Abstract
Background:
Published guidelines recommend providing at least 2 g/kg/d of protein for critically ill surgical patients. It may be difficult to achieve this level of intake using standard enteral formulas, thus necessitating protein or amino acid supplementation. Herein, we report our approach to enteral protein supplementation and its relationship with urinary nitrogen excretion and serum transthyretin concentrations.
Methods:
This was a retrospective cohort study in which we reviewed critically ill trauma and surgical patients treated with supplemental enteral protein according to a protocol aiming to deliver a total of 2 g/kg/d of protein. We collected detailed nutrition data over a 2-week period after admission and obtained additional data through discharge to determine caloric and protein intake as well as complications. We also compared urine nitrogen excretion and transthyretin concentrations between these patients and a control group who did not receive supplemental protein.
Results:
Fifty-three subjects received early protein supplementation. Formula and protein supplement each provided ≈1.2 g/kg/d of protein by intensive care unit day 4. This resulted in a median total protein intake of 2.2 g/kg/d through day 14. One patient developed acute kidney injury, and 1 patient had 3 episodes of vomiting. By the third week, serum transthyretin concentrations increased to a median of 21 mg/dL compared with 13 mg/dL in subjects not receiving early supplementation.
Conclusion:
It is safe to deliver supplemental protein enterally to critically ill surgical and trauma patients and reach 2 g/kg/d of protein intake during the first week of illness.
Keywords: critical care, critical illness, enteral nutrition, intensive care unit, protein
Background
Nutrition support is essential to restoring organ function, healing wounds, and mitigating the effects of the metabolic response to surgery, trauma, and sepsis. Published guidelines, consensus recommendations, and expert opinion are placing increasing emphasis on the importance of protein intake in critically ill patients, with recommendations of up to 2.5 g/kg of protein intake each day.1–3 Recommendations are based upon the notion that outcomes may be most closely linked to the amount of protein that a patient receives.3
The response to surgical stress, trauma, and sepsis includes metabolic and physiologic changes that influence the inflammatory, acute phase, hormonal, and genomic responses.4,5 This is characterized by increased catabolism and leads to impaired immune function, poor wound healing, organ failure, nosocomial infection, muscle wasting, and death.6 Artificial nutrition support is an essential part of managing critically ill patients and is one of the most commonly used interventions in intensive care units (ICUs). Clinical guidelines recommend that enteral nutrition should be the primary mode of support rather than parenteral nutrition and that it should be initiated within the first 24–48 hours following injury or admission.7,8 Several factors limit or prevent the use of the gastrointestinal tract and result in the delivery of insufficient nutrients and substrates during and often beyond the first few weeks of critical illness. Critically ill surgical patients often require multiple procedures over the first few days, limiting adequate caloric and nutrient intake. The most common consequence of an enteral-based regimen is the development of caloric, nitrogen, and other substrate deficits and the potential for complications related to underfeeding.9 Most patients receive insufficient protein, even in comparison to the previously recommended goals.2 The 2016 American Society for Parenteral and Enteral Nutrition/Society of Critical Care Medicine (ASPEN/SCCM) guidelines suggest that higher protein intake is associated with improved outcomes, recommend 2 g/kg/d of protein, and suggest needs may likely be higher for critically ill trauma patients.1 Given the many barriers to enteral support, these higher recommended targets are not likely to be achieved with standard and even high-protein enteral formulas. Evidence supporting the benefits of higher protein is limited, and to determine whether additional protein leads to improved outcomes, we must develop safe and effective ways to administer more protein.
We developed an approach based upon the ASPEN/SCCM recommendations that aimed to achieve 2 g/kg/d of enteral protein without waiting to reach target enteral caloric intake. In this primarily descriptive study, we describe the methods and report the results of our approach. We also compared nitrogen excretion and serial serum transthyretin concentrations between the supplemented cohort and a nonsupplemented group of critically ill surgical patients.
