Cardiopulmonary Effects of Constant-Rate Infusion of Lidocaine for Anesthesia during Abdominal Surgery in Goats

Abstract

Lidocaine is commonly used in ruminants but has an anecdotal history of being toxic to goats. To evaluate lidocaine's effects on selected cardiopulmonary parameters. Isoflurane-anesthetized adult goats (n = 24) undergoing abdominal surgery received a loading dose of lidocaine (2.5 mg/kg) over 20 min followed by constant-rate infusion of lidocaine (100 μg/kg/min); control animals received saline instead of lidocaine. Data collected at predetermined time points during the 60-min surgery included heart rate, mean arterial blood pressure, pO₂, and pCO₂. According to Welch 2-sample t tests, cardiopulmonary variables did not differ between groups. For example, after administration of the loading dose, goats in the lidocaine group had a mean heart rate of 88 ± 28 bpm, mean arterial blood pressure of 70 ± 19 mm Hg, pCO₂ of 65 ± 13 mm Hg, and pO₂ of 212 ± 99 mm Hg; in the saline group, these values were 90 ± 16 bpm, 76 ± 12 mm Hg, 61 ± 9 mm Hg, and 209 ± 83 mm Hg, respectively. One goat in the saline group required an additional dose of butorphanol. Overall our findings indicate that, at the dose provided, intravenous lidocaine did not cause adverse cardiopulmonary effects in adult goats undergoing abdominal surgery. Adding lidocaine infusion during general anesthesia is an option for enhancing transoperative analgesia in goats.

Unique aspects of the anatomy and physiology of the goat (Capra hircus) provide a basis for the choice of this species in research and teaching. Research using goats includes such diverse fields as orthopedics, reproduction, infectious disease, genetics, and endocrinology.^9,20,35 The US Department of Defense uses goats for various research applications and training exercises.⁹ In addition, some veterinary schools are using goats instead of dogs in surgical training labs because of public sentiment and increasing costs associated with dogs.¹⁰ Although goats represent a small percentage of the total number of animals used in research, their use as an accepted experimental animal model is increasing.^9,20 An important aspect of these uses is the need to offer adequate analgesia when these animals are exposed to any type of noxious stimulation.

Compared with sheep, goats are considered to have greater sensitivity to pain and intolerance to some painful procedures.¹¹ The mechanism underlying sudden death due to poor management of postsurgical pain has been suggested to involve either catecholamine-induced ventricular fibrillation or vagal stimulation leading to cardiac asystole.¹³ Pain in animals can be recognized and evaluated by using physiologic and behavioral parameters. The assessment of pain in goats is often challenging, because pain may manifest through diverse signs, including increased vocalization, tachycardia, tachypnea, hypertension, inappetence, bruxism, immobility, and abnormal gait.^22,36 Local anesthetics are the most common analgesic agents used in goats for surgical procedures such as dehorning and castration. These drugs, especially lidocaine, can be used to prevent behavioral responses associated with painful procedures. The primary mechanism of action of local anesthetics is sodium channel inhibition, thus preventing nerve conduction in Aδ and C fibers.^2,36 However, lidocaine for analgesia can also be provided intravenously through constant-rate infusion (CRI) and thus decreases the minimum alveolar concentration of inhalation anesthetics in humans,²² horses,⁸ ponies,⁶ dogs,³⁸ cats,²⁹ and goats.⁷ In addition, intravenous lidocaine reportedly provides analgesia and reduces opioid consumption after abdominal surgeries in humans¹⁷ and calves.³⁷ The analgesic effects of intravenous lidocaine may be due to suppression of tonic neural discharges in injured peripheral fibers, and a direct action on spinal transmission in the dorsal horn of the spinal cord has been proposed and likely involves N-methyl-D-aspartate receptor antagonism.^17,24,40

The objective of the present study was to evaluate the effect on selected cardiovascular and pulmonary parameters of lidocaine infusion as additional analgesia in goats undergoing surgery in a clinical setting. We hypothesized that lidocaine CRI in anesthetized goats would maintain clinically acceptable cardiopulmonary variables and enhance analgesia in goats anesthetized by using xylazine, ketamine, butorphanol, and isoflurane.

Materials and Methods

Animals.

