Intracranial pressure monitoring in acute liver failure. A procedure with clear indications.
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Comment↗
Biomedical subjects
Fin Stolze Larsen
Publications and source records attributed to Fin Stolze Larsen.
Prognostic implications of hyperlactatemia, multiple organ failure, and systemic inflammatory response syndrome in patients with acetaminophen-induced acute liver failure.
OBJECTIVE: Hyperlactatemia has been suggested as a prognostic marker in acetaminophen-induced fulminant hepatic failure, and a modification of the King's College Hospital criteria to incorporate arterial lactate measurements has recently been proposed. The aims of the present study were to further evaluate arterial lactate as a prognostic marker in acetaminophen-induced fulminant hepatic failure and to analyze its relationship to known causes of hyperlactatemia such as multiple organ failure and inflammation. DESIGN: Data were collected early after admission and again at the time of onset of grade 3-4 hepatic encephalopathy from acetaminophen-induced fulminant hepatic failure. Multiple organ failure and inflammatory response were assessed by the sequential organ failure assessment (SOFA) score and manifestation of the severe inflammatory response syndrome (SIRS), respectively. SETTING: A specialized liver intensive care unit at a tertiary liver center. PATIENTS: One hundred and one consecutive patients with acetaminophen-induced fulminant hepatic failure and grade 3-4 hepatic encephalopathy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Arterial lactate was higher in nonsurvivors than in survivors both early after admission (9.8 +/- 6.5 mmol/L vs. 5.2 +/- 4.2 mmol/L, p = .00004) and at the time of onset of hepatic encephalopathy (6.9 +/- 5.6 mmol/L vs. 3.2 +/- 2.0 mmol/L, p < .00001). At both time points, arterial lactate significantly correlated with SOFA score and the number of SIRS components fulfilled. Applying the lactate modification of the King's College Hospital criteria increased their sensitivity but reduced their specificity to <50%. CONCLUSIONS: The study confirmed arterial lactate as a prognostic marker in acetaminophen-induced fulminant hepatic failure. Arterial lactate correlated with SOFA score and with the number of SIRS components fulfilled. The lactate modification of the King's College Hospital criteria showed no obvious advantages over the existing selection criteria.
Acetaminophen↗
[Pregnancy's effects on the liver].
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Adult↗
Cerebral metabolic disturbances in the brain during acute liver failure: from hyperammonemia to energy failure and proteolysis.
Several observations suggest that patients with fulminant hepatic failure may suffer from disturbances in cerebral metabolism that can be related to elevated levels of arterial ammonia. One effect of ammonia is the inhibition of the rate limiting TCA cycle enzyme alpha-ketoglutarate dehydrogenase (alphaKGDH) and possibly also pyruvate dehydrogenase, but this has been regarded to be of no quantitative importance. However, recent studies justify a revision of this point of view. Based on published data, the following sequence of events is proposed. Inhibition of alphaKGDH both enhances the detoxification of ammonia by formation of glutamine from alpha-ketoglutarate and reduces the rate of NADH and oxidative ATP production in astrocytic mitochondria. In the astrocytic cytosol this will lead to formation of lactate even in the presence of sufficient oxygen supply. Since the aspartate-malate shuttle is compromised, there is a risk of depletion of mitochondrial NADH and ATP unless compensatory mechanisms are recruited. One likely compensatory mechanism is the use of amino acids for energy production. Branched chain amino acids, like isoleucine and valine can supply carbon skeletons that bypass the alphaKGDH inhibition and maintain TCA cycle activity. Large-scale consumption of certain amino acids can only be maintained by cerebral proteolysis, as has been observed in these patients. This hypothesis provides a link between hyperammonemia, ammonia detoxification by glutamine production, cerebral lactate production, and cerebral catabolic proteolysis in patients with FHF.
Ammonia↗
Effects of porta-systemic shunting and ammonia infusion on cerebral blood flow autoregulation in the rat.
