This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To review the efficacy, benefits, harms, feasibility and tolerability of the different management options for frostbite injuries.
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). 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 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 further amplified by vasospasm (contraction of the arteries). Countermechanisms such as cold-induced vasodilation (widening of blood vessels) moderates perfusion by periodically reducing vasoconstriction in the hypoxic areas (McMahon 2012). Prolonged cold exposure prevents this mechanism from working, as upon reheating and reperfusion, further tissue damage occurs. Hypercoagulability of the blood resulting from platelet and erythrocyte (red blood cell) aggregation causes thrombosis (clots), thus increasing tissue hypoxia (Imray 2009). Prostaglandin F2-alpha and thromboxane A2 (TXA2) mediate these changes, and increased concentrations of both have been found in frostbite blisters (Robson 1981). Depending on the degree of tissue damage, rewarming is followed by either 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 frost-bitten 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 (MCP; base of the fingers) or metatarsophalangeal (MTP; middle of the foot) joints 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 mild form of frostbite presenting with symptoms similar to first degree 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 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 might 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
Current guidelines for management of frostbite injuries have recently been summarised by an expert panel, however, evidence is often low-quality due to lack of randomised controlled trials (RCTs) (McIntosh 2014). The proposed management of frostbite injuries can be divided into three phases; a prehospital pre-thaw field-care phase, a hospital care phase, and a post-thaw phase. Prehospital management includes reduction of further exposure to cold, removal of wet garments and replacement with dry ones, placement of the frost-bitten extremity in a companion's armpit (axilla) or groin for 10 minutes, administration of 75 mg aspirin (antiplatelet effect) and 800 mg ibuprofen (anti-prostaglandin 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 (toxoid) or antibiotics. Ibuprofen 400 mg administered orally every 12 hours provides systemic antiprostaglandin activity and limits the 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 such as hyperbaric oxygen therapy, sympathectomy (nerve block), thrombolytic (blood-thinning) therapy and vasodilating agents such as iloprost, reserpine, pentoxiphylline 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 might ensure some degree of reperfusion.
Aloe vera is a potent anti-prostaglandin 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 vasodilatation 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.
Hyperbaric oxygen therapy might have potential benefits in frostbite. Studies show that in a pressurised high-oxygen environment, erythrocytes might increase in flexibility and deformability, and oedema is reduced in ischaemic tissues. Furthermore, there might be a bacteriostatic and antioxidant effect (Handford 2014; Imray 2009; von Heimburg 2001).
Sympathetic nerve blocks to the upper extremity 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.
Preferably, auto-amputation (i.e. allowing the demarcation between vital and non-vital tissue to occur naturally, and permitting the necrotic tissue to fall off without performing surgical intervention), should be applied since tissue that seems 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 when uncontrolled infection occurs.
Why it is important to do this review
Many different treatment regimens have been proposed, but most are based on anecdotal evidence. Very few interventions have been properly investigated and evaluated for the management of frostbite injury. To our knowledge a systematic review 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.
To review the efficacy, benefits, harms, feasibility and tolerability of the different management options for frostbite injuries.
Criteria for considering studies for this review
Types of studies
We will include all RCTs investigating medical interventions for frostbite injuries in the review. We will consider cluster trials but exclude cross-over trials, as they are inappropriate for the condition we are examining.
According to Cochrane Injuries Group policy, we will only include prospectively registered studies, unless the study report was published before 2010 (Roberts 2015).
Types of participants
We will include all RCTs conducted on men and women of all ages. We will exclude animal studies. Trials covering management of chilblains, frostnip and non-freezing cold injuries (NFCI) will not be included.
Types of interventions
We will include trials that compare 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 relevance and relevance to patients. We have avoided inclusion of surrogate outcome measures. For the analysis, we will group measurement of the outcomes into studies with similar, clinically meaningful follow-up categories of:
short-term follow-up (one week to < one month);
medium-term follow-up (one to < 12 months); and
long-term follow-up (one to three years).
Incidence of amputations.
Rate of serious and non-serious adverse events. Serious adverse events are defined as any untoward medical occurrence that results in death, is life threatening, or persistent, or leads to significant disability; or any medical event that jeopardises the patient or requires intervention to prevent it (ICH-GCP 1997). We consider all other adverse events (that is, any medical occurrence not necessarily having a causal relationship with the treatment, but that does, however, 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%. Since we assume that all participants in frostbite studies are suffering from frostbite, we have 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.
