Suspended animation

OVERVIEW

Suspended animation is defined as the therapeutic induction of a state of tolerance to temporary complete systemic ischaemia (Bellamy et al, 1996)

• i.e. protection-preservation of the whole organism during prolonged circulatory arrest (e.g > 1h), followed by resuscitation to survival without brain damage (Bellamy et al, 1996)
• Emergency preservation and resuscitation (EPR) is a protocol for hypothermia-induced suspended animation being studied in trauma patients (Tisherman et al, 2017).

RATIONALE

Induction of a profound hypometabolic state can greatly decrease metabolic demands during systemic ischemia and limit tissue injury

• Mechanism:
  • Profound hypothermia  (≤10°C): reduces cellular metabolism and oxygen demand
    • CMRO₂ is reduced to less than 10% of its normothermic value
    • Brain function is nearly abolished (isoelectric EEG), and oxygen consumption is minimal
  • Pharmacological agents: that induce reversible hypometabolic states; such as:
    • Hydrogen sulphide (H₂S), or Na₂S and NaSH (compounds that slowly release H2S have also been developed)
    • SNC80 (a delta opioid receptor agonist)
    • Donepezil (cholinesterase inhibitor)
• Other animal species are known to undergo hibernation, dormancy, and anabiosis by entering states resembling suspended animation
• Deep hypothermic cardiac arrest (e.g. 15-20C) is currently used for extensive aortic surgery, cerebral aneurysms and AVMs, tumours with caval involvement, and repair of some forms of congenital heart disease
• It has been proposed that multi-organ dysfunction syndrome (MODS) in critical illness is (to some degree) an adaptation to physiological stress to maintain ATP-homeostasis through energy expenditure, rather than sustain permanent organ injury (Singer et al, 2004)

OUTLINE OF PROCEDURES FOR SUSPENDED ANIMATION

Induction of suspended animation with hypothermia

• Preparation
  • Provide general anaesthesia then insert large-bore catheter into the aorta
  • Begin continuous invasive monitoring
• Induction Phase
  • Rapid intravenous infusion of ice-cold saline (0–10°C)
  • Target core temperature: ~10°C.
  • Replace blood with cold saline to halt oxygen delivery and reduce metabolic demand.
• Maintenance Phase
  • Maintain hypothermic state for up to 2 hours.
  • Perform therapeutic interventions during this time window.
  • Monitor for coagulopathy, acidosis, and electrolyte imbalances.
• Rewarming and Resuscitation
  • Gradually reintroduce oxygenated blood or blood substitutes.
  • Rewarm patient slowly to normothermia.
  • Use defibrillation or bypass support if spontaneous circulation does not resume.
• Post-Recovery Monitoring
  • Assess neurological function and organ recovery.
  • Monitor for reperfusion injury, infection, and metabolic disturbances.

Induction of suspended animation with H2S

• Subject Preparation (animal models, such as mice)
  • Begin continuous monitoring
• Gas Setup:
  • Prepare gas mix e.g. 5% H₂S / 95% nitrogen
  • Use precision flow controllers (1–10 sccm)
• Induction Phase:
  • Expose to low-dose H₂S (20–80 ppm).
  • Observe drop in metabolic rate and core temperature.
• Maintenance Phase:
  • Sustain exposure for up to several hours.
  • Monitor for stability and avoid toxic thresholds.
• Recovery Phase:
  • Stop H₂S flow; flush with ambient or oxygenated air.
  • Allow gradual rewarming and metabolic normalization.
• Post-Recovery:
  • Assess vitals and behavior.
  • Check for organ damage or inflammation.

ADVANTAGES

• Potential clinical benefits:
  • Extends time window for life-saving procedures
  • Decreased or cessation of blood flow can improve visualisation during surgical procedures
• Pharmacologically-induced suspended animation
  • Potential to avoid adverse effects of profound hypothermia and cardiac bypass
  • H2S can be non-invasively administered via inhalation
  • H2S appears to have anti-oxidant, anti-inflammatory, and anti-apoptotic properties, and is associated with better maintenance of mitochondrial integrity and function  (Asfar et al, 2014)
  • SN80 may have beneficial antinociceptive, antihyperalgesic, and antidepressant-like effects as well as protecting the spinal cord from ischemia
  • Donepezil is already FDA approved for Alzheimer’s disease
• Hypothermia
  • Proof of concept for prolonged survival from hypothermic cardiac arrest
• If successful, future applications could include “hypersleep” during prolonged space travel…

DISADVANTAGES

• Lack of robust evidence in humans for feasibility, efficacy, or safety
• Hypothermia-induced suspended animation
  • Many of the benefits can be achieved with deep hypothermic circulatory arrest at ~15C ((e.g. can be maintained for 30+ minutes; achieves isoelectric EEG, CMRO2 ~10-15% of normal) with less potential for adverse effects and shorter rewarming times.
  • Main adverse effects of hypothermia
    • Metabolic Acidosis: Due to decreased metabolic rate and impaired lactate clearance.
    • Coagulopathy: Impaired coagulation cascade leading to bleeding complications.
    • Prolonged Inflammation: Increased inflammatory response post-rewarming.
  • Risk of complications of cardiac bypass surgery, which is highly invasive and requires surgical expertise and equipment.
• Pharmacologically-induced suspended animation
  • H2S
    • Toxicity: High doses can inhibit mitochondrial respiration by blocking cytochrome c oxidase, leading to cellular energy failure; inhalation causes airway mucosal injury
    • Inflammation: Potential to aggravate systemic inflammation
    • Variable Efficacy: Inconsistent results across different models and conditions – less effects apparent in larger animals (Asfar et al, 2014)
    • Administration Challenges: Optimal dosing, timing, and route of administration (inhalation vs. intravenous) are not well established
    • Anaesthetics alter the effects of H2S: of uncertain significance but most animal studies were in awake, spontaneously breathing rodents
    • Challenges in larger animals (such as humans):
      • higher absolute oxygen demands and slower metabolic suppression, requiring higher doses of H2S
      • low surface area-to-volume ratio means heat loss is slower, H2S is less effective at inducing hypothermia
      • vasodilation, hypotension, and bradycardia are more common, and high doses induce cardiac arrest
      • Uniform gas delivery through lungs and cardiovascular system is more difficult to achieve
      • Narrower therapeutic window (e.g. similar doses to those required for hypometabolism can cause respiratory paralysis)
  • SNC80
    • Unknown long-term effects: promising in organ preservation, its systemic effects in humans are uncertain
    • Risk of seizures
    • Reversibility concerns: Although reversible in studies, the full safety profile in humans is not yet established
  • Donepezil
    • Lack of human data – however, it does induce a reversible hibernation-like state in tadpoles!