Methods
Study Design and Data Collection
This is a retrospective analysis of our approach designed to increase enteral protein intake in critically ill surgical patients. We developed guidelines (see following section) aiming to improve early enteral protein delivery in our surgical and trauma ICU, which we implemented for 6 months (April to September, 2016) to determine its safety and effectiveness. All patients were admitted to our surgical ICU and identified by one of the investigators (M. S.) as being appropriate for protein supplementation. Our guidelines required that patients (i) were deemed ready to start enteral nutrition support by the attending intensivist within 72 hours of admission to the ICU, (ii) had no contraindications to full enteral support, (iii) had no history of chronic liver disease, and (iv) had serum creatinine <1.5 mg/dL (in the final month, we increased the allowable serum creatinine to 2.0 mg/dL). For the purposes of this study, the dietitian (M. S.) reviewed the medical record daily and recorded episodes of emesis and pulmonary aspiration for the previous 24 hours. Diarrhea is managed first by modifying the enteral formula to include higher fiber and testing for Clostridium difficile infection. We did not specifically record the incidence of diarrhea in this study. Caloric and protein intake was recorded daily while the patient was in the ICU for a maximum of 14 days.
Approach to Nutrition Support and Protein Supplementation
Our overall approach to nutrition support in our ICU is standardized according to evidence-based guidelines, has been previously described, and is summarized here.8 Once deemed ready to receive enteral nutrition, the patient is prescribed a polymeric formula with 1–1.5 kcal/mL. Continuous infusion starts at 20 mL/h, and the rate is advanced over 24 hours to an initial goal of 25 kcal/kg/d delivered by continuous infusion via an orogastric or nasogastric tube. Caloric and protein targets are determined using actual body weight for patients with body mass index (BMI) ≤30 and adjusted body weight for those with BMI >30. Adjusted body weight is calculated as the mean of actual and ideal body weight as we have previously reported.8 Replete (Nestlé Health Science, Bridgewater, NJ, USA; 1.0 kcal/mL, 62.4 g/L protein, 25% kcal from protein) is the primary enteral formula that we use in our ICU. In this cohort, all subjects were initially started on Replete with subsequent changes as determined by the dietitian. Overall, approximately 70% of the enteral caloric intake was from Replete. Monitoring for intolerance is primarily by clinical examination. At the time of this study, we measured gastric residual volume every 4 hours and used >500 mL as an indicator of potential intolerance.
The dietitian calculated caloric and protein needs for each patient based on either actual or adjusted body weight as indicated above. Supplemental protein (2 g/kg/d of Prosource; Medtrition, Lancaster, PA, USA) was administered via the nasal/oral feeding tube in 60–180 mL bolus infusions 2–4 times per day, independently of the enteral formula received. That is, the daily target amount of protein was initially administered as the supplement boluses, and only after the enteral formula infusion approached the target rate was the amount of supplement decreased. Supplemental protein was reduced by 50% once the patient received 75% of targeted caloric intake over the previous day (0700–0700). Once the patient reached the target caloric intake for 48 hours, the amount of supplemental protein was decreased so that the total protein prescribed equaled 2 g/kg/d.
As part of our standard clinical practice, we obtain measurement of urine nitrogen excretion in patients who are in the ICU and receiving nutrition support for >1 week. We use 24-hour total urinary nitrogen (TUN) excretion measurements in concert with measuring energy expenditure to modify nutrition support in patients in whom we want more information about caloric needs and when there is a clinical concern for a nitrogen deficit. In addition to measuring TUN, we also monitor the response to nutrition support and recovery from critical illness using serum transthyretin. Although not in widespread use, there is evidence that serum transthyretin can be used to monitor response to nutrition support and recovery from critical illness.10
Selection of Control Subjects for Comparison of Nitrogen Excretion and Serum Markers
We wanted to measure the effect of early supplemental protein treatment on nitrogen excretion and on serum transthyretin concentrations as the patients recovered. We used the electronic medical record to identify all patients admitted to the surgical ICU who were in the ICU who underwent measurement of TUN excretion according to our practice guidelines, from January to December 2016.8 This identified a control group who did not receive early supplemental protein for comparison.
Data Presentation and Analyses
Unless otherwise indicated, categorical data are presented as counts (percentages), and continuous data are presented as medians with 25th–75th percentiles. Data management and statistical analyses were performed using Stata 12.1 (StataCorp, College Station, TX, USA) and Prism 5 (GraphPad Software, San Diego, CA, USA). The specific statistical test for each comparison is indicated in the relevant results subsection and briefly summarized here. We conducted comparisons within the 53 patients receiving protein supplementation, primarily by nonparametric methods. Similarly, differences in urinary nitrogen excretion and serum transthyretin between the supplemented and nonsupplemented patients were tested using nonparametric methods.
