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1 5/11/99 1:35 PM Page 1042

J Neurosurg 90:1042–1052, 1999

Propofol in the treatment of moderate and severe head injury:

a randomized, prospective double-blinded pilot trial

DANIEL F. KELLY, M.D., DAVID B. GOODALE, D.D.S., PH.D., JOHN WILLIAMS, M.D.,
DANIEL L. HERR, M.D., E. THOMAS CHAPPELL, M.D., MICHAEL J. ROSNER, M.D.,
JEFF JACOBSON, M.D., MICHAEL L. LEVY, M.D., MARTIN A. CROCE, M.D.,
ALLEN H. MANIKER, M.D., GERALD J. FULDA, M.D., JAMES V. LOVETT, M.D.,
OLGA MOHAN, M.D., AND RAJ K. NARAYAN, M.D.
Division of Neurosurgery, University of California Medical Center, Los Angeles, California; University
of California–Harbor Medical Center, Torrance, California; Washington Hospital Center, Washington,
DC; Highland Hospital, University of California: Davis–East Bay, Oakland, California; University of
Alabama Hospital, Birmingham, Alabama; New Jersey Medical School and Hospital, Newark, New
Jersey; University Medical Center, Las Vegas, Nevada; University of Southern California–Los Angeles
County, Los Angeles, California; Medical Center of Delaware, Newark, Delaware; University of
Tennessee Medical Center, Memphis, Tennessee; and Temple University Hospital, Philadelphia,
Pennsylvania

Object. Sedation regimens for head-injured patients are quite variable. The short-acting sedative–anesthetic agent pro-
pofol is being increasingly used in such patients, yet little is known regarding its safety and efficacy. In this multicenter
double-blind trial, a titratable infusion of 2% propofol accompanied by low-dose morphine for analgesia was compared
with a regimen of morphine sulfate in intubated head-injured patients. In both groups, other standard measures of control-
ling intracranial pressure (ICP) were also used.
Methods. Forty-two patients from 11 centers were evaluated to assess both the safety and efficacy of propofol: 23
patients in the propofol group (mean time of propofol usage 95  87 hours) and 19 patients in the morphine group (mean
time of morphine usage 70  54 hours). There was a higher incidence of poor prognostic indicators in the propofol group
than in the morphine group: patient age older than 55 years (30.4% compared with 10.5%, p  0.05), initial Glasgow Coma
Scale scores of 3 to 5 (39.1% compared with 15.8%, p  0.05), compressed or absent cisterns on initial computerized
tomography scanning (78.3% compared with 57.9%, p  0.05), early hypotension and/or hypoxia (26.1% compared with
10.5%, p = 0.07). During treatment there was a trend toward greater use of vasopressors in the propofol group. However,
the mean daily ICP and cerebral perfusion pressure were generally similar between groups and, on therapy Day 3, ICP was
lower in the propofol group compared with the morphine group (p  0.05). Additionally, there was less use of neuro-
muscular blocking agents, benzodiazepines, pentobarbital, and cerebrospinal fluid drainage in the propofol group (p 
0.05). At 6 months postinjury, a favorable outcome (good recovery or moderate disability) was observed in 52.1% of
patients receiving propofol and in 47.4% receiving morphine; the mortality rates were 17.4% and 21.1%, respectively.
Patients who received the highest doses of propofol for the longest duration tended to have the best outcomes. There were
no significant differences between groups in terms of adverse events.
Conclusions. Despite a higher incidence of poor prognostic indicators in the propofol group, ICP therapy was less inten-
sive, ICP was lower on therapy Day 3, and long-term outcome was similar to that of the morphine group. These results
suggest that a propofol-based sedation and an ICP control regimen is a safe, acceptable, and, possibly, desirable alterna-
tive to an opiate-based sedation regimen in intubated head-injured patients.

KEY WORDS • propofol • traumatic brain injury • intracranial hypertension •

neuroprotection

in the acute phase after moderate or severe be supported by published data on the use of these agents.

P
ATIENTS
head injury often exhibit agitation and fluctuations Only the following “option” was offered: “Sedation and
in ventilatory capacity. A variety of sedatives, nar- neuromuscular blockade can be useful in optimizing
cotics, and neuromuscular blocking agents are used to transport of the head-injured patient. However, both treat-
control ventilation and prevent agitation-related intracra- ments interfere with the neurological examination. In the
nial pressure (ICP) spikes in these patients. Sedative reg- absence of outcome-based studies, the choice of sedative
imens in head-injured patients, however, remain non- is left to the physician. Neuromuscular blockade should
standardized and largely unproven. In a recently published be employed when sedation alone proves inadequate, and
set of guidelines,12 no “standards” or “guidelines” could short-acting agents should be used when possible.”12

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Propofol in traumatic brain injury

