Expert consensus on the prevention, diagnosis and treatment of cold injury in China, 2020.

Cold injury refers to local or systemic injury caused by a rapid, massive loss of body heat in a cold environment. The incidence of cold injury is high. However, the current situation regarding the diagnosis and treatment of cold injury in our country is not ideal. To standardize and improve the level of clinical diagnosis and treatment of cold injury in China, it is necessary to make a consensus that is practical and adapted to the conditions in China. We used the latest population-level epidemiological and clinical research data, combined with relevant literature from China and foreign countries. The consensus was developed by a joint committee of multidisciplinary experts. This expert consensus addresses the epidemiology, diagnosis, on-site emergency procedures, in-hospital treatment, and prevention of cold injury.

In pursuit of the unicorn.

This short review was prompted by The Physiological Society's recent online symposium on variability. It does not deal with a specific methodology, but rather with the myth that certain environmentally-induced clinical conditions can be identified, quantified, simplified and monitored with a single methodology. Although this might be possible with some clinical conditions, others resist the prevailing reductionist approach of minimizing rather than exploring variation in pathogenesis and pathology, and will not be understood fully until the variation in cause and effect are embraced. This is likely to require comprehensive methodologies and collaboration.

Nonfreezing Cold Injuries Among Long-Distance Polar Rowers.

INTRODUCTION: Nonfreezing cold injury (NFCI) is a peripheral cold injury that occurs when the extremities are exposed to cold temperatures, at or near the freezing point, for sustained periods of time (48-96 h at temperatures of usually around 0 to 6°C with associated wind chill). Although NFCI often goes unreported and may be underdiagnosed, it is a cause of significant morbidity in those working in cold conditions, particularly those in the military. Thus, further research into the prevention, recognition, and treatment of NFCI is warranted. METHODS: The height, body weight, and body composition of 6 rowers taking part in 1 or 2 legs of the 2017 Polar Row expedition were measured. The weather conditions of the 2 legs of the journey were recorded, and symptoms relating to NFCI were documented. RESULTS: All incidences of NFCI occurred during Leg 2 of the expedition, which was colder and wetter. Of the Leg 2 rowers, those who developed NFCI had a trend toward higher pre-row body weight and body mass index and a trends toward losing more weight and body water relative to those who did not. CONCLUSIONS: The main factor contributing to the incidence of NFCI appeared to be weather; NFCI only occurred during the colder and wetter leg of the expedition. We also tentatively suggest that nutrition and dehydration may be linked to the incidence of NFCI as predisposing factors. More work, with sample sizes greater than those reported here, is required to investigate these associations to further characterize risk factors.

Case series of non-freezing cold injury: the modern clinical syndrome.

BACKGROUND: Non-freezing cold injury (NFCI) occurs when peripheral tissue is damaged by cold exposure but not to the extent of freezing. Historically, the phenotype of NFCIs sustained was severe, whereas today the spectrum of injury represented in the UK military predominantly comprises subtler injuries. The diagnostic challenge of recognising these injuries, both in the acute and chronic settings, can lead to mismanagement and subsequent morbidity. METHODS: We characterised a recent case series of 100 UK Service Personnel referred with suspected NFCI to a Military UK NFCI clinic. We characterised the acute and chronic phenotype of those diagnosed with NFCI (n=76) and made comparison to those who received alternate diagnoses (n=24), to find discriminatory symptoms and signs. RESULTS: The most common acute symptoms of NFCI were the extremities becoming cold to the point of loss of feeling for more than 30 min (sensitivity 96%, specificity 90%, p<0.001), followed by a period of painful rewarming (sensitivity 81%, specificity 67%, p<0.001). In-field foot/hand inspections took place in half of the NFCI cases. Importantly, remaining in the field and undergoing multiple cycles of cooling and rewarming after an initial NFCI was associated with having double the risk of the NFCI persisting for more than a week. The most common and discriminant chronic symptoms and signs of NFCI were having extremities that behave differently during cold exposures (sensitivity 81%, specificity 75%, p<0.001) and having abnormal pinprick sensation in the affected extremity (sensitivity 88%, specificity 88%, p<0.001). CONCLUSIONS: A small collection of symptoms and signs characterise acute and chronic NFCIs and distinguish this vasoneuropathy from NFCI mimics.

