Parenteral nutrition and calorie delivery in the ICU: controversy, clarity, or call to action?

Transcription

1 EDITORIAL C URRENT OPINION Parenteral nutrition and calorie delivery in the ICU: controversy, clarity, or call to action? Paul Wischmeyer Purpose of review This review will highlight recent data evaluating the role of parenteral nutrition and calorie delivery in the intensive care setting. Specific focus will be placed on recent trials of early and/or supplemental parenteral nutrition (SPN) and optimization of calorie delivery in ICU patients on the basis of nutrition risk and acuity of illness. The potential key role of protein delivery in outcome will also be discussed. Recent findings Recent randomized clinical trial (RCT) evidence reveals conflicting results around the use of SPN utilized to augment insufficient enteral nutrition. These trials had significant differences with regard to acuity of illness (mortality risk), method of calorie delivery, and protein intake. Recent observational trials reveal a patient s preillness nutrition status and adequacy of protein intake may be vital determinants of the effect of SPN and optimal calorie delivery on outcome. Summary The conflicting results of recent RCTs of SPN have provided clarity into the factors defining which patients may benefit from additional calories/protein and which may not. These data, combined with key, large observational studies elicit a clear call to action for trials examining the benefit of optimal calorie/protein delivery in high mortality risk, high preillness nutrition risk patients. Keywords calories, clinical outcome, critical care, nutrition risk, parenteral nutrition, protein, total parenteral nutrition INTRODUCTION Worldwide, there is considerable controversy around the optimal amount of and route of feeding in critically ill patients. Practice guidelines in Europe, Canada, and the United States endorse enteral feeding for patients who are critically ill and hemodynamically stable [1 3]. Enteral nutrition is preferred over parenteral nutrition for most ICU patients, an evidence-based practice supported by numerous clinical trials involving a variety of critically ill patient populations, including those with trauma, burns, head injury, major surgery, and acute pancreatitis [3,4]. For ICU patients who are hemodynamically stable and have a functioning gastrointestinal tract, early enteral feeding (within h of arrival in the ICU) has become a recommended standard of care [1 3]. To evaluate the success of enteral nutrition delivery in the ICU, a recent observational cohort study of nutrition practices in 167 ICUs across 21 countries was conducted to evaluate worldwide nutrition practices in 2772 patients [5 ]. Despite the multiple international guidelines recommending early initiation of enteral nutrition in the ICU, the data revealed practitioners worldwide are only successful in delivering approximately 50% of prescribed daily calories for the entire first 2 weeks of ICU admission. In addition, in some major developed countries, like the United States, it takes over 60 h to initiate any enteral feeding at all. Because of this consistent and long-standing failure to deliver prescribed enteral nutrition in critically ill patients, parenteral nutrition has been utilized in 35 70% (based on large observational datasets) [5 ] of critically ill patients who do not Nutrition Therapy Services, University of Colorado School of Medicine, Aurora, Colorado, USA Correspondence to Paul Wischmeyer, MD, Professor of Anesthesiology, Associate-Chairman for Clinical and Translational Research, Director of Nutrition Therapy Services, University of Colorado School of Medicine, East 19th Avenue, Box 8602, RC2 P , Aurora, CO 80045, USA. Tel: ; fax: ; Paul.Wischmeyer@ucdenver.edu Curr Opin Crit Care 2012, 18: DOI: /MCC.0b013e be5 Volume 18 Number 2 April 2012

2 Parenteral nutrition and calorie delivery in the ICU Wischmeyer KEY POINTS Recent randomized controlled trials (RCTs) of parenteral nutrition use in the ICU show conflicting results with regard to clinical benefit of early parenteral nutrition and parenteral nutrition supplementation of enteral nutrition. Recent trials of parenteral nutrition use in the ICU reveal potential benefit of parenteral nutrition and early, aggressive calorie support may be dependent on mortality risk of the patient, with high mortality risk patients more likely to benefit from early parenteral nutrition use and low mortality risk patients showing no benefit of early parenteral nutrition use. Recent data indicate that patients with significant preillness malnutrition (as evaluated by BMI <25 or >35) are more likely to benefit from early, aggressive calorie and protein delivery. Adequate protein delivery ( g/kg per day), as prescribed by current ICU nutrition guidelines, is likely required to show any optimal benefit from early calorie delivery, this benefit of protein delivery may be independent of reaching energy goals alone. The conflicting results of current parenteral nutrition and calorie delivery studies, and the lack of a definitive multicenter RCT delivering adequate protein requirements indicates there is a great need for a multicenter RCT of parenteral nutrition supplementation of enteral nutrition (with appropriate protein delivery). This type of definitive trial, in which basic guidelinebased calorie and protein goals are reached, in high mortality risk ICU patients is needed before any generalized practice recommendation regarding ICU parenteral nutrition use can be made. have an intact gastrointestinal tract or who can not meet goal calories via the enteral route, but current guidelines do not agree on when to initiate parenteral nutrition in the ICU [6 & ]. For patients who are intolerant or have other contraindications to enteral nutrition, European (ESPEN) guidelines recommend starting parenteral nutrition within h if the patient is not expected to be on full oral nutrition within 3 days [7]. US [American Society for Parenteral and Enteral Nutrition (ASPEN)/Society of Critical Care Medicine] guidelines hesitate to recommend early parenteral nutrition in the ICU; standard care (intravenous fluids) is recommended first, with parenteral nutrition reserved and initiated only after 7 