The short-acting sedative–anesthetic nonanalgesic TABLE 1

agent propofol (Diprivan; Zeneca Pharmaceuticals, Wil- Stepwise control of ICP
mington, DE) is being increasingly used in patients in
the neurosurgical intensive care unit (ICU), particularly Step Therapy
for head-injured patients.41 However, only a few studies base- mild hyperventilation (PaCO2 30–35 mm Hg); normothermia
have addressed its efficacy in these patients.18,43,58 Propofol line (temperature 37.4˚C)
is potentially advantageous in this setting, given its wide 1 ventricular CSF drainage: every 5–10 mins until ICP 20 mm Hg
dose response, short elimination halflife (24–64 minutes), 2* increase sedation: increase Infusions A & B per titration sched-
and neuroprotective effects.2,6,29,33,69,72 Low infusion rates ule
3 neuromuscular blockade: if patient remains agitated, is over-
result in light-to-moderate sedation and high rates result in breathing ventilator, bucking, or shivering (0.1 mg/kg vecuro-
electroencephalographic (EEG) burst suppression similar nium given intravenously, repeat every 30 mins as needed)
to that achieved with high-dose pentobarbital.22,51,65 Pre- 4 mannitol: if ICP remains elevated for 5 mins, administer 25–50
viously, propofol has been dispensed as a 1% infusion. g every 2 hrs as needed to maintain ICP 20 mm Hg (maximum
A new 2% formulation was produced to reduce infusion 250 g/24 hrs & maintain serum osmolality 310)
volumes, and the additive ethylenediamine tetraacetic acid 5 high-dose pentobarbital: for intractable intracranial hypertension
may be instituted after Infusions A & B have been titrated to
(EDTA) was included to reduce the risk of bacterial colo- max rates & ICP remains 30 mm Hg w/ CPP 70 mm Hg or
nization of the lipid vehicle. Using this new formulation, ICP 40 mm Hg w/ CPP 70 mm Hg; titrate to achieve burst
a prospective randomized double-blinded pilot trial was suppression on EEG
undertaken to assess the safety and efficacy of a propo-
* If systolic blood pressure drops to less than 100 mm Hg or CPP to less
fol-based sedation regimen compared with a regimen of than 60 mm Hg, both Infusions A and B should be lowered accordingly. If
morphine sulfate in head-injured patients requiring me- the blood pressure does not improve, both infusions should be stopped.
chanical ventilation. Although the primary study end point
was determination of drug safety, the clinical end points
included: 1) control of ICP and maintenance of cerebral
perfusion pressure (CPP); 2) therapy intensity for ICP gories (3, 4–5, 6–8, or 9–12) and randomized in a double-
control, CPP control, and sedation; 3) 6-month neurologi- blind fashion to either the propofol or morphine sedation
cal outcome; and 4) treatment-related adverse events. regimens. All patients received three simultaneous in-
fusions, A, B, and C. Infusion A was a white emulsion
containing either propofol or Intralipid (Pharmacia Up-
Clinical Material and Methods john, London, United Kingdom) as placebo. Infusion B
was a clear solution composed of either morphine sulfate
Ethical Considerations or normal saline as placebo. Infusion C was a low-dose
This protocol was independently reviewed and ap- morphine sulfate infusion for analgesia. For the propofol
proved by the institutional review board of each partici- group patients, Infusion A consisted of propofol (ZD08-
pating institution. The trial was conducted in compliance 59#1 2% [20 mg/ml] with 0.005% EDTA) and Infusion B
with the regulations governing informed consent promul- was normal saline. For morphine group patients, Infusion
gated by the United States Food and Drug Administration A was Intralipid and Infusion B was morphine. Given that
(Code of Federal Regulations 21, Parts 50 and 56). Writ- propofol lacks analgesic effects, both groups also received
ten informed consent for participation was required from an initial 2.5-mg bolus of morphine followed by Infusion
the next of kin of each patient. The trial was also designed C of morphine at 1 to 3 mg/hour for at least 48 hours.
and monitored in accordance with the procedures of Zen- Patient Management and Dosing Regimens
eca Ltd., which include the key elements of good clinical
practices as required by regulatory authorities. All patients were admitted to the ICU after initial stabi-
lization or after craniotomy for evacuation of an intra-
Patient Population cranial hematoma. Management was in concordance with
previously published guidelines for managing patients
Inclusion and Exclusion Criteria. Eligible patients in- with severe head injury12 and included an algorithm for
cluded those who were aged 17 years or older, had sus- maintaining ICP less than 20 mm Hg and CPP higher than
tained a closed or penetrating traumatic brain injury 70 mm Hg.12 Intracranial pressure therapy was imple-
resulting in a postresuscitation Glasgow Coma Scale mented in a stepwise fashion as outlined in Table 1. The
(GCS)61 score of 3 to 12, and required mechanical ventila- mode of ICP monitoring was left to the discretion of the
tion. Patients were excluded from the efficacy analysis if investigator, although use of a ventriculostomy was en-
trial medication therapy was not begun within 96 hours couraged. The sedation schedule outlined in Table 2 was
of injury and medications were not administered for a used forall patients. As trial drug infusions began, patients
minimum of 12 hours. Other exclusion criteria included a were weaned from sedatives, narcotics, and neuromuscu-
history of hypersensitivity to propofol or its constituents, lar blocking agents. Infusions A and B were initiated
renal insufficiency, hepatic failure, a known lipid metabo- simultaneously at Step 1 and were increased as needed for
lism disorder, spinal cord injury with paraplegia or quad- agitation, bucking on the ventilator, abnormal posturing,
riplegia, participation in another investigational drug trial or ICP levels persisting above 20 mm Hg. Trial Infusions
within 31 days of trial entry, or body weight more than A and B could be increased at a maximum rate of one step
130 kg. every 5 minutes. In patients without physiological evi-
Group Assignment and Randomization. Patients were dence of pain (for example, those with tachypnea, tachy-
stratified by postresuscitation GCS score into four cate- cardia, or hypertension), administration of low-dose mor-

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D. F. Kelly, et al.

