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Parenteral nutrition


General information

Parenteral nutrition should be tailored to the needs of the individual, but on average should provide about 25 kcal/kg/day. Solutions for long-term parenteral nutrition should contain:

  • about 30% carbohydrate, usually in the form of glucose, providing 60% of the energy requirements;

  • 30–50% fat in the form of a lipid emulsion such as soya oil;

  • amino acids, 150–250 kcal/g of nitrogen;

  • sodium and potassium;

  • calcium, phosphate, and magnesium;

  • bicarbonate;

  • vitamins;

  • trace elements (chromium, cobalt, copper, fluoride, iodide, iron, manganese, molybdenum, selenium, zinc).

Parenteral nutrition has been considerably improved by innovative strategies, such as supplementation with medium-chain triglycerides, glutamine, or branch-chain amino acids.

General adverse effects and adverse reactions

Many of the harms in parenteral nutrition relate to the fact that the process is inherently unphysiological [ ]. Instead of periodic ingestion of nutrients via the gastrointestinal tract, resulting in gradual entry of nutrients into the blood, nutrients are infused directly at a constant rate. The gastrointestinal tract as a mediator of nutrient absorption, the periodicity of nutrient administration, and the natural biorhythms of hormone secretion are all lost.

Common problems in the past were fat overload syndrome, metabolic acidosis, hyperglycemia, and hypertriglyceridemia [ ]. These are now rare. Increasing efforts have been made to avoid adverse effects such as central venous catheter infection and hepatic dysfunction. Major developments in the future are likely to be achieved with the identification of nutrients, hormones, or other active compounds that can positively influence outcomes beyond the safe provision of 40 essential nutrients in proper amounts, which is what principally has been achieved to date [ ]. Liver damage is still a major problem. The most common micronutrient deficiency is of thiamine.

In an assessment of the clinical use of nutrients, and the tendency that has been noted in the past to overfeed with carbohydrate, lipid, and micronutrients, attention has been drawn to the adverse effects of oversupply [ ].

Drug studies

Observational studies

GAB-88 is an infusion solution that contains amino acids (3%), dextrose (7.5%), and electrolytes in a dual-chamber plastic bag. It has been evaluated in 39 non-operative patients who were unable to tolerate oral feeding or to take adequate amounts by mouth [ ]. When it was given in a daily dose of 1.0–2.5 liters for 7–19 days, there was an improvement in nutritional status without obvious adverse effects or reactions. There was mild vascular pain in four patients, but no phlebitis.

In 28 Japanese institutions, GAB-88 was infused continuously via a peripheral vein at a rate of 30–45 ml/kg/day for 5 postoperative days after partial gastrectomy for gastric cancer in 92 patients and compared with a similar commercial formulation; no particular adverse events emerged [ , ].

No serious adverse effects or reactions were noted in a phase I clinical study of GAB-88 aimed at determining its safety and pharmacokinetics in eight healthy men who were given three different doses (0.15 g/kg/hour, 0.3 g/kg/hour, and 0.5 g/kg/hour) at 1-week intervals. Serum electrolytes did not change significantly, except for zinc [ ].

Organs and systems

Cardiovascular

Infusion phlebitis presents a problem in parenteral nutrition. Various alternative techniques of administration have been compared in order to identify means of countering this problem [ ]. Mechanical trauma appears to be a causative factor; it can be reduced by limiting the time of exposure of the vein wall to nutrient infusion and by minimizing the amount of prosthetic material within the vein [ ]. This is likely to be even more important in small veins. In one study the addition of heparin (500 U/l) and hydrocortisone (5 micrograms/ml) significantly reduced the risk of thrombophlebitis from 0.43 to 0.11 episodes per patient-day, and a reduction in osmolality of the solution resulted in a further 10-fold fall in the incidence of thrombophlebitis [ ]. Other work has concluded that the incidence of infusion phlebitis is minimized during parenteral nutrition by cyclic infusion of nutrient solutions and by rotation of venous access sites [ ].

Respiratory

The clinical differentiation of chylothorax from leakage of parenteral nutrition fluid into the pleural space can be difficult. However, in one case the diagnosis of leakage of parenteral nutrition fluid was made by additional tests of electrolytes, showing very high concentrations of potassium (11.3 mmol/l) and glucose (128 mmol/l), ruling out chylothorax [ ].

In an acute experiment, infusion of fat emulsion (Intralipid) for 60 minutes (mean dose 0.07–0.16 g/kg/hour) in neonates with lung disease was found to lead consistently to a 10% fall in transcutaneous PO 2 (transcutaneous oxygen tension). There was no change in PCO 2 . This is evidence that Intralipid contributes to the hypoxia of respiratory distress in neonates; it should be used with caution in this group, and not at all in infants with pulmonary disease [ ].

