735089

research-article2017

NCPXXX10.1177/0884533617735089Nutrition in Clinical PracticeDavila and Konrad

Invited Review

Metabolic Complications of Home Parenteral Nutrition

Nutrition in Clinical Practice Volume XX Number X Month 201X 1­–16 © 2017 American Society for Parenteral and Enteral Nutrition https://doi.org/10.1177/0884533617735089 DOI: 10.1177/0884533617735089 journals.sagepub.com/home/ncp

Jamie Davila, RD, LD, CNSC1; and Denise Konrad, RD, LD, CNSC2

Abstract Home parenteral nutrition (HPN) has benefited countless patients since its initiation almost 5 decades ago. Over time, HPN has been found to be associated with various complications, including metabolic disorders. Metabolic complications can be grouped into short-term (eg, fluid imbalance, electrolyte disturbances, glucose abnormalities) and long-term (eg, hepatobiliary disorders, metabolic bone disease, iron deficiency anemia, manganese toxicity) categories. There are a number of treatment options for each complication. It is important to evaluate the entire clinical picture prior to initiating an intervention and use evidence-based interventions when available. A dedicated multidisciplinary team is best suited to prevent and manage complications when they are identified. (Nutr Clin Pract. XXXX;xx:xx-xx)

Keywords home nutrition support; parenteral nutrition; nutritional and metabolic diseases; water-electrolyte imbalance; glucose intolerance; metabolic bone diseases

The first patient was sent home on parenteral nutrition (PN) in 1968. Countless patients with intestinal failure have benefited from this therapy since its initiation. Like all other medical therapies, home PN (HPN) has associated risks. Short-term HPN is typically defined as 6 months. The risks are categorized as infectious, mechanical, or metabolic. A study by de Burgoa et al1 found that about onethird of new HPN patients experienced a therapy-related complication within 90 days. Most complications were infectious (56.8%), followed by mechanical (25%) and then metabolic (18.2%). In another study by Richards et al,2 metabolic complications were found to be common (0.12–0.61 episodes per catheter year). The focus of this article is to review the metabolic complications associated with HPN therapy, monitoring and prevention strategies, and guidelines for treatment. Metabolic complications can be classified into short-term and long-term categories. Short-term complications include fluid, electrolyte, and glucose abnormalities and are common complications of HPN that patients are likely to experience within the first year of therapy but can occur at any time.3 These complications may occur as a result of physical and environmental factors while patients are making the adjustment from the hospital to home setting. Long-term complications generally occur as therapy progresses and include hepatobiliary disorders, metabolic bone disease, iron deficiency anemia, and manganese toxicity. Both short-term and long-term complications associated with HPN therapy can be minimized with close monitoring of these patients by a multidisciplinary nutrition support team during the entire course of therapy. Multidisciplinary nutrition support teams, including physicians, dietitians, pharmacists, and nurses, have been shown to decrease metabolic complications in this patient population.4

Short-Term Metabolic Complications Fluid Imbalance Two types of fluid disturbance can occur—fluid overload (hypervolemia) and dehydration (hypovolemia). Although patients receiving HPN are at risk for both complications, dehydration is more commonly seen in clinical practice likely because the indication of therapy for many patients is intestinal malabsorption.5,6 It is necessary to diagnose and correct the underlying cause of fluid imbalance prior to developing a treatment plan to ensure successful resolution of symptoms. Dehydration.  Dehydration is the decrease in total body water (TBW) that results from increased losses from renal, cutaneous, respiratory, and gastrointestinal (GI) sources.7 Dehydration will persist until adequate repletion is achieved. The kidneys play an important role in controlling the body’s water balance, which is primarily regulated by arginine vasopressin (AVP), an antidiuretic hormone. During dehydration, plasma osmolarity increases and plasma volume decreases, which stimulates AVP production and thirst.8 Increased AVP levels From the 1Center for Gut Rehabilitation and Transplantation Clinician, Cleveland Clinic, Cleveland, Ohio, USA; and 2Home Nutrition Support Clinician, Cleveland Clinic, Cleveland, Ohio, USA. Financial disclosure: None declared. Conflicts of interest: None declared. Corresponding Author: Jamie Davila, RD, LD, CNSC, Center for Gut Rehabilitation and Transplantation Clinician, Cleveland Clinic, 9500 Euclid Ave, A10, Cleveland, OH 44195, USA. Email: [email protected]

2

Nutrition in Clinical Practice XX(X)

Table 1.  Evaluation of Fluid Balance. Type of Parameter

Assessment Type

Sign or Symptom of Dehydration

Subjective or physical symptom

Patient reported

•• •• •• •• •• •• •• ••

Objective sign

Intake and output documentation

•• ≥2 kg weight loss in 48 hours •• Negative fluid balance (O > I for 48 hours) •• O by 1 L for 2 consecutive days) •• Decreased GI losses from baseline Levels decrease: •• Sodium •• Chloride •• Creatinine •• Albumin •• Hypertension