TABLE 2 Efficacy Assessment

Titration scheme* Intracranial pressure and CPP measurements were re-
Infusion A Infusion B† corded on an hourly basis as previously described.38 For
Infusion Step ml/hr (µg/kg/min) ml/hr (µg/kg/min) each patient, baseline ICP and CPP before receiving study
drugs, mean daily ICP and CPP, and total number of hours
1 initial rate 2 (10) 1 (0.25) that ICP was greater than 20 mm Hg and CPP was lower
2 4 (20) 2 (0.50)
3 6 (30) 3 (0.75) than 70 mm Hg were recorded. The frequency of use of
4 8 (40) 4 (1.00) mannitol, neuromuscular blocking agents, benzodiaze-
5 10 (50) 5 (1.25) pines, barbiturates, and vasopressors, and the daily vol-
6 12 (60) 6 (1.50) ume of CSF drainage were recorded. Neurological out-
7 14 (70) 7 (1.75) come was determined at 6 months postinjury by obtaining
8 benzodiazepines allowed 16 (80) 8 (2.00) the Glasgow Outcome Scale (GOS)31 and Disability Rat-
9 18 (90) 9 (2.25)
10 20 (100) 10 (2.50) ing Scale (DRS)52 scores. Favorable outcome was defined
11 22 (110) 11 (2.75) as a GOS score of good recovery or moderate disability or
12 23 (120) 12 (3.00) a DRS score of no, partial, or moderate disability (DRS
13 25 (130) 13 (3.25) score of 0–6).
14 27 (140) 14 (3.50)
15 maximum rate‡ 29 (150) 15 (3.75)
16 31 (160) 16 (4.00) Safety Assessment
17 33 (170) 17 (4.25)
18 35 (180) 18 (4.50) Clinical Laboratory Assessments. Multiple blood sam-
19 37 (190) 19 (4.75)
20 39 (200) 20 (5.00)
ples were drawn to measure ionized calcium, total calci-
um, total magnesium, potassium, sodium, inorganic phos-
* For the propofol group, Infusion A consisted of 2% propofol and phate, blood urea nitrogen, creatinine, triglyceride, and
Infusion B consisted of normal saline; for the morphine group, Infusion A
consisted of 10% Intralipid and Infusion B consisted of morphine sulfate.
parathyroid hormone concentration.
Dosages of all trial medications were calculated using patient’s baseline Hemodynamics. Systolic, diastolic, and mean arterial
body weight (kg). The rates shown above were calculated only as an exam- blood pressures, heart rate, central venous pressure, cardi-
ple using the weight of a 65-kg adult.
† Infusion B rates are based on a MgSO4 concentration of 1 mg/ml.
ac index, and body temperature were recorded immedi-
‡ Rates higher than this were allowed only with permission of Zeneca. ately before initiation of trial drug therapy, 4 hours after
start time, and daily thereafter until 24 hours after admin-
istration of trial drugs was discontinued.
phine (Infusion C) could be stopped after 48 hours. Neu- Adverse Events. Fatalities, life-threatening events asso-
romuscular blocking agents could be given at any time ciated with trial drug use, and any other adverse events
if the patient was not adequately responsive to trial medi- that were both serious and unexpected were reported. Pa-
cations. Benzodiazepines could be used after Step 8 had tients were also evaluated daily for signs or symptoms of
been reached. Mannitol could also be administered if ele- sepsis. Criteria included: 1) tachycardia (heart rate  90
vated ICP was not responsive to ventricular cerebrospinal beats/minute); 2) hyperthermia (temperature  38˚C); 3)
fluid (CSF) drainage and to increasing Infusions A and B. hypothermia (temperature  36˚C); 4) white blood cell
Metabolic suppressive therapy, using high-dose pentobar- elevation ( 12,000/mm3); 5) white blood cell depression
bital, could be introduced for intractable intracranial hy- ( 4000/mm3); and 6) positive blood culture(s). Patients
pertension only after patients reached maximum rates for were considered to have sepsis if two of the first five cri-
Infusions A and B (Table 2). Cerebral perfusion pressure teria and the sixth criterion were met.
was maintained with the use of intravascular volume ex-
pansion and vasopressor therapy. Statistical Considerations and Sample Size

Injury Severity Determinants

The primary end point of the trial was determination of
drug safety. Specifically, the study sought to determine
Prognostic indicators were documented, including pa- whether ZD0859#1 2% propofol significantly altered ion-
tient age, postresuscitation GCS score, systemic hypoten- ized calcium, serum total calcium, total magnesium, po-
sion (systolic blood pressure  90 mm Hg), hypoxia (ar- tassium, sodium, inorganic phosphate, or parathyroid
terial oxygen saturation  60 mm Hg), and abnormal hormone levels when administered for sedation of severe-
pupillary responses (poorly reactive or an asymmetry of ≥ ly head injured patients. Given this objective, the power
2 mm) in the prehospital setting or during the first 24 analysis was determined on the basis of projected standard
hours of hospitalization.13,37,39,67 The first two computerized deviations (SDs) for changes in ionized calcium. Al-
tomography (CT) scans obtained in each patient were also though the original protocol called for 100 patients, a low-
analyzed for perimesencephalic cistern effacement, dif- er number of patients was deemed sufficient because
fuse swelling, diffuse swelling with a midline shift greater no clinically significant changes in calcium homeostasis
than 4 mm, diffuse injury with punctate hemorrhages, were reported in an earlier Diprivan 1% trial, approved
subarachnoid hemorrhage, evacuated mass lesions, multi- by the Food and Drug Administration in June 1996. Both
ple contusions, and gunshot wounds.17,23,40,63 An Injury Se- the 1% and 2% formulations have the same concentration
verity Scale5 score was also calculated for each patient of EDTA (0.005%). For these reasons, this trial was ter-
(Table 3). minated earlier than expected because sufficient safety

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Propofol in traumatic brain injury

