Anesthesia and Analgesia in Laboratory Animals: Chapter 1: Pharmacology of Injectable Anesthetics



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Chapter 11: Anesthesia and Analgesia of Nonhuman Primates

This book chapter is very well written and organized. The subject matter covers all of the drugs used in anesthesia and analgesia for nonhuman primates. There is an excellent table at the end of the chapter that summarizes the drugs and dosages for NHP’s. The purpose of this chapter was to provide a review of the literature on techniques, methodologies, and agents that have been reported in NHP’s, along with the those found to be effective by the authors or knowledgeable clinicians. The overall goal was to provide information that will help to ensure that NHP’s are provided with optimal anesthesia and analgesia. Since this book is out of print and not available, I’ve abridged important excerpts from the chapter.


INTRODUCTION: Competent clinical management of nonhuman primates has helped to assure the most effective use of these valuable animals. Advances in methods of anesthesia and analgesia have played an important role in ensuring their humane treatment. The wide range in body size and weight of nonhuman primates plays an important role in selecting an appropriate anesthetic, the route of administration, and dosage of the drug. Extrapolation of anesthetic or analgesic doses from one primate species to another should be done with caution because of differences in the responses of some species to certain agents. The authors purpose of this chapter is to provide the reader with a review of the literature on techniques, methodologies, and agents that have been reported in commonly used nonhuman primates, along with those that have been found to be effective by the authors. In some instances in which there is little information available in the literature and for which the authors have had insufficient experience, non-peer-reviewed information has been obtained from knowledgeable clinicians by personal communication. The overall goal is to provide veterinarians and investigators with information that will help ensure that nonhuman primates are provided with optimal anesthesia and analgesia during their use as research subjects.
PREOPERATIVE EVALUATION: Nonhuman primates with induced hypertension may be less tolerant to repeated doses of ketamine and might be better managed with volatile anesthetics such as isoflurane and halothane. Although the optimal fasting time in nonhuman primates has not been established, it is conventional practice to fast primates for at least 12 hours in order to decrease the risk of pulmonary aspiration. Exceptions to this are the Callitrichidae (marmosets and tamarins) and other small species that generally are fasted only 6 to 8 hours to help avoid perioperative hypoglycemia.

In situations requiring emergency surgery or in pregnant animals in which gastric emptying is delayed, inclusion of H2 antagonists may reduce the risk of aspiration pneumonia by blocking the histamine-induced secretion of gastric fluid. The addition of H2 antagonists such as cimetidine (10 mg/kg) or ranitidine (1.5 mg/kg) 30–40 minutes before induction was shown to protect against aspiration pneumonia in Papio spp.


ANTICHOLINERGIC DRUGS: The addition of atropine (0.02–0.05 mg/kg) will effectively reduce xylazine- and fentanyl-induced bradycardia. When an antisiallagogue effect is desired, glycopyrrolate (0.0005–0.01 mg/kg) is preferable to atropine because it is twice as potent and has a longer duration of action. Noteworthy is that atropine possesses arrhythmogenic properties and may predispose nonhuman primates to ventricular tachycardia and bigeminal patterns.
PARENTERAL ANESTHETICS: Ketamine has a wide margin of safety in nonhuman primates, and it has been used in dosages varying from 5 to 20 mg/kg IM in many species as an agent for restraint and induction for subsequent administration of other injectable or gaseous anesthetics. Leukocyte and lymphocyte counts and total plasma protein levels were reduced in the ketamine-treated animals. Bennett et al. (1992) reported similar findings with significant decreases in erythrocyte, lymphocyte, and total leukocyte counts, hemoglobin, hematocrit, and serum concentrations of glucose, total protein, cholesterol, and albumin. Ketamine produced no significant changes in mean arterial blood pressure, plasma insulin, glocuse, or cortisol concentrations. Ketamine (7 mg/kg) and xylazine (0.6 mg/kg) given to M. mulatta, varying in weight from 1 to 11 kg, provided adequate anesthesia for cisternal and lumbar spinal puncture, insertion of urinary catheters, tattooing, and digit amputations. However, xylazine or xylazine combined with ketamine produced statistically significant decreases in mean arterial blood pressure and heart rate compared to animals given ketamine alone.

Ketamine-medetomidine has been successfully used to anesthetize P. troglodytes, medetomidine (30–60 µg/kg) IM and ketamine (2–6 mg/kg) IM produced a rapid induction, prolonged and stable immobilization excellent relaxation, and calm recovery.

