Because of their side effects (ex. decreased vascular resistance and subsequent hypotension), it may be advantageous to reduce the requirement for volatile anesthetics during general anesthesia. Multiple intravenous agents are available to accomplish this task, and four are included here – opiates, lidocaine, ketamine, and dexmedetomidine. Propofol, which reduces the requirement for volatile agent, is not included as its hemodynamic effects are similar to those of the volatile agents, thus little is to be gained by reducing inhaled agents if propofol is to make up the difference

MAC-Reducing Agents

Opiates

(from Glass PSA et. al. Journal of Clinical Anesthesia 9:18S–22S, 1997)

McEwan et al. demonstrated a 50% MAC reduction with 1.7 ng/ml fentanyl (loading dose of 4 ucg/kg followed by 1.75 ucg/kg/hr). The steepest reduction in MAC occurs within the analgesic concentration range of fentanyl, and beyond 5 ng/ml a ceiling effect is seen with a maximum MAC reduction of 80%. Alfentanil [Westmoreland CL et. al. Anesth Analg 78: 23, 1994], sufentanil [Brunner MD et. al. Br J Anaesth 72: 42, 1994], and remifentanil [Lang E et. al. Anesthesiology 85: 721, 1996] produce similar reductions in isoflurane MAC, with an initial steep reduction at lower concentrations and a plateau effect at higher concentrations.

MAC Reduction With Opiates: How To Use

Concentration (ng/ml) Resulting in 50% MAC Reduction of Isoflurane

	Concentration (ng/ml) Resulting in 50% MAC Reduction of Isoflurane	Calculated Potency
Fentanyl	1.67	1x
Sufentanil	0.14	12x
Alfentanil	28.8*	1/16x (61/25)†
Remifentanil	1.37‡	1.2x

50% MAC Reduction of Isoflurane: IV Opiate Dosing[edit]

	Target Plasma Concentration (ng/ml)	Bolus (ug/kg)	Infusion Rate (ug/kg/min)
Fentanyl	1	3	0.020
Alfentanil	40	20	0.25
Sufentanil	0.15	0.15	0.003
Remifentanil	1	0.25	0.025

Remifentanil and alfentanil bolus should given as a rapid infusion over 1–2 minutes.

Maximal MAC Reduction of Isoflurane: IV Opiate Dosing[edit]

	Target Plasma Concentration (ng/ml)	Bolus (ug/kg)	Infusion Rate (u/kg/min)
Fentanyl	4	10	0.070
Alfentanil	160	80*	1.00
Sufentanil	0.50	0.50	0.010
Remifentanil	5–15	1*	0.2–1.0

*Remifentanil and alfentanil bolus should given as a rapid infusion over 1–2 minutes.

Concerns re: MAC Reduction: Opiate Sensitization

Note, however, that use of remifentanil runs the risk of opiate sensitization. A study of 50 abdominal surgery patients randomized to 0.5 MAC desflurane vs. remifentanil (average 0.3 ucg/kg/min) or remifentanil at 0.1 ucg/kg/min plus desflurane titrated to autonomic response. Postoperative pain scores were worse for the high-dose group, and need 59 mg morphine in 24 hrs (as opposed to 32 mg in the low-dose group, p < 0.01) [Guignard B et. al. Anesthesiology 93: 409, 2000]. See Opioid Induced Hyperalgesia (Controversies) for a more complete discussion

Midazolam

Inagaki et al used the Dixon up-down method to study the use of IV midazolam to reduce halothane MAC in 50 patients undergoing radical hysterectomies. Group A was given no midazolam. Groups B, C, and D were given preoperative IV midazolam at 0.1, 0.2, and 0.4 mg/kg followed by infusions of 1, 2, and 4 ucg/kg/min, respectively. Halothane MAC was 0.78% (0% reduction, control), 0.47% (40% reduction), 0.38% (50% reduction), and 0.23% (70% reduction) in groups A, B, C, and D, respectively. The interaction between halothane and midazolam in the anesthetic efficacy conformed to an exponential fit [Inagaki Y et al. Anesth Analg 76: 613, 1993]

Lidocaine

Systemic local anesthetics reduce MAC of volatile anesthetics in rats by approximately 40% [DiFazio CA et al. Anesth Analg 55: 818, 1976], and in cats by as much as 59% [Pypendop BH et al. Anesth Analg 100: 97, 2005] FREE Full-text at Anesthesia & Analgesia. Wilson’s study of IV lidocaine (50-200 ucg/kg/min) in dogs anesthetized with sevoflurane showed MAC reductions of 23-40% (and up to 63% when combined with ketamine) [Wilson J et al. Vet Anaesth Analg, March 18, 2008 {E pub}]

