Pharmacological control of temperature and shivering

This chapter is not relevant to any section of the 2023 CICM Primary Syllabus, as there is no specific syllabus item or pharmacopea category dealing with these agents. The main reason it exists is to act as a reference for anybody who is trying to interfere with human temperature regulation. This is usually an activity of the intensivist or anaesthetist, who often need to do something to a patient's temperature that the patient fiercely resists. The direction of this interference is typically down, i.e. where we want to suppress the normal thermoregulatory defences while we cool a patient, and realistically this should receive the greatest attention as it has the greatest clinical relevance, but this is Deranged Physiology, and remaining relevant or realistic has never been a priority here. Thus:

Drug targets and mechanisms:

  • Controller circuits  (where the hypothalamus is driving but we want to take its hands off the wheel) - these are agents that control fever:
    • Paracetamol and NSAIDs, by interference with the synthesis of PGE2 by cyclooxygenase in the CNS.
    • Corticosteroids (by interrupting IL-6 signalling)
    • Vasopressin, physostigmine, baclofen, pregabalin, thalidomide, by poorly understood central mechanisms

Effectors and their neuroeffector pathways

  • Cutaneous blood flow:
    • General anaesthetics (vasodilate and promote hypothermia)
  • Shivering thermogenesis:
    • ​​​​​​​Opioids (especially meperidine), by a κ-opioid receptor mediated effect
    • α-2 agonists dexmedetomidine and clonidine
    • General anaesthetics
    • Neuromuscular junction blockers (obviously)
  • Sweating:
    • ​​​​​​​Increased sweating:
      • Anticholinesterase drugs, sympathomimetics, antidepressants, opioids
    • Decreased sweating:
      • Anticholinergic drugs, antipsychotics, antihistamines, botulinum toxins
  • Non-shivering thermogenesis:
    • ​​​​​​​Drugs that cause malignant hyperthermia:
      • ​​​​​​​volatile anaesthetics, by exploiting a mutation of the ryanodine calcium channel receptor which causes a hypermetabolic crisis in skeletal muscle
    • Drugs that uncouple oxidative phosphorylation:
      • Sympathomimetics, thyroid hormones, 2,4-dinitrophenol, sibutramine
    • Drugs that inhibit mitochondrial thermogenesis:
      • ​​​​​​​Glucocorticoids, antiretrovirals, β-blockers and α2 blockers, antithyroid medications

The literature on drug-induced thermoregulatory disturbance is surprisingly scarce, which is remarkable because of how ubiquitous one finds the practice of meddling with the temperature of a patient. Surely, one might have thought, somebody somewhere would have created a great review titled something like "Drugs that do things to body temperature" and listed all the possible ways in some kind of sensible classification. In the absence of such a definitive resource, the author reached to his own modest mental commodities for a structure, and came up with the system in the box above, which classifies these agents into groups in terms of what regulatory mechanism they influence. It is based on the excellent works of Clark & Clark (1979-1981), but the reader should not mistake this for some kind of official classification, and in general should guard against taking any of this very seriously, as thermoregulatory physiology is not the primary area of expertise for this author, and he feels somewhat a fraud for even venturing there. 

The best resources for this was actually not the excellent compilations by Wesley and Yvonne Clark, spanning from 1979 to 1981, who in a series of articles covered:

Though dated, this excellent series represents an attempt by the authors to produce a structure for classifying the effects of drugs on temperature, and a quest to list all the possible and impossible drugs and chemicals into a grand reference work where one might be able to quickly look up (checks notes) floropipeton and immediately get a reference to a rat study that tested its effects on temperature regulation. On the other hand, nobody in their right mind would read these for any sort of exam-related reasons. The CICM questions that come even close to this subject matter were:

Therefore the reader is advised to make themselves familiar with the drugs listed in the CICM syllabus document without specific regard for their thermoregulatory properties, and to limit their reading to something like "Antipyretic therapy" by Botting (2004) and "Pharmacologic options for reducing the shivering response to therapeutic hypothermia" by Weant et al (2010). 

Drugs that influence fever

Putting aside the discussion of whether fever is useful, the rest of this section will assume that the reader is interested in lowering the temperature of a febrile patient. We remind ourselves that

"Fever is a regulated elevation of core temperature induced by the central thermoregulatory system itself."