GI, gastrointestinal; I, input; O, output.

decrease renal water excretion, causing darker, more concentrated urine output. The perception of thirst is highly sensitive to changes in plasma osmolarity with an increase of only 2%– 3% being enough to trigger the mechanism.9 Alterations in heart rate and blood pressure (especially orthostatic intolerance), changes in laboratory parameters from baseline, rapid weight loss, and cramping in the extremities among other signs are additional indicators of dehydration (Table 1).8,10 Dehydration can occur at any time during HPN therapy, although incidence is generally higher at the beginning and decreases over time as patients become more familiar with HPN, dietary modifications, and their new anatomy, if applicable. Vallabh et al5 looked at 30-day hospital readmissions for patients newly discharged with HPN and found that 21% of total readmissions were HPN related. Of those, one third were the result of dehydration. A prospective study by Lauverjat et al11 assessed renal function in 40 HPN patients and found that 52.5% had a decrease in glomerular filtration rate. More than 70% of these cases were attributed to chronic hypovolemia, highlighting the importance of close monitoring and treatment of dehydration.11 The effects of dehydration can be worse for a long-term HPN patient because glomerular sclerosis can result over time. Fluid overload. Fluid overload is the abnormal increase of extracellular fluid volume and typically occurs in patients with impaired renal function or while receiving excessive parenteral fluids.12 Patients with underlying cardiac and liver diseases

who have preexisting fluid retention are more likely to develop worsening symptoms while receiving HPN.12 Typical symptoms are shortness of breath, tachypnea, edema (especially in the lower extremities), acute weight gain, jugular venous distention, and hypertension.12 Laboratory results may reveal hyponatremia, decreased creatinine, or decreased serum albumin (Table 1).

Risk Factors Patients with the greatest risk of developing dehydration are those with increased GI losses as a result of intestinal malabsorption, venting gastrostomy tubes, and drains or those receiving inadequate volume via HPN. Intestinal malabsorption has many causes, including bowel resections resulting in short bowel syndrome (SBS) or a high-output enterostomy, highoutput fistula, or intestinal ischemia. The majority of nutrient absorption occurs in the first 150 cm of small bowel.13 The ileum has good adaptation, so the absorptive capacity of the small bowel is preserved when the jejunum is resected. However, the jejunum does not adapt to take over the ileum’s functions when it is resected, which results in rapid intestinal transit time.14 Similarly, patients who have had colon resections or have their colon out of continuity have an increased risk of developing dehydration because of its role in absorption of fluid and electrolytes, promoting intestinal adaptation and increasing intestinal transit time.15 Patients who have increased

Davila and Konrad risk of developing fluid overload include patients with underlying cardiac, liver, and renal diseases and those receiving too much volume via HPN or other intravenous (IV) medications.

Monitoring Strategies Intake and output recording.  In addition to knowing the signs and symptoms of dehydration and fluid overload, teaching patients to keep accurate intake and output (I/O) records allows them to take a more active role in their medical care. I/O records should be tracked daily and continue for the duration of therapy or until stable. Tracking I/Os should resume if changes to HPN therapy are made (eg, volume change, weaning). Records should include weight, all intake (oral, enteral, and IV), urine output, and all GI output (emesis, venting tubes, drains, enterostomy, fistula, and diarrhea). Measuring containers (eg, stool hat) and standardized I/O record forms should be provided to assist with accurately tracking data. Patients should be instructed to read their infusion pump daily to see how much fluid infused as the pumps have as much as a ±10% error rate, which can cause patients to receive amounts other than what is prescribed. Patients should be given parameters of when to contact their HPN provider based on trends from I/O data. Weight loss or gain of 1 kg for 2 consecutive days, urine output 1 L for 2 consecutive days, and changes in GI losses from baseline are a few examples.12,16 Monitoring blood pressure and heart rate is another option if a blood pressure cuff is available. Physical assessment may be necessary if I/O data reveal abnormalities and can be done by the HPN physician, primary care physician, or home care nurse. Laboratory testing.  Although there is no set standard of practice for monitoring laboratory values for HPN patients, many home nutrition support services have developed their own protocols. Testing should be done at baseline (start of therapy) and on a routine basis afterward to assess for signs of fluid imbalance. Parameters to assess include sodium, chloride, potassium, serum urea nitrogen, and creatinine, which are included in the basic metabolic panel (BMP). While serum urea nitrogen is useful in assessing dehydration, many HPN patients have elevated levels and therefore the whole clinical picture and laboratory trends need to be considered before determining the cause. Typically, laboratory values should be checked weekly for the first month and incrementally spaced out to monthly, or less frequent, as the HPN prescription becomes stable.17 Increased monitoring is recommended if fluid imbalance, changes to clinical condition, or changes to medications that could affect HPN prescription or hydration status are identified, especially if changes are made to the HPN formula.

