Ulrike Auer

Observations on the muscle relaxant rocuronium bromide in the horse--a dose-response study.

OBJECTIVE To investigate the onset and duration of neuromuscular blockade of rocuronium bromide and its associated haemodynamic effects at three doses in healthy horses. STUDY DESIGN Prospective, randomized experimental study. ANIMALS Seven adult horses aged 3-20 (mean 10.3) years and weighing 466 ± 44 (mean ± SD) kg. METHODS Horses were anaesthetized three times with at least 2 weeks between. They were pre-medicated with 0.6 mg kg-1 xylazine and 0.01 mg kg-1 butorphanol IV. Anaesthesia was induced with 2.2 mg kg-1 ketamine and 0.1 mg kg-1 diazepam IV. Following orotracheal intubation anaesthesia was maintained with isoflurane in 100% oxygen. Intermittent positive pressure ventilation was initiated and the horses were ventilated at a respiratory rate (fr) of 4-8 breaths minute-1. Neuromuscular function was monitored with an acceleromyograph. The peroneal nerve was stimulated with train-of-four (TOF) mode at 2 Hz every 15 seconds. Each horse received, in randomly assigned order, one of the three doses of rocuronium: 0.2 mg kg-1 (D02), 0.4 mg kg-1 (D04) or 0.6 mg kg-1 (D06) IV. Lag time, onset time, time of no response, duration of action and the TOF ratio 0.7 and 0.9 were measured. Recovery time (T125-75) was calculated. Vital parameters were recorded at 5-minute intervals on a standard anaesthetic record form. RESULTS Rocuronium produced a dose-dependent duration of action in isoflurane-anaesthetized horses. 100% block was observed in D04 and D06 but not in D02, in which the maximum decrease of the first twitch of TOF attained was 91.5 ± 16.5%. Time to T125 was 13.1 ± 5.5 minutes, 38.6 ± 10.1 minutes and 55 ± 9.8 minutes in D02, D04 and D06 respectively. There was a significantly shorter time for TOFR 0.9 with 0.2 mg kg-1 compared with 0.4 and 0.6 mg kg-1 rocuronium. T125-75 in D04 and D6 was not statistically significantly different. Heart rate, systolic, diastolic and mean arterial blood pressure increased slightly during the observation period. CONCLUSION Rocuronium is an effective nondepolarizing muscle relaxant in horses under isoflurane anaesthesia. It had a dose-dependent onset and duration of action. Rocuronium did not produce significant changes in the measured cardiovascular parameters.

Measurement of tidal volume using Respiratory Ultrasonic Plethysmography in anaesthetized, mechanically ventilated horses

OBJECTIVE To compare tidal volume estimations obtained from Respiratory Ultrasonic Plethysmography (RUP) with simultaneous spirometric measurements in anaesthetized, mechanically ventilated horses. STUDY DESIGN Prospective randomized experimental study. ANIMALS Five experimental horses. METHODS Five horses were anaesthetized twice (1 week apart) in random order in lateral and in dorsal recumbency. Nine ventilation modes (treatments) were scheduled in random order (each lasting 4 minutes) applying combinations of different tidal volumes (8, 10, 12 mL kg(-1)) and positive end-expiratory pressures (PEEP) (0, 10, 20 cm H(2)O). Baseline ventilation mode (tidal volume=15 mL kg(-1), PEEP=0 cm H(2)O) was applied for 4 minutes between all treatments. Spirometry and RUP data were downloaded to personal computers. Linear regression analyses (RUP versus spirometric tidal volume) were performed using different subsets of data. Additonally RUP was calibrated against spirometry using a regression equation for all RUP signal values (thoracic, abdominal and combined) with all data collectively and also by an individually determined best regression equation (highest R(2)) for each experiment (horse versus recumbency) separately. Agreement between methods was assessed with Bland-Altman analyses. RESULTS The highest correlation of RUP and spirometric tidal volume (R(2)=0.81) was found with the combined RUP signal in horses in lateral recumbency and ventilated without PEEP. The bias ±2 SD was 0±2.66 L when RUP was calibrated for collective data, but decreased to 0±0.87 L when RUP was calibrated with individual data. CONCLUSIONS AND CLINICAL RELEVANCE A possible use of RUP for tidal volume measurement during IPPV needs individual calibration to obtain limits of agreement within ±20%.