- Boron & Bouelpaep (2017, p.1202)

and so all attempts to control fever must therefore be viewed as attempts to overpower, undermine or sabotage the normal control systems that regulate body temperature. The process is made more difficult by the fact that millions of years of evolution have produced excellent heat retention and generation mechanisms that will defend against all efforts to lower the body temperature artificially, eg. by cooling. The underlying reason for this conflict is the elevation of the interthreshold range by the hypothalamus, which results to vigorous thermogenic responses to normal core temperatures, such as shivering (which by convention becomes rigors in this context). 

In short, the process of fever is an application of the usual mechanisms of thermoregulation. Which brings the question, why do the febrile patients sweat? Surely that must be counterproductive. Indeed, sweating is probably the most potent mechanism for heat loss available to the human organism, and it would be puzzling to see it deployed at a time when the hypothalamus seems to want a higher temperature. The answer can be observed directly in this excellent graph from Palmes & Park (1965), relating the recordings taken from a nude US infantryman suspended on netting in a small experimental chamber. The fever was stimulated by injection of 1ml of the US Army triple typhoid vaccine, which is basically a puree of stool.

Observe: by the timing of the onset of sweating, we can actually identify the exact point where the hypothalamus lost interest in overheating this GI. With the abrupt realignment of temperature goals, the normal thermoregulatory mechanisms suddenly realised that they were well above their setpoint values, and began to actively cool the body; shivering stops, the patient no longer complains of the cold, and as the renromalisation of temperature does not happen instantaneously, over the subsequent hour or two this person remains hyperthermic but now also sweating. In the excellent French's Index of Differential Diagnosis, one of the last people to be named Dudley wrote, 

"...this shivering lasts for perhaps an hour, gradually dying away as the patient feels warmer and presently over-hot. Thus the initial stage of the fever passes into the second stage in which the complaint is of sweating, thirst, and sensation of undue heat"

By this stage, the patient reader will calmly remark that of course none of this has any relationship to the pharmacological control of fever, and they will be entirely correct. Still, the discussion of the unknowable but clearly visible change in the influence of the temperature control centre was important, because that is the main drug target for antipyretic agents.

Mechanisms of action of antipyretic agents

"Antipyretic" is broadly the term that is used to describe drugs that deals with fever specifically, in the sense that they will have no thermal effect in the afebrile individual, as distinct from drugs that lower body temperature (such as anaesthetic agents) or drugs that interfere with specific thermoeffectors directly (like muscle relaxants). To legitimise this description, the official definition from the IUPAC Glossary of Terms Used in Toxicology is simply:

"Antipyretic: Substance that relieves or reduces fever"

But what are these, apart from paracetamol and NSAIDs?  Surely there must be a lot. The mechanism of fever, thought to be related to complicated collaboration between inflammatory cytokines and arachidonic acid derivatives, has so many potential drug targets that one would expect a massive number of options, but in fact it was surprisingly hard to find a range of antipyretics all collected in the same space. Most of the ink that gets spilled over this topic sensibly flows in the direction of whether we should control fever, rather than how we could control it. Still, some papers stand out as exceptional, and of these Aronoff & Neilson (2001) is probably the best, followed by Prajitha et al (2019) and Botting (2004). What follows was cobbled together from snippets of these articles, as well as whatever references are quoted in the text below.


Paracetamol has its own pharmacology chapter because it is the most ubiquitous antipyretic with any evidence behind it, and probably the only one applicable to the fragile ICU population in whom the NSAIDs are largely contraindicated. There are potentially multiple mechanisms by which it exerts this effect (Mirrasekhian et al, 2018), of which the most widely accepted hypothesis is interference with the synthesis of PGE2 by cyclooxygenase in the CNS. The reader is reminded that this is also the mechanism of action of NSAIDs, and so will not be elaborated in extensive detail here, except to remember that most of them act by competing with the substrate (arachidonic acid) for the COX active site, especially at the site of inflammation. In contrast, paracetamol reduces the enzyme to its inactive state, which is harder in the presence of abundant hydrogen peroxide, and this seems to be responsible for the lack of peripheral antiinflammatory activity, where its usual concentration ends up being about ten times lower than what would be required for a clinically meaningful effect.

