Enteral and parenteral nutrition

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Chapter 87 Enteral and parenteral nutrition

Richard Leonard

It is standard practice to provide nutritional support to critically ill patients, in order to

• treat existing malnutrition
• minimise wasting of lean body mass

However, despite the universality of this practice, the evidence underlying it is often conflicting and of disappointingly poor quality.1 The failings in the evidence seem to extend to some of the resulting debates, in which certainty appears inversely proportional to justification.2 Inevitably, these difficulties have led many to seek clarity in meta-analysis; perhaps equally inevitably,3 they have usually been disappointed. On so basic a question as the relative merits of enteral and parenteral routes of feeding, the two most recent meta-analyses have produced conflicting results.4,5 Instead of choosing on which trials to base patient care, it seems the clinician must now decide which meta-analysis to believe.

The problem persists with the publication of numerous clinical practice guidelines,6–11 which differ in important areas, although one at least has been used in a cluster randomised trial showing a 10% reduction in mortality that just failed to reach statistical significance in those intensive care units (ICUs) randomised to use the guideline – the ACCEPT study.6 While such validation does not mean that each component of the ACCEPT guideline (Figure 87.1) is optimal, it does at least provide some support.

image

Figure 87.1 Algorithm for nutritional support used in the ACCEPT trial.6 EN, enteral nutrition, PN, parenteral nutrition.

NUTRITIONAL ASSESSMENT

Objective assessment of nutritional status is difficult in ICU, because disease processes confound methods used in the general population. Anthropometric measures such as triceps skin-fold thickness and mid-arm circumference may be obscured by oedema. Voluntary handgrip strength, a test of functional capacity, is impractical in unconscious patients. Laboratory measures, including transferrin, pre-albumin and albumin levels, lymphocyte counts and skin-prick test reactivity, are abnormal in critical illness. Clinical evaluation – the so-called Subjective Global Assessment – is better than objective measurement at predicting morbidity.12 Historical features of malnutrition include weight loss, poor diet, gastrointestinal symptoms, reduced functional capacity and a diagnosis associated with poor intake. Physical signs include loss of subcutaneous fat, muscle wasting, peripheral oedema and ascites.

While laboratory measures are of little value in assessing nutritional status in critically ill patients, intensivists are increasingly involved in preoperative assessment of patients undergoing major surgery. In these patients the serum albumin and operative site were closely associated with the risk of postoperative complications.13 This raises the possibility that outcomes may be improved by treating preoperative malnutrition identified by a simple screening test.

PATIENT SELECTION AND TIMING OF SUPPORT

There are reasonable grounds to believe that it is better to provide nutritional support to critically ill patients than not to do so. This belief is based on the close association between malnutrition, negative nitrogen and calorie balance and poor outcome, and the inevitability of death if starvation continues for long enough. In otherwise healthy humans this takes several weeks to occur. There is also some direct evidence from small studies of parenteral nutrition in patients with severe head injuries14 and of jejunal feeding in those operated on for severe pancreatitis,15 in which the control groups received little or no nutritional support. Both studies showed decreased mortality in the groups receiving adequate nutrition.

Two questions arise from this, relating to the important problem of when nutritional support should start:

• How long is it safe to leave a critically ill patient without nutrition? In other words, which patients need to be fed artificially because they will be starved for too long, and which can safely wait until they are able to eat?
• If the patient will clearly exceed whatever period is deemed reasonable, is it better to begin feeding immediately? In other words, when should we start to feed?

Quite good evidence now supports the early institution of nutritional support, and the trend is both to tolerate much shorter periods without nutrition and to begin feeding more rapidly after initial resuscitation.

