CLINICAL INVESTIGATION
Ketofol as an Anesthetic Agent in Patients With Isolated
Moderate to Severe Traumatic Brain Injury: A Prospective,
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Randomized Double-blind Controlled Trial
Neha Maheswari, MD, DM,* Nidhi B. Panda, MD,* Shalvi Mahajan, MD, DM,†
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Ankur Luthra, MD, DM,† Smita Pattnaik, MD,‡ Nidhi Bhatia, MD,†
Madhivanan Karthigeyan, MCH,§ Narender Kaloria, MD, DM,† Rajeev Chauhan, MD, DM,†
Shiv Soni, MD, DM,† Kiran Jangra, MD, DM,* and Hemant Bhagat, MD, DM*
Background: The effects of ketofol (propofol and ketamine ad-
mixture) on systemic hemodynamics and outcomes in patients
undergoing emergency decompressive craniectomy for traumatic
brain injury (TBI) are unknown and explored in this study.
Methods: Fifty patients with moderate/severe TBI were random-
ized to receive ketofol (n = 25) or propofol (n = 25) for induction
and maintenance of anesthesia during TBI surgery. Intraoperative
hemodynamic stability was assessed by continuous measurement
of mean arterial pressure (MAP) and need for rescue interventions
to maintain MAP within 20% of baseline. Brain relaxation scores,
serum biomarker-glial fibrillary acidic protein levels, and extended
Glasgow Outcome Scale (GOSE) at 30 and 90 days after discharge
were also explored.
Results: MAP was lower and hemodynamic fluctuations more
frequent in patients receiving propofol compared with those re-
ceiving ketofol (P < 0.05). MAP fell > 20% below baseline in 22
(88%) patients receiving propofol and in 10 (40%) receiving ke-
tofol (P = 0.001), with a greater requirement for vasopressors (80%
vs. 24%, respectively; P = 0.02). Intraoperative brain relaxation
scores and GOSE at 30 and 90 day were similar between groups.
Glial fibrillary acidic protein was lower in the ketofol group
(3.31 ± 0.43 ng/mL) as compared with the propofol (3.41 ± 0.17
ng/mL; P = 0.01) group on the third postoperative day.
Conclusion: Compared with propofol, ketofol for induction and
maintenance of anesthesia during decompressive surgery in patients
with moderate/severe TBI was associated with improved hemodynamic
stability, lower vasopressor requirement, and similar brain relaxation.
Key Words: ketamine, ketofol, propofol, blood pressure, traumatic
brain injury, outcome
(J Neurosurg Anesthesiol 2023;35:49–55)
Received for publication October 15, 2020; accepted March 28, 2021.
From the *Department of Anesthesia and Intensive Care, Division of
Neuroanesthesia; Departments of †Anesthesia and Intensive Care;
‡Pharmacology; and §Neurosurgery, Post Graduate Institute of
Medical Education and Research (PGIMER), Chandigarh, India.
The authors have no conflicts of interest.
Address correspondence to: Nidhi B. Panda, MD. E-mail: nidhibp@gmail.com.
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/ANA.0000000000000774
J Neurosurg Anesthesiol  Volume 35, Number 1, January 2023
Copyright r 2021 Wolters Kluwer Health, Inc. All rights reserved.
T raumatic brain injury (TBI) is a global problem, with
an annual incidence rate of almost 939 per 100,000
population.1 The initial (primary) injury to brain tissue is
irreversible and nonmodifiable. Subsequent (secondary)
brain injury can exacerbate the primary injury and worsen
clinical outcomes and is potentially modifiable. The peri-
operative period is a risk time for secondary brain injury,
particularly if secondary systemic insults are not prevented
or adequately controlled. Hypotension is a secondary in-
sult and a potent cause of secondary brain injury, and is
directly associated with mortality after TBI.2 Hemody-
namic instability, particularly reductions in mean arterial
pressure (MAP) and subsequent decreases in cerebral
perfusion pressure (CPP), may worsen preexisting neuro-
logical insults.3 In addition, a reduction in CPP triggers
cerebral vasodilatation and a consequent increase in cer-
ebral blood volume which in turn can increase ICP and
precipitate further injury in potentially salvageable at-risk
brain regions, that is, “penumbral” zones.
Propofol is a popular intravenous anesthetic agent in
neurosurgery; it decreases cerebral electrical activity and,
because of substantial preservation of flow-metabolism
coupling, decreases cerebral blood flow.4 However, sys-
temic vasodilatory effects of propofol result in dose-
dependent systemic hypotension. In contrast, ketamine, a
phencyclidine derivative, increases cerebral metabolic rate
and cerebral blood flow, and has strong sympathomimetic
activity. For these reasons, it has been infrequently used
during neurosurgical cases.5 However, sympathomimetic
actions of ketamine increase MAP and possibly increase
CPP in “at-risk” brain regions, with potential to prevent
or minimize secondary ischemic brain injury. Preclinical
data also suggest that ketamine attenuates excitotoxicity
and offers neuroprotection.6
We hypothesized that ketofol (a ketamine and pro-
pofol admixture) for induction and maintenance of anes-
thesia in patients with TBI could minimize intraoperative
hemodynamic variability without compromising brain
relaxation compared with propofol anesthesia. Therefore,
we aimed to compare the use of ketofol and propofol for
anesthesia during TBI surgery. The primary outcome of
this study was intraoperative hemodynamic stability
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 Maheswari et al
(MAP variation > 20% of baseline). Secondary outcomes
included quality of brain relaxation, serum glial fibrillary
acidic protein (GFAP) levels, duration of mechanical
ventilation and hospital length of stay, and clinical out-
comes at 30 and 90 days after discharge from hospital.
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METHODS
This prospective, randomized double-blind trial was
approved by the Institutional Ethics Committee (INT/