Distribution of ventilation in pregnant Shetland ponies measured by Electrical Impedance Tomography.

The regional distribution of ventilation in conscious standing pregnant Shetland pony mares was investigated by Electrical Impedance Tomography (EIT). Six ponies were repeatedly examined a minimum of four weeks prior to (antepartum, AP) until three weeks after parturition (postpartum, PP). From the cross-sectional ventilation image the ventral to dorsal (V/D), left to right (L/R) ventilation distribution ratio and the relative ventilation in four horizontal regions of interest (ROI) placed symmetrically in the chest was analyzed. Antepartum V/D was 0.74 ± 0.09 on day -28 ± 3 (AP28) and decreased to 0.68 ± 0.10 on day -3 ± 2 (AP3). Postpartum V/D increased significantly (p<0.05) to 0.96 ± 0.08 on day 7 ± 2 (PP7). The L/R ventilation distribution remains unaffected. Ventilation in the most ventral ROI was significantly lower on days AP28 and AP3 compared to PP7. These results suggest that in Shetland ponies late pregnancy compromises the ventilation in ventral (dependent) lung regions. We demonstrated the feasibility of a repeated EIT measurement in standing conscious ponies.

Neuromuscular blockade with rocuronium bromide for ophthalmic surgery in horses

PURPOSE The production of a central eye to ease surgical access for intraocular surgery is generally dependent on the depth of anesthesia. The aim of this study was to evaluate the eyeball position under muscle relaxation with rocuronium during general anesthesia. MATERIAL AND METHODS Twenty horses, body weight 480 ± 62 kg; age 12.6 ± 6.2 years (mean ± SD) were anesthetised for various ophthalmic surgeries. Horses were premedicated with acepromazine, xylazine, and butorphanol intravenously and anesthesia induced with ketamine and diazepam. Anesthesia was maintained with isoflurane in 100% oxygen and 0.6 mL/kg/h of an infusion containing midazolam, ketamine, and xylazine diluted in 500 mL 0.9% NaCl. Horses were mechanically ventilated. Neuromuscular function was assessed with an acceleromyograph (TOF-Guard®) and the N. peroneus superficialis was stimulated every 15 s with a train-of-four stimulation pattern. A dose of 0.3 mg/kg rocuronium was administered intravenously. The changes in the eyeball position were recorded. RESULTS The dose of 0.3 mg/kg rocuronium produced a 100% neuromuscular block in all horses. Onset time and clinical duration of block was 2.38 ± 2.02 min (range 0.5-8) and 32 ± 18.6 min (range 7.7-76.2), respectively. The globe rotated to central position within 31 ± 2.8 s. The whole iris was visible after 42 ± 7.7 s in all horses. No additional bolus of rocuronium was necessary for any surgery. CONCLUSION Neuromuscular blockade with rocuronium bromide can be used safely to facilitate ophthalmic surgery in equines.

TOTAL INTRAVENOUS ANESTHESIA WITH MIDAZOLAM, KETAMINE, AND XYLAZINE OR DETOMIDINE FOLLOWING INDUCTION WITH TILETAMINE, ZOLAZEPAM, AND XYLAZINE IN RED DEER (CERVUS ELAPHUS HIPPELAPHUS) UNDERGOING SURGERY

Sixteen captive female red deer were successfully anesthetized to surgically implant a telemetry system. The deer were immobilized with (mean±SD) 1.79±0.29 mg/kg xylazine and 1.79±0.29 mg/kg tiletamine/zolazepam given intramuscularly with a dart gun. Anesthesia was maintained for 69±2 min using a total intravenous protocol with a catheter placed in the jugular vein. Group X received xylazine (0.5±0.055 mg/kg/hr) and group D, detomidine (2±0.22 μg/kg/hr), both in combination with ketamine (2±0.02 mg/kg/hr) and midazolam (0.03±0.0033 mg/kg/hr), as a constant rate infusion. Anesthesia was reversed with 0.09±0.01 mg/kg atipamezole and 8.7±1.21 μg/kg sarmazenil given intravenously in both groups. These drug combinations provided smooth induction, stable anesthesia for surgery, and rapid recovery. Respiratory depression and mild hypoxemia were seen, and we, therefore, recommend using supplemental intranasal oxygen.

