Table 2. published studie anoxie

Table 2. Published

Table 2. Published studies upon cerebral blood flow in patients with FHF.No. OfAuthor (paper and year) patients HE CBF methodede (gastroenterol jpn, 1988) [62]. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 IV 195 (122-310)* 133 xe injectionalmdal (sc and J gastroenterol,1989) [59] . . . . . . . . . . . . . . . . . . . . . . . . 12 II-IV 31 ± 4 133 xe injectionaggarwal (transpl proc, 1991) [60] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 IV 30 (4-60) 133 xe-inj / xe-ctaggarwal (hepatology, 1994) [12] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 IV 42 (16-95) 133 xe-inj / xe-ctwendon (hepatology, 1994) [14] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 IV 30 (14-71) 133 xe injectiondurham (JCBF, 1995) [58] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 IV 38 (18-66) xenon-ctlarsen (liver transpl surg, 1996) [61] . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 IV 34 (12-54) 133 xe injectionjalan (lancet, 1999) [63] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 # IV 103 (25-134) N 2 O inhalationjalan (hepatology, 2001) [93]. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 # IV 111 (69-134) N 2 O inhalationstrauss (liver transpl, 2001) (III) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 IV 43 (36-60) 133 xe injectionstrauss (gastroenterol, 2001) (IV). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 IV 39 ± 8 133 xe injectionjalan (J hepatol, 2004) [65] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 # IV 85 (24-134) N 2 O inhalation13 -do- 45 (23-56) -do-jalan (gastroent., 2004) [64]. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 # IV 78 ± 9.7 § N 2 O inhalation*) normal value for this study was reported to be 120 ml/100g/min#) patients with increased intracranial pressure§) mean ± semintracranial hypertension had increased CBF, i.E., 85 (23-134)ml/(100g × min), whereas the patients without intracranial hypertensionhad a reduced CBF, i.E., 45 (23-56) ml/(100g × min), correspondingto other studies of patients with FHF without intracranialhypertension (table 2).Anoxie


thus, there seems to be evidence to supportthat CBF is low unless intracranial hypertension has evolved inpatients with FHF. Whether this increase in CBF develops graduallyor immediately before surges of intracranial hypertension in theclinical setting is not possible to unravel from the present studies inthis thesis (I-VII) but studies of rats have shown that CBF graduallyincreases during the course of FHF [67]. The pathophysiological reason for the decreased CBF found inthis thesis may rely on a number of different mechanisms:3.1.1 hepatic encephalopathy and sedationincreased neural activity increases the energy expenditure for ionpumping and transmitter synthesis, resulting in increased energyproduction due to increased oxidative glucose consumption,which is supplied by an increase in CBF.Anoxie conversely, CBF decreasesduring states with decreased neuronal activity, such as duringcoma [68, 69] and sleep [70]. Patients with FHF in the presentstudy were in deep coma; hence the finding of a reduced CBF ismost probable due to the decreased cerebral metabolism and neuronalactivity (VII). Additionally, administration of midazolammay also have contributed to the reduced CBF in the presentstudies. In healthy volunteers intravenous administration of midazolam(0.15 mg/kg) given as a single bolus over 15 sec, resulted ina reduction in CBF of ~30% 6 minutes after the injection [71].After a bolus injection of diazepam, sari et al [72] showed thatcbf was maximally reduced after 10 minutes, and reached normalvalues after 90-120 minutes.Anoxie the studied patients in this thesiswere administered midazolam continuously (~0.125 mg/kg/h).Thus, the percent reduction in CBF due to administration of bolusinjection of midazolam is not directly comparable to the data inthis thesis. During craniotomy of patients with cerebral tumorswhere midazolam was administered continuously (0.125 mg/kg/hvs. 0.250 mg/kg/h) knudsen et al found reduced CBF values withno relationship to the dose administered [73]. However, CBF wasnot measured prior to administration of midazolam, thus it is notpossible to determine to what extent CBF was reduced from normalvalues.3.1.2 hyperammonia and glutamineto avoid the deleterious effects of ammonia, humans detoxify ammoniaby incorporating it into urea.Anoxie urea is generated in the liver bythe urea cycle, when the liver is failing blood ammonia levels increase.At high levels ammonia is neurotoxic, and leads to functionaldisturbances of the central nervous system [74], but it is conflictingwhether ammonia per se affects CBF. Some studies have demonstratedthat acute ammonia infusion dilate cerebral vessels and increasescbf [10], while others found that CBF decrease [75]. In thepresent thesis, there was no relationship between CBF and arterialammonia levels in patients with FHF (figure 2) (IV). Contrary, jalanet al [65] found a positive correlation between CBF and arterialammonia. This discrepancy may be due to time differences, as thepatients in this thesis were investigated well before the development of cerebral edema and intracranial hypertension, while the patientsin the study by jalan et al [65] were investigated later during the cerebral illness of FHF.Since the brain lacks urea cycle enzymes, ammonia removal fromthe brain relies on the formation of different amino acids, mostlyglutamine and alanine, which are the main nitrogen carriers out ofthe brain (IV).Anoxie A recent study shows that accumulation of glutamineper se only plays a limited role as a cause of cerebral edema infhf, as mild hypothermia prevented cerebral edema in an animalmodel of FHF despite glutamine accumulation [76]. However, thesefindings do not preclude other important contributions ofglutamine to the cerebral complications in FHF as hypothermia mayhave several other effects on the brain that may have contributed tothe protective effect. In accordance with the experimental study bymaster et al [77] we found that patients who subsequently died ofintracranial hypertension had significantly higher cerebral ammoniauptake and cerebral glutamine efflux as compared to patientswho survived (IV), suggesting that ammonia and glutamine playsan important role for the subsequent surges of intracranial hyper-CBF (ml/(100 g × min))60504030201000 50 100 150 200 250 300ammonia (µmol/L)figure 2.Anoxie arterial ammonia concentration plotted against CBF in patientswith FHF.102 DANISH MEDICAL BULLETIN VOL. 54 NO. 2/MAY 2007

Tension. Whether or not this effect is cytotoxic, or is a combination of a cytotoxic and vasogenic effect is not possible to settle from thepresent study (IV).Although the exact mechanism of ammonia toxicity is unresolved,hyperammonemia and cerebral glutamine accumulation appears tohave several other effects on brain and cerebral metabolism that maycontribute to or aggravate cerebral edema formation and induce cerebral vasodilation, including effects on cerebral energy metabolism[78], lactate/pyruvate production [79], astrocytic glutamatetransport [80], brain ATP depletion by activation of NMDA receptors[81], nitrosactive/oxidative stress and induction of the mitochondrialpermeability transition in cultured astrocytes [82].Anoxie thepresent clinical studies do not allow for any conclusions on the cellular effects of hyperammonemia and cerebral glutamine accumulation,nor do they allow for conclusion on their effects upon cbflater during the disease course of FHF. However, in the early stages of FHF hyperammonemia and glutamine accumulation did not affectcbf and cerebral oxidative metabolism (VII).3.1.3 acetaminophen and cbfrecent studies have revealed evidence that acetaminophen inhibitsprostagl andin E 2 production in rat cerebral endothelial cells possiblyby acting against cyclooxygenase-2 [83]. Accordingly, inhibition ofprostagl andin E 2 production could also to some extent have influencedcbf in patients with FHF, as prostagl andin E 2 is a vasodilator and acetaminophen intoxication was the reason for FHF in most ofthe patients (I-VII).Anoxie notwithst anding, CBF in patients withoutacetaminophen intoxication was similar to patients with acetaminophenintoxication, i.E., 38 (28-55) vs. 40 (28-54) ml/(100g ×min) (NS). Patients with acetaminophen intoxication appears tohave a better outcome in larger series of FHF, and it is possible thatthis inhibitory effect upon cyclooxygenase-2 may play a role in thissetting by inhibiting the gradual increase in CBF that seems toevolve during the disease course.In conclusion CBF is reduced within the first 24 h after development of stage III-IV hepatic encephalopathy. Increase in CBF seemsto be a phenomenon that takes place later during the disease course, and only evolve in patients who subsequently develop intracranialhypertension.Anoxie the low CBF values found in the studied patients inthis thesis can be explained by the presence of hepatic encephalopathy and sedation by midazolam.3.2 THE EFFECT OF HYPERVENTILATION ON CBFAND METABOLISM IN fhfcerebral CO 2 reactivity is the change in CBF per unit change inpaco 2, defined as the % change in CBF divided by the ∆paco 2 (inmmhg). At first the relationship