Effective Approaches to Reduce Occurrence Patient education. Providing adequate patient education on preventing fluid imbalance and its signs and symptoms prior to

3 hospital discharge with HPN is imperative and helps ensure success.18 A caregiver should be included in the education lessons to serve as a backup and reinforcement for information taught, as the patient may not be able to retain all of the information received due to physical limitations such as pain, nausea, or fatigue. Education should be patient specific and completed outside of the hospital room to avoid interruptions, if possible. All verbal instructions should be reinforced with written material and provided at a fifth-grade to sixth-grade reading level.19 Patients should know which provider to contact if symptoms occur and have their contact information readily available. Education should be reinforced by the home care nurse at routine visits. In addition, home nutrition support clinicians should follow up often with new HPN patients via phone call or with office visits to ensure comprehension of information and to monitor for symptoms. Patient support groups, newsletters, and webinars are other effective ways that patients can continue learning.20 Diet modifications.  Diet modifications may be recommended to improve intestinal absorption for patients depending on their remaining anatomy and risk of dehydration. Most patients with SB benefit from a low simple sugar (eg, sucrose and fructose), high-starch diet because this reduces the osmotic load to the intestines, which in turn decreases osmotic diarrhea.15,21,22 Dietary fat should be restricted for patients with their colon in continuity to reduce fat malabsorption.22 Protein is liberalized and does not contribute to malabsorption. The addition of soluble fiber can help to thicken stool or enterostomy output by slowing gastric emptying and intestinal transit time and enhancing sodium and water absorption. It can also provide a significant source of calories when metabolized into shortchain fatty acids for patients who have their colon in continuity.23 Restricting oral food and fluid is often recommended for patients with ultra-SBS or excessive stool output despite dietary and pharmacologic interventions. Limiting overall intake reduces GI losses (emesis, venting tubes, drains, enterostomy, fistula, and diarrhea). Nil per os (NPO) status is recommended in specific cases when GI losses are so significant that it is difficult to maintain a positive fluid balance or for conservative management of an enterocutaneous fistula. Patients with underlying cardiac, liver, and renal disease may benefit from a low-sodium, volume-restricted diet to help reduce risk of fluid overload. Oral rehydration solution (ORS) is recommended as the primary drink for patients with intestinal malabsorption. ORS maximizes fluid absorption by using the sodium glucose cotransport mechanism. ORS has the optimal concentrations of sodium (90–120 mmol/L) and glucose (110–140 mmol/L) and the same osmolality of body fluids (290 mOsm/L).15 ORS is most effective when sipped throughout the day, as opposed to drinking large volumes at once or with meals. Many commercially available ORS products are convenient but can be expensive and difficult for patients to find. Recipes for homemade ORS are widely available, are easy to make, and use common

4 ingredients or modify commercially available sports drinks to meet the above standards.21,24,25 Abrupt increases to ORS consumption or improper mixing of recipes to increase sodium concentration can lead to fluid overload. Water and hypertonic fluids (eg, juice, soda) should be limited or avoided altogether as these can increase stool output. Medications. Over-the-counter and prescription medications can be used to help reduce GI losses. Medications may be available in a variety of forms, including oral (eg, capsule, tablet, liquid, sublingual), subcutaneous, intramuscular, or IV. Delayed or extended-release medications should be avoided when possible. Antidiarrheal medications prolong intestinal transit time and give the remaining bowel additional time in contact with food to enhance absorption of fluid, electrolytes, and nutrients. They are most effective when taken 30–60 minutes before meals and at bedtime. Histamine 2 (H2) blockers and proton-pump inhibitors (PPIs) are antisecretory agents that reduce gastric acid production and therefore secretions. Octreotide, another antisecretory agent, decreases a variety of GI secretions and also slows jejunal transit time. Glucagonlike peptide 2 (GLP-2), a growth factor, is a newer medication that has shown promise to increase intestinal absorption in patients with SBS, although it requires chronic, lifetime administration to reduce PN dependency. Recommended doses of these medications have been discussed in depth elsewhere.15,26 As-needed IV fluids. Home nutrition support services have been prescribing as-needed (PRN) IV fluids (IVFs) for patients to have on hand to infuse when symptoms of dehydration occur for almost 10 years. This is a novel and proactive solution as opposed to previous practices that were more reactive in waiting until dehydration was identified and then having IVFs delivered to the patient. The reactive approach caused delays in service, especially for patients residing in rural areas or during inclement weather. This practice has been effective in treating the early signs of dehydration at home when patients and clinicians work together to identify dehydration from I/O records, laboratory values, or physical symptoms. Patients who recognize the early signs of dehydration can be treated at home in most cases and avoid hospital admissions, emergency department visits, and healthcare costs.6,16 In these studies, patients had 24-hour access to a home nutrition support clinician to contact with concerns. A protocol was followed to provide 3 1-L bags of IVFs over 3 consecutive days in addition to the prescribed HPN. Dehydration was resolved in almost 85% of episodes after the implementation of the protocol.16 Caution should be used in providing PRN IVFs for patients at risk of developing fluid overload. Decreased IVF volume (ie, 500 mL vs 1000 mL) or reduced days of PRN IVF infusions should be considered to prevent additional complications. The HPN volume should be increased if GI losses do not decrease back to baseline to reduce the need to routinely use PRN IVFs going forward.