days in well nourished patients [3]. Both the ESPEN and ASPEN guidelines recommend early parenteral nutrition use (within 24 h of ICU admission) in patients who are malnourished [3,7]. However, no clear definition of who is malnourished has been defined. Examining existing clinical trial data for parenteral nutrition use in the ICU reveals there have been numerous trials comparing enteral nutrition versus parenteral nutrition. In these randomized controlled trials (RCTs), patients in parenteral nutrition groups achieve target energy intake rapidly after initiation, whereas patients in enteral nutrition groups may take several days to achieve target intake, and often never achieve targeted energy goals. This failure results in a substantial energy debt. Four meta-analyses of enteral nutrition versus parenteral nutrition (three in critically ill patients [1,4,8] and one that also included hospitalized patients [9]) have reached conflicting conclusions. In ICU analyses, two concluded there was no difference in mortality between patients receiving enteral nutrition or parenteral nutrition, but fewer infectious complications were associated with enteral nutrition use [1,4]. The third concluded in patients unable to receive enteral nutrition within 24 h of ICU admission, the addition of parenteral nutrition led to a mortality benefit of parenteral nutrition use. It should be noted that virtually all the trials in these analyses were more than 10 years old, quite small/ underpowered, many utilized antiquated hyperalimentation practices, and all were performed prior to initiation of standard glycemic control protocols in the ICU. Thus, given that various national guidelines make opposing recommendations on the role of parenteral nutrition in critical illness, international audits revealing considerable practice variations, and with existing clinical trial data being inconclusive a great need for further evidence and controlled trials of parenteral nutrition use in the ICU has clearly existed. RECENT TRIALS OF PARENTERAL NUTRITION USE IN THE ICU As enteral nutrition alone is often inadequate to meet prescribed caloric needs in the ICU, many experts have called for the use of supplemental parenteral nutrition (SPN) given in addition to enteral nutrition to meet energy and protein targets [6 &,10 12]. Three recent RCTs have addressed the potential clinical benefit of this strategy in ICU patients. Impact of early parenteral nutrition completing enteral nutrition in adult critically ill patients trial Casaer et al. [13 ] conducted a large, single center prospective, randomized trial [impact of early parenteral nutrition completing enteral nutrition in adult ß 2012 Wolters Kluwer Health Lippincott Williams & Wilkins 165

3 Gastrointestinal system critically ill patients (EPaNIC) trial] comparing outcomes in critically ill patients on enteral nutrition who had early (early-parenteral nutrition) versus late initiation of parenteral nutrition (late-parenteral nutrition) (early-parenteral nutrition <48 h after ICU admission, n ¼ 2312; late-parenteral nutrition: parenteral nutrition initiated at day 8 or later after ICU admission; n ¼ 2328). Results revealed patients in the late-parenteral nutrition group had a relative increase of 6% in the likelihood of being discharged alive earlier from the ICU and from the hospital (P ¼ 0.04). Those in the late-parenteral nutrition group also had significantly fewer ICU infections, shorter duration of mechanical ventilation, and a shorter course of renal replacement therapy. No differences in ICU, hospital, or 90-day mortality were observed. Several aspects of the study limit generalizability of the findings to all ICU populations: (1) Patients with chronic malnutrition were not included in the study and many well nourished patients may have been included. The investigators excluded malnourished patients with a BMI less than 17 and used a nutrition risk assessment tool to define nutrition risk for ICU patients [the nutrition risk scores (NRS)]. This tool, although quite useful in hospitalized patients, is less useful in the ICU. The NRS methods study [14] states that this is a scoring system developed to detect the presence of malnutrition and the risk of developing malnutrition in the hospital. This tool is most effective at detecting the potential risk for malnutrition in the routine hospital setting. The NRS s utility in the ICU setting is limited as elderly patients (>70) get 1 point and ICU patients with an APACHE II score more than 10 get 3 points (most all ICU patients). Thus, most ICU patients (whether well nourished or malnourished) get a minimum of 3 points; if elderly, they get 4 points. The inclusion criteria for the EPaNIC trial included adult patients admitted to the ICU with an NRS more than 3, who were not chronically malnourished prior to ICU admission but were potentially at-nutrition risk. Thus, many reasonably well nourished patients admitted to the ICU (i.e., elective surgery, cardiac surgery, myocardial infarction, etc.) would get at least 3 points and would be eligible for enrollment. (2) Patients in the trial received a very low protein delivery [median of 0.8 g/kg per day protein (after day 3)] for the study period in both study groups. (The trial utilized a low protein concentration parenteral nutrition formulation limiting the target protein prescription in the parenteral nutrition patients to 0.8 g/kg per day). This protein target is significantly below what is recommended by most guidelines for critically ill patients [typical recommendation: g/kg per day (ESPEN guidelines [2])]. (3) The trial examined a low mortality risk patient group with an average ICU mortality of 6.2% (90-day mortality 11.2%) and a relatively low acuity patient group with a median ICU length of stay (LOS) of 3.5 days, and mechanical ventilation period of 2 days (median). (4) This trial utilized tight glucose control across all ICU patients and supplemented trace elements, vitamins, and electrolytes in all patients (partial parenteral nutrition) for the entire study period regardless of whether they were in the early-parenteral nutrition or earlyenteral nutrition group. This may have corrected the potential vitamin and trace element deficiencies that could frequently occur