Nervous system

Two children developed neurological complications of fat emulsion therapy, including focal and generalized seizures, weakness, and altered mental status, before any systemic findings were in evidence [ ]. Biopsy and autopsy findings included cerebral endothelial and intravascular lipid deposition. These complications are potentially reversible by altering the parenteral nutrition content, highlighting the importance of early recognition.

  • Acute hemiplegia and seizure developed in a 24-year-old patient following accidental catheterization of the right common carotid artery for parenteral nutrition infusion [ ]. Magnetic resonance imaging of the brain showed lesions in the frontal lobe and putamen, consistent with an ischemic stroke.

Critical illness polyneuropathy during artificial nutrition, initially functional, but proceeding to an axonal polyneuropathy, demonstrable postmortem by histological evidence of axonal degeneration, is familiar to intensive care units, and it is an important cause of weaning failure [ ]. The neurological disability can last for some 6 months, but it is likely to be reversible if the cause is recognized early and treatment withdrawn before permanent axonal changes occur. There is a strong association with sepsis and multiple organ dysfunction syndrome, the nervous system being yet another focus of organ failure. The autonomic nervous system is commonly involved, and patients are likely to show early cardiovascular instability requiring antihypotensive medication. It seems that artificial feeding after starvation leads to reduced activity of the enzymes involved in glucose oxidation, with the result that nutrient glucose causes accumulation of phosphorylated glycolytic intermediates; this in turn causes a block in the energy cascade, which is an essential element in the development of axonal polyneuropathies. Although the exact chain of events is not known, there is evidence that there are disturbances of the microcirculation and increased microvascular permeability, which can lead to endoneural edema, with resulting primary axonal degeneration of peripheral nerves [ ]. A sensitive bioassay capable of identifying a low molecular weight fraction toxic to rat spinal motor neurons has been identified in the sera of these patients [ , ].

Wernicke’s encephalopathy caused by thiamine deficiency during parenteral nutrition has been reported [ ].

  • A 13-year-old girl with acute myeloid leukemia received parenteral nutrition and chemotherapy. After a second cycle of chemotherapy she developed persistent nausea and vomiting, nystagmus, ophthalmoplegia, and brisk deep tendon reflexes on the left. Her level of consciousness deteriorated progressively. A CT scan was normal, but an MRI scan showed caudate nucleus lesions, cortical involvement, and typical diencephalic and mesencephalic abnormalities. She was given mannitol and dexamethasone, but without improvement. However, after intravenous thiamine her symptoms gradually improved; she recovered within 1 month and the MRI abnormalities disappeared.

The authors suggested that this case showed how MRI can play a role in the diagnosis of Wernicke’s encephalopathy, but that there was unusual involvement of the frontal and parietal cortex and the caudate nuclei.

In one case Wernicke’s encephalopathy associated with thiamine deficiency in a patient receiving parenteral nutrition was due to failure to include multivitamins in the regimen [ ].

  • A 30-year-old woman developed peritonitis and a digestive tract fistula after elective surgery for a benign gastric tumor. She was given parenteral nutrition and antimicrobial drugs. After 30 days, she reported fatigue. Hyponatremia and hypophosphatemia were corrected, but she became stuporose and was intubated and ventilated. Micronutrients (multivitamins and trace elements) were added. After 3 days, her neurological status improved, allowing extubation, but she had horizontal nystagmus and a lateral ophthalmoplegia. An MRI scan showed no sign of central pontine myelolysis but hyperintense lesions in the medial thalami. Thiamine was increased to 200 mg/day and the oculomotor signs and MRI scans regressed. However, a severe cognitive deficit with vertigo and loss of sphincter control persisted for at least 2 years. She remained totally dependent and disorientated with memory disturbances.

While the authors emphasized the difficulties in diagnosing Wernicke’s encephalopathy, this case clearly illustrates yet again the dangers of omitting micronutrients from parenteral nutrition. It also shows that the commonest manifestation of vitamin deficiency in parenteral nutrition when micronutrients have been excluded is likely to be thiamine deficiency, as has been previously reported. It has also provided some indication of the approximate time before such symptoms become evident.

Metabolism

Ammonium

Hyperammonemia has occurred during parenteral nutrition as a component of therapy for renal insufficiency [ ]. The hyperammonemia presented as a change in mental status, developing about 3 weeks after initiation of parenteral nutrition therapy; in most cases the episodes are of increasing duration and paroxysmal. In three of the patients, serum amino acid analysis in the acute phase showed reduced concentrations of ornithine and citrulline (the respective substrate and product of condensation with carbamyl phosphate at its entry into the urea cycle). Concentrations of arginine, the precursor to ornithine, were raised.

