Clinical and pharmaceutical management of deficiencies, excesses and infection with nutrition support

Hardy, Gila; Campos, Antoniob

Current Opinion in Clinical Nutrition & Metabolic Care:
Editorial Comment
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aSchool of Biological and Molecular Sciences, Oxford Brookes University, Oxford OX3 0BP UK. bRua Comendador Araujo, 143 cj 113, 804020-000-Curitiba, PR Brazil

Correspondence to Professor Gil Hardy, Professor of Pharmaceutical Nutrition, School of Biological and Molecular Sciences, Oxford Brookes University, Gipsy Lane Campus, Oxford OX3 0BP. Tel/fax: 01865 483449; e-mail:

Abbreviations ARF: acute renal failure BMI: body mass index CRI: catheter-related infections CRRT: continuous renal replacement therapy CVC: central venous catheters FDP: fructose-1,6-diphosphate HPN: home parenteral nutrition ICU: intensive care unit

Article Outline

Topics in the current issue of Current Opinion in Clinical Nutrition and Metabolic Care encompass ‘technical aspects of nutritional support’ primarily by the parenteral rather than the enteral route. As enteral nutrition has not been in widespread use for as long as parenteral nutrition this is perhaps to be expected. New developments are not necessarily ‘rocket science’, but may involve refinements in design, procedural changes or incorporate new pharmaceutical or nutritional understanding. These may not always lead to major publications. Many of the technical parenteral nutrition ‘problems’ have been around for more than 30 years, but because they have almost become routine, individual workers or clinical centres have evolved their own techniques, procedures and practices to overcome and minimize inconvenience or dangers to patient health. Nevertheless, we would encourage health professionals to document and report their practical experiences as early as possible, in order to share their data with other practitioners.

Although there is no overall theme, the contributed reviews, to a large extent, relate to ‘unphysiological’ chemical interactions, contact between synthetic materials and the body, either by inserting a catheter into a patient's vein for nutrient access, or through blood contact with a semi-permeable membrane for the dialysis of toxins. In these situations, the design, innovation and technical advances of polymer technology, surgical techniques etc. have dramatically improved therapeutic support for patients. Nevertheless, metabolic imbalances and the potential for infection, as a result of over-enthusiastic or inexperienced use of these invasive techniques, require constant vigilance.

All reviews serve to emphasize the importance of appropriate patient selection where nutritional support is concerned and the benefits that can be obtained when multidisciplinary teams are involved.

Until now we have tended to think of nutritional support as an often life-saving therapy for seriously malnourished patients. The review by Coelho and Campos (pp. 201-206) reminds us that the prevalence of ‘over-nutrition’ and obesity is increasing and poses a major health problem, especially in the western world. Obesity is defined as a body mass index (BMI) of more than 30 kg/m2 but super-obese patients have a BMI greater than 50 kg/m2. Morbid obesity increases the incidence of many serious medical, psychological and social problems. Moreover, premature death from cancer or other chronic diseases is more common in the severely obese. Because the usual weight reduction programmes are often ineffective for many patients, bariatric surgery has become a useful tool for the morbidly obese. The inclusion of this review in the technical aspects section aims to give an insight into the technical aspects of bariatric surgery to those not familiar with the different surgical options available to treat morbid obesity. The procedures involve gastric restriction, with or without bypass and intestinal malabsorption, and usually produce permanent weight loss, with few complications. Restriction alone is satisfactory for many patients, but the results are unsatisfactory with high energy, high osmolar diets. Combination with gastric bypass is now the choice of many surgeons. It not only prevents the ingestion of large meals but also increases the transit of food through the gastrointestinal tract. Unfortunately, this also results in nutrient deficiencies. These include calcium, iron, vitamin B12, folic acid and the fat-soluble vitamins A, D and E.

A third surgical method combines a distal gastrectomy with a gastroileostomy, so that undigested food is transported along the distal small intestine to the remaining ileum, where digestion and absorption is limited. Although a very effective procedure, protein, mineral and vitamin deficiencies have also been reported. However, if the nutritionist/dietitian monitors the situation and prescribes the necessary nutritional supplements then the quality of life of the patients is significantly improved. The importance of the multidisciplinary team is thus further confirmed.

Central venous catheters (CVC) are now used, not only for parenteral nutrition, but also for the monitoring of central venous pressure, haemodialysis, plasmapheresis and drug infusions. Arenas-Marquez et al. (pp. 207-210) estimate that over 5 million a year are used. Complications and infections are consequently to be expected. Strong emphasis must be placed on preventing air embolism during insertion, catheter use or maintenance, or after disconnection and removal. The prevention of catheter-related thrombosis is also important. New heparin-bonded catheters led to a significant reduction in infection and catheter-related thrombosis in a prospective randomized double-blind study [1]. Our reviewers suggest that the modest incremental cost of such catheters may well outweigh the cost of treating a bloodstream infection, making them potentially cost-effective.

