British Journal of Anaesthesia 99 (4): 522–7 (2007)

doi:10.1093/bja/aem218 Advance Access publication August 6, 2007

Low-dose ketamine affects immune responses in humans during

the early postoperative period
B. Beilin1*, Y. Rusabrov2, Y. Shapira2, L. Roytblat2, L. Greemberg2,
I. Z. Yardeni1 and H. Bessler3
1
Department of Anaesthesiology and Research Institute, Rabin Medical Center, Hasharon Hospital,
7, Keren Kayemet Street, Petah Tiqva 47372, Israel. 2Division of Anaesthesiology, Soroka Medical
Center, Faculty of Health Science, Ben-Gurion University of the Negev, Beer-Sheba, Israel.
3

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The Sackler School of Medicine, Tel-Aviv University, Ramat Aviv, Israel
*Corresponding author. E-mail: beilinb@clalit.org.il
Background. Anaesthesia and surgery are associated with impairment of the immune system
expressed as an excessive proinflammatory immune response and suppression of cell-mediated
immunity that may affect the course of the postoperative period. Addition of anaesthetic
agents capable of attenuating the alterations in perioperative immune function may exert a
favourable effect on patients’ healing. We have assessed the effect of preoperative adminis-
tration of a sub-anaesthetic dose of ketamine on the mitogen response and production of
interleukin (IL)-1b, IL-2, IL-6, and tumour necrosis factor (TNF)-a by peripheral blood mono-
nuclear cells (PBMCs), as well as natural killer cell cytotoxicity (NKCC) in patients undergoing
abdominal surgery.
Methods. Seventeen patients admitted for elective abdominal surgery were given ketamine
0.15 mg kg21 i.v. 5 min before induction of general anaesthesia. Nineteen patients received a
similar volume of isotonic saline 5 min before induction of the anaesthesia. PBMCs were
isolated from venous blood before and 4, 24, 48, and 72 h after operation for IL-1b, IL-2,
IL-6, and TNF-a secretion, and NKCC assessment.
Results. Four hours after operation, the cells from patients in the ketamine group showed
a significantly suppressed production of IL-6 (P,0.01) compared with controls. The pro-
duction of IL-2 did not change from that of the preoperation samples. TNF-a secretion was
significantly elevated in the control group 4 h after operation (P,0.05).
Conclusions. Addition of small doses of ketamine before induction of anaesthesia resulted
in attenuation of secretion of the proinflammatory cytokines IL-6 and TNF-a, and in preser-
vation of IL-2 production at its preoperative level. It is suggested that this anaesthetic may
be of value in preventing immune function alterations in the early postoperative period.
Br J Anaesth 2007; 99: 522–7
Keywords: anaesthetics, i.v., ketamine; immune response; natural killer cells
Accepted for publication: May 31, 2007

The immune system of patients undergoing surgery is
affected by both anaesthesia and surgical trauma, with
possible sequelae on the postoperative outcome. Altered
immune reactions including natural killer (NK) cell
activity have been observed after the use of volatile anaes-
thetics and opioids, such as morphine and large doses of
fentanyl.1 – 4 The in vivo and in vitro effect of volatile
anaesthetics on various parameters of the immune system
has been reviewed by Homburger and Meiler.1 Elena and
colleagues5 have reported a decrease in the absolute
number of both leucocytes and lymphocytes in the periph-
eral blood of mice exposed to repeated administration of
sevoflurane anaesthesia. Brand and colleagues6 have
shown a decrease in circulating NK cells associated with
an increase in B cells, CD8-T lymphocytes, interferon
(IFN)-g, IFN-a, tumour necrosis factor (TNF)-a, and