Carbohydrates

The effects of parenteral nutrition on endocrine and exocrine functions of the pancreas have been investigated in experimental rats [ ]. The conclusion was that after parenteral nutrition treatment the insulin secretory response to glucose is impaired, the exocrine pancreas is hypoplastic, and the storage pattern of pancreatic exocrine enzymes is altered.

Lipids have an adverse effect on carbohydrate metabolism under basal conditions. The infusion of 20% triglyceride emulsion with heparin during basal insulin and glucose turnover conditions resulted in a rise of plasma free fatty acids from 0.4 to 0.8 mmol/l at a low rate of infusion (0.5 ml/minute for 2 hours) to between 1.6 and 2.1 mmol/l at a high rate (1.5 ml/minute for 2 hours). There were similar increases in plasma concentrations of glycerol, acetoacetate, and hydroxybutyrate. The infusions resulted in significant increases in C-peptide concentrations, but had no effects on any of the other indices of carbohydrate metabolism that were examined (plasma glucose, lactate, and pyruvate concentrations), or on carbohydrate oxidation rates. By blocking the compensatory release of insulin by the intravenous administration of somatostatin and by simultaneous replacement of basal insulin and glucagon concentrations, these workers found that there was a significant increase in plasma glucose and in hepatic glucose output, and reduced glucose clearance. It was concluded that exogenous lipids may have adverse effects on carbohydrate metabolism under basal conditions, and that healthy individuals normally compensate for this by additional secretion of insulin [ ].

Preoperative parenteral nutrition can be a major cause of hyperglycemia, which has been associated with an increased risk of postoperative infection. The frequency of hyperglycemia and infectious complications has been studied in a prospective, randomized, controlled, non-blind trial in 40 patients who required parenteral nutrition for at least 5 days [ ]. They were given either a hypocaloric regimen (1 liter containing nitrogen 70 g and dextrose 1000 kcal) or a standard weight-based regimen begun with similar amounts initially but with gradual increases in calorie and nitrogen contents to 25 kcal and 1.5 g nitrogen/kg, up to one-third of the calories being given as fat. There were no significant differences between the two groups with regard to hyperglycemia or infections. The higher calorie regimen provided significant nutritional benefit in terms of nitrogen balance compared with the hypocaloric regimen.

Some children receiving parenteral nutrition have abnormal glucose tolerance. When this was studied in 12 patients, aged 5.7–19 years, receiving cyclic nocturnal parenteral nutrition, patients with normal glucose tolerance had an insulin response to intravenous glucose tolerance testing similar to that of normal people of the same age [ ]. Two patients with abnormal glucose tolerance had a reduced capacity to release insulin, whereas insulin sensitivity was unchanged in one of them. Patients with a limited capacity to release insulin, either constitutional or acquired, may not be able to produce enough insulin in these conditions and they may develop glucose intolerance during parenteral nutrition. Insulin sensitivity was not a key factor in the alteration of glucose tolerance in this study.

In five patients with multiple trauma given sodium lactate as part of parenteral nutrition there was a 20% fall in glycemia, a 43% fall in insulinemia, a 34% reduction in net carbohydrate oxidation (assessed by indirect calorimetry), and a 54% fall in plasma glucose oxidation (assessed using 13 CO 2 ). Respiratory oxygen exchange was increased by 3.7% owing to a 20% thermic effect of lactate, but respiratory CO 2 exchange was not altered. PaO 2 fell by 11.3 mmHg, suggesting that the increased oxygen consumption was matched by an appropriate increase in spontaneous ventilation. Arterial pH increased from 7.41 to 7.46. It appears that sodium lactate given in parenteral nutrition during short intravenous nutrition in critically ill patients as a metabolic substrate limits hyperglycemia but contributes to metabolic alkalosis and does not spare ventilatory demand [ ].

Lipids

The fat overload syndrome, characterized by a sudden rise in serum triglycerides, hepatosplenomegaly, intravascular coagulopathy, and end-organ dysfunction, is today an uncommon complication of intravenous administration of fat emulsion. Its higher incidence in the past may have been due to the greater phospholipid content of intravenous solutions in use at the time. The syndrome is a consequence of fat sludging within the microvasculature in organs such as the spleen, liver, kidney, lungs, brain, and retina. Necrosis in these organs suggests that emboli are responsible for the clinical symptoms and functional impairment that results. Plasma exchange has been successfully used in a patient with this syndrome who had not responded adequately to conventional medical therapy [ ].

