Karine Portier

Development of a romifidine constant rate infusion with or without butorphanol for standing sedation of horses

OBJECTIVE To elaborate constant rate infusion (CRI) protocols for xylazine (X) and xylazine/butorphanol (XB) which will result in constant sedation and steady xylazine plasma concentrations. STUDY DESIGN Blinded randomized experimental study. ANIMALS Ten adult research horses. METHODS Part I: After normal height of head above ground (HHAG = 100%) was determined, a loading dose of xylazine (1 mg kg(-1) ) with butorphanol (XB: 18 μg kg(-1) ) or saline (X: equal volume) was given slowly intravenously (IV). Immediately afterwards, a CRI of butorphanol (XB: 25 μg kg(-1) hour(-1)) or saline (X) was administered for 2 hours. The HHAG was used as a marker of depth of sedation. Sedation was maintained for 2 hours by additional boluses of xylazine (0.3 mg kg(-1)) whenever HHAG >50%. The dose of xylazine (mg kg(-1) hour(-1)) required to maintain sedation was calculated for both groups. Part II: After the initial loading dose, the calculated xylazine infusion rates were administered in parallel to butorphanol (XB) or saline (X) and sedation evaluated. Xylazine plasma concentrations were measured by HPLC-MS-MS at time points 0, 5, 30, 45, 60, 90, and 120 minutes. Data were analyzed using paired t-test, Wilcoxon signed rank test and a 2-way anova for repeated measures (p < 0.05). RESULTS There was no significant difference in xylazine requirements (X: 0.69, XB: 0.65 mg kg(-1) hour(-1)) between groups. With treatment X, a CRI leading to prolonged sedation was developed. With XB, five horses (part I: two, part II: three) fell down and during part II four horses appeared insufficiently sedated. Xylazine plasma concentrations were constant after 45 minutes in both groups. CONCLUSION Xylazine bolus, followed by CRI, provided constant sedation. Additional butorphanol was ineffective in reducing xylazine requirements and increased ataxia and apparent early recovery from sedation in unstimulated horses. CLINICAL RELEVANCE Data were obtained on unstimulated healthy horses and extrapolation to clinical conditions requires caution.

Castration of horses under total intravenous anaesthesia: analgesic effects of lidocaine

OBJECTIVE To evaluate the effects of local anaesthesia with lidocaine for castration of horses under intravenous anaesthesia. STUDY DESIGN Prospective, randomized, blinded clinical trial. ANIMALS Fifteen equidae, scheduled to undergo castration under total intravenous anaesthesia, were randomly distributed in two groups. One group received lidocaine injections (group L: two ponies, four horses, two donkeys) and the other received saline (group S: two ponies, three horses, two donkeys). METHODS Behaviour, heart rate (HR) and respiratory rate (f(R)) were evaluated prior to anaesthesia. Body mass was measured using an electronic scale and testicular volumes were estimated. The animals were anaesthetized with acepromazine intramuscularly and romifidine intravenously followed 10 minutes later by ketamine. Following romifidine administration lidocaine or saline was administered subcutaneously along the incision line and by intratesticular and intrafunicular injection. Based on clinical observations (movement, f(R), and cranial nerve reflexes) incremental intravenous doses of ketamine and romifidine were administered. HR, f(R), oscillometric mean arterial blood pressure (MAP), duration of surgery, movement and additional doses were recorded. Surgical conditions were assessed using a visual analogue scale (VAS) and a simple descriptive scale (SDS). Recovery was assessed by two assistants, unaware of treatment, acting separately using a VAS and a SDS. Group means were compared using Mann-Whitney and Wilcoxon tests and the Kruskal-Wallis signed rank test for matched pairs used to compare groups at different points (p < 0.05). RESULTS The number (median, range) of incremental doses (4 [1-5] compared to 1.5 [1-4]) and movements (1 [1-5] compared to 0 [0-1]) were higher (p = 0.01 for both) in the control group than in the lidocaine group. Groups were similar for other recorded variables. CONCLUSIONS AND CLINICAL RELEVANCE These results show the effectiveness of lidocaine used as a local anaesthetic adjunct to intravenous anaesthesia in horses undergoing castration.

Effects on cardiopulmonary function and oxygen delivery of doses of romifidine and xylazine followed by constant rate infusions in standing horses.

