Abstract

A balanced approach to anesthesia and analgesia in zoo species should be considered utilizing multiple drug administration modalities and classes. Constant rate infusion (CRI), manually controlled infusion (MCI), or total intravenous anesthesia (TIVA) of anesthetic/analgesic agents are effective tools to level the plane of anesthesia, address pain, improve recovery times, and decrease drug volumes to be used. Various formulations have been published, mostly in domestic species.^1-20 Individual and species variation will exist for these various modalities. Choosing protocols must take into account species, immobilization conditions, comparative published data, and the level of anesthesia desired. Because calculating CRI dosages can be a mental quagmire, math is often the only limitation to using these valuable tools; therefore, a ‘cheat sheet’ or computer program can be utilized and is recommended.

Overview

CRI, MCI, and TIVA modalities are based on the principle that a plasma drug concentration needed to produce anesthesia and analgesia has to be reached quickly and maintained over the planned event time. The steady flow of drug eliminates the “peak and valley” effect that can occur with other supplementary anesthetic protocols.⁵ This can still be a risk of MCI where boluses are administered reactively or at specific intervals.; however, this regimen can still offer the advantage of providing the patient with consistent, effective maintenance of anesthesia and analgesia.^5,13 These infusion protocols are best utilized for field work, imaging or radiation procedures when an anesthetic machine is not available, surgical procedures that involve the upper airway (when placement of an endotracheal tube will interfere with surgery), bronchoscopic evaluation in smaller patients, and anesthesia for patients with intracranial hypertension concerns (inhalants increase blood flow to the brain while IV agents like propofol reduces the cerebral blood flow).¹⁴ These regimens can decrease the impact that pain and rousal can have on physiologic parameters during maintenance of anesthesia. The eventual result is a lower drug dosage delivered steadily over time and overall reduced dose amounts during anesthesia thus reducing cost and the incidence of dose-related side effects. CRI allows for better control over drug administration with real time ease to change doses. The dose delivered during CRI can easily be decreased or increased based on patient need by adjusting the rate of the flow. Additionally, the use of CRI has been reported to lower gas anesthetic needs since these volatile agents are some of the most cardiac depressant drugs used in veterinary anesthesia. Studies have shown that the mean alveolar concentrations of inhalant anesthetics are lower with the use of a CRI. Contraindications and side effects of CRI vary depending on the drug that is used.^{5, 13,14}

IV induction regimens are unlikely in zoological species, but once patient access is established for i.v. catheterization, CRI and other TIVA regimens can be used effectively to maintain smooth planes of anesthesia and reduce or eliminate the need for inhalant anesthetics. Loading doses are typically given initially to achieve initial therapeutic blood levels and are based on the volume of distribution as well as the initial plasma based on pharmacokinetic studies in domestic animals.^13,14,18 A drug in the same class as the agent to be used in the CRI is often utilized in the loading dose. Loading doses are needed prior to the initiation of the CRI in order to achieve initial therapeutic blood levels since these initial doses are typically both redistributed to tissues and eliminated.^13,18 Therefore, to maintain the desired plasma drug concentration, a CRI is initiated. The infusion rate is determined by the clearance of the drug and the drug concentration in plasma based on pharmacokinetic studies.¹⁴

Syringe and fluid pumps are ideal for CRI drug administration but gravity flow can be used as well. Programmable syringe pumps are cost effective and minimize error of drip rate and mathematic calculations making CRIs an inexpensive tool in your anesthetic arsenal. For example, Stein reports that an 8-hr mid-dose rate morphine/lidocaine/ketamine CRI for a 20 kg patient can cost a small animal practice less than $1.50. As with any drug use, the suitability of a given drug infusion should be based on a sound understanding of that drug’s use in an individual, patient health status, and pharmacokinetic data in that or comparative species.¹⁸ Fleming reported that by moving to a MCI dose of (0.4 mg per 10 min i.v. of M99) in over 100 elephant translocations reduced the total mg amount of M99 by50% when switching to a uniform MCI vs. topping off i.v. when the elephant was showing signs of arousal.

CRI Drug Classes/Agents

When considering CRI, MCI, or TIVA, one must examine the properties of the drugs to be used. The drugs utilized should be water-soluble to minimize toxicity associated with the solvent, stable in solution, and possess minimal risk of perivascular sloughing if extravasated. An ideal drug can be given as a concentrated solution to avoid fluid overloading, should not be absorbed by plastics and should not promote bacterial growth. Other desirable characteristics include rapid onset of action, rapid clearance from the body for quick recovery, no adverse side effects, good potency, lipid-solubility, relatively inexpensive, and chemically compatible with other drugs. There is no single agent that possesses all these properties, but these characteristics are important considerations when making drug choices.¹⁴

Propofol, a hypnotic agent, is the most commonly used agent for TIVA, CRI, and MCI. It has a higher elimination clearance and a shorter elimination half-life compared with other injectable agents. The clearance rate of propofol is faster than the liver blood flow.¹⁴

Opioids are often used in CRI alone or in combination with other classes. For domestic small animals, morphine, hydromorphone, and fentanyl are the most commonly used opioids. These drugs have good analgesic effects with mild to moderate sedation and offer the benefit of reversibility. CRI of concentrated narcotics can be used in megavertebrate anesthesia to reduce overall drug use during anesthetic events. Published and anecdotal doses are listed in Table 1.

