Four decades of experience with parenteral nutrition (PN) have established not only the life-saving promise of intravenous feeding but also the reality that serious infectious and metabolic complications can accompany treatment. Early enthusiasm for intravenous feeding led to overzealous use of PN in clinical situations, ranging from routine preoperative care to adjunctive treatment for individuals undergoing radiation or chemotherapy. Subsequent studies revealed that not all patients benefit from intravenous feeding. Some PN patients showed no difference in outcomes compared with those receiving standard therapy. In other cases, PN seemed to contribute to unfavorable results, especially with respect to infectious complications.1 Adherence to evidence-based clinical guidelines is a key step in avoiding complications related to PN therapy.2,3
Safe and effective PN begins with judicious selection of candidates for PN and continues with the development of a prescription specifically tailored to the needs of each patient. In addition, all PN recipients require close monitoring of their metabolic and clinical status, with prompt responses to situations that call for adjustments in the PN regimen. A coordinated, multidisciplinary approach to nutrition therapy is most effective in producing optimal clinical outcomes.4,5
INDICATIONS
"If the gut works, use it." This guiding principle for selecting PN candidates has taken on even greater significance as substantial clinical benefits of enteral nutrition (EN) have come to light. Compared with PN, tube feeding lowers the risk of metabolic and infectious complications and, when initiated in the early phases of critical illness, improves outcomes and shortens lengths of stay-all at a fraction of the cost of intravenous feeding. Many of these benefits occur simply because EN maintains normal digestive and absorptive pathways. Other benefits are related to preservation of immune activity. The presence of nutrients within the gut supports intestinal cells that produce a variety of immune factors, in part explaining why EN carries a lower risk of infectious complications than PN. Because of these advantages, PN is reserved for situations in which the enteral route is not an option.2 Appropriate PN recipients typically have medical conditions that prevent oral or EN, such as impaired digestion and absorption of nutrients, persistent vomiting or diarrhea, or inability to achieve enteral access.5,6Table 1 provides more detail regarding PN indications.
Baseline nutritional status can guide the decision to begin PN. For example, preoperative PN has been shown to benefit severely malnourished patients, whereas well-nourished individuals gain no advantage by delaying surgery for nutritional support.7 Additional factors such as vascular access, the potential for clinical benefit, prognosis, and the patient's views regarding artificial feeding also come into play when deciding whether PN is appropriate.
Timing fo Nutritional Intervention
Severity of illness and underlying nutritional status determine the appropriate time for introducing nutritional support.8 Clinically stable, well-nourished adults can be maintained on conventional intravenous fluids for 7 to 14 days without negative consequences.2,9 On the other hand, preexisting nutritional deficits and conditions marked by nutrient losses or catabolic illness demand more immediate attention.
For the critically ill, guidelines regarding the timing of nutritional intervention vary according to the route used to provide nutrition. Strong evidence supports the use of EN within 24 to 48 hours of admission to an intensive care unit to improve outcomes, but the benefits seen with early EN do not carry over to early PN. When EN is not feasible, PN should not be initiated until the seventh day of hospitalization for those who were healthy and well nourished before the onset of critical illness.10
Regardless of the clinical circumstances, the initiation of PN should never take on the urgency of an emergency situation. The risk of adverse events can be greatly reduced by first achieving hemodynamic stability, controlling blood glucose levels, and correcting electrolyte sisturbanced before initiating PN. Table 2 provides examples of clinical situations that warrant a cautious approach to initiating PN.
CENTRAL VERSUS PERIPHERAL ADMINISTRATION
Although delivery of PN into the central venous circulation is most common, in specific clinical circumstances, the peripheral route can serve as an alternative. The role of peripheral PN (PPN) is limited, however, by an increased risk for phlebitis due to the hyperosmolar nature of the formulations. Compared with central formulations, PPN contains a lower concentration of nutrients, but the osmolarity of peripheral formulations often exceeds the 600 mOsm/L limit for peripheral infusion.11 To a certain extent, this phlebitis risk may be mitigated by other measures such as limiting the duration of PPN, changing the catheter every 24 to 48 hours, and administering lipid emulsion through the same vein or as a component of the PN admixture.11
The relatively low nutrient content of PPN makes this route more appropriate for preventing malnutrition than for correcting existing nutritional deficits. Patients with elevated nutritional requirements due to hypermetabolic illness and those who require fluid restriction are not suitable candidates. Overall, PPN is indicated for short-term use, usually 2 weeks or less. It is most useful as a bridge therapy during transition periods when oral enteral intake is suboptimal or in circumstances that do not justify placing a central venous catheter.12
DEVELOPING INDIVIDUALIZED PN FORMULATIONS
A key aspect of developing appropriate PN formulations involves tailoring the prescription to meet the patient's unique requirements. In addition to water, PN formulations contain carbohydrate, fat, protein, electrolytes, vitamins, and trace elements. Manufacturers produce many of the core components of PN formulations as combination products in "standard" doses; yet, in clinical practice, nutrient requirements frequently fall outside established ranges.13 To develop customized PN formulations, clinicians must have an understanding of the role that specific nutrients play in metabolic processes and the impact of illness on nutrient use and energy requirements.
