Complications and use of intracranial pressure monitoring in patients with acute liver failure and severe encephalopathy.

Abstract

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 < 0.001). ICP monitoring was strongly associated with the indication of LT (P < 0.001). 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.

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SHORT REPORTS
Complications and Use of Intracranial Pressure
Monitoring in Patients With Acute Liver Failure and
Severe Encephalopathy
Javier Vaquero,1Robert J. Fontana,2Anne M. Larson,3Nathan M.T. Bass,4
Timothy J. Davern,4A. Obaid Shakil,5Steven Han,6M. Edwyn Harrison,7
Todd R. Stravitz,8Santiago Mun ˜oz,9Robert Brown,10William M. Lee,11and
Andres T. Blei1
Monitoring of intracranial pressure (ICP) in acute liver
failure (ALF) is controversial as a result of the reported
complication risk (?20%) and limited therapeutic
optionsforintracranialhypertension.Usingprospectively
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 out-
comeafterlivertransplantation(LT).ICPmonitoringwas
usedin92patients(28%ofthecohort),butthefrequency
of monitoring differed between centers (P < 0.001). ICP
monitoring was strongly associated with the indication of
LT (P < 0.001). A survey performed in a subset of 58
patients with ICP monitoring revealed intracranial hem-
orrhage in 10.3% of the cohort, half of the complications
being incidental radiological findings. However, intracra-
nial 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 non-
monitored groups (85% vs. 85%). In conclusion, the risk
of intracranial hemorrhage following ICP monitoring
may have decreased in the last decade, but major compli-
cationsarestillpresent.IntheabsenceofICPmonitoring,
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. (Liver
Transpl 2005;11:1581-1589.)
B
liver failure (ALF).1The exact role of intracranial pres-
sure (ICP) monitoring in the management of ALF,
however, is still debated. While a recent position paper
from the American Association for the Study of Liver
Diseases2statesthatICPmonitoringisespeciallyuseful
inthedecisiontoexcludepatientsfromemergencyliver
transplantation (LT), other experts have noted the abil-
ity to manage ALF in the absence of such data.3The
main concern with placement of such monitors is the
rain edema and intracranial hypertension are
major causes of morbidity and mortality in acute
risk of intracranial hemorrhage. In a survey across med-
ical centers in the United States in the early 1990s, an
overall prevalence of intracranial bleeding of 20% was
noted with the procedure.4Hemorrhage was more
likely when the dura mater was pierced for the place-
ment of subdural or parenchymal transducers. It was
recommended that epidural transducers be utilized, as
the risk of bleeding appeared to be reduced with such
devices.
In the decade that has elapsed since the report,43
developments have occurred that call for a reassessment
of the experience with ICP monitoring. First, the man-
ufacture of epidural transducers has ceased, as patients
in whom monitoring is frequently used (for head
trauma) are better served by the more precise measure-
ments of ICP obtained by subdural or parenchymal
transducers. Second, newer approaches to the correc-
Abbreviations: ALF, acute liver failure; ICP, intracranial pres-
sure; OT, orthotopic liver transplantation; ALFSG, ALF Study
Group.
From1Northwestern University Feinberg School of Medicine, Chi-
cago, IL;2University of Michigan Medical Center, Ann Arbor, MI;
3University of Washington, Seattle, WA;4University of California San
Francisco, San Francisco, CA;5University of Pittsburgh Medical Center,
Pittsburgh, PA;6University of California Los Angeles, Los Angeles, CA;
7Mayo Clinic, Scottsdale, AZ;8Virginia Commonwealth University,
Richmond, VA;9Albert Einstein Medical Center, Philadelphia, PA;
10Columbia University College of Physicians & Surgeons, New York,
NY; and11University of Texas Southwestern Medical Center at Dallas,
Dallas, TX.
Received June 16, 2005; accepted August 18, 2005.
SupportedbyNIHRO1DK583369-01,theStephenB.TipsMemo-
rial Fund at Northwestern Memorial Hospital, and a grant from Fondo
de Investigacion Sanitaria (Instituto de Salud Carlos III, Spain) (J.V.).
