Enteral and Parenteral Nutrition
Enteral nutrition is defined as providing nourishment to a patient utilizing a diet that is delivered directly into the gastrointestinal tract (nasogastric tube, nasointestinal tube, gastrostomy tube, jejunostomy tube). Parenteral nutrition is defined as delivery of nutrients directly into the venous circulation (peripheral vein or central vein). The term total parenteral nutrition (TPN) is utilized when the only source of nutrient supply is via the parenteral route. Nutritional support is characterized as the use of enteral or parenteral nutrition rather than or in addition to an oral diet. Preexisting TPN should be continued during the perioperative period, whereas enteral nutrition should be discontinued about 6 hours before surgery (reflecting recommendations for food ingestion prior to elective surgery).
Nutritional Support
TPN is intended to supply all the essential inorganic and organic nutritional elements necessary to maintain optimal body composition. Alimentation by the gastrointestinal tract (enteral nutrition) is preferred to intravenous (IV) alimentation (parenteral nutrition) because it is more physiologic. Enteral nutrition provides nutrients that stimulate trophic factors (e.g., gastrin, cholecystokinin, bombesin) released from the lumen that maintains gut integrity (e.g., tight junctions between the intraepithelial cells and villous height) and the absorptive activity of the small intestine. These factors reduce the translocation of bacteria from the gastrointestinal tract and, at the same time, promote development of IgA-producing immunocytes, which reside in gut-associated lymphoid tissue (GALT).1–3 Indeed, the route of feeding is more important than the amount of nutrition provided, and outcome correlates with the enteral protein intake in injured patients. Thus, even if the patient’s caloric and nitrogen requirements cannot be met with luminal nutrition, the enteral route of feeding should be used unless it is contraindicated (bowel obstruction, inadequate bowel surface area, intractable diarrhea). If it is contraindicated and the patient is not malnourished or severely stressed, then parenteral nutrition is not necessary for the first week following surgery or intensive care unit (ICU) admission because it has not been shown to be of benefit.4 The enteral and parenteral routes may be used simultaneously to meet nutritional requirements, although there is no evidence that the combination of the two to meet caloric needs improves outcome.5 Furthermore, a recent large prospective study conducted in patients who were critically ill demonstrated that the administration of enteral glutamine supplemented with parenteral glutamine was correlated with an increase in hospital mortality, 28-day mortality, and 6-month mortality.6 Preoperative nutritional support should be reserved for malnourished patients undergoing major elective surgery; this recommendation is not commonly followed for a variety of reasons, but if time permits, improvement in nutritional status is associated with an improvement in outcome.
Most patients do not need nutritional support, and clear-cut benefits of this expensive intervention have been established for only a select group of patients (Table 36-1).7 Patients not expected to resume adequate oral feedings within 7 to 10 days of surgery should begin nutritional support within 2 to 4 days postoperatively, within 1 to 2 days if they are in an ICU. Although the benefits of parenteral nutrition in the perioperative period are controversial, postoperative enteral feeding has been shown to decrease complication rates in malnourished patients although mortality rates are unchanged.8
Severely injured patients, burn patients, and those with sepsis often are hypermetabolic, so directed nutritional support within 24 to 48 hours of admission may be beneficial. For example, energy requirements may double and protein requirements may triple in severely burned patients. Conversely, the increase in basal metabolic rate that occurs during and soon after major uncomplicated elective surgery is less than 10%, so that providing glucose solutions (~500 kcal per day) in the postoperative period is sufficient, and further nutritional support does not improve outcome.
Minimally stressed patients require about 25 to 30 cal/kg and 1 g/kg of protein daily to remain in nitrogen and energy equilibrium. Moderately to severely stressed patients should be resuscitated first and then started on a hypocaloric regimen (20 cal/kg) until the stress response abates. Lipid calories from infusions of propofol may be significant and should be included when calculating caloric intake.9
Enteral Nutrition
Unless contraindicated (e.g., short gut syndrome, circulatory shock10), enteral nutrition is preferred over parenteral nutrition in almost every circumstance for the reasons mentioned earlier. Three decades ago, it was thought that the main goal of nutrition support in the hospitalized patient was to meet energy requirements and to make the patient anabolic. Current goals include meeting and attenuating the metabolic response to stress and, in addition, attenuating cellular injury and modulating the immune response to injury. Nutritional support of the moderately to severely injured patient includes enteral nutrition started sooner rather than later, pharmacotherapy (the provision of nutrients that modulate the body’s response to injury) and glycemic control. Delivering early nutrition support, primarily using the enteral route, is seen as a proactive therapeutic strategy that may reduce disease severity, diminish complications, decrease length of stay in the ICU, and favorably impact patient outcome after severe injury. A variety of enteral solutions containing various amounts of protein (amino acids), carbohydrates (glucose), fat (medium- and long-chain triglycerides), micronutrients, macronutrients, and electrolytes are available. No single formulation has been found to be ideal for all patients. Carbohydrates can be the source of up to 90% of the calories, which increases the osmolarity of these solutions. Fat has a higher caloric density than carbohydrates, and because it does not increase the osmolarity of the formula as much as carbohydrates, iso-osmolar solutions can be constituted. Unless the patient has maldigestion or malabsorption of fat (and even then a formula containing medium-chain triglycerides can be tried), formulas with a normal range of fat content (~30%) are preferred. Selection of a formula that provides sufficient total nitrogen as protein (1 to 1.5 g protein per kilogram per day) or amino acids is essential for all patients. It was once thought that low-protein formulations were indicated for patients with severe renal dysfunction; however, we now recognize that these patients require the same amount of protein as do other patients, even if one has to resort to dialysis to maintain homeostasis.11 Specialized formulas are available for nutritional deficiencies associated with renal disease, but they are rarely indicated.12 The same can be said for patients with liver disease—standard enteral formulas work well. The only exception is the patient with hepatic encephalopathy for whom an enteral or parenteral formula containing branched-chain amino acids may improve the encephalopathy, but if not, one should change back to a standardized formula.13 Increased amounts of protein are indicated when the nitrogen requirement is increased, as in patients with trauma, burns, or sepsis. The efficient use of protein for anabolism depends on adequate caloric intake. Enteral formulas containing glutamine, specifically when administered to patients with burns, reduce hospital and ICU length of stay, primarily through a reduction in infection.14,15
Enteral Tube Feeding
Enteral tube feeding may be necessary when patients are unable to consume nutritionally complete, liquefied food orally. Commercial formulations of natural foods can be so finely suspended that they pass through small-bore tubes. Defined-formula diets are necessary when luminal hydrolysis or absorption is impaired, as in malabsorption syndromes. An important consideration when utilizing enteral nutrition is placement and positioning of the small-bore (8 to 12 French) silastic delivery tube. Most often, patients receive continuous infusions of enteral nutrition through a nasoenteric tube positioned in the stomach, duodenum, or jejunum. Several groups of investigators have studied whether there is a clinical significance between gastric versus postpyloric feeding in various medical and surgical ICU settings. Two meta-analyses of these studies did not show a difference in the incidence of pneumonia whether the feeding tube was in the stomach or through the pylorus, nor was there a difference in mortality based on the position of the feeding tube; however, a contrary finding by Taylor was not included.16–18
Surgical placement of an esophagostomy or gastrostomy tube may be indicated for long-term feeding. For continuous enteral feeding, an automated infusion pump to control the rate of administration of the nutritional formula is useful. Indeed, absorption and tolerance are improved and the incidence of side effects is decreased by slow constant feeding over several hours. The rate of infusion is typically 100 to 120 mL per hour. This slow rate of infusion prevents the dumping syndrome, which may occur when hyperosmolar solutions are introduced rapidly into the small intestine.
