Ludo J. Hellebrekers

Dexmedetomidine constant rate infusion for 24 hours during and after propofol or isoflurane anaesthesia in dogs

OBJECTIVE To evaluate cardiovascular and respiratory effects and pharmacokinetics of a 24-hour intravenous constant rate infusion (CRI) of dexmedetomidine (DMED) during and after propofol (PRO) or isoflurane (ISO) anaesthesia in dogs. STUDY DESIGN Prospective, randomized, cross-over study. ANIMALS Ten healthy adult Beagles. METHODS Instrumented dogs received a DMED-loading bolus (25 microg m(-2)) at time 0 followed by a 24-hour CRI (25 microg m(-2) hour(-1)), with PRO or ISO induction/maintenance of anaesthesia during the first 2 hours (PRO and ISO treatment groups, respectively). Cardiovascular, respiratory, blood gas, airway gas, serum chemistry variables and DMED plasma concentration data were collected at -15, 5, 15, 30, 45, 60, 90 and 120 minutes. A number of cardiorespiratory and tissue oxygenation variables were calculated from the above data. After the 2-hours of anaesthesia, heart and respiratory rates and electrocardiograms were recorded and DMED plasma concentrations were determined for up to 26 hours. RESULTS Vasopressor effects and the decrease in heart rate (HR) and cardiac index induced by DMED were greater for PRO than ISO, but were within clinically acceptable ranges. Adequate oxygenation was maintained above the critical O(2) delivery level. The overall incidence of unfavourable arrhythmias was low and tended to vary inversely with HR. Mean DMED plasma concentration ranged from 0.23 to 0.47 ng mL(-1) for both groups during the 24-hour CRI with a mean elimination half-life of approximately 0.46 hour. CONCLUSION AND/CLINICAL RELEVANCE: DMED CRI resulted in typical alpha(2)-agonist induced haemodynamic changes with minimal respiratory effects, and appeared to be an efficacious adjunct during and after PRO or ISO anaesthesia in healthy dogs.

A comparison between medetomidine-ketamine and medetomidine-propofol anaesthesia in rabbits

We investigated the effects of combinations of the α2-agonist medetomidine with either ketamine or propofol for their overall quality of anaesthesia, including the possible concomitant changes in respiratory and circulatory function in New Zealand White rabbits. Medetomidine was administered at 0.35 mg/kg, intramuscularly. Following sedation, ketamine (5 mg/kg) or propofol (2 and 3 mg/kg) were administered intravenously via the ear vein. Data on reflexes (palpebral, corneal, ear-pinch and toe-pinch), jaw muscle tone and physiologic parameters (heart rate, blood pressure, respiration rate, body temperature) were recorded before and after administration of drugs. Intermittent arterial blood sampling was performed at predetermined intervals before and after anaesthesia. The results show that the ear-pinch and toe-pinch reflexes and the jaw muscle tone are reliable indices to determine surgical anaesthetic depth. A surgical level of anaesthesia could be obtained reliably with the combination medetomidine-ketamine and medetomidine-propofol (3 mg/kg) with a duration of 19 min (variation 10 to 40 min, n=6) and 11 min (variation 5 to 15 min, n=6), respectively. Propofol administered at 2 mg/kg did not produce an adequate anaesthetic level. The data from this study demonstrate a high degree of predictability in achieving a fast induction and adequate anaesthetic depth together with a low incidence of untoward side-effects and a zero mortality with the combinations investigated. The data from the medetomidine-ketamine group show that, although adequate anaesthetic depth of medium duration is achieved, the arterial oxygen tension is reduced to hypoxemic levels. With the use of this combination, the supplemental administration of oxygen is advised. With the combination of medetomidine-propofol (3 mg/kg) a short duration anaesthesia of adequate depth was achieved, whereby physiological variables all remained within acceptable ranges. The use of medetomidine-propofol, in combination with the α2-antagonist atipamezole to shorten recovery time, will provide reliable and very versatile anaesthesia in rabbits.

