Thomas J. Doherty

Effect of systemic lidocaine on visceral and somatic nociception in conscious horses.

REASONS FOR PERFORMING STUDY Commonly used analgesics (nonsteroidal anti-inflammatory agents, opioids and alpha2-agonists) have unwanted side effects. An effective alternative with minimal adverse effects would benefit clinical equine pain management. OBJECTIVES To compare the effect of lidocaine or saline on duodenal and rectal distension threshold pressure and somatic thermal threshold in conscious mature horses. HYPOTHESIS Systemically administered lidocaine would increase somatic and visceral nociceptive thresholds. METHODS Lidocaine (2 mg/kg bwt bolus followed by 50 microg/kg bwt/min for 2 h) or saline was administered to 6 horses each carrying a permanently implanted gastric cannula, in a randomised, blinded cross-over design. Thermal threshold was measured using a probe containing a heater element placed over the withers which supplied heat until the horse responded. A barostatically controlled intraduodenal balloon was distended until a discomfort response was obtained. A rectal balloon was inflated until extruded or signs of discomfort noted. RESULTS Thermal threshold was increased significantly 30 and 90 mins after the start of lidocaine infusion. There was no change in duodenal distension pressure and a small but clinically insignificant change in colorectal distension pressure in the lidocaine group. CONCLUSIONS At the dose used, systemically administered lidocaine produced thermal antinociception but minimal changes in visceral nociception. POTENTIAL RELEVANCE At these doses, lidocaine may play a role in somatic analgesia in horses.

Effects of intravenous lidocaine, ketamine, and the combination on the minimum alveolar concentration of sevoflurane in dogs

OBJECTIVE To evaluate the effects of intravenous lidocaine (L) and ketamine (K) alone and their combination (LK) on the minimum alveolar concentration (MAC) of sevoflurane (SEVO) in dogs. STUDY DESIGN Prospective randomized, Latin-square experimental study. ANIMALS Six, healthy, adult Beagles, 2 males, 4 females, weighing 7.8 - 12.8 kg. METHODS Anesthesia was induced with SEVO in oxygen delivered by face mask. The tracheas were intubated and the lungs ventilated to maintain normocapnia. Baseline minimum alveolar concentration of SEVO (MAC(B)) was determined in duplicate for each dog using an electrical stimulus and then the treatment was initiated. Each dog received each of the following treatments, intravenously as a loading dose (LD) followed by a constant rate infusion (CRI): lidocaine (LD 2 mg kg(-1), CRI 50 microg kg(-1)minute(-1)), lidocaine (LD 2 mg kg(-1), CRI 100 microg kg(-1) minute(-1)), lidocaine (LD 2 mg kg(-1), CRI 200 microg kg(-1) minute(-1)), ketamine (LD 3 mg kg(-1), CRI 50 microg kg(-1) minute(-1)), ketamine (LD 3 mgkg(-1), CRI 100 microg kg(-1) minute(-1)), or lidocaine (LD 2 mg kg(-1), CRI 100 microg kg(-1) minute(-1)) + ketamine (LD 3 mg kg(-1), CRI 100 microg kg(-1) minute(-1)) in combination. Post-treatment MAC (MAC(T)) determination started 30 minutes after initiation of treatment. RESULTS Least squares mean +/- SEM MAC(B) of all groups was 1.9 +/- 0.2%. Lidocaine infusions of 50, 100, and 200 microg kg(-1) minute(-1) significantly reduced MAC(B) by 22.6%, 29.0%, and 39.6%, respectively. Ketamine infusions of 50 and 100 microg kg(-1) minute(-1) significantly reduced MAC(B) by 40.0% and 44.7%, respectively. The combination of K and L significantly reduced MAC(B) by 62.8%. CONCLUSIONS AND CLINICAL RELEVANCE Lidocaine and K, alone and in combination, decrease SEVO MAC in dogs. Their use, at the doses studied, provides a clinically important reduction in the concentration of SEVO during anesthesia in dogs.

