Evidence Report/Technology Assessment 

Number 148 

The Uses of Heparin To Treat Burn Injury 

Prepared for: 

Agency for Healthcare Research and Quality 

U.S. Department of Health and Human Services 

540 Gaither Road 

Rockville, MD 20850 

www.ahrq.gov 

Contract No. 290-02-0020 

Prepared by: 

McMaster University Evidence-based Practice Center 

Hamilton, Ontario, Canada 

Task Order Leaders: 

Mark Oremus, Ph.D. 

Mark Hanson, M.D., M.Ed., F.R.C.P.C. 

Authors: 

Mark Oremus, Ph.D. 

Mark Hanson, M.D., M.Ed., F.R.C.P.C. 

Richard Whitlock, M.D., M.Sc. 

Ed Young, Ph.D. 

Alok Gupta, M.S. 

Arianna Dal Cin, M.D., B.Sc., F.R.C.S.C. 

Carolyn Archer, M.Sc. 

Parminder Raina, Ph.D. 

AHRQ Publication No. 07-E004 

December 2006 

 
This report is based on research conducted by the McMaster University Evidence-based Practice 

Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), 

Rockville, MD (Contract No. 290-02-0020). The findings and conclusions in this document are 

those of the author(s), who are responsible for its content, and do not necessarily represent the 

views of AHRQ. No statement in this report should be construed as an official position of AHRQ 

or of the U.S. Department of Health and Human Services. 

The information in this report is intended to help clinicians, employers, policymakers, and others 

make informed decisions about the provision of health care services. This report is intended as a 

reference and not as a substitute for clinical judgment. 

This report may be used, in whole or in part, as the basis for the development of clinical practice 

guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage 

policies. AHRQ or U.S. Department of Health and Human Services endorsement of such 

derivative products may not be stated or implied. 
ii

This document is in the public domain and may be used and reprinted without permission except 

those copyrighted materials noted for which further reproduction is prohibited without the 

specific permission of copyright holders. 

Suggested Citation: 

Oremus M, Hanson M, Whitlock R, Young E, Gupta A, Dal Cin A, Archer C, Raina P. The Uses 

of Heparin To Treat Burn Injury. Evidence Report/Technology Assessment No. 148. (Prepared 

by the McMaster University Evidence-based Practice Center, under Contract No. 290-02-0020). 

AHRQ Publication No. 07-E004. Rockville, MD: Agency for Healthcare Research and Quality. 

December 2006. 

Dr. Young is affiliated with the Henderson Research Center, which has interests in Heparin. 

Drs. Oremus, Hanson, Whitlock, Gupta, Dal Cin, and Raina have no financial interest in this 

field, nor does Ms. Archer. 
iii

Preface 

 The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-based 

Practice Centers (EPCs), sponsors the development of evidence reports and technology 

assessments to assist public- and private-sector organizations in their efforts to improve the 

quality of health care in the United States. The reports and assessments provide organizations 

with comprehensive, science-based information on common, costly medical conditions and new 

health care technologies. The EPCs systematically review the relevant scientific literature on 

topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to 

developing their reports and assessments. 

 To bring the broadest range of experts into the development of evidence reports and health 

technology assessments, AHRQ encourages the EPCs to form partnerships and enter into 

collaborations with other medical and research organizations. The EPCs work with these partner 

organizations to ensure that the evidence reports and technology assessments they produce will 

become building blocks for health care quality improvement projects throughout the Nation. The 

reports undergo peer review prior to their release. 

 AHRQ expects that the EPC evidence reports and technology assessments will inform 

individual health plans, providers, and purchasers as well as the health care system as a whole by 

providing important information to help improve health care quality. 

We welcome comments on this evidence report. They may be sent by mail to the Task 

Order Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road, 

Rockville, MD 20850, or by e-mail to epc@ahrq.gov. 

Carolyn M. Clancy, M.D. 

Director 

Agency for Healthcare Research and Quality 

Jean Slutsky, P.A., M.S.P.H. 

Director, Center for Outcomes and Evidence 

Agency for Healthcare Research and Quality 

Beth A. Collins Sharp, Ph.D., R.N. 

Director, EPC Program 

Agency for Healthcare Research and Quality 

Gurvaneet Randhawa, M.D., M.P.H. 

EPC Program Task Order Officer 

Agency for Healthcare Research and Quality 
iv

Acknowledgments 

The researchers at the Evidence-based Practice Center would like to acknowledge the 

following people for their contributions. 

Our thanks go out to the members of the technical expert panel for their invaluable advice 

and consultations in defining the scope of this review: Dr. B. Atiyeh, Dr. David Herndon, Dr. 

Leo Klein, Dr. Ján Koller, Dr. Gurvaneet Randhawa, Dr. Michael Saliba, Dr. Glenn Warden, and 

Dr. Steven Wolf. 

We would also like to thank Elena Prigoda for running the searches and Josh Fagbemi for 

managing the references in Refman and SRS. 

We are grateful to Jessica Cheeseman, Dorothy Kendry, and Sarah Smith for their assistance 

in article retrieval. 

Thank you to Jesmin Antony, Fulvia Baldassarre, Agata Dzierzgowska, Simo Goshev, Dr. 

Janusz Kaczorowski, Ritz Kakuma, Inna Lantsouzovski, Dr. Carolina Ruiz, Dr. Lina Santaguida, 

Arnd Sett, Elizabeth Simmons, and Dr. Lufang Yang for the many hours of screening, data 

abstraction, and translation of the non-English articles. 

Finally, we would like to say a big thank you to Mary Gauld for managing all aspects of the 

project as well as Maureen Rice, Roxanne Cheeseman, and Cecile Royer for their invaluable 

input in the editing and formatting of this report. 
v

Structured Abstract 

Objectives: To assess the evidence for using heparin in the treatment of burn injury or the 

complications of burn injury in adults and children. 

Data Sources: The following databases were searched: MEDLINE® (1966-current), EMBASE 

(1980-current), Cumulative Index to Nursing & Allied Health (CINAHL) (1982-current), The 

Cochrane Central Database of Controlled Trials (1995-current), Web of Science (1976-current), 

and BIOSIS (1976-current). Additional data sources included the U.S. and European Patent 

Offices, technical experts, the partner organization, and reference lists. 

Review Methods: Studies identified from the data sources went through two levels of title and 

abstract screening. Passing studies advanced to full text screening. Studies that met the full text 

screening criteria were abstracted. Criteria for abstraction included publication in any language, 

human patients of any age, and burns of any type, grade, or total body surface area. All 

formulations of heparin, and all application methods (e.g., topical, subcutaneous), were eligible 

for inclusion in the report. Abstracted studies required a comparison group. Outcomes of 

interest included mortality, pain, length of stay in hospital, thrombosis and emboli, psychiatric 

adjustment, and adverse effects (e.g., bleeding). 

Results: Nineteen articles from 18 unique studies were abstracted and included in this report. In 

these articles, there were multiple uses of heparin to treat burns (e.g., wound healing, inhalation 

injury, sepsis, pain). However, the overall quality of the articles was weak. Examples of 

weakness included unclear or inappropriate treatment allocation, no blinding, no control of 

confounding, poorly defined burn characteristics (e.g., thickness), unclear duration of treatment, 

incomplete description of heparin treatment, and use of inadequately described or invalid 

outcome measures. Overall, the evidence from these weak articles was insufficient to determine 

whether the effectiveness of heparin to treat burn injury was different from the effectiveness of 

other treatments, or whether treatment effectiveness varied according to (a) the method of 

applying heparin to (b) burn etiology. 

Four studies mentioned contraindications to using heparin to treat burns. These 

contraindications were bleeding diathesis, bleeding history, active bleeding or associated trauma 

with potential bleeding, active intestinal ulcer, thrombocytopenia, liver disease, renal disorders, 

or allergy to heparin. 

Conclusion: There is no strong evidence in the 19 abstracted articles to suggest that heparin 

should be used in the treatment of burn injury on account of its non-anticoagulant properties. 

However, since the lack of evidence is largely a function of the poor quality of the articles, 

further research is needed to investigate the potential uses of heparin in the treatment of burn 

injury. 
vii

Contents 

Executive Summary........................................................................................................................ 1 

Evidence Report............................................................................................................................ 7 

Chapter 1. Introduction ................................................................................................................... 9 

Heparin........................................................................................................................................ 9 

 Low Molecular Weight Heparins ........................................................................................... 9 

 Non-Anticoagulant Effects of Heparin................................................................................. 10 

 Anti-Inflammatory Effects.................................................................................................... 10 

 Antiangiogenic and Antimetastatic Effects .......................................................................... 10 

 Wound Healing Effects......................................................................................................... 10 

 Clinical Uses of Heparin........................................................................................................... 10 

 Thrombosis Prevention......................................................................................................... 11 

 Thrombosis Treatment.......................................................................................................... 11 

 Burn Injury................................................................................................................................ 13 

 Definition and Description of Burn Injury ........................................................................... 13 

 Burn Care.............................................................................................................................. 14 

 Psychosocial Aspects of Burn Injury.................................................................................... 14 

 Heparin and Burns .................................................................................................................... 15 

Chapter 2. Methods....................................................................................................................... 17 

 Analytic Framework ................................................................................................................. 17 

 Topic Assessment and Refinement........................................................................................... 17 

 General Methods....................................................................................................................... 19 

 Key Questions....................................................................................................................... 19 

 Literature Search Strategy .................................................................................................... 19 

 Data Collection and Reliability of Study Selection .................................................................. 20 

 Quality Assessment of Abstracted Studies ........................................................................... 21 

 Summary of Findings: Descriptive and Analytic Approaches ................................................. 21 

 Peer Review Process................................................................................................................. 21 

Chapter 3. Results ......................................................................................................................... 23 

Literature Review and Screening.............................................................................................. 23

 General Characteristics of the Abstracted Articles............................................................... 23 

 Key Questions........................................................................................................................... 25 

 Question 1. What is the Evidence for the Benefits and Harms of Heparin Use in Thermal 

Injury Care? .......................................................................................................................... 25 

 Question 2. What are the Contraindications of Heparin Use in Burns? ............................... 28 

 Quality Assessment of Abstracted Articles .............................................................................. 30 

 Overview............................................................................................................................... 30 

 Selection Bias........................................................................................................................ 30 

 Study Design......................................................................................................................... 31 

 Control of Confounding........................................................................................................ 32 
viii

 Statistical Methods................................................................................................................ 32 

 Conclusion ............................................................................................................................ 32 

Chapter 4. Discussion and Future Research ................................................................................. 43 

 Overall Summary of Evidence from the Abstracted Studies.................................................... 43 

 Contextual Issues Regarding the Evidence from Abstracted Studies....................................... 43 

 Conclusion ................................................................................................................................ 46 

 Future Research into Heparin as a Treatment for Burns........................................................... 46 

 Design of Studies of Heparin in the Treatment of Burns.......................................................... 46 

 Issues to Consider ................................................................................................................. 46 

 Focus of Future Studies of Heparin in the Treatment of Burn Injury................................... 47 

References...... ............................................................................................................................... 51 

Acronyms and Abbreviations ....................................................................................................... 57 

Figures 

Figure 1: Analytical Framework................................................................................................... 18 

Figure 2. Flow diagram showing the final number of articles meeting the eligibility criteria ..... 24 

Tables 

Table 1. Accepted indications for heparin prophylaxis ................................................................ 11 

Table 2. Accepted indications for heparin treatment – venous..................................................... 12 

Table 3. Accepted indications for heparin treatment – arterial and other..................................... 12 

Table 4. Grades of evidence.......................................................................................................... 12 

Table 5. General characteristics of the abstracted studies ............................................................ 33 

Table 6. Heparin treatment regimens and results – abstracted studies ......................................... 36 

Table 7. Quality assessment of abstracted articles – Group A ..................................................... 40 

Table 8. Quality assessment of abstracted articles – Group B...................................................... 41 

Appendixes 

Appendix A: Technical Expert Panel 

Appendix B: Search String 

Appendix C: List of Excluded Studies 

Appendix D: Forms 

Appendix E: Quality Assessment – Effective Public Health Practice Project Quality Assessment 

 Tool 2003 

Appendixes are provided electronically at http://www.ahrq.gov/clinic/tp/heparntp.htm
ix
1

Executive Summary 

Introduction

The non-anticoagulant effects of heparin and related molecules form the rationale for using 

heparin in the treatment of burns. Recent basic science literature suggests heparin may have a 

biological role as an anti-inflammatory, anti-angiogenic, and anti-metastatic agent. More 

importantly, at the molecular level, heparin may be an enhancer of wound healing, which has 

enormous implications for the treatment of acute and chronic burn wounds. In the immediate 

post-burn setting, the benefits of heparin’s postulated anti-inflammatory and enhanced wound 

healing properties could include reduced pain (hence better compliance with dressing changes or 

physiotherapy), infection, length of hospital stay, and mortality. The long-term benefits of this 

expanded range of uses of heparin in the treatment of burn injury could include improved 

function and range of motion of extremities, reduced scarring, and possibly decreased psychiatric 

or psychosocial sequalae. 

An expanded range of treatment options for burn injury is desirable given that 1.25 million 

people on average are treated annually for burns in the United States. Four percent of these 

people will require hospitalization and specialized burn care. Approximately 25 percent of 

people with severe burn injuries (greater than 75 percent of total body surface area) will die even 

after receiving advanced treatment at specialized burn centers. The morbidity from burn injury 

is also great. Short term morbidity includes the pain of the injury and subsequent surgical 

therapy. Over the medium to long term, the psychosocial impact of disfigurement, and the 

potential for post-traumatic stress disorder, can have lasting ill effects on patients and patients’ 

loved ones. 

This report was commissioned to address two key questions about the uses of heparin in the 

treatment of burn injury: 

1. What is the evidence for the benefits and harms of heparin use in thermal injury care? 

a. Does the method of application make a difference? 

b. Do the outcomes vary by the type or degree of burn? 

c. How do the outcomes of burn treatment with heparin compare to current 

treatment without heparin? 

2. What are the contraindications of heparin use in burns? 

Addressing these questions will serve to identify the strength of the evidence for using 

heparin to treat burns and gaps in existing research. As well, answering these questions will 

facilitate the establishment of future research priorities. 

Methods

A comprehensive search of the literature was conducted to capture all relevant, published 

studies on the topic of heparin and burns. The following electronic databases were searched: 

1. MEDLINE® (1966-current); 

2. EMBASE (1980-current); 
2

3. CINAHL (Cumulative Index to Nursing & Allied Health) (1982-current); 

4. The Cochrane Central Database of Controlled Trials (1995-current); 

5. Web of Science (1976-current); and 

6. BIOSIS (1976-current). 

In addition, literature in the U.S. and European Patent Offices was searched for relevant 

studies, members of the TEP and the partner organization were asked to supplement the database 

search with additional references of published and unpublished studies, and the reference lists of 

articles that passed full text screening were also searched for relevant studies. 

Inclusion/exclusion criteria. A list of inclusion/exclusion criteria was developed to screen 

studies for this evidence report. The criteria were: 

Language. There was no language restriction. Studies published in any language could be 

included in the report. 