in patients receiving insufficient enteral nutrition and late-parenteral nutrition administration. These practices (tight glycemic control and partial parenteral nutrition to all patients) are not standard of care in the majority of ICUs worldwide. However, accounting for the aforementioned limitations, the EPaNIC trial is unquestionably a key contribution to the literature on SPN use in critical care. The key conclusion appears to be that in low mortality risk, nonchronically malnourished patients, early aggressive calorie delivery, with low protein delivery, via parenteral nutrition does not appear to be beneficial. Tight calorie control study trial In contrast, the recently completed tight calorie control study (TICACOS) trial revealed additional calorie and protein delivery via an enteral nutrition and SPN strategy reduced mortality in a high mortality risk critical care population in a singlecenter RCT [15 ]. The patients were randomly allocated to receive targeted goal nutritional therapy according to indirect calorimetry performed every other day (intervention group), or according to the 25 kcal/kg per day calculation (control group). Enteral nutrition was the preferred route for administering nutrition, but SPN was introduced when enteral nutrition was inadequate. Patients in the intervention group received approximately 600 more calories per day (approximately 30%) than the control group (intervention group mean 2096 kcal per day versus control group mean 1480 kcal per day; Volume 18 Number 2 April 2012

4 Parenteral nutrition and calorie delivery in the ICU Wischmeyer P < 0.05). This was largely achieved by additional parenteral nutrition calorie support (intervention groups 479 parenteral nutrition kilocalories per day versus control group 139 parenteral nutrition kilocalories per day; P < 0.05). Although the intervention group had a longer ICU stay and a greater duration of ventilation, these morbidity parameters were offset by a significant reduction in hospital mortality (28 versus 48%, P < 0.03). In a Cox regression analysis, protein intake, as well as energy balance on day 2 3 were the main factors influencing outcome. Limitations of this trial include the single center nature and lack of generalizability of metabolic cart-based energy targets, as our clinical practice observational survey data from 2010 reveals a limited number of ICUs utilize metabolic cart measures. Swiss trial Finally, a very recently completed two-center Swiss trial [16 ] of enteral nutrition and SPN versus enteral nutrition alone was completed in all patients admitted to two ICUs on enteral nutrition having 60% or less enteral nutrition adequacy by day 3 after ICU admission. Patients were required to have a likely ICU length of stay more than 5 days and had a high mortality risk (postdischarge mortality 23%). Energy target was determined by indirect calorimetry on day 3 or set as 25/30 kcal/kg body weight per day for women and men, respectively. Two hundred and seventy five patients were enrolled and significant calorie/protein delivery differences were observed between days 4 8. The results indicate enteral nutrition and SPN allowed optimal energy delivery and was associated with reduced infection rate, antibiotic use, and duration of mechanical ventilation. This trial is limited, as it was not powered for mortality differences. As only abstract data were published at the time of this review more limited data on this trial are available for discussion. In comparing the three recently completed trials of SPN or early parenteral nutrition and enteral nutrition (Table 1), the acuity of illness (as defined by length of stay and need for mechanical ventilation) and mortality of the patients in the negative EPaNIC trial and the positive (for potential benefit of SPN) TICACOS and Swiss trials are quite different. The EPaNIC trial was a lower acuity, lower mortality patient group with an average ICU mortality of 6.2% (90-day mortality 11.2%), an ICU LOS of 3.5 day, and mechanical ventilation period of 2 days (all medians). The TICACOS trial had an ICU mortality of 25.4% (60-day mortality 47%), ICU LOS of 12 days, and a mechanical ventilation period of days. The Swiss trial had a postdischarge mortality of 23%. In the EPaNIC trial a very short median ICU LOS (3.5 days) was observed, it is key to note that no parenteral nutrition (or other trial-based feeding Table 1. Comparison of recent trials of parenteral nutrition in the ICU EPaNIC trial TICACOS trial Swiss Trial ICU LOS (median) 3.5 days 12 days ICU LOS >5 days Hospital LOS (median) 15 days 25 days N/A Mechanically ventilated 2 days days N/A days (median) Mortality ICU 6.2% 25.4% N/A Hospital 10.65% 38.3% N/A Postdischarge 11.2% 47% 23% BMI (mean, unless indicated) 51.6% patients from Target calorie delivery Early-PN 2500; Late-PN 700 SPN-1976; control-1950 SPN-1896; control-1938 (kcal per day) Actual calorie delivery Early-PN 1850; Late-PN 750 SPN-2086; control-1480 SPN-1912; control-1369 (kcal per day) Protein delivery <60 g per day both groups; (mean: 0.8 g/kg after 3 days) Study-76 g/day; (1.0 g/kg per day); control-53 g/day; (0.68 g/kg per day) N/A Metabolic cart targets No Yes Yes Clinical benefit of PN ( ) (þ) Mortality (þ) Infection More limited data available from Swiss trial due to recent completion. EPaNIC, impact of early parenteral nutrition completing enteral nutrition in adult critically ill patients; PN, parenteral nutrition; SPN, supplementation parenteral nutrition; TICACOS, tight calorie control study ß 2012 Wolters Kluwer Health Lippincott Williams & Wilkins 167

