Abstract

The cardiovascular and pulmonary systems of non-avian reptiles are diverse and complex, making anesthetic management of these species challenging. Inhalant anesthetics are commonly chosen to induce and maintain general anesthesia in many reptilian species for prolonged diagnostic and surgical procedures. Although these anesthetic agents are routinely celebrated for their ease of use and rapid ability to titrate the depth of anesthesia in mammalian species, it has been well documented that induction and recovery with these agents in reptiles are both prolonged and unpredictable. The cause of this is likely multifaceted and affected by factors such as optimal body temperature of the species, degree of cardiopulmonary circulation, and changes in ventilation that occur as a result of general anesthesia. Understanding the impact these various factors have on the speed of induction and recovery using inhalant agents in reptiles will allow practitioners and anesthetists to appropriately alter the course of inhalant anesthesia across different reptilian species, with a goal of improving overall anesthetic management.

General anesthesia is a necessity in veterinary practice to provide unconsciousness, analgesia, and muscle relaxation for surgical and diagnostic procedures. It is commonly utilized for these purposes in reptilian medical and surgical practices, with the added benefit of facilitating safe handling of dangerous species. Volatile inhalant agents are generally favored for induction and maintenance of general anesthesia, as they allow careful titration of anesthetic depth and are reversible, allowing a smooth transition to consciousness once administration is discontinued. Although these advantageous properties are often described for mammals and birds, these benefits do not necessarily cross over to other species, particularly reptiles.

Use of inhalant anesthetics, specifically isoflurane and sevoflurane, has been described in chelonians, snakes, and varanid and non-varanid lizards. For these species, inhalant agents have been associated with a slow induction of anesthesia, an inadequate anesthetic plane, as well as delayed or unpredictable recoveries.¹ Likewise, the minimum alveolar concentration (MAC) of isoflurane reported in reptiles is extremely variable compared to what is reported in other species, where MAC is generally well conserved across mammalian and avian species.¹ There are a variety of factors contributing to these species differences, including a unique cardiovascular and thermoregulatory physiology that alters the traditional understanding of inhalant pharmacokinetics in reptiles.

Modern inhalants including isoflurane, sevoflurane, and desflurane are a distinctive class of drugs, as they are vaporized and administered through the respiratory system to be absorbed into the bloodstream and carried to the central nervous system, where they exert their effects. As inhalants are vapors, these agents behave in the body like gases, and their pharmacokinetic properties are heavily influenced by this fact. The speed of anesthetic induction using inhalant agents is dependent on a balance between the rate of delivery of anesthetic into the lungs and the uptake of anesthetic away from the lungs into pulmonary circulation.² Delivery of volatile anesthetics into the lungs is dependent upon creating an appropriate driving pressure from the anesthetic machine into the patient’s respiratory system as well as the rate of pulmonary ventilation.² Uptake of anesthetic into pulmonary circulation is dependent on several major factors: the creation of an adequate pressure differential between the lungs and pulmonary circulation to drive inhalants into the bloodstream, the ability of inhalants to dissolve into the bloodstream (known an inhalant solubility), and the animal’s cardiac output.² Inhalant solubility is heavily influenced by body temperature, as the colder the patient becomes, the more the gaseous agent will dissolve into the bloodstream. Lower blood solubility is associated with a faster anesthetic induction, as less inhalant needs to be dissolved into the bloodstream to be carried to the brain and spinal cord to exert its effects.² Recovery from inhalant agents is also dependent on these factors, as they undergo minimal hepatic metabolism and elimination is dependent on pulmonary ventilation.² However, the duration of general anesthesia plays a significant role with certain inhalant agents, such as isoflurane.² Factors that directly affect anesthetic induction and recovery using inhalant agents can be altered significantly by the unique physiologic properties of reptiles.

All reptiles can shunt blood away from pulmonary circulation. Non-crocodilian reptiles possess a single ventricle where mixing of oxygenated and deoxygenated blood occurs during diastole. The degree of intracardiac right-to-left shunting is influenced by a variety of overlapping factors, including pressure differentials between the systemic and pulmonary circulation, ventilation patterns, and the amount of blood remaining in the cavum dorsale at the end of systole.^1,3-6 Crocodilian shunting patterns are similarly complex even though they possess a completely separated ventricle similar to mammals and birds. Extracardiac right-to-left shunting is facilitated through several mechanisms. In crocodilians, the right aorta exits from the left ventricle while the left aorta comes from the right ventricle along with the main pulmonary artery. Two connections exist between the right and left aortas that facilitate extracardiac shunting: one at the base of the heart, known as the foramen of Panizza, and another connection known as the abdominal anastomosis.^1,7,8 An additional shunting mechanism exists within the subpulmonary conus located within the pulmonary outflow tract in the right ventricle that contains a cog-teeth valve.⁸ The diameters of both the subpulmonary conus and foramen of Panizza can change in size depending on a variety of neurohormonal substances and adrenergic influences.^7,8 As the diameter of the subpulmonary conus narrows, a greater fraction of blood is directed out of the left aorta, thereby bypassing pulmonary circulation.⁸

