Paper
Paper Fentanyl and methadone used as adjuncts to bupivacaine for lumbosacral epidural analgesia in sheep R. DeRossi, R. C. Pagliosa, A. Q. de Carvalho, G. G. Macedo, L. C. Hermeto Six healthy, female, mixed-breed 18–24-month-old sheep weighing 30–48 kg were submitted to lumbosacral epidural bupivacaine in combination with either methadone or fentanyl. Epidural catheters were placed in six sheep that were given three treatments: (Bup) bupivacaine (0.5 mg/kg) alone; (BupMet) bupivacaine (0.25 mg/kg) plus methadone (0.3 mg/kg); and (BupFent) bupivacaine (0.25 mg/kg) plus fentanyl (0.002 mg/kg). Haemodynamic variables, respiratory rate, rectal temperature, analgesia by applying a standard painful stimulus, motor block and sedative scores were compared among the three treatments. These parameters were determined before epidural administration and at 5, 10, 20, 30, 60, 90, 120 minutes after treatment administration, and then every 60 minutes thereafter until the end of analgesic effect. Parametrical data were analysed by proc glimmix (SAS) for repeated measures on time and means tested by ls-means. Non-parametrical data were analysed by Fisher’s exact test. Duration of analgesia was longer with BupMet (240 minutes) compared with BupFent (180 minutes; P=0.0127), but BupMet was similar to Bup (240 minutes). Both treatments with opioids produced moderate motor blockade. BupMet and BupFent produced mild sedation. Only treatment with bupivacaine alone induced cardiovascular and respiratory rate changes that stayed within acceptable limits. Introduction Lumbosacral epidural analgesia has been extensively used to provide pain relief in flank, perineal and pelvic limb surgeries in sheep (Skarda and Tranquilli 2007). Bupivacaine is a long-acting local anaesthetic agent that has been widely used for epidural blockade in human beings (Sinatra and others 2002). High concentrations of drugs administered epidurally can cause neurotoxicity by decreasing neuronal blood flow (Malinovsky and Pinaud 1996). Despite the fact that a low concentration of bupivacaine (0.25 per cent) shortens the duration of anaesthesia over a higher concentration, the safety of epidural injections will be increased (Dahl and others 1992). Several combinations of drugs have been used for epidural administration with the aim of reducing the dose of the local anaesthetic agent and increasing the duration of analgesia in Veterinary Record (2016) R. DeRossi, DVM, PhD, R. C. Pagliosa, DVM, MSc, A. Q. de Carvalho, DVM, MSc, Department of Veterinary Medicine– Surgery and Anesthesiology, Faculty of Veterinary Medicine and Animal Science, Federal University of Mato Grosso do Sul, Campo Grande, Mato Grosso do Sul, Brazil G. G. Macedo, DVM, PhD, Department of Animal Reproduction, Faculty of Veterinary Medicine, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil
doi: 10.1136/vr.103860 L. C. Hermeto, DVM, PhD, Postdoctoral Postgraduate Program on Veterinary Sciences, Faculty of Veterinary Medicine and Animal Science, Federal University of Mato Grosso do Sul (UFMS), Campo Grande, Brazil E-mail for correspondence: [email protected] Provenance: not commissioned; externally peer reviewed Accepted October 5, 2016
small ruminants (Aithal and others1996, DeRossi and others 2005, Habibian and others 2011, DeRossi and others 2012a). An epidural opioid acting through the spinal cord receptors improves the quality and duration of analgesia (Niemi and Breivik 2001). Fentanyl is a highly lipid-soluble phenyl piperidine derivative with strong m-receptor agonist activity, rapid onset and short duration of action (Moore and others 1982). Nevertheless, high lipid solubility increases systemic absorption and reduces bioavailability in the dorsal horn of the spinal cord, which results in a short duration of epidural analgesia (Bernards 2004). Studies in both human beings and animal models have demonstrated that pharmacological interaction between intrathecal fentanyl and bupivacaine is synergistic (Saito and others 1998, Ngan Kee and others 2014). Methadone is primarily a m-agonist of opioid receptors with pharmacological properties qualitatively similar to those of morphine (Jaffe and others 1993). Methadone is an intermediately lipophilic opioid that readily transfers from the epidural space into the spinal cord, but it is also taken up systemically via the epidural and spinal blood supply (Tung and Yaksh 1982, He and others 2010). Previous studies have compared the use of methadone and fentanyl alone or in combination with a local anaesthetic for epidural analgesia in human beings (Nyska and others 1986), horses (Olbrich and Mosing 2003, Ganidagli and others 2004) and dogs (Bosmans and others 2012, Diniz and others 2013). None of the studies has compared fentanyl and methadone as adjuncts to bupivacaine for lumbosacral epidural anaesthesia/analgesia in sheep. The present study was undertaken to compare the analgesic effect and efficacy of epidural methadone versus epidural fentanyl in combination with bupivacaine for lumbosacral epidural analgesia in sheep and to test the hypothesis that epidural methadone or fentanyl combined with bupivacaine would January 28, 2017 | Veterinary Record
Paper provide a more intense and long-lasting analgesia than bupivacaine alone.