5 Gastrointestinal system protocol) was continued per protocol following ICU discharge. Thus, a majority of patients received very limited (<4 days) SPN or clinical study-based calorie delivery. Thus, it is difficult to actually assess impact of SPN calories in these ICU patients as, in most patients, very few days of additional calories were given. Other key differences include the use of metabolic cart-based calorie targets in the TICACOS and Swiss trial, which demonstrated clinical benefit, with no metabolic cart targets utilized in the EPaNIC trial. Metabolic cart targeting of caloric delivery may be key to preventing unintended underfeeding, and equally as important preventing potentially dangerous overfeeding in sick patients. Finally, protein delivery was lower in the EPaNIC trial than in the SPN groups of the other trials. OTHER RECENT CALORIE DELIVERY TRIALS Two other recent clinical trials have examined the outcome effects of different calorie goals on outcome in the ICU. The study by Arabi et al. [17 ] compared permissive underfeeding with target feeding (n ¼ 120 patients/group). In this study, the target-feeding group was set at % of the requirements, whereas the permissive underfeeding group was set at 60 70% of the energy expenditure using the Harris Benedict equation. A significant difference in calories delivery was achieved between the groups. However, this difference was quite small (185 kcal per day) and the percentage of energy administered was % for the target feeding group and % for the permissive underfeeding group (i.e., both groups similarly underfed). Despite this significant limitation, the study conclusion was that permissive underfeeding was associated with lower hospital mortality rates than the group designed to receive target feeding. No other significant outcome differences were observed. This study also achieved a quite insufficient protein delivery (per ESPEN guidelines) in both groups. In the study by Rice et al. [18 ] in mechanically ventilated patients, an even lower energycontaining enteral nutrition strategy was tested with the goal of assessing trophic feeding versus providing optimal nutrition support ( full energy ) [Early Versus Delayed Enteral Feeding (EDEN) pilot trial]. A target of 25 kcal/kg ideal body weight per day was the goal in the full-energy group, reaching 1400 kcal per day (75% of the target) compared with the trophic regimen group (300 kcal per day) for the first 6 days following ICU admission. The authors did not observe any significant difference in clinical outcome between the two groups. Both groups had a median of 21.0 ICU-free days and a median of 23.0 ventilator-free days (VFDs). Mortality to hospital discharge was 22.4% for the trophic group versus 19.6% for the full-energy group (P ¼ 0.62). It should be noted that full-energy delivery was associated with a statistically significant increase in the number of patients discharged to home versus a rehabilitation facility (P < 0.04). Most of the measurements using indirect calorimetry in critically ill patients reach an average of 1800 kcal per day (24 kcal/kg per day) [19], suggesting that in the Rice et al. [20 & ] study, relative underfeeding was compared with trophic feeding. Again, protein delivery was considerably below recommended guidelines in both treatment groups [2]. Adequate protein delivery may be a key factor in optimizing outcomes with nutrition in critical illness, given the results of the recently published trials, which will be subsequently described. Another key recent study addressed the role of preillness nutritional status on the effect of ICU calorie/protein delivery on mortality in high mortality risk ICU patients [12]. This large dataset [2772 ICU patients (defined as expected to require mechanical ventilation >72 h) in 167 ICUs] was generated from an international, prospective, observational, cohort study of nutrition practices in ICUs across the world. BMI (kg/m 2 ) was used as a surrogate marker of nutritional status prior to ICU admission. The average length of mechanical ventilation in this patient group was 9 days (i.e., required prolonged mechanical ventilation). Regression models were developed to explore the relationship between nutrition received and 60-day mortality and VFDs, and examine how BMI modifies this relationship. There was a significant inverse linear relationship between the odds of mortality and total daily calories received. An increase of 1000 kcals per day was associated with an overall reduction in mortality [odds ratio for 60 day mortality 0.76, 95% confidence intervals (CI) , P ¼ 0.014] and an increase in VFDs (3.5 VFD, 95% CI, , P ¼ 0.003). This beneficial treatment effect of increased calories on mortality was observed in patients with a BMI less than 25 kg/ m 2 and more than 35 kg/m 2 with no benefit for patients with a BMI 25 to less than 35 kg/m 2 group. Similar results were observed for feeding an additional 30 g of protein per day (Table 2). All analyses were adjusted for nutrition days, BMI, age, admission category, admission diagnosis, and APACHE II. Given the limitations of BMI as a measure of preinjury nutrition status, this large observational study suggests that the benefit of more aggressive calorie and protein delivery may be dependent on preillness nutrition status in high mortality risk ICU patients Volume 18 Number 2 April 2012

6 Parenteral nutrition and calorie delivery in the ICU Wischmeyer Table 2. Comparison of recent PN and calorie delivery studies in ICU patients EPaNIC TICACOS Swiss EDEN Trial (Rice et al.) (pilot-200 patients) Arabi Trial Alberda International Critical Care Nutrition Survey Weijs Dutch Trial ICU LOS (median) 3.5 days 12 days ICU LOS > 5 days 13.1 days 12 days 19 days Hospital LOS (median) 15 days 25 days 68.7 days 24.2 days 39 days Mechanically ventilated days (median) Mortality days (mean vent days in survivors) 11.9 days 9.0 days 17 days ICU 6.2% 25.4% 19.6% 20.4% Hospital 10.65% 38.3% 21% 36% 34.4% Postdischarge 11.2% 47% 23% 38.6% 29.1% BMI (mean, unless indicated) Protein delivery <60 g/day- both groups (mean: 0.8 g/kg after 3 days) 51.6% patients kg/m kg/m kg/m kg/m 2 <25 kg/m 2, >35 kg/m 2 from kg/m 2 Study-76 g/day (1.0 g/kg per day) control-53 g/day (0.68 g/kg per day) Full energy 54 g per day; trophic 11 g per day (first 7 days then 50 g per day); ( 0.8 g/kg per day) for both groups after 7 days Full feed 43.6 g per day; underfed 47.5 g/d; (0.6 g/kg per day for both groups) for optimal benefit of calorie delivery Recommended: g/kg per day Metabolic cart targets No Yes Yes No No Variable Yes Clinical benefit of PN or additional calorie/ protein delivery 26 kg/m 2 Protein and energy target ¼ 89 g per day (1.31 g/kg per day); energy target ¼ 78 g per day (1.06 g/kg per day); no target ¼ 67 g/day (0.83 g/kg per day) ( ) (þ) Mortality (þ) Infection ( ) ( ) (þ) Mortality (þ) Reduced mortality risk for reaching protein and energy target More limited data for the Swiss trial due to only abstract data being available. EDEN trial utilized ICU-free, hospital-free, and mechanically ventilated free days as outcome measures so more limited comparison data are available. EPaNIC, impact of early parenteral nutrition completing enteral nutrition in adult critically ill patients; PN, parenteral nutrition; TICACOS, tight calorie control study ß 2012 Wolters Kluwer Health Lippincott Williams & Wilkins 169