The study was classified as exempt by our institutional review board because we only obtained data from the electronic medical record that was then stripped of identifying information.
Results
Demographics and Outcome Characteristics of the Patients Receiving Early Supplementation
A total of 53 patients received early protein supplementation. Their demographic and outcome characteristics are shown in Table 1 and summarized here. The majority (47/53) were trauma victims who sustained multiple injuries, and the remaining underwent emergency (n = 5) or major elective (n = 1) surgery. Most (42) were male and white (36). The median age was 46 years. Comorbidities were uncommon; cardiovascular disease and diabetes were the most frequent. The median injury severity score for the trauma victims was 34. Twenty-seven (51%) of the participants had a severe traumatic brain injury, 29 (55%) had a severe thoracic injury, and 13 (25%) had a severe abdominal injury.
Table 1.
Demographic Information for Patients Receiving Early Protein Supplementation (n = 53).
| Demographics | Injury Characteristics (Trauma Only) (n = 47) |
||
|---|---|---|---|
| Age (years) | 46 (30–64) | Injury severity score | 33 (22–43) |
| Sex | Severe brain injury | 27 (51) | |
| Male | 42 (79) | Severe face injury | 6 (11) |
| Female | 11 (21) | Severe neck injury | 6 (11) |
| Race/ethnicity | Severe thoracic injury | 29 (55) | |
| Caucasian | 39 (74) | Severe abdominal injury | 13 (25) |
| African American | 4 (7) | Severe lower extremity injury | 18 (34) |
| Hispanic | 0 | Severe upper extremity injury | 8 (15) |
| Asian/Pacific Islander | 1 (2) | Severe spine injury | 5 (9) |
| American Indian | 2 (4) | Injury mechanism | |
| Other/NA | 7 (14) | Blunt | 44 (94) |
| Chronic comorbidities | Penetrating | 3 (6) | |
| Diabetes mellitus | 5 (10) | ||
| Cancer | 0 | Outcomes | |
| Chronic liver disease | 1 (2) | Died | 5 (9) |
| Hypertension | 6 (12) | ICU length of stay (days) | 11 (8–18) |
| Chronic pulmonary disease | 2 (4) | Hospital length of stay (days) | 22 (17–39) |
| Heart disease | 5 (10) | Pneumonia | 16 (30) |
| BMI | 27 (23–29) | ARDS | 6 (11) |
| Trauma | 47 (89) | Acute renal failure | 1 (2) |
| Nontrauma | 6 (11) | ||
ARDS, acute respiratory distress syndrome; BMI, body mass index; ICU, intensive care unit; NA, not applicable.
Details of Nutrition Support for Those Receiving Protein Supplementation
Enteral caloric intake for the initial 14 days after admission is shown in Figure 1 and includes the calories that are associated with the supplemental protein. Information for all patients is included for a maximum of 14 days or to the point they were discharged from the ICU. The median ICU length of stay was 11 days (interquartile range [IQR]: 8–18 days), and 19 patients were in the ICU on day 14. The initial caloric target of 25 kcal/kg was reached in >50% of patients by day 4 and remained at that level for the 14 days. Daily protein intake for the 53 patients is shown in Figure 2. Looking first at formula protein (Figure 2A), intake gradually rose over the first few days to a median of 1.2 g/kg/d by day 5 and did not substantially change after that point. Median supplemental protein was 1.2 g/kg/d by day 4 (Figure 2B). Together, these 2 protein sources totaled a median daily protein intake of 2.2 g/kg by day 4, which was maintained in patients remaining in the ICU for 14 days (Figure 2C). We did not include parenteral caloric intake in Figure 1. However, many patients received propofol and some intravenous glucose, primarily during the first few days in the ICU. The median number of parenteral calories was lowest (1 kcal/kg/d) on day 1 and highest (3.7 kcal/kg/d) on day 3.
Figure 1.
Enteral caloric intake during initial 14 days. Data are shown for days 1–14 of hospitalization. Box-and-whisker plots illustrate median values, 25th–75th percentiles (box), and 10th–90th percentiles (whiskers). The initial target of 25 kcal/kg (dashed line) is reached in over 50% of the patients by day 4. The caloric intake represented here includes the calories contained in the protein supplement but not intravenous caloric intake. ICU, intensive care unit.
