Midazolam is increasingly used in reptiles as part of a multidrug induction for general anesthesia. Studies of its use as a sole sedative are limited to a few reports in turtles and crocodiles. A retrospective review was carried out to assess the clinical efficacy of midazolam as a sedative in reptiles at the National Aquarium, Baltimore, Maryland. Medical procedures from 48 events involving 34 individuals were included in the review. Information obtained included species, age, sex, body weight, type of procedure performed, dosage of midazolam administered, use of a concurrent analgesic, time to effect, use of a reversal agent, and efficacy of sedation (acceptable vs. unacceptable). Midazolam was used in a wide variety of small- to medium-sized turtles, lizards, and snakes. Diagnostic imaging (e.g., radiography) and minor surgical procedures—in combination with local anesthetics (e.g., distal digit amputation)—were the most common procedures performed. The median dosage of midazolam was 0.3 mg/kg (range 0.1–1.0 mg/kg). Acceptable sedation was achieved in 80% of events. Midazolam can provide acceptable sedation to facilitate minor procedures in a variety of reptiles using dosages that are lower than previously reported in the literature.

Midazolam is a short-acting, water-soluble benzodiazepine with sedative, anticonvulsant, amnestic, anxiolytic, and skeletal muscle relaxant properties (Kanto and Allonen, 1983; Dundee et al., 1984). In human medicine, midazolam is used as a premedication and for procedural sedation because of its well-known sedative and amnestic properties, as a sleep aide for moderate to severe insomnia, and as a treatment for seizures (Kanto, 1985; Olkkola and Ahonen, 2008).

In veterinary medicine, midazolam is most commonly used as a premedication or as part of a multidrug induction for general anesthesia in small animal medicine; it is also frequently used as a sedative in avian and small mammal exotic medicine. Reports of midazolam use in reptiles as a procedural sedative are limited. Previous prospective studies have evaluated midazolam at 0.5–5 mg/kg IM in red-eared sliders (Trachemys scripta elegans), common snapping turtles (Chelydra serpentina), red-footed tortoises (Chelonoidis carbonaria), Indian star tortoises (Geochelone platynota), and saltwater crocodiles (Crocodylus porosus), with variable effects ranging from no sedation to profound sedation (Bienzle and Boyd, 1992; Holz and Holz, 1994; Oppenheim and Moon, 1995; Olsson and Phalen, 2013a; Emery et al., 2014). Recent case reports describe its use in a Galapagos tortoise (Chelonoidis nigra), three African spurred tortoises (Geochelone sulcata), and a Komodo dragon (Varanus komodoensis) as a standing sedative in combination with opioids and other sedative agents (e.g., ketamine, medetomidine, dexmedetomidine); however, the effectiveness of the sedation was not specifically described in these case reports (Aitken-Palmer et al., 2010; O'Shea and Ball, 2010; Mans and Sladky, 2012).

A retrospective review was carried out to assess the effectiveness of midazolam as a sedative in reptiles at the National Aquarium, Baltimore, Maryland. The goal was to determine whether the use of midazolam as a sedative facilitated restraint of reptiles in a busy clinical setting.

Medical records from 1 January 2009 through 31 December 2011 were reviewed using the Tracks® electronic medical records system (Denver Zoological Foundation and National Aquarium Institute, Inc., 1999). Key words used for the search included “midazolam,” “mida,” and “Versed.” Reptiles included in this review were administered midazolam (Hospira, Inc., Lake Forest, IL) for sedation to facilitate medical or surgical procedures. General anesthetic events and sedation events with no procedure performed were excluded. Individual medical records were then analyzed for species, order of reptile, age, sex, body weight, procedures performed, midazolam dosage, concurrent opioid or local analgesia use, time to effect, reversal agent use, and whether the sedation was considered acceptable or unacceptable by the clinician. Acceptable sedation was one that allowed the procedure to be performed with minimal to no restraint and/or was stated in the medical records as an effective sedation.

Logistic regression was used to evaluate whether the aforementioned variables (species, order of reptile, age, sex, body weight, procedures performed, midazolam dosage, concurrent opioid or local analgesia use, time to effect, and reversal agent use) were more likely to result in an acceptable or unacceptable sedation event. A P < 0.05 was used to determine statistical significance. Reference Value Advisor (Geffré et al., 2011) on Excel (Microsoft Excel for Mac 2011, version 14.4.8) was used to determine normal distributions of dosages and weights. Data were analyzed using SPSS software (vers. 15.0, IBM Statistics, Armonk, NY).

Midazolam was used as a sedative for minor procedures in a total of 48 events involving 34 individuals. A complete list of species evaluated can be found in Table 1. Of these 34 individuals, there were 12 species (N = 17) of turtles with a median weight of 2.38 kg (range: 0.38–42 kg). Only one animal, a loggerhead sea turtle (Caretta caretta), weighed more than 9 kg (40 and 42 kg at two sedation events). Midazolam was used for sedation in six species of lizards (N = 9) with a median weight of 0.46 kg (range: 0.11–2.40 kg) and seven species of snakes (N = 8) with a median weight of 4.08 kg (range: 0.22–6.34 kg). Only the weights for the snake species had a normal distribution, with a mean weight of 3.54 kg and standard deviation of 1.92.

