Introduction
Guinea pigs (GPs) can be a challenge for the anesthesiologist due to their oral anatomy and gastrointestinal physiology, predisposition to subclinical respiratory diseases, and highly variable response to anesthetics. Complications after sedation or anesthesia such as respiratory infections, digestive disturbances, and generalized depression and inappetence are frequently seen.1 The reported anesthetic- and sedation-related risk of death in GPs is 3.80%, the highest mortality rate among the studied small mammals (dogs, cats, rabbits, hamsters, chinchillas, and rats).2
It is not uncommon to perform blood sampling and imaging techniques with pet GPs sedated to reduce the stress, facilitate the technique, avoid complications, and improve the quality of the images obtained; however, there is a lack of literature that describes drugs and dosages used clinically in pet GPs. The use of inhalational anesthetic agents for “sedation” using a face mask is commonplace in small rodents, but this carries potential health hazards to personnel from exposure, and these agents play an important role as greenhouse gases.3 Additionally, the minimum alveolar concentration of isoflurane in GPs is lower than in other rodents, and they are more vulnerable to its vasodilatory and myocardial depressor effects.4 Therefore, the development of new sedation protocols based on the use of injectable agents could be helpful.
The main objectives of this study were to compare the cardiorespiratory effects and evaluate the quality and duration of sedation achieved with alfaxalone administered SC alone or its combination with midazolam to perform diagnostic noninvasive procedures in 3 different age groups of pet GPs. Our hypotheses were that both SC protocols will produce enough sedation to perform noninvasive procedures and that the combination of alfaxalone and midazolam will achieve a deeper sedation with longer duration in all age groups.
Materials and Methods
Animals
The Animal Care Committee of the Catholic University of Valencia approved this study (UCV/2017-2018/83). Guinea pigs belonging to the Catholic University of Valencia for educational purposes were enrolled in the study from 2017 to 2019.
Each GP was included according to its age in 1 of 3 groups: infant (3 to 4 weeks), juvenile (3 to 4 months), and adult (≥ 1 year). All infant GPs were already weaned, and the juvenile and adult GPs were friendly because they were used to being handled due to undergraduate clinical training. The presedation assessment consisted of complete history, physical examination, and accurate body weight. If possible, blood was collected from the jugular vein before the sedation; otherwise, blood samples were obtained at the end of the sedation.
Animals were excluded if any abnormality was detected during physical examination or if any female GP was pregnant.
Animal husbandry
Animals were housed in an exclusive ward for rodents with an environmental temperature of 21 to 22 °C, 45% to 50% humidity, and 12 hours of light. The cages were rectangular with solid-bottom and cellulose bedding. Guinea pigs were allowed to acclimatize in their kennels for at least 2 days with a minimum of 2 GPs for each kennel to facilitate their social behavior. If housed in groups, their male-dominated social hierarchy was taken into account, and they were continuously monitored to be compatible. Kennels were enriched with cardboard boxes to facilitate a hiding place and minimize their stress as prey animals. Water was available ad libitum in bowls and sipper bottles, and food was offered following the hospital protocol: ad libitum hay, 25 g/animal of commercial dry food for GPs and fresh vegetables (spinach, lettuce, rocket, a portion of red pepper or orange). Cages were spot cleaned daily and deep cleaned twice a week.
Study design
Two SC sedation protocols were studied: alfaxalone at 5 mg/kg in group A or alfaxalone and midazolam at 5 mg/kg each in group A + M. Each patient was sedated twice, once in each protocol in a crossover fashion, with a washout period of at least 7 days observed between protocols. Randomization was performed by means of cards picked from an envelope by an investigator that prepared the drugs but was not involved in the sedation assessment.
An initial power analysis was calculated employing a statistical program (G*Power version 3.1.2.9; Buchner A, Erdfelder E, Faul F, Lang A-G) with a power of 0.8 and α value of 0.05 using the data obtained from the first 6 juvenile GPs.5 The number of GPs needed to find a difference in the duration of the sedation between treatments using a crossover design was 8/age group. Therefore we included 24 GPs in the study: 8 infantile, 8 juveniles, and 8 adults.