Horses Auto-Recruit Their Lungs by Inspiratory Breath Holding Following Recovery from General Anaesthesia

This study evaluated the breathing pattern and distribution of ventilation in horses prior to and following recovery from general anaesthesia using electrical impedance tomography (EIT). Six horses were anaesthetised for 6 hours in dorsal recumbency. Arterial blood gas and EIT measurements were performed 24 hours before (baseline) and 1, 2, 3, 4, 5 and 6 hours after horses stood following anaesthesia. At each time point 4 representative spontaneous breaths were analysed. The percentage of the total breath length during which impedance remained greater than 50% of the maximum inspiratory impedance change (breath holding), the fraction of total tidal ventilation within each of four stacked regions of interest (ROI) (distribution of ventilation) and the filling time and inflation period of seven ROI evenly distributed over the dorso-ventral height of the lungs were calculated. Mixed effects multi-linear regression and linear regression were used and significance was set at p<0.05. All horses demonstrated inspiratory breath holding until 5 hours after standing. No change from baseline was seen for the distribution of ventilation during inspiration. Filling time and inflation period were more rapid and shorter in ventral and slower and longer in most dorsal ROI compared to baseline, respectively. In a mixed effects multi-linear regression, breath holding was significantly correlated with PaCO2 in both the univariate and multivariate regression. Following recovery from anaesthesia, horses showed inspiratory breath holding during which gas redistributed from ventral into dorsal regions of the lungs. This suggests auto-recruitment of lung tissue which would have been dependent and likely atelectic during anaesthesia.

Reversal of neuromuscular block in companion animals

OBJECTIVE To review the evidence regarding the reversal of neuromuscular block (NMB) in companion animals with emphasis on the development and use of newer agents. DATABASE USED Data sources include scientific reviews and original research publications in both human and veterinary literature using Pubmed and Scopus as search data bases. Unpublished and locally published data on reversal of NMB are presented. CONCLUSIONS Residual NMB has been shown to increase morbidity and mortality in humans and needs to be avoided. It can be detected only by adequate neuromuscular monitoring. The proper use of reversal agents avoids residual NMB and recurarization should not occur. Anticholinesterase inhibitors, such as edrophonium and neostigmine have been used to reverse NMB when the need for this has been established. Reversal is influenced by several factors and a number of undesirable side- effects of these drugs have been reported. Sugammadex, a γ-cyclodextrin, which was designed specifically to encapsulate rocuronium, is more rapid in its actions, has fewer side effects and can reverse profound NMB induced by aminosteroidal muscle relaxants.

Reversal of profound rocuronium or vecuronium-induced neuromuscular block with sugammadex in isoflurane-anaesthetised dogs.

This study evaluated the use of sugammadex for reversal of profound neuromuscular blockade induced with rocuronium or vecuronium in dogs. Anaesthesia was induced and maintained with isoflurane in oxygen in eight dogs on two occasions. Neuromuscular blockade was monitored using peroneal nerve stimulation and acceleromyography. Rocuronium 0.6 mg/kg or vecuronium 0.1mg/kg was administered intravenously (IV), followed 5 min later by sugammadex 8 mg/kg IV. Lag and onset time of rocuronium and vecuronium, lag time from sugammadex injection to recovery of first twitch response, recovery of T1/T0 to 25% and 75%, recovery index, and time to recovery of the train-of-four ratio (T4/T1) to 0.9 were recorded. Cardiovascular and respiratory parameters were also noted. Statistical analysis was performed using one-way ANOVA. Onset time for rocuronium (37 ± 18s; [mean ± SD]) was significantly shorter than for vecuronium (62 ± 15s) (P<0.04). No other significant differences were found between the two groups. After both rocuronium and vecuronium blockade, T4/T1 recovered to 0.9 in under 2 min after sugammadex (58.1 ± 67.8s and 98.1 ± 70.3s, respectively; P<0.32). Sugammadex can reverse profound neuromuscular blockade induced by vecuronium or rocuronium safely and rapidly in isoflurane-anaesthetised dogs.

