Integrative human cardiovascular control. Ph.D. course, Copenhagen, 2019 Nothing to disclose Cerebral blood flow in liver failure Fin Stolze Larsen, MD, PhD, DMSc Professor Div. of Hepatology, Rigshospitalet, University Hospital of Copenhagen, Denmark
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
Main regulatory mechanisms of CBF CBF to metabolism coupling 8 CMRO2 (ml/100g/min) seizures 7 6 5 4 3 2 1 coma 0 0 20 40 60 80 100 CBF (ml/100g/min) Seymour S. Kety Roy & Sherrington 1893 Magistretti
CBF in liver disease • Global CBF reduced in HE • Cognitive impairment correlates with rCBF in • basal ganglia and limbic cortex • cerebellum • frontotemporal regions • Reversible after liver transplantation • 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
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
Intestine Liver - Glu HCO3 + NH4 CP a -KG x Asp x Pyr Ala Glu Glu + Pyr NH4 +Glu + NH4 + NH4 Ala a -KG Urea + 206 ± 69 242 ± 118 NH4 Urea 2264 ± 1791 2393 ± 1807 Gln Ala 612 ± 417 421 ± 263 Clemmesen et al. Gastroenterol 2001
Cerebral mechanisms in HE: astrocyte swelling Ammonia is metabolised in brain astrocytes by glutamine synthetase: Although ammonia is important in pathogenesis, Glutamate + ATP + NH3 1 levels do not necessarily correlate with severity Other factors can precipitate HE 1 Glutamine + ADP + phosphate without high ammonia concentrations Hyponatraemia Benzodiazepines (sedatives) Inflammatory cytokines etc Intra-cellular glutamine is osmotically active 2 Induce astrocyte swelling in vitro and draws H2O into astrocytes Different neurotoxins may contribute to astrocyte 1 swelling and precipitate HE NH4 Gln H2O Glu (Ala) 1 Haussinger et al, Gut, 2012. 2 Haussinger et al, J Hepatol, 2000; 32(6):1035 – 8. H2O
Hyperammonemia increases CBF Chung et al. Hepatology 2001 Larsen et al. J Hepatol 2001
Why ?
Cerebral microdialysis in patients with liver failure ICP Glutamat 50 5 Glucose Lactat 45 4,5 40 4 Glucose & lactate (mmol/l) 35 3,5 Glutamate (umol/l) & ICP (mmHg) 30 3 25 2,5 20 2 15 1,5 10 1 5 0,5 0 0 0 7 24 45 79 86 53,5 72,5 96,5 105 119 126 128 147 172 189 141,5 154,5 158,5 Time (hours) Tofteng, Larsen. Hepatology 2002
Monitoring of ICP and cortex 35 concentration of glutamine Glutamine causes mitochondrial failure in the brain in liver failure? 30 Bjerrings et al. Neurocritical Care 2008 50 25 Intracranial pressure (mmHg) 45 40 lactate-pyruvate ratio 20 35 30 15 25 20 10 15 10 5 5 0 0 2000 4000 6000 8000 10000 12000 0 0 2000 4000 6000 8000 10000 12000 Glutamine concentration (umol/l) Cerebral glutamine concentration (umol/l) Tofteng et al. J Cerebral Blood Flow & Metabol. 2006
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
CBF in severe liver failure - interpretation HE grade I II III IV ICP CH NH 3 CMRO 2 [lactate]e CBF Adenosine? -------------- - - - - - - - - - - - - - - -
Main regulatory mechanisms of CBF II Vasoreactivity EH Starling WM Bayliss 1903, London
1 Main regulatory mechanisms of CBF - II 7 Mogens Fog. Cerebral circulation. Arch Neurol Psychiatry 1937; 37:351 – 364 Cerebral Autoregulation 180 160 Niels A Lassen 140 CBF (%change) Definition of CBF Lower Limit Plateau Phase 120 autoregulation in 100 1959 80 60 40 Upper Limit 20 0 0 20 40 60 80 100 120 140 160 180 200 Cerebral Perfusion Pressure (= MAP- ICP) (mm Hg)
CBF autoregulation is impaired in liver failure Strauss & Larsen. Hepatol 1997 and J Hepatol 1998 Larsen FS & Secher N. J Hepatol Jalan et al. Hepatology 2001 1995, CCM 1997 Tofteng & Larsen. J CBF & M 2004
What impairs CBF autoregulation in liver failure ? Which mediator ?!
Loss of liver mass and liver function PHx 90% - pooled data, plateau 140 120 CBF change (%) 100 80 60 40 y = 0,7735x + 41 ,733 R 2 = 0,231 2 20 Paracetamol intoxication - pooled data, plateau 0 0 20 40 60 80 100 120 140 CPP (mm Hg) 140 120 CBF change (%) 100 80 60 40 y = 0,4858x + 52,077 R 2 = 0,207 20 0 0 20 40 60 80 100 120 140 20 CPP (mm Hg)
Systemic inflammation and CBF autoregulation: Effect of LPS and TNF α TNF infusion - pooled data 140 120 100 CBF change (%) 80 60 40 y = 0.31x + 71.64 20 0 0 20 40 60 80 100 120 CPP change (%) 21
Additional effect of systemic inflammation on CBF autoregulation = Corresponding group without LPS PHx90 + LPS - pooled data Control + LPS - pooled data GLN + LPS - pooled data 140 140 140 120 120 120 100 100 100 CBF change (%) CBF change (%) CBF change (%) 80 80 80 60 60 60 AI-comparison: Control 0.10 Control + LPS 0.28 y = 0.28x + 73.58 40 40 40 y = 0.90x + 12.87 y = 0.85x + 22.27 p < 0.0001 ANOVA 20 20 20 0 0 0 0 0 0 20 20 20 40 40 40 60 60 60 80 80 80 100 100 100 120 120 120 CPP change (%) CPP change (%) CPP change (%) 22
New method needed to detect adenosine in vivo - not microdialysis • Bilateral cranial windows on anaesthetized rats • Brain surface perfusion was evaluated with speckle contrast imaging . • 30 min topical exposure to 10 mM NH 4 Cl and aCSF
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)
Inhibition of adenosine receptor A2a by ZM 241385 prevents a high CBF during experimental hyperammonia Bjerring P & Larsen FS. J Hepatol 2018; 68 j 1137 – 1143
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.
Conclusion - 1 • CBF fluctuates in liver failure • CBF autoregulation is impaired • Cerebral vasodilation evolves due to • loss of liver mass • hyperammonemia • sepsis / systemic inflammation
Conclusion - 2 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
Thanks to • Prof. Niels Secher • Prof. Gitte Moos Knudsen • Dr. Peter Bjerring • Dr. Otto Clemmesen • Dr. Gitte Strauss • Dr. John Hauerberg • Dr. Ellen Ejlersen • Dr. Flemming Tofteng • Dr. Hans R. Pedersen • Prof. Andres Blei • Dr. Thomas Dethloff • Prof. Kirsten Møller • Dr. Martin Eefsen • Dr. Hans-Jørgen Frederiksen • Dr. Bent Adel Hansen • Prof. Julia Wendon
Hyperammonemia also causes brain edema and death Clemmesen JO, Larsen fs & Ott P. Hepatology 1999;29:648-653 Bernal W Hepatology 2007
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