Pharmaconutrition in PICU Gan Chin Seng

Paediatric Intensivist

UMMC

Pharmaconutrition in Critical Care Unit

Gan Chin Seng

Paediatric Intensivist

UMMC

Definition

• New concept

• “ Treatment with specific nutrients to improve host defences and improve the outcome of critically ill patients”

• E.g. glutamine, arginine, omega-3 fatty acids, selenium

• Less about energy requirements or nitrogen balance

• “Pharmacological nutrition”, “ Nutritional pharmacology”

Background

• Critical illness causes systemic inflammation, altered immunity, & metabolic changes resulting in hypermetabolism

• Inability to maintain adequate nutrition leads to nutrient deficiencies, which may in turn increase the risk for infection, organ failure, & mortality

Artificial Nutrition

• Enteral (EN)/ parenteral (PN)

• ADJUNCTIVE support

• Debates on energy requirements & protein losses in past 40 years

• Early EN once haemodynamically stable within 3 days to avoid mucosal atrophy

• No immediate benefit with supplemented PN when intolerant to early EN in the absence of malnutrition • ESPEN 2009: early

• ASPEN 2009: 7- 10 days (Heidegger et al. Lancet. 2012; 381-93)

Immunonutrition

• Immune- enhancing diet (IED)

• Past 3 decades

• Enteral formulations or “cocktails” enrished in various nutrients

• Macronutrients: glutamine, arginine, omega-3 FAs

• Micronutrients: Vits A, C & E, selenium & zinc

• Various concentrations (special formula)

• To optimize immune function & cell recovery

• Current evidence suggests that IED is beneficial in major elective surgery, trauma, burns, head and neck cancer, & non-septic critically ill patients on mechanical ventilation

• IED in severe sepsis/ critically ill patients is controversial (McClave SA et al. JPEN 2009;33:277–316)

• ↑Mortality rate (Zaloga GP. Crit Care Med, 1998; 26:1143±1146)

• Canadian Clinical Practice Guidelines Committee recommended that IEDs should not be used in critically ill patients

(Heyland DK. J Parenter Enteral Nutr 2003; 27:355–373)

• Over 30 RCTs of immunonutrition in over 2000 critically ill patients

• No benefit on outcome

• No evident to support (Kieft H et al. Intensive Care Med. 2005;31:524–32; Ochoa JB. Crit Care Med 2008;36:347–8)

• 597 patients, high-protein formula enriched with arginine, glutamine, antioxidants, & omega-3 FAs

• No change in outcome (Heyland et al. Crit Care Med. 2013;2743-53)

• Poor methodological quality & small sample size

• Various nutrient combinations

• Heterogeneous patient population (“MIXED COCKTAIL” approach)

Pharmaconutrition

• In 2008, Jones & Heyland proposed “administration of specific nutrients in supranormal amounts has ‘pharmacological’ effects on the inflammatory response to critical illness & can improve clinical outcomes”

• ACTIVE therapeutic treatment

(Jone and N.E. Heyland. Current Opinion in Gastroenterology. 2008;24:215-222)

(Preiser et al. Critical Care. 2015; 19:35)

• Meguid et al. (Ann Surg 2009) & Dupertuis et al. (Curr Opin Clin Nutr Metab Care 2009) suggested pharmaconutrition with “disease-dedicated therapy” approach

• Last decade

• Increasing evidences of therapeutic effects

• Impact on clinical outcomes

• NO Paediatric data

(Meguid MM et al. Ann Surg 2009;249:364–5)

(Dupertuis YM et al. Curr Opin Clin Nutr Metab Care 2009;12:398–403)

Glutamine

• Non-essential amino acid

• Fuel for rapidly dividing cells e.g. lymphocytes, enterocytes, & colonocytes

• Protects structural & functional integrity of intestinal mucosa

• Augments cellular immune functions

• Precursor for endogenous synthesis of arginine

• Most extensively studied

• Early small studies, benefits: antioxidant defenses, immune function, & N2 retention

• Enhance tissue Heat Shock Protein (HSP) expression & reduce cellular apoptosis & cytokine release

• Improve tissue metabolic function

• Enhance stress tolerance

• ↓ Infectious complications (RR 0.79, 95% CI 0.68–0.93, P = 0.005)

• ↓Mortality, especially with PN (RR 0.75, 95% CI 0.61–0.93, P = 0.008)

• Decreased length of hospital stay & ventilator time

(Wischmeyer PE. Crit Care Med. 2007;35(suppl 9):S541–4)