Even when catheters are placed by an experienced physician there is still a 5-10% incidence of mechanical complications and/or catheter-related infections (CRI). In critically ill patients CRI can increase morbidity and mortality by up to 56%, with both medical and economical repercussions. The incidence of CRI ranges from 0.9 per 1000 catheter days for tunnelled home parenteral nutrition (HPN), and 2.1 per 1000 in respiratory intensive care units (ICU) up to 30.2 per 1000 days for a burns ICU. Hub contamination does not appear to be responsible for short-term catheter colonization, but as the frequency of changing the end cap of a needleless access device increased there was a five-fold decrease in CRI. These findings may be more important in the home setting. Colomb and co-workers [2] demonstrated that children have more than twice the number of CRI as adult HPN patients. Peripheral access ports are also associated with a lower risk of infection and longer life than CVC, but management is more difficult once a thrombus is formed.

A rapid and reliable method of diagnosing CRI without removing the catheter is still an important goal. Although paired qualitative blood cultures have good specificity and predictive value, they are currently too complex and expensive to be used routinely. ‘Strict adherence to aseptic technique therefore remains the cornerstone of CRI prevention.’

In a three-centre randomized study involving more than 300 ICU patients [3], tunnelled femoral polyurethane catheters reduced catheter colonization and CRI significantly. Surprisingly, in a well-designed prospective study over 2 years, Ma et al. [4] concluded that parenteral nutrition via a double- or triple-lumen catheter did not increase the risk of catheter-related sepsis. If these results are reproducible, then extended cautious use of multi-lumen catheters for concurrent antibiotic or chemotherapy is proposed by the reviewers Attar and Messing (pp. 211-218). Metal ions, such as silver, complex with sulphydryl groups in cellular enzyme systems and interfere with the trans-membranous energy and electron transport of micro-organisms. By impregnating polyurethane catheters with silver it was possible to reduce CRI by one third in a randomized study [5], involving relatively short-term (9 days) catheterization of the internal jugular vein. In contrast, a silver coating did not improve the frequency of colonization in a group of cardiac surgical patients with double lumen CVC.

Antiseptic- or antibiotic-impregnated catheters are a recent innovation that have been shown to reduce CRI. In a meta-analysis of published controlled trials from 1966 to 1998, Veenstra et al. [6] concluded that CVC impregnated with chlorhexidine-silver sulphadiazine reduce CRI in high-risk ICU patients. However, additional studies are required for HPN patients. In a subsequent randomized trial [7], catheters coated with minocycline and rifampicin showed a lower rate of bloodstream infection than those coated with chlorhexidine-silver sulphadiazine. Through-catheter antibiotic treatment could be useful for treating septicaemia, especially in children. A vancomycin-lock technique has been shown to prevent CRI in high-risk parenteral nutrition patients.

A retrospective study of almost 1000 cancer patients [8] goes against the perceived wisdom in favour of infusion therapy teams. The authors concluded that, with strictly enforced aseptic protocols, the responsibility for catheter care, dressing changes etc. could be assigned to ward nurses, without a significant increase in the risk of CRI. It is claimed that more than US$90 000 per year could thus be saved. The practicalities of enforcing the strict protocols required to achieve these results must be evaluated in other centres, before advocating such a radical change, but the cost benefits seem impressive.

On the other hand, the value of continuing education was further demonstrated in a study by Sheretz et al. [9]. CRI decreased by 28% after physicians attended an infection control course, and the use of full-size sterile drapes was monitored for 6 months. Cost savings could have exceeded US$800 000 by this relatively simple and well-proven intervention to reduce infection risks. Again, the importance of a well-educated, multidisciplinary catheter care team trained in meticulous aseptic technique is emphasized. In many hospitals, no formal training for central venous access exists, despite the documented fact that inexperienced practitioners induce twice as many complications as experienced physicians. A more formal educational programme is called for, with enhanced supervision and periodic peer review in order to minimize the occurrence of serious, life-threatening complications (Arenas-Marquez et al., pp. 207-210).

Bacterial translocation of enteric organisms has long been associated with high infection rates from Gram-negative bacteria. As glutamine or short-chain fatty acids ameliorate gut mucosal atrophy, it is encouraging to see that in a total parenteral nutrition model both intravenous glutamine and short-chain fatty acids significantly reduced catheter infection. Glutamine also decreased bacterial translocation [10]. This conditionally essential amino acid may also be important for patients suffering from acute renal failure (ARF).

The incidence of ARF seems to be increasing. High mortality rates, especially in surgical or post-traumatic patients, can range from 40 to 80%, and are generally associated with poor nutritional status. The replacement of nutrient losses over and above standard nutritional support may have some benefit.