Healthy, mixed-breed, adult goats (n = 24; female, 6; male, 18; age, 1 to 2 y; body weight [mean ± 1 SD], 31.9 ± 9.8 kg) were anesthetized for a surgical teaching laboratory in the department of Veterinary Clinical Sciences. All goats were of appropriate body condition and determined to be in good health on the basis of results of physical examination. Goats were group-housed in indoor pens and were allowed an acclimation period of at least 14 d before undergoing surgery. The animal care followed the recommendations outlined in the Guide for the Care and Use of Laboratory Animals.^15,31 Food was withheld for 24 h and water for 12 h prior to anesthesia. The Washington State University IACUC approved this study.

Experimental design.

By using a random-number generator (Excel, Microsoft, Redmond, WA), the goats were randomized into 2 groups of 12 animals each to receive either lidocaine or saline by bolus intravenous injection followed by CRI. The investigators were blinded to the treatments. Planned interventions for hypotension and hypoventilation during surgery were included as described following.

Anesthesia and monitoring.

All goats were premedicated with xylazine (0.13 mg/kg IM; AnaSed 20 mg/mL, Akorn, Decatur, IL). After 10 min, a 20-gauge catheter was placed in a jugular vein for the injection of ketamine (2.2 mg/kg IV; Ketaset 100 mg/mL, Boehringer Ingelheim Vetmedica, St Joseph, MO) and butorphanol (0.1 mg/kg IV; Torbugesic 10 mg/mL, Fort Dodge Animal Health, New York, NY) to induce anesthesia. The animals were promptly intubated with a cuffed endotracheal tube. Once the endotracheal tube was secured and the cuff pressure was checked, the goats were connected to a small-animal anesthetic machine, and anesthesia was maintained with initial 1% isoflurane (Isothesia, Henry Schein Animal Health, Dublin, OH) in 100% oxygen at a flow rate of 3 L/min delivered via a circle rebreathing system. Goats were positioned in dorsal recumbency with the head slightly lower than the body. Lactated Ringers solution (Veterinary Lactated Ringers Injection USP; Abbott Laboratories, North Chicago, IL) was infused through the jugular catheter at rate of 10 mL/kg/h.

Selected cardiovascular and pulmonary variables were monitored during anesthesia by using a multiparameter monitor (MindRay DPM, MindRay DS USA, Mahwah, NJ). Electrocardiographic electrodes were placed on each goat in a lead II configuration for monitoring heart rate and rhythm, and arterial SpO₂ was estimated by using a lingual probe. Expired gases were sampled continually with a side-stream gas analyzer at a rate of 50 mL/min for measurement of the end-tidal isoflurane and CO₂ concentrations. The gas analyzer unit was automatically calibrated at the start of each anesthesia. Body temperature was monitored through an esophageal probe, and blankets helped to maintain the body temperature between 38.2 °C to 39.5 °C. End-tidal isoflurane and CO₂ values, respiratory rate, heart rate, and SpO₂ were measured every 5 min during anesthesia. To maintain normocapnia, ventilation was assisted when end-tidal CO₂ exceeded 45 mm Hg. Blood pressure was monitored continuously by using a disposable calibrated pressure transducer placed at the level of the right atrium and connected to a 24-gauge catheter introduced into either the medial branch of the rostral auricular artery or the medial facial artery. Systolic, diastolic, and mean arterial blood pressures were monitored continuously and recorded every 5 min. To maintain normotension, a dobutamine CRI (Dobutamine injection USP, Hospira, Lake Forest, IL) at 1 to 5 μg/kg^/min was started when mean arterial blood pressure was less than 60 mm Hg. To maintain an adequate surgical depth of anesthesia, end-tidal isoflurane was adjusted on the basis of clinical signs, such as purposeful movements in response to surgical stimuli, eye reflexes (corneal and palpebral), and jaw tone and from cardiopulmonary responses monitored. Arterial pO₂ and pCO₂, pH, arterial SaO_2, bicarbonate concentration, lactate concentration, and base excess were measured from 0.5-mL arterial blood samples collected in heparinized syringes and immediately assayed by using a calibrated point-of-care analyzer (Vetscan, Abaxis, Union City, CA). The samples were obtained before (T0) and immediately after (T1) the loading bolus was administered. A final arterial blood sample was collected after the termination of CRI, which was given for at least 1 h.

Drug administration.

