A Case of Frostbite on Hands due to Liquid Nitrogen.

This study examines a rare case of frostbite on the hands caused by liquid nitrogen, focusing on the scar maturation process. Frostbite is typically less prone to abnormal scarring compared to burns, and this report contrasts the differences in scar maturation between the two. A 31-year-old male hospital employee sustained first- to second-degree frostbite on his gloved hands from a 20-second exposure to liquid nitrogen while changing a cylinder. Conservative treatment was applied, and the patient was monitored for 9 months. The deeply affected area took 50 days to epithelialize but healed without hypertrophic scarring. A mild extension contracture was noted in the distal interphalangeal joint of the right index finger, but the skin remained supple and soft. Incidents of liquid nitrogen-induced frostbite are uncommon, with only 14 cases reported in PubMed® previously. In frostbite, the wound healing involves a slow replacement of damaged connective tissue, which acts as an internal splint, reducing wound contraction. This contrasts with burns, where rapid connective tissue replacement occurs, often leading to significant wound contraction due to the presence of myofibroblasts in granulation tissue. In the presented case, the slow healing process and minimal wound contraction led to mature scarring without abnormalities, underlining a distinctive healing trajectory in frostbite injuries compared to burns.

Cold Injury.

Cold injury has been documented for centuries and remains a concern for military personnel, winter recreationalists, and urban homeless populations. Treatment advances in the last decades have included thrombolytic and prostaglandin therapies however the mainstay remains early recognition and rapid rewarming. This chapter focuses on frostbite, with a brief overview of other cold related conditions.

Frostbite secondary to antimycobacterial-induced peripheral neuropathy: a case report.

This case report describes a unique scenario in which antimycobacterial-induced peripheral neuropathy (PN) culminates in severe bilateral foot frostbite. Drug-induced peripheral neuropathy (DIPN) is explored in the context of TB treatment, highlighting the role of medications such as isoniazid (INH) and their potential to cause PN. The report highlights the importance of identifying PN in patients undergoing antimycobacterial treatment. Early recognition and proper management of PN is crucial to prevent complications. Notably, the report advocates for patient education regarding medication side effects and avoiding harmful practices, such as ice immersion, to alliviate neuropathic pain. Emphasis is directed towards the need for a multidisciplinary approach to patient care and a focus on preventative strategies to improve patient outcomes and avoid severe debilitating complications.

Changes in Fingertip Cold-Induced Vasodilatation (Hunting Reaction) on Acute Exposure to Altitude.

Fossati, Alexandre, and Aleid C. J. Ruijs. Changes in fingertip cold-induced vasodilatation (hunting reaction) on acute exposure to altitude. High Alt Med Biol. 00:000-000, 2024. Objective: Cold-induced vasodilation (CIVD) of the extremities is an interesting part of human physiology. Although the physiology of the CIVD reaction remains unknown, there are indications that hypoxia influences our CIVD reaction. The objective of this study is to measure the influence of acute hypoxia on the CIVD reaction of the fingertips. Methods: The CIVD reaction was measured using immersion of one hand in a water bath of 0°C in 12 healthy volunteers at low (1,235 m) and high (3,800 m) altitude during 35 minutes. High altitude was reached by a 20-minute cable car ride. Testing was performed indoors (room temperature, 22-25°C) at both altitudes. Data analysis was performed measuring the parameters of the CIVD reaction. Differences were found using the paired Student's t-test. Results: There was no significant difference in baseline finger temperature, onset time, peak time, and frequency of the CIVD reaction. However, at high altitude, maximum temperature and amplitude were significantly higher, slope was steeper, and minimum temperature was lower. Conclusion: We did not find evidence for a diminished CIVD reaction at high altitude due to hypoxia.

Wilderness Medical Society Clinical Practice Guidelines for the Prevention and Treatment of Frostbite: 2024 Update.