Side Effects
Enteral feeding is frequently stopped because of patient’s complaints of bloating or distention; emesis; high gastric residuals (usually 200 to 250 mL); diarrhea; distended abdomen on physical exam; reduced passage, or absence, of flatus; or abnormal findings on abdominal radiographs. With the exception of high gastric residuals and diarrhea, these are legimate criteria for interrupting enteral feedings. One should not interrupt enteral feedings for gastric residual volumes of less than 500 mL, in the absence of other symptoms or signs of intolerance.19 The presence of diarrhea is always a concern, but one should consider alternative explanations before deciding that the diarrhea is caused by the osmolarity of the enteral product. Even if it is, osmotic diarrhea is relatively benign and short lasting.20 Osmotic diarrhea in this situation is a diagnosis of exlusion, and one must try to identify other causes such as enteral medications containing sorbitol, Clostridium difficile, or other infection, by performing an abdominal exam, sending stool for an assessment for fecal leukocytes, stool culture, and toxin assay.21 If clinically indicated, serum electrolyte levels should be measured to identify excessive loss or signs of dehydration.
Pulmonary aspiration is always a danger when enteral tube feeding is used. Patients should be maintained in a semi-sitting position (head of bed elevated 30 degrees) and, in patients at the highest risk of aspiration, the feeding tube should be placed through the pylorus. Preparations containing large amounts of electrolytes should be administered cautiously to patients with cardiovascular, renal, or hepatic disease. Many commercial formulas contain large amounts of sodium. Dry preparations mixed with water are excellent culture media unless they are kept sterile and refrigerated.
Parenteral Nutrition
Parenteral nutrition is indicated for patients who are unable to ingest or digest nutrients or to absorb them from the gastrointestinal tract. Parenteral nutrition using isotonic solutions delivered through a peripheral vein is acceptable when the patient requires less than 2,000 calories daily and the anticipated need for nutritional support is brief. Peripheral veins do not tolerate infusion of solutions with an osmolarity that exceeds 750 mOsm/L (equivalent to 12.5% glucose) thus limiting the number of calories that can be administered. When nutritional requirements are greater than 2,000 calories daily or prolonged nutritional support is required, a catheter is placed in the central venous system to permit infusion of a hypertonic (1,900 mOsm/L) nutrition solution.
Short-Term Parenteral Therapy
Short-term parenteral therapy (3 to 5 days in patients without nutritional deficits) after uncomplicated surgical procedures is most often provided by hypocaloric, non-nitrogen glucose-electrolyte solutions. For example, glucose solutions, 5% to 10%, with supplemental sodium, chloride, and other electrolytes are commonly administered for short-term therapy. These solutions provide total fluid and electrolyte needs and sufficient calories to decrease protein catabolism and prevent ketosis. For example, daily infusion of approximately 150 g of glucose maintains brain and erythrocyte metabolism and decreases protein catabolism from skeletal muscles and viscera.
Amino acids may have a greater protein-sparing effect than glucose, but amino acids without glucose do not completely prevent negative nitrogen balance after major surgery. The higher cost of amino acid solutions relative to potential benefit has prevented their popularity for use in place of glucose for short-term therapy.
Peripheral infusion of fat emulsions may be administered as a nonprotein source of calories to augment those supplied by glucose.
Long-Term TPN
TPN (IV hyperalimentation) is the technique of providing total nutrition needs by infusion of amino acids combined with glucose and varying amounts of lipids. Lean body mass is preserved, wound healing may be enhanced, and there may even be improvement of an impaired immune response mechanism.
TPN solutions contain a large proportion of calories from glucose and thus are hypertonic. For this reason, these solutions must be infused into a central vein with a high blood flow to provide rapid dilution. A catheter is often placed percutaneously into the subclavian vein and guided into the right atrium. The parenteral nutrition solution is usually infused continuously over 24 hours. Because the solutions in current use are not nearly as hypertonic and hypercaloric as they once were, there is little concern about the patient becoming hypoglycemic if the infusion is discontinued abruptly but should be considered.
Serum electrolytes, blood glucose concentrations, and blood urea nitrogen should be measured periodically during TPN. Tests of hepatic and renal function are also recommended but can be performed at less frequent intervals.
Side Effects
The side effects of TPN include infectious, mechanical, and metabolic complications. Amongst infectious complications, catheter-related sepsis is one of the most common and associated with significant morbidity. The mechanical complications such as pneumothorax and thrombosis if the catheter is left in place for extended periods, are complications related to the placement of a central line and with which anesthesiologists are familiar. There are a number of metabolic complications seen more often with parenteral nutrition than with enteral nutrition (Table 36-2).
Sepsis
TPN solutions infused through an IV catheter can support the growth of bacteria and fungi. A spiking temperature most likely reflects contamination via the delivery system or catheter. The catheter should be removed and the tip cultured to determine the appropriate antibiotic therapy. In view of the hazard of contamination, the use of a central venous hyperalimentation catheter for administration of medications, as during the perioperative period, or for sampling of blood is not recommended.
Fatty Acid Deficiency
Fatty acid deficiency may develop during prolonged TPN but only if no intralipid is administered as part of the 3-in-1 formulation (protein, glucose, lipid). Possible immunosuppressive effects of lipid emulsions and an increased incidence of infections has led to recommendations to limit fat calories to about 30% of total TPN calories.22
Hyperglycemia
Blood glucose concentrations should be monitored until glucose tolerance is demonstrated, which usually occurs after 2 to 3 days of therapy as endogenous insulin production increases. In addition, blood glucose concentrations should be periodically monitored during the perioperative period in patients maintained on TPN. The degree of hyperglycemia accompanying TPN is directly related to the rate of glucose infusion, and to the degree of stress. A 2001 study demonstrated improved outcomes in patients with hyperglycemia in whom blood glucose levels were kept below 110 mg/dL with intensive insulin therapy23; however, subsequent studies failed to confirm the original findings.24 Current guidelines suggest a target of 140 to 200 mg/dL and avoidance of targets below 140 mg/dL.25
Hypoglycemia
Accidental sudden discontinuation of the infusion of TPN solutions containing large amounts of glucose (catheter kink or disconnection) may cause hypoglycemia. Indeed, TPN infusion should be discontinued gradually over 60 to 90 minutes. Hypoglycemia occurs because the pancreatic insulin response does not always cease in parallel with discontinuation of the parenteral nutrition solution. As a result, a high plasma concentration of insulin may persist in the absence of continued infusion of glucose. If administration of the TPN solution must be stopped abruptly, exogenous glucose should be infused for up to 90 minutes to prevent hypoglycemia. The incidence of hypoglycemia has decreased because clinicans have a lower daily caloric goal (e.g., 1,400 to 2,000 kcal per day) compared to prior therapies (3,000 to 4,000 kcal per day).26
Hepatobiliary Complications
Excessive caloric intake is associated with hepatic steatosis and steatohepatitis. An increased alkaline phosphatase or serum bilirubin concentrations warrant additional evaluation (e.g., cholehepatic ultrasound).
