Most central venous access devices for PN can be safely flushed and lock with standard saline solution when not in use. Also, since heparin may facilitate the precipitation of lipids, saline flushing is mandatory during PN with lipids before any flushing with heparin.
Heparinised solutions should be used as a lock (after proper flushing with saline), when recommended by the manufacturer, in the case of implanted ports or opened-ended catheter lumens which are scheduled to remain closed for more than 8 hours.

What measures are recommended to prevent catheter-related central venous thrombosis?
Prevention of catheter-related central venous thrombosis should include

• US guided catheter insertion to minimise damage to the vein.
• Use of lowest calibre catheter
• Appropriate position of the tip of the catheter in proximity of the atrio-caval junction and
• Prophylaxis with a daily single dose of LMWH 100 IU/kg, exclusively in patients at high risk for thrombosis (family history or previously h/o idiopathic venous thrombotic events)

How do you treat catheter-related central venous thrombosis?

• Remove catheter only if infected or malpositioned or obstructed.  There is a risk of embolization during or immediately after catheter removal; nonetheless, catheter should be removed if infected, obstructed or malpositioned.
• Thrombolytic drugs should be used only in acute symptomatic cases (diagnosis <24 hours after the first symptoms). Efficacy of systemic versus local thrombolysis is still matter of debate, especially for large thrombi.
• Chronic symptomatic cases should be treated with a combination of LMWH and then oral anticoagulants, or LMWH long term alone, depending on the clinical setting.

How do you manage blocked catheter?

• The most appropriate action is exchange over guidewire or removal in case of nontunneled CVC).
• Pharmacological disobstruction in case of PICCs or long term venous access devices. Disobstruction can be done using 10 ml syringe (or bigger), so to avoid inappropriate high pressure which may damage the catheter, and using the solution most adequate for the presumed type of obstruction (ethanol for lipid aggregates; urokinase or rTPA for clots; NaOH or HCl for drugs; Na Bicarbonate for contrast medium).

Ref

1. ESPEN (2006) guidelines.

CRBSI is defined bacteremia or fungemia in a patient who has an intravascular device and more than 1 positive blood culture result obtained from the peripheral vein, clinical manifestations of infection (e.g., fever, chills, and/ or hypotension), and no apparent source for bloodstream infection (with the exception of the catheter). One of the following should be present:

• A positive result of semi quantitative (>15 colony forming unit- cfu per catheter segment) or quantitative (> 102 cfu per catheter segment) catheter culture, whereby the same organism (species) is isolated from a catheter segment and a peripheral blood culture;
• Simultaneous quantitative cultures of blood with a ratio of >3:1 cfu/mL of blood (catheter vs. peripheral blood);
• Differential time to positivity (growth in a culture of blood obtained through a catheter hub is detected by an automated blood culture system at least 2 h earlier than a culture of simultaneously drawn peripheral blood of equal volume).

NB- A positive culture result for a blood sample drawn through a catheter requires clinical interpretation, but a negative result excludes CRBSI

What organisms commonly cause CRBSI?

Coagulase negative staphylococci, S. aureus, aerobic gram negative bacilli and Candida albicans.
Coagulase-negative staphylococci are the most common cause of catheter-related infection. However, if a catheterized patient has a single positive blood culture that grows coagulase negative Staphylococcus species, then additional cultures of blood samples obtained through the suspected catheter and from a peripheral vein should be performed before the initiation of antimicrobial therapy and/or catheter removal to be certain that the patient has true bloodstream infection and that the catheter is the likely source.

What empirical antibiotics should be used when CRBSI is suspecte?

• Vancomycin is usually recommended because of its activity against coagulase negative staphylococci and S. aureus (including MRSA)
• Additional empirical coverage for gram negative bacilli and Pseudomonas (ceftazidime etc) is recommended for neutropenic, severely ill or immunocompromised pts
• Empirical therapy (echinocandin or fluconazole) for candida species should be used for septic patients with any of the following risk factors: total parenteral nutrition, prolonged use of broad-spectrum antibiotics, hematologic malignancy, receipt of bone marrow or solid-organ transplant, femoral catheterization, or colonization due to Candida species at multiple sites.

When would you remove the catheter in CRBSI?