(Canadian clinical practice guidelines, ESPEN guideline on PN, SCCM & ASPEN 2009)

• More recent studies, conflicting results

• In the Scottish Intensive Care Glutamine or Selenium Evaluative Trial • No measurable improvement in new infection rates or survival

(Andrews PJ et al. BMJ. 2011;342:d1542)

• Scandinavian glutamine trial • Reduction in mortality when received glutamine for more than 3 days

(Wernerman J et al. Acta Anaesthesiol Scand. 2011;55:812–8)

• 3 meta-analysis: conflicting results (Fadda V et al. Clin Nutr. 2013;32:492–3; Bollhalder L et al. Clin Nutr. 2013;32:213–23;

Heyland D, et al. N Engl J Med. 2013;368:1489–97)

• Very different approaches in dosing, timing, & backgrounds

• Used with caution, & harmful effects yet to be clarified

Arginine

• Metabolized by NO synthase to NO

• Stimulates release of hormones: GH, prolactin & insulin

• ↑number & function of T cells

• Depletion of arginine & ↓ T-cell activation & immunocompetence, ↑risk of infection

• With sepsis NO synthase upregulated, high arginine could be harmful

• Catabolic state, low serum arginine • ↓Dietary intake • ↑Uptake in endothelium, liver, and intestine • ↑ Metabolism

• ↑Mortality & worsened shock In sepsis (Bertolini G. Intensive Care Med. 2003;29:834–40)

• Beneficial for elective surgery patients in reducing post-op infection (Drover JW. J Am Coll Surg. 2011;212:385–99)

Omega-3 Fatty Acid

• Fish oil, borate oil

• Incorporation into inflammatory cell membrane phosopholipids, ↓ leukotriene B4 ,thromboxane A2 & prostaglandin E2 production

• Mixed report

• 60% mortality reduction ALI & ARDS

(Pontes-Arruda A . J Parenter Enteral Nutr. 2008;32:596–605)

(Zhu D et al. Intensive Care Med. 2014;40:504–12 )

• 2013 & 2015 Canadian Clinical Practice guideline (www.criticalcarenutrition.com)

• Insufficient data to recommend use of fish oil alone for critically ill

• Lack of treatment effect on outcome

• Too sparse data

• 2008 meta-analysis of 3 studies demonstrated that enteral formula enriched with fish oils, borate oils & antioxidants significantly reduces mortality (RR 0.63, 95% CI 0.48, 0.84, P=0.002) in ARDS

(http://www.criticalcarenutrition.com)

• Canadian Clinical Practice guideline (www.criticalcarenutrition.com)

• 2013 & 2015: enteral formula with fish oils, borage oils & antioxidants in ALI & ARDS should be considered

• Overall treatment effect on mortality decreased

• Lack good control group in several studies ( high fat formula, additional protein

• Lack of a treatment effect

Selenium & Antioxidants

• Part of a complex endogenous defence system protecting tissues from the damaging effects of oxidative stress

• ↓Antioxidants, ↑oxygen free radicals, ↑systemic inflammatory response, subsequent cell injury, ↑organ failure, & even higher mortality

• Selenium either alone or in combination with other trace elements & vits (Zn & vits A, C & E)

• High-dose selenium (1000mcg/day) supplementation in 249 pts with severe systemic inflammatory response syndrome, sepsis, & septic shock demonstrated a large, but not significant, reduction in mortality [odds ratio (OR) 0.66, 95% CI 0.39, 1.10, P=0.109]

• Greater treatment effect detected in high normal levels of selenium compared with normal levels

(Angstwurm MW et al. Crit Care Med 2007; 35:118–126)

↓Mortality (RR 0.69, 95% CI 0.59, 0.82, P=0.0001), but had no effect on infectious complications or ICU length of stay in critically ill patients (Heyland DK et al. Intensive Care Med 2005; 31:327–337)

• High normal serum selenium was proposed as a target for result

• Antioxidant strategies, particularly selenium, should be considered for critically ill patients

Challenges

• Defining individual optimal dose

• Duration, efficacy, & routes of nutrient supplementation

• Heterogeneous patient populations

Summary

• Pharmaconutrition is an interesting field in critical area

• No Paediaric data yet

• Artificial nutrition/ immunonutrition/pharmaconutrition

• Glutamine/ arginine/ Omega-3 FAs (fish oil & borate oil)/selenium & antioxidants

• Arginine: not recommended for sepsis

• Glutamine: needs further clarification

• Enteral fish oils, borage oils & antioxidants in ALI & ARDS should be considered

• High dose selenium could be helpful

THANK YOU