IEC/2018/000917, 25/06/2018; NK/4290/DM) and regis-
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tered with Clinical Trial Registry of India (CTRI/2019/03/
018131). The study was conducted at the Advanced
Trauma Centre, Post Graduate Institute of Medical Ed-
ucation and Research, Chandigarh, India between April
2019 and December 2019. Written informed consent was
obtained from patients’ next of kin.
Participants and Study Drug
The patients were aged from 18 to 65 years with
isolated moderate or severe TBI planned for primary de-
compressive surgery for unilateral intracranial lesions, in-
cluding subdural hemorrhage, contusions, or a combination
of subdural hemorrhage and contusion, with a midline
shift. Exclusion criteria were extradural hematoma, poly-
trauma, history of uncontrolled hypertension, coronary
artery disease, psychiatric disorder, neurodegenerative dis-
order, renal or hepatic dysfunction, pregnancy, and refusal
of consent.
Study Drugs and Randomization
An initial pilot study was carried out in 15 neuro-
surgical patients (not included in the current study) to
determine the optimal ratio of ketamine to propofol in the
ketofol used in this study. We assessed heart rate and
MAP during anesthesia with 3 different ketamine/propo-
fol mixtures (1:3, 1:4, and 1:5) and found that hemody-
namic stability was optimal with a ketamine/propofol
ratio of 1:5. Previous studies have confirmed that a ket-
amine/propofol admixture is stable without any ill effects
or precipitation of components.7,8 Similarly, in our pilot
study we did not observe any precipitation, color change,
or any detectable layering or oily droplet formation on
ketofol.
Patients were randomized using a computer-gen-
erated random number table into 2 groups; those in group
KP received ketofol (ketamine/propofol ratio 1:5) and
those in group P received propofol alone for induction and
maintenance of anesthesia. The opaque sealed envelope
method was used for concealment, with consecutive en-
velopes opened just before a patient’s arrival in the oper-
ating room. The neuroanesthesiologist managing the case,
the operating neurosurgeon (having at least 2 y experience
of trauma neurosurgery), and the neuroanesthesiologist
collecting the data were blinded to group allocation. The
study drug infusion was prepared by an anesthesiologist
who did not participate in the study. Forty milliliters of
propofol with 8 mL of ketamine (10 mg/mL) was loaded
into a 50 mL syringe for use in patients allocated to group
KP, and 48 mL of propofol (10 mg/mL) was loaded into a
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J Neurosurg Anesthesiol  Volume 35, Number 1, January 2023
50 mL syringe for use in those allocated to group P. Thus,
1 mL of the study drug contained 8.3 mg of propofol and
1.7 mg of ketamine in group KP, and 10 mg of propofol in
group P.
Anesthesia Protocol
Following a detailed preanesthesia assessment, the
patients were moved to the operation room where stand-
ard American Society of Anesthesiologists monitoring
with 5-lead electrocardiogram, noninvasive blood pres-
sure, pulse oximetry, capnography, temperature, and urine
output was instituted. A radial arterial catheter was in-
serted before induction of anesthesia for continuous
monitoring of blood pressure and blood gas analysis.
A standard anesthesia protocol was followed. All
patients were preloaded with 8 mL/kg 0.9% saline, before
induction of anesthesia with 0.5 to 1 mL/kg of the relevant
study drug (ketofol or propofol) administered over 40 to
60 seconds. Following muscle relaxant with vecuronium
(0.1 mg/kg), an appropriately sized endotracheal tube was
inserted. Intraoperative analgesia was provided with a
2 µg/kg bolus of fentanyl followed by fentanyl infusion
(1 µg/kg/h). The infusion rate of ketofol or propofol was
titrated (0.6 to 0.9 mL/kg/h) to maintain MAP within 20%
of baseline values. Ventilation was provided with a 50%
oxygen/air mixture and titrated to maintain a PaCO2 of
between 35 and 40 mm Hg. All patients received an in-
fusion of 20% mannitol (1 g/kg) before craniotomy. The
study drug infusion was stopped at the end of skin suture.
If MAP fell below 20% of baseline, a fluid challenge
(5 mL/kg 0.9% saline) was administrated and the study
drug infusion reduced by 20%. If hypotension persisted
despite these interventions, bolus doses of intravenous
phenylephrine (50 μg) were administered at 5-minute in-
tervals. If MAP was not restored to within 20% of baseline
after 2 boluses of phenylephrine, an intravenous infusion
of norepinephrine (0.01 to 0.1 μg/kg/min) was started. If
MAP increased above 20% of baseline, an esmolol bolus
(0.5 to 1 mg/kg over 30 s) was administered and repeated
at 5-minute intervals as necessary. Labetalol (20 mg over
2 min) was administered if hypertension was not con-
trolled after 2 bolus doses of esmolol. Packed red blood
cells were transfused if hemoglobin fell below 9 g/dL.
Data Collection
Intraoperative parameters, including heart rate,
MAP, oxygen saturation, end-tidal carbon dioxide, tem-
perature, and urine output were recorded. Heart rate and
MAP were recorded at the following timepoints: baseline
(after fluid preloading), at induction of anesthesia, in-
tubation, drilling of burr hole, beginning of craniotomy,
removal of bone flap, dural opening, and thereafter at
5-minute intervals until the end of anesthesia. The total
volume of the study drug used during anesthesia, and the
duration of anesthesia and surgery were recorded.
Following craniotomy, the degree of brain relaxa-
tion was assessed by the operating neurosurgeon (who was
blinded to the study drug) according to the following
scale: Grade 1, fully relaxed brain; Grade 2, tense brain
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 J Neurosurg Anesthesiol  Volume 35, Number 1, January 2023 Ketofol as Anesthetic Agent in TBI Surgery