Study Design. Studies required a comparison group for inclusion. Case series, case reports, 

editorials, letters, comments, opinions, abstracts, animal experiments, and conference 

proceedings were excluded from the report.

Population. Human patients of any age, with burns of all types, grades, and total body 

surface area (TBSA) involvement, could be included in the report. 

Outcomes. Studies with the following outcomes could be included:

• Need for surgical procedure (e.g., grafting, debridement, fasciotomy, quality of graft take 

[percentage], re-grafting, reconstructive surgery); 

• Pain; 

• Mortality (prior to, or after, discharge from hospital); 

• Length of stay in hospital; 

• Scarring (size, hypertrophic scarring); 

• Decrease in range of motion, function, or activities of daily living; 

• Respiratory measures (e.g., length of intubation); 

• Thrombosis and emboli; 

• Complications (e.g., bleeding, infection); 

• Rehabilitation; 

• Quality of Life; and 

• Psychiatric adjustment (e.g., post-traumatic stress disorder [PTSD], anxiety, depression). 

Data Collection and Reliability of Study Selection 

A team of raters was trained to apply the inclusion/exclusion criteria. Standardized forms 

were developed for this purpose, as well as for data abstraction. The forms were created and 

stored online using Systematic Review Software (SRS; TrialStat Corp., Ottawa, Ontario). 

For title and abstract screening, two independent raters evaluated the citations that were 

obtained from the literature search. Articles that met the inclusion/exclusion criteria, or for 

which there was insufficient information to determine if they met the criteria, were retrieved for 

further assessment. Once retrieved, the entire text of the article was screened to determine if the 

inclusion/exclusion criteria were satisfied. At this stage, an article could be excluded from 

further review only if both raters agreed that it did not satisfy the inclusion/exclusion criteria. In 
3

cases of disagreement, the raters met to arrive at a consensus. Articles that successfully passed 

the full text screening phase went on to full data abstraction. 

Quality assessment of abstracted studies. The quality of the studies that passed full text 

screening was assessed using the Effective Public Health Practice Project, Quality Assessment 

Tool for Quantitative Studies. Two raters, either a local expert or a MU-EPC staff member, 

conducted the quality assessment for each article. Differences were resolved by consensus.

Results 

The search strategy yielded 471 citations. Of these, 132 proceeded to full text screening and 

19 (representing 18 unique studies) advanced to the data abstraction phase. The countries of 

origin for the 19 abstracted articles were: U.S. (n = 8), Soviet Union (n = 2), India (n = 2), 

Bulgaria, Italy, United Kingdom, China, Japan, El Salvador, and Mexico (n = 1 each for the last 

seven countries). Sample sizes ranged from 6 to 327, with a mean of 62. The samples were 

composed of patients who presented to hospital burn units or emergency rooms with burn 

injuries. Nine articles contained reports of the breakdown of patients by sex; males formed the 

majority in eight articles. Mean ages were reported in seven articles. In the five articles with 

adult populations, the lowest mean age was 30 years and the highest mean age was 57 years. In 

the two articles with pediatric populations, the lowest mean age was 3.2 years and the highest 

mean age was 8 years. The etiology of burn, reported in eight articles, included flame, inhalation 

injury, and ‘thermal’ injury. One article contained patients with any burn etiology. Eight articles 

also contained information about the degree of burn. 

Key Question 1. What is the evidence for the benefits and harms of 

heparin use in thermal injury care? 

Does the method of application make a difference? There were insufficient data in the 

abstracted articles to answer this question. None of the articles contained comparisons of 

systemic heparin (intravenous or subcutaneous) or topical heparin in the treatment of burn injury. 

Do the outcomes vary by the type or degree of burn? There were insufficient data to 

answer this question. None of the abstracted articles contained analyses of heparin stratified by 

the type or degree of burn. In fact, the abstracted articles were characterized by vague reports of 

the etiology, type, or degree of burn in the samples. 

How do the outcomes of burn treatment with heparin compare to current treatment 

without heparin? Multiple roles for heparin in the treatment of burns were examined in the 

abstracted articles. These roles included wound healing and pain control, as well as the 

treatment of sepsis, inhalation injury, and venous thrombosis. However, there was insufficient 

data available to answer the key question. This was because only 10 of the abstracted studies 

contained clinical outcomes (the remaining nine were primarily laboratory studies that did not 

contain clinical outcomes), publication dates spanned three decades, and the research was 

conducted in a multitude of different countries with varying standards of burn care. Thus, the 

available evidence was severely limited with respect to its relevance and applicability to current 

treatment standards in many locales. Another issue concerned the many methodological 
4

deficiencies of the abstracted articles. These deficiencies hampered the ability to judge the 

reported effectiveness of heparin in burn treatment. Deficiencies included: 

1. Poorly defined burn etiology and degree; 

2. Unclear method of treatment allocation; 

3. Unclear duration of treatment, especially the point at which heparin was first 

administered; 

4. Outcome variables that were vague and unlikely to be reproducible; and 

5. Use of descriptive statistics only (no comparative statistics). 

Key Question 2. What are the contraindications of heparin use in 

burns? 

Four of the abstracted articles listed contraindications to the use of heparin in burn patients. 

These contraindications were bleeding diathesis, bleeding history, active bleeding or associated 

trauma with potential bleeding, active intestinal ulcer, thrombocytopenia, liver disease, renal 

disorders, or allergy to heparin. The authors of two of these articles wrote that these 

contraindications served as study exclusion criteria, while the authors of the other two articles 

wrote that none of the patients in their studies had any of these contraindications. 

Quality Assessment of Abstracted Articles 

The overall quality of the 19 abstracted articles was poor. Selection bias could not be ruled 

out for many of the articles because the authors did not report on patient recruitment or 

participation rate. Similarly, non-reporting was a problem in the area of study design: only one 

article contained a specific description of how treatments (exposures) were allocated amongst 

study participants. None of the authors discussed blinding. For confounding, half of the articles 

had reports of potential differences between treatment groups on important confounders, and no 

attempts were made in any of the articles to control for possible confounding. Statistical 

methods (when reported) were simple between-group comparisons. Many authors did not 

mention the type of statistical test used in the comparisons, nor did they provide p-values. In 

some instances, no statistical comparisons were performed. 

Limitations 

There was insufficient evidence from the abstracted articles to answer the first key question. 

Although the authors of some of the articles claimed that heparin had benefits for outcomes such 

as pain, cosmesis, and wound healing, this evidence was of limited clinical utility because of the 

poor quality of the research. Some articles were beset by vague descriptions of study 

participants, burn etiology, or treatment regimen. Articles without these deficiencies had 

problems regarding the use of invalid comparison groups or invalid outcomes. The major issue 

with comparison groups was the use of controls that were treated at earlier points in time, or at 

different hospitals, than people who received heparin. In both cases, different treatment 

protocols could have confounded the observed associations between treatment and outcome. 

Regarding outcomes, an important one in burn injury – pain – was never examined using a 

validated measurement instrument such as the McGill Pain Scale. Instead, surrogate measures 
5

(e.g., amount of pain medication used during hospitalization) were employed to estimate the 

degree of pain relief in heparin versus control patients. For cosmesis, pictures were used to 

demonstrate the benefit associated with heparin use, but there were no apparent standards 

employed to govern the timing, photographic angles, or interpretation of the pictures. 

Confounding was not controlled in any of the abstracted articles. Furthermore, confounding 

could not be ruled out for the randomized controlled trials because none of the authors 

mentioned how subjects were randomized to treatment. 

The evidence from the abstracted articles was not applicable to all clinical contexts. This 

was because the treatment protocols employed in the articles did not demonstrate a common 

standard of burn care. Reasons for the absence of commonality were temporal, i.e., the research 

was done before current standards were adopted, or contextual, i.e., the research was countryspecific and standards of burn care differ between countries. 

Conclusions 

There is no strong evidence in the 19 abstracted articles to indicate that the non-anticoagulant 

properties of heparin improve clinical outcomes in the treatment of burn injury. The lack of 

evidence is largely a function of the poor quality of the articles. However, some data in these 

poor quality articles suggest the possibility of clinical benefit, so the authors of this evidence 

report recommend future research into the use of heparin to treat burn injury. 

Future Research 

Two sets of studies are recommended for future research. The first set would investigate 

heparin’s wound healing properties. One randomized trial would involve the application of 

topical heparin to donor areas (commonly the upper leg) after skin graft in adult and adolescent 

populations. Comparisons would be done with controls who receive standard treatment for the 

donor areas. Outcomes would include the healing time of the donor area, pain, itching, and 

scarring. In addition, research of this type may have an impact on factors that contribute to the 

psychiatric morbidity associated with burn injuries and their care, especially morbidity in 

relation to skin grafting and the pain and discomfort of donor sites. Psychiatric outcomes that 

would be evaluated include Acute Stress Disorder (ASD) and PTSD. If heparin is shown to 

promote wound healing of the donor area, then the next study would involve people (adults, 

adolescents, and children) with bilateral extremity burns to the arms, hands, or legs. People 

would serve as their own controls: topical heparin plus standard treatment would be applied to 

one extremity and standard treatment alone would be applied to the other extremity. Outcomes 

would be the same as in the first study, plus there would be an evaluation of quality of life. 

The second study would consist of a randomized controlled trial to investigate the use of 

aerosolized heparin in the treatment of burn-related inhalation injury. The study would be 

conducted in both the adult and pediatric populations. The objectives regarding treatment of 

inhalation injury would be to decrease the reintubation rate, and length of stay in the intensive 

care unit (ICU). Other objectives would be to reduce the incidence of acute respiratory distress 

or atelectasis. As with the first set of studies, there should be an investigation of psychiatric 

outcomes. In addition to ASD, PTSD, and quality of life, the ICU context of the inhalation 

injury trial requires the inclusion of two additional psychiatric outcomes, i.e., ICU psychosis and 

delirium. 
6

All these studies would have to be organized at multiple sites to ensure that adequate 

numbers of patients are recruited to achieve high statistical power (≥ 80%). A general list of 

potential outcomes includes: 

• Mortality; 

• Incidence of medical procedures following initial treatment with heparin or standard 

therapy (e.g., reintubation, excision, grafting); 

• Functional performance (e.g., thumb opposition score, fingertip-to-palm distance, 

prehensile score); 

• Pain (measured using the McGill Pain Scale); 

• Scarring (measured using the Vancouver Scar Scale); 

• Itching (measured via the amount of anti-pruritic medications used [e.g., Benadryl®]) 

• Quality of Life (measured using the Health Outcomes Burn Questionnaire for children 

and the Burn-Specific Health Scale for adults); and 

• Post-traumatic Stress Disorder (measured using the Child Stress Disorders Checklist for 

children and a selected range of measurement methodologies for adults). 
Evidence Report

9

Chapter 1. Introduction 

Heparin 

Heparin belongs to a family of polyanionic polysaccharides called glycosaminoglycans 

(GAGs). The structure of GAGs is described in terms of their prevalent repeating disaccharide 

sequences, which consist of alternating uronic acid and amino sugar residues. Heparin is a highly 

sulfated polysaccharide composed of hexuronic acid and D-glucosamine residues joined by 

glycosidic linkages.1

Heparin is a polydisperse compound with a molecular weight ranging from 3,000 to 30,000 

Da (Daltons) (mean weight, approximately 15,000 Da). Commercial heparin, or unfractionated 

heparin (UFH), is isolated from mammalian tissues rich in mast cells. Heparin acts as an 

anticoagulant by activating antithrombin and accelerating the rate at which antithrombin 

inactivates clotting enzymes, particularly thrombin (factor IIa) and factor Xa. UFH also enhances 

the inhibition of factor IXa, factor XIa, and factor VIIa bound to tissue factor by antithrombin. 

Heparin binds to antithrombin through a high affinity pentasaccharide, which is present on about 

one-third of heparin molecules. Binding of heparin to antithrombin via its unique 

pentasaccharide sequence causes a conformational change in the reactive center loop of 

antithrombin that accelerates its interaction with factor Xa, but not with thrombin. For inhibition 

of thrombin, heparin must bind to both the coagulation enzyme and antithrombin. This bridging 

effect requires a heparin chain that contains at least 18 saccharides. By inactivating thrombin, 

heparin not only prevents fibrin formation, but also inhibits thrombin-induced activation of 

platelets and factors V and VIII.2

Besides binding to antithrombin, heparin also binds to a wide range of other proteins via 

electrostatic interactions. These proteins include heparin cofactor II, receptors, and growth 

factors. The relative strength of binding depends on the sulfation pattern, charge density, and 

molecular weight.2

Low Molecular Weight Heparins 

During the last decade, low molecular weight heparins (LMWHs) have gradually replaced 

UFH for some clinical indications. LMWH is prepared from UFH by controlled enzymatic or 

chemical depolymerization. Like heparin, LMWHs are polydisperse and comprise heparin chains 

from 1,000 to 10,000 Da. The mean molecular weight of LMWHs is between 3,600 and 6,500 

Da. About 15 to 20 percent of LMWH chains contain the antithrombin-binding pentasaccharide 

sequence. At least half of the pentsaccharide-containing chains of LMWH are too short to bridge 

thrombin to antithrombin. For this reason, LMWHs have reduced ability to inactivate thrombin. 

In contrast, the smaller molecular weight chains retain their ability to inactivate factor Xa 

because bridging between antithrombin and factor Xa is less critical. Compared to UFH, 

LMWHs exhibit a better subcutaneous bioavailability, a more predictable anticoagulant 

response, and a longer half-life.3

 More recently, synthetic analogs of the antithrombin-binding 

pentasaccharide sequence have been developed.4
10

Non-Anticoagulant Effects of Heparin 

Heparin possesses both a flexible structure and a high anionic charge that permits 

electrostatic interactions with a variety of different molecules. While heparin has been used 

largely for its anticoagulant effects, there is evidence that heparin and related molecules also 

possess anti-inflammatory and antiangiogenic properties, as well as a capacity for wound 

healing. These effects are discussed separately below. 

Anti-Inflammatory Effects 

Although the mechanisms responsible for the anticoagulant effects of heparin are well 

understood, the mechanisms underlying heparin’s anti-inflammatory activity are not. The 

evidence that heparin possess anti-inflammatory properties comes mainly from cell culture and 

animal studies. The anti-inflammatory and immunomodulating effects are far-reaching and 

include influencing monocyte, T-cell and neutrophil activity, nitric oxide production, chemokine 

and cytokine activity, complement activity, platelet activation and aggregation, and smooth 

muscle cell proliferation.5

Antiangiogenic and Antimetastatic Effects 

There is increasing interest in a potential role for heparin and related molecules in the 

management of cancer patients.6

 LMWHs have generated particular interest because they have 

been validated in both the treatment and prevention of thromboembolic disease in patients with 

malignancy. More interestingly, the benefits of LMWH therapy appear to be independent of any 

anticoagulant properties, which suggests that direct effects on tumor cell biology can help to 

explain the mechanism. Possible mechanisms include the inhibition of selectin-mediated cell-cell 

interactions, heparanase inhibition, binding of proangiogenic growth factors (e.g., basic 

fibroblast growth factor [bFGF] and vascular endothelial growth factor [VEGF]), and stimulation 

of tissue factor pathway inhibitor (TFPI) release.7

Wound Healing Effects 

A persistent inflammation with the accumulation of large numbers of neutrophils is 

characteristic of chronic wounds. Secretory products released from these cells, such as elastase, 

cathepsin G, and proteinases, are detrimental to wound healing because they degrade the 

extracellular matrix and growth factors and further recruit neutrophils to the wound area. Heparin 

and related molecules are thought to inhibit the action of these secretory products via 

electrostatic interactions.8,9

Clinical Uses of Heparin 

Since its discovery in 1917, heparin preparations have been used as an effective 

anticoagulant for thromboembolic prophylaxis and treatment.10-13 With over half a century of 

use, other roles for heparin have been elicited, including angiogenesis regulation, lipoprotein 

lipase modulation, maintenance of endothelial competence, and inhibition of vascular smooth 
11

muscle proliferation after injury.14 This section will focus on clinically proven and accepted 

applications of heparin. 

