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Low-Dose Ketamine Affects Immune Responses in Humans
Low-Dose Ketamine Affects Immune Responses in Humans
The immune system of patients undergoing surgery is has been reviewed by Homburger and Meiler.1 Elena and
affected by both anaesthesia and surgical trauma, with colleagues5 have reported a decrease in the absolute
possible sequelae on the postoperative outcome. Altered number of both leucocytes and lymphocytes in the periph-
immune reactions including natural killer (NK) cell eral blood of mice exposed to repeated administration of
activity have been observed after the use of volatile anaes- sevoflurane anaesthesia. Brand and colleagues6 have
thetics and opioids, such as morphine and large doses of shown a decrease in circulating NK cells associated with
fentanyl.1 – 4 The in vivo and in vitro effect of volatile an increase in B cells, CD8-T lymphocytes, interferon
anaesthetics on various parameters of the immune system (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
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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
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
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)**
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Beilin et al.
The role of IL-6, TNF-a, and IFN-g as proinflammatory 3 Beilin B, Shavit Y, Hart J, et al. Effects of anesthesia based on large
cytokines is well established. It has been reported that versus small dose of fentanyl on natural killer cell cytotoxicity in
these cytokines may be increased in patients with sepsis, the perioperative period. Anesth Analg 1996; 82: 492 – 7
4 Gilliland HE, Armstrong MA, Carabine U, McMurray TJ. The
asthma, heart failure, trauma, and burns.28 – 32 The way choice of anesthetic maintenance technique influences the antiin-
they participate in both humoral and tissue responses flammatory cytokine response to abdominal surgery. Anesth Analg
during injury is detailed in the excellent review by Feghali 1997; 85: 1394 – 8
and colleagues.33 TNF-a and IL-6 are involved in both 5 Elena G, Amerio N, Ferrero P, et al. Effect of repetitive sevoflur-
acute and chronic inflammation, and in the case of polymi- ane anesthesia on immune response, selected biochemical
crobial sepsis in rats34 and in horses,35 36 IL-6 acts as a parameters and organ histology in mice. Lab Anim 2003;
mediator of cellular responses. It is therefore suggested 37: 193 – 203
6 Brand JM, Kirchner H, Poppe C, Schmucker P. The effect of
that ketamine-induced prevention of IL-6 and TNF-a pro- general anesthesia on human peripheral immune cell distribution
duction may exert a favourable effect on a patient’s recov- and cytokine production. Clin Immunol Immunopathol 1997; 83:
ery. Since IL-2 plays a major role in the regulation of both 190 –4
cellular and humoral inflammatory responses, the ability 7 Ni Choileain N, Redmond HP. Cell response to surgery. Arch Surg
of ketamine to preserve its secretion at the preoperative 2006; 141: 1132 – 40
level observed in the present study is an additional contri- 8 Dinarello CA. Proinflammatory and anti-inflammatory cytokines
bution to avoiding postoperative complications. In the as mediators in the pathogenesis of septic shock. Chest 1997;
112: 321S– 7S
present study, ketamine exerted an effect on PHA-induced 9 Lin E, Lowry SF. Inflammatory cytokines in major surgery: a func-
proliferation of PBMCs, whereas the other two mitogens tional perspective. Intensive Care Med 1999; 25: 255 – 7
examined were not affected. Considering the fact that 10 Watkins LR, Mair SF, Goehler LE. Immune activation: the role of
PHA and Con A activate T cells, whereas PWM activates pro-inflammatory cytokines in inflammation, illness responses,
B cells, it is plausible that ketamine may affect the lym- and pathological pain states. Pain 1995; 63: 289 – 302
phocyte subpopulations differently. 11 Beilin B, Shavit Y, Trabekin E, et al. The effects of postoperative
It appears that ketamine may exert a beneficial effect on pain management on immune response to surgery. Anesth Analg
2003; 97: 822 – 7
the post-surgical immune response via several mechan-
12 Kohrs R, Durieux ME. Ketamine: teaching an old drug new tricks.
isms. Acting as an analgesic, it causes alleviation of pain, Anesth Analg 1998; 87: 1186 – 93
which by itself is a promoter of proinflammatory cytokine 13 Wong CS, Lu CC, Cherng CH, Ho ST. Ketamine potentiates
production and suppressor of IL-2 secretion.37 Therefore, analgesic effect of morphine in postoperative epidural pain
it may be useful in administration of pre-emptive analgesia control. Reg Anesth 1996; 21: 534 – 41
via suppression of inflammation.37 The direct suppressive 14 Weinbroum AA. A single dose of postoperative ketamine pro-
effect of ketamine on proinflammatory cytokine pro- vides rapid and substantial improvement in morphine analgesia in
the presence of morphine-resistant pain. Anesth Analg 2003; 96:
duction by PBMCs demonstrated in the present ex vivo 789– 95
study and in other works using serum21 23 and whole 15 Cherry DA, Plummer JL, Gourlay GK, Coates KR, Odgers CL.
blood27 is an additional indicator for its valuable effect. Ketamine as an adjunct to morphine in treatment of pain. Pain
Furthermore, ketamine exerts an anti-inflammatory effect 1995; 62: 119 – 21
by inhibition of leucocyte reactivity and suppression of 16 Menigaux C, Guignard B, Fletcher D, Sessler DI, Dupont X,
increased superoxide anion production by neutrophils after Chauvin M. Intraoperative small-dose ketamine enhances analge-
coronary artery bypass grafting.38 39 Since proinflamma- sia after outpatient knee arthroscopy. Anesth Analg 2001; 93:
606– 12
tory cytokines suppress cAMP accumulation in heart cells, 17 Guignard B, Coste C, Costes H, et al. Supplementing
the inhibitory effect of ketamine on these cytokines will desflurane-ramifetanil anesthesia with small-dose ketamine
improve cAMP build-up with a subsequent beneficial reduces perioperative opioid analgesic requirements. Anesth Analg
effect on cardiac output and arterial pressure.29 40 2002; 95: 103 – 8
In conclusion, the results of the study indicate that 18 De Kock M, Lavand’homme P, Waterloos H. ‘Balanced analgesia’
addition of a small dose of ketamine before induction of in the perioperative period: is there a place for ketamine? Pain
anaesthesia induces an attenuation of IL-6 and TNF-a pro- 2001; 92: 373 – 80
19 Tverskoy M, Oz Y, Isakson A, Finger J, Bradley EL, Kissin I.
duction, both acting as proinflammatory cytokines, and a
Preemptive effect of fentanyl and ketamine on postoperative pain
preservation of IL-2 at its preoperative level. These find- and wound analgesia. Anesth Analg 1994; 78: 205 – 9
ings favour the value of ketamine in preventing immune 20 Roytblat L, Korotkoruchko A, Katz J, Glazer M, Greenberg L,
function alterations caused by anaesthesia and surgery. Fisher A. Postoperative pain: the effect of low-dose keta-
mine in addition to general anesthesia. Anesth Analg 1993; 77:
1161–3
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