Review article: the management of long-term parenteral
`
`nutrition
`
`M. Dibb, A. Teubner, V. Theis, J. Shaffer & S. Lal
`
`Intestinal Failure Unit, Saliord Royal
`Foundation Trust, Salford, UK.
`
`SUMMARY
`
`Correspondence to:
`Dr M. Dibb, Department of
`Gastroenterology, Royal Liverpool
`University Hospital, Prescott Street,
`Liverpool L7 8><P, UK.
`E—mai|: rnartyn.dibb@nhs.net
`
`Publication darta
`
`Submitted 8 May 2012
`First decision 8 June 2012
`Resubmitted 4 December 2012
`Accepted 21 December 2012
`EV Pub Online 17 January 2013
`
`This commissioned review article was
`subject to full peer~review.
`
`Background
`Home parenteral nutrition (HPN) is currently the management of choice for
`patients with chronic intestinal failure.
`
`
`
`Methods
`
`A literature search using PubMed and MEDLINE databases was performed.
`
`Results
`
`Safe delivery of HPN relies upon individualised formulations of parenteral
`nutrition administered via carefully maintained central venous catheters by
`trained patients or carers, supported by a skilled multidisciplinary team. Early
`diagnosis and treatment of complications including catheter—associated blood
`stream infection (reported incidence 0.14-0.83 episodes/patient-year on HPN)
`and central venous thrombosis (reported incidence 0.03 episodes/patient—year)
`is important to minimise mortality and morbidity. There is a significant varia-
`tion in the reported incidence of both hepatobiliary complications (19—75%)
`and advanced liver disease (0—50%). Five—year survival rates in large centres are
`reported between 60% and 78% with survival primarily related to underlying
`diagnosis. Long-term survival remains higher on HPN than with intestinal
`transplantation. The role of intestinal lengthening procedures is yet to be vali-
`dated in adults.
`
`
`
`
`
`
`
`Aliment Pharmacol Ther 2013; 37: 587-603
`
`NPS EX. 2165
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`© 2013 Blackwell Publishing Ltd
`doi:10.1l11/apt.12209
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`M. Dibb et al.
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`INTRODUCTION
`
`Parenteral nutrition (PN) was first pioneered in the late
`1940s for patients intolerant of, or not receiving adequate
`nutrition via the enteral route." 2 This was an essential
`
`medical development, as it had been recognised, over a
`decade earlier,
`that malnutrition was associated with a
`
`poor clinical outcome.3 As practice evolved, an increasing
`number of malnourished patients received PN in the hos-
`
`pital setting, and it was not until the 19705 that patients
`could be managed at home on a long-term basis.4
`Currently, PN has become the mainstay of managing
`patients with intestinal failure (IF), a term first coined in
`
`1981 as ‘a reduction in the functioning gut mass below
`the minimal amount necessary for adequate digestion
`and absorption of nutrients’.5 IF can be further subclassi—
`fied into three types to take into account the duration or
`severity of the disease process“:
`
`IF is self-limiting IF that occurs following
`Type 1
`abdominal surgery, whereby patients require fluid, elece
`trolyte, enteral and/or parenteral nutritional support for
`a limited period of time, before making a full recovery
`without complication.
`
`Type 2 IF occurs in severely ill patients, who develop
`septic, metabolic and nutritional complications following
`gastrointestinal surgery. These patients need multidisci-
`plinary input and nutritional support to permit recovery.
`Type 3 is chronic IF requiring long-term nutritional
`support; usually home parenteral nutrition (HPN), but
`
`also surgical procedures such as intestinal
`and transplantation.
`
`lengthening
`
`the recent National
`IF is relatively common:
`Type 1
`Confidential Enquiry into Patient Outcome and Death
`(NCEPOD), into the care of hospital patients receiving
`PN support, identified that 93% of patients in hospitals
`throughout the UK received PN for <30 days, with the
`majority of these patients needing nutritional support as
`a result of postsurgical complications.7 By contrast, and
`fortunately, the more severe types 2 and 3 IF are less
`
`common. The annual British artificial nutrition survey
`(BANS) reported that 624 adult patients with IF were
`receiving HPN in 2010.“
`
`METHODS
`
`short bowel syndrome AND trophic factors/GLP-2, IGF-
`I, EGF, (total) parenteral nutrition AND central venous
`linelcatheterl (total) parenteral nutrition AND line/ cath-
`
`eter sepsislthrombosisl mechanical complicationsl prob-
`lem,
`(total) parenteral nutrition AND outcomelweanl
`
`quality of life/survival, fistuloclysis, intestinal adaptation,
`autologous intestinal reconstruction AND Bianchi/ STEP.