# The Board of Management and Trustees of the British Journal of Anaesthesia 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
 Ketamine and cytokine production
soluble interleukin (IL)-2 receptor. The cytokine cascade
activated in response to surgical trauma consists of a
complex biochemical network with diverse effects on the
injured host, that is, some components of the immune
system, such as proinflammatory cytokines, are stimulated
to an excessive degree, whereas other functions, for
instance cell-mediated immunity, are dramatically sup-
pressed.7 Any significant amplification in the proinflamma-
tory response potentially predisposes the host to
undesirable consequences, including hypotension, shock,
and even multiple organ failure.8 Thus, excessive pro-
duction of proinflammatory cytokines due to anaesthesia
and surgery may induce severe inflammation and post-
operative complications.9 In addition, the immune system
and the nervous system communicate bidirectionally and it
has been suggested that nociception and proinflammatory
cytokines play a mutual up-regulatory role;10 thus,
increased production of proinflammatory cytokines may
exacerbate pain, and vice versa. Therefore, it is conceiva-
ble that effective pain management may affect the immune
responses during the postoperative period.11 An attempt to
diminish the deleterious side-effects of the opiates on the
immune system could be achieved by addition of drugs
with marked analgesic activity capable of attenuating pain
stimuli and therefore allowing reduction of the dosage of
opiates. Ketamine, a neurotransmitter acting as a
N-methyl-D-asparate receptor antagonist, has been shown
to enhance the effect of morphine in control of periopera-
tive pains.12 – 14 Cherry and colleagues15 have achieved a
reduction in morphine dosage and pain score by addition
of ketamine, with a direct relationship between ketamine
dosage and pain score. Similar results have been observed
in patients undergoing knee or abdominal surgery.16 – 18 It
has been shown that small doses of ketamine exert analge-
sic action in the early stages of formation of pain stimuli;
therefore, it may be useful in inducing pre-emptive anaes-
thesia.19 20 The question of whether ketamine, in addition
to its beneficial action as a pain reliever, may attenuate the
immunosuppressive effect of opioids in patients exposed
to surgery is of interest to the clinician. Roytblat and col-
leagues21 22 have reported a decrease in serum IL-6, an
activator of the inflammatory cytokine cascade, in patients
undergoing coronary artery bypass surgery and in women
submitted to abdominal hysterectomy who received small
doses of ketamine. The present study was designed to
assess the immunomodulatory effect of small doses of
ketamine on the mitogen response and production of
IL-1b, IL-2, IL-6, and TNF-a, by peripheral blood mono-
nuclear cells (PBMC) from patients undergoing abdominal
surgery. In addition, the influence of the drug on NK cell
cytotoxicity (NKCC) was evaluated. The rationale of the
study was to contribute to understanding the role of sub-
anaesthetic doses of ketamine in attenuating the undesir-
able effect of anaesthesia and surgery on the immune
system.
523
Methods
Patients
The Helsinki Committee of the Soroka Medical Center
approved the study that comprised 36 patients undergoing
abdominal surgery. The patients were premedicated with
diazepam 5 – 10 mg given orally 90 min before operation
and with i.v. administration of midazolam 2 – 3 mg upon
arrival at the operating theatre. Thereafter, the patients
were assigned to two groups according to randomized
sequences without duplicates. Group A comprised 17
patients who received racemic ketamine 0.15 mg kg21 i.v.
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5 min before induction of general anaesthesia. This dose
was chosen according to previous experience with the
drug.16 20 Group B consisted of 19 patients who received a
similar volume of isotonic sodium chloride 5 min before
induction of anaesthesia. There was no significant difference
between patients from the two groups with respect to age,
body weight, type, and duration of surgery and there was no
requirement for blood transfusions (Table 1). Anaesthesia
was induced by i.v. administration of fentanyl 2–3 mg kg21,
thiopentone 4–6 mg kg21, and vecuronium 0.1 mg kg21,
and was maintained with nitrous oxide, isoflurane, and
addition of fentanyl. The total dose of fentanyl and thiopen-
tone, and the average dose of isoflurane administered to the
patients, is given in Table 1. Mean arterial pressure was
maintained within 20% of baseline values with isoflurane
and fentanyl. The patients received upper body forced-air
warming, and the i.v. fluids were warmed to 378C.
Immunological assays
Venous blood samples (15 ml) were collected before
surgery and at 4, 24, 48, and 72 h after operation. PBMCs
were isolated from heparinized venous blood using histopa-
que (Sigma) gradient centrifugation. The cells were washed
twice in RPMI-1640 medium containing penicillin 1%,
streptomycin, and nystatin and supplemented with 10% fetal
calf serum (FCS), designated as complete medium (CM).
Thereafter, they were suspended in FCS containing dimethyl
sulphoxide 10% (DMSO, Sigma) and frozen at 2708C until
used. On the day of assay, the cells were thawed quickly,
Table 1 Patients’ characteristics and dosage of administered analgesics. The
values are expressed as mean (range) or mean (SEM). SRVG, silastic vertical
ring gastroplasty
Control Ketamine
Type of surgery
Hysterectomy 10 9
Gastroplasty (SRVG) 9 8
Age (yr) 43.5 (29 –58) 39.0 (28 –55)
Sex (M/F) 5/14 4/13
Duration of operation (min) 113 (7.34) 105 (6.51)
Body weight (kg) 97.5 (26.3) 95.4 (29.9)
Fentanyl (mg) (total dose) 387 (46.1) 395 (49.1)
Thiopentone (mg) (total dose) 353 (29.3) 367 (32.1)
Isoflurane (average dose) 1–1.5% 1– 1.5%
 Beilin et al.