Advantages of the ketamine-medetomidine combination over ketamine alone were better muscle relaxation and a lengthened period of anesthesia. Another advantage of combining medetomidine with ketamine is that medetomidine can be reversed with atipamezole, a specific α2-antagonist. In S. sciureus, 100 µg/kg of medetomidine given either IM or SC facilitates mask induction with isoflurane. The combination of ketamine (5 mg/kg IM) and medetomidine (100 µg/kg IM), produced excellent sedation and muscle relaxation in Cecopithecus aethiops and Papio species.

The addition of diazepam to ketamine eliminates excessive involuntary movements and helps maintain adequate immobilization. The combination of ketamine (10 mg/kg) and diazepam (0.2 to 0.35 mg/kg) given IM has been reported to produce effective restraint in an adult male Papio species. In S. sciureus, ketamine (15–20 mg/kg) and diazepam (1 mg/kg) given IM provide light to moderate anesthesia. Midazolam offers certain advantages over diazepam. Compared to diazepam, it is better absorbed after IM injection, provides more effective anxiolytic sedation, and has a shorter elimination half-life.

Telazol is a 1:1 combination of the dissociative anesthetic tiletamine and the benzodiazepine tranquilizer zolazepam. In juvenile M. mulatta, the minimum dosage for restraint is 1.5 mg/kg IM and 3.0 mg/kg for anesthesia sufficient for minor surgical procedures. Telazol provides a rapid onset and smooth recovery, and with the exception of depressed myocardial contractility, it has minimal cardiopulmonary effects. At 4 to 6 mg/kg IM, chemical restraint is achieved for about 45 to 60 minutes in M. mulatta, M. nemestrina, M. arctoides, and P. papio. Telazol given to P. troglodytes at 3–5 mg/kg IM provides sufficient chemical restraint. The occurrence of cyclohexylamine-induced seizures is nearly eliminated in comparison to ketamine.

Propofol provides a smooth induction with adequate muscle relaxation sufficient for procedures of short duration. Because rapid clearance of propofol contributes to a relatively fast awakening, repeated boluses of 2–5 mg/kg IV can be administered to extend the duration of anesthesia without delaying recovery. Unlike other intravenous agents, propofol is formulated in an emulsion of soybean oil, glycerol, and egg lecithin which readily supports bacterial growth. It is important that sterile techniques be practiced when this agent is used in nonhuman primates.

Prior to the general use of inhalant anesthetics in veterinary medicine, pentobarbital was almost exclusively used to anesthetize nonhuman primates. The major difficulties with pentobarbital are a severe respiratory depression at high dosages necessary for adequate analgesia, an inability to modulate the depth of anesthesia well, and a very long period of recovery from anesthesia. The usual dosage in nonhuman primates for pentobarbital, without the use of other agents, is 20–30 mg/kg IV.

Opioids have been used in nonhuman primates to reduce the requirement for inhalational anesthetic and to enhance intraoperative analgesia during balanced anesthesia. In the authors’ experience, fentanyl is a valuable supplement to inhalational anesthesia for cardiovascular procedures in Old World primates. It can be administered either as an intravenous bolus (5 to 10 µg/kg) or as a continuous infusion (10 to 25 µg/kg/hr) in combination with a low inspired concentration of isoflurane with minimal effects on heart rate and blood pressure.

Muscle relaxants are not anesthetics or analgesics and should only be used in fully anesthetized animals. Used as an adjunct in adequately anesthetized nonhuman primates, they can facilitate mechanical ventilation and reduce skeletal muscle tone during surgery. The authors use pancuronium (0.08–0.1 mg/kg IV) and vecuronium (0.04–0.06 mg/kg IV) to produce muscle relaxation during maintenance of inhalational anesthesia.
INHALATIONAL ANESTHESIA: The induction of anesthesia in most nonhuman primate species is usually initiated with ketamine (5–10 mg/kg IM) to provide chemical restraint and intravenous access. As an alternative to thiopental, the authors have found that propofol given at 2–5 mg/kg IV as a bolus followed by additional amounts to effect provides a very satisfactory and smooth induction in macaques and Papio spp. Isoflurane is a widely used inhalational agent in nonhuman primates and is the anesthetic of choice of the authors for most applications. Isoflurane, unlike halothane, does not sensitize the myocardium to the arrhythmogenic properties of circulating catecholamines. Heart rhythm remains stable with isoflurane, and based on the authors’ experience, ectopic cardiac beats are very uncommon in normocapnic nonhuman primates. Isoflurane produces minimal depression of cardiac output, but there is a dose-dependent decrease in blood pressure due to reductions in systemic vascular resistance. The hypotension is especially pronounced if isoflurane is mask-induced at inspired concentrations of 3–4% or when animals are maintained at or above 2%.
INTRAOPERATIVE MONITORING: Intraoperative monitoring provides the means to assess physiological function during anesthesia and to ascertain the proper functioning of anesthetic equipment. Heart rhythm and rate are best evaluated by displaying the electrocardiogram of the animal on an oscilloscope. Lead II is commonly used for the detection of cardiac dysrhythmia because it produces an easily recognizable P wave and depicts the relationship of atrial to ventricular depolarization. The authors find that an intravenous bolus of lidocaine (1.0–2.0 mg/kg) followed by lidocaine infusion (20-500 µg/kg/min) is helpful in suppressing recurring premature ventricular contractions. Indirect arterial blood pressure can be measured by placing a pediatric cuff on the lower arm or leg of the nonhuman primate. Direct arterial pressure monitoring is achieved by percutaneous cannulation or cutdown of the femoral artery in small nonhuman primates.