All this discussion of concentration dependence of effect raises the question, what if moar paracetamol, and faster? Would an oral dose of 2g produce a more rapid antipyretic effect, or giving it intravenously via a quick push? Of course somebody has already done an RCT of this, and yes, the  same dose of intravenous drug was marginally faster as well as marginally more effective overall (Paramba et al, 2013), but not to the extent that one might implicate superior CNS penetration as the main reason.

This chapter would be colourless without the mention of chemically related substances that were/are available to perform paracetamol-like duties in the service of defervescence. These include acetanilide (the prodrug of paracetamol), the discontinued phenacetin, the largely abandoned antipyrine, the banned and toxic amidopyrine and the similarly toxic but still-popular dipyrone (metamizole). The links take the reader to the Wikipedia pages because none of these are serious options that merit a scientific reference, nor was there often a good reference to point at. For the majority of these, the mechanism of action is underinvestigated, but through to be a similar CNS-like effect on PGE2 synthesis.

Whichs begs the question, why not just give an NSAID?


It would be fair to say that all NSAIDS from the extract of willow bark to parecoxib have some antipyretic effect, and that for the majority of them, the magnitude of effect is greater than for paracetamol, when comparing sensible doses.  For example in the abovementioned study by Paramba et al (2013), this results graph demonstrates the superiority of intramuscular diclofenac over both forms of paracetamol:

Are any of them more antipyretic than others? Potentially, yes. Plaisance & Mackowiak (2000) list some pre-2000 work, suggesting that:

  • Nimesulide and dipyrone are more effective than aspirin, which is not saying much (because the effective dose of aspirin for fever seems to be 500mg)
  • Ibuprofen is less effective than nimesulide, but more effective than paracetamol
  • Ketorolac is only as effective as paracetamol

The antipyretic effects of COX-2 selective agents are less well established but appear to be no weaker than those of nonselective agents. Fabricio et al (2005) tested indomethacin against the modestly selective celecoxib and the highly selective lumiracoxib and determined that the coxibs were, if anything, more effective; but the study population were rats who were getting endothlin-1 injections into the brain, which makes the findings somewhat difficult to generalise. 


If complicated cytokine cascades and inflammatory mediator signalling from immune cells are responsible for fever, then surely suppressing the entire immune system should have an antipyretic effect? This is indeed the case with corticosteroids. Coelho et al (1995) lists several mechanisms of action and lists specific cytokine pathways that are interrupted, to a level of detail which would be in excess of  most readers' needs. It will suffice to say that interruption of IL-6 appears to be the main mediator of this effect, which means that they will all have the capacity to do this, although among the steroids dexamethasone seems to be the best-studied antipyretic. It would seem a heavy-handed response to something like fever, but if one were to use steroids for that indication,  doses as low as 1.5mg bd of dexamethasone or 100mg/day of methylprednisolone seem to have some clinical effect in this old study. Incidentally in the same study naproxen was superior. 

Monoclonal antibodies

Following from the above, one might naturally arrive at the conclusion that to suppress the whole immune system to relieve fever seems inelegant, especially if we know that IL-6 is a key factor and especially considering that we have targeted anti-IL6 agents such as tocilizumab. It is in fact surprising that there is so little published material on this specific matter. A little experience with this does find light, for example in this report of two cases of patients with SLE. Anakinra, an IL-1 blocker, also seemed effective in controlling fever in Kawasaki disease (Koné‐Paut et al, 2021). Though this may sound promising, most normal people would agree that if "overkill" was the concern with steroids, then surely the same concern is doubled with agents that cut such proximal branches in the cytokine cascade, especially when they cost in excess of AU$1000. One must of necessity put these agents together with other substances that have antipyretic effects as a part of their spectrum of activity, but which are generally avoided outside of their primary indication. And these are many:

Substances with incidentally antipyretic activity

While reading about antipyretics, one forms the distinct impression that their classification falls into "paracetamol", "NSAIDs", "steroids", and a huge diffuse "other" that stretches into the fog of  obscure botany and pseudoscience. It is perhaps worth making a list of these "other", but perhaps not worth including their citations, to keep the reference section under control. Where possible, the link points to a peer-reviewed resource. Just by using the literature it was impossible to separate these into drugs which have specifically antipyretic activity during fever vs. those that have a depressant effect on the thermoregulatory control centre.