DETERMINING EHT MACRONUTRIENT CONTENT
PN sormulationf must furnish adequate energy and protein to preserve lean muscle mass and to support metabolic activities. The macronutrient base of all complete PN regimens consists of protein, carbohydrate, and fat. Figure 1 summarizes the caloric contribution and dosing range of each of these substrates.
For most adults, caloric intake of 25 to 30 kcal/kg supplies sufficient energy, but factors such as age, body size, physical activity, and clinical status can alter energy needs. Medical conditions that elevate metabolic rate or result in nutrient losses can push energy expenditure into the range of 30 to 35 kcal/kg. The optimal energy intake in obese and critically ill patients remains uncertain. For these populations, some evidence suggests that energy delivery of approximately 20 to 22 kcal/kg based on ideal body weight may be most appropriate.10,14 Ideal body weight can be determined by using a simple formula (Table 3).15 Despite uncertainty regarding optimal levels of nutrient intake, the hazards of overfeeding are clear. Studies have demonstrated a link between excessive caloric intake and respiratory and hepatic dysfunction in PN recipients. Although carbohydrate was the substrate first associated with overfeeding complications, administration of excessive levels of protein and fat can also lead to metabolic abnormalities. See Table 4 for more details pertaining to overfeeding.
Carbohydrate
Carbohydrate, in the form of dextrose monohydrate, is the principal source of energy in PN formulations, usually providing 70% to 85% of the nonprotein calories. Adults have a minimum dextrose requirement of approximately 100 g/d for glucose-dependent metabolic activities, but the maximum dose is governed by energy requirements and glucose tolerance. For patients with diabetes mellitus and stress-induced hyperglycemia, the initial dextrose content should be limited to a maximum of 150 g/d and advanced only as glucose tolerance permits.3,16
To avoid hyperglycemia, the infusion rate of dextrose should not exceed 7 mg/kg/min.3 In recent years, questions regarding optimal glucose control, particularly for the critically ill, have generated much debate. Initial evidence of reduced morbidity and mortality in patients receiving tight glucose control led to a rigorous approach for managing hyperglycemia in patients receiving PN.17 Subsequent studies not only failed to replicate the benefits of tight glucose control but also revealed increased mortality, possibly related to hypoglycemia.18 As a result, many professional organizations have recommended more relaxed goals for glycemic control, but further research is needed to delineate the optimal target range.19
Fat
The intravenous lipid emulsions (IVLEs) used in PN formulations provide essential fatty acids as well as a dense source of calories. In the United States, soybean oil serves as the primary fat source in IVLEs. Like dietary fat, each gram of oxidized lipid yields 9 kcal, but IVLEs contain an emulsifier that contributes additional calories. Lipid emulsions are isotonic, making them appropriate for administration by either peripheral or central vein.3 Symptoms of essential fatty acid deficiency (EFAD), which can appear within 3 weeks of fat-free PN administration (with no oral or enteral fat intake), include scaly dermatitis, hair loss, poor wound healing, and thrombocytopenia. Although EFAD is currently uncommon, trends toward using hypocaloric, fat-free PN for obese patients have raised some concern that these regimens could lead to a resurgence of this condition.3,14 Adults require 100 g of fat per week (250 mL of 20% IVLE 2 times per week) to avert EFAD, but IVLE is often given daily as a source of nonprotein calories.20 Guidelines set the maximum daily lipid dose at 2.5 g/kg/d or 0.11 g/kg/h, but some evidence suggests that 1 g/kg/d may be a safer limit, especially for the critically ill.6,21,22
Serum triglyceride levels should be measured before beginning PN and at regular intervals during administration to monitor lipid clearance. Patients with hypertriglyceridemia (levels of 400 mg/dL or greater) should not receive IVLE because of an increased risk for developing pancreatitis.21 Especially close monitoring of triglyceride levels is needed during administration of lipid-based drugs, such as propofol or clevidipine butyrate in conjunction with PN, to avoid adverse effects of excessive lipid administration, including fever, leukocytosis, thrombocytopenia, and impaired pulmonary gas diffusion.21
Because serious hypersensitivity reactions can occur with IVLE, an initial test dose of IVLE should be given; this can be done by limiting the infusion to 0.1 g of fat per minute for the first 15 to 30 minutes, which translates to a 30-mL/h infusion rate for 20% IVLE.23 During this slow infusion period, patients must be observed for signs and symptoms of an adverse reaction including fever and chills, nausea/vomiting, hives, back pain, headache, dyspnea, and chest pain. Untoward reactions typically resolve with termination of the IVLE infusion.
