冻伤的干预措施
摘要
研究背景
冻伤是由于皮肤组织长时间暴露于零下（摄氏度）气温导致细胞间形成冷冻冰晶从而造成的热损伤。根据组织的受损程度，可能引起的症状有：血栓症、心肌缺血、坏死（组织坏死）、坏疽甚至是截肢。现已提出了几种针对冻伤的干预措施，例如高压氧疗、交感神经切除术（神经阻滞）、溶栓（血液稀释）治疗和血管扩张剂（如伊洛前列素，利血平，己酮可可碱和丁咯地尔）疗法，但这些干预措施的利弊尚不清楚。
研究目的
评估针对冻伤的不同疗法的利弊。
检索策略
我们于2020年2月25日检索了Cochrane图书馆中的Cochrane随机对照试验中心注册库（CENTRAL）、Ovid MEDLINE（R）、Ovid MEDLINE（R）进行中及其它未索引引文、Ovid MEDLINE（R）Daily和Ovid OLDMEDLINE（R）、 Embase（OvidSP）、ISI 科学网：科学引文索引（SCI扩展版）、Conference Proceedings Citation Index‐Science 以及试验注册库 。在本综述发表前不久（2020年11月9日），我们再次检索了Clinicaltrials.gov、世界卫生组织（WHO）国际临床试验注册平台（International Clinical Trials Registry Platform）、OpenGrey和GreyLit。我们调查了相关文章的参考文献，并联系了其中一位试验作者。
纳入排除标准
纳入了如下随机对照试验（RCT）：这些试验对比了针对冻伤的医学干预措施，如药物治疗、局部治疗以及回温技术和其他疗法、使用安慰剂或不治疗。
资料收集与分析
两位综述作者各自独立提取资料。使用Review Manager 5对具有风险比（RR）和95％置信区间（CI）的二元资料进行统计分析。使用Cochrane“偏倚风险”工具评估了纳入试验的偏倚风险。评估了截肢率、严重和非严重不良事件的发生率、急性疼痛、慢性疼痛、日常生活能力、生活质量、由不良事件导致的治疗退出率、工作所受影响和死亡率。使用GRADE评估了证据的质量。
主要结果
纳入了一项非盲随机试验，涉及47位严重冻伤的受试者。我们认为该试验的实施偏倚风险较高，损耗偏倚风险尚不明确，其他偏倚的风险均较低。
所有受试者都接受了快速回温疗法，使用了250 mg阿司匹林和静脉注射了400 mg丁咯地尔（至药物停用），并在接下来的八天中随机加入三个治疗组中任一组第1组每天都接受一小时的400mg丁咯地尔静脉注射。第2组每天都接受六小时的0.5ng‐2 ng / kg / min前列环素和伊洛前列素静脉注射。第3组每天都接受六小时2 ng / kg / min伊洛前列素静脉注射，且仅在第一天注射了纤维蛋白溶解，即100 mg rtPA。
结果表明，与单独使用丁咯地尔相比，使用伊洛前列素或伊洛前列素加rtPA可能会降低严重冻伤患者的截肢率，（RR=0.05, 95％CI [0.00, 0.78]； P=0.03；极低质量证据）和（RR=0.31, 95 ％CI [0.10, 0.94]； P=0.04；极低质量证据）。在降低截肢率效果上，使用伊洛前列素或伊洛前列素加rtPA可能一样有效，（RR=0.14, 95％CI [0.01, 2.56]； P=0.19；极低质量证据）。三组中都没有因不良事件而退出或死亡的报告；我们评估后认为这两种结局的质量都极低。不良事件（包括潮热，恶心，心悸和呕吐）很常见，但没有对照组对其进行单独报告（极低质量证据）。这项被纳入的研究未测量急性疼痛、慢性疼痛、日常生活能力、生活质量和工作所受影响的结局。
作者结论
关于冻伤伤害的干预措施的证据很少。单个小型试验中的极低质量证据表明，在使用丁咯地尔的基础上再使用伊洛前列素或伊洛前列素加rtPA与单独使用丁咯地尔相比可能降低严重冻伤患者的截肢率。但是，丁咯地尔已被停用。还需高质量的随机试验为确定冻伤的最佳疗法提供确凿证据。
PICOs
简语概要
哪种疗法对治疗冻伤最有效？
什么是冻伤？
冻伤是因皮肤暴露于寒冷环境而对皮肤及皮下组织造成的损伤。严寒气温使皮肤组织中形成冷冻冰晶，导致组织血液供应减少进而破坏组织。冻伤常见于手指、脚趾、鼻子、耳朵和脸颊等部位。冻伤症状包括受冻部位麻木和皮肤变苍白及褐色，最终长水泡和皮肤红肿。如果未对受冻部位进行回温，并且继续将其暴露在严寒中，可能会影响更深层的组织，最终导致“组织丧失”，即切除手指或脚趾（截肢）。
对冻伤区域进行回温可能会导致严重的疼痛。目前，治疗包括：
‐使用37°C至39°C的漩涡浴对受冻部位进行快速复温；
‐给病人服用镇痛药如阿司匹林和布洛芬；以及
‐如果在回温后受冻部位未恢复正常，须将患者送往医院接受进一步治疗。
医院能提供一些专业的治疗方法，包括伊洛前列素疗法，这种药物可能会加快血液流向冻伤部位。伊洛前列素有望逆转冻伤组织遭受的损伤。
证据是最新的吗？
本次综述中的证据包括截至2020年2月25日发表的研究。
我们做了什么？
我们检索了如下研究：这些研究把作用全身的药物疗法、作用皮肤的疗法（局部疗法）或治疗冻伤的回温方法与其他冻伤疗法、虚拟治疗（安慰剂）或无治疗进行对比。。我们检索了受试者的治疗方法随机而定的随机对照试验，因为这类试验通常可以提供有关疗效最可靠的证据。
我们想知道：
‐截肢的风险；
‐治疗的严重不良作用和非严重不良作用（不良事件）；
‐剧烈的疼痛，特别是回温时的疼痛；
‐持久的疼痛；
‐冻伤患者日常生活能力；
‐冻伤患者的生活质量；
‐由治疗引起的问题而退出治疗的人数；
‐由于冻伤没有上班的时长；
‐完全复工前的休养时长；和
‐死亡人数。
我们发现了什么？
我们找到了一项随机对照试验（RCT）涉及47位受试者，这些受试者曾被法国阿尔卑斯山脉的山地救援队营救。每位受试者都使用了两种药物，即阿司匹林和丁咯地尔，随后被分配至三组中任一组接受进一步治疗。
第一组再次使用了丁咯地尔（此次RCT之后，因为丁咯地尔引发了严重不良事件，故该种药物已被停用）；
第二组使用了伊洛前列素。
第三组使用了伊洛前列素和一种帮助溶解血栓的物质（重组组织纤溶酶原激活物（rtPA））。
我们的研究结果是什么？
与使用丁咯地尔的受试者相比，使用伊洛前列素或伊洛前列素加rtPA的受试者的截肢情况更少。与使用伊洛前列素的受试者相比，使用伊洛前列素加rtPA的受试者的截肢情况几乎没有差异。
该试验报告了不良反应，但没有将其归因于治疗方法的不同。不良反应包括潮热，恶心，心悸和呕吐。没有受试者因为治疗的不良影响而退出试验，也没有人员死亡。
此次RCT未报告剧烈疼痛、持久疼痛、日常活动、生活质量、没有上班的时长和完全复工前休养的时长。
还需高质量的RCT来证实这项研究的结果，并确立治疗冻伤的最佳方法。
这些研究结果的可信度如何？
由于我们仅纳入了一份报告质量不佳的RCT，并且其设计可能存在问题，加上受试者人数很少，因此该发现的质量极低。
Authors' conclusions
Summary of findings
| Iloprost versus buflomedil for frostbite injuries | |||||
| Patient or population: people with severe frostbite injuries Settings: hospital Intervention: iloprost Comparison: buflomedil | |||||
| Outcomes | Illustrative comparative risks* | Relative effect | No of participants | Quality of the evidence | |
|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | ||||
| Buflomedil | Iloprost | ||||
| Incidence of amputation in participants (3‐month follow‐up) | Study population | RR 0.05; 95% CI 0.00 to 0.78 | 31 (1 study) | ⊕⊝⊝⊝ Very lowa | |
| 9/15 | 0/16 | ||||
| Adverse events | ‐ | ‐ | ‐ | ‐ | Very lowb Not reported by intervention, but overall included flushing in 55% of participants, nausea in 25%, palpitations in 15%, and vomiting in 5%. |
| Acute pain | ‐ | ‐ | ‐ | ‐ | Not reported |
| Chronic pain | ‐ | ‐ | ‐ | ‐ | Not reported |
| Withdrawal from intervention due to adverse events | 0/15 | 0/16 | Not estimable | 31 (1 study) | ⊕⊝⊝⊝ Very lowc No withdrawals due to adverse events |
| Occupational effects | ‐ | ‐ | ‐ | ‐ | Not reported |
| Mortality | 0/15 | 0/16 | Not estimable | 31 (1 study) | ⊕⊝⊝⊝ Very lowc No deaths reported |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence: | |||||
| aQuality of the evidence is very low, and has been downgraded once for imprecision due to small participant number in one trial. We further downgraded the evidence (once for indirectness and once for risk of bias) because buflomedil, which was given to all participants as the primary treatment before randomisation, has been withdrawn from practice, yet may have influenced the effects seen in all active treatment groups. bQuality of the evidence is very low, for reasons stated in footnote a (imprecision, indirectnesss and risk of bias). For this outcome, we downgraded the evidence a second time for indirectness, as evidence for adverse events was presented in crude rates, but not reported by intervention group. cQuality of the evidence is very low, for reasons stated in footnote a (imprecision, indirectness and risk of bias). For this outcome, we downgraded the evidence a second time for imprecision, as this outcome is considered a rare event. | |||||
| Iloprost + rtPA compared with buflomedil for frostbite injuries | |||||
| Patient or population: people with severe frostbite injuries Settings: hospital Intervention: iloprost + rtPA Comparison: buflomedil | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | |
|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | ||||
| Buflomedil | Iloprost + rtPA | ||||
| Incidence of amputation in participants (3‐month follow‐up) | Study population | RR 0.31; 95% CI 0.10 to 0.94 | 31 (1 study) | ⊕⊝⊝⊝ | |
| 9/15 | 3/16 | ||||
| Adverse events | ‐ | ‐ | ‐ | ‐ | ⊕⊝⊝⊝ Very lowb Not reported by intervention, but overall included flushing in 55% of participants, nausea in 25%, palpitations in 15%, and vomiting in 5%. |
| Acute pain | ‐ | ‐ | ‐ | ‐ | Not reported |
| Chronic pain | ‐ | ‐ | ‐ | ‐ | Not reported |
| Withdrawal from intervention due to adverse events | 0/15 | 0/16 | Not estimable | 31 (1 study) | ⊕⊝⊝⊝ Very lowc No withdrawals due to adverse events |