Figure 2.
Enteral protein intake during initial 14 days. Enteral protein administered over the initial 14 days is illustrated. Box-and-whisker plots illustrate median values, 25th–75th percentiles (box), and 10th–90th percentiles (whiskers). (A) Protein administered as enteral formula reached a median of 1 g/kg/d by day 4. Median protein intake associated with formula protein leveled at ≈1.3 g/kg/d. (B) Supplemental protein intake was a median of ≈1.3 g/kg/d on day 4 and gradually decreased to a median of ≈0.5 g/kg/d on day 14. (C) Total enteral protein intake was a median of 2.2 g/kg/d on day 4 and remained ≈2 g/kg/d throughout the 14-day period. ICU, intensive care unit.
Figure 3 shows serum creatinine and serum urea nitrogen (SUN) for the supplemented cohort. One developed acute kidney injury (Creatinine of 2.7 on day 14) but did not require hemodialysis. Near the end the 6 months, we liberalized entry criteria to include patients with serum creatinine up to 2 mg/dL. One was enrolled with an initial creatinine of 1.7 mg/dL, which returned to normal by the end of the first week.
Figure 3.
Serum creatinine and SUN in patients receiving protein supplementation. Box-and-whisker plots illustrate median values, 25th–75th percentiles (box), and 10th–90th percentiles (whiskers). (A) Serum creatinine decreased from the first to second week (P-value < 0.001, by Wilcoxon signed rank test). (B) SUN increased between the first and second week (P-value < 0.001 by Wilcoxon signed rank test). The relationship between protein received during the first week and serum creatinine and SUN is shown in C and D. We divided the patients into quartiles based upon the average amount of protein received each day they were in the ICU during the first week as follows: Group 1: 0.2–0.9 g/kg/d, Group 2: 1.0–1.15 g/kg/d, Group 3: 1.2–1.6 g/kg/d, Group 4: 1.7–2.6 g/kg/d. Patients receiving more protein during the first week generally had lower serum creatinine and SUN concentrations during the second week. The differences between the groups were not statistically significant by Kruskal-Wallis test for serum creatinine (P = 0.16) and SUN (P = 0.09). ICU, intensive care unit; SUN, serum urea nitrogen.
Overall, serum creatinine (Figure 3A) was lower in the second week than the first. In contrast, SUN (Figure 3B) was slightly higher during the second week than the first. None required renal replacement therapy. We wanted to explore whether the overall amount of protein received during the first week in the ICU might have led to an increase in SUN or creatinine in the second week, hypothesizing that a larger average protein intake during the first week would lead to higher SUN concentrations during the second. In order to do this, we generated quartiles based upon the average amount of protein a patient received each day during the first week and limited our analyses to those with SUN and creatinine measured in during the second week. Serum creatinine (Figure 3C) and SUN (Figure 3D) during the second week (postadmission day 8–14) are shown according to the amount of enteral protein received during the first week. Both serum creatinine and SUN appeared to be inversely related to the amount of protein received during the first week, but the differences were not statistically significant.
Organ failure was not common. One patient developed acute renal failure (not requiring dialysis), and 4 (8%) developed acute respiratory distress syndrome (ARDS). Ventilator-associated pneumonia developed in 16 patients (30%). One of the 53 patients vomited tube feeding during the 14-day study period. We also observed that the average amount of protein received during the first week was not related to other complications, such as ARDS or ventilator-associated pneumonia. The 5 deaths in this cohort were related to severe traumatic brain injury or advanced age. These deaths were reviewed, and we found no evidence of complications related to enteral nutrition support or early protein administration.
Comparison of TUN Excretion and Serum Transthyretin in Those Receiving Early Enteral Protein Supplementation With Those Who Did Not
The search of the electronic medical record resulted in a cohort of 118 patients who underwent at least 1 TUN measurement. Twenty-seven patients were from the early supplementation cohort, and 91 did not receive early supplementation. Basic demographic features of these 2 groups are shown in Table 2. The cohorts differed in some ways. The nonsupplemented group were less likely to be trauma victims and were slightly older. Most notable is that the nonsupplemented patients had a higher incidence of acute renal failure. Because kidney injury influences urine nitrogen excretion, we excluded these from our evaluation of urinary nitrogen excretion. Therefore, the comparison of urine nitrogen excretion excludes 18 nonsupplemented and 1 supplemented patient who developed acute kidney injury during their hospitalization and 1 other in whom review of the record indicated that the urine collection was incomplete. Urine nitrogen excretion was higher, but not statistically significantly so, in those who received protein supplementation (Figure 4A).
