Marcel E. Durieux

Local anesthetics and the inflammatory response: a new therapeutic indication?

Local Anesthetics and the Inflammatory Response: A New Therapeutic Indication? Markus Hollmann;Marcel Durieux; Anesthesiology

Intravenous lidocaine infusion facilitates acute rehabilitation after laparoscopic colectomy

Background:Intravenous infusion of lidocaine decreases postoperative pain and speeds the return of bowel function. The authors therefore tested the hypothesis that perioperative lidocaine infusion facilitates acute rehabilitation protocol in patients undergoing laparoscopic colectomy. Methods:Forty patients scheduled to undergo laparoscopic colectomy were randomly allocated to receive intravenous lidocaine (bolus injection of 1.5 mg/kg lidocaine at induction of anesthesia, then a continuous infusion of 2 mg · kg−1 · h−1 intraoperatively and 1.33 mg · kg−1 · h−1 for 24 h postoperatively) or an equal volume of saline. All patients received similar intensive postoperative rehabilitation. Postoperative pain scores, opioid consumption, and fatigue scores were measured. Times to first flatus, defecation, and hospital discharge were recorded. Postoperative endocrine (cortisol and catecholamines) and metabolic (leukocytes, C-reactive protein, and glucose) responses were measured for 48 h. Data (presented as median [25–75% interquartile range], lidocaine vs. saline groups) were analyzed using Mann–Whitney tests. P < 0.05 was considered statistically significant. Results:Patient demographics were similar in the two groups. Times to first flatus (17 [11–24] vs. 28 [25–33] h; P < 0.001), defecation (28 [24–37] vs. 51 [41–70] h; P = 0.001), and hospital discharge (2 [2–3] vs. 3 [3–4] days; P = 0.001) were significantly shorter in patients who received lidocaine. Lidocaine significantly reduced opioid consumption (8 [5–18] vs. 22 [14–36] mg; P = 0.005) and postoperative pain and fatigue scores. In contrast, endocrine and metabolic responses were similar in the two groups. Conclusions:Intravenous lidocaine improves postoperative analgesia, fatigue, and bowel function after laparoscopic colectomy. These benefits are associated with a significant reduction in hospital stay.

Ketamine for Perioperative Pain Management

Ketamine thereforerepresents a promising modality in several perioperativestrategies to prevent pathologic pain.Another reason for the renewed interest in ketamine isthe availability of S( ) ketamine. Ketamine has a chiralcenter at the carbon-2 atom of the cyclohexanone ring,and therefore exists as the optical stereoisomers S( )and R(-) ketamine.

Revising a dogma: ketamine for patients with neurological injury?

We evaluated reports of randomized clinical trials in the perioperative and intensive care setting concerning ketamine’s effects on the brain in patients with, or at risk for, neurological injury. We also reviewed other studies in humans on the drug’s effects on the brain, and reports that examined ketamine in experimental brain injury. In the clinical setting, level II evidence indicates that ketamine does not increase intracranial pressure when used under conditions of controlled ventilation, coadministration of a &ggr;-aminobutyric acid (GABA) receptor agonist, and without nitrous oxide. Ketamine may thus safely be used in neurologically impaired patients. Compared with other anesthetics or sedatives, level II and III evidence indicates that hemodynamic stimulation induced by ketamine may improve cerebral perfusion; this could make the drug a preferred choice in sedative regimes after brain injury. In the laboratory, ketamine has neuroprotective, and S(+)-ketamine additional neuroregenerative effects, even when administered after onset of a cerebral insult. However, improved outcomes were only reported in studies with brief recovery observation intervals. In developing animals, and in certain brain areas of adult rats without cerebral injury, neurotoxic effects were noted after large-dose ketamine. These were prevented by coadministration of GABA receptor agonists.

Review article: the role of the perioperative period in recurrence after cancer surgery.

A wealth of basic science data supports the hypothesis that the surgical stress response increases the likelihood of cancer dissemination and metastasis during and after cancer surgery. Anesthetic management of the cancer patient, therefore, could potentially influence long-term outcome. Preclinical data suggest that beneficial approaches might include selection of induction drugs such as propofol, minimizing the use of volatile anesthetics, and coadministration of cyclooxygenase antagonists with systemic opioids. Retrospective clinical trials suggest that the addition of regional anesthesia might decrease recurrence after cancer surgery. Other factors such as blood transfusion, temperature regulation, and statin administration may also affect long-term outcome.

Modulation of NMDA receptor function by ketamine and magnesium: Part I.

