Continuing Education Activity

Total parenteral nutrition is a medication used to manage and treat malnourishment. It is in the nutrition class of drugs. Total parenteral nutrition is indicated when there is impaired gastrointestinal function and contraindications to enteral nutrition. Total parenteral nutrition (TPN) is when the IV administered nutrition is the only source of nutrition the patient is receiving. This activity describes the indications, action, and contraindications for total parenteral nutrition as a valuable agent in managing malnourishment and the nonfunctional gastrointestinal system. In addition, this activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the interprofessional team in the management of patients with malnourishment and nonfunctional gastrointestinal system and related conditions.

Objectives:

• Identify the indications for total parenteral nutrition.
• Describe the potential adverse effects of total parenteral nutrition
• Review the appropriate monitoring of total parenteral nutrition.
• Outline interprofessional team strategies for improving care coordination and communication to advance total parenteral nutrition and improve outcomes.

Indications

Parenteral nutrition is the intravenous administration of nutrition outside of the gastrointestinal tract. Total parenteral nutrition (TPN) is when the IV administered nutrition is the only source of nutrition the patient is receiving. Total parenteral nutrition is indicated when there is impaired gastrointestinal function and contraindications to enteral nutrition. Enteral diet intake is preferred over parenteral as it is inexpensive and associated with fewer complications such as infection and blood clots but requires a functional GI system.[1]According to Chowdary and Reddy (2010), TPN has several indications.[2] These include:

• Chronic intestinal obstruction as in intestinal cancer[3]
• Bowel pseudo-obstruction with food intolerance. 
• TPN can also be used to rest the bowel in cases of GI fistulas with high flow[4]
• When an infant’s gastrointestinal system is immature or has a congenital gastrointestinal malformation
• When there is a post-operative bowel anastomosis leak
• When the patient is unable to maintain nutritional status due to severe diarrhea or vomiting
• Small bowel obstruction
• Hypercatabolic states due to sepsis, polytrauma, and major fractures[5]
• An anticipated period of nothing by mouth (NPO) status greater than seven days as in patients with inflammatory bowel disease exacerbations as well as critically ill patients[6]

The Food and Drug Administration (FDA) regulates parenteral nutrition in the United States, and the FDA requires statistically significant evidence of the efficacy and safety of parenteral nutrition products. Consequently, there are postapproval clinical trial requirements for parenteral nutrition products.[7]

Mechanism of Action

TPN is a mixture of separate components which contain lipid emulsions, dextrose, amino acids, vitamins, electrolytes, minerals, and trace elements.[8][9] Clinicians should adjust TPN composition to fulfill individual patients' needs. The main three macronutrients are lipids emulsions, proteins, and dextrose. 

Lipid Emulsions

• It provides calories and prevents fatty acid deficiency. Essential fatty acid deficiency may develop within three weeks of fat-free TPN.[2]
• 25% to 30% of the total calories are in the form of lipids.

Proteins

• A solution that contains essential and non-essential amino acids except arginine and glutamine
  • Healthy adult requirements are 0.8 to 1 gm of protein/kg/day.
• This change is based on the condition of the patient. Critically ill patients require 1.5 gm/kg/day, patients with chronic renal failure are given 0.6 to .0.8 gm/kg/day, and patients with acute hepatic encephalopathy need temporary protein restriction to 0.8 gm/kg/day, patients on hemodialysis need 1.2 to 1.3 gm/kg/day.[2]

Carbohydrate

• Provided through dextrose monohydrate in a variety of concentrations, most commonly 40,50, and 70%
• Glucose utilization maximum rate is 5 to 7 mg/kg/min.
• Excess carbohydrate supplementation can result in hyperglycemia and hypertriglyceridemia.

Electrolytes, Trace Elements, and Vitamins are Micro-nutrients

• Trace elements and vitamin dosing can be according to recommended daily requirements.
• Electrolytes recommendation per liter of parenteral nutrition:
  • Sodium: 100 to 150 mEq
  • Magnesium: 8 to 24 mEq
  • Calcium: 10 to 20 mEq
  • Potassium: 50 to 100 mEq
  • Phosphorus: 15 to 30 mEq

Total nutrition is an admixture, a 3-in-1 solution of the three macronutrients (dextrose, amino acids, lipid emulsions).

• A 3-in-1 solution and intravenous lipid emulsions) mixed with electrolytes, trace elements, vitamins, and water. Parenteral solution with only dextrose and amino acids with a separate intravenous lipid emulsions infusion, the 2-in-1 solution, has also been previously used.[8] Research has shown TNA to be the standard of care for adult TPN.

