Veterinary Anaesthesia and Analgesia, 2014, 41, 430–437
doi:10.1111/vaa.12133
RESEARCH PAPER
Analgesic and gastrointestinal effects of epidural morphine in horses after laparoscopic cryptorchidectomy under general anesthesia Manuel Martin-Flores*, Luis Campoy*, Marc A Kinsley†, Hussni O Mohammed‡, Robin D Gleed* & Jonathan Cheetham* *Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA †College of Veterinary Medicine, Cornell University, Ithaca, NY, USA ‡Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
Correspondence: J Cheetham, Box 32, Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA. E-mail: [email protected]
Abstract Objective To evaluate the hypothesis that epidural morphine (0.1 mg kg 1) decreases pain in horses after laparoscopic surgery without adversely affecting gastrointestinal (GI) motility. Study design Randomized clinical trial. Animals Eighteen horses undergoing laparoscopic cryptorchidectomy under general anesthesia. Methods Horses were randomly assigned to receive either epidural morphine (0.1 mg kg 1) or no epidural before the start of surgery. Pain behaviors were assessed during the first two post-operative days using a numerical rating scale. Barium-filled spheres were administered through a nasogastric tube before anesthesia. GI motility was assessed by recording manure production, by quantitating the spheres in the manure, and by abdominal auscultation of intestinal sounds. Heart rates and cortisol concentrations were also measured during the post-operative period.
Manuel Martin-Flores and Jonathan Cheetham contributed equality.
Results Pain scores increased for 12 hours after surgery in the control group and were significantly higher than in the morphine group for the first 6 hours. Pain scores remained unaltered in the morphine group throughout the observation period. Heart rate and plasma cortisol concentrations did not differ between groups or with time. No signs of colic were observed in any horse. Conclusion and clinical relevance Epidural morphine (0.1 mg kg 1) did not adversely affect GI motility in horses after laparoscopic surgery under general anesthesia. Keywords analgesia, anesthesia, epidural, equine, gastrointestinal, morphine.
Introduction Systemic administration of opioids to horses has been associated with reduced gastrointestinal (GI) motility (Senior et al. 2004; Boscan et al. 2006). Consequently, many clinicians are reluctant to prescribe opioids perioperatively to avoid exacerbation of ileus. Opioids, including morphine, can be administered into the epidural space from which they diffuse readily to interact with opioid receptors in the dorsal horn of the spinal cord (Chiari & 430
Epidural morphine in horses M Martin-Flores et al.
Eisenach 1998). The dose rate of morphine needed to produce a given level of analgesia may be less when injected epidurally compared to other parenteral routes. Reducing the dose rate may result in a lower prevalence and severity of systemic side effects, such as decreased GI motility, associated with activity of the drug at receptors outside the spinal cord (Bennett & Steffey 2002). Epidural morphine (0.1 mg kg 1) provided analgesia for horses undergoing standing laparoscopic ovariectomy (Van Hoogmoed & Galuppo 2005). A higher dose rate of epidural morphine (0.2 mg kg 1) administered to healthy, unmedicated horses increased mean GI transit time by approximately 5 hours without detectable decreases in GI sounds or signs of colic (Sano et al. 2011). Gastrointestinal function is influenced in clinical patients by a variety of factors, including surgical stimulation, pre-anesthetic fasting, and co-administered drugs. The analgesic and GI effects of epidural morphine have not been systematically evaluated in clinical equine patients subjected to abdominal surgery under general anesthesia. The hypothesis of this study was that administration of epidural morphine (0.1 mg kg 1) to anesthetized horses before the start of laparoscopic surgery for correction of cryptorchidism would 1) reduce post-operative pain and 2) not decrease GI motility during the first 2 post-operative days. Materials and methods All horses undergoing laparoscopic cryptorchidectomy at the Equine Hospital of Cornell University between April 2005 and September 2008 were eligible for inclusion in the study. This project was approved by the Institutional Animal Care and Use Committee, and informed client consent was obtained from the owners of all animals enrolled. All horses were considered healthy based on a physical examination. Except during surgery and anesthesia, the horses were housed in conventional loose boxes bedded with shavings. Each horse was hospitalized for a total of 4 days and provided with water ad libitum. Food was withheld overnight prior to induction of anesthesia. The evening before surgery, 200 barium-filled plastic spheres (LDPE Barium Filled Ball; Precision Plastic Ball Company, IL, USA) were administered with water and mineral oil (1:1 v/v; 9 mL kg 1) by nasogastric tube. These spheres served as markers of GI transit (Lippold et al. 2004) and their presence in the manure was verified radiographically. 431
Anesthesia and surgical procedures On the morning of surgery, a 14-gauge catheter was placed in the left jugular vein, and each horse received potassium penicillin (22,000 IU kg 1) intravenously (IV) pre- and 6 hours post-operatively and phenylbutazone (4 mg kg 1) IV pre-operatively and 2 mg kg 1 IV every 12 hours post-operatively. Horses were sedated with xylazine (0.7 mg kg 1; AnaSed; Lloyd Inc., IA, USA) IV and anesthesia was induced with midazolam (0.1 mg kg 1; Midazolam hydrochloride; Hospira Inc., IL, USA) and ketamine (2.2 mg kg 1; Ketaset; Fort Dodge Animal Health, IA, USA) IV. After orotracheal intubation, anesthesia was maintained with isoflurane in oxygen. Monitoring consisted of an electrocardiogram (ECG), heart rate (HR), pulse oximetry, invasive arterial blood pressure and end-tidal carbon dioxide pressure (PE′CO2) and isoflurane concentration (FE′Iso). Ventilation was controlled to maintain partial pressure of arterial carbon dioxide (PaCO2) between 38 and 42 mmHg. A balanced electrolyte solution (Plasma-lyte A, Baxter Healthcare Corporation, IL, USA) was administered