`
`Long-term parenteral nutrition was defined as a period
`of >3 months.
`
`INDICATIONS FOR LONG-TERM PN
`
`A significant proportion (around 50%) of patients with
`type 2 IF will go on to develop type 3 IF and require
`long—term PN.6 Some patients will develop type 3 IF de
`novo without preexisting type 2 IF; for example, patients
`with dysmotility (e.g.
`systemic sclerosis) or radiation
`enteritis, who have not undergone previous intestinal sur-
`gery, may become dependent on HPN after a prolonged
`period of nutritional impairment that cannot be managed
`via the enteral route. In the UK, Crohn’s disease, intesti~
`
`nal ischaemia and surgical complications account for the
`
`bulk of underlying pathologies of patients requiring HPN
`(Figure I).9 Data from other European and Canadian
`centres would seem to suggest similar aetio1ogies,1°‘ ”
`whereas a diagnosis of cancer forms a principle indication
`for HPN in the USA (42%) and Iapan (40%).”- ‘3
`Patients with active cancer received PN for the indica—
`
`tions of malignant small bowel obstruction, short bowel
`syndrome or high output fistulae.”
`
`PARENTERAL NUTRITION FORMULATIONS
`
`Parenteral nutrition requirements — protein, calories,
`electrolytes, vitamins and micronutrients and fluid — are
`
`tailored to the individual patient’s need. Historically, PN
`feeds consisted of multiple bottles of different nutrients,
`
`with trace elements added as necessary to minimise deg»
`radation or precipitation; this meant that the patient had
`to connect multiple bottles of PN per day.” Modern
`nutritive mixtures can now be compounded in single
`bags (called ‘all-in—one’) or, sometimes, in ‘bipartite’ bags
`(the second compartment for a lipid emulsion is opened
`and mixed with other compounds before infusion). PN
`formulations contain both essential and non-essential
`amino acids with a reduced infusion volume achieved
`
`A PubMed search was performed looking for English
`language only papers. The following search terms were
`used alone or in combination:
`(total) parenteral nutri~
`tion,
`(T)PN,
`intravenous nutrition,
`(total) parenteral
`nutrition AND hepatic/liver/bone/renal/metabolic com-
`
`using amino acids with nitrogen contents above 18 g/L.
`The primary energy source in PN formulations can be
`
`derived either from a combined carbohydrate and fat
`emulsion administered together or from separate glucose
`and fat PN formulations administered on different
`
`plications,
`
`intestinal
`
`failure,
`
`intestinal
`
`transplantation,
`
`days.“/’
`
`588
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`Review: |ong—term parenteral nutrition
`
`‘
`
`n 2000
`D 2010
`
`Percentageofpatients
`
`
`
`Lipid emulsions were initially from soybean oil, which
`contains relatively high levels of omega—6 essential fatty
`acids and may be associated with hepatotoxicity (see
`below).17 Newer preparations containing long and med-
`ium chain triglycerides with a more physiological balance
`of omega 3 and 6 fatty acids have since been created.”
`An example of such a preparation is SMOFlipid, an emul-
`
`sion containing soya bean, medium chain triglycerides,
`olive and fish oil, yielding an improved ratio of omega 3
`and 6 fatty acids, which, in the acute, post-operative set-
`
`ting, has been associated with a better hepatic tolerance
`and reduced length of hospital stay. 19 Further evidence is
`needed to assess the advantages and disadvantages of
`alternative lipid emulsions in longer term HPN.