CVCs in patients with mild to moderate CRBSI should not be routinely removed. Always remove the catheter if

• CVCs in patients with mild to moderate CRBSI should not be routinely removed. Always remove the catheter if
• Clinical signs of sepsis with organ dysfunction
• Erythema or purulence overlying the catheter exit site. In tunnelled catheters, pocket infections or port abscess require removal of catheter.
• For complicated infections like septic thrombosis, endocarditis, osteomyelitis
• Persistent bacteremia (i.e. positive cultures from the catheter 72 h after the initiation of appropriate therapy) despite appropriate antibiotics
• Infections due to S. aureus, P. aeruginosa, fungi, or mycobacteria
• CRBSI due to less virulent microbes that are difficult to eradicate (e.g., Bacillus species, Micrococcus species, or Propionibacteria), catheters should generally be removed after blood culture contamination is ruled out on the basis of multiple positive culture results, with at least 1 blood culture sample drawn from a peripheral vein

Remember

• Have a low threshold for removal of non tunneled CVCs
• Antibiotic lock therapy should be used for 2 weeks when the catheter is not removed with CRBSI

What is antibiotic lock therapy?

• This is filling the catheter lumen with antibiotic solution and leaving them there for hours or days.
• Antibiotic solutions in strength of 1-5mg/ml are mixed with 50-100 U of heparin or normal saline in sufficient volume to fill the catheter lumen (usually 2-5 ml) and are installed or locked into the catheter lumen during periods when the catheter is not being used (e.g. 12 hr period at night). The volume of installed antibiotic is removed before infusion of IV medication or solution.
• Cefazolin (5mg/ml with 2500-5000IU/ml of heparin) is the preferred agent for treatment of methicillin-susceptible staphylococci, and vancomycin (2.5-5mg/ml with 2500-5000IU/ml of heparin) is the preferred agent for treatment of MRSA. Ceftazidime (0.5mg/ml with 100 U of heparin) gentamicin (1mg/ml with 2500IU/ml of heparin), or ciprofloxacin (0.2mg/ml with 5000IU/ml of heparin) can be used for treatment of gram-negative microorganisms. Ampicillin (10mg/ml with 5000IU/ml of heparin) is the preferred agent for infections due to ampicillin-sensitive Enterococcus species, and vancomycin is the preferred agent for treatment of ampicillin-resistant enterococci other than vancomycin-resistant enterococci. The use of an ethanol (70%) lock can be considered for the treatment of a mixed gram-positive and gram-negative infection.
• If antibiotic lock therapy cannot be used in this situation, systemic antibiotics should be administered through the colonized catheter

When can CVCs be re inserted after old catheter has been removed?

• Non-tunneled catheters may be reinserted after appropriate systemic antimicrobial therapy is begun
• Reinsertion of tunneled devices should be postponed until after appropriate systemic antimicrobial therapy is begun and after repeat cultures of blood samples yield negative results.

What is the recommended duration of therapy for CRBSI?

• Uncomplicated bacteremia- 10-14 days other than for coagulase negative staphylococci (5-7 days if catheter is removed, 10-14 days if catheter is retained). Coagulase negative staphylococcal infection may resolve with removal of the catheter and no antibiotic therapy, yet many experts believe that such infections should be treated.
• Complicated infections- 4-6 week’s antibiotic therapy should be considered if there is persistent bacteremia or fungemia after catheter removal or if there is evidence of endocarditis, or septic thrombosis, and 6-8 weeks of therapy should be considered for the treatment of osteomyelitis. (suspect these complications if there is persistent bacteremia or fungemia, or a lack of clinical response)
• Duration of antifungal treatment for candidemia should be for 14 days after the last positive blood culture result and when signs and symptoms of infection have resolved. Amphotericin (0.5 mg/kg/day) or fluconazole (400mg/day) can be used.

Discuss S. aureus CRBSI?

• Highest mortality  amongst CRBSI
• Patients with S. aureus CRBSI should have the infected catheter removed, and they should receive 4–6 weeks of antimicrobial therapy. Patients can be considered for a shorter duration of antimicrobial therapy (i.e., a minimum of 2 weeks) if the patient is not diabetic; if the patient is not immunosuppressed; if the infected catheter is removed; if the patient has no prosthetic intravascular device (e.g., pacemaker or recently placed vascular graft); if there is no evidence of endocarditis or suppurative thrombophlebitis on TOE and ultrasound, respectively; if fever and bacteremia resolve within 72 h after initiation of appropriate antimicrobial therapy; and if there is no evidence of metastatic infection on physical examination and sign- or symptom-directed diagnostic tests
• TOE should be done because of high rates of complicating endocarditis; if TEE is not available and results of transthoracic echocardiography are negative, the duration of therapy should be decided clinically for each patient. TOE should be performed at least 5–7 days after onset of bacteremia to minimize the possibility of false-negative results
• For MRSA- vancomycin is the drug of choice. However it should not be used with b-lactam susceptible S. aureus because vancomycin has higher failure rates that do either oxacillin or nafcillin, and it results in slower clearance of bacteremia among patients with S. aureus endocarditis.