Table 1.

Species and number of individuals that received midazolam as a sedative.

Species and number of individuals that received midazolam as a sedative.
Species and number of individuals that received midazolam as a sedative.

Midazolam was used for a variety of procedures. The majority of these procedures were radiographs (35%) and minor surgical events (35%; Table 2). All minor surgical events were performed with the addition of topical (EMLA cream [lidocaine 2.5% and prilocaine 2.5%], AstraZeneca LP, Wilmington, DE) or intralesional anesthesia (lidocaine hydrochloride 2%, Vedco, Inc., Saint Joseph, MO).

Table 2.

List of procedures and the number of events considered acceptable, unacceptable, or not stated.

List of procedures and the number of events considered acceptable, unacceptable, or not stated.
List of procedures and the number of events considered acceptable, unacceptable, or not stated.

The median dosage of midazolam given to all species was 0.30 mg/kg (range: 0.10–1.00 mg/kg). Midazolam was administered IM in every patient. For the majority of cases, the patient was placed in a warm, quiet, dark box for 10–20 min postinjection; therefore, the exact time of initial effect could not be determined. Of the 48 events, the time to initial effect and maximal effect was recorded in 25 and 22 events, respectively. The median time to initial effect was 10 min (range: 5–30 min), whereas the median time to maximal effect was 20 min (range: 9–45 min).

Concurrent systemic opioids and/or local anesthesia were used in 21 (44%) of the 48 events. Of these 21 events, 11 included lidocaine topically or as an intralesional injection, three included buprenorphine IM (Buprenex, Reckitt and Colman Products, Ltd., Hull, U.K.) alone, and seven included both lidocaine and buprenorphine. Buprenorphine and/or local analgesia were used for potentially painful procedures (e.g., distal toe/tail amputation, shell debridement) in 20 (95%) of the 21 cases. One turtle was given buprenorphine with midazolam for radiographs at the clinician's discretion.

Flumazenil (Romazicon, Roche, Nutley, NJ) was used as a reversal agent in 31 events (65%) at a median of 0.01 mg/kg IM (range: 0.01–0.02 mg/kg). The midazolam dosage in cases where reversal was used was 0.1–1.0 mg/kg. In three cases, one spiny-tailed monitor (Varanus acanthurus), one central bearded dragon (Pogona vitticeps), and one pignosed turtle (Carettochelys insculpta), given midazolam at 0.20, 0.10, and 0.40 mg/kg, respectively, continued sedation was noted after initial flumazenil administration of 0.01 mg/kg IM and administration at the same dosage was repeated. The bearded dragon was still lethargic 95 min post–initial reversal and the pig-nosed turtle was still lethargic 60 min post–initial reversal. All three were reported to have full reversal after the second injection of flumazenil.

In four events, the acceptability of sedation was not reported. Of the 44 events where acceptability of sedation was known, sedation was considered acceptable in 35 (80%) of 44 cases (Table 2). In 9 (20%) of 44 events, sedation was considered insufficient, and the procedure was modified or, in one case, canceled. The canceled event was for a grid keratectomy in a red-headed Amazon River turtle (Podocnemis erythrocephala) following a midazolam dose of 0.22 mg/kg IM. Only two individuals of this species were sedated using midazolam; the other red-headed Amazon River turtle was sedated using a midazolam dosage of 0.3 mg/kg IM with an acceptable level of sedation for an abscess debridement. In one event (2%, 1/48), sedation was considered unacceptable because of excessive depth: a pig-nosed turtle—with no known underlying medical conditions—following a midazolam dosage of 0.4 mg/kg IM. Only two examples of this species were sedated using midazolam; the other pig-nosed turtle was sedated using a midazolam dosage of 0.3 mg/kg IM, with an acceptable level of sedation for radiographs and wound debridement.

The logistic regression showed that species, order of reptile, age, sex, body weight, dosage, and concurrent opioid or local anesthesia had no significant effect on whether the sedation was acceptable or unacceptable (P > 0.05). There was, however, a positive—although not significant—relationship between the dosage of midazolam used and the invasiveness of the procedure. For example, midazolam dosage was typically higher for a distal tail amputation than radiography.

This review showed that midazolam can provide useful sedation for minor procedures in a variety of reptile species. The majority of midazolam dosages used in this study were lower than previous reported in red-eared sliders, common snapping turtles, and saltwater crocodiles (Bienzle and Boyd, 1992; Holz and Holz, 1994; Oppenheim and Moon, 1995; Mans et al., 2013; Olsson and Phalen, 2013a; Delgado et al., 2014). In one case report, the dosage of midazolam was similar to the dosages in this study; a Galapagos tortoise was given 0.3 mg/kg IM concurrently with morphine, although the level of sedation was not discussed (Aitken-Palmer et al., 2010).