Most of the side effects of opioids are dose dependent, including respiratory depression, bradycardia, vomiting, nausea, and occasional dysphoria. This class of drugs should be used with caution in felid species, starting at the low end of the dosing spectrum; higher rates may induce dysphoria, mydriasis, and excitation. Full agonists are the most commonly used opioids in domestic small animals but butorphanol, an agonist-antagonist, offers more sedation than excitement in cats.^5,13,18

Benzodiazepines can be used for CRI and MCI as well. Midazolam is water-soluble; therefore, it should not precipitate, as diazepam will, when combined with other drugs. Benzodiazepines do not have analgesic effects of their own but do have excellent sedative and muscle-relaxing effects and are best utilized synergistically with an opioid resulting in an opioid sparing effect. Studies have shown benefits, including a reduction in the use of opiates and gas anesthetic mean alveolar concentration when midazolam was used as a CRI. Published and anecdotal doses are listed in Table 1. This class does also offer the addition benefit of antagonistic drugs to improve recovery time if indicated.^5,13

Dissociatives in the NMDA-receptor antagonist class are often used in CRI. The use of drugs such as ketamine, which keeps the NMDA receptors from being overstimulated, can be very helpful in preventing central hypersensitization of the spinal cord when analgesia is needed during surgery. Additionally, studies suggest that antagonizing these receptors improves opioid receptor sensitivity, reduces opioid tolerance and minimizes the development of rebound hyperalgesia (the phenomenon of markedly increased pain when opioids are withdrawn). Although very beneficial, that mediation does not provide true analgesia, thus, these drugs must be administered in conjunction with true analgesic drugs (e.g., opioids or NSAIDs) when pain control is a concern.^5,13,18

Local anesthetics such as lidocaine can be useful in CRI combinations, but be cautious that felid species can be sensitive to this class of drugs. Monitor closely and consider lower dosing when used in felids. Lidocaine has the additional antioxidant and anti-inflammatory modulation effects. It has also been reported to prevent ileus in small animals but its effect in domestic large animals is unknown. Lidocaine is light sensitive and should be kept covered if long-term use is planned.^13,18

Alpha 2 agonists are used effectively for both sedation and analgesia in CRI and the effects are reversible. Human studies have shown that medetomidine significantly reduces the need for benzodiazepine and opioid use and does not seriously impair cardiovascular parameters (e.g., respiratory function).¹³

Synergistic combinations are commonly used in domestic small and large animal medicine and surgery and have great benefit for reducing inhalant anesthesia and improving cardiovascular function during anesthesia. The most commonly used combination is morphine and ketamine with or without lidocaine. Large animal literature reports guaifenesin, ketamine ± alpha 2 combinations as well. These combinations are listed in Table 1. This table was formulated from a domestic and exotic literature review with a collection of clinically applied dosages in select zoological species. It is not intended to be all-inclusive but rather common comparative regimens from the domestic industry that can be clinically applied to the variety of zoo taxa. Many of the dosages in the exotic species are, as typical of our field, based on empirical data, observations, and experience.

Calculation and Preparation of CRI

Generally, dosing tables or individualized spread sheets should be used for constant rate infusions if accessible. They can prove more efficient for initiation of CRIs and reduce the risk of mathematic errors. Easy to use calculators are available online at:

www.vasg.org/resources_and_support_material.htm

www.vasg.org/drug_delivery_calculators.htm

www.vasg.org/drug_dose_charts.htm

www.vasg.org/forms_and_text_resources.htm

These resources allow you to vary the IV bag size, fluid delivery rate, and drug dose rates to satisfy any combination.¹⁸

CRI dosages can also be calculated using the formula: A x B x C x 60/D x E x 1000=mls of drug to add to diluent . A=desired dose in μg/kg/min, B=body wt in kg , C=diluent volume in mls , D=desired fluid rate in mls/hr, and E=drug concentration in mg/ml.¹³

Remember, any time a large volume of drug is added to a fluid bag for a CRI, an equal volume of fluid should be removed before adding the drug to keep the dose and volume accurate. The drugs should be added to the bag and the bag agitated to mix them before priming the fluid line and delivering the CRI to the patient.^13,18

Literature Cited

1.  Carpenter J. (ed.). Exotic Animal Formulary, 4th ed. W. B. Saunders Co., Philadelphia, Pennsylvania.

2.  Elfenbein J. R., Robertson, S. A., Corser, A. A., Urion, R. J., Sanchez, L. C. Systemic Effects of a Prolonged Continuous infusion of ketamine in healthy horses, J Vet Intern Med. 2011;25:1134–1137.