Nutrition in Clinical Practice XX(X)

Electrolyte Disturbances Electrolytes (eg, potassium, magnesium, phosphorus) play an important role in many of the body’s functions, including cell metabolism, neural and muscular function, bone composition, and maintenance of normal blood pH levels.10 Requirements of each electrolyte are highly individualized and depend on GI losses, renal function, other underlying diseases, and acute changes to the clinical condition. Both over-the-counter and prescription medications can influence electrolyte status and should be taken into account when ordering HPN (Table 2). Although there are many electrolytes, this article reviews potassium, magnesium, and phosphorus as these are commonly abnormal in HPN patients, easily treated with alterations in HPN prescription, and can be acutely life threatening. Potassium abnormalities. Potassium is the most abundant intracellular cation (98% is found within the cells) that plays a significant role in the function of all cells, tissues, and organs in the body.10 It is fundamental in cardiac function as well as smooth muscle and skeletal contraction. Potassium balance is also partially dependent on sodium and magnesium blood levels. Estimated daily parenteral potassium requirements range from 0.5 to 1.5 mEq per kilogram (kg) of body weight per day.10 Hyperkalemia is most commonly seen in patients with impaired renal function but can also be a result of metabolic or respiratory acidosis, medication administration, or receiving too much IV potassium.27 Nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin-converting enzyme (ACE) inhibitors, β-blockers, potassium-sparing diuretics, angiotensin II receptor blockers, antibiotics (eg, trimethoprim, pentamidine), immunosuppressants (eg, cyclosporine, tacrolimus), IV amino acids (eg, lysine, arginine), salt substitutes, and heparin all increase risk of developing hyperkalemia.10,28 Pseudohyperkalemia is the rise in serum potassium caused by trauma to the vein during a blood draw, marked leukocytosis (100,000/mm3) or thrombocytosis (400,000/mm3), when the blood sample is contaminated with PN, or when the sample is hemolyzed.10 Pseudohyperkalemia is a laboratory artifact and not a clinical concern. A repeat measurement should be completed to obtain an accurate value prior to providing any treatment. Symptoms of hyperkalemia include muscle cramping, numbness or tingling in the extremities, unusual nausea or vomiting, weakness, chest pain, electrocardiogram (ECG) changes, and arrhythmias.12 Patients symptomatic of hyperkalemia should be treated in a clinical setting where they can be constantly monitored and may require emergency department or intensive care unit (ICU) admission. Treatment may include IVFs, IV administration of sodium bicarbonate, regular insulin and dextrose, loop diuretics, or, in severe cases, IV administration of calcium gluconate or hemodialysis.10,28 Hypokalemia is a common occurrence, especially for patients with intestinal malabsorption since it typically results from increased potassium losses via stool or urine. It can also

Davila and Konrad

5

Table 2.  Causes of Electrolyte Abnormalities. Electrolyte Abnormality

Initiation of Medication

Change in Clinical Condition

Hyperkalemia

•• •• •• •• •• •• •• •• •• ••

Hypokalemia

•• •• •• •• •• •• •• •• •• •• ••

Insulin Catecholamines Loop diuretics Glucocorticoids Immunosuppressants Phenolphthalein Theophylline Verapamil Sorbitol Caffeine Medications associated with magnesium depletion •• Recent decrease in HPN potassium or infusion days

•• Increased losses from urine or the GI tract •• Hypomagnesemia •• Metabolic alkalosis •• Refeeding syndrome

Hypermagnesemia

•• Oral magnesium supplementation •• Magnesium-containing antacids •• Recent increase in HPN magnesium or infusion days

•• Impaired renal function •• Dehydration •• Decreased losses from the GI tract

Hypomagnesemia

•• •• •• •• •• •• ••

Thiazide and loop diuretics Cisplatin Immunosuppressants Amphotericin B Aminoglycosides Foscarnet Recent decrease in HPN magnesium or infusion days

•• Increased losses from urine or the GI tract •• Diabetic ketoacidosis •• Hyperparathyroidism •• Refeeding syndrome •• Alcoholism

Hyperphosphatemia

•• •• •• ••

Phosphate-containing laxatives Bisphosphonates Cytotoxic agents Recent increase in HPN phosphorus or infusion days

•• •• •• •• •• •• ••

Hypophosphatemia

•• •• •• •• •• •• ••

Aluminum-based or magnesium-based antacids Phosphate binders Glucagon Epinephrine Dialysis Large increase in HPN dextrose Recent decrease in HPN phosphorus or infusion days

•• Increased losses from urine •• Steatorrhea •• Metabolic alkalosis •• Respiratory alkalosis •• Hyperparathyroidism •• Vitamin D deficiency •• Refeeding syndrome •• Severe sepsis •• Trauma •• Alcoholism

NSAIDs ACE inhibitors β-blockers Potassium-sparing diuretics Angiotensin II receptor blockers Antibiotics Immunosuppressants Heparin Salt substitutes Recent increase in HPN potassium or infusion days

•• Impaired renal function •• Dehydration •• Decreased losses from the GI tract •• Metabolic acidosis •• Respiratory acidosis

Impaired renal function Dehydration Metabolic acidosis   Respiratory acidosis Tumor lysis syndrome Hypoparathyroidism Vitamin D toxicity

ACE, angiotensin-converting enzyme; GI, gastrointestinal; HPN, home parenteral nutrition; NSAIDs, nonsteroidal anti-inflammatory drugs.