The Wilderness Medical Society convened an expert panel to develop a set of evidence-based guidelines for the prevention and treatment of frostbite. We present a review of pertinent pathophysiology. We then discuss primary and secondary prevention measures and therapeutic management. Recommendations are made regarding each treatment and its role in management. These recommendations are graded on the basis of the quality of supporting evidence and balance between the benefits and risks or burdens for each modality according to methodology stipulated by the American College of Chest Physicians. This is an updated version of the guidelines published in 2019.

Climate, diseases and medicine: the welfare of soldiers during the East Asian War of 1592-1598.

This article examines the care provided for the welfare of soldiers by the three combatant countries - China, Korea and Japan - during the East Asian War of 1592-8. Also known as the Imjin War, this large-scale military conflict can also be understood as an encounter between different state cultures and strategies of military medicine. This study focuses on cold-induced injuries, epidemic outbreaks and external wounds suffered during the war. I illuminate provision of prophylactic measures against cold by the Ming state, as well as attempts by the Sino-Choson medical alliance to manage epidemics and treat wounded soldiers. I contrast these measures with the lack of similar centralised support for the Japanese forces, and examine the effect these differences had upon on military outcomes during the war. The difference in the amount of time, efforts and resources that the three combatant states devoted to sick and injured soldiers has implications not only for our understanding of the war but also for illuminating the early modern history of military medicine in East Asia. By exploring East Asian military medicine during and after the Imjin War, this article responds to recent calls for more detailed examination of histories of military medicine in premodern periods and non-European regions.

Tat-CIRP Peptide Facilitates Frozen Wound Healing by Ameliorating Inflammation and Promoting Angiogenesis.

Background: Frostbite is a chemia resulting from cold-induced skin damage. The process of frostbite is often accompanied by inflammation, and the therapeutic strategies focusing on anti-inflammation are the main direction to data. Tat-CIRP is a 15 amino acid peptide containing HIV protein and cold-inducible RNA-binding protein (CIRP), which is believed to compete with endogenous CIRP for myeloid differentiation 2 (MD2) binding. This study aims to investigate the efficacy of Tat-CIRP in the treatment of frostbite. Methods: A mouse model of frostbite was established, and on the first day after frostbite occurrence, Tat-CIRP peptide was administered intravenously via the tail with a dosage interval of one day for a total of three doses. Frozen mouse skin sections were subjected to histological analysis, including hematoxylin-eosin (HE) staining, Masson staining, and immunohistochemical examination. Western blotting was performed to detect the expression level of Ki-67 in mouse skin tissue. Results: One day after frostbite, mice exhibited skin swelling and a solid appearance. From day 1 to 5 after frostbite, MD2 expression was significantly upregulated, while CIRP expression was downregulated. Compared to the frostbite group, mice treated with Tat-CIRP showed accelerated frostbite recovery, reduced levels of inflammatory factors and MD2. Furthermore, the expression of cell proliferation-associated protein Ki-67 and angiogenesis-related protein CD31 was upregulated. Conclusion: Tat-CIRP promotes frozen wound healing via inhibiting inflammation and promoting angiogenesis in frostbitten mice.

Feet Salvage Using Anterolateral Thigh Flaps after Severe Frostbite Injury: A Case Report.