with mild but acceptable swelling; Grade 3, tight brain the extended Glasgow Coma Scale (GOSE). Outcome was
with moderate brain swelling but no specific change in dichotomized into favorable (GOSE 5 to 8) and un-
management required; and Grade 4, bulging brain with favorable (GOSE 1 to 4) outcomes.10
severe swelling requiring some specific change in man-
agement (eg, administration of mannitol, propofol bo-
luses, etc.).9
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GFAP, a biomarker of brain injury, was measured
3 times to assess the immediate and delayed impact of the
study drug on brain injury. Intravenous blood samples
(2 mL) were taken before starting the study drug infusion
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Statistical Analysis
In the absence of similar literature at the time of
planning the study, we calculated the sample size using
MAP data collected during the pilot study described
above. Assuming a mean MAP of 94.6 mm Hg in the

(preoperative), at the end of the study drug infusion (im-
mediate postoperative), and on the third postoperative
day. The samples were allowed to clot in plain Vacutainers
at room temperature, and then centrifuged at 2000 rpm for
15 minutes to separate the serum which was pipetted into
cryovials. The serum samples were immediately stored at
−80°C in the pharmacology laboratory until analysis. All
samples were analyzed in duplicate at the end of the study.
GFAP levels were measured using a quantitative
enzyme-linked immunosorbent assay kit with precoated
antigen wells and a double-antibody sandwich technique
(Genxbio Health Sciences Private Ltd).
Duration of mechanical ventilation and hospital
length of stay (d) were recorded, and neurological out-
comes at 30- and 90-day postdischarge were assessed using
ketofol group, a pooled SD of 4.74 and an α error of 0.05,
we calculated that a sample size of 46 (23 per group)
would be required to identify a 10% difference in MAP in
the propofol group with 80% power (www.openepi.com/
SampleSize/SSMean.htm). To allow for dropouts we
planned to recruit 50 participants (25 per group).
Statistical analysis was carried out using the Sta-
tistical Package for the Social Sciences (version 21.0;
SPSS Inc. Chicago, IL). Normally distributed continuous
data was presented as mean ± SD, and the 2 groups were
compared using Student t test. Categorical and nominal
data was described as proportions, and χ2 test or Fisher
exact test were used to identify any significant associations.
Paired sample t test was also used for baseline comparison.
P < 0.05 were considered statistically significant.