`
`Electrolytes can be delivered either in commercially
`available carbohydrate and amino acid solutions or may
`be added to PN formulations to meet individual require-
`
`ments. Commercial preparations of appropriate amounts
`of trace elements and multivitamins can also be added to
`
`lipid, glucose or electrolyte preparations. Drug additions
`are not recommended given the complexity of PN solu-
`
`tions, although heparin is sometimes added to glucose-
`based PN formulations to reduce the thrombogenic risk
`of hyper-osmolar solutions.” 2'
`
`Aliment Pharmacol Ther 2013; 37: 587-603
`© 2013 Blackwell Publishing Ltd
`
`Stability and storage
`
`Stability of the PN formulation is paramount, as degra-
`dation of components can result
`in lack of sufficient
`nutrient provision or even in the production of poten-
`tially
`toxic degradation products. PN formulations
`should be designed to minimise the risk of precipitation,
`destabilisation and degradation. Precipitation may be
`affected by solution pH, type of amino acids and phos-
`phates, trace element concentrations and temperature.“
`Once compounded,
`the stability of the PN solution is
`prolonged significantly by refrigeration.” Fat emulsions
`can also be destabilised by the addition of electrolytes,
`which may neutralise the negative charge on the emul-
`sion surface, leading to precipitation and creation of a
`cream layer.” Furthermore, lipid emulsions are thermo-
`dynamically unstable; destabilisation of lipid emulsions is
`characterised by formation of increasing sizes of lipid
`
`droplets and sizes above 5 pm may lead to embolic com-
`plications.23 Therefore, PN mixtures should be visually
`inspected for lipid emulsion coalescence, as well as cal-
`cium phosphate precipitates, prior to use.21
`The addition of vitamins to PN mixtures may acceler-
`
`ate chemical degradation, including vitamin C oxidation,
`vitamin B1 reduction and vitamin A and E photodegrada-
`
`589
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`
`M. Dibb et al.
`
`tion, each of which will reduce shelf life.“ Because of this,
`some patients will opt to add vitamins themselves to their
`
`HPN bags immediately before use, to increase their PN
`
`bag shelf life and reduce the frequency of PN deliveries to
`their homes. Vitamin C oxidation can be minimised using
`ethyl vinyl multilayered bags, which prevent oxygen
`influx,” whereas photodegradation can be minimised by
`covering bags and giving sets
`from sunlight and/or
`administrating HPN at night and away from windows.24
`
`Timing and frequency of PN infusion
`
`The amount of intravenous energy and protein that a
`patient requires is determined by a number of factors,
`such as body mass index and metabolic rate, and is bal-
`
`anced against any nutrition that the patient may absorb
`via the oral or enteral route. Most patients will eat as
`much as their disease or their faecal
`losses will allow.
`
`Fluid and electrolyte requirements, on the other hand,
`are principally determined by gastrointestinal losses. The
`patient with a high output proximal small bowel stoma
`or
`fistula will have excessive fluid losses and such
`
`patients usually have to receive nightly intravenous infu-
`sions. On the other hand, the patient who still has his/
`
`her colon in continuity with small bowel will usually
`have lower intravenous fluid requirements due to the
`ability of their colon to absorb water and electrolytes
`and consequently will be able to have at least one night/
`week without the need for PN.
`
`Shorter infusion durations are associated with lower
`
`rates of thrombophlebitis in animal models“ and shorter
`infusion periods may, of course, also improve patients’
`quality of life (QOL). Consequently,
`infusion times are
`reduced to the minimum tolerated and interference with
`
`daily living limited by nocturnal administration where
`possible.
`
`INTRAVENOUS FEEDlNG CATHETERS
`
`Establishing a suitable and reliable long-term intravenous
`feeding catheter is imperative for HPN delivery. Expert
`practitioners achieve best safe catheter insertion in an
`
`aseptic environment. Image guidance with real time ultra-
`sound has been shown in several meta—analyses to be
`associated with both reduced procedure failure rates (RR:
`
`0.14-0.32) and reduced complication rates (RR: 0.22) and
`is recommended by the National Institute of Clinical
`Excellence.27’3" Around 2% chlorhexidine is preferred for
`skin preparation prior to procedure as this demonstrated
`lower catheter—related infection rates (2.7 per 100 cathe—
`ters) than either alcohol— or iodine-based solutions (7.1
`and 9.3 per 100 catheter insertions P = 0.02).“ There is
`
`590
`
`currently no evidence to support the use of preprocedural
`antibiotics. A meta-analysis of five RCTs and 530 catheter
`insertions has demonstrated an increased risk of blood-
`stream infections in catheters with more than one lumen
`
`(odds ratio, 2.58; 95% CI, 1.24-5.37; number needed to
`
`treat, 19); therefore, most centres would advocate single
`lumen catheters where possible.”