data had been acquired. All patients treated with trial TABLE 3
drugs, regardless of duration, were included in the safety Characteristics of 42 patients with moderate or
analyses. severe head injury*
Because this was a multicenter trial, all statistical analy-
ses and results were based on appropriate pooling of data Propofol Morphine
Characteristic (23 patients) (19 patients)
across centers. Between-group analysis of continuous
variables was assessed using Student’s t-test or analysis of time from injury to protocol entry (hrs) 34  21 38  26
variance (ANOVA) for comparison of more than two time on study medications (hrs) 95  87 70  54
groups. Multiple comparisons were not adjusted for an mean propofol dose (µg/kg/min) 55  42 0
mean morphine dose (mg/hr) 1.3  0.7 10  6.7
inflated alpha. Percentage comparisons were performed age (yrs) 39  18 33  13
using a Bernoulli process (binomial distribution). The no. of patients 55 yrs† 7 (30.4%) 2 (10.5%)
Mann–Whitney U-test was used to assess differences for median postresuscitation GCS score (range) 7 (3–9) 6 (3–10)
nonparametric factors such as median GCS score and postresuscitation GCS score 3–5† 9 (39.1%) 3 (15.8%)
median number of CT diagnoses. All variances were ex- male/female ratio 18:5 17:2
pressed as an SD. All differences for which the probabili- no. of patients w/ abnormal pupils 14 of 22 10 (52.6%)
(1 or both) (63.6%)
ty value was less than 0.05 were considered significant. no. of patients w/ abnormal pupils (both) 10 of 22 10 (52.6%)
(45.5%)
no. of patients w/ early hypotension 6 (26.1%) 2 (10.5%)
Results &/or hypoxia‡
median CT diagnoses (range) 3 (0–7) 4 (0–6)
Enrollment and Patient Exclusions absent or compressed cisterns† 18 (78.3%) 11 (57.9%)
diffuse swelling w/ or w/o shift 11 (47.8%) 11 (57.9%)
From September 1, 1995 to August 18, 1996, 70 acute- evacuated hematomas (all) 10 (43.5%) 9 (47.4%)
ly head injured adults from 11 centers were randomized; epidural 4 (17.4%) 3 (15.8%)
however, five were withdrawn before being given trial subdural 6 (26.1%) 4 (21.1%)
drugs. Of the remaining 65 patients, a total of 23 patients intracerebral 3 (13%) 5 (26.3%)
multiple contusions 10 (43.5%) 8 (42.1%)
were not included for evaluation of efficacy of trial drugs gunshot wounds 2 (8.7%) 3 (15.8%)
for the following reasons. In two patients (one from each Injury Severity Scale score 27  9 24  8
treatment group), trial drugs were not administered within
96 hours of injury and, in seven patients, trial drugs were * Values are expressed as the mean  SD.
† p  0.05.
not given for at least 12 hours (four in the propofol group ‡ p  0.07.
and three in the morphine group). In seven patients in the
morphine group varying amounts of 1% propofol were
administered before beginning trial medications. Three (39.1% compared with 15.8%, p  0.05). The GCS score
patients from this group were excluded because they re- was 8 or less in 22 patients (95.7%) in the propofol group
ceived relatively large amounts of propofol during a peri- and in 17 (89.5%) in the morphine group. Pupillary abnor-
od of at least 24 hours. The remaining four patients were malities were documented within the 1st day postinjury
included for analysis because they received small sedating with approximately equal frequency. Systemic hypoten-
amounts of 1% propofol for less than 12 hours, all less sion and/or hypoxic insults were documented through the
than 20 g/kg/minute and averaging 12.3 g/kg/minute. 1st day postinjury in six patients (26.1%) receiving pro-
Two patients, both in the propofol group, were excluded pofol and in two patients (10.5%) receiving morphine (p =
because only telephone consent was obtained. Also, one 0.07). The median number of major CT diagnoses was
patient in the propofol group was excluded because police similar in both groups. However, the propofol group had
records and autopsy findings had indicated the patient sus- a higher number of patients with compressed or absent
tained a primary anoxic injury from strangulation with a cisterns on initial CT scans (78.3% compared with 57.9%,
resultant common carotid occlusion and multiple cerebral p  0.05). The frequency of other CT diagnoses was sim-
infarctions within 2 days of injury. Of the remaining ilar between the two groups (Table 3).
50 patients (27 in the propofol regimen and 23 in the
morphine regimen), eight patients (four in each treatment Trial Drug Administration
group) were lost to follow-up review, leaving 23 patients The average times after injury that trial infusions were
in the propofol group and 19 in the morphine group with initiated in the propofol and morphine groups were 34 
a 6-month follow up. These 42 patients are the focus of 21 hours and 38  26 hours, respectively. The mean dura-
this paper. tion of therapy was 95  87 hours in the propofol group
and 70  54 hours in the morphine group (p = 0.26). The
Patient Characteristics and Predictors of Outcome by average infusion rates for the propofol group were 55 
Patient Group 42 g/kg/minute of propofol and 1.3  0.7 mg/hour of
The patients’ median ages did not differ significantly morphine. For the morphine group, combining the titrat-
but there was a higher proportion of patients older than 55 able and low-dose infusions, the mean morphine infusion
years in the propofol group (30.4%) compared with the rate was 10  6.7 mg/hour.
morphine group (10.5%) (p  0.05). The median postre-
suscitation GCS score was 7 in the propofol group and 6 Intracranial Pressure, CPP, and Therapy Intensity
in the morphine group; however, the propofol group had a The modes of ICP monitoring in the propofol group
higher proportion of patients with a GCS score of 3 to 5 included ventriculostomy in 16 patients and a parenchy-

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D. F. Kelly, et al.

TABLE 4
Therapy intensity for ICP and CPP control*
Propofol Morphine
Therapy (21 patients) (19 patients) p Value

drug treatment†
mannitol 45.5% 43.6% 0.09
NMB 33.7% 47.4% 0.01
benzodiazepines 3.0% 12.8% 0.001
pentobarbital 1.0% 6.4% 0.01
vasopressors 65.3% 61.5% 0.07
total no. of treatment days 101 78
CSF drainage by therapy day (mean ml  SD)
Day 1 48  55 (16) 77  112 (15) 0.38
Day 2 77  74 (15) 191  102 (16) 0.002
Day 3 75  105 (12) 179  127 (13) 0.05
Day 4 86  108 (9) 134  80 (8) 0.31
* Number of patients with CSF drainage is shown in parentheses. Ab-
breviation: NMB = neuromuscular blocking agents.
† The frequency of daily use of a given drug is expressed as a percent-
age of the total number of treatment days for each group.

propofol group (34.4  5.9 mm Hg) and the morphine

group (36  4.2 mm Hg) while patients were receiving
study drugs (p = 0.32).
Neurological Outcome
At 6 months postinjury, a favorable outcome, as as-
sessed using the GOS, was observed in 12 (52.2%) of the
propofol patients and in nine (47.4%) of the morphine pa-
tients; the mortality rates were 17.4% and 21.1%, respec-
tively (Table 5). If the two patients without ICP monitor-
ing in the propofol group are excluded, the favorable
outcome rate is unchanged. Similarly, 14 patients (60.9%)
FIG. 1. Graphs demonstrating daily ICP and CPP for the propo-
in the propofol group and 11 (57.9%) in the morphine
fol (PRO) and morphine (MS) groups. Values are expressed as the group had favorable outcomes, as assessed using the DRS.
mean  SD. The only significant difference (asterisk) was ob- Adverse Events and Cause of Death
served for ICP on therapy Day 3 in which ICP averaged 14 mm Hg
in the propofol group and 18 mm Hg in the morphine group (p  The number of patients sustaining adverse events re-
0.05). The numbers of patients in each group on each therapy day sulting in study withdrawal was five (21.7%) in the propo-
are shown at the top of each graph. In one patient in the morphine fol group and eight (42.1%) in the morphine group. How-
group, baseline ICP and CPP values were considered erroneous by ever only four events (17.4%) in the propofol group and
the site investigator and were excluded. In another patient in the six (31.6%) in the morphine group were considered severe
morphine group, no CPP value was recorded for therapy Day 1. in intensity (Table 6). Uncontrollable intracranial hyper-
tension was the cause of withdrawal in three patients in
mal monitor in five patients; two patients did not under- the propofol group and in five in the morphine group (p =
go monitoring. The monitoring modes in the morphine 0.06) and was considered a key factor in three of four
group included ventriculostomy in 16 patients and a deaths in both groups. One patient in the propofol group
parenchymal monitor in three patients. For the 21 moni- was withdrawn after 23 hours of trial medications because
tored patients in the propofol group and the 19 patients of hypotension. She was receiving a moderate dose of pro-
pofol, averaging 55 g/kg/minute. She had sustained se-
in the morphine group, daily mean ICP and CPP are vere multiple trauma with chest injuries and experienced
displayed in Fig. 1. Values were generally similar between a hypotensive episode before beginning the study medi-
the two groups, except on therapy Day 3 when ICP was cations. She recovered to a level of moderate disability.
lower in the propofol group (p  0.05). Additionally, Another patient in the propofol group was withdrawn
in patients with ventriculostomies, the amount of CSF because of low CPP after 29 hours of therapy. He was
drainage was less in the propofol group on therapy Days 2 receiving a relatively low dose of propofol, averaging 28
and 3 than in the morphine group (p  0.002 and p  g/kg/minute, and also recovered to a level of moderate
0.05, respectively; Table 4). Use of neuromuscular block- disability. Pneumonia was documented in five patients
ing agents, benzodiazepines, and pentobarbital was also (21.7%) in the propofol group and in two (10.5%) in the
less in the propofol group (p  0.05 for all comparisons). morphine group (p = 0.13). Sepsis occurred in three pa-
However, there was a trend toward greater use of vaso- tients (13%) in the propofol group and in one (5.3%) in the
pressors (p = 0.07) and mannitol (p = 0.09) in the propo- morphine group (p = 0.2). None of the infections reported
fol group. The mean daily PaCO2 was similar between the were considered directly related to the trial medications.