Address reprint requests to: Andres T. Blei, MD, Northwestern Uni-
versity Feinberg School of Medicine, Tarry 14-707, 303 East Chicago
Ave., Chicago, IL 60611. Telephone: 312-503-3453; FAX: 312-640-
2401; E-mail: a-blei@northwestern.edu
Copyright © 2005 by the American Association for the Study of
Liver Diseases
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/lt.20625
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Liver Transplantation, Vol 11, No 12 (December), 2005: pp 1581-1589

Page 2

tion of the coagulopathy of ALF have been proposed.
Among them, the combination of recombinant factor
VII and fresh frozen plasma holds promise as a tool to
reduce the complications associated with invasive pro-
cedures in ALF.5Finally, as we enter an era of large
therapeutictrialsinALF,oneofthemrecentlycomplet-
ed,6the interpretation of survival results could be
affected by the availability (or not) of results of ICP
monitoring.
The U.S. ALF Study Group (ALFSG) has been
actively maintaining a prospective registry of patients
with this condition since its inception in 1998.7A
diverse practice of ICP monitoring was noted among
the different centers that constitute the group. With
such differing practices, a controlled evaluation of the
role of ICP monitoring could not be undertaken.
Rather,weexaminedtheexperienceoftheU.S.ALFSG
with placement of ICP monitors in adult patients, with
specialreferencetotherateofcomplications;changesin
clinical management and outcomes of patients in
whom ICP monitors were placed prior to the perfor-
mance of LT were also examined. Our results note the
continued presence of complications from the proce-
dure.
While the outcome of the transplant procedure was
similar in the presence or absence of ICP monitoring,
marked differences in management of intracranial
hypertension may be of importance for the long-term
neurological recovery of patients surviving ALF.
Patients and Methods
Between January 1998 and March 2004, information from
704 patients with ALF admitted to the 25 centers that con-
stitute the U.S. ALFSG was prospectively collected in a stan-
dard protocol form. Inclusion criteria were those defining
ALF,8namely the presence of coagulopathy (prothrombin
time?15secorinternationalnormalizedratio?1.5)andany
grade of hepatic encephalopathy within 26 weeks of the first
symptoms in a patient with acute liver injury and no previous
liver disease. We excluded 190 of the 704 patients from our
study because the item collecting information on ICP moni-
toring was not included in the protocol forms at the time of
their data collection (prior to April 2000). A further group of
182 patients did not reach grade III-IV hepatic encephalopa-
thy during the data collection period and was also excluded.
Therefore, 332 patients with ALF and grade III-IV hepatic
encephalopathy were examined.
No standardized management protocol was used by the
centers during the collection of the data. Thus, monitoring
andtherapeuticinterventionswereimplementedbyeachcen-
ter according to their own standard of care. Data regarding
the use of surrogate markers of intracranial pressure, such as
cerebralbloodflow/velocity,forhelpingtheindicationofICP
were not collected in the forms. The U.S. ALFSG protocol
was approved by the institutional review board of all partici-
pant institutions. Since patients were by definition encepha-
lopathic, informed consent was obtained from the patient’s
next of kin or guardian in all cases.
Registry Form Description and Data Collection
Each case report form was divided into 2 parts. The initial
form, filled out at study admission, included demographic,
epidemiological, clinical, and laboratory data. A second out-
come form was completed at death, at discharge, or 3 weeks
after study admission if the patient was still in hospital. This
form included detailed information about the hospital course
and patient outcome. Clinical findings, laboratory data, and
monitoring and therapeutic measures employed during the
first 7 days of the study were also collected. After completion,
each site sent the protocol forms to the University of Texas
SouthwesternMedicalSchool.Beforedataentryintothecen-
traldatabase,siteswerequeriedaboutmissingorquestionable
data items, source documents were reviewed, and corrections
were made. In addition, annual audits at each site helped to
confirm accuracy of data.