Heparin is the most widely used parenteral antithrombotic in clinical medicine due to its ease 

of administration and titration, availability, cost, known side-effect profile, and demonstrated 

clinical efficacy. Other parenteral antithrombotic agents available include heparinoids such as 

fondaparinux or direct thrombin inhibitors such as hirudin and bivalirudin. These drugs are more 

expensive, not as easily titrated and reversed, and have been studied in fewer clinical 

applications relative to heparin. Numerous guidelines define the role of heparin in thrombosis 

prevention and treatment; the American College of Chest Physicians (ACCP) guidelines are 

perhaps the most frequently cited. See Baglin et al. for a review of these guidelines.15 Clinical 

indications for heparin have been divided into (1) thrombosis prevention and (2) thrombosis 

treatment (See Tables 1 to 3 below). 

Thrombosis Prevention

Subcutaneous heparin has been demonstrated to reduce the incidence of venous 

thromboembolism in several clinical scenarios. Table 1 summarizes both the clinical indications 

and level of evidence for using heparin in this treatment area. Grades of evidence from Tables 1 

to 3 are explained in Table 4. 

Table 1. Accepted indications for heparin prophylaxis 

Indication for Heparin Prophylaxis Grade of 

Evidence 

Literature Reference 

Major non-orthopedic surgery Grade A Clagett & Reisch 198816

Major elective orthopedic surgery Grade A Nurmohamed et al. 1992,17 Koch et 

al. 199718

Hip fracture Grade A

 

Handoll et al. 200219 

Medical patient at high risk of VTE Grade A

 

Mismetti et al. 2000,20 Leizorivcz et al. 

200421

Major trauma with no contraindications Grade B

 

Upchurch et al. 1995,22 Geerts et al. 

199623

Lower limb plaster immobilization Grade B Lassen et al. 200224

Thrombosis Treatment 

Heparin, in the absence of heparin induced thrombocytopenia (drop in platelet number), is 

the initial anticoagulant of choice for treating thrombotic processes (blood clots) involving veins 

and arteries. Tables 2 and 3 contain generic summaries of clinical scenarios where therapeutic 

heparin is indicated for treating thrombotic processes. 
12

Table 2. Accepted indications for heparin treatment – venous 

Indication for Treatment: 

Venous 

Grade of 

Evidence 

Literature Reference 

Deep vein thrombosis (DVT) and 

pulmonary embolism (PE) 

Grade A Barritt & Jordan 1960,25 Douketis et 

al. 1998,26 Gould et al. 199927

Cerebral venous sinus thrombosis Grade B Bousser et al. 1985,28 Einhaupl et 

al. 199129

Intraabdominal venous thrombosis Grade C Abdu et al. 198730

Superficial vein thrombosis (SVT) Grade C Wichers et al. 200531

Table 3. Accepted indications for heparin treatment – arterial and other 

Indication for Treatment: 

Arterial and Other 

Grade of 

Evidence 

Literature Reference 

Acute myocardial infarction postlysis with any of: 

Anterior Q wave , LV dysfunction, CHF, 

history of PE or systemic embolism, 

mural thrombus, atrial fibrillation 

 Grade A Collins et al. 1996,32 Hirsh & Raschke 

200433 

Acute coronary syndrome Grade A Oler et al. 1996,34 Magee et al. 200335

Peripheral vascular surgery Grade C Thompson et al. 199636

Central venous and arterial catheters Grade C Merrer et al. 200137

Hemodialysis Grade A Lim et al. 200438

Cardiopulmonary bypass surgery (CPB) Grade A Beijering et al. 199739

As shown above, in the realm of thromboembolic pathology, heparin plays a major role in 

clinical medicine. 

Table 4. Grades of evidence 

Grade of 

Evidence 

Explanation 

A Consistent evidence from well performed randomized, controlled trials or 

overwhelming evidence of some other form. Further research is unlikely to 

change our confidence in the estimate of benefit and risk 

B Evidence from randomized, controlled trials with important limitations 

(inconsistent results, methodological flaws, indirect or imprecise), or very strong 

evidence of some other research design. Further research (if performed) is likely 

to have an impact on our confidence in the estimate of benefit and risk and may 

change the estimate 

C Evidence from observational studies, unsystematic clinical experience, or from 

randomized, controlled trials with serious flaws. Any estimate of effect is 

uncertain 

Source: Guyatt G, Gutterman D, Baumann MH, et al. Grading strength of recommendations and quality of evidence in clinical 

guidelines: report from an American College of Chest Physicians Task Force. Chest 2006;129(1):174-181. 
13

Burn Injury 

Approximately 1.25 million people are treated annually for burn injuries in the United States. 

Four percent of these people require hospitalization and specialized burn care. High-risk 

populations for burn injuries include children, elderly, physically or mentally disabled, and 

people in military service.40,41

Definition and Description of Burn Injury 

Burn injuries are either partial thickness or full thickness in nature. Partial thickness burns 

involve the epithelium and various depths of the underlying dermis. These burns are diagnosed 

both clinically and temporally. Partial thickness burns can be divided into superficial or deep 

partial thickness burns. 

Superficial partial thickness burns appear as an erythema (first degree) or blistering (second 

degree) on the skin. Very superficial burns correlate with injury to the epithelial layer of skin 

and usually heal without medical intervention or scarring (except for possible 

hyperpigmentation, which is usually temporary in nature [e.g., sunburn]). Superficial partial 

thickness burns heal within 7 to 14 days. 

A superficial partial thickness burn may also involve the superficial aspect of the dermis 

(second degree), which can result in blistering and scarring of the skin. The presence of varying 

shades of foci of pallor indicates deep partial thickness burns that heal within six weeks. 

However, healing may be incomplete. These burns scar the skin and frequently require surgical 

debridement and grafting. 

Full thickness burns result in injury and loss of the entire epithelium and dermis (third 

degree). A full thickness burn may also involve injury to underlying structures such as muscles, 

nerves, tendons, or bones (fourth degree). If left on their own, without surgical intervention, 

these burns would take well in excess of six weeks, or even months, to heal. These burns may 

cause significant scarring and, if present around joints, may severely limit the range of motion .42

Partial Thickness

First degree → superficial (erythema) 

Second degree → deep (blister, pallor) 

Full Thickness

Third degree → white, tan, beige, red, etc. skin color 

Fourth degree → involves tendon, bone, etc. 

Burn injuries may also be classified according to the type of noxious agent causing the burn 

(e.g., flame, scald, flash, contact, smoke inhalation, electrical). Scald injuries, the most common 

burn injury in civilian populations, are secondary to contact with hot liquids. Hot water is the 

most common cause of scald injury, but other agents can include coffee, tea, soup, sauces, hot 

grease, or oil. Burns secondary to contact with tar and asphalt are also considered scald injuries. 

Intentional scalding of children is a common method of child abuse. 

Flame burns are secondary to contact with a source of open flame. House fires, careless 

smoking, automobile accidents, inappropriate use of flammable materials, and ignition of 

clothing are common factors associated with flame burn injury. Flame burns are associated with 
14

a serious and potentially fatal condition known as smoke inhalation injury. Inhalation injury is 

due to the exposure of the respiratory tract to steam and toxic inhalants from the smoke of a 

fire.43

Flash burns are secondary to exposure to explosions of combustible or flammable materials. 

Contact burns are secondary to skin contact with hot items such as metal, glass, chemicals, 

plastic, or coals. Electrical burns are thermal injuries that occur when electrical energy is 

converted into heat upon contact with the skin.44 Electrical burns can severely affect deeper 

structures such as nerves or bones even when there is minimal damage to the overlying skin. 

Burn Care 

In the past three decades, North American burn care has undergone significant transformation, 

and this has led to markedly improved survivability.45-47 The North American health care system 

has developed a sophisticated approach to hospital burn care that is predicated on a network of 

specialized burn treatment centers. These centers are well equipped and professionally staffed to 

treat local injuries and to handle the transfer and treatment of serious burn injuries from more 

distant locales. This transformation of burn care reflects advancements in multiple areas of 

medicine, including critical care, wound infection control and antimicrobial therapy, surgical 

therapy (e.g., early excision and grafting), specialized burn care research, and coordinated 

methods of burn patient transfer (e.g., air ambulance and accompanying medical support 

services).45 Early excisional therapy of deep partial thickness or full thickness burns is a 

common component of the North American standard of care for burn injury.46,47 Burns that heal 

within three weeks commonly do well and are less likely to produce hypertrophic scarring or 

functional impairment. Burns that require more than three weeks to heal are commonly 

associated with hypertrophic scarring or functional impairment. For patients with small to 

moderate burn injuries where the healing time will exceed three weeks, early excision and 

grafting is the recommended course of treatment. The benefits of early excision and grafting 

include decreased hospitalization, early return to work or school, enhanced functional status, and 

improved physical appearance. However, properly estimating the time to healing for a burn 

remains an important clinical challenge.44 Risk factors associated with mortality in burn injury 

include total body surface area (TBSA) greater than 40 percent, age over 60 years, and inhalation 

injury.48 Temporary or permanent disabilities are common in patients with significant burn 

injuries who are admitted to specialized burn care facilities.49 Reconstructive surgery and longterm rehabilitation are routine components of extended care for disabled burn patients. 

Psychosocial Aspects of Burn Injury 

The morbidity associated with burn injury is not limited to physical conditions such as pain 

or scarring. Psychiatric and psychosocial morbidities form important and often overlooked 

aspects of burn injury. Psychiatric and psychosocial morbidities are classified into pre- and postinjury conditions.50,51 Pre-injury psychiatric conditions in adults may include depression, 

suicidality, substance abuse, and personality disorders. In children, pre-injury conditions may 

include behavioral disorders such as conduct disorder or attention deficit hyperactivity 

disorder.50,51

In the post-injury phase, hospitalization and acute burn care can lead to psychiatric and 

psychosocial stresses for patients.50,51 Common psychiatric conditions include delirium, acute 
15

stress disorder (ASD), post-traumatic stress disorder (PTSD), and depression. Psychological 

suffering (i.e., PTSD) may also be manifest in the parents of children or adolescents with burn 

injury.52

The first year post-burn injury may be particularly psychologically stressful for patients,51,53

but most adult50,51 and pediatric54 burn patients do not suffer long-term, burn-related, psychiatric 

sequelae. 

For a minority of burn injured patients, altered patterns of socialization may develop, 

especially for men with visible disfigurement. In women, decreased levels of sexual satisfaction 

are a frequent long-term result of burn injury.51

Heparin and Burns 

The non-anticoagulant effects of heparin and related molecules form the rationale for the use 

of heparin in the treatment of burns. This report will address two main questions related to 

heparin and burns: 

1. What is the evidence for the benefits and harms of heparin use in thermal injury care? 

a. Does the method of application make a difference? 

b. Do the outcomes vary by the type or degree of burn? 

c. How do the outcomes of burn treatment with heparin compare to current treatment 

without heparin? 

2. What are the contraindications of heparin use in burns? 

Addressing these questions will serve to identify both the strength of the evidence for using 

heparin to treat burns and gaps in existing research. As well, answering these questions will 

facilitate the establishment of future research priorities. 
17

Chapter 2. Methods 

Analytic Framework 

An analytic framework is a schematic representation of the strategy for organizing topics for 

review and guiding literature searches. Figure 1 illustrates the inter-relationships between the 

questions being asked in this evidence report. The key areas addressed are the use of heparin to 

treat burns, heparin’s method of application (e.g., topical, intravenous), the clinical outcomes and 

contraindications of said treatment, and a comparison of heparin to other burn treatments. 

Heparin can be applied topically (e.g., cream or dressing material impregnated with heparin), 

subcutaneously, by infusion, via aerosol, or by a combination of any of the aforementioned 

methods. Burns are described by degree (first, second, third), total body surface area (TBSA) 

involvement, and type (flame, scald, flash, contact, smoke inhalation, electrical, or any 

combination of these types). The clinical outcomes are separated into early and late outcomes. 

Early outcomes include the need for acute hospitalization and surgery (e.g., grafting, 

debridement, and fasciotomy), quality of graft take (percentage), pain, mortality (prior to 

discharge from hospital), length of hospital stay, scarring (size, hypertrophic scarring, 

contractures), rehabilitation outcomes (decreased range of motion), intensive care unit (ICU) 

admissions and respiratory measures (e.g., length of intubation), incidence of thromboses and 

emboli, complications such as bleeding or infection, and acute psychiatric adjustment (delirium, 

acute stress disorder [ASD] and post-traumatic stress disorder [PTSD]). Late outcomes include 

rehabilitation, re-grafting, reconstructive surgery, quality of life, psychiatric adjustment (anxiety, 

depression), and mortality (after discharge from hospital). The three major contraindications to 

heparin use are thrombocytopenia, bleeding, and osteoporosis (after long term use). The benefits 

of heparin use in burn care, compared to other burn treatments without heparin, will be explored 

in the results and discussion sections of this report. 

Topic Assessment and Refinement

Research Team 

A multidisciplinary, local research team (‘local experts’) with expertise in epidemiology and 

systematic reviews (M. Oremus, PhD; P. Raina, PhD), pediatric psychiatry and pediatric burn 

injury consultation (M. Hanson, MD), clinical chemistry (E. Young, PhD), and surgery (R. 

Whitlock, MD; A. Dal Cin, MD) was assembled at the McMaster University Evidence-based 

Practice Center (MU-EPC) to plan an approach to completing this evidence report in a thorough, 

timely, and efficient manner. This team had regular meetings to reach consensus on key 

methodological issues. 

A ‘kick-off’ teleconference with the partner organization (Saliba Burns Institute), the Agency 

for Healthcare Research and Quality (AHRQ) Task Order Officer (TOO), the local experts, and 

MU-EPC staff was held at the start of this project to define the magnitude of the topic and refine 

and clarify the preliminary research questions for this evidence report. A Technical Expert Panel 

(TEP), composed of internationally recognized experts in the field of burns, was assembled to 

provide high-level content expertise on heparin use and burns. Members of the TEP were 
18

requested to participate in teleconferences on an as-needed basis throughout the data refinement 

and data abstraction phases of this evidence report. 

