Parenteralnutrition: Indications, Access, and Complications

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P a re n t e r a l N u t r i t i o n

Indications, Access, and Complications

Brian M. Lappas, MD, MPHa, Dhyanesh Patel, MDb, Vanessa Kumpf, PharmD, BCNSP
b
,
Dawn Wiese Adams, MD, MSb, Douglas L. Seidner, MDb,*

KEYWORDS
 Parental nutrition  Intestinal failure  Malnutrition  Central venous catheter
 Complications

KEY POINTS
 Parenteral nutrition (PN) is indicated in patients who are malnourished and have intestinal
failure.
 Initiation and monitoring of PN is best done by a multidisciplinary team composed of phy-
sicians, nutritionists, pharmacists, and nurses who are specially trained in PN prescribing
and compounding methods.
 Tunneled central venous catheters are the preferred access for delivery of long-term PN.
 Patients on PN need close monitoring to reduce the risk of thromboembolic, infectious,
and metabolic complications.

INTRODUCTION

Parenteral nutrition (PN) is a mixture of solutions that include dextrose, amino


acids, electrolytes, vitamins, minerals, trace elements, and lipid emulsions. The
formulation is delivered via a catheter device placed directly into the venous sys-
tem of patients with intestinal failure. The modern PN was clinically implemented in
the 1960s, with a recent study estimating that approximately 25,000 patients
receive home PN (HPN) in the United States.1 This article reviews the indications
and complications of PN and discusses the various types and indications for
devices.

Disclosure: The authors have nothing to disclose.


a
Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA;
b
Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Cen-
ter, Nashville, TN, USA
* Corresponding author. Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt
University Medical Center, 1211 21st Avenue South, 514 Medical Arts Building, Nashville, TN
37232.
E-mail address: [email protected]

Gastroenterol Clin N Am 47 (2018) 39–59


https://doi.org/10.1016/j.gtc.2017.10.001 gastro.theclinics.com
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40 Lappas et al

PARENTERAL NUTRITION INDICATIONS

PN is indicated in patients who are malnourished and cannot tolerate enteral nutrition
(EN). Malnutrition is defined as “an acute, subacute or chronic state of nutrition, in
which a combination of varying degrees of over nutrition or under nutrition with or
without inflammatory activity have led to a change in body composition and dimin-
ished function.”2 The European Society for Clinical Nutrition and Metabolism (ESPEN)
released a consensus statement in 2015 further defining malnutrition as either a body
mass index (BMI) less than or equal to 18.5 kg/m2 or the combined findings of weight
loss greater than 10% of habitual weight, greater than 5% over 3 months, and 1 of the
following: (1) reduced BMI less than 20 kg/m2, or less than 22 kg/m2 in adults older
than 70 years; or (2) reduced fat-free mass index, of less than 15 kg/m2 in females
or less than <17 kg/m2 in men.3
Malnutrition may be from starvation or an acute or chronic disease state. The inflamma-
tory response in acute disease or injury may cause high cytokine levels resulting in meta-
bolic alterations; specifically, increased energy expenditure, muscle catabolism, fluid
shifts, and hyperglycemia. All patients being admitted to the hospital or diagnosed with
a chronic disease should be assessed for malnutrition risk and severity. The assessment
should consider factors such as weight loss, muscle loss, subcutaneous fat loss, dimin-
ished hand-grip strength or another measure of functional status, visceral protein levels,
albumin and/or prealbumin levels, and inflammatory markers such as C-reactive protein
and/or interleukin-6 (IL-6). Multiple assessment tools have been validated to classify pa-
tients into low-risk and high-risk malnutrition groups, such as the Nutritional Risk
Screening (NRS 2002) and Nutrition Risk in the Critically Ill (NUTRIC) score.
The NRS 2002 tool was developed from the retrospective review of 128 randomized
controlled trials (RCTs) of hospitalized patients who were at risk for malnutrition.4 Pa-
tients were included if they had at least 1 of the following: BMI less than 20.5 kg/m2,
weight loss within the last 3 months, reduced dietary intake during the last week, or
severe illness. The degree of weight loss, impaired food intake, and severity of disease
were all used to create a scale of 0 to 10 points. Patients were then classified into a
high-risk group (score 3) that would benefit from supplemental nutrition.
The NUTRIC score was validated by a prospective, observational study in Europe of
597 patients in the intensive care unit (ICU) to classify critically ill patients into a low-
risk or high-risk malnutrition group.5 The NUTRIC score includes age, Acute Physi-
ology And Chronic Health Evaluation (APACHE II) score, Sequential Organ Failure
Assessment (SOFA) score, number of comorbidities, days from hospital admission,
and IL-6 level. Score greater than or equal to 5 (without using IL-6) was associated
with increased mortality and longer ventilation times and patients with those scores
were most likely to benefit from aggressive nutrition therapy including PN.
Patients who are identified at high risk should be started on a nutrition care plan un-
der the direction of a certified nutrition specialist who will assess enteral or parenteral
supplementation. EN is always preferred to PN unless there is a contraindication to its
use. Absolute contraindications to EN include bowel trauma, intestinal obstruction,
active gastrointestinal hemorrhage, and ischemic bowel with hemodynamic instability.
Other conditions that may limit EN include gastrointestinal inflammation or infection,
severe malabsorption, and small bowel fistulas. If PN is used, the nutrition team should
reassess the patient at regular intervals to consider initiating EN and oral feeding when
clinically appropriate. PN can usually be discontinued when at least 60% of the
patient’s nutrition needs are met via EN or oral feeding.6
Patients who require PN may be classified as having intestinal failure. This term was
recently redefined by ESPEN as “the reduction of gut function below the minimum

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Parenteral Nutrition 41

necessary for the absorption of macronutrients and/or water and electrolytes, such
that intravenous supplementation is required to maintain health and/or growth.”7
Intestinal failure can be grouped into 3 different classification schemes: functional,
pathophysiologic, and clinical. The functional classification includes types I, II, and
III based on the onset, metabolic, and expected outcomes of the illness (Box 1). There
are 5 different groups in the pathophysiologic classification of intestinal failure: short
bowel, intestinal fistula, intestinal dysmotility, mechanical obstruction, and extensive
small bowel mucosal disease. Diseases within pathophysiologic classifications can
shift between functional types over the course of an illness. The clinical classification
scheme stratifies patients into one of 16 groups based on the average daily parenteral
fluid (<1 L, 1–2 L, 2–3 L, and >3 L) and energy (0 kcal, 1–10 kcal, 11–20 kcal, >20 kcal)
requirements to sustain health. The rationale for these classification schemes is to
improve the categorization of patients recruited for clinical trials, standardize
language, and to guide effective diagnosis and therapy with respect to individual
patients. The designation of a subtype may not influence the decision to initiate PN
but may provide a framework for the patient’s long-term needs and potential
complications.

