Safety and Feasibility of a Sheath Cryoprobe for Bronchoscopic Transbronchial Biopsy: The FROSTBITE Trial.

BACKGROUND: Bronchoscopic lung biopsy is typically performed using transbronchial forceps. However, this method is limited by small sample size and presence of crush artifact. Cryobiopsy offers the potential to overcome these limitations with larger artifact-free samples but has not been widely adopted due to concerns over increased rates of bleeding and pneumothorax. A new, smaller 1.1-mm cryoprobe has been developed that operates in a similar fashion to forceps, though the safety profile of this cryoprobe has not yet been prospectively studied. OBJECTIVE: The aim of this study was to investigate the safety of transbronchial biopsy using a novel 1.1-mm cryoprobe. METHODS: This prospective, single-arm study enrolled patients referred for transbronchial biopsy. All procedures were performed using the 1.1-mm cryoprobe with oversheath. The primary outcome was the composite of significant complications related to the cryobiopsy procedure (bleeding Grade ≥3, pneumothorax Grade ≥2, and respiratory failure). Bleeding and pneumothorax were graded according to previously published scales. RESULTS: Fifty participants from two academic medical centers underwent transbronchial cryobiopsy. Indications for biopsy included evaluation of lung transplant allograft (50%), diffuse lung disease (44%), and pulmonary parenchymal lesion (6%). There were two pneumothoraces (4%), neither of which required aspiration or chest tube placement. There were no Grade 3 or 4 bleeding events. Mild bleeding (Grade ≤2) was observed in 25 cases (50%). No complications occurred that met the a priori primary outcome of bleeding Grade ≥3, pneumothorax Grade ≥2, and respiratory failure. CONCLUSIONS: Transbronchial cryobiopsy using a 1.1-mm cryoprobe is feasible with an acceptable safety profile.

Pedicled Abdominal Flaps for Enhanced Digital Salvage After Severe Frostbite Injury.

Extremities are the area of the body most commonly affected by frostbite, which can also affect the face, ears, perineum, or genitals. Optimum management has moved away from early amputation and debridement toward maximizing tissue preservation and delaying surgical intervention. Increasing length of digit amputation increases morbidity, in terms of loss of hand function, experienced by patients. Reconstruction of affected digits is limited by bone necrosis, which often leads to shortened residual stumps and limited functional outcomes. This case describes the management of a severe frostbite injury affecting both hands and feet in a 39-y-old man, sustained during descent of Mount Everest. The use of a pedicled abdominal flap to provide soft-tissue cover permitted optimized digit length and function and sensate digits. The case highlights the benefits of early multidisciplinary team involvement in the management of severe frostbite to optimize functional outcome.

Reversed First Dorsal Metatarsal Artery Island Flap for First Ray Defects.

Reconstruction of the first ray is challenging because of poor skin laxity, bone and tendon exposure, and limited local flap options. Repair using full- or split-thickness skin grafts is generally not an option because of the bone and tendon exposure. Reconstructive options using local flaps from the distal foot area are restricted owing to insufficient soft tissue. Many reconstructive options have been described to overcome these difficult situations. We present 2 cases in which the great toe and first ray defect were repaired using a reversed first dorsal metatarsal artery island flap. The findings from these clinical cases and anatomic studies have shown that the reversed first dorsal metatarsal artery island flap is an alternative and suitable option for reconstruction of soft tissue defect of the distal foot, especially first and second ray defects, because it is thin and simple, has anatomic characteristics similar to those at the recipient site, and results in minimal donor site morbidity.

Analytical expressions for estimating endurance time and glove thermal resistance related to human finger in cold conditions.