The decision not to discuss these obscure alternatives stems largely from the authors' awareness of the ICU as a bastion of safety culture, reluctant to expose a vulnerable population to experimental therapies. It is therefore pointless to know about the antipyretic effects of the venom of Conus vexillium or  Naja nubiae, as no director of services would view them as an excuse to keep a marine aquarium and/or spitting cobra in the back offices of the ICU. On the other hand, curare is perfectly acceptable:

Drugs that influence shivering

If we are using drugs to hack the interthreshold range, and the drugs aren't working, we may resort to crudely blocking the specific mechanisms of thermoregulation instead. Shivering is probably the most effective mechanism of increasing the body temperature that does not involve jogging. This makes sense because skeletal muscle is a large fraction of the body's solid mass that can be asked to increase its heat output through repeated contractions, and then to share it with the rest of the organism by vasodilating and funnelling a large proportion of the cardiac output through itself. That's great for the arctic explorer but completely useless for the ICU patient who needs to be two degrees cooler for intracranial pressure reasons. Shivering can frustrate the cooling process, increase the total body oxygen demand of the patient, stress their coronary circulation with a higher cardiac output demand, and disturb the visitors.

To restore peaceful composure to the process of hypothermia, the conventional response is muscle relaxant. This is one of the "weak" recommendations from the SCCM (Murray et al, 2016), which they based on "very low quality of evidence", consisting of one study with 18 cardiac arrest survivors, each of whom got paralysed for 24 hours. The study outcome (a mortality benefit of 78% vs 41%!) was so obviously preposterous that it is only mentioned here with the greatest reluctance, as a segue into the discussion of how exactly you would even measure the outcomes of a study that looks at this specific aspect of NMJ blockade. From the mechanism of their action, and from the known fact that shivering can potentially increase the total body oxygen consumption by about five times (at around 35 ºC), we can expect NMJ blockers to reduce the potential oxygen consumption by the same degree. For example, when Horvath et al (1956) exposed naked volunteers to -3 ºC, they responded by consuming about 200% more oxygen and producing about 300% more calories of heat energy after about fifteen minutes:

Metabolic cost of fever, from Horvath et al, 1956

Conversely, when you take people who are merely sedated and then also paralyse them with pancuronium like McCall et al (2003), their energy expenditure drops by about 20%. One should also take into account the drop in metabolic rate which then results from actually being able to achieve your goal temperature. In short, neuromuscular junction blockers are an extremely reliable method of preventing shivering and allowing the patient to get the maximum benefit from their therapeutic hypothermia, whatever that might be.

On the other hand, sustained neuromuscular blockade is not exactly benign. Fortunately, there are other options. Jain et al (2018) describes a selection of agents that can be grouped into broad categories by their mechanism:

Vasodilators to fool the surface temperature receptors

Vasodilators as mediators of a more rapid core-surface heat exchange make effective agents to suppress shivering by a curious mechanism of effect, where they attract warm blood flow to the skin, calming the cutaneous receptors that mediate shivering by perceiving the sensation of cold. Is this for real? This assertion can be traced tot Zweifler et al (2004), who reported on the effects of adding magnesium (a weak peripheral vasodilator) to ondasentron and meperidine for induction of hypothermia by surface cooling in a group of clearly insane volunteers. The magnesium not only reduced their shivering but improved their subjective comfort and increased the rate of cooling, which the investigators attributed to peripheral vasodilation (which they measured by the temperature gradient from the fingertip to the forearm). The dose of magnesium required for this effect was 4 to 6 g (16.4-24.6 mmol) as a bolus followed by 1 to 3 g/hr  (4.1-12.3 mmol/hr) continuous infusion. 