What is the treatment of septic thrombosis?

• Always remove the catheter
• Incision and drainage and excision of the infected peripheral vein and any involved tributaries should be done. Surgical exploration is needed when infection extends beyond the vein into surrounding tissue.
• Surgical excision and repair is needed in cases of peripheral arterial involvement with pseudoaneurysm formation
• Heparin is needed in the treatment of septic thrombosis of the great central veins and arteries but not peripheral veins
• Appropriate antibiotics for 4-6 weeks
• Thrombolysis is not recommended.

What is the evidence based interventions which effectively reduce the risk of catheter related bloodstream infections?

• Tunneled catheters by decreasing the extent of extraluminal contamination.
• Antimicrobial coated short term CVCs are effective in reducing CRBSI
• A single lumen CVC is to be preferred. If a multi lumen catheter is used, it is recommended to identify and designate one port exclusively for PN.
• US placement of catheters may indirectly reduce the risk of contamination and infection
• The catheter exit site of a non-tunneled central venous access should be covered preferably with a sterile, transparent, semi-permeable polyurethane dressing, which should be routinely changed every 7 days or sooner if they are no longer intact or moisture collects under the dressing. If a patient has profuse perspiration or if the insertion site is bleeding or oozing, a sterile gauze dressing is preferable to a transparent, semi-permeable dressing.
• Chlorhexidine impregnated dressing are effective in reducing the extraluminal contamination of the catheter exit site with non-tunneled CVCs at high risk infection. Stitches should not be use routinely to stabilise CVCs as they may be associated with a high risk of contamination of the exit site. Use manufactured catheter stabilization devices.
• The most appropriate skin antiseptic for prevention of catheter related blood stream infection is chlorhexidine as 2% solution in 70% isopropyl alcohol, and it should be preferred for both skin preparation and cleaning of the catheter exit site. Alcoholic povidone-iodine solution should be used in patients with a history of chlorhexidine sensitivity
• Stopcocks, catheter hubs and sampling ports of needle-free connectors are an important route of intraluminal contamination and subsequent CRBSI, and they should always be disinfected before access, preferably using 2% chlorhexidine gluconate in 70% isopropyl alcohol.
• The intravenous catheter administration set should be changed every 24 hrs (when using lipid PN) or every 72 hrs (if lipids are not infused)
• Low-dose systemic anticoagulation or catheter flushing with heparin do not reduce the risk of catheter contamination, and are not recommended for prevention of CRBSI
• Proper education and specific training of the staff is universally recommended as one of the most evidence based strategy for reducing the risk of catheter related infections
• Adequate policy of hand washing

Ref

1. ESPEN (2006) guidelines
2. Guidelines for the Management of Intravascular Catheter–Related Infections. Clinical Infectious Diseases 2009; 49:1-45

Intestinal failure–associated liver disease develops in 15% to 40% of adults on home parenteral nutrition. The clinical spectrum includes hepatic steatosis, cholestasis, cholelithiasis, and hepatic fibrosis. Progression to biliary cirrhosis and the development of portal hypertension and liver failure occurs in a minority but is more common in infants and neonates than in adults.

What is the pattern of LFTs in PNALD?

Markers of liver dysfunction include GGT, AP, ALT and AST. An elevated level of bilirubin is less common.

Is PNALD reversible?

Abnormalities of LFT in patients receiving short term PN are usually transient, but in individuals receiving long-term parenteral nutrition substantial liver damage and ultimately ESLD may occur.

What is the aetiology of parenteral nutrition-associated liver disease?