Metabolic Acidosis
Hyperchloremic metabolic acidosis may occur because most of the amino acids in TPN are administered as their chloride salts.
Hypercarbia
In a patient with inadequate respiratory reserve, respiratoy failure can develop with aggressive nutritional support that increases carbon dioxide production. Because glucose has a respiratory quotient of 1, excessive glucose was blamed on the respiratory failure associated with TPN, but we now know that excessive calories per se independent of their source increases carbon dioxide production and leads to respiratoy failure in susceptible patients.27
Monitoring during TPN
Acutely ill patients receiving TPN must be followed closely for the development of treatment-related complications. Access sites are observed for signs of infection. Substitution of sodium or potassium acetate (metabolized to bicarbonate) for sodium or potassium chloride may be helpful should signs of hyperchloric metabolic acidosis appear. Plasma triglyceride concentrations may increase in patients with diabetes mellitus, sepsis, and impaired hepatic or renal function. Vitamin K may need to be added to the TPN or administered intravenously based on measurement of prothrombin and plasma thromboplastin times. Monitoring of daily caloric intake, to ensure that caloric goals are being met, and fluid intake and output is needed as patients who are critically ill often experience significant fluid shifts.
Preparation of TPN Solutions
TPN solutions are prepared from commercially available solutions by mixing hypertonic glucose with an amino acid solution. Sodium, potassium, phosphorus, calcium, magnesium, and chloride are added to TPN solutions. Trace elements including zinc, copper, manganese, chromium, and selenium must also be added if the need for parenteral therapy is prolonged. Requirements for vitamins may be increased, emphasizing the need to add a multivitamin preparation to TPN solutions. Vitamin B12 and folic acid may be administered as components of a multivitamin preparation or separately. Vitamin D should be used sparingly because metabolic bone diseases may be associated with use of this vitamin in some patients on long-term parenteral nutrition. Vitamin K can be administered separately once every week. The U.S. Food and Drug Administration (FDA) disallowed routine addition of vitamin K to TPN because of concern about side effects, and its routine administration would complicate the use of anticoagulants such as warfarin in patients who require such therapy. The serum albumin concentration will usually increase over several days to weeks as the stress response abates and if patients receive adequate nutrition support. The administration of supplemental albumin is not necessary in the absence of symptoms or signs of hypoalbuminemia, which usually do not occur until the serum albumin concentration is less than 2.4 g/dL.
Fat emulsions (Intralipid) can be administered separately or together with the glucose and amino acids to create a 3-in-1 TPN solution, as mentioned previously. To decrease the possibility of bacterial contamination, TPN solutions are prepared aseptically under a laminar air-flow hood, refrigerated, and administered within 24 to 48 hours.
Immunonutrition
Cellular immunity decreases during acute stress, as may accompany multiple organ system failure, sepsis, and shock. Immunonutrition is an attempt to enhance immunity and cellular integrity by incorporating specific additives (omega-3 fatty acids, arginine to enhance lymphocyte cytotoxicity, purines as a precursor of RNA and DNA and antioxidants) into enteral diets. Currently, there are no well-controlled clinical studies that demonstrate improved outcomes with immunonutrition in patient populations that might benefit from their use, and there are no clinical guidelines that suggest their routine use in these patient populations.
Vitamins, Dietary Supplements, and Herbal Remedies
Vitamins
Vitamins are a group of structurally diverse organic substances (water soluble or fat soluble) that must be provided in small amounts in the diet for subsequent synthesis of cofactors that are essential for various metabolic reactions (Table 36-3). Food is the best source of vitamins, and healthy persons consuming an adequate balanced diet will not benefit from supplemental vitamins. Nevertheless, many persons do not consume adequate amounts of vitamin-rich foods, especially patients with alcoholism and malabsorbtion syndromes, the elderly, and the economically disadvantaged.
Antioxidant vitamins can retard atherogenesis, and antioxidants may lower the risk of carcinogenesis. There is a demonstrated relationship between low dietary intake of antioxidants or low plasma concentrations of antioxidants and an increased risk of atherosclerosis and cancer. Studies have linked low plasma concentrations of folic acid, vitamin B6, and vitamin B12 with increased plasma concentrations of homocysteine and increased cardiovascular risks.28A vitamin supplement that combines antioxidants with zinc can slow progression of macular degneration. Individuals who consume multivitamins appear to have a decreased risk of cardiovascular disease and colon cancer, which may represent protection from folic acid and the B vitamins.29
It is clear that additional information and studies are necessary to clarify the need for vitamin supplements in the presence of an adequate diet. The present recommendation is for parturients, the elderly, and those individuals receiving a suboptimal nutritional diet to take a single multivitamin tablet daily. Strict vegetarians should take vitamin B12 supplements.
Use of megadose vitamin preparations is not encouraged. Brand name and so-called all-natural preparations are no more effective than generic vitamin preparations. Regardless, vitamin supplements should never be used as a substitute for a balanced healthful diet that provides abundant quantities of vitamin-rich foods.
Water-Soluble Vitamins
Water-soluble vitamins include members of the vitamin B complex (thiamine, riboflavin, nicotinic acid, pyridoxine, pantothenic acid, biotin, cyanocobalamin, folic acid) and ascorbic acid (vitamin C) (Fig. 36-1).
Thiamine
Thiamine (Vitamin B1) is converted to a physiologically active coenzyme known as thiamine pyrophosphate. This coenzyme is essential for the decarboxylation of α-keto acids such as pyruvate and in the use of pentose in the hexose-monophosphate shunt pathway. Indeed, increased plasma concentrations of pyruvate are a diagnostic sign of thiamine deficiency.
Causes of Deficiency
The requirement for thiamine is related to the metabolic rate and is greatest when carbohydrate is the source of energy. This is important in patients maintained by hyperalimentation in which the majority of calories are provided in the form of glucose. Such patients should receive supplemental amounts of thiamine. Thiamine requirements are also increased during pregnancy and lactation30 and in patients with chronic alcoholism.31
Symptoms of Deficiency
Symptoms of mild thiamine deficiency (beriberi) include loss of appetite, skeletal muscle weakness, a tendency to develop peripheral edema, decreased systemic blood pressure, and low body temperature. Severe thiamine deficiency (Korsakoff syndrome), which may occur in alcoholics, is associated with peripheral polyneuritis, including areas of hyperesthesia and anesthesia of the legs, impairment of memory, and encephalopathy. High-output cardiac failure with extensive peripheral edema reflecting hypoproteinemia is often prominent. There is flattening or inversion of the T-wave prolongation of the QTc interval on the electrocardiogram (ECG).