Complications and Details of ICP Monitoring
InformationregardingcomplicationsanddetailsofICPmon-
itoring was not included in the standard protocol forms.
Thus, centers that used ICP monitoring in more than 5
patients were contacted and asked to provide specific infor-
mation regarding (1) type of ICP transducer used (epidural,
subdural, intraparenchymal, or intraventricular), (2) hemo-
static preparation used for ICP placement (fresh frozen
plasma,platelets,cryoprecipitate,recombinantfactorVIIa,or
plasmapheresis), (3) number of days with ICP monitoring,
(4)majorreasonforremovalofICPdevice(medicalimprove-
ment, death, malfunction of transducer, or other), and (5)
complicationsofICPmonitoring(hemorrhage,infections,or
other).
Analysis of Outcome
Due to the nonrandomized nature of our study, we focused
theanalysisofoutcomeonthepatientsundergoinglivertrans-
plantation. A survey was sent to all centers, and information
regarding the 30-day survival post-LT was collected.
Statistical Analysis
Numerical results are expressed as mean ? SD. Categorical
data are expressed as counts (%). Differences of categorical
andcontinuousvariableswereassessedusingthechi-squareor
Fisher exact test, and the independent samples t test, respec-
tively. The natural logarithms of aspartate aminotransferase
and alanine aminotransferase were used in the analysis to
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Vaquero et al.

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reduce the heterogeneity of variance. The Cochran-Mantel-
Haenszel test for general association was used, when indi-
cated, to control for differences between centers. P values
?0.05 were considered significant.
Results
General Patient Characteristics
Intracranial pressure monitoring was used in 92
(27.7%) out of the 332 patients with ALF and grade
III-IV hepatic encephalopathy included in the analysis.
GeneralcharacteristicsofpatientswithICPmonitoring
(ICP group) and without (non-ICP group) are shown
inTable1.Thedistributionofsexandracewassimilar,
but patients with ICP monitoring were significantly
younger.Theetiologyofliverfailurewascomparablein
bothgroups,althoughtheproportionofviralandinde-
terminate etiologies tended to be higher in the ICP
group.Intervalbetweenfirstsymptomsandappearance
of encephalopathy, mean arterial pressure, presence of
variousclinicalcomplications,andlaboratorytestswere
alsosimilarintheICPgroup(atthedayofplacementof
Table 1. Demographic, Clinical, and Biochemical Characteristics of Patients With and Without ICP Monitoring
No ICP MonitoringICP Monitoring
P ValueN
Number (%) or
Mean?SDN
Number (%) or
Mean?SD
Sex (female)
Age (yr)
Race
White
African-American
Other
Etiology
Acetaminophen
Viral hepatitis
Drug-induced
Indeterminate
Other
Days from onset of symptoms to coma
MAP*
Clinical complications
Seizures
Gastrointestinal bleeding
Cardiac arrhythmias
Chest X-ray abnormalities
Acute renal failure
Laboratory tests*
Hemoglobin (g/dL)
WBC (? 109/L)
Platelets (? 109/L)
INR
Prothrombin time (s)
Bilirubin (mg/dL)
ALT (IU/L)
AST (IU/L)
Creatinine (mg/dL)
Arterial pH
pCO2(mm Hg)
Negative drug screen at admission
Listed for LT
239
240
240
164 (68.6)
40 ? 14
92
92
92
59 (64.1)
36 ? 12
0.4
? 0.01
0.1
183 (76)
39 (16)
18 (8)
71 (77)
9 (10)
12 (13)
240920.06
118 (49.2)
22 (9.2)
28 (11.7)
30 (12.5)
42 (17.5)
8.9 ? 13.9
84 ? 20
40 (43.5)
16 (17.4)
8 (8.7)
18 (19.6)
10 (10.9)
10.6 ? 13.2
88 ? 19
238
224
90
82
0.3
0.1
238
239
238
235
236
17 (7.1)
28 (11.7)
60 (25.2)
144 (61.3)
155 (65.7)
90
90
88
85
90
5 (5.6)