Acute Disease Indications


Critically ill patients
Optimizing overall nutrition improves morbidity and mortality in critically ill patients,
patients with trauma, and surgical patients.6 Critically ill patients are inherently at
greater risk for malnutrition given the increased hypermetabolic or catabolic state.
These patients should be evaluated with a malnutrition screening tool. As previously
discussed, the NRS 2002 and NUTRIC scores have been validated in the critically ill
population and stratify patients into high-risk and low-risk groups for the development
of complications associated with malnutrition.5,8
PN is only indicated when the enteral route fails or cannot be safely accessed to
meet daily nutritional requirements. Early EN, which is defined as the initiation of EN
within 24 to 48 hours of ICU admission, has been shown to decrease the risk of infec-
tious complications and ICU length of stay, although few studies have shown differ-
ences in mortality.6,9 Early RCTs indicated a mortality benefit between early EN

Box 1
Summary of intestinal failure by functional and pathophysiologic definition

Intestinal failure by functional type:


 Type I
 Acute and short-term. Usually self-limiting condition. Often seen in perioperative setting,
abdominal surgery, or critical illness requiring PN for days to weeks.
 Type II
 Prolonged acute condition causing metabolic unstable patients. Requires PN over weeks to
months. Often seen in intra-abdominal catastrophe (eg, mesenteric ischemia, volvulus,
trauma) with massive enterectomy and often a need for enterocutaneous fistula.
 Type III
 Chronic condition in metabolic stable patients, requiring PN more than months to years.
May be reversible of irreversible and often seen in short bowel syndrome, radiation
enteritis, or malignancy.

Data from Pironi L, Arends J, Bozzetti F, et al. ESPEN guidelines on chronic intestinal failure in
adults. Clin Nutr 2016;35(2):247–307.

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42 Lappas et al

compared with early PN in the critically ill.10 This finding may have been affected by
excessive caloric delivery in the PN groups (>40 kcal/kg/d) and permissive hypergly-
cemia. Several other RCTs have shown no mortality difference between EN and PN
when the caloric intake was reduced to 15 to 28 kcal/kg (approximating energy expen-
diture) and tighter glucose control was maintained11–13 A large meta-analysis in 2016
evaluated 18 RCTs of critically ill patients found no difference in mortality (relative risk
[RR] 1.04; 95% confidence interval [CI], 0.82–1.33; P 5 .75).14 The meta-analysis also
confirmed an overall decrease in infectious complications when including all 11 trials
that followed mortality (RR 0.64; 95% CI, 0.48–0.87; P 5 .004). A subgroup analysis
found no difference in infectious complications when the caloric delivery was similar
between EN and PN groups.
“One multicenter RCT showed that ICU patients with an absolute contraindication to
EN, who were started on PN on day 3 were less likely to be discharged alive than those
started on day 8”.15 Therefore, PN should be withheld for the first 7 days in patients at
low nutritional risk (NRS 2002 <3 or NUTRIC score <5) if EN is not feasible. In contrast,
patients who are at high risk for nutritional deficiency (NRS 2002 3 or NUTRIC score
5) or severely malnourished (defined as recent weight loss 10%–15% of their previ-
ous weight, or weight <90% of their ideal body weight) should start PN at presentation
if EN is not feasible or inadequate.6 Fig. 1 shows a proposed evidence-based algo-
rithm that can be used by clinicians to determine when to initiate PN in critically ill
patients.

Surgical patients
Patients with abdominal trauma or gastrointestinal surgery may not tolerate EN and
are at increased risk for malnutrition. The perioperative period is usually associated
with an increase in proinflammatory mediators that increase catabolism of glycogen,

Fig. 1. Proposed algorithm of when to initiate parenteral nutrition in critically ill patients.
a
Not including IL-6. GI, gastrointestinal. (Data from McClave SA, Taylor BE, Martindale RG,
et al. Guidelines for the provision and assessment of nutrition support therapy in the adult
critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Paren-
teral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr 2016;40(2):159–211; with
permission.)

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Parenteral Nutrition 43

fat, and protein with release of glucose, free fatty acids, and amino acids into the cir-
culation. Furthermore, undernutrition is an independent risk factor for increased mor-
tality, infectious complications, length of hospital stay, and increased cost in this
population.16
PN should only be considered in preoperative patients who are severely malnour-
ished and unable to tolerate EN or maintain greater than 50% of oral intake for
more than 7 days. Several studies have shown that 7 to 10 days of preoperative PN
improves outcomes in severely undernourished patients but has no benefit and might
increase morbidity in well-nourished patients.17–19 One meta-analysis has shown that
PN in severely malnourished surgical patients may have a lower mortality20; however,
these results were not confirmed in another meta-analysis, with an expert group rec-
ommending EN when feasible.21,22

Chronic Disease Indications


There are many chronic disease states that may eventually progress to type III or
chronic intestinal failure. These patients are often hemodynamically stable and have
little or no inflammation but require PN for months to years. These patients can clearly
benefit from HPN because this therapy has been shown to prolong life and improve
quality of life. However, there are many complications that have been associated
with long-term PN administration, which underscores the importance of proper patient
selection, training, and monitoring of this treatment so that beneficial clinical out-
comes are maximized.
Conditions that require HPN include inflammatory bowel disease, intestinal pseudo-
obstruction, scleroderma, and gastrointestinal cancers. Radiation enteritis is a condi-
tion that is an important indication for HPN and is discussed later. It is important to
remember that the condition is not the sole criterion for PN administration. A full
assessment is necessary to determine whether PN is indicated and includes appraisal
of nutritional status; evaluation of the functional status of the bowel, which is affected
by the remaining bowel length; functional status of the upper gastrointestinal tract and
integrity of the intestinal mucosa; and whether the patient is able to consume a well-
balanced diet of an adequate amount.

