Cerebral blood flow in liver failure Fin Stolze Larsen, MD, PhD, - - PowerPoint PPT Presentation

Cerebral blood flow in liver failure

Fin Stolze Larsen, MD, PhD, DMSc Professor

• Div. of Hepatology, Rigshospitalet,

University Hospital of Copenhagen, Denmark Integrative human cardiovascular control. Ph.D. course, Copenhagen, 2019 Nothing to disclose

Liver failure

complications that may influence CBF

• Hepatic encephalopathy
• High ICP
• Hyperventilation - low PaCO2
• hypoglycemia
• Systemic vasodilatation
• sepsis
• Hypoxia / ARDS
• renal failure (ATN, HRS)
• Low sodium and phosphate
• coagulopathy
• thrombocytopenia
• Lactate acidosis

CBF to metabolism coupling

1 2 3 4 5 6 7 8 20 40 60 80 100

CBF (ml/100g/min) CMRO2 (ml/100g/min)

seizures coma

Magistretti Roy & Sherrington 1893 Seymour S. Kety

Main regulatory mechanisms of CBF

CBF in liver disease

• O`Carrol et al. Lancet 1991
• Lockwood et al. J CBF Metab 1991, Hepatology 1993
• Van Thiel et al. J Neuropsychiatry Clin Neurosci 1994
• Larsen et al. Hepatology 1995
• Dam, J Hepatology 1998
• Lockwood et al. Metabol Brain Dis 2001
• Bjerring PN et al. J Clin Exp Hepatol. 2018
• Global CBF reduced in HE
• Cognitive impairment correlates with rCBF in
• basal ganglia and limbic cortex
• cerebellum
• frontotemporal regions
• Reversible after liver transplantation

CBF in acute liver failure with hepatic encephalopathy

• A wide CBF variation (14 to 240 ml/100g/min) in spite
• CMRO2 ~ 1.0 ml/100g/min
• Cerebral vasodilation develops during liver failure (Kindt, J

Neurosurgery 1986; Larsen, J Hepatol 1997)

• CBF is higher in patients with oedema than in those without

(Larsen. Sem Liv Dis 1999)

• Cerebral hyperperfusion is reversed by hepatectomy

(Ejlersen, Larsen & Secher. Transpl Proc 1994)

Liver failure

Complications

Severe hyperammonemia

Urea NH4 +

Intestine

Glu NH4 + Pyr a-KG Ala

Gln Ala

Glu NH4 + HCO3

• CP

Urea Asp Ala NH4 + a-KG Glu Pyr NH4 + +Glu

x x

Liver

242±118 206±69 2264±1791 2393±1807 612±417 421±263 Clemmesen et al. Gastroenterol 2001

Cerebral mechanisms in HE:

astrocyte swelling

1Haussinger et al, Gut, 2012. 2Haussinger et al, J Hepatol, 2000; 32(6):1035–8.

Intra-cellular glutamine is osmotically active and draws H2O into astrocytes

Ammonia is metabolised in brain astrocytes by glutamine synthetase:

Glutamate + ATP + NH3 Glutamine + ADP + phosphate

Glu NH4 Gln (Ala) H2O H2O

 Although ammonia is important in pathogenesis,

levels do not necessarily correlate with severity 1

Other factors can precipitate HE

without high ammonia concentrations 1

 Hyponatraemia  Benzodiazepines (sedatives)  Inflammatory cytokines etc  Induce astrocyte swelling in vitro

2

 Different neurotoxins may contribute to astrocyte

swelling and precipitate HE 1

Hyperammonemia increases CBF

Chung et al. Hepatology 2001 Larsen et al. J Hepatol 2001

Why ?

5 10 15 20 25 30 35 40 45 50

7 24 45 53,5 72,5 79 86 96,5 105 119 126 128 141,5 147 154,5 158,5 172 189

Time (hours) Glutamate (umol/l) & ICP (mmHg) 0,5 1 1,5 2 2,5 3 3,5 4 4,5 5 Glucose & lactate (mmol/l)

ICP Glutamat Glucose Lactat

Cerebral microdialysis in patients with liver failure

Tofteng, Larsen. Hepatology 2002

Cerebral glutamine concentration (umol/l)

2000 4000 6000 8000 10000 12000

Intracranial pressure (mmHg)

5 10 15 20 25 30 35

Tofteng et al. J Cerebral Blood Flow & Metabol. 2006

Monitoring of ICP and cortex concentration of glutamine

5 10 15 20 25 30 35 40 45 50 2000 4000 6000 8000 10000 12000 lactate-pyruvate ratio Glutamine concentration (umol/l)

Glutamine causes mitochondrial failure in the brain in liver failure?