`
`Vascular access
`
`Achieving long—term vascular access requires placement
`of a central venous catheter (CVC) in either the subcla-
`vian or internal jugular vein.” CVCs are usually placed
`using the Seldinger technique, positioning the catheter
`tip between the lower third of the superior vena cava
`and the atrio-caval junction, a site that is associated with
`a lower incidence of venous thrombosis (P 3 0.00O5).33
`
`tunnelled or implanted subcutaneously
`CVCs are best
`for long—term use to minimise the risk of displacement:
`‘Hickman’ or ‘Broviac’ single lumen CVCs are tunnelled
`subcutaneously to an external site and secured in place
`with an internal cuff, while ‘portacaths’ are implanted
`and terminate in a subcutaneous reservoir. The choice
`
`between tunnelled lines and ports will be determined by
`patient choice and nursing staff experience: ports will
`certainly be less attractive if the patient requires frequent
`access due to the repeated skin puncture required.”
`Peripherally inserted central venous catheters (PICCS)
`and peripheral midline catheters are also used for PN
`
`administration, but the higher risk of displacement and/
`or thrombosis inherent to these lines usually limits their
`use to 2-3 months.34’ 35 Furthermore, PICC lines also
`
`tend to be unsuitable for long—term HPN as patients find
`them difficult to self—access as they are sited in the an-
`ticubital fossa or upper arm. Some practitioners advocate
`the use of arteriovenous fistulae to administer long-term
`PN, with recent experience suggesting very low infection,
`but high occlusion rates.“
`
`When standard neck central venous access approaches
`have failed due to venous thrombosis and/or stenosis,
`
`the femoral approach can be considered although the
`risk of bacterial contamination is high.” Beyond this,
`translumbar,
`transhepatic
`and
`transcardiac
`catheter
`placements have been described.” 39 Patients with
`threatened loss of vascular access should be considered
`
`early for intestinal transplantation (ITx) as loss of access
`may preclude ITx.
`
`Catheter care
`
`Aseptic care of CVCS for patients with IF is mandatory.
`Any patient with type 2 IF requiring PN could progress
`
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`
`IF, and therefore maintaining sustainable
`to type 3
`venous access is vital. Stringent adherence to catheter
`care protocols reduces CVC sepsis and thrombosis, so
`prolonging CVC viability.“ These protocols are key to
`the success of all HPN programmes.
`
`Catheter training and care exemplifies the importance
`of the multidisciplinary IF team, with the patient at the
`centre, in achieving a successful HPN programme. The
`
`core of any IF team consists of medical doctors with an
`interest in nutrition, nursing staff with extensive experi-
`ence of PN, dieticians and clinical pharmacists.” In
`addition,
`the team receives dedicated input from psy-
`
`ther-
`chology, biochemistry, microbiology, occupational
`and
`apy
`and physiotherapy
`colleagues. Telephone
`videoconferences have been explored as ways of stream-
`
`lining lines of support for patients and their carers to
`ensure that catheter care is optimised.‘“’ 42 Limited avail-
`able evidence from retrospective studies suggests that PN
`management by dedicated teams with clear management
`protocols is associated with lower catheter complications
`rates and perhaps lower overall costs.43“45
`
`COMPLICATIONS OF LONG—TERM PN
`
`Catheter-related problems
`
`Catheter infection. Central Venous catheter-related sepsis
`
`rates are a surrogate measure of overall quality of cathe-
`ter care.45 Complications in patients with type 3 IF can
`be
`devastating with
`sepsis-related mortality
`being
`reported to be as high as 30% in one French series, half
`of which originate from infected CVCs.46 CVC-related
`sepsis rates have recently been variably reported as 0.14-
`0.83 episodes/patient—year.47’5'