Although a variety of shunting patterns have been documented in both non-crocodilians and crocodilians, in theory, bypassing pulmonary circulation can significantly slow the rate of both induction and recovery using inhalant agents. Although a variety of mechanisms are involved in controlling cardiovascular shunting patterns in reptiles, alteration in autonomic drive to the pulmonary or systemic circulatory systems is one proven mechanism of physiologic shunting.^3-6 In the red-eared slider turtle (Trachemys scripta elegans), increasing parasympathetic tone results in greater pulmonary vascular resistance, subsequently decreasing pulmonary blood flow.³ The opposite occurs in the face of increasing sympathetic tone, where intracardiac shunting patterns favor pulmonary outflow and pulmonary vascular resistance reduces, resulting in greater pulmonary blood flow.³ Pharmacologic manipulation of the autonomic nervous system shows potential to hasten anesthetic recovery and provide a stable plane of anesthesia in some chelonian species. In the common snapping turtle (Chelydra serpentina), intramuscular administration of epinephrine at 0.1 mg/kg during recovery from isoflurane resulted in faster return to spontaneous ventilation, spontaneous movement, and extubation times while in loggerhead sea turtles (Caretta caretta), intramuscular epinephrine results in a significantly faster return of spontaneous movement.^4,5 Pulmonary blood flow was significantly increased using intravenous atropine at 1 mg/kg in red-footed tortoises (Chelonoidis carbonaria), resulting in a decrease in isoflurane concentration required to maintain a light plane of anesthesia in this species.⁶

Although intracardiac right-to-left shunting does not occur in crocodilians, the diameter of extracardiac structures involved in regulating vascular shunting, such as the foramen of Panizza and the subpulmonary conus, are under autonomic control.^7,8 Therefore, similar to chelonians, the administration of intramuscular epinephrine at 0.1 mg/kg during recovery from isoflurane anesthesia in American alligators (Alligator mississippiensis) significantly hastens the time to spontaneous ventilation and the time to extubation.⁹ Echocardiographic evaluation of American alligators after epinephrine administration shows a complete closure of the foramen of Panizza and an overall increase in pulmonary outflow.¹⁰ Although no long-term adverse effects were noted in these studies following a single dose of epinephrine or atropine, other studies in alligators have linked epinephrine administration to a significant increase in intracranial pressure.¹¹ Therefore, the use of epinephrine to hasten anesthetic recovery may be detrimental for animals with intracranial disease. The degree of vagal tone has also been shown to affect cardiac shunting patterns in the South American rattlesnake (Crotalus durissus).¹² However, pharmacologic manipulation of the autonomic nervous system to alter inhalant anesthetic recovery has not been documented in snakes. It should be noted that pythons, in particular, have a low capacity for significant right-to-left intracardiac shunting due to their unique cardiac anatomy compared to other squamates.

The rate of ventilation and the efficiency of gas exchange play a critical role in inhalant induction and elimination. Pulmonary physiology and central control of ventilation vary significantly between reptilian species. Generally speaking, reptiles have a larger tidal volume but lower respiratory surface area compared to similarly sized mammals.¹ However, varanids and other reptiles with higher metabolic demands tend to have a higher respiratory surface area than snakes or chelonians.¹ Various breathing patterns exist across different species. While many reptiles exhibit episodic breathing, aquatic species can hold their breath for prolonged periods of time.¹ The amount of pulmonary blood flow can be intermittent depending on these breathing patterns.^1,5 Pulmonary perfusion and heart rate have been shown in chelonians to increase significantly during spontaneous ventilation, and chelonians, crocodilians, and lizards possess the ability to decrease right-sided perfusion during periods of pulmonary hypoxia.¹³ While the physiologic goals are to maintain appropriate ventilation and perfusion matching during various degrees of pulmonary ventilation, the introduction of general anesthesia can cause significant changes to these breathing patterns. For example, both inspiration and expiration are active processes in reptiles, and in some species ventilation is invariably linked to locomotion.¹ The elimination of these active processes as a result of muscle relaxation with inhalant anesthesia can contribute to ventilatory depression, which can slow the rate of anesthetic induction or recovery. In snakes and lizards, increasing carbon dioxide tensions (which can occur as a result of ventilatory depression with general anesthesia) can decrease minute ventilation further.¹