Effects of tramadol on the minimum alveolar concentration of sevoflurane in dogs

OBJECTIVE To evaluate the effect of tramadol on sevoflurane minimum alveolar concentration (MAC(SEVO)) in dogs. It was hypothesized that tramadol would dose-dependently decrease MAC(SEVO). STUDY DESIGN Randomized crossover experimental study. ANIMALS Six healthy, adult female mixed-breed dogs (24.2 +/- 2.6 kg). METHODS Each dog was studied on two occasions with a 7-day washout period. Anesthesia was induced using sevoflurane delivered via a mask. Baseline MAC (MAC(B)) was determined starting 45 minutes after tracheal intubation. A noxious stimulus (50 V, 50 Hz, 10 ms) was applied subcutaneously over the mid-humeral area. If purposeful movement occurred, the end-tidal sevoflurane was increased by 0.1%; otherwise, it was decreased by 0.1%, and the stimulus was re-applied after a 20-minute equilibration. After MAC(B) determination, dogs randomly received a tramadol loading dose of either 1.5 mg kg(-1) followed by a continuous rate infusion (CRI) of 1.3 mg kg(-1 )hour(-1) (T1) or 3 mg kg(-1) followed by a 2.6 mg kg(-1 )hour(-1) CRI (T2). Post-treatment MAC determination (MAC(T)) began 45 minutes after starting the CRI. Data were analyzed using a mixed model anova to determine the effect of treatment on percentage change in baseline MAC(SEVO) (p < 0.05). RESULTS The MAC(B) values were 1.80 +/- 0.3 and 1.75 +/- 0.2 for T1 and T2, respectively, and did not differ significantly. MAC(T) decreased by 26 +/- 8% for T1 and 36 +/- 12% for T2. However, there was no statistically significant difference in the decrease between the two treatments. CONCLUSION AND CLINICAL RELEVANCE Tramadol significantly reduced MAC(SEVO) but this was not dose dependent at the doses studied.

Evaluation of dimethyl sulphoxide effects on initial response to endotoxin in the horse

REASONS FOR PERFORMING STUDY Endotoxaemia is one of the most severe and ubiquitous disease processes in horses. Although dimethyl sulphoxide (DMSO) is used clinically in horses, there is no study indicating its efficacy in endotoxaemic horses. HYPOTHESIS DMSO ameliorates the clinical response to i.v. lipopolysaccharide (LPS) administration. METHODS Eighteen horses were assigned randomly to one of 4 groups: Normosol-LPS (0.2 mug/kg bwt, i.v.); DMSO (1 g/kg bwt, i.v.)-saline; high-dose DMSO (1 g/kg bwt, i.v.)LPS; low-dose DMSO (20 mg/kg bwt, i.v.)-LPS. Horses participating in the DMSO-saline group were later assigned randomly to one of the LPS groups. Data for physical parameters, white blood cell counts, plasma TNF-alpha, and blood lactate and glucose concentrations were examined for the effect of treatment using a repeated-measures mixed-model ANOVA. A value of P<0.05 was considered significant. RESULTS Endotoxaemia occurred in all horses receiving LPS, as indicated by the clinical score, physical parameters, haemoconcentration and leucopenia. High-dose DMSO ameliorated the effect of LPS on fever. DMSO, at either dose, but did not have a significant effect on LPS-induced changes in all other evaluated parameters. CONCLUSIONS In this study, DMSO had minimal effects on clinical signs of induced endotoxaemia in horses. The effects were manifested by amelioration of LPS-induced fever.