EVIDENCE

Hypothermic cardiac arrest

• Bellamy et al (1996): Profound hypothermia in dogs (n=20) resulted in complete reversibility of 1-hour circulatory arrest
• Lexow, 1991: The longest duration of cardiac arrest from which a human has survived neurologically intact following accidental hypothermia is 6h 30 min
• Niazi and Lewis, 1958: The lowest core temperature from which a human has survived neurologically intact following induced hypothermia is 9C

Traumatic cardiac arrest

• Emergency Preservation and Resuscitation (EPR) for Cardiac Arrest From Trauma (EPR-CAT) is an ongoing clinical trial (Tisherman et al, 2017)
• Moffet et al (2018): systematic review of 20 animals studies of EPR;  N=327 animals were cooled to ≤20°C after haemorrhagic shock.  Most studies (19/20) showed that EPR improved survival and preserved neurological function, even after prolonged periods of circulatory arrest or minimal flow.

H2S-induced suspended animation studies

• Blackstone et al (2005): Hydrogen sulfide (20-80 ppm) exposure of awake healthy mice (n=30) induced hypometabolism (decreased energy expenditure by 90%) and decreased core temperature to close to ambient temperature. Effects were completely reversed following washout of H2S.
• Asfar et al (2014): multiple rodent studies (awake, spontaneously breathing) show that gaseous H2S exposure mitigates organ dysfunction from multiple mechanisms including: ventilator induced lung injury, ischaemia/ reperfusion, bacterial sepsis, endotoxin exposure, hemorrhagic shock, and hypoxic hypoxaemia.

CONCLUSION

Suspended animation – whether induced by drugs or by profound hypothermia to ~10C – remains an interesting area for discussion and research, but currently has no role in clinical practice.

REFERENCES

Journal articles

1. Asfar P, Calzia E, Radermacher P. Is pharmacological, H2S-induced ‘suspended animation’ feasible in the ICU? Crit Care. 2014;18(2):215. PMID: 24642178.
2. Bellamy R, Safar P, Tisherman SA, Basford R, Bruttig SP, Capone A, Dubick MA, Ernster L, Hattler BG Jr, Hochachka P, Klain M, Kochanek PM, Kofke WA, Lancaster JR, McGowan FX Jr, Oeltgen PR, Severinghaus JW, Taylor MJ, Zar H. Suspended animation for delayed resuscitation. Crit Care Med. 1996 Feb;24(2 Suppl):S24-47. PMID: 8608704.
3. Blackstone E, Morrison M, Roth MB. H2S induces a suspended animation-like state in mice. Science. 2005;308(5721):518. PMID: 15845845.
4. Brown DJ, Brugger H, Boyd J, Paal P. Accidental hypothermia. N Engl J Med. 2012 Nov 15;367(20):1930-8. doi: 10.1056/NEJMra1114208. Erratum in: N Engl J Med. 2013 Jan 24;368(4):394. PMID: 23150960.
5. Lexow K. Severe accidental hypothermia: survival after 6 hours 30 minutes of cardiopulmonary resuscitation. Arctic Med Res. 1991;50 Suppl 6:112-4. PMID: 1811563.
6. Hartmann C, Nussbaum B, Calzia E, Radermacher P, Wepler M. Gaseous Mediators and Mitochondrial Function: The Future of Pharmacologically Induced Suspended Animation? Front Physiol. 2017 Sep 19;8:691. doi: 10.3389/fphys.2017.00691. PMID: 28974933; PMCID: PMC5610695.
7. Moffatt SE, Mitchell SJB, Walke JL. Deep and profound hypothermia in haemorrhagic shock, friend or foe? A systematic review. J R Army Med Corps. 2018 Jul;164(3):191-196. doi: 10.1136/jramc-2016-000723. Epub 2017 May 11. PMID: 28495952.
8. Niazi SA, Lewis FJ. Profound hypothermia in man; report of a case. Ann Surg. 1958 Feb;147(2):264-6. doi: 10.1097/00000658-195802000-00019. PMID: 13498651; PMCID: PMC1450560.
9. Singer M, De Santis V, Vitale D, Jeffcoate W. Multiorgan failure is an adaptive, endocrine-mediated, metabolic response to overwhelming systemic inflammation. Lancet. 2004 Aug 7-13;364(9433):545-8. doi: 10.1016/S0140-6736(04)16815-3. PMID: 15302200.
10. Tisherman SA, Alam HB, Rhee PM, Scalea TM, Drabek T, Forsythe RM, Kochanek PM. Development of the emergency preservation and resuscitation for cardiac arrest from trauma clinical trial. J Trauma Acute Care Surg. 2017 Nov;83(5):803-809. doi: 10.1097/TA.0000000000001585. PMID: 28538639.