washed three times in CM, and their viability tested by All reactions were carried out in triplicate and the specific
51
trypan blue dye exclusion was more than 95%. Cr release was calculated as described earlier.3

IL-1b, IL-2, IL-6, and TNF-a production Statistical analysis

PBMCs (2106) suspended in 1 ml of RPMI-1640
Data were analysed for each measure using analysis of var-
medium supplemented with FCS 5% were incubated for
iance with repeated measures (for time period before and
24 h in the presence of 10 mg ml21 lipopolysaccharide
after surgery) and Student’s t-test to compare the differ-
(Escherichia coli, LPS, Sigma) for evaluation of IL-1b,
ence between the two groups at each individual time
IL-6, and TNF-a production. For IL-2 production, 2106
point. Probability values of P,0.05 were considered as
PBMCs were suspended in 1 ml of CM and incubated for
significant. The results are expressed as means (SEM).
48 h with phytohaemagglutinin 1% (PHA-M, Difco).
After incubation, the culture media were collected, the

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cells were removed by centrifugation, and the supernatants
were kept at 2708C until assayed for cytokine content.
Cytokine concentration in the supernatants was tested
using ELISA (enzyme-linked immunosorbent assay) kits
specific for human IL-1b (Biosource International,
Camarillo, CA, USA), IL-6 and TNF-a (Pharmingen, San
Diego, CA, USA), and IL-2 (R&D systems, Minneapolis,
MN, USA), as detailed in the guideline provided by the
manufacturers. The detection level of these cytokines in
the assays was 30 pg ml21 for IL-1b, IL-2, and TNF-a,
and 15 pg ml21 for IL-6.
Mitogen response
0.1 ml of PBMC suspension (2106 cells ml21) was
aliquoted into each of 96-well plates (flat bottom, Nunc)
containing 0.1 ml of CM or PHA (Difco, 2%), concanava-
lin A (Con A, 10 mg ml21), or pokeweed mitogen (PWM,
Sigma, 20 mg ml21). Cultures set-up in triplicate were
incubated for 3 days. About 0.5 mCi per well of [3H]TdR
(methyl-[3H]thymidine, 5 mCi mmol21, Amersham, UK)
was added 18 h before harvesting. Radioactivity was
measured with an LKB liquid scintillation counter model
3380.
NKCC assay
Cytotoxicity was assessed by a standard chromium specific
release assay with the 51Cr-labelled K562 cell line used as
target cells, and PBMC serving as effector cells. The final
effector to target (E:t) ratio was 100:1. After 4 h of incu-
bation at 37oC, the supernatants were collected, and the
radioactivity was measured using a gamma counter (LKB).
Results
Interleukin production
Interleukin-1b
There was no significant difference in IL-1b production
before surgery between the two groups (Table 2).
However, in patients from both groups, the IL-1b level
increased significantly at 24, 48, and 72 h after surgical
intervention.
Interleukin-2
The secretion of IL-2 by PHA-stimulated PBMCs from
individuals in the control and study groups was similar
before surgery. At 4, 24, 48, and 72 h after the operation,
IL-2 production decreased significantly in patients from
the control group, whereas in the study group it did not
differ from that before surgery at any of these time points.
The difference between the two groups did not reach stat-
istical significance at any experimental point.
Interleukin-6
IL-6 production by PBMCs from patients in the control
and study groups was similar before surgery. At 4 h after
operation, IL-6 secretion was elevated in the control, but
not in the study group. The difference between the results
from the two groups was statistically significant (P,0.05).
Increased production of IL-6 was found at 24, 48, and 72
h after operation in both groups. However, there was no
significant difference between the two groups at the later
postoperative times.