Studies of IV lidocaine as a MAC sparing agent in humans are sparse. Himes studied 20 human patients (as well as dogs) anesthetized with nitrous oxide and halothane, and found that IV lidocaine reduced MAC requirements by between 10 and 28% [Himes RS Jr et al. Anesthesiology 47: 437, 1977]. Senturk’s study of 40 patients divided between IV lidocaine and controls showed that maintenance of BIS scores from 40-50 required 29% less propofol, and that the amount of propofol required to keep BIS < 45 at induction was 23% less (p < 0.001 in both instances) [Senturk M et al. Br J Anaesth 89: 849, 2002]

Lidocaine also may reduce post-operative analgesic requirements – a prospective, randomized study of 50 patients suggested that in addition to decreasing the requirement for volatile anesthetics, lidocaine may reduce PACU fentanyl requirements [Lauwick S et al. Can J Anaesth 55: 754, 2008], however the results of this study was complicated by different fentanyl dosages on induction (3 ucg/kg in the control group versus 1.5 ucg/kg in the lidocaine group).

In a recent randomized, controlled study of 40 patients under remifentanil/propofol anesthesia, Lidocaine was found to decrease propofol requirements (P < 0.05) only during surgery. In the absence of surgical stimulation, lidocaine did not affect BIS nor haemodynamic variables, whereas it reduced BIS increase (P = 0.036) and haemodynamic response (P= 0.006) secondary to surgery [Hans G et al. Br J Anaesth in press]. The authors concluded that sparing effect of lidocaine on anaesthetic requirements seems to be mediated by an anti-nociceptive action.

Magnesium

IV Magnesium appears to decrease the amount of intravenous anesthetic required during TIVA – Schultz-Stubner found that 50 mg/kg of IV magnesium after induction reduced remifentanil requirements by 36%, without affecting propofol requirements [Schulz-Stubner S et al. Eur J Anaesthesiol 18: 723, 2001]. Telci et al. found that 30 mg/kg reduced propofol requirements by 38% and remifentanil requirements by over 50% [Telci L et al. Br J Anaesth 89: 594, 2002]

The effects of magnesium on volatile anesthetics, however, appear to be opposite – in a study of 60 patients magnesium was shown to increase the sevoflurane requirements for both intubation (10% increase) and skin incision (15% increase) [Durmus M et al. Eur J Anaesthesiol 23: 54, 2006]

Ketamine

There are no ketamine-based human MAC reduction studies, thus the ability of ketamine to reduce anesthetic requirements in humans must be deduced from animal data. Doherty studied lidocaine and ketamine in goats (24-51 kg) anesthetized with isoflurane and found that ketamine at 50 ucg/kg/min after a loading dose of 1.5 mg/kg reduced MAC by 49.6% (and 69.4% when combined with lidocaine at 100 ucg/kg/min after 2.5 mg/kg loading dose)) [Doherty T et al. Vet Anaesth Analg 34: 125, 2007]. Studies in dogs (7.8 – 12.8 kg) anesthetized with sevoflurane showed that ketamine infusions of 50 and 100 ucg/kg/min significantly reduced MAC by 40.0% and 44.7%, respectively. The combination of ketamine and lidocaine reduced MAC by 62.8% [Wilson J et al. Vet Anaesth Analg, March 18, 2008 {E pub}]

Dexmedetomidine

Aantaa et. al. studied 49 women undergoing abdominal hysterectomy and used the Dixon up-down method to determine the effects of dexmedetomidine at two different doses – low dose (75 ucg/h for the first 15 min and 60 ucg/h thereafter, target plasma concentration 3.0 ng/mL) and high dose (150 ucg/h for the first 15 min and 120 ucg/h thereafter, target plasma concentration 6.0 ng/mL) – at higher doses, dexmedetomidine reduced the isoflurane requirement by 47% [Aantaa R et al. Anesthesiology 86: 1055, 1997]. An earlier study of IM dexmedetomidine in 192 women undergoing abdominal hysterectomy showed that 2.5 ucg/kg IM dexmedetomidine given 45-90 minutes preoperatively reduced mean isoflurane concentrations from 0.34% to 0.24% when given alone and from 0.34% to 0.14% when combined with 1.5 ucg/kg fentanyl as compared to standard midazolam/fentanyl (0.08 mg/kg and 1.4 ucg/kg) premedication [Erkola O et al. Anesth Analg 79: 646, 1994] Dexmedetomidine, when used to with a propofol/remifentanil anesthetic combination can also help supplement analgesia postoperatively.

Agents Which Do Not Reduce MAC

Gabapentin

While gabapentin has not been studied in humans, animal studies (cats) seem to suggest that intravenous administration of gabapentin up to a target concentration of 16 ucg/mL had no effect on MAC during isoflurane-based anesthesia [Reid P et al. Anesth Analg 111: 633, 2010 Full Text]

Agents Which Increase MAC

Ephedrine

In a canine study of vasopressor infusions during halothane anesthesia, Steffey and Eger showed that ephedrine can increase the MAC of halothane by as much as 50%, presumably by increasing the concentration of norepinephrine in the CNS [Steffey EP, Eger EI. Br J Anaesth 47: 435, 1975]