Bjerrings et al. Neurocritical Care 2008

The higher LP ratio the higher hypoxanthine in the brain during liver failure: A microdialysis study

Bjerring & Larsen. J Hepatol 2010;53:1054–58

Adenosine and CBF in liver failure:

Biosensor study

Bjerring P, Larsen FS. Neurochem Res. 2014

NH3 HE grade I II III IV ICP CH

• ------------- - - - - - - - - - - - - - - -

CBF CMRO2

CBF in severe liver failure - interpretation

[lactate]e Adenosine?

Vasoreactivity

Main regulatory mechanisms of CBF II

1903, London

WM Bayliss EH Starling

Main regulatory mechanisms of CBF - II

1 7

Cerebral Autoregulation

20 40 60 80 100 120 140 160 180 20 40 60 80 100 120 140 160 180 200

Cerebral Perfusion Pressure (= MAP- ICP) (mm Hg) CBF (%change)

Lower Limit Upper Limit Plateau Phase

Mogens Fog. Cerebral circulation. Arch Neurol Psychiatry 1937; 37:351–364 Niels A Lassen Definition of CBF autoregulation in 1959

CBF autoregulation is impaired in liver failure

Jalan et al. Hepatology 2001

Larsen FS & Secher N. J Hepatol 1995, CCM 1997 Tofteng & Larsen. J CBF & M 2004 Strauss & Larsen. Hepatol 1997 and J Hepatol 1998

What impairs CBF autoregulation in liver failure ?

Which mediator ?!

20

y = 0,4858x + 52,077 R2 = 0,207

20 40 60 80 100 120 140 20 40 60 80 100 120 140

CBF change (%) CPP (mm Hg) Paracetamol intoxication - pooled data, plateau

PHx 90% - pooled data, plateau

y = 0,7735x + 41 ,733 R2 = 0,231 2

20 40 60 80 100 120 140 20 40 60 80 100 120 140

CPP (mm Hg) CBF change (%)

Loss of liver mass and liver function

Systemic inflammation and CBF autoregulation: Effect of LPS and TNFα

TNF infusion - pooled data

y = 0.31x + 71.64

20 40 60 80 100 120 140 20 40 60 80 100 120

CPP change (%) CBF change (%)

21

Additional effect of systemic inflammation on CBF autoregulation

Control + LPS - pooled data

y = 0.28x + 73.58 20 40 60 80 100 120 140 20 40 60 80 100 120 CPP change (%) CBF change (%)

22 AI-comparison: Control 0.10 Control + LPS 0.28 p < 0.0001 ANOVA

= Corresponding group without LPS

GLN + LPS - pooled data

y = 0.90x + 12.87 20 40 60 80 100 120 140 20 40 60 80 100 120 CPP change (%) CBF change (%)

PHx90 + LPS - pooled data

y = 0.85x + 22.27 20 40 60 80 100 120 140 20 40 60 80 100 120 CPP change (%) CBF change (%)

• Bilateral cranial windows on anaesthetized rats
• Brain surface perfusion was evaluated with speckle contrast

imaging.

• 30 min topical exposure to 10 mM NH4Cl and aCSF

New method needed to detect adenosine in vivo

• not microdialysis

Biosensors to measure adenosine in real-time in rats exposed to NH3

Perivascular adenosine signal

CBF autoregulation is impaired by high NH3

CBF mapping of autoregulation in various brain areas (per pixel)

Bjerring P & Larsen FS. J Hepatol 2018; 68 j 1137–1143

Inhibition of adenosine receptor A2a by ZM 241385 prevents a high CBF during experimental hyperammonia

Impaired CBF autoregulation in experimental liver failure is mediated true adenosin receptors

Cerebral microcirculation in hyperammonemia

• Cerebral microcirculation is disturbed by topical NH3 exposure.
• NH3 exposure leads to increased perivascular adenosine tone.
• Adenosine receptor antagonism can restore the regulation of

microcirculation during arterial hypotension.

• CBF fluctuates in liver failure
• CBF autoregulation is impaired
• Cerebral vasodilation evolves due to
• loss of liver mass
• hyperammonemia
• sepsis / systemic inflammation

Conclusion - 1

The mediator of cerebral vasodilation and loss of autoregulation is Adenosine Antagonism of Adenosine receptor A2a restores CBF and CBF autoregulation Perspective Clinical use of Theophyllamine, ZM or just Coffee

Conclusion - 2

• Prof. Niels Secher
• Dr. Peter Bjerring
• Dr. Gitte Strauss
• Dr. Ellen Ejlersen
• Dr. Hans R. Pedersen
• Dr. Thomas Dethloff
• Dr. Martin Eefsen
• Dr. Bent Adel Hansen

Thanks to

• Prof. Gitte Moos Knudsen
• Dr. Otto Clemmesen
• Dr. John Hauerberg
• Dr. Flemming Tofteng
• Prof. Andres Blei
• Prof. Kirsten Møller
• Dr. Hans-Jørgen Frederiksen
• Prof. Julia Wendon

Clemmesen JO, Larsen fs & Ott P. Hepatology 1999;29:648-653 Bernal W Hepatology 2007

Hyperammonemia also causes brain edema and death