Azoulay E, Mokart D, Lambert J, Lemiale V, Rabbat A, Kouatchet A, et al. Diagnostic strategy for hematology and oncology patients with acute respiratory failure: randomized controlled trial. Am J Respir Crit Care Med. 2010;182:1038–46.View ArticleGoogle Scholar
- Azoulay E, Pene F, Darmon M, Lengline E, Benoit D, Soares M, et al. Managing critically ill hematology patients: time to think differently. Blood Rev. 2015;29:359–67.View ArticleGoogle Scholar
- Kreymann KG, Berger MM, Deutz NE, Hiesmayr M, Jolliet P, Kazandjiev G, et al. ESPEN guidelines on enteral nutrition: intensive care. Clin Nutr. 2006;25:210–23.View ArticleGoogle Scholar
- McClave SA, Taylor BE, Martindale RG, Warren MM, Johnson DR, Braunschweig C, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2016;40:159–211.View ArticleGoogle Scholar
- Seguy D, Duhamel A, Rejeb MB, Gomez E, Buhl ND, Bruno B, et al. Better outcome of patients undergoing enteral tube feeding after myeloablative conditioning for allogeneic stem cell transplantation. Transplantation. 2012;94:287–94.View ArticleGoogle Scholar
- Dvir D, Cohen J, Singer P. Computerized energy balance and complications in critically ill patients: an observational study. Clin Nutr. 2006;25:37–44.View ArticleGoogle Scholar
- Arends J, Bodoky G, Bozzetti F, Fearon K, Muscaritoli M, Selga G, et al. ESPEN guidelines on enteral nutrition: non-surgical oncology. Clin Nutr. 2006;25:245–59.View ArticleGoogle Scholar
- Bozzetti F, Arends J, Lundholm K, Micklewright A, Zurcher G, Muscaritoli M. ESPEN guidelines on parenteral nutrition: non-surgical oncology. Clin Nutr. 2009;28:445–54.View ArticleGoogle Scholar
- Singer P, Berger MM, van den Berghe G, Biolo G, Calder P, Forbes A, et al. ESPEN guidelines on parenteral nutrition: intensive care. Clin Nutr. 2009;28:387–400.View ArticleGoogle Scholar
- Mokart D, Sannini A, Brun JP, Faucher M, Blaise D, Blache JL, et al. N-terminal pro-brain natriuretic peptide as an early prognostic factor in cancer patients developing septic shock. Crit Care. 2007;11:R37.View ArticleGoogle Scholar
- Mokart D, Saillard C, Zemmour C, Bisbal M, Sannini A, Chow-Chine L, et al. Early prognostic factors in septic shock cancer patients: a prospective study with a proteomic approach. Acta Anaesthesiol Scand. 2018;62:493–503.View ArticleGoogle Scholar
- Mourad M, Chow-Chine L, Faucher M, Sannini A, Brun JP, de Guibert JM, et al. Early diastolic dysfunction is associated with intensive care unit mortality in cancer patients presenting with septic shock. Br J Anaesth. 2014;112:102–9.View ArticleGoogle Scholar
- Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, Wheeler A. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342:1301–8.View ArticleGoogle Scholar
- Knaus WA, Draper EA, Wagner DP, Zimmerman JE. Prognosis in acute organ-system failure. Ann Surg. 1985;202:685–93.View ArticleGoogle Scholar
- Jr Le Gall, Lemeshow S, Saulnier F. A new simplified acute physiology score (SAPS II) based on a European/North American multicenter study. JAMA. 1993;270:2957–63.View ArticleGoogle Scholar
- Vincent JL, Moreno R. Clinical review: scoring systems in the critically ill. Crit Care. 2010;14:207.View ArticleGoogle Scholar
- Reignier J, Boisrame-Helms J, Brisard L, Lascarrou JB, Ait HA, Anguel N, et al. Enteral versus parenteral early nutrition in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2). Lancet. 2018;391:133–43.View ArticleGoogle Scholar
- Baumgartner A, Bargetzi A, Zueger N, Bargetzi M, Medinger M, Bounoure L, et al. Revisiting nutritional support for allogeneic hematologic stem cell transplantation-a systematic review. Bone Marrow Transpl. 2017;52:506–13.View ArticleGoogle Scholar
- Berger MM, Que YA. Bioinformatics assistance of metabolic and nutrition management in the ICU. Curr Opin Clin Nutr Metab Care. 2011;14:202–8.View ArticleGoogle Scholar
- Conseil M, Carr J, Molinari N, Coisel Y, Cisse M, Belafia F, et al. A simple widespread computer help improves nutrition support orders and decreases infection complications in critically ill patients. PLoS ONE. 2013;8:e63771.View ArticleGoogle Scholar
- Heidegger CP, Berger MM, Graf S, Zingg W, Darmon P, Costanza MC, et al. Optimisation of energy provision with supplemental parenteral nutrition in critically ill patients: a randomised controlled clinical trial. Lancet. 2013;381:385–93.View ArticleGoogle Scholar
- Harvey SE, Parrott F, Harrison DA, Bear DE, Segaran E, Beale R, et al. Trial of the route of early nutritional support in critically ill adults. N Engl J Med. 2014;371:1673–84.View ArticleGoogle Scholar
- Preiser JC, van Zanten AR, Berger MM, Biolo G, Casaer MP, Doig GS, et al. Metabolic and nutritional support of critically ill patients: consensus and controversies. Crit Care. 2015;19:35.View ArticleGoogle Scholar
- Nicolo M, Heyland DK, Chittams J, Sammarco T, Compher C. Clinical outcomes related to protein delivery in a critically ill population: a multicenter, multinational observation study. JPEN J Parenter Enteral Nutr. 2016;40:45–51.View ArticleGoogle Scholar
- Arabi YM, Aldawood AS, Haddad SH, Al-Dorzi HM, Tamim HM, Jones G, et al. Permissive underfeeding or standard enteral feeding in critically ill adults. N Engl J Med. 2015;372:2398–408.View ArticleGoogle Scholar
- Weijs PJ, Wischmeyer PE. Optimizing energy and protein balance in the ICU. Curr Opin Clin Nutr Metab Care. 2013;16:194–201.View ArticleGoogle Scholar
- van Zanten AR. Should we increase protein delivery during critical illness? JPEN J Parenter Enteral Nutr. 2016;40:756–62.View ArticleGoogle Scholar
- Hoffer LJ, Bistrian BR. Appropriate protein provision in critical illness: a systematic and narrative review. Am J Clin Nutr. 2012;96:591–600.View ArticleGoogle Scholar
- Wernerman J. How to understand the results of studies of glutamine supplementation. Crit Care. 2015;19:385.View ArticleGoogle Scholar