Opioids to blunt thermoregulatory responses

All opioids, including the eternally popular morphine fentanyl alfentanil and to a lesser extent tramadol,  have all been demonstrated to have some anti-shivering activity, and some (specifically meperidine, known locally as pethidine) seem to be uniquely superior. Ikeda et al (1997), comparing the effects of different opioids on shivering, found that meperidine had a substantially greater effect on shivering:  

meperidine vs alfentanil for reduction of shivering, from Ikeda et al (1997)

The authors attributed this difference to the greater κ-opioid receptor effect, which is known to be associated with impaired thermoregulation. So potent are these effects that opioid-heavy hypothermia protocols (eg. Choi et al, 2011) describe patient series where more than half the patients did not require a muscle relaxant because of some combination of opioid and dexmedetomidine. Speaking of which:

α-2 agonists to inhibit central temperature regulation

Dexmedetomidine (Talke et al, 1997) and clonidine (Nicolaou et al, 1997) are both known to impair thermoregulation by a combination of preventing cutaneous vasoconstriction (by their sympatholytic effect) and by inhibiting the central control mechanisms that control these responses. Noradrenergic neurotransmission seems to be at the core of these regulatory mechanisms, and the reason we know this is because Quan et al (1992) first infused noradrenaline, and then α-2 agonists, into the preoptic area of guinea pigs. At a dexmedetomidine concentration of 08. ng/ml (corresponding to rouseable sedation),  the healthy volunteers could be cooled down to 34 degrees without triggering shivering, and the effect seems to be linear, i.e. it would be theoretically possible to push this even further with higher doses; though in that scenario the effect of the drug would put it firmly in the range of general anaesthesia. Which leads to:

General anaesthetics to inhibit central temperature regulation

If you are using a sedative to control shivering, and you are using so much of it that the patient is unrouseable, then you may as well be using a "proper" general anaesthetic. Thermoregulation is definitely affected by high doses of propofol (Matsukawa et al, 1995) and ketamine (Sadeh et al, 2020). For propofol the effect was linear and at high doses (levels of 8 μg/ml) extended to below even 31 ºC, which is roughly where you'd normally stop shivering anyway. Nobody has pushed ketamine quite as hard, but it does seem to have a substantial effect even as single shots of 0.25 mg/kg (for patients waking up to a core temperature of around 35.8 ºC following hysterectomy). However, the most important and immediate effect of general anaesthetics on thermoregulation is probably their effect on the distribution of blood flow to the skin and extremities.

Drugs that influence cutaneous perfusion

Cutaneous vasodilation due to general anaesthesia is the result of several mechanisms and produces a redistribution of blood flow from the core to the periphery, the result of which is a drop in core temperature (as the peripheral tissues are generally cooler). This leads to the rapid drop in core temperature seen within the first hour after the induction of anaesthesia. Moreover, the resulting loss of the insulating effect of the superficial tissue layers increases the rate of heat exchange between the core and the external environment. 

Magnesium, and the vasodilatory effect it has as a mechanism to control shivering, is already described above. Does this mean that all substances that cause vasodilation can have this effect? Interestingly, no, for some reason, they do not, and the question is surprisingly under-explored, considering that everybody everywhere is on an ACE inhibitor or nitrate. Even drugs which are attributed this property in the common knowledge (eg. alcohol) are often found to have no such effect when it is tested empirically. Albin (1984) reviewed the contribution of alcohol to heat loss and demonstrated that it is probably a hoax, as sober victims are observed to lose heat at approximately the same rate as "skid-row drunks", to borrow their turn of phrase. The rumour also exists for other vasodilators such as GTN, to which various counter-thermoregulatory properties are occasionally attributed (for example by Harrison & Ponte, 1996).  Some data to support these assertions does exist; for example, if you are started on an ACE-inhibitor/diuretic combo pill, you are almost three times more likely to be admitted to hospital that summer with a heat-related illness (though admittedly much of that has to do with volume depletion and impaired thirst sensation due to ACE inhibition).

Conversely, is the opposite true? Do vasoconstrictors interfere with rewarming of a hypthermic core by means of surface warming, like Bair huggers and the like? No, they do not seem to, at least in doses that are used in normal clinical practice. In fact even endogenous noradrenergic thermoregulatory vasoconstriction also does not seem to impede aggressive rewarming, which is bizarre because hypothermia and rewarding certainly induces a generous release of catecholamines (quadrupled, but probably underestimated by plasma levels, which probably only measure overflow from synaptic release).  When  Clough et al (1996) directed hot air at some vasoconstricted volunteers, their core heat content increased at a rate comparable with those who were vasodilated due to isooflurane, suggesting that whatever cutaneous blood flow regulation was happening was not a major barrier to heat exchange. In short, though theoretically vasoactive agents should be able to interrupt the normal thermoregulatory blood flow manoeuvres of the skin, in reality this effect seems to be unique to anaesthetic agents (and specifically to volatile anaesthetics).   

