Intestinal failure and parenteral nutrition and how to avoid them

There is a common misconception that serum albumin is an appropriate indicator of nutritional status, and it is often used by clinicians as the sole marker for malnutrition. This can influence a clinician’s decision to refer patients for PN.

Hypoalbuminaemia is common in hospitalised patients as serum albumin levels are influenced by acute and chronic illness, systemic inflammation and multiple other factors.^3,4

During periods of acute inflammation, hepatic production of both albumin and prealbumin is markedly reduced while the production of proteins such as C-reactive protein (CRP) increases. During this acute inflammatory phase, hepatic protein synthesis shifts from intrinsic hepatic proteins to acute-phase proteins and as a result, albumin and prealbumin are downregulated.

Several other interactions and processes can contribute to low levels of albumin during inflammation: 

• Increased capillary permeability leads to an escape of serum albumin from the intravascular to the extravascular compartments. As a result, albumin half-life is shortened.⁵
• Increased albumin losses in the gastrointestinal (GI) tract, known as protein-losing enteropathy, and loss from the renal tract due to nephrotic syndrome or chronic kidney disease.⁶

Low serum albumin and prealbumin levels are seen with all systemic inflammation, regardless of aetiology and nutritional status. As a result, serum albumin and prealbumin levels should not be used as markers of nutritional status but as markers of inflammation.^7,8 Indeed, normal albumin levels are often found in extreme cases of undernutrition, such as in patients suffering from advanced anorexia nervosa. Guidelines from ESPEN⁹ now categorically state that albumin should not be used as a nutritional marker.

The assessment of micronutrients is vital in monitoring patients receiving PN. Interpretation of levels, however, can be difficult and is influenced by the acute phase response. This systemic inflammatory response is a series of metabolic changes that occur in the body in response to infection, surgery or trauma,¹⁰ situations often associated with patients requiring PN. This response can lead to significant changes to plasma levels of various micronutrients that are not necessarily indicative of nutritional status.

When serum CRP levels exceed 20 mg/L, the impact of inflammation becomes notable.¹¹ During active inflammation, serum concentrations of iron, zinc, selenium and vitamin A typically decrease while copper and ferritin concentrations increase.¹² These changes are due to the redistribution of their binding proteins, which includes albumin for zinc,¹³ and increased tissue uptake rather than reflecting true deficiency and are summarised in Table 1. Other micronutrients, including vitamin B12 and folate, are not influenced by the inflammatory response and, therefore, low serum concentrations likely indicate true deficiency.

Table 1 | Effect of acute phase response on micronutrient blood/plasma levels.^11–13

PN formulations are a complex admixture. As with any medication, the patient’s allergy status must always be checked before prescribing PN. PN lipid solutions can contain common food allergens such as soybean oil, fish oil, peanut protein and egg phospholipids, depending on the product.^14,15 Additional factors, including religious requirements or dietary preferences, such as vegetarian, kosher, or halal, may also affect the suitability of components in the PN formulation. For such considerations, individual advice should be sought directly from the manufacturer.

Most multi-chamber bags containing lipids are composed of egg lecithin and are, therefore, unsuitable for vegans or those with an egg allergy. The extent of the allergic reaction needs to be considered, and this can be mitigated by changing PN prescriptions to lipid-free formulations. Patients with a fish allergy should not receive lipid formulations containing fish oil.

Summaries of product characteristics for individual formulations should be checked before prescribing these to patients. Table 2 highlights allergens commonly found in PN products.

Recommendations as to which PN product should be avoided in case of a given allergy. *There is a known risk for cross-reactivity between those allergic to peanut protein and soy protein.¹⁶ If the patient has already received soybean oil from propofol with no observed reaction, the lipid can usually be given after discussing this with the medical team.

Table 2 | Recommendations as to which PN product should be avoided in case of a given allergy. *There is a known risk for cross-reactivity between those allergic to peanut protein and soy protein.¹⁶ If the patient has already received soybean oil from propofol with no observed reaction, the lipid can usually be given after discussing this with the medical team.

Careful consideration of fluid balance is crucial in patients with IF because of altered fluid absorption and/or fluid loss.