Radiation enteritis
Radiation therapy in the region of the abdomen and pelvis can result in chronic radi-
ation enteritis. This condition affects one-fifth of all patients undergoing abdomen/pel-
vic radiation therapy and may present as early as 6 to 12 months or as late as 1 to
2 decades after treatment.23 A multicenter survey in 1998 found that 8% of patients
on HPN had radiation enteritis as an indication for PN. Acute radiation injury, which
causes edema and neutrophilic infiltration of all 3 layers of the bowel wall, subsides
in nearly all patients. Patients with chronic radiation enteritis have histologic changes
of mononuclear infiltrates, fibrosis and vasculitis that may result in stenosis, ulcera-
tions, necrosis, and possibly perforation of the bowel. Surgery is indicated for
segmental strictures with bowel obstruction, refractory or severe gastrointestinal
bleeding, and bowel perforation. Most patients have intestinal dysmotility that can
be managed with an oral diet and medications to provide symptomatic relief of diar-
rhea and abdominal pain. A small subset of patients may require supplemental EN
and an even smaller group may need PN. The prognosis of patients with radiation en-
teritis in large HPN programs is quite good, with a 5-year survival rate of nearly 90%.24
Importantly, the possibility of EN should be reassessed frequently because an obser-
vational study in 2006 found that one-third of patients were able to resume oral intake
after chronic HPN.25

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44 Lappas et al

PARENTERAL NUTRITION FORMULATION

A multidisciplinary team of experienced clinicians, including physicians, dietitians,


pharmacists and nurses, is recommended to ensure the prescribing of a complete
and balanced PN formulation.26 The PN formulation contains protein (amino acids),
carbohydrate (dextrose), fat (intravenous lipid emulsion [ILE]), electrolytes, minerals,
vitamins, trace elements, and water. It should be individualized to the needs of the
patient and typically involves sterile compounding of 10 to 15 components. A total
nutrient admixture (TNA), or 3-in-1 formulation, refers to all 3 macronutrients (amino
acid, dextrose, ILE) included in the same bag. When ILE is administered separately, it
is referred to as a 2-in-1 formulation. Advantages of a TNA compared with 2-in-1
formulation include convenience, reduced cost, and reduced risk of microbial
growth. However, there are certain factors that limit emulsion stability that should
be considered, such as mixture with neonatal amino acid solutions or addition of
iron. Regulations are in place to foster safe and accurate compounding of sterile
products and it is the pharmacist’s duty to review the PN formulation for appropriate
stability and compatibility.27 Automated compounding devices are available that pro-
vide computer-assisted commands and incorporate safety features into the com-
pounding process of individual PN formulations. Alternatively, standardized
premixed PN formulations are commercially available in a variety of fixed nutrient
doses that are designed to meet standard nutrient requirements in non–critically ill
patients but not necessarily for patients with nutrient requirements outside a standard
range.
Standard ranges for protein and energy requirements are age specific and incorpo-
rate metabolic demand and dosing weight, adjusted for obesity (Table 1). The usual
distribution of nonprotein calories is 70% to 85% as carbohydrate and 15% to 30%
as fat. This distribution may be adjusted based on tolerance and to minimize potential
immune-suppressive effects of soybean oil–based ILE. Use of intermittent ILE admin-
istration (eg, 2–3 times weekly) instead of daily administration is a strategy that allows
for provision of estimated essential fatty acid requirements while minimizing potential
adverse effects. Standard ranges for electrolytes and minerals are age specific and
based on normal organ function and normal losses but may also be limited by compat-
ibility issues. A parenteral multivitamin preparation that contains 13 vitamins should be
added daily. Guidelines for trace element content are provided in Table 1; however,
variations may exist among individual patients on long-term PN and in patients with
chronic cholestatic liver disease and renal insufficiency.28 Our approach is to monitor
blood levels of trace elements in all HPN patients every 6 months and to modify dosing
as needed. In addition, nearly every component of the PN formulation has been and
continues to be affected by product shortages that expose patients to risk of harm
related to nutrient deficiency. Practice recommendations for dealing with PN product
shortages are available from the American Society for Parenteral and Enteral Nutrition
(ASPEN) that incorporate measures to ration supply and identify alternative therapeu-
tic options.29 Initiation of PN should occur in a hospital setting where daily monitoring
of fluid intake/output along with laboratory monitoring (serum electrolytes, glucose,
calcium, magnesium, and phosphate) can be accurately measured. Special circum-
stances, like major electrolyte imbalances or refeeding syndrome, may require more
frequent and prolonged laboratory monitoring. Once electrolytes and nutrient levels
have stabilized, the intervals of monitoring may be increased. Table 2 shows a
schedule of proposed monitoring needs for patients on long-term PN. This article
briefly reviews some special considerations of PN formulations in different disease
states.

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Parenteral Nutrition 45

Table 1
Estimated daily fluid, electrolyte, carbohydrate, protein, and lipid requirements in
hospitalized patients receiving parenteral nutrition

Nutritional Requirement Dose


Protein (catabolic) 1.2–2 g/kg/d
Calories 25–30 kcal/kg/d

Fluid and Electrolytes Dose


Water 25–35 mL
Sodium 1–2 mEq/kg
Potassium 1–2 mEq/kg
Chloride As needed to maintain acid-base
balance
Phosphorus 20–40 mmol
Magnesium 8–20 mEq
Calcium 10–15 mEq

Trace Elements Dose


Zinc 2.5–5 mg
Copper 0.3–0.5 mg
Manganese 60–100 mg
Chromium 10–15 mg
Selenium 20–60 mg
Iron Not routinely added

Vitamins Dose
Vitamin A 3300 IU
Vitamin E 10 IU
Vitamin K 150 mg
Vitamin D 200 IU
Vitamin B1 6 mg
Vitamin B2 3.6 mg
Vitamin B6 6 mg
Niacin 40 mg
Folic acid 600 mg
Vitamin B12 5 mg
Biotin 60 mg
Vitamin C 200 mg