The objective of this study was to compare the cardiopulmonary effects of a xylazine or romifidine loading-dose, followed by a constant rate infusion (CRI) of the same α(2)-agonist. Nine research horses were treated in a randomized, blinded, crossover design with xylazine or romifidine. After instrumentation, a loading dose of intravenous xylazine (1mg/kg) or romifidine (80μg/kg) was administered, immediately followed by a CRI of xylazine (0.69mg/kg/h) or romifidine (30μg/kg/h) for a duration of 2h. Cardiopulmonary variables were recorded before bolus administration, during CRI, and for 1h after discontinuing drug administration. A significant decrease in haemoglobin concentration (tHb), arterial oxygen content (CaO(2)), oxygen delivery (D˙O(2)), mixed venous partial pressure of oxygen, heart rate, and cardiac output (Q˙t) followed the loading dose with both treatments. Carotid arterial blood pressure (ABP), systemic vascular resistance, and right atrial pressure (RAP) increased significantly. The increased ABP was followed by a significant decrease compared to baseline. Mean pulmonary arterial pressure increased significantly with romifidine only. No significant changes in stroke volume, arterial partial pressure of oxygen, and oxygen consumption were observed. Changes in Q˙t and RAP were more pronounced with romifidine. During CRI, tHb, and CaO(2) were significantly higher with romifidine, whereas D˙O(2) did not differ between treatments. Overall, cardiopulmonary effects were more pronounced and lasted longer with romifidine compared to xylazine. However, during CRI, there was no difference in D˙O(2) between drugs. With both α(2)-agonists, cardiovascular effects were most pronounced after loading dose administration and tended to stabilize during CRI.

The effects of a loading dose followed by constant rate infusion of xylazine compared with romifidine on sedation, ataxia and response to stimuli in horses

OBJECTIVE To compare xylazine and romifidine constant rate infusion (CRI) protocols regarding degree of sedation, and effects on postural instability (PI), ataxia during motion (A) and reaction to different stimuli. STUDY DESIGN Blinded randomized experimental cross-over study. ANIMALS Ten adult horses. METHODS Degree of sedation was assessed by head height above ground (HHAG). Effects on PI, A and reaction to visual, tactile and acoustic stimulation were assessed by numerical rating scale (NRS) and by visual analogue scale (VAS). After baseline measurements, horses were sedated by intravenous loading doses of xylazine (1 mg kg(-1) ) or romifidine (80 μg kg(-1) ) administered over 3 minutes, immediately followed by a CRI of xylazine (0.69 mg kg(-1 ) hour(-1) ) or romifidine (30 μg kg(-1 ) hour(-1) ) which was administered for 120 minutes. Degree of sedation, PI, A and reaction to the different stimuli were measured at different time points before, during and for one hour after discontinuing drug administration. Data were analysed using two-way repeated measures anova, a Generalized Linear Model and a Wilcoxon Signed Rank Test (p < 0.05). RESULTS Significant changes over time were seen for all variables. With xylazine HHAG was significantly lower 10 minutes after the loading dose, and higher at 150 and 180 minutes (i.e. after CRI cessation) compared to romifidine. Reaction to acoustic stimulation was significantly more pronounced with xylazine. Reaction to visual stimulation was greater with xylazine at 145 and 175 minutes. PI was consistently but not significantly greater with xylazine during the first 30 minutes. Reaction to touch and A did not differ between treatments. Compared to romifidine, horses were more responsive to metallic noise with xylazine. CONCLUSIONS Time to maximal sedation and to recovery were longer with romifidine than with xylazine. CLINICAL RELEVANCE With romifidine sufficient time should be allowed for complete sedation before manipulation.

Synergistic protective effect of cyclosporin A and rotenone against hypoxia-reoxygenation in cardiomyocytes.

Reperfusion of the heart after an ischemic event leads to the opening of a nonspecific pore in the inner mitochondrial membrane, the mitochondrial permeability transition pore (mPTP). Inhibition of mPTP opening is an effective strategy to prevent cardiomyocyte death. The matrix protein cyclophilin-D (CypD) is the best-known regulator of mPTP opening. In this study we confirmed that preconditioning and postconditioning with CypD inhibitor cyclosporin-A (CsA) reduced cell death after hypoxia-reoxygenation (H/R) in wild-type (WT) cardiomyocytes and HL-1 mouse cardiac cell line as measured by nuclear staining with propidium iodide. The complex I inhibitor rotenone (Rot), alone, had no effect on HL-1 and WT cardiomyocyte death after H/R, but enhanced the native protection of CypD-knocked-out (CypD KO) cardiomyocytes. Reduction of cell death was associated with a delay of mPTP opening challenged by H/R and observed by the calcein loading CoCl(2)-quenching technique. Simultaneous inhibition of complex I and CypD increased in a synergistic manner the calcium retention capacity in permeabilized cardiomyocytes and cardiac mitochondria. These results demonstrated that protection by complex I inhibition was CypD dependent.

