Hypothermia, shivering and cryonics

The objective of cryonics stabilization is to arrest metabolism of the patient so that he can be preserved indefinitely until resuscitation and rejuvenation technologies are available. Induction of hypothermia is the principal method employed in cryonics to reduce metabolism, thereby slowing down the rate of all chemical reactions in the body, including the ischemia-induced cellular cascades leading to cell injury and eventual post-mortem decay. Consequently, in order to mitigate ischemic damage that occurs at initially high “post-mortem” body temperatures, hypothermia is induced in cryonics patients as rapidly as possible after pronouncement of legal death.

While several factors limit achievable surface cooling rates (e.g., ratio of body mass to surface area, subcutaneous fat thickness, and current technological capabilities for cooling in the field), an often overlooked and less understood limitation arises from the normal physiological mechanism of thermoregulation, or the body’s own attempt to maintain physiological temperature.

Core temperature in humans is normally kept within a range of 36.5 – 37.5 degrees Celcius, known as the “interthreshold range.” Compensatory mechanisms are triggered when core temperature rises above or falls below this range.

Thermoregulatory processes during cold defense fall broadly into two categories: heat conservation and heat production. The body conserves heat by regulating skin blood flow (cutaneous vasoconstriction) and by piloerection (i.e., erection of the hair on the skin). The body also produces heat via two mechanisms: shivering thermogenesis (skeletal muscle activity) and non-shivering thermogenesis (increased heart rate and brown adipose tissue sympathetic nerve activity). Of these, shivering presents the largest obstacle to metabolism reduction and temperature management. The hypothalamic region of the brain plays an important part in shivering by integrating temperature input from the body and controlling efferent responses to temperature variations.

Therapeutic hypothermia, such as used to manage patients with acute cerebral injury, is known to cause shivering, which can make rapid induction of hypothermia impractical. Rapid and effective induction and maintenance of therapeutic hypothermia requires that shivering is inhibited. Several pharmacologic and non-pharmacologic interventions have been evaluated for their efficacy in shivering inhibition.

In a recent (2007) paper, Mahmood and Zweifler review the various treatments for shivering inhibition. Their review includes discussions of several drug classes, including anesthetics, opioids, α2 agonists, 5-HT uptake inhibitors, 5-HT agonists/antagonists, cholinomimetics, and NMDA antagonists, as well as physiologic maneuvers and skin surface warming.

General anesthesia impairs thermoregulation and can increase the interthreshold range up to 4.0 degrees Celcius. Mahmood and Zweifler report that both classes of anesthetics, thermogenesis inhibitors (i.e., volatile anesthetics) and thermogenesis non-inhibitors (nonvolatile anesthetics), reduce the shivering threshold proportional to the vasoconstriction threshold in a dose-dependent manner. Propofol, in particular, markedly impairs the vasoconstriction and shivering thresholds. Propofol is the current anesthetic of choice in cryonics to reduce cerebral metabolism and prevent return to consciousness during stabilization procedures.

Opioids are peptides that can effect changes in body temperature, generally by stimulating formation of cyclic adenosine monophosphate (cAMP), which increases thermosensitivity in neurons. The authors report that meperidine “is unique among opioids due to its special antishivering effect,” decreasing the shivering threshold by almost twice as much as the vasoconstriction threshold. Because of its effectiveness, meperidine has played an important part in many protocols of therapeutic hypothermia. Disadvantages include respiratory suppression, nausea/vomiting, and potential induction of seizures with prolonged administration – all of which are arguably non-important to cryonics patients. Fentanyl and butorphanol have also been shown to be effective antishivering agents, though more research into these agents is necessary.

Clonidine is an α2 agonist that lowers the threshold for cutaneous vasoconstriction and shivering and has been widely investigated for its antishivering benefit. In trials directly comparing clonidine with meperidine for prevention of postoperative shivering, 89% of patients in clonidine groups did not shiver, while 85% of meperidine groups did not shiver.

5-HT is reported to impact thermoregulatory responses through its action on different sites in the hypothalamus, midbrain, and medulla. The authors note that “these actions appear to be site and species specific and it is likely the balance between the modulatory 5-HT and norepinephrine inputs that is important for short and long-term thermoregulatory control of the shivering threshold.” Studies have shown that 5-HT uptake inhibitors such as tramadol and nefopam, both analgesics, have antishivering properties comparable to those of clonidine. Additionally, the 5-HT1A partial agonist busprione acts synergistically with meperidine in reducing the shivering threshold.

The cholinomimetic drug physostigmine has been shown to be as effective in controlling postanesthetic shivering as meperidine and clonidine, and more effective than mefopam, though its mechanism remains unknown. Magnesium sulfate (MgSO4) is effective in postanesthetic shivering control, is a neuroprotectant, and has also been shown to increase cooling rate during surface cooling. However, it only modestly reduces the shivering threshold. The NMDA antagonist ketamine has also been shown to be equivalent to meperidine in prevention of postoperative shivering.

Another agent that reduces the threshold for shivering is dantrolene, although dantrolene produces relatively little central thermoregulatory inhibition. Dantrolene is also interesting as a neuroprotective agent because it inhibits excitotoxicity-induced calcium release from the endoplasmic reticulum. Dantrolene further enhances the action of CNS depressants through its effects on GABA receptors. However, conflicting observations about its blood brain barrier permeability exist.

The authors also report the apparent effectiveness of physiologic maneuvers such as breath holding, muscle relaxation, exercise, upright posture, and mental arithmetic on shivering inhibition. Obviously, such maneuvers are not practical for cryonics patients, who are not conscious. Skin surface warming, especially focal facial warming, is also reported to facilitate therapeutic hypothermia by lowering the shivering threshold in some studies but failed to produce clinically significant shivering inhibition in other studies.

