Introduction

Marine and freshwater amphibious mammals comprise a surprising number of species, including pinnipeds (seals), mustelids (otters), rodents (capybaras and beavers), as well as artiodactylids (hippopotami). The larger species (hippos and seals) present the anaesthetist with a number of challenges, both in the captive and free-ranging environment. These animals are often aggressive and potentially dangerous. They tend to escape into the water when threatened and risk drowning if they do so after anaesthetic drugs have been administered. Their large size makes them difficult to manipulate during anaesthesia and their adaptation to a cold aquatic environment has provided them with a thick skin and subcutaneous fat layer with limited peripheral vasculature which restricts vascular access. Anaesthetic mortality rates in some seal species are alarmingly high (10 to 31%),¹ with similar mortalities reported in common hippopotami². Although many of these mortalities are attributed to specific drug combinations, apnoea, bradycardia and peripheral vasoconstriction which progress to cardiac arrest are often blamed on the so called "dive reflex." The term is frequently used loosely without a clear understanding of the triggers, or physiology involved. What is the dive reflex, when does it occur and does it have any clinical significance?

Diving Bradycardia

Diving bradycardia occurs in all air-breathing vertebrates, but is particularly pronounced in mammals. The degree of bradycardia varies tremendously between species. The reflex is initiated by stimulation of mainly cold receptors of the afferent trigeminal nerves of the forehead, periorbital area and nasal passages. These impulses are thought to be carried via the brain stem to the vagal nerve (parasympathetic), resulting in bradycardia, decreased cardiac output, hypertension, and vasoconstriction (sympathetic) of selected peripheral vascular beds.³ The vasoconstriction reduces blood flow to near zero in hypoxia-resistant tissue, redirecting blood flow to oxygen-sensitive organs such as the heart, lungs, and brain as well as the adrenal glands. The reflex is triggered by immersion of the face or whole body in water colder than 15°C. In humans the response is variable, but generally results in a decline in heart rate of between 15 and 40%. A similar reflex is seen without immersion during simple apnoea. The two reflexes act synergistically when both immersion and apnoea occur at the same time in cold water. Bradycardia has been shown to occur before the onset of hypertension, indicating that these two effects are independent of each other and that the bradycardia is not initially mediated through the baroreceptors.⁴ Pretreatment with atropine effectively prevents the dive-induced bradycardia, but does not affect peripheral vasoconstriction.

Alarm Bradycardia

Most species exhibit the characteristic fight-or-flight response when threatened. This is typically associated with sympathetic stimulation resulting in tachycardia and hypertension. In contrast, some species exhibit a fear-induced tonic immobility, presumably to evade detection by predators. Dive-induced bradycardia has consistently been shown to be exacerbated in diving mammals and birds during forced dives when compared to voluntary dives. The heart rates of submerged seals have also been shown to decrease dramatically (to as low as 3 to 5 beats/min with occasional cardiac pause) when threatened by the presence of a boat.⁵

Diving Physiology in Seals

Many seal species spend 80% or more of their lives at sea. Their ability to stay submerged for long periods of time in search of prey seems to be dependent to a large extent on their size. Southern elephant seals (Mirounga leonina) are the largest and the deepest diving, air-breathing non-cetaceans. Maximum dive depths of 2133 m have been recorded. Dive times of up to 2 hours have been recorded, but most occur for about 20 minutes and are only interrupted by short surfacing periods of approximately two minutes.⁶ Two factors influence the ability of these animals to stay submerged: their total O₂ storage capacity before the dive and the rate of O₂ utilisation while they are submerged.⁷ In phocid seals, the blood O₂ storage capacity is increased due to a large blood volume (3 times the human mass-specific volume) and high haemoglobin concentration (double the human concentration). Myoglobin stores, particularly in primary locomotors muscles are 25 times higher than in humans.⁸ Minimum PaO₂ (12–23 mm Hg) and SaO₂ (8–26%), measured in elephant seals during dives, demonstrate an extreme hypoxaemic tolerance.⁹ High PvO₂ values during the initial phase of the dive suggest limited O₂ extraction by tissues and the presence of significant arteriovenous shunts (possibly in the skin or spleen). In seals and humans, the spleen appears to be a dynamic erythrocyte storage unit, capable of releasing oxygen stored in erythrocytes, during episodes of relative hypoxia. The splenic contraction is induced by a catecholamine-mediated α-adrenoceptor response, causing an increase in haematocrit and available oxygen-rich haemoglobin. Harbour seal hearts have been shown to tolerate very low cardiac blood flow rates that would normally cause heart failure or myocardial damage in humans or dogs.⁵ Hepatic sinus PvO₂ values approach 0 mm Hg near the end of a dive, which is far lower than the 10 mm Hg threshold below which hypoxic brain damage is thought to occur in humans.⁵

Clinical Implications

The diving reflex could have significant clinical implications. The evidence indicates that the primary purpose of the dive reflex is to limit the negative effects of hypoxia, especially on organs that have a high oxygen demand like the heart and brain. The resistance of some amphibious mammals to extreme hypoxia should provide a significant advantage during anaesthetic-induced respiratory depression. However, the possible dysregulation of the dive reflex during anaesthesia in seals and other diving mammals has not been investigated and there are several possible pharmacological interactions that warrant further investigation.