The currently used TPN amino acid mixture continues to be incomplete, with only 19 amino acids.[10] The non-essential amino acid glutamine has been used as a complement to TPN to complete the amino acid content of TPN (Glutamine 8 to 10% in PN is a compliment). Surgical critical care patients have decreased glutamine levels on admission, which continues to decline until the third hospital ICU day. Per a study by Tsuji, both high ≥700 nmol/mL and low  <400 nmol/mL of glutamine levels in ICU patients showed a statistical correlation with increased mortality in those patients between 400 to 700 nmol/mL.[11] Glutamine should serve as a complement to TPN rather than pharmaco-nutrition at supra nutritional doses. Patients who should not receive glutamine complementation above what may be present in basal TPN, as referenced by Heyland et al., include patients in septic shock, hemodynamic instability with increased vasopressor doses, and patients with renal failure.[12]

The pharmaceutical perspective of parenteral nutrition and Y site incompatibility:

• Parenteral nutrition(PN) mixtures should be physicochemically and microbiologically stable. In addition, the preparation of TPN requires analyzing their composition and any interactions that might occur during preparation, storage, and administration.[13] 
• Hospitalized patients requiring parenteral nutrition (PN) need intravenous medications. In one study, researchers evaluated the physical compatibility of various drugs with neonatal total parenteral nutrition (TPN) solution during Y-site administration. In this study, amiodarone, phenobarbital, and rifampin formed visible precipitation with neonatal TPN and should not be coadministered via Y-site injection.[14] 
• Clinicians should refer to individual compatibility of drugs with parenteral nutrition to avoid potential hazards such as crystal formation.[15]

Administration

Total parenteral nutrition administration is through a central venous catheter. A central venous catheter is an access device that terminates in the superior vena cava or the right atrium and is used to administer nutrition, medication, chemotherapy, etc. Establishing this access could be through a peripheral inserted central catheter (PICC), central venous catheter, or an implanted port.[16]

Clinicians can insert a PICC line into the basilic, cephalic, brachial, or median cubital vein. The basilic vein is preferable due to its larger size and superficial location. The catheter courses through the basilic into the axillary vein, to the subclavian vein, to settle in the superior vena cava.[17] PICC lines could be used when TPN is administered for several weeks to months.

The insertion of central venous catheters can be through one of the large three central veins: femoral vein, subclavian vein, or internal jugular vein. Central venous catheters are used when administering TPN for several months to years.[18]

An implanted port is a device implanted under the chest's skin with an attached catheter inserted into the superior vena cava. Implantable ports have been used when administering TPN for years.[18]

Due to its high osmolarity, total parenteral nutrition is not administered through a peripheral intravenous catheter (Peripheral Parenteral Nutrition, PPN). PPN osmolarity needs to be less than 900 mOsm. The lower concentration necessitates larger volume feedings, and high-fat content is necessary. High osmolarity irritates peripheral veins; hence TPN is given through central venous access.

Use in Specific Patient Population

Patients with Hepatic Impairment: Rapid initiation of parenteral nutrition is recommended in moderately or severely malnourished cirrhotics who cannot be nourished sufficiently by either oral or enteral route. Parenteral nutrition is recommended in patients with unprotected airways and encephalopathy (HE) due to the risk of aspiration in these patients. In patients with liver disease,  substantial inter-individual variability exists. Hence resting energy expenditure (REE) should be calculated using indirect calorimetry, if available.[19][20]

Patients with Renal Impairment: Patients with renal impairment, especially patients with ESRD, are at increased risk of nutritional disorders. In hospitalized patients with AKI or CKD  requiring medical nutrition therapy, indirect calorimetry should be used to estimate energy expenditure to guide nutritional therapy and avoid under or overfeeding. In case of contraindications to ONS and EN, PN(parenteral nutrition) should be started within three to seven days. To promote positive nitrogen balance in acute kidney injury, clinicians should adjust protein intake according to catabolic rate, renal function, and dialysis losses. Common laboratory abnormalities associated with prolonged RRT include hypophosphatemia, hypokalemia, and hypomagnesemia. Hence electrolyte intake in patients should be adjusted by monitoring serum concentrations. Trace elements should be monitored and supplemented as there are increased requirements during ESRD, critical illness, and extensive effluent losses during renal replacement therapy(RRT). Clinicians should give specific attention to selenium, zinc, and copper.[21][22]