• Patient dependent factors-
  • Underlying disease- Abnormal LFTs may be related to underlying liver disease (PSC in IBD, previous fatty liver) rather than the effects of the parenteral nutrition itself, although the effects of the latter may exacerbate the former.
  • Sepsis- major precipitating factor for abnormal LFTs
  • Intestinal anatomy- there is an increased risk of chronic cholestasis in adults with a small intestinal length of less than 50cms. This may be due to impairment of enterohepatic bile salt circulation and abnormal bile acid metabolism. Others have argued that bowel length may simply be a surrogate marker of parenteral energy requirement.
  • Bacterial overgrowth- relatively common due to intestinal stasis. This may cause liver dysfunction due to bacterial translocation and the effects of bacterial endotoxin and also because of the generation of secondary bile salts such as lithocholic acid as a result of bacterial dehydroxylation of chenodeoxycholic acid.
  • Lack of enteral nutrition- this causes reduced secretion of GI hormones causing reduced intestinal motility, promoting bacterial overgrowth, and may predispose to biliary stasis. Lack of enteral food also causes mucosal atrophy, which in turn allows increased bacterial translocation across the gut mucosal barrier.
• Parenteral nutrient deficiency
  • Essential fatty acid deficiency- may cause liver dysfunction, although unlikely unless fat free parenteral regimes are used
  • Deficiencies of a number of methionine metabolites, such as carnitine, choline and taurine, may be responsible for both steatosis and cholestasis in patients receiving parenteral nutrition. Carnitine, choline and taurine are not routinely administered as part of parenteral formulations.
• Nutrient toxicity
  • Glucose infusion at rates of >5 mg/body weight (BW) per min have been demonstrated to result in steatosis in human subjects. Excess glucose infusion causes hyperinsulinemia, which then enhances glucose conversion to fat within the liver. Insulin hypersecretion may also explain why continuous parenteral nutrition infusion is associated with a greater extent of hepatic dysfunction than cyclic infusion. Allowing 8 h or more each day without parenteral glucose infusion has been shown to lower insulin levels and improve LFT.
  • Lipid emulsions- parenteral intake of soyabean-based lipid emulsion of
  • >1 g/kg BW per d has been shown to be associated with an increased risk of liver disease. This may be due to lipid overloading of hepatic macrophages might impair phospholipid excretion into bile and cause intrahepatic cholestasis
  • Aluminium- Al has been shown to cause cholestasis in animal models but is not found in modern parenteral formulations in substantial quantities
  • Manganese- withdrawal of parenteral Mn improves hepatic function in children with high plasma level.

How do you manage parenteral nutrition-associated liver disease?

• Manage non-nutritional causes
  • Avoid and treat sepsis
  • Treat extrahepatic biliary obstruction- Cholelithiasis in patients receiving PN can be prevented by encouraging enteral feeding and administration of cholecystokinin or prophylactic cholecystectomy
  • Avoid hepatotoxic medications
  • Treat bacterial overgrowth- maneuvers to reduce bacterial translocation such as increased dietary fibre intake and parenteral glutamine supplementation, have not been shown to have a beneficial effect on liver dysfunction
  • Treat underlying liver disease
• Modify enteral and parenteral nutrition
  • Avoid overfeeding- UK guidelines suggest a total daily energy intake of
  • 25–35 kcal/kg BW and a daily protein intake of 0.8–1.5 g/kg BW. The total daily calories from dextrose should be limited to 65% or less. Glucose oxidation reaches the maximal level at 4gm/kg/day). Exceeding this limit may cause lipogenesis, hypercapnia and hyperglycemia  and increased incidence of liver dysfunction.
  • Maximise enteral nutrition
  • Optimise parenteral lipid- US guidelines suggest that parenteral lipid infusion should supply 20–30% total energy and daily intake should be <2.5 g/kg BW and ideally <1.5 g/kg BW. However, experimental data suggest that the intake of soyabean-based lipid should be <1.0 g/kg BW per d. There is growing evidence that lipid emulsions containing a mixture of long-chain and medium-chain triacylgylcerol (TAG) emulsions with a high MUFA content and emulsions containing fish oils may be preferable to soyabean-based emulsions in relation to hepatic complications, but the latter remain in widespread use. Further clinical trials are necessary to explore this area further. At the onset of liver dysfunction, consider reducing or suspending lipids such as limiting lipid infusions to 5 per week.
  • Cyclical parenteral nutrition- cyclical rather than continuous PN should be administered to minimise the adverse effects of prolonged insulin hypersecretion. Allowing an 8 h break from PN has been shown to improve LFT and reduce insulin levels. When prolonged PN therapy is expected, cycling should be started as soon as possible.
• Pharmacological treatment
  • UDCA- Evidence of a benefit of UDCA in adults is limited. UDCA (15-20mg/kg/day) may be associated with an improvement in cholestatic LFTs. is UDCA is commonly prescribed although there is no clear evidence of efficacy. UDCA may also worsen diarrhoea in some individuals.
  • Taurine and choline- evidence supporting the widespread use of parenteral choline and taurine supplementation in the prevention or treatment of liver dysfunction remains limited.
• Small intestinal and/or liver transplantation
  • Impending or overt liver failure associated with PNALD is recognised as an indication for small intestinal transplantation, and PNALD is one of the commonest reasons for performing intestinal transplantation.   UK transplant units have suggested consideration of transplantation only if there is portal hypertension, cirrhosis or bridging fibrosis.