Sedation protocol
The day of the sedation, GPs were isolated in a cage withholding water and food 20 minutes before the beginning of the procedure. The mouth was gently rinsed with 1 mL of tap water administered with a 1-mL plunger syringe and cleaned with cotton swabs impregnated with chlorhexidine to remove all the remaining vegetable material and reduce the risk of aspiration pneumonia or airway obstruction.
Initial baseline assessment (t0) included animal temperament (friendly, nervous, feisty) and vital parameters including respiratory rate (RR), heart rate (HR), oxygen saturation as measured by pulse oximetry (SpO2) and rectal temperature. Respiratory rate was counted by direct observation of the chest movements for 60 seconds while the animal remained within its enclosure. Heart rate was measured with a Doppler ultrasound device positioned at the left thoracic wall by listening and counting the number of beats. Considering that the HR is very high in this species, the number of beats were counted for 10 seconds and multiplied by 6 to obtain beats per minute. Peripheral oxygen saturation and a plethysmogram were obtained by positioning the pulse oximeter probe at the paw. Rectal temperature was measured using a digital thermometer with flexible tip covered with a disposable sleeve and lubricated with water gel.
An investigator, blinded to the sedation protocol allocation, performed the injections, sedation assessment, and patient monitoring throughout the study period. Alfaxalone and saline (0.9% NaCl) solution (group A) or alfaxalone and midazolam (group A + M) were injected SC in the interscapular area, in 2 different syringes with 1 cm of separation between injections. The alfaxalone was administered using a 1-mL plunger syringe with a 25-gauge, 1.6-cm needle. Midazolam or an equal volume of sterile saline solution was injected with a 0.5-mL insulin syringe with an incorporated thin-walled 30-gauge, 0.8-cm needle to be more accurate with smaller volumes. The reaction to injection was recorded (nothing, vocalization, or trying to escape). Animals were then left undisturbed in a quiet room inside a cage with constant veterinary surveillance until the GPs became sedated. Then, each GP was placed over an absorbent pad with an electric heating blanket underneath during monitoring and abdominal ultrasonography or between radiograph acquisitions.
The degree of sedation was assessed using a modified version of a previously published sedation scoring system for GPs6 that included palpebral reflex, jaw tone, and ear and toe pinch (0 = normal, 1 = decreased, and 2 = absent); reaction to handling (0 = not possible to manipulate without struggling, 1 = mild struggling but without enough strength, and 2 = no reaction to handling); righting reflex (0 = regained sternal recumbency immediately after positioning, 1 = regained sternal recumbency 5 to 10 seconds after positioning, 2 = unsuccessfully attempts to regain sternal recumbency, and 3 = dorsal recumbency maintenance without righting attempts); posture (0 = normal, 1 = head up but sternal recumbency, 2 = head down and sternal recumbency, 3 = lateral recumbency, 4 = dorsal recumbency with partial relaxation of the limbs, and 5 = dorsal recumbency with total relaxation); temperament (0 = friendly, 1 = nervous, and 2 = feisty); and sedation score (0 = unsedated, 1 = mild sedation, and 2 = deep sedation or anesthesia). The palpebral reflex was evaluated by touching the medial and the lateral canthus of the eye with a cotton swab. The GP was placed in dorsal recumbency and righting reflex was assessed. Immediately after, posture was recorded. The reaction to handling simulates the positioning for radiography (GP in dorsal recumbency and extension of the limbs). Jaw tone was assessed by attempting to open the GP’s mouth. The pedal withdrawal reflex (PWR) or toe pinch was assessed by lightly pinching the interdigital webbing of all four limbs. The assessment for ear pinch was the same as for PWR but in both ears’ base.