Assessed for eligibility (n= 56)

Excluded (n= 06)

Not meeting inclusion criteria (n= 06)
Declined to participate (n= 0)
Other reasons (n= 0)

Randomized (n= 50)

Allocation

Allocated to Group KP (n= 25) Allocated to Group P (n= 25)

Received allocated intervention (n= 25) Received allocated intervention (n= 25)

Lost to follow-up Lost to follow-up

30 Day Post-discharge(n=4) 30 Day Post-discharge(n=5)
90 Day Post-discharge (n= 0) 90 Day Post-discharge (n= 0)

Analysis

Analysed Analysed
Primary Outcome (n= 25) Primary Outcome (n= 25)
Secondary Outcome(n=21) Secondary Outcome(n=21)

FIGURE 1. Study flow diagram. KP indicates ketamine/propofol; P, propofol.

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 Maheswari et al J Neurosurg Anesthesiol  Volume 35, Number 1, January 2023

compared with those who received ketofol (group KP)

TABLE 1. Demographic Characteristics and TBI Morphology
(P < 0.05). Twenty-two (88%) patients in group P had a
Ketofol Propofol greater than 20% reduction in MAP compared with 10
(Group KP) (Group P)
patients (40%) in group KP (P = 0.001) despite similar fluid
Parameters (n = 25) (n = 25) P
requirements (2304+124 in group P vs. 2306+127 mL in
group KP; P = 0.95) (Table 2). As a consequence, more
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Age (y) 37.52 ± 11.31 36.28 ± 11.29 0.70