Data from Refs.7,27,37

Pulmonary Failure
Macronutrient metabolism can adversely affect respiratory function in mechanically
ventilated patients with acute or chronic respiratory failure. Excess amino acid and
glucose infusion may increase minute ventilation and carbon dioxide production,
whereas soybean oil–based ILE may adversely affect immune function. Current clin-
ical guidelines recommend using indirect calorimetry to determine energy require-
ments or, if this equipment is not available, to prescribe 25 to 30 kcal/kg/d.6 They
also recommend 1.2 to 2.0 g/kg/d of protein, withholding or limiting soybean oil–based
ILE to 100 g in a divided dose during the first week of critical illness. This group also

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46 Lappas et al

Table 2
Recommended laboratory monitoring for patients receiving parenteral nutrition

Frequency
Initiation of Therapy
Parameter (Acute Care) Long-term Therapy
Capillary glucose Every 6 h until advanced to Not routine
goal and as needed to As needed basis to coordinate
maintain 140–180 mg/dL with PN infusion cycle
Basic metabolic panel Daily, until advanced to Weekly, then decrease frequency
Phosphorus, magnesium goal and stable; then 1–2 as stable
times/wk
CBC (with differential) Baseline; then 1–2 times/wk Monthly, then decrease frequency
as stable
Liver function: ALT, AST, Baseline; then weekly Monthly, then decrease frequency
ALP, total bilirubin as stable
Serum triglycerides Baseline if at risk; then as Not routine
needed As needed
Iron studies, 25-OH Not routine Baseline, then every 3–6 mo
vitamin D
Zinc, copper, selenium, Not routine Baseline, then every 6 mo
manganese

Abbreviations: ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase;
CBC, complete blood count; 25-OH vitamin D, 25-hydroxyvitamin D.

recommends close monitoring of serum phosphorous because up to 30% of patients


in the ICU may develop phosphorous deficiency, which may result in diaphragmatic
weakness and increased ventilator time.30 Strict monitoring of intake and output is
also important in pulmonary failure to reduce the risk of pulmonary edema.

Renal Failure
Protein goals in patients with renal failure should be based on the degree of renal insuf-
ficiency, the use of renal replacement therapy, and the degree of illness. The recom-
mended dose of protein is 0.6 to 0.8 g/kg/d for patients with chronic kidney disease
(CKD) who are not receiving hemodialysis (HD), 1.2 g/kg/d for patients with CKD on
maintenance HD, and 1.5 g/kg/d for non–critically ill patients with acute kidney injury
(AKI) on intermittent HD. In critically ill patients with AKI, the recommended protein
amount is 1.2 to 2 g/kg/d. This amount should be increased to 1.8 to 2.5 g/kg/d during
continuous renal replacement therapy because of increased losses of amino acids
and protein with this treatment modality.6,31 In most cases, a standard 10% amino
acid PN solution is appropriate in critically ill patients with renal failure. If excess fluid
is a management challenge, a 15% amino acid concentrated formulation should be
considered. Because of electrolyte imbalances, initiating PN in malnourished patients
with renal failure increases the risk of refeeding syndrome; thus, serum potassium,
magnesium, calcium, and phosphorus levels should be monitored closely. In addition,
energy requirements for critically ill patients with renal failure are similar to those
without, ranging from 25 to 30 kcal/kg/d.6

Hepatic Failure
PN should be started immediately for patients with alcoholic steatohepatitis or
cirrhosis with moderate to severe malnutrition and in those with acute liver failure

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Parenteral Nutrition 47

who may not be able to start EN within 5 to 7 days. The recommended protein goal for
alcoholic steatohepatitis and cirrhosis is 1.2 to 1.5 g/kg/d, whereas for acute or sub-
acute liver failure it should be reduced slightly to 0.8 to 1.2 g/kg/d.32 Patients with he-
patic encephalopathy (HE) should be given protein at the lower end of this range until
the causes of encephalopathy have been identified and treated. Once patients show
signs of improvement, protein intake should be increased as tolerated to goals as
noted earlier to help maintain nitrogen balance and promote recovery.33 In nearly all
patients with liver disease, standard amino acid solutions should be used. Concen-
trated formulas with 15% amino acids may be used in the management of patients
who need fluid restriction. Branched chain amino acid (BCAA)–enriched formulas for
patients with liver disease consist of an 8% amino acid solution with 36% of total
amino acids provided as BCAAs (eg, valine, isoleucine, and leucine) and 2% as aro-
matic amino acids (eg, tryptophan, phenylalanine, and tyrosine). These formulas
have been shown to reduce symptoms of HE but are no better than standard medical
intervention.34 The authors therefore reserve the use of BCAA formulas in PN solutions
to patients with greater than or equal to grade III HE who do not improve after 48 hours
of medical therapy and 0.8 g/kg/d of standard amino acids. Energy requirements are
similar to amounts used for patients with pulmonary and renal disease.6

VASCULAR ACCESS

PN is delivered via a catheter that is placed directly into the venous system. The choice
of vascular access location, catheter type, site of the vein entry, and routine care are
vital for patient safety and quality of life. The choices of vascular access location and
catheter type are based on multiple factors and should be decided by a multidisci-
plinary team of PN specialists. Anticipated duration of administration, PN formulation,
and patient-specific factors are the main determinants of access choice. Special
attention to wounds, systemic illness, social situation, and the ability of the patient
to care for the access is needed when making this decision. There are few RCTs
that directly compare venous access type in PN patients. In general, tunneled cathe-
ters are the preferred method for home or long-term (>3 months) PN delivery, espe-
cially for patients requiring daily access to a catheter device. Table 3 highlights the
limitations and advantages of different types of vascular catheter access.

