Mammalian hibernation: a unique model for medical research

Hibernation is an adaptive behavior for some small animals to survive cold winter. Hibernating mammals usually down-regulate their body temperature from ~37°C to only a few degrees. During the evolution, mammalian hibernators have inherited unique strategies to survive extreme conditions that may lead to disease or death in humans and other non-hibernators. Hibernating mammals can not only tolerant deep hypothermia, hypoxia and anoxia, but also protect them against osteoporosis, muscle atrophy, heart arrhythmia and ischemia-reperfusion injury. Finding the molecular and regulatory mechanisms underlying these adaptations will provide novel ideas for treating related human diseases.

Cold protection allows local cryotherapy in a clinical-relevant model of traumatic optic neuropathy

Therapeutic hypothermia (TH) is potentially an important therapy for central nervous system (CNS) trauma. However, its clinical application remains controversial, hampered by two major factors: 1) Many of the CNS injury sites, such as the optic nerve (ON), are deeply buried, preventing access for local TH. The alternative is to apply TH systemically, which significantly limits the applicable temperature range. 2) Even with possible access for "local refrigeration", cold-induced cellular damage offsets the benefit of TH. Here we present a clinically translatable model of traumatic optic neuropathy (TON) by applying clinical trans-nasal endoscopic surgery to goats and non-human primates. This model faithfully recapitulates clinical features of TON such as the injury site (pre-chiasmatic ON), the spatiotemporal pattern of neural degeneration, and the accessibility of local treatments with large operating space. We also developed a computer program to simplify the endoscopic procedure and expand this model to other large animal species. Moreover, applying a cold-protective treatment, inspired by our previous hibernation research, enables us to deliver deep hypothermia (4°C) locally to mitigate inflammation and metabolic stress (indicated by the transcriptomic changes after injury) without cold-induced cellular damage, and confers prominent neuroprotection both structurally and functionally. Intriguingly, neither treatment alone was effective, demonstrating that in situ deep hypothermia combined with hibernation-mimicking cold protection constitutes a breakthrough for TH as a therapy for TON and other CNS traumas.

The Efficacy of Renal Replacement Therapy for Rewarming of Patients in Severe Accidental Hypothermia—Systematic Review of the Literature

Background: Renal replacement therapy (RRT) can be used to rewarm patients in deep hypothermia. However, there is still no clear evidence for the effectiveness of RRT in this group of patients. This systematic review aims to summarize the rewarming rates during RRT in patients in severe hypothermia, below or equal to 32 °C. Methods: This systematic review was registered in the PROSPERO International Prospective Register of Systematic Reviews (identifier CRD42021232821). We searched Embase, Medline, and Cochrane databases using the keywords hypothermia, renal replacement therapy, hemodialysis, hemofiltration, hemodiafiltration, and their abbreviations. The search included only articles in English with no time limit, up until 30 June 2021. Results: From the 795 revised articles, 18 studies including 21 patients, were selected for the final assessment and data extraction. The mean rate of rewarming calculated for all studies combined was 1.9 °C/h (95% CI 1.5–2.3) and did not differ between continuous (2.0 °C/h; 95% CI 0.9–3.0) and intermittent (1.9 °C/h; 95% CI 1.5–2.3) methods (p > 0.9). Conclusions: Based on the reviewed literature, it is currently not possible to provide high-quality recommendations for RRT use in specific groups of patients in accidental hypothermia. While RRT appears to be a viable rewarming strategy, the choice of rewarming method should always be determined by the specific clinical circumstances, the available resources, and the current resuscitation guidelines.

The Role of Deep Hypothermia in Cardiac Surgery

Hypothermia is defined as a decrease in body core temperature to below 35°C. In cardiac surgery, four stages of hypothermia are distinguished: mild, moderate, deep, and profound. The organ protection offered by deep hypothermia (DH) enables safe circulatory arrest as a prerequisite to carrying out cardiac surgical intervention. In adult cardiac surgery, DH is mainly used in aortic arch surgery, surgical treatment of pulmonary embolism, and acute type-A aortic dissection interventions. In surgery treating congenital defects, DH is used to assist aortic arch reconstructions, hypoplastic left heart syndrome interventions, and for multi-stage treatment of infants with a single heart ventricle during the neonatal period. However, it should be noted that a safe duration of circulatory arrest in DH for the central nervous system is 30 to 40 min at most and should not be exceeded to prevent severe neurological adverse events. Personalized therapy for the patient and adequate blood temperature monitoring, glycemia, hematocrit, pH, and cerebral oxygenation is a prerequisite and indispensable part of DH.