In 1997, recommendations from a conference sponsored by the US National Institutes of Health, the American Society for Parenteral and Enteral Nutrition and the American Society for Clinical Nutrition suggested that nutritional support be started in any critically ill patient unlikely to regain oral intake within 7–10 days.10 The basis for this was that at a typical nitrogen loss of 20–40 g/day dangerous depletion of lean tissue may occur after 14 days of starvation. Others have suggested a maximum acceptable delay of 7 days. A meta-analysis comparing early (first 48 hours after admission to ICU) with late enteral feeding revealed a reduction in infectious complications.16 Two subsequent meta-analyses comparing early enteral feeding with no artificial nutritional support, and early parenteral feeding with delayed enteral feeding, both found a reduction in mortality with early support.17 Finally, early institution of enteral feeding was an important component of the ACCEPT study guideline.6 Patients in this study received nutritional support if they were thought unlikely to tolerate oral intake in the next 24 hours, and the goal was to start feeding within 24 hours of admission to ICU. The weight of evidence is presently in favour of this more aggressive approach.18

NUTRITIONAL REQUIREMENTS OF THE CRITICALLY ILL

ENERGY

Some muscle wasting and nitrogen loss are unavoidable in critical illness, despite adequate energy and protein provision.19 This fact, coupled with the realisation that caloric requirements had previously been overestimated, has led to downward revision of intake, a process which may still be ongoing. In 1997, the American College of Chest Physicians (ACCP) published guidelines recommending a daily energy intake of 25 kcal/kg,9 and this has remained the standard target energy intake for critically ill patients. More recently, concerns have been raised that this may be excessive. An observational study found lower mortality in those patients who received 9–18 kcal/kg/day than in those with higher and lower intakes.20 However, meaningful benefits of hypocaloric feeding have yet to be demonstrated in prospective trials. It is, moreover, extremely important to realise that enterally fed patients frequently fail to achieve their target intake, and that significant underfeeding is certainly associated with worse outcomes.20–22

Attempts have also been made to tailor the energy provided to critically ill patients to their individual needs. Two methods are commonly used, indirect calorimetry and predictive equations.

Indirect calorimetry is the gold standard, and its use is becoming easier with the availability of devices designed for ICU patients. It permits measurement of the resting energy expenditure (REE). This value excludes the energy cost of physical activity, which increases later in the course of an ICU admission.23 Calorimetry reveals deviations from values predicted by equations, such that two thirds of patients in one study were being either under- or overfed.24 On the other hand, it could not be shown that outcomes are improved by the use of calorimetry.25 Moreover, there are no clear data to relate measured REE to total energy expenditure in the individual patient. As a result, many units do not use calorimetry; in those that do, a target energy provision of 1.3 × measured REE is usual.22

There are a large number of equations claiming to predict basal metabolic rate (BMR) on the basis of weight, sex and age. The best known is the Harris–Benedict equation, which dates back more than 80 years. Schofield’s equations were derived anew in the 1980s.26 Correction factors exist to convert predictions of BMR into estimated energy expenditure by adjusting for such variables as diagnosis, pyrexia and activity. In the past these correction factors have been excessive and may have contributed to overfeeding; a more conservative approach is now advocated. The recommendations of the British Association for Parenteral and Enteral Nutrition are:27

1 Determine BMR from Schofield equations (Table 87.1)
2 Adjust BMR for stress (Table 87.2)
3 Add a combined factor for activity and diet-induced thermogenesis

bed-bound, immobile +10%
bed-bound, mobile/sitting +20%
mobile around ward +25%

Table 87.1 Basal metabolic rate in kcal/day by age and gender26

Age Female Male
15–18 13.3 W + 690 17.6 W + 656
18–30 14.8 W + 485 15.0 W + 690
30–60 8.1 W + 842 11.4 W + 870
> 60 9.0 W + 656 11.7 W + 585

W = weight in kg.

Table 87.2 Stress adjustment in the calculation of basal metabolic rate27

Partial starvation (> 10% weight loss) Subtract 0–15%
Mild infection, inflammatory bowel disease, postoperative Add 0–13%
Moderate infection, multiple long bone fractures Add 10–30%
Severe sepsis, multiple trauma (ventilated) Add 25–50%
Burns 10–90% Add 10–70%

Despite the popularity of measurements or estimates of energy expenditure it is not clear that their routine use improves outcome. Many clinicians dispense with both and simply aim to deliver the ACCP’s recommended target of 25 kcal/kg per day.