IV throughout anesthesia at approximately 5 mL kg 1 hour 1. Dobutamine was infused as necessary to maintain mean arterial pressure (MAP) above 70 mmHg. The absence of at least one scrotal testicle was confirmed immediately after induction of anesthesia with the animals in lateral recumbency. Then each horse was assigned randomly to one of two treatment groups by removing labels from an opaque envelope: epidural morphine (0.1 mg kg 1) or no epidural (control). Unilateral and bilateral cryptorchid horses were assigned a treatment by separate block randomization. The puncture site (sacro-coccygeal area) of all horses was clipped, regardless of treatment group. An 18-gauge 8.75 cm (3.5 inch) Tuohy needle (Perifix Tuohy epidural needle; B Braun Medical Inc., PA, USA) was inserted perpendicular to the skin and correct placement was verified by the loss-of-resistance to air technique. All horses assigned to receive epidural morphine were injected with preservative-free morphine (0.1 mg kg 1; Preservative free morphine, 1% compounded by the Pharmacy of Cornell University Hospital for Animals and diluted with sterile saline to a final volume of 0.04 mL kg 1). Insertion of the epidural needle was performed by one investigator before the horses were positioned in dorsal recumbency. In all cases, epidural administration of morphine was completed at least 35 minutes before
© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 430–437
Epidural morphine in horses M Martin-Flores et al. the start of surgery. No puncture was performed in the control group. The attending anesthetist and all other personnel involved in the study were blinded to the treatment allocated to each horse. A standard technique was used to remove the abdominal testes laparoscopically (Ragle et al.1998). Horses that were unilateral cryptorchid had the remaining scrotal testis removed by a standard technique (closed castration with primary skin closure) as described by Schumacher (1999). After surgery, the horses were moved to a padded recovery stall and extubated once ventilation became spontaneous, at which time they received xylazine (0.25 mg kg 1) IV. The horses recovered from anesthesia unassisted. Recovery was recorded on VHS tape from extubation to the time at which the horse was led out of the recovery stall. All horses were fed 1.8 kg hay every 4 hours and observed at 2 hour intervals until the first feces were passed, when the time was recorded. Observations and data collection A set of observations was made at 0 hours (before anesthesia) and 6, 12, 18, 24, 36 and 48 hours after induction of general anesthesia. Horses were discharged from the hospital after the 48 hour observation time. At each observation time, a modified numerical rating score (NRS) was used to assess post-operative pain (Pritchett et al. 2003; Table 1).
The NRS was a composite of three categories, gross pain behavior (e.g. pawing, sweating), a postural score (e.g. head and ear positions) and a socialization score (e.g. response to opening the door and offering food). Higher scores indicated greater pain. On each occasion the horse was observed for 2 minutes by two observers before they entered the stall. The only modifications from the scale originally described by Pritchett et al. (2003) were that the response to lifting feet was not evaluated in our study, and that each category (gross pain behavior, postural and socialization scores) was analyzed independently, rather than as a composite score. After observations for the NRS were completed, HR was obtained by auscultation. At the same observation times, the number of fecal piles in the stall was counted, then all of the manure in the stall was collected and stored in an impermeable labeled sack, weighed and then radiographed to determine the number of radiopaque spheres in each fecal sample (Sano et al. 2011). Auscultation of the four abdominal quadrants each for 1 minute provided a score for GI motility. Each quadrant was scored on a 0–3 scale, where 0, 1, 2, and 3 represented 0, 1, 2, and ≥3 sounds per minute, respectively. The scores from each quadrant were added to give a cumulative score for analysis. Jugular venous blood was collected by percutaneous puncture at each observation time, centrifuged for 10 minutes at 5500 g, and the plasma frozen at
Table 1 Numerical rating scale used to score post-operative pain in horses after laparoscopic cryptorchidectomy (modified from Pritchett et al. 2003)
Score Category
1
Gross pain signs* Head position† Ear position† Location in stall†
None Above withers Forward, frequent movement At door watching environment
Spontaneous locomotion† Response to open door‡ Response to approach‡
Moves freely Moves to door Moves to observer, ears forward Moves to door and reaches for grain
Response to grain‡
2
Standing in middle facing door Occasional steps Looks at door Looks at observer, ears forward Looks at door
3
4
Occasional At withers Slightly back, little movement Standing in middle facing sides
Continuous Below withers
Moves away from observer
Standing in middle facing back No movement No response Does not move, ears back No response
*Gross pain behaviors (pawing, sweating, looking at the flank, flehmen, and lying down/standing up repeatedly). †Posture category. ‡Socialization category. © 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 430–437
432
Epidural morphine in horses M Martin-Flores et al.