Materials and methods Animals This experiment was approved by the Ethics Committee of Federal University of Mato Grosso do Sul and all applicable institutional guidelines for the care and use of animals were followed. Six healthy, female, mixed-breed sheep weighing between 30 kg and 48 kg (36±5 kg; mean±sd) and aged 18–24 months were used in this study. All animals were maintained at the Faculty of Veterinary Medicine and Animal Science facilities throughout the experiment. Food and water were withdrawn on the morning of the experiments. In a pilot study, epidural methadone or fentanyl alone was administered epidurally in three sheep (not included in the study) weekly to establish a clinically relevant dose to be used in the present study, based on previous studies in human beings and animals.
Experimental preparation An18 G epidural catheter (Smiths Medical ASD) was inserted percutaneously at the lumbosacral junction into the epidural space in all animals one week before the experiments were initiated. Catheter placement was performed with the sheep sedated with xylazine (Bayer SA) (0.2 mg/kg, intramuscular) and subcutaneous infiltration with 2 per cent lidocaine (2 ml) at the needle entry point. All sheep were maintained in sternal recumbency with the pelvic limbs positioned cranially during localisation of the lumbosacral space. The area was clipped then aseptically prepared with iodine. An 18 G, 7.6 cm Tuohy needle (Braun Laboratory) was inserted into the lumbosacral space. Correct positioning of the epidural needle was confirmed by the hanging-drop technique and by noting no resistance during catheter insertion. The catheter was advanced cranially 8–10 cm into the epidural space, based on the marks of the catheter excluding the length of the Tuohy needle inserted to reach the epidural space, and also by externally measuring the distance from the lumbosacral junction to the midlumbar level (L4–L5). The catheter was cut (total length, 10 cm) and connected to a valve without a filter. Proper insertion of the catheter was ensured by injecting 3 ml of 1 per cent lidocaine to induce bilateral analgesia. The catheter was fixed on the skin with cyanoacrylate glue and wrapped in gauze. At the end of each experiment, the catheters were filled with saline. At the end of the experiments, the catheters were removed and examined for evidence of kinking or looping and were tested for bacterial contamination using culture on blood agar.
Procedures All six sheep were randomly assigned to receive one of the three treatments: 0.25 per cent bupivacaine (Cristália Chemical and Pharmaceutical Products) (0.5 mg/kg, treatment Bup); 0.25 per cent bupivacaine (0.25 mg/kg) with methadone (Cristália Chemical and Pharmaceutical Products) (0.3 mg/kg, 10 mg/ml; treatment BupMet); and 0.25 per cent bupivacaine (0.25 mg/kg) with fentanyl (Cristália Chemical and Pharmaceutical Products) (0.002 mg/kg, 0.05 mg/ml, treatment BupFent). Total volumes injected for all animals were mean±sd) 7.2±1.6 ml in BUP, 4.8 ±0.8 ml in BupMet, and 5.0±0.4 ml in BupFent. All treatments were injected into the lumbosacral space over 30 seconds. The washout period between treatments was seven days. All involved anaesthesia personnel, including those individuals recording analgesia scores were unaware of the treatment administered. As the authors used a subjective scale for assessing analgesia, measures were always performed by the same person to reduce a variation between the researchers.
