Nutritional support in the ICU

Malnutrition in the critically ill patient

Synonyms

Starvation

Protein-calorie malnutrition

Underfeeding

Related conditions

Marasmus

Kwashiorkor

Sarcopenia

1. Description of the problem

What every clinician needs to know

Malnutrition is common in acutely ill patients, occurring in 30-50% of hospitalized patients. This number may be higher in critically ill patients. Hospital malnutrition has been associated with an increased risk of complications, particularly in surgical patients. Malnutrition in hospitalized patients also increases hospital costs and is associated with increased long-term mortality.

Unfortunately, most patients’ nutritional status often becomes significantly more compromised during their ICU stay. This malnutrition is due to a number of factors, some intrinsic to the patient and some iatrogenic. Most troubling is data showing that more than half of all ICU patients worldwide are significantly underfed based on the calories they are prescribed to receive for the first 2 weeks of ICU care.

In addition to nutrition’s probable key role in survival in the ICU setting following an acute illness/injury, significant mortality occurs after critically ill patients are discharged from the hospital. More than 50% of the 6-month mortality following severe sepsis occurs after the patient has been discharged from the ICU. Many of these deaths are believed to occur indirectly as a result of catabolism, loss of lean body mass, lack of therapeutic physical activity, and ultimately weakness and inability to walk.

These patients often go to rehabilitation centers or go home only to die of pulmonary embolus or pneumonia because they are unable to stand, get out of bed, or perform activities of daily life.

We as acute care physicians see these patients as a “success” because they survived their acute illness and left the ICU. But, many of these patients ultimately die or have severely limited qualities of life. Thus, our job as ICU physicians not only involves providing care for the acute phase of illness with vasopressors, resuscitation, ventilation and antibiotics to enhance survival; we also must learn to minimize the mandatory catabolism that occurs during the acute phase and learn to manage the convalescent phase of severe illness when the key intervention becomes nutrition, anabolism and rehabilitation.

Finally, malnutrition may not be limited to protein, calorie or macronutrient deficits. We have recently discovered that optimal nutrition may hinge not only on how many calories we provide, but also on our ability to provide key pharmacologically acting nutrients (such as glutamine and arginine). This data has helped spawn the new field of “nutritional pharmacology”.

Clinical features

Clinical features of malnutrition in the critically ill patient include:

Loss of more than 10% of usual body weight over last 6 months.
Cachexia, muscle wasting, loss of lean body mass, sarcopenia.
Peripheral edema, anasarca (in the absence of cardiac/vascular cause).
Weakness, failure to wean from ventilator, inability to ambulate.
Immune dysfunction.
Impaired GI motility, digestion or absorption.
Impaired wound healing.
Increased risk of infection, organ failure, death.

1. A qualified ICU dietician should perform nutrition assessment, as this has been shown to improve nutritional outcomes in the ICU.

2. Early enteral nutrition (EN) should be initiated in all critically ill patients with a functioning gut who are not expected to be taking adequate PO intake (more than 50% of needs) in 48 hours.

3. Patients should receive 1.3-2.0 g/kg/d of protein to ensure adequate protein delivery.

4. feeding should be initiated via nasogastric tube.

5. Promotility agents (metoclopramide and/or erythromycin) should be initiated if EN is not tolerated.

6. Gastric residuals of greater than 350-500 cc’s should be considered GI intolerance of EN.

7. Small bowel feeding tubes should be placed if nasogastric feeding with a promotility agent is not successful.

8. Parenteral nutrition (PN) should be initiated if EN is not at 80% of goal after 48 hours in nutritionally high-risk patients. Defined as: 1. BMI under 25 or BMI over 35; 2. More than 10% weight loss of usual body weight; 3. NPO more than 5 days.

9. PN should likely be initiated at 5-7 days in patients with normal pre-ICU nutritional status who are not taken more than 8-% of goal nutrition via enteral/oral route.

10. EN with supplemental PN does not appear to beneficial in non-chronically malnourished patients with low risk of IC mortality and/or short length of ventilation (less than 3 days) or short expected ICU LOS (less than 5 days). However, signals of benefit are present for supplemental PN in high mortality risk, long-staying ICU patients.