N- methyl-d-aspartate (NMDA) receptors are important components of pain processing. Ketamine and Mg2+ block NMDA receptors and might therefore be useful analgesics, and combinations of Mg2+ and ketamine provide more effective analgesia. We investigated their interactions at NMDA receptors. Xenopus oocytes, expressing NR1/NR2A or NR1/NR2B glutamate receptors, were studied. The effects of Mg2+, racemic ketamine and its isomers, and the combination of Mg2+ and S(+)-ketamine on NMDA signaling were determined. Mg2+ and ketamine alone inhibited NMDA receptors noncompetitively (half-maximal inhibitory effect concentration: Mg2+ 4.2 ± 1.2 × 10−4 M at NR1/NR2A and 6.3 ± 2.4 × 10−4 M at NR1/NR2B; racemic ketamine 13.6 ± 8.5 × 10−6 M at NR1/NR2A and 17.6 ± 7.2 × 10−6 M at NR1/NR2B; S(+)-ketamine 4.1 ± 2.5 × 10−6 at NR1/NR2A and 3.0 ± 0.3 at NR1/NR2B; R(−)-ketamine 24.4 ± 4.1 × 10−6 M at NR1/NR2A and 26.0 ± 2.4 × 10−6 M at NR1/NR2B). The combined application of Mg2+ and ketamine decreased the half-maximal inhibitory effect concentration >90% at both receptors. Isobolographic analysis demonstrated super-additive interactions. Ketamine and Mg2+ inhibit responses of recombinantly expressed NR1/NR2A and NR1/NR2B glutamate receptors, and combinations of the compounds act in a super-additive manner. These findings may explain, in part, why combinations of ketamine and Mg2+ are more effective analgesics than either compound alone.

Inhibition by ketamine of muscarinic acetylcholine receptor function

Although ketamines primary site of action appears to be the phencyclidine receptor on the N-methyl-D-aspartate (NMDA) receptor complex, additional activity on opiate and quisqualate receptors is suggested. Some phencyclidines have been shown to interact with muscarinic receptors, but this has not been determined for ketamine. We studied the interaction between ketamine and the m1 muscarinic receptor, the most prominent subtype in cortex and hippocampus. Receptors were expressed recombinantly in Xenopus oocytes, and intracellular Ca2+ release in response to the agonist acetyl-beta-methylcholine (MCh, 10-6 M) was assessed by measuring charge movement through Ca2+-activated Cl- channels. Average responses to MCh were 4.1 +/- 0.7 mu C. Ketamine inhibited responses to MCh, with complete inhibition at approximately 200 micro Meter ketamine. The IC50 was 5.7 micro Meter, (1.56 micro gram/mL), well within the clinically relevant concentration range. To demonstrate that intracellular signaling pathways and the Ca2+ activated Cl- channel were not affected by ketamine, we tested the effect of ketamine (365 micro Meter) on currents induced by angiotensin II (10-6 M) in oocytes expressing the AT1A angiotensin receptor. No inhibitory effect was noted. In summary, ketamine profoundly inhibits muscarinic signaling. This effect might explain some of the anticholinergic clinical effects of ketamine, both central (effects on memory and consciousness) and peripheral (prominent sympathetic tone, bronchodilation, mydriasis). (Anesth Analg 1995;81:57-62)

Modulation of NMDA receptor function by ketamine and magnesium. Part II: interactions with volatile anesthetics.

Mg2+ and ketamine interact superadditively at N- methyl-d-aspartate (NMDA) receptors, which may explain the clinical efficacy of the combination. Because patients are usually exposed concomitantly to volatile anesthetics, we tested the hypothesis that volatile anesthetics interact with ketamine and/or Mg2+ at recombinantly expressed NMDA receptors. NR1/NR2A or NR1/NR2B receptors were expressed in Xenopus oocytes. We determined the effects of isoflurane, sevoflurane, and desflurane on NMDA receptor signaling, alone and in combination with S(+)-ketamine (4.1 &mgr;M on NR1/NR2A, 3.0 &mgr;M on NR2/NR2B) and/or Mg2+ (416 &mgr;M on NR1/NR2A, 629 &mgr;M on NR1/NR2B). Volatile anesthetics inhibited NR1/NR2A and NR1/NR2B glutamate receptor function in a reversible, concentration-dependent, voltage-insensitive and noncompetitive manner (half-maximal inhibitory concentration at NR1/NR2A receptors: 1.30 ± 0.02 minimum alveolar anesthetic concentration [MAC] for isoflurane, 1.18 ± 0.03 MAC for desflurane, 1.24 ± 0.06 MAC for sevoflurane; at NR1/NR2B receptors: 1.33 ± 0.12 MAC for isoflurane, 1.22 ± 0.08 MAC for desflurane, and 1.28 ± 0.08 MAC for sevoflurane). On both NR1/NR2A and NR1/NR2B receptors, 50% inhibitory concentration for volatile anesthetics was reduced approximately 20% by Mg2+, approximately 30% by S(+)-ketamine, and approximately 50% by the compounds in combination. Volatile anesthetic effects on NMDA receptors can be potentiated significantly by Mg2+, S(+)-ketamine, or—most profoundly—both. Therefore, the analgesic effects of ketamine and Mg2+ are likely to be enhanced in the presence of volatile anesthetics.

Hydroxyethyl starch: safe or not?

H ydroxyethyl starch (HES) and albumin are the two colloids administered most frequently for intravascular volume expansion during the perioperative period. Ideally, the selection between the two would be based only on relative risks and benefits in each individual patient. However, economic issues have become increasingly important in choosing between medical therapies. In terms of cost-containment, HES is an attractive choice, because it is considerably less expensive than albumin. As an example, at the University of Virginia Medical Center, the hospital cost of 500 mL (1 unit) HES is

Muscarinic signaling in the central nervous system : recent developments and anesthetic implications

43, whereas 500 mL albumin costs