3.  Fielding, C. L., Brumbaugh, G. W., Matthews, N. S., Peck, K. E., Roussel, A. J. Pharmacokinetics and clinical effects of a subanesthetic continuous rate infusion of ketamine in awake horses. Am J Vet Res. 2006;67(9):1484–1490.

4.  Grimm K. A., Tranquilli, W. J., Gross, D. R., Sisson, D. D., Bulmer, B. J., Benson, G. J., Greene, S. A., Martin-Jimenez, T. M. Cardiopulmonary effects of fentanyl in conscious dogs and dogs sedated with a continuous rate infusion of medetomidine. Am J Vet Res. 2005;66(7):1222–1226.

5.  Grubb, T. Incorporating constant rate infusions into your anesthetic protocol. Proceedings Conv. Vet. Comm., 2010.;212–214.

6.  Kaartinen, J. M., Pang, D. S. J., Moreau, M., Vainio, O. M., Beaudry, F., Chema, P., del Castillo, J. R. E., Lamont, L. A., Cuvelliez, S. G., Troncy, E. Hemodynamic effects of an intravenous infusion of medetomidine at six different dose regimens in isoflurane-anesthetized dogs, Veterinary Therapeutics, 2010;11(1);E1–E16.

7.  Langan, J. N., Ramsay, E.C., Blackford, J. T., Schumacher, J. Cardiopulmonary and sedative effects of intramuscular medetomidine-ketamine and intravenous propofol in ostriches (Struthio camelus), Journal of Avian Medicine and Surgery, 2000;14(1):2–7.

8.  Lankveld, D. P. K., Driessen, B., Soma, L. R., Moate, P. J., Rudy, J., Uboh, C. E., Van Dijk, P. V., Hellebrekers, L. J. Pharmacodynamic effects and pharmacokinetic profile of a long-term continuous rate infusion of racemic ketamine in healthy conscious horses. J Vet Pharmacol Therap. 2006;29:477–488.

9.  Lin, H. C., Thurmon, J. C., Benson, G. J., Tranquilli, W. J., Oslon, W. A., Guaifenesin-Ketamine-Xylazine anesthesia for castration in ponies: a comparative study with two different doses of ketamine. J Eq Vet Sci, 13(1):29–32.

10.  Lukasik, M., Gentz, E.J., Erb, H.N., Ludder, J. W., Scarlett, J. M., J Av Med Surg, 1997;11(2):93–97.

11.  Machin, K.L., Caulkett, N, A., Cardiopulmonary Effects of Propofol Infusion in Canvasback Ducks (Aythya valisineria), J Av Med Surg. 1999;13(3):167–172.

12.  Muller, K., Holzapfel, J., Brunnberg, L. Total intravenous anaesthesia by boluses or by continuous rate infusion of propofol in mute swans (Cygnus olor), Vet Anaesth Analg, 2011;38:286–291.

13.  Ortel, S. Back to basics: continuous rate infusion therapy. Vet Tech. 2006;27(1).

14.  Pablo, L. S. Total IV anesthesia. University of Florida, Gainesville, Florida.

15.  Picavet, J. E., Gasthuys, F. M. R., Laevens, H. H., Watts, SA. Cardiopulmonary effects of combined xylaizne-guaphenesin-ketamine infusion and extradural (intercoccygeal lidocaine) anesthesia in calves. J Vet Anesth Analg, 2004;31:11–19.

16.  Rezende, M. L., Wagner, A. E., Mama, K. R., Ferreira, T. H., Steffey, E. P. Effects of intravenous administration of lidocaine on the minimum alveolar concentration of sevoflurane in horses. Am J Vet Res, 2011;72(4):446–451.

17.  Schauvliege, S., Narine, K., Bouchez, S., Desmet, D., Van Parys, V., Van Nooten, G., Gasthuys, F. Refined anaesthesia for implantation of engineered experimental aortic valves in the pulmonary artery using a right heart bypass in sheep, Laboratory Animals Ltd. Laboratory Animals, 2006;40: 341–352.

18.  Stein, B., Thompson, D. 2005. Analgesic constant rate infusions. VIN.

19.  Vesal, N., Spadavecchia, C., Steiner, A., Kircher, F., Levionnois, O. L. Evaluation of the isoflurane-sparing effects of lidocaine infusion during umbilical surgery in calves, Vet Anaesth Analg, 2011;38:451–460.

20.  Vnuk, D., Musulin, M., Kreszinger, M., Pecin, I., Bata, D., Zubcic, N. Balanced anesthesia in the Capuchin monkey (Cebus capucinus)—a case report. Vet Archive. 2009;79: 421–428.