Vital parameters were registered every 5 minutes until the GPs were fully recovered. The parameters assessed that required most stimulation were performed last to minimize their influence in others: RR, HR, palpebral reflex, reaction to manipulation, righting reflex, posture, jaw tone, ear pinch, PWR, SpO2, and, finally, rectal temperature. If the sedation score was < 2, the ear and PWR were no longer tested to preserve animal welfare. During sedation, eye lubrication was applied every 20 minutes to avoid exposure keratitis.
The onset time to achieve sedation (ti) was defined as the time from drug administration until the GP achieved a score posture of 3 (lateral recumbency), which suggested loss of the righting reflex. The duration of sedation (td) was defined as the time from ti until a sedation score of 0. Recovery time (tr) was defined as the time from a sedation score of 0 until a posture score of 0.
Lateral and ventrodorsal whole-body radiography was performed in all GPs during one of the sedation protocols, and abdominal ultrasonography was carried out during the opposite protocol. The order of these procedures depended on the hospital flow and availability of imaging clinicians and equipment.
After recovery was achieved, GPs were kept in an incubator until they ate, urinated, and defecated at least once and the temperature was normalized. Then they were individually housed for the next 24 hours to allow subjective evaluation of individual water and food intake, urination, and defecation. After this 24-hour period, animals were returned to their original kennel and were examined for 48 hours more to check that behavior, food, water intake, and fecal output continued being normal. All adverse events (bruxism, facial twitching, or generalized muscle fasciculations) were recorded throughout the procedure, and postsedation gastrointestinal effects (abnormal or no stool, gastrointestinal stasis or hypomotility, or diarrhea) or behavioral signs (apathy, feeding disorders, self-mutilation, or injection site pain) were recorded.
Statistical analysis
Data obtained were assessed for normality by the evaluation of descriptive statistics using histograms and the Shapiro-Wilk test. Variables were summarized as frequency (percentage) for categorical variables; mean ± SD for continuous, normally distributed variables; and median (range) for skewed data.
Using the Student t test, td was compared between groups. Additionally, 2-way ANOVA was used to compare the td among age groups and between sedation groups. The Mann-Whitney U test was used to compare body weight, ti, and tr between study groups. The t test was used to compare rectal temperature between sedation groups and among age groups. Paired-samples t tests were used to compare initial rectal temperature with the rectal temperature on recovery.
Multiple logistic regression and repeated-measures ANOVA were used to compare HR and RR were between sedation groups at the different time points. The Kruskal-Wallis test with Tukey post hoc test was used to compare sedation scores at the different time points. The presence of facial or generalized muscle fasciculations was compared between sedation groups using the χ2 test. All analyses were performed with standard software (SPSS Statistics version 20; SPSS Inc), and statistical significance was set at P < 0.05.
Results
Twenty American GPs, 3 Abyssinian GPs, and 1 Peruvian pet GP were recruited for the study, for a total of 8/age group. Gender distribution was 15 females and 9 males. Mean ± SD body weight was 0.24 ± 0.03 kg in infants, 0.40 ± 0.14 kg in juveniles, and 0.89 ± 0.15 kg in adults. Age ranged from 3 to 4.5 weeks in infants and 12 to 15 weeks in juveniles. Median age in adults was 26 months (range, 13 to 66 months). All GPs were deemed healthy based on vital parameters and blood work results, and 5 protocols were used to clip and clean superficial bite wounds found during physical examination.
Animal temperament was friendly in 11 of 24 GPs, nervous in 9, and feisty in 4. Regarding reaction to injection, all GPs tried to escape when handled and vocalized during handling, injection, or drug administration.