EFFECTIVENESS OF ANTAGONISTS FOR TILETAMINE-ZOLAZEPAM/XYLAZINE IMMOBILIZATION IN FEMALE WHITE-TAILED DEER

A combination of tiletamine-zolazepam/xylazine (TZ/X) is effective in the chemical immobilization of white-tailed deer (Odocoileus virginianus); however, the lengthy duration of immobilization may limit its usefulness. From October to November 2002, 21 captive female deer were assigned randomly to an α2 antagonist treatment to reverse xylazine-induced sedation (seven does per group). All deer were given 220 mg of TZ (4.5±0.4 mg/kg) and 110 mg of X (2.2±0.2 mg/kg) intramuscularly (IM). Antagonist treatments were either 200 mg of tolazoline (4.0±0.4 mg/kg), 11 mg of atipamezole (0.23±0.02 mg/kg), or 15 mg of yohimbine (0.30±0.02 mg/kg) injected, half intravenously and half subcutaneously, 45 min after the IM TZ/X injection. In addition, 10 other deer (five per group) were immobilized as before and then given tolazoline (200 mg) after 45 min, with either a carrier (dimethyl sulfoxide [DMSO]) or carrier (DMSO) plus flumazenil (5 mg) to reverse the zolazepam portion of TZ. Mean times from antagonist injection until a deer raised its head were different for α2 antagonist treatments (P = 0.02). Times were longer for yohimbine (62.3±42.7 min) than for either atipamezole (24.3±17.1 min) or tolazoline (21.3±14.3 min). Mean times from antagonist injection until standing were not different (P=0.15) among yohimbine (112.0±56.4 min), atipamezole (89.7±62.8 min), or tolazoline (52.6±37.2 min). A sedation score based on behavioral criteria was assigned to each deer every 30 min for 5 hr. On the basis of sedation scores, tolazoline resulted in a faster and more complete reversal of immobilization. Flumazenil treatment did not affect recovery.

Local Anesthetics as Pain Therapy in Horses

This article describes the rationale behind the use of systemically administered lidocaine as an analgesic. The analgesic efficacy of intravenously administered lidocaine is well documented by studies in human patients and laboratory animals. The mechanism by which systemically administered lidocaine produces analgesia is uncertain but is thought to include action at sodium, calcium, and potassium channels and the N-methyl-D-aspartate acid receptor. In addition, the anti-inflammatory actions of lidocaine are important in producing analgesia because inflammatory mediators augment neuronal excitability. The available studies of systemically administered lidocaine in horses provide evidence for the analgesic and anesthetic effects of intravenous lidocaine in this species.

Postoperative Ileus: Pathogenesis and Treatment

Surgical manipulation of the intestines activates intestinal macrophages that release cytokines and nitric oxide, which results in inhibition of intestinal motility. Subsequent infiltration of circulating leukocytes into the intestinal wall contributes to cytokine and nitric oxide release and exacerbates ileus. Other factors contributing to ileus are endotoxemia; edema of the intestine wall subsequent to excessive fluid therapy; hypocalcemia; and long abdominal incisions. Because treatment of ileus with prokinetic drugs has not proven to be very effective, efforts should be directed at reducing its severity. Strategies which reduce the severity of ileus include pretreatment with a nonsteroidal anti-inflammatory drug, minimizing the length of the abdominal incision, reducing intestinal manipulation, intraoperative lidocaine infusion, correction of hypocalcemia, limiting the volume of intravenous fluids to prevent intestinal edema, and administration of alpha(2) antagonists.

Determination of oral tramadol pharmacokinetics in horses.

The determination of the pharmacokinetic parameters of tramadol in plasma and a better characterization of its metabolites after oral administration to horses is necessary to design dosage regimens to achieve target plasma concentrations that are associated with analgesia. The purpose of this study was to determine the pharmacokinetics and elimination pattern in urine of tramadol and its metabolites after oral administration to horses. Tramadol was administered orally to six horses and its half-life, T(max) and C(max) in plasma were 10.1, 0.59 h, and 132.7 ng/mL, respectively. The half-life, T(max) and C(max) for M1 in plasma were 4.0, 0.59 h, and 28.0 ng/mL, respectively. Tramadol and its metabolites were detectable in urine between 1 and 24 h after the administration. In conclusion, the PK data reported in this study provides information for the design of future studies of tramadol in horses.