Analgesia assessment All experiments were performed in conscious animals without sedation. Animal behaviour, physiological variables, and analgesia and motor block determinations were recorded before Veterinary Record | January 28, 2017
treatment administration as the mean of three readings taken at 5 minute intervals (baseline) and at 5, 10, 20, 30, 60, 90 and 120 minutes after treatment administration, and then every 60 minutes thereafter until the end of sensory block. Physiological variables measured were heart rate (HR), noninvasive systolic arterial pressure (SAP), diastolic arterial pressure (DAP), mean arterial pressure (MAP), respiratory rate (RR) and rectal temperature (RT). Arterial blood pressure was measured using a non-invasive oscillometric device with the cuff (width, 8.5–9.0 cm) (Dixtal Biomédica Ind e Com) attached to the proximal third of the radius with the sheep in left lateral recumbency. The other variables were measured with the sheep standing or in sternal recumbency: HR was by auscultation and RR by counting the number of chest movements counted over one minute. RTwas measured with a digital thermometer. Analgesic and sedative effects and motor blockade were assigned scores (see online supplementary appendix 1). The time to the onset and duration of the analgesic, sedative and motor effects, as well as, the anatomical distribution of the analgesia were recorded. Time to onset of analgesia was considered the time from drug administration to the appearance (score 3) of analgesia. Sensory blockade was evaluated bilaterally using a 23 G hypodermic needle inserted into the skin (superficial prick) and muscle (deep prick, approximately 1 cm) in successive dermatomes starting at the tail and proceeding cranially to the lumbar region. Dermatomes tested were lumbar L5-S2 ( perineum and feet), L2-L5 (lateral aspects of upper pelvic limbs) and thoracic T12-L2 (dorsocaudal aspects of the ribs and thoracolumbar region). Analgesia was considered satisfactory (score 4) when the sheep did not respond to needle pricks in all the surveyed regions. Changes in behaviour were evaluated to assess the central effects produced by drug absorption from the epidural space. The sheep were evaluated for motor blockade or the presence of ataxia when stimulated to walk.
Statistical analysis Statistical analysis was performed by use of a commercial software program (SAS Institute). Continuous variables were assessed for normality of residuals by the UNIVARIATE procedure and submitted to the Bartlett test to analyse the homogeneity of variances. Only data from RR were not normally distributed and thus were transformed to inverse square root. Data were grouped and summarised as mean±se of the mean and median and IQR for non-parametrical tested parameters. Data for HR, SAP, DAP, MAP, RR and RT were analysed by Proc GLIMMIX for repeated measures, with treatment and time as independent variables. When a significant difference or interaction was obtained, least-squares means test or planned comparison was performed as appropriate. For analgesia, sedation and motor blockade variables, the non-parametrical Friedman’s test was used, followed by multiple comparisons for ranked data using Dunnett’s test, with time 0 as the baseline. In each analysis, differences were considered statistically significant if P0.05), but duration of analgesia varied. The duration of analgesia was significantly shorter (P=0.0127) for the BupFent treatment (180 minutes) compared with both Bup and BupMet; (240 minutes, score median of 4). The distribution of analgesia was from the S3 dermatomes to the T12-L2 dermatomes for all treatments. Motor blockade and associated ataxia were observed in all animals, however with varying degree and duration related to the respective treatments. Motor blockade
Paper Bup 5
4 Analgesic score
aaa ***
aaa ***
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aaa ***
aaa ***
aa a** *
BupMet
b *b * a *
BupFent
a a* *
3
b
b
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2
a b a a a
1
a
0 0
5
10
20
30
60
90
120
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Time after epidural injection (min.)