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Propofol in traumatic brain injury

TABLE 5 TABLE 6
Outcomes of 42 patients with moderate or severe head injury* Adverse events resulting in withdrawal from study
Propofol Morphine Propofol Morphine
6-Mo Outcome (23 patients) (19 patients) Event (23 patients) (19 patients)

good recovery 3 (13%) 5 (26.3%) uncontrollable intracranial hypertension* 3 (13%)† 5 (26.3%)†

moderate disability 9 (39.1%) 4 (21.1%) reduced CPP 1 (4.3%)†‡ 0
severe disability 5 (21.7%) 6 (31.6%) hypotension 1 (4.3%)‡ 0
vegetative state 2 (8.7%) 0 (0%) cardiac arrhythmia 0 1 (5.3%)†
death 4 (17.4%) 4 (21.1%) hyperlipemia 0 1 (5.3%)‡
lost to follow up 4 of 27 (14.8% ) 4 of 23 (17.4%) agitation 0 1 (5.3%)†‡
* Outcomes based on GOS. * p = 0.06.
† Considered severe in intensity. In the morphine group four of five
instances of uncontrollable ICP were considered severe in intensity and
one was deemed mild.
Regarding the effects of Intralipid administration, only ‡ Considered related to study medications.
one patient was withdrawn because of hyperlipemia (peak
triglyceride level 471 mg/dl, normal range 10–250 mg/dl).
This patient from the morphine group had been receiving
high doses of trial infusions for 6 days. In the propofol these criteria. The 10 patients in the high-dose subgroup
group, seven patients (30.4%) had at least one episode of were compared with 13 patients in the low-dose subgroup
transient elevation in serum triglycerides. These patients and 19 patients in the morphine group (Tables 7 and 8).
were receiving propofol averaging 64  53 g/kg/minute Predictors of Outcome. The propofol high-dose sub-
for 164  113 hours. They tended to be older with a mean group was more severely injured according to the initial
age of 47 years. The patient with elevated triglycerides GCS score and had a higher incidence of multiple contu-
who received study medications for the shortest time (45 sions compared with both the low-dose subgroup and the
hours) and with the lowest mean dose (19 g/kg/minute), morphine group. There was also a trend toward a higher
was also the oldest (75 years). He recovered to a level of incidence of abnormal cisterns in the high-dose group
moderate disability. compared with the morphine group. The low-dose sub-
group, however, consisted of patients who were signifi-
Data Analysis With Inclusion of Patients Lost to cantly older than both the high-dose subgroup and the
Follow Up morphine group and had a higher incidence of evacuated
subdural hematomas compared with the high-dose sub-
When the eight patients lost to follow-up review were group.
included in the prognostic indicator and ICU data analy-
ses, similar differences were seen between the two treat- Intracranial Pressure and CPP Control. There were no
ment groups for most analyses. Specifically, the propofol significant differences across the three groups regarding
group (27 patients) continued to have a higher incidence mean daily ICP and CPP values. On therapy Day 2, how-
of poor prognostic indicators than the morphine group (23 ever, there was a trend toward a higher mean CPP in the
patients): patient age older than 55 years, GCS score of high-dose propofol subgroup (81  8 mm Hg) compared
3 to 5, early hypotension and/or hypoxia (p  0.05 for with the low-dose (68  19 mm Hg) subgroup and the
all comparisons), and compressed or absent cisterns on morphine group (72  12 mm Hg) (p = 0.16, ANOVA).
CT scan (p = 0.1). Regarding ICP, the difference seen on Similarly, on therapy Day 3 there was a trend toward
therapy Day 3 was no longer significant. However, the lower ICP in the high-dose (14  5 mm Hg) and low-dose
amount of CSF drainage remained less on therapy Days (15  6 mm Hg) subgroups compared with the morphine
2 and 3 in the propofol group (p  0.01 and p  0.05, group (18  4 mm Hg) (p = 0.12, ANOVA).
respectively). Use of neuromuscular blocking agents, ben- Therapy Intensity for CPP and ICP Control. Use of CSF
zodiazepines, and pentobarbital was also less in the propo- drainage was less in both the high-dose and low-dose pro-
fol group (p  0.05 for all comparisons). However, use of pofol subgroups on therapy Days 2 and 3 compared with
mannitol (p  0.05) and vasopressors (p = 0.06) was less the morphine group (p  0.01 and p = 0.11, respectively).
in the morphine group. Regarding adverse events, there Additionally, on therapy Day 4, there was a trend of less
were no intergroup differences in incidence of uncontrol- CSF drainage in the high-dose subgroup compared with
lable intracranial hypertension, systemic hypotension, low the morphine group (p = 0.06). Use of mannitol and neu-
CPP, or infections. romuscular blocking agents was greater in the high-dose
subgroup and the morphine group, whereas benzodiaze-
Propofol Subgroup Analysis—Dose Effect pine and pentobarbital use was greatest in the morphine
Patients in the propofol group were further categorized, group. In contrast, use of vasopressors was significantly
retrospectively, into either high-dose or low-dose sub- greater in the high-dose subgroup compared with both the
groups based on the total amount of propofol received, the low-dose subgroup and the morphine group.
time to initiation of therapy, and infusion duration. High- Neurological Outcome. A favorable neurological out-
dose patients were defined as receiving a total propofol come, as assessed using the GOS and DRS, was achieved
dose of at least 100 mg/kg, beginning propofol within 48 in 70% and 80% of patients in the high-dose propofol sub-
hours of injury, and remaining on infusion for a minimum group, compared with 38.5% and 46.2% in the low-dose
of 24 hours; low-dose patients did not meet at least one of subgroup, respectively (p  0.05 for both GOS and DRS

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D. F. Kelly, et al.