6 occur when potassium is shifted from the extracellular fluid to the intracellular space as a result of metabolic alkalosis, refeeding syndrome, or administration of insulin and catecholamines (eg, epinephrine, dopamine). Other medications, including loop diuretics, glucocorticoids, immunosuppressants, phenolphthalein, theophylline, verapamil, sorbitol, caffeine, and those related to magnesium depletion, are associated with hypokalemia. Symptoms vary in severity and range from generalized weakness, apathy, unusual nausea or vomiting, and anorexia to muscle necrosis, paralysis, cardiac arrhythmias, and death.12 Hypokalemia is corrected either with oral or IV supplementation depending on medical history and severity. Mild hypokalemia can be treated by increasing potassium in the HPN prescription; however, symptomatic or severe hypokalemia should be treated in a clinical setting where an IV bolus can be administered. Hypomagnesemia should be treated before potassium repletion is initiated since magnesium deficiency increases renal potassium losses and disrupts the equilibrium of the sodium-potassium adenosine triphosphatase (ATPase) pump.29 Magnesium abnormalities. Magnesium is the second most prominent intracellular cation with over half of the body’s stores being found in the bone followed by the muscle and soft tissue.30 Magnesium is an essential cofactor in >300 enzyme systems, including the sodium-potassium ATPase pump, glycolysis, fatty acid synthesis and breakdown, DNA and protein metabolism, and immune function.10,30 Magnesium homeostasis is regulated by the kidneys, small intestines, and bone. Absorption occurs primarily in the jejunum and ileum via active and passive mechanisms, although the specific factors that control absorption are uncertain.31 Renal magnesium reabsorption is regulated by the extracellular calcium sensing receptor and accounts for about one-third of absorbed magnesium. Urinary losses of magnesium increase in situations when excess amounts are received via the oral or IV routes to maintain normal levels.10 Serum magnesium concentration is the only practical measurement of magnesium status but is the not best indicator since most of the body’s magnesium is located intracellularly and in the bone. Hypermagnesemia is uncommon and is typically only seen in patients with renal impairment or after high-dose magnesium supplementation is received via oral or IV routes. Magnesium-containing antacids may contribute to patients receiving excess magnesium and may not be reported unless specifically asked about since they are purchased over the counter. Patients with end-stage renal disease are at greatest risk. Symptoms typically do not occur until serum levels reach almost twice the upper normal limit of the reference range.10 Physical symptoms include unusual nausea or vomiting, headache, flushing of the skin, diaphoresis, stumbling, decreased mental awareness, hypotension, bradycardia, and respiratory paralysis.12 Treatment includes decreasing magnesium intake via the oral and IV routes, providing loop diuretics, and

Nutrition in Clinical Practice XX(X) infusing IV calcium in a monitored, clinical setting in instances of severe hypermagnesemia.32 Hypomagnesemia is commonly found in acutely ill, hospitalized patients, but no data exist for the frequency in nonhospitalized patients.30 Risk factors include intestinal malabsorption, alcoholism, and intracellular shifts that occur during refeeding of malnourished patients, diabetic ketoacidosis, hyperparathyroidism, and myocardial infarction. The magnesium content of GI fluids varies from approximately 1 mEq/L for gastric fluids to 15 mEq/L from intestinal fluids (eg, stool, intestinal fistula, or biliary drain output).30 Increased renal losses of magnesium may be medication related. Some of these medications include thiazide and loop diuretics, cisplatin, immunosuppressants (eg, cyclosporine, tacrolimus), amphotericin B, aminoglycosides, and foscarnet.33 Hypomagnesemia often occurs with hypokalemia, hypocalcemia, and metabolic alkalosis and therefore may be difficult to determine which abnormality the symptoms are attributed to. Hypocalcemia is a classic sign of hypomagnesemia, especially when serum magnesium concentration is 1 bag per day, which further complicates ordering. Furthermore, phosphorus can be ordered as millimoles or milliequivalents and is an inherent component of certain amino acids. Implementing a standardized PN order reduces prescribing errors.39 Ideally, the order form should be electronic, thereby limiting errors related to illegible writing and compatibility standards (eg, calcium-phosphorus product, calcium-magnesium amount per liter) that cannot automatically be calculated on paper orders. The American Society for Parenteral and Enteral Nutrition (ASPEN) published PN safety consensus recommendations in 2013, which states all PN ingredients should be ordered in amounts per day for adult patients.40 In addition, electrolytes should be ordered as the complete salt form rather than the individual ion.40 Inherent electrolytes, such as phosphate in amino acid products, should be accounted for in the HPN prescription.