80 °C. Cortisol concentrations were measured using a solid phase chemiluminescent immunoassay [Immunolite; Diagnostic Products Corporation (DCP), CA, USA]. In accordance with hospital practice, and at the discretion of the primary clinician who was unaware of which experimental treatment each horse had received, supplemental post-operative analgesia was available if a patient demonstrated signs of moderate to severe abdominal pain. At that point, the horse would be removed from the project and no further data collected. Analyses A median value for HR, MAP, and FE′Iso during anesthesia was calculated for each horse. MAChours were calculated for each animal, assuming a minimal alveolar concentration (MAC) for isoflurane of 1.31% (Steffey et al. 1977). Recovery from anesthesia was scored from the VHS recordings by two observers who were unaware of treatment allocation, using a composite scale published previously (Clark-Price et al. 2008). Variables related directly to anesthesia were compared between the two groups using the Wilcoxon rank-sum test. The weight of feces produced since the previous observation point (kg feces per hour), and the number of spheres counted per kg of feces collected (spheres per kg feces) were measured. Gross pain behavior, postural score and socialization score were treated as separate entities and as continuous variables for data analyses (Sellon et al. 2004). All continuous variables (gross pain behavior, postural score, and socialization score, HR, GI sounds, and plasma cortisol concentrations) were assessed for normality. For these variables, the effect of time and treatment on each outcome measure was determined using a mixed effect model with horse as a random effect and time (0, 6, 12, 18, 24, 36, and 48 hours) and treatment (control or epidural) as fixed effects. A time*treatment interaction was included in the model. Time was treated as a categorical variable to allow for a potential non linear effect. Comparisons for differences in outcome at appropriate time points were made using linear contrasts. Statistical analysis was performed using JMP (JMP; SAS Institute, NC, USA) and significance was set at p < 0.05. Results were expressed as median (min, max) and mean SEM for non-parametric and parametric data, respectively. 433
Results Population Eighteen horses were enrolled in the study. They were ten Quarter Horses, four Appaloosas, two Paint Horses, one Thoroughbred and one Warmblood. Median age was 2 (1, 7) years and weight was 450 (341, 582) kg. There were two bilateral and seven unilateral cryptorchid horses in each treatment group. There were no significant differences between groups during anesthesia for HR, MAP, and FE′Iso, or for MAC-hours, anesthesia time, surgery time, or anesthesia recovery scores (Table 2). Anesthesia recovery scores were not significantly different between the two observers (p = 0.92). Supplemental post-operative analgesia was not administered to any of the horses. Gross pain behavior score increased above baseline at 6 and 12 hours in the control group and at 12 hours in the morphine group (Fig. 1a). This score was significantly higher in the control group than in the morphine group at 6 hours (p = 0.01, linear contrast). Postural score at 6 hours was
Table 2 Median (range) for heart rate (HR), mean arterial blood pressure (MAP), end-tidal isoflurane concentration (FE′Iso), MAC-hours, anesthesia and surgery times, and recovery score measured in horses administered epidural morphine (0.1 mg kg 1, n = 9) or no epidural (controls, n = 9) during anesthesia for laparoscopic cryptorchidectomy. Values for HR, MAP and FE′Iso were collected before anesthesia and at 6, 12, 18, 24, 36 and 48 hours after induction of general anesthesia. Possible recovery scores are 11 (best) to 100 (worst)
Treatment Variable HR (beats minute 1) MAP (mmHg) FE′Iso (%) MAC-Hours Anesthesia time (minutes) Surgery time (minutes) Recovery score
Control 38 (34–45) 83 1.6 1.12 90
(79–92) (1.2–1.7) (0.70–1.80) (70–120)
Epidural 40 (33–50) 86 1.2 0.79 83
(85–88) (1.0–1.3) (0.77–0.80) (75–90)
p-value 0.18 0.73 0.27 0.16 0.74
50 (35–75)
43 (40–45)
0.68
30 (20–44)
30 (18–61)
0.75
© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 430–437
Epidural morphine in horses M Martin-Flores et al. (a)
(b)
occurring at 6 hours. At 18 hours, HR was 14% lower in the control group than in the morphine group (p = 0.02, linear contrast) but there were no significant differences between groups at any other time (Fig. 2). There were no differences in the GI scores between the two groups or within group over time (Fig. 3). Median score (range) were 6.0 (0–12) and 6.5 (0–9) for controls and morphine epidural groups, respectively. The number of spheres present in the manure increased over time. More spheres were counted in the manure collected at 36 and 48 hours after surgery than at the other times (both p < 0.05, Tukey’s post hoc). There was no significant difference between groups in the number of spheres collected in each observation period or in the cumulative number of spheres by each observation time (Fig. 4a). There
(c)
Figure 2 Post-operative heart rates in horses administered epidural morphine (0.1 mg kg 1, n = 9) or no epidural morphine (controls, n = 9) during anesthesia for laparoscopic cryptorchidectomy. Mean SEM. *Significant difference between groups.
Figure 1 Post-operative gross pain behavior score (a), posture score (b), and socialization score (c) in horses administered epidural morphine (0.1 mg kg 1, n = 9) or no epidural morphine (controls, n = 9) during anesthesia for laparoscopic cryptorchidectomy. Mean SEM. *Significant difference between groups. †Significant difference from baseline.
higher than at other times (p < 0.002, linear contrast) but was not significantly different between groups at any time (Fig. 1b). No temporal or treatment effects were observed for the socialization score (Fig. 1c). There was a gradual decrease in HR following surgery in both groups, with the highest HR
Figure 3 Post-operative GI auscultation scores in horses administered epidural morphine (0.1 mg kg 1, n = 9) or no epidural morphine (controls, n = 9) during anesthesia for laparoscopic cryptorchidectomy. Mean SEM.
© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 430–437
434
Epidural morphine in horses M Martin-Flores et al.
SEM, control = 0.43 0.078 kg hour 1 epidural = 0.38 0.078 kg hour 1, p = 0.65) (Fig. 4c). The interaction term (time*treatment) was not significant (p = 0.66). There were no significant differences in plasma cortisol concentration at any time (p = 0.07) or between groups (adjusted mean SEM, control = 142.64 13.52 nmol L 1, epidural = 155.33 13.52 nmol L 1, p = 0.51).
(a)
Discussion (b)
(c)
Figure 4 Post-operative percentage of spheres recovered in the manure (a), number of spheres per kg of feces over time (b), and weight of feces per hour over time (c) in horses administered epidural morphine (0.1 mg kg 1), n = 9) or no epidural morphine (controls, n = 9) during anesthesia for laparoscopic cryptorchidectomy. Mean SEM.