BACKGROUND: Portacaval shunting of blood, hyperammonemia, and impaired cerebral blood flow (CBF) autoregulation are assumed to be involved in the development of high intracranial pressure (ICP) in liver failure. In this study, we determined whether CBF autoregulation is impaired by portacaval anastomosis and hyperammonemia. METHODS: Four groups of pentobarbital-sedated and mechanically ventilated rats were investigated after construction of a portacaval anastomosis or following sham operation. Half of the rats received either infusion of ammonia (55 micromol/kg/minute) or saline for 180 minutes. Arterial pressure and ICP was monitored, and lower limit of CBF autoregulation was determined. RESULTS: Lower limit of autoregulation was preserved in all four groups of studied animals; vehicle lower limits were 40 +/- 2.3, 40 +/- 2, 54 +/- 1, and 51 +/- 3 mmHg in sham-operated rats, sham rats receiving ammonia infusion, portacaval anastomosis-vehicle animals, and portacaval anastomosis-hyperammonemia animals, respectively. The lower limit of auto regulation was higher in portacaval anastomosis rats (p = 0.01) compared to the sham- operated rats. Hyperammonemia in portacaval anastomosis rats did not aggravate this. CONCLUSION: Portacaval anastomosis and hyperammonemia does not impair the lower limit of CBF autoregulation. However, shunting of portal blood to the systemic circulation shifts the lower limit of autoregulation to higher blood pressure values, making the brain more sensitive to episodes of arterial hypotension.
Ammonia↗
Cerebral blood flow and metabolism during infusion of norepinephrine and propofol in patients with bacterial meningitis.
BACKGROUND AND PURPOSE: In patients with severe bacterial meningitis, norepinephrine is often infused to increase mean arterial pressure (MAP). This increases cerebral blood flow (CBF), but it is unknown if this increase is caused by impaired cerebral autoregulation or by a cerebral effect of norepinephrine through increased cerebral metabolism. The latter possibility implies a CBF-metabolism coupling. This has not been studied during meningitis. We studied the effect of norepinephrine and propofol on CBF and oxidative metabolism in patients with severe bacterial meningitis. METHODS: In seven patients with pneumococcal meningitis and 7 healthy subjects, norepinephrine was infused intravenously; patients also underwent intravenous propofol infusion. Global CBF was measured by the Kety-Schmidt technique; cerebral oxidative metabolism and net flux of norepinephrine and epinephrine were calculated from measured arterial-to-jugular venous concentration differences (a-vD). RESULTS: During norepinephrine infusion, MAP increased from a median value of 79 (range, 70 to 89) to 99 (98 to 129) mm Hg in patients, and from 87 (72 to 103) to 123 (112 to 132) mm Hg in controls. CBF increased in patients (51 [48 to 60] to 59 [54 to 77] mL/100 g per minute) but remained unchanged in controls. The cerebral metabolic rate of oxygen (CMRO2) decreased in patients and remained unchanged in controls. No cerebral net flux of norepinephrine or epinephrine was found at any time in the 2 groups. During propofol infusion, CMRO2, and the a-vDO2 decreased whereas CBF was unchanged. CONCLUSIONS: In patients with severe bacterial meningitis, norepinephrine increases both MAP and CBF but not CMRO2, indicating impaired autoregulation. Propofol reduces CBF relatively less than cerebral metabolism, suggesting a resetting of the CBF-CMRO(2) relationship.
Adult↗
Optimal management of patients with fulminant hepatic failure: targeting the brain.
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Brain Edema↗
Tacrolimus ameliorates cerebral vasodilatation and intracranial hypertension in the rat with portacaval anastomosis and hyperammonemia.
Arterial hyperammonemia and cerebral vasodilatation correlate with cerebral herniation in patients with fulminant hepatic failure (FHF). Tacrolimus is a calcineurin inhibitor that passes the blood-brain barrier and may increase cerebrovascular tone and restrict cerebral ammonia influx. In this study, we determined if tacrolimus prevents cerebral vasodilatation and high intracranial pressure (ICP) in the rat with portacaval anastomosis (PCA) challenged to high arterial ammonia (NH4+) concentration. Seven groups of mechanically ventilated rats, with 6-9 rats in each group, were investigated within 48 hours after construction of a PCA (4 groups) or after sham operation (3 groups). Three groups of the rats received infusion of NH4+ and 4 groups received saline for approximately 180 minutes. Two groups of the PCA rats receiving either NH4+ or saline had an i.v. injection of tacrolimus (0.4 mg/kg) or vehicle before start of NH4+ or saline infusion. Cerebral blood flow (CBF) was monitored by a laser Doppler probe in brain cortex. ICP was monitored by placement of a catheter in the cerebrospinal fluid. CBF and ICP increased in PCA rats receiving NH4+ infusion compared to PCA controls and to all groups of sham-operated animals (P <.05). In the group of PCA rats pre-treated with tacrolimus before receiving ammonia infusion, the increase in ICP was ameliorated compared to the ammonia infused group receiving vehicle (P <.03). Tacrolimus also prevented an increase in CBF in the PCA group receiving NH4+ (P <.05) compared to the control groups. In conclusion, Tacrolimus prevents cerebral vasodilatation and ameliorates intracranial hypertension in PCA rats receiving NH4+ infusion. These findings indicate that tacrolimus could be of clinical value in the prevention of cerebral hyperemia, high ICP, and serious brain damage in patients with FHF.