8 (8.9)
19 (21.6)
52 (61.2)
55 (61.1)
0.8
0.6
0.6
1.0
0.4
232
232
229
231
221
227
225
228
234
212
213
174
239
10.6 ? 2.3
12.9 ? 10.3
127 ? 83
3.65 ? 3.05
34.1 ? 21.4
12.9 ? 11.0
2,765 ? 3102
3,247 ? 4592
2.72 ? 2.17
7.40 ? 0.14
30.9 ? 8.7
78 (44.8)
76 (31.8)
86
88
89
88
86
88
88
88
88
89
89
64
92
10.4 ? 1.9
11.2 ? 6.4
136 ? 83
3.28 ? 3.04
31.3 ? 21.0
15.0 ? 12.0
2,294 ? 2484
2,196 ? 2820
2.85 ? 2.04
7.46 ? 0.09
31.2 ? 7.7
43 (67.2)
68 (73.9)
0.4
0.2
0.4
NS
0.3
0.1
0.5
0.1
0.6
? 0.001
0.8
? 0.01
? 0.001
Abbreviations: MAP, mean arterial pressure; WBC, white blood cell count; INR, international normalized ratio; NS, not significant;
ALT, alanine aminotransferase; AST, aspartate aminotransferase; pCO2, partial pressure of carbon dioxide.
*Values refer to the day of placement of the ICP monitoring device or, in patients without ICP monitoring, to the day of grade III-IV
hepatic encephalopathy.
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the ICP monitoring device) and in the non-ICP group
(at the day of development of grade III-IV encephalop-
athy), except for a higher arterial pH in patients with
ICP monitoring.
At the time of placement of the ICP transducer, 61
of the 92 patients (66.3%) had grade IV encephalopa-
thy. Similarly, 168 of the 240 patients (70%) in the
non-ICP group reached grade IV encephalopathy dur-
ing the study. Forty-eight percent of ICP transducers
were placed the first day of the data-collection period,
24% the second day, and 28% the third day or after-
ward. The progression to grade III-IV encephalopathy
in patients without ICP monitoring followed a similar
chronologicalpattern(firstday,58%;secondday,19%;
third day or afterward, 23%, not significant).
Factors Associated With the Placement of ICP
Monitoring Devices
ThefrequencyofutilizationofICPmonitoringdiffered
significantly between individual centers (P ? 0.001).
AsshowninFigure1,3centersusedICPmonitoringin
50% or more of the patients, 8 centers used it in 25 to
50%ofthepatients,and8centersuseditinlessthan25
% of the patients (2 of these centers did not use ICP
monitoring for any patient). The different practice of
ICP monitoring across centers was more evident in
patients who were not listed for LT (P ? 0.01) than in
patients listed for LT (P ? 0.086).
A negative drug-screening test at admission and list-
ing for urgent LT were positively associated with mon-
itoring of ICP, with a higher proportion of patients
being listed for LT in the ICP (68 of 92 [73.9%]) than
in the non-ICP group (76 of 239 [31.8%], P? 0.001)
(Table 1). The association between ICP monitoring
and listing for LT was also present after controlling for
center (P? 0.001, Cochran-Mantel-Haenszel test for
general association).
Complications and Details of ICP Monitoring
Specificinformationregardingcomplicationsandother
details of ICP monitoring was obtained from 58
patients (mean age, 35 ? 13.1 yr, 34 [59%] females)
who underwent ICP monitoring in 8 centers. Acet-
aminophen intoxication was the etiology of ALF in 24
patients (41%). Subdural transducers were the most
commonly used (37 of 58 [63.8%]), followed by the
parenchymal (12 of 58 [20.7%]) and epidural localiza-
tions (9 of 58 [15.5%]) (Figure 2A). Intraventricular
transducers were not used in any of the centers. The
intracranial localization, however, was highly center-
dependent,with6centersusingsubduraltransducersin
80-100% of the cases, 1 center using a parenchymal
device in 91% (10 of 11 patients), and another using
only epidural transducers (7 of 7 patients).