Lipid products in the United States contain omega-6 fatty acids as the predominant fat source. Evidence suggests that omega-6 fatty acids follow metabolic pathways that produce proinflammatory mediators, raising concern about the potential for IVLE to exacerbate conditions in which systemic inflammation plays a role. Although clinical studies have produced conflicting evidence of lipid effects on immune function, cautious use of IVLE in severely stressed and critically ill patients is recommended.10,24
Protein
As the primary functional and structural component of all cells, proteins play a critical role in virtually all biological processes. In PN, amino acids serve as the protein source, with 1 g of amino acids being equivalent to 1 g of protein. Protein typically constitutes 15% to 20% of the total calories in PN formulations, but illness can dramatically alter protein needs. When renal or hepatic failure impairs nutrient use or excretion, protein intake at the low end of the range may be appropriate (Figure 1). Although severe protein restriction is no longer common in renal or hepatic failure, close monitoring for signs of toxicity, such as azotemia or encephalopathy, is critical in determining the appropriate protein dose for individuals with organ failure. Conditions that trigger severe catabolism, such as multiple trauma and sepsis, can raise protein requirements to as much as 2 g/kg/d.8
THE MICRONUTRIENT COMPONENTS OF PN
Electrolytes
Electrolytes perform vital physiologic functions, giving them an essential place in all PN formulations. The electrolyte content of the PN prescription is adjusted on the basis of the patient's clinical status, laboratory results, acid-base balance, and medication profile. PN recipients are especially prone to electrolyte disturbances. Gastrointestinal disorders severe enough to require PN are often associated with high losses of fluid and electrolytes through diarrhea, fistula output, or gastric drainage. Conversely, renal insufficiency may require a reduction in the electrolyte dose, particularly with regard to the potassium and phosphorous content of the formulation.
Electrolyte products used in PN formulations contain no sodium bicarbonate because of the risk of forming precipitates with other electrolytes. Instead, PN formulations contain acetate salts that are converted by the liver to bicarbonate. Both sodium and potassium can be added to PN formulations as either the chloride or acetate salt. This choice allows the PN formulation to be balanced according to acid-base requirements.25Table 5 shows the dosing range for each electrolyte found in PN formulations and the typical daily maintenance requirements.
In cases of severe weight loss or long-standing malnutrition, nutritional repletion can induce a condition known as refeeding syndrome. Characterized by electrolyte disturbances and fluid shifts, refeeding syndrome occurs early in the course of therapy, often in association with overzealous caloric replacement. As nutrition is introduced, glucose stimulates an insulin response, which, in turn, promotes uptake of intracellular ions and a subsequent drop in serum concentrations.26 Profound hypophosphatemia, the hallmark of refeeding syndrome, can be life threatening if not detected and treated promptly. Low levels of potassium and magnesium are also typical of the condition. Fluid overload due to sodium retention is another common manifestation that can lead to pulmonary edema, heart failure, and dysrhythmias.