The monitored cardiorespiratory variables were compared between sedation groups during the first 40 minutes due to data loss in group A because of shorter duration of the sedation with that protocol. The results from the general lineal model and repeated-measures ANOVA indicated statistically significant (P = 0.001) changes occurred in mean HR between sedation groups at the different time points. An initial increase in HR was seen in both groups compared with baseline, but after that peak, the HR remained lower in group A than in group A + M (Figure 1). Although there was a significant (P = 0.001) reduction in mean RR during sedation, the difference between sedation groups in this reduction was not significant (P = 0.066). The SpO2 remained above 95% during sedation, and there were no differences between sedation groups (P = 0.750). Hypothermia (T < 37.2 °C) was observed in 18 out of 48 of the sedations. There was a statistically significant difference between initial and recovery T (P = 0.001); however, there were no differences between sedation protocols or age groups and recovery T.
Changes from baseline at various points for mean heart rate (HR) in guinea pigs (n = 24) sedated with alfaxalone (5 mg/kg, SC; group A) or alfaxalone and midazolam (5 mg/kg and 0.5 mg/kg, respectively, SC; group A + M) in a crossover study design. Squares: group A. Circles: group A + M.
Citation: Journal of the American Veterinary Medical Association 260, 9; 10.2460/javma.21.02.0104
The median ti for group A was 5.25 minutes (range, 0.78 to 9.42 minutes), and median ti for group A + M was 2.40 minutes (range, 1.33 to 5.50 minutes; P = 0.020). The mean td was also statistically (P = 0.001) different between sedation groups, being much longer in group A + M with a mean ± SD td of 62 ± 15.70 minutes (vs 36.70 ± 10.80 minutes for group A). There were also differences in td between age groups (Table 1). Sedation persisted longer in adults than in juveniles and infants (Figure 2). To assess the depth of the sedation, a total sedation score was evaluated. The score included the sum of the following parameters: palpebral reflex, posture, righting reflex, PWR, ear pinch, mandibular tone, and reaction to manipulation. Total sedation scores were statistically (P = 0.001) different between groups, being higher in group A + M at all time points (Figure 3).
Mean ± SD duration of sedation (minutes) achieved by SC administration of alfaxalone (5 mg/kg; group A) or alfaxalone and midazolam (5 mg/kg and 0.5 mg/kg, respectively; group A + M) in guinea pigs of 3 different age groups.
| Age group | Group A | Group A + M |
|---|---|---|
| Infant (n = 8) | 30.86 ± 8.37 | 45.59 ± 8.60 |
| Juvenile (n = 8) | 35.13 ± 8.45 | 62.18 ± 5.05 |
| Adult (n = 8) | 44.31 ± 11.78 | 78.25 ± 10.33 |
Values differed significantly among age groups (P = 0.001) and between sedation groups (P = 0.003).
Mean duration of sedation in infant (n = 8; dark gray), juvenile (n = 8; medium gray), and adult (n = 8; light gray) guinea pigs in the sedation groups of Figure 1. Error bars represent 95% CIs. See Figure 1 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 260, 9; 10.2460/javma.21.02.0104
Mean total sedation scores at various points for guinea pigs in group A (circles) and group A + M (squares).
Citation: Journal of the American Veterinary Medical Association 260, 9; 10.2460/javma.21.02.0104
All procedures were carried out without complications, and no major adverse effects were observed in any animals, either during or after sedation. Minor reactions like bruxism, hectic movements, twitching and some degree of hyperreactivity to auditory stimulus were observed at some points during the sedation period in 41 of 48 sedations. Fourteen sedations had only facial twitches, 6 had only generalized muscle movements, and 21 had facial or generalized muscle movements at some point during the study period. There was no statistical difference in the incidence of these reactions between sedation protocols.
No oral syringe feeding was needed after recovery, as all patients were eating at the end of the sedation.
Discussion
In the present study, alfaxalone and an alfaxalone-midazolam combination administered SC provided reliable, good-quality sedation for noninvasive and diagnostic imaging procedures with minimal side effects. The sedation was more pronounced as the GPs’ age increased, and midazolam-alfaxalone produced deeper and longer sedation in all age groups.