11. Pharmaconutrients are indicated in selected populations:

A. Glutamine: strongly recommended for all ICU patients on PN (0.5 gr/kg/day where IV glutamine is available); recommend enterally in burns and trauma patients (0.5 gr/kg/day).

B. Arginine-containing formulas: strongly recommended (enterally) in all pre-surgical patients having major GI, cardiac and ENT surgery regardless of nutritional status; not recommended in sepsis or shock.

C. Fish oil: recommended to be given as continuous enteral infusion with complete enteral feeding in ARDS patients. Does not appear to be efficacious in patients when given as a single agent and/or as bolus doses.

2. Emergency Management

Nutritional management of the ICU patient

Key considerations nutritional therapy for ICU patient: (1) route of feeding: enteral versus parenteral; (2) when to feed: begin within 24-48 hours of ICU admission preferred (early enteral feeding); and (3) what to feed: a standard enteral formula or one with targeted functional pharmaconutrients.

Many ICU patients are incapable or intolerant of a food diet; therefore a clinician’s first nutritional decision is whether to tube-feed enterally, parenterally or a combination of both.

Practice guidelines in the U.S., Canada and Europe endorse enteral feeding for patients who are critically ill and hemodynamically stable. Enteral nutrition is preferred over parenteral nutrition (PN) 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.

For ICU patients who are hemodynamically stable and have a functioning GI tract, early enteral feeding (within 24-48 hours of arrival in the ICU) has become a recommended standard of care. Experts identify these early hours as a window of opportunity to provide nutrition that maintains gut barrier function and supports immune responses.

Even though early enteral nutrition is favored for most ICU patients, caloric and protein needs are often not met by enteral feeding. Nutritional intake may be hampered by setting target levels too low, interruption of feeding for procedures, issues of airway management, and poor tolerance of feedings.

One key take away point from all of the recent trials of PN and calorie delivery is that trials delivering 1.0 – 1.5 g/kg/d of protein consistently show clinical outcome benefit to critically ill patients, whereas studies delivering < 1.0 g/kg/d of protein (such as EDEN and EPaNIC) do not demonstrate outcome benefit. This suggests, as supported by both European and North American Guidelines, that 1.2-2.0 g/kg/day of protein should be delivered to the critically patient.

To enhance the use of enteral feeding in ICU patients, several feeding strategies have been proposed recently: shift from an hourly-rate feeding goal to a 24-hour volume goal, which would allow nurses to “make-up” for interruptions and meet feeding targets; accept gastric residual volumes up to 500 mL to increase the volume of formula delivered in practice; and use a promotility agent to help reduce gastric residual volume.

PN is necessary in critically ill patients who do not have an intact GI tract, but current guidelines do not agree on when it should be initiated. For patients who are intolerant or have other contraindications to enteral feeding, European guidelines recommend starting PN within 24-48 hours if the patient is not expected to be on oral nutrition within 3 days. U.S. guidelines hesitate to recommend PN on admission to the ICU in well-nourished patients. In these previously well-nourished patients ASPEN/SCCM guidelines suggest standard care (intravenous fluids), with PN reserved and initiated only after 7 days.

Both the ESPEN and ASPEN guidelines recommend early PN use (within 24 hours of ICU admission) in patients who are malnourished. Canadian guidelines state that PN should not be used in patients with an intact GI tract.

When enteral feeding alone is inadequate, some experts are calling for use of PN and EN together to meet energy and protein targets. Combination regimens are justified by observations that actual enteral intake typically meets only half of prescribed calories in ICU patients. For patients who are expected to be mechanically ventilated more than 72 hours and have body mass index (BMI) scores under 25 or greater than 35, each additional 1000 kcal/day or 30 g protein/day was reported to be associated with reduced mortality.

(Figure 1)

For ICU patients, this algorithm guides how, when, and what feeding formulation to select in order to improve outcomes. It highlights targeted use of anti-inflammatory and immune-modulating formulas.(Abbreviations- AOX- Anti-oxidants, ARG- Arginine, GLN- Glutamine, ω-3- Omega-3 Fatty Acids)

Nutritional management of ICU patients on vasopressors

Patients with extreme hemodynamic instability – with rising plasma/blood/serum lactate concentrations or escalating requirements for vasopressors – are generally not considered candidates for enteral feeding. However, early findings suggest use of early enteral feeding in other vasopressor-dependent patients. In one study, vasopressor-dependent patients who were given enteral feeding within the first 48 hours had a significant survival advantage compared to those whose feeding was delayed; in fact, the sickest patients (on multiple vasopressors) experienced the greatest benefit. It should be noted that this finding is based on an observational study. A confirmatory prospective, controlled study is warranted.