A loading dose of lidocaine (2.5 mg/kg IV; Lidocaine HCl injection, 2%, USP, Hospira) or equal volume of saline was given over 20 min and a CRI was delivered by using a syringe pump (Medfusion 3500, Smiths Medical MD, St Paul, MN). For the lidocaine group, 20 mL of the lidocaine solution was drawn into an unlabeled 20-mL syringe and delivered at a rate of 100 μg/kg/min. For the control group, a 20-mL syringe with isotonic saline solution was placed in a syringe pump and given at the same rate. This lidocaine loading dose and rate of infusion were selected based on a previous study in goats.⁷ CRI was administered for at least 1 h or until the surgical procedure was completed.

Surgical procedure.

Goats (n = 8 per group) were randomly selected to undergo one of the following abdominal surgeries: tube cystotomy, right paramedian abomasopexy, or right paralumbar fossa celiotomy. All surgical procedures were performed according to previously described techniques.^34,39 The duration of the surgical stimuli for this study was standardized to be at least 60 min and no more than 120 min. Whenever a marked rise in the cardiovascular or respiratory system in response to the abdominal surgery occurred, suggesting pain, the goat received an addition intravenous dose of butorphanol. None of the goats was allowed to recover from anesthesia, and all were euthanized by using an overdose of intravenous pentobarbital at the end of the surgical procedure.

Data analysis.

Statistical analysis was performed by using Welch 2-sample t tests to compare the treatment groups over time. In addition, the data were compared visually by using a plotting technique (https://www.r-project.org/). Significance was set at a P value of less than 0.05. The cardiovascular and pulmonary parameters are presented as mean ± 1 SD.

Results

One goat from the control group was removed from this study because we were unable to place the required arterial catheter.

Cardiopulmonary effects due to CRI did not differ between the lidocaine and saline groups nor within each group over time (Table 1). Because of the unreliability of the type of probe used (fingertip ‘clothespin’ style), values for SpO₂ by pulse oximetry were not analyzed. Instead, tissue oxygenation was assessed from the arterial blood samples collected during anesthesia. There was no significant difference between groups in pO₂, SaO₂, or lactate concentration, which are oxygen-associated parameters, or in pCO₂, pH, base excess, or HCO₃.

Table 1.

Cardiopulmonary and arterial blood-gas values from isoflurane-anesthetized goats that received lidocaine by constant-rate infusion (100 μg/kg/min) during abdominal surgery

		T0	T1	15 min	30 min	45 min	60 min	T2
Heart rate, bpm
	Saline	86 ± 14	90 ± 18	91 ± 18	98 ± 19	101 ± 22	100 ± 17	101 ± 23
	Lidocaine	91 ± 20	88 ± 28	82 ± 23	79 ± 19	81 ± 17	80 ± 20	85 ± 20
Systolic arterial blood pressure, mm Hg
	Saline	86 ± 23	91 ± 17	91 ± 19	91 ± 25	92 ± 21	95 ± 25	89 ± 23
	Lidocaine	72 ± 18	84 ± 21	91 ± 17	80 ± 18	77 ± 15	87 ± 17	84 ± 17
Diastolic arterial blood pressure, mm Hg
	Saline	57 ± 19	68 ± 11	71 ± 18	69 ± 19	73 ± 20	69 ± 6	66 ± 15
	Lidocaine	48 ± 12	61 ± 18	70 ± 12	62 ± 16	61 ± 14	60 ± 11	63 ± 13
Mean arterial blood pressure, mm Hg
	Saline	67 ± 20	76 ± 12	77 ± 16	76 ± 21	79 ± 18	83 ± 16	74 ± 18
	Lidocaine	56 ± 14	70 ± 19	76 ± 13	68 ± 17	68 ± 12	68 ± 12	69 ± 14
Respiratory rate, breaths per minute
	Saline	14 ± 10	14 ± 10	14 ± 9	13 ± 8	12 ± 5	11 ± 4	12 ± 6
	Lidocaine	13 ± 7	11 ± 8	14 ± 10	16 ± 16	13 ± 9	15 ± 13	14 ± 12
End-tidal CO2, mm Hg
	Saline	45 ± 10	48 ± 13	44 ± 9	47 ± 8	48 ± 14	51 ± 7	46 ± 12
	Lidocaine	53 ± 8	47 ± 8	44 ± 10	47 ± 13	45 ± 9	39 ± 10	44 ± 17
End-tidal isoflurane, %
	Saline	0.9 ± 0.2	0.9 ± 0.2	1.0 ± 0.3	1.1 ± 0.3	1.0 ± 0.2	1.0 ± 0.2	1.2 ± 0.3
	Lidocaine	1.0 ± 0.3	1.0 ± 0.3	1.2 ± 0.3	1.2 ± 0.2	1.2 ± 0.2	1.1 ± 0.2	1 ± 0.2

The control group received saline instead of lidocaine.