Figure 1: Analytical Framework

 

Heparin 

Method of Application

Topical Subcutaneous Infusion Aerosol Combination

Burns

 Clinical Outcomes

Other treatments 

without Heparin

Early (e.g. pain, 

length of stay, scarring, bleeding, 

 infection, 

 thrombosis...)

Late (e.g. quality of

life, psychiatric 

adjustment, 

mortality...)

Contraindications of

Heparin

Thrombocytopenia

Bleeding

Osteoporosis

Degree

Type

Scald Contact Electrical

 First 

Second

Third

Flame Flash Smoke 

Inhalation

TBSA
19

Technical Expert Panel Teleconference Calls

The first TEP teleconference took place on November 29, 2005. Technical experts 

participating included Dr. Bishara Atiyeh (Clinical Professor Of Surgery, Plastic And 

Reconstructive Surgery, American University of Beirut Medical Center, Beirut, Lebanon), Dr. 

Leo Klein (Head, Department of Burns Medicine, Charles University and Teaching Hospital, 

Prague, Czech Republic), Dr. Jan Koller (Slovak Society of Plastic and Aesthetic Surgery, 

Bratislava, Slovakia), and Dr. Glenn Warden (Editor, Journal of Burn Care and Research, Salt 

Lake City, Utah) (see Appendix A∗

). A second TEP teleconference took place on February 3, 

2006. Several topics were discussed during both calls, including the definition and scope of the 

key questions, search strategies, inclusion and exclusion criteria, and the composition of the 

screening and data abstraction forms. 

General Methods 

Key Questions 

The original set of key questions for this evidence report was revised by the local experts and 

discussed during the TEP teleconferences. Additional discussants included the partner 

organization and the TOO.

The revised key questions are: 

1. What is the evidence for the benefits and harms of heparin use in thermal injury care? 

a. Does the method of application make a difference? 

b. Do the outcomes vary by the type or degree of burn? 

c. How do the outcomes of burn treatment with heparin compare to current 

treatment without heparin? 

2. What are the contraindications of heparin use in burns? 

Literature Search Strategy 

We conducted a comprehensive search of the literature to capture all relevant, published 

studies on the topic of heparin and burns. The following electronic databases were included in 

the search: 

1. MEDLINE (1966-current); 

2. EMBASE (1980-current); 

3. CINAHL (Cumulative Index to Nursing and Allied Health) (1982-current); 

4. The Cochrane Central Database of Controlled Trials (1995-current); 

5. Web of Science (1976-current); and 

6. BIOSIS (1976-current). 

In addition, literature in the U.S. and European Patent Offices was searched for relevant 

studies, members of the TEP and the partner organization were asked to supplement the database 

search with additional references of published and unpublished studies, and the reference lists of 

 

∗

 Appendixes are provided electronically at http://www.ahrq.gov/clinic/tp/heparntp.htm. 
20

articles that passed full text screening were also searched for relevant studies. Please see 

Appendix B for a detailed description of the search strategies used for this review. 

Inclusion/exclusion criteria. A list of inclusion/exclusion criteria was developed to screen 

studies for this evidence report. The criteria are as follows: 

Language. There was no language restriction. Studies published in any language could be 

included in the report.

Study design. Studies required a comparison arm for inclusion. Case series, case reports, 

editorials, letters, comments, opinions, abstracts, animal experiments, and conference 

proceedings were excluded from the report. 

Population. Human patients of any age, with burns of all types, grades, and TBSA 

involvement, could be included in the report. 

Outcomes. Studies with the following outcomes could be included: 

1. Need for surgical procedure (e.g., grafting, debridement, fasciotomy, quality of graft take 

[percentage], re-grafting, reconstructive surgery); 

2. Pain; 

3. Transfusion rate; 

4. Mortality (prior to, or after, discharge from hospital); 

5. Length of stay in hospital; 

6. Scarring (size, hypertrophic scarring); 

7. Decrease in range of motion, function, or activities of daily living; 

8. Respiratory measures (e.g., length of intubation); 

9. Thrombosis and emboli; 

10. Complications (e.g., bleeding, infection); 

11. Rehabilitation; 

12. Quality of life; and 

13. Psychiatric adjustment (e.g., PTSD, anxiety, depression). 

Appendix C∗

 contains the list of excluded studies. 

Data Collection and Reliability of Study Selection 

A team of research assistants was trained to apply the inclusion/exclusion criteria. 

Standardized forms were developed for this purpose, as well as for data abstraction (see 

Appendix D). The forms were created and stored online using Systematic Review Software 

(SRS; TrialStat Corp., Ottawa, Ontario). 

For title and abstract screening, two independent raters evaluated the citations that were 

obtained from the literature search. Articles that met the inclusion/exclusion criteria, or for 

which there was insufficient information to determine if they met the criteria, were retrieved for 

further assessment. Once retrieved, the entire text of the article was screened to determine if the 

inclusion/exclusion criteria were satisfied. At this stage, an article could be excluded from 

further review if both raters agreed that it did not satisfy the inclusion/exclusion criteria. In cases 

of disagreement, the raters met to arrive at a consensus.

 

∗

 Appendixes are provided electronically at http://www.ahrq.gov/clinic/tp/heparntp.htm. 
21

Articles that survived the full text screening phase went on to full data abstraction. Either a 

local expert or a MU-EPC staff member abstracted the data. Local experts who were responsible 

for addressing the key questions in the results chapter reviewed the abstractions to confirm the 

accuracy of the work. 

Quality Assessment of Abstracted Studies 

The quality of the studies that passed the full text screening was assessed using the Effective 

Public Health Practice Project Quality Assessment Tool for Quantitative Studies (EPH Tool [see 

Appendix E∗

]).55 The EPH Tool was developed for systematic reviews of the effectiveness of 

public health interventions. 

The EPH Tool can be utilized with observational studies or clinical trials. It is divided into 

several sections, including selection and allocation bias, confounding, blinding, validity and 

reliability of data collection instruments, analysis (e.g., use of appropriate statistical methods), 

and intervention integrity (e.g., percentage of participants who actually received the allocated 

intervention or exposure). Each section contains from one to seven questions; algorithms56 are 

used to transform question responses into a qualitative score for each section. The score options 

are weak, moderate, or strong. 

Two raters, either a local expert or a MU-EPC staff member, conducted the quality 

assessment for each article that passed the full text screening phase. Differences were resolved 

by consensus. 

Summary of Findings: Descriptive and Analytic Approaches 

Descriptive approaches were used to summarize the characteristics of abstracted articles and 

answer the key questions. The local experts judged that a meta-analysis was not feasible because 

the abstracted articles were far too heterogeneous with respect to study participants, study 

design, treatment modalities, and outcomes. Instead, data were collected on the characteristics of 

study participants, methods of diagnosis, treatments, and outcomes. The quality of this 

information was judged and the findings were summarized in both text and tables. This evidence 

report provides a greater understanding of the effectiveness of using heparin in burn treatment, 

identifies gaps in existing research, and suggests a plan for future research. 

Peer Review Process 

The partner organization, local experts, and members of the TEP were asked to identify 

potential peer reviewers from relevant professional organizations, consumer organizations, and 

purchasers of care. A list of potential reviewers was compiled by the MU-EPC and submitted to 

AHRQ for approval prior to the circulation of the draft report. The reviewers were asked to 

review the report and provide feedback on clinical and methodological content, as well as on the 

readability and presentation of information. Their comments and suggestions will be 

incorporated into the report where possible. 

 

∗

 Appendixes are provided electronically at http://www.ahrq.gov/clinic/tp/heparntp.htm. 
23

Chapter 3. Results 

Literature Review and Screening 

The literature search yielded 470 citations. A search of the reference lists of abstracted 

articles yielded one additional citation of interest, which passed through all levels of screening 

and went on to be abstracted. In total, 339 citations were excluded from further review following 

the two initial levels of title and abstract screening; 132 citations proceeded to full text screening. 

Of these 132 articles, 112 were excluded from further review and 19 advanced to the data 

abstraction phase. One article could not be retrieved despite persistent inter-library loan requests 

and attempts to contact the authors and publishing journal. Figure 2 depicts the flow of articles 

through the screening process. The remainder of this chapter contains a description of the 

general characteristics of the abstracted articles, a section addressing how the abstracted articles 

answer the two key questions, and a quality assessment of the abstracted articles. 

General Characteristics of the Abstracted Articles

Nineteen articles describing 18 unique research projects contained data on the use of heparin 

to treat burns (Table 5). In two articles from the University of Michigan, the same group of 

patients was used to assess outcomes related to deep vein thrombosis.57,58 Eight of the abstracted 

articles were based on research conducted in the U.S..57-64 The remainder were from the Soviet 

Union,65-68 United Kingdom,69 China,70 Japan,71 India,72,73 El Salvador,74 and Mexico.75 Sample 

sizes ranged from 664 to 327.63 The sample size was not reported in one article.62 The mean 

sample size, counting the Michigan articles as one, was 62. Samples were composed of patients 

who presented to hospital burn units or emergency rooms with burn injuries. 

In eight of nine articles where the complete breakdown of patients was reported by sex, the 

majority of patients were male.58,63,66,68,70,72-75 The largest proportion of males was 0.95 (19/20)70

and the smallest proportion of males was 0.49 (49/100).72

The authors of seven articles reported the mean age of patients.58,59,63,68,70,74,75 In the five 

articles with adult populations, the lowest mean age was 30 years75 and the highest mean age was 

57 years.68 In the two articles with pediatric populations, the lowest mean age was 3.2 years74

and the highest mean age was approximately 8 years.59 Age ranges, reported in ten 

articles,58,63,64,66-68,72-75 were as wide as 21 to 77 years68 and as narrow as 0.25 (3 months) to 8 

years.74

The etiology of burn, reported in eight articles,58-60,63,66,72,74,75 included flame,58,72,74,75

scald,72,74 inhalation injury,58,59,66 and ‘thermal’.60 One article contained patients with any burn 

etiology.63 Eight articles also contained information about the degree of burn.59,63,65,67,69,72,74,75 

Patients with first degree burns were included in two articles,65,69 second degree in six 

articles,63,65,67,72,74,75 and third degree in six articles.59,63,65,73-75
24

Figure 2. Flow diagram showing the final number of articles meeting the eligibility criteria 

Literature search 

and search of 

reference lists: 

n = 471 

Title and abstracts 

screened: 

n = 471

Excluded: 

n = 339 

Reasons for exclusion* 

Ineligible study design: n = 224 

Animal study: n = 131

Full text articles 

for screening: 

n = 132 

Excluded: 

n = 112 

Reasons for exclusion* 

Ineligible study design: n = 103 

Animal study: n = 7

Abstracted 

articles: 

n = 19 

Articles not retrievable: n = 1 

Full text articles 

screened: 

n = 131 

*Articles may have been excluded for more than one reason. 
25

Total body surface area (TBSA) involvement was reported by the authors of 17 articles 

(exceptions were the authors of the Bulgarian67 and British69 articles). Reporting was in the form 

of a range (e.g., 8.5 to 90 percent TBSA),59,60,64,66,68,72 mean TBSA (e.g., 65.8 ± 13.7 

percent),57,58,62,63,70,74,75 or the upper or lower bound of TBSA that would be required for a patient 

to be included in a research project (e.g., TBSA > 30 percent).61,65,71,73 No common level of 

TBSA involvement marked the articles. For example, one article included patients with TBSA 

involvement between 8.5 and 90 percent.60 Other articles included patients with TBSA > 30 

percent61,71 or TBSA in the range of 50 to 60 percent.59,62

Key Questions 

Question 1. What is the Evidence for the Benefits and Harms of 

Heparin Use in Thermal Injury Care? 

The 19 abstracted articles did not contain strong evidence for the efficacy of heparin in 

treating burns. Three of the articles were randomized controlled trials (RCTs) in adult and 

pediatric burn patients. The first, by Srivastava et al., was a comparison of heparin and standard 

therapy to standard therapy alone. Heparin use was found to improve the following outcomes: 

mortality, infection rate, graft healing, and eschar separation.73 For mortality, three out of 25 

people died in the heparin group, while 11 out of 25 people died in the control group. Infection 

rates were lower in the heparin group, with 20 people having wound infection versus all 25 

people in the control group. Grafts healed 11 days faster on average in the heparin group and 

eschar separation was a mean of 9 days faster in the heparin group. The study had a clear 

monitoring protocol for adverse effects and no increases in bleeding were found as a result of 

heparin use. Despite the encouraging results, these findings must be weighed against the study’s 

limitations. The authors described the study as randomized, but they did not discuss the 

allocation method. If allocation was improper, then healthier patients may have been 

disproportionately assigned to the heparin group. The authors also failed to address blinding, did 

not clearly define the clinical outcomes, and only reported descriptive statistics. Lastly, the 

treatment regimen was a combination of systemic and topical heparins, so any potential 

therapeutic benefits could not be attributed to one route of administration over the other. 

The second RCT showed that topical heparin significantly reduced primary scarring in 37 

heparin-treated adults and children.67 These people were compared to 27 controls who received 

standard therapy. However, the method of treatment allocation was not described in the 

publication and the outcome measures were not validated in burned patients. Thus, it is difficult 

to attribute the favorable outcome to heparin alone. 

The third RCT, an unpublished study by Venkatachalapathy et al., was conducted to examine 

the effect of topical heparin on clinical outcomes in people with second degree burns (age 

range:15 to 35 years).72 Control patients received usual treatment, which included topical 

antimicrobial cream, debridements, and skin graftings in the early post-burn period. Outcomes 

included length of hospital stay, mortality, and number of skin grafts. The authors found a 

significantly (p<0.001) shorter length of hospital stay in the heparin-treated patients (all 50 

heparin-treated patients had lengths of stay ≤ 40 days, while 28 of 50 control patients had stays 

of 40 to 50 days). There was also less mortality (0 heparin versus 5 controls) and fewer skin 

grafts (4 heparin versus 10 controls) in the heparin group. However, it was unclear how patients 
26

were allocated to treatment. The authors simply described the process as “randomly selected.” 

Indeed, there was an imbalance in the study groups: the control group had more patients with a 

larger burned surface area (a major predictor of morbidity and mortality in burns). If the controls 

were sicker, then that fact alone (not the use of heparin) could explain the better outcomes in the 

heparin group. 

Two articles contained investigations of heparin’s use in adult-only burn populations. The 

first, by Reyes et al., was a non-randomized, comparative (cohort) study of nine patients who 

were injured in a thermal disaster.75 Four patients received topical heparin immediately after 

hospital admission and they were reported to have better pain relief, less swelling, fewer 

fasciectomies, a shorter length of hospital stay, and earlier burn revascularization than five 

control patients who did not receive topical heparin until 5 days after hospitalization. While the 

results were positive for heparin, they must be interpreted cautiously due to two study 

limitations. First, the important outcome of pain relief was measured using doses of pain 

medication. Besides the fact that the degree of patient pain is not necessarily associated with 

doses of pain medication, patients’ impressions of pain were never directly assessed in the study. 

Second, two patients in the control group received daily subcutaneous heparin before day 5 of 

hospitalization. This ‘contamination’ of the control group diminishes the ability to conclude that 

inter-group differences were due to the use versus non-use of heparin. The observed differences 

may have occurred because of random chance owing to the small sample size. Or, given that the 

heparin and control groups were not treated at the same hospital, subtle variations in institutional 

practice patterns (e.g., protocols for administering medications) could have led to the observed 

differences. 