Partition coefficients (n-octanol/water) of N-butyl-p-aminobenzoate and other local anesthetics measured by reversed-phase high-performance liquid chromatography

For the determination of the logarithmic partition coefficients between n-octanol and water (log P(o/w)) of local anesthetics, the pH of the aqueous phase needs to be adjusted to high values to ensure that the local anesthetics are in the unionized form. Using the shake-flask or the stir-flask method, this high pH may catalyze hydrolysis, leading to increasing amounts of impurities in time. These impurities exclude non-selective quantification methods like UV spectrometry and require repetitive quantitative analysis of both liquid phases resulting in a tedious and time-consuming method. A rapid reversed-phase HPLC method was developed to measure log P(o/w) of the local anesthetics N-butyl-p-aminobenzoate, methyl-p-aminobenzoate, benzocaine, procaine, mepivacaine, prilocaine, lidocaine, bupivacaine, etidocaine, tetracaine and oxubuprocaine.

Clinical evaluation of the efficacy and safety of a constant rate infusion of dexmedetomidine for postoperative pain management in dogs.

OBJECTIVE To compare postoperative analgesia provided by a constant rate infusion (CRI) of dexmedetomidine (DMED) to that of a well-established positive control [morphine (MOR)] in critically ill dogs. The sedative, cardiorespiratory effects and clinical safety of a 24-hour DMED CRI were also evaluated. STUDY DESIGN Prospective, randomised, blinded, positive-controlled parallel-group clinical study. ANIMALS Forty hospitalised, client-owned dogs requiring post-operative pain management after invasive surgery. METHODS After surgery, a loading dose of either DMED (25 microg m(-2)) or MOR (2500 microg m(-2)) followed by a 24-hour CRI of DMED (25 microg m(-2) hour(-1)) or MOR (2500 microg m(-2) hour(-1)) was administered. Pain was measured using the Short Form of the Glasgow Composite Measure Pain Scale, sedation and physiological variables were scored at regular intervals. Animals considered to be painful received rescue analgesia and were allocated to a post-rescue protocol; animals which were unresponsive to rescue analgesia were removed from the study. Data were analysed with anova, two-sample t-tests or Chi-square tests. Time to intervention was analysed with Kaplan-Meier methodology. RESULTS Forty dogs were enrolled. Twenty dogs (9 DMED and 11 MOR) did not require rescue analgesia. Eleven DMED and eight MOR dogs were allocated to the post-rescue protocol and seven of these removed from the study. Significant differences in pain scores between groups were not observed during the first 12 hours, however, DMED dogs were less (p = 0.009) painful during the last 12 hours. Sedation score over the entire 24-hour study was not significantly different between groups. CONCLUSION / CLINICAL RELEVANCE: Dexmedetomidine CRI was equally effective as MOR CRI at providing postoperative analgesia and no clinically significant adverse reactions were noted. This study shows the potential of DMED to contribute to a balanced postoperative analgesia regimen in dogs.

Medetomidine as a premedicant for ketamine, propofol or fentanyl anaesthesia in dogs

This study evaluated the quality of anaesthesia and the cardiorespiratory effects induced by the combination of medetomidine with either ketamine, propofol or fentanyl. Medetomidine premedication (1000 or 1500 μg/m2 body surface area) was followed by intravenous induction of anaesthesia with ketamine (3.0 mg/kg), propofol (2.0 mg/kg) or fentanyl (2.0 μg/kg) in bitches undergoing elective ovariohysterectomy. Anaesthesia was prolonged by incremental doses of the induction agents as necessary. The mean (sem) overall doses (including induction) were 0.09 (0.01) mg/kg/min for ketamine, 0.06 (0.01) mg/kg/min for propofol and 0.07 (0.005) μg/kg/min for fentanyl during procedures which lasted 88 (6) minutes, 72 (3) minutes and 79 (7) minutes, respectively. At the end of the procedure, medetomidine was antagonised with atipamezole. The quality of anaesthesia, heart rate and arterial blood pressure were recorded continuously and arterial blood gases were measured at intervals. At the end of the procedure, the animals received 10 μg/kg buprenorphine intramuscularly for postoperative analgesia. From the adequacy of anaesthesia, the lack of significant adverse side effects and the reliable and rapid recovery it is concluded that, in healthy dogs anaesthetised with ketamine or propofol, medetomidine is a satisfactory sedative-analgesic premedicant. The differences in haemodynamics and the quality of recovery suggest that the combination of medetomidine with propofol provided the better quality anaesthesia. The combination of medetomidine with fentanyl was unsuitable for obtaining surgical anaesthesia in spontaneously breathing animals owing to the severity of the respiratory depression at dosages needed for general anaesthesia.