Over-administration of IV fluids, particularly 0.9% sodium chloride, is a common cause of fluid overload and oedema. Inappropriate IV fluid prescription practices are unfortunately common and contribute to patient morbidity and mortality.¹⁷ This can occur when patients continue to receive IV fluid infusions despite the commencement of PN, which also contains sodium and water. The PN prescription ordered may have been prescribed to meet the patient’s full fluid requirements. It is, therefore, imperative to consider the constituents of the PN prescription before prescribing IV fluids. If additional IV fluids are required, recognising the patient’s GI losses in addition to baseline requirements is essential. Table 3 highlights daily baseline electrolyte requirements.^18,19 Table 4 shows the electrolyte content of GI losses that may need to be replaced.²⁰

Table 3 | Baseline daily electrolyte requirements^18,19

Table 4 | Sodium and potassium concentrations in GI secretions

Patients receiving PN frequently require additional IV fluids and medications. If these are administered simultaneously through the same central venous catheter (CVC) as the PN, it is important to consider whether the ingredients of the PN and the second IV preparation interact with one another.

If a CVC has multiple lumens, infusions administered simultaneously do not mix within the catheter. This is because each lumen exits the catheter at a different point along its length and the IV solutions administered through the individual lumens are rapidly diluted by the fast-flowing bloodstream. However, caution is still advised with IV medications. For example, ceftriaxone should not be simultaneously infused with calcium-containing solutions due to the risk of precipitation, even if administered via separate lumens in one line.^21,22

If a CVC has a single lumen, a ‘Y-site’ connector/giving set is required to run two preparations simultaneously via the catheter. At the Y-site, the two infusions will mix before entering the CVC, meaning the ingredients of the various preparations can interact with one another. Information on the compatibility of the different solutions administered is critical in this situation.

This information is not always readily available, and if no information can be obtained, co-administration of two infusions via a Y-site should be avoided. It is usually possible to obtain information regarding the compatibility of PN with other IV fluid preparations and commonly used medications on request from PN manufacturers. Locally written guidelines may also contain information. It is always advisable to seek input from a specialist pharmacist regarding fluid compatibility and a clinician with line knowledge is vital to ensure safety.

Catheter-related blood stream infection (CRBSI) refers to a bacteraemia accompanied by clinical signs of sepsis, originating from an IV catheter. IV nutrition solutions are an ideal growth medium for microorganisms, and CRBSI is a feared complication in patients requiring PN since it can lead to severe morbidity.¹ Patients with CRBSI can deteriorate rapidly hence prompt diagnosis and treatment are essential.

Recognising CRBSI

Fever and rigors, especially within 30–60 minutes of starting PN infusions, are highly suggestive of CRBSI. However, patients can also present with non-specific symptoms or signs such as headache, malaise, jaw and shoulder pain, deranged liver function tests and hypoalbuminaemia.^1,23 If any of the above symptoms are reported, patients must seek medical support urgently. If a CRBSI is suspected, paired blood cultures should be taken, one from a peripheral vein and one from the catheter hub.¹

Diagnosing CRBSI

The CRBSI definition proposed by ESPEN is based on the criteria of the Centers for Disease Control and Prevention (CDC). CRBSI is defined by a “positive culture of the catheter (on removal), or paired blood cultures from a peripheral vein and the catheter (when left in place) with isolation of identical organisms (both species and antibiograms) from cultures of catheter segments and blood drawn from a peripheral vein in a patient with clinical symptoms of sepsis and the absence of another source of infection.”¹

Quantitative and/or qualitative microbiological analysis of the blood sample should be used to diagnose CRBSI. In quantitative analysis, CRBSI can be diagnosed using pour plates when colony counts from the catheter hub blood sample are at least three times higher than the colony count from the peripheral blood sample.²⁴ When using qualitative analysis, differential time to positivity should be used. A diagnosis of CRBSI is made when blood from the catheter hub demonstrates microbial growth at least 2 hours earlier than growth detected in blood collected simultaneously from a peripheral vein.²⁵

Management of CRBSI

Empirical antibiotics should initially provide cover for both Gram-positive and Gram-negative bacteria. These should be administered via a peripheral catheter. Once blood culture results are available, systemic antibiotics based on sensitivities should be administered.²⁶

Catheter salvage is generally not recommended if the patient is clinically unstable and/or has a CVC tunnel or cuff infection, metastatic infection, fungal infection or septic thrombosis – in these circumstances, the central line should be removed. Sometimes, it is possible to treat the infected line and leave the catheter in place. A targeted antibiotic lock should be used for catheter salvage if the central line is not removed. Antibiotic line lock therapy involves instilling a high concentration of an antibiotic to which the causative microbe is susceptible in the catheter lumen, thereby eradicating the present bacterial biofilm. According to ESPEN, a 14-day duration of the antibiotic lock is recommended.^1,27 However, local guidance may vary. A strict aseptic technique is critical whilst accessing a central line for not only PN but also drug administration, blood sampling and administration of IV fluids to avoid CRBSI.