`As outlined above, maintaining low sepsis
`
`rates
`
`requires careful catheter care protocols, with multiple
`studies reiterating the importance of a multidisciplinary
`nutrition support
`team in reducing CVC-related sep-
`sis.45’ 52434 The patient is key to minimising CVC-related
`sepsis rates at home. While patients accessing their line
`
`more frequently during the week may be at higher risk
`than those who receive PN less
`frequently,55 with
`approximately 20% of patients on HPN are responsible
`for around 75% of the total number of CVC-related sep-
`sis episodes.47 It remains to be seen if this increased risk
`is in part linked to the bacterial skin and/or nasal eco-
`system and/or
`to patient behaviour.“ Antimicrobial
`(taurolidine)
`flush solutions and antibiotic lock tech-
`
`niques have been proposed for patients with recurrent
`CVC infections.57‘ 58 A recent randomised study of 30
`patients found taurolidine lock to be highly effective in
`
`Aliment Pharmacol Ther 2013; 37: 587-603
`© 2013 Blackwell Publishing Ltd
`
`Review: long-term parenteral nutrition
`
`reducing subsequent CVC infection with a mean infec-
`tion—free survival of 175 days compared with 641 days
`with
`the
`introduction
`of
`taurolidine
`locks
`
`locks should
`(P 2 O.0001).59 The use of antimicrobial
`not, however, be considered a substitute for meticulous
`catheter care.
`
`Patients with CVC infections usually present with
`
`symptoms and signs such as pyrexia and tachycardia dur-
`ing infusion. However, this may not always be the case
`and a high index of suspicion for CVC sepsis is required
`in a patient with IF who may display other features of
`infection; in a retrospective case series of 37 line infec-
`tions, 13/37 episodes of catheter-related sepsis did not
`
`present with a pyrexia and; while most patients displayed
`an elevated C-reactive protein,
`less than a third had a
`raised blood white cell count.“ Other pointers to CVC-
`related sepsis may be a low albumin or raised bilirubin.°°
`As catheter maintenance is crucial to HPN patients and
`
`repeated catheter removal/re—insertion can lead to loss of
`venous access, it is recommended to attempt salvage of an
`infected tunnelled CVC wherever possible.” Clearly, if the
`patient
`is too unwell with CVC-associated sepsis with
`signs of shock,
`then the catheter should be removed
`immediately. Otherwise,
`if CVC-related sepsis is sus-
`pected, then line use should be discontinued and periph-
`eral and central cultures taken while antimicrobial therapy
`
`(as per local policy) is commenced pending culture results.
`A recent systematic review demonstrated that Coagulase
`negative Staphylococcus, S. epidermis epidermis or other
`staphlococci was the causative agent in 378/759 (50%) epi-
`sodes of CVC-associated sepsis, with Staphylococcus aur-
`gram- negative
`eus,
`and
`polymicrobial
`infections
`accounting for
`the majority of the remainder.“ 60762
`Small retrospective studies have shown that catheter sal-
`
`vage can be obtained in up to 95% of CVCs in the context
`of a coagulase-negative staphylococcal
`infection using
`standard antibiotic protocols, compared with 65% of cath-
`eters infected with other organismsfifl Catheter salvage is
`rarely, if ever, possible in the presence of fungal line sepsis.
`Catheter infection is not limited to the catheter lumen,
`but can occur within the catheter exit site and/or subcu-
`
`taneous tunnel. Exit site infections manifest as erythema,
`tenderness and sometimes discharge and can usually be
`
`successfully treated with a combination of systemic anti-
`biotics
`together with antimicrobial dressings. Tunnel
`infections, however, usually require line removal.
`
`Catheter occlusion
`
`Central venous catheters may be occluded by fibrin and/
`
`or lipid deposits, with an incidence in the HPN population
`
`591
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`
`M. Dibb et al.