BACKGROUND: Frostbite is a severe injury characterized by tissue damage due to exposure to freezing temperatures. It often necessitates prompt medical intervention to prevent further complications such as necrosis and amputation. This case report explores the successful use of bilateral anterolateral thigh (ALT) free flaps for feet salvage in a 19-year-old male refugee from Gambia who suffered severe frostbite injuries. CASE REPORT: The patient, found after six days in freezing conditions, exhibited necrosis on multiple toes. Initial management included stabilization, intravenous fluids, and rewarming. Subsequent necrectomy and amputation revealed exposed metatarsal bones, necessitating a meticulous reconstructive strategy. Bilateral ALT flaps were chosen to preserve walking function, with a staged reconstruction involving multiple operations. The patient's progress, from inpatient care to outpatient follow-ups, is detailed, emphasizing the challenges and decisions in managing severe frostbite injuries. RESULTS: The surgical intervention utilizing bilateral ALT flaps successfully salvaged the patient's feet. Throughout the postoperative period, wound care, rehabilitation, and outpatient monitoring contributed to positive outcomes. Despite challenges associated with the patient's ethnic background and nutritional status, the staged reconstruction facilitated effective healing and functional recovery. The use of ALT flaps provided a reliable solution with minimal donor site morbidity. CONCLUSION: This case highlights the efficacy of bilateral ALT flap reconstruction in salvaging feet following severe frostbite injury. The successful restoration of foot function underscores the importance of early intervention and tailored reconstructive approaches in frostbite management. Despite patient-specific challenges, including nutritional status and limited healthcare resources, the use of ALT flaps facilitated optimal recovery and functional outcomes. Importantly, this report is unique as it describes a novel case of feet salvage using bilateral ALT flaps in severe frostbite injury, with only one similar case previously reported in the literature. This emphasizes the rarity and significance of this specific surgical approach in frostbite management.

Accuracy of infrared thermography evaluation in burn wound healing: a systematic review and meta-analysis.

OBJECTIVE: Accurate assessment of burn depth and burn wound healing potential is essential to determine early treatments. Infrared thermography (IRT) is a non-invasive and objective tool to do this. This systematic review evaluated the accuracy of IRT to determine burn wound healing potential. METHOD: This systematic review and meta-analysis used MEDLINE, EMBASE, CINAHL, PEDro, DiTA and CENTRAL databases. IRT data were extracted from primary studies and categorised into four cells (i.e., true positives, false positives, true negatives and false negatives). Subgroup analysis was performed according to methods used to capture thermal images. RESULTS: The search strategy identified 2727 publications; however, 15 articles were selected for review and 11 for meta-analysis. In our meta-analysis, the accuracy of IRT was 84.8% (63% sensitivity and 81.9% specificity). CONCLUSION: IRT is a moderately accurate tool to identify burn depth and healing potential. Thus, IRT should be used carefully for evaluating burn wounds.

The Assessment of a Novel Endoscopic Ultrasound-Compatible Cryocatheter to Ablate Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease that may be treated utilizing thermal therapies. Cryoablation is an effective, minimally invasive therapy that has been utilized for the treatment of various cancers, offering patients a quicker recovery and reduced side effects. Cryoablation has been utilized on a limited basis for the treatment of PDAC. With the recent reports on the success of cryoablation, there is a growing interest in the use of cryoablation as a standalone, minimally invasive procedure to treat PDAC. While offering a promising path, the application of cryoablation to PDAC is limited by current technologies. As such, there is a need for the development of new devices to support advanced treatment strategies for PDAC. To this end, this study investigated the performance of a new endoscopic ultrasound-compatible cryoablation catheter technology, FrostBite. We hypothesized that FrostBite would enable the rapid, effective, minimally invasive delivery of ultra-cold temperatures to target tissues, resulting in effective ablation via an endoscopic approach. Thermal properties and ablative efficacy were evaluated using a heat-loaded gel model, tissue-engineered models (TEMs), and an initial in vivo porcine study. Freeze protocols evaluated included single and repeat 3 and 5 min applications. Isotherm assessment revealed the generation of a 2.2 cm diameter frozen mass with the -20 °C isotherm reaching a diameter of 1.5 cm following a single 5 min freeze. TEM studies revealed the achievement of temperatures ≤ -20 °C at a diameter of 1.9 cm after a 5 min freeze. Fluorescent imaging conducted 24 h post-thaw demonstrated a uniformly shaped ellipsoidal ablative zone with a midline diameter of 2.5 cm, resulting in a total ablative volume of 6.9 cm3 after a single 5 min freeze. In vivo findings consistently demonstrated the generation of ablative areas measuring 2.03 cm × 3.2 cm. These studies demonstrate the potential of the FrostBite cryocatheter as an endoscopic ultrasound-based treatment option. The data suggest that FrostBite may provide for the rapid, effective, controllable freezing of cancerous pancreatic and liver tissues. This ablative power also offers the potential of improved safety margins via the minimally invasive nature of an endoscopic ultrasound-based approach or natural orifice transluminal endoscopic surgery (NOTES)-based approach. The results of this pre-clinical feasibility study show promise, affirming the need for further investigation into the potential of the FrostBite cryocatheter as an advanced, minimally invasive cryoablative technology.