were no significant differences in spheres kg feces 1 hour 1 between groups (adjusted mean SEM, control = 20.4 6.4 spheres kg 1 hour 1, epidural = 12.4 5.5 spheres kg 1 hour 1,p = 0.36) (Fig. 4b). The interaction term (time*treatment) was not significant (p = 0.34). There were no significant differences in weight of feces per hour between groups (adjusted mean 435
Horses in the control group showed an increase in pain behavior score at 6 hours after surgery, which was not evident in the epidural group. There was no difference between groups from 12 to 48 hours. This result suggests that epidural morphine provided analgesia of short duration, and that post-operative pain from this surgical procedure decreased substantially during the observation period. The measures used in this study to monitor GI motility did not detect significant differences between the epidural and control groups. Furthermore, no signs of colic were observed in any of the horses receiving the epidural treatment. The results of this study differ from those reported previously by Sano et al. (2011) in which epidural morphine caused a temporary, but significant, decrease in GI motility. Important differences between the two studies are that in Sano et al. (2011) the epidural morphine dose rate was twice that administered in this study, the horses were not anesthetized, and they were not subjected to painful stimuli. In this study, HR and cortisol concentrations were similar between groups, suggesting a lack of difference in post-operative stress response or pain between treatment and control horses. Cortisol concentrations were lower in horses treated with systemic opioids after abdominal surgery when compared with a control group as previously described (Sellon et al. 2004). Whether a difference could be found when the stressful stimulus is of a greater magnitude, such as a laparotomy, needs further investigation. The maximum total number of radio-opaque plastic spheres collected in the manure was 67%. This rate of recovery at 48 hours following surgery is consistent with other work using radio-opaque plastic spheres as a surrogate for GI activity (Lippold et al. 2004). These clinical patients were discharged from the hospital at 48 hours precluding subsequent
© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 430–437
Epidural morphine in horses M Martin-Flores et al. evaluation of GI transit time. However, Sano et al. (2011) reported a percentage of recovered spheres that was only a fraction of those administered, even when the observation period extended for a week. The reasons for the lack of full recovery of spheres were not evident. In this study, the spheres were administered with water and mineral oil via nasogastric intubation. Pre-operative administration of mineral oil is standard practice for horses undergoing laparoscopic surgery at this institution. Since the same volume of mineral oil and water (mL kg 1) was administered to all horses, it is unlikely that this practice introduced a bias for comparison between treatments. Epidural morphine was associated with reduced hospitalization time in human patients undergoing GI surgery and provided better analgesia than systemic opioids on each post-operative day (Block et al. 2003). The results of our study suggest that epidural morphine may have a useful role in providing analgesia to equine patients undergoing abdominal surgery. Epidural analgesia has the potential for minimizing morbidity associated with analgesic therapy since we did not encountered any clinically relevant side effects. The previously published NRS was modified for this investigation to better identify individual manifestations of pain that may be overlooked when the score is analyzed as a composite. The horses in this study had minimally invasive surgery and presumably experienced less intense pain compared with the animals evaluated by Pritchett et al. (2003). Appropriate postoperative pain management in horses has been shown to improve outcome in terms of pain relief, costs and hospitalization length, however it did cause delayed transit time, which may have lasted for as long as 24 hours (Sellon et al. 2004). Of importance, no ill effects were observed as a consequence of delayed GI transit. Epidural morphine provided analgesia of short duration in our experiment, but without noticeable effects in GI function and it may provide an alternative for post-operative pain relief in horses following abdominal surgery. Some limitations in the present study need to be addressed. This study evaluated the analgesic effects of epidural morphine in horses subjected to laparoscopic surgery, a minimally invasive surgical intervention. Although our findings show a difference in pain score between the groups studied, this difference was modest and rescue analgesia was not needed in any horses of the control group. Improvement in post-operative analgesia was, in
this model, of little clinical impact. It is possible that results after a more severe painful stimulus may differ. A similar criterion should be used when analyzing the results regarding post-operative HR and cortisol plasma concentrations, where no major differences were found between groups. At 18 hours, the HR was lower in the control group. It is not evident from our data what could have caused such difference between groups. HR was equal between groups at the following observation time. This population of horses was chosen since it is usually comprised of healthy, young adults, whereas horses undergoing laparotomy at our institution usually require surgery for GI disease and have varying health status. GI motility was evaluated with several techniques, such as GI auscultation scores, fecal output, and fraction of spheres recovered, and no statistical differences were found. Although this study did not detect a difference in GI motility between the two groups, this does not mean that a difference was not present. Our samples sizes were relatively small and this limited the power of the study. Nonetheless, these data suggest that if a decrease in GI transit was introduced by morphine epidural administration, it was of no clinical impact in this subpopulation of horses. In conclusion, epidural morphine (0.1 mg kg 1) did not adversely affect GI motility in this group of horses after laparoscopic surgery under general anesthesia. Acknowledgements This study was funded by Cornell University, College of Veterinary Medicine, Dean’s Fund for Clinical Excellence. References Bennett RC, Steffey EP (2002) Use of opioids for pain and anesthetic management in horses. Vet Clin North Am Equine Pract 18, 47–60. Block BM, Liu SS, Rowlingson AJ et al. (2003) Efficacy of postoperative epidural analgesia: a meta-analysis. J Am Med Assoc 290, 2455–2463. Boscan P, Van Hoogmoed LM, Farver TB et al. (2006) Evaluation of the effects of the opioid agonist morphine on gastrointestinal tract function in horses. Am J Vet Res 67, 992–997. Chiari A, Eisenach JC (1998) Spinal anesthesia: mechanisms, agents, methods and safety. Reg Anesth Pain Med 23, 357–362.
© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 430–437
436
Epidural morphine in horses M Martin-Flores et al.
Clark-Price SC, Posner LP, Gleed RD (2008) Recovery of horses from general anesthesia in a darkened or illuminated recovery stall. Vet Anaesth Analg 35, 473– 479. Lippold BS, Hildebrand J, Straub R (2004) Tegaserod (HTF 919) stimulates gut motility in normal horses. Equine Vet J 36, 622–627. Pritchett LC, Ulibarri C, Roberts MC et al. (2003) Identification of potential physiological and behavioral indicators of postoperative pain in horses after exploratory celiotomy for colic. Appl Anim Behav Sci, 80, 31–43. Ragle CA, Southwood LL, Howlett MR (1998) Ventral abdominal approach for laparoscopic cryptorchidectomy in horses. Vet Surg 27, 138–142. Sano H, Martin-Flores M, Santos LC et al. (2011) Effects of epidural morphine on gastrointestinal transit in unmedicated horses. Vet Anaesth Analg 38, 121–126. SSchumacher J (1999) The testis and associated structures. The reproductive system. In: Equine Surgery (2nd edn).
437
Auer JA, Stick JA (eds). WB Saunders, Philadelphia, USA. pp. 515–538. Sellon DC, Roberts MC, Blikslager AT et al. (2004) Effects of continuous rate intravenous infusion of butorphanol on physiologic and outcome variables in horses after celiotomy. J Vet Intern Med 18, 555–563. Senior JM, Pinchbeck GL, Dugdale AH et al. (2004) Retrospective study of the risk factors and prevalence of colic in horses after orthopaedic surgery. Vet Rec 155, 321–325. Steffey EP, Howland D Jr, Giri S et al. (1977) Enflurane, halothane, and isoflurane potency in horses. Am J Vet Res 38, 1037–1039. Van Hoogmoed LM, Galuppo LD (2005) Laparoscopic ovariectomy using the endo-GIA stapling device and endo-catch pouches and evaluation of analgesic efficacy of epidural morphine sulfate in 10 mares. Vet Surg 34, 646–650. Received 5 October 2012; accepted 21 June 2013.
© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 430–437
doi:10.1111/vaa.12133
RESEARCH PAPER
Analgesic and gastrointestinal effects of epidural morphine in horses after laparoscopic cryptorchidectomy under general anesthesia Manuel Martin-Flores*, Luis Campoy*, Marc A Kinsley†, Hussni O Mohammed‡, Robin D Gleed* & Jonathan Cheetham* *Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA †College of Veterinary Medicine, Cornell University, Ithaca, NY, USA ‡Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
Correspondence: J Cheetham, Box 32, Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA. E-mail: [email protected]
Abstract Objective To evaluate the hypothesis that epidural morphine (0.1 mg kg 1) decreases pain in horses after laparoscopic surgery without adversely affecting gastrointestinal (GI) motility. Study design Randomized clinical trial. Animals Eighteen horses undergoing laparoscopic cryptorchidectomy under general anesthesia. Methods Horses were randomly assigned to receive either epidural morphine (0.1 mg kg 1) or no epidural before the start of surgery. Pain behaviors were assessed during the first two post-operative days using a numerical rating scale. Barium-filled spheres were administered through a nasogastric tube before anesthesia. GI motility was assessed by recording manure production, by quantitating the spheres in the manure, and by abdominal auscultation of intestinal sounds. Heart rates and cortisol concentrations were also measured during the post-operative period.
Manuel Martin-Flores and Jonathan Cheetham contributed equality.
Results Pain scores increased for 12 hours after surgery in the control group and were significantly higher than in the morphine group for the first 6 hours. Pain scores remained unaltered in the morphine group throughout the observation period. Heart rate and plasma cortisol concentrations did not differ between groups or with time. No signs of colic were observed in any horse. Conclusion and clinical relevance Epidural morphine (0.1 mg kg 1) did not adversely affect GI motility in horses after laparoscopic surgery under general anesthesia. Keywords analgesia, anesthesia, epidural, equine, gastrointestinal, morphine.
Introduction Systemic administration of opioids to horses has been associated with reduced gastrointestinal (GI) motility (Senior et al. 2004; Boscan et al. 2006). Consequently, many clinicians are reluctant to prescribe opioids perioperatively to avoid exacerbation of ileus. Opioids, including morphine, can be administered into the epidural space from which they diffuse readily to interact with opioid receptors in the dorsal horn of the spinal cord (Chiari & 430
Epidural morphine in horses M Martin-Flores et al.
Eisenach 1998). The dose rate of morphine needed to produce a given level of analgesia may be less when injected epidurally compared to other parenteral routes. Reducing the dose rate may result in a lower prevalence and severity of systemic side effects, such as decreased GI motility, associated with activity of the drug at receptors outside the spinal cord (Bennett & Steffey 2002). Epidural morphine (0.1 mg kg 1) provided analgesia for horses undergoing standing laparoscopic ovariectomy (Van Hoogmoed & Galuppo 2005). A higher dose rate of epidural morphine (0.2 mg kg 1) administered to healthy, unmedicated horses increased mean GI transit time by approximately 5 hours without detectable decreases in GI sounds or signs of colic (Sano et al. 2011). Gastrointestinal function is influenced in clinical patients by a variety of factors, including surgical stimulation, pre-anesthetic fasting, and co-administered drugs. The analgesic and GI effects of epidural morphine have not been systematically evaluated in clinical equine patients subjected to abdominal surgery under general anesthesia. The hypothesis of this study was that administration of epidural morphine (0.1 mg kg 1) to anesthetized horses before the start of laparoscopic surgery for correction of cryptorchidism would 1) reduce post-operative pain and 2) not decrease GI motility during the first 2 post-operative days. Materials and methods All horses undergoing laparoscopic cryptorchidectomy at the Equine Hospital of Cornell University between April 2005 and September 2008 were eligible for inclusion in the study. This project was approved by the Institutional Animal Care and Use Committee, and informed client consent was obtained from the owners of all animals enrolled. All horses were considered healthy based on a physical examination. Except during surgery and anesthesia, the horses were housed in conventional loose boxes bedded with shavings. Each horse was hospitalized for a total of 4 days and provided with water ad libitum. Food was withheld overnight prior to induction of anesthesia. The evening before surgery, 200 barium-filled plastic spheres (LDPE Barium Filled Ball; Precision Plastic Ball Company, IL, USA) were administered with water and mineral oil (1:1 v/v; 9 mL kg 1) by nasogastric tube. These spheres served as markers of GI transit (Lippold et al. 2004) and their presence in the manure was verified radiographically. 431
Anesthesia and surgical procedures On the morning of surgery, a 14-gauge catheter was placed in the left jugular vein, and each horse received potassium penicillin (22,000 IU kg 1) intravenously (IV) pre- and 6 hours post-operatively and phenylbutazone (4 mg kg 1) IV pre-operatively and 2 mg kg 1 IV every 12 hours post-operatively. Horses were sedated with xylazine (0.7 mg kg 1; AnaSed; Lloyd Inc., IA, USA) IV and anesthesia was induced with midazolam (0.1 mg kg 1; Midazolam hydrochloride; Hospira Inc., IL, USA) and ketamine (2.2 mg kg 1; Ketaset; Fort Dodge Animal Health, IA, USA) IV. After orotracheal intubation, anesthesia was maintained with isoflurane in oxygen. Monitoring consisted of an electrocardiogram (ECG), heart rate (HR), pulse oximetry, invasive arterial blood pressure and end-tidal carbon dioxide pressure (PE′CO2) and isoflurane concentration (FE′Iso). Ventilation was controlled to maintain partial pressure of arterial carbon dioxide (PaCO2) between 38 and 42 mmHg. A balanced electrolyte solution (Plasma-lyte A, Baxter Healthcare Corporation, IL, USA) was