`
`of 0.07 episodes/year.55' 63 Such deposits often act as a
`one—way valve allowing PN infusion, but preventing
`blood withdrawal. Complete occlusion can result
`if a
`
`sluggish line remains unattended, often necessitating line
`removal.“ Fibrin occlusions can be resolved by locking
`the catheter with urokinase or recombinant tissue plas-
`minogen activator,“ 67 while lipid occlusions can be
`minimised by flushing the CVC with saline before and
`
`after lipid infusion and treated, once developed, using a
`70% ethanol
`line
`lock.“ Endoluminal brushing of
`occluded CVCs has been shown to be more effective at
`
`catheter clearance then urokinase locks, although these
`brushes are no longer available in the UK.“
`
`Central venous thrombosis
`
`Catheter-associated central vein thrombosis may occur at
`a rate of between 0.01 and 0.03 episodes per catheter
`year,“ 69’ 7" and is positively correlated with CVC-
`related sepsis episodes.“ There is no clear evidence that
`
`all patients requiring HPN should receive prophylactic
`anticoagulation to prevent
`line thrombosis, unless at
`underlying high risk.” 72‘74 The role of heparin flushes
`to prevent catheter-related thrombosis remains unclear,
`
`and may be associated with an increased risk of line
`
`infection; furthermore, long-term heparin administration
`carries the inherent risk of osteoporosis and hair loss, as
`well as the risk of lipid precipitation if mixed with a
`
`lipid emulsion — therefore, currently saline flushing is
`recommended. ' 6
`
`Patients with diagnosed venous thrombosis may be
`considered for thrombolytic therapy or thrombectomy if
`diagnosed early and all patients should be screened for
`thrombophilic risk and receive anticoagulation therapy
`(low molecular weight heparin or warfarin depending on
`the patient’s intestinal absorptive ability).4° If venous
`thrombosis is associated with CVC sepsis, then the line
`will likely have to be removed; otherwise, the decision to
`
`remove the catheter depends on patency: if intravenous
`infusion is impossible or induces pain or swelling, then
`the nonfunctioning catheter has to be removed, but
`if
`flow is unimpeded,
`the catheter can be maintained as
`
`CVC lifespan will not necessarily be impaired if the
`patient is anticoagulated.”
`
`Mechanical problems
`
`Mechanical problems due to catheter displacement or
`fracture can lead to malfunction. This can be assessed
`
`using a radio—opaque dye study and salvaged by reposi-
`tioning or repair.” Tunnelling catheters cuffs to at least
`2.5 cm reduces the risk of displacement,4"' 77 but exit
`
`592
`
`site sutures increase the risk of catheter contamination
`
`and are not advised. Complete catheter
`
`fracture has
`
`rarely been reported and warrants emergency removal of
`all parts.78’ 79
`
`METABOLlC COMPLlCATlONS
`
`Renal complications
`
`Patients with short bowel syndrome on long-term PN
`are at risk of nephrolithiasis. This is particularly true for
`patients with a short bowel and retained colon (jejunoco-
`lonic anastamosis), who are at increased risk of calcium
`
`oxalate stones, with almost a quarter of developing asso-
`ciated symptoms,8° although asymptomatic decline in
`renal function is not uncommon.“ Clearly, all patients
`with a short bowel are at risk of dehydration, which
`
`in patients
`compounds the risk of nephrolithiasis, but
`with a jejunocolonic anastamosis, unabsorbed fatty acids
`in the short bowel will preferentially bind to calcium
`rather than oxalate;
`the latter is then absorbed in the
`
`colon leading to high urinary levels and an increased risk
`of calcium oxalate stone formation.” Patients with a
`
`short bowel and a retained colon, who are able to eat,
`should therefore consume a diet low in oxalate.
`
`Liver disease
`
`Hepatobiliary complications occur in patients on long-
`term PN with a reported incidence of between 19% and
`75%.” 82”“ The incidence of advanced liver disease
`
`(fibrosis or cirrhosis) varies between 0% and 50% of
`
`patients in retrospective cohorts on long—term PN, with
`an associated reported mortality rate of up to 2296.17’ 82’
`85 This discrepancy in the incidence in severe liver dis-
`ease between different patient cohorts may reflect an
`increased use of parenteral lipid predisposing to higher
`rates of severe liver disease.” Patients with ultra-short
`
`bowel (<50 cm) are at greatest risk of severe liver dis-
`ease, which this may, of course, reflect their greater calo-
`rie requirement.”