Treatment of Deficiency
Severe thiamine deficiency is treated with IV administration of the vitamin. Once severe thiamine deficiency has been corrected, oral supplementation is acceptable.
Riboflavin
Riboflavin (Vitamin B2) is converted in the body to one of two physiologically active coenzymes: flavin mononucleotide (FMN) or flavin adenine dinucleotide (FAD). Because of their ability to “accept” two hydrogen atoms, these coenzymes primarily influence hydrogen ion transport in oxidative enzyme systems, including cytochrome C reductase, succinic dehydrogenase, and xanthine oxidase.
Symptoms of Deficiency
Pharyngitis and angular stomatitis are typically the first signs of riboflavin deficiency. Later, glossitis, red denuded lips, seborrheic dermatitis of the face, and dermatitis over the trunk and extremities occur. Riboflavin deficiency is classically associated with angular cheilitis, photophobia, and scrotal dermatitis—the oral-ocular-genital syndrome. Anemia and peripheral neuropathy may be prominent. Corneal vascularization and cataract formation occur in some subjects. Treatment is with oral vitamin supplements that contain riboflavin.
Nicotinic Acid
Nicotinic acid (Niacin, B3) is converted to the physiologically active coenzyme nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP); NAD is converted to NADP by phosphorylation. These coenzymes are necessary to catalyze oxidation-reduction reactions essential for tissue respiration.
Symptoms of Deficiency
Nicotinic acid is an essential dietary constituent, the lack of which leads to nausea, skin and mouth lesions, anemia, headaches, and tiredness. Chronic niacin deficiency is manifested by pellagra in which the skin characteristically becomes erythematous and rough in texture, especially in areas exposed to sun, friction, or pressure. The chief symptoms referable to the digestive tract are stomatitis, enteritis, and diarrhea. The tongue becomes very red and swollen. Salivary secretions are excessive, and nausea and vomiting are common. In addition to dementia, motor and sensory disturbances of the peripheral nerves also occur, mimicking changes that accompany a deficiency of thiamine.
The dietary requirement for niacin can be satisfied not only by nicotinic acid but also by nicotinamide and the amino acid tryptophan. The relationship between nicotinic acid requirements and the intake of tryptophan explains the association of pellagra with tryptophan-deficient corn diets. Carcinoid syndrome is associated with diversion of tryptophan from the synthesis of nicotinic acid to the production of serotonin (5-hydroxytryptamine), leading to symptoms of pellagra. Isoniazid inhibits incorporation of nicotinic acid into NAD and may produce pellagra.
Pellagra is uncommon in the United States, reflecting the supplementation of flour with nicotinic acid. Common causes of pellagra include chronic gastrointestinal disease and alcoholism, which are characteristically associated with multiple nutritional deficiencies. When pellagra is severe, IV administration of nicotinic acid is indicated. In less severe cases, oral administration of nicotinic acid is adequate. The response to nicotinic acid is dramatic, with symptoms waning within 24 hours after initiation of therapy.
Toxic effects of nicotinic acid include flushing, pruritus, hepatotoxicity, hyperuricemia, and activation of peptic ulcer disease. Nicotinic acid has also been prescribed to decrease the plasma concentrations of cholesterol and to increase the concentration of high-density lipoprotein (HDL).
Pyridoxine
Pyridoxine (Vitamin B6) is converted to its physiologically active form, pyridoxal phosphate, by the enzyme pyridoxal kinase. Pyridoxal phosphate serves an important role in metabolism as a coenzyme for the conversion of tryptophan to serotonin and methionine to cysteine.
Symptoms of Deficiency
Pyridoxine deficiency is uncommon and, when present, is associated with deficiencies of other vitamins and, if seen, is more likely to be seen in the elderly, patients with alcoholism, and patients who are severly malnourished. Other patients who are at increased risk of manifesting deficiency are those with chronic renal failure on dialysis, those with hepatic failure, patients with rheumatoid arthritis, women with type 1 diabetes, and those patients infected with HIV. Certain drugs such as anticonvulsants and corticosteroids can interfere with pyridoxine metabolism, as can isoniazid, cycloserine, penicillamine, and hydrocortisone. Seizures accompanying deficiency of pyridoxine and peripheral neuritis such as carpal tunnel syndrome are common. The lowered seizure threshold may reflect decreased concentrations of the inhibitory neurotransmitter γ-aminobutyric acid, the synthesis of which requires a pyridoxal phosphate-requiring enzyme.
As described previously, a person with a deficiency of pyridoxine may also have a deficiency of the other B vitamins.
Drug Interactions
Isoniazid and hydralazine act as potent inhibitors of pyridoxal kinase, thus preventing synthesis of the active coenzyme form of the vitamin. Indeed, administration of pyridoxine decreases the incidence of neurologic side effects associated with the administration of these drugs. Pyridoxine enhances the peripheral decarboxylation of levodopa and decreases its effectiveness for the treatment of Parkinson disease. There is a decrease in the plasma concentration of pyridoxal phosphate in patients taking oral contraceptives.
Pantothenic Acid
Pantothenic acid is converted to its physiologically active form, coenzyme A, which serves as a cofactor for enzyme-catalyzed reactions involving transfer of two carbon (acetyl) groups. Such reactions are important in the oxidative metabolism of carbohydrates, gluconeogenesis, and the synthesis and degradation of fatty acids.
Pantothenic acid deficiency in humans is rare, reflecting the ubiquitous presence of this vitamin in ordinary foods as well as its production by intestinal bacteria. No clearly defined uses of pantothenic acid exist, although it is commonly included in multivitamin preparations and in hyperalimentation solutions.
Biotin
Biotin is an organic acid that functions as a coenzyme for enzyme-catalyzed carboxylation reactions and fatty acid synthesis. In adults, a deficiency of biotin manifests as glossitis, anorexia, dermatitis, and mental depression. Seborrheic dermatitis of infancy is most likely a form of biotin deficiency. For this reason, it is recommended that formulas contain supplemental biotin.
Cyanocobalamin
Cyanocobalamin (Cobalamin, Vitamin B12) and vitamin B12 are generic designations that are used interchangeably to describe several cobalt-containing compounds (cobalamins). Dietary vitamin B12 in the presence of hydrogen ions in the stomach is released from proteins and subsequently binds to a glycoprotein intrinsic factor. This vitamin-intrinsic factor complex travels to the ileum, where it interacts with a specific receptor and is then transported across the intestinal endothelium. After absorption, vitamin B12 binds to a β-globulin, transcobalamin II, for transport to tissues, especially the liver, which serves as its storage depot.
Causes of Deficiency
Although humans depend on exogenous sources of vitamin B12, a deficient diet is rarely the cause of a deficiency state. Instead, gastric achlorhydria and decreased gastric secretion of intrinsic factor are more likely causes of vitamin B12 deficiency in adults. Antibodies to intrinsic factor may interfere with attachment of the complex to gastrin receptors in the ileum.32 Bacterial overgrowth may also prevent an adequate amount of vitamin B12 from reaching the ileum. Surgical resection or disease of the ileum predictably interferes with the absorption of vitamin B12. Nitrous oxide irreversibly oxidizes the cobalt atom of vitamin B12 such that the activity of two vitamin B12–dependent enzymes, methionine synthetase and thymidylate synthetase, are decreased.