administered IV throughout anesthesia at approximately 5 mL kg 1 hour 1. Dobutamine was infused as necessary to maintain mean arterial pressure (MAP) above 70 mmHg. The absence of at least one scrotal testicle was confirmed immediately after induction of anesthesia with the animals in lateral recumbency. Then each horse was assigned randomly to one of two treatment groups by removing labels from an opaque envelope: epidural morphine (0.1 mg kg 1) or no epidural (control). Unilateral and bilateral cryptorchid horses were assigned a treatment by separate block randomization. The puncture site (sacro-coccygeal area) of all horses was clipped, regardless of treatment group. An 18-gauge 8.75 cm (3.5 inch) Tuohy needle (Perifix Tuohy epidural needle; B Braun Medical Inc., PA, USA) was inserted perpendicular to the skin and correct placement was verified by the loss-of-resistance to air technique. All horses assigned to receive epidural morphine were injected with preservative-free morphine (0.1 mg kg 1; Preservative free morphine, 1% compounded by the Pharmacy of Cornell University Hospital for Animals and diluted with sterile saline to a final volume of 0.04 mL kg 1). Insertion of the epidural needle was performed by one investigator before the horses were positioned in dorsal recumbency. In all cases, epidural administration of morphine was completed at least 35 minutes before
© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 430–437
Epidural morphine in horses M Martin-Flores et al. the start of surgery. No puncture was performed in the control group. The attending anesthetist and all other personnel involved in the study were blinded to the treatment allocated to each horse. A standard technique was used to remove the abdominal testes laparoscopically (Ragle et al.1998). Horses that were unilateral cryptorchid had the remaining scrotal testis removed by a standard technique (closed castration with primary skin closure) as described by Schumacher (1999). After surgery, the horses were moved to a padded recovery stall and extubated once ventilation became spontaneous, at which time they received xylazine (0.25 mg kg 1) IV. The horses recovered from anesthesia unassisted. Recovery was recorded on VHS tape from extubation to the time at which the horse was led out of the recovery stall. All horses were fed 1.8 kg hay every 4 hours and observed at 2 hour intervals until the first feces were passed, when the time was recorded. Observations and data collection A set of observations was made at 0 hours (before anesthesia) and 6, 12, 18, 24, 36 and 48 hours after induction of general anesthesia. Horses were discharged from the hospital after the 48 hour observation time. At each observation time, a modified numerical rating score (NRS) was used to assess post-operative pain (Pritchett et al. 2003; Table 1).
The NRS was a composite of three categories, gross pain behavior (e.g. pawing, sweating), a postural score (e.g. head and ear positions) and a socialization score (e.g. response to opening the door and offering food). Higher scores indicated greater pain. On each occasion the horse was observed for 2 minutes by two observers before they entered the stall. The only modifications from the scale originally described by Pritchett et al. (2003) were that the response to lifting feet was not evaluated in our study, and that each category (gross pain behavior, postural and socialization scores) was analyzed independently, rather than as a composite score. After observations for the NRS were completed, HR was obtained by auscultation. At the same observation times, the number of fecal piles in the stall was counted, then all of the manure in the stall was collected and stored in an impermeable labeled sack, weighed and then radiographed to determine the number of radiopaque spheres in each fecal sample (Sano et al. 2011). Auscultation of the four abdominal quadrants each for 1 minute provided a score for GI motility. Each quadrant was scored on a 0–3 scale, where 0, 1, 2, and 3 represented 0, 1, 2, and ≥3 sounds per minute, respectively. The scores from each quadrant were added to give a cumulative score for analysis. Jugular venous blood was collected by percutaneous puncture at each observation time, centrifuged for 10 minutes at 5500 g, and the plasma frozen at
Table 1 Numerical rating scale used to score post-operative pain in horses after laparoscopic cryptorchidectomy (modified from Pritchett et al. 2003)
Score Category
1
Gross pain signs* Head position† Ear position† Location in stall†
None Above withers Forward, frequent movement At door watching environment
Spontaneous locomotion† Response to open door‡ Response to approach‡
Moves freely Moves to door Moves to observer, ears forward Moves to door and reaches for grain
Response to grain‡
2
Standing in middle facing door Occasional steps Looks at door Looks at observer, ears forward Looks at door
3
4
Occasional At withers Slightly back, little movement Standing in middle facing sides
Continuous Below withers
Moves away from observer
Standing in middle facing back No movement No response Does not move, ears back No response
*Gross pain behaviors (pawing, sweating, looking at the flank, flehmen, and lying down/standing up repeatedly). †Posture category. ‡Socialization category. © 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 430–437
432
Epidural morphine in horses M Martin-Flores et al.