Measurements of cardiac output and calculation of systemic and pulmonary vascular resistance can be obtained with a pulmonary artery catheter (Swan-Ganz). The Swan-Ganz catheter is essential for assessment of cardiac function, preload volume status, and responses to therapeutic interventions during major cardiovascular surgery. Assessment of oxygenation and ventilation during the administration of anesthetics is essential. The color of the mucous membranes is the simplest method to ascertain adequacy of oxygenation. Pulse oximetry provides continuous measurement of arterial oxygen saturation. Because the tongue site seems to be less influenced by intraoperative conditions such as hypothermia or hypotension, the authors find it preferable to an ear site. It is well recognized that the measurement of expired CO2 is the single most effective method of determining airway patency and adequacy of ventilation. End-tidal CO2 monitors sample gas from the airway of an animal, usually at the site where the breathing circuit is connected to the endotracheal tube. In addition to displaying CO2 levels, it also generates a CO2 waveform called a capnogram.

Anesthetic depth is usually assessed by monitoring a variety of parameters. It is not uncommon for a nonhuman primate to lose a significant amount of body heat during anesthesia and surgery. Intraoperative monitoring of body temperature is routinely performed by inserting a temperature probe into the esophagus or rectum and connecting it to the monitor. The drawback of rectal temperature is that it does not accurately reflect blood or “core” temperature when changes in temperature are very rapid. Urinary output is a direct indicator of renal function and serves as a useful guide of intravascular volume status.
INTRAOPERATIVE SUPPORT: Infusion of crystalloid solutions during surgery helps to maintain normovolemia necessary for adequate tissue perfusion. For minor procedures in nonhuman primates, administration of isotonic electrolyte solutions such as lactated Ringer’s solution at the rate of 5–10 ml/kg/hr is sufficient to maintain normal fluid composition. Minor to moderate blood loss can be replaced with crystalloid solutions given in the amounts equal to about three times the amount of blood loss. If the hematocrit falls below 20%, blood is usually administered as part of the replacement solution. The authors consider phenylephrine as the drug of choice in treating isoflurane-induced hypotension. A 1-to-2 µg/kg bolus of phenylephrine, followed by an infusion of 0.5-1.0 µg/kg/min, will elevate blood pressure by increasing systemic vascular resistance. For macaques and Papio spp., when hypotension is accompanied by bradycardia, 1.5- to 2.5-mg intravenous bolus of ephedrine, repeated if needed will increase blood pressure and improve cardiac output. During cardiovascular collapse characterized by decreased cardiac output and markedly reduced blood pressure, dopamine and norepinephrine infusions can be used.
POSTOPERATIVE CARE: Postoperative monitoring ensures prompt recognition of post-surgical complications and helps provide for an overall safe recovery from anesthesia. Physiological disorders most commonly encountered during postoperative recovery include pulmonary and circulatory complications, hypothermia, and pain.

It is not uncommon for nonhuman primates to vomit when they emerge from anesthesia. Extubation should be delayed until the animal regains the swallowing reflex or other signs of voluntary movement. If vomiting occurs after extubation, the animal should be placed in a prone position with its head lowered to avoid aspiration of the vomitus and the oropharynx suctioned. Before extubation, the oropharynx and trachea are thoroughly suctioned to clear secretions and blood that may have accumulated during surgery. Suctioning of the trachea is particularly important for smaller nonhuman primates because respiratory passages can be easily obstructed with bronchial secretions. Animals may require careful clinical evaluation for inadequate surgical hemostasis. Hypotension and tachycardia are common circulatory complications associated with the early postoperative period. Residual effects of anesthetics and inadequate replacement of blood lost during surgery are often causes for hypotension. Postoperative hypothermia is frequently encountered during a surgical procedure. Severe hypothermia may delay awakening by reducing metabolism and excretion of anesthetic drugs. Hypothermia and associated shivering should be treated with warming lights or heating blankets to raise the body temperature. Space heaters may be used to preheat the recovery area.