TABLE 7 tensity for ICP control was less, and there was a trend for
Propofol subgroup analysis* fewer patient withdrawals for intractable intracranial hy-
pertension in the propofol group. Furthermore, 6 months
Propofol Group postinjury neurological outcome was similar in the two
High Low Morphine groups. When the eight patients lost to follow-up review
Patient Characteristics & Outcome Dose Dose Group were included in the acute data analysis, the propofol
group still had a significantly greater incidence of poor
no. of patients 10 13 19
time from injury to protocol entry (hrs) 21  12 43  23 38  26
prognostic indicators and a lower therapy intensity, as
time on study medications (hrs) 128  63 69  97 70  54 measured by use of neuromuscular blocking agents, ben-
average propofol dose (µg/kg/min) 78  44 36  31 0 zodiazepines, pentobarbital, and CSF drainage. However,
average morphine dose (mg/hr) 1.6  1.0 1.1  0.4 10  6.7 mannitol and vasopressor use was more frequent in the
age (mean  SD in yrs)† 30  14 46  18 33  13 propofol group.
patients’ age 55 yrs† 10% 46.2% 10.5% The subgroup analysis of propofol patients demonstrat-
median GCS score (range)‡ 4.5 (3–7) 7 (3–9) 6 (3–10)
GCS score 3–5‡ 60% 23.1% 15.8%
ed that the high-dose subgroup and the morphine group
abnormal pupils (1 or both) 66.7% 58.3% 52.6% were well matched in terms of age, incidence of hypoten-
(6 of 9) sion, hypoxia, and abnormal pupils. However, the high-
median CT diagnoses (range) 3.5 (1–7) 3 (0–5) 4 (0–6) dose propofol patients were more severely injured, as
absent or compressed cisterns§ 80% 76.9% 57.9% determined by GCS scores, and tended to have more unfa-
diffuse swelling w/ or w/o shift 60% 38.5% 57.4% vorable CT findings compared with the morphine group.
evacuated hematomas (all) 30% 53.8% 47.4%
epidural 30% 7.7% 15.8%
Despite these poor prognostic factors, the high-dose pro-
subdural§ 10% 38.5% 21.1% pofol subgroup tended to have better ICP and CPP con-
intracerebral 10% 15.4% 26.3% trol and required less CSF drainage and benzodiazepine
multiple contusions§ 70% 23.1% 42.1% and pentobarbital therapy. However, vasopressor use was
favorable outcome greatest in the high-dose subgroup. Finally, the high-dose
GOS score 4 or 5 70% 38.5% 47.4% propofol subgroup had the highest favorable neurological
DRS score 0–6 80% 46.2% 57.9%
outcome rate compared with both the low-dose subgroup
* High-dose propofol criteria: minimum total dose 100 mg/kg, propofol and the morphine group.
infusion started within 48 hours of injury, infusion received for minimum
of 24 hours. The average propofol dose was significantly higher in the
high-dose subgroup when compared with the low-dose subgroup (p  Methodological Problems
0.05, Student’s t-test).
† The age effect was significant across groups according to ANOVA The original target number of 100 patients for this trial
(p  0.05). The percentage of patients older than 55 years was greater in was not reached because sufficient drug safety data were
the low-dose subgroup compared with the high-dose subgroup and the obtained with fewer patients than expected. The sample
morphine group (p  0.05). size was further reduced by patient exclusions deemed
‡ The median GCS score was lower in the high-dose subgroup compared
with the low-dose subgroup (p  0.05) and the morphine group (p = 0.07). necessary to maintain study validity. Specifically, a mini-
The percentage of patients with GCS scores 3 to 5 was greater in the high- mum of 12 hours on trial drugs and onset of therapy with-
dose subgroup (p  0.05 compared with the low-dose subgroup; p  0.002 in 96 hours of injury were thought to constitute reason-
compared with the morphine group). able, albeit not ideal, windows for inclusion. It would
§ The appearance of abnormal cisterns on CT scans was more common
in the high-dose subgroup compared with the morphine group (p = 0.1). have been preferable to have a longer minimum time on
Subdural hematomas were more common in the low-dose subgroup com- trial drugs and a narrower time window for trial entry. The
pared with the high-dose subgroup (p  0.05). Multiple contusions were issue of wide variability in total dose and duration of
more common in the high-dose subgroup compared with the low-dose sub- propofol was addressed by the high- and low-dose propo-
group (p  0.01) and the morphine group (p = 0.06).
 There was a higher incidence of favorable outcome in the high-dose
fol subgroup analysis. Another confounding problem was
subgroup compared with the low-dose subgroup (p  0.05 for both GOS that seven patients in the morphine group received vary-
and DRS scores) and the morphine group (p = 0.09 for GOS scores and ing amounts of 1% propofol before trial entry. Four of
p = 0.1 for DRS scores). these patients received such small amounts that they were
included for analysis, despite the obvious methodologi-
scores), and compared with 47.4% and 57.9% in the mor- cal problem this creates. Ideally, these four patients also
phine group, respectively (p = 0.09 for GOS and p = 0.1 would have been excluded. The potential bias of exclud-
for DRS). ing the eight patients lost to follow-up review was ad-
dressed by including them in the prognostic-indicator and
ICU data analysis. The variability in treatment regimens
Discussion across centers is also a methodological issue that is seen
frequently in such clinical studies. For example, the fact
Summary of Study Findings
that ventriculostomies were used in only 16 of 23 patients
Despite randomization in this pilot study, the propofol in the propofol group and in 16 of 19 patients in the mor-
and morphine groups were not evenly matched in prog- phine group may have created bias in the analysis of ther-
nostic indicators. Specifically, the propofol group had apy intensity for ICP and CPP control. The differences in
more patients who were older than 55 years of age, had an CSF drainage on therapy Days 2 and 3 remained signifi-
initial GCS score of 3 to 5, had early hypotension and/or cant, however, even with a relatively small number of pa-
hypoxia and compressed or absent basilar cisterns on the tients with ventriculostomies.
initial CT scan. Even with this preponderance of adverse A titratable morphine infusion was used for the “stan-
risk factors, ICP was lower on therapy Day 3, therapy in- dard therapy” group because opiate-based sedative regi-