7 Gastrointestinal system ADEQUATE PROTEIN DELIVERY: THE KEY TO OPTIMAL NUTRITION DELIVERY IN THE ICU? ESPEN guidelines for nutrition support in the critically ill patient recommend a protein delivery of g/kg per day for optimal outcomes [7] (grade B recommendation). The results of the aforementioned EPaNIC trial [13 ] revealed significant protein delivery deficits in both early-parenteral nutrition and late-parenteral nutrition groups. As stated, this was because of the utilization of a lowprotein parenteral nutrition solution, which limited protein delivery to a median of 0.8 g/kg per day throughout the trial period (even out to as long as 15 days in the ICU). This trial also appeared to deliver a maximum of approximately 1.0 g/kg per day to any patient. The TICACOS trial [15 ] delivered approximately 25 g more protein per day in the SPN group versus the standard feeding group. This may be an important increase in protein delivery as the Alberda et al. [12] study revealed that an additional 30 g per day of protein was all that was required to attain a significant reduction in mortality in high mortality risk ICU patients (60-day mortality of 29.1%, ICU LOS 12 days, length of mechanical ventilation 9 days). This concept of a small increase in protein delivery improving outcome may also be supported by the recently reported OMEGA trial [20 & ]. The OMEGA trial had a primary aim to study the effects of eicosapentaenoic acid (EPA)/gamma-linolenic acid (GLA)/antioxidants on clinical outcomes in ICU patients with acute respiratory distress syndrome (ARDS). Although no clinical effect of the EPA/GLA/antioxidants on mortality or other clinical outcomes was observed, there was a presently unexplained significant mortality benefit in patients receiving the control treatment. This group experienced one of the lowest mortalities ever recorded in an ARDS trial. It is interesting to note the EPA/GLA/ antioxidants treated group had a similar mortality to the previously reported optimal mortality in ARDS in the Fluid and Catheter Treatment Trial (FACCT) trial [mortality: OMEGA 26.6% versus FACCT (conservative fluid group) 25.5%]. The observed mortality in the control formula from OMEGA was a surprising 16.3%. A possible explanation for this mortality benefit lies in the realization that the control formula given in the OMEGA trial delivered over five times the amount of protein per day to patients in the higher survival control group (20 g/protein per day from control supplement versus 3.8 g/protein per day from study EPA/ GLA/antioxidant supplement). Although this is only a hypothesis and the OMEGA trial was not designed to detect this possible effect, the protein delivery difference achieved nearly approximates the 30 g per day of protein shown to reduce mortality in ICU patients by Alberda et al. Finally, a recent trial by Wejis et al. [21 ] examined the effect on ICU mortality of reaching protein and energy targets versus reaching only energy targets or neither energy nor protein targets in high mortality risk, (ICU mortality 20.4%, hospital mortality 34.4%) mechanically ventilated ICU patients. This prospective observational cohort trial examined 886 consecutively admitted ICU patients. Only patients requiring prolonged mechanical ventilation and artificial nutrition support (expected length of nutrition support: minimum 7 10 days) were included in the study. Metabolic cart measures were utilized to target energy delivery for all patients. The authors examined the outcomes of three groups of patients on the basis of the success of nutrition delivery during the period of mechanical ventilation. These groups were defined as patients who reached neither energy nor protein target achieved (no target); only energy targets achieved and not protein targets (energy target); protein and energy targets achieved (protein and energy target). Achieving protein target required patients reach a minimum protein delivery of 1.2 g/kg per day. The authors found no difference in age, diagnosis type, or entry APACHE II score. Utilizing hazard ratio analysis, the results showed that significant reductions in the risk of 28-day and hospital mortality were only achieved for the group of patients who achieved protein and energy targets, not energy targets alone. This significant reduction in mortality risk by reaching protein and energy targets became more pronounced when adjusting for sex, age, BMI, diagnosis, hyperglycemic index, and Acute Physiology and Chronic Health Evaluation II score. Adjusting for time to reach energy target and use of parenteral nutrition delivery did not affect the reduction in risk of mortality by reaching both protein and energy targets. Interestingly, as noted in the TICACOS trial, this reduced mortality risk was accompanied by patients in the protein and energy target group demonstrating a longer length of ICU and hospital stay. Other limitations include that the aggressive nutrition support protocol was not continued following weaning from mechanical ventilation and ICU discharge and that actual mean mortality rates were not statistically different between the groups (as was seen in the EPaNIC trial). It is key to note that the protein and energy target group received an average of 1.31 g/kg per day of protein versus 1.06 g/kg per day protein in the energy target alone group and 0.83 g/kg per day protein in the no target achieved group. For reference purposes, in a 70 kg patient, this difference is Volume 18 Number 2 April 2012