Peripheral Venous Access


The safest and easiest way to access the vascular system is through a small-caliber
peripheral venous catheter. These devices are often inserted into a readily accessible
forearm vessel but may also be placed in the upper extremity or neck. The fragility of
such vessels limits the duration and formulation of PN. They are generally used for less
than 6 days in patients who are not fluid restricted because formulations must be
diluted to avoid the development of phlebitis, which often limits the total number of
calories that can be delivered. Peripheral PN is compounded with a final concentration
of amino acids less than 5%, glucose less than 10%, and an osmolarity of less than
900 mOsm/L.35,36 Peripheral venous catheters have the highest risk of thrombophle-
bitis compared with other access methods. However, they have the lowest risk of
catheter-related infections, which may be related to their limited duration.36
Midline catheters are becoming an increasingly popular way to administer PN in the
hospital setting. PN through a midline catheter may be administered over a period
longer than 6 days, although the same formulation restrictions as for short cannula de-
vices apply. Although convenient, midline catheters are not appropriate for HPN
administration. They also carry a significant risk for thrombophlebitis, which may be

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48 Lappas et al

Table 3
Comparison of insertion site, duration, advantages, and limitations of various types of
vascular access

Type of
Access Insertion Site Duration Limitations Advantages
Short Superficial Days Fragile, solutions Ease of access and
peripheral upper <600 mOsm/L, placement, cost,
catheter extremity or high phlebitis risk, lowest infection risk
neck vein hospital use only
PICC Basilic, cephalic, Weeks to Difficult access for Central access with
or brachial months self-care, lowest risk of
vein uncomfortable, pneumothorax or
placed by trained arterial damage,
technician only acute or home
setting
Nontunneled Jugular, 1 wk Hospital setting only, Quick procedure, cost,
CVC subclavian, highest infectious easy to remove
femoral vein risk, uncomfortable,
placement
complications
operator
dependent
Tunneled Subclavian Months to Requires placement in Long-term home use,
CVC or jugular years procedure room by self-care easy,
vessels trained radiologist decreased infection
or surgeon risk
Implanted Subclavian or Months to — —
CVC jugular years
vessels

Abbreviations: CVC, central venous catheter; PICC, peripherally inserted central catheter.
From Kryzyda EA, Andris DA, Edmiston CE. Parenteral access devices. In: Mueller CM, editor. The
A.S.P.E.N. adult nutrition support core curriculum. 2nd edition. Silver Spring (MD): American Soci-
ety for Parenteral and Enteral Nutrition; 2012. p. 265–83; with permission.

reduced by ultrasonography placement in the basilic or brachial veins. Midline cathe-


ters have an average life span of 2 to 6 weeks.

Centrally Placed Venous Catheters


Central venous access is the preferred delivery of medium-term and long-term PN.
The most common insertion sites include the subclavian, internal jugular, cephalic,
and basilic veins. The catheter tip should terminate near the junction of the superior
vena cava (SVC) and right atrium. The advantages of central venous catheter (CVC)
use include that they are not limited by the type, pH, osmolarity, or volume of the
PN infusion. Percutaneous CVCs placed in the subclavian or jugular venous systems
are usually indicated for short-term use because they are often placed in urgent or
emergent conditions. Because of the higher risk of infection compared with other
CVCs, they are not appropriate for home PN administration.
Peripherally inserted central catheters (PICCs) are CVCs that are typically placed by
a trained nurse and interventional radiologist using ultrasonography guidance into the
basilic, cephalic, or brachial vein. Because of the location of the insertion site, PICC
placement is associated with a significantly lower risk of thoracic placement compli-
cations such as pneumothorax, uncontrolled bleeding, and arterial puncture. PICCs

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Parenteral Nutrition 49

are ideal for administration of PN in the hospital, rehabilitation facility, and the home
setting when therapy is indicated for less than 3 months.37 Although most studies
have shown that the incidence of central line–associated bloodstream infection
(CLABSI) is greater with PICCs compared with tunneled CVCs, a nonrandomized pro-
spective trial of patients with a cancer receiving HPN found a significant decrease in
infections in patients with PICCs compared with those with tunneled CVCs or porta-
caths.38 Other advantages include lower overall cost compared with tunneled central
lines.36,39,40 Difficulties include home care and convenience of the antecubital place-
ment, which may be a barrier to patient quality of life.
Tunneled CVCs are the preferred method of HPN delivery in patients requiring this
therapy for 3 months or more. With proper care, they may be safely used for years.
Most often, the skin insertion site is on the upper chest with the venipuncture occurring
in the right internal jugular vein. Tunneled catheters are placed by trained interven-
tional radiologists or vascular surgeons in the operating room and also require a pro-
cedure for removal. The decrease in risk of CLABSI is attributed to the barrier of soft
tissue that separates the vein entrance site from the catheter exit site. Importantly,
tunneled catheters provide a discrete catheter option that is easy to access and main-
tain for patients on long-term PN.
Another type of tunneled CVC is an implanted portacath. These devices have a
catheter attached to a self-sealing silicone elastomer septum that is placed into a sub-
cutaneous pocket in the anterior chest wall and must be accessed with a noncoring
needle that is intermittently placed percutaneously. The advantage of these CVCs is
that they require minimal maintenance aside from routine cleaning during access
and monthly heparin flushes if they are not in use. When they are not accessed, pa-
tients can maintain normal activities with minimal restriction, including bathing.
Although these devices may be accessed 2000 to 3000 times, they are better suited
for intermittent use as opposed to daily access. As a result, they are used infrequently
for the administration of PN.

PARENTERAL NUTRITION COMPLICATIONS

Some of the common and most serious complications associated with PN are dis-
cussed here, which we have arbitrarily categorized as either acute or chronic. It should
be noted that complications associated with PN can be avoided or mitigated through
selection of the most appropriate CVC; careful preparation and monitoring of the PN
formula; and, in patients requiring long-term PN, training of the patient or caregiver on
the catheter care and PN delivery. Many hospitals have pharmacists and dietitians
with expertise in nutrition support to assist in the management of patients in the acute
care setting. Referral to a multidisciplinary team at a tertiary center that specializes in
the management of intestinal failure should be considered for patients requiring HPN
for greater than 3 to 6 months.

