Vaquero J, Fontana RJ, Larson AM, Bass NMT, Davern TJ, Shakil AO, Han S, Harrison ME, Stravitz TR, Munoz S, Brown R, Lee WM, Blei AT. Complications and use of intracranial pressure monitoring in patients with acute liver failure and severe encephalopathy. Liver Transpl 2005;11:1581-1589. (Reprinted with permission.)
Monitoring of intracranial pressure (ICP) in acute liver failure (ALF) is controversial as a result of the reported complication risk (approximately 20%) and limited therapeutic options for intracranial hypertension. Using prospectively collected information from 332 patients with ALF and severe encephalopathy, we evaluated a recent experience with ICP monitoring in the 24 centers constituting the U.S. ALF Study Group. Special attention was given to the rate of complications, changes in management, and outcome after liver transplantation (LT). ICP monitoring was used in 92 patients (28% of the cohort), but the frequency of monitoring differed between centers (P < .001). ICP monitoring was strongly associated with the indication of LT (P < .001). A survey performed in a subset of 58 patients with ICP monitoring revealed intracranial hemorrhage in 10.3% of the cohort, half of the complications being incidental radiological findings. However, intracranial bleeding could have contributed to the demise of 2 patients. In subjects listed for LT, ICP monitoring was associated with a higher proportion of subjects receiving vasopressors and ICP-related medications. The 30-day survival post-LT was similar in both monitored and nonmonitored groups (85% vs. 85%). In conclusion, the risk of intracranial hemorrhage following ICP monitoring may have decreased in the last decade, but major complications are still present. In the absence of ICP monitoring, however, patients listed for LT appear to be treated less aggressively for intracranial hypertension. In view of the high 30-day survival rate after LT, future studies of the impact of intracranial hypertension should also focus on long-term neurological recovery from ALF.
In patients with acute liver failure (ALF) and grade III-IV encephalopathy, acute intracranial hypertension (ICH) due to brain edema has an inhomogeneous 25% to 50% prevalence and affects preferentially patients with hyperacute and acute development of encephalopathy, especially those younger than 35 years,1i.e., patients with the highest survival rates. Severe acute ICH, defined by intracranial pressure (ICP) above 25 mm Hg, is one of the most dangerous complications of ALF. In the last 20 years, while emergency liver transplantation (LT) became available, hepatologists and liver surgeons hypothesized that controlling increased ICP (prior, during or after LT) would be better and, thus, allow to increase global survival of patients with ALF. This hypothesis derived from the accepted beneficial effects of ICP monitoring (and closely linked treatment of ICH) on survival both in comatose patients with traumatic brain injury2, 3 and, less convincingly, in patients with the most severe forms of Reye's syndrome.4 Up to now, no randomized controlled trial (RCT) supports this hypothesis and this lack of evidence-based practice makes the prospective, albeit uncontrolled, study by Vaquero et al.,5 an important piece of work regarding the still controversial issue: is it useful to monitor ICP in patients with grade III-IV encephalopathy secondary to ALF?
The most important result in Vaquero et al.'s study5 is the simultaneous finding of the lack of influence of ICP monitoring on survival of patients with ALF and grade III-IV encephalopathy coupled with life-threatening side-effects due to this invasive monitoring. The apparent failure of ICP monitoring to improve survival in these patients might be disregarded by those who are both supporters of evidence-based medicine and experienced users of ICP monitoring since the study by Vaquero et al.5 is not a RCT. However, Vaquero et al.'s data on post-LT survival5 are in accordance with both the lack of influence of ICP monitoring on overall survival in the King's College Hospital's study6 and the lack of significant difference in the rate of ICP monitoring between survivors and non-survivors (whether transplanted or not) among 101 consecutive Danish patients with acetaminophen-induced ALF and grade III-IV encephalopathy.7 Finally, in patients transplanted for ALF and grade III-IV encephalopathy, post-LT survival remained in the usual range while the pre-LT ICP monitoring rate was 15% recently in Birmingham (UK)8 and even zero in the late 80's in Chicago9 and in the 90's at Hopital Beaujon.10 So it may be anticipated that a RCT aiming to show a beneficial effect of ICP monitoring (and ensuing therapeutic measures) on survival of patients with ALF and grade III-IV encephalopathy both will require a very large number of patients and is at high risk to end in a negative result.
Intracranial hemorrhage is the main complications of ICP monitoring in patients with severely decreased coagulation factors activity, and sometimes thrombopenia, such as patients with ALF. Among 58 patients with ICP monitoring in the Vaquero et al's study,5 symptomatic intracranial hemorrhage occurred in 2 patients (3.4%), who died with brain edema, including one of 18 (5.5%) who died without LT (A. Blei, personal communication). In addition, patients with ALF managed with ICP monitoring might have various, indirect and hidden, side-effects related to the many treatments administered for the placement of the ICP transducer and to decrease surges of ICH.5 Large amounts of fresh plasma5 may cloud accurate prognostic evaluation of coagulation factors and, when barbiturates are used, possible hypotension may alter regeneration of surviving hepatocytes.11
The lack of demonstration by RCT of the efficacy of ICP monitoring on survival of patients with ALF along with the results reported by Vaquero et al.,5 and others,6, 7 are the background of the uneven prevalence of using ICP monitoring in patients with ALF and grade III-IV encephalopathy: 28% in the Vaquero et al.'s study,5 but more than 60% in some U.S. centers5 and at King's College Hospital,12 to 20% to 30% in Birmingham (UK)13 or Copenhagen,7 and only 16% in Spain (A. Mas, personal communication). ICP monitoring is not used in other U.S. centers5, 9 or at Hopital Beaujon and is no longer used at Hôpital Paul-Brousse (Villejuif, France) after 2 fatal cases of intracranial hemorrhage (D. Samuel, personal communication).