PROTEIN

Assessment of nitrogen balance by measuring urinary urea nitrogen is too variable to be useful in estimating protein requirements in ICU.28 As there is an upper limit to the amount of dietary protein that can be used for synthesis,29 there is no benefit from replacing nitrogen lost in excess of this. A daily nitrogen provision of 0.15–0.2 g/kg per day is therefore recommended for the ICU population; this is equivalent to 1–1.25 g protein/kg per day. Severely hypercatabolic individuals, such as those with major burns, are given up to 0.3 g nitrogen/kg per day, or nearly 2 g protein/kg per day.27

MICRONUTRIENTS

Critical illness increases the requirements for vitamins A, E, K, thiamine (B1), B3, B6, vitamin C and pantothenic and folic acids.30 Thiamine, folic acid and vitamin K are particularly vulnerable to deficiency during total parenteral nutrition (TPN). Renal replacement therapy can cause loss of water-soluble vitamins and trace elements. Deficiencies of selenium, zinc, manganese and copper have been described in critical illness, in addition to the more familiar iron-deficient state. Subclinical deficiencies in critically ill patients are thought to cause immune deficiency and reduced resistance to oxidative stress. Suggested requirements for micronutrients in critically ill patients vary between authors and depending on route of administration; the most comprehensive guidance30 is reproduced in Tables 87.3 and 87.4. More recent but broadly similar recommendations for some compounds are also available.31

Table 87.3 Vitamin requirements in critical illness30

Vitamin Function Dose
Vitamin A Cell growth, night vision 10000–25000 IU
Vitamin D Calcium metabolism 400–1000 IU
Vitamin E Membrane antioxidant 400–1000 IU
β-Carotene* Antioxidant 50 mg
Vitamin K Activation of clotting factors 1.5 μg/kg per day
Thiamine (vitamin B1) Oxidative decarboxylation 10 mg
Riboflavin (vitamin B2) Oxidative phosphorylation 10 mg
Niacin (vitamin B3) Part of NAD, redox reactions 200 mg
Pantothenic acid Part of coenzyme A 100 mg
Biotin Carboxylase activity 5 mg
Pyridoxine (vitamin B6) Decarboxylase activity 20 mg
Folic acid Haematopoiesis 2 mg
Vitamin B12 Haematopoiesis 20 μg
Vitamin C Antioxidant, collagen synthesis 2000 mg

* Not strictly a vitamin.

Table 87.4 Trace element requirements in critical illness30

Element Function Dose
Selenium Antioxidant, fat metabolism 100 μg
Zinc Energy metabolism, protein synthesis, epithelial growth 50 mg
Copper Collagen cross-linking, ceruloplasmin 2–3 mg
Manganese Neural function, fatty acid synthesis 25–50 mg
Chromium Insulin activity 200 mg
Cobalt B12 synthesis  
Iodine Thyroid hormones  
Iron Haematopoiesis, oxidative phosphorylation 10 mg
Molybdenum Purine and pyridine metabolism 0.2–0.5 mg

Commercial preparations of both enteral and parenteral feeding solutions contain standard amounts of micronutrients. Supplementation of intake of certain antioxidant vitamins and trace elements above these levels is discussed below.

WATER AND ELECTROLYTES

Water and electrolyte requirements vary widely depending on the patient’s condition; typical basal intakes are shown in Table 87.5.

Table 87.5 Water and electrolyte requirements/kg per day

Water 30 ml
Sodium 1–2 mmol
Potassium 0.7–1 mmol
Magnesium 0.1 mmol
Calcium 0.1 mmol
Phosphorus 0.4 mmol

ROUTE OF NUTRITION

When possible patients should be fed enterally. The advantages over the parenteral route are:

• lower cost
• greater simplicity
• possibly fewer infective complications

These appear to be the only advantages of the enteral route. Despite the fervour with which some pursue the debate,2 there is little basis for the widespread belief that the enteral route provides a clear benefit in terms of outcome, and that the advantages of enteral feeding are unassailable.

Two hypotheses are commonly advanced in support of the putative superiority of enteral feeding. First, it appears that the lipid contained within TPN is immunosuppressive. Intravenous lipid is known to suppress neutrophil and reticuloendothelial system function, and a comparison of TPN with and without lipid in critically ill trauma patients showed a lower complication rate in those not receiving lipid.32 Second, enteral feeding may protect against infective complications. Absence of complex nutrients from the intestinal lumen is followed in rats by villus atrophy and reduced cell mass of the gut-associated lymphoid tissue (GALT). Starved humans show these changes to a much lesser extent. Lymphocytes produced in the GALT are redistributed to the respiratory tract, and contribute heavily to mucosal immunity. In mice, this contribution is lost during TPN.