Glucose Abnormalities Hyperglycemia.  Hyperglycemia is the most common complication of PN, especially at the beginning of therapy when patients are often acutely ill and malnournished.41,42 The production of cytokines and counterregulatory hormones (eg, cortisol, epinephrine, glucagon, growth hormone) is upregulated during periods of stress or inflammation. The increased concentrations of counterregulatory hormones decrease peripheral glucose uptake and cause the liver to increase glucose production.43 Short-term consequences of hyperglycemia include glycosuria, leading to dehydration, impaired immune function, and increased inflammation.43 Hyperglycemiarelated adverse outcomes, including sepsis, acute renal failure, and death, have been well documented in hospitalized, critically ill patients receiving PN, but evidence is lacking for the home setting.44,45 In 1 study, a mean blood glucose level of >180 mg/dL during PN infusion in hospitalized, non–critically ill patients correlated with a 5.6 times greater risk of mortality than those with a mean blood glucose of 70 mg/dL. Capillary glucose.  It may be necessary for certain patients to continue capillary glucose measurements at home. Patients with diabetes, insulin in the HPN, hypoglycemia in the hospital, and those taking medications known to cause alterations in glucose are most likely to benefit. If patients are not diabetic or have not ever had to check their blood glucose level, they will need a glucometer and instruction on how to use it. Capillary glucose

9 should be checked 1 hour after the HPN infusion is complete or if symptoms of hypoglycemia are present. Abnormal results (180 mg/dL) should be reported to the home nutrition support service. More frequent monitoring that mimics the hospital setting may be necessary to determine how best to treat the abnormal level. Adjusting tapers, adding or adjusting insulin dose, and lengthening the HPN infusion are all options. Urine glucose.  If patients do not experience glucose abnormalities in the hospital and do not require insulin in the HPN, it is not necessary for patients to continue capillary glucose monitoring at home. Urine glucose screening can be used as a surveillance mechanism instead. It is important to note that urine glucose only screens for hyperglycemia and not hypoglycemia. Urine should be collected in a clean container with the first void of the morning prior to eating or drinking anything containing sugar. A dipstick with a color-sensitive pad is submerged in the urine sample and removed immediately. The strip should be evaluated for change in color exactly 30 seconds after coming in contact with the urine. The strip will not change color if glucose is not detected and represents a negative test. A positive test results when the strip changes color; the darker the color, the more glucose that is detected, which corresponds to blood glucose levels. If 2 positive tests occur, capillary glucose levels should be checked either at home by the patient or home care nurse or at an outpatient appointment (HPN provider office, primary care office, or laboratory).

Long-Term Metabolic Complications Hepatobiliary Disorders Intestinal failure–associated liver disease (IFALD) is hepatic dysfunction that occurs secondary to intestinal failure in the presence of PN. Development of IFALD occurs in 15%–85% of adults on HPN receiving soy-based IV fat emulsions and is concerning because its occurrence and severity increase with longer durations of PN.42,52 Identification and management of IFALD are multifactorial and complex in the HPN population. The 3 types of hepatobiliary disorders associated with PN are steatosis, PN-associated cholestasis (PNAC), and gallbladder stasis.53 Steatosis is hepatic accumulation of fat, typically a result of overfeeding, and presents in the HPN patient as mild elevations in aminotransferase enzymes (eg, alanine aminotransferase [ALT], aspartate aminotransferase [AST]).42,54 Steatosis is commonly benign, although progression to fibrosis or cirrhosis can be a concern for the long-term HPN patient.42 PNAC is caused by a biliary obstruction or impaired secretion of bile. The primary indicator of PNAC is an elevated serum conjugated bilirubin (>2 mg/dL). PNAC is a serious complication that can progress to liver failure. Gallbladder stasis, including sludge and stones, is generally related to lack of enteral stimulation rather than the HPN infusion. The lack of enteral stimulation results in decreased GI hormone release