Weight (kg) 70.00 ± 6.30 68.57 ± 4.98 0.42
Sex (male/female)† 22/3 19/6 0.46
patients in group P required phenylephrine to treat
GCS 7.00 ± 1.50 6.92 ± 1.61 0.85 hypotension; 20 patients (80%) and 6 (24%) patients in
ASA status (I/II)† 22/3 22/3 1.00 group P and group KP, respectively (P = 0.001). No patient
Duration of surgery (min) 107.14 ± 14.28 113.57 ± 16.59 0.18 required norepinephrine infusion. There was no difference
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Duration of anesthesia (min) 135.71 ± 13.99 140.95 ± 17.00 0.28 between groups in the number of patients with > 20%
Acute SDH/contusion/both† 6/12/7 10/11/4 0.39
Total intravenous fluid (mL) 2306.09 ± 127.16 2304.00 ± 124.06 0.95 increases in MAP above baseline; 4 (16%) and 6 (24%) in
Total urine output (mL) 658 ± 93.09 673 ± 89.90 0.54 groups P and KP, respectively (P = 0.47) (Table 2). Similarly,
Total blood loss (mL) 724 ± 140.77 691 ± 150.49 0.432 the number of patients requiring esmolol for hypertension was
Total propofol (mg) 702.6 ( ± 28.3) 949.3 ( ± 34.8) 0.001* similar between groups; 3 (12%) and 5 (20%) in groups P and
Data are shown as mean ± SD unless otherwise indicated. KP, respectively (P = 0.70). No patient required labetalol.
*P < 0.05 (independent sample t test). There was also no difference in heart rate between groups at
†Presented as number.
ASA indicates American Society of Anesthesiologists; GCS, Glasgow Coma
different timepoints (P = 0.65).
Scale score; KP, ketamine/propofol; P, propofol; SDH, subdural hematoma; TBI, Brain relaxation scores were similar in the 2 groups
traumatic brain injury. (P = 1.00) (Fig. 3A). In group KP, 3 patients had Grade I, 9
patients had Grade II, 13 patients had Grade III, and no
patient had Grade IV brain relaxation scores. In group P, 5
patients had Grade I, 8 patients had Grade II, 12 patients
RESULTS had Grade III, and no patient had Grade IV brain
Fifty-six patients were assessed for eligibility. Six were relaxation scores. Mean EtCO2 was 34.7 ± 2.0 and
excluded because they did not meet the predefined inclusion 35.0 ± 1.0 mm Hg in groups KP and P, respectively
criteria, leaving 50 patients (randomized equally into the 2 (P = 0.58). Other intraoperative variables were also similar
groups) eligible for inclusion in the study (Fig. 1). between groups, except for total propofol dose which was
Demographic characteristics and TBI morphology were higher in group P (949.3 ± 34.8 mg) compared with that in
comparable between groups (Table 1). group KP (702.6 ± 28.3 mg; P = 0.001) (Table 1).
Blood pressure changes are shown in Figure 2. Baseline Baseline and immediate postoperative serum GFAP
MAP was similar between groups (P = 0.38), but patients who levels were similar in the 2 groups, whereas GFAP was
received propofol (group P) had lower intraoperative MAP lower in group KP (3.31 ± 0.43 ng/mL) as compared with

FIGURE 2. Intraoperative mean arterial blood pressure. Data are shown as mean+SD. *P < 0.05. KP indicates ketamine/propofol;
P, propofol.