Table 2 Cytokine production by PBMCs from patients in the two groups. *P,0.01, **P,0.05 (statistically significant different from the values before
operation). †Statistically significant different from the values in the control group at the same amount of time after operation

Cytokine Controls Ketamine

(mg ml21)
Before Hours after operation Before Hours after operation
operation operation
4 24 48 72 4 24 48 72

IL-1b 6.6 (0.3) 7.9 (0.8) 8.5 (0.7)* 8.3 (0.8)** 8.1 (0.9)** 6.6 (0.5) 8.2 (0.8) 8.9 (0.6)* 9.2 (0.8)* 8.8 (0.9)*
IL-2 5.3 (0.5) 3.7 (0.5)** 3.4 (0.5)* 3.2 (0.5)* 3.8 (0.5) 5.5 (0.5) 4.6 (0.6) 5.3 (0.5) 4.3 (0.5) 4.8 (0.4)
IL-6 71.4 (5.4) 111.4 (16.7)* 120.7 (14.1)* 129.5 (14.8)* 113 (16.7)* 62.4 (9.4) 68.3 (10.6)† 122.0 (19.1)* 116.3 (12.5)* 109.0 (13.9)*
TNF-a 12.5 (0.8) 15.4 (1.3)** 15.0 (1.7)** 16.5 (1.7)** 16.6 (1.3)** 11.5 (1.1) 14.8 (1.2)† 16.5 (1.7)** 15.9 (2.2)** 71.4 (5.4)**