between paco 2 and CBF wasthought to be linear, however, later studies have shown that it is sigmoid,with a CO 2 reactivity that increases at high paco 2 levels anddecreases at low paco 2 levels.3.2.1 global cerebral CO 2 reactivityin this thesis global CO 2 reactivity was found normal in patientswith FHF compared to controls.Anoxie all clinical studies of cerebral CO 2reactivity to hypocapnia performed on patients with FHF are displayedin table 3 (III) [12, 14, 58, 84, 85]. All these studies reportedalmost similar cerebral CO 2 reactivity, except for one study wherethe hypocapnic CO 2 reactivity appeared much higher [85]. One explanationfor this apparent discrepancy could be that by sari et al[85], contained pooled data of patients with hepatic encephalopathy and septic encephalopathy. Thus, that study was not completelycomparable with the other studies, which only contained patientswith FHF. As can be seen from table 3, values of CO 2 reactivity variedwidely among patients with FHF. In two of the studies [12, 58] aparadox increase in CBF to hypocapnia, i.E., a negative CO 2 reactivity,was found in one patient (table 3).Anoxie neither mean arterial bloodpressure nor intracranial pressure was measured in these studies. Alteration of these pressures during the study period may have accountedfor the apparent increase in CBF to hypocapnia. That is, ifintracranial pressure was high before institution of hypocapnia, andsubsequently was reduced during hypocapnia, then the resultant cerebral perfusion pressure is increased, and thereby also CBF. Likewise,if mean arterial pressure drops significantly during hyperventilation,then the resultant cerebral perfusion pressure is reduced andthereby CBF. Methodological problems should also be considered aswell as time difference, as it cannot be excluded that cerebral CO 2 reactivityis completely lost later during the course of FHF [84].Anoxie the cerebral CO 2 reactivity is influenced both by the oxygen status and by the mean arterial blood pressure, as both hypoxia and hypotensioninduce vasodilation [86]. Thus, vasodilation induced byeither hypoxia or hypotension may blunt the cerebral CO 2 reactivityduring hypercapnia. In 1996, larsen et al [84] explored the cerebralco 2 reactivity in a prospective study including both patients withfhf and rats with thioacetamide-induced liver failure. It was foundthat patients with FHF had a reduced cerebral CO 2 reactivity duringhypercapnia as compared to healthy subjects, ~2.2 vs. ~4.6%mmhg -1 , while it was normal during hypocapnia (table 3) [84].This finding was in accordance with a retrospective study of patientswith FHF published by durham et al a year before [58].Anoxie accordingly,larsen et al suggested that the cerebral CO 2 reactivity curve isleft-shifted in FHF, i.E., CO 2 reactivity decreases during hypercapnia,while it is relatively preserved during hypocapnia (figure 3)[84].Animal studies have reported that cerebrovascular reactivity tohypercapnia is blunted following acute elevation of blood ammonialevels [87-89]. Thus, it could speculated that the increased bloodtable 3. Previous published studies on cerebral CO 2 reactivity to hypocapnia in healthy subjects and patients with FHF.NormoventilationHyperventilationMAP paco 2 CBF MAP paco 2 CBF CO 2 reactivitymmhg mmhg ml (100 g min) -1 mmhg mmhg ml (100 g min) -1 %mmhg -1healthy subjlarsen (1996) [84] . . . . . . . . . . — 39 (24-44) 66(38-88) § — 20 (13-27) 35 (20-45) § 3.0 (1.7-5.0)moller (2002) [102] . . . . . . . . . — 42 (37-43) 71 (49-79) — 25 (20-31) 47 (34-50) 2.1 (1.6-2.7)fhfsari (1990) [85]. . . . . . . . . . . . . 86 ± 25 43 ± 5 52 ± 31 86 ± 25 35 ± 5 26 ± 7 ~6.2 awendon (1994) [14] . . . . . . . . — 37 (31-41) 36 (15-57) — 28 (25-31) 28 (9-35) ~2.5*aggarwal (1994) [12] . . . . . . . — 32 (19-43) 47 (23-78) — ∆CO 2 ≈ 8 — 3.1 (-1.5–6.1)durham (1995) [58] . . . . . . . . . — 36 (15-45) 40 (28-57) — 28 (10-32) 28 (14-50) 3.5 (-1–11)larsen (1996) [84] . . . . . . . . . . 72 (56-88) 36 (27-44) 61 (28-116) § 72 (56-88) 28 (23-39) 44 (23-100) § 4.0 (1.1-7.4)strauss (2001) (III) . . . . . . . . . . 80 (60-92) 37 (34-41) 43 (36-60) 75 (55-88) 28 (26-33) 32 (27-39) 2.5 (0.8-4.9)52 (39-66) § 43 (31-55) § 1.4 (0.6-2.7) ba) this study contains patients with both septic and hepatic encephalopathy*) calculated from the reported values§) not an absolute measure of CBF, but a relative measure of CBF obtained by transcranial doppler (TCD) mean flow velocity (cm s -1 )b) significantly lower CO2 reactivity obtained by the TCD technique compared to the kety schmidt technique.DANISH MEDICAL BULLETIN VOL. 54 NO. 2/MAY 2007 103