Should we only think green?

Update on hepatosplanchnic monitoring

Alexander Wilmer, M.D., Ph.D.

Medical Intensive Care University Hospital Gasthuisberg

Catholic University of Leuven

Why hepatosplanchnic monitoring?

Tissue hypoxia within the GIT can occur under adequate

global perfusion and oxygenation

Loss of gut barrier function + bacterial translocation

Mostly, assessment of liver function in the ICU is

based on “static” tests

Dynamic liver function tests can reveal

otherwise hidden hepatocellular

dysfunction

Conventional monitoring does not permit timely or differential detection of liver or GIT dysfunction and does not allow for

monitoring of selective therapeutic targets

1) Techniques for monitoring of the GIT

2) Techniques for monitoring liver function

Pubmed search, applicability for current ICU practice

Evidence based criteria and experience based medicine

No conflict of interests

Techniques for monitoring of the GIT

• Measurement of splanchnic blood flow (imaging techniques)

• Gastrointestinal tonometry

• Measurement of intestinal permeability

• Biomarkers of intestinal enterocyte mass or function

• Indocyanine green plasma disappearance rate

Measurement of splanchnic blood flow with imaging techniques

Vermeulen M et al: Eur J Rad 2012, Takahashi H et al: Alcohol Clin Exp Res 2010, Sorbron S et al: Radiology 2012

1) Duplex Doppler ultrasound (DDUS)Useful for assessing thrombosis, flow patency before and after LTX + TIPS and for estimation of portal vein pressure.Inter- and intraobserver variability, imaging difficulties, outcome studies?

2) Mucosal laser Doppler flowmeteryAssesses gastric mucosal perfusion, positioning? Experimental

3) MRIcomparable to DDUS in the preoperative setting, less interobserver variability

4) Xenon-CTTotal hepatic blood flow correlates well with Child-Pugh score and ICG disappearance

Gastrointestinal tonometry for measuring intestinal hypoperfusion

Principle: Regional PCO2 = CO2 tissue production and removal => pHi (intramucosal)

Pathophysiological assumption:Low pHi (↓ regional blood flow, DO2) is causally related to increased gut permeability

Clinical studies: cause / effect relationship difficult to interprettogether with lactate OK for prognosis

Methodological problems:assumption of equal HCO3- in arterial blood + mucosaenteral feedingTime for CO2 equilibration

Current applicability in the ICU for daily clinical practice:nihil

Measurement of intestinal permeability

Principle: urinary excretion of oligosaccharides after oral administration

Pathophysiological assumption:Increased gut permeability facilitates MOF

Clinical studies: increased permeability in burn, trauma, mixed critically ill patients

Methodological problems:no ideal test at present: problems with either delivery, permeation, disposal or

analysisCurrent applicability in the ICU:

Permeability is increased: and now what? -> FXR agonists in the future?

Measurement of biomarkers of enterocyte necrosis and GI dysfunction: citrulline (a nonessential AA)

Piton G et al: Int Care Med 2010 + 2011, Crenn P et al.: Clin Nutrition 2008, Luo M et al.: JPEN 2007, Luiking YC et al.: AM J Clin Nutr 2009Oalled S et al.: Nutr Clin Pract. 2012

Synthesis: mainly from Glutamine (via glutamate tot ornithine) in mitochondria of enterocytes mainly in the small bowel

Breakdown: 80% of citrulline produced is degraded to arginine in the kidney

Reliable marker of enterocyte mass in chronic SB disease

In critically ill patients: decreased, progressive decrease when in shock, related to intestinal dysfunction

Low citrulline = marker of reduced enterocyte mass or of dysfunction

Measurement of biomarkers of enterocyte necrosis and dysfunction: fatty acid binding protein

Kanda T et al:. Gastroenterology 1996

Physiology: L-FABP and I-FABP: proteins used within enterocytes to deliver FA to specific metabolic sites, comprise about 4-6% of metabolic proteins

Pathophysiology: Marker of enterocyte necrosisincreased in SAP, intestinal infarctioncorrelated with SB permeability and bacterial translocation

In critically ill patients: If acutely reduced enterocyte mass: increased I-FABPIf acute dysfunction: i-FABP expected to be normal

Grootjans J et al.: World J Gastroenterol 2010

Techniques for monitoring of the GIT: usefulness for current ICU practice?