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 J Neurosurg Anesthesiol  Volume 35, Number 1, January 2023
TABLE 2. Intraoperative Hemodynamic Parameters and
Rescue Drugs
Ketofol Propofol
(Group KP) (Group P)
(N = 25) (N = 25)
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Hypotension: MAP <20% 10 (40) 22 (88)
baseline
Vasopressor requirement 6 (24) 20 (80)
Hypertension: MAP > 20% 6 (24) 4 (16)
baseline
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Esmolol requirement 5 (20) 3 (12)
Data shown as n (%).
*P < 0.05 (independent sample t test).
KP indicates ketamine/propofol; MAP, mean arterial pressure; P, propofol.
that in group P (3.41 ± 0.17 ng/mL; P = 0.01) on the third
postoperative day (Fig. 3B). There was no difference in the
duration of mechanical ventilation (group KP, 3.44 ± 2.16
d vs. group P, 3.24 ± 1.56 d; P = 0.70) or length of hospital
stay (group KP, 6 ± 2.71 d vs. group P, 6.45 ± 2.18 d;
P = 0.53) between groups. Unfavorable outcome (GOSE
score < 5) at 30-day postdischarge was reported in 17 and
16 patients in groups KP and P, respectively (P = 0.93)
(Fig. 3C). Four patients in group KP and 5 patients in
group P were lost to 90-day follow-up; in those for which
data are available, 16 patients in both groups had an
unfavorable outcome at 90 days (P = 1.00).
DISCUSSION
In this prospective, randomized clinical trial, we
observed that ketofol provided better hemodynamic sta-
bility as compared with propofol for induction and
maintenance of anesthesia in patients with moderate/
severe TBI undergoing cranial decompressive surgery.
Patients receiving ketofol had higher intraoperative MAP
than those receiving propofol and required fewer doses of
phenylephrine to maintain MAP despite similar fluid re-
quirements. Maintenance of systemic hemodynamics is a
key goal of anesthesia during decompressive surgery for
TBI. A single episode of hypotension doubles mortality
following TBI,11 and increases in MAP are also detri-
mental because of potential to worsen vasogenic brain
edema and intracranial hypertension. We chose a low dose
of ketamine (ketamine-propofol ratio 1:5) in the ketofol
FIGURE 3. Secondary outcomes: (A) brain relaxation score, (B) serum glial fibrillary acidic protein, (C) extended Glasgow Outcome
Score Scale. Data are shown as mean ± SD. *P < 0.05. KP indicates ketamine/propofol; P, propofol.
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Ketofol as Anesthetic Agent in TBI Surgery
mixture used on this study (based on our pilot study),
anticipating that this would be sufficient to minimize re-
duction in MAP secondary to propofol-induced vaso-
dilation while minimizing the risk of increases in heart rate
P and MAP above baseline because of ketamine’s sym-
pathomimetic effects. We found that hemodynamic fluc-
0.001* tuations were greater in patients receiving propofol
0.001* compared with those receiving ketofol; episodes of MAP
0.479 reduction greater than 20% below baseline occurred in
88% of patients receiving propofol compared with only
0.702 40% of patients receiving ketofol, with consequent in-
creased use of vasopressors in those receiving propofol.
This finding could be explained by the sympathomimetic
action of ketamine as described above. In addition, the
total propofol dose was lower in the ketofol group than in
the propofol group, and this may have contributed to the
lower incidence of intraoperative hypotension in patients
receiving ketofol. Similar to our findings, 2 recently pub-
lished studies reported superior hemodynamic stability
and decreased vasopressor requirement in good grade
aneurysmal subarachnoid hemorrhage patients receiving
ketofol (ketamine/propofol ratio 1:5) compared with those
receiving propofol during craniotomy for aneurysmal
clipping.12,13 In another study, ketofol provided superior
hemodynamic stability compared with propofol during
induction of anesthesia; propofol was more likely than
ketofol to be associated with a ≥ 20% reduction in systolic
blood pressure from baseline at 5 minutes (48.8% vs. 12%)
and at 10 minutes (67.4% vs. 39%) after induction.14
A tight brain during craniotomy can further ag-
gravate brain injury because of the greater force required
by the surgeon’s retractor to achieve an adequate surgical
field. Thus, optimal brain relaxation is another essential
goal of neuroanesthesia during intracranial surgeries. In
this study, there was no difference in the quality of brain
relaxation in patients receiving ketofol or propofol, and
most patients had moderate brain swelling that did not
require intervention (Grade III brain relaxation). Thus,
the addition of ketamine to propofol in 1:5 ratio did not
worsen brain relaxation compared with propofol alone, a