Frostbite is considered the severest form of cold injury and can lead to necrosis and loss of peripheral appendages. Therefore, prediction of endurance time of limb's tissue in cold condition is not only necessary but also crucial to estimate cold injury intensity and to choose appropriate clothing. According to the previous work which applied a 3-D thermal model for human finger to analyze cold stress, in this study, an expression is presented for endurance time in cold conditions to prevent cold injury. A formula is also recommended to select a proper glove with specific thermal resistance based on the ambient situation and cold exposure time. By employing linear extrapolation and real physical conditions, the proposed formulas were drawn out from numerical simulation. Analytical results show good agreement with numerical data. The used numerical data had been also validated with experimental data existed in the literature. Furthermore, the effect of different parameters such as glove thermal resistance and ambient temperature is investigated analytically.

A 3D thermal model to analyze the temperature changes of digits during cold stress and predict the danger of frostbite in human fingers.

The existing computational models of frostbite injury are limited to one and two dimensional schemes. In this study, a coupled thermo-fluid model is applied to simulate a finger exposed to cold weather. The spatial variability of finger-tip temperature is compared to experimental ones to validate the model. A semi-realistic 3D model for tissue and blood vessels is used to analyze the transient heat transfer through the finger. The effect of heat conduction, metabolic heat generation, heat transport by blood perfusion, heat exchange between tissues and large vessels are considered in energy balance equations. The current model was then tested in different temperatures and air speeds to predict the danger of frostbite in humans for different gloves. Two prevalent gloves which are commonly used in cold climate are considered for investigation. The endurance time and the fraction of necrotic tissues are two main factors suggested for obtaining the response of digit tissues to different environmental conditions.

Effects of low-frequency pulsed electromagnetic fields on plateau frostbite healing in rats.

Plateau frostbite (PF) treatments have remained a clinical challenge because this condition injures tissues in deep layers and affected tissues exhibit unique pathological characteristics. For instance, low-frequency pulsed electromagnetic field (PEMF) can affect tissue restoration and penetrate tissues. Therefore, the effect of PEMF on PF healing should be investigated. This study aimed to evaluate the effects of low-frequency PEMF on PF healing systematically. Ninety-six Sprague-Dawley rats were randomly and equally divided into three groups: normal control, partial thickness plateau frostbite (PTPF), and PTPF with low-frequency PEMF exposure (PTPF + PEMF). PTPF wounds were induced in the dorsum of the rats. The PTPF + PEMF group was exposed to low-frequency PEMF daily. During PF healing, wound microcirculation in each group was monitored through contrast ultrasonography. Wound appearance, histological observation, and wound tensile strength were also evaluated. Results showed that the rate of the microcirculation restoration of the PTPF + PEMF group was nearly 25% faster than that of the PTPF group, and wound appearance suggested that the healing of the PTPF group was slower than that of the PTPF + PEMF group. Histological observation revealed that PEMF accelerated the growth of different deep tissues, as confirmed by tensile strength examination. Low-frequency PEMF could penetrate PF tissues, promote their restoration, and provide a beneficial effect on PF healing. Therefore, this technique may be a potential alternative to treat PF.

Application of a novel rectal cooling device in hypothermia therapy after cerebral hypoxia-ischemia in rats.

BACKGROUND: A new rectal cooling device for therapeutic hypothermia (TH) therapy is designed and is applied in TH treatment of SD rats with ischemic-hypoxic brain damage. METHODS: Healthy adult SD rats (n = 45) were randomly assigned into four groups: the healthy control group (n = 5), the ischemia and hypoxia group (n = 10), the rectal TH cooling group (n = 18), and the ice blanket TH cooling group (n = 11). The rats in the rectal cooling and ice blanket TH groups received 12 h treatment after hypoxic-ischemic brain damage had been established, while those in the ischemia and hypoxia group did not. Taking the start of TH as the zero point, rats were sacrificed after 24 h and the brain and rectum tissues were sampled for histological analysis. RESULTS: The TH induction time (37.3 ± 14.7 min) in the rectal cooling group was significantly shorter (F = 4.937, P < 0.05) than that in the ice blanket cooling group (75.6 ± 27.2 min). The HE and NISSL staining results showed that rats in the rectal TH cooling group had significantly decreased (P < 0.01) positive neurons cell count compared to those in ischemia and hypoxia group. In addition, TUNEL staining indicated that the number of apoptotic cells (3.9 ± 1.8 cells / × 400 field) and the apoptosis index (4.4 % ± 1.5) were significantly lower in rectal TH cooling group (P < 0.05) than in ischemia and hypoxia group (23.2 ± 12.1 cells / × 400 field, 26.6 % ± 12.1). Also, no rectal frostbite or inflammatory infiltration was observed in rats in the rectal TH treatment groups. CONCLUSION: Our new cooling device realized rapid TH induction in SD rats with ischemic-hypoxic brain damage, inhibited the apoptosis of cells in the hippocampal CAl region, and did not cause histological damage to the rectal tissues.