The possibility that multiple organ failure may be driven by translocation of bacteria or endotoxin across an impaired mucosal barrier has been extensively investigated in animals. While it is known that TPN is associated with increased gut permeability to macromolecules in humans, this does not seem to result in translocation.33 Although translocation does occur following surgery, and seems to be associated with sepsis;34 a causal relation with multiple organ failure is unproven. In fact, a reduction in septic morbidity has only been found in certain groups, primarily abdominal trauma victims,35,36 in whom parenteral nutrition was associated with a higher incidence of abdominal abscess and pneumonia. A third study found no difference.37 In head-injured patients there is one trial showing no effect and one each supporting either route; however in the study favouring TPN the enteral nutrition group were grossly underfed.14,38,39

None of these studies is less than 15 years old, and the techniques of both enteral and parenteral feeding have changed a great deal in that time. Reductions in septic complications have also been found using enteral feeding in pancreatitis.40 In contrast, no benefit was found in sepsis, though enteral feeding was instituted late.41 A review of 31 clinical trials comparing enteral with parenteral feeding found no consistent difference.42

More recent systematic analyses have, as mentioned earlier, produced conflicting results. One found a reduction in infectious complications with enteral feeding, but no difference in mortality.5 The most recent and most robust meta-analysis considered only high-quality trials using an intention-to-treat principle. It showed a clear reduction in mortality in patients fed parenterally.4

The same authors performed a prospectively defined subgroup analysis comparing early enteral with parenteral feeding, which showed no difference in mortality. Another recent meta-analysis of this question reached the same conclusion.43 On this basis, as in the ACCEPT study, the authors recommended early use of the enteral route, with rapid recourse to parenteral nutrition if this was not possible.6,17 At present it appears that timing of nutritional support matters as much as the route used.

A well-powered randomised study comparing early parenteral with enteral feeding will soon start.18 However, in view of the practical and financial advantages of enteral feeding, it will probably need to find a significant mortality difference in favour of the parenteral route if it is to change the present preference for enteral feeding.

ENTERAL NUTRITION

ACCESS

Nasal tubes are preferred to oral, except in patients with a basal skull fracture, in whom there is a risk of cranial penetration. A large-bore (12–14 Fr) nasogastric tube is usually used at first. Once feeding is established and gastric residual volumes no longer need to be checked this can be replaced with a more comfortable fine-bore tube. A stylet is needed to assist in passage of fine-bore tubes. The position of all tubes must be checked on X-ray before feeding is started, as misplacement is not uncommon and intrapulmonary delivery of feed is potentially fatal.

Nasojejunal tubes are beneficial if impaired gastric emptying is refractory to prokinetic agents6 (see below) or in pancreatitis. Spontaneous passage through the pylorus following blind placement is not reliable, but may be increased by the administration of single doses of 200 mg erythromycin or 20 mg metoclopramide.44 However endoscopic or fluoroscopic assistance is needed for truly reliable transpyloric tube placement, although new developments in tube technology may soon obviate the logistic difficulties these methods entail. Unsurprisingly, two meta-analyses of various inconclusive studies have produced conflicting results on the question of whether nasojejunal feeding reduces the risk of aspiration or ventilator-associated pneumonia.7,45 At present, the uncertain quality of the evidence concerning their benefits, coupled with the cost and logistic difficulty of placing them, precludes the routine use of nasojejunal tubes for all patients.

An alternative method of access in those needing long-term enteral feeding is percutaneous gastrostomy, which is usually performed endoscopically. Percutaneous jejunal access can be obtained either via a gastrostomy or by direct placement during incidental laparotomy.