Update on Cold-Induced Injuries.

Cold-induced injuries are a major challenge for burn surgeons, leading to significant sequelae for the patients including amputations, long-term disability, and death. Rapid assessment and diagnosis are essential for optimal outcomes. Various therapies have emerged to improve outcomes. Topical, oral, and intravenous agents have shown to minimize the impact of cold-induced injuries. Thrombolytics have shown the greatest promise in improving tissue perfusion outcomes in cold-induced injuries. This article provides an update on the evidence-based assessment and management of cold-induced injuries, as well as reviews outcomes and future directions of this challenging pathology.

Oropharyngeal Swelling and Airway Obstruction from Environmental Cold Exposure: A Case Report.

A 19-year-old male presented with facial frostbite and severe oropharyngeal edema after prolonged riding of a snowmobile without any facial covering. The diffuse swelling eventually progressed to airway obstruction, requiring a surgical airway. No alternative explanation was found for his presentation, making this the first case found in the literature of airway obstruction secondary to environmental cold exposure.

Prolonged critical avalanche burial for nearly 23 h with severe hypothermia and severe frostbite with good recovery: a case report.

BACKGROUND: Accidental hypothermia with severe frostbite is a rare combination of injuries with a high risk for long-term sequelae. There are widely accepted recommendations for the management of avalanche victims and for frostbite treatment, but no recommendation exists for the treatment of frostbite in severe hypothermic patients, specifically for the management of hypothermic avalanche victims presenting with frostbite. CASE PRESENTATION: We present a case of a previously healthy, 53-year-old male skier who was critically buried by an avalanche at 2300 m of altitude at an ambient temperature of - 8 °C for nearly 23 h. The victim was found with the right hand out of the snow and an air connection to outside. He was somnolent with Glasgow Coma Scale 11 (Eye 4, Verbal 2, Motor 5) and spontaneously breathing, in a severely hypothermic state with an initial core temperature of 23.1 °C and signs of cold injuries in all four extremities. After rescue and active external forced air rewarming in the intensive care unit, the clinical signs of first-degree frostbite on both feet and the left hand vanished, while third- to fourth-degree frostbite injuries became apparent on all fingers of the right hand. After reaching a core body temperature of approximately 36 °C, aggressive frostbite treatment was started with peripheral arterial catheter-directed thrombolysis with alteplase, intravenous iloprost, ibuprofen, dexamethasone and regional sympathicolysis with a right-sided continuous axillary block. After ten months, the patient had no tissue loss but needed neuropathic pain treatment with pregabalin. CONCLUSION: The combination of severe accidental hypothermia and severe frostbite is rare and challenging, as drug metabolism is unpredictable in a hypothermic patient and no recommendations for combined treatment exist. There is general agreement to give hypothermia treatment the priority and to begin frostbite treatment as early as possible after full rewarming of the patient. More evidence is needed to identify the optimal dosage and time point to initiate treatment of frostbite in severely hypothermic patients. This should be taken into consideration by future treatment recommendations.

Development and validation of clinically Mimicable model of frostbite injury-induced chronic pain.