Time points include before bolus administration of loading dose (T0), immediately after administration of loading dose (T1) and 15, 30, 45, and 60 min after beginning constant-rate infusion; constant-rate infusion was discontinued after 60 min or when the surgery was completed (T2).

In both groups, assisted ventilation had to be initiated to ensure normocapnia during anesthesia (lidocaine group, 9 of 12 [75%]; saline group, 7 of 11 [63%]). Inotropic support with dobutamine to maintain normotension (that is, mean arterial pressure, 60 mm Hg or greater) was provided to 3 of the 12 goats (25%) in the lidocaine group and to 3 of the 11 goats (27%) in the control group. Gross movement in response to the surgical procedure occurred in 17% of the goats in the lidocaine group and in 18% of those in the control group. One animal from the control group had to receive an additional dose of butorphanol (0.1 mg/kg IV) immediately after the surgery started. Atropine (0.04 mg/kg IV; Vetone 0.54 mg/mL, MWI, Boise, ID) had to be given to 2 of the 12 goats in the lidocaine group for treatment of bradycardia (heart rate, < 55 bpm), which occurred during traction and manipulation of the urinary bladder. There was no electrocardiographic evidence of arrhythmias in any of the goats.

Discussion

The results of this study suggest that the use of lidocaine CRI (dosage, 100 μg/kg/min) after a loading dose (2.5 mg/kg IV) had minimal effects on cardiopulmonary status yet improved the analgesia in these goats undergoing abdominal surgery. Another finding was that the cardiopulmonary effects of the drugs used for the premedication for, induction of, and maintenance of anesthesia in this study likely were greater than those due to intravenous infusion of lidocaine.

In the current study, blood gas values remained within the normal range, thus confirming the previously identified absence of changes in tissue oxygenation associated with continuous infusion of lidocaine.²⁵ Other studies also have reported no significant changes in blood gas parameters in dogs and cats anesthetized with isoflurane and receiving lidocaine CRI during spontaneous ventilation.^23,28 The rate of lidocaine infusion in our study was based on a minimal alveolar concentration study of inhalant anesthetics in goats.⁷ In contrast with the previous study,⁷ where the stimulus was standardized (that is, clamping a claw between the jaws of a Vulsellum forceps), the present study used abdominal surgery as the source of the noxious stimulus. The main disadvantage associated with a standardized mechanical noxious stimulus that is evoked during phasic pain testing is that nonspecific, low-threshold mechanoreceptors are activated¹⁹ and therefore produce predominantly somatic pain. In contrast, the types of abdominal surgeries performed during the present study likely evoked both visceral and somatic pain and therefore provided a more clinically relevant assessment of the additional analgesia from the lidocaine CRI in goats. Furthermore, another previous study⁷ reported that the lidocaine loading dose of 2.5 mg/kg prior to 100-μg/kg/min lidocaine CRI in goats resulted in a mean plasma concentration (1617 ng/mL) that was much lower than values obtained in dogs (at least 1500ng/ml) and horses (greater than 3000 ng/ml). Plasma lidocaine concentrations less than 1000 ng/mL offered somatic analgesia in conscious horses³⁰ but not in cats.²⁷

The limitations of the present study primarily are associated with the concurrent surgical teaching laboratory. The times for the beginning of the surgical stimulus and duration of anesthesia varied markedly among goats and might have insufficient for the lidocaine plasma concentration to reach its steady-state. Previous authors⁷ estimated a 45-min period between the end of the loading dose and the first noxious stimulus. In addition, we did not measure the plasma concentration of lidocaine, and further studies are necessary to quantify the steady-state after a 20-min loading bolus infusion and whatever might be the range of therapeutic plasma lidocaine concentrations that promote both somatic and visceral analgesia in the goat.