Table 2.
Demographic, Injury, and Outcome Characteristics of Patients Who Had Measurement of 24-Hour Urine Nitrogen Excretion According to Whether They Received Early Protein Supplementation (n = 118).
| Early Supplemental Protein (n = 27) | No Early Supplemental Protein (n = 91) | P-Value | |
|---|---|---|---|
| Demographics | |||
| Age (years) | 44 (30–64) | 51 (32–64) | 0.50 |
| Sex | |||
| Male | 19 (70) | 66 (72) | 0.83 |
| Female | 8 (30) | 25 (28) | |
| Race/ethnicity | 0.22 | ||
| Caucasian | 21 (78) | 47 (52) | |
| African American | 2 (7) | 10 (11) | |
| Other | 4 (15) | 34 (37) | |
| Chronic comorbidities | 0.06 | ||
| Diabetes mellitus | 0 | 12 (13) | |
| Cancer | 0 | 5 (5) | 0.58 |
| Chronic liver disease | 0 | 3 (3) | 1.0 |
| Hypertension | 3 (11) | 24 (26) | 0.12 |
| Chronic pulmonary disease | 0 | 9 (10) | 0.12 |
| Heart disease | 3 (11) | 12 (13) | 1.0 |
| BMI | 26 (23–31) | 27.5 (24–31) | 0.13 |
| Trauma Patient | 24 (89) | 65 (71) | 0.08 |
| Outcomes | |||
| Died | 3 (11) | 11 (12) | 1.0 |
| ICU length of stay (days) | 17 (12–27) | 21 (13–28) | 0.24 |
| Hospital length of stay (days) | 36 (20–49) | 34 (23–55) | 0.69 |
| Pneumonia | 11 (41) | 43 (47) | 0.55 |
| ARDS | 5 (19) | 21 (23) | 0.79 |
| Acute renal failure | 1 (4) | 18 (20) | 0.01 |
ARDS, acute respiratory distress syndrome; BMI, body mass index; ICU, intensive care unit.
Figure 4.
Urinary nitrogen excretion and trend in serum transthyretin concentrations in patients who did and did not receive early protein supplementation. Box-and-whisker plots illustrate median values, 25th–75th percentiles (box) and 10th–90th percentiles (whiskers). (A) The analysis includes data from patients who underwent TUN measurement within 3 weeks of admission to the ICU and shows that TUN was slightly higher in the supplemented patients (P = 0.07; Mann-Whitney U test). We used only 1 measurement per patient (earliest reliable measurement). TUN is reported as adjusted for body weight (ideal body weight if BMI > 30 kg/m2). (B) Serum transthyretin measurements were generally obtained weekly as part of a nutrition panel of tests in patients remaining hospitalized. The low normal value is 20 g/dL. Serum transthyretin gradually increased over time, and the median was above 20 g/dL by the third week in patients receiving early supplemental protein and was higher in the supplemented than in the nonsupplemented group (P = 0.009 by Mann-Whitney U test). BMI, body mass index; ICU, intensive care unit; TUN, 24-hour total urine nitrogen.
Patients also had serum transthyretin concentrations measured over their hospital course, and these data are shown in Figure 4B. We observed that concentrations gradually increased overall and were more likely reach normal concentrations in those receiving early protein supplementation. During the first week, the median serum concentration was 9 mg/dL and not different between the 2 groups. By the third week, the concentration in the supplemented group increased to 21 mg/dL (14–25; IQR), and only increased to 13 mg/dL (10–19; IQR) in the nonsupplemented patients (P-value = 0.009 by Mann-Whitney U test). These data suggest that enteral protein supplementation is associated with increased visceral protein concentrations in critically ill patients after 14 days from admission to the ICU.
