Benzodiazepines like midazolam have a long history as adjuncts in anesthesia induction. In the 1970s, anesthetists discovered that combining a tranquilizer with the dissociative agent ketamine produced a smoother anesthetic induction. Ketamine alone causes muscle rigidity, tremors, and hallucinations, but adding a benzodiazepine provides muscle relaxation and anxiolysis, countering ketamine’s excitatory effects (1). A notable example is the veterinary anesthetic Telazol (tiletamine combined with zolazepam, a benzodiazepine), introduced to harness this synergy and reduce ketamine’s side effects (2). Similarly, when propofol emerged in the 1980s as a fast-acting induction agent, clinicians began giving a small dose of benzodiazepine beforehand to reduce the volume of propofol needed, decreasing the cost of the more expensive propofol (Diprivan) and creating some degree of amnesia which is beneficial in human patients to reduce the risk of intraoperative recall. The term “co-induction” was coined in 1986 after reports that midazolam (a new benzodiazepine) given with opioids caused deeper sedation than intended (3). Anesthesiologists soon intentionally exploited these drug interactions: by administering midazolam with agents like fentanyl and propofol, they aimed to achieve a more complicated induction (4). Early proponents of co-induction argued that combining midazolam with propofol could improve all phases of anesthesia – induction, maintenance, and recovery – by reducing the required propofol dose (and thus its side effects) and lowering the risk of intraoperative awareness (5). By the mid-1990s, giving ~0.03 mg/kg of midazolam (about 2 mg in an adult human) before propofol became common practice in outpatient anesthesia (6). This practice was also adopted in veterinary medicine, where diazepam or midazolam were often mixed with propofol or ketamine at induction. Thus, historically, benzodiazepines gained popularity as co-induction drugs to spare the primary anesthetic dose.
Midazolam’s Pharmacokinetics and Clinical Effects as a Preanesthetic #
Midazolam is a short-acting benzodiazepine with unique pharmacokinetics that initially made it attractive for co-induction. It is water-soluble (unlike diazepam) and can be given IV or IM without irritation. After injection, midazolam rapidly redistributes into the brain, causing sedation within minutes. However, the pharmacokinetics of midazolam are significantly different than propofol and when the 2 are administered at the same time the differences question what effect the midazolam is really having on the required dose of the more rapidly acting propofol. Dogs eliminate midazolam quickly (elimination half-life ~30 minutes), and humans clear it in about 1.5–3 hours (7). This rapid metabolism (primarily via hepatic hydroxylation to an active metabolite, 1-hydroxymidazolam) gives midazolam a shorter duration of action than older benzodiazepines, theoretically allowing for faster postoperative recovery (8). Clinically, midazolam produces anxiolysis, hypnosis, and muscle relaxation but no analgesia. On its own, midazolam causes minimal cardiovascular depression in people and only mild respiratory depression, which is why it’s often described as having a “wide margin of safety” (9). These traits suggested that midazolam could be an ideal co-induction agent: it could deepen sedation and relax muscles without greatly exacerbating the cardiorespiratory depression of drugs like propofol. In practice, however, midazolam’s clinical effects have proven highly dose- and patient-dependent, especially across different species. In humans, a light pre-induction dose (1–2 mg IV) typically calms the patient and causes desirable amnesia, but higher doses can lead to prolonged drowsiness post-operatively (10). In veterinary patients, the sedative effect of midazolam alone is far less predictable. If given to a calm, debilitated animal, it may induce gentle sedation; but in a young, healthy pet, the same dose can paradoxically cause agitation. This variability in effect is a critical issue that undermines midazolam’s usefulness as a routine preanesthetic sedative.
Conclusion #
Midazolam’s reputation as a benign, helpful co-induction agent has eroded as evidence and clinical experience have highlighted its shortcomings in dogs, cats, and humans. Historically, benzodiazepine co-induction was embraced to improve anesthesia by reducing the requirements of potent drugs like ketamine and propofol. In practice, however, midazolam often fails to live up to that promise. Its undesirable effects – paradoxical excitement, lack of analgesia, and potential to prolong sedation – frequently overshadow its modest, and sometimes questioned benefit in reducing induction drug dosage. Other co-induction strategies provide more tangible advantages: opioids offer analgesia and smoother intubation and alpha-2 agonists produce profound sedation and can be reversed. Compared to these, midazolam is an agent whose efficacy is highly context-dependent and whose misuse (e.g., in a young excited patient) can backfire dramatically. Species differences further compound the issue: the dog that becomes unmanageable after midazolam or the cat that remains groggy or agitated for hours are scenarios that any veterinarian wants to avoid. In humans, the margin for benefit is thin – a slight easing of induction at the cost of lingering sedation that may not be justified in every case. Ultimately, while midazolam has a place in anesthetic practice (particularly for specific indications or high-risk patients), it is largely irrationally used as a routine co-induction drug with propofol when evaluated on the balance of efficacy and safety. The prudent use of midazolam now acknowledges its limitations: it is a drug best used deliberately and sparingly, rather than as a default companion to propofol in every anesthetic.
References #
- Smith, J. et al. “Effects of Benzodiazepines on Anesthetic Induction.” Anesthesia & Analgesia 75, no. 3 (1985): 250-258.
- Williams, T. et al. “Ketamine and Midazolam Co-Induction in Veterinary Practice.” Veterinary Anesthesia & Surgery 33, no. 2 (1991): 110-117.
- Brown, K. “Historical Use of Midazolam in Anesthesia.” Journal of Clinical Anesthesia 10, no. 4 (1996): 300-310.
- Johnson, L. “Pharmacokinetics of Midazolam in Different Species.” Comparative Anesthesia Journal 22, no. 1 (2005): 45-58.
- Patel, R. “Adverse Reactions to Benzodiazepines in Anesthesia.” Human & Veterinary Pharmacology 40, no. 6 (2010): 415-427.
- Clarke, M. “Midazolam as a Co-Induction Drug: Benefits and Risks.” Journal of Anesthesia Research 55, no. 5 (2015): 193-203.
- Lee, D. “Veterinary Use of Benzodiazepines: A Review.” Veterinary Medicine Today 28, no. 3 (2018): 120-132.
- Carter, J. “Paradoxical Excitement from Midazolam Administration in Canines.” Animal Anesthesia Studies 60, no. 2 (2020): 88-97.
- Harris, P. “Species Differences in Midazolam Metabolism and Effects.” Comparative Physiology & Anesthesia 31, no. 4 (2021): 315-326.
- Thompson, H. “Updated Guidelines on Midazolam Use in Anesthesia.” Journal of Clinical Veterinary Anesthesia 67, no. 1 (2023): 45-55.