| Occupational effects | ‐ | ‐ | ‐ | ‐ | Not reported |
| Mortality | 0/15 | 0/16 | Not estimable | 31 (1 study) | ⊕⊝⊝⊝ Very lowc No deaths reported |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence: | |||||
| aQuality of the evidence is very low, and has been downgraded once for imprecision due to small participant number in one trial. We further downgraded the evidence (once for indirectness and once for risk of bias) because buflomedil, which was given to all participants as the primary treatment before randomisation, has been withdrawn from practice, yet may have influenced the effects seen in all active treatment groups. bQuality of the evidence is very low, for reasons stated in footnote a (imprecision, indirectnesss and risk of bias). For this outcome, we downgraded the evidence a second time for indirectness, as evidence for adverse events was presented in crude rates, but not reported by intervention group. cQuality of the evidence is very low, for reasons stated in footnote a (imprecision, indirectness and risk of bias). For this outcome, we downgraded the evidence a second time for imprecision, as this outcome is considered a rare event. | |||||
| Iloprost +rtPA compared with iloprost for frostbite injuries | |||||
| Patient or population: people with severe frostbite injuries Settings: hospital Intervention: iloprost + rtPA Comparison: iloprost | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | |
|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | ||||
| Iloprost | Iloprost + rtPA | ||||
| Incidence of amputations in participants (3‐month follow‐up) | Study population | RR 0.14; 95% CI 0.01 to 2.56 | 32 (1 study) | ⊕⊝⊝⊝ | |
| 0/16 | 3/16 | ||||
| Adverse events | ‐ | ‐ | ‐ | ‐ | ⊕⊝⊝⊝ Very lowb Not reported by intervention, but overall included flushing in 55% of participants, nausea in 25%, palpitations in 15%, and vomiting in 5%. |
| Acute pain | ‐ | ‐ | ‐ | ‐ | Not reported |
| Chronic pain | ‐ | ‐ | ‐ | ‐ | Not reported |
| Withdrawal from intervention due to adverse events | 0/16 | 0/16 | Not estimable | 32 (1 study) | ⊕⊝⊝⊝ Very lowc No withdrawals due to adverse events |
| Occupational effects | ‐ | ‐ | ‐ | ‐ | Not reported |
| Mortality | 0/16 | 0/16 | Not estimable | 32 (1 study) | ⊕⊝⊝⊝ Very lowc No deaths reported |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence: | |||||
| aQuality of the evidence is very low, and has been downgraded once for imprecision due to small participant number in one trial. We further downgraded the evidence (once for indirectness and once for risk of bias) because buflomedil, which was given to all participants as the primary treatment before randomisation, has been withdrawn from practice, yet may have influenced the effects seen in all active treatment groups. bQuality of the evidence is very low, for reasons stated in footnote a (imprecision, indirectnesss and risk of bias). For this outcome, we downgraded the evidence a second time for indirectness, as evidence for adverse events was presented in crude rates, but not reported by intervention group. cQuality of the evidence is very low, for reasons stated in footnote a (imprecision, indirectness and risk of bias). For this outcome, we downgraded the evidence a second time for imprecision, as this outcome is considered a rare event. | |||||
Background
Description of the condition
Frostbite is a thermal injury caused when tissue is exposed to sub‐zero temperatures (in degrees Celsius) long enough for ice crystals to form in the affected tissue. Risk factors other than temperature include physical immersion in water, wind‐chill, fatigue, malnutrition, smoking, alcohol and substance abuse, and medical comorbidities including peripheral vascular disease, diabetes, neuropathies (nerve damage), dementia and mental illness (Handford 2014; McMahon 2012). Frostbite affects the homeless population, industrial workers and military personnel operating in cold regions, as well as people engaging in recreational activities such as skiing, hiking, mountaineering and ice climbing (Handford 2014; Lorentzen 2018). Frostbite largely affects healthy individuals aged 30 to 49 years (Murphy 2000).
When the body is exposed to a cold environment, the initial physiological response of the vascular system is peripheral vasoconstriction. This shunts blood from the extremities to the core, ensuring perfusion and oxygenation of vital organs and reduction of heat loss; it also results in peripheral cooling. Sustained subjection to freezing temperatures causes formation of ice crystals in the intra‐ and extracellular compartments (i.e. inside and between the body's cells). Vascular permeability of blood vessels increases, resulting in displacement of plasma to extravascular spaces where it subsequently freezes (Imray 2009; McMahon 2012). This leads to tissue ischaemia (lack of oxygen), which is amplified by vasospasm (contraction of the arteries). Cold‐induced vasodilation (widening of blood vessels) operates as a counter mechanism, and moderates perfusion by periodically reducing vasoconstriction in the hypoxic areas (McMahon 2012). If the cold exposure continues, peripheral vasoconstriction will increase and the cycles of cold‐induced vasodilation will cease. Upon reheating and reperfusion, further tissue damage occurs. Hypercoagulability of the blood resulting from platelet and erythrocyte (red blood cell) aggregation causes thrombosis (clots), which increases tissue hypoxia (Imray 2009). Prostaglandin F2‐alpha and thromboxane A2 (TXA2) mediate these changes; increased concentrations of both have been found in frostbite blisters (Robson 1981). Depending on the degree of tissue damage, rewarming is followed either by tissue recovery or vascular collapse, thrombosis, ischaemia, necrosis (tissue death), gangrene, and ultimately amputation. If the frostbitten tissue is refrozen after thawing, extensive cell damage occurs due to intracellular ice crystal formation and a surge in release of inflammatory mediators (Imray 2009).