Discussion
Enteral protein supplementation is one of a number of possible ways to increase protein intake in critically ill patients.2,11 Other options include the approach taken by the “PEPuP” investigators who applied a collection of evidence-based guidelines, feeding protocols, staff education, and other methods to increase enteral intake. Like our approach, they focused on enteral nutrition support. The PEPuP approach was effective, increasing the average caloric intake to 23 kcal/kg/d and the average protein intake to 1.2 g/kg/d.11 Unlike our approach, the PEPuP investigators did not specifically increase or supplement protein intake independently of other nutrients and calories.
Intravenous amino acids are an alternative to supplemental enteral protein and have the advantage of not requiring enteral absorption. They can therefore be administered when patients are not tolerating or are slow to tolerate enteral nutrition. They potentially can be administered earlier and more broadly in critically ill patients. Whether intravenous amino acids are effectively used, rather than metabolized as an energy source in critically ill patients, is not clear. Shaw and Wolfe demonstrated that parenteral nutrition is associated with a reduction in negative nitrogen balance loss in trauma patients or those with sepsis. However, their studies are limited by not having control subjects and instead rely on before-and-after comparisons.4,12
Potential complications of enteral nutrition are many and may be underappreciated. Gastrointestinal intolerance, manifesting as abdominal distention, pain, diarrhea, and vomiting, are potential consequences that can lead to insufficient caloric intake. More ominous are aspiration and intestinal ischemia. The incidences of these adverse events are uncertain, but some reports are notable. For example, the recent NUTRIREA-2 study reported vomiting in 34% and intestinal ischemia in 2% of patients randomized to enteral nutrition.13 These percentages seem high for critically ill patients in general and may reflect the fact that the NUTRIREA-2 study enrolled patients who were receiving vasopressor support for shock (typically norepinephrine at a median rate of 0.50 μg/kg/min), patients who are often excluded from other studies. In contrast, we observed vomiting in 1 of our 53 patients. This low rate is likely due to a number of factors related to our general approach to enteral nutrition, including elevating the head of the bed, avoiding enteral feeding in patients being actively resuscitated with vasopressor medications, and gradually increasing tube-feeding infusion rates. In addition, patients were selected for supplementation and inclusion in this study based upon our clinical expectation that they would tolerate gastric feeding. Rates of vomiting and potential aspiration may be higher in a broader range of critically ill patients, but there is no evidence that our approach to protein supplementation would increase this risk.
There are a number of important limitations to this study. First, the cohort of supplemented patients were eligible to start enteral nutrition within 3 days, had no indications to limit enteral support, and therefore were a relatively select group of patients. The decision to enroll the patient was made together by 2 investigators (G. O. and M. S.), who discussed the patient and determined they would be a good candidate for supplementation. They were expected to be successfully fed and in fact were; the median caloric intake was >25 kcal/kg by the fourth day following admission. This cohort likely does not represent all critically ill surgical patients. For example, those who have absolute contraindications to enteral feeding, such as intestinal discontinuity, obstruction, or ileus, are not amenable to this approach. On the other hand, it is possible that patients in whom enteral nutrition is delayed or otherwise difficult to advance may obtain greater benefit from enteral protein supplementation.
The next important limitation is related to the group of nonsupplemented patients and how they may differ from the supplemented patients. We drew our control group from patients admitted to our surgical ICU from January to September 2016, some of whom were admitted prior to enrollment of the supplemented patients and others admitted contemporaneously. We chose those who underwent TUN testing, given that these would have been in the ICU for at least 7 days. Some characteristics of the nonsupplemented group differed from the supplemented group that may limit the strength of our conclusion that early supplemental protein increases visceral protein synthesis. Also, because we did not prospectively record nutrition intake in this group as we did for the supplemented group, we cannot directly compare the amount of protein they received. We only indirectly know that they received less protein by virtue of there being no modular protein administration recorded in the medical record. Despite this limitation, we think our comparisons provide some important insight into the potential biochemical effects of early protein administration.
Finally, our study was neither large enough nor designed to determine the effects of early supplemental protein on important clinical outcomes and instead sought to determine effects on biomarkers. We do not assume that these markers correlate with important clinical outcomes; nevertheless, we are encouraged by our observation that early enteral protein supplementation increases visceral protein synthesis. We have previously reported that serum transthyretin concentrations, measured after 2–3 weeks of critical illness, do reflect early nutrition intake and also correlate with clinical outcomes.10 Although it is therefore reasonable to consider restoration of serum transthyretin concentrations as a surrogate measure of effective nutrition support, we recognize that guidelines do not recommend their use in the management of critically ill patients. Ongoing inflammation, corticosteroid treatment, and organ failure may influence circulating concentrations independently of nutrition support adequacy, and we do not assume our observations are necessarily due to the supplemental protein.