Breastfeeding Considerations: A literature review suggests that breastfeeding women receiving total parenteral nutrition have breastfed their infants. In addition, using intravenous amino acids in parenteral nutrition in postpartum mothers may hasten the onset of lactation and improve weight gain in breastfed infants.[23] 

Pregnancy Considerations: The association between low pre-pregnancy BMI and poor weight gain in pregnancy with adverse perinatal outcomes has been well described; still, information regarding the outcome of pregnancy in women on TPN is lacking. Substantial advancements in TPN technology have now minimized maternal safety concerns.[24] However, according to the American College of Obstetricians and Gynecologists (ACOG) guidelines, Clinicians should utilize enteral tube feeding to provide nutritional support to a pregnant woman, as life-threatening complications such as sepsis and thromboembolism associated with parenteral nutrition have been reported. In addition, clinicians can insert peripherally inserted central catheter (PICC)  lines to avoid some complications associated with central lines. However, PICC lines are still associated with substantial morbidity and should be used only when enteral feeding is not feasible.[25] 

COVID-19 Considerations: Critically ill intubated patients with COVID-19 usually require a prolonged ICU stay and are prone to significant energy and protein deficit. Therefore, when enteral nutrition is not possible, there is a need to switch to parenteral nutrition. The significant change in prescribing PN therapy was a change from soybean oil-based lipid injectable emulsions (ILEs) to alternative ILE products with a lower inflammation profile. In addition, the requirement for multi-chamber-bag PN products increased during the pandemic. This practice reduced pharmacist and pharmacy technician time in the sterile compounding area to decrease the use of PPE and divert resources to other pharmacy responsibilities. For parenteral nutrition, nurses guard the tubing with a protective layer, a critical consideration from an infection-control perspective. In addition, for patients with COVID-19, consolidation of timing for medication administration and parenteral nutrition is recommended. Finally, patients with COVID-19 are prone to develop hypertriglyceridemia; hence serum triglyceride concentrations are obtained at baseline and within 24–48 hours of initiating parenteral nutrition.[26]

Adverse Effects

The main adverse effects can be metabolic abnormalities, infection risk, or associated venous access.

Venous Access: It is associated with the insertion of the central line catheter. 

• Pneumothorax
• Air embolism
• Bleeding
• Venous thrombosis
• Vascular injury[27][2]

Catheter Site Infections

• Central line-associated bloodstream infection(CLABSI)[28]
• Local skin infection at insertion or exit site

Metabolic Abnormalities

• Refeeding syndrome in chronic alcoholic patients and in patients who have nothing-by-mouth status (NPO) for more than 7 to 10 days
• Hyperglycemia
• Sudden discontinuation can lead to hypoglycemia. Hypoglycemia is correctable with 50% dextrose. 
• Serum electrolyte abnormalities
• Wernicke’s encephalopathy[29][2]
• Parenteral-associated cholestasis

Due to safety concerns and the complexity of administration, parenteral nutrition is considered high risk by the ISMP(Institute for Safe Medication Practice).[30]

Contraindications

According to Maudar (2017), TPN is generally contraindicated in the following conditions:

• Infants with less than 8 cm of the small bowel
• Irreversibly decerebrate patients
• Patients with critical cardiovascular instability or metabolic instabilities; such instabilities require correction before administering intravenous nutrition. 
• When gastrointestinal feeding is possible
• When the nutritional status is good, only short-term TPN is needed
• The lack of a therapeutic goal, as TPN should not be used to prolong life when death is unescapable.[5]

Boxed Warning: FDA has issued a boxed warning for some intravenous fat emulsions due to increased risk of death in preterm neonates related to intravascular fat accumulation in the lungs. Therefore clinicians must be cautious in choosing the right TPN therapy for preterm infants according to evidence-based guidelines.[31]

ASPEN (American Society for Parenteral and Enteral Nutrition) evidence-based guidelines suggest using a 1.2-micron in-line filter. Although 1.2-micron filters are not advised for use as standard infection control, these filters are efficacious in preventing Candida albicans infection in patients receiving parenteral nutrition.[32]

Monitoring

Per the American College of Gastroenterology, the identification of critically ill patients who can benefit from parenteral nutrition should be made using a validated scoring system such as Nutrition Risk Screening 2002 (NRS-2002) or Nutrition Risk in Critically ill (NUTRIC) score.[20]

Per Maudar 2017, several variables require monitoring while on TPN.[5] Among these are:

• Intake and output 12-hour charts
• Urine sugar monitoring every 8 hours
• Serum electrolytes: daily sodium, potassium, bicarbonate, calcium, and chloride values
• Serum creatinine and blood urea daily values
• Serum protein levels twice daily
• Liver function tests twice daily

The American Society for Parenteral and Enteral Nutrition (ASPEN) guidelines also offer monitoring guidelines.[33] These include:

• Patients who recently received TPN should be monitored daily until stable. They require frequent monitoring if metabolic abnormalities are detected or the patient has a risk of refeeding syndrome. Refeeding syndrome can occur in severely malnourished and cachectic individuals when feeding is reintroduced and can lead to severe electrolyte instabilities. Refeeding syndrome can correlate with hypophosphatemia, respiratory distress, rhabdomyolysis, and acute kidney injury. Prevention of refeeding syndrome is critical and achievable with a slower initial infusion of TPN than expected.[34]
• Unstable and critically ill patients should be monitored daily until stable.
• Stable hospital patients with no formulation changes for one week should be monitored every 2 to 7 days.
• Stable hospital, home, or long-term care setting, patients with no formulation changes for one week should be monitored every 1 to 4 weeks if clinically stable.

Toxicity

Generally, the toxicity of TPN is related to the individual toxicity of its components. Increased caloric amounts due to TPN glucose and lipid excess can lead to hepatic toxicity; this risk can decrease by using decreased glucose and greater lipid content. A glucose infusion rate greater than 5 mg/Kg/min can result in a fatty liver because increased glucose in the blood induces hepatic lipogenesis, and increased glucose levels induce increased insulin levels leading to more lipogenesis.[35] This effect is preventable by decreased dextrose dosage to under 5 g/kg day, less than 5mg/kg min, cyclic PN for 8 hours as it decreases excessive insulin secretion and substituting 30% of dextrose energy with lipids.

Parenteral nutrition supplementation rather than total parenteral nutrition is harmful to pediatric patients in the pediatric intensive care unit (PICU). Clinicians should withhold parenteral nutrition supplementation in the first week in the PICU independent of age or nutritional status; this is because amino acids in the PN suppress the autophagy process needed for cellular damage removal. Excess amino acids a shuttled to urea production. Increased urea levels can pose harm to the kidney and liver.[36]

Long-term usage of TPN, ranging from weeks to months, can be associated with the rare complication of manganese toxicity. Manganese exposure via TPN is characterized by high bioavailability due to bypassing the GI tract regulatory mechanisms. Over time, this high manganese concentration leads to its deposition in the liver, brain, and bone. However, the brain is most likely to be affected as manganese will deposit and affect the globus pallidus and striatum of the basal ganglia. Manganese preferentially affects dopaminergic neurons in the basal ganglia, resulting in extrapyramidal symptoms similar to Parkinson's disease. Idiopathic Parkinson's disease can be differentiated based on the location of neurons affected, i.e., in the substantia nigra.[37]

Peroxide(Reactive oxygen species (ROS) formation in parenteral nutrition(PN) happens when PN are exposed to light and phototherapy. Premature infants are susceptible to the consequences of peroxide formation in PN (e.g., bronchopulmonary dysplasia, necrotizing enterocolitis, and retinopathy of prematurity). Hence, the ASPEN guidelines suggest photoprotection of parenteral nutrition products beginning from the compounding process and continuing until the entire PN is administered.[38]

Enhancing Healthcare Team Outcomes

TPN administration needs a well-coordinated health care team with an interprofessional approach. The team includes:

• Clinician
• Pharmacist
• Dietician
• Nutrition nurse specialist

The clinician determines the treatment and the form of needed nutrition. The clinician coordinates care with the patient's primary health care team. The pharmacist provides sterile parenteral nutrition. The pharmacist advises on the stability of the compound and any drug/nutrient interactions that may arise. The dietician assesses the patient's nutritional status, calculates the daily requirement, and designs the feeding regimen. The nutrition nurse specialist supervises catheters and tube care. They are the patient's advocate and train the patient/caretaker to manage the tubes at home. Extended staff includes: social workers, occupational therapists, and wound management nurses.[39] All interprofessional team members must engage in open communication and accurately document any changes in patient status so everyone involved in care can have access to the most accurate and current information from which to make care decisions.

The ASPEN guidelines recommend comprehensive education and competency for clinicians, pharmacists, dieticians, and pharmacy technicians. The study revealed that interprofessional education programs and collaboration could significantly optimize parenteral nutrition-related patient safety and outcomes.[40] [Level 5]