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 will be used.
Chronic pain, measured as a dichotomous variable, stating whether the patient has chronic pain or not.
Ability to perform activities of daily living, assessed by any measure.
Quality of life, assessed by validated scales.
Withdrawal rate from medical therapy due to adverse events.
Occupational effects; e.g. mean duration of absence due to sickness and mean time to full return to work.
Search methods for identification of studies
In order to reduce publication and retrieval bias we will not restrict our search by language, date, or publication status.
The Cochrane Injuries Group's Information Specialist will search the following databases:
Cochrane Injuries Group's specialised register (present version);
The Cochrane Library (www.cochranelibrary.com) (latest issue);
Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R) (1946 to present);
Embase (OvidSP) (1947 to present);
ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) (1970 to present);
ISI Web of Science: Conference Proceedings Citation Index-Science (CPCI-S) (1970 to present);
World Health Organization (WHO) International Clinical Trials Registry Platform (apps.who.int/trialsearch).
Search strategies are listed in Appendix 1.
Searching other resources
We will review 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 will attempt to have personal contact with the principal authors to identify further trials, as data might be limited. We will also search the World Health Organization (WHO) International Clinical Trials Registry Platform (apps.who.int/trialsearch) and www.clinicaltrials.gov. We will contact pharmaceutical companies to obtain data from unpublished RCTs. We will also search military resources, e.g. www.sto.nato.int. We will report the results of the searches according to the PRISMA guidelines (Moher 2009).
Data collection and analysis
We will perform this review according to Cochrane recommendations (Higgins 2011a). The analyses will be performed using Review Manager 5.3 (RevMan 2014).
Selection of studies
We will obtain titles and abstracts of studies that could be relevant for the review from the search strategies described in Appendix 1. Trial eligibility will be assessed independently by two authors (AKL and LP). We will list excluded studies with their reasons for exclusion. Disagreements will be solved by discussion or in consultation with a third author (CD).
Data extraction and management
Two authors (AKL and LP) will carry out data extraction using standard data extraction forms (Higgins 2011a; Moher 2009). When more than one publication of a study exists, we will group reports together and the publication with the most complete data will be marked as the primary publication. Where relevant outcomes are published in earlier versions only, we will use these data, and add information about this to the 'Notes' section of the trial in the 'Characteristics of included studies' table. We will highlight any discrepancies between published versions. We will resolve disagreements, should any occur, through discussion with all authors.
We will extract the following information from each trial:
name and contact details of all authors;
details of where the study was conducted, details of study registration;
inclusion and exclusion criteria;
number of participants randomised;
characteristics of participants: age range (mean or median) and sex ratio;
severity of frostbite, affected body part, number of affected body parts;
therapeutic regimens used;
dose of therapeutic agent, duration, frequency and mode of administration (for hyperbaric oxygen: altitude, time initiated, duration; for sympathectomy: location, dose of local anaesthetic);
timing, type and dose of additional interventions, and
Furthermore, we will also report whether the therapeutic agent was used off-label (i.e. the agent is approved for a condition other than frostbite) or has been registered for frostbite treatment. We will contact trial authors for information that is not available in the published reports, in order to assess the trials correctly.
Assessment of risk of bias in included studies
We will follow 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 will assess all 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 bias. For each domain, and based on the trial's conduct and reporting, we will assess whether there is a 'low', 'uncertain' or 'high' risk of bias.
Measures of treatment effect
We will express dichotomous data as risk ratios (RR) with 95% confidence intervals (CI) and continuous data as mean difference (MD) and 95% CI. Where outcomes have been measured in scales we will 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 expect to find clinical trials with simple parallel group design. However, potential variations might be found, such as multiple observations or cross-over trials. For such events, we will follow the instructions given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a).
Where studies randomise at the participant level and measure outcomes at the frostbite level, e.g. healing, we will treat the participant as the unit of analysis when the number of frostbites assessed appears equal to the number of participants (e.g. one frostbite per person).
Where a cluster trial has been conducted and correctly analysed, effect estimates and their standard errors may be meta-analysed using the generic inverse variance method in RevMan. If possible we will approximate the correct analyses based on Cochrane Handbook guidance (Higgins 2011c), using information on:
the number of clusters (or groups) randomised to each intervention group; or the average (mean) size of each cluster;
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
an estimate of the intracluster (or intraclass) correlation coefficient (ICC).