When the potential for refeeding syndrome exists, correction of existing electrolyte disturbances should take place before PN begins. Then, the initial PN should provide a reduced level of calories. The recommended starting point for energy intake for patients at risk for refeeding syndrome ranges from 25% of estimated needs to as low as 10 kcal/kg/d, with slow progression toward goals across 5 to 7 days.26,27 Because thiamine deficiency can occur in conjunction with refeeding syndrome, supplementation with this vitamin in the first 3 days of PN is also recommended. Vigilant monitoring of serum electrolytes and aggressive correction of deficits are especially critical in avoiding the serious consequences associated with this condition. Electrolyte supplementation is often required in relatively high doses, over several days, before metabolic stability is achieved.
Vitamins
Although vitamins are required in relatively small amounts, these compounds participate in a diverse range of critical biochemical activities. Humans cannot synthesize vitamins in sufficient quantities to avoid deficiency states and must therefore receive them from exogenous sources. All PN recipients must receive both fat-soluble and water-soluble vitamins. Experience with manufacturing shortages of intravenous vitamins has demonstrated that patients who receive PN without vitamins can rapidly develop life-threatening deficiencies.28 In cases where intestinal absorption is adequate, a multivitamin can be taken orally, but patients must be diligent about taking the prescribed dose consistently.
The components contained in parenteral vitamin products are formulated to prevent deficiency without causing toxicity in clinically stable PN recipients. Existing deficits or markedly elevated requirements may make supplemental vitamins necessary, but high intake of the fat-soluble vitamins A, D, E, and K can lead to toxicity.29 Current intravenous multivitamin products lack 2 nutrients with vitamin-like properties, choline and carnitine, which may be conditionally essential in some clinical situations.29 In the presence of liver or kidney disease, the vitamin content of standard products may prove excessive, highlighting the need for monitoring vitamin status, especially in patients receiving long-term PN.
Trace Minerals
Trace minerals are elements that act as cofactors for enzymes or assist in the transport of substances across cell membranes. Although trace mineral deficiencies rarely occur in individuals who eat even small amounts of food, patients on PN require supplementation with these elements. PN formulations routinely supply chromium, copper, manganese, and zinc. Long-term PN recipients receive selenium to avoid the risk of cardiomyopathy associated with a deficiency of this mineral.16 Selenium supplementation is also associated with improved outcomes in the critically ill who receive PN.10 Although iron is an essential trace mineral, the potential for iron overload and concern about the stability of iron in PN formulations prevent routine administration of iron to PN recipients.29 Instead, patients with evidence of iron deficiency receive supplementation with an intravenous iron product as a separate infusion. At present, parenteral trace mineral products contain no iodine because, in the past, sufficient cutaneous absorption of the element occurred with the use of iodine-based skin disinfectants for central line care. The shift to chlorhexidine disinfectants may lead to a need to supplement iodine in PN formulations as well.29
Illness and organ function have an impact on trace mineral requirements. Patients experiencing excessive gastrointestinal losses from diarrhea, ileostomy, or fistula output may require additional zinc. Liver disease, on the other hand, impairs excretion of copper and manganese, leaving patients vulnerable to toxicity. Long-term PN recipients are especially at risk for developing trace mineral abnormalities. Reports of Parkinson-like symptoms due to manganese toxicity have appeared in the literature.30 Other studies have raised concerns that the dose provided by commercially available trace mineral products may exceed actual requirements.31 As with other micronutrients, trace mineral levels should be monitored regularly during chronic PN administration. Trace minerals may need to be added to PN formulations individually to achieve appropriate levels for those who develop abnormal trace element levels.
DETERMINING THE VOLUME OF PN FORMULATIONS
Within the constraints imposed by stability and solubility limits, PN formulations can be concentrated or diluted according to clinical status and fluid tolerance. The major substrates that form the base of all PN formulations-the protein, carbohydrate, and fat-are manufactured in a variety of percentage solutions that offer flexibility in designing PN formulations appropriate for patients' hydration status.
Under normal circumstances, adults require approximately 30 to 40 mL/kg of fluid daily.6 Water requirements are highly individualized, however, because numerous factors influence fluid needs, such as metabolic rate, fever, catabolic illness, activity level, organ function, fluid losses, and ambient temperature. Careful physical assessment, appraisal of intake and output records, and a review of pertinent laboratory values are essential to determining the appropriate volume for PN formulations.