• Measurement of splanchnic blood flow with imaging: DDUS yes

• Gastrointestinal tonometry: no

• Measurement of intestinal permeability: no

• Biomarkers of intestinal enterocyte mass or function: yes (potential)

Techniques for monitoring the liver: static tests

Static

• Cholestasis

• Hepatocellular integrity

• Synthesis

• Liver perfusion: CT, MRI

The Effect of Strict Blood Glucose Control on Biliary Sludge and Cholestasis in Critically Ill Patients. Dieter Mesotten, Joost Wauters, Greet Van den Berghe, Pieter J. Wouters, Ilse Milants, and Alexander Wilmer. J Clin Endocrinol Metab 2009; 2345-52. (n =658, 60% sepsis )

Cholestasis = bili > 3 mg/dl or ALP > 400 + GGT > 80 IU/l

Ischem hep = AST > 800 IU/l + ALT > 800 IU/l + PT < 70%

Mixed = bili > 3 mg/dl + AST > 800 IU/l + + ALT > 800 IU/l + PT < 70%

% o f p a ti e n t s

Daily prevalence of liver dysfunction in the ICU

Kortgen A at al.: Shock 2009

Techniques for monitoring the liver: static versus dynamic tests

Static

• Cholestasis

• Hep.cellular integrity

• Synthesis

• Liver perfusion:

CT, MRI

Dynamic• Elimination capacity:

Galactose• Metabolite function:

Lidocaine, aminopyrine

• Clearance half life:

caffeine, BSP

indocyanine green (ICG)

Measurement of galactose elimination capacity (GEC)

Principle:

galactose phosphorylation by ATP in the liver, plotting of galactose serum

concentrations in blood over time (4 h urine collection, blood sampling from min 20 to 45)

Pathophysiological assumption:

Elimination capacity reflects hepatocellular function and energetic status

Clinical studies:

decreased GEC in hepatitis, cirrhosis, liver donors, prognostication

Methodological problems:

galactose intolerance, cumbersome application

Current applicability in current daily ICU practice:

nihil

Measurement of lidocaine conversion (MEGX test)

Principle:

hepatic conversion of lidocaine to MEGX by cytochrome system (CYP 3A/4A), determination of MEGX at time 0 and after 15 min after 1 mg/kg lidocaine

Pathophysiological assumption:

Reflects microsomal liver function, estimates functional liver reserve

Clinical studies:

prognostication in critically ill, pre + post-transplant liver function

Methodological problems:

interaction of cytochrome system with other medications affecting lidocaine conversion, need for special lab equipment

Current applicability in current daily ICU practice:

nihil

Measurement of aminopyrine metabolism (antipyrine breath test)

Principle:

oral intake of radioactively labeled aminopyrine, demethylation + oxidation in the liver by cytochtome P-450 to antipyrine, measurement of exhaled 14CO2

Pathophysiological assumption:

Reflects microsomal liver function, estimates functional liver reserve

Clinical studies:

prognostication in patients with chronic liver disease, studied in cardiac surgery patients and biliary obstruction

Methodological problems:

dependent on GI-motility, BMR, time consuming, special lab, radioactivity

Current applicability in current daily ICU practice:

nihil

Measurement of caffeine metabolism or bromosulfophtalein (BSP) clearance

Principle:

- oral caffeine -> paraxanthine, theobromine, theophylline. Ratio metabolites/caffeine after 4, 8 and 12 h. Also described: caffeine breath test

- iv BSP clearance at 30 and 45 min

Pathophysiological assumption:

Reflects microsomal liver function, estimates functional liver reserve

Clinical studies:

prognostication in patients with chronic liver disease or before liver resection

Methodological problems:

BSP: possibly fatal systemic reactions, special lab equipment

Current applicability in current daily ICU practice:

nihil

Measurement of indocyanine green (ICG) plasma disappearance rate (PDR)

PDR (%/min)

• Water-soluble, fluorescent dye• binds to albumin + beta-

lipoproteins• Selectively taken up by

hepatocytes without ATP• Excreted unchanged in bile via

ATP-dependent system• PDR = nl 18-25%/min, reflects: • sinusoidal perfusion• ICG uptake by hepatocytes• excretion into bile Sakka SG et al. Int Cre Med 2000

Kortgen A et al: Shock 2009 (n=48 with severe sepsis), Sakka SG 2007,

PDR upon ICU admission =

prognostic value comparable to

APACHE II and SAPS

Good data in the setting of

• Abdominal compartment

syndrome

• Complications after LTx

• Morbidity after liver resection

PV = 75% flow25% oxygenation

Hypothesis: TIPSS, being a shunting procedure, can alter liver

parenchymal perfusion, at least temporarily (n=15)

HA = 25% flow75% oxygenation

TIPSS

PDR baseline

Admission MICU

PDR 2 hr after TIPSS

PDR 24 hr after TIPSS

Methods: Protocol

Results: PDR (%/min) before and after TIPSS

Child A (n=4) Child B (n=6) Child C (n=5)

Before TIPSS BL BL BL

2 hr after TIPSS - 12.4% -12.0% -20.3%

24 hr after TIPSS

-9.4% -5.7% -22.2%

Results: Change of PDR (%/min) from baseline

Summary

Techniques for monitoring of the GIT or liver function:usefulness for current ICU practice?

• Measurement of splanchnic blood flow: DDUS yes but not really monitoring

• Biomarkers of intestinal enterocyte mass or function: yes (potential)

• ICG-PDR: yes, think green