Neurophysiological assessment of the sedative and analgesic effects of a constant rate infusion of dexmedetomidine in the dog

The sedative and analgesic effects of continuous rate infusion (CRI) of dexmedetomidine (DEX) were investigated in Beagle dogs (n=8) using auditory and somatosensory evoked potentials (AEPs and SEPs) recorded before, during and after a CRI of saline or DEX (1.0, 3.0, 5.0 μg/kg bolus, followed by 1.0, 3.0, 5.0 μg/kg/h CRI, respectively). The results showed a significant reduction in AEP at doses of 1.0 μg/kg/h and above and a significant reduction of the SEP at doses of 3.0 and 5.0 μg/kg/h. Neither the AEP nor the SEP was further reduced at 5.0 μg/kg/h when compared to 3.0 μg/kg/h, although a slower return towards baseline values was observed at 5.0 μg/kg/h. The mean plasma levels (±SEM) of DEX during infusion were 0.533±0.053 ng/mL for the 1.0 μg/kg/h dose, 1.869±0.063 ng/mL for the 3.0 μg/kg/h dose and 4.017±0.385 for the 5.0 μg/kg/dose. It was concluded that in adult dogs, a CRI of DEX had a sedative and analgesic effect that could be described quantitatively using neurophysiological parameters. Sedation was achieved at lower plasma levels than required for analgesia, and DEX had a longer (but not larger) effect with infusion rates above 3.0 μg/kg/h.

Clinical efficacy and safety of propofol or ketamine anaesthesia in dogs premedicated with medetomidine

Combinations of medetomidine with either propofol or ketamine were compared for the sedation and induction of anaesthesia in dogs undergoing a variety of surgical (60 per cent) and non.surgical (40 per cent) procedures. Eighty.four dogs were used at four sites. Medetomidine was administered intramuscularly at a dose of 1000 μg/m2 body surface area 10 to 15 minutes before the induction of anaesthesia by the administration of propofol (n = 44) or ketamine (n = 40) dosed to effect. The dogs became sedated by medetomidine after a mean (sd) time of 6.7 (5.4) minutes, and their heart rates and respiration rates decreased. Sixteen of the dogs suffered an adverse effect, 13 of them vomited. Anaesthesia was induced by the intravenous administration of propofol (2.1 [0.7] mg/kg) or ketamine (3.7 [1.9] mg/kg), and further doses of the anaesthetic were given, depending on the length of the operation, once in 17 per cent, twice in 11 per cent and three or more times in 24 per cent of the cases. The heart rate of the dogs anaesthetised with ketamine was significantly higher than that of the dogs anaesthetised with propofol, but there were no other significant physiological differences. There were 11 adverse side.effects in the ketamine group compared with five in the propofol group and they were generally more severe. The quality of the recovery from anaesthesia was considered to be smooth in 89 per cent of the propofol group but in only 63 per cent of the ketamine group.

Differences in response to anaesthetics and analgesics between inbred rat strains.