Management of Severe Frostbite in a Grey-Headed Parrot (Poicephalus fuscicollis suahelicus).

An approximately 5-year-old female grey-headed parrot (Poicephalus fuscicollis suahelicus) was evaluated after exposure to outdoor temperatures below -20°C (-4°F) for approximately 22 hours. Severe frostbite affecting multiple digits, as well as dehydration and a depressed attitude, were diagnosed. Treatment included oral antibiotics, antifungals, nonsteroidal anti-inflammatories (NSAIDs), pentoxifylline, and topical aloe vera. Surgical amputation of the affected toes was not performed. Mild to moderate pododermatitis over the intertarsal joints developed because of a shift in weight bearing after the loss of most digits. Within 5 months after initial presentation, all frost-damaged toes had self-amputated, and the bird was able to function independently with no limitations in mobility.

Lymphocyte-platelet interactions in patients with deep frostbites with various nutritional statuses.

The purpose of the study was to determine the relative number and degree of lymphocyte-platelet adhesion in patients with frostbites of III-IV degree of extremities with malnutrition and eutrophia. Methods: Non-randomized prospective controlled study was performed in 49 patients of both sexes, aged from 16 to 60 years, with frostbites of III-IV degree of extremities. The object of the study was the blood plasma. Test subjects were divided into two groups according to the trophic status on the scale of Luft V.M and Kostyuchenko A.L. By the original method of the Professor Vitkovsky Yu.A. (1999) number of lymphocyte-platelet coaggregations was counted in 100 cells (percentage), which is relative number of the lymphocyte-platelet adhesion (LTA). In this case lymphocyte which adhered to its surface one or more platelets was named the coaggregation. Lymphocyte-platelet index (LTI) or the degree of LTA was determined as the arithmetic mean of the number of platelets which have adhered to a single lymphocyte. Results: The relative number of LTA greater in patients with eutrophia (n = 19) vs. (p<0.001) the control group (n = 20) and vs. (p = 0.008) patients with malnutrition (n = 20). The relative number of LTA is not different in patients with malnutrition vs. (p = 0.085) the control group. LTI greater in patients with eutrophia vs. the control group (p<0.001), and vs. patients with malnutrition (p = 0.020). LTI greater in patients with malnutrition vs. the control group (p = 0.006). Conclusion: It was established that LTI increased irrespective of premorbid trophic status, and LTA percentage increased only in patients with eutrophia. In patients with malnutrition LTA degree and LTA percentage were detected less than in patients with normal nutritional status.

Frostbite of both first digits of the foot treated with delayed hyperbaric oxygen:a case report and review of literature.