Frostbite, a debilitating condition, significantly affects the well-being of military veterans and high-altitude residents, causing severe clinical complications such as chronic pain that markedly impacts overall quality of life. There has been a notable increase in the development of pre-clinical models for studying frostbite injury, but their suitability for pain evaluation remains limited. The major hurdle in the development of novel therapeutics for the treatment of frostbite-induced chronic pain is the unavailability of well-established preclinical models. In this study, we employed deep-frozen magnets to induce frostbite injury and conducted validation for chronic pain through assessments of face, predictive, and mechanistic validity. Behavioral assays demonstrated that frostbite injury exhibited significant mechanical, thermal & cold hypersensitivity in rats. Further, molecular analysis indicated that frostbite injury triggered the activation of TRP channels (TRPA1, TRPV1 and TRPM8), microgliosis, and neuroinflammation in the dorsal root ganglion (DRG) and spinal cord of rats. Notably, NR2B protein expressions were significantly upregulated in the DRG of injured rats, while no changes were observed in spinal NR2B expressions. Furthermore, the administration of ibuprofen (25, 50, and 100 mg/kg, i.p.) resulted in a significant improvement in behavioral, biochemical, and molecular alterations in frostbite-injured rats. Overall, results suggested that established frostbite model effectively recapitulates face, pharmacological, and mechanistic validity, highlighting its potential for screening future treatment modalities and exploring the intricate mechanisms associated with frostbite-induced chronic pain.

Surgery under siege: A case study of leg amputation in 18th century Louisbourg, Nova Scotia, Canada.

OBJECTIVE: Paleopathological analysis of a below-knee amputation was conducted to explore the sociocultural reasons why the amputation took place. MATERIALS: Older adolescent male (18-21 years) from the New Englander mass burial at the 18th century Fortress of Louisbourg. METHODS: Macroscopic assessment and archival data. RESULTS: A surgical amputation of the right tibia and fibula, distal to the knee was identified. The cross-sectional diaphysis of the leg has kerf marks and a splinter (breakaway point) at the posterior-lateral border of the tibia suggesting the leg gave way from its own weight or was manually removed once most of the sawing was complete. CONCLUSIONS: Archival records suggest frostbite from prolonged exposure to freezing temperatures and trauma from unsafe working conditions at the Fortress were the main causes that led to amputation. SIGNIFICANCE: This case study highlights the importance of contextualizing cases of amputation to understand factors leading to the amputation procedure and techniques used in the past, and the social and living conditions of the individual. LIMITATIONS: Observations were restricted to skeletal material as soft tissue decomposed and there was no material evidence suggestive of amputation associated with this individual in their grave. SUGGESTIONS FOR FUTURE RESEARCH: Full trauma assessment of the Fortress of Louisbourg skeletal collection to provide additional insight into injury sustained at Louisbourg and 18th century surgical practices.

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.

Acupuncture and herbal medicine in preventing amputation and promoting tissue regeneration in severe frostbite: A case series.

BACKGROUND: Frostbite is a medically significant form of tissue injury that can lead to the potential need for amputation or necessitate tissue regeneration. It occurs most frequently at cryogenic temperatures in extreme altitude climbing, winter sports, and military activities. While acupuncture and herbal medicine have been reported to possess tissue regeneration effectiveness, there is currently no clinical evidence supporting their use in treating grade 3 frostbite cases at risk of amputation. CASE PRESENTATION: Three patients were diagnosed with grade 3 frostbite based on the extent and severity of tissue damage after alpine climbing in the Himalayas. After an urgent treatment, partial body amputation was advised. In order to seek any complementary treatment options and avoid amputation, they were referred to a frostbite expert in traditional Korean medicine. They received a comprehensive treatment consisting of acupuncture, bloodletting, direct moxibustion, and herbal medicine. All the patients showed notable healing of the damaged tissue, which prevented the need for amputation. No adverse effects or other sequelae were observed. CONCLUSION: This case series suggests that complementary medicine, primarily acupuncture and herbal medicine, could be effective for severe frostbite. Further studies with larger sample sizes and control groups are needed to determine the efficacy and safety of this treatment modality for frostbite management.

Cold-induced vasodilation during sequential immersions of the hand.