Latest data on supplemental parenteral nutrition in ICU patients

However, clinical evidence for combination EN plus PN feeding remains unclear. Two recent randomized trials have helped clarify this subject. Casaer et al conducted a large, single center prospective, randomized trial (EPaNIC trial) comparing outcomes in critically ill patients on enteral nutrition who had early versus late initiation of PN (early: < 48h after ICU admission, n=2312; late: day 8 or later after ICU admission; n=2328).

Results revealed patients on late-initiation PN had a relative increase of 6% in the likelihood of being discharged alive earlier from the ICU and from the hospital (P=0.04). Those in the late-initiation group also had significantly fewer ICU infections, shorter duration of mechanical ventilation and a shorter course of renal replacement therapy.

Several aspects of the study limit generalizing the findings to all ICU populations:

Patients with chronic malnutrition were not included in the study.
The trial PN formulation did not contain either glutamine or immune-modulating ingredients, nor was there any adjustment for presence/absence of immune-modulating ingredients in enteral feedings.
Patients in the trial received a low protein delivery (median of 0.8 g/kg/day protein [after day 3]) for the study period in the early PN group. This protein target is below what is recommended by most guidelines for critically ill patients (typical recommendation: 1.3-1.5 g/kg/day [ESPEN guidelines]).
The trial examined a low mortality-risk patient group with an average ICU mortality of 6.2% (90d mortality-11.2%) and a relatively low acuity patient group with an ICU LOS of 3.5 days, and a mechanical ventilation period of 2 days.

Accounting for the aforementioned limitations, the EPaNIC trial is unquestionably a key contribution to the literature on supplemental PN use in critical care. We believe the key conclusion is that in low mortality risk, non-chronically malnourished patients, early aggressive calorie delivery via PN does not appear to be beneficial. In contrast, the recently published, single center TICACOS trial showed hospital and 60-day mortality was reduced (p< 0.02 for both timepoints) in a higher mortality-risk group of ICU patients receiving additional calories via enteral nutrition supplemented with PN.

In comparison to the EPaNIC trial, the TICACOS trial was conducted in a higher mortality-risk ICU patient group with an ICU mortality of 25.4% (60 day mortality 47%), ICU LOS of 12 days, and a mechanical ventilation period of 10.75 days. Thus, it is possible that in high mortality risk ICU patients, supplemental PN may improve outcome. Additional trials on the use of enteral nutrition with supplemental PN have recently been completed or are under way. These forthcoming results should continue to clarify the utility of supplemental PN use in the ICU.

3. Diagnosis

Diagnostic criteria and tests

Key diagnostic criteria for malnutrition in an ICU patient: loss of greater than 10% of usual body weight over last 6 months (non-voluntary weight loss).

Key risk factors for malnutrition:

Overweight patients (BMI > 35).
Underweight patients (BMI < 20).
Alcoholism.
NPO > 5 days.
Major GI surgery, oncology, bone marrow transplant, chronic renal failure, liver failure (acute and chronic).
Increased nutritional losses: large open wounds, open abdomen, enteral fistula, major burn injury.

Diagnostic approach

The only literature supported and consistent indicator of ICU malnutrition is a greater than 10% loss of usual body weight in the last 3-6 months. Other physical exam findings and laboratory tests can support this diagnosis; however, they can be caused or influenced by the stress response, inflammation, dilution and other medical conditions.

Physical exam findings include:

Cachexia, muscle wasting, loss of lean body mass, sarcopenia (usually first evidenced by quadriceps wasting).
Peripheral edema, anasarca (in the absence of cardiac/vascular cause).
Loss of subcutaneous fat, evidenced by loose skin, especially on extremities.
Poor healing of chronic wounds or pressure sores.

Diagnostic tests

Laboratory tests including albumen, transferrin, and pre-albumin can be of use in diagnosing malnutrition. However as stated they are affected by many other issues commonly seen in the ICU setting.