Effects of high and low inspired fractions of oxygen on horse erythrocyte membrane properties, blood viscosity and muscle oxygenation during anaesthesia

OBJECTIVES To evaluate whether a period of hyperoxia or after a period of hypoxia produced changes attributable to reactive oxygen species in anaesthetized horses. STUDY DESIGN Prospective randomized experimental study. ANIMALS Six healthy (ASA I) geldings, aged 4.5-9.5 years and weighing 510-640 kg(-1). METHODS After 30 minutes breathing air as carrier gas for isoflurane, horses were assigned randomly to breathe air as carrier gas (CG0.21) or oxygen as carrier gas (CG1.00) for a further 90 minutes. After an interval of 1 month each horse was re-anaesthetized with the other carrier gas for the 90 minute test period. Ventilation was controlled throughout anaesthesia. Arterial blood was sampled to measure gas tensions, lactate, cholesterol, vitamin E, 4-hydroxy-alkenals, 8-epi-PGF(2 alpha), half haemolysis time, half erythrolysis time, and erythrocyte membrane fluidity. Muscle blood flow and oxygenation were evaluated by near infrared spectroscopy and coloured Doppler. RESULTS After the first 30 minutes horses were hypoxemic. Subsequently the CG1.00 group became hyperoxaemic (PaO(2) approximately 240 mmHg) whereas the CG0.21 group remained hypoxaemic (PaO(2) approximately 60 mmHg) and had increased lactate concentration. No significant changes in vitamin E, 4-hydroxy-alkenals, or 8-epi-PGF(2 alpha) concentrations were detected. During the 90 minute test period the CG0.21 group had increased resistance to free-radical-mediated lysis in erythrocytes, whereas the CG1.00 group had slightly decreased resistance of whole blood to haemolysis. CG0.21 induced a progressive muscle deoxygenation whereas CG1.00 induced an increase in muscle oxygen saturation followed by progressive deoxygenation towards baseline. CONCLUSIONS and clinical relevance During isoflurane anaesthesia in horses, the hyperoxia induced by changing from air to oxygen induced minimal damage from reactive oxygen species. Using air as the carrier gas decreased skeletal muscle oxygenation compared with using oxygen.

Blood glucose, acid–base and electrolyte changes during loading doses of alpha2-adrenergic agonists followed by constant rate infusions in horses

The aim of the present study was to investigate changes in blood glucose concentration ([Glu]B), acid-base status and electrolyte concentrations during constant rate infusions (CRI) of two alpha2-adrenergic agonists in seven horses treated in a blinded, randomised, crossover design with xylazine or romifidine. An intravenous (IV) bolus of xylazine (1mg/kg) or romifidine (80 μg/kg) was administered followed by an IV CRI of xylazine (0.69 mg/kg/h) or romifidine (30 μg/kg/h) for 2h. Blood samples were collected from the pulmonary artery before and after loading doses, during the CRI, and for 1h after discontinuing drugs. Blood glucose, base excess (BE), pH, partial pressure of carbon dioxide (Pv¯CO2), strong ion difference (SIDest) and bicarbonate concentration ( [Formula: see text] ) increased significantly during the CRI with both alpha2-adrenergic agonists. Chloride concentration ([Cl(-)]B) and anion-gap (AG) decreased significantly compared to baseline. The decrease in sodium concentration ([Na(+)]B) was only significant with xylazine. From 1h after starting the CRI onwards, [Glu]B was significantly higher with romifidine compared to xylazine. Except [Glu]B, SIDest, and Pv¯CO2, all variables returned to normal values 1h after discontinuing xylazine. After stopping romifidine, all variables except pH remained altered for at least 1h. It was concluded that loading doses of alpha2-adrenergic agonists followed by CRIs produce [Glu]B, acid-base and electrolyte changes. The clinical significance of the reported changes remains to be investigated and absolute values should be interpreted with caution, as fluid boli were used for cardiac output measurements, but may become important during prolonged infusion and in critically ill patients.