Pain is a predictable response as the effect of anesthetics dissipates in the early postoperative period. The goal of postoperative pain management is, on the one hand, to decrease an animal’s experience of a noxious stimuli, and on the other hand, to maintain normal physiological and cardiovascular stability. The drugs available to treat nonhuman primates can be broadly divided into two groups: nonsteroidal anti-inflammatory drugs (NSAID) and opioids. The authors have also used the injectable NSAID, ketorolac (15–30 mg IM in macaques and Papio spp.), to provide analgesia for moderate postoperative pain. The traditional management of pain usually consists of opioid administration given either intramuscularly or intravenously.

Effective postoperative analgesia can be provided by 1–2 mg/kg morphine IM or SQ every 4 hours, 0.15 mg/kg (Old World primates) and 0.075 mg/kg (New World primates) oxymorphone IM every 4–6 hours, or 2–4 mg/kg meperidine IM every 2–4 hours. Oxymorphone is often considered to be the analgesic of choice in nonhuman primates because it provides effective postoperative pain relief without producing noticeable respiratory depression. For mild to moderate postoperative pain, oral codeine plus acetaminophen or other oral opioids are given at 4-hr intervals for 24 to 48 hours. Oxycodone appears to be more effective and better tolerated. Opioid agonist-antagonists (buprenorphine and butorphanol) have been used to provide postoperative analgesia in nonhuman primates. Buprenorphine (0.01 mg/kg IM, IV) has been recommended for use in nonhuman primates. The long duration of effect (6–8 hr) and relative absence of respiratory depression make buprenorphine an attractive alternative to other analgesia regimens. In case of potential overdose with opiate analgesics, naloxone can be of invaluable assistance. The usual dose of naloxone is 0.1–0.2 mg IV, repeated as needed. Naloxone given in the lower dosage range may reverse the respiratory depression without completely reversing analgesia.


QUESTIONS


  1. T/F Extrapolation of anesthetic or analgesic doses from one primate species to another should be done with caution because of differences in the responses of some species to certain agents?

  2. What type of anesthesia should be used in Nonhuman primates with induced hypertension that are less tolerant to repeated doses of Ketamine?

  3. Which species of NHP’s are generally fasted only 6 to 8 hours (instead of 12 hours) to help avoid preoperative hypoglycemia?

  4. T/F Atropine possesses arrhythmogenic properties and may predispose nonhuman primates to ventricular tachycardia and bigeminal patterns?

  5. T/F Ketamine produced significant changes in mean arterial blood pressure, plasma insulin, glucose, or cortisol concentrations?

  6. Which specific α2-antagonist is used to reverse medetomidine?

  7. Name a drug that can be used in conjunction with ketamine to eliminate excessive involuntary movements and helps maintain adequate immobilization.

  8. T/F Telazol provides a rapid onset and smooth recovery, and with the exception of depressed myocardial contractility, it has minimal cardiopulmonary effects.

  9. Which anesthetic is formulated in an emulsion of soybean oil, glycerol, and egg lecithin and requires that sterile techniques be practiced when this agent is used in nonhuman primates?

  10. Why is fentanyl a valuable supplement to inhalation anesthesia for cardiovascular procedures in Old World primates?

  11. Which EKG lead is commonly used for the detection of cardiac dysrhythmia because it produces an easily recognizable P wave and depicts the relationship of atrial to ventricular depolarization?

  12. Which IV drug is helpful in suppressing recurring premature ventricular contractions?

  13. What type of pulmonary artery catheter is recommended to measure cardiac output and calculate systemic and pulmonary vascular resistance?

  14. T/F Pulse oximetry provides continuous measurement of arterial oxygen saturation.

  15. What is the drug of choice in treating isoflurane-induced hypotension?

  16. T/F Hypertension and bradycardia are common circulatory complications associated with the early postoperative period.

  17. Name 2 goals of postoperative pain management.

  18. What analgesic used in nonhuman primates provides effective postoperative pain relief without producing noticeable respiratory depression?

  19. What opioid agonist-antagonist is used for NHP’s because of its long duration of effect (6-8 hours)?

  20. Which short-acting antagonist given in the lower dosage range may reverse the respiratory depression caused by buprenorphine or butorphanol without completely reversing the analgesic effects.


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