Fluid prescribing during line sepsis treatment

It is important to consider the patient’s usual PN prescription and current IV requirements. The usual prescription should be used as a base when prescribing IV fluids and electrolytes. These must be administered via a peripheral catheter, the central line used for PN should not be used during this time, and PN should not be administered.

Abnormalities of liver function tests (LFTs) are common in adults receiving both short-term and long-term PN but are often not caused by PN. There are many contributors to abnormal LFTs in patients with IF who require PN. The aetiology of liver disease is often multifactorial, relating to both nutritional and non-nutritional factors.

Non-PN causes of acutely deranged LFTs

In patients receiving short-term PN, impaired liver function is usually temporary. Exacerbations of pre-existing liver disease, which can occur in up to one-third of patients on PN, should be considered. Common causes include alcohol-related liver disease, chronic viral hepatitis and metabolic dysfunction-associated steatotic liver disease.

Infection, of any aetiology, is a common cause of abnormal LFTs in patients receiving PN. Deranged LFTs occur in 34–46% of patients receiving PN developing an infection of any kind.^28,29 Thus, every effort should be made to check for infection in patients receiving PN with abnormal LFTs. In a study³⁰ looking at patients who developed abnormal or worsening LFTs on PN, the cause was thought to be infection in 46% of cases.

Medications, such as antibiotics and antifungals, can also affect liver function. Reviewing all prescribed drugs is essential to identifying possible drug-related causes of LFTs.

Non-PN-related causes of chronic deranged LFTs

Non-PN-related factors of chronic deranged LFTs include short residual gut length, specifically ultra-short bowel (defined as ≤20 cm residual small bowel length from the duodenojejunal flexure) and the absence of a colon.³¹ Frequent CRBSIs, small intestinal bacterial overgrowth^32,33 and prolonged lack of enteral nutrition¹ can also lead to chronic deranged LFTs.

PN-related causes of acute deranged LFTs

Excessive overfeeding can lead to the development of liver disease. Excess parenteral glucose and infusion rates exceeding the maximum glucose oxidation rate can result in steatosis by stimulating insulin release and inhibiting fatty acid oxidation.³⁴ Excess lipid infusion can also result in hepatic complications due to the inability of the liver to clear phospholipids and fatty acids, leading to an accumulation of lipids within liver cells.³³

PN-related causes of chronic deranged LFTs

Liver disease can be a major consequence of long-term PN and chronic IF. As highlighted above, this is more likely to occur with prolonged use of PN, especially when delivering first-generation soybean-based lipid emulsion exceeding 1 g per kg of body weight per day.³² New lipid preparations, including second-generation (medium to long-chain triglycerides and monounsaturated fatty acids) and third-generation (fish oil-based) mixed lipid emulsions, may be associated with less hepatotoxicity.^35,36

Deficiencies in nutrients such as choline, taurine and carnitine have also been associated with hepatic abnormalities.^1,37 Conversely, excessive intake of nutrients, including copper and manganese, can lead to their accumulation in the liver, causing hepatotoxicity.¹

The aetiology of liver disease is often complex and multifactorial, impacted not only by PN but also by patient and nutritional factors, as depicted in Figure 1. For patients in this setting who are diagnosed with liver disease, this is referred to as IF-associated liver disease (IFALD). Strategies to minimise the risk of IFALD should be initiated, when possible, in all patients dependent on PN, as outlined in Table 5. IFALD can lead to fibrosis, cirrhosis and end-stage liver failure. Once this has developed, treatment options are limited, and an intestinal or combined liver/intestinal transplantation remains the only viable option.

