1. Journal Reading
Postoperative Ketamine Administration Decreases Morphine Consumption in Major Abdominal Surgery: A Prospective, Randomized, Double-Blind, Controlled Study
Presented by 江易穎

2. BACKGROUND
acute tolerance after opioid exposure as early as immediate post-op period
Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology 2000;93:409 –17
Intra-operative remifentanil might influence pain levels in the immediate post-operative period after major abdominal surgery. Acta Anaesthesiol Scand 2005;49:1464–70

3. BACKGROUND
Tolerance and delayed hyperalgesia from opioid exposure are associated with activation of NMDA receptors in CNS
Dickenson AH. Spinal cord pharmacology of pain. Br J Anaesth
1995;75:193–200
Petrenko AB, Yamakura T, Baba H, Shimoji K. The role of
N-methyl-d-aspartate (NMDA) receptors in pain: a review. Anesth Analg 2003;97:1108–16
Woolf CJ, Chong MS. Preemptive analgesia–treating postoperative
pain by preventing the establishment of central sensitization. Anesth Analg 1993;77:362–79

4. BACKGROUND
Ketamine, a NMDA antagonist, prevents experimentally opioid-induced hyperalgesia
ketamine + morphine decreases both pain and morphine consumption postoperatively.
Peri-operative ketamine for acute post-operative pain: a quantitative and qualitative systematic review (Cochrane review). Acta Anaesthesiol Scand 2005;49:1405–28
The influence of timing of systemic ketamine administration on postoperative morphine consumption. J Clin Anesth 2005;17:592–7
Ketamine and postoperative pain–a quantitative systematic review of randomised trials. Pain 2005; 113:61–70
Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes. Pain 1999;82: 111–25

5. BACKGROUND
Low-dose ketamine induces a morphine-sparing effect when this administration is limited to the intra-op period or extended to the post-op period
‘Balanced analgesia’ in the perioperative period: is there a place for ketamine? Pain 2001;92:373–80
A randomised, controlled study of peri-operative low dose- ketamine in combination with postoperative patient-controlled -ketamine and morphine after radical prostatectomy. Anaesthesia 2004;59:222–8
The addition of a small-dose ketamine infusion to tramadol for postoperative analgesia: a double-blinded, placebo-controlled, randomized trial after abdominal surgery. Anesth Analg 2007;104:912–7

6. BACKGROUND optimal dosing and duration
abd op: ketamine intra-op +/- post-op 48 h
postoperative morphine-sparing effect, pain reduction, and side effects

7. METHODS
independent ethics committee approval (No. 99H43, CCPPRB of Amiens University, France)
>18 yr major abdominal, urologic, or vascular surgery
Excluded: chronic pain, opioid abuse, psychiatric disorders
signed informed consent from each patient

8. METHODS Pre-mx: 1 mg/kg of po hydroxyzine 1 h pre-op
Induction: sufentanil 0.5 g/kg, propofol 1.5 mg/kg, and cisatracurium 0.15 mg/kg
Maintained: sufentanil 0.5g/kg/h, desflurane/50% N2O/O2 and cisatracurium.
1 g of IV paracetamol 30 min before the end of the surgical procedure. * 48 h (1 g/6 h)
PCA only, lockout 7 min. no limit 1 mg/mL of morphine and 2.5mg/50 mL of DHBP *48 h.
In the PACU, if VAS>40, morphine 3 mg IV q5m

9. METHODS gender, age, ASA, surgical procedure and duration
dose of intra-op sufentanil
Morphine use in the PACU, PCA morphine requirements at 4, 24, and 48 h
sedation score and a nausea and vomiting score were recorded 24 and 48 h postoperatively
Nightmares, psychiatric disorders, such as hallucinations, dysphoria, or other psychomimetic adverse effects

10. METHODS
Sedation score no: awake light: verbal stimulation mod: multiple verbal stimulations deep: painful stimulation
Nausea and vomiting score none, mild nausea; severe nausea; vomiting

11. METHODS
Prospectively randomized double-blind computer-generated opaque envelopes containing the patient number and group assignment.
groups: (1) PERI: intra-op 0.5mg/kg+2ug/kg/min * 48 h (2) INTRA: intra-op 0.5 mg/kg + 2ug/kg/min (3) CTRL: 10 mL N/S + 1mL/h *48 h

12. METHODS morphine 50 mg+/-20 in CTRL group / previous data.
40% difference between PERI and CTRL group for an α-risk of 0.05 and a power of 0.90
minimum of 66 patients (22 per group) would be
81 patients (27 per group)
Bonferroni correction for post hoc analysis. Kruskal–Wallis test and Mann–Whitney U-test Chi2 with Yates’ correction or Fisher tests P was considered significant.

13. RESULTS 81 p’t (27 per group)
4 p’t excluded (protocol violation, not blinded)
77 (27 CTRL, 27 INTRA and 23 PERI)

14. (P 0.003 by repeated measure analysis of variance).
RESULTS
(P by repeated measure analysis of variance).
0.01
0.02
0.05
0.02

15. RESULTS
Post-op 24 h cumulative morphine dose (1) PERI: median 27 mg, interquartile range [19] (2) INTRA: 48 mg [41.5] (3) CTRL: 50 mg [21] PERI<INTRA, CTRL (P=0.008)

16. (P 0.001 by repeated measure analysis of variance)
RESULTS
(P by repeated measure analysis of variance)
0.004
0.004
0.0001
0.001
0.0001
0.001

17. RESULTS

18. DISCUSSION lower incidence of nausea ketamine reduced PONV
Peri-operative ketamine for acute post-operative pain: a quantitative and qualitative systematic review (Cochrane review). Acta Anaesthesiol Scand 2005;49:1405–28
morphine-sparing effect
morphine PCA with DHBP

19. DISCUSSION optimal ketamine dosage?
0.5 mg/kg IV + 2 ug/kg/min theoretical plasma concentration 100 ug/mL no significant signs of accumulation.
7.8 ug/kg/min= psychomimetic effects

20. DISCUSSION S(+) ketamine = 4* R(-) ketamine
R(-) ketamine was used in this study because it is the only form commerciallyavailable in France.

21. (P 0.003 by repeated measure analysis of variance).
DISCUSSION
(P by repeated measure analysis of variance).
0.01
0.02
0.05
0.02

22. (P 0.001 by repeated measure analysis of variance)
DISCUSSION
(P by repeated measure analysis of variance)
0.004
0.004
0.0001
0.001
0.0001
0.001

23. DISCUSSION subanesthetic Ketamine: emotional and behavioral
patient’s performance ≠ pain intensity.
N2O enhance ketamine effect on NMDA
timing of ketamine administration
central sensitization: intra-op and also post-op

24. CONCLUSIONS
Low-dose ketamine improved postoperative analgesia with a significant decrease of morphine consumption when its administration was continued for 48 h postoperatively, with a lower incidence of nausea and with no side effects of ketamine.