Acute Complications
Vascular access
Placing a catheter, whether peripherally or centrally, has inherent risks that can arise
immediately or postprocedure. Peripherally placed catheters have the lowest risk of
complications compared with CVC placement. CVC placement results in pneumo-
thorax, arterial puncture, and line malposition in approximately 1% to 4% of attempts.
One large multicenter trial in 2015 compared complication rates of internal jugular, sub-
clavian, and femoral nontunneled central venous access. Pneumothorax requiring
chest tube insertion occurred in 1.5% of subclavian insertions compared with 0.5%

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50 Lappas et al

of the internal jugular attempts.41 Femoral central access is generally not recommen-
ded for administration with PN because of sanitary challenges and increased infection
risk.42 Jugular and subclavian CVCs should be placed using ultrasonography and this is
now standard of practice in the United States. Multiple RCTs and meta-analyses have
confirmed that ultrasonography-guided techniques have a higher first-attempt rate and
a decrease in bleeding and pneumothorax rates.43 The number of unsuccessful inser-
tion attempts is the most powerful predictor of immediate complications.44

Hyperglycemia
Hyperglycemia is a common occurrence in hospitalized patients initiated on PN. One
observational study found that up 50% of hospitalized patients on PN experienced an
episode of hyperglycemia.45 The development of hyperglycemia during PN in the hos-
pital is independently associated with higher rates of mortality, infections, organ
dysfunction, and length of hospital stay.45–48 Patients with acute illness, surgery, or
trauma have an increased risk of developing hyperglycemia because of increased he-
patic glucose production and increased peripheral insulin resistance with reduced
glucose use. There are no specific clinical trials to evaluate the effect of glucose levels
on hospitalized patients on PN; however, ASPEN recommends a blood glucose target
of 140 to 180 mg/dL.49
Hyperglycemia tends to occur more frequently during the initiation of PN as the
dextrose infusion is being titrated to goal and need for supplemental insulin is being
determined. PN formulations are typically initiated with 2 g/kg/d of glucose to limit
gluconeogenesis derived from protein catabolism. One study showed that PN formu-
lations with a lower glucose load (1.8  1.3 g/kg/d compared with 2.6  1.4 g/kg/d)
had decreased incidence of hyperglycemia and improved mortality in ICU patients.50
Dextrose administration of more than 4 mg/kg/min is a significant predictor of hyper-
glycemia.51 In average-sized adults the authors follow the current guidelines and limit
the initial glucose load to between 150 and 200 g/d6 Hyperglycemia should be treated
with scheduled divided insulin doses or a continuous inulin infusion in critical ill pa-
tients. If a moderate dose of insulin is required, then a portion of this is typically added
to the PN formulation. A prospective cohort study in 2012 showed that initiating PN
with insulin at a dose of 1 U/20 g of glucose in hyperglycemic patients resulted in
improved glycemic control compared with a sliding-scale replacement method.52

Refeeding syndrome
Malnourished patients who undergo rapid nutritional repletion are at risk for refeeding
syndrome, which is characterized by cardiac, respiratory, and neurologic symptoms
caused by hypophosphatemia, hypokalemia, and hypomagnesemia. Patients with
anorexia, alcoholism, prolonged starvation, bariatric surgery, and chronic illnesses
(such as cancer or cirrhosis) are at higher risk for this condition. In starvation, insulin
concentrations decrease and permit a shift in metabolism from using glucose as a pri-
mary source of fuel to ketones and free fatty acids to help spare nitrogen. During this
catabolic process, total-body phosphorus, magnesium, and potassium levels are
depleted as these electrolytes are released from intracellular sources. When sufficient
dietary or nutrition support is provided to these patients, insulin concentrations in-
crease, especially in response to glucose, and to a lesser extent protein, and lead
to cellular uptake of phosphorus, magnesium, and potassium. This process may result
in dangerously low concentrations of these electrolytes in the serum and lead to symp-
toms associated with refeeding syndrome. Hypophosphatemia is especially
dangerous because it may result in respiratory failure, cardiac dysfunction, and ar-
rhythmias, as well as hematologic, endocrine, and neuromuscular dysfunction. The

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Parenteral Nutrition 51

risk of refeeding syndrome can be tempered by decreasing the number of calories


provided while PN is initiated. Our approach has been modeled on the recommenda-
tions of the United Kingdom National Institute for Health and Care Excellence (NICE)
on nutrition support in adults who are at high risk for developing refeeding problems
[www.nice.org.uk/guidance/cg32]. The authors provide 45% to 50% of total dextrose
calories for the first 24 to 48 hours, based on initial total energy goals in the ICU of
25 kcal/kg/d (30 kcal/kg/d for ambulatory patients), where the patients’ current
body weight is used up to a BMI of 25 kg/m2 and an adjusted body weight is used
in overweight and obese individuals. A basic metabolic panel with magnesium and
phosphorus should be monitored daily and electrolyte abnormalities should be cor-
rected immediately. We slowly advance the formula to goal over 5 to 7 days if the pa-
tient is metabolically stable. We also provide supplemental thiamine 100 mg and folate
1 mg daily over this time frame.

Chronic Complications
Thromboembolic complications
Cather-related venous thrombosis can result in patient discomfort, emergency room
visits, hospital admissions, and delays in PN administration. One large multicenter
study of 50,470 patients on HPN found a thrombosis rate of 0.23 per 1000 catheter
days.53 Another recent retrospective cohort study found an incidence of catheter-
related venous thrombosis of 11.4% within the first year of HPN use.54 PICC lines
also have higher rates of thromboembolic events, up to 5%, as shown by one study
of 102 hospitalized patients.39 In general, shorter peripherally placed catheters have
higher rates of thrombophlebitis than CVCs. This risk can be reduced by using aseptic
placement techniques, smaller-gauge catheters, avoiding Teflon cannulas, and proper
fixation techniques.
Using ultrasonography-guided placement for CVCs and confirming catheter tip
placement in the cavoatrial junction with a chest radiograph reduces the rates of
thromboembolic complications. Comparing types of CV access, subclavian CVC
had lower risks of symptomatic deep vein thrombosis compared with jugular and
femoral access. Femoral access has the highest rates of thromboembolism and
should be avoided in HPN administration.41
Multiple RCTs and meta-analyses have determined that intermittent prophylaxis
with flushing of catheters with heparin is no more beneficial than flushing with normal
saline alone.51,55–57 Many manufacturers of portacaths or open-ended catheter lu-
mens recommend a heparin flush when locking the device. This method may be help-
ful when devices are scheduled to remain closed for more than 8 hours. However,
heparin should not be flushed immediately before or after lipid-containing PN because
of the risk of lipid precipitation. This problem is generally avoided because patients
who use heparin as a lock solution are instructed to administer it with saline before
and after medication administration (saline, administer medication, saline, heparin
[SASH]). Closed-ended valve catheters should be flushed and locked with saline only.