A common practice for those operating in cold environments includes repetitive glove doffing and donning to perform specific tasks, which creates a repetitive cycle of hand cooling and rewarming. This study aimed to determine the influence of intraday repeated hand cooling on cold-induced vasodilation (CIVD), sympathetic activation, and finger/hand temperature recovery. Eight males and two females (mean ± SD age: 28 ± 5 year; height: 181 ± 9 cm; weight: 79.9 ± 10.4 kg) performed two 30-min hand immersions in cold (4.3 ± 0.92 °C) water in an indoor environment (18 °C). Both immersions (Imm1; Imm2) were performed on the same day and both allowed for a 10-min recovery. CIVD components were calculated for each finger (index, middle, ring) during each immersion. CIVD onset time (index, p = 0.546; middle, p = 0.727; ring, p = 0.873), minimum finger temperature (index, p = 0.634; middle, p = 0.493; ring, p = 0.575), and mean finger temperature (index, p = 0.986; middle, p = 0.953; ring, p = 0.637) were all similar between immersions. Recovery rates generally demonstrated similar responses as well. Findings suggest that two sequential CIVD tests analyzing the effect of prior cold exposure of the hand does not impair the CIVD response or recovery. Such findings appear promising for those venturing into cold environments where hands are likely to be repeatedly exposed to cold temperatures.

A 15-year review of characteristics and outcomes of patients leaving against medical advice.

PURPOSE: Discharging against medical advice can have significant, detrimental effects on burn patient outcomes as well as higher hospital readmission rates and healthcare expenditures. The goal of this study is to identify characteristics of patients who left against medical advice and suggest solutions to mitigate these factors. Data were collected at our American Burn Association verified Burn Unit over a 15-year period. RESULTS: Between 2007 and 2022, 37 patients were identified as having left against medical advice from the burn unit. The average patient age was 37 years old with 64.9% being male, and 70.2% were identified as having a substance abuse history. The majority (51.4%) had Medicaid or State health insurance, 29.7% had no insurance, and 18.9% had private insurance. The mechanism of injury was most commonly frostbite (43.2%). The majority sustained < 1% total body surface area injuries. Most (83.7%) had social work and/or case management involved during their admission, and all (100%) had their involvement if the length of admission was greater than one day. Over half (59.5%) returned to the ED within 2 weeks with complications. CONCLUSIONS: This study found that patients discharging against medical advice from the burn unit suffered from smaller injuries, often due to cold related injuries. These patients had comorbid substance abuse or psychiatric histories, and the majority had Medicaid or state health insurance. Recruiting interdisciplinary care members, including social work, psychiatry, and addiction medicine, early may help these patients by encouraging completion of their hospital care and setting up crucial follow-up care.

Frostbite treatment: a systematic review with meta-analyses.

INTRODUCTION: Our objective was to perform a systematic review of the outcomes of various frostbite treatments to determine which treatments are effective. We also planned to perform meta-analyses of the outcomes of individual treatments for which suitable data were available. MAIN BODY: We performed a systematic review and meta-analyses in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. We searched PubMed, Cochrane Trials, and EMBase to identify primary references from January 1, 1900, to June 18, 2022. After eliminating duplicates, we screened abstracts to identify eligible studies containing information on treatment and outcomes of Grade 2 to 4 frostbite. We performed meta-analyses of groups of articles that provided sufficient data. We registered our review in the prospective registry of systematic reviews PROSPERO (Nr. 293,693). We identified 4,835 potentially relevant studies. We excluded 4,610 studies after abstract screening. We evaluated the full text of the remaining 225 studies, excluding 154. Ultimately, we included 71 articles with 978 cases of frostbite originating from 1 randomized controlled trial, 20 cohort studies and 51 case reports. We found wide variations in classifications of treatments and outcomes. The two meta-analyses we performed both found that patients treated with thrombolytics within 24 h had better outcomes than patients treated with other modalities. The one randomized controlled trial found that the prostacyclin analog iloprost was beneficial in severe frostbite if administered within 48 h. CONCLUSIONS: Iloprost and thrombolysis may be beneficial for treating frostbite. The effectiveness of other commonly used treatments has not been validated. More prospective data from clinical trials or an international registry may help to inform optimal treatment.