Fresh frozen plasma was the most common product
used to correct coagulation prior to placement of the
ICP transducer (53 of 58 patients, [91%]), but it was
usedincombinationwithotherproductsin59%ofthe
cases (Figure 2B). Other products used were platelets
(18 of 58 patients), cryoprecipitate (11 of 58) and
recombinant factor VIIa (15 of 58), mostly in combi-
nations between them and/or with fresh frozen plasma.
In one center, plasmapheresis was used in 3 patients (in
combination with other measures in 2 of them).
The mean duration of ICP monitoring was 4.4 ?
2.3days(median,4days;range,1to10).Improvement
of the medical condition was the reason for removal of
the ICP transducer in 34 patients (59%), whereas in 19
cases (33%) it was due to the death of the patient
Figure 1. Frequency of utilization of ICP monitoring in patients with ALF and stage III-IV hepatic encephalopathy by
individualcenteroftheU.S.ALFSG.“Totalnumberofpatients,”inthefirstrowoftheabscissasaxis,referstothenumber
of patients included in the study at each center. Center 20 represents data from 5 centers in which the total number of
patients was less than 4.
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(Figure 2C). Malfunction led to the removal of the
transducer in 3 patients with subdural devices.
Complications attributed to ICP monitoring were
noted in 6 of the 58 patients (10%), all of them con-
sistinginintracranialhemorrhages.Freshfrozenplasma
was used in the haemostatic preparation in the 6
patients, and it was combined with recombinant factor
VII in 2 of them. Three of the hemorrhages (5.2%)
were associated with clinical symptoms. One occurred
in a patient who had an epidural transducer placed the
same day of undergoing LT; he is currently alive after 2
years of follow-up. The other 2 clinically relevant hem-
orrhages occurred in patients with subdural transduc-
ers; both of them died with severe brain edema, 1 after
undergoing LT.
The remaining 3 complications consisted in small
subarachnoid or parenchymal hemorrhages noted in
computed tomography scans of the brain in 2 patients
with subdural transducers and in 1 patient with an
intraparenchymal device. Two of these patients sur-
vived ALF, 1 after undergoing LT. The third patient
died without LT as a consequence of refractory hypo-
tension.
Management of ICP With and Without ICP
Monitoring
Because the severity of disease in patients listed for
urgent LT is relatively homogenous, this population
was chosen to study the impact of ICP monitoring on
clinical management (Table 2). After placement of the
ICP transducer, the management of patients with ICP
monitoring differed significantly from that of patients
who did not undergo such monitoring. In particular,
monitoringofICPwasassociatedwithahigherpropor-
tion of patients being treated with mannitol (35 of 65
[53.8%]) vs. non-ICP group (10 of 74 [15.7%], P ?
0.001), barbiturates (14 of 64 [21.9%] vs. 4 of 76
[5.3%], P? 0.01), and vasopressors (39 of 65 [60.0%]
vs. 27 of 76 [35.5%], P? 0.01). The proportion of
patientstreatedwithsuchmedicationsduringthefirst3
daysofICPmonitoring(ICPgroup)ordevelopmentof
stage III-IV encephalopathy (non-ICP group) is shown
in Figure 3.
One hundred and forty-four patients were listed for
urgentLT;theproportionofpatientsremovedfromthe
waiting list was similar regardless of ICP monitoring
(ICP group, 25 of 68 [37%] vs. non-ICP group, 27 of
76 [36%], not significant). Information regarding the
primary reason for removal was available in 14 of 25
patients of the ICP group and 19 of 27 of the non-ICP
group: improvement of liver function (5 of 14 vs. 6 of
Figure 2. Main features of ICP monitoring in 58 patients
from the 8 centers with more experience in its use. (A)
Intracranial localization of ICP transducer. (B) Prepara-
tion used for placement of ICP transducer. Empty bars
representpreparationusedalone.Barswithdiagonallines
represent preparation used in combination. (C) Main rea-
son for removal of ICP transducer. Parenchy, parenchy-
mal; Intraventr, intraventricular; FFP, fresh frozen plas-
ma; Plat., platelet; Cryopr., cryoprecipitates; Fct-VII,
factor seven; Plasmaph., plasmapheresis.