The other article about heparin use in adult burn patients was written by Acharya, who 

compared the effects of three therapies: 1) topical heparin, 2) topical heparin with topical steroid 

and antibiotic, and 3) topical steroid and antibiotic alone.69 In the article, the type and degree of 

burn were poorly defined (e.g., “superficial burn”) and the outcomes (e.g., pain and reduced 

inflammation) were vague and poorly validated. The study showed no difference between 

treatment groups, but the author failed to use statistical hypothesis tests and instead relied on 

descriptive statistics (e.g., number of patients in each group with “speedy” relief of pain) to make 

inter-group comparisons. 

Three studies focused on the use of heparin to treat burns in pediatric populations. Desai et 

al. conducted a non-randomized trial (cohort study) to examine the effect of aerosolized heparin 

with acetylcysteine for 7 days on inhalational burn injuries in children.59 The 

heparin/acetylcysteine group (n = 47) had significantly less reintubations, less atelectasis, and a 

lower mortality rate than the standard therapy group (n = 43, p < 0.05). However, the results 

were beset by two major limitations. First, the standard therapy group was a historical cohort 

whose members received treatment between 1 and 5 years before the first members of the active 

treatment group received heparin/acetylcysteine. If there were changes in the protocols for 

managing pediatric burns during this 5 year period, then the observed differences could have 

been due to these changes, rather than to any possible effect of heparin. Second, heparin and 

acetylcysteine were tested together, so the impact of either active agent cannot be separated from 

the other. 

Another pediatric study was a 20-year chart review of burned children who developed renal 

vein thrombosis (RVT).64 Six such children were identified in the review; three received heparin 

and three did not. The three children who did not receive heparin died within 5 days of 

developing RVT, while the children who received heparin survived. The authors conclude by 
27

recommending heparin therapy for burned children with RVT, but the comparison upon which 

this recommendation is based may be invalid. Although the historical cohort and small sample 

size are problematic, the main difficulty is that the controls may not have had the same exposure 

opportunity as the treated patients. Even if there were no contraindications to heparin in the 

controls, they were diagnosed with RVT within 24 hours of death (n = 2) or at necropsy (n = 1). 

Thus, the controls may not have had the chance to receive heparin, and they may have been 

sicker than the children who were treated with heparin. 

The final pediatric article was an unpublished cohort study to compare nine children 

undergoing standard burn therapy in 1998 to 10 children undergoing standard therapy plus 

heparin (intravenous followed by topical) in 1999.74 The authors reported lower mortality (four 

versus eight deaths) and less pain in the heparin group. The mortality result must be interpreted 

carefully because the study groups were different with respect to co-morbidity. All nine children 

in the 1998 (control) group had sepsis, while three children in the 1999 (heparin) group had 

sepsis. The treatment for sepsis was not well described and may have changed over time, 

thereby accounting for the difference in mortality. The authors measured pain using subjective, 

observational criteria like patient behavior (e.g., crying, struggling) and a decrease in the “noisy 

din and distressing emotional ambience” of the hospital ward. These observations were not 

measured in a systematic, quantitative fashion and therefore should not be taken as indicative of 

a treatment effect. 

Several abstracted articles met the inclusion criteria at the screening phase, but upon data 

abstraction they were found to contain little or no clinical data on the use of heparin to treat 

burns. Four such studies contained no presentation of clinical outcomes, with the focus instead 

on laboratory outcomes such as autologous red blood cell survival,62 fibrin degradation 

products,61 platelet aggregation,60 and blood coagulation.65 Another three studies examined 

treatment modalities such as continuous renal replacement and had mentioned heparin in 

passing, but no outcomes were presented based on heparin therapy.68,70,71 One study contained 

treatment regimens that included heparin, but it was not possible to separate the effect of heparin 

from concomitant therapies such as nicotinic acid, contrical, thrental, phytin, and alphatocopherol.66 Three studies focused on the possible risk factors for, and incidence of, deep vein 

thrombosis/pulmonary embolism (DVT/PE) in burn patients.57,58,63 Each study identified the 

number of patients with DVT/PE who had been on heparin prophylaxis, but reported no other 

outcomes by this grouping. 

Given the above discussion (summarized in Table 6), some of the abstracted studies contain 

evidence that heparin has potential clinical benefits in the areas of reducing mortality,59,72-74

reducing pain,72,75 improving cosmesis, 67,73,75 and alleviating lung injury in inhalational burns.59 

However, these studies suffer from numerous limitations (see above and the quality assessment 

section below). In light of these limitations, the evidence supporting the use of heparin in burn 

injury cannot be considered strong. 

The a priori defined sub-questions to be answered by this review are: 

1. Does the method of application make a difference? 

2. Do the outcomes vary by the type or degree of burn? 

3. How do the outcomes of burn treatment with heparin compare to current treatment 

 without heparin? 
28

Does the method of application make a difference? As illustrated above, there are insufficient 

data available to determine if the method of application of heparin in burn patients makes a 

difference with respect to clinical outcomes. 

The following gaps exist within the literature. Four published studies67,69,73,75 and two 

unpublished manuscripts72,74 comparatively examined (e.g., treatment versus control) clinical 

outcomes in the use of heparin to treat burns. Another study had clinical outcomes, but the effect 

of heparin could not be separated from concomitant therapy.59 In these studies, no comparisons 

were made of systemic heparin (intravenous or subcutaneous) or topical heparin applications to 

the burn site. 

Do the outcomes vary by the type or degree of burn? There are insufficient data available to 

answer this question. None of the abstracted studies contained analyses where the effectiveness 

of heparin was stratified by type or degree of burn. In fact, the abstracted studies were often 

characterized by vague reports of the etiology, type, or degree of burn in the samples. 

How do the outcomes of burn treatment with heparin compare to current treatment 

without heparin? Multiple roles for heparin in the treatment of burns were examined in the 

abstracted studies. These roles included wound healing and pain control, as well as the treatment 

of sepsis, inhalation injury, and venous thrombosis. However, there were insufficient data 

available to answer the key question. This was because the abstracted studies were conducted in 

eight different countries with varying standards of burn care and published over a time span of 

three decades. Thus, the studies simply did not encompass any standard, current burn treatment. 

In addition, nine abstracted studies were primarily laboratory studies without clinical outcomes. 

57,58,60-63,65,68,70

The ability to address the key question was further hampered by the major methodologic 

deficiencies that characterized many of the abstracted articles. Common problems included: 

1. Poorly defined burn etiology and degree; 

2. Unclear method of treatment allocation; 

3. Absence of a control group with no topical anti-inflammatory; 

4. Unclear duration of treatment, especially the point at which heparin is first administrated; 

5. Outcome variables that are vague and unlikely to be reproducible; and 

6. Use of descriptive statistics (no comparative statistics). 

Conclusion. Further studies with well-defined populations, treatment regimens, and outcomes 

are needed to address all three of the above sub-questions. Outcomes must be valid, quantitative, 

and reproducible. The adverse effects of heparin treatment in burns must also be examined 

because there is a void on this topic in the literature. 

Question 2. What are the Contraindications of Heparin Use in Burns? 

Findings from the abstracted articles. Four of the abstracted articles specifically addressed the 

issue of contraindications to the use of heparin in burn patients.72-75 This was limited to listing 

contraindications for subcutaneous or intravenous applications of heparin such as bleeding 

diathesis, bleeding history, active bleeding or associated trauma with potential bleeding, active 

intestinal ulcer, thrombocytopenia, liver disease, renal disorders, or allergy to heparin. The 

authors of two articles72,73 wrote that these contraindications were exclusion criteria, while the 
29

authors of the other two articles74,75 wrote that none of the patients in their studies had any of 

these contraindications. 

Application of existing evidence to the domain of burn treatment. When using heparin in 

burn patients, it would be prudent to apply the same precautions as would be applied to the use 

of heparin in patients with thromboembolic disease. 

The most common contraindication for heparin in patients with thromboembolic disease is 

bleeding. The risk of bleeding increases with higher heparin doses and is associated with 

patients’ anticoagulant responses, the method of heparin administration, the co-administration of 

anti-platelet or fibrinolytic agents, and recent trauma or surgery. Bleeding is as frequent with 

low molecular weight heparins (LMWHs) as with unfractionated heparin (UFH). In one study, 

bleeding was observed in 5.2 percent of patients who were given continuous intravenous heparin 

and in 4.1 percent of patients who were given subcutaneous heparin.2

 Both groups received 

approximately the same mean dose over 24 hours. 

Heparin can cause thrombocytopenia and is therefore contraindicated in patients who have 

had recent surgery (primarily for venous problems) or pre-existing cardiovascular disease 

(primarily arterial).76 The incidence of thrombocytopenia was reported to be 0.3 percent in 

patients treated with heparin prophylaxis and 2.4 percent in patients treated with heparin 

therapeutically.2 Heparin-induced thrombocytopenia is an antibody-mediated process that can 

lead to arterial or venous thrombosis. 

The estimated incidence of vertebral fractures in people receiving long-term UFH therapy is 

three out of 100. Approximately 30 out of 100 people who receive therapeutic doses of heparin 

for longer than one month will experience reduced bone density that can lead to osteopoenia or 

osteoporosis.77 The risk of osteoporosis was observed in groups of patients who had received 

long-term heparin therapy (> 6 months) at doses greater than 15,000 anti-Xa units. Much of the 

research on heparin and osteoporosis has been confined to pregnant women, so prolonged 

heparin use is contraindicated in this group.76 Osteoporosis is less common with LMWHs than 

with UFH. 

Much of the available evidence regarding contraindications to heparin concerns subcutaneous 

or intravenous applications of the substance. In some of the abstracted articles, heparin was 

applied topically and there is no information regarding the contraindications of heparin when 

administered by this route. 

Reported adverse effects of heparin in treating burns. Fifteen of the abstracted articles did 

not contain reports of adverse effects in the use of heparin to treat burns. The methods sections 

of these articles did not indicate that monitoring for adverse effects was an objective of any of 

this research. Srivastava et al. reported a clear monitoring protocol for adverse effects (in their 

case, bleeding) and they did not find any increases in bleeding secondary to heparin use.73 Two 

other articles contained reports of bleeding in heparin-treated patients74;

75 and one article70 had 

mention of the fact that no heparin-related adverse effects were observed in the sample. 

The incidence of bleeding was low when reported. One heparin-treated patient in a pediatric 

study (n = 19) bled on the burn surface, but the role of heparin as a contributing factor was 

unclear because the patient also had sepsis, which was a major cause of this person’s death.74 In 

another study (n = 9), three patients who received topical heparin beginning on the fifth day of 

hospital admission developed bleeding on day 8 of the study.75 However, the authors attribute 
30

the bleeding to a treatment error: the dose of heparin was not reduced following burn 

revascularization. The bleeding may have been avoided if heparin was titrated properly. 

Quality Assessment of Abstracted Articles 

Overview 

Ten of the nineteen abstracted articles (Group A) pertained directly to the use of heparin to 

treat burns or the complications of burns.59,64,66,67,69,71-75 The other nine articles (Group B) 

contained information that could be used to make indirect inferences about heparin and 

burns.57,58,60-63,65,68,70 

Given that nine of the abstracted articles were published in 1988 or before, and five were 

RCTs, certain sections of the EPH Tool applied to only a fraction of the entire set of 19 articles. 

For example, the questions in the EPH Tool about sample size and power calculations applied to 

only the more recently published articles because reporting guidelines for published manuscripts 

are a relatively new phenomenon. Consequently, articles published two decades ago do not 

reflect the same reporting standards as today. Another example of the EPH Tool’s restricted 

applicability is the section on intervention integrity, which is designed for RCTs because the 

investigator assigns the exposure. 

To standardize the EPH Tool across all 19 articles, the questions that were universally 

applicable to all of the articles were considered in the quality assessment. These questions were: 

(1) selection bias – participants representative of study population, percentage of selected 

participants who agreed to participate, completion rate; (2) study design – allocation to treatment 

groups, use of valid data collection instruments; (3) control of confounding – reported 

differences between exposure groups with respect to important confounders, attempts to control 

confounding; (4) statistical methods – use of appropriate statistical methods, finding of statistical 

significance. The removal of certain questions meant that the EPH Tool’s qualitative scoring 

algorithms could not be used to assign scores of weak, moderate, or strong to the various sections 

of the scale. Instead, written commentary is provided below on what the answers to the EPH 

Tool suggest for study quality. This information is summarized in Table 7. 

Selection Bias 

At least half of the articles were vulnerable to selection bias. The authors of five Group A 

articles64,67,69,71,73 and five Group B articles60,62,65,68,70 simply reported the numbers of patients 

that participated in the research. The authors did not mention the recruitment time period, nor 

whether consecutive sets of patients were assessed for study eligibility. The omissions in 

reporting, coupled with a conservative approach to quality assessment, meant that one could not 

rule out the possibility that highly selected groups of patients were used in these articles. Indeed, 

the authors of one article wrote that they used “a selected series” of patients.69 These ten articles 

were rated as not likely to contain participants who were representative of the study population. 

Conversely, two Group A articles66,72 were rated as very likely to contain representative 

participants, two74,75 were rated somewhat likely, and one59 was rated not to somewhat likely. Of 

the Group B articles, one63 was rated as somewhat to very likely, two were rated somewhat 

likely,57,58 and one61 was rated not to somewhat likely. 
31

The omissions in reporting extended to the participation rate (e.g., the percentage of recruited 

patients who actually participated in the research). The authors of six Group A 

articles59,66,67,69,71,73 did not report any data on this subject, nor did the authors of four Group B 

articles.60,61,65,68 In articles that did contain information, the participation rate was 80 percent or 

better in four articles.57,62,70,75 In four Group A articles59,64,69,71 and six Group B articles,57,58,60-

62,65 the authors reported little or no data (e.g., age, sex) on the characteristics of people who did 

participate. 

Reporting was better for completion rates. Excluding a chart review,64 the other nine Group 

A articles had completion rates of 80 percent or more. One Group B article58 had a completion 

rate of 75 percent and six57,60-62,68,70 (excluding a database review63) had completion rates of 80 

percent or more. Completion rates were not reported in one Group B article.65

Study Design 

Eight59,64,66,69,71,73-75 Group A articles reported on non-randomized, comparative (e.g., cohort) 

studies and two reported on RCTs.67,72 The major problem with the cohort studies was a lack of 

information on how the treatments (exposures) were allocated between exposure groups. 

Without this information, it is impossible to ascertain whether the characteristics of the different 

exposure groups could have influenced treatment allocation or treatment outcome. For example, 

in the chart review, all of the patients who did not receive heparin died.64 If these patients would 

not have been eligible to receive heparin, perhaps because they were too sick, then the 

comparison with heparin-treated patients is invalid. In the two RCTs, the method of 

randomization was not reported, thus raising questions about whether confounding variables had 

been evenly distributed among the treatment groups. Indeed, in one of the RCTs, more severely 

burned patients were randomized to the control group.72

In Group B, three articles61,62,70 were RCTs, three58,63,65 were non-randomized, comparison 

(cohort) studies, two60,68 were non-randomized, comparative laboratory studies, and one57 was a 

before/after study. Treatment allocation was also an issue in this group. The authors of the 

RCTs did not report the method of randomization, and one of the non-RCTs had an explanation 

for the allocation of heparin treatment.68 Of course, it should be noted that none of the studies in 

Group B were designed to evaluate the direct effect of heparin treatment in burn injury. 