`The term intestinal failure~associated liver disease (IF-
`ALD) has broadly replaced the use of PN—associated liver
`
`disease. The aetiology of IFALD is broad and not limited
`solely to PN, but often has multiple aetiological contrib-
`uting factors.“
`
`Nonnutritient causes of IFALD
`
`Patients receiving PN with abnormal liver function test
`should be assessed and treated for nonnutrient-related
`
`abnormalities such as drugs, sepsis, biliary obstruction,
`bacterial
`overgrowth,
`hepatotoxic medications
`and
`
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`
`underlying intrinsic liver disease, while evaluating nutri-
`tient-related factors.“ Sepsis is a common cause of liver
`function test abnormalities in IF and should be actively
`sought and treated.87’ 88 Bilary stone formation is com-
`mon in patients needing long-term PN, with up to 38%
`of patients having ultrasonographic evidence of choleli—
`thiasis after 2 years.” Stone formation is significantly
`more likely in patients who have minimal oral
`intake,
`which likely relates to TPN-associated alterations in bile
`acidification as well
`as
`reduced gallbladder contrac-
`tion.9”’ 91 Various pharmacological treatments have been
`proposed to prevent biliary stone formation with limited
`
`clinical benefit, including cholecystokinin, pulsed amino
`acids, nonsteroidal antiinflammatory drugs, metronida-
`zole and cisapride.92“9f’ Prophylactic cholecystectomy has
`been proposed at the time of the last intestinal resection
`particularly in patients with an intestinal
`remnant
`<12O cm and an absent ileocaecal junction.97
`
`Nutritient-related causes of IFALD
`
`Both parenteral nutrient toxicity and parenteral nutrient
`
`deficiency have been implicated as possible causes of IF-
`ALD. Nutrient toxicity has been documented as a result
`of excess calories (either lipid or glucose based), phytos-
`
`terols, manganese and aluminium toxicity. Nutrient defi-
`ciencies identified as causes of IFALD include essential
`
`fatty acids, choline, taurine and carnitine.98”°2
`Care should be taken to ensure that patients receiving
`PN receive the correct daily amount of both calories
`
`(25-35 kcal/kg) and protein (0.8—1.5 g/kg) as both mal-
`nutrition and overfeeding can lead to steatosiswo’ 103
`Steatosis is the commonest initial histological finding in
`liver disease associated with PN, followed by later by the
`development of persistent intrahepatic cholestasis, fibro-
`sis and cirrhosis.” A recent
`retrospective histological
`study demonstrated a 58% incidence of steatosis in 36
`predominantly adult patients who underwent a liver
`
`function
`liver
`biopsy while on TPN for abnormal
`tests.'°4 Cholestatic complications have long been noted
`to be associated with higher lipid contents and, particu-
`larly, a parenteral
`lipid intake >1 g/kg of body weight
`per day.'7’ 98 Lipid emulsions containing a mixture of
`long-chain
`and medium-chain
`triacylglycerol,
`high
`monounsaturated fatty acid content emulsions and fish
`oil emulsions may reduce the risk of cholestatic compli-
`cations compared with soybean—based emulsions.'05’ '06
`Maintaining oral/enteral nutrition and cyclical adminis-
`tration of PN have both been shown to attenuate liver
`
`dysfunction and are routinely recommended wherever
`possible.1°7
`
`Aliment Pharmacol Ther 2013; 37: 587603
`© 2013 Blackwell Publishing Ltd
`
`Review: long-term parenteral nutrition
`
`Pharmacological treatments
`
`Pharmacological treatments for cholestasis including ur-
`sodeoxycholic acid, parenteral choline and taurine have a
`limited evidence base in adult patients needing HPN,
`
`although have been explored in the paediatric popula-
`tion.’°8‘1” Orally ingested methionine is converted to
`choline and taurine Via hepatic trans-sulphuration path-
`ways; however, when methionine is administered paren-
`terally to the systemic circulation rather than to the
`portal circulation,
`it
`is
`transaminated to mercaptans,
`
`reducing the synthesis of these metabolites. Deficiencies
`of both taurine and choline have been documented in
`
`small
`
`(11 3 50) retrospective studies of patients receiv-
`
`ing long-term HPN and are associated with increased
`biochemical markers of liver function."”’ 102’ “Z A study
`of 10 adult patients with short bowel syndrome receiving
`taurine supplementation did not show an improvement
`
`in
`improvement
`in cholestasis, although a significant
`AST (from 2.3x ULN to 1.3 ULM P 3 0.02) was
`
`supplementation perhaps
`choline
`seen.”2 Parenteral
`shows the most promise in the adults on HPN, with a
`small study of 15 patients suggesting significant improve-
`ments in liver enzyme function (ALT/AST/alkaline phos-
`
`phatase) and hepatic steatosis (non—invasively measured
`by liver computed tomography).""