10 with impaired bile flow and gallbladder contractility, leading to the development of gallstones and biliary sludge that can progress into acute cholecystitis.42,53 PN-related risk factors.  Nutrient composition of the HPN prescription can contribute to IFALD. Overfeeding of any or all nutrient substrates can promote hepatic fat deposition and lead to the development of steatosis.42,55 Continuous HPN infusions over 24 hours can also increase the risk for hepatic complications by causing hyperinsulinemia and promoting fat deposition into the liver. Steatosis is generally seen in patients receiving glucosepredominant HPN.56 Infusion of dextrose calories greater than oxidative capacity can result in excess carbohydrates depositing into the liver as fat.42,55 HPN with excess dextrose calories may also result in steatosis by contributing to essential fatty acid deficiency and in turn leading to impaired lipoprotein formation and triglyceride secretion.42 The role of amino acids in cholestasis is uncertain, although the replacement of protein hydrolysate with crystalline amino acids has significantly decreased the overall aluminum contamination in HPN; therefore, aluminum toxicity associated with amino acids is no longer considered a risk factor for the development of IFALD.42 The dosing of IV fat emulsions, the source of fat, and the phytosterol content of the IV fat emulsions are all of concern regarding development of steatosis and cholestasis. Hepatic complications can occur when the IV fat emulsion dose is excessive and can result in steatosis if the infusion rate exceeds the liver’s ability to clear the phospholipids and fatty acids. In a study published in 2000, Cavicchi et al52 showed that cholestasis was related to an intake of IV fat emulsion >1 g/kg/d in long-term HPN patients, despite nonhypercaloric parenteral formulations. Currently, most IV fat emulsions in the United States are soybean oil based, with high concentrations of ω-6 fatty acids and phytosterols. The high ω-6 fatty acid content of soybean oil–based IV fat emulsion has been shown to impair biliary secretions while also provoking a proinflammatory cascade, causing impaired immune function.57,58 A study by Buchman et al59 confirmed that HPN patients receiving soybean oil–based IV fat emulsion more than twice weekly compared with those receiving fats less than twice a week had a higher frequency of catheter-related bloodstream infections (CRBSIs; 69% vs 50% respectively). While the mechanism is only speculative, excess ω-6 fatty acids may trigger macrophage activation, leading to an accumulation of hepatic phospholipids and phytosterols.54 The liver is inefficient at metabolizing phytosterols to bile acids, which then impairs bile flow, resulting in biliary sludge and stones.42 In a study of an ω-3 fish oil–based IV fat emulsion in 15 adult patients with SBS who developed cholestasis while receiving soybean oil– based IV fat emulsion, 12 of the 15 patients had a normalized direct bilirubin within 4 weeks of starting the fish oil–based IV fat emulsion, and serial liver biopsies showed progressive

Nutrition in Clinical Practice XX(X) improvement.57,60 A new IV fat emulsion product containing a combination of soybean oil, olive oil, fish oil, and mediumchain triglycerides has been approved by the Food and Drug Administration (FDA) for use in the United States. Although its use is currently limited, clinical studies have shown this IV fat emulsion to have less inflammatory properties, high antioxidant content, and decreased risk of cholestasis in HPNdependent patients.61 Choline and carnitine have essential roles in fat metabolism and transport. Low plasma-free choline has been associated with hepatic steatosis. While choline is low in >90% of longterm HPN patients, it is not necessary to supplement choline as it can be endogenously synthesized from methionine in the crystalline amino acid solution, and there is currently no commercially available choline injection.42,57,62 The role of carnitine in the prevention and treatment of IFALD is not well established; therefore, carnitine is not regularly added to HPN and may lead to decreased plasma concentrations.42 In a study where carnitine-deficient HPN patients were supplemented with IV L-carnitine (1 g/d), the plasma and total hepatic carnitine concentrations were normalized, but there were no significant improvements in mean serum liver tests, plasma triglycerides, plasma free fatty acids, hepatic free fatty acid, or triglyceride concentrations. There was also no significant improvement in the severity of hepatic steatosis, suggesting that carnitine deficiency is not a major cause of steatosis in HPN patients.56 Effective monitoring strategies and approaches to reduce occurrence.  Routine laboratory values should be monitored in the HPN patient, to include liver function tests (eg, ALT, AST, total bilirubin, alkaline phosphatase). When a HPN-dependent patient is suspected to have hepatic complications, it is essential to evaluate all aspects of care to identify and treat contributing factors. Rarely should HPN be stopped secondary to hepatic abnormalities.56 If possible, enteral nutrition (EN) should be initiated and optimized in long-term HPN patients to stimulate enterohepatic circulation of bile acids. Introducing even minimal amounts of enteral feeding can encourage normal biliary dynamics, improve bile flow, and decrease gallbladder size.54 Although there is limited evidence, oral medications can also be used to stimulate bile flow and reduce gallbladder stasis, including Ursodiol (ursodeoxycholic acid).54 It is also important to review all medications to identify any possible hepatotoxic medications that could potentially be minimized or changed. Cyclic HPN infusions should be used to allow for time off HPN and aid in reducing the risk of IFALD.42 To minimize the risk of steatosis, the distribution of nonprotein calories should be 70%–85% carbohydrate and 15%–30% fat. Strict adherence to sterile catheter care protocols and precautions should always be followed to reduce the risk of CRBSI and sepsis.63 In the case of a long-term HPNdependent patient who has developed significant liver disease, an isolated intestinal transplant or combined intestinal/liver

Davila and Konrad

11

Table 3.  World Health Organization Criteria for Clinical Diagnosis of Osteoporosis. Bone Mineral Density T-score T-score ≥ −1 −1 > T-score > −2.5 T-score ≤ −2.5 T-score ≤ −2.5 with existing fracture