Clinically, frostbite injuries present with loss of sensation and a pale, waxy, bluish skin discolouration (cyanosis). Blisters and oedema may be present in the affected areas. Clear fluid in the blisters, retained sensation and normal skin colour are favourable prognostic signs (Imray 2009). Poor prognostic signs include cloudy or haemorrhagic (bloody) fluid in the blisters, cyanosis, lack of oedema and firm skin in the frostbitten area.
Frostbite injuries can be classified into grades 1 to 4 depending on the clinical presentation after rewarming, with grades 1 to 2 comprising superficial frostbite injuries, and grades 3 to 4 deep frostbite injuries. In grade 1, cyanosis is absent, and the risk of amputation is minimal. Grade 2 frostbite presents with cyanosis on the distal phalanx of fingers or toes, and is associated with a moderate risk of amputation. Cyanosis up to the metacarpophalangeal joint (MCP; base of the fingers) or metatarsophalangeal joint (MTP; middle of the foot) bears a high risk of amputation, and is classified as a grade 3 frostbite injury. In grade 4 injuries, cyanosis is seen proximal to the MCP or MTP joint, and the risk of amputation is almost 100% (Cauchy 2001).
Frostnip is a precursor to frostbite that presents with symptoms similar to grade 1 frostbite. Frostnip is fully reversible and holds no long‐term effects. Chilblains are painful, non‐dangerous skin lesions induced by cold. Non‐freezing cold injuries are caused by prolonged exposure to cold and usually wet environments, with symptoms similar to frostbite.
Significant pain and a burning sensation usually accompany re‐establishment of perfusion, to the extent that parenteral analgesia can be necessary upon rewarming. The dull continuous pain reperfusion causes evolves into a throbbing sensation after 48 to 72 hours. This throbbing pain often persists until tissue demarcation (when the distinction between vital and non‐vital tissue) becomes evident several weeks to months later, and may progress into chronic pain in the recovered tissue. In addition to chronic pain, other long‐term sequelae include hypersensitivity to cold, numbness and reduced sensitivity to touch (Handford 2014).
Distal sections of the extremities and exposed regions of the face and head are susceptible to frostbite. Thus digits, toes, ears, nose and cheeks are often areas at risk. Amputation of multiple digits, or in extreme cases limbs, causes extensive morbidity, reducing the ability to perform activities of daily living. This severely decreases quality of life.
Description of the intervention
An expert panel has summarised current guidelines for management of frostbite injuries (McIntosh 2014). However, evidence is often low quality due to lack of randomised controlled trials (RCTs). The proposed management of frostbite injuries can be divided into three phases: a pre‐hospital, pre‐thaw, field‐care phase; a hospital care phase; and a post‐thaw phase. Pre‐hospital management includes: reduction of further exposure to cold; removal of wet garments and replacement with dry ones; placement of the frostbitten extremity in a companion's armpit (axilla) or groin for 10 minutes; administration of 75 mg aspirin (antiplatelet effect); and administration of 800 mg ibuprofen (to produce an antiprostaglandin effect) (Imray 2009; Syme 2002). If sensation in the extremity does not return, medical treatment in a healthcare facility should be sought. The hospital phase includes rewarming the extremity in a 37 °C to 39 °C recirculating antiseptic waterbath for 15 to 60 minutes, until a red/purple colour appears and the limb becomes pliable.
The post‐thawing phase includes debridement (removal) of clear blisters, use of Aloe vera cream, splinting, dressing and elevation of the affected body part. Haemorrhagic blisters should be left intact, but can be drained with their roofs on if they restrict movement (Imray 2009). It may be appropriate to administer tetanus vaccine or prophylactic antibiotics. Ibuprofen 400 mg administered orally every 12 hours provides systemic antiprostaglandin activity and limits inflammatory damage. Rehydration with oral or intravascular fluids might be useful in dehydrated hypothermic individuals, especially at altitude, but is not required for isolated frostbite injuries.
Adjunctive therapies including: hyperbaric oxygen therapy; sympathectomy (nerve block); thrombolytic (blood‐thinning) therapy; and vasodilating agents such as iloprost, reserpine, pentoxifylline and buflomedil, have been proposed as pharmacological agents for frostbite treatment (Cauchy 2001; Grieve 2011; Handford 2014; Hayes 2000; Imray 2009).
How the intervention might work
Reheating the frostbitten extremity in a 37 °C to 39 °C whirlpool bath containing an antiseptic solution is the first step in the treatment protocol for frostbite injuries. Rewarming the affected areas brings the frost‐induced damage to a halt and may ensure some degree of reperfusion.
Aloe vera is a potent antiprostaglandin agent, and thus might decrease the detrimental effects of the prostaglandin cascade in frostbitten tissue (Handford 2014; Imray 2009). Non‐steroidal anti‐inflammatories also reduce prostaglandin activity, thus reducing the inflammatory damage.
Vasodilating agents work by increasing blood flow to hypoxic areas, thus re‐establishing perfusion and reducing the risk of tissue necrosis. Iloprost is a synthetic prostacyclin analogue. Its main effects are vasodilation of systemic and pulmonary arterial beds, inhibition of platelet aggregation, and cytoprotection (Grant 1992). Intravenous administration of iloprost has been shown to be effective in reducing amputations up to 48 hours after rewarming (Cauchy 2011; Groechenig 1994). Pentoxifylline, a methyl‐xanthine‐derived phosphodiesterase inhibitor, increases perfusion to the affected extremity, decreases platelet hyperactivity, and helps normalise the prostacyclin‐to‐thromboxane A2 ratio (Hayes 2000). Buflomedil, an alpha‐blocker, increases peripheral blood flow, and thus might improve perfusion to hypoxic tissue (Cauchy 2001).
Thrombolytics dissolve clots in the microvasculature, thus improving perfusion to compromised areas. Tissue plasminogen activator activates plasminogen, which in turn yields the proteolytic enzyme plasmin via cleavage. Plasmin breaks the links between fibrin molecules, thus disrupting the integrity of blood clots. Ultimately, blood clots are dissolved and blood flow is restored (Handford 2014; Twomey 2005).
Hyperbaric oxygen therapy might have potential benefits in frostbite. Studies show that the flexibility and deformability of erythrocytes (red blood cells) may increase in a pressurised high‐oxygen environment, causing oedema to be reduced in ischaemic tissues. Furthermore, hyperbaric oxygen therapy may bestow a bacteriostatic and antioxidant effect (Handford 2014; Imray 2009; von Heimburg 2001).
Sympathetic nerve blocks to the arms cause vasodilatation and increased skin temperature of the fingers (Cauchy 2016). Performing nerve blocks with local anaesthesia may provide both pain relief and vasodilatation, and thus be useful in treatment of frostbite injuries.
It is preferable to permit auto‐amputation (i.e. allowing the demarcation between vital and non‐vital tissue to occur naturally, and allowing the necrotic tissue to fall off without surgery), as tissue that appears to be non‐vital may recover. Surgery should not be performed prematurely, as early amputation increases morbidity and leads to poor function. In cases where perfusion is compromised by compartment syndrome ‐ when pressure within the muscles restricts blood flow ‐ it may be necessary to make a fasciotomy (cut along the sheet of connective tissue that lies beneath the skin) to release pressure and ensure tissue perfusion (Handford 2014). Early surgery may be necessary if uncontrolled infection occurs.