Fig 1: Combined analgesic score for all tested regions (median±95 per cent confidence interval) over time after epidural administration of bupivacaine (Bup, 0.5 mg/kg), bupivacaine plus methadone (BupMet, 0.25 mg/kg+0.3 mg/kg, respectively), or bupivacaine plus fentanyl (BupFent, 0.25 mg/kg+0.002 mg/kg, respectively). Tested regions were dorsocaudal ribs and lumbar area (upper and lower flanks), both lateral aspects of the upper pelvic limbs (sacral area), and perineal and feet areas in six sheep. Error bars represent the third quartile at each given time period. *Significantly different from time 0 (baseline) (P
Paper Fentanyl and methadone used as adjuncts to bupivacaine for lumbosacral epidural analgesia in sheep R. DeRossi, R. C. Pagliosa, A. Q. de Carvalho, G. G. Macedo, L. C. Hermeto Six healthy, female, mixed-breed 18–24-month-old sheep weighing 30–48 kg were submitted to lumbosacral epidural bupivacaine in combination with either methadone or fentanyl. Epidural catheters were placed in six sheep that were given three treatments: (Bup) bupivacaine (0.5 mg/kg) alone; (BupMet) bupivacaine (0.25 mg/kg) plus methadone (0.3 mg/kg); and (BupFent) bupivacaine (0.25 mg/kg) plus fentanyl (0.002 mg/kg). Haemodynamic variables, respiratory rate, rectal temperature, analgesia by applying a standard painful stimulus, motor block and sedative scores were compared among the three treatments. These parameters were determined before epidural administration and at 5, 10, 20, 30, 60, 90, 120 minutes after treatment administration, and then every 60 minutes thereafter until the end of analgesic effect. Parametrical data were analysed by proc glimmix (SAS) for repeated measures on time and means tested by ls-means. Non-parametrical data were analysed by Fisher’s exact test. Duration of analgesia was longer with BupMet (240 minutes) compared with BupFent (180 minutes; P=0.0127), but BupMet was similar to Bup (240 minutes). Both treatments with opioids produced moderate motor blockade. BupMet and BupFent produced mild sedation. Only treatment with bupivacaine alone induced cardiovascular and respiratory rate changes that stayed within acceptable limits. Introduction Lumbosacral epidural analgesia has been extensively used to provide pain relief in flank, perineal and pelvic limb surgeries in sheep (Skarda and Tranquilli 2007). Bupivacaine is a long-acting local anaesthetic agent that has been widely used for epidural blockade in human beings (Sinatra and others 2002). High concentrations of drugs administered epidurally can cause neurotoxicity by decreasing neuronal blood flow (Malinovsky and Pinaud 1996). Despite the fact that a low concentration of bupivacaine (0.25 per cent) shortens the duration of anaesthesia over a higher concentration, the safety of epidural injections will be increased (Dahl and others 1992). Several combinations of drugs have been used for epidural administration with the aim of reducing the dose of the local anaesthetic agent and increasing the duration of analgesia in Veterinary Record (2016) R. DeRossi, DVM, PhD, R. C. Pagliosa, DVM, MSc, A. Q. de Carvalho, DVM, MSc, Department of Veterinary Medicine– Surgery and Anesthesiology, Faculty of Veterinary Medicine and Animal Science, Federal University of Mato Grosso do Sul, Campo Grande, Mato Grosso do Sul, Brazil G. G. Macedo, DVM, PhD, Department of Animal Reproduction, Faculty of Veterinary Medicine, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil
doi: 10.1136/vr.103860 L. C. Hermeto, DVM, PhD, Postdoctoral Postgraduate Program on Veterinary Sciences, Faculty of Veterinary Medicine and Animal Science, Federal University of Mato Grosso do Sul (UFMS), Campo Grande, Brazil E-mail for correspondence: [email protected] Provenance: not commissioned; externally peer reviewed Accepted October 5, 2016
small ruminants (Aithal and others1996, DeRossi and others 2005, Habibian and others 2011, DeRossi and others 2012a). An epidural opioid acting through the spinal cord receptors improves the quality and duration of analgesia (Niemi and Breivik 2001). Fentanyl is a highly lipid-soluble phenyl piperidine derivative with strong m-receptor agonist activity, rapid onset and short duration of action (Moore and others 1982). Nevertheless, high lipid solubility increases systemic absorption and reduces bioavailability in the dorsal horn of the spinal cord, which results in a short duration of epidural analgesia (Bernards 2004). Studies in both human beings and animal models have demonstrated that pharmacological interaction between intrathecal fentanyl and bupivacaine is synergistic (Saito and others 1998, Ngan Kee and others 2014). Methadone is primarily a m-agonist of opioid receptors with pharmacological properties qualitatively similar to those of morphine (Jaffe and others 1993). Methadone is an intermediately lipophilic opioid that readily transfers from the epidural space into the spinal cord, but it is also taken up systemically via the epidural and spinal blood supply (Tung and Yaksh 1982, He and others 2010). Previous studies have compared the use of methadone and fentanyl alone or in combination with a local anaesthetic for epidural analgesia in human beings (Nyska and others 1986), horses (Olbrich and Mosing 2003, Ganidagli and others 2004) and dogs (Bosmans and others 2012, Diniz and others 2013). None of the studies has compared fentanyl and methadone as adjuncts to bupivacaine for lumbosacral epidural anaesthesia/analgesia in sheep. The present study was undertaken to compare the analgesic effect and efficacy of epidural methadone versus epidural fentanyl in combination with bupivacaine for lumbosacral epidural analgesia in sheep and to test the hypothesis that epidural methadone or fentanyl combined with bupivacaine would January 28, 2017 | Veterinary Record
Paper provide a more intense and long-lasting analgesia than bupivacaine alone.