Drugs that influence sweating

Whereas the connection between vasodilators and heat loss is tenuous, nobody will argue with the effect of agents that prevent normal sweating. Of these, anticholinergic side-effects of antipsychotic agents and antihistamines are probably the best studied. In the same heat-related-illness admission study (Ellett et al, 2016, from South Australia) the adjusted sequence ratios were something in the order of 1.2-1.4, i.e. a relative risk increase by 20-40%. However these agents represent the merest tip of a weird sweaty iceberg. Cheshire & Fealey (2008), listing agents that tip the balance of sweat production in either direction,  generated a tremendous table of classes and examples which is reproduced below as a tribute to their obsessive thoroughness:

 Drugs that can cause hyperhidrosis
Drug Class Common examples Mechanism
  • Pyridostigmine
Cholinesterase inhibition
Antidepressants: selective serotonin reuptake inhibitors
  • Citalopram
  • Duloxetine
  • Escitalopram
  • Fluoxetine
  • Fluvoxamine
  • Mirtazapine
  • Paroxetine
  • Trazodone
  • Venlafaxine
Serotonergic effect on hypothalamus or spinal cord
Antidepressants: tricyclics
  • Amitriptyline
  • Desipramine
  • Doxepin
  • Imipramine
  • Nortriptyline
  • Protriptyline
Norepinephrine reuptake inhibition with stimulation of peripheral adrenergic receptors
Antiglaucoma agents
  • Physostigmine
  • Pilocarpine
Physostigmine = cholinesterase inhibition
Pilocarpine = muscarinic receptor agonism
Bladder stimulants
  • Bethanechol
Muscarinic receptor agonism
  • Fentanyl
  • Hydrocodone
  • Methadone
  • Morphine
  • Oxycodone
Histamine release
  • Cevimeline
  • Pilocarpine
Muscarinic receptor agonism
 Drugs that can cause hypohidrosis
Drug Class Common examples Mechanism
  • Glycopyrrolate
  • Hyoscyamine
  • Scopolamine
  • Propantheline
  • Dicycloverine
  • Belladonna
  • Atropine
Antimuscarinic effect
Antidepressants: tricyclics
  • Amitriptyline
  • Desipramine
  • Doxepin
  • Imipramine
  • Nortriptyline
  • Protriptyline
Antimuscarinic effect (high for amitriptyline, doxepin; moderate for imipramine and protriptyline; low for nortriptyline)
  • Topiramate
  • Zonisamide
  • Carbamazepine
Topiramate and zonisamide = carbonic anhydrase inhibition
Carbamazepine = central anticholinergic effect
  • Cyproheptadine
  • Diphenhydramine
  • Promethazine
Antimuscarinic effect
  • Clonidine
Central adrenergic effect
Antipsychotics and antiemetics
  • Chlorpromazine
  • Clozapine
  • Olanzapine
  • Thioridazine
  • Quetiapine
Antimuscarinic effect
Antivertigo drugs
  • Meclozine
  • Scopolamine
Antimuscarinic effect
Bladder antispasmodics
  • Darifenacin
  • Oxybutynin
  • Solifenacin
  • Tolterodine
Antimuscarinic effect
Gastric antisecretory drugs
  • Propantheline
Antimuscarinic effect
Muscle relaxants
  • Cyclobenzaprine
  • Tizanidine
Uncertain, possibly inhibition of spinal excitatory interneurons; possibly central and peripheral antimuscarinic effect
Neuromuscular paralytics
  • Botulinum toxins
Cleavage of SNAP-25 inhibiting pre-synaptic release of acetylcholine
  • Fentanyl
  • Hydrocodone
  • Methadone
  • Morphine
  • Oxycodone
Elevation of hypothalamic set point; calcium channel antagonism

That's quite a selection, the CICM exam candidate may say as they recoil in horror from their screen, but the possibility of any of these becoming a matter for CICM exam questions is very remote, as the ability or inability to sweat is rarely an influence on decisionmaking in ICU management. In other words, one would never be prevented from using (checks notes) morphine or pyridostigmine for its primary indication by the concern that it might cause a disastrous excess of sweating. 