Ref-

1. Lloyd DA, Gabe SM. Managing liver dysfunction in parenteral nutrition. Proc Nutr Soc. 2007 Nov; 66(4):530-8.

• Inadequate or unsafe oral and/or enteral nutritional intake
• A non-functional, inaccessible or perforated (leaking) gastrointestinal tract.

So enteral feeding is contraindicated in diffuse peritonitis, intestinal obstruction, intractable vomiting, paralytic ileus, intractable diarrhoea and gastrointestinal ischaemia.

How many days would you wait before initiating PN?

In many studies of the use of PN, the majority of patients are able to eat orally within 6-8 days; it is unlikely that these patients benefit from such short-duration PN. This is likely to be true even in malnourished patients. So based on these data, PN is often recommended if enteral intake has been, or is anticipated to be inadequate for 7-10 days.

NICE 2006 – There is no minimum length of time for the duration of parenteral nutrition.

How would you deliver PN?

• Continuous administration of parenteral nutrition should be offered as the preferred method of infusion in severely ill people who require parenteral nutrition.
• A gradual change from continuous to cyclical delivery (12-14 hrs) should be considered in patients requiring parenteral nutrition for more than 2 weeks.  Cyclic infusion is used with a tapering-up period at the beginning and a tapering-down period at the end to avoid hyper-/hypoglycemia.

Discuss the protocol for laboratory monitoring of nutrition support?
NICE 2006
Monitoring of patients’ tolerance to parenteral nutrition includes careful measurements of fluid intake and output, and selected laboratory studies.

• Baseline- FBC, U&ES, LFTs including albumin and INR, CRP, Glucose, B12, Folate, ferritin, Mg, PO4, Ca, Zn, copper, selenium.
• Frequency of monitoring
  • Daily until stable- U&ES (then 1-2 weekly), Glucose (twice daily, till stable then weekly) Mg, Po4 (daily if risk of refeeding, 3/weekly otherwise till stable, then weekly)
  • Weekly- LFTs (twice weekly till stable), Ca, albumin, CRP (2-3/week till stable), FBC
  • 2-4 weekly depending on results- Zn, Cu, folate, B12,
  • 3-6 monthly- Ferritin, Manganese (if on home TPN)
  • 6 monthly- 25 OH Vit D if on long term support.

What is the composition of PN solution?
The initial composition of the parenteral nutrition solution should be determined by a patient’s tolerance to:

• Parenteral glucose (patients with diabetes or critical illness are susceptible to hyperglycemia)
• Amino acids (renal or hepatic disease may cause intolerance to protein loads)
• Fats (eg, critical illness or sepsis may result in hypertriglyceridemia)

Initial infusion rates of these macronutrients generally begin at 2 to 4 mg/kg/min of CHO in adults, 0.5-1.0 g of protein/kg/day, and 1.0 g of lipid/kg/day.
Electrolytes, minerals, trace elements and a multivitamin preparation are generally added to the parenteral solution.
For details see the chapter on Calorie requirements.

What are the routes of administration of PN?

• Peripheral PN- PN may be safely used by a peripheral access (short cannula or midline catheter), using a solution with low osmolarity, when a significant portion of the non-protein calories are given as lipids. Midline catheters are a preferable option when peripheral i.v. therapy is expected for more than 6 days.
• Central PN- Central venous accesses (i.e. venous devices whose tip is centrally placed) can be classified as short term and long term accesses. Long term (> 3 months) home parenteral nutrition (HPN) requires a long term venous access device, such as a tunneled central catheter (Hickman, Broviac, Groshong, etc.) or a totally implanted port. PICC or a centrally inserted CVC can be used for short or medium term use. PICCs catheters can be used for prolonged PN (up to 3-6 months) both in hospitalized patients and for home TPN.
• PICC is a central line placed via peripheral vasculature. Midline is a shorter version of the PICC. It is inserted in the same fashion, but it terminates in the axillary veins rather than in the central circulation. Midline catheters can b used for  up to 2 weeks.

Which is the most appropriate position of the tip of a central venous access for parenteral nutrition?

Central PN (i.e. high osmolarity PN) should be delivered through a catheter whose tip is positioned in the lower third of the superior vena cava, or at the atrio-caval junction, or in the upper portion of the right atrium. This is associated with the least incidence of mechanical and thrombotic complications.

Ref

1. NICE guidance: Nutrition support in adults