CENTRAL LINE-ASSOCIATED BLOODSTREAM INFECTION
Central venous access is critical to the delivery of PN, yet access devices are also a leading source of complications associated with therapy, most notably central line-associated bloodstream infection (CLABSI). Because PN recipients are often malnourished, immunocompromised, and require intravenous therapy for extended periods of time, they are at particularly high risk for CLABSIs.32 In recent years, striking decreases in CLABSI rates have been achieved using a "bundle" of evidence-based guidelines promoted by the Institute for Healthcare Improvement (IHI).33,34 In 2009, intensive care units in the United States reported 58% fewer CLABSIs than in 2001.33 Despite this progress, PN remains an independent risk factor for CLABSI.35 Two recent reports cite CLABSI rates of 18.8 and 16.02 per 1000 catheter days for patients receiving PN, a level substantially higher than for catheters not used for PN.36,37 Another study noted a 4-fold increase in the odds ratio for CLABSI related to PN administration.38 Furthermore, exposure to PN also increases the risk for fungemia, which carries a mortality rate exceeding 30%.39,40
The etiology of the PN-associated risk for CLABSI is unclear. In the past, hyperglycemia was widely accepted as the source of the problem, but recent studies cast doubt on this hypothesis.37,38 Another concern is that the PN components could increase risk by serving as media for microbial growth. Because of a relatively low pH, PN formulations containing only dextrose and amino acids seem to inhibit the growth of most microbes, with the exception of fungi.41 Lipid emulsions, whether infused separately or in an admixture with dextrose and amino acids, do in fact support the growth of a broad range of pathogens.41,42 There is also some evidence that IVLEs suppress immune function, thus further increasing the risk for infection.43 Although rare, contamination of PN formulations can have serious consequences. This point was recently highlighted when PN contaminated with Serratia marcescens led to 19 cases of bacteremia that claimed the lives of 9 patients.44,45
Growing evidence implicates biofilm as a predisposing factor in the development of CLABSI in PN recipients by rendering bacteria more resistant to host defenses and antibiotics.46,47 Dextrose-containing fluids also promote some Candida species to produce biofilm similar to that of their bacterial counterparts, potentially explaining the increased proportion of CLABSIs caused by fungal pathogens among patients receiving PN.42 A study designed to evaluate trends in PN-associated CLABSI and fungemia recently demonstrated that although PN contributes a sizable proportion of CLABSIs, preventive strategies can mitigate the risk. A review of a total of 92505 device days for 2007 and for 2009 demonstrated an 82% reduction in PN-associated CLABSIs after a multidisciplinary endeavor aimed at reducing CLABSI rates. Still, 50% of all fungemias occurred in the PN group.48
The hyperosmolar nature of PN formulations also contributes to CLABSI risk by inducing inflammation and thrombosis within the vein.49 For this reason, the tip of the vascular access device must be positioned in the central venous system for PN formulations containing a final dextrose concentration that exceeds 10%.11 Professional organizations concur that central line placement in the proximal (upper) superior vena cava accentuates the risk of thrombosis. However, the question of whether the tip of the catheter should rest in the distal superior vena cava or the proximal right atrium is a source of some controversy.50 Advances in tip verification technology may eventually provide the evidence needed to resolve this debate.51
A multifaceted approach to the prevention of CLABSI can achieve impressive reductions in infection rates.52 Adherence to the components of the IHI central line bundle serves as the foundation of this process. Other evidence-based elements, including sutureless catheter stabilization devices and chlorhexidine patches, may also reduce infection.42 These measures focus primarily on CLABSI that occurs as a result of microbial migration along the extraluminal pathway, the most common route for central line contamination. In this era of heightened awareness regarding health care-associated infections, efforts to protect against intraluminal contamination has taken on greater significance.53,54 As with all central lines, PN protocols must include strategies to ensure aseptic management of the catheter hub. The selection of a needleless connector with a proven safety record and appropriate disinfection of the septum are critical components of this effort.11,35,42,54 The impact of mechanical valves on CLABSI rates merits further investigation.55 Research is also needed to explore the effects of various flushing practices on CLABSI rates and to delineate optimal techniques for locking vascular access devices.54 Measures aimed at limiting manipulation of the catheter hub may reduce the risk of CLABSI.35 In acute care settings, policies that restrict tubing-catheter disconnections during routine patient care should be considered. The Centers for Disease Control and Prevention makes no recommendation regarding the use of a designated lumen for PN.42 However, some limited evidence supports this practice. One study achieved a 5-fold decrease in catheter colonization using a dedicated, single-lumen subclavian catheter for PN administration.32 In addition, the anecdotal association between frequent blood sampling from central lines and CLABSI warrants further study.56-58 For long-term catheters, the prophylactic use of antimicrobial lock solution may be advantageous in situations where CLABSI has recurred despite adherence to all other standard infection control measures.42
Progress in reducing CLABSIs underscores the preventability of these infections. Without question, an educational plan that involves health care personnel, the patient, and family caregivers forms the cornerstone of all prevention efforts.11,35,42,59 Further research into areas such as lipid-induced immune dysfunction, hyperglycemia, and biofilms may uncover additional techniques for reducing the risk of PN-associated CLABSI.