Anastomosis, Surgical↗
Blood-brain barrier permeability to ammonia in liver failure: a critical reappraisal.
In patients with acute liver failure (ALF), hyperammonemia is related to development of cerebral edema and herniation. The present review discusses the mechanisms for the cerebral uptake of ammonia. A mathematical framework is provided to allow a quantitative examination of whether published studies can be explained by the conventional view that cerebral uptake of ammonia is restricted to diffusion of the unprotonated form (NH(3)) (the diffusion hypothesis). An increase in cerebral blood flow (CBF) enhanced ammonia uptake more than expected, possibly due to recruitment or heterogeneity of brain capillaries. Reported effects of pH on ammonia uptake were in the direction predicted by the diffusion hypothesis, but often less pronounced than expected. The published effects of mannitol, cooling, and indomethacin in experimental animals and patients were difficult to explain by the diffusion hypothesis alone, unless dramatic changes of capillary surface area or permeability for ammonia were induced. Therefore we considered the possible role of membrane protein mediated transport of NH(4)(+) across the blood-brain barrier (BBB). Early tracer studies in Rhesus monkeys suggested that NH(4)(+) is responsible for 20% or even more of the transport of ammonia from plasma to brain. In other locations, such as in the thick ascending limb of Hendle's loop and in isolated astrocytes, transport protein mediated translocation of NH(4)(+) is predominant. Many of the ion-transporters involved in renal NH(4)(+) reabsorbtion are also present in brain capillary membranes and could mediate uptake of NH(4)(+). Astrocytic uptake of NH(4)(+) is associated with increased extracellular K(+), which is a potent cerebral vasodilator. Such interference between transport of NH(4)(+) and other cations could be clinically important because increased cerebral blood flow often precedes cerebral herniation in acute liver failure. We suggest that protein mediated transport of NH(4)(+) through the brain capillary wall is a realistic possibility that should be more intensely studied.
Ammonia↗
Management of patients with fulminant hepatic failure and brain edema.
Cerebral edema in acute liver failure is associated with a poor prognosis. Optimization of cerebral perfusion pressure and blood flow plays a key role in contemporary management of these patients. However, understanding of the pathophysiology of brain edema is required for optimal patient management. This review explains the relationships between cerebral perfusion and edema and summarizes therapies that are currently used in patients with acute liver failure to prevent and reduce intracranial pressure.
Blood-Brain Barrier↗
Splanchnic metabolism in acute liver failure and sepsis.
PURPOSE OF REVIEW: A number of papers have suggested that the splanchnic circulation and oxidative metabolism are compromised in critical illness. This review discusses this hypothesis and outlines the recent advances in the understanding of splanchnic metabolism with special focus on acute liver failure and hyperdynamic sepsis. RECENT FINDINGS: Splanchnic blood flow, oxygen delivery, and consumption are increased in both acute liver failure and sepsis. The capability of the liver to extract oxygen, even under extreme conditions, renders the liver less prone to hypoxia. A common feature of acute liver failure and sepsis is a hypermetabolic state with enhanced glycolysis and production of lactate and pyruvate. Human studies on other features of intermediary metabolism are sparse, but there are indications that several intermediary processes are severely compromised in patients with acute liver failure, whereas these processes are maintained in sepsis. SUMMARY: There is increasing evidence that both acute liver failure and sepsis are accompanied by a hypermetabolic state in the hepatosplanchnic area, characterized by enhanced glycolysis and hyperlactatemia. This should not be rigorously interpreted as an indication of hypoxia. In fact, clinically important splanchnic hypoxia may be a relatively uncommon phenomenon in such patients.
Humans↗
The effect of indomethacin on intracranial pressure, cerebral perfusion and extracellular lactate and glutamate concentrations in patients with fulminant hepatic failure.