Differences in response to analgesic and anaesthetic drugs can partly be attributed to variations in the genetic background of experimental animals. This study was carried out to determine differences in the response of inbred rat strains to a selection of analgesics and drugs used in anaesthetic protocols. A cross between the most contrasting strains can then be phenotyped in future studies in order to localize quantitative trait loci (QTLs) involved in analgesic/anaesthetic drug sensitivity. Eight inbred strains (n = 6 rats/strain) were selected for the study: the pigmented ACI, BN and COP strains and the albino F344, LEW, SHR, WAG and WKY strains. Each rat was injected intravenously with two analgesics (buprenorphine 0.05 mg/kg and nalbuphine 1 mg/kg) and three drugs used in anaesthetic protocols (propofol 25 mg/kg, medetomidine 50 μg/kg and ketamine 10 mg/kg), respectively, using a crossover design. Analgesic responses were assessed using an analgesiometric procedure. The sleep time of the rat and, where applicable, the interval between injection and loss of righting reflex were used to determine the anaesthetic response. Six out of eight strains responded significantly different from each other to the analgesic effect of buprenorphine with the ACI strain as hyper-responder. The tail withdrawal latency at 55°C of the F344 and WKY rats using buprenorphine was not significantly different from baseline tail withdrawal latencies. In this study, all strains were non-responsive to the analgesic effects of nalbuphine. The response to all three drugs used in anaesthetic protocols differed significantly among the strains. The F344 and BN strains were relatively resistant to the sedative effects of medetomidine. Use of ketamine was abandoned in the ACI and BN strains when the first two animals of both strains died soon after induction. With all three drugs the sleep time of albino rats was significantly longer compared with that of the pigmented ones. We conclude that the results from this study can be used in future studies where QTLs for the sensitivity to anaesthetic/analgesic drugs are localized.

Analgesics in mice used in cancer research: reduction of discomfort?

During the last decades, an increase is apparent in the use of analgesics for laboratory animals in situations where this was previously considered unnecessary. Mice with advanced tumours often show clear signs of discomfort which may be a result of chronic pain or a result of general ill-being. The syngeneic murine tumour model most frequently used in our experiments was used to investigate whether this discomfort can be reduced with an analgesic. Twenty DBA/2 mice bearing SL2 lymphoma were given 0.5 mg/kg buprenorphine (Temgesic®) in food gel twice daily, 20 tumour-bearing mice were given control food gel at the same times. Indicators of well-being were monitored daily. These included behavioural parameters such as exploration, grooming, and posture; food and water consumption and fur quality. All mice showed a clear increase of discomfort with time: explorative behaviours and grooming decreased, while sitting in hunched posture increased. Food and water consumption and fur quality also decreased. Major significant differences between the buprenorphine treated group and the control group were not apparent. In conclusion, we could not document a positive effect or buprenorphine on discomfort in mice as evaluated by our scoring system. It remains possible that pain itself was not the primary cause of the discomfort in mice bearing these tumours, or that the analgesic effect of buprenorphine was insufficient under these circumstances.

Effects of a local anaesthetic and NSAID in castration of piglets, on the acute pain responses, growth and mortality.

The present study addresses the questions whether on-farm use of local anaesthesia with lidocaine leads to a reduction in pain responses during castration, and whether the non-steroidal anti-inflammatory drug meloxicam improves technical performance after castration of piglets. Five treatments were included in the study: (1) castration without anaesthesia or analgesia (CAST), (2) castration after local anaesthesia with lidocaine (LIDO), (3) castration after administration of meloxicam (MELO), (4) castration after lidocaine and meloxicam (L + M) and (5) sham castration (SHAM). To reduce litter influences, each treatment was present in each of the 32 litters (n = 32 per treatment). During castration, vocalizations were recorded continuously. Blood samples were collected 15 min before and 20 min after castration for determination of plasma levels of total cortisol, glucose, lactate and creatine kinase (CK). Mortality was registered and piglets were weighed several times to calculate growth. Several aspects of vocalizations during castration showed consistent and significantly different levels in CAST compared with LIDO, L + M and SHAM. CAST piglets squealed longer, louder and higher. Vocalizations of MELO piglets most resembled those of CAST. An increase in cortisol was seen in all treatments. However, in SHAM piglets this increase was significantly lower than in the other treatments. LIDO piglets showed a significantly smaller increase in plasma cortisol levels compared with CAST and MELO. L + M piglets differed significantly only from the SHAM group. Lactate levels differed significantly between LIDO and MELO, the level in LIDO being decreased after castration. In the other treatments an increase was measured. No treatment effects were found in plasma glucose and CK levels, nor in growth and mortality of the piglets. In conclusion, on the basis of vocalizations and plasma cortisol, local anaesthesia with lidocaine reduces pain responses in piglets during castration. A positive effect of meloxicam on technical performance was not found.