REGIMEN

Slowly building up the rate of feeding is not proven to avoid diarrhoea or high gastric residual volumes. Head-injured patients fed with target intake from the outset have fewer infective complications.46 Nonetheless, it is presently common practice to start delivering around 30 ml/hour and build up to the target intake depending on tolerance, as judged by gastric residual volumes. These are assessed by aspiration of the tube every 4 hours. Gastric residual volumes over 150 ml on two successive occasions have been associated with an increased incidence of ventilator-associated pneumonia;47 contrastingly, others have found no link between high residual volumes and the risk of aspiration.48 Nevertheless, if the residual volume is consistently greater than 200 ml, treatment with prokinetic agents (metoclopramide 10 mg every 8 hours or erythromycin 250 mg every 12 hours intravenously) appears to increase tolerance of feeding, though there is no discernible effect on mortality or morbidity.44 In refractory cases a nasojejunal tube often permits successful enteral feeding, because small bowel function is resumed quicker than gastric emptying. A nasogastric tube is still needed to drain the stomach. Diarrhoea, abdominal distension, nausea and vomiting may suggest intolerance, despite low gastric volumes. Absence of bowel sounds is common in ventilated patients and should not be taken to indicate ileus.

Fine-bore tubes should not be aspirated as this causes them to block. Various folk remedies have been tried for unblocking tubes, including instillation of Coca-ColaTM fruit juice and pancreatic enzyme supplements. The instillates should be left in situ for an hour or more.

COMPOSITION

Commercially available enteral feeding solutions vary widely in composition. Polymeric feeds contain intact proteins (derived from whey, meat, soy isolates and caseinates) and carbohydrates in the form of oligo- and polysaccharides. These require pancreatic enzymes for absorption.

Elemental feeds with defined nitrogen sources (amino acids or peptides) are not of benefit when used routinely, but may enable feeding when small bowel absorption is impaired, for instance in pancreatic insufficiency or following prolonged starvation. Lipids are usually provided by vegetable oils consisting mostly of long-chain triglycerides, but some also contain more easily absorbed medium-chain triglycerides. The proportion of non-protein calories provided as carbohydrate is usually two thirds.

Electrolyte composition varies widely, with sodium- and potassium-restricted formulations available. Vitamins and trace elements are usually added by the manufacturers so that daily requirements are present in a volume containing roughly 2000 kcal. The possible benefits of providing additional doses of some of these substances to critically ill patients are considered below.

COMPLICATIONS

Enteral feeding is an independent risk factor for ventilator-associated pneumonia.49 Sinusitis due to nasogastric intubation may necessitate changing to an orogastric tube. Fine-bore tubes are vulnerable to misplacement in the trachea or to perforation of the pharynx, oesophagus, stomach or bowel. Percutaneous endoscopic gastrostomy is associated with a high 30-day all-cause mortality in acutely ill patients, in whom it may be best avoided.50 Other complications include insertion site infection, serious abdominal wall infection and peritonitis. Surgically placed jejunostomies can cause similar problems, and may also obstruct the bowel.

Diarrhoea is common in ICU patients, particularly those being fed enterally. It is often multifactorial and causes considerable distress and morbidity, particularly when the patient is repeatedly soiled with watery stool. Common causes include antibiotic therapy, Clostridium difficile infection, faecal impaction and a non-specific effect of critical illness. Malabsorption, lactose intolerance, prokinetic agents, magnesium, aminophylline, quinidine and medications containing sorbitol (e.g. paracetamol syrup and cimetidine) are occasional culprits. Rate of administration of enteral feed also plays a role. Faecal impaction, medication-induced diarrhoea and C. difficile infection must be excluded or treated, while malabsorption may respond to elemental diet. Slowing the rate of feeding sometimes helps; diluting the formula does not.

Metabolic complications include electrolyte abnormalities and hyperglycaemia. Severely malnourished patients are at risk of refeeding syndrome (see below) if nutritional support is begun too rapidly.

PARENTERAL NUTRITION

Parenteral nutritional support is indicated when adequate enteral intake cannot be established within an acceptable time. In some cases, absolute gastrointestinal failure is obvious, while in others it only becomes apparent after considerable efforts to feed enterally have failed. As discussed above, there is increasing evidence that if enteral feeding cannot be established early, then the parenteral route should be used until it can. Nevertheless, the aim in all patients fed intravenously should be to revert to enteral feeding as this becomes possible.