Critically ill patients are at greatest risk of fat overload syndrome when they are given lipid emulsions intravenously. Some of these patients already have impaired lipid metabolism and they are at risk of developing fat intolerance. These are the very patients who are likely to be given parenteral nutrition, including fat emulsions. Patients with increased serum triglyceride concentrations (for example, in hypothyroidism, with inborn errors of lipid metabolism, renal insufficiency, and severe sepsis, especially gram-negative sepsis) are at greatest risk. There is impaired metabolism of fats in advanced liver disease. Continuous heparin infusion may also lead to a decreased elimination capacity [ ].

Fatty acids

Patients undergoing home parenteral nutrition for severe malabsorption or reduced oral intake can exhaust their stores of essential fatty acids, causing clinical effects, mainly dermatitis. In a comparative study of fatty acid profiles in 37 healthy control subjects and 56 patients receiving home parenteral nutrition, reduced small bowel length was associated with aggravated biochemical signs of essential fatty acid deficiency [ ]. This applied to total n-6 fatty acids and not to n-3 fatty acids. There were skin problems in 25 of the 56 patients receiving home parenteral nutrition. Patients receiving home parenteral nutrition had biochemical signs of essential fatty acid deficiency. Parenteral fluids did not increase the concentration of essential fatty acids to values comparable with those of control subjects. However, 500 ml of 20% fat emulsion (Intralipid) once a week was sufficient to prevent an increase in the Holman index (an indicator that reflects optimum proportions of polyunsaturated fatty acids).

Linoleic acid and alpha-linoleic acid are essential fatty acids that are provided in any long-term parenteral nutrition by administering fat emulsions at least twice a week. Fatty acid deficiency is a common complication of severe end-stage liver disease. The ability of short-term intravenous lipid supplementation to reverse fatty acid deficiencies has been studied in patients with chronic liver disease and low plasma concentrations of fatty acids [ ]. Short-term supplementation failed to normalize triglycerides.

Phospholipids

Although choline is not regarded as an essential nutrient for humans, it has been described as being “conditionally essential” in patients receiving parenteral nutrition. Choline is a methyl-group donor, a component of phospholipids, and a precursor of acetylcholine and lecithin. In animal models and healthy human beings, choline deficiency impairs liver function. Studies in patients receiving long-term parenteral nutrition have shown that low plasma choline concentrations are common and are associated with hepatic steatosis.

  • Choline deficiency developed in a 41-year-old woman with advanced cervical cancer who underwent prolonged parenteral nutrition [ ]. Her liver function tests became abnormal and she became jaundiced and complained of nausea and vomiting. The serum choline concentration was 5.77 mmol/l and there was histological evidence of hepatic steatosis. There was steady improvement with oral choline supplementation, 3 g/day, and with oral glutamine 15 g/day. There was a 45% improvement in serum choline concentration over baseline.

Intravenous fat emulsions contain choline, but not in sufficient amounts to prevent choline deficiency [ , ].

Nutrition

Amino acids

Carnitine . In septicemic patients with multi-organ dysfunction syndrome serum carnitine concentrations are in the reference range, and they remain unchanged over treatment for 10 days with parenteral nutrition without carnitine supplementation. This has been established in 28 septicemic patients, mean age 53 years, whose mean APACHE II score on admission was 17. Of these patients, 10 had septicemia with multi-organ dysfunction syndrome and 18 had uncomplicated septicemia. There were no differences in patients given long-chain triglycerides (n = 16) and a 1:1 mixture of long-chain and medium-chain triglycerides (n = 12). It does not appear from these findings that carnitine deficiency plays a significant role in the pathogenesis of multi-organ dysfunction syndrome complicating septicemia, whether or not parenteral nutrition is given in the acute phase of the illness [ ].

Deficiency of carnitine has been described in all of a series of surgical neonates receiving parenteral nutrition [ ]; carnitine intake was far below the recommended minimal need of 11 mmol/kg per day. Although only three of the infants had clinical symptoms suggestive of carnitine deficiency, the authors recommended carnitine supplementation for all neonates receiving parenteral nutrition for more than 2 weeks. It has been suggested that a deficiency of l -carnitine may be responsible for steatosis and steatohepatitis in patients on parenteral nutrition, but one experimental study in adult women throws much doubt on this theory [ ]. However, in another series of patients who had depletion of erythrocyte and plasma glutathione peroxidase activity during parenteral nutrition [ ], supplementation with selenium resulted in normalization of glutathione peroxidase activity within 3–4 months, which is consistent with the time-course for bone marrow erythrocyte production.