Infectious complications
Infections remain a common and serious complication of PN that is inherent to both
the type of PN formulation and CVC line that is selected for the administration of
this therapy. CLABSI remains the most morbid complication of PN. For our purposes,
CLABSI is defined by the Centers for Disease Control and Prevention (CDC) as a
laboratory-confirmed bloodstream infection in a patient with a central line more than
48 hours from symptom onset and unrelated to an infection from another site.58 The
CDC estimates that 30,100 cases of CVC-associated bloodstream infections occur

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52 Lappas et al

annually in United States.58 A large systematic review showed that PN rates of infec-
tions range from 0.38 to 4.58 episodes per 1000 catheter days.59 An additional multi-
center observational study in 2016 followed 1046 patients on HPN in the United States
and found that 10.7% experienced a CLABSI event over 3 years, totaling 0.87 epi-
sodes per 1000 PN days.60 Patients on PN, compared with intravenous fluid and other
parenteral therapies, have inherently higher rates of CLABSI. A large single-center
study showed an odds ratio of 2.65 (95% CI 2.20–3.19; P<.0001) of CLABSI with
PN compared with patients with CVC not receiving PN.61 Patients also had higher
odds of developing CLABSI if they had longer line duration, renal failure, human immu-
nodeficiency virus, or malignancy.61
The most prevalent organisms cultured include coagulase-negative staphylococci,
Staphylococcus aureus, and Klebsiella pneumoniae.60 There are many techniques to
decrease CLABSI incidence, and these are summarized in Box 2 based on the ESPEN
guidelines of 2009. Tunneled catheters and implanted venous access devices have
the lowest rates of CLABSI, especially for patients with long-term PN administration.62
PICC lines may also be considered for short-term and medium-term access because
they have decreased rates of CLABSI compared with temporary percutaneous CVCs
placed in the jugular, subclavian, or femoral vein.36 Single-lumen CVCs are preferred
to multilumen catheters, as shown in multiple RCTs, although recent quantitative
meta-analysis has found the difference in CLABSI rates to be nonsignificant.63,64 Pre-
cautions taken during the insertion of CVC access greatly decrease the rates of
CLABSI. In a multicenter prospective study, a bundle including hand washing, full-
barrier precautions during insertion, chlorhexidine antisepsis, removing unnecessary
catheters, and avoiding the femoral site resulted in up to a 66% reduction in CLABSI
incidence.65 The use of antimicrobial locking solutions to prevent CLABSI is contro-
versial.7 Antibiotic locks have not been shown to reduce the incidence of CLABSI in
HPN and may result in the development of antibiotic resistance.62 Ethanol (70%)
lock has been shown to reduce the rate of CLABSI from 10.1 to 2.9 per 1000 catheter
days in a series of 31 HPN patients.66 However, its regular use has not been endorsed
because there is concern that this solution may increase the risk of catheter occlusion
and venous thrombosis.67 If these solutions are used, then ethanol lock is only

Box 2
Techniques that can be used to reduce risk of central line–associated bloodstream infections

Summary of techniques used to decrease risk of CLABSI


 Appropriate choice of the insertion site
 Using tunneled and implanted catheters (value only confirmed in long-term use)
 Using antimicrobial coated catheters (value only shown in short-term use)
 Using lowest number of lumens possible; single-lumen catheters preferred
 Using peripheral access (PICC) when possible
 Ultrasonography-guided venipuncture for all central line placements
 Use of maximal barrier precautions during insertion
 Proper education and specific training of staff
 An adequate policy of hand washing
 Use of 2% chlorhexidine as skin antiseptic; let dry completely before applying
 Appropriate dressing of the exit site
 Disinfection of hubs, stopcocks, and needle-free connectors; change weekly
 Regular change of administration sets

From Pittiruti M, Hamilton H, Biffi R, et al. ESPEN guidelines on parenteral nutrition: central
venous catheters (access, care, diagnosis and therapy of complications). Clin Nutr
2009;28(4):365–77; with permission.

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Parenteral Nutrition 53

appropriate for tunneled silicone catheters because it is not compatible with polyure-
thane, which is used to manufacture most of the infusion devices.
Other infectious complications of long-term vascular access devices (VADs) include
exit site and tunnel infections. These infections present with localized signs and symp-
toms and are generally not accompanied by systemic inflammation and bacteremia.
Localized exit site infections of tunneled catheters can usually be managed with local
care and oral antibiotics. Exit site infections of PICCs and pocket infections of implanted
portacaths should be managed with line removal and, in some instances, antibiotics to
prevent systemic infection. Infections limited to the tunneled segment of a CVC are very
difficult to clear with antibiotics and often necessitate removal of the device.

Hepatic complications
Hepatobiliary disease associated with PN includes intestinal failure–associated liver
disease (IFALD) and biliary tract disease. IFALD (previously referred to as parenteral
nutrition-associated liver disease) includes PN factors that adversely affect meta-
bolism or direct injury of the liver, in addition to liver injury attributed to the primary dis-
ease for which PN is being used.68 PN factors that may contribute to liver injury include
excess glucose calories, phytosterols contained in plant-based lipid emulsions,
essential fatty acid deficiency, taurine deficiency, and hypermanganesemia. Factors
unrelated to PN include inflammation associated with the patient’s underlying disease,
bacterial infection, bacterial overgrowth, and bile acid deficiency or toxicity. These
factors generally lead to either steatosis or cholestasis. Excessive glucose calories
result in steatosis through a combination of factors including hyperglycemia,
increased insulin to glucagon ratio, and perhaps choline and carnitine deficiency. It
can be prevented by avoiding overfeeding, is often reversible, and rarely leads to stea-
tohepatitis or cirrhosis. Cholestasis is more common in children than in adults, often
presents after long-term PN use, and is more likely than steatosis to progress to
cirrhosis. The incidence of end-stage liver disease in adults on long-term PN is un-
known but estimates range from 15% to 30%.69,70 In contrast, mild increase of liver
enzyme levels is common in adults during the first few weeks of PN and often resolves
as long as patients are not overfed.
Management of increased liver enzyme levels includes the avoidance of overfeeding
after the patient’s nutritional status is replete. The infusion of soybean oil–based ILE
should not be greater than 1 g/kg/d.70 If a formula that is predominantly glucose based
can be tolerated, then soybean oil–based ILE can be reduced to 100 g/wk to meet
essential fatty acid requirements. If appropriate, a diet should be initiated in patients
who are nil per os. Other actions should include maintenance of good glycemic con-
trol, discontinuation of hepatotoxic drugs, avoidance of alcohol consumption, and
control of any underlying infection or inflammatory process. If available, alternative
ILEs that contain lower concentrations of soybean oil may be considered if enzyme
improvement does not occur. Evaluation for other causes of liver disease should be
undertaken if enzyme levels remain chronically increased, especially for treatable
causes of liver disease. If possible, restoration of intestinal continuity should be
considered if the increase in liver enzyme levels is moderate or severe. Referral to a
center that performs intestinal transplants may be considered for patients with
impending liver failure, defined as a total bilirubin level greater than 3 to 6 mg/dL, or
symptomatic liver failure.7

Biliary complications
Long-term PN is associated with biliary complications including cholelithiasis, biliary
sludge, and acalculous cholecystitis. These complications may result in pain or

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54 Lappas et al

infection requiring percutaneous cholecystostomy tube or surgical cholecystectomy.