Parenteral feeding solutions may be prepared from their component parts under sterile conditions. Ready-made solutions also exist, but any necessary additions must be made in the same way.

In ICU patients the daily requirements are infused continuously over 24 hours. Careful biochemical and clinical monitoring is important, particularly at the outset (Table 87.6).

Table 87.6 Minimum monitoring during total parenteral nutrition. Less stable patients may require more intensive surveillance

Nursing Temperature
Pulse
Blood pressure
Respiratory rate
Fluid balance
Blood sugar (4 hourly when commencing feed)
Daily (at least) Review of fluid balance
Review of nutrient intake
Blood sugar
Urea, electrolytes and creatinine
Weekly (at least) Full blood picture
Coagulation screen
Liver function tests
Magnesium, calcium and phosphate
Weight
As indicated Zinc
Uric acid

ACCESS

The major concern with central venous access for TPN is prevention of infection. The following considerations apply:51

• insertion site: subclavian lines have lower infection rates than internal jugular or femoral lines
• tunnelling may reduce infection rates in internal jugular lines but apparently not in short-term subclavian lines. It is not recommended for routine use
• expertise of operator and adequacy of ICU nurse staffing levels affect infection rate
• skin preparation: 2% chlorhexidine in alcohol is the most effective
• sterile technique: maximal sterile barrier procedures (mask, cap, gown, gloves, and large drape) are known to reduce catheter-related bacteraemia rates sixfold. There is a bewildering resistance to use of these precautions outside ICUs
• dressings: permeable polyurethane transparent dressings are superior to impermeable
• antimicrobial catheters: catheters coated with either chlorhexidine and silver sulfadiazine or rifampicin and minocycline are several times less likely to cause bacteraemia than standard polyurethane catheters. The duration of the anti-infective effect appears to be longer with the antibiotic-coated catheters (2 weeks versus 1 week)
• scheduled exchange has not been proven to reduce catheter-related sepsis
• guide-wire exchange is associated with increased bacteraemia rates, which in routine use outweigh the reduced mechanical complications

In practice, pre-existing central access is used in the first instance. If a multilumen catheter is used, one lumen should be dedicated to administration of TPN and not used for any other purpose. Three-way taps should be avoided and infusion set changes carried out daily under sterile conditions. For long-term TPN (more than 2 months) specialised catheters with a tunnelled cuff or a subcutaneous port are recommended.

COMPOSITION

ENERGY

Energy is provided by a combination of carbohydrate and lipid. The optimal balance between the two is unknown; often 30–40% of non-protein energy is given as lipid. Alternatively, glucose may be relied upon for almost all the energy, with lipid being infused once or twice a week to provide essential fatty acids.

Glucose is the preferred carbohydrate and is infused as a concentrated solution. Exceeding the body’s capacity to metabolise glucose (4 mg/kg per min in the septic patient) can lead to hyperglycaemia, lipogenesis and excess CO2 production. Endogenous insulin secretion increases to control blood sugar levels. However, many patients require additional insulin, particularly diabetics. This may be infused separately, but when requirements are stable it is more safely added to the TPN solution. Persistent hyperglycaemia is better addressed by reducing the glucose infusion rate than by large doses of insulin.

Lipid provides essential fatty acids (linoleic and linolenic acids) and a more concentrated energy source than glucose. It may thus avoid the complications of excess glucose administration. However, there are concerns of immunosuppression from lipid infusion, as discussed above. Current lipid preparations consist of soybean oil emulsified with glycerol and egg phosphatides.

NITROGEN

Nitrogen is supplied as crystalline solutions of L-amino acids. Commercially available preparations vary in their provision of conditionally essential amino acids. Glutamine, tyrosine and cysteine are absent from many because of instability.

MICRONUTRIENTS

Vitamin and trace element preparations are added to TPN solutions in appropriate amounts. Thiamine, folic acid and vitamin K are particularly vulnerable to depletion and additional doses may be necessary.

ELECTROLYTES

Amino acid preparations contain varying quantities of electrolytes; additional amounts may need to be added to the solution.

COMPLICATIONS

Parenteral nutrition has the potential for severe complications.