Elephant seals have been noted to have an irregular breathing pattern while on land, with periods of apnoea that can extend for longer than 20 minutes in adults during normal sleep. The physiological changes during sleep apnoea in seals are comparable to those experienced during diving.¹⁰ Anesthetised seals often show apneustic breathing patterns with long periods of apnoea. Central nervous system depression by anaesthetic agents may result in similar periods of apnoea to those seen during normal sleep. This effect is likely to be dose dependent regardless of the anaesthetic agent used, resulting in moderate to severe hypoxia. Given the extreme tolerance for hypoxia in these animals, this should not be of any real concern. However, if anaesthetic agents increased cardiac workload and myocardial oxygen consumption, then the protective mechanisms employed by the dive reflex would be counteracted. Ketamine and tiletamine are commonly used in seal and hippo anaesthesia and have both been shown to increase cardiac rate and workload. The low doses typically used for field immobilizations should not cause significant problems, but higher doses for surgical anaesthesia may result in significant mortalities. The use of anticholinergic drugs like atropine and glycopyrrolate to counteract bradycardia may also increase myocardial oxygen demand and may therefore be contraindicated.

Alpha-2 agonists are increasingly used in combination with benzodiazepines and opioids for the immobilization and anaesthesia of seals and hippos. This group of drugs is specifically mentioned here because they cause almost identical physiological effects as seen during the dive reflex. Medetomidine has been shown to induce bradycardia and reduce cardiac output through cardiac vagal stimulation and reduced central sympathetic tone. Medetomidine may therefore provide some levels of cardioprotection during periods of hypoxia in anaesthetised seals.

The rapid and severe, hypoxia-induced peripheral vasoconstriction seen in amphibious mammals also has potential clinical implications during anaesthesia. Drugs that are delivered subcutaneously may be only partially absorbed prior to the onset of peripheral vasoconstriction. This may result in partial, inadequate, or delayed anaesthesia. Once peripheral vasoconstriction has set in, absorption of additional intramuscular anaesthetic drugs or reversal agents may be severely impaired. It is therefore important to deliver anaesthetic drugs rapidly by either deep intramuscular administration or intravenously. Reversal agents may have to be administered into the trachea or attempts need to be made to reduce the level of hypoxia through the administration of oxygen and/or assisted ventilation prior to the intramuscular or intravenous administration of reversal agents.

The provision of supplementary oxygen during anaesthesia remains the safest and most reliable method of preventing severe hypoxia. Seals have a large amount of oropharyngeal soft tissue that easily obstructs respiration during anaesthesia and endotracheal intubation is strongly advised for deeper levels of anaesthesia. In hippos, supplementary O₂ can be supplied by placing an endotracheal tube into a nostril. In larger seals and hippos, positive pressure ventilation may be necessary for long procedures or procedures that require a deeper level of anaesthesia.

References

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2.  Miller M. Hippopotami. In: West G, Heard D, Caulkett N, eds. Zoo Animal and Wildlife Immobilization and Anesthesia. Chapter 50. 1st ed. Ames, IA, USA: Blackwell Publishing; 2007: 579–584.

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4.  Khurana RK, Wu R. The cold face test: a non-baroreflex mediated test of cardiac vagal function. Clin Auton Res. 2006;16(3):202–207.

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6.  McIntyre T, De Bruyn P, Ansorge I, Bester M, Bornemann H, Plötz J, et al. A lifetime at depth: vertical distribution of southern elephant seals in the water column. Polar Biol. 2010;33(8):1037–1048.

7.  Castellini MA, Kooyman GL, Ponganis PJ. Metabolic rates of freely diving Weddell seals: correlations with oxygen stores, swim velocity and diving duration. J Exp Biol. 1992;165:181–194.

8.  Ponganis PJ, Meir JU, Williams CL. In pursuit of Irving and Scholander: a review of oxygen store management in seals and penguins. J Exp Biol. 2011;214(Pt 20):3325–3339.

9.  Meir JU, Champagne CD, Costa DP, Williams CL, Ponganis PJ. Extreme hypoxemic tolerance and blood oxygen depletion in diving elephant seals. Am J Physiol Regul Integr Comp Physiol. 2009;297(4):R927–939.

10. Blackwell SB, Le Boeuf BJ. Developmental aspects of sleep apnoea in northern elephant seals, Mirounga angustirostris. J Zool. 1993;231(3):437–447.