BACKGROUND: Frostbite is an uncommon event that can occur from exposure to temperatures below -4 degrees C and can lead to potential serious tissue damage and necrosis. This in turn can result in debilitating amputations in otherwise healthy people. The pathophysiological mechanisms of frostbite have marked similarities to those seen in thermal burns, ischemia/reperfusion injuries and crush injuries--i.e., non-healing wounds and inflammatory processes. These injuries are commonly treated with hyperbaric oxygen therapy. OBJECTIVES: Evidence for treating frostbite with hyperbaric oxygen (HBO2) is scarce, and to date HBO2 is not a standard addition in the multidisciplinary care of freezing injuries. We aim to contribute to the available evidence with a case report and review the literature to reassess the multidisciplinary treatment of frostbite injuries. CASE REPORT AND REVIEW OF LITERATURE: We present a case report of a woman with deep frostbite of the toes treated with hyperbaric oxygen therapy, after a delay of 21 days, with good results. No surgical intervention was needed. A literature search revealed 17 human case reports on frostbite and four animal studies in which hyperbaric oxygen was applied. All case reports showed positive effects, and in none of the cases was amputation necessary. In the animal studies, two showed significant positive results regarding tissue loss and reduction of inflammatory markers, whereas two did not. CONCLUSIONS: Based on our case report as well as the literature and the mechanisms of hyperbaric oxygen, we make the recommendation that this therapy be considered as an addition to the multidisciplinary treatment of frostbite, even after significant delay of treatment.

Poly-L-arginine topical lotion tested in a mouse model for frostbite injury.

BACKGROUND: Frostbite injury occurs when exposure to cold results in frozen tissue. We recently reported a novel mouse model for frostbite injury to be used in screening potentially therapeutic drugs and other modalities. OBJECTIVE: We used the mouse skin frostbite model to evaluate the effect of poly-l-arginine contained in lotion (PAL) applied topically to involved skin. METHODS: Sixty mice were studied in a randomized, double-blind method. Standardized 2.9-cm-diameter circles were tattooed on the mouse dorsum. Magnets snap frozen in dry ice (-78.5°C) were used to create a frostbite injury on skin within the circle as a continuous 5-minute freeze. Mice were treated with prefreeze placebo, postthaw placebo, combined prefreeze and postthaw placebo, prefreeze with PAL, postthaw with PAL, or combined prefreeze and postthaw with PAL. Appearance, healing rate, tissue loss, and histology were recorded until the wounds were healed. RESULTS: Application of PAL before inducing frostbite injury resulted in decreased tissue loss as compared with other treatment conditions. CONCLUSIONS: Applying PAL topically to frostbitten mouse skin caused decreased tissue loss. Poly-l-arginine should be studied further to determine whether it is a beneficial therapeutic modality for frostbite injury.

Dermorphin [D-Arg2, Lys4] (1-4) Amide Alleviates Frostbite-Induced Pain by Regulating TRP Channel-Mediated Microglial Activation and Neuroinflammation.

Cold injury or frostbite is a common medical condition that causes serious clinical complications including sensory abnormalities and chronic pain ultimately affecting overall well-being. Opioids are the first-choice drug for the treatment of frostbite-induced chronic pain; however, their notable side effects, including sedation, motor incoordination, respiratory depression, and drug addiction, present substantial obstacle to their clinical utility. To address this challenge, we have exploited peripheral mu-opioid receptors as potential target for the treatment of frostbite-induced chronic pain. In this study, we investigated the effect of dermorphin [D-Arg2, Lys4] (1-4) amide (DALDA), a peripheral mu-opioid receptor agonist, on frostbite injury and hypersensitivity induced by deep freeze magnet exposure in rats. Animals with frostbite injury displayed significant hypersensitivity to mechanical, thermal, and cold stimuli which was significant ameliorated on treatment with different doses of DALDA (1, 3, and 10 mg/kg) and ibuprofen (100 mg/kg). Further, molecular biology investigations unveiled heightened oxido-nitrosative stress, coupled with a notable upregulation in the expression of TRP channels (TRPA1, TRPV1, and TRPM8), glial cell activation, and neuroinflammation (TNF-α, IL-1ß) in the sciatic nerve, dorsal root ganglion (DRG), and spinal cord of frostbite-injured rats. Treatment with DALDA leads to substantial reduction in TRP channels, microglial activation, and suppression of the inflammatory cascade in the ipsilateral L4-L5 DRG and spinal cord of rats. Overall, findings from the present study suggest that activation of peripheral mu-opioid receptors mitigates chronic pain in rats by modulating the expression of TRP channels and suppressing glial cell activation and neuroinflammation.