Albumin

Albumin has a half-life of about 20 days, and large amounts are stored in the body; thus, patients may already be malnourished before serum albumin levels drop. Serum albumin below 3.5 g/dL is considered low and a level below 2.5 g/dL indicates seriously deficient protein stores. The low values are usually associated with nonhealing pressure sores. Pre-operative albumin levels less than 2.3 are associated with a significant increase in post-operative complications following upper GI surgery. Non-nutritional factors also lower the serum albumin level. These include trauma, sepsis, liver disease and wounds. Albumin is also subject to dilutional effects, as it is a long half-life protein and is rarely useful post-operatively or more than 24-48 hours into an ICU admission.

Transferrin

Transferrin is a more accurate indicator of protein stores. It responds more rapidly than serum albumin to acute changes in nutritional status. Serum transferrin has a shorter half-life (8-10 days) and smaller body stores than albumin. A serum transferrin level below 200 mg/dL is considered low and below 100 mg/dL is considered severe. However, transferrin is a “negative” acute phase reactant and will also be decreased by inflammation and infection.

Pre-Albumin

As a short half-life protein pre-albumin has been hypothesized to be a better marker of acute malnutrition. However, actual experimental data has not shown this to be true. It appears to be a useful marker in states of low or minimal inflammation, likely reflected by a CRP less than 2-5. However, as an acute anabolic protein, pre-albumin will not be produced in the face of significant inflammation or infection. Thus, in the ICU setting it has minimal utility when the CRP is elevated. It will remain low until the infectious source has been resolved or inflammatory response has subsided.

Summary

In most ICUs weekly pre-albumins and CRPs are obtained. When the CRP is less than 2-5 the pre-albumin is looked on as a reasonable marker of nutritional adequacy and presence of malnutrition. Patients with a persistent elevation of their CRP level can be assumed to be at significant risk. However, a chronically reduced pre-albumin in the face of an elevated CRP should not necessarily be an impetus to increase calorie delivery if it is already adequate based on published guidelines.

Other key procedures

Metabolic cart measures can be very useful guides to targeting caloric delivery. Two recently completed randomized controlled trials of targeted calorie delivery in high mortality risk ICU patients have been completed. These trials seem to indicate a mortality or infectious morbidity benefit to targeted calorie delivery using a repeated metabolic cart measure. Metabolic carts measures do have limitations (i.e., cannot be used in patients on > 60% FiOs) and few ICU centers have access to this technology; however, when available they appear highly useful in improving outcomes in high-risk patients.

Pathophysiology

The last 50 years of medicine and critical care have brought great advances in the treatment of disease with novel pharmacologic agents. Largely ignored has been the vital role of basic nutrients and calories in the treatment of critical illness and injury. The shortcomings of our field in delivering nutrition to our sick patients are highlighted by recent data from a worldwide survey of critical care nutrition practice involving nearly 3,000 patients. This data reveals ICUs worldwide deliver approximately 50% of the calories we as physicians prescribe to our patients for the first 2 weeks of ICU care.

Imagine if you as an ICU physician prescribed 1 gram of vancomycin be given daily to your patient dying of MRSA sepsis and you discovered 2 weeks later that only 500 mg were delivered each day? This would never be tolerated, yet when it comes to critical care nutrition delivery it is a daily occurrence in every ICU in the world (except, ironically, Burn Intensive Care Units, where perhaps the most severely injured patients in the hospital reside).

This poor critical care nutrition delivery has resulted from years of poorly designed or non-generalizable trials in the fundamental feeding and nutrition support of our patients. Further, there has been a lack of laboratory-based exploration into the mechanistic science underlying the risks and benefits of nutrition and nutrient administration following injury and illness.

Traditionally, the lack of focus on nutrition as vital therapy in the critical care setting has been due to the observation that in nature acute illness reduces food intake by inducing anorexia, loss of appetite or simply not permitting the organism to forage for food. At its discovery, tumor necrosis factor-alpha (TNF-α) was known as cachexin. This and other cytokines released in the first few hours following stress and injury induces anorexia and catabolism.

The early systemic inflammatory response (SIRS) pathway has been preserved through many years of evolution. Thus, the body has previously utilized anorexia and catabolism in the face of stress and injury as a key survival mechanism. However, it must be realized until the last 150 years if the proverbial “saber-tooth” tiger attacked, you had perhaps 48 hours to recover before you died. Even if you survived your initial injury you were often left behind by your tribe as a liability, for you could not gather food, reproduce, and they likely had to carry you which was less than ideal when other “tigers” were lurking.