HEPATIC COMPLICATIONS
Complications of the liver and biliary system are among the most common and serious problems associated with PN. Symptoms of PN-associated liver disease (PNALD) range from transient elevations in liver function tests (LFTs) to fibrosis, cirrhosis, and irreversible hepatic failure. Hepatic complications are particularly concerning for patients dependent on long-term PN therapy. Cholestasis occurs in 55% of patients on PN for 2 years and 72% at 6 years, with complicated liver disease noted in 50% of patients on PN for 6 years.22 Up to 22% of deaths in this situation are related to PNALD.60 eecausB liver complications are particularly concerning for patients dependent on long-term PN therapy, a treatment plan aimed at avoiding hepatic damage during PN therapy is essential.
PNALD disorders are generally categorized into 3 distinct morphologies: steatosis, cholestasis, and cholelithiasis. Steatosis, or fat accumulation in liver, occurs mainly in adults and is usually benign. The stored triglycerides can, however, cause an inflammatory reaction that results in elevated LFTs within the first few weeks of therapy. The hepatic enzymes typically return to normal after PN discontinuation, although progression to cirrhosis or fibrosis may develop in patients receiving PN for longer periods.61
PN-associated cholestasis is characterized by impaired bile secretion or biliary obstruction. Although adults on long-term PN are at risk for this disorder, it is more prevalent in children and can also progress to cirrhosis and liver failure. Elevations in serum direct bilirubin and alkaline phosphatase, with or without jaundice, are the main diagnostic indicators. Cholestasis can result in sludge and stones, which may progress to acute cholecystitis.62
The mechanisms for the development of PNALD are poorly understood but are currently thought to be associated with a complex set of risk factors (Table 6). Sepsis from bacterial and fungal infections induces proinflammatory cytokines and liver inflammation; this is especially concerning when there are recurrent central venous catheter infections. Overgrowth of bacteria in the small intestine may also contribute to PNALD when large numbers of anaerobic organisms within the lumen of the intestine produce hepatotoxins.63
A small bowel length of less than 50 cm is associated with chronic cholestasis. Massive small bowel resection places patients at risk for PNALD due to bacterial overgrowth, and short bowel syndrome can also lead to liver damage related to abnormal bile acid metabolism.22 Long periods of fasting also contribute to cholelithiasis and gallbladder sludge by decreasing cholecystokinin secretion, enterohepatic circulation, and gallbladder motility.22,63
The components of PN itself may contribute to PNALD. The infusion of excess calories, from both dextrose and lipid sources, increases lipogenesis in the liver and impairs fat mobilization, which is thought to promote hepatic steatosis. High doses of lipid also contribute to hepatic dysfunction by exceeding the liver's capacity to clear fatty acids and phospholipids, which accumulate in the Kupffer cells and hepatocytes, eventually reducing bile volume and flow.61,64 As noted earlier, the IVLEs currently available in the United States present another concern. These lipid emulsions are also associated with increased rates of oxidative stress and infection, especially in the critically ill.65 Phytosterols, found in vegetable oils, are present in considerable amounts in IVLEs and pose another potential threat to liver function. Because they are inefficiently metabolized to bile acids, phytosterols have been implicated in contributing to cholestasis and hepatocyte damage.66,67
Novel lipid products containing different combinations of fats, such as medium-chain triglycerides, olive oil, and omega-3 fatty acids derived from fish oil, are available in Europe and are currently being studied for use in the United States.68 These newer intravenous lipid products may bring clinical benefits and reduce the incidence of complications associated with PN. Further research into the role of IVLE is needed to determine its optimal composition.43,69
Advances in delineating the mechanisms and disease progression of PNALD have led to many recommendations for the prevention and treatment of the condition. In all cases, using PN therapy for the shortest period of time possible is the best approach to prevent hepatic complications.60 With a rise in serum LFTs, other causes for cholestasis should be excluded. Obtaining a history for hepatitis risk factors and hepatotoxic drugs, including herbal preparations, is warranted. Many herbals are associated with hepatotoxicity, but, in particular, the supplements valerian root, comfrey, and Chinese herbs are problematic.62 rurtheF workup includes obtaining a liver ultrasound, viral serology, and, possibly, liver biopsy.62 Because sepsis is associated with cholestasis and, often, a rapid onset of jaundice, appropriate cultures and treatment for suspected infection are prudent.