Why it is important to do this review
Many different treatment regimens for frostbite injuries have been proposed, but most are based on anecdotal evidence. Very few interventions have been properly investigated and evaluated for their management. To the best of our knowledge, a systematic review containing a meta‐analysis has not yet been published on this topic. Since frostbite injuries are linked to a high degree of morbidity, it is important to establish evidence‐based treatment regimens accessible to medical professionals across the globe.
Objectives
To assess the benefits and harms of the different management options for frostbite injuries.
Methods
Criteria for considering studies for this review
Types of studies
We included all randomised controlled trials (RCTs) investigating medical interventions for frostbite injuries in the review. We planned to consider cluster‐randomised trials but to exclude cross‐over trials, as they are inappropriate for the condition we are examining.
In accordance with Cochrane Injuries Group policy, we planned to include only prospectively registered studies, unless the study report was published before 2010 (Roberts 2015). An exception was made for the one identified study (Cauchy 2011), as recruitment commenced in 1996.
Types of participants
We included RCTs conducted on men and women of all ages. Trials covering management of chilblains, frostnip and non‐freezing cold injuries (NFCI) were not included. A separate Cochrane Review of interventions for non‐freezing cold injuries is currently in preparation (Lorentzen 2020).
Types of interventions
We included trials that compared any medical intervention, e.g. pharmacological therapy, topical treatments, or rewarming techniques, for frostbite injuries to another treatment, placebo or no treatment.
Types of outcome measures
We chose the outcome measures on the basis of clinical and patient relevance. We avoided inclusion of surrogate outcome measures. For the analysis, we planned to group measurement of the outcomes into studies with similar, clinically meaningful follow‐up categories of:
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short‐term follow‐up (one week to less than one month);
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medium‐term follow‐up (one month to less than 12 months); and
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long‐term follow‐up (one to three years).
Primary outcomes
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Incidence of amputations
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Rate of serious and non‐serious adverse events. We defined serious adverse events as any untoward medical occurrence that resulted in death, was life‐threatening, persistent, or led to significant disability; or any medical event that jeopardised the patient or required intervention to prevent it (ICH‐GCP 1997). We considered all other adverse events (that is, any medical occurrence not necessarily having a causal relationship with the treatment, but that did cause a dose reduction or discontinuation of the treatment) as non‐serious.
Sample size calculation
Mäkinen 2009 reported the annual incidence of mild and severe frostbite as 14.0% in the Finnish population, based on data from two national surveys. Since we assumed that all participants in frostbite studies were suffering from frostbite, we calculated the required information size for the primary outcome 'incidence of amputations' on the basis of a two‐armed single study with an assumed maximum baseline risk of amputation of 60% (Cauchy 2011), a risk reduction of 20%, an alpha value of 0.05 and a power of 90%, to be a total of 416 participants, or 208 participants in each arm.
Secondary outcomes
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Acute pain, measured as a continuous variable: in particular, for acute pain upon rewarming, a reduction in pain intensity of 50% or more on a scale from 1 to 10 compared with baseline value
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Chronic pain, measured as a dichotomous variable; that is, whether or not participants have chronic pain
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Ability to perform activities of daily living, assessed by any measure
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Quality of life, assessed by validated scales
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Withdrawal rate from medical therapy due to adverse events
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Occupational effects: for example, mean duration of absence due to sickness, and mean time to full return to work
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Mortality
Search methods for identification of studies
In order to reduce publication and retrieval bias we did not restrict our search by language, date, or publication status.
Electronic searches
The Cochrane Injuries Group's Information Specialist Sarah Dawson searched the Cochrane Injuries Group Specialised Register and the databases listed below on 4 April 2017. These searches were rerun on 25 February 2020 by Kate Perris (assistant librarian at the London School of Hygiene and Tropical Medicine), with the exception of the Cochrane Injuries Group Specialised Register, as that is now part of the Cochrane Central Register of Controlled Trials (CENTRAL). Top‐up searches of registries were run shortly before publication (9 November 2020). The databases searched were:
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the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (www.cochranelibrary.com) (25 February 2020);
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Ovid MEDLINE(R), Ovid MEDLINE(R) In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R) (25 February 2020);
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Embase (OvidSP) (25 February 2020);
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ISI Web of Science: Science Citation Index Expanded (SCI‐EXPANDED) (25 February 2020);
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ISI Web of Science: Conference Proceedings Citation Index‐Science (CPCI‐S) (25 February 2020);
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Clinicaltrials.gov (www.clinicaltrials.gov) (9 November 2020);
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World Health Organization (WHO) International Clinical Trials Registry Platform (apps.who.int/trialsearch) (9 November 2020);
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OpenGrey (9 November 2020).
Original searches conducted in April 2017 are listed in Appendix 1.
The updated searches performed on 25 February 2020 did not yield any additional studies eligible for inclusion. The updated search strategy is listed in Appendix 2. As mentioned already, we performed a prepublication check of trials registries on 9 November 2020. Trials registry search terms are reported in Appendix 3.
Searching other resources
We reviewed the reference lists of review articles and relevant trials, as well as the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) drug approval reviews. We attempted to have personal contact with the principal authors to identify further trials, as data were limited. We contacted pharmaceutical companies to obtain data from unpublished RCTs. We also searched military resources, for example, www.sto.nato.int. We reported the results of the searches according to the PRISMA guidelines (Moher 2009).
Data collection and analysis
We performed this review according to Cochrane recommendations (Higgins 2011a). We performed the analyses using Review Manager 5.4 (RevMan 5) (Review Manager 2020).
Selection of studies
We obtained titles and abstracts of studies that might be relevant for the review from the search strategies described in the appendices. Trial eligibility was assessed independently by two authors (AKL and LP). We have listed excluded studies with their reasons for exclusion. We resolved disagreements by discussion or through consultation with a third author (CD).
Data extraction and management
Two authors (AKL and LP) carried out data extraction using standard data extraction forms (Higgins 2011a; Moher 2009). When more than one publication of a study existed, we grouped reports together and marked the publication with the most complete data as the primary publication. Where relevant outcomes were published in earlier versions only, we planned to use these data, and add information about this to the 'Notes' section of the trial in the 'Characteristics of included studies' table. We planned to highlight any discrepancies between published versions. We planned to resolve disagreements through discussion amongst all authors.
We extracted the following information from the included trial:
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name and contact details of all authors;
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details of where the study was conducted, details of study registration;
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trial design;
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inclusion and exclusion criteria;
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number of participants randomised;
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characteristics of participants: age range (mean or median) and sex ratio;
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severity of frostbite, affected body part(s), number of affected body parts;
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therapeutic regimens used;
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dose of therapeutic agent, duration, frequency and mode of administration (for hyperbaric oxygen: altitude, time initiated, and duration; for sympathectomy: location, and dose of local anaesthetic);
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timing, type and dose of additional interventions;
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outcomes.
Furthermore, we also reported whether the therapeutic agent was used off‐label (i.e. the agent was approved for a condition other than frostbite) or was registered for frostbite treatment. We contacted trial authors for information that was not available in the published reports, in order to assess the trials correctly.
Assessment of risk of bias in included studies
We followed instructions given in the Cochrane Handbook for Systematic Reviews of Interventions to assess risk of bias (Higgins 2011a).
Methodological quality is defined as the confidence one might have that the design and reporting of the trial have restricted bias in the intervention comparison (Moher 1998). In randomised trials of inadequate methodological quality, there is a risk of overestimation of intervention effects (Gluud 2006; Kjaergard 2001; Moher 1998; Savovic 2012; Schulz 1995; Wood 2008). Using the Cochrane 'Risk of bias' tool (Higgins 2011b), we assessed all included trials for risk of bias for the domains of sequence generation; allocation concealment; blinding of participants, personnel and outcome assessors; incomplete outcome data; selective outcome reporting; and other biases. For each domain, and based on the trial's conduct and reporting, we assessed whether there was a 'low', 'uncertain' or 'high' risk of bias.