Many other pharmaceutical agents have been tested for antishivering properties, though the majority of these drugs have been evaluated in the peri-operative setting because induction of hypothermia and shivering are perceived to be undesirable in postoperative recovery. Pharmacologic inhibition of shivering for therapeutic hypothermia has been largely neglected as an area of study, therefore data specific to the achievement of this goal remain limited.

There are currently no specific agents in cryonics stabilization protocol to inhibit shivering. There are no case reports that document shivering in a cryonics patient, although it is a possibility that the lack of shivering in cryonics patients is the consequence of rapid administration of general anesthetics such as propofol. Other possible explanations for the absence of shivering in cryonics patients include old age impairment of thermoregulation, the long terminal and agonal phase that most cryonics patients experience, and the adverse effects of circulatory arrest, ischemia, and hypoperfusion on thermoregulation.

In the past metocurine has been administered in cryonics to inhibit shivering. Neuromuscular blockers, however, are not recommended for treating cryonics patients because of the risk of criminal prosecution. Because it is questionable that most “post-mortem” cryonics patients have a properly functioning hypothalamus that registers the temperature drop induced by hypothermia, specific antishivering agents may be redundant, especially in light of the fact that the first medication typically given at the start of cryonics procedures, propofol, has a mitigating effect on shivering as well.

Fever and brain injury

Elevation of body temperature occurring as a result of hypothalamic coordination of autonomic, neuroendocrine, and behavioral responses in reaction to physiological injury or invasion is generally known as fever. Traditional thought is that the “febrile response” is beneficial in preventing the proliferation of invading microorganisms, but some caregivers consider fever to be harmful and prescribe antipyretic agents and/or physical cooling methods to suppress fever. In their recent publication, Aiyagari and Diringer summarize the data that exists concerning the efficacy of physical and pharmacological treatments in reducing temperature and improving outcome in a variety of acute neurological disorders including stroke, traumatic brain injury, and cardiac arrest.

Several rationales exist for treating fever, including the relief of discomfort associated with fever, reduction of fever-imposed increase in metabolic demand, reduction in morbidity and mortality, reduction of fever-induced cognitive impairment, and prevention of febrile seizures. Most of these rationales are beneficial in theory, but have not been proven in practice. In the case of morbidity/mortality reduction, treatment with antipyretics has been shown to prolong certain infections; similarly, fever is known to improve survival of patients with community acquired pneumonia, Eschericia coli bacteremia, and Pseudomonas aeruginosa sepsis. Compounding these issues is the fact that traditional methods of lowering temperature in febrile patients are ineffective.

Elevated temperature exacerbates neuronal injury caused by cerebral ischemia or traumatic brain injury (TBI) and, conversely, hypothermia acts as a neuroprotectant in such cases. Well-controlled animal models of global and focal ischemia demonstrate a significantly detrimental effect of hyperthermia on clinical outcome and neuropathological changes. Ginsberg and Busto ( 1998 ) list a number of mechanisms through which hyperthermia worsens outcome in cerebral ischemia: increased neurotransmitter release, increased free radical production, opening of the blood-brain barrier, increased depolarizations within the penumbra, impaired brain metabolism and second messenger inhibition, and cytoskeletal degradation. The authors also note that “the action of otherwise neuroprotective drugs in ischemia may be nullified by mild hyperthermia.” Meticulous brain temperature monitoring and treatment of elevated temperature in patients suffering from neurological insult may, therefore, help prevent secondary injury.

Clinical studies of TBI and survivors of cardiac arrest have demonstrated an independent relationship between fever and poor outcome. Although fever is extremely common in neurological intensive care unit patients, the lack of effective fever treatment options has severely limited the availability of data regarding the benefits of fever reduction in such patients. However, recent advances in surface and intravascular cooling devices have lead to improvements in ability to reduce temperature, especially in patients with neurological injuries. An external cooling device known as the Medivance Arctic Sun temperature management system appears to be quite effective at reducing temperature in febrile patients (75% reduction in fever burden) as compared with more traditional means of fever reduction such as air- or water-circulating cooling blankets. Similarly, a newly-devised catheter-based heat exchange system (Cool Line/Cool Gard) has been tested in patients with subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), cerebral infarction, or TBI, showing a 64% reduction in fever burden as compared to the conventional treatment group (antipyretic, cooling blanket, and ice packs). Unfortunately, no data exists concerning these interventions’ impact on outcome.

As cooling devices and methods are improved and proven to be effective, more data concerning the effect of fever reduction on outcome should be forthcoming. Importantly, as Aiyagari and Diringer point out in the conclusion of their review:

“In the absence of conclusive data, the approach to fever management should be based on the balance between the potential for fever to exacerbate brain insults vs. enhance the ability to fight infections. Fortunately, the risk of ongoing brain injury is usually limited to the early phase in the course of most acute insults while the risk of infection rises as time goes on. Thus it would seem reasonable to aggressively control fever during the first few hours to days following ischemic stroke, intracerebral hemorrhage and head injury. Subsequently, aggressive fever control is less likely to be of help and could be detrimental.”

In cryonics patients, infection exacerbation is less important than protecting the brain from injury and warrants immediate induction of rapid cooling to protect patients from injury due to elevated temperatures. The benefits of treating fever in brain injury also highlights the importance of maintaining normothermia, or even hypothermia, in agonal (hypoxic) patients that present for cryopreservation.