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Page 6

19), presence of irreversible brain damage (4 of 14 vs.
4 of 19), and medical instability (4 of 14 vs. 5 of 19).
Sepsis, comorbidities, and refusal of LT by the family
were causes of removal in 5 more patients. In addi-
tion, there were 7 patients (4 with ICP monitoring)
who were not removed from the list but who did not
receive an organ; only 2 of them survived (1 in each
group).
Table 2. Demographic, Clinical, and Biochemical Variables of Patients With and Without ICP Monitoring Who Underwent Liver
Transplantation
No ICP Monitoring ICP Monitoring
P ValueN
Number (%) or
Mean?SDN
Number (%) or
Mean?SD
Sex (female)
Age (yr)
Etiology
Acetaminophen
Viral hepatitis
Drug induced
Indeterminate
Other
Days from onset of symptoms to coma
MAP
Laboratory tests
Hemoglobin (g/dL)
WBC (? 109/L)
Platelets (? 109/L)
Prothrombin time (s)
Bilirubin (mg/dL)
ALT (IU/L)
AST (IU/L)
Creatinine (mg/dL)
Arterial pH
pCO2(mm Hg)
45
45
45
30 (66.7)
37 ? 15
40
40
40
26 (65.0)
34 ? 12
1
0.4
0.9
11 (24.4)
8 (17.8)
9 (20.0)
9 (20.0)
8 (17.8)
12.8 ? 13.7
88 ? 19
9 (22.5)
9 (22.5)
5 (12.5)
9 (22.5)
8 (20.0)
16.2 ? 15.9
90 ? 14
43
37
38
32
0.3
0.7
39
39
39
39
39
39
38
39
37
38
10.3 ? 1.7
12.0 ? 8.7
141 ? 94
35.1 ? 22.4
17.5 ? 12.2
1,668 ? 2,121
2,371 ? 3,531
1.69 ? 1.10
7.41 ? 0.13
34.0 ? 8.5
36
36
36
36
35
35
35
36
35
35
10.3 ? 1.4
12.3 ? 6.2
124 ? 76
28.0 ? 14.7
17.3 ? 12.5
1,282 ? 2,159
1,163 ? 1,913
2.07 ? 1.91
7.48 ? 0.07
34.3 ? 6.1
0.9
0.9
0.4
0.1
1.0
0.08
? 0.05
0.3
? 0.05
0.9
Abbreviations: MAP, mean arterial pressure; WBC, white blood cell count; ALT, alanine aminotransferase; AST, aspartate aminotrans-
ferase; pCO2, partial pressure of carbon dioxide.
Figure 3. Proportion of patients, with and without ICP monitoring, who were treated with mannitol, barbiturates,
and/or vasopressors. All patients were on the list for urgent LT. Day1 refers to the day of placement of ICP monitoring
device (ICP group) or the day of development of stage III-IV hepatic encephalopathy (non-ICP group). Empty bars
representthenon-ICPgroup.GraybarsrepresenttheICPGroup.*P<0.05,non-ICPvs.ICPgroup.**P<0.01non-ICP
vs. ICP group. ***P < 0.001 non-ICP vs. ICP group.
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Outcome of Patients undergoing Liver
Transplantation
In addition to the nonrandomized nature of our study,
the strong association between listing for LT and indi-
cation of ICP monitoring precludes a valid comparison
of global outcomes between the ICP and non-ICP
groups. Therefore, we focused the outcome analysis on
the more restricted and homogeneous setting of the
patients that underwent LT.
Eighty-five patients underwent LT, 45 in the non-
ICP group and 40 in the ICP group. Sex, age and
etiology of liver failure were similar in both subgroups
of patients (Table 2). Most laboratory data within 24
hours prior to LT were also similar in both subgroups.