524
 Ketamine and cytokine production
Tumour necrosis factor-a
TNF-a values before surgery did not differ significantly
between the control and the study group. Four hours after
operation, the production of TNF-a in the study group was
similar to that before surgery, whereas in the control group
it was significantly elevated. TNF-a level was higher at
24, 48, and 72 h after operation in both groups.
Mitogen-induced lymphocyte proliferation
The lymphocyte proliferative response to PHA was sup-
pressed in the control group for the first 24 h after oper-
ation and was lower, but not statistically significant, in the
study group (Fig. 1). Forty-eight hours after operation, the
proliferative response to PHA in both groups returned to
preoperative values. Con A and PWM-induced prolifer-
ation did not change significantly 72 h after operation in
both groups (data not shown).
Natural killer cell cytotoxicity
Before operation, NKCC was similar in the control and
study group and was suppressed in both groups at 24 and
48 h after surgery (Fig. 2). This cell function partially
recovered to preoperative values 72 h after operation.
Discussion
The results of the study show that addition of low-dose
ketamine during induction of anaesthesia attenuates the
ex vivo enhancement of IL-6 and TNF-a production
by patients’ PBMCs, at least at 4 h after operation.
Furthermore, ketamine supplementation preserved the pre-
operative IL-2 level and PHA-induced cell proliferation up
to 24 h. In a previous study,20 we demonstrated that pre-
emptive low-dose ketamine significantly decreased post-
operative pain and reduced morphine requirement.
Fig 1 Proliferative response to PHA by PBMCs from patients of the two
groups. Data are expressed as mean (SEM). Asterisks represent a statistically
significant difference from values before operation (**P,0.01).
525
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Fig 2 NKCC of PBMCs from patients of the two groups. Data are
expressed as mean (SEM). Asterisks represent a statistically significant
difference from values before operation (*P,0.05, **P,0.01).
Moreover, attenuation of postoperative pain reduced the
suppression of the lymphocyte proliferative response to
mitogens and attenuated the proinflammatory cytokine
reaction to surgery.11 These findings are in accordance
with those of Roytblat and colleagues,21 who have
reported that patients undergoing cardiopulmonary bypass,
who were given small doses of ketamine during induction
of anaesthesia, showed significantly lower serum levels of
IL-6 during the course of seven postoperative days.
Taniguchi and colleagues23 have shown that ketamine
administration dose-independently inhibited hypotension,
metabolic acidosis, and cytokine responses when injected
with endotoxin. In another study,22 it was found that
addition of low-dose ketamine to fentanyl anaesthesia sup-
presses IL-6 production at 4 – 72 h after abdominal hyster-
ectomy. Patients with severe burn injuries given small
doses of ketamine with or without fentanyl in the course
of patient-controlled i.v. analgesia showed a decrease in
serum IL-1, IL-6, and TNF-a.24 In a study with rats, it has
been found that ketamine improved the survival in those
with burn injuries complicated by sepsis, an effect
explained by decreased IL-6 production observed in septic
animals.25 Kawasaki and colleagues26 27 have carried out
in vitro studies with human whole blood and reported a
suppressive effect of ketamine on LPS-induced TNF-a,
IL-6, and IL-8 production. TNF-a is the first cytokine
which stimulates IL-6 and IL-8 production by macro-
phages. In view of the fact that ketamine also suppressed
rhTNF-a-induced IL-6 and IL-8 production, the authors
suggested that the decrease in IL-6 and IL-8 is due not
only to suppression of TNF-a, but also to a direct inhibi-
tory effect of the drug on the production of these cytokines
in whole blood. Since the immune parameters in the
present study were determined at fixed time points, it is
possible that the reduced cytokine secretion observed
during the postoperative period in patients treated with
low-dose ketamine may reflect either an attenuated or
delayed proinflammatory response.
 Beilin et al.
The role of IL-6, TNF-a, and IFN-g as proinflammatory
cytokines is well established. It has been reported that
these cytokines may be increased in patients with sepsis,
asthma, heart failure, trauma, and burns.28 – 32 The way
they participate in both humoral and tissue responses
during injury is detailed in the excellent review by Feghali
and colleagues.33 TNF-a and IL-6 are involved in both
acute and chronic inflammation, and in the case of polymi-
crobial sepsis in rats34 and in horses,35 36 IL-6 acts as a
mediator of cellular responses. It is therefore suggested
that ketamine-induced prevention of IL-6 and TNF-a pro-
duction may exert a favourable effect on a patient’s recov-
ery. Since IL-2 plays a major role in the regulation of both
cellular and humoral inflammatory responses, the ability
of ketamine to preserve its secretion at the preoperative
level observed in the present study is an additional contri-
bution to avoiding postoperative complications. In the
present study, ketamine exerted an effect on PHA-induced
proliferation of PBMCs, whereas the other two mitogens
examined were not affected. Considering the fact that
PHA and Con A activate T cells, whereas PWM activates
B cells, it is plausible that ketamine may affect the lym-
phocyte subpopulations differently.
It appears that ketamine may exert a beneficial effect on
the post-surgical immune response via several mechan-
isms. Acting as an analgesic, it causes alleviation of pain,
which by itself is a promoter of proinflammatory cytokine
production and suppressor of IL-2 secretion.37 Therefore,
it may be useful in administration of pre-emptive analgesia
via suppression of inflammation.37 The direct suppressive
effect of ketamine on proinflammatory cytokine pro-
duction by PBMCs demonstrated in the present ex vivo
study and in other works using serum21 23 and whole
blood27 is an additional indicator for its valuable effect.
Furthermore, ketamine exerts an anti-inflammatory effect
by inhibition of leucocyte reactivity and suppression of
increased superoxide anion production by neutrophils after
coronary artery bypass grafting.38 39 Since proinflamma-
tory cytokines suppress cAMP accumulation in heart cells,
the inhibitory effect of ketamine on these cytokines will
improve cAMP build-up with a subsequent beneficial
effect on cardiac output and arterial pressure.29 40
In conclusion, the results of the study indicate that
addition of a small dose of ketamine before induction of
anaesthesia induces an attenuation of IL-6 and TNF-a pro-
duction, both acting as proinflammatory cytokines, and a
preservation of IL-2 at its preoperative level. These find-
ings favour the value of ketamine in preventing immune
function alterations caused by anaesthesia and surgery.
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