How could we explain the fact that 3 independent (2 recent) studies5–7 show that survival of patients with ALF and grade III-IV encephalopathy is not improved by ICP monitoring? At least three hypotheses could be forwarded. The first hypothesis is that actual benefits provided by ICP monitoring are counterbalanced by its deleterious influence on the patient's condition, as discussed above.
The second hypothesis is that beneficial effect of ICP monitoring could be restricted to a small subgroup of patients with ALF. Accordingly, patients in whom ICP monitoring would be useful may be difficult to identify on clinical grounds, even among those with grade III-IV encephalopathy. Clinical signs of ICH are not specific and may be lacking,14 and, in some centers, ICP monitoring is used as a tool to prevent raised ICP.13 Moreover, clinical features of encephalopathy may be aggravated by insufficient fluid resuscitation15 or recent administration of neurotropic drugs or terlipressin.16 As a consequence, despite the presence of grade III-IV encephalopathy and even clinical symptoms ascribed to ICH,6, 14 no surge of ICH may be recorded by monitoring as recently observed in 37% of 27 patients in Birmingham (UK)17 (J. Neuberger, personal communication). In such patients with ICP lower than 25 mm Hg (and therefore at low risk of life-threatening ICH), fatality rate is relatively low – 2 of 11 patients in a recent report by Aggarwal et al.18 Therefore, it might be that using invasive monitoring unnecessarily expose at least some patients with “normal” ICP to deleterious side-effects and, thus, appear as a noticeable drawback of this invasive surveillance. Recently, Bernal et al.12 showed that admission level of arterial ammonia both was significantly increased (> 140 μmol/L) in patients who did develop raised ICP and correlated with the peak ICP. Using this criteria (arterial ammonia > 150 μmol/L)15 as well as “clinical suspicion”, Schmidt and Larsen7 reported a 15% rate of ICP monitoring in spontaneous survivors (vs. 22% in spontaneous survivors of the Vaquero et al.'s study5) (A. Blei, personal communication). Since survival is not depending on ICP monitoring, one may question whether at least some spontaneous survivors managed with this invasive monitoring were overmonitored. Indeed, the often rapid recovery of their liver function is depending much more on the relatively limited destruction of their liver tissue together with effective liver regeneration than on ICP monitoring.
The third hypothesis is that actual benefits provided by invasive ICP monitoring are likely to be modest ones. Experts supporting the use of ICP monitoring emphasize that the procedure facilitates the cerebral management of the patients19 and one cannot refute the idea that, among patients who died from brain death in a center (such as ours) where ICP is not used, some may have survived (at least up to LT) with ICP monitoring. However, that ICP monitoring by itself fails to improve overall survival of patients with ALF and grade III-IV encephalopathy has a two-side implication. The first one is the failure to improve the capacity of adequate nursing and medical therapy alone to increase spontaneous survival. The second implication is the failure to obviate emergency LT or fatal outcome because of the lack of effective therapy against the most severe cases of acute ICH secondary to ALF. The main cause of ICH secondary to ALF is brain edema due to massive and rapid (often hyperacute) destruction of the liver: ICH secondary to ALF is, therefore, quite different from, and difficult to compare to, posttraumatic ICH the cause of which lies exclusively inside the brain.
In conclusion, there is no definite answer to the question: is it useful to monitor ICP in patients with grade III-IV encephalopathy secondary to ALF ? However, it should be possible to reduce the number of patients exposed to the risk of intracranial hemorrhage with an improved selection of the patients to be managed with ICP monitoring. This selection could be based on several features (etiology, hemodynamic condition, arterial ammonia, spontaneous activity of coagulation factors, serum creatinine, natremia) allowing to exclude from monitoring those patients with the highest probability of spontaneous survival. However, the best answer to the above-mentioned challenge is, when possible, to prevent the sometimes avoidable aggravating, or accelerating, factors of encephalopathy in patients with acute liver disease and severe coagulopathy but still without neurological symptoms. In such patients, this prevention should include the early prescription of specific treatments, severe restriction of neurotropic and potentially hepatotoxic drugs and finally the transfer of the patient to a liver unit prior to the onset of clinical encephalopathy.20
The authors gratefully acknowledge Pr A. Blei, Pr A. Mas, Pr J. Neuberger and Pr D. Samuel for kindly providing them with some unpublished data and Pr D. Valla for useful suggestions.