Biliary sludge is very common in long-term PN. One observational study showed that
50% of participants on PN developed sludge after 4 weeks and 100% developed
sludge after 6 weeks.71 A lack of enteral feeding prevents the release of cholecysto-
kinin (CCK), which is required to stimulate gallbladder contraction and emptying. A
small, prospective study found that no patients developed biliary sludge or cholelithi-
asis after 4 weeks of continuous enteral tube feeds.72 In addition, Messing and col-
leagues71 found that patients who developed biliary sludge on PN had resolution
after 4 weeks of enteral feeding. Methods to decrease the incidence of biliary sludge
and therefore cholelithiasis formation are challenging but early oral intake should al-
ways be encouraged. Some studies have shown that empiric CCK injections may
reduce biliary sludge by inducing gallbladder contractions.73 However, CCK injections
are not routine practice because of increased rates of flushing, nausea, and
cholecystitis.

Metabolic bone disease


Metabolic bone disease (MBD) was first described in the 1980s after large studies
reported symptoms of bone pain, weakness, hypercalciuria, and hypercalcemia in
long-term HPN patients. Originally, bone biopsies from these patients reported find-
ings of both osteoporosis and osteomalacia.74 MBD remains prevalent in patients
on long-term HPN, with a large survey in Europe showing a prevalence of at least
osteopenia in 84% of participants who had been on PN for an average of 61 months.75
Up to one-third of patients experience symptoms of bone pain, fractures, or weak-
ness, whereas most patients with MBD are asymptomatic. In the early 1980s, MBD
was likely related to increased levels of aluminum in formulations containing casein hy-
drolysate as the primary nitrogen source.76 Decreased serum 1,25-dihydroxyvitamin
D levels, reduced bone formation, and osteomalacia are typical features of aluminum
toxicity. However, MBD persists in long-term HPN patients despite limiting aluminum
by switching to crystalline free amino acid–based PN formulas.77
The pathogenesis of MBD associated with long-term PN is poorly understood and
may be related to various components of PN formulations and the patient’s underlying
risk factors and medical conditions. Sufficient amounts of protein, energy, calcium,
phosphorus, magnesium, and vitamins D and K are needed for adequate bone devel-
opment and turnover. Increased amounts of amino acid in PN formulations in combi-
nation with sulfate, acid, and insulin can cause hypercalciuria and a negative total
calcium balance. PN formulation should have 1:2 calcium to phosphorus ratio with
at least 15 mEq/d of calcium to avoid excessive calcium excretion.78,79 Vitamin D defi-
ciency (as defined by <20 ng/mL of serum 25-hydroxyvitamin D) may be inadequate to
stimulate osteoblast formation as part of the bone remodeling process. Excess
vitamin D may also contribute to MBD because one study showed that removal of
vitamin D from PN formulations had benefits on bone remodeling.80 Current formula-
tions contain 200 IU daily of vitamin D.
Few controlled trials have evaluated strategies proposed to prevent and treat long-
term PN–associated MBD. Patients should be counseled in lifestyle changes to stop
smoking, limit alcohol consumption, and participate in weight-bearing exercise and
careful sunlight exposure. PN formulation should have less than 25 mg/L of aluminum,
the calcium to phosphorus ratio should be less than 1:2, and vitamin D infusion should
be 200 IU/daily. Sodium should be dosed to meet renal, diarrheal, and other nonrenal
losses because excessive infusion can induce hypercalciuria. Amino acid dosing
should be reduced to a maintenance level (1–1.2 g/kg) after patients recover from hos-
pitalization because doses given during repletion (1.5–2.0 g/dL) can induce

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Parenteral Nutrition 55

hypercalciuria as well. Dual energy x-ray absorptiometry scan is the gold standard for
diagnosing osteoporosis and should be performed every 2 years. Vitamin D levels
should be checked if symptomatic bone pain, fracture, or previous diagnosis of oste-
oporosis, osteomalacia, or osteopenia is known.
Renal
Although uncommon, PN-associated nephropathy may occur with long-term PN
characterized by a decrease in creatinine clearance and impaired tubular function
with a potential for glomerular sclerosis. Renal disorders such as hyperoxaluria,
hypercalciuria, and tubular renal defects may occur. Risks for renal dysfunction
include higher amino acid loads, concurrent nephrotoxic drugs, and previous
bloodstream infections.81 Hyperoxaluria and hypercalciuria occur in adult PN pa-
tients but are not directly related to an increased incidence of nephrolithiasis.82
The incidence of hyperoxaluria is probably related to the vitamin C content in PN
formulations.

SUMMARY

PN is a safe and effective means of providing nutrition in patients with intestinal failure
who are unable to tolerate EN or in whom the enteral route cannot be safely accessed.
The optimal timing of PN initiation depends on the level of nutrition risk and should fac-
tor both disease severity and nutritional status. Type and location of the VAD should
be meticulously evaluated based on type of PN, length of therapy, and risk of infection.
Measures should be taken to minimize risk of infection, and thromboembolic and me-
chanical complications associated with the VAD. Initiation of PN should typically occur
in the hospital setting to allow for close monitoring of fluid and electrolyte status and
glucose control. Metabolic complications associated with long-term use of PN may
include MBD, renal disease, and hepatobiliary disease. A multidisciplinary team of
experienced clinicians is recommended to promote safe use of PN and minimize
risk of complications.

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