Survival from acute injury involved achieving hemostasis and preventing rapid, overwhelming infection. Thus, eating and anabolism were not part of this primal fight for survival. Our understanding and management of this survival mechanism has changed dramatically since the evolution of emergency medicine, surgery, and critical care. Now, we support severely ill and injured individuals through massive injuries.

Thus, while we have learned to accept that lean body mass catabolism is mandatory, long-term survival mandates that we minimize lean body loss by early calorie/substrate delivery in the acute phase. Aggressive feeding, and perhaps pro-anabolic therapy should follow this in the recovery or convalescent phase. We have recently discovered that adequate nutrition may hinge not only on how many calories we provide, but also on our ability to provide key pharmacologically acting nutrients.

For example, rapid mobilization of amino acids stored in muscle is a vital mechanism for survival following acute illness or injury. These amino acids (such as arginine and glutamine) are utilized as obligate nutrient sources for the immune system and gut. Recent data indicates that these amino acids also serve as a key stress signals that initiate activation of fundamental cell protective pathways following an insult. For various teleological reasons, the body becomes rapidly depleted of these substrates and their supplementation may be fundamental for optimal recovery. This data has helped spawn the new field of “nutritional pharmacology.”

Epidemiology

Epidemiology and nutrition’s role in outcome of critical illness

Malnutrition occurs in 30-50% of hospitalized patients. A recent review of the world literature found that in 20 studies since 1990 the mean malnutrition rate in the hospital was 41.7%. Hospital malnutrition has been associated with an increased risk of complications, particularly in surgical patients. Malnutrition in hospitalized patients also increases hospital costs and is associated with increased long-term mortality.

The key to providing successful nutrition therapy appears to begin with initiation of enteral or oral feeding within 24-48 hours of admission to the ICU and appropriate resuscitation. A recent observational cohort study of nutrition practices in 167 ICUs across 21 countries was conducted to evaluate worldwide nutrition practices in 2772 patients.

Despite multiple international guidelines recommending early initiation of enteral nutrition in the ICU, we 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 U.S, it takes over 60 hours to initiate any enteral feeding at all.

As with any pharmacologic therapy, it appears that not all ICU patients are created equal when it comes to need for calories and protein. With the data from the same 3,000 patient multi-national observational cohort study discussed above, body mass index (BMI, kg/m2) was utilized as a surrogate marker of nutritional status prior to ICU admission. Regression models were developed to explore the relationship between nutrition received and 60-day mortality and examine how BMI modifies this relationship.

Overall, study patients received a mean of 1034 kcal/day and 47 g protein/day for the first 14 days. There was a significant inverse linear relationship between the odds of mortality and total daily calories received. An increase of 1000 calories per day was associated with an overall reduction in mortality (odds ratio for 60 day mortality 0.76, 95% confidence intervals [CI] 0.61-0.95, p=0.014).

This beneficial treatment effect of increased calories on mortality was observed in patients with a BMI under 25 and at or above 35 with no benefit for patients in the BMI 25-35 group. Mortality was also reduced for every additional 30 g protein per day given to these patients. This mortality benefit held true after adjusting for acuity of illness and other patient factors. Thus, as with all pharmacologic interventions, some patients may benefit a great deal from provision of calories early in their ICU stay whereas others may not benefit at all. This is key when considering the use of early parenteral nutrition (PN) whether as a primary calorie source or more appropriately as a supplement to often inadequate enteral feeding.

From this data one it might be inferred that early use of PN might be of benefit in patients with a BMI of below 25, or above 35, whereas a patient with a BMI of 25-35 may not benefit from early PN use, and in fact may only be exposed to the inherent risks that PN can carry. A number of large randomized controlled trials (RCTs) are now planned or under way to study this question.

In addition to nutrition’s probable key role in survival in the ICU setting following an acute illness/injury, significant mortality occurs after critically ill patients are discharged from the hospital. More than 50% of the 6-month mortality following severe sepsis occurs after the patient has been discharged from the ICU. Recent data reveal that one third of patients discharged following community acquired pneumonia are dead 1 year later.