Consequently, these authors cannot be expected to comment on the allocation of heparin. 

None of the studies in either group contained mention of whether people who assessed study 

outcomes were blinded to treatment allocation. This raises the specter of bias due to differential 

misclassification. However, the presence and impact of said bias cannot be assessed given the 

dearth of information in the published study reports. 

Valid data collection instruments were used in one article from Group A.66 In another article 

from Group A, a non-validated, and not fully explained, four-point scale was used to measure 

pain.69 For Group B, eight studies had valid data collection instruments. These instruments were 

primarily laboratory tests to measure biological factors such as platelet aggregation60 or D-dimer 

levels.57 One Group B article did not contain mention of the data collection instruments that 

were used in the research.65
32

Control of Confounding 

There was no attempt to control for possible confounding in any of the 19 articles. In three 

Group A articles64,69,71 and three Group B articles,60,63,65 there was no mention of basic potential 

confounders such as age, sex, or comorbidity. Differences between exposure groups with respect 

to important confounders were reported in five Group A articles64,66,72,74,75 and four Group B 

articles.58,60,63,70 Six non-RCTs57,59,65,68,69,73 in Groups A and B did not contain specific mention 

of any differences. Three of the RCT publications did not include comparisons of study 

participants across treatment groups.61,62,67 The authors of one RCT did report such comparisons 

for age, sex, and TBSA.70

Statistical Methods 

Statistical methods were basic between-group comparisons of data such as the mean number 

of doses of pain medication. This was the case for five Group A articles59,67,72,74,75 and five 

Group B articles.57,58,63,68,70 In Group A, which involved articles that directly examined heparin 

in burns, three64,66,69 of the articles did not appear to contain any comparative statistical methods 

and the authors of two articles71,73 made no attempt to do any statistical comparisons whatsoever. 

In three Group B articles,60-62 standard errors were reported and comparisons were done, but the 

types of statistical tests used in the analyses were not reported, nor were p-values provided. 

Four articles in Group A59,72,74,75 and four articles in Group B61,62,68,70 contained information 

on whether statistically significant differences were found at the 5 percent level for outcomes 

involving heparin. This information was not contained in the remaining articles from either 

group. 

Conclusion 

The overall quality of the 19 abstracted articles on heparin use in burn care is poor. Selection 

bias cannot be ruled out for many of the articles because the authors did not report on patient 

recruitment or participation rate. Similarly, non-reporting was a problem in the area of study 

design because only one published manuscript contained a report of how treatments (exposures) 

were allocated amongst study participants.68 As well, none of the authors provided information 

on whether outcome assessors were blinded as to treatment allocation. For confounding, 

potential differences between treatment groups on important confounders were reported in half 

of the articles, and no attempts were made in any of the articles to address possible confounding. 

Statistical methods – when reported – were simple between-group comparisons. Many authors 

did not report the type of statistical test nor provide a p-value. In some instances, no statistical 

comparisons were performed at all. 
33

Table 5. General characteristics of the abstracted studies

Study Study 

Design 

Length of 

Follow-up 

Description of 

Sample 

Sample Size Number/ 

% Male 

Mean Age/ 

Range 

Etiology of 

Burn 

Acharya, 1973, United Kingdom69

Cohort NR Accident 

department admissions 

Hirudoid cream: n = 36* Anacal ointment: n = 16* Antibiotics: n = 33 *Includes heparin 

NR/NR NR/NR NR 

Curreri et al., 1975, U.S.61

RCT 14 days Hospital 

admissions 

3 groups: heparin, aspirin, control (numbers in each group not reported) 

NR/NR NR/NR NR 

Desai et al., 1988, U.S.59

Cohort 7 days Pediatric hospital 

admissions 

Heparin: n = 47 (admitted 1990-1994) Control: n = 43 (admitted 1985-1989) 

NR/NR Control group: 

8.2 years/NR Heparin group: 7.7 years/NR 

Inhalation injury 

Iashvili et al., 1986, Soviet Union (Georgia)66

Cohort 80 days 

(mean follow-up over four groups) 

Burn center admissions 

Heparin + nicotinic acid: n = 36 Heparin + Contrical: n = 36 Heparin + nicotinic acid + thrental + phytin + alphatocopheral: n = 36 Control: n = 36 

87/60% NR/16 - 60 

years 

Group receiving 5 drugs and controls: inhalation injury Other two groups: NR 

Khadzhiiski et al., 2001, Bulgaria67

RCT 3 years Hospital 

admissions 

Heparin: n = 32 Control: n = 27 

NR/NR NR/1 year and 

up (upper bound NR) 

NR 

Kuz’muk et al., 1971, Russia65

Cohort 20 days Hospital 

admissions 

Heparin: n = 50 (divided into two groups based on degree of burn and TBSA) Control: n = 30 

NR/NR NR/NR NR 
34

Table 5. General characteristics of the abstracted studies (continued)

Study Study 

Design 

Length of 

Follow-up 

Description of 

Sample 

Sample Size Number/ 

% Male 

Mean Age/ 

Range 

Etiology of 

Burn 

Mariano et al., 2004, Italy68

NRC Group 1: ~ 1 

month Group 2: ~2 months 

Intensive care unit admissions with burns, septic shock, polytrauma, and acute renal failure 

Group 1: n = 6 (treated with citrate + Coupled Plasma Filtration Adsorption) Group 2: n = 7 (treated with heparin + Coupled Plasma Filtration Adsorption) 

10/77% Group 1: 57 

years/26 - 77 years Group 2: 44 years/21 - 60 years 

NR 

Mims et al., 1977, U.S.60

NRC 10 minutes per 

experiment (laboratory study) 

Burn unit admissions 

34 blood samples from seven burn patients; unknown number of blood samples from 10 controls (normal volunteers) 

NR/NR NR/NR Thermal 

Ono et al., 1984, Japan71

Cohort N/A Burn patients Heparin: n = 4 

Control: n = 8 

N/A/N/A N/A/N/A NR 

Peng et al., 2005, China70

RCT 4 months Burn unit 

admissions 

Heparin + venovenous continuous renal replacement therapy: n = 10 Controls: n = 10 

19/95% Heparin + 

veno-venous: 34.3 years/NR; Controls: 32.0 years/NR 

NR 

Reyes et al., 2001, Mexico75

Cohort NR Admission to 

emergency room or intensive care unit following industrial explosion 

Heparin on admission: n = 4 Heparin starting day 5: n = 5 (2 patients received heparin before day 5) 

8/89% 30 years/ 

17 - 40 years 

Flame 

Srivastava et al., 1988, India73

Cohort NR Admissions to 

burns and plastic surgery unit 

Heparin (topical and systemic): n = 25 Control: n = 25 

Heparin: 11/44% Control: 14/56% 

8 - 55 years NR 

Venkatachalapathy et al., Unpublished, India72

RCT 7 days Burn unit 

admissions 

Heparin: n = 50 Control: n = 50 

 49/49% NR/15 - 35 

years 

Flame, scald 
35

Table 5. General characteristics of the abstracted studies (continued)

Study Study 

Design 

Length of 

Follow-up 

Description of 

Sample 

Sample Size Number/ 

% Male 

Mean Age/ 

Range 

Etiology of 

Burn 

Wahl et al., 2002, U.S. (a)57 + 

(b)58†

Cohort NR Hospital 

admissions 

DVT: n = 7 No DVT: n = 23 

22/73% DVT: 49 ± 23 

years/NR; No DVT: 44 ± 17 years/NR 

Flame or flash: n = 25 (9 with inhalation injury) 

Wahl and Brandt, 2001, U.S.63

Cohort (database review) 

3.5 years Burn center 

admissions 

DVT: n = 8 (3 given low molecular weight heparin) No DVT: n = 319 

DVT: 7/88%; No DVT: NR/NR 

DVT: 44 ± 17 years; No DVT: 43 ± 19 years 

NR 

Waymack et al., 1988, U.S.64

Cohort (chart review) 

N/A Pediatric burn 

unit admissions with renal vein thrombosis 

Heparin: n = 3 Control: n = 3 

NR/NR NR/1.5 - 9 

years 

NR 

Zayas et al., Unpublished, El Salvador74

Cohort 1 year Pediatric 

hospital admissions 

Heparin: n = 10 (admitted 1999) Control: n = 9 (admitted 1998) 

11/58% 3.5 years/ 0.25 

- 8 years 

Flame, scald 

TBSA = total body surface area involvement; NR = not reported; RCT = randomized controlled trial; NRC = non-randomized comparison; DVT = dee

not applicable. 

†Wahl et al. studies labeled (a)57 and (b)58 were conducted using the same group of patients. 
36

Table 6. Heparin treatment regimens and results – abstracted studies 

Author Type of 

Heparin 

Method of 

Heparin 

Administration 

Heparin 

Treatment 

Regimen 

Outcomes Results 

Acharya69 Hirudoid anticoagulant 

(100 g equivalent to 25,000 units of heparin) 

Topical NR 1) Pain relief (relief 

within 5 minutes to 3 hours) 2) Healed (reduction of the burned or inflamed surface by ≥ 50% within 

3 days) 

1) Hirudoid cream group: 27/36 pain relief and 19/36 healed 2) Anacal ointment group: 16/16 pain relief and 4/16 healed 3) Antibiotic group: 24/33 pain relief a16/33 healed 

Curreri et al.61 NR Subcutaneous 5,000 units Fibrin split-product concentration No quantitative data reported in the published article Desai et al.59

NR Aerosolized 5,000 units of 

aerosolized heparin alternating with 3 ml of a 20% solution of acetylcystine, every 2 hours for the first 7 days after injury 

1) Reintubation 2) Atelactasis 3) Mortality 

1) Reintubation: heparin group 3/47, control group 12/43. 2) Atelactasis: heparin group 20/47, control group 30/43 3) Mortality: heparin group 2/47, contgroup 8/43†

Iashvili et al.66

NR Subcutaneous 6,000 units in the 

3 groups treated with heparin 

1) Changes in the gastrointestinal mucosa (e.g., ulcers, erosions, and hemorrhages) 2) Separation of the burn eschar 3) Time between burning and development of the wound surface ready for auto grafting 4) The period of treatment between burning and complete healing 

1) Changes in the gastrointestinal mucosa: control group12/20, group 4 (complete therapeutic regimen) 7/20 2) Separation of the burn eschar: 7-9 days faster in group 4 3) Time between burning and development of the wound surface ready for auto grafting: 44% shorter in group IV 4) The period of treatment between burning and complete healing: Reduced 30 days in group 4 

Khadzhiiski et al.67

Heparin (cream and dressing) 

Topical 5,000 IU Cicatrisation Significant reduction in primary 

cicatrisation in 37 treated children and adults compared to 27 controls†
37

Table 6. Heparin treatment regimens and results – abstracted studies (continued) 

Author Type of 

Heparin 

Method of 

Heparin 

Administration 

Heparin 

Treatment 

Regimen 

Outcomes Results 

Kuz’muk et al.65 NR NR NR 1) Prothrombin activity 2) Thrombotest value 

3) Plasma recalcification time 4) Plasma tolerance to heparin 5) Fibrinogen concentration 

No quantitative data reported in the published article 

Loebl et al.62

NR Subcutaneous 20,000 units in 

four divided doses 

Autologous half-life of erythrocytes 

No quantitative data reported in the published article 

Mariano et al.68

NR Continuous 

infusion 

Heparin + CPFA as renal replacement therapy 

1) Blood flow 2) Used cartridges/session 3) Blood iCa2+.

4) Blood pH and bicarbonates 

No quantitative data reported in the published article 

Mims et al.60 Beef lung and intestinal 

mucosal 

NR Heparin not used 

for treatment (heparin was used as a reagent) 

Platelet aggregation In contrast to controls, 15% of blood 

samples from burn patients demonstrated spontaneous aggregation, and 69% showed either first or second phase aggregation afteexposure to heparin 

Ono et al.71

NR Infusion 10,000 - 20,000 

IU daily 

1) Platelet counts 2) Fibrinogen levels 3) Plasminogen levels 4) Fibrin degradation product levels 

No quantitative data reported in the published article 

Peng et al.70 Heparin and low molecular 

weight heparin 

Intravenous 100 - 1,500 units 1) Median stay in ICU 

2) Total days in hospital 3) Mortality 

No quantitative data reported in the published article 
38

Table 6. Heparin treatment regimens and results – abstracted studies (continued)

Author Type of 

Heparin 

Method of Heparin 

Administration 

Heparin 

Treatment 

Regimen 

Outcomes Results 

Reyes et al. 200175

NR Infusion, 

subcutaneous, sprayed or dripped via needle, aerosolized 

1st application was 5,000 IU/ml dripped or sprayed on open burn surfaces or injected into burn blisters - retreatment at 5 - 10 minute intervals for 20 - 30 minutes 

1) Mean doses of pain medication 2) Swelling 3) Fasciectomy 4) Burn revascularization 

1) Mean doses of pain medication: heparin group (received heparin day 4 doses, control group (received hepaday 5 and later) = 24 doses† 

2) Patients given heparin on day 1 haless burn swelling and body swelling, no fasciectomies, compared to patiengiven heparin on day 5 3) Burn revascularization was faster ipatients given heparin on day 1 

Srivastava et al.73 NR Topical and systemic 1) Systemic route: 10,000 

units/10% burn area, repeated every 4-6 hours; increased to maximum 300-400 units/15% burn/kilogram body weight 2) Topical application: 25,000 units/10% burn 

1) Mortality 2) Mean healing time 3) Full thickness Eschar separation 4) Raw area fit for grafting 5) Graft take 

1) Mortality: heparin group 3/25, contgroup 11/25 2) Mean healing time: heparin group 6 days (superficial) and 15 days (deep dermal), control group 10 days (superficial) and 28 days (deep derma3) Eschar separation: heparin group 1days, control group 21 days 4) Fit for grafting: heparin group 20 dacontrol group 36 days 5) Graft take: heparin group 95%, congroup 65% 

Venakatachalapathy et al.72

Heparin sodium solution (bovine intestinal mucosa) 

Dripped onto burn surfaces or injected into burn blisters 

200 IU/ml 1) Mortality 

2) Days in hospital 3) Number of skin grafts 

1) Mortality: heparin group 0/50, contgroup 5/50 2) Days in hospital: heparin group had patients discharged in ≤ 10 days, con

group had 3 patients discharged in ≤ days†

3) Number of skin grafts: heparin grou4/50, control group 10/50 

Wahl et al. (a)57 + (b)58‡

Lowmolecularweight heparin (enoxaparin) 

Subcutaneous 40 units 4x/day Development of upper 

or lower extremity DVT or pulmonary embolism 

7 patients had DVT (1 patient had upextremiy DVT and 2 patients had both upper and lower extremity DVT). 6 patients had Superficial Vein Thrombosis (SVT) in the upper extremities. 
39

