The recent paper by Vaquero et al. in Liver Transplantation,1 is a particularly timely publication, given that treatment options for acute liver failure (ALF) have advanced significantly with improved outcome seen in those proceeding to transplantation and in those receiving medical management. The Acute Liver Failure Study Group (ALFSG) collated data from multiple centres responsible for the care of patients with ALF; management and monitoring being determined by the local centres. Demographic, epidemiological and clinical data are collated on day of admission and day of discharge, death or at 3 weeks, incorporating data on clinical course, laboratory data and therapeutic measures employed in the first 7 days. Details of intracranial pressure (ICP) monitoring are not routinely registered. The authors undertook to obtain extra data from centres regularly utilizing such monitoring. This was an observational study undertaken between 1998 and 2004. The authors concentrated on those patients who underwent liver transplantation in order to try and focus on a homogeneous group.
The limitations of an observational dataset in a focused group should be considered when the data from this study are interpreted and extrapolated to daily practise.
Patients who progressed to grade III/IV coma were considered; 92 underwent ICP monitoring, 239 did not. Patients undergoing monitoring were younger, there was no difference in time from symptoms to coma between the groups but data are not given on ratio of subacute, acute or hyperacute liver failure. This may be pertinent given the increased incidence of cerebral complications in the later two groups2 albeit with the greatest potential for spontaneous survival.
ICP monitoring was more prevalent in those patients listed for liver transplant, suggesting that listing was a significant determinant for monitoring (73.9% vs 31.8%). This may be driven by a desire to measure ICP during dissection and reperfusion, however cerebral complications are also prevalent in those not proceeding to OLT. Keays et al.3 have previously shown that monitoring of ICP increases the number of interventions and prolongs time to eventual death. Although this may not seem to be pertinent, in that there was no survival advantage, the increased time to death could be interpreted as increased time to find a suitable liver or if expanded to a study with appropriate power may have the capacity to provide data on survival benefit and neurological outcome. Furthermore this study was undertaken when many of the current interventions that may now be instituted were not available.
In only 3 patients was the monitor removed due to malfunction, suggesting that the technology is functioning well and providing appropriate information. In only 3 of the 6 cases were there clinical symptoms. One was associated with an epidural catheter, the patient underwent liver transplant and survived. In the remaining 2 cases subdural catheters had been utilized. Both died of cerebral oedema – we are not told the size of the bleed, intervention or its relationship to clinical outcome. The study demonstrates a complication rate of 10% with a clinically important intracranial bleed rate of 5%. The authors suggest that dural puncture is associated with increased complications. Is this reasonable? The data are not that conclusive given that epidural monitoring was an under represented technique: 9 episodes as compared to 37 for the sub-dural technique.
Vaquero et al.1 examined in detail those patients who were listed for liver transplantation. Patients who fulfilled criteria for liver transplantation but for whatever reasons were not listed would not have been included in this analysis nor would those who may have succumbed without reaching transplant criteria or those who survived with medical management – it may be that these patient groups have as much if not greater potential for benefit to optimize their condition and provide an environment for regeneration.
85 cases underwent liver transplantation, 40 of whom had ICP monitoring. The time to wait for a suitable organ was similar in both groups. Those patients who were monitored had more interventions, mannitol (58% vs. 15.7%), barbiturates (21.9% vs. 5.3%) and pressors (60% vs. 35.5%). It would seem reasonable to assume that mannitol and barbiturates were administered in response to elevations in ICP or pupillary abnormalities (however, no treatment thresholds are given). With respect to pressors however the indication is less clear, were they administered for cardiovascular failure or in order to maintain a cerebral perfusion pressure (CPP) – a difficult concept in patients who are not monitored as presence or absence of cerebral autoregulation cannot be determined. Such therapies can only be examined as to efficacy if the intracranial pressure is measured – it is analogous to treating arterial hypertension – drug changes would not be considered without measuring blood pressure!
ICP monitoring had no impact on 30 day survival and this remained the case when controlled for centre or aetiology. Again this is not surprising given that all patients proceeded to OLT and survival will have been determined largely by graft function.
Monitoring ICP in ALF does carry a morbidity and mortality, as is demonstrated by the authors although the incidence is less than that of a previous report.4 Given the incidence of cerebral oedema as a cause of death in ALF has decreased (14 of 101 cases) are we justified in considering ICP monitoring?5 Perhaps we should first consider a broader question - When has any monitoring tool been shown to be of benefit in the management of the critically ill? It is not the monitor and the data it provides per se that affect outcome but rather the actions and responses that are undertaken. As such it is in no way surprising that an observational study of a relatively small number of cases with no treatment protocol showed no survival benefit.
What is required of us, as clinicians, is to delineate in a dynamic manner that group of patients with ALF who are at greatest risk of cerebral complications and provide them with optimal care and monitoring.6
We can draw on published data to determine those at risk for development of fatal brain damage. Patients who fulfil poor prognostic criteria particularly those with acute and hyperacute liver failure2, 5 are at increased risk, as should those who have developed pupillary abnormalities.
There is increasing evidence for the role of the systemic inflammatory response (SIRS) in the evolution of encephalopathy and cerebral oedema. This has been demonstrated by Rolando et al.7 and Vaquero et al.,1 increasing SIRS markers being associated with increased encephalopathy. In a recent paper5 SIRS in association with onset of HE was seen in 26% of survivors as compared to 83% of non-survivors. Fever is also pertinent in this regard. Jalan et al.8, 9 have demonstrated that cooling patients to 32 C results in decreases in ICP, cerebral blood flow, ammonia level and cerebral uptake and brain cytokine production. As such patients with fever should be viewed as at risk of cerebral oedema, although active cooling requires examination in a controlled trial.10
Arterial ammonia may also be used to stratify risk for cerebral complications. Clemmesen et al.11 noted that cerebral herniation was associated with ammonia of > 150μmol//L. This has been further substantiated by Bhatia et al.,12 who noted that an arterial ammonia of >124 μmol/l determined complications including cerebral oedema. Hyponatremia may also be important,13, 14 with low levels being associated with increased risk.
Patients at high risk for development of brain oedema may also be identified by those requiring pressors. Loss of cerebral autoregulation, frequent in ALF,15, 16 results in a situation where optimal level of blood pressure is impossible to determine without knowledge of ICP.
Surrogate measures of cerebral blood flow (reverse jugular saturations or middle cerebral artery Doppler monitoring) allow identification of cerebral hyperaemia or inadequate flow who are also likely to benefit from invasive monitoring.17
Without ICP monitoring the effect of interventions cannot be examined. ICP monitoring allows an ICP trigger to be established, and efficacy of treatment to be determined, be that mannitol, hypertonic saline or indomethacin. Coupled with reverse jugular17 or cerebral microdialysis16 monitoring it allows informed decisions to be made as to the benefits and duration of hyperventilation. In those with pupillary abnormalities without ICP elevation, treatment of seizures may be undertaken.
Optimal neurological care of patients requires clinical attentiveness, physiological manipulation and appropriate intervention. To undertake this without ICP measurement may be possible but will not allow focus and clarity of actions – after all it may be possible to drive without lights at night but it is certainly easier with appropriate illumination. It is for us to undertake trials to examine further novel treatment protocols that will ultimately provide safer patient care. Far from throwing out the concept of ICP monitoring the study of Vaquero et al.1 demonstrates increased safety of ICP monitoring and should encourage all those who care for such patients to undertake ICP monitoring and no longer fumble in the dark, but switch on the light; obtain measurements and act on them in an appropriate manner.