A 4-year follow-up of non-freezing cold injury with cold allodynia and neuropathy in 26 naval soldiers.

Background and aims Non-freezing cold injuries (NFCI), which typically may occur in military personnel, may result from exposure to cold, at temperatures around 0 °C or above, and worsened by wind and moisture. The injury is due to cooling but not freezing of tissue like in frostbite. NFCI may result in in chronic neuropathy and cold hypersensitivity. A recent retrospective study of small-and large fibres has suggested that NFCI results in neuropathic pain due to a sensory neuropathy and question a longitudinal study to verify a possible observation of improvement of NFCI over time. The present study is a 4-year follow-up investigation of large - and small-fibre function in 26 naval cadets and officers who were exposed to cold injury during the same military expedition. Methods The 26 soldiers were investigated clinically (with investigation of motor function, reflexes, sensibility), with nerve conduction studies (NCS) of major nerves in upper- and lower extremity, small fibre testing (QST, measurement of thermal thresholds), measurements of subcutaneous fat tissue and maximal O2 uptake. Investigations found place 2 months following the actual military expedition, with follow-up investigations of affected soldiers at 6-12 months and up to 3-4 years. In order to elucidate possible mechanisms (disinhibition of cold pain by myelinated nerve fibres) of cold allodynia, cold pain thresholds were measured following an ischemic block of conduction of large and small myelinated nerve fibres. Results Of 26 soldiers, 19 complained of numbness in feet and a large majority of 16 of cold hypersensitivity 2 months following injury. There were significant alterations of both large- and small-fibre function, indicating a general large- and small-fibre neuropathy. The most prominent finding was a pronounced cold allodynia, inversely correlated with the amount of subcutaneous fat. During the first year, results of NCS and thermal testing gradually normalized in most. Seven soldiers developed chronic symptoms in the form of cold hypersensitivity and with findings of cold allodynia, which was not further enhanced, but abolished following block of conduction of myelinated nerve fibres. Seven soldiers were free of symptoms from that start of the investigation, probably because they had been more eager to keep their legs moving during the exposure to cold. Conclusions Of a total of 26 soldiers, only seven developed chronic symptoms of cold hypersensitivity, corresponding to the finding of cold allodynia by thermal testing. The cold allodynia may not be explained by disinhibition of cold pain by myelinated fibres as in healthy subjects. A large majority recovered from an initial large-and small fibre neuropathy, demonstrating that recovery from NFCI may occur. Implications Although large-and small fibre neuropathy may be restored following cold injury, there is a risk of a permanent and disabling cold hypersensitivity, corresponding to the findings of cold allodynia. It is of uttermost importance to secure military personnel from the risk of cold injuries. It seems important to avoid immobilisation of extremities during exposure to cold.

Relation between finger cold-induced vasodilation and rewarming speed after cold exposure.

PURPOSE: The risk for local cold injuries has been linked to poor cold-induced vasodilation (CIVD) during cold exposure and to poor rewarming after cold exposure. The purpose of this study is to establish the relation between CIVD and rewarming speed. METHODS: Twelve participants immersed one hand in ice water for 30 min to evoke CIVD and the other hand in ice water for 10 min to investigate the rewarming profile. The ring, middle and index fingertip temperatures were monitored during hand immersion and the resistance index of frostbite (RIF) was calculated. RIF depends on minimal (Tmin) and mean (Tmean) finger skin temperature and onset time. Rewarming was quantified using an infrared imaging system and the rewarming speed over 19 min was determined. RESULTS: Tmin (5.8 ± 3.0 °C) and Tmean (10.4 ± 3.0 °C) caused non-distinctive contributions to the total RIF-scores so that onset time (12.7 ± 3.1 min) became the dominant factor. A significant negative correlation between RIF and rewarming speed was found (rs = - 0.60, p = 0.041). CONCLUSIONS: The negative relation between RIF and rewarming speed may be explained by the common observation that onset time relates to the temperature of fingertip tissue, while Tmin, Tmean and rewarming speed relates to body thermal status. The rewarming test is to be preferred over the CIVD test in terms of ease of use, but the predictive value of the rewarming test for cold injuries is limited, cannot replace the RIF since onset time of finger vasodilation is not included and should be further investigated.

Injury-induced cold sensitization in Drosophila larvae involves behavioral shifts that require the TRP channel Brv1.