Table 6. Heparin treatment regimens and results – abstracted studies (continued)

Author Type of 

Heparin 

Method of 

Heparin 

Administration 

Heparin 

Treatment 

Regimen 

Outcomes Results 

Wahl and Brandt63

Lowmolecularweight heparin 

NR NR DVT NR (for heparin) 

Waymack et al.64

NR NR NR 1) Mortality 

2) Normal pyelogram (heparin group) 

1) Mortality: heparin group 0/3, controgroup 3/3 2) Normal pyelogram: heparin group 3/3, control group not given test 

Zayas et al.74

Sodium aqueous heparin (swine intestine) 

Intravenous and topical liquid 

1) Scald burns: intravenous oneday dose was 400 IU/kg body weight/15% burn size 2) Explosion-firesmoke burns: total one-day dose was 1,000 - 1,200 IU/kg body weight/15% burn size 3) Topical use (2 - 3X daily): 5,000 IU/ml sprayed via needle onto burn wound surfaces or injected into burn blisters 

1) Survival 2) Days in hospital 3) Sepsis 4) Bleeding 

1) Survival: heparin group 6/10, contrgroup 1/ 9†

2) Days in hospital: heparin group average 36.6 days, control group average 11.4 days (n = 7) 3) Sepsis: heparin group 4/10, controgroup 9/9†

4) Bleeding: heparin group 1/10, contgroup 0/9 

NR = not reported; DVT = deep vein thrombosis; SVT = superficial vein thrombosis; CFPA = Coupled Plasma Filtration Adsorption. †p < 0.05 (in studies without this indication, the results were not statistically significant at the 5% level or the authors did not report whether the result‡Wahl et al. studies labeled (a)57 and (b)58 were conducted using the same group of patients.
40

Table 7. Quality assessment of abstracted articles – Group A 

Selection Bias Study Design Control of Confounding 

Authors Participants 

Representative of 

Study Population 

PR CR Explained 

Treatment 

Assignment 

of Subjects 

Blinding Use of 

Valid Data Collection 

Tools 

Groups 

Differ on 

Confoun

-ders 

Control of 

Confounding 

Acharya69 Not likely NR ≥ 80% No NR No NR No Desai et al.59 Not to somewhat 

likely 

NR ≥ 80% No NR No NR No 

Iashvili et al.66 Very likely NR ≥ 80% No NR Yes Yes No Khadzhiiski et al.67

Not likely NR ≥ 80% No NR No NR No 

Ono et al.71 Not likely NR ≥ 80% No NR No No Reyes et al.75 Somewhat likely ≥

80% 

≥ 80% Yes NR No Yes No 

Srivastava et al.73 Not likely NR ≥ 80% No NR No NR No Venakatachalapathy et al.72 Very likely ≥80% ≥ 80% No NR No Yes No Waymack et al.64 Not likely N/A N/A No NR No Yes No Zayas et al.74 Somewhat likely ≥

80% 

≥ 80% Yes NR No Yes No 
41

Table 7. Quality assessment of abstracted articles – Group B 

 Selection Bias Study Design Control of 

Confounding 

Authors Participants 

Representative of 

Study Population 

PR CR Explained 

Treatment 

Assignment 

of Subjects 

Blinding Use of 

Valid Data Collection 

Tools 

Groups 

Differ on 

Confoun

-ders 

Control of 

Confounding 

Curreri et al.61 Not to somewhat 

likely 

NR ≥ 80% No NR Yes NR No 

Kuz’muk et al.65 Not likely NR NR No NR NR NR No Loebl et al.62 Not likely ≥

80% 

≥ 80% No NR Yes NR No 

Mariano et al.68 Not likely NR ≥ 80% Yes NR Yes NR No Mims et al.60 Not likely NR ≥ 80% No NR Yes Yes No Peng et al.70 Not likely ≥

80% 

≥ 80% No NR Yes No 

Wahl et al.57 Somewhat likely ≥

80% 

≥ 80% No NR Yes NR No 

Wahl et al.58 Somewhat likely ≥

80% 

75% No NR Yes Yes No 

Wahl et al.63 Somewhat to very 

likely 

N/A N/A No NR Yes Yes No 

PR = participation rate; CR = completion rate; SS = statistical significance; NRC = non-randomized comparison; NR = not reported; RCT trial; N/A = not applicable. 
42
43

Chapter 4. Discussion and Future Research 

Overall Summary of Evidence from the Abstracted Studies 

There is no strong evidence in the 19 abstracted articles to indicate that the non-anticoagulant 

properties of heparin improve clinical outcomes in the treatment of burn injury. The lack of 

evidence is largely a function of the poor quality of the articles. Many of the articles did not 

contain clinical outcomes and in those that did, these outcomes were not always well defined. 

Additionally, the quality of several of the studies was low, with high potential for selection bias, 

inadequate control of confounding, and no mention of the use of blinding during exposure and 

outcome assessment. 

Pain and cosmesis—outcomes of high clinical interest in burn injury—were often improperly 

measured in the studies in which they were considered. Instead of using a valid and reliable tool 

such as the McGill Pain Scale78 to measure pain, the authors of two studies72,75 measured pain by 

looking at the degree of use of pain medication. The problem with this approach is that 

physician judgment may be substituted for patient judgment when it comes to the use (and 

degree of use) of pain medication. Since the studies were not blinded, there may also have been 

an a priori belief that heparin-treated patients would not need pain medication, and this might 

have influenced whether they actually got the medication. Thus, one cannot be sure that use of 

pain medication adequately measures patient pain. In another study, the authors asserted that 

heparin provided more pain relief than conventional treatment because of the anecdotal 

observation that “The noisy din and distressing emotional ambience of the Emergency Room or 

the Burn Ward was soon replaced by a quiet calm [once patients received heparin].”74 Anecdotal 

observations such as this do not constitute evidence of a treatment effect. 

For cosmesis, two studies relied on patient photographs to show a benefit for heparin-treated 

patients.72,75 However, in one of these studies, the authors did not show photographs of all of the 

patients.72 In both studies, the number of days after injury on which the published photographs 

were taken varied, as did the parts of the patients’ bodies that were photographed. To be 

acceptable for demonstrating treatment efficacy in a research study, photographic evidence must 

be standardized, e.g., all patients should be photographed, each patient’s photographs should be 

taken at the same points in time during follow-up, and the same parts of each patient’s body 

should be photographed (from the same angles). As well, a protocol must be developed to 

ensure that photographic evidence is interpreted in a standardized manner, much like is done in 

studies where imaging tests are used to assess treatment efficacy. 

Contextual Issues Regarding the Evidence from 

Abstracted Studies 

The time and location of many of the abstracted studies deserve particular note. The studies 

spanned more than three decades, beginning in 1971. During this period, burn care underwent a 

major transformation, the hallmark of which was markedly improved survival.45,46 At one 

American burn center, burn survivability—measured by the LA50— improved from 43 percent 

(young adults) and 23 percent (older adults) in 1940 to 60.8 percent (young) and 39.2 percent 

(older) in the late 1970s and early 1980s. Even more dramatic was the improvement in pediatric 
44

burn survival at this center, which was 51 percent in 1940 and 93 percent in 1986.45 Further 

transformation occurred with the development of networks of specialized burn treatment centers 

in some countries. These centers are capable of handling local injuries and the treatment of 

people with serious burn injuries who are transferred from distant locales. Burn care was aided 

by advancements in multiple areas of medicine, including critical care medicine, wound infection 

control, antimicrobial therapy, surgical therapy, specialized burn care research, and coordinated 

methods of burn patient transfer. Early excision therapy became possible within the context of 

these advances and it has become a standard component of surgical care for full thickness burn 

injuries in some countries.46

In the articles abstracted for this evidence report, the treatment protocols employed by some 

of the researchers did not match these aforementioned approaches to burn care. Thus, even if the 

evidence for using heparin in the treatment of burn injury was stronger, it would be difficult to 

apply this evidence to all clinical contexts. For example, Venkatachalapathy et al.,72 who 

conducted their work in Pondicherry, India, reported a lag of 1 to 8 hours between the time of 

burn injury and the initiation of treatment. The lags were caused by either medico-legal matters 

at referral hospitals or referral distances of up to 150 kilometers. In contrast, the regionalization 

of specialized burn care in the United States has enabled the development of burn patient transfer 

protocols, including use of air ambulances and accompanying medical support services, that 

minimize transfer delays due to bureaucracy or distance.45 In the studies by Zayas et al.,74 Reyes 

et al.,75 and Srivastava et al.,73 burn injuries included full thickness burns, but none of the authors 

reported whether early excision or grafting was used in the treatment of these injuries. Early 

excision and grafting of full thickness burn injuries is currently common practice in some 

countries.47

Some of the differences between study protocols and standards of burn care were temporal in 

nature. For example, Waymack et al.’s chart review was published in 1988 and included charts 

from 20 years earlier.64 Therefore, this study was not likely to contain treatment protocols that 

reflect the current state of the art. Additionally, given the publication dates of the articles, the 

types of heparin that were studied are probably not used today. Low molecular weight heparins 

(LMWHs) have largely replaced unfractionated heparin (UFH) for some clinical indications 

because LMWHs possess superior pharmacodynamic and pharmacokinetic properties, as well as 

fewer side effects.3

 Recently, a synthetic LWMH was developed and is now available for 

clinical use.4

The other reason for the difference between study protocols and standards of burn care 

related to the originating country or region of the study. Of the 10 abstracted articles that 

pertained directly to the use of heparin in the treatment of burns (Table 7 – Group A), two were 

from India and two were from Latin America. In both locations, the research focus was on 

heparin’s wound healing effects in relation to cosmesis, function, and mortality. In the United 

States, the research focus was on heparin’s anticoagulant effects in relation to venous thrombosis 

(deep vein thrombosis,57,58,63 renal vein thrombosis64, as well as on heparin’s anti-inflammatory 

effects in relation to inhalation injury.59

Heparin and Sepsis 

In the abstracted studies, claims regarding heparin use in burn care included beneficial effects 

with respect to the treatment of sepsis in pediatric73,74 and adult burn patients.73 Sepsis is 
45

associated with a heightened inflammatory response and adverse activation of the coagulation 

cascade.79 Eradication of sources of infection is one goal of sepsis treatment. 

Early excision and grafting therapy has been utilized to ameliorate factors that can contribute 

to the development of sepsis. This therapy has led to improved survivability for pediatric burn 

patients.80 Wound sepsis and contamination both decreased in one study comparing early 

excision and grafting to conventional wound debridement therapy.81 Yet early excision and 

grafting may not be the current standard of burn care in some countries. New therapeutic efforts 

for treatment of sepsis have been targeted at the dysregulation of the coagulation system during 

sepsis. Heparin’s place within this new area of research is both complicated and controversial. 

In phase III trials regarding sepsis and anticoagulant agents such as activated protein C (APC), 

tissue factor pathway inhibitor, and antithrombin III, heparin may have been a confounder. 

Hypothesized explanations for this effect included heparin’s reversal of the pro-coagulant effects 

of sepsis or the negation of the anticoagulant effects of the aforementioned agents.79 Heparin 

may therefore have singular beneficial effects on the survival of patients with critical illness 

(including sepsis).79 The studies of Zayas et al.74 and Srivastava et al.,73 albeit methodologically 

weak, suggest that heparin’s hypothetical role in the care of sepsis and burn injury specifically 

warrants further investigation. Furthermore, the investigation of heparin’s role in the treatment 

of sepsis may be of particular importance due to issues of cost. Both Reyes et al.75 and Zayas et 

al.74 commented on the low cost of heparin. The implication is that this substance might entail a 

more affordable and sustainable medical intervention for patients with burn injury and sepsis in 

some countries. Davidson et al.82 reported comparable survival benefits with heparin relative to 

APC in the treatment of sepsis and Kent et al.83 noted that heparin was less expensive than APC 

(e.g., $8.00 for a 96-hour heparin infusion versus $6,700 for a 96-hour APC infusion). 

Heparin and smoke inhalation 

Heparin may entail benefits for the treatment of smoke inhalation. One of the abstracted 

studies contained reports of beneficial outcomes in this area.59 Further investigation is warranted 

because inhalation injury remains a significant factor related to mortality in burn injury.84

Heparin and Psychiatric and Psychosocial Outcomes 

 The pain associated with a burn injury or wound debridement can adversely affect the 

psychiatric or psychosocial health of people with burn injury. Wound healing, accompanied by 

hypertrophic scarring, contractures, functional disability, or cosmetic disfigurement, may also 

detract from adequate post-burn psychiatric and psychosocial adjustment. The abstracted studies 

were reviewed to see if there was any evidence to suggest that the use of heparin to treat burns 

would lead to improved psychiatric and psychosocial outcomes for burn victims. 

The authors of the abstracted studies did not systematically examine the psychiatric or 

psychosocial adjustment of patients with burn injury. Zayas et al. anecdotally addressed the 

problem in their study of severe pediatric burn injury.74 They reported that heparin use 

eliminated burn pain and the concomitant ‘distress’ associated with wound care. The authors 

described children who received heparin as “cooperative” during wound care. Similar results 

were reported for adult patients who had significant burn injuries.72 However, the adult reports 

were also anecdotal and not based on any reliable and valid measures of psychiatric or 

psychosocial adjustment. 
46

There has been considerable academic and clinical attention focused on the 

psychopharmacological and non-pharmacological means of ameliorating burn pain and the 

distress associated with acute wound care.85-88 Hospitalized, burn-injured children and 

adolescents in the acute injury phase have been identified to be at risk for developing acute stress 

disorder (ASD) or post-traumatic stress disorder (PTSD).89-91 In pediatric and adult patients with 

burn injury, the pain associated with the injury and subsequent care is thought to be an 

etiologically significant component of patients’ early psychiatric and psychological 

adjustment.51,92 Zayas et al.,74 Venakatachalapthy et al.,72 and Srivastava et al.73 employed a 

mixture of anecdotal and objective measures of wound healing, scarring, and contractures, but 

they reported only immediate clinical outcomes at the time of discharge. They did not consider 

the psychiatric or psychosocial impact of the burn injuries. Heparin’s place as an effective 

intervention for the prevention or amelioration of psychiatric and psychosocial outcomes 

associated with burn injuries awaits further systematic research. 

Conclusion 

In conclusion, this report summarizes the evidence for the use of heparin to treat burns. After 

a thorough and systematic literature search and article screening process, 19 articles from 18 

unique studies were abstracted and included in this report. From the perspective of heparin’s 

non-anticoagulant properties, there was some evidence that heparin use might result in improved 

outcomes for burn patients in areas such as mortality, wound healing, pain, and cosmesis. 

However, this evidence was not strong, and therefore not supportive of, the use of heparin in the 

treatment of burns. The lack of strong evidence largely resulted from the fact that many of the 

abstracted studies suffered from serious methodological weaknesses and were altogether of poor 

quality. Although the evidence is beset by these problems, there still remains a great deal of 

clinical interest in, and active use of, heparin in burn care. This report contains 

recommendations for future research into heparin’s use in the treatment of burn injury. 