Injectable sedation protocols (IP or IM routes) with acepromazine, alfaxalone-alphadolone, α-2 adrenergic receptor agonists (xylazine, medetomidine, and dexmedetomidine), benzodiazepines (diazepam and midazolam), ketamine, and fentanyl combinations (fentanyl-droperidol and fentanyl-fluanisone) have been described for laboratory GPs.1
In veterinary medicine, midazolam is a widely used benzodiazepine with multiple effects, including anxiolytic, hypnotic, anticonvulsant, and centrally mediated muscle relaxant.7 In companion exotic animals, it is common to use midazolam as a sedative, with the benefit that it is water soluble and thus can be administered by nearly any route with good absorption. Midazolam is eliminated almost exclusively by the liver and has a rapid elimination and clearance in GPs8 with the possibility of being antagonized with flumazenil. Although there are few publications regarding the use of benzodiazepines for sedation and anesthesia in GPs, to the author’s knowledge there are no reports of midazolam in combination with SC alfaxalone in pet GPs. The midazolam dose suggested for rodents is 1 to 2 mg/kg,9 but in the present study the dose was reduced to 0.5 mg/kg, as it was combined with an injectable anesthetic.
Alfaxalone is a progesterone derivative with anesthetic properties as a neuroactive steroid that acts on the γ aminobutyric acid A receptor. This molecule is insoluble in water, and it was initially formulated as alfaxalone-alphadolone acetate, withdrawn from the market nowadays due to anaphylactic reactions caused by the preservatives. Alfaxalone solubilized in 2-hydroxypropyl-β-cyclodextrin is licensed for use in rabbits, cats, and dogs and used off-license in a broad range of exotic species to achieve sedation or general anesthesia depending on the dose administered, with an increasing scientific bibliography available.10 Alfaxalone appears to be rapidly metabolized by the liver in most species, with a very short half-life and a dose-dependent clearance.10
The preferred routes of alfaxalone administration in small mammals are the IP, IM, and IV routes; however, there is 1 article11 in GPs that reports SC administration. The SC route was selected in our study because it is simple, safe, and less painful to perform in small conscious animals, decreasing the stress and avoiding muscle damage and pain related to the IM injection.12 Intramuscular injection in small rodents may cause self-mutilation,13 tissue reactions, myositis, and muscle necrosis14 even when only saline solution is administered.15 These side effects were related to the pH of the drug, the excipients, and the volume used. Alfaxalone has a pH close to the physiological pH (6.5) and no excipient, making it suitable for IM or SC injection. Due to the concentration of alfaxalone (10 mg/mL) and the high doses required in rodents (eg, 5 mg/kg used by d’Ovidio et al6 or 15 and 20 mg/kg used by Doerning et al12), the volumes of injection could be quite large and painful and exceed the maximum IM safe volume described in rodents (0.05 to 0.1 mL/kg/site).16
In our study, almost all GPs reacted when handled (vocalization, attempts to run away) regardless of the temperament; therefore, no differences in pain during injection were found; however, this parameter was not an aim of the study. Surprisingly, Doerning et al12 found that only 2 of 12 animals displayed reaction to injection, maybe explained by the habituation of handling in experimental GP breeds (albino Hartley GPs).
Baseline HR and RR in the present study were higher than the physiological range described for GPs, probably because of stress. Even with high baseline HR, we observed initial tachycardia in group A at 5 minutes after injection; however, the addition of midazolam diminished this tachycardia. After that time period, HR remained lower in group A between time points 10 and 30 minutes when compared with group A + M. Respiratory rate decreased significantly during sedation in both groups, possibly due to a combination of muscle relaxation and respiratory depression caused by the sedative drugs. Peripheral oxygen saturation was measured in an attempt to evaluate desaturation, which is not uncommon in sedated or anesthetized patients with alfaxalone,17,18 but SpO2 stayed above 95% with both protocols.
In our study, SC administration prolonged the onset of sedation of alfaxalone, compared with IM route used in the d’Ovidio’s study.6 This time difference may not be clinically relevant, and the SC route provided a longer td when compared with IM administration (36.70 ± 10.80 minutes vs 10 to 15 minutes, respectively).6 Additionally, the median ti was significantly shortened by the combination of midazolam with alfaxalone.