• Catheter-related sepsis is addressed above. Other complications of central venous cannulation are discussed elsewhere
• Electrolyte abnormalities include hypophosphataemia, hypokalaemia and hypomagnesaemia, especially in the first 24–48 hours
• Hyperchloraemic metabolic acidosis may result from amino acid solutions with a high chloride content. Replacing some chloride with acetate in the TPN solution will resolve this where necessary
• Rebound hypoglycaemia may occur when TPN is discontinued suddenly. TPN should be weaned over a minimum of 12 hours. If it cannot be continued, an infusion of 10% dextrose should be started and blood sugars closely monitored
• Refeeding syndrome may occur when normal intake is resumed after a period of starvation. It is associated with profound hypophosphataemia, and possibly hypokalaemia and hypomagnesaemia. With the restoration of glucose as a substrate, insulin levels rise and cause cellular uptake of these ions. Depletion of ATP and 2,3-DPG results in tissue hypoxia and failure of cellular energy metabolism. This may manifest as cardiac and respiratory failure, with paraesthesiae and seizures also reported. Thiamine deficiency may also play a part
• Liver dysfunction is common during TPN. Causes include hepatic steatosis, intrahepatic cholestasis and biliary sludging from gallbladder inactivity. The problems necessitating TPN in the first place may also cause liver dysfunction
• Deficiencies of trace elements and vitamins (especially thiamine, folic acid and vitamin K) may occur

NUTRITION AND SPECIFIC DISEASES

ACUTE RENAL FAILURE

The advent of continuous renal replacement therapy means that dietary fluid and protein restriction is rarely necessary in ICU. Use of specialised lipid or amino acid formulations in TPN is not supported by evidence, and in general normal nutritional support is appropriate in acute renal failure.

LIVER DISEASE10,52

Energy requirements in ICU patients are not altered by the presence of chronic liver disease. Lipolysis is increased, so lipid must be used with caution to avoid hypertriglyceridaemia (not more than 1 g/kg per day). Protein restriction may be required in chronic hepatic encephalopathy; starting with 0.5 g/kg per day, the dose may be cautiously increased towards a normal intake. Hepatic encephalopathy may in part be due to depletion of branched-chain amino acids (BCAAs) permitting increased cerebral uptake of aromatic amino acids, which produce inhibitory neurotransmitters. In protein-intolerant patients the use of feeds enriched with BCAAs may permit greater protein intake without worsening encephalopathy. Their routine use is not indicated.17 Thiamine and fat-soluble vitamin deficiencies are common in patients with chronic liver disease.

Fulminant hepatic failure reduces gluconeogenesis; hypoglycaemia is a common problem necessitating glucose infusion. Lipid is well tolerated. Energy and protein requirements are similar to those above. BCAAs have not been shown to be superior to standard amino-acid solutions.

RESPIRATORY FAILURE

Oxidation of fat produces less carbon dioxide than glucose. There have been attempts to use this to assist in weaning from mechanical ventilation by providing 50% of energy intake as lipid, with mixed results. Avoidance of overfeeding is much more important.

ACUTE PANCREATITIS

Until recently, TPN was a cornerstone of the management of severe acute pancreatitis to minimise pancreatic stimulation. This has changed with the publication of studies showing jejunal feeding to be safe, effective and associated with reductions in infective complications compared with TPN.40 Elemental feeds and pancreatic enzyme supplements are logical if malabsorption is a problem. Despite the shift towards enteral feeding of patients with pancreatitis, some can only be fed intravenously.

OBESITY

The possibility that obese patients specifically may benefit from hypocaloric feeding was assessed by comparing 40 obese patients fed target intakes of < 20 or 25–30 kcal/kg per day.53 Other than a reduction in ICU stay, no benefit was shown. At present there is insufficient evidence to justify feeding obese patients differently from others.

ADJUNCTIVE NUTRITION

Certain substances have been used as adjuncts to feeding solutions, in attempts to modulate the metabolic and immune responses to critical illness. While this is an area of much promise, in general no conclusive benefit has yet been shown in unselected critically ill patients. The situation has been complicated by a tendency to study several compounds simultaneously, at arbitrary doses and in heterogeneous populations, then to perform retrospective subgroup analysis in order to demonstrate an effect. The evidence would be a great deal clearer if supplements with an established therapeutic window were evaluated individually. Such interventions are at least as much matters of pharmacology as of nutrition, and should be investigated as such.