Measures of treatment effect
We expressed dichotomous data as risk ratios (RR), which are the ratio of the probability of an outcome in an intervention group to the probability of an outcome in a control group, with 95% confidence intervals (CIs), and continuous data as mean differences (MD) and 95% CIs. Where outcomes were measured using scales, we planned to treat them as continuous variables (Thompson 2002). Mean differences based on changes from baseline can usually be assumed to address exactly the same underlying intervention effects as analyses based on final measurements (Higgins 2011a).
Unit of analysis issues
Given the outcomes defined for this review, we expected to find clinical trials with simple parallel group designs. Had there been multiple observations or cross‐over trials, we planned to follow the instructions given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). However, we encountered no such trials.
Where studies were randomised at the participant level, but measured outcomes at the frostbite level, e.g. healing, we treated the participant as the unit of analysis when the number of frostbites assessed appeared equal to the number of participants (e.g. one frostbite per person).
Where studies that were randomised at the participant level measured outcomes at the body part level (amputation of digits), we analysed the data using the method for cluster‐randomised trials; that is, considering each participant as one cluster, and considering the average number of affected digits or toes per participant as the average cluster size. We analysed the data using an intracluster coefficient of 0.02, and analysed the effective sample size and modified outcome results (Higgins 2020).
Had a cluster trial been conducted and correctly analysed, we planned to meta‐analyse effect estimates and their standard errors using the generic inverse variance method in RevMan 5. If possible, we planned to approximate the correct analyses based on the Handbook guidance (Higgins 2011c), using information about:
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the number of clusters (or groups) randomised to each intervention group; or the average (mean) size of each cluster;
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the outcome data ignoring the cluster design for the total number of individuals (for example, number or proportion of individuals with events, or means and standard deviations); and
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an estimate of the intracluster (or intraclass) correlation coefficient (ICC).
If we could not analyse the study data correctly, we planned to extract and report the outcome data, but not analyse them further.
We also planned to note when randomisation had been undertaken at the frostbite level ‐ that is, in a split‐site or split‐body design. We planned to assess whether the correct paired analysis had been undertaken in the study. Where analysis with inappropriate methodology had been undertaken, we planned to try and approximate a correct analysis, if the required data were available from the study report or the study authors. If this was possible, we planned to extract and report the relevant outcome data, but not analyse them further. However, we encountered no such trials.
Dealing with missing data
We planned to use the following strategy when confronted with missing data. In the first instance, we intended to contact the original investigators to request missing data. If this approach failed, and more than 20% of the data were missing, we planned to perform best‐worst case scenarios, and ultimately imputation. Finally, we intended to address the potential impact of all 'missing data' situations on the findings of the review in the Discussion section. However, the only included study did not have any issues regarding missing data.
Assessment of heterogeneity
We planned to analyse heterogeneity between studies using a Chi2 test with a P value of 0.10 used for statistical significance. In addition, we planned to quantify the degree of heterogeneity observed in the results using the I2 statistic, with values over 75% indicating high levels of heterogeneity (Higgins 2002). However, as we included only one study, it was not possible to investigate statistical heterogeneity.
Assessment of reporting biases
We considered reporting biases (e.g. publication, time lag, multiple publications) at all points of data analysis and interpretation. Had we identified at least 10 RCTs that contributed to a meta‐analysis, we planned to make attempts to analyse for publication bias using funnel plots (Egger 1997; Macaskill 2001), bearing in mind that asymmetry is not necessarily caused by publication bias, but may have other causes. However, as we included only one study in the review, we did not carry out any formal tests for reporting biases.
Data synthesis
For dichotomous data, we used the Mantel‐Haenszel test for reporting pooled risk ratios and 95% CIs. For continuous data, we planned to use the inverse variance method for reporting the pooled mean differences. Where scales were used for continuous outcomes, we planned to make sure that all scales were similar. If they were not, we intended to pool data using standardised mean differences, and report the result by back‐transforming into the most common scale. We planned to combine data that were reported as change from baseline values with the final measurement values in the meta‐analyses. However, the only study we included did not contain continuous data.
We planned to report both random‐effects and fixed‐effect models as a means of exploring heterogeneity. Had there been important differences in the results produced by the two models, we planned to provide both results. Had the difference in the results not been important, we would have presented the results of the random‐effects model (Higgins 2002). However, as we included only one study, we did not perform these analyses. Had we included cluster trials, we would have employed the generic inverse variance method for meta‐analysis. However, we included no cluster trials.
Zero‐events trials
Trials with zero‐events do occur. As it seemed unjustified and unreasonable to exclude such trials, and potentially risk inflating the magnitude of the pooled treatment effects (Keus 2009; Sweeting 2004), we planned to include zero‐event trials in the statistical analyses. Zero‐event trials require statistical analysis using Peto's odds ratio, which is designed to cope with zero‐event situations (Higgins 2011a). In future versions, if more studies present with zero‐events, we will consider Peto’s odds method.
Subgroup analysis and investigation of heterogeneity
We performed subgroup analyses for:
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different degrees of severity of frostbite, e.g. superficial frostbite (grades 1 and 2) versus deep frostbite (grades 3 and 4);
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different time intervals between injury and administration of medical intervention. We planned to perform analyses for both the first medical intervention and the in‐hospital intervention, where possible.
Sensitivity analysis
We planned to perform sensitivity analyses by temporarily removing trials with high risks of bias in the domains of sequence generation, allocation concealment and incomplete outcome data from the pooled analysis.
Summary of findings and assessment of the certainty of the evidence
We employed the GRADE approach for interpretation of findings, and used the GRADE profiler to import data from Review Manager to create 'Summary of findings' (SOF) tables (GRADEpro GDT). These tables provide outcome‐specific information concerning the overall quality of evidence from studies included in the comparison, the magnitude of effect of the interventions examined, and the sum of available data. We created SOF tables that included all the review outcomes, and we indicated when no data were available for an outcome. A separate SOF table was created for each intervention. We reported the same outcome measures for each intervention. We provided SOF tables with the following outcomes.
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Incidence of amputations.
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Adverse events.
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Acute pain.
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Chronic pain.
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Withdrawal from intervention due to adverse events.
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Occupational effects.
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Mortality.
Results
Description of studies
Results of the search
Figure 1 shows the results of our search. Our predefined search identified 1775 references, we found a further 26 in additional sources, making a total of 1801. After eliminating duplicates, 1047 studies remained. Exclusion of irrelevant references left one randomised clinical trial in two publications (see Characteristics of included studies; Characteristics of excluded studies). We found no RCTs from searching military resources.
Study flow diagram
Included studies
We included one randomised trial with a total of 47 participants, which was published as a 'Letter to the Editor' in the New England Journal of Medicine (Cauchy 2011), and as a medical thesis (Cheguillaume 2011). The study population consisted of 44 men and three women with a mean age of 33 years (range 18 to 55 years). The participants were from 15 different countries. Forty‐five (95.7%) people acquired frostbite lesions during sport activities in altitudes over 2000 metres. Frostbite occurred in the feet of 33 participants, in the hands of 29, and in both the hands and feet of 15. Severe frostbite was defined as having at least one digit (finger or toe) with grade 3 frostbite (lesion extending just past the proximal phalanx) or grade 4 (lesion extending proximal to the metacarpal or metatarsal joint).
All participants who met the inclusion criteria (adults, no contraindications to use of aspirin or study drug, no severe trauma, no hypothermia, no mental conditions preventing co‐operation with the treatment) were included in the study directly after mountain rescue. All underwent rapid rewarming, received 250 mg of aspirin and 400 mg intravascular (IV) buflomedil, and were then randomised to one of three treatment groups for the following eight days.
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Group 1 received additional IV buflomedil 400 mg for one hour per day.
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Group 2 received an IV prostacyclin, iloprost, 0.5 ng/kg/min to 2 ng/kg/min for six hours per day.
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Group 3 received IV iloprost 2 ng/kg/min for six hours per day plus fibrinolysis 100 mg rtPA for the first day only.