`
`Osteopathy
`
`Metabolic bone disease has long been associated with
`HPN administration.”3 Historically, PN formulations
`containing high levels of aluminium were a significant
`cause of bone disease until aluminium was removed
`
`from PN formulations in the 19805.99’ "4 Most cases of
`PN-associated metabolic bone disease now relate to
`
`abnormalities in the handling of calcium, phosphorus,
`vitamins D and K as well as underlying medical condi-
`tions such as Crohn’s disease."5’ H6 Metabolic bone dis-
`
`ease remains a significant problem with 41—46% of HPN
`patients reported to have established osteoporosis on
`bone densitometry. 1 15’ 117
`Patients needing HPN should undergo surveillance for
`metabolic bone disease, and appropriate measures taken
`to correct vitamin D deficiency and address any evidence
`of osteopaenia or osteoporosis. Adequate administration
`of calcium and phosphate in TPN solutions is essential
`for skeletal health,“8 while metabolic acidosis should be
`
`this can
`excluded in patients with a short bowel, as
`impair vitamin D metabolism and directly affect bone-
`buffering systems.”6 General measures such as hormone
`replacement
`therapy in postmenopausal women and
`
`regular exercise are also recommended, although their
`
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`
`Page 7
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`Page 7
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`

`
`M. Dibb et al.
`
`benefits in patients on long—term PN have yet to be eval-
`uated. Bisphosphonate therapy may have to be adminis-
`
`tered parenterally if there is a question of impaired drug
`absorption in a patient with IF. The role of glucagon-like
`peptide 2 (GLP-2)
`in attenuating bone loss has been
`evaluated in patients with short bowel; however, recent
`
`reduction in bone
`suggests no significant
`evidence
`resorption after 2 months of therapy."9’ 12°
`
`OUTCOME OF LONG-TERM PN
`
`Weaning from Long-term PN
`
`The amount of functioning small bowel is clearly para-
`mount in determining whether a patient will ultimately
`require long—term PN support; in general, patients with
`<75~100 cm of healthy small bowel
`to an end—enteros-
`
`tomy tend to require long-term parenteral fluid and/or
`protein—energy support.“ '2‘ The presence of a retained
`colon (jejuno-colonic anastamosis) may allow patients to
`
`remain nutritionally autonomous with shorter lengths
`(sometimes <60 cm) of small
`intestine.‘“’’ 12‘ However.
`
`levels may be a useful biomarker of small bowel mass and
`function, reflecting absorptive capacitym In an observa-
`tional study of 57 patients, a plasma citrulline level of
`<20 umol/L predicted the development of permanent IF
`with a sensitivity of 92% and specificity of 9096.122‘ ‘23
`A retrospective European study assessing 124 patients
`receiving HPN demonstrated that
`the probability of
`
`weaning patients from HPN is <6% if not successfully
`undertaken in the first 2 years following the last digestive
`tract modification, ostensibly because the chance of
`intestinal adaptation thereafter
`is minimal.’*5 Current
`work evaluating the role of trophic factors aimed at pro-
`moting intestinal adaptation that holds some promise;
`
`these include both nutrient (e.g. enteral delivery of satu-
`rated fatty acids,“”’ 125 dietary carbohydrates,m’ gluta-
`minem and ornithinem) and nonnutrient factors (e.g.
`growth hormone,129_13° epidermal gro