When it comes to random drugs causing an unexpected thermal surplus,  for the intensivist two main areas of interest are prominent: those agents that cause extreme hyperthermia on their own accord, and among those specifically, agents that cause malignant hyperthermia

Drugs that influence non-shivering thermogenesis

When it comes to random drugs causing an unexpected thermal surplus,  for the intensivist two main areas of interest are prominent: those agents that cause extreme hyperthermia on their own accord, and among those specifically, agents that cause malignant hyperthermia

Malignant hyperthermia

For the anaesthetic trainee accidentally reading this website (god knows for some reason there seem to be many of you), malignant hyperthermia would be a significant area of concern, as it appears in ANZCA exams. The local page on this topic probably represents only the barest possible minimum, but to elaborate on this topic here would be inappropriate as it probably deserves its own page. As such, the reader will be left with a good reference (Rosenberg et al, 2015), and the summary statement that this disease entity is a mutation of the ryanodine calcium channel receptor which causes a hypermetabolic crisis in skeletal muscle in response to volatile anaesthetics.  It is worth mentioning here most because it would have been extremely weird to visibly omit it from a discussion of drug-induced hyperthermia. But then, if you discuss malignant hyperthermia here, you also commit yourself to discussing neuroleptic malignant syndrome and serotonin syndrome, and this is in fact the strategy accepted by good review articles such as Dao et al (2014) or Chan et al (1997). On the other hand the time-poor exam candidate would agree that this would be an extension into increasingly unrelated territory. None of those are "drug effects" per se, and similarly malignant hyperthermia is really a trick of genetics, in the sense that conventionally volatile anaesthetics would not be expected to cause hyperthermia in the course of their normal use. Sure, the same could be said of, for example, MDMA. But the activation of thermogenesis by sympathomimetics is an extension of their "desirable" effects, and feels like it belongs in this section. Thus:

Hyperthermia due to recreational sympathomimetic drugs

For the intensivist working in metropolitan Australia, serving a population of the world's most gluttonous amphetamine consumers, a presentation with drug-induced hyperthermia due to a sympathomimetic toxidrome is wearily ubiquitous, as sometimes it feels as if waking up in the ICU on a Sunday morning is a part of some kind of coming of age ritual for Australian youths. Sympathomimetic-induced hyperthermia is probably the most damaging consequence of this toxidrome (next to seizures and hypoxia) because of the relatively rapid rate of rise in temperature and the time-sensitive organ damage that results. Only aggressive cooling can convert a tragedy into a potentially hilarious case report.

The mechanism of this is the same as the mechanism from serotonin syndrome, namely the uncoupling of the electron transport chain in skeletal muscle and brown adipose tissue. This has therapeutic implications; it is not as if the muscles of a patient with severe sympathomimetic toxicity are contracting vigorously to produce this extra heat, i.e neuromuscular junction blockers will not solve this problem.

This mechanism  is best summarised as a point form list of essential steps:

  • Noradrenaline released at peripheral nerve endings by sympathomimetic activation binds to β-adrenergic receptors (mostly β3) on the surface of brown tissue adipocytes
  • This is a Gs-protein-coupled receptor, so the result is an adenylyl cyclase-mediated increase in the production of cyclic AMP
  • This activates lipases.
  • Lipases then catalyse the catabolism of triglycerides into free fatty acids.
  • In mitochondria, free fatty acids bind to uncoupling proteins.
  •  Uncoupling Protein 3 (UCP3) is a mitochondrial porin protein that mediates brown adipose tissue heat production and non-shivering thermogenesis by skeletal muscle because it permits the traffic of protons from the mitochondrial intercristae space back into the matrix.
  • The result of this is a reduced efficiency of ATP synthesis, resulting in more glucose and oxygen being "combusted", and therefore greater heat generation.

