Introduction #
Midazolam, a widely used benzodiazepine, has been traditionally employed as a co-induction agent with propofol in anesthesia. However, its utility in this role is questionable due to its undesirable pharmacokinetic and pharmacodynamic properties. While benzodiazepines like midazolam have historically been used in combination with ketamine and propofol to mitigate side effects such as emergence reactions and excessive cardiovascular depression, and to reduce the cost when propofol was originally adopted into veterinary use (human formulation Diprivan) advances in anesthesia practices have rendered this rationale less compelling. This essay explores why midazolam is a suboptimal co-induction agent with propofol and delves into its historical role in anesthesia.
The Historical Rationale for Benzodiazepine Co-Induction #
The use of benzodiazepines as adjuncts to anesthetic induction dates back to the mid-to-late 20th century when ketamine emerged as a widely used dissociative anesthetic. Ketamine, while providing profound analgesia and maintaining hemodynamic stability, was associated with significant psychotomimetic effects, including hallucinations and delirium upon emergence. To counteract these effects, benzodiazepines such as diazepam and later midazolam were introduced as adjuncts, leveraging their anxiolytic and amnestic properties.
With the rise of propofol in the 1980s, benzodiazepine co-induction remained common practice, particularly to reduce the dose of propofol required for induction. The rationale was that midazolam’s potentiation of gamma-aminobutyric acid (GABA) receptors could enhance sedation and anesthesia, thereby allowing lower propofol doses, theoretically reducing adverse hemodynamic effects such as hypotension. However, contemporary understanding suggests that midazolam may actually increase the risk of propofol-hypotension adding to the growing evidence that midazolam’s drawbacks outweigh these theoretical benefits.
Undesirable Pharmacokinetic Properties of Midazolam #
Midazolam has a pharmacokinetic profile that is poorly suited for co-induction with propofol. It has a relatively slow onset compared to propofol, which contradicts the need for a rapid and predictable induction sequence. Unlike propofol, which acts within 30-45 seconds of intravenous administration, midazolam has a delayed peak effect, often taking several minutes to reach its full hypnotic potential. This mismatch in pharmacodynamics can lead to an unpredictable depth of anesthesia, requiring additional propofol boluses and negating any supposed dose-sparing effect.
Additionally, midazolam has a longer context-sensitive half-time than propofol, leading to prolonged sedation postoperatively. This is particularly undesirable in outpatient settings where rapid recovery is a priority.
Hemodynamic Effects and Dose-Sparing Fallacy #
One of the primary arguments for midazolam co-induction is that it reduces the required dose of propofol, thereby mitigating its hypotensive effects. However, studies have shown that this effect is marginal and does not significantly alter hemodynamic parameters in a clinically meaningful way. Propofol-induced hypotension is primarily dose-dependent and related to its potent vasodilatory and negative inotropic effects. While midazolam has a mild synergistic effect on sedation, it also possesses its own dose-dependent hemodynamic depressant properties, particularly in elderly or hypovolemic patients.
The notion that midazolam co-induction significantly spares propofol dosing is also flawed because any reduction in propofol use is often offset by the lingering sedative effects of midazolam. This prolongs the recovery period, increasing the likelihood of postoperative sedation, airway obstruction, and delayed discharge.
Adverse Effects on Recovery and Cognitive Function #
Postoperative cognitive dysfunction (POCD) and delayed emergence from anesthesia are significant concerns with benzodiazepines in human patients. Midazolam, due to its prolonged elimination half-life and active metabolites, has been implicated in prolonged sedation and cognitive impairment postoperatively. This is especially problematic in elderly patients, where benzodiazepine use is associated with an increased risk of delirium, falls, and extended hospital stays.
Compared to propofol alone, the use of midazolam has been linked to delayed return to baseline cognitive function. Propofol’s rapid clearance allows for precise titration and a predictable emergence profile, making it superior for cases requiring a quick recovery, such as ambulatory surgery. In contrast, midazolam’s lingering effects can impair coordination, memory, and judgment for hours postoperatively, even after discharge.
Respiratory Depression and Airway Complications #
Benzodiazepines are potent central respiratory depressants, an effect that is exacerbated when combined with opioids or other anesthetics. Midazolam’s suppression of central respiratory drive, in conjunction with propofol’s own depressive effects, increases the risk of perioperative hypoventilation and airway obstruction. Unlike ketamine, which preserves airway reflexes and spontaneous respiration, midazolam does not provide any protective advantages against upper airway collapse.
In cases where rapid airway control is needed, midazolam’s use can delay induction and complicate mask ventilation due to increased airway resistance and reduced muscle tone. Furthermore, in human patients with obesity or obstructive sleep apnea (OSA), the combination of midazolam and propofol significantly increases the risk of perioperative hypoxia and the need for airway intervention.
Alternatives to Midazolam for Co-Induction #
Given midazolam’s limitations, alternative strategies for co-induction should be considered. Dexmedetomidine, an alpha-2 agonist, provides anxiolysis and mild sedation without significant respiratory depression and has been shown to reduce propofol requirements. Similarly, low-dose ketamine can be employed to counteract propofol-induced hypotension while providing analgesia and maintaining respiratory drive.
Opioid-based co-induction strategies, particularly with remifentanil or fentanyl, offer a more predictable pharmacokinetic profile than midazolam. These agents can blunt the sympathetic response to intubation and provide sufficient analgesia without the prolonged sedation seen with benzodiazepines. Furthermore, lidocaine pre-administration can reduce propofol’s pain on injection and modestly decrease the required induction dose without the drawbacks of midazolam.
Conclusion #
Midazolam’s role as a co-induction agent with propofol is based on outdated assumptions regarding dose-sparing effects and hemodynamic benefits. Its slow onset, prolonged sedative effects, and unfavorable impact on respiratory function make it a poor choice compared to alternative strategies. Historical practices of benzodiazepine use alongside ketamine and propofol were rooted in mitigating emergence reactions and dose-related hypotension, but modern anesthetic techniques render these concerns largely irrelevant.
In contemporary anesthesia practice, rapid, predictable, and hemodynamically stable induction is paramount. Propofol alone, or in combination with agents such as ketamine, dexmedetomidine, or short-acting opioids, offers superior control over induction and recovery. As such, midazolam should be reconsidered as a routine co-induction agent, with preference given to approaches that optimize patient safety, recovery, and perioperative outcomes.
References #
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- Mazzeo AT, et al. “Benzodiazepine use and risk of delirium: a systematic review and meta-analysis.” Crit Care Med 2019.
- Gupta A, Stierer T, Zuckerman R, Sakima N, Parker SD, Fleisher LA. “Comparison of recovery after anesthesia with propofol-remifentanil versus propofol-midazolam-fentanyl in elderly patients.” Anesthesiology 2008.
- Tanaka M, Nishikawa T. “Propofol requirement for anesthesia is reduced by clonidine.” Anesth Analg 1999.
- Vanlersberghe C, Camu F. “Propofol and ketamine: the good and the bad.” Curr Opin Anaesthesiol 2008.