Taken together, these limitations are important and consistent with the limitations of intervention studies that use a nonrandomized design. The best way to test the possible usefulness and benefits of our approach will be in a clinical trial that should have fairly liberal inclusion criteria to allow us to understand whether patients at even greater risk for inadequate nutrition following surgery or traumatic injury benefit from 2 g/kg/d of enteral protein.
Conclusions
Protein intake in critically ill surgical patients can be increased to >2 g/kg/d by using modular enteral protein supplementation. In many patients, this target was achieved by day 3 post admission to the ICU. Complications known to be related to enteral nutrition were uncommon, suggesting this approach is safe.
Footnotes
Statement of Authorship
G. E. O’Keefe and M. Shelton equally contributed to the conception and design of the research; G. E. O’Keefe and M. Shelton contributed to the design of the research; G. E. O’Keefe, M. Shelton, Q. Qiu, and J. C. Araujo-Lino contributed to the acquisition and analysis of the data; G. E. O’Keefe and Q. Qiu contributed to the interpretation of the data; and G. E. O’Keefe drafted the manuscript. All authors critically revised the manuscript, agree to be fully accountable for ensuring the integrity and accuracy of the work, and read and approved the final manuscript.
References
- 1.McClave SA, Taylor BE, Martindale RG, 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. 2016;40(8):159–211. [DOI] [PubMed] [Google Scholar]
- 2.Heyland DK, Weijs PJ, Coss-Bu JA, et al. Protein delivery in the intensive care unit: optimal or suboptimal? Nutr Clin Pract. 2017;32 (suppl 1):58S–71S. [DOI] [PubMed] [Google Scholar]
- 3.Hurt RT, McClave SA, Martindale RG, et al. Summary points and consensus recommendations from the international protein summit. Nutr Clin Pract. 2017;32(suppl 1):142S–151S. [DOI] [PubMed] [Google Scholar]
- 4.Shaw JH, Wolfe RR. An integrated analysis of glucose, fat, and protein metabolism in severely traumatized patients. Studies in the basal state and the response to total parenteral nutrition. Ann Surg. 1989;209(1): 63–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Xiao W, Mindrinos MN, Seok J, et al. A genomic storm in critically injured humans. J Exp Med. 2011;208(13):2581–2590. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Moore FA, Phillips SM, McClain CJ, Patel JJ, Martindale RG. Nutrition support for persistent inflammation, immunosuppression, and catabolism syndrome. Nutr Clin Pract. 2017;32(suppl 1):121S–127S. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Heyland DK, Dhaliwal R, Drover JW, Gramlich L, Dodek P, Committee CCCCPG. Canadian clinical practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients. JPEN. 2003;27(5):355–373. [DOI] [PubMed] [Google Scholar]
- 8.O’Keefe GE, Shelton M, Cuschieri J, et al. Inflammation and the host response to injury, a large-scale collaborative project: patient-oriented research core–standard operating procedures for clinical care VIII–Nutritional support of the trauma patient. J Trauma. 2008;65(6): 1520–1528. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Parent BA, Mandell SP, Maier RV, et al. Safety of minimizing preoperative starvation in critically ill and intubated trauma patients. J Trauma Acute Care Surg. 2016;80(6):957–963. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Parent B, Seaton M, O’Keefe GE. Biochemical markers of nutrition support in critically ill trauma victims. JPEN. 2018;42: 335–342. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Heyland DK, Murch L, Cahill N, et al. Enhanced protein-energy provision via the enteral route feeding protocol in critically ill patients: results of a cluster randomized trial. Crit Care Med. 2013;41(12): 2743–2753. [DOI] [PubMed] [Google Scholar]
- 12.Shaw JH, Klein S, Wolfe RR. Assessment of alanine, urea, and glucose interrelationships in normal subjects and in patients with sepsis with stable isotopic tracers. Surgery. 1985;97(5):557–568. [PubMed] [Google Scholar]
- 13.Reignier J, Boisramé-Helms J, Brisard L, 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(10116):133–143. [DOI] [PubMed] [Google Scholar]