Physiologic Factors Influencing the Arterial-To-End-Tidal CO2 Difference and the Alveolar Dead Space Fraction in Spontaneously Breathing Anesthetised Horses

The arterial to end-tidal CO2 difference (P(a-ET)CO2) and alveolar dead space fraction (VDalvfrac = P(a-ET)CO2/PaCO2), are used to estimate Enghoff’s “pulmonary dead space” (V/QEng), a factor which is also influenced by venous admixture and other pulmonary perfusion abnormalities and thus is not just a measure of dead space as the name suggests. The aim of this experimental study was to evaluate which factors influence these CO2 indices in anesthetized spontaneously breathing horses. Six healthy adult horses were anesthetized in dorsal recumbency breathing spontaneously for 3 h. Data to calculate the CO2 indices (response variables) and dead space variables were measured every 30 min. Bohr’s physiological and alveolar dead space variables, cardiac output (CO), mean pulmonary pressure (MPP), venous admixture (Q˙s/Q˙t), airway dead space, tidal volume, oxygen consumption, and slope III of the volumetric capnogram were evaluated (explanatory variables). Univariate Pearson correlation was first explored for both CO2 indices before V/QEng and the explanatory variables with rho were reported. Multiple linear regression analysis was performed on P(a-ET)CO2 and VDalvfrac assessing which explanatory variables best explained the variance in each response. The simplest, best-fit model was selected based on the maximum adjusted R2 and smallest Mallow’s p (Cp). The R2 of the selected model, representing how much of the variance in the response could be explained by the selected variables, was reported. The highest correlation was found with the alveolar part of V/QEng to alveolar tidal volume ratio for both, P(a-ET)CO2 (r = 0.899) and VDalvfrac (r = 0.938). Venous admixture and CO best explained P(a-ET)CO2 (R2 = 0.752; Cp = 4.372) and VDalvfrac (R2 = 0.711; Cp = 9.915). Adding MPP (P(a-ET)CO2) and airway dead space (VDalvfrac) to the models improved them only marginally. No “real” dead space variables from Bohr’s equation contributed to the explanation of the variance of the two CO2 indices. P(a-ET)CO2 and VDalvfrac were closely associated with the alveolar part of V/QEng and as such, were also influenced by variables representing a dysfunctional pulmonary perfusion. Neither P(a-ET)CO2 nor VDalvfrac should be considered pulmonary dead space, but used as global indices of V/Q mismatching under the described conditions.

Fetal articular cartilage regeneration versus adult fibrocartilaginous repair: secretome proteomics unravels molecular mechanisms in an ovine model

ABSTRACT Osteoarthritis (OA), a degenerative joint disease characterized by progressive cartilage degeneration, is one of the leading causes of disability worldwide owing to the limited regenerative capacity of adult articular cartilage. Currently, there are no disease-modifying pharmacological or surgical therapies for OA. Fetal mammals, in contrast to adults, are capable of regenerating injured cartilage in the first two trimesters of gestation. A deeper understanding of the properties intrinsic to the response of fetal tissue to injury would allow us to modulate the way in which adult tissue responds to injury. In this study, we employed secretome proteomics to compare fetal and adult protein regulation in response to cartilage injury using an ovine cartilage defect model. The most relevant events comprised proteins associated with the immune response and inflammation, proteins specific for cartilage tissue and cartilage development, and proteins involved in cell growth and proliferation. Alarmins S100A8, S100A9 and S100A12 and coiled-coil domain containing 88A (CCDC88A), which are associated with inflammatory processes, were found to be significantly upregulated following injury in adult, but not in fetal animals. By contrast, cartilage-specific proteins like proteoglycan 4 were upregulated in response to injury only in fetal sheep postinjury. Our results demonstrate the power and relevance of the ovine fetal cartilage regeneration model presented here for the first time. The identification of previously unrecognized modulatory proteins that plausibly affect the healing process holds great promise for potential therapeutic interventions. Summary: Secretome proteomics identifies differential regulation of inflammation modulators during fetal and adult articular cartilage defect healing, offering novel strategies for therapy.