Successful induction of deep hypothermia by isoflurane anesthesia and cooling in a non-hibernator, the rat

The aim of the present study was to establish a novel method for inducing deep hypothermia in rats. Cooling rats anesthetized with isoflurane caused a time-dependent decrease in rectal temperature, but cardiac arrest occurred before their body temperature reached 20 °C when isoflurane inhalation was continued during the cooling process. Stopping inhalation of isoflurane when the rectal temperature reached 22.5 °C successfully induced deep hypothermia, although stopping the inhalation at 27.5 °C resulted in spontaneous recovery of rectal temperature. The hypothermic condition was able to be maintained for up to 6 h. A large number of c-Fos-positive cells were detected in the hypothalamus during hypothermia. Both the maintenance of and recovery from hypothermia caused organ injury, but the damage was transient and recovered within 1 week. These findings indicate that the established procedure is appropriate for inducing deep hypothermia without accompanying serious organ injury in rats.

Does deeper hypothermia reduce the risk of acute kidney injury after circulatory arrest for aortic arch surgery?

OBJECTIVES The impact of hypothermic circulatory arrest (HCA) temperature on postoperative acute kidney injury (AKI) has not been evaluated. This study examined the association between circulatory arrest temperatures and AKI in patients undergoing proximal aortic surgery with HCA. METHODS A total of 759 consecutive patients who underwent proximal aortic surgery (ascending ± valve ± root) including arch replacement requiring HCA between July 2005 and December 2016 were identified from a prospectively maintained institutional aortic surgery database. The primary outcome was AKI as defined by Risk, Injury, Failure, Loss, End Stage Renal Disease (ESRD) criteria. The association between minimum nasopharyngeal (NP) and bladder temperatures during HCA and postoperative AKI was assessed, adjusting for patient-level factors using multivariable logistic regression. RESULTS A total of 85% (n = 645) of patients underwent deep hypothermia (14.1–20.0°C), 11% (n = 83) low-moderate hypothermia (20.1–24.0°C) and 4% (n = 31) high-moderate hypothermia (24.1–28.0°C) as classified by NP temperature. When analysed by bladder temperature, 59% (n = 447) underwent deep hypothermia, 22% (n = 170) low-moderate, 16% (n = 118) high-moderate and 3% mild (n = 24) (28.1–34.0°C) hypothermia. The median systemic circulatory arrest time was 17 min. The incidence of AKI did not differ between hypothermia groups, whether analysed using minimum NP or bladder temperature. In the multivariable analysis, the association between degree of hypothermia and AKI remained non-significant whether analysed as a categorical variable (hypothermia group) or as a continuous variable (minimum NP or bladder temperature) (all P > 0.05). CONCLUSIONS In patients undergoing proximal aortic surgery including arch replacement requiring HCA, degree of systemic hypothermia was not associated with the risk of AKI. These data suggest that moderate hypothermia does not confer increased risk of AKI for patients requiring circulatory arrest, although additional prospective data are needed.

RECOVERY OF RAT'S HEART AND RESPIRATION FUNCTIONING DURING EMERGENCE FROM DEEP HYPOTHERMIA IN THE PROCESS OF SELF-HEATING AND WITH AN EXTERNAL HEATER

The article presents modeling of the organism emergence from hypothermia preceded by cardiac arrest. Experiments were performed with anaesthetized Wistar male rats and monitoring the breathing rate, heart rate, blood pressure, arterial oxygen saturation, rectal and esophagal temperature. Rats were kept immersed in water at 8–10 °С till the respiratory arrest and cardiac activity reduction. In 5 minutes, artificial ventilation was administered to restore a normal cardiac rhythm and rate. In one model, the rats had to warm themselves after withdrawal from water. In the other, the rats were held in water till arrest of the previously activated heart. Afterwards the rat's chest wall was heated to restore the cardiac activity. Artificial ventilation was stopped when animal showed signs of breathing. According to the results, in the second model anoxia together with a deeper cooling slowed down recovery of the cardiac and breathing functions. These experimental models can be used for verification of procedures of emergence from deep hypothermia and testing resuscitation pharmaceuticals.