There are of course other mechanisms, which can be best summarised as a point-form list:

  • Peripheral vasoconstriction, which conserves core temeprature
  • Increased neuromuscular activity and agitation
  • Central thermoregulatory centre dysregulation (Sprague et al, 2018)

How much heat can this process produce? How much MDMA did you take, to answer a question with a question. Conventionally, nonshivering thermogenesis can increase the basal metabolic activity of skeletal muscle by a factor of about 2 (Blondin et al, 2017), but it is unknown how much effect sympathomimetics should be expected to have, or what the dose-effect relationship is. A solid effort to assess these effects from MDMA was undertaken by Parrott (2012) and Liechti (2014). The effect in healthy volunteers constrained from partying by the buzzkill vibes of the lab environment were modest (0.3-0.8 ºC elevation of core body temperature was all they seemed to get out of this), and core temperatures did not exceed 38 ºC for the most (where the dose was about 125mg, which is about typical for a recreational user). Hyperthermia-associated deaths are usually seen in subjects with overdose presentation, such as those reported by  Dar & McBrien (1996), where perhaps tens of tablets are taken, and no real confident statements can be made about these, as the true total dose is unknown.

Thyroxine and thyrotoxicosis-induced hyperthermia

Thyroid hormone regulates the expression of UCP3. Following from the above, it would therefore be expected to do something similar to sympathomimetics, and also to sensitise the organism to the thermogenic effects of sympathomimetics. This is indeed observed in the wild, but is probably not the whole picture; thyroid hormones reach everywhere and have effects on everything, including the hypothalamus. Dittner et al (2019) suggests that at least some of the response is fever rather than hyperthermia, i.e. the hyperthyroid patient intends to be hyperthermic and will obstinately defend their right to remain at a core temperature of 41 ºC.

But that is hyperthyroidism, where the thyroid hormone levels presumably increase gradually and "naturally". What about drug effects? Can a large enough exogenous thyroxine dose stimulate enough thermogenesis to become a threat? The answer is surprisingly difficult to track down. Amazingly large doses (eg. 60 tablets of 150 μg in a case report by Gill et al, 2023) had basically no effect on the temperature, even though "malignant hyperthermia" is occasionally listed as one of the possible complications (Unal, 2019). Rat studies like Dittner do demonstrate a 1-2 ºC increase in temperature, but those guys injected rats with 2mg/kg each day for three days, an equivalent dose of 2799 tablets for a 70-kg human. In short, yes thyroid hormones can probably produce hyperthermia, but getting there would be hard work. 

So, you've decided to uncouple your electron transport chain.

"Hard work" is often insufficient as a disincentive for the industrious humans, who under the influence of the currently prevailing culture value thinness and muscularity above all other aesthetic features, and would risk multiorgan system failure to achieve them. This group act as an excellent test population for exotic agents that influence thermogenesis. Substances that produce hyperthermia by a combination of different effects include:

Thankfully these agents are largely banned, and the black market that has developed to serve people who are still interested in them is full of counterfeits and fraud, overall making society slightly safer through internet crime. One may go through their whole career in a large ICU without having seen a single case of 2.4-dinitrophenol toxicity. 

Drugs that cause hypothermia by mitochondrial mechanisms

To be clear, we have already discussed agents which suppress fever, agents which interrupt the normal neureffector pathways of thermoregulation, and agents that increase thermogenesis by meddling with the metabolism; which means what's left are drugs that depress temperature by acting at the mitochondrial level. Less known in the literature because less relevant to anaesthesia and therefore unsexy, hypothermia resulting directly from the effects of drugs is a poorly described phenomenon, and most senior clinicians will grasp for even one or two substances which they could list under this heading. This was certainly the case for the author. It was therefore astonishing to find the excellent compilations by Wesley and Yvonne Clark,  because it lists every possible substance known to man, among which a very large number seem to depress the body temperature by a whole host of mechanisms. Of these, a selected group of "mitochondrial cryogens" include:

  • Glucocorticoids, because they decrease the expression of UCP1 in brown adipose tissue
  • Dolutegravir, by a similar mechanism (interferes with UCP1 function)
  • β-blockers, because they inadvertently block β3 receptors (thus, indirectly influencing UCP3)
  • α2 blockers, by a similar mechanism (decreased sympathomimetic activity)
  • All drugs that depress thyroid hormone synthesis, logically
  • Most agents that inhibit mitochondrial function also tend to cause hypothermia (listed by Nadanaciva & Will, 2009); which means:
  • Cyanide, obviously (but then you are dead, which is cheating)


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