Materials and methods Animals This experiment was approved by the Ethics Committee of Federal University of Mato Grosso do Sul and all applicable institutional guidelines for the care and use of animals were followed. Six healthy, female, mixed-breed sheep weighing between 30 kg and 48 kg (36±5 kg; mean±sd) and aged 18–24 months were used in this study. All animals were maintained at the Faculty of Veterinary Medicine and Animal Science facilities throughout the experiment. Food and water were withdrawn on the morning of the experiments. In a pilot study, epidural methadone or fentanyl alone was administered epidurally in three sheep (not included in the study) weekly to establish a clinically relevant dose to be used in the present study, based on previous studies in human beings and animals.
Experimental preparation An18 G epidural catheter (Smiths Medical ASD) was inserted percutaneously at the lumbosacral junction into the epidural space in all animals one week before the experiments were initiated. Catheter placement was performed with the sheep sedated with xylazine (Bayer SA) (0.2 mg/kg, intramuscular) and subcutaneous infiltration with 2 per cent lidocaine (2 ml) at the needle entry point. All sheep were maintained in sternal recumbency with the pelvic limbs positioned cranially during localisation of the lumbosacral space. The area was clipped then aseptically prepared with iodine. An 18 G, 7.6 cm Tuohy needle (Braun Laboratory) was inserted into the lumbosacral space. Correct positioning of the epidural needle was confirmed by the hanging-drop technique and by noting no resistance during catheter insertion. The catheter was advanced cranially 8–10 cm into the epidural space, based on the marks of the catheter excluding the length of the Tuohy needle inserted to reach the epidural space, and also by externally measuring the distance from the lumbosacral junction to the midlumbar level (L4–L5). The catheter was cut (total length, 10 cm) and connected to a valve without a filter. Proper insertion of the catheter was ensured by injecting 3 ml of 1 per cent lidocaine to induce bilateral analgesia. The catheter was fixed on the skin with cyanoacrylate glue and wrapped in gauze. At the end of each experiment, the catheters were filled with saline. At the end of the experiments, the catheters were removed and examined for evidence of kinking or looping and were tested for bacterial contamination using culture on blood agar.
Procedures All six sheep were randomly assigned to receive one of the three treatments: 0.25 per cent bupivacaine (Cristália Chemical and Pharmaceutical Products) (0.5 mg/kg, treatment Bup); 0.25 per cent bupivacaine (0.25 mg/kg) with methadone (Cristália Chemical and Pharmaceutical Products) (0.3 mg/kg, 10 mg/ml; treatment BupMet); and 0.25 per cent bupivacaine (0.25 mg/kg) with fentanyl (Cristália Chemical and Pharmaceutical Products) (0.002 mg/kg, 0.05 mg/ml, treatment BupFent). Total volumes injected for all animals were mean±sd) 7.2±1.6 ml in BUP, 4.8 ±0.8 ml in BupMet, and 5.0±0.4 ml in BupFent. All treatments were injected into the lumbosacral space over 30 seconds. The washout period between treatments was seven days. All involved anaesthesia personnel, including those individuals recording analgesia scores were unaware of the treatment administered. As the authors used a subjective scale for assessing analgesia, measures were always performed by the same person to reduce a variation between the researchers.