A novel mouse model for frostbite injury.

BACKGROUND: Frostbite injury occurs when exposure to cold results in frozen tissue. To screen drugs and other field therapies that might improve the outcome for a frostbite victim, it would be helpful to have a reliable and cost-effective preclinical in vivo model. OBJECTIVE: We sought to create a novel mouse skin model of induced frostbite injury. This model would allow quantification of the surface area of involved skin, histology of the wound, rate of wound healing, and skin loss in a standardized fashion after the frostbite injury. METHODS: Thirty-six mice were studied. Standardized 2.9-cm diameter circles were tattooed on the mouse dorsum. Magnets frozen in dry ice (-78.5°C) were used to create a frostbite injury on skin within the circle, either as a continuous 5-minute freeze or as 3 repeated freeze (1-minute) and thaw (3-minute) cycles. Appearance, healing rate, skin surface area loss, and histology were recorded until the wounds were healed. RESULTS: The amount of skin surface area loss was approximately 50% for both freeze methods. Although the time to surface skin healing was similar for both freeze methods, the initial healing rate was significantly (P = .001) slower in mice exposed to the freeze-thaw cycles compared with the continuous freeze model. Histopathology reflected inflammatory changes, cell death, and necrosis. CONCLUSIONS: This novel in vivo mouse model for frostbite allows quantification of affected skin surface area, histology, healing rate, and skin loss and has the potential of being utilized to screen future treatment modalities.

Frostbite injury: a paragliding accident at 5500 meters.

Frostbite as a result of mountaineering or arctic expeditions is a well-known problem. In this article a rare case of frostbite injury following a paragliding accident at high altitude is described. A cumulonimbus cloud formation drifted the patient up with a high velocity to approximately 5500 m. He acquired frostbite injuries of the neck, wrists, hands and left leg, affecting 5% of the total body surface area. The frostbite was initially treated by rewarming, with later debridement and local application of silver sulfadiazine and povidone-iodine dressings. Within three months all the injuries were healed.

Oral frostbite due to dry ice.

OBJECTIVES: Dry ice is a commercially available cryogen that is used worldwide. It may cause frostbite if misused. However, frostbite of the oral cavity due to dry ice has not been previously reported. Here, we describe the first case of dry ice-induced frostbite of the oral cavity. METHODS: We present a case of oral frostbite due to dry ice and subsequent swelling of the submandibular area and lower lip. We discuss the clinical features of oral frostbite due to volatile substance abuse. RESULTS: Oral frostbite not only may result in the impairment of the affected mucosae directly, but also may adversely affect the tissues in the vicinity of the oral cavity floor indirectly. Oral frostbite may cause edema of the upper airway tract. In case of severe pharyngolaryngeal edema, either tracheal intubation or tracheostomy is necessary. Steroids and antibiotics may be effective in preventing the development of pharyngolaryngeal edema. CONCLUSIONS: It is important to bear in mind that volatile substance abuse may possibly induce unusual events. In particular, special attention should be paid to delayed unusual events.

Determination of microcirculatory changes and angiogenesis in a model of frostbite injury in vivo.