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Propofol in traumatic brain injury

mens are commonly used in intubated head-injured pa- TABLE 8

tients. However, it was somewhat surprising that the mor- Propofol subgroup analysis: therapy intensity for ICP
phine dose was so high, averaging 10 mg per hour, even and CPP control*
though the titration protocol allowed for relatively liberal
use of CSF drainage and therapy with mannitol and neu- Propofol Group
Morphine
romuscular blocking agents. This fact may attest to the Therapy High Dose Low Dose Group
relative ineffectiveness of opiates for achieving sedation
and ICP control. Their routine use in head-injured patients drug treatment intensity
is also of questionable wisdom, given that opiate antago- mannitol† 48.4% 37.8% 43.6%
NMB‡ 45.3% 13.5% 47.4%
nists have been shown in some spinal cord injury models benzodiazepines§ 3.1% 2.7% 12.8%
to be neuroprotective.71 These and other disadvantages pentobarbital§ 1.6% 0 6.4%
of an opiate-based sedation regimen are further discussed vasopressors 84.4% 32.4% 61.5%
later. total no. of treatment days 64 37 78
CSF drainage by therapy day (mean ml  SD)**
Previous Head Injury Studies Using Propofol Day 1 44  34 (10) 55  59 (6) 77  112 (15)
Day 2 88  83 (10) 55  54 (5) 191  102 (16)
Relatively few studies of propofol use for posttraumat- Day 3 72  103 (9) 84  132 (3) 179  127 (13)
ic coma have been reported during the last decade. In one Day 4 57  68 (8) ID (1) 134  80 (8)
of the first such studies, 10 severely head-injured patients
* Number of patients with CSF drainage is shown in parentheses.
were given a 1% propofol infusion over 24 hours after Abbreviations: ID = insufficient data; NMB = neuromuscular blocking
having been started initially on infusions of morphine (5– agents.
10 mg/hour), midazolam (5–10 mg/hour), and vecuroni- † Mannitol use was less in the low-dose subgroup compared with the
um (0.1 mg/kg/hour).18 Propofol infusion rates averaged high-dose subgroup (p = 0.06).
‡ Use of NMB was less in the low-dose subgroup compared with the
48 g/kg/minute, which is similar to the mean rate in the high-dose subgroup and the morphine group (p  0.01).
present study. The ICP was unchanged but CPP took an § Use of benzodiazepine and pentobarbital was less in the low- and high-
upward trend and was significantly higher at the end of 24 dose subgroups compared with the morphine group (p  0.05, except
hours. In another 24-hour study, severely head injured pa- p = 0.06 for the high-dose subgroup compared with the morphine group for
pentobarbital).
tients were randomized to receive either a 1% propofol in-  Use of vasopressor agents was less in the low-dose subgroup and the
fusion or a fentanyl infusion; both groups received pan- morphine group compared with the high-dose subgroup (p  0.001).
curonium.43 In the 15 patients randomized to propofol ** The CSF drainage was less in the high- and low-dose subgroups on
(dose range 17–50 g/kg/minute), CPP increased signifi- therapy Day 2 (p  0.05) and Day 3 (p = 0.11) as determined by ANOVA.
cantly from 75 to 93 mm Hg. The ICP remained stable in On therapy Day 4, CSF drainage was less in the high-dose subgroup com-
pared with the morphine group (p = 0.06, Student’s t-test).
the low ICP subgroup and decreased in the high ICP sub-
group. In the 16 patients receiving fentanyl, ICP also
decreased in the high ICP subgroup, but CPP decreased dant and inhibitor of lipid peroxidation, unlike barbiturate
slightly. In a more recent study of intubated moderately medications.1,26,27,32,46
and severely head injured patients, nine patients were giv- Similar to barbiturate agents, etomidate, and benzodi-
en a 1% propofol infusion (mean dose 55 g/kg/minute, azepines, propofol causes cerebral metabolic suppression
range 36–95 g/kg/minute) and six were sedated with in- primarily by potentiating the GABAergic receptor-chan-
fusions of morphine (range 0–4 mg/hour) and midazolam nel complex.28,29 Propofol-induced EEG burst suppression
(range 0–5 mg/hour).58 Throughout a mean data collection results in a decrease in cerebral blood flow of 38 to 58%,
period lasting 40 hours, no differences were observed be- a decrease in the cerebral metabolic rate of oxygen of 22
tween groups for blood pressure, ICP, CPP, or outcome. to 43%, and a decrease in the cerebral metabolic rate of
However, propofol was associated with a significant fall glucose of 36 to 55%.3,14,22,30,51,65 This metabolic depressant
in the arteriovenous difference in oxygen at 4 hours after effect is thought to be a key factor in enhanced neuro-
onset of propofol infusion. At 8 hours postinfusion this logical recovery and reduced neuronal damage in experi-
difference disappeared. The findings from these studies mental ischemia and reperfusion models.33,69,72 The clinical
suggest that a propofol-based regimen is safe and as ef- importance of other actions of propofol is unclear. Spe-
fective as a narcotic-based regimen for sedation and ICP cifically, the effects on NMDA and calcium channels are
control. It is difficult, however, to draw further conclu- uncertain. However, given the role of excitotoxicity and
sions from these reports. intracellular calcium influx in posttraumatic mitochon-
drial dysfunction, attenuation of this influx by propofol
Propofol as a Neuroprotectant may be beneficial.4,49,66 The addition of the calcium chela-
Given the significant disparity in injury severity be- tor EDTA to the propofol formulation, albeit in relatively
tween the two treatment groups in this study, both acute small quantities, may further reduce the harmful effects of
and long-term outcome data suggest a propofol-based reg- calcium. Propofol’s potent free-radical scavenging effects
imen may be superior to an opiate-based regimen in head- and ability to inhibit lipid peroxidation may also be rele-
injured patients. Several neuroprotective actions of propo- vant in the clinical setting by enhancing cell membrane
fol may help explain this favorable effect on neurological viability.1,26,27,32,46
recovery. These include potentiation of -aminobutyrateA In the present study, the mean propofol dose was 55
(GABAergic) inhibition28,29 and inhibition of N-methyl- g/kg/minute. Infusion rates typically resulting in an
D-aspartate glutamate receptors and voltage-dependent EEG burst suppression range from 100 to 220 g/kg/min-
calcium channels.4,25,49 Propofol is also a potent antioxi- ute.30,56,64 Given that cerebral metabolic measurements