Nociceptive sensitization involves an increase in responsiveness of pain sensing neurons to sensory stimuli, typically through the lowering of their nociceptive threshold. Nociceptive sensitization is common following tissue damage, inflammation, and disease and serves to protect the affected area while it heals. Organisms can become sensitized to a range of noxious and innocuous stimuli, including thermal stimuli. The basic mechanisms underlying sensitization to warm or painfully hot stimuli have begun to be elucidated, however, sensitization to cold is not well understood. Here, we develop a Drosophila assay to study cold sensitization after UV-induced epidermal damage in larvae. Larvae respond to acute cold stimuli with a set of unique behaviors that include a contraction of the head and tail (CT) or a raising of the head and tail into a U-Shape (US). Under baseline, non-injured conditions larvae primarily produce a CT response to an acute cold (10°C) stimulus, however, we show that cold-evoked responses shift following tissue damage: CT responses decrease, US responses increase and some larvae exhibit a lateral body roll (BR) that is typically only observed in response to high temperature and noxious mechanical stimuli. At the cellular level, class III neurons are required for the decrease in CT, chordotonal neurons are required for the increase in US, and chordotonal and class IV neurons are required for the appearance of BR responses after UV. At the molecular level, we found that the transient receptor potential (TRP) channel brivido-1 (brv1) is required for these behavioral shifts. Our Drosophila model will allow us to precisely identify the genes and circuits involved in cold nociceptive sensitization.

Ingestion of Coffee Polyphenols Improves a Scaly Skin Surface and the Recovery Rate of Skin Temperature after Cold Stress: A Randomized, Controlled Trial.

Coffee polyphenols (CPPs) derived from coffee beans have beneficial effects on blood pressure and vascular endothelial function. In addition, CPPs suppress ultraviolet light induced erythema. However, the effects of CPPs on dry skin and cutaneous vascular function have not been clarified. We investigated the effects of CPPs on dry skin and the recovery rate (RR) of skin temperature after a cold-stress test as a measure of vascular function in subjects with visible scaliness in a double-blind, placebo-controlled, randomized study. The subjects were divided into two groups, the CPP group and the Placebo group. In the CPP group, the subjects ingested a beverage containing 297.8 mg CPPs every day for 4 wk. The degree of skin dryness was assessed quantitatively using a Visioscan to evaluate skin scaliness and smoothness. A subjective evaluation using a visual analog scale (VAS) of skin smoothness was also used. As a result, the scaliness and smoothness of cheek skin was significantly improved after 4 wk in the CPP group compared to the Placebo group. The improvements of the VAS score on 'skin smoothness' and the RR were also observed in the CPP group but the difference was not statistically significant. However, when the CPP group was divided into subgroups of high RR and low RR, the improvement of the RR was significant in the low RR subgroup. In conclusion, our results suggest that CPPs improve skin scaliness and play a role in cutaneous blood flow regulation after cold stress.

Impairment of cold injury-induced muscle regeneration in mice receiving a combination of bone fracture and alendronate treatment.

Alendronate, a nitrogen-containing bisphosphonate, is well established as a treatment for osteoporosis through regulation of osteoclast activity. Previously, the pharmacological effects of bisphosphonates on cells outside the bone environment have been considered irrelevant because bisphosphonates target bone. Here we show that administration of alendronate impairs muscle regeneration in mice after bone fracture. A series of injections of alendronate alone or bone fracture alone did not affect muscle regeneration induced by cold injury. In contrast, alendronate treatment plus bone fracture severely impaired the regeneration of muscle that closely contacts the bone fracture site after cold injury. After cold injury, M-cadherin-positive myogenic cells disappeared in the damaged muscle areas of mice receiving the combination of alendronate treatment and bone fracture. The present results suggest that the muscle regeneration capacity is impaired by bone fracture in mice receiving alendronate treatment. The present research on the pharmacological effects of alendronate on muscle regeneration will aid in understanding of the in vivo action of alendronate on skeletal muscles.

Potential new treatment for non-freezing cold injury: is Iloprost the way forward?