Treatment was evaluated after eight days by technetium bone scintigraphy, and participants were seen at follow‐up after three months.
Both iloprost and buflomedil were used off‐label.
We also found an ongoing randomised trial investigating the effect of hyperbaric oxygen on tissue regeneration, number of surgeries, level of amputation and level of function of the damaged body part after frostbite injury, registered in 2011 (NCT01270477). We attempted to contact the study authors inquiring about the status of the trial and preliminary data in May 2017, but received no reply.
Excluded studies
Our searches identified 1034 studies that had titles or abstracts which were clearly irrelevant to the subject of the review. We excluded 11 further studies after reading the full text of the articles. These studies were not randomised or did not assess interventions for frostbite injuries. The reasons for exclusion are described in the Characteristics of excluded studies.
Risk of bias in included studies
The one included study was considered to be a trial with an unclear risk of bias for one risk of bias domain (Cauchy 2011) (Figure 2; Figure 3).
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
The only included trial used a telephone service that was available 24 hours per day to randomise the people using a randomly generated list (Cheguillaume 2011). We judged risk of selection bias as being low.
Blinding
The one included trial was an open label study that did not report blinding of people, personnel and outcome assessors (Cauchy 2011). The three interventions differed substantially in their mode of administration (infusion over one hour versus infusion over six hours versus infusion over six hours plus a bolus). As such, it is hard to imagine that people and personnel were blinded to the intervention given. Therefore, we judged the risk of bias to be high for blinding of people and personnel.
The main outcome was amputation rate. Since amputation is not a subjective outcome, its evaluation cannot be subject to bias in assessors. Therefore, we judged the risk of bias due to lack of blinding of outcome assessors to be low.
Incomplete outcome data
The one included trial reported that there were no withdrawals from the study, and data from all 47 participants were given in the study. However, the supplementary material stated that seven people were not seen at the three‐month follow‐up (Cauchy 2011). Therefore, we judged the risk of bias for this domain to be unclear.
Selective reporting
Whilst it appears clear that a committee of the Rhône‐Alpes gave ethical approval for the study, no study protocol was available for the one included trial (nor was it common practice to produce one in 1996) (Cauchy 2011 ). The primary investigator for the study has died, and the medical thesis which also reports on the trial was not begun for more than 10 years after recruitment started (Cheguillaume 2011). In these circumstances, it was not possible to assess whether the outcomes were prespecified, or whether data were provided for all prespecified outcomes (Cauchy 2011).
It is our judgement, however, that all outcomes reported are relevant for this topic, and are patient‐relevant, and so we judged the study to have low risk of bias for selective reporting.
Other potential sources of bias
We identified no other sources of bias, including industry support.
Effects of interventions
See: Summary of findings 1 Summary of findings; Summary of findings 2 Summary of findings; Summary of findings 3 Summary of findings
Amputations
The one included trial reported the incidence of amputations on both the participant level and body‐part (fingers and toes) level.
Participant level
Amputations were much less common in:
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the iloprost group (0/16; 0%) compared to the buflomedil group (9/15; 60%; RR 0.05, 95% CI 0.00 to 0.78; 1 study, 47 participants; very low‐quality evidence; Analysis 1.1), and
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the iloprost plus rtPA group (3/16; 19%) compared to the buflomedil group (9/15; 60%; RR 0.31, 95% CI 0.10 to 0.94; 1 study, 47 participants; very low‐quality evidence; Analysis 2.1).
There may have been little or no difference between the iloprost group (0/16; 0%) and the iloprost plus rtPA group (3/16; 19%; RR 0.14, 95% CI 0.01 to 2.56; 1 study, 47 participants, very low‐quality evidence; Analysis 3.1).
Body‐part level
A total of 407 digits were frostbitten in the 47 participants, and 47 of these (11.5%) were amputated from 12 individuals. Forty‐two of the 106 (39.6%) frostbitten digits treated with buflomedil were amputated. None of 142 frostbitten digits treated with iloprost were amputated. Five of the 159 frostbitten digits treated with iloprost plus rtPA were amputated. We analysed the data by applying the method for cluster randomised trials, and calculated an effective sample size in the control/treatment group as well as the modified number of events.
This showed that:
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amputations may have occurred less often in the iloprost group (0/142; 0%) compared to the buflomedil group (42/106; 39.6%; RR 0.01, 95% CI 0.01 to 0.14; 1 study, 47 participants; very low‐quality evidence; Analysis 1.2);
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amputations may have occurred less often in the iloprost plus rtPA group (5/159; 3%) compared to the buflomedil group (42/106; 39.6%; RR 0.08, 95% CI 0.03 to 0.19; 1 study, 47 participants; very low‐quality evidence; Analysis 2.2);
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there may be little or no difference in amputations between the iloprost group (0/142; 0%) and the iloprost plus rtPA group (5/159; 3%; RR 0.10, 95% CI 0.01 to 1.82; 1 study, 47 participants; very low‐quality evidence; Analysis 3.2).
Adverse effects
Adverse events were reported for all the included people regardless of intervention, but were not reported separately by comparator arm. Therefore, we could not assess whether the rate of serious and non‐serious adverse events differed in the intervention groups, and assessed the evidence as being of very low quality. Adverse events included hot flushes in 55% of participants, nausea in 25%, heart palpitations in 15%, and vomiting in 5%. Despite this, the study reported no withdrawals due to adverse events.
Withdrawal from the study due to adverse events
None of the participants withdrew from the study due to reactions to the study medication (very low‐quality evidence).
Mortality
The only included study did not report any deaths. As this is a small study, and the event is anticipated to be rare, we assessed this finding as being of very low quality.
Other outcomes
The only included study did not report on our prespecified outcomes acute pain, chronic pain, ability to perform activities of daily living, quality of life and occupational events.
Subgroup analyses
Superficial versus deep frostbite injuries
Superficial frostbite injuries (grade 2) affected a total of 155 digits, and deep frostbite injuries (grades 3 and 4 combined) affected 252 digits. Four amputations occurred in the superficial frostbite group, versus 43 in the deep frostbite group. For superficial frostbite injuries, two of 31 digits were amputated in the group treated with buflomedil. In the iloprost group, none of the 64 digits were amputated. For the iloprost plus rtPA group, two of 60 affected digits were amputated. For deep frostbite injuries, 40 out of 75 affected digits were amputated in the buflomedil group, none of the 78 digits in the iloprost group, and three of the 99 digits in the iloprost plus rtPA group. See Analysis 1.3; Analysis 2.3; Analysis 3.3.
Treatment initiated within or after 12 hours
We initially planned a subgroup analysis investigating time to medical intervention within or after 24 hours of injury. As the only included study did not report data within these time frames, we were not able to perform the initially specified subgroup analysis. However, the only included study did report amputation rates for all grades of frostbite injury treated within or after 12 hours.
A total of 271 digits received medical treatment within 12 hours of injury, of which 13 (4.8%) were amputated. A further 136 digits presented more than 12 hours after injury, and 34 (25%) were amputated. This shows that risk for amputation was significantly reduced in the participants who received any treatment within 12 hours (13/271 = 4.8%) compared with the group who received treatment after 12 hours (34/136 = 25%) (P < 0.001, Fischer's exact test) (Analysis 1.4; Analysis 2.4; Analysis 3.4).
For the groups presenting for treatment within 12 hours: none of the 79 digits in the iloprost group were amputated; two of the 144 digits in the iloprost plus rtPA group were amputated; and 11 of the 48 digits in the buflomedil group were amputated.
For the groups presenting for treatment after 12 hours: none of the 63 digits in the iloprost group were amputated; three of the 15 digits in the iloprost plus rtPA group were amputated; and 31 of the 58 digits in the buflomedil group were amputated.