Future Research into Heparin as a Treatment for Burns 

Future research into the use of heparin to treat burns should have the following minimum 

design requirements: well-defined study populations, clearly defined and relevant clinical 

outcomes (measured using accepted and objective criteria), and valid comparison groups. Future 

studies should also utilize strong designs that minimize confounding (e.g., randomized controlled 

trials [RCTs]) and avoid the pitfalls of the 19 articles that were abstracted for this evidence 

report. These pitfalls included unclear methods of allocation and treatment,67,69,93 no power 

calculations or use of validated, well-defined outcomes,67,69,72 and little discussion of potential 

biases or study limitations (a problem with all of the abstracted studies). For RCTs, manuscripts 

should be written in accordance with the Consolidated Standards of Reporting Trials 

(CONSORT) guidelines, which promote consistent and transparent reporting of RCT results so 

that readers can assess study quality.94
47

Design of Studies of Heparin in the Treatment of Burns

Issues to Consider 

The following issues are important to consider when designing studies of heparin in the 

treatment of burns. 

 

Population. There is great heterogeneity within the burn patient population. These patients can 

be categorized by burn etiology, burn depth, and burn surface area. Each of these domains has 

important effects on clinical outcomes such as pain, scarring, length of stay, and mortality. Few 

of the abstracted studies appropriately defined the populations of interest with respect to these 

domains. Future studies should be sufficiently powered to perform subgroup analyses by these 

domains, or they should be designed to focus on a specific type of burn patient (e.g., patients 

with bilateral upper or lower extremity burns). 

To maximize the applicability of study results, researchers should seek to enroll consecutive 

patients during a pre-specified time period rather than to rely on convenience samples that may 

be more atypical of the general patient population. For RCTs, which generally have poor 

generalizability, researchers should attempt to focus on less selective study populations.95

 

Intervention. Some of the abstracted studies contained poor definitions of the type of heparin 

that was used to treat patients. The following issues must be clarified in future studies: 

• Heparin type, concentration, and carrier; 

• Time of application, including how soon after injury, frequency of application, and 

duration of application; and 

• Method of application, including concomitant treatments such as dressings. 

Control group. Controls must be recruited during the same time frame and from the same 

locations as people who will be receiving active heparin. For RCTs, the determination of 

whether a study participant goes into the control or heparin group should be made randomly 

using a computer-generated algorithm. 

The use of historical controls is inappropriate because temporal differences in patient 

characteristics or treatment protocols might lessen the comparative similarity of the study 

groups. 

Modes of treatment between groups must be as similar as possible, save for the use of 

heparin in the active treatment group. For example, if heparin is applied using an oil-based 

carrier, then the control group must have the same carrier applied without heparin. A failure to 

do so might exaggerate the potential treatment benefits of heparin because it is plausible that the 

application of the carrier itself could create a protective barrier for the burns. Similar arguments 

can be made for other carriers. 

Outcomes. Many of the abstracted studies focused on non-clinical, or poorly defined clinical, 

outcomes. To influence medical practice, well-defined, valid, and clinically relevant outcomes 

must be used in future studies. Validated outcome measures have been developed for use in 

burns, but they have not yet been applied to assess heparin. For example, one extremely 
48

germane outcome in burn injury is scar appearance, which can be measured using the Vancouver 

Scar Scale.96

Focus of Future Studies of Heparin in the Treatment of Burn Injury

Two sets of studies are proposed to investigate the efficacy of heparin in the treatment of 

burn injury. 

First set of studies. In some countries, the wound healing effects of heparin have been the focus 

of much research. However, the abstracted evidence is not strong enough to support heparin use 

as the standard of care for wound healing. Since the lack of strong evidence is due to the poor 

quality of the abstracted articles, further research into heparin’s wound healing properties is 

justifiable and recommended. As discussed in Chapter 1, there is basic science evidence for 

heparin’s use as a wound healing agent in burn injury, and there is clinical evidence that a 

temporary dermal replacement consisting of cross-linked collagen and chondroitin-6-sulfate (a 

molecule similar in structure to heparin) with a silicone coating can promote wound healing in 

the burned hand.97 Indeed, improved wound healing and the possibility of correspondingly 

improved cosmesis and function are desired objectives for burn care.47

Given that research into heparin’s ability to heal burn wounds is in its early stages, a 

preliminary trial is recommended to study whether heparin can accelerate the healing of donor 

areas for skin grafts. The study population would consist of adults and adolescents who would 

be randomized to receive heparin plus standard treatment or standard treatment alone as wound 

care for the donor area of a skin graft (a wound equivalent to a partial thickness burn). In the 

heparin group, standard, UFH would be applied topically to the donor area approximately 24 

hours after stoppage of bleeding. Outcomes would include healing time of the donor area, pain, 

itching, and scarring. If bleeding persists, heparinoids (e.g., non-anticoagulant heparin) instead 

of UFH can be used in the heparin group. Research of this type may have an impact on the 

psychiatric morbidity associated with burn injuries and care, especially morbidity from skin 

grafting and the pain and discomfort of donor areas. Therefore, psychiatric outcomes such as 

ASD and PTSD should be evaluated in the proposed study. 

If outcomes in the preliminary trial are better in the heparin versus control group, then a 

second trial could be conducted in adults, adolescents, and children. This trial would involve 

people with bilateral upper or lower extremity burns (i.e., both hands, arms, or legs). Topical 

heparin would be applied to one extremity and standard care would be applied to both 

extremities. Each participant would act as his or her own control, and the extent to which the 

burn on each extremity heals would be compared using the same outcomes as in the preliminary 

trial discussed above. Extremity-specific outcomes may also be used in the comparison. For 

example, if burned hands are the extremity in question, then outcomes could include a thumb 

opposition score, fingertip-to-palm distance measure, and prehensile score.97 Psychiatric 

outcomes would also be the same as in the preliminary trial, plus there would be an assessment 

of quality of life. 

The trials would be multi-center so that an adequate number of people could be recruited to 

obtain a power of at least 80 percent. In the case of burn injuries that require early excision and 

grafting, the route of heparin administration might be of particular relevance. Intravenous and 

subcutaneous routes may be preferable in this research arena because there would not be direct 
49

contamination of graft sites, whereas topical heparin in combination with early excision and 

grafting might negatively affect graft take and present an unethical risk for patients. 

Second study. The second proposed study would involve a single RCT to examine the use of 

aerosolized heparin to treat critically injured burn patients who are suffering from inhalation 

injury. Pediatric and adult populations would be randomized to receive standard treatment plus 

aerosolized heparin or standard treatment alone. Based on the anti-inflammatory properties of 

heparin (which are summarized in the introduction), it is thought that heparin could contribute to 

improved outcomes in people with inhalation injury. One of the abstracted studies found 

positive benefits from using aerosolized heparin and acetylcystine in the treatment of inhalation 

injury in children, but selection bias could not be ruled out because the control and heparin 

groups were recruited at different points in time, the authors were not clear as to whether 

consecutive patients were approached for recruitment into the study, and the authors did not 

report a participation rate.59

Possible outcomes for the RCT on inhalation injury would include mortality, reintubation 

rate, length of stay in the intensive care unit (ICU), and incidence of pulmonary complications 

(e.g., acute respiratory distress syndrome, atelectasis, and pneumonia). As with the first set of 

studies, there should be an investigation of the psychiatric morbidity associated with burn injury 

and care. In addition to evaluating ASD, PTSD and quality of life, two additional psychiatric 

outcomes should be examined on account of the ICU context of the RCT, namely ICU psychosis 

and delirium. The RCT would be carried out in burn centers with advanced levels of 

technological support to meet patients’ intensive care needs and facilitate the use of aerosolized 

heparin. In addition, burn care centers with advanced technological support would likely enable 

the identification and description of an optimal patient population. This is particularly important 

because inhalation injury is strongly associated with mortality, which may act as a confounder in 

this type of research if not well documented. Multi-site research will be necessary to ensure 

adequate patient recruitment and meet sample size requirements. 

Additional basic science research. The trial of heparin’s wound healing properties on donor 

areas for skin grafts could involve a basic science component. Blood samples or tissue biopsies 

could be taken from trial participants and examined to gain information on the mechanisms of 

heparin’s action (e.g., heparin’s effect on wound-healing cytokines). 

Study outcomes. A variety of clinical outcomes should be considered for the next generation of 

studies on heparin and burns. The outcomes would vary slightly depending on whether adult or 

pediatric populations are studied. Some of these outcomes are: 

1. Mortality; 

2. Incidence of medical procedures following initial treatment with heparin or standard 

therapy (e.g., reintubation, excision, grafting); 

3. Pain (measured using the McGill Pain Scale78); 

4. Scarring (measured using the Vancouver Scar Scale96); 

5. Itching (measured via the amount of anti-pruritic medications used [e.g., Benadryl®]) 

6. Quality of Life (measured using the Health Outcomes Burn Questionnaire98,99

 for children and the Burn-Specific Health Scale100 for adults); and 

7. Post-traumatic Stress Disorder (measured using the Child Stress Disorders 

 Checklist101 for children and a selected range of measurement methodologies102 for adults). 
50

Studies that are designed with the above precepts in mind will overcome the pitfalls of the 

abstracted articles and provide the clinical community with a clearer picture of the efficacy of the 

various uses of heparin in the treatment of burns. 
51

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Heparin in the management of extensive burns. 

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dis-improved: on the evaluation and use of less 

effective, less expensive medical interventions. 

Med Decis Making 2004 May;24(3):281-6. 

 84. Ryan CM, Schoenfeld DA, Thorpe WP, et al. 

Objective estimates of the probability of death 

from burn injuries. N Engl J Med 1998 Feb 

5;338(6):362-6. 

 85. Tarnowski KJ, Rasnake LK, Drabman RS. 

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 86. Stoddard FJ, Sheridan RL, Saxe GN, et al. 

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 88. Martin-Herz SP, Thurber CA, Patterson DR. 

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 89. Stoddard FJ, Saxe G, Ronfeldt H, et al. Acute 

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Jan;45(1):87-93. 

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 91. Drake JE, Stoddard FJ, Jr., Murphy JM, et al. 

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57

Acronyms and Abbreviations

ACCP American College of Chest Physicians 

AHRQ Agency for Healthcare Research and Quality 

APC Activated Protein C 

ASD Acute Stress Disorder 

bFGF basic Fibroblast Growth Factor 

CFPA Coupled Plasma Filtration Absorption 

CHF Chronic Heart Failure 

CONSORT Consolidated Standards of Reporting Trials 

CPB Cardio Pulmonary Bypass Surgery 

Da Daltons 

DVT Deep Vein Thrombosis 

EPH Tool Effective Public Health Practice Project Quality 

Assessment Tool for Quantitative Studies 

GAGs Glycosaminoglycans 

ICU Intensive Care Unit 

LA50 

Lethal Level of Accumulation at 50 Percent Effect Level 

LMWH Low Molecular Weight Heparin 

LV Left Ventricular 

MU-EPC McMaster University Evidence-based Practice Center 

PE Pulmonary Embolism 

PTSD Post-Traumatic Stress Disorder 

RCT Randomized Controlled Trial 

RVT Renal Vein Thrombosis 
58

SRS Systematic Review Software 

SVT Superficial Vein Thrombosis 

TBSA Total Body Surface Area 

TEP Technical Expert Panel 

TFPI Tissue Factor Pathway Inhibitor 

TOO Task Order Officer 

U.S. United States 

UFH Unfractionated Heparin 

VEGF Vascular Endothelial Growth Factor 

VTE Venous Thromboembolism 
A - 1 

Appendix A – Technical Expert Panel 

Bishara Atiyeh, MD, FACS, PhD 

Secretary General, WHO: Mediterranean Council for Burns & Fire Disasters 

Clinical Professor, Division of Plastic and Reconstructive Surgery 

American University of Beirut Medical Center 

Beirut, Lebanon 

David Herndon, MD 

President, International Society for Burn Injuries 

Chief of Staff, Galveston Shriners Hospital 

Galveston, Texas 

Leo Klein, MD, PhD 

Brigadier General, Surgeon General of the Czech Armed Forces (retired) 

Head, Dept. of Burns Medicine, Prague Burn Center 

Associate Professor, 3rd Medical Faculty, Charles University 

Prague, Czech Republic 

Ján Koller, MD, CSc, PhD 

President, European Association of Tissue Banks 

Head, Teaching Department for Burns and Reconstructive Surgery 

Central Tissue Bank 

University Hospital Bratislava Ruzinov 

Bratislava, Slovak Republic 

Gurvaneet Randhawa, MD, MPH 

Task Order Officer, Agency for Healthcare Research and Quality 

Rockville, Maryland 

Michael J. Saliba Jr., MD 

Nominator of the heparin and burns topic to AHRQ 

Chairman, The Saliba Burns Institute 

La Jolla, California 

Glenn Warden, MD, MBA 

President and CEO, Warden BioScience Associates 

Salt Lake City, Utah 

Steven E. Wolf, MD 

Professor, Department of Surgery 

University of Texas Health Science Center at San Antonio 

Director, US Army Institute of Surgical Research Burn Center 

Brooke Army Medical Center 

Fort Sam Houston, Texas 
B-1 

Appendix B – Search Strings 

Ovid MEDLINE(R) December 2005 

1 exp BURNS/ (34176) 

2 (burn or burns or scald$).ti,ab. (27779) 

3 (burn or burns or scald$).kw,kf. (39) 

4 thermal injur$.mp. (3113) 

5 or/1-4 (41466) 

6 Glycosaminoglycans/ (18154) 

7 exp Heparin/ (43913) 

8 heparin, therapeutic/ (0) 

9 anticoagulant$.mp. (45650) 

10 fibrinolytic agent$.mp. (15759) 

11 glucosaminoglycan$.mp. (227) 

12 heparin.mp. (62357) 

13 (heparinic acid or alpha-heparin or alpha heparin or liquaemin or sodium heparin).mp. 

[mp=title, original title, abstract, name of substance word, subject heading word] (304) 

14 or/6-13 (120774) 

15 or/7-8,12-13 (63236) 

16 5 and 15 (178) 

17 5 and 14 (293) 

18 animals/ not (humans/ and animals/) (3013652) 

19 17 not 18 (204) 

20 16 not 18 (120) 

21 limit 20 to (clinical trial or clinical trial, phase i or clinical trial, phase ii or clinical trial, 

phase iii or clinical trial, phase iv or comment or congresses or consensus development 

conference or consensus development conference, nih or controlled clinical trial or "corrected 

and republished article" or dictionary or directory or duplicate publication or editorial or 

evaluation studies or festschrift or government publications or guideline or historical article or 

interview or journal article or lectures or legal cases or legislation or letter or meta analysis or 

multicenter study or news or newspaper article or overall or patient education handout or 

periodical index or practice guideline or randomized controlled trial) (120) 

22 limit 21 to (clinical trial or clinical trial, phase i or clinical trial, phase ii or clinical trial, 

phase iii or clinical trial, phase iv or controlled clinical trial or evaluation studies or randomized 

controlled trial) (5) 

23 limit 20 to (addresses or bibliography or biography or case reports or comment or congresses 

or dictionary or directory or editorial or interview or lectures or letter) (20) 

24 16 not 23 (158