These deaths are believed to occur indirectly as a result of catabolism, loss of lean body mass, lack of therapeutic physical activity, and ultimately, weakness and inability to walk. These patients often go to rehabilitation centers or go home only to die of pulmonary embolus or pneumonia because they are unable to stand, get out of bed, or perform activities of daily life. We as acute care physicians see these patients as a “success” because they survived their acute illness and left the ICU.

But, as many of these patients ultimately die or have severely limited quality of life, our job as ICU physicians not only involves providing care for the acute phase of illness with vasopressors, resuscitation, ventilation and antibiotics to enhance survival. We also must learn to minimize the mandatory catabolism that occurs during the acute phase and learn to manage the convalescent phase of severe illness when the key intervention becomes nutrition, anabolism and rehabilitation.

Special considerations for nursing and allied health professionals.

What's the evidence?

Critical Care Nutrition.Com/Canadian clinical practice guidelines. (Website that is updated with latest evidence in many topics in critical care nutrition. Best resource on internet for true evidenced based recommendations for nutrition therapy in the ICU.)

McClave, SA, Martindale, RG, Vanek, VW. “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. vol. 33. 2009. pp. 277-316. (Expert consensus guideline for nutrition therapy in critical care setting from ASPEN and SCCM societies.)

Singer, P, Berger, MM, Van den Berghe, G, Biolo, G, Calder, P. “ESPEN Guidelines on Parenteral Nutrition: intensive care”. Clin Nutr. vol. 28. 2009. pp. 387-400. (Expert consensus guideline for parenteral nutrition therapy in critical care setting from European Nutrition Society [ESPEN] societies.)

Kreymann, KG, Berger, MM, Deutz, NE. “ESPEN Guidelines on Enteral Nutrition: Intensive care”. Clin Nutr. vol. 25. 2006. pp. 210-23. (Expert consensus guideline for enteral nutrition therapy in critical care setting from ESPEN societies.)

Cahill, NE, Dhaliwal, R, Day, AG, Jiang, X, Heyland, DK. “Nutrition therapy in the critical care setting: what is "best achievable" in practice? An international multicenter observational study”. Crit Care. vol. 38. Med. pp. 395-401. (Data from a ~3,000 patient international survey of ICU nutrition practices in 158 ICUs showing that large gaps exist between many clinical recommendations and actual practice in ICUs, and consequently nutrition therapy is suboptimal. Data reveals only 50-60% of prescribed calories are delivered to critically ill patients for first 12 days of ICU stay.)

Alberda, C, Gramlich, L, Jones, N. “The relationship between nutritional intake and clinical outcomes in critically ill patients: results of an international multicenter observational study”. Intensive Care Med. vol. 35. 2009. pp. 1728-37. (Data from International Nutrition Survey of ~3,000 patients demonstrating significant inverse linear relationship between the odds of mortality and total daily calories received. An increase of 1000 calories/day or 30 grams protein/day was associated with an overall reduction in mortality. Effect was greatest in BMIs below 25 or above 35.)

Wischmeyer, P. “Nutritional Pharmacology in surgery and critical care: "You must unlearn what you have learned"”. Curr Opin in Anaesthesiol. vol. 24. 2011. pp. 381-8. (Current review of pharmaconutrition in the critically ill patient.)

Wischmeyer, PE, Heyland, DK. “The future of critical care nutrition therapy”. Crit Care Clin. vol. 26. 2010. pp. 433-41, vii. (Overview of latest thinking in critical care nutrition.)

Drover, JW, Dhaliwal, R, Weitzel, L, Wischmeyer, PE. “Perioperative Use of Arginine-supplemented Diets: A Systematic Review of the Evidence”. J Am Coll Surg. vol. 212. 2011. pp. 385-99. (Key systematic meta-analysis of peri-operative arginine therapy in over 3,200 patients and 32 separate trials. Results reveal peri-operative arginine therapy can reduce infection by 40% following major GI, cardiac and ENT surgery.)

Norman, K, Pichard, C, Lochs, H, Pirlich, M. “Prognostic impact of disease-related malnutrition”. Clin Nutr. vol. 27. 2008. pp. 5-15. (Excellent analysis of all trials examining incidence of malnutrition in hospitalized patients since 1990.

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