The shorter interval between onset and coma, and the
higher platelet counts and aminotransferases, however,
could indicate an earlier time point in the course of the
disease in the non-ICP group.
The time that patients spent on the waiting list
before receiving a donor organ tended to be longer in
patientswithICPmonitoring(3.3?3.5days;median,
2 [range 0 to 19]) than in patients without (2.1 ? 2.2
days; median, 1 [range 0 to 10]) (P ? 0.08). Informa-
tion regarding survival post-LT was obtained in 80 of
the 85 patients undergoing LT. Importantly, 30-day
survivalpost-LTwassimilarregardlessofICPmonitor-
ing in the global series (ICP group: 34 of 40 [85%] vs.
non-ICP group: 34 of 40 [85%], P ? 1.0), as well as
when controlling for center (P ? 0.63, Cochran-Man-
tel-Haenszel test for general association). The 30-day
survival post-LT for specific etiologies was also similar
(Figure 4).
Discussion
Monitoring of ICP in patients with ALF provides two
possible important benefits. First, it allows detection
and management of an elevated ICP, as intracranial
hypertension can be clinically silent.9In addition, it
allows improved decision-making for the emergency
liver transplant candidate, as persistent reductions of
cerebral perfusion pressure (mean arterial pressure ?
ICP) signal a high likelihood of ischemic brain injury
and risks poor neurological recovery after the proce-
dure.10While low cerebral perfusion pressures have
been associated with good outcomes,11such results
should be viewed as the exception,12rather than the
norm.
The single factor that precludes a wider use of ICP
monitoring in ALF is concern with intracranial hemor-
rhage associated with its use. Indeed, the practices
regarding ICP monitoring of the different centers that
constitute the U.S. ALFSG differ widely, with some
centers managing patients without ICP monitoring at
all (Figure 1). Such an approach is not an exception,
evenamongprominentEuropeancenters,3Morethana
decadeago,asurveyoftheresultsofICPmonitoringin
the United States showed an incidence of intracranial
hemorrhage of 21%.4In this report, detailed informa-
tion on 58 cases from the U.S. ALFSF denotes compli-
cations in 6 subjects (10.3%), 3 of which were inciden-
tal findings at the time of computed tomography
scanning. While the prevalence of hemorrhage appears
tohavedecreased,theseriousnessofthecomplicationis
highlighted by 2 cases in whom intracranial bleeding
may have contributed to death. Fatalities were seen in
patients in whom the dura mater was pierced with the
monitor, a factor associated with increased rates of
bleeding in these patients.4Measures to correct the
coagulopathy prior to insertion of the monitor now
include the administration of recombinant factor VIIa,
whose effects include a prompt correction of the pro-
thrombin time.5In 1 center’s experience, no intracra-
nial bleeding was seen after its use in 15 subjects.13In
our series, 2 bleeds occurred on recombinant factor
VIIa. The exact role, dosing and safety of this com-
pound in ALF await evaluation in a controlled trial, as
its use can also be associated with an increased rate of
thromboembolic events.14
To minimize the risk of hemorrhage, it was recom-
mended that epidural transducers be used to monitor
ICP.4Whiletheaccuracyofsuchtransducersisinferior
tothosewheretheduraistraversed,alowerincidenceof
both fatal and nonfatal hemorrhage provided a coun-
terbalance to the technical inferiority of the device. At
Figure 4. Thirty-day survival (%) of patients with and
without ICP monitoring undergoing urgent liver trans-
plantation. Empty bars represent the non-ICP group.
Gray bars represent the ICP Group.
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Page 8

the present time, the manufacturer of epidural trans-
ducers has discontinued production of this monitor; in
the current series, the use of epidural transducers was
based on the adaptation of existing parenchymal mon-
itors for use in the extradural space (the case of the
Camino monitor, Camino Laboratories, San Diego,
CA). Hemorrhage can still be seen with epidural place-
ments, as seen in the past and in one of the cases of this
series.Nonetheless,fatalitieswerenotseenintheprior4
or current experiences, suggesting that the epidural
approach is still the safest one.