If the study data cannot be analysed correctly, outcome data will be extracted and reported but not analysed further.
We will also note when randomisation has been undertaken at the frostbite level – that is a split-site or split-body design. We will assess whether the correct paired analysis has been undertaken in the study. If an incorrect analysis has been undertaken we will try and approximate a correct analysis, if the required data are available from the study report or the study authors. If this is not possible the relevant outcome data will be extracted and reported but not analysed further.
Dealing with missing data
We will use the following strategy when confronted with missing data. In the first instance we will contact the original investigators to request missing data. If this approach fails, and more than 20% of the data are missing, we will perform best/worst case scenarios and ultimately imputation. Finally, we will address the potential impact of all 'missing data' situations on the findings of the review in the Discussion section.
Assessment of heterogeneity
We will analyse heterogeneity between studies using a Chi2 test with a P value of 0.10 used for statistical significance. In addition, we will quantify the degree of heterogeneity observed in the results using the I2 statistic, with values over 75% indicating high levels of heterogeneity (Higgins 2002).
Assessment of reporting biases
We will consider reporting biases (e.g. publication, time lag, multiple publication) at all points of both data analysis and interpretation. If at least 10 RCTs are identified in a particular field, we will make attempts to analyse for publication bias using funnel plots (Egger 1997; Macaskill 2001), bearing in mind that publication bias does not necessarily cause asymmetry, and that asymmetry may have causes other than publication bias.
For dichotomous data we will use the Mantel-Haenszel test for reporting pooled risk ratios and 95% CIs. For continuous data we will use the inverse variance method for reporting the pooled mean differences. Where scales have been used for continuous outcomes we will make sure that all scales are similar; if not, we will pool data using standardised mean differences, and we will report the result by back-transforming into the most common scale. We will combine data that are reported as change from baseline values with the final measurement values in the meta-analyses.
We will report both random-effects and fixed-effect models as a means of heterogeneity exploration. In case of important differences in the results produced by the two models, we will provide both results. If the difference in the results is not important, then we will present the results of the random-effects model (Higgins 2002). If there are cluster trials, we will employ the generic inverse variable method for the meta-analysis. We are not expecting to record rare events for any of our outcomes, however, if we encounter rare events, we will consider Peto's odds ratio if all criteria are fulfilled.
Subgroup analysis and investigation of heterogeneity
We will perform subgroup analyses for:
different degrees of severity of frostbite, e.g. superficial frostbite (grades 1 and 2) versus deep frostbite (grades 3 and 4);
different time intervals for administration of medical intervention, e.g. intervention within 24 hours versus after 24 hours. If possible, we will perform analyses for both the first medical intervention and the in-hospital intervention.
RevMan 5 software is unable to handle studies with zero events in both intervention groups when meta-analyses are performed as RR or odds ratios (ORs). As it seems unjustified and unreasonable to exclude zero-event trials, and potentially create the risk of inflating the magnitude of the pooled treatment effects (Keus 2009), we will also perform a random-effects meta-analysis with an empirical continuity correction of 0.01 in trials with zero events (Sweeting 2004). To perform the zero-event trials analysis, we will use the trial sequential analysis software (Engstrøm 2011).
We will perform sensitivity analyses by temporarily removing from the pooled analysis trials with high risk of bias in the domains sequence generation, allocation concealment and incomplete outcome data.
'Summary of findings' tables
We will employ the GRADE approach for interpretation of findings, and the GRADE profiler will allow us to import data from Review Manager 5.3 to create 'Summary of findings' (SOF) tables (GRADEPRO). These tables will 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 will create SOF tables for all outcomes, and will indicate if no data are available for an outcome. A separate SoF table will be created for each intervention. We will report the same outcome measures for each intervention. We will provide SOF tables with the following outcomes:
incidence of amputations;
withdrawal from intervention due to adverse events;
occupational effects; and
We would like to thank the Cochrane Injuries Group for their support in preparing this protocol.
This project was supported by the UK National Institute for Health Research, through Cochrane Infrastructure funding to the Cochrane Injuries Group. The views and opinions expressed are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.
Contributions of authors
Drafting the protocol: AKL, LP
Critical revision of the protocol: AKL, LP, CD
Final acceptance of the protocol: all authors