INTRODUCTION: Non-freezing cold injury (NFCI) remains largely under-reported, and is of particular importance in the armed forces where its prevalence is greatest. Iloprost, a synthetic prostaglandin I2 analogue, has previously been used with some success in the treatment of vasospastic and freezing cold injuries, although its role in NFCI remains unclear. CASE REPORT: An Iloprost infusion was used to treat the long-term sequelae of an ex-soldier suffering with ongoing pedal pain and loss of function 20 years after the initial NFCI insult sustained on military exercise. Following 5 days of iloprost infusion, he reported 4 weeks of markedly reduced pain and increased mobility before symptom relapse. A second infusion was thus given 3 months later, which resulted in increased pain and analgesic requirements. DISCUSSION: The use of iloprost in the treatment of NFCI is discussed and its use in a condition which physicians consistently struggle to treat effectively is considered. Careful counselling is recommended as symptoms may be worsened.

Comparative Study of Injury Models for Studying Muscle Regeneration in Mice.

BACKGROUND: A longstanding goal in regenerative medicine is to reconstitute functional tissues or organs after injury or disease. Attention has focused on the identification and relative contribution of tissue specific stem cells to the regeneration process. Relatively little is known about how the physiological process is regulated by other tissue constituents. Numerous injury models are used to investigate tissue regeneration, however, these models are often poorly understood. Specifically, for skeletal muscle regeneration several models are reported in the literature, yet the relative impact on muscle physiology and the distinct cells types have not been extensively characterised. METHODS: We have used transgenic Tg:Pax7nGFP and Flk1GFP/+ mouse models to respectively count the number of muscle stem (satellite) cells (SC) and number/shape of vessels by confocal microscopy. We performed histological and immunostainings to assess the differences in the key regeneration steps. Infiltration of immune cells, chemokines and cytokines production was assessed in vivo by Luminex®. RESULTS: We compared the 4 most commonly used injury models i.e. freeze injury (FI), barium chloride (BaCl2), notexin (NTX) and cardiotoxin (CTX). The FI was the most damaging. In this model, up to 96% of the SCs are destroyed with their surrounding environment (basal lamina and vasculature) leaving a "dead zone" devoid of viable cells. The regeneration process itself is fulfilled in all 4 models with virtually no fibrosis 28 days post-injury, except in the FI model. Inflammatory cells return to basal levels in the CTX, BaCl2 but still significantly high 1-month post-injury in the FI and NTX models. Interestingly the number of SC returned to normal only in the FI, 1-month post-injury, with SCs that are still cycling up to 3-months after the induction of the injury in the other models. CONCLUSIONS: Our studies show that the nature of the injury model should be chosen carefully depending on the experimental design and desired outcome. Although in all models the muscle regenerates completely, the trajectories of the regenerative process vary considerably. Furthermore, we show that histological parameters are not wholly sufficient to declare that regeneration is complete as molecular alterations (e.g. cycling SCs, cytokines) could have a major persistent impact.

Finger and Toe Temperature Responses to Cold After Freezing Cold Injury in Elite Alpinists.

OBJECTIVE: To assess whether previous freezing cold injuries (FCI) would affect digit skin temperatures and rewarming rates during a follow-up cold stress test protocol. DESIGN: Nonrandomized control trial. METHODS: Twenty elite alpinists participated; alpinists with previous FCI requiring digit amputations (injured, INJ: n = 10 total, n = 8 male) were compared with ability-matched, uninjured alpinists (control, CON: n = 10, all male). Digit skin temperature was measured using infrared thermography as an index of peripheral digit perfusion after a cold stress test, which consisted of 30 minutes of immersion in 8°C water. RESULTS: The INJ alpinists' injured toes were warmer (approximately 6%) than their uninjured toes immediately after cold immersion (95% CI, 0.01°C to 1.00°C; P = .05); there were no differences between the rates of rewarming of injured and uninjured toes (INJ, 0.5° ± 0.1°C/min; CON, 0.7° ± 0.3°C/min; P = .16). Although the INJ alpinists had colder injured fingers immediately after the 35°C warm bath compared with their own uninjured fingers (32.2° ± 2.0°C vs 34.5° ± 0.5°C; P = .02), there were no differences observed between the rates of rewarming of injured and uninjured fingers after cold exposure (INJ, 1.1° ± 0.2°C/min; CON, 1.3° ± 0.5°C/min; P = .22). CONCLUSIONS: Even after FCI that requires digit amputation, there is no evidence of different tissue rates of rewarming between the injured and uninjured fingers or toes of elite alpinists.