Diagnosis Normal Osteopenia Osteoporosis Severe osteoporosis

transplant should be considered. The decision between an isolated intestinal or combined intestinal/liver transplant will depend on the cause and extent of the liver disease.42

Metabolic Bone Disease Osteoporosis and osteomalacia are of concern in all patients requiring long-term HPN.42 The National Institute of Health Consensus Development Panel on Osteoporosis defines osteoporosis as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength is estimated by noninvasive assessment of bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA). According to the World Health Organization (WHO), the clinical diagnosis of osteoporosis is based on BMD measurements and the presence of fractures.64 For diagnostic criteria, BMD is converted into a T-score, which reflects the number of standard deviations (SDs) above or below the mean in ethnicity-matched and sex-matched healthy young adults (Table 3).42 Osteomalacia is the softening of the bones caused by impaired bone metabolism and osteoid tissue that has failed to calcify. Osteomalacia most commonly occurs because of vitamin D deficiency. Risk factors.  Patients receiving long-term HPN for intestinal failure have many risk factors that can contribute to metabolic bone disease.65 While some bone loss may be related to the patients’ underlying conditions, studies have shown an acceleration in bone loss during long-term HPN therapy.66 Specifically, the nutrient composition of HPN has been suggested to affect bone metabolism.42 Calcium contributes to the maintenance of bone integrity by slowing bone loss and decreasing bone turnover. Increased urinary calcium loss and limited oral calcium intake put longterm HPN patients at high risk for negative calcium balance. There is a limitation on PN calcium dosing due to the physical compatibility of calcium and phosphorus.42 The recommended dose for calcium gluconate in HPN is 10–15 mEq/d. Phosphorus also enhances calcium reabsorption, supporting a positive calcium balance. The recommended dose for phosphorus in PN is 20–40 mmol/d.67 High doses of protein exceeding 2g/kg/d also increase urinary calcium loss. Metabolic acidosis can directly

lead to bone loss.68 Correction of metabolic acidosis with adequate acetate in the HPN prescription has been associated with reduced urinary calcium excretion.42 Hypocalcemia can also manifest from hypomagnesemia as low magnesium decreases the mobilization of calcium from the bone. Severe chronic hypomagnesemia inhibits the release of parathyroid hormone (PTH), resulting in excessively low PTH levels for the degree of hypocalcemia. Hypomagnesemic hypocalcemia should be treated by magnesium repletion as it is often refractory to only calcium repletion.42 Historically, significant aluminum contamination of HPN due to protein hydrolysate has been associated with osteomalacia. In recent years, osteomalacia has almost disappeared with the replacement of protein hydrolysate with crystalline amino acids.65 There is, however, still the presence of aluminum in various HPN additives (eg, trace elements), but the amount is so low it is not felt to have a significant contribution to metabolic bone disease.68 Although trace element deficiencies are relatively uncommon in HPN patients, copper deficiency can cause osteoporosis as low serum copper levels impair bone formation.42 Screening for vitamin D levels using plasma total 25-hydroxyvitamin D is recommend as routine care for all longterm HPN patients.69 The prevalence of vitamin D deficiency in HPN patients ranges from 60% to 70%, with deficiency leading to bone disease. Vitamin D supplementation can be challenging in HPN patients due to the lack of high-dose parenteral formulations. The adult multivitamin (MVI) used for HPN contains 5 mcg (200 IU) of vitamin D, which is less than the recommended dietary allowance of 600–800 IU/d. An alternative source of vitamin D should be recommended in deficient patients, either in oral form (if the patient is able to absorb) or exposure to sunlight.70 Vitamin D toxicity can also lead to bone disease as excessive vitamin D doses can suppress PTH secretion and promote bone resorption. Although the removal of vitamin D from HPN may be beneficial for patients with low serum PTH concentration, total removal is not feasible as there are currently no commercially available MVI preparations without vitamin D. One option to decrease vitamin D intake would be to decrease the frequency of MVI to less than daily. Monitoring strategies. Close monitoring and screening for bone disease is important because patients are most often asymptomatic. Identifying risk factors can be accomplished by obtaining a thorough history of bone health, monitoring laboratory values, and performing nutrition-focused physical examinations. A baseline DXA is recommended for all long-term HPN patients with follow-up every 1–3 years based on results.71 Effective approaches to reduce occurrence.  Strategies for the prevention and treatment of PN-associated metabolic bone disease should be established for all long-term HPN patients. In an effort to reduce PN-associated risk factors, HPN prescriptions should contain adequate calcium, phosphorus,

12

Nutrition in Clinical Practice XX(X)

Table 4.  Evaluation of Iron Status. Laboratory Iron, µg/dL Ferritin, µg/L TIBC, µg/dL Transferrin saturation, % Hemoglobin, g/dL  Men  Women MCV, fL

Normal 115 100 330 35

± 50 ± 60 ± 30 ± 15

>13 >12 80–100

Iron Deficiency

Iron Deficiency Anemia

≤115 ↓ 20 ↓ 360 ↑ 30 ↓