Uncontrolled increase in intracranial pressure (ICP) continues to be one of the most significant causes of early death in patients with acute liver failure (ALF). In this study, we aimed to determine the effects of indomethacin on ICP and cerebral perfusion pressure in twelve patients with ALF and brain edema (9 females/3 males, median age 49,5 (range 21 to 64) yrs.). Also changes in cerebral perfusion determined by transcranial Doppler technique (Vmean) and jugular bulb oxygen saturation (SvjO2) were measured, as well as brain content of lactate and glutamate by microdialysis technique. Finally, we determined the cerebral blood flow autoregulation before and after indomethacin injection. We found that indomethacin reduced ICP from 30 (7 to 53) to 12 (4 to 33) mmHg (P < 0.05). The cerebral perfusion pressure increased from 48 (0 to 119) to 65 (42 to 129) mmHg (P < 0.05), while Vmean and SvjO2 on average remained unchanged at 68 (34 to 126) cm/s and 67 (28 to 82) %, respectively. The lactate and glutamate in the brain tissue were not altered (2.1 (1.8 to 7.8) mmol/l and 34 (2 to 268) micromol/l, respectively) after injection of indomethacin. Cerebral blood flow autoregulation was impaired in all patients before injection of indomethacin, but was not restored after administration of indomethacin. We conclude that a bolus injection of indomethacin reduces ICP and increases cerebral perfusion pressure without compromising cerebral perfusion or oxidative metabolism in patients with ALF. This finding indicates that indomethacin may be valuable as rescue treatment of uncontrolled intracranial hypertension in fulminant hepatic failure.
Adult↗
Blood lactate as a prognostic marker in acetaminophen-induced acute liver failure.
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Comment↗
Cerebral glucose and oxygen metabolism in patients with fulminant hepatic failure.
Hyperammonemia and hyperventilation are consistent findings in patients with fulminant hepatic failure (FHF), which may interfere with cerebral glucose and oxygen metabolism. The aim of the present study is to evaluate whether cerebral oxidative metabolism is preserved early in the course of FHF and whether hyperventilation has an influence on this. We included 16 patients with FHF, 5 patients with cirrhosis of the liver, and 8 healthy subjects. Concomitant blood sampling from an arterial catheter and a catheter in the jugular bulb and measurement of cerebral blood flow by the xenon 133 wash-out technique allowed calculation of cerebral uptake of glucose (CMRgluc) and oxygen (CMRO2). Both CMRgluc and CMRO2 were reduced in patients with FHF compared with those with cirrhosis and healthy subjects, i.e., 11.8 +/- 2.7 v 18.3 +/- 5.5 and 28.5 +/- 6.6 micromol/100 g/min (P <.05) and 86 +/- 18 v 164 +/- 42 and 174 +/- 27 micromol/100 g/min (P <.05). Arteriovenous difference in oxygen and oxygen-glucose index were normal in patients with FHF. Institution of mechanical hyperventilation did not affect glucose and oxygen uptake and hyperventilation did not affect lactate-pyruvate ratio or lactate-oxygen index. In conclusion, we found that cerebral glucose and oxygen consumption are proportionally decreased in patients with FHF investigated before clinical signs of cerebral edema. Our data suggest that cerebral oxidative metabolism is retained at this stage of the disease without being compromised by hyperventilation.
Acetoacetates↗
Cerebral oxygenation determined by near-infrared spectrophotometry in patients with fulminant hepatic failure.
BACKGROUND/AIMS: In severe cases of acute liver failure (ALF), cerebral hyperperfusion may result in high intracranial pressure and brain damage. The aim of this study was to determine if near-infrared spectrophotometry (NIRS) could detect a raise in cerebral blood flow and oxygenation induced by noradrenaline (NA) infusion. METHODS: In seven ALF patients (five females and two males; median age 49 years (range 20-70)) changes in cerebral concentration of oxy-(deltaHbO(2)) and total-haemoglobin (deltaHbT) were compared to the jugular bulb saturation (SvjO(2)) and cerebral blood flow velocity (Vmean) during NA infusion. RESULTS: Mean arterial pressure increased from 68 (64-86) to 103 (87-118) mmHg and the cerebral perfusion pressure from 61 (53-79) to 95 (74-110) mmHg (P<0.05), while the intracranial pressure (7 (6-15) mmHg) was not significantly changed. In six patients cerebral deltaHbO(2) and deltaHbT increased 2.7 (0.3-9.6) and 2.0 (0.3-14.8) micromol l(-1), respectively, but cerebral oxygenation decreased in one patient. SvjO(2) increased from 68 (55-76) to 74 (64-78) % (P<0.05) concomitant with an increase in Vmean from 47 (34-65) to 68 (50-86) cm s(-1) (P<0.05). deltaHbO(2) covariated with changes in SvjO(2) during NA in all but one patient. CONCLUSIONS: In ALF patients, a change in cerebral perfusion was detected by NIRS. The combination of NIRS and transcranial Doppler sonography may be valuable non-invasive techniques to detect cerebral hyperperfusion before intracranial hypertension becomes manifest.