The majority of events resulted in an acceptable level of sedation. Nine events (20%) were considered unacceptable. Subjectively, this was particularly common with debridement of shell lesions in turtles; however, the authors prefer general anesthesia and analgesia for these procedures. There was also variability in the time to initial effect and time to maximum effect, with ranges from 5–30 min and 9–45 min, respectively.

This variability in pharmacodynamics may be attributable to species or individual differences, temperature effects, or differences in injection sites (Bienzle and Boyd, 1992; Holz and Holz, 1994; Oppenheim and Moon, 1995). In this study, differences in species and order of reptile did not have a significant effect on sedation classification as acceptable or unacceptable, the time to initial effect, or the time to maximal effect, although the small sample size limits this interpretation.

The effects of temperature on absorption of midazolam are unknown. Although temperature can affect drug pharmacokinetics in poikilotherms, most commonly thought of as an increased metabolism with warmer temperature, this effect is not consistent between species or different drugs (Caligiuri et al., 1990; Johnson et al., 1997; Kischinovsky et al., 2013; Olsson and Phalen, 2013b; Shepard et al., 2013). During the sedation events reviewed here, supplemental heat was provided routinely, but animal temperatures were rarely recorded, and analysis was not possible. The location of intramuscular injections can also affect drug absorption and elimination. For example, the absorption of intramuscular buprenorphine was greater and faster following injections into the forelimb than into the hind limb (Kummrow et al., 2008). This effect may be attributable to enterohepatic recirculation of drugs (e.g., buprenorphine and midazolam) that are glucuronidated in the liver (Kronbach et al., 1989). Intramuscular sedatives and analgesics at the National Aquarium are typically administered into the forelimb, but the injection site was not recorded consistently; therefore, it was not possible to determine whether it had any influence on the outcome.

Clinicians combined opioids or local anesthesia with midazolam for many of the procedures included in this review. Analgesics may increase the efficacy of midazolam by reducing the sensory input of noxious stimuli (Greenacre et al., 2006; Schumacher and Yelen, 2006; Sladky et al., 2007, 2008; Wambugu et al., 2010; Baker et al., 2011; Mans et al., 2012). Opioid or local anesthetic administration did not affect sedation classification as acceptable or unacceptable. The opioid used in this review was buprenorphine, and although pharmacokinetic reports for this drug have proved promising, subsequent antinociceptive papers suggest it does not provide adequate analgesia and instead recommend morphine, hydromorphone, or tramadol as better alternatives (Kummrow et al., 2008; Wambugu et al., 2010; Baker et al., 2011; Mans et al., 2012). Although butorphanol appears to have limited antinociceptive properties in lizards (e.g., green iguanas [Iguana iguana] and bearded dragons), it did have apparent antinociceptive responses in corn snakes (Pantherophis guttata) (Greenacre et al., 2006; Sladky et al., 2008; Fleming and Robertson, 2012).

A limitation of this retrospective review was the inability to quantify the level of sedation and recovery seen in each individual animal. The variability with which clinicians reported the efficacy of midazolam in the medical records made it necessary to report the level of sedation as either acceptable or unacceptable. In future prospective studies, levels of sedation and recovery times should be standardized and quantified. Another limitation was the small sample size reported in this review, which should cause clinicians to use the data cautiously. Future prospective studies should look into larger sample sizes and help minimize variation between species and/or order of reptiles.

The primary reasons clinicians used midazolam for these cases were to reduce the forcefulness of manual restraint, improve physical manipulation of the reptile's body for diagnostics procedures, and reduce the reptile's stress response to the procedure. Olsson and Phalen (2013a) compared physiological parameters in juvenile saltwater crocodiles following manual restraint with and without midazolam at 5 mg/kg IM. Crocodiles given midazolam had lower heart and respiratory rates, blood glucose and lactate concentrations, and less acidosis than crocodiles under manual restraint (Olsson and Phalen, 2013a). Sedation with midazolam for routine procedures also improved staff safety by reducing the requirement for strong physical restraint, reducing the risk of trauma, and avoiding manual restraint for radiography.

This review demonstrates that midazolam can provide an acceptable level of short-term, reversible sedation for minor procedures in a variety of small- to medium-sized reptiles at lower dosages than previously reported. It is now used routinely in reptiles at the National Aquarium to improve diagnostic procedures (e.g., radiograph positioning), reduce stress in reptiles, and improve staff safety. Clinicians should consider midazolam to facilitate minor procedures in reptiles.

The authors would like to thank Dr. Ben Rossi (National Aquarium, Baltimore, MD), Dr. Stephen Cassle (University of Florida, Gainesville, FL), and Travis J. Weiland (University of Massachusetts, Dartmouth) for their help with statistical analyses.

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