Diagnosis of Deficiency
The plasma concentration of vitamin B12 (cobalamin) is less than 200 pg/mL when there is a deficiency state. Measurements of gastric acidity may provide indirect evidence of a defect in gastric parietal cell function, whereas the Schilling test (radioactivity in the urine measured after oral administration of labeled vitamin B12) can be used to quantitate ileal absorption of vitamin B12. Observation of reticulocytosis after a therapeutic trial of vitamin B12confirms the diagnosis.
Symptoms of Deficiency
Deficiency of vitamin B12 results in defective synthesis of DNA, especially in tissues with the greatest rate of cell turnover. In this regard, symptoms of vitamin B12 deficiency manifest most often in the hematopoietic and nervous systems. Changes in the hematopoietic system are most apparent in erythrocytes, but when vitamin B12 deficiency is severe, a pronounced cytopenia may occur. Clinically, the earliest sign of vitamin B12 deficiency is megaloblastic (pernicious) anemia. Anemia may be so severe that cardiac failure occurs, especially in elderly patients with limited cardiac reserves.
Encephalopathy is a well-recognized complication of vitamin B12 deficiency, manifesting as myelopathy, optic neuropathy, and peripheral neuropathy, either alone or in any combination. Neurologic complications do not parallel the presence of megaloblastic anemia. Damage to the myelin sheath is the most obvious symptom of nervous system dysfunction associated with vitamin B12 deficiency. Demyelination and cell death occur in the spinal cord and cerebral cortex, manifesting as paresthesias of the hands and feet and diminution of sensation of vibration and proprioception with resultant unsteadiness of gait. Deep tendon reflexes are decreased, and, in advanced states, loss of memory and mental confusion occur. Indeed, vitamin B12 deficiency should be considered in elderly patients with psychosis. Folic acid therapy corrects the hematopoietic, but not nervous system, effects produced by vitamin B12deficiency.
Treatment of Deficiency
Vitamin B12 is available in a pure form for oral or parenteral use or in combination with other vitamins for oral administration. These preparations are of little value in the treatment of patients with deficiency of intrinsic factor or ileal disease. In the presence of clinically apparent vitamin B12 deficiency, oral absorption is not reliable; the preparation of choice is cyanocobalamin administered intramuscularly. For example, in the patient with neurologic changes, leukopenia, or thrombocytopenia, treatment must be aggressive. Initial treatment is with intramuscular administration of vitamin B12 and oral administration of folic acid. An increase in the hematocrit does not occur for 10 to 20 days. The plasma concentration of iron, however, usually declines within 48 hours, because iron is now used in the formation of hemoglobin. Platelet counts can be expected to reach normal levels within days of initiating treatment; the granulocyte count requires a longer period to normalize. Memory and sense of well-being may improve within 24 hours after initiation of therapy. Neurologic signs and symptoms that have been present for prolonged periods, however, often regress slowly and may never return to completely normal function. Indeed, neurologic damage after pernicious anemia develops that is not reversed after 12 to 18 months of therapy is likely to be permanent. Once initiated, vitamin B12 therapy must be continued indefinitely at monthly intervals. It is important to monitor plasma concentrations of vitamin B12 and examine the peripheral blood cells every 3 to 6 months to confirm the adequacy of treatment.
Hydroxocobalamin has hematopoietic activity similar to that of vitamin B12 but appears to offer no advantage despite its somewhat longer duration of action. Furthermore, some patients develop antibodies to the complex of hydroxocobalamin and transcobalamin II. Large doses of hydroxocobalamin have been approved for treatment of cyanide poisoning due to nitroprusside. Conceptually, cyanide reacts with the cobalt in cyanocobalamin, decreasing cyanide ion concentration.
Folic Acid
Folic acid is transported and stored as 5-methylhydrofolate after absorption from the small intestine, principally the jejunum. Conversion to the metabolically active form, tetrahydrofolate, is dependent on the activity of vitamin B12. Tetrahydrofolate acts as an acceptor of 1-carbon units necessary for (a) conversion of homocysteine to methionine, (b) conversion of serine to glycine, (c) synthesis of DNA, and (d) synthesis of purines. Supplies of folic acid are maintained by ingestion of food and by enterohepatic circulation of the vitamin. Virtually all foods contain folic acid, but protracted cooking can destroy up to 90% of the vitamin.
Causes of Deficiency
Folic acid deficiency is a common complication of diseases of the small intestine, such as sprue, that interfere with absorption of the vitamin and its enterohepatic recirculation. Patients with alcoholism have reduced intake of folic acid because of their decreased intake of food, and enterohepatic recirculation may be impaired by the toxic effect of alcohol on hepatocytes. Indeed, alcoholism is the most common cause of folic acid deficiency, with decreases in the plasma concentrations of folic acid manifesting within 24 to 48 hours of continuous alcohol ingestion. Drugs that inhibit dihydrofolate reductase (methotrexate, trimethoprim) or interfere with absorption and storage of folic acid in tissues (phenytoin) may cause folic acid deficiency.
Symptoms of Deficiency
Megaloblastic anemia is the most common manifestation of folic acid deficiency. This anemia cannot be distinguished from that caused by a deficiency of vitamin B12. Folic acid deficiency, however, is confirmed by the presence of a folic acid concentration in the plasma of less than 4 ng/mL. Furthermore, the rapid onset of megaloblastic anemia produced by folic acid deficiency (1 to 4 weeks) reflects the limited in vivo stores of this vitamin and contrasts with the slower onset (2 to 3 years) of symptoms and signs of vitamin B12 deficiency.
Treatment of Deficiency
Folic acid is available as an oral preparation alone or in combination with other vitamins and either an oral preparation or as a parenteral injection. The therapeutic uses of folic acid are limited to the prevention and treatment of deficiencies. For example, pregnancy increases folic acid requirements, and oral supplementation, usually in a multivitamin preparation, is indicated. In the presence of megaloblastic anemia because of folic acid deficiency, the administration of the vitamin is associated with a decrease in the plasma concentration of iron within 48 hours, reflecting new erythropoiesis. Likewise, the reticulocyte count begins to increase within 48 to 72 hours, and the hematocrit begins to increase during the second week of therapy.
Folate Therapy
Vitamin therapy to lower homocysteine levels has been recommended for the prevention of restenosis after coronary angioplasty. This is based on the belief that homocysteine is thrombogenic and is a risk factor for coronary artery disease. Folate supplementation is an effective treatment of homocystinemia. Nevertheless, folate therapy (combination of folic acid, vitamin B6, and vitamin B12) may actually increase the risk of in-stent restenosis and the need for revascularization.33
Leucovorin
Leucovorin (citrovorum factor) is a metabolically active, reduced form of folic acid. After treatment with folic acid antagonists, such as methotrexate, patients may receive leucovorin (rescue therapy), which serves as a source of tetrahydrofolate that cannot be formed due to drug-induced inhibition of dihydrofolate reductase.