Adult↗
Systemic hemodynamic effects of treatment with the molecular adsorbents recirculating system in patients with hyperacute liver failure: a prospective controlled trial.
The aim of the study is to evaluate the effect of a single treatment with the molecular adsorbents recirculating system (MARS) on systemic hemodynamics and oxygen consumption (VO(2)) in patients with hyperacute liver failure (HALF). In a controlled design, eight patients with HALF were assigned to a 6-hour MARS treatment, and five patients, to a control group that was mechanically cooled to match the MARS group. Systemic hemodynamic variables were determined hourly during the study period. In the MARS group, systemic vascular resistance index increased by 46% from 1,215 +/- 437 to 1,778 +/- 710 dynes x s x cm(-5) x m(-2) (P <.0001), which significantly exceeded a 6% increase in the control group. Mean arterial pressure increased from 69 +/- 5 to 83 +/- 11 mm Hg in the MARS group (P <.0001) and was unchanged in the control group. Cardiac index decreased by 20% from 4.6 +/- 1.8 to 3.7 +/- 1.1 L/min x m(-2) (P =.0007) in the MARS group and by 7% in the control group. Heart rate decreased from 105 +/- 21 to 85 +/- 15 beats/min in the MARS group (P <.0001) and was unchanged in the control group. In the MARS group, oxygen delivery decreased from 621 +/- 198 to 486 +/- 141 mL/min x m(-2) (P <.05), and VO2, from 142 +/- 31 to 112 +/-21 mL/min x m(-2) (P <.05). Arterial lactate and pH levels were unchanged. In conclusion, systemic hemodynamic values tend to normalize, whereas systemic VO(2) decreases during MARS treatment in patients with HALF. These effects cannot be explained by the degree of cooling associated with MARS.
Acetaminophen↗
[Non-biological liver support in hepatic failure].
Liver failure leads to the accumulation of a range of toxins that may be implicated in the development of the multiorgan failure associated with liver failure. A device capable of removing toxins would thus be useful in the treatment of liver failure by stabilising the patient until either the liver begins to regenerate or liver transplantation can take place. A number of non-biological devices based on modifications and combinations of haemodialysis, haemofiltration, haemoperfusion, and plasma separation have been investigated and are reviewed in this article. So far, the most promising results have been demonstrated with devices that remove a wide range of toxins, including those bound to albumin.
Dialysis↗
Cerebral blood flow in hyperammonemia: heterogeneity and starling forces in capillaries.
In the brain hyperammonemia interferes with ion homeostasis, membrane potentials, neurotransmission, and neurotransmitter recycling and reduces metabolic rates for oxygen and glucose. Because, cerebral blood flow (CBF) is closely coupled to metabolism, CBF is most often reduced in diseases associated with hyperammonemia. However, in severe cases of hyperammonemia, as in patients with acute liver failure, Reye's syndrome, and inherited metabolic disorders of the urea cycle, the normal regulation of CBF is also impaired. One of the most prominent findings is a failure of CBF autoregulation that uncouples metabolism from CBF. Clinically failure of autoregulation may imply that both cerebral hypoxia and hyperaemia may develop in the patient depending on the driving pressure of the brain, i.e., cerebral perfusion pressure. In addition a gradual "nonreactive" dilatation of the cerebral arterioles often aggravates the mismatch between nutritive demands and delivery in the brain. The reason for arteriolar dilation and homogeneous capillary blood flow is not settled but seems not to be mediated by excessive release of nitro oxide. More likely the arachidonic acid cascade with increased synthesis of prostaglandins, cytochrome P450 metabolites, and potassium channel activation are implicated in this vasodilatation. The combination of cerebral hyperaemia, increased hydrostatic capillary blood pressure, and accumulation of organic and nonorganic osmolytes within the brain during hyperammonemia clearly will favor cerebral capillary water influx. This imbalance between colloid osmotic and hydrostatic pressures in patients with severe hyperammonemia means that simple interventions based on physiological principles may help ameliorate cerebral hyperaemia and water influx. Thus, it is suggested that not only monitoring of intracranial pressure (ICP) and cerebral perfusion are pivotal to help prevent high ICP but also basic clinical information, such as Tp, PaCO2, and plasma sodium/glucose concentrations, should be closely followed and corrected.
Capillaries↗