Figure 4 | Factors associated with the aetiology of IFALD. Adapted from Gabe and Culkin, 2010.³³

Table 5 | Management of IF-related liver disease

Micronutrients are essential components of PN, and serious complications can result from vitamin and trace element deficiencies. Assessing each patient individually is crucial, taking into account the original indication for PN. With more and more off-the-shelf multi-chamber bags being used without the addition of vitamins and trace elements – separate IV infusions are often prescribed, which results in additional connections and can be onerous.

Many micronutrients are absorbed in the proximal small bowel and, consequently, patients may be able to absorb oral vitamins and trace elements.

Monitoring is essential to ensure the absorption of micronutrients to avoid deficiencies. Figure 2 outlines the key GI sites for absorption.³⁸

Figure 2 | Sites of absorption of micronutrients from the GI tract. Adapted from BAPEN 2017 (BIFA position paper).³⁸

HPN can be challenging for patients and can significantly impact patients’ and families’ quality of life (QoL). Since severe fatigue has been reported as one of the most frequent complaints, in up to 63% of HPN patients,³⁹ it is important to consider what can be done to minimise this. Giving patients, whenever feasible, a night off PN can help enhance QoL by facilitating uninterrupted sleep, instilling a sense of normality and allowing a night away from home without having to take PN and all the necessary equipment. This may be particularly beneficial for younger patients in employment. This can be achieved by maximising nutritional delivery and fluid in 5 or 6 bags instead of 7 whilst considering the tolerance and complications of the HPN regimen. IF centres should have a regular review process to identify those patients and alter PN prescriptions as necessary.

PN is a lifesaving treatment that improves survival in patients with chronic IF. Despite advances in PN, HPN is time-consuming and can impair everyday life by restricting social interactions, disturbing sleep and hindering patients from leaving their homes.⁴⁰ In addition, it is associated with a range of serious complications, including CRBSI, complex technological support issues, electrolyte abnormalities, cramps and oedema.

The challenge of balancing lifesaving HPN and its complications with severe underlying diseases affects patients’ QoL.⁴¹ Counselling patients and their families on the impact of PN, including potential complications prior to discharge home, is essential to prepare patients for the challenge of living with HPN. Education should allow patients to regain autonomy and independence, thus improving QoL.⁴² ESPEN recommends that QoL should be part of nutrition therapy monitoring.⁹ Patients should also be signposted to patient support groups where available.

The use of PN in patients with advanced cancer is increasing.⁴³ There is, however, significant international variation in the use of HPN in this patient group. For example, in Italy, Belgium, the USA and Canada, more than 50% of all HPN prescriptions are for patients with advanced cancer, whereas Denmark and the UK report a prevalence of 25% or less.⁴⁴

The provision of palliative PN can be considered controversial as it prolongs survival and can result in complications and hospital admissions. More prospective studies are required to show if HPN improves QoL or survival in patients with malignant bowel obstruction.

A British Intestinal Failure Alliance position statement⁴⁵ highlights that although PN may not improve nutritional status in advanced disease, the benefit can be seen in terms of QoL (including improved hydration, energy levels and general well-being) and increased life expectancy. This may allow patients to achieve personal goals, including spending time with family, putting their affairs in order, achieving a personal ambition or attending an event.⁴⁵

All patients with advanced cancer considered for HPN should have an early MDT review by the nutrition team, oncologists and palliative care teams. The decision to start HPN in patients with advanced malignancy requires careful consideration, taking into account all the below aspects on an individual basis:

• Prognosis
• Benefits of potential treatment
• Nutritional status
• Potential effect of PN
• Risks and burdens versus benefits of PN
• Cachexia
• Wishes and expectations of patients and relatives

Discussions with patients and family should include the aim of starting PN, monitoring plans, frequency of blood tests and advance care planning, including the options for withdrawing HPN towards the end of life. It is important to note that in the last days of life, continuing PN may cause more discomfort than benefit.

To summarise, IF is a complex condition which requires multi-disciplinary and specialist input. PN can be provided safely and efficiently when healthcare professionals are equipped with the appropriate knowledge and skills to prescribe and manage PN. This article addresses various aspects and misconceptions about PN. Key take-away messages include the importance of an MDT approach to provide safe and high-quality care, that IF management should be individualised for each patient and that detailed communication is essential to empower patients to enhance their QoL whilst receiving this complex treatment.