Analgesia assessment All experiments were performed in conscious animals without sedation. Animal behaviour, physiological variables, and analgesia and motor block determinations were recorded before Veterinary Record | January 28, 2017
treatment administration as the mean of three readings taken at 5 minute intervals (baseline) and at 5, 10, 20, 30, 60, 90 and 120 minutes after treatment administration, and then every 60 minutes thereafter until the end of sensory block. Physiological variables measured were heart rate (HR), noninvasive systolic arterial pressure (SAP), diastolic arterial pressure (DAP), mean arterial pressure (MAP), respiratory rate (RR) and rectal temperature (RT). Arterial blood pressure was measured using a non-invasive oscillometric device with the cuff (width, 8.5–9.0 cm) (Dixtal Biomédica Ind e Com) attached to the proximal third of the radius with the sheep in left lateral recumbency. The other variables were measured with the sheep standing or in sternal recumbency: HR was by auscultation and RR by counting the number of chest movements counted over one minute. RTwas measured with a digital thermometer. Analgesic and sedative effects and motor blockade were assigned scores (see online supplementary appendix 1). The time to the onset and duration of the analgesic, sedative and motor effects, as well as, the anatomical distribution of the analgesia were recorded. Time to onset of analgesia was considered the time from drug administration to the appearance (score 3) of analgesia. Sensory blockade was evaluated bilaterally using a 23 G hypodermic needle inserted into the skin (superficial prick) and muscle (deep prick, approximately 1 cm) in successive dermatomes starting at the tail and proceeding cranially to the lumbar region. Dermatomes tested were lumbar L5-S2 ( perineum and feet), L2-L5 (lateral aspects of upper pelvic limbs) and thoracic T12-L2 (dorsocaudal aspects of the ribs and thoracolumbar region). Analgesia was considered satisfactory (score 4) when the sheep did not respond to needle pricks in all the surveyed regions. Changes in behaviour were evaluated to assess the central effects produced by drug absorption from the epidural space. The sheep were evaluated for motor blockade or the presence of ataxia when stimulated to walk.
Statistical analysis Statistical analysis was performed by use of a commercial software program (SAS Institute). Continuous variables were assessed for normality of residuals by the UNIVARIATE procedure and submitted to the Bartlett test to analyse the homogeneity of variances. Only data from RR were not normally distributed and thus were transformed to inverse square root. Data were grouped and summarised as mean±se of the mean and median and IQR for non-parametrical tested parameters. Data for HR, SAP, DAP, MAP, RR and RT were analysed by Proc GLIMMIX for repeated measures, with treatment and time as independent variables. When a significant difference or interaction was obtained, least-squares means test or planned comparison was performed as appropriate. For analgesia, sedation and motor blockade variables, the non-parametrical Friedman’s test was used, followed by multiple comparisons for ranked data using Dunnett’s test, with time 0 as the baseline. In each analysis, differences were considered statistically significant if P0.05), but duration of analgesia varied. The duration of analgesia was significantly shorter (P=0.0127) for the BupFent treatment (180 minutes) compared with both Bup and BupMet; (240 minutes, score median of 4). The distribution of analgesia was from the S3 dermatomes to the T12-L2 dermatomes for all treatments. Motor blockade and associated ataxia were observed in all animals, however with varying degree and duration related to the respective treatments. Motor blockade
Paper Bup 5
4 Analgesic score
aaa ***
aaa ***
aaa ***
aaa ***
aaa ***
aaa ***
aa a** *
BupMet
b *b * a *
BupFent
a a* *
3
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b
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a
0 0
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Time after epidural injection (min.)
Fig 1: Combined analgesic score for all tested regions (median±95 per cent confidence interval) over time after epidural administration of bupivacaine (Bup, 0.5 mg/kg), bupivacaine plus methadone (BupMet, 0.25 mg/kg+0.3 mg/kg, respectively), or bupivacaine plus fentanyl (BupFent, 0.25 mg/kg+0.002 mg/kg, respectively). Tested regions were dorsocaudal ribs and lumbar area (upper and lower flanks), both lateral aspects of the upper pelvic limbs (sacral area), and perineal and feet areas in six sheep. Error bars represent the third quartile at each given time period. *Significantly different from time 0 (baseline) (P