A study of the correlation between objective and subjective indices of recovery quality after inhalation anaesthesia in equids

OBJECTIVE To examine the association between objective and subjective descriptors used for assessing recovery quality in horses after anaesthesia. STUDY DESIGN Prospective clinical study. ANIMALS Two hundred and seventy-six equids (110 mares, 85 entire males and 81 geldings), ASA 1-5, weighing 50-850 kg and aged 1 month - 25 years. METHODS Recoveries after general anaesthesia were assisted with head and tail ropes by two anaesthetists. One scored dichotomous objective descriptors (DOD) of recovery. Two dichotomous objective scales (DOS) were then generated from those descriptors. The same individual also scored overall recovery quality using a visual analogue scale (VAS). The second anaesthetist scored recovery (good or bad) using a dichotomous subjective scale (DSS). Each DOD, the DSS and VAS were compared with each other using Pearsons chi-square test. DOSs were compared to the DSS using Wilcoxons test and to the VAS using a Spearmans correlation test. RESULTS Most DODs were associated (p < 0.05) with DSS and VAS. The DSS was not associated with resting/not resting in sternal recumbency (p = 0.535) nor with the time spent in sternal recumbency (p = 0.09). VAS and DSS scores were strongly associated (p < 0.0001). The two DOSs were in agreement with DSS (p < 0.0001) and negatively correlated to VAS (r(1)(2) = 0.38, r(2)(2) = 0.34, respectively, p-value <0.0001). CONCLUSION Objective descriptors were linked closely with the subjective evaluations of recovery quality except for the presence or absence of a sternal recumbency phase and its duration. CLINICAL RELEVANCE These components may not be essential in recovery scoring systems. The DOS were in agreement with DSS and VAS and could be a useful tool for further studies on recoveries.

Comparison of xylazine-butorphanol and xylazine-morphine-ketamine infusions in horses undergoing a standing surgery

GENERAL anaesthesia presents a particularly high mortality and morbidity risk in horses (Johnston and others 2002). Several sedative protocols have been proposed for standing surgery in horses, all involving α2-adrenoreceptor agonists with or without opioids (Bettschart-Wolfensberger and others 1999, Sellon and others 2001, 2004). Opioids (μ or κ agonists) act synergistically to α2-adrenoceptor agonists and improve analgesia and balance sedation. By reducing the required dose of α2-adrenoceptor agonists, deleterious cardiopulmonary side effects can be reduced (England and Clark 1996). Butorphanol has been used as a constant rate infusion (CRI) and its efficacy has been proven in combination with xylazine or as a sole agent in horses (Robertson and Muir 1983, Sellon and others 2001). Ketamine has analgesic properties in horses when administered at subanaesthetic doses (Fielding and others 2006, Lankveld and others 2006, Peterbauer and others 2008) but it does not provide sedation at plasma concentrations that result in an analgesic effect (Lankveld and others 2006). In horses, xylazine is the shortest-acting α2-adrenoceptor agonist and its cardiovascular side effects are also of shorter duration (England and others 1992). The purpose of this study was to compare the dose of xylazine necessary to maintain sufficient sedation and analgesia to perform common carotid translocation in standing horses and to compare the influence of butorphanol CRI with morphine-ketamine CRI on the rate of infusion of xylazine. Eight horses classified …

Evaluation of the non-calibrated pulse contour cardiac output monitor FloTrac/Vigileo against thermodilution in standing horses.

OBJECTIVE To evaluate the non-calibrated, minimally invasive cardiac output (CO) monitor FloTrac/Vigileo (FloTrac) against thermodilution (TD) CO in standing horses. STUDY DESIGN Prospective, experimental trial. ANIMALS Nine adult horses weighing a median (range) of 535 (470-602) kg. METHODS Catheters were placed in the right atrium, pulmonary artery and carotid artery under local anaesthesia. CO was measured 147 times by TD and FloTrac and indexed to body weight. Changes in CO were achieved with romifidine or xylazine and dobutamine constant rate infusions. Bland-Altman analysis, concordance and polar plot analysis were used to assess agreement and ability to track changes in CO. RESULTS Mean ± standard deviation COTD of 48 ± 16 mL kg(-1) minute(-1) (range: 19-93 mL kg(-1) minute(-1) ) and mean COF loTrac of 9 ± 3 mL kg(-1) minute(-1) (range: 5-21 mL kg(-1) minute(-1) ) were measured. Low agreement with a large mean bias of 39 mL kg(-1) minute(-1) and wide limits of agreement of 8-70 mL kg(-1) minute(-1) were found. The percentage error of 108% and precision of TD of ± 18% resulted in an estimated precision of FloTrac of ± 106%. Comparison of changes in COF loTrac with changes in COTD gave a concordance rate of 52% in the four-quadrant plot, and a mean polar angle of -11° with radial limits of agreement of ± 61 ° in the polar plot. Mean arterial pressure (MAP) and COF loTrac were positively correlated (r = 0.5, p < 0.0001). No correlation of MAP with COTD was observed. CONCLUSIONS AND CLINICAL RELEVANCE The FloTrac system, originally designed for use in humans, neither measured absolute CO in standing horses accurately nor tracked relative changes in CO measured by TD correctly. The false dependence of COF loTrac on arterial blood pressure further discourages the use of this technique in horses.