Determination of the toxic dose of lidocaine in dogs and its corresponding serum concentration

LIDOCAINE is a local analgesic drug that is often used in dogs and cats, and also in other domestic, wild, exotic and laboratory animals. It is used in a variety of ways: topically, by local infiltration, by epidural injection, by nerve block, or by intravenous injection into a peripheral vein to provide limb analgesia. In human beings, lidocaine has been used intravenously in low doses to reduce the pain associated with the injection of some intravenous agents (Nolan 2000). Lidocaine also has an anti-arrhythmic effect, and is used for the acute control of life-threatening ventricular arrhythmia in dogs and cats (Lunney and Ettinger 1995). In equine medicine, it is also used in the treatment of postoperative ileus (Malone and others 1998). Lidocaine has significant side effects: the most common sign of intoxication is seizure, while bradyarrhythmia and conduction disturbances are more rare (Lunney and Ettinger 1995). Muscle tremor is a common clinical sign of lidocaine intoxication in horses (Meyer and others 2001). The approximate maximum dose by infiltration before toxic signs become apparent is not known with any certainty, although Hall and others (2000a) have quoted it to be 6 to 10 mg/kg in dogs. According to Skarda (1998), the convulsive toxic dose of intravenously administered lidocaine in conscious dogs is 11 to 20 mg/kg and the lethal dose is 16 to 28 mg/kg. Lidocaine in biological samples has been analysed by immunoassay (Elin and others 1997, Liu-Allison and others 1997), reversed-phase liquid chromatography (Manna and others 2002), and gas chromatography-mass spectrometry (GC-MS) (Ohshima and Takayasu 1999). This short communication describes a study to describe lidocaine intoxication in dogs, to determine the total toxic dose of lidocaine and serum lidocaine concentrations that resulted in clinical signs of intoxication, and to record the effects of lidocaine on the cardiovascular system. It was hypothesised that lidocaine intoxication is common because the therapeutic and toxic doses are similar. The study was approved by a legal committee; 19 dogs were studied, three males and 16 females aged between three and 60 months (mean [sd] 19·3 [16·3] months), and weighing between 2·2 and 24·8 kg (14·5 [7·9] kg). During the experiment, the animals were placed in sternal recumbency on the table, and a standard microclimate was maintained in the room. Emotional reassurance (gentle restraint, petting and talking) was provided by the handler throughout the whole procedure. Food was withheld for six hours before the study. The health of the dogs was determined by means of a clinical examination. The dogs’ blood pressure was measured by an oscillometric method using a cuff width of 40 per cent of the circumference of the metacarpus, and the heart rate was measured at the femoral artery. An oscillometric manometer was used (Neonatal model BC 203 NC automated sphygmomanometer; Air-shields). An electrocardiogram (ECG) was also recorded (Ultraview 1050 anesthesia monitor; Spacelabs Medical). An intravenous catheter (20, 22 or 24 G) was inserted into the cephalic vein, and a 3·5 ml blood sample was taken from the catheter (BD vacutainer SST II Advance 3·5 ml). For drug administration, a syringe pump (SEP 11S; Ascor) was used. The syringe was connected to the intravenous catheter by means of an extension line. An initial dose of 4 mg/kg lidocaine (Lidokain 2 per cent; Belupo) was administered intravenously, followed by a constant-rate infusion at a dose of 0·3 mg/kg per minute. After the lidocaine was administered, the following parameters were measured at 10-minute intervals until a toxic effect was observed: the systolic, diastolic and mean blood pressures, heart rate and ECG. Blood samples were taken at 10minute intervals from another limb, from the cephalic vein or the lateral saphenous vein, using a needle. A toxic effect was determined when a muscle tremor was seen, and the infusion of lidocaine was immediately discontinued. The total dose administered (that is the toxic dose) was recorded, and the systolic, diastolic and mean blood pressures, heart rate and the ECG were recorded again. A final blood sample was then taken. A saline infusion was administered, and the dog was monitored for the next hour. After centrifugation, a minimum of 1 ml serum was removed and frozen at –70°C. Lidocaine in the serum was analysed by GC-MS. Statistica 5.0 for Windows was used for the statistical analysis (Statsoft). Shapiro Wilks’ W test was used to determine the distribution of the lidocaine concentration measurements and the distribution of heart rate and blood pressures. Analysis of variance and Duncan’s test were used to compare between age groups. Significance was set at P<0·05 for all tests. The mean (sd) serum lidocaine concentration 10 minutes after the initial administration of lidocaine as 2·4 (0·6) μg/ml, and after 20 minutes it was 2·7 (1·0) μg/ml. The mean serum lidocaine concentration at the time of observation of toxic effect (LTC) was 2·7 (1·1) μg/ml. The mean time from the beginning of lidocaine administration to the observation of a toxic effect was 24 (13·6) minutes, and the total toxic dose of lidocaine was 11·1 (4·1) mg/kg. Six of the dogs (31·58 per cent) were three to five months old, six (31·58 per cent) were seven to 23 months old, and seven (36·84 per cent) were 24 to 60 months old. To determine whether there was any age-dependent variation in the parameters, the data were broken down by age; the mean (sd) values for dogs in the three age groups are shown in Table 1. Before the administration of lidocaine, the mean (sd) was 136·7 (15·1) bpm; on observation of the toxic effect it was 129·4 (24·8) bpm. The mean systolic blood pressure before the administration of lidocaine was 113·3 (12·3) mmHg, and at the observation of toxic effect it was 82·6 (8·5) mmHg, this decrease was significant. The corresponding mean diastolic blood pressures were 75·8 (13·8) mmHg and 85·9 (13·7) mmHg, respectively, and the overall mean blood pressures were 94·6 (8·4) mmHg before the administration of lidocaine and 91·9 (14·4) mmHg, upon observation of toxic effect. During the study, no changes in ECG parameters (P-wave duration, P=R interval, R-R interval and Q-T interval) were observed that were considered to be outside the normal range. The LTC in the present study (2·7 [1·1] μg/ml) was significantly lower than in the only other published LTC in dogs, 8·21 (1·69) μg/ml (Wilcke and others 1983). This difference could be explained by different modes of lidocaine administration (rapid v slow rate of administration) or the use of a different sign to indicate the time when toxic effects began (muscle tremor in the present study; the toxic extension phase in the study of Wilcke and others [1983]). In cats, the mean highest serum concentration of lidocaine after intravenous regional anaesthesia was 3·10 (1·11) μg/ml; signs of intoxication were not observed (Kushner and others 2002). In human volunteers, muscle fasciculations Veterinary Record (2007) 160, 374-375