A randomized controlled trial of ICP monitoring in
ALF has never been performed, and the U.S. ALFSG
couldnotreachaconsensusonthismatter.Wechoseto
examinetheoutcomeofpatientswhounderwentemer-
gency LT, as both monitored and nonmonitored
groups had similar epidemiological and laboratory
characteristicsatthetimeoftransplant.Ofthe85trans-
plants of patients with ALF and stage III-IV encepha-
lopathy, half were performed with ICP monitoring and
half were done without this device. Survival at 30 days
was similar in the patients with and without ICP mon-
itoring, regardless of etiology (Figure 4). Such results
are in concordance with previous reports of outcomes
afterICPmonitoring,9,15whereimprovedmanagement
of intracranial hypertension was not synonymous with
improvedsurvival.Infact,othermeasuresinstitutedfor
thetreatmentofALFdonotimpactsurvival,suchasthe
use of prophylactic antibiotics.16Survival in this condi-
tion is mainly dependent on the recovery of liver func-
tion, as exemplified by the good results seen with emer-
gency liver transplantation.
Several considerations should be brought forth
regarding the applicability of the results of our study.
First, all centers participating in this experience were
tertiary centers with familiarity with LT; local factors
suchascenter/surgeonknowledgeofICPmonitoringas
wellasorganavailability,however,mayhaveinfluenced
the decision of measuring ICP.
Second,ourstudyhaslimitationsrelatedtothenon-
randomized assignment of ICP monitoring. It is possi-
ble that in transplant candidates, monitoring was
undertaken in sicker patients, though the epidemiolog-
ical and clinical variables were similar prior to the oper-
ation. However, we note an important difference in the
management of subjects in whom ICP monitors were
placed.TheyreceivedmoretreatmentsforelevatedICP
values,includingmannitolandbarbiturates,thanthose
in whom monitoring was not undertaken. The use of
vasopressors was also more common, probably as a
resultofclinicalinformationoncerebralperfusionpres-
sure.Wecannotascertainwhethersuchtherapiestrans-
lated into better neurological outcomes after recovery
from ALF, but neurological deficits have been reported
in survivors of LT17and other conditions associated
with intracranial hypertension.18The U.S. ALFSG is
currently conducting a long-term outcome study of
patients with ALF, evaluating neurological function 1
and 2 years after the transplant procedure or in sponta-
neous survivors. With an improved operative survival,
improvement in outcomes in ALF has new goals,
including a reduction in the 90-day mortality (much
higher than in other conditions where LT is per-
formed19and which reflects the impact of multiorgan
failureatthetimeoftheprocedure)aswellaslong-term
neurological function.
Finally, the role of ICP monitoring in the patients
who did not undergo LT could not be explored in our
study. This subpopulation is a heterogeneous group
that includes less sick patients, patients very ill who can
not be considered for LT, and patients not listed due to
other medical/social reasons. The role of ICP monitor-
ing in this population, therefore, remains unclear.
Insummary,ourresultsnoteadecreaseintherateof
intracranial hemorrhage with ICP monitoring, but in
spite of newer tools to overcome the severe coagulopa-
thy of ALF, the risks of the procedure are still consider-
able. Most patients receiving ICP monitoring in the
experience of the U.S. ALFSF are listed for LT, with
only a minority of centers using it for nontransplant
candidates. Nonetheless, half of transplants were per-
formed without such monitors, with similar 30-day
outcomes. As patients with ICP monitoring receive
more treatments for intracranial hypertension, the pos-
sibility arises that greater neurological deficits may be
seen in the subjects not receiving ICP monitoring.
Studies of long-term outcome after ALF, currently
under way, should provide answers to this important
question.
Acknowledgement
The authors thank Jie Huang, PhD, for assistance in the
statistical analysis.
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