finding similar to those reported in previous studies.13,14
Historically, ketamine was reported to be associated with
increases in intracranial pressure,15,16 but more recent data
do not support these findings. In one study, a bolus dose
of ketamine (1 mg/kg) during isoflurane anesthesia in
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 Maheswari et al
neurosurgical patients resulted in a decrease in intracranial
pressure and middle cerebral artery blood flow velocity in
the absence of changes in MAP.17 In another study,
ketamine administered to mechanically ventilated TBI
patients sedated with propofol did not result in an increase
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in ICP, rather a significant reduction in ICP was seen after
different doses of ketamine (1.5, 3, and 5 mg/kg).18
TBI results in excitotoxicity and activation of ex-
trasynaptic N-methyl-D-aspartate (NMDA) receptors
following release of large amounts of glutamate.19 This
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further activates postsynaptic NMDA receptor protein
kinase C and tyrosine kinase signaling cascades, which
leads to phosphorylate of NMDA receptors and upregu-
lation of the signaling currents, resulting in more NMDA
receptor activation.20,21 Ketamine is an NMDA receptor
antagonist and could be expected to mitigate some of the
excitotoxic sequelae of TBI. GFAP, an intermediate fila-
ment protein of the astrocytic cytoskeleton, has been used
to assess injury severity and prognosis in the acute TBI
setting and is reported to have a greater prognostic value
than other biomarkers.22,23 To assess any immediate or
delayed effect of the 2 study drugs on brain injury, we
compared baseline GFAP levels with those immediately
postoperatively and at 72 hours after surgery. Pre-
operative and immediate postoperative serum GFAP
levels were similar in the groups, but GFAP was lower in
the ketofol group on the third postoperative day. This
might reflect some degree of neuroprotection by ketamine
secondary to NMDA receptor antagonism, and improved
maintenance of MAP due to the sympathomimetic actions
of ketamine. In addition, preclinical studies have demon-
strated that the neuroprotective role of ketamine may be
related to its ability to increase MAP and CPP without
increasing cerebral oxygen consumption or reducing glu-
cose metabolism. In rat models, ketamine was reported to
decrease cell injury and improve neuronal survival24 and
have neuroprotective effects on isoflurane-induced cogni-
tive impairment.25 In this study, we also investigated the
impact of ketofol and propofol on other postoperative
variables and found no difference in the duration of
mechanical ventilation or length of hospital stay in pa-
tients receiving ketofol or propofol. Neurological out-
comes (assessed by GOSE) at 30 and 90 days after
discharge from hospital were also similar in the 2 groups.
Despite its prospective, randomized design, this
study has several limitations. First, because of its single-
center design our findings cannot be generalized to other
settings. Second, although the sample size was sufficient
to assess the impact of ketofol and propofol on systemic
hemodynamics (the primary outcome), the study was not
adequately powered for the assessment of clinical out-
comes and other secondary outcomes. Moreover, in-
adequate initial stabilization of systemic hemodynamics
before arrival at hospital, delayed presentation at our
tertiary referral care center after TBI, and lack of ad-
equate rehabilitation facilities after discharge from hos-
pital may have impacted the observed 30- and 90-day
clinical outcomes. Third, we were not able to confirm a
similar depth of anesthesia between ketofol and propofol
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J Neurosurg Anesthesiol  Volume 35, Number 1, January 2023
groups because electroencephalographic-based monitor-
ing anesthetic depth is not reliable during ketamine
anesthesia. Finally, the volume of intracranial hema-
tomas and extent of midline shift was not measured
before surgery.
CONCLUSIONS
We found that ketofol (ketamine/propofol admix-
ture) for the induction and maintenance of anesthesia was
associated with better hemodynamic stability and lower
vasopressor requirement than propofol anesthesia during
emergent decompressive cranial surgery in patients with
moderate or severe TBI. Hence, ketofol may have ad-
vantages over propofol anesthesia in patients undergoing
intracranial surgery for moderate to severe isolated TBI.
However, larger multicenter trials designed to assess the
impact of these 2 anesthesia regimens on neurological
outcome are required before ketofol can be recommended
for routine clinical use.
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