Glutamine . Animal studies have shown that raised plasma glutamate concentrations increase cerebral edema whenever the blood–brain barrier is disturbed. In a prospective study of 23 neurosurgical patients requiring parenteral nutrition, glutamine-containing regimens were compared with parenteral nutrition regimens that excluded glutamine [ ]. The former doubled plasma glutamine concentrations compared with controls, and the authors concluded that glutamine-containing solutions cannot be recommended for patients with a disturbed blood–brain barrier.

In a study of the safety and efficacy of l -glutamine when added to parenteral nutrition solutions of patients being treated at home, glutamine was stable in home parenteral nutrition solutions for at least 22 days. Supplementation of home parenteral nutrition solutions with l -glutamine in a dose of 0.285 g/kg for 4 weeks in seven stable patients resulted in increases in hepatic enzymes in two patients, requiring withdrawal of the glutamine/parenteral nutrition mixtures at the end of weeks 2 and 3. A third patient’s liver enzymes rose at the end of week 4. These abnormalities subsided after withdrawal. Plasma concentrations of glutamine rose during the first 3 weeks of supplementation, but these increases were not statistically significant. It appears that hepatic toxicity can be associated with supplementation of home parenteral nutrition solutions with l -glutamine, without a demonstrable beneficial effect on intestinal absorptive capacity, as measured by d -xylose absorption [ ]. Other work seems to confirm the lack of benefit from adding glutamine in the form of its dipeptide, though it proved harmless [ ].

Thiamine . Thiamine deficiency has been reported [ ].

  • A young man developed marked deterioration in his vision and oscillating vision, despite normal optic fundi, during parenteral nutrition; he went on to develop a characteristic Wernicke’s encephalopathy, confirmed by characteristic findings on MRI brain scan [ ]. The serum vitamin B 1 concentration was 110 pg/ml (reference range: 200–500). He responded fully to thiamine 300 mg/day in addition to betamethasone for 4 weeks.

  • Parenteral nutrition was used to support a patient requiring autologous blood stem-cell transplantation, but vitamins were excluded (the reason was not identified). After about 28 days, the patient suddenly developed severe metabolic acidosis, heart failure, and deep coma. Thiamine was immediately infused, with rapid improvement.

In the second case, the authors were unsure if the associated graft failure was due to the acute metabolic acidosis or thiamine deficiency, since absence of thiamine in the diet leads to poor glucose oxidation, resulting in accumulation of lactic acid and metabolic acidosis, which is refractory to any treatment except thiamine supplementation.

Vitamins

More than 40 cases of fulminant beriberi have been described in patients receiving parenteral nutrition [ ]. The condition becomes evident 4–40 days after the start of parenteral nutrition, and is more likely to develop in patients with malignancies, ulcerative colitis, and short bowel syndrome, and in those receiving chemotherapy. The severity of metabolic acidosis is very high and refractory to bicarbonate administration, but it responds quickly to intravenous thiamine. Rapid intravenous administration of thiamine is imperative, and the patient should be transferred urgently to an intensive care unit when parenteral nutrition-induced fulminant beriberi develops.

A further consequence of thiamine depletion during parenteral nutrition can be severe lactic acidosis [ ]. Six cases have been described from Japan with associated hypotension, Kussmaul’s respiration, and clouding of consciousness, as well as abdominal pain not directly related to the underlying disease. During parenteral nutrition administration there was blockade of oxidative decarboxylation of alpha-keto acids such as pyruvate and alpha-ketoglutarate, resulting in pyruvate accumulation and massive lactate production. None of the patients responded to sodium bicarbonate or other conventional emergency treatments for shock and lactic acidosis. Thiamine replenishment with intravenous doses of 100 mg every 12 hours resolved the lactic acidosis and improved the clinical condition of three patients.

These various reports stress the need to supplement parenteral nutrition with thiamine-containing vitamins unless there is adequate dietary intake, and to monitor serum thiamine and erythrocyte transketolase activity so that supplementary thiamine can be given in good time, if necessary intravenously [ ]. Giving thiamine will not rectify the various disorders if hepatic function is severely disturbed, because then thiamine is not phosphorylated and hence remains physiologically inactive.

Electrolyte balance

Hyperkalemia in one published case was attributed to combined treatment with octreotide and heparin (enoxaparin) in parenteral nutrition [ ]. It was suggested that both enoxaparin and octreotide had contributed in this case to the development of hyperkalemia since they reduce urinary potassium excretion.

Mineral balance

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