8 Parenteral nutrition and calorie delivery in the ICU Wischmeyer only an average of 17.5 g per day of protein increase in the protein and energy group versus the energy alone group, and a difference of 33.6 g per day protein versus the no target group. Again, this finding is quite consistent with the results of the Alberda et al. trial showing a mortality benefit of 30 g per day of additional protein. These authors showed similar benefits of reaching protein and energy targets in reducing hospital length of stay in hospitalized, non-icu patients [22 & ]. Thus, the importance of protein delivery may not be limited to high acuity critical care patients alone. How do we achieve clarity from the conflicting results of recent SPN and calorie delivery studies? The results of the aforementioned studies of SPN and calorie delivery are summarized in Table 2. The results of these trials reveal there appear to be key variables affecting whether aggressive nutrition delivery (with SPN or via enteral nutrition alone) improves clinical outcome. Clearly, all therapeutic interventions in the ICU are not beneficial to all patients. Further, the dose of a particular drug (such as norepinephrine or vancomycin) clearly is not a one-size fits all prescription. All therapies we utilize in the ICU setting have risks and benefits, as such optimal benefit is based on appropriate timing of intervention and doses targeted to the correct patient. There is no reason to believe that nutrition delivery, even simple calorie and protein delivery targets, would be any different. The clarity of the existing data reveals that if we are to make rational decisions about the optimal delivery of nutrition in the ICU a number of factors must be considered as described below. Protein delivery Although RCT confirmation of the benefit of optimal protein delivery is desperately needed, all available data from recent trials point to a benefit of even an additional g per day of protein reducing mortality. This, of course, appears to also require a baseline delivery of protein of 1.0 g/kg per day or greater. However, optimal outcomes may require the ESPEN nutrition guidelines [7] that recommend g/kg per day of protein. It should be noted in patients on hemodialysis, especially continuous hemodialysis (CVVH), greater than 2.0 g/kg per day of protein may be required because of dialysis-driven amino acid loss. It is possible, although unproven, that this fundamental issue confounds the results of virtually all nutrition delivery trials performed in the ICU to date. Achieving guideline recommended protein delivery should be a key focus of any future RCTs in the ICU. Further, given that there is no downside (or clinical risk) to this optimal protein delivery guideline, present clinical practice should become more consistent with published guidelines to deliver g/kg per day of protein. This also requires that parenteral and enteral nutrition formulations need to be produced to allow for the easy delivery of g/kg per day of protein by clinicians. Mortality risk/acuity of illness It appears the acuity of illness and mortality risk of a given patient may be a key predictor of the benefit or risk of aggressive nutrition support with SPN. It will likely be important in future trials (and clinical practice) to ask and evaluate such variables as follows: Is this a patient we expect to be mechanically ventilated more than 3 days? Do we believe this patient has a hospital or long-term (28, 60, or 90 day) mortality risk of greater than 20%? Is this a long stayer? (a patient we expect to be in the ICU >5 days). If the answer to these questions is affirmative, current data says it is more likely the patient will benefit from supplementation of enteral nutrition by SPN. If not, there may be risk to the early use of parenteral nutrition (prior to 5 7 days). Any future trials of this concept likely will need to include an adequate protein delivery (minimum of 1.3 g/kg per day). Preillness nutritional status As described by the data of Alberda et al. it is likely an obvious observation that preinjury malnutrition or lack of nutritional reserve (which appears to occur in obese patients as well as underweight patients) affects the benefit of aggressive nutrition support via enteral nutrition or enteral nutrition and SPN. NRS like the recently published NUTRIC score [23 ] may be quite promising to define this nutrition risk. It is also possible that preillness lean body mass is the best predictor of preillness nutrition status, which can now potentially be assessed by bedside ultrasound in the ICU. This concept of nutrition delivery based on BMI and bedside lean body mass ultrasound assessment is currently being tested by the multicenter, multinational TOP-UP trial of SPN in high mortality risk ICU patients with BMIs less than 25 kg/m 2 or more than 35 kg/m 2. Metabolic cart energy targets An interesting and unexpected finding of the recent SPN and calorie delivery trials is that trials utilizing ß 2012 Wolters Kluwer Health Lippincott Williams & Wilkins 171

9 Gastrointestinal system metabolic cart to guide energy targets consistently led to a benefit of SPN or more aggressive calorie/ protein delivery in high mortality risk ICU patients. This may be because of proper energy targets avoiding both underfeeding and overfeeding. This is a practice with quite limited focused study and outcome data that should be tested in future RCTs. CONCLUSION AND CLINICAL RECOMMENDATIONS Clearly, more research is needed prior to any definitive recommendations for the use of parenteral nutrition in critically ill patients. However, some conclusions can be reached that will likely optimize safety and potentially outcomes for our current patients. These suggested guidelines are based on an interpretation of existing data rather than on any definitive multicenter RCT(s) (as none exist) and no multicenter RCT has yet achieved optimal guideline-recommended protein intake with sufficient power to make any definitive recommendations at this point. (1) In low mortality risk (<10% expected hospital mortality, with expected mechanical ventilation period <48 h, and ICU LOS <5 days), nonmalnourished (BMI 25 35kg/m 2?) ICU patients SPN is not indicated if enteral nutrition can reach goal prescribed calories and a protein delivery more than 1.3 g/kg per day in less than 5 7 days post-icu admission. (2) In high mortality risk patients (with an expected mechanical ventilation period of >48 h and an ICU LOS >5 days) SPN may be useful if goal enteral nutrition is not reached in 48 h. This assumes that adequate protein delivery