Because caloric overload from both dextrose and lipid is thought to be a major cause of hepatic steatosis, modification of PN components often starts with reduction of these nutrients.70 Carbohydrate and lipid doses should not exceed current guidelines, but reductions in both of these macronutrients are often needed if hepatic dysfunction develops. Evaluating the ratio of nutrients in the PN therapy and conducting a trial period of a lower calorie formulation may be useful. If liver dysfunction progresses despite using a balanced PN formula, the practitioner may consider further reduction of IVLE. Evidence suggests that reducing lipid to a few times per week or a short-term trial of suspending fat completely may prove beneficial.16,60,67
The method of administration can also influence PN tolerance. Continuous infusion across 24 hours contributes to a fatty liver via the constant production of insulin, stimulating lipogenesis. Cyclic PN, typically given across 10 to 16 hours, allows for a daily period of fasting in which fat can be mobilized. Hwang et al71 reported improvements in liver enzyme and total bilirubin elevations using a 12-hour infusion cycle. Most practitioners cycle the PN infusion down in "steps," placing the patient on a trial 16-hour cycle while monitoring tolerance to glucose and fluid volume before moving to the final goal. The shorter infusion time can contribute significantly to quality of life, especially when therapy is prolonged.
Initiation of enteral feeding is a highly effective intervention for the prevention and treatment of PNALD. Patients with short bowel syndrome are especially vulnerable to hepatic complications and benefit from maximizing oral intake. Even when patients are acutely ill and tolerate only small amounts of food, efforts should be made to provide nutrition either by mouth or tube, administering promotility or antidiarrheal medications if needed. Stimulating the enterohepatic circulation of bile acids minimizes cholestasis.72 EN supports intestinal mucosal immunity and suppresses overgrowth of bacteria in the gut, limiting liver damage.60,63
To decrease intestinal bacterial overgrowth and translocation, evidence suggests that use of antibiotics such as oral metronidazole or neomycin are effective not only in reducing liver enzymes but also for symptoms including bloating, gas, foul-smelling stool, and diarrhea.73 Practitioners can also administer medications to stimulate gallbladder contractility and bile flow. Ursodeoxycholic acid is often used to this end and has been shown to decrease serum bilirubin.61 Copper and manganese are 2 of the trace elements routinely given as part of a multitrace element additive. Both of these elements undergo biliary excretion and can reach toxic levels if biliary obstruction is present. Copper and manganese should be removed from PN when serum bilirubin is elevated, leaving only zinc, chromium, and selenium.3,62
Progressive chronic liver disease, especially cholestasis, carries with it a significant mortality rate and can be an indication for intestinal or combined liver-intestinal transplantation.60,74 Although some evidence has shown bowel transplantation to improve quality of life in patients with PNALD compared with those receiving long-term PN, patients and practitioners must carefully weigh the risks and benefits of this option because complications of surgery and lifelong immunosuppression can be life threatening.75,76
METABOLIC BONE DISEASE
Metabolic bone disease (MBD) refers to abnormal bone metabolism characterized by microarchitectural breakdown of the skeleton, resulting in decreased bone density and increased fracture risk.72 Although the exact cause of MBD is unknown, patients on long-term PN will often develop osteoporosis or osteomalacia, 2 of the most common types of MBD. Some degree of bone demineralization was reported in 40% to 100% of adults receiving chronic PN.77 Many were asymptomatic, but others suffered incidental fracture or pain in the bone or back.