Discussion
Summary of main results
Evidence from randomised trials on interventions for frostbite injuries is very limited. We found one small randomised controlled three‐arm trial comparing buflomedil, iloprost, and iloprost combined with fibrinolysis (rtPA) (Cauchy 2011). The trial suggests that iloprost and iloprost plus rtPA may result in a large reduction in the rate of amputations compared to buflomedil alone, when analysed on both patient and body‐part levels (very low‐quality evidence). There may be little or no difference in amputations between iloprost and iloprost plus rtPA (very low‐quality evidence). There were no deaths or withdrawals due to adverse events in any of the study arms (very low‐quality evidence). The included study provided very low‐quality evidence on adverse events, which it did not report separately by comparator arm, and it did not measure the outcomes of acute pain, chronic pain, ability to perform activities of daily living, quality of life or occupational effects.
Overall completeness and applicability of evidence
There is a paucity of evidence in this field, and drawing conclusions from a very small evidence base is difficult. This systematic review examined the evidence from one included RCT comparing three interventions for the treatment of frostbite injuries. We could not obtain data for all our predefined outcome measures, as the trial did not report on all of them. The trial reported on amputations and mortality, but did not report the adverse events by comparator arm. We do know, however, that there were no withdrawals due to adverse events, and no deaths.
Iloprost and rtPA are still available on the market. However, buflomedil, which was given to all people as the primary treatment in this study before randomisation to the three interventional groups, has been withdrawn because of reports of severe adverse neurological and cardiac events after its administration. This means that the treatment option which was given to all three groups before randomisation and to one group after randomisation can no longer be administered. In the absence of a control group that did not receive buflomedil, we cannot be sure that the effects seen in the iloprost and iloprost plus rtPA groups were not influenced by buflomedil. This factor caused us to downgrade the evidence for indirectness.
The trial included participants with severe frostbite injuries (grades 3 and 4), but some also presented with grade 2 injuries. A subgroup analysis showed that the iloprost interventions reduced the amputation rate for both severe and superficial frostbite injuries. Frostbite injuries of grades 1 and 2 do not usually lead to amputations, but grades 3 and 4 usually do. The population included in this trial was relevant to the review question, and included no restrictions regarding age and sex, so indirectness is not an issue with regard to the target population.
The only included trial investigated the effect of buflomedil, iloprost and rtPA on amputation rates. We found no trials investigating rewarming techniques, Aloe vera treatment, sympathectomy or other interventions for frostbite injuries. Therefore, the evidence in this review lacks completeness in terms of breadth of scope.
Quality of the evidence
The included trial was poorly reported and the methods were not sufficiently well described to enable us to assess attrition bias. The study did not report blinding of participants, personnel or outcome assessors. Due to the differences in the interventions given, we judged the risk of bias to be high for blinding of people and personnel. However, as the nature of the main outcome was objective, and could hardly be subject to bias in assessors, we judged the risk of bias due to lack of blinding of outcome assessors to be low. We also assessed the risk of bias to be low for the domains of sequence generation, allocation concealment and selective outcome reporting. We downgraded for risk of bias.
Our primary concern regarding this evidence base was imprecision. The only included study recruited 47 participants, yet our sample size calculation showed that a minimum of 416 participants total, or 209 participants in each arm, would be required to have a sufficiently powered study to calculate a precise effect estimate. Therefore our review is very underpowered and the consequent imprecision, for which we downgraded, means that we have greatly reduced confidence in the effect estimates.
The included study recruited a representative population of adults of both sexes, focused on severe frostbite injuries but also included extremities with superficial frostbite injuries (i.e. grade 2 frostbite). Regarding these domains, we did not consider indirectness to be of concern. However, all intervention groups received buflomedil, and as no control group was present that did not receive buflomedil, we cannot be certain whether the administration of buflomedil influenced the effect seen in the iloprost and iloprost plus rtPA group. This caused us to downgrade for indirectness. Likewise, we did not have concerns about inconsistency. We could not detect publication bias via a funnel plot as there were insufficient studies. However, we do not suspect publication bias: we did not find any registered trials that had not been published, and we suspect that there are very few studies in this field because of how difficult they are to coordinate and conduct.
Potential biases in the review process
We performed a comprehensive literature search for this systematic review across languages and including trial registries. We prespecified inclusion and exclusion criteria, and two authors independently screened studies and extracted data in order to reduce bias. However, only one RCT was eligible for inclusion, and we found one ongoing trial. This means that it is very difficult to draw conclusions because the evidence base is so limited.
We acknowledge that the judgements regarding risk of bias and GRADE have an element of subjectivity which may have introduced some bias into the review process.
Agreements and disagreements with other studies or reviews
No other meta‐analysis on interventions for frostbite injuries has been published, although Hutchinson and colleagues published a systematic review in 2019 (Hutchinson 2019). This included cohort studies and case reports that investigated the use of tissue plasminogen activator (tPA) for the treatment of frostbite injuries, in addition to the RCT included in this review. Due to a high degree of heterogeneity in the treatment protocols, inclusion criteria and outcome measures, Hutchinson and colleagues performed no meta‐analysis. The included trials reported that tPA may have been useful in reducing amputation rates. Due to low quality evidence, the authors concluded that the efficacy of tPA in reducing amputation rates cannot be established. This conclusion is in agreement with the findings of this review.
In 1994, a small study reported on treatment of four patients with severe frostbite with iloprost, in which no amputations occurred (Groechenig 1994). Even though these results were very promising, no other studies with iloprost were published until the randomised trial included in this review (Cauchy 2011). In contrast, some non‐randomised studies report on the use of rtPA with promising results (Bruen 2007; Twomey 2005). In one retrospective review, digital amputations occurred at a rate of 41% in patients that did not receive rtPA compared to 10% in those who received rtPA within 24 hours of injury (P < 0.05) (Bruen 2007). In another case‐series, the number of amputations of digits in patients who had an absence of Doppler pulses and no perfusion with a technetium (Tc) 99m three‐phase bone scan, was much lower than expected after treatment with rtPA (Twomey 2005). In this study, some patients received rtPA intra‐arterially and some intravenously. Two of the patients treated intra‐arterially suffered bleeding complications (Twomey 2005). Administration of rtPA requires a facility used to giving thrombolysis, and adequate intensive monitoring facilities (Handford 2014). Furthermore, rtPA is contraindicated with presence of trauma or increased bleeding risk due to the risk of haemorrhage.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1: Iloprost vs buflomedil, Outcome 1: Incidence of amputations (patients)
Comparison 1: Iloprost vs buflomedil, Outcome 2: Incidence of amputations (body parts)
Comparison 1: Iloprost vs buflomedil, Outcome 3: Incidence of amputations (severity)
Comparison 1: Iloprost vs buflomedil, Outcome 4: Incidents of amputations (time)
Comparison 1: Iloprost vs buflomedil, Outcome 5: Withdrawal due to study medication
Comparison 1: Iloprost vs buflomedil, Outcome 6: Mortality
Comparison 2: Iloprost + rtPA vs buflomedil, Outcome 1: Incidence of amputations (patients)
Comparison 2: Iloprost + rtPA vs buflomedil, Outcome 2: Incidence of amputations (body parts)
Comparison 2: Iloprost + rtPA vs buflomedil, Outcome 3: Incidence of amputations (severity)
Comparison 2: Iloprost + rtPA vs buflomedil, Outcome 4: Incidence of amputations (time)
Comparison 2: Iloprost + rtPA vs buflomedil, Outcome 5: Withdrawal due to study medication
Comparison 2: Iloprost + rtPA vs buflomedil, Outcome 6: Mortality
Comparison 3: Iloprost vs iloprost + rtPA, Outcome 1: Incidence of amputations (patients)
Comparison 3: Iloprost vs iloprost + rtPA, Outcome 2: Incidence of amputations (body parts)
Comparison 3: Iloprost vs iloprost + rtPA, Outcome 3: Incidence of amputations (severity)