Continuous renal replacement therapy (CRRT) by various types of access (arteriovenous or venovenous) is finding widespread acceptance, and has been shown to improve haemodynamic stability, optimize fluid balance for unlimited nutritional support, and continuously remove urea. Nevertheless, blood contact with high-flux synthetic plastic membranes can cause metabolic side-effects and nutritional imbalances, as the haemodiafilters cannot discriminate between uraemic toxins and nutrients. The nutritional status of the patient steadily declines as a result of amino acid, plasma protein and water soluble vitamin losses, impaired glucose utilization and toxicity-related symptoms.

As renal dietitian, Angela Marin, points out in her review (Marin and Hardy, pp. 219-225) amino acid losses are usually 10-15 g/day but may reach 30 g/day. Glutamine metabolism and distribution in particular appears to be affected, with serum decreases of up to 35% and daily losses of 3-4 g being reported. Glutamine is thought to be a precursor of glutathione, and intravenous supplementation has certainly decreased mortality in ARF patients. Whole-blood concentrations of the indispensable anti-oxidants, vitamin C, folic acid and selenium (which acts as a co-factor for glutathione peroxidase), are appreciably lower during CRRT.

Whereas the significance of these losses is unproven, their clinical relevance requires further investigation, and when designing a nutritional regimen for CRRT this obligatory loss of water-soluble substrates must be taken into account. However, nutritional assessment is difficult, anthropometric measurements have limited use in the critically ill, and calculations of BMI must be adjusted for oedema. For the moment, therefore, the replacement of nutrient losses may have to be based on biochemical determinations and frequent monitoring. For adults, the glutamine intake should thus be increased by 3-4 g/day above the daily flux value of 24 g/day, and the water-soluble vitamins and trace elements should be closely monitored [11].

Whether parenteral nutrition admixtures are prepared in hospitals under the control of a pharmacist or by industry, there needs to be pharmaceutical assessment of the potentially hazardous physical and chemical incompatibilities that can arise from the clinical objective of meeting individual patient requirements. This is especially important in the paediatric context. Debate still continues around the pros and cons of ‘standard’ versus ‘patient-specific’ regimens, but in our opinion both approaches offer certain advantages. There is no doubt, however, that with the expanding clinical interest in immuno-nutrition, antioxidant therapy and other potential uses of nutraceuticals, the need for more complex admixtures to be compounded will increase.

Nutrients such as glutamine, arginine and n-3 fatty acids can already be safely included in parenteral nutrition regimens. Stability studies with more novel substrates such as glutathione are beginning to be published, and there is a resurgence of interest in organic phosphates, such as fructose-1,6-diphosphate (FDP). This interesting molecule appears to enhance calcium uptake in ischaemia, improves hypothermic heart preservation, and beneficially increases respiratory muscle strength in malnourished chronic obstructive pulmonary disease patients. It also provides a means of preparing parenteral nutrition admixtures containing high levels of calcium and phosphate, without fear of precipitation, compared with the hazards associated with use of inorganic phosphates. As reported in the review by Hicks and Hardy (pp. 227-233), balance studies with FDP in very low birthweight babies have demonstrated high phosphate retention rates with admixtures providing an optimum calcium:phosphate ratio of 1 : 1.3. FDP is unique in this respect, because the phosphate molar ratio is double that of other organic or inorganic sources.

Hypophosphataemia is yet another frequently unrecognized side-effect of other therapies. It has been observed in up to 28% of critically ill patients, and is well documented in Crohn's disease, radiation enteritis and chronic alchoholism. The early establishment of phosphate-supplemented nutritional support is important and must be carried out with due regard for the calcium and other electrolyte requirements of the patient. The fact that calcium and phosphate can precipitate when admixed is well documented, but the use of organic phosphates such as FDP can now minimize this possibility, and should allow pharmacists to provide an expanded range of more physiological nutrition support solutions.

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1 Marin MG, Lee JC, Skurnick JH. Prevention of nosocomial blood stream infections: effectiveness of antimicrobial-impregnated and heparin-bonded central venous catheters. Crit Care Med 2000; 28:3332-3338.
2 Colomb V, Fabeiro M, Dabbas M, et al. Central venous catheter-related infections in children on long-term home parenteral nutrition: incidence and risk factors. Clin Nutr 2000; 19:355-359.
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7 Darouiche RO, Raad II, Heard SO, et al. A comparison of two antimicrobial-impregnated central venous catheters. Catheter Study Group. N Engl J Med 1999; 340:1-8.
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11 Kuhlmann MK, Kohler H. Catabolism in acute renal failure: strategies for the application of amino acids. Anaesthetist 2000; 49:353-358.

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Current Opinion in Clinical Nutrition & Metabolic Care
Practical nutrition support for chronic diseases in the young and the old
Hardy, G; Campos, A
Current Opinion in Clinical Nutrition & Metabolic Care, 5(3): 287-291.

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