Ascorbic Acid
Ascorbic acid (Vitamin C) is a six-carbon compound structurally related to glucose. This vitamin acts as a coenzyme and is important in a number of biochemical reactions, mostly involving oxidation. For example, ascorbic acid is necessary for the synthesis of collagen, carnitine, and corticosteroids. Ascorbic acid is readily absorbed from the gastrointestinal tract, and many foods, such as orange juice and lemon juice, have a high content of ascorbic acid. When gastrointestinal absorption is impaired, ascorbic acid can be administered intramuscularly or intravenously. Apart from its role in nutrition, ascorbic acid is commonly used as an antioxidant to protect the natural flavor and color of many foods.
Despite contrary claims, controlled studies do not support the efficacy of even large doses of ascorbic acid in treating viral respiratory tract infections.34 A risk of large doses of ascorbic acid is the formation of kidney stones resulting from the excessive secretion of oxalate. Excessive ascorbic acid doses can also enhance the absorption of iron and interfere with anticoagulant therapy.
Symptoms of Deficiency
A deficiency of ascorbic acid is known as scurvy. Humans, in contrast to many other mammals, are unable to synthesize ascorbic acid, emphasizing the need for dietary sources of the vitamin to prevent scurvy. Specifically, humans lack the hepatic enzyme necessary to produce ascorbic acid from gluconate. Manifestations of scurvy include gingivitis, rupture of the capillaries with formation of numerous petechiae, and failure of wounds to heal. An associated anemia may reflect a specific function of ascorbic acid on hemoglobin synthesis. Scurvy is evident when the plasma concentration of ascorbic acid is less than 0.15 mg/dL.
Scurvy is encountered among the elderly, alcoholics, and drug addicts. Ascorbic acid requirements are increased during pregnancy, lactation, and stresses such as infection or after surgery. Infants receiving formula diets with inadequate concentrations of ascorbic acid can develop scurvy. Patients receiving TPN should receive supplemental ascorbic acid. Urinary loss of infused ascorbic acid is large, necessitating daily doses of 200 mg to maintain normal concentrations in plasma of 1 mg/dL. Increased urinary excretion of ascorbic acid is caused by salicylates, tetracyclines, and barbiturates.
Fat-Soluble Vitamins
The fat-soluble vitamins are vitamins A, D, E, and K (Fig. 36-2). They are absorbed from the gastrointestinal tract by a complex process that parallels absorption of fat. Thus, any condition that causes malabsorption of fat, such as obstructive jaundice, may result in deficiency of one or all these vitamins. Fat-soluble vitamins are stored principally in the liver and excreted in the feces. Because these vitamins are metabolized very slowly, overdose may produce toxic effects.
Vitamin A (Retinol, Retinoic Acid)
Vitamin A exists in a variety of forms, including retinal and 3-dehydroretinal. This vitamin is important in the function of the retina, integrity of mucosal and epithelial surfaces, bone development and growth, reproduction, and embryonic development. It also has a stabilizing effect on various membranes and regulates membrane permeability. Vitamin A may exert transcriptional control of the production of specific proteins, a process that has important implications with respect to regulation of cellular differentiation and development of malignancies. Limitations in the therapeutic use of vitamin A for antineoplastic uses are the associated hepatotoxicity and its failure to distribute to specific organs.
Major dietary sources of vitamin A are liver, butter, cheese, milk, certain fish, and various yellow or green fruits and vegetables. Fish liver oils contain large amounts of vitamin A. Sufficient vitamin A is stored in the liver of well-nourished persons to satisfy requirements for several months. Plasma concentrations of vitamin A are maintained at the expense of hepatic reserves and thus do not always reflect a person’s vitamin A status. Vitamin A may interact with cellular proteins, which function analogously to receptors for estrogens and other steroids.
Symptoms of Deficiency
Plasma concentrations of vitamin A of less than 20 µg/dL indicate the risk of deficiency. Most deficiencies occur in infants or children. Signs and symptoms of mild vitamin A deficiency are easily overlooked. Skin lesions such as follicular hyperkeratosis and infections are often the earliest signs of deficiency. Nevertheless, the most recognizable manifestation of vitamin A deficiency is night blindness (nyctalopia), which occurs only when the depletion is severe. Pulmonary infections are increased as mucous secretion from bronchial epithelium is decreased because the epithelial cells undergoe keratinization. Keratinization and drying of the epidermis occurs. Urinary calculi are frequently associated with vitamin A deficiency, which may reflect epithelial changes that provide a nidus around which a calculus is formed. Abnormalities of reproduction include impairment of spermatogenesis and spontaneous abortion. Impairment of taste and smell is common in patients with vitamin A deficiency, presumably reflecting a keratinizing effect. Decreased erythropoiesis may be masked by abnormal losses of fluids.
Hypervitaminosis A
Hypervitaminosis A is the toxic syndrome that results from excessive ingestion of vitamin A, particularly in children. Typically, high vitamin A intake has resulted from overzealous prophylactic vitamin A therapy. Plasma concentrations of vitamin A of greater than 300 µg/dL are diagnostic of hypervitaminosis A. Treatment consists of withdrawal of the vitamin source, which is usually followed within 7 days by disappearance of the manifestations of excess vitamin A activity.
Early signs and symptoms of vitamin A intoxication include irritability, vomiting, and dermatitis. Fatigue, myalgia, loss of body hair, diplopia, nystagmus, gingivitis, stomatitis, and lymphadenopathy have been observed. Hepatosplenomegaly is accompanied by cirrhosis of the liver, portal vein hypertension, and ascites. Intracranial pressure may be increased, and neurologic symptoms, including papilledema, may mimic those of a brain tumor (pseudotumor cerebri). The diagnosis is confirmed by radiologic demonstration of hyperostoses underlying tender swellings on the extremities and the occipital region of the head. Plasma alkaline phosphatase concentrations are increased, reflecting osteoblastic activity. Hypercalcemia may occur because of bone destruction. Bones continue to grow in length but not in thickness, with increased susceptibility to fractures. Congenital abnormalities may occur in infants whose mothers have consumed excessive amounts of vitamin A during pregnancy. Psychiatric disturbances may mimic mental depression or schizophrenia.