80 °C. Cortisol concentrations were measured using a solid phase chemiluminescent immunoassay [Immunolite; Diagnostic Products Corporation (DCP), CA, USA]. In accordance with hospital practice, and at the discretion of the primary clinician who was unaware of which experimental treatment each horse had received, supplemental post-operative analgesia was available if a patient demonstrated signs of moderate to severe abdominal pain. At that point, the horse would be removed from the project and no further data collected. Analyses A median value for HR, MAP, and FE′Iso during anesthesia was calculated for each horse. MAChours were calculated for each animal, assuming a minimal alveolar concentration (MAC) for isoflurane of 1.31% (Steffey et al. 1977). Recovery from anesthesia was scored from the VHS recordings by two observers who were unaware of treatment allocation, using a composite scale published previously (Clark-Price et al. 2008). Variables related directly to anesthesia were compared between the two groups using the Wilcoxon rank-sum test. The weight of feces produced since the previous observation point (kg feces per hour), and the number of spheres counted per kg of feces collected (spheres per kg feces) were measured. Gross pain behavior, postural score and socialization score were treated as separate entities and as continuous variables for data analyses (Sellon et al. 2004). All continuous variables (gross pain behavior, postural score, and socialization score, HR, GI sounds, and plasma cortisol concentrations) were assessed for normality. For these variables, the effect of time and treatment on each outcome measure was determined using a mixed effect model with horse as a random effect and time (0, 6, 12, 18, 24, 36, and 48 hours) and treatment (control or epidural) as fixed effects. A time*treatment interaction was included in the model. Time was treated as a categorical variable to allow for a potential non linear effect. Comparisons for differences in outcome at appropriate time points were made using linear contrasts. Statistical analysis was performed using JMP (JMP; SAS Institute, NC, USA) and significance was set at p < 0.05. Results were expressed as median (min, max) and mean SEM for non-parametric and parametric data, respectively. 433
Results Population Eighteen horses were enrolled in the study. They were ten Quarter Horses, four Appaloosas, two Paint Horses, one Thoroughbred and one Warmblood. Median age was 2 (1, 7) years and weight was 450 (341, 582) kg. There were two bilateral and seven unilateral cryptorchid horses in each treatment group. There were no significant differences between groups during anesthesia for HR, MAP, and FE′Iso, or for MAC-hours, anesthesia time, surgery time, or anesthesia recovery scores (Table 2). Anesthesia recovery scores were not significantly different between the two observers (p = 0.92). Supplemental post-operative analgesia was not administered to any of the horses. Gross pain behavior score increased above baseline at 6 and 12 hours in the control group and at 12 hours in the morphine group (Fig. 1a). This score was significantly higher in the control group than in the morphine group at 6 hours (p = 0.01, linear contrast). Postural score at 6 hours was
Table 2 Median (range) for heart rate (HR), mean arterial blood pressure (MAP), end-tidal isoflurane concentration (FE′Iso), MAC-hours, anesthesia and surgery times, and recovery score measured in horses administered epidural morphine (0.1 mg kg 1, n = 9) or no epidural (controls, n = 9) during anesthesia for laparoscopic cryptorchidectomy. Values for HR, MAP and FE′Iso were collected before anesthesia and at 6, 12, 18, 24, 36 and 48 hours after induction of general anesthesia. Possible recovery scores are 11 (best) to 100 (worst)
Treatment Variable HR (beats minute 1) MAP (mmHg) FE′Iso (%) MAC-Hours Anesthesia time (minutes) Surgery time (minutes) Recovery score
Control 38 (34–45) 83 1.6 1.12 90
(79–92) (1.2–1.7) (0.70–1.80) (70–120)
Epidural 40 (33–50) 86 1.2 0.79 83
(85–88) (1.0–1.3) (0.77–0.80) (75–90)
p-value 0.18 0.73 0.27 0.16 0.74
50 (35–75)
43 (40–45)
0.68
30 (20–44)
30 (18–61)
0.75
© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 430–437
Epidural morphine in horses M Martin-Flores et al. (a)
(b)
occurring at 6 hours. At 18 hours, HR was 14% lower in the control group than in the morphine group (p = 0.02, linear contrast) but there were no significant differences between groups at any other time (Fig. 2). There were no differences in the GI scores between the two groups or within group over time (Fig. 3). Median score (range) were 6.0 (0–12) and 6.5 (0–9) for controls and morphine epidural groups, respectively. The number of spheres present in the manure increased over time. More spheres were counted in the manure collected at 36 and 48 hours after surgery than at the other times (both p < 0.05, Tukey’s post hoc). There was no significant difference between groups in the number of spheres collected in each observation period or in the cumulative number of spheres by each observation time (Fig. 4a). There
(c)
Figure 2 Post-operative heart rates in horses administered epidural morphine (0.1 mg kg 1, n = 9) or no epidural morphine (controls, n = 9) during anesthesia for laparoscopic cryptorchidectomy. Mean SEM. *Significant difference between groups.
Figure 1 Post-operative gross pain behavior score (a), posture score (b), and socialization score (c) in horses administered epidural morphine (0.1 mg kg 1, n = 9) or no epidural morphine (controls, n = 9) during anesthesia for laparoscopic cryptorchidectomy. Mean SEM. *Significant difference between groups. †Significant difference from baseline.
higher than at other times (p < 0.002, linear contrast) but was not significantly different between groups at any time (Fig. 1b). No temporal or treatment effects were observed for the socialization score (Fig. 1c). There was a gradual decrease in HR following surgery in both groups, with the highest HR
Figure 3 Post-operative GI auscultation scores in horses administered epidural morphine (0.1 mg kg 1, n = 9) or no epidural morphine (controls, n = 9) during anesthesia for laparoscopic cryptorchidectomy. Mean SEM.
© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 430–437
434
Epidural morphine in horses M Martin-Flores et al.
SEM, control = 0.43 0.078 kg hour 1 epidural = 0.38 0.078 kg hour 1, p = 0.65) (Fig. 4c). The interaction term (time*treatment) was not significant (p = 0.66). There were no significant differences in plasma cortisol concentration at any time (p = 0.07) or between groups (adjusted mean SEM, control = 142.64 13.52 nmol L 1, epidural = 155.33 13.52 nmol L 1, p = 0.51).
(a)
Discussion (b)
(c)
Figure 4 Post-operative percentage of spheres recovered in the manure (a), number of spheres per kg of feces over time (b), and weight of feces per hour over time (c) in horses administered epidural morphine (0.1 mg kg 1), n = 9) or no epidural morphine (controls, n = 9) during anesthesia for laparoscopic cryptorchidectomy. Mean SEM.