The effect of midazolam on the end-tidal concentration of isoflurane necessary to prevent movement in dogs

OBJECTIVE To determine the possible additive effect of midazolam, a GABA(A) agonist, on the end-tidal concentration of isoflurane that prevents movement (MAC(NM) ) in response to noxious stimulation. STUDY DESIGN Randomized cross-over experimental study. ANIMALS Six healthy, adult intact male, mixed-breed dogs. METHODS After baseline isoflurane MAC(NM) (MAC(NM-B) ) determination, midazolam was administered as a low (LDS), medium (MDS) or high (HDS) dose series of midazolam. Each series consisted of two dose levels, low and high. The LDS was a loading dose (Ld) of 0.2 mg kg(-1) and constant rate infusion (CRI) (2.5 μg kg(-1) minute(-1)) (LDL), followed by an Ld (0.4 mg kg(-1)) and CRI (5 μg kg(-1) minute(-1)) (LDH). The MDS was an Ld (0.8 mg kg(-1)) and CRI (10 μg kg(-1) minute(-1)) (MDL) followed by an Ld (1.6 mg kg(-1)) and CRI (20 μg kg(-1) minute(-1)) (MDH). The HDS was an Ld (3.2 mg kg(-1)) and CRI (40 μg kg(-1) minute(-1)) (HDL) followed by an Ld (6.4 mg kg(-1)) and CRI (80 μg kg(-1) minute(-1)) (HDH). MAC(NM) was re-determined after each dose in each series (MAC(NM-T)). RESULTS The median MAC(NM-B) was 1.42. MAC(NM-B) did not differ among groups (p > 0.05). Percentage reduction in MAC(NM) was significantly less in the LDS (11 ± 5%) compared with MDS (30 ± 5%) and HDS (32 ± 5%). There was a weak correlation between the plasma midazolam concentration and percentage MAC(NM) reduction (r = 0.36). CONCLUSION AND CLINICAL RELEVANCE Midazolam doses in the range of 10-80 μg kg(-1) minute(-1) significantly reduced the isoflurane MAC(NM) . However, doses greater than 10 μg kg(-1) minute(-1) did not further decrease MAC(NM) indicating a ceiling effect.

The effect of ketamine on the MACBAR of sevoflurane in dogs.

OBJECTIVE To determine the effect of intravenous ketamine on the minimum alveolar concentration of sevoflurane needed to block autonomic response (MAC(BAR)) to a noxious stimulus in dogs. STUDY DESIGN Randomized, crossover, prospective design. ANIMALS Eight, healthy, adult male, mixed-breed dogs, weighing 11.2-16.1 kg. METHODS Dogs were anesthetized with sevoflurane on two occasions, 1 week apart, and baseline MAC(BAR) (B-MAC(BAR)) was determined on each occasion. MAC(BAR) was defined as the mean of the end-tidal sevoflurane concentrations that prevented and allowed an increase (≥15%) in heart rate or invasive mean arterial pressure in response to a noxious electrical stimulus (50 V, 50 Hz, 10 ms). Dogs then randomly received either a low-dose (LDS) or high-dose series (HDS) of ketamine, and treatment MAC(BAR) (T-MAC(BAR)) was determined. The LDS had an initial loading dose (LD) of 0.5 mg kg(-1) and constant rate infusion (CRI) at 6.25 μg kg(-1) minute(-1), followed, after T-MAC(BAR) determination, by a second LD (1 mg kg(-1)) and CRI (12.5 μg kg(-1) minute(-1)). The HDS had an initial LD (2 mg kg(-1)) and CRI (25 μg kg(-1) minute(-1)) followed by a second LD (3 mg kg(-1)) and CRI (50 μg kg(-1) minute(-1)). Data were analyzed with a mixed-model anova and are presented as LSM ± SEM. RESULTS The B-MAC(BAR) was not significantly different between treatments. Ketamine at 12.5, 25, and 50 μg kg(-1) minute(-1) decreased sevoflurane MAC(BAR), and the maximal decrease (22%) occurred at 12.5 μg kg(-1) minute(-1). The percentage change in MAC(BAR) was not correlated with either the log plasma ketamine or norketamine concentration. CONCLUSIONS AND CLINICAL RELEVANCE Ketamine at clinically relevant doses of 12.5, 25, and 50 μg kg(-1) minute(-1) decreased sevoflurane MAC(BAR), although the reduction was neither dose-dependent nor linear.