In order to stabilize gas exchange, support ventilation, and prevent hypoxemia, mechanical ventilation is often performed during inhalant anesthesia. Mechanical ventilation is oftentimes used with inhalant agents to stabilize the anesthetic plane, as it allows for uninterrupted delivery of inhalant agents to the pulmonary system. In mammals, the positive pressure conferred into the thoracic cavity during the inspiratory cycle is linked to an initial increase in pulmonary flow as blood is compressed into the pulmonary artery, followed by a subsequent drop to pulmonary outflow from an increase in pulmonary vascular resistance due to transluminal compression of these low-resistance vessels during the subsequent cardiac cycle. Therefore, although mechanical ventilation ensures continuous delivery of inhalants, variations in pulmonary outflow throughout the ventilatory cycle can affect uptake into pulmonary circulation. Although mechanical ventilation is recommended during inhalant anesthesia of all reptiles, its effect on inhalant kinetics among various reptilian species is not well known. In the pond slider (Trachemys scripta), mechanical ventilation had no impact on pulmonary or systemic blood flow.¹⁴ In ball pythons (Python regius), mechanically ventilating to high minute volumes (125–250 ml/kg/min) during 60 minutes of isoflurane anesthesia resulted in significantly faster recovery times—possibly due to faster washout of the anesthetic agent from the snakes and ventilation system.¹⁵

Inhalants are frequently delivered to patients combined with oxygen as a carrier gas. Breathing high concentrations of oxygen has been associated with respiratory depression in snakes and chelonians and may contribute to slowing the rate of anesthetic recovery in these species. For example, in green iguanas (Iguana iguana), ventilating with room air (21% oxygen) rather than 100% oxygen in the post-anesthetic period was associated with a faster anesthetic recovery.¹ However, the use of high concentrations of oxygen to deliver inhalants had no significant effect on the duration of anesthetic induction or recovery in various species of lizards, including the bearded dragon (Pogona vitticeps) and the Dumeril’s monitor (Varanus dumerilii).^1,16

The efficiency of gas diffusion from the functional lung unit into pulmonary circulation may play a small role in the speed of anesthetic induction and recovery, as modern inhalants readily cross this barrier. While mammals possess a bronchoalveolar tidal volume system, it has been recently shown that crocodilians, as well as the Savannah monitor lizard (Varanus exanthematicus), evolved a unidirectional pulmonary airflow system similar to the avian respiratory system.¹⁷ Conventional wisdom suggests that this airflow system creates a cross-current for gas exchange that would result in less work of breathing as well as higher gas extraction ratios. The efficiency of this type of respiratory system and its significance when using inhalant anesthetic agents can be demonstrated in birds, as many flying avian species undergo relatively rapid induction and recovery when modern inhalant agents are used alone for general anesthesia. However, for reptilian species with relatively low metabolic rates and oxygen consumption rates, the evolutionary significance of a unidirectional respiratory system is speculative at best. Recent studies in crocodilians have demonstrated that the unidirectional airflow system allows for continued flow through gas exchange parenchyma facilitated by the beating heart even during periods of prolonged apnea.¹⁷ At this point, the impact of this unidirectional airflow system on inhalant kinetics in reptiles is unknown.

Although modern inhalants undergo minimal metabolism prior to elimination, the underlying metabolic rate has a significant impact on anesthesia in reptiles. The metabolic rate of reptiles varies between species and can be altered with changes in body temperature and physical activity, during states of hibernation, and between meals.¹ As reptiles are ectotherms, cardiac shunting plays a significant role in body temperature regulation. Right-to-left shunting facilitates warming, as it increases the fraction of blood flow directed to the periphery for heating before returning to the core.¹ Increasing body temperature has also been documented to increase heart rate and cardiac output, which can facilitate recovery from inhalant anesthetics.¹ Although body temperature has been shown to affect the onset and duration of injectable anesthetic agents in both chelonians and lizards, the impact of body temperature on the onset, duration, and recovery from inhalant anesthetic agents has not been evaluated in reptilian species.¹⁸ As previously mentioned, inhalant solubility, or the ability of inhalants to saturate into the blood from a gaseous state, is altered by body temperature. Inhalant agents with a low solubility in blood, such as sevoflurane, are associated with a faster rate of induction and recovery than agents like isoflurane with a higher blood solubility.² In the green iguana, differences in the blood solubility between isoflurane and sevoflurane had no impact on the speed of induction or recovery with these agents.¹⁹ However, the influence of altering body temperatures on the speed of induction and recovery with these two different agents was not evaluated in this species.

Inhalant anesthetic agents are vital to the practice of anesthesia in reptiles. However, a thorough understanding of their pharmacokinetic application to an individual reptilian species is important to utilize these agents appropriately. Although recent studies have shown promise in the use of sympathomimetic agents to speed anesthetic recovery from inhalant agents, more studies are still needed to minimize the unpredictability of induction and recovery when utilizing inhalant anesthetics in various reptilian species.

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