Vitamin D
Vitamin D (Calciferol) has two forms, D2 (ergocalciferol) and D3 (cholecalciferol) with identical chemical structure except that D2 has an additional methyl group on Carbon 24. D2 comes from the diet, whereas D3 is synthesized in the skin by ultraviolet light’s action on 7-dehydrocholesterol. D2 and D3 are metabolically inert and require two chemical reactions to acquire activity. In hepatic cells 25-hydroxylase adds a hydroxyl group to the molecule to form 25-hydroxyvitamin D or 25-(OH)D, and the second reaction takes place in the kidney where 1α-hydroxylase converts 25-(OH)D to the biologically active 1,25(OH)2 vitamin D (calcitriol), which regulates calcium and phosphate concentrations in the blood. 25-(OH)D is transported in the blood by vitamin D–binding protein (DBP). Following its production in the kidney, calcitriol binds to DBP for transport to sites of action. 25-(OH)D bound to DBP circulates in the blood, and, when calcium levels decrease, 25-(OH)D is absorbed by the kidney and hydroxylated to the biologically active calcitriol, and then released back into the bloodstream. The process is quite regulated and, unless there is a need, calcitriol is not produced in the kidney. Traditionally, calcitriol has been thought to be the biologically active molecule and 25-(OH)D is a prohormone, but more recent studies in knockout mice deficient in 1α-hydroxylase have demonstrated that sufficient calcium in diet can normalize serum calcium levels,35 presumably because of the action of 25-(OH)D.
Calcitriol exerts its effects by binding and activating vitamin D receptors (VDRs) in the nuclei of many differenct cell types.
Calcitriol’s primary function is to maintain calcium and phosphorous homeostasis.36 Calcium levels are maintained through three mechanisms: absorption of calcium in the duodenum and jejunum, release of calcium from bone,37and increased uptake of calcium in the distal tubule of the kidney.38
When phosphate levels are low, calcitriol inceases its absorption in the small intestine, or conversely, when phosphate levels are elevated, calcitriol acts on osteocytes to release fibroblast growth factor 23, which in turn increases the loss of phosphorous in the renal distal tubule.39
VDRs are identified in the nuclei of a wide variety of cells that do not play a role in calcium or phosphorus homeostasis, and it is not suprising then that vitamin D has a role in the regulation of many different genes.36
Retrospective studies have shown a 21% reduction in mortality from cardiovascular disease and conversely a reduction by as much as 28% in mortality in those with vitamin D levels twice that of controls. However, supplementation with vitamin D to decrease the incidence of cardiovascular disease has not been shown,40 but there are advocates of such an approach to decrease the morbidity associated with cardiovascular disease.41
Other studies have demonstrated a correlation between vitamin D concentrations and outcome in cancer patients. Calcitriol has a role in malignant disease,42 attenuating the proliferation of malignant cells through several mechanisms.43,44 Calcitriol may regulate the progression of malignant cell growth by suppressing the protooncogene myc, the cyclin-dependent kinases, and retinoblastoma protein phosphorylation and via interference of growth factor receptor–mediated signaling pathways.45–48 Calcitriol’s impact on apoptosis may also have a role in its modulation of malignant cancerous cells.45,46
Calcitriol may also influence immune function,49 through similar metabolic pathways. In monocytes, calcitriol stimulates cathelicidin, a peptide with bactericidal and mycobactericidal properties. Calcitriol also inhibits the number and activity of T helper cells. These effects may be clinically important with the former benefiting patients who are septic, and the latter, patients with myeloproliferative diseases.
Calcitriol might have a role in both type I and type II diabetes through its binding to the VDRs of pancreatic cells or through its effects on calcium metabolism.50 In addition to calcitriol’s theoretical role in cardiovascular disease, cancer, immune function, and diabetes, it may also have an effect on morbidity and mortality patients who are critically ill.51
Symptoms of Deficiency
A deficiency of vitamin D results in decreased plasma concentrations of calcium and phosphate ions, with the subsequent stimulation of parathyroid hormone secretion. Parathyroid hormone acts to restore plasma calcium concentrations at the expense of bone calcium. In infants and children, this results in failure to mineralize newly formed osteoid tissue and cartilage, causing formation of soft bone, which, with weight bearing, results in deformities known as rickets. In adults, vitamin D deficiency results in osteomalacia. Anticonvulsant therapy with phenytoin increases target organ resistance to vitamin D, resulting in an increased incidence of rickets and osteomalacia. There is evidence that vitamin D supplementation reduces the risk of falling among elderly individuals.52
Hypervitaminosis D
Administration of excessive amounts of vitamin D results in hypervitaminosis, manifesting as hypercalcemia, skeletal muscle weakness, fatigue, headache, and vomiting. Early impairment of renal function from hypercalcemia manifests as polyuria, polydipsia, proteinuria, and decreased urine-concentrating ability. In addition to withdrawal of the vitamin, treatment includes increased fluid intake, diuresis, and administration of corticosteroids.
Vitamin E
Vitamin E (α-Tocopherol) is not a single molecule but, rather, a group of fat-soluble substances occurring in plants. There is little persuasive evidence that vitamin E is nutritionally significant in humans.53 α-Tocopherol is the most abundant and important of the eight naturally occurring tocopherols that constitute vitamin E. An important chemical feature of the tocopherols is that they are antioxidants. In acting as an antioxidant, vitamin E presumably prevents oxidation of essential cellular constituents or prevents the formation of toxic oxidation products. There seems to be a relationship between vitamins A and E in which vitamin E facilitates the absorption, hepatic storage, and use of vitamin A. In addition, vitamin E seems to protect against the development of hypervitaminosis A by enhancing the use of the vitamin. Vitamin E is stored in adipose tissue and is thought to stabilize the lipid portions of cell membranes. Other functions attributed to vitamin E are inhibition of prostaglandin production and stimulation of an essential cofactor in corticosteroid metabolism.
Vitamin E requirements may be increased in individuals exposed to high oxygen environments or in those receiving therapeutic doses of iron or large doses of thyroid hormone replacement. Vitamin E may be important in hematopoiesis, with occasional forms of anemia responding favorably to the administration of α-tocopherol.
Despite absence of conclusive supportive evidence, vitamin E has been administered to women with a history of recurrent spontaneous abortions and for sterility in both sexes. In animals, vitamin E deficiency leads to the development of muscular dystrophy, but there is no evidence that a similar sequence occurs in humans. Changes similar to those observed in skeletal muscles have occurred in cardiac muscle of animals. A necrotizing myopathy with proximal skeletal muscle weakness and increased plasma concentrations of creatine kinase may occur in patients self-medicated with large doses of vitamin E. There are data that support an association between low plasma levels of vitamin E and the risk of developing lung cancer.54
Epidemiologic studies have provided evidence of an inverse relationship between coronary artery disease and antioxidant intake, and vitamin E supplementation in particular.55 This association has been attributed to the finding that antioxidants prevent oxidation of lipids in low-density lipoproteins. It is proposed that oxidation of lipids in low-density lipoproteins (lipid peroxidation) initiates the process of atherogenesis.
Vitamin K
Vitamin K is a lipid-soluble dietary compound that is essential for the biosynthesis of several factors required for normal blood clotting. Phytonadione (vitamin K1) is present in a variety of foods and is the only natural form of vitamin K available for therapeutic use. Vitamin K2 represents a series of compounds that are synthesized by gram-positive bacteria in the gastrointestinal tract. Synthesis of vitamin K provides approximately 50% of the estimated daily requirement of vitamin K; the rest is supplied by the diet. Vitamin K is absorbed from the gastrointestinal tract only in the presence of adequate quantities of bile salts. Vitamin K accumulates in the liver, spleen, and lungs, but, despite its lipid solubility, significant amounts are not stored in the body for prolonged periods.