GLUTAMINE

Glutamine serves as an oxidative fuel and nucleotide precursor for enterocytes and immune cells, mainly lymphocytes, neutrophils and macrophages. It also appears to regulate the expression of many genes related to signal transduction and to cellular metabolism and repair. During catabolic illness glutamine is released in large quantities from skeletal muscle, in order to supply this need. In these circumstances it may become ‘conditionally essential’ and is vulnerable to depletion, with potentially adverse effects on gut barrier and immune function, which may in turn impair the ability to survive a sustained period of critical illness once glutamine stores are depleted.

The evidence on glutamine supplementation in critical illness is as contradictory as in other areas of nutritional support. Reductions in infectious complications and length of ICU stay were shown in small early studies of enterally fed trauma and burns patients, but a much larger study in unselected ICU patients found no effect on any outcome.54 TPN solutions have historically contained no glutamine because of problems with stability and solubility. These are now being overcome by use of dipeptides, but clinical studies of intravenous glutamine supplementation during TPN have also been conflicting. One early trial in ICU patients requiring TPN showed a reduction in late mortality which only became apparent after 20 days, and which persisted at 6 months.55 There are suggestions from meta-analysts that there is now a demonstrable mortality benefit from higher doses of parenteral glutamine;56 this awaits confirmation in a prospective trial. In the meantime, it seems that the patients most likely to benefit are those requiring TPN for more than 10 days.55

SELENIUM

Selenium is crucial to the regulation of glutathione peroxidase, the major scavenging system for oxygen free radicals. Low plasma selenium levels are common in ICU patients, and a number of small studies have shown potential benefits, again mostly when larger doses are given intravenously. A very recent large randomised trial of selenium 1000 μg intravenously for 14 days has shown a reduction in mortality when patients breaching trial protocols were excluded, but the intention-to-treat analysis did not reach statistical significance.57 Parenteral selenium supplementation may well soon be proven to be beneficial in unselected ICU patients.

ANTIOXIDANT VITAMINS

Vitamins A, C and E are also involved in systemic defence against oxidant stress, and have been studied in various combinations and doses, with and without selenium. Of the trials not using selenium, only one has shown a reduction in deaths using large enteral doses of vitamins C and E; the control group, however, had a very high mortality rate.58 It is hard to recommend routine supplementation with antioxidant vitamins on present evidence.

ARGININE AND IMMUNONUTRITION

Arginine is a non-essential amino acid which acts as a precursor of nitric oxide, polyamines (important in lymphocyte maturation) and nucleotides. Animal studies suggest enhanced cell-mediated immunity and survival when arginine is supplemented. Several commercially available enteral feeding solutions combine omega-3 fatty acids, arginine, nucleotides and in one case glutamine to produce so-called immune-enhancing diets. They have been assessed in a number of trials, few of them in patient groups likely to be admitted to ICU outside North America. Meta-analysis has suggested reductions in hospital stay and infections, but not in mortality.59,60 Subgroup analysis revealed an increase in mortality when arginine supplementation was given to septic patients;60 interim safety assessment of a randomised controlled trial61 led to its early cessation when this finding was replicated in the subgroup of patients with sepsis, though this may have been a chance effect.17

At present it appears that such diets should not be used in septic patients. While there are suggestions of benefit in other groups, notably patients undergoing major surgery or suffering a burn injury, there is little basis for their general use in ICU patients unless it is justified by future adequately powered prospective trials comparing their individual components with meaningful controls.

REFERENCES

1 Doig GS, Simpson F, Delaney A. A review of the true methodological quality of nutritional support trials conducted in the critically ill: time for improvement. Anesth Analg. 2005;100:527-533.

2 Marik PE, Pinsky M. Death by parenteral nutrition. Intensive Care Med. 2003;29:867-869.

3 LeLorier J, Gregoire G, Benhaddad A, et al. Discrepancies between meta-analyses and subsequent large randomized, controlled trials. N Engl J Med. 1997;337:536-542.

4 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;31:12-23.

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