BACKGROUND: The breakdown of skin microcirculation and the leukocyte-endothelium interaction are assumed to play a key role in the pathophysiology of frostbite injuries. However, little is known as yet. The aim was to develop an in vivo frostbite model to monitor microcirculatory changes and angiogenesis after frostbite injury. MATERIALS AND METHODS: Deep partial thickness frostbite injuries were inflicted with a no-touch-technique to the ears of hairless mice (n=9). To this end, a gas jet of nitrogen vapor (T=-195,8±2.7°C) was delivered onto an area of 1.9 mm(2) for 1,5 s. Intravital fluorescent microscopy in combination with FITC-dextran and Rhodamin 6G as fluorescent dyes was used to assess microcirculatory changes, leukocyte behavior, and angiogenesis during the 14 d of wound healing. RESULTS: The area of no perfusion decreased significantly over the observed period, and perfusion was almost completely restored due to angiogenesis by d 14 (day 1: 1.89 [mm(2)]±0.44SEM, d 14: 0.02±0.01). No post-traumatic extension of the trauma could be observed. Edema formation increased significantly up to d 7. The number of adherent leukocytes showed a significant increase during the first 7 d. Functional vessel density showed a significant post-frostbite decrease to 60% of the baseline value. CONCLUSIONS: This novel frostbite model provides a simple and nonetheless highly effective technique of creating locally limited reproducible frostbite injuries using a no touch technique. Tissue damage can be fully attributed to the thermal trauma, and the model allows repetitive intravital fluorescent microscopy of the microcirculation, leukocyte-endothelium interaction, and angiogenesis.

Intravital pathophysiologic comparison of frostbite and burn injury in a murine model.

BACKGROUND: The breakdown of skin microcirculation and the leukocyte-endothelium interaction are assumed to play key roles in the pathophysiology of burn and frostbite injuries. Available data on frostbite and burn injuries were collected using different experimental models and setups, which limits direct comparisons of these thermal traumata significantly. To determine pathophysiologic similarities and differences, two comparable in vivo frostbite and burn models were used to assess microcirculatory and angiogenetic changes in burn and frostbite injuries. MATERIALS AND METHODS: Either deep partial thickness no-touch burns or frostbite injuries were inflicted to the ears of hairless mice (n = 40) by a hot or cold gas jet (117.0 ± 2.1°C for 1 s and -195.8 ± 2.7°C for 1.5 s, respectively) resulting in a necrotic, nonperfused area of about 1.56 ± 0.28 mm2. Intravital fluorescent microscopy was used in combination with fluorescent dyes in order to assess the microcirculation, angiogenesis, and leukocyte-activity over a 12-d period. RESULTS: The angiogenesis occurred significantly faster after frostbite than after burn (16.4% ± 4.5% versus 30.6% ± 2.8% nonperfused area, compared with the baseline value on d 7 (P = 0.009)). The loss of functional vessel density was significantly more pronounced after frostbite (57.6% ± 2.2% versus 89.2% ± 4.9% (P < 0.001)). However, the area recovered faster. The edema formation, as a parameter for endothelial integrity, was significantly more pronounced and lasted longer after frostbite, compared with the burn injury, and reached its maximum level on d 7 after trauma (162.4% ± 4.2% versus 142.% ± 5.9%; P = 0.007). In contrast to the rolling leukocytes, which showed the same increase on d 1 and then a subsequent decrease in both groups, the number of adherent leukocytes after the burn was markedly higher on d 1 (480% versus 167%; P = 0.001) but decreased much faster. The number of adherent leukocytes after frostbite remained significantly higher than those of the burn group during the entire observation. CONCLUSION: The comparison of analogous intravital burn and frostbite models indicates that despite the similarities, decisive microcirculatory differences in extension and recovery from these two types of thermal trauma exist.

A clinical review of the management of frostbite.

Frostbite is a thermal injury that can occur when temperatures drop low enough for tissue to freeze. On rewarming the tissues, an inflammatory process develops which is often associated with tissue loss. The extent of the tissue loss reflects the severity of the cold exposure and includes factors such as temperature, duration, wind chill, altitude, and systemic hypothermia. This review discusses the epidemiology, the pathophysiological processes involved, and the clinical management of frostbite injuries. Practical advice is given on both the field and hospital management and how to seek expert advice from remote situations. The review also discusses newer developments in frostbite treatment such as intra-vascular thrombolysis and adjunctive treatments such as the use of intravenous vasodilators.