PN-associated bone disease is diagnosed using dual-energy X-ray absorptiometry (DEXA) to measure mineral density of the spine and hip. A T score below -2.5 is reported as osteoporosis, whereas a score between -1 and -2.5 is considered osteopenia or low bone mass.72 Patients on chronic PN often have at least one of the underlying conditions that predispose them to bone loss, such as endocrine disease, short bowel syndrome, Crohn's disease, multiple myeloma, or postmenopause.78 The use of medications including steroids, anticoagulants, Dilantin, and phenobarbital increase risk as well, so the exact role that PN plays in MBD is not clear.72 Calcium is pivotal to slowing bone loss, and some patients on PN are vulnerable to calcium deficiency because PN stability limits the amount of calcium, phosphorus, and magnesium that can be compounded into the daily bag. Because phosphorus enhances calcium reabsorption in the kidney, suboptimal phosphorus dosing contributes to negative calcium balance.77 Higher protein doses, metabolic acidosis, and cyclic PN administration are also associated with increased urinary calcium loss. Vitamin D requirements are controversial because both deficiency and toxicity may cause MBD. Excess vitamin D suppresses parathyroid hormone, promoting bone resorption.77 Magnesium deficiency contributes to hypocalcemia by decreasing mobilization of calcium from the bone, and it may cause hypophosphatemia by increasing phosphorus excretion.70
Strategies to prevent and treat bone disease in long-term PN recipients include monitoring bone density with a DEXA scan at baseline and every 2 to 5 years in stable patients and every 12 to 18 months in those who are newly diagnosed or receiving medications known to affect bone metabolism.77 Clinical assessment for bone, back, and atraumatic fractures, in addition to examination for loss of height, provides supporting evidence of MBD. Along with laboratory tests for serum calcium, phosphorus, and magnesium, a 24-hour urine collection to test for calcium and magnesium every 6 to 12 months is recommended.61 For all chronic PN patients, measures to minimize calcium loss in the urine and provide adequate calcium and phosphorus are a fundamental part of care. The PN formulation should contain at least 10 to 15 mEq/d of calcium and 20 to 40 mmol/d of phosphorus.3 If the PN stability limits these minerals, oral supplementation may be necessary. Adequate amounts of acetate will buffer acidosis and decrease calcium absorption from the bone. PN prescriptions designed to maintain normal serum magnesium levels and to avoid excess protein doses will minimize ongoing calcium loss.77,78 Collaboration with the infusion pharmacist will yield optimal results. Patients benefit greatly from education on lifestyle modification, including the importance of low-impact, weight-bearing exercise and fall prevention, smoking cessation, and alcohol and caffeine reduction.
Useful medications for decreasing fracture risk include oral calcium and antiresorptive agents, of which bisphosphonates are the most commonly used. Bisphosphonates are effective in improving bone strength in both men and women and are particularly helpful for those on corticosteroid therapy as well as chronic PN. Intravenous administration often yields better outcomes because these drugs are poorly absorbed and can lead to ulcerations of the intestine, which can be especially problematic in patients with gut failure.77,78 Teriparatide is a recombinant human parathyroid hormone, approved by the Food and Drug Administration in 2002, that stimulates bone formation. Although several cases of bone density normalization have been reported, prospective studies are still needed to recommend its use for prevention of bone fracture associated with long-term PN.79
MONITORING RESPONSE TO THERAPY
Careful PN monitoring detects complications early and allows practitioners to judge the effectiveness of therapy. Monitoring should include physical assessments, laboratory data, and a subjective and objective evaluation of the response to therapy: body weight, hydration and electrolyte status, glycemic control, performance status, and psychosocial response.5,11 The results of laboratory tests must be monitored closely. Guidelines suggest following electrolyte levels, including calcium, phosphorous, and magnesium daily until stable, gradually reducing the frequency of testing on the basis of the patient's clinical status. As noted earlier, in cases of severe malnutrition and for long-term PN recipients, monitoring should include periodic measurement of vitamin and trace element levels. The nutritional plan of care should be evaluated and revised on the basis of the results of ongoing monitoring.5
CONCLUSIONS
PN is a complex form of intravenous therapy that has life-saving potential but also carries risks for serious complications. A multidisciplinary effort that begins with careful selection of candidates and develops PN prescriptions based on clinical status is essential to achieving positive outcomes. Adherence to standards for optimal care of the vascular access device can largely eliminate infectious complications related to PN. Close monitoring and prompt response to changes in the patient's status are needed to avoid the most adverse effects associated with PN.
REFERENCES