more than 1.3 g/kg per day will also be achieved. (3) In high mortality risk, malnourished patients, with a BMI of less than 25 kg/m 2 and more than 35 kg/m 2, reaching goal calories by 48 h is likely beneficial. These patients should likely receive SPN if more than 80% goal calories and protein is not being achieved within 48 h or ICU admission. This assumes that an adequate protein delivery of more than 1.3 g/kg per day will also be achieved. (4) In normally nourished ICU patients (BMI kg/m 2?) SPN may not be indicated unless patients fail to meet enteral nutrition calories and protein goals by 5 7 days post- ICU admit. (5) Consistent with existing guidelines, a protein goal of g/kg per day of protein should be reached in all high mortality risk ICU patients. Protein deliveries of g/kg per day should be strongly considered in patients being treated with CVVH. (6) Metabolic cart guidance for determining energy delivery targets should be considered when available. A CALL TO ACTION FOR THE GLOBAL ICU COMMUNITY Undoubtedly, the EPaNIC trial, one of the largest critical care nutrition delivery trials ever performed, is a vital contribution to our understanding of energy delivery. It has provided a foundation that provides a call to action for the ICU community to perform nutrition trials with the size and careful design of other large ICU intervention multicenter RCTs. However, the single-center EPaNIC trial, is not a trial that should lead to generalizable or widespread practice change in the commonly seen highmortality risk ICU patient. It is interesting to note that the results of the EPaNIC trial are quite analogous to the original tight glycemic control data [24], which showed a mortality benefit of tight glycemic control in a low mortality (ICU mortality 6.3%; 90-day mortality of 11.2%) and low acuity group of ICU patients (almost identical to the EPaNIC mortality outcomes). However, when a similar trial was repeated in multicenter fashion in a high mortality (90-day mortality 26.2%) group of ICU patients by the NICE-SUGAR investigators [25], the opposite results were obtained showing an increased risk of death with tight glycemic control. We fear that widespread generalization of the EPaNIC trial to high mortality risk ICU patients will lead to an increase in the already rampant worldwide practice of underfeeding and iatrogenic malnutrition in high mortality risk ICU patients (including patients with significant preillness malnutrition). This type of generalization was observed worldwide following the widespread misinterpretation of the original tight glycemic control trial. The original tight glycemic control study, led to a major shift in glucose control practice for many ICU patients (regardless of mortality risk) that was ultimately shown to be harmful in the higher mortality ICU patients studied in the NICE-SUGAR trial. Given this previous experience and the potential clinical benefits of SPN observed in smaller studies with high mortality risk patients (TICACOS and Swiss trial), it is vital that the potential for benefit of SPN in high mortality, higher nutrition risk patients be explored in a large multicenter RCT before global practice change can be contemplated. We believe this recent history lesson from the glycemic control literature makes the need for additional SPN trials in high mortality risk patients Volume 18 Number 2 April 2012

10 Parenteral nutrition and calorie delivery in the ICU Wischmeyer (utilizing adequate protein delivery), like the ongoing TOP-UP trial, greater then ever. Acknowledgements None. Conflicts of interest P.W. has served as a consultant to Baxter Inc and Fresenius Inc on the subject of appropriate Parenteral Nutrition use in the ICU setting. P.W. receives funding from the National Institutes of Health, U.S. Department of Defense, and the American Burn Association. REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 217). 1. Heyland DK, Dhaliwal R, Drover JW, et al. Canadian clinical practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients. JPEN J Parenter Enteral Nutr 2003; 27: Kreymann KG, Berger MM, Deutz NE, et al. ESPEN Guidelines on enteral nutrition: intensive care. Clin Nutr 2006; 25: McClave SA, Martindale RG, Vanek VW, 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 2009; 33: Gramlich L, Kichian K, Pinilla J, et al. Does enteral nutrition compared to parenteral nutrition result in better outcomes in critically ill adult patients? A systematic review of the literature. Nutrition 2004; 20: Cahill NE, Dhaliwal R, Day AG, et al. Nutrition therapy in the critical care setting: what is best achievable practice? An international multicenter observational study. Crit Care Med 2010; 38: This is a prospective observational study of nutrition practice in over 2700 high mortality risk ICU patients in over 160 ICUs worldwide. This study revealed significant incidence of underfeeding and failure to reach prescribed calorie and protein goals worldwide. 6. & Singer P, Pichard C, Heidegger CP, Wernerman J. Considering energy deficit in the intensive care unit. Curr Opin Clin Nutr Metab Care 2010; 13: This is a critical review of the role of calorie deficit in outcome in the critical care setting. 7. Singer P, Berger MM, Van den Berghe G, et al. ESPEN Guidelines on parenteral nutrition: intensive care. Clin Nutr 2009; 28: Simpson F, Doig GS, Parenteral VS. Enteral nutrition in the critically ill patient: a meta-analysis of trials using the intention to treat principle. Intensive Care Med 2005; 31: Peter JV, Moran JL, Phillips-Hughes J. A metaanalysis of treatment outcomes of early enteral versus early parenteral nutrition in hospitalized patients. Crit Care Med 2005; 33: ; discussion Heidegger CP, Romand JA, Treggiari MM, Pichard C. Is it now time to promote mixed enteral and parenteral nutrition for the critically ill patient? Intensive Care Med 2007; 33: Heidegger CP, Darmon P, Pichard C. Enteral vs. parenteral nutrition for the critically ill patient: a combined support should be preferred. Curr Opin Crit Care 2008; 14: Alberda C, Gramlich L, Jones N, et al. The relationship between nutritional intake and clinical outcomes in critically ill patients: results of an international multicenter observational study. Intensive Care Med 2009; 35: Casaer MP, Mesotten D, Hermans G, et al. Early versus late parenteral nutrition in critically ill adults. N Engl J Med 2011; 365: Large, single center RCT of early-parenteral nutrition versus late-parenteral nutrition initiation in low moratlity risk ICU patients. Revealed no benefit of ealryparenteral nutrition use on mortality or other outcomes. Late-parenteral nutrition use led to reduced infectious complications and 6% increase in the likelihood of being discharged alive earlier from the ICU. 14. Kondrup J, Rasmussen HH, Hamberg O, Stanga Z. Nutritional risk screening (NRS 2002): a new method based on an analysis of controlled clinical trials. Clinical nutrition 2003; 22: Singer P, Anbar R, Cohen J, et al. The tight calorie control study (TICACOS): a prospective, randomized, controlled pilot study of nutritional support in critically ill patients. Intensive care medicine 2011; 37: This is a single center RCT of metabolic cart-guided goal-targeted nutrition delivery versus routine standard nutrition delivery in high mortality risk ICU patients. Patients in the target calorie group received an additional approximately 600 kcal per day and approximately 25 g per day protein, predominantly via supplemental parenteral nutrition. Patients receiving additional calories and protein in the targeted nutrition group experienced a statistically significant reduction in hospital mortality. 16. Heidegger CP, Graf S, Thibault R, et al. Supplemental parenteral nutrition (SPN) in intensive care unit (ICU) patients for optimal energy coverage: improved clinical outcome. Clin Nutr Suppl 2011; 1:2 3 Two center Swiss RCT of standard enteral feeding versus use of supplemental parenteral nutrition in patients having 60% or less enteral nutrition adequacy by day 3 after ICU admission. Patients were required to have a likely ICU length of stay more than 5 days and had a high mortality risk (postdischarge mortality 23%). All nutrition goals guided by metabolic cart. The results indicate enteral nutrition and supplemental PN allows for optimal energy delivery and is associated with reduced infection rate, antibiotic use, and duration of mechanical ventilation. 17. Arabi YM, Tamim HM, Dhar GS, et al. Permissive underfeeding and intensive insulin therapy in critically ill patients: a randomized controlled trial. Am J Clin Nutr 2011; 93: This is an RCT of permissive underfeeding with target feeding. A small, yet significant difference in calorie delivery (185 kcal per day) was achieved between the groups. Despite this limitation, the study conclusion was that permissive underfeeding was associated with lower hospital mortality rates than the group designed to receive target feeding. 18. Rice TW, Mogan S, Hays MA, et al. Randomized trial of initial trophic versus full-energy enteral nutrition in mechanically ventilated patients with acute respiratory failure. Crit Care Med 2011; 39: Randomized controlled pilot trial (EDEN trial) of standard enteral nutrition versus trophic feeding for the first week of ICU care in mechanically ventilated patients. No differences in clinical outcome were noted between the groups, with exception of the full energy delivery group having a statistically significant increase in the likelihood of being discharged home versus a rehabilitation setting. 19. Miles JM. Energy expenditure in hospitalized patients: implications for nutritional support. Mayo Clin Proc 2006; 81: & Rice TW, Wheeler AP, Thompson BT, et al. Enteral omega-3 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury. JAMA 2011; 306: This is a multicenter RCT of EPA/GLA/antioxidant supplement versus a control supplement in ARDS patients. No clinical benefit of experimental supplement was observed. However, an excpetionally low control formula mortality was observed (among the lowest ARDS mortality ever reported in a clinical trial setting 16%). As the control formula contained approximately five times more protein than the experimental formula, increased protein delivery may have contributed to the exceptionally low mortality in the control group. 21. Weijs PJ, Stapel SN, de Groot SD, et al. Optimal protein and energy nutrition decreases mortality in mechanically ventilated, critically ill patients: a prospective observational cohort study. JPEN J Parenter Enterl Nutr 2011; 36: This is a prospective observational cohort trial in 886 high mortality risk, mechanically ventilated ICU patients. The authors examined the outcomes of three groups of patients based on the success of nutrition delivery during the period of mechanical ventilation. These groups were defined as patients who reached neither energy nor protein target achieved (no target); only energy targets achieved and not protein targets (energy target); protein and energy targets achieved (protein and energy target). Achieving protein target required patients reach a minimum protein delivery of 1.2 g/kg per day. Metabolic cart was used to guide energy delivery. Results revealed a statistically significant reduction in the risk of death at 28 days, which was only optimal if both protein and energy targets were achieved. 22. & Weijs PJ, Leistra E, Schipper M, et al. Achieving protein and energy targets in malnourished hospitalized patients on day 4 of admission improves length of hospital stay [abstract]. Clin Nutr Suppl 2011; 1:1219. This is an observational cohort study of hospitalized patients showing reduction in hospital stay was optimal only when both protein and energy goals were reached during hospital stay. 23. Heyland DK, Dhaliwal R, Jiang X, Day AG. Identifying critically ill patients who benefit the most from nutrition therapy: the development and initial validation of a novel risk assessment tool. Critical care 2011; 15:R268. This study describes the development and early validation of a composite nutrition risk score (the NUTRIC score) to predict the risk for malnutrition in critically ill patients. Score appears to be useful for predicting which patients will achieve optimal clinical benefit from aggressive early calorie delivery in the ICU. 24. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001; 345: Finfer S, Chittock DR, Su SY, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009; 360: ß 2012 Wolters Kluwer Health Lippincott Williams & Wilkins 173