Mechanism of Action
Vitamin K functions as an essential cofactor for the hepatic microsomal enzyme that converts glutamic acid residues to γ-carboxyglutamic acid residues in factors II (prothrombin), VII, IX, and X. The γ-carboxyglutamic acid residues make it possible for these coagulation factors to bind calcium ions and attach to phospholipid surfaces, leading to clot formation. If vitamin K deficiency occurs, the plasma concentrations of these coagulation factors decrease and a hemorrhagic disorder develops. Vitamin K deficiency is characterized by ecchymoses, epistaxis, hematuria, and gastrointestinal bleeding. Vitamin K activity is assessed by monitoring the prothrombin time.
Clinical Uses
Vitamin K is administered to treat its deficiency and attendant decrease in plasma concentrations of prothrombin and related clotting factors. Deficiency of vitamin K may be due to (a) inadequate dietary intake, (b) decreased bacterial synthesis due to antibiotic therapy, (c) impaired gastrointestinal absorption resulting from obstructive biliary tract disease and absence of bile salts, or (d) hepatocellular disease. Neonates have hypoprothrombinemia due to vitamin K deficiency until adequate dietary intake of the vitamin occurs and normal intestinal bacterial floras are established. Indeed, at birth, the normal infant has only 20% to 40% of the adult plasma concentrations of clotting factors II, VII, IX, and X. These plasma concentrations decrease even further during the first 2 to 3 days after birth and then begin to increase toward adult values after approximately 6 days. In premature infants, plasma concentrations of clotting factors are even lower. Human breast milk has low concentrations of vitamin K. Administration of vitamin K, 0.5 to 1.0 mg intramuscularly at birth, to the normal neonate prevents the decrease in concentration of vitamin K–dependent clotting factors in the first days after birth but does not increase these concentrations to adult levels.
Vitamin K replacement therapy is not effective when severe hepatocellular disease is responsible for the decreased production of clotting factors. In the absence of severe hepatocellular disease and the presence of adequate bile salts, the administration of oral vitamin K preparations is effective in reversing hypoprothrombinemia. Phytonadione and menadione are the vitamin K preparations most often used to treat hypoprothrombinemia.
Phytonadione
Phytonadione (vitamin K1) is the preferred drug to treat hypoprothrombinemia, particularly if large doses or prolonged therapy is necessary. Hypoprothrombinemia of the neonate is treated with phytonadione, 0.5 to 1.0 mg intramuscularly, within 24 hours of birth. A frequent indication for phytonadione is to reverse the effects of oral anticoagulants. For example, phytonadione, 10 to 20 mg orally or administered intravenously at a rate of 1 mg per minute, is usually adequate to reverse the effects of oral anticoagulants. The oral and intramuscular routes of administration are less likely than the IV injections of phytonadione to cause side effects and are thus preferred for nonemergency reversal of oral anticoagulants. Even large doses of phytonadione are ineffective against heparin-induced anticoagulation. Vitamin K supplementation is also indicated for patients receiving prolonged TPN, especially if antibiotics are concomitantly administered.
IV injection of phytonadione may cause life-threatening allergic reactions characterized by hypotension and bronchospasm. Intramuscular administration may produce local hemorrhage at the injection site in hypoprothrombinemic patients. In neonates, doses of phytonadione of greater than 1 mg may cause hemolytic anemia and increase the plasma concentrations of unbound bilirubin, thus increasing the risk of kernicterus. The occurrence of hemolytic anemia reflects a deficiency of glycolytic enzymes in some neonates.
Menadione
Menadione has the same actions and uses as phytonadione (Fig. 36-3). Water-soluble salts of menadione do not require the presence of bile salts for their systemic absorption after oral administration. This characteristic becomes important when malabsorption of vitamin K is due to biliary obstruction.
Menadione hemolyzes erythrocytes in patients genetically deficient in glucose-6-phosphate dehydrogenase, as well as in neonates, particularly premature infants. This hemolysis and occasionally hepatic toxicity reflect a combination of menadione with sulfhydryl groups in tissues. Kernicterus has occurred after menadione administration to neonates. For this reason, menadione is not recommended for treatment of hemorrhagic disease of the neonate. Administration of large doses of menadione or phytonadione may depress liver function, particularly in the presence of preexisting liver disease.
Dietary Supplements
Dietary supplements (vitamins, minerals, herbs, amino acids, enzymes) are products ingested orally and intended to supplement the diet with nutrients thought to improve health. Herbs include flowering plants, shrubs, seaweed, and algae. It is estimated that 25% of patients use alternative therapies characterized as dietary supplements or herbal remedies (more than 3 billion doses). These products are not subject to FDA approval because they are considered nutrients (do not undergo scientific testing to prove efficacy and plants and parts of plants are not patent eligible) although they cannot be promoted specifically for treatment, prevention, or cure of disease. Nevertheless, these products can be labeled with statements describing their alleged effects. The FDA has no control over the herbal industry in terms of safety guidelines that would regulate purity and consistency of therapeutic medications.
Adverse Effects and Drug Interactions
Individuals who take dietary supplements and/or herbal remedies in combination with prescription drugs may be at risk for experiencing adverse interactions (Tables 36-4 and 36-5).56 The most serious side effects associated with these substances include cardiovascular instability, bleeding tendency particularly in conjunction with other anticoagulants such as warfarin, and delayed awakening from anesthesia.
Ephedra (ma huang) is a common ingredient in herbal weight-loss products, stimulants, decongestants, and bronchodilators. The active moiety in ephedra is ephedrine, a sympathomimetic amine structurally related to amphetamines. Serious adverse reactions, including hypertension, cardiac arrhythmias, prolonged QTc interval on the ECG, myocardial infarction, stroke, and death, have been described in patients taking ephedra.57 The chances of experiencing an adverse reaction when taking ephedra are estimated to be 100-fold greater than with any other dietary supplement or herbal remedy. Although tachycardia and vasoconstriction can occur in healthy patients, those with heart disease or systemic hypertension, or those who engage in strenuous physical exercise, seem to be at greatest risk for ephedra-related side effects. Based on the risk of adverse reactions, the FDA concluded that dietary supplements containing ephedra present an unreasonable risk of illness or injury. The FDA banned sales of dietary supplements containing ephedra in April 2004.
Ginseng may cause tachycardia or systemic hypertension, particularly in combinations with other cardiac stimulant drugs. In addition, ginseng may decrease the anticoagulant effects of warfarin. Fever may enhance bleeding by inhibition of platelet activity. Warfarin may also be potentiated by concomitant use of garlic, ginkgo biloba, and ginger. Ginkgo biloba has been suggested to possess antiplatelet effects, and spontaneous hemorrhage has been reported.58 St. John’s wort, which is alleged to be a natural antidepressant, has been shown to inhibit serotonin, dopamine, and norepinephrine reuptake and thus presents the possibility of interactions with monoamine oxidase inhibitors and other serotoninergic drugs.59 Valerian, kava-kava, and possibly St. John’s wort may delay awakening from anesthesia by prolonging sedative effects of anesthetic drugs.
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