We used an injectable anesthetic for premedication and induction of anesthesia in the present study to make it more clinically relevant. Xylazine is commonly used in small ruminants to produce sedation and analgesia³⁶ but has been associated with respiratory depression, hypercapnia, and significant hypoxemia as a result of pulmonary edema and extravasation of erythrocytes into the alveoli both in goats and sheep.^4,14,32 In addition, intravenous ketamine can cause mild respiratory depression in goats, characterized by an increase in pCO₂, decrease in pO₂, and decrease in tidal volume with a small not significant increase, in respiratory rate.^1,26 All of the veterinary general anesthetics currently available, especially inhalant anesthetics, cause dose-dependent decreases in sensory input and the central response to carbon dioxide.¹⁸ In addition, goats are reported to be more sensitive to the respiratory depression effect of enflurane, halothane, and isoflurane than are humans, dogs, and cats.³ The respiratory side effects of isoflurane, xylazine, and ketamine likely are responsible for the need for assisted ventilation to maintain normocapnia in 44% of the goats in the present study.

In the present study, 26% of all goats needed inotropic support with dobutamine to maintain normotension. This hypotension is likely due to the effects of isoflurane, xylazine, and ketamine. Inhalant anesthetics can cause significant dose-dependent cardiovascular depression, characterized by decreases in stroke volume, blood pressure,³⁵ and cardiac output in ruminants.¹⁶ Therefore decreasing the concentration of the inhalant agent that is required to maintain a light to moderate plane of anesthesia would reduce this cardiovascular depression.³⁷ Lidocaine CRI similar to that we used here reduced the isoflurane minimal alveolar concentration in goats by 18.3%, thus decreasing their end-tidal isoflurane concentration to an average of 0.98% ± 0.06%,⁷ which is similar to the value we obtained in the current study. However, decreasing the minimal alveolar concentration of isoflurane we used did not decrease the incidence of hypotension compared with that of the saline controls. Some authors¹ have suggested that the sympatholytic effect of xylazine can offset the sympatholytic action of ketamine on arterial blood pressure. In that study,¹ using xylazine–ketamine in goats caused a significant decrease in the mean arterial blood pressure which began 15 to 60 min after administration and lasted as long as 120 min.

Lidocaine is used as a local anesthetic, an antiarrhythmic agent,⁸ an antioxidant, and an inflammatory modulator in clinical situations to prevent reperfusion injury.⁵ Although lidocaine is commonly used in goats, this local anesthetic has a reputation of increased toxicity in this species.³⁶ This reputation is probably due to the common clinical use of lidocaine in animals of low body mass, such as when injecting lidocaine into the horn bud of a kid goat. Because the toxic dose is related to blood concentrations of the local anesthetic, the small body mass of kids in addition to the high vascularization of the horn bud can readily result in a toxic concentration of lidocaine.³⁵ The toxic dose of infiltrated lidocaine solution is generally reported to be 10 mg/kg in goats.³³ Research in sheep has demonstrated that the plasma concentration of lidocaine measured at the onset of a toxic manifestation in adult animals is 11.7 ± 2, 27.6 ± 2.1, 34.2 ± 5.2 and 41.2 ± 6.7 μg/mL for convulsions, hypotension, respiratory arrest and circulatory collapse, respectively.²¹ Compared with the cardiovascular system, the CNS is more sensitive to lidocaine toxicity; CNS signs of toxicity include visual disturbances, muscle twitching, and seizures followed by unconsciousness and coma.¹² Hypotension, respiratory arrest, and circulatory arrest in sheep occur at plasma lidocaine concentrations that are 2 to 4 times higher than that associated with convulsions. However, fetal and neonatal lambs are no more sensitive to lidocaine toxicity than are adult sheep,²¹ likely because of the larger volume of distribution and greater renal clearance of lidocaine in newborns than in adults. Even though we did not measure advanced cardiovascular parameters, such as cardiac output and systemic vascular resistance index, the combination of loading and CRI dosages used lacked adverse effects for the parameters we monitored in these goats. The lack of lidocaine toxicity in goats undergoing abdominal surgery that we noted supports a previous study,⁷ where the same lidocaine dose and rate lacked signs of toxicity in a laboratory investigation.

In conclusion, intravenous injection of lidocaine followed by administration by CRI caused minimal cardiopulmonary effects and may have improved analgesia in these adult goats undergoing abdominal surgery. Delivery of the initial bolus of lidocaine was completed over a 20-min period to minimize the risk for hypotension and appeared to be effective for this purpose.