were no significant differences in spheres kg feces 1 hour 1 between groups (adjusted mean SEM, control = 20.4 6.4 spheres kg 1 hour 1, epidural = 12.4 5.5 spheres kg 1 hour 1,p = 0.36) (Fig. 4b). The interaction term (time*treatment) was not significant (p = 0.34). There were no significant differences in weight of feces per hour between groups (adjusted mean 435
Horses in the control group showed an increase in pain behavior score at 6 hours after surgery, which was not evident in the epidural group. There was no difference between groups from 12 to 48 hours. This result suggests that epidural morphine provided analgesia of short duration, and that post-operative pain from this surgical procedure decreased substantially during the observation period. The measures used in this study to monitor GI motility did not detect significant differences between the epidural and control groups. Furthermore, no signs of colic were observed in any of the horses receiving the epidural treatment. The results of this study differ from those reported previously by Sano et al. (2011) in which epidural morphine caused a temporary, but significant, decrease in GI motility. Important differences between the two studies are that in Sano et al. (2011) the epidural morphine dose rate was twice that administered in this study, the horses were not anesthetized, and they were not subjected to painful stimuli. In this study, HR and cortisol concentrations were similar between groups, suggesting a lack of difference in post-operative stress response or pain between treatment and control horses. Cortisol concentrations were lower in horses treated with systemic opioids after abdominal surgery when compared with a control group as previously described (Sellon et al. 2004). Whether a difference could be found when the stressful stimulus is of a greater magnitude, such as a laparotomy, needs further investigation. The maximum total number of radio-opaque plastic spheres collected in the manure was 67%. This rate of recovery at 48 hours following surgery is consistent with other work using radio-opaque plastic spheres as a surrogate for GI activity (Lippold et al. 2004). These clinical patients were discharged from the hospital at 48 hours precluding subsequent
© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 430–437
Epidural morphine in horses M Martin-Flores et al. evaluation of GI transit time. However, Sano et al. (2011) reported a percentage of recovered spheres that was only a fraction of those administered, even when the observation period extended for a week. The reasons for the lack of full recovery of spheres were not evident. In this study, the spheres were administered with water and mineral oil via nasogastric intubation. Pre-operative administration of mineral oil is standard practice for horses undergoing laparoscopic surgery at this institution. Since the same volume of mineral oil and water (mL kg 1) was administered to all horses, it is unlikely that this practice introduced a bias for comparison between treatments. Epidural morphine was associated with reduced hospitalization time in human patients undergoing GI surgery and provided better analgesia than systemic opioids on each post-operative day (Block et al. 2003). The results of our study suggest that epidural morphine may have a useful role in providing analgesia to equine patients undergoing abdominal surgery. Epidural analgesia has the potential for minimizing morbidity associated with analgesic therapy since we did not encountered any clinically relevant side effects. The previously published NRS was modified for this investigation to better identify individual manifestations of pain that may be overlooked when the score is analyzed as a composite. The horses in this study had minimally invasive surgery and presumably experienced less intense pain compared with the animals evaluated by Pritchett et al. (2003). Appropriate postoperative pain management in horses has been shown to improve outcome in terms of pain relief, costs and hospitalization length, however it did cause delayed transit time, which may have lasted for as long as 24 hours (Sellon et al. 2004). Of importance, no ill effects were observed as a consequence of delayed GI transit. Epidural morphine provided analgesia of short duration in our experiment, but without noticeable effects in GI function and it may provide an alternative for post-operative pain relief in horses following abdominal surgery. Some limitations in the present study need to be addressed. This study evaluated the analgesic effects of epidural morphine in horses subjected to laparoscopic surgery, a minimally invasive surgical intervention. Although our findings show a difference in pain score between the groups studied, this difference was modest and rescue analgesia was not needed in any horses of the control group. Improvement in post-operative analgesia was, in
this model, of little clinical impact. It is possible that results after a more severe painful stimulus may differ. A similar criterion should be used when analyzing the results regarding post-operative HR and cortisol plasma concentrations, where no major differences were found between groups. At 18 hours, the HR was lower in the control group. It is not evident from our data what could have caused such difference between groups. HR was equal between groups at the following observation time. This population of horses was chosen since it is usually comprised of healthy, young adults, whereas horses undergoing laparotomy at our institution usually require surgery for GI disease and have varying health status. GI motility was evaluated with several techniques, such as GI auscultation scores, fecal output, and fraction of spheres recovered, and no statistical differences were found. Although this study did not detect a difference in GI motility between the two groups, this does not mean that a difference was not present. Our samples sizes were relatively small and this limited the power of the study. Nonetheless, these data suggest that if a decrease in GI transit was introduced by morphine epidural administration, it was of no clinical impact in this subpopulation of horses. In conclusion, epidural morphine (0.1 mg kg 1) did not adversely affect GI motility in this group of horses after laparoscopic surgery under general anesthesia. Acknowledgements This study was funded by Cornell University, College of Veterinary Medicine, Dean’s Fund for Clinical Excellence. References Bennett RC, Steffey EP (2002) Use of opioids for pain and anesthetic management in horses. Vet Clin North Am Equine Pract 18, 47–60. Block BM, Liu SS, Rowlingson AJ et al. (2003) Efficacy of postoperative epidural analgesia: a meta-analysis. J Am Med Assoc 290, 2455–2463. Boscan P, Van Hoogmoed LM, Farver TB et al. (2006) Evaluation of the effects of the opioid agonist morphine on gastrointestinal tract function in horses. Am J Vet Res 67, 992–997. Chiari A, Eisenach JC (1998) Spinal anesthesia: mechanisms, agents, methods and safety. Reg Anesth Pain Med 23, 357–362.
© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 430–437
436
Epidural morphine in horses M Martin-Flores et al.
Clark-Price SC, Posner LP, Gleed RD (2008) Recovery of horses from general anesthesia in a darkened or illuminated recovery stall. Vet Anaesth Analg 35, 473– 479. Lippold BS, Hildebrand J, Straub R (2004) Tegaserod (HTF 919) stimulates gut motility in normal horses. Equine Vet J 36, 622–627. Pritchett LC, Ulibarri C, Roberts MC et al. (2003) Identification of potential physiological and behavioral indicators of postoperative pain in horses after exploratory celiotomy for colic. Appl Anim Behav Sci, 80, 31–43. Ragle CA, Southwood LL, Howlett MR (1998) Ventral abdominal approach for laparoscopic cryptorchidectomy in horses. Vet Surg 27, 138–142. Sano H, Martin-Flores M, Santos LC et al. (2011) Effects of epidural morphine on gastrointestinal transit in unmedicated horses. Vet Anaesth Analg 38, 121–126. SSchumacher J (1999) The testis and associated structures. The reproductive system. In: Equine Surgery (2nd edn).
437
Auer JA, Stick JA (eds). WB Saunders, Philadelphia, USA. pp. 515–538. Sellon DC, Roberts MC, Blikslager AT et al. (2004) Effects of continuous rate intravenous infusion of butorphanol on physiologic and outcome variables in horses after celiotomy. J Vet Intern Med 18, 555–563. Senior JM, Pinchbeck GL, Dugdale AH et al. (2004) Retrospective study of the risk factors and prevalence of colic in horses after orthopaedic surgery. Vet Rec 155, 321–325. Steffey EP, Howland D Jr, Giri S et al. (1977) Enflurane, halothane, and isoflurane potency in horses. Am J Vet Res 38, 1037–1039. Van Hoogmoed LM, Galuppo LD (2005) Laparoscopic ovariectomy using the endo-GIA stapling device and endo-catch pouches and evaluation of analgesic efficacy of epidural morphine sulfate in 10 mares. Vet Surg 34, 646–650. Received 5 October 2012; accepted 21 June 2013.
© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 430–437