Comparison 3: Iloprost vs iloprost + rtPA, Outcome 4: Incidence of amputations (time)
Comparison 3: Iloprost vs iloprost + rtPA, Outcome 5: Withdrawal due to study medication
Comparison 3: Iloprost vs iloprost + rtPA, Outcome 6: Mortality
| Iloprost versus buflomedil for frostbite injuries | |||||
| Patient or population: people with severe frostbite injuries Settings: hospital Intervention: iloprost Comparison: buflomedil | |||||
| Outcomes | Illustrative comparative risks* | Relative effect | No of participants | Quality of the evidence | |
|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | ||||
| Buflomedil | Iloprost | ||||
| Incidence of amputation in participants (3‐month follow‐up) | Study population | RR 0.05; 95% CI 0.00 to 0.78 | 31 (1 study) | ⊕⊝⊝⊝ Very lowa | |
| 9/15 | 0/16 | ||||
| Adverse events | ‐ | ‐ | ‐ | ‐ | Very lowb Not reported by intervention, but overall included flushing in 55% of participants, nausea in 25%, palpitations in 15%, and vomiting in 5%. |
| Acute pain | ‐ | ‐ | ‐ | ‐ | Not reported |
| Chronic pain | ‐ | ‐ | ‐ | ‐ | Not reported |
| Withdrawal from intervention due to adverse events | 0/15 | 0/16 | Not estimable | 31 (1 study) | ⊕⊝⊝⊝ Very lowc No withdrawals due to adverse events |
| Occupational effects | ‐ | ‐ | ‐ | ‐ | Not reported |
| Mortality | 0/15 | 0/16 | Not estimable | 31 (1 study) | ⊕⊝⊝⊝ Very lowc No deaths reported |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence: | |||||
| aQuality of the evidence is very low, and has been downgraded once for imprecision due to small participant number in one trial. We further downgraded the evidence (once for indirectness and once for risk of bias) because buflomedil, which was given to all participants as the primary treatment before randomisation, has been withdrawn from practice, yet may have influenced the effects seen in all active treatment groups. bQuality of the evidence is very low, for reasons stated in footnote a (imprecision, indirectnesss and risk of bias). For this outcome, we downgraded the evidence a second time for indirectness, as evidence for adverse events was presented in crude rates, but not reported by intervention group. cQuality of the evidence is very low, for reasons stated in footnote a (imprecision, indirectness and risk of bias). For this outcome, we downgraded the evidence a second time for imprecision, as this outcome is considered a rare event. | |||||
| Iloprost + rtPA compared with buflomedil for frostbite injuries | |||||
| Patient or population: people with severe frostbite injuries Settings: hospital Intervention: iloprost + rtPA Comparison: buflomedil | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | |
|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | ||||
| Buflomedil | Iloprost + rtPA | ||||
| Incidence of amputation in participants (3‐month follow‐up) | Study population | RR 0.31; 95% CI 0.10 to 0.94 | 31 (1 study) | ⊕⊝⊝⊝ | |
| 9/15 | 3/16 | ||||
| Adverse events | ‐ | ‐ | ‐ | ‐ | ⊕⊝⊝⊝ Very lowb Not reported by intervention, but overall included flushing in 55% of participants, nausea in 25%, palpitations in 15%, and vomiting in 5%. |
| Acute pain | ‐ | ‐ | ‐ | ‐ | Not reported |
| Chronic pain | ‐ | ‐ | ‐ | ‐ | Not reported |
| Withdrawal from intervention due to adverse events | 0/15 | 0/16 | Not estimable | 31 (1 study) | ⊕⊝⊝⊝ Very lowc No withdrawals due to adverse events |
| Occupational effects | ‐ | ‐ | ‐ | ‐ | Not reported |
| Mortality | 0/15 | 0/16 | Not estimable | 31 (1 study) | ⊕⊝⊝⊝ Very lowc No deaths reported |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence: | |||||
| aQuality of the evidence is very low, and has been downgraded once for imprecision due to small participant number in one trial. We further downgraded the evidence (once for indirectness and once for risk of bias) because buflomedil, which was given to all participants as the primary treatment before randomisation, has been withdrawn from practice, yet may have influenced the effects seen in all active treatment groups. bQuality of the evidence is very low, for reasons stated in footnote a (imprecision, indirectnesss and risk of bias). For this outcome, we downgraded the evidence a second time for indirectness, as evidence for adverse events was presented in crude rates, but not reported by intervention group. cQuality of the evidence is very low, for reasons stated in footnote a (imprecision, indirectness and risk of bias). For this outcome, we downgraded the evidence a second time for imprecision, as this outcome is considered a rare event. | |||||
| Iloprost +rtPA compared with iloprost for frostbite injuries | |||||
| Patient or population: people with severe frostbite injuries Settings: hospital Intervention: iloprost + rtPA Comparison: iloprost | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | |
|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | ||||
| Iloprost | Iloprost + rtPA | ||||
| Incidence of amputations in participants (3‐month follow‐up) | Study population | RR 0.14; 95% CI 0.01 to 2.56 | 32 (1 study) | ⊕⊝⊝⊝ | |
| 0/16 | 3/16 | ||||
| Adverse events | ‐ | ‐ | ‐ | ‐ | ⊕⊝⊝⊝ Very lowb Not reported by intervention, but overall included flushing in 55% of participants, nausea in 25%, palpitations in 15%, and vomiting in 5%. |
| Acute pain | ‐ | ‐ | ‐ | ‐ | Not reported |
| Chronic pain | ‐ | ‐ | ‐ | ‐ | Not reported |
| Withdrawal from intervention due to adverse events | 0/16 | 0/16 | Not estimable | 32 (1 study) | ⊕⊝⊝⊝ Very lowc No withdrawals due to adverse events |
| Occupational effects | ‐ | ‐ | ‐ | ‐ | Not reported |
| Mortality | 0/16 | 0/16 | Not estimable | 32 (1 study) | ⊕⊝⊝⊝ Very lowc No deaths reported |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence: | |||||
| aQuality of the evidence is very low, and has been downgraded once for imprecision due to small participant number in one trial. We further downgraded the evidence (once for indirectness and once for risk of bias) because buflomedil, which was given to all participants as the primary treatment before randomisation, has been withdrawn from practice, yet may have influenced the effects seen in all active treatment groups. bQuality of the evidence is very low, for reasons stated in footnote a (imprecision, indirectnesss and risk of bias). For this outcome, we downgraded the evidence a second time for indirectness, as evidence for adverse events was presented in crude rates, but not reported by intervention group. cQuality of the evidence is very low, for reasons stated in footnote a (imprecision, indirectness and risk of bias). For this outcome, we downgraded the evidence a second time for imprecision, as this outcome is considered a rare event. | |||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Incidence of amputations (patients) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.2 Incidence of amputations (body parts) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.3 Incidence of amputations (severity) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.3.1 Superficial frostbite injuries | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.3.2 Deep frostbite injuries | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.4 Incidents of amputations (time) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.4.1 12 h or less from frostbite to treatment | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.4.2 More than 12 h from frostbite to treatment | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.5 Withdrawal due to study medication Show forest plot | 1 | 31 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 1.6 Mortality Show forest plot | 1 | 31 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Incidence of amputations (patients) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.2 Incidence of amputations (body parts) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.3 Incidence of amputations (severity) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.3.1 Superficial frostbite injuries | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.3.2 Deep frostbite injuries | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.4 Incidence of amputations (time) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.4.1 12 h or less from frostbite to treatment | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.4.2 More than 12 h from frostbite to treatment | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.5 Withdrawal due to study medication Show forest plot | 1 | 31 | Risk Ratio (M‐H, Random, 95% CI) | Not estimable |
| 2.6 Mortality Show forest plot | 1 | 31 | Risk Ratio (M‐H, Random, 95% CI) | Not estimable |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 Incidence of amputations (patients) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3.2 Incidence of amputations (body parts) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3.3 Incidence of amputations (severity) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3.3.1 Superficial frostbite injury | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3.3.2 Deep frostbite injury | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3.4 Incidence of amputations (time) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3.4.1 12 h or less from frostbite to treatment | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3.4.2 More than 12 h from frostbite to treatment | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3.5 Withdrawal due to study medication Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3.6 Mortality Show forest plot | 1 | 32 | Risk Ratio (M‐H, Random, 95% CI) | Not estimable |