Adult GPs showed longer sedation times than juvenile or infantile GPs with both sedation protocols in the present study. Drug absorption and distribution depend upon regional blood flow and in younger animals are higher; therefore, the drug should reach the target receptor faster, but also clear more rapidly.19 The sedation depth for the infant GPs of the present study was mild, and 1 infant GP in group A only achieved mild sedation (score 1) for 5 minutes, which may have indicated that higher doses or the addition of other drugs may be considered if deep or longer sedation is needed in this age group. This finding agrees with a study20 in 10-day-old neonatal rats, which showed lower anesthetic sensitivity in this age group. Another possibility is that dose calculation should be based on body surface area instead of body weight, especially for infant and juvenile rodents.
The depth of sedation in small rodents is difficult to assess objectively21; however, we tried to improve the sedation assessment adapting a previously published sedation scale for this species,6 although this scale has not been validated. Surgical depth of anesthesia was not achieved because the ear and the PWR were present,22 except in some patients for short periods of time (probably when the peak of the sedation was achieved). This finding implies that these protocols are not suitable for surgery, and the addition of an analgesic would be necessary for invasive procedures.
The side effects encountered in this study were mild and include muscle twitches and limb movements. Other reported side effects of alfaxalone are myoclonus or muscle twitching, generalized convulsions, apnea, and myoclonic jerk.23,24 Only 1 adult GP had some hyperreactivity and rigidity, similar to the opisthotonus-like posture described in cats,25 limb rigidity described in horses,26 or hyperactivity/excitation seen in dogs27 and cats.28 Bruxism was commonly observed at any sedation point in all groups, as occurred in the study by Doerning et al.12 It seems that the muscle relaxation provided by midazolam was not sufficient to counteract this side effect.
There was a significant difference between baseline and recovery temperature values despite the use of active heating, but no differences between groups were found. Hypothermia is common in rodents under sedation or anesthesia, as they have greater exposed surface relative to their body weight,29 and it will influence recovery times because drug metabolism and excretion may be reduced. The results from our study suggested that more than 1 active warming method may be necessary to reduce the incidence of hypothermia during anesthesia and its unwanted side effects.
In exotic small mammals, gastrointestinal stasis is common, and some references state that prokinetic drugs should be administered to GPs and chinchillas to avoid postanesthetic ileus.30 In our study, almost all patients presented obvious intestinal movements and postprocedure fecal output was subjectively normal despite not having administered prokinetic drugs.
This study had some limitations. First, not all diagnostic imaging procedures and blood sampling were carried on at the same sedation time point, and this could have influenced the sedation depth or duration and the vital parameters monitored. A second limitation was the heterogeneity of the adult group, which included 6 adults and 2 geriatric GPs (more than 5 years old). The literature recommends diminishing doses in geriatric populations,31 but the protocol was standardized. The inclusion of 2 geriatric GPs could have increased the duration of the sedation and recovery in this age group. Another limitation was that blood pressure measurements were not included in the monitoring. Invasive blood pressure was not possible, as it was a clinical study, and for noninvasive blood pressure measurements there are no validated ranges or sized cuffs for these patients. Additionally, most oscillometric monitors fail to detect blood pressure, and Doppler ultrasound monitoring was not compatible with the PWR test. Further studies are needed to highlight the impact of these protocols on GPs’ blood pressure. Finally, the population included in our study was healthy, and the results cannot be extrapolated to ill patients.
In the present study, alfaxalone administered SC and an alfaxalone-midazolam combination administered SC in healthy GPs provided reliable, good-quality sedation for noninvasive and diagnostic imaging procedures with minimal side effects. The 2 sedation protocols studied did not affect food intake and fecal output.
Acknowledgments
No third-party funding or support was received in connection with this study or the writing or publication of the manuscript. The authors declare no conflict of interest.
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