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D. F. Kelly, et al.

were not routinely performed in this trial, it is unknown minute and does not increase by more than 10 g/kg/min-
whether significant metabolic suppression was achieved ute every 5 minutes.56 In the absence of vasopressors, a
in these patients. Additionally, it is unclear if other neuro- propofol bolus followed by an infusion rate of greater than
protective mechanisms, including effects on NMDA re- 50 to 100 g/kg/minute reliably causes a transient reduc-
ceptors, calcium channels, and lipid peroxidation are bio- tion in blood pressure of up to 25% of baseline values,
logically relevant when propofol is administered at these similar to that seen when using high-dose pentobarbital
levels. The favorable trends in ICP control and therapy administration.14,30,45 This rapid dosing method is not rec-
intensity in the propofol group and the high favorable out- ommended for neurosurgical ICU patients, given the like-
come rate in the high-dose propofol subgroup suggest that lihood of hypotension and possible precipitous drops in
moderately high doses, even below those needed to induce cerebral blood flow. Of note, both midazolam and the opi-
EEG burst suppression, may enhance neurological re- ates also decrease blood pressure and CPP when given in
covery. bolus form to severely head injured patients.34,50
Elevated triglyceride levels from the lipid vehicle can
occur with prolonged high-dose propofol infusion and are
Advantages and Disadvantages of Propofol more likely to occur in older patients. This side effect is
In addition to its neuroprotective qualities, there are shortlived once the infusion is stopped or diminished.7,55
several other properties that make propofol an attractive The new 2% formulation should reduce the lipid load by
sedative for head-injured patients. First, its short elimi- 50% compared with an equipotent drug dose with the 1%
nation halflife of less than an hour facilitates rapid ti- formulation. Regarding risk of infection due to the lipid
tration to a desired clinical effect and permits frequent vehicle, the addition of EDTA appears to be safe from an
neurological assessments.2,6,54,55 Second, the wide dose re- infection standpoint. Although there was a trend toward a
sponse allows it to be used as a sedative or as a metabolic higher pneumonia rate in patients in the propofol group,
suppressive and neuroprotective agent. In contrast, the these pneumonias were not attributed to drug administra-
short-acting neuroprotectant, etomidate, is not suited for tion per se. Further studies confirming the safety of this
prolonged use because of renal toxicity related to its pro- formulation from an infection standpoint are nearing com-
pylene glycol vehicle35 and because it suppresses adreno- pletion.
cortical steroid production.19,44 Pentobarbital, the metabol- Finally, regarding the issue of cost, propofol is clearly
ic suppressant that is traditionally used, has a halflife of 15 more expensive than morphine on a per unit basis. How-
to 48 hours and typically requires a minimum of 48 hours ever, as this study confirms, most intubated head-injured
after drug stoppage before patients can be assessed neuro- patients are not adequately sedated with morphine alone.
logically.6,24 Third, propofol reduces ICP as demonstrated In contrast, a propofol-based sedation regimen appears to
in previous reports43,45,53 and as suggested by this study, reduce the need for concomitant narcotics and muscle
although this effect has not been seen consistently.18,58 In relaxants significantly. Given the lipid vehicle used with
contrast, neither midazolam (Versed) nor the opiates mor- propofol, the daily need for lipid nutritional supplements
phine, fentanyl, or sufentanil reliably decrease ICP in is also decreased. Additionally, as other studies have
severely head injured patients.34,50,68 In one report, both shown, patients receiving propofol emerge from sedation
fentanyl and sufentanil increased ICP in severely head more rapidly compared with those receiving benzodiaze-
injured patients.57 Fourth, propofol is a potent anticonvul- pines, which may, in turn, shorten mechanical ventilation
sant medication and is now often used for refractory sta- time and the number of days in the ICU.7,21,54,55 Overall,
tus epilepticus.8,15,70 Reports of propofol-induced seizure- these factors appear to make a propofol sedation regimen
like activity are uncommon and the clinical significance of cost-effective; however, further study of this issue is war-
such proconvulsant properties is controversial.48,60 Fifth, ranted.
transcranial Doppler studies indicate that high-dose pro-
pofol anesthesia does not impair CO2 reactivity or cerebral
pressure autoregulation in noninjured humans.42,59,62 This Conclusions
property is particularly relevant in head-injured patients In this preliminary study, we have demonstrated the
who often have derangements in cerebral vasoreactivi- potential advantages of a propofol-based sedation and
ty.9,36,47 Sixth, in contrast with the benzodiazipines and opi- ICP control regimen in intubated head-injured patients.
ates, long-term propofol use does not result in addiction The similar favorable outcome rate in the two treatment
or withdrawal phenomena.7 Increasing dose requirements, groups and the lower therapy intensity for ICP control,
however, may occur.10,11,20 Whether this problem is related despite a preponderance of poor prognostic factors in the
to tolerance or an increased rate of drug clearance remains propofol group, suggests that a propofol-based regimen
unclear. with low-dose opiate analgesia is a safe and, possibly,
Regarding hemodynamic effects, this study suggests, as desirable alternative to an opiate-based regimen in head-
have previous reports, that propofol infusion is relatively injured patients. Further studies are clearly needed to
well tolerated compared with opiate infusions.18,43,58 In this define the neuroprotective dose range of propofol in both
study, vasopressors were used for CPP maintenance on experimental and human head injury. A randomized phase
65% of the therapy days in the propofol group compared II trial of early high-dose propofol during the period of
with 61% for the morphine group. The tendency toward acute brain swelling in severely head injured patients is
hypotension with propofol can be minimized if patients currently being planned, based on the findings of this
have a normal intravascular volume before initiating pro- study and in light of the favorable results of high-dose bar-
pofol; the infusion begins at a rate of less than 20 g/kg/ biturate studies performed over a decade ago.16,47

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58. Stewart L, Bullock R, Rafferty C, et al: Propofol sedation in Address reprint requests to: Daniel F. Kelly, M.D., Division of
severe head injury fails to control high ICP, but reduces brain Neurosurgery, Room 18-218A NPI, Box 957039, University of
metabolism. Acta Neurochir 60:544–546, 1994 California, Los Angeles, California 90095–7039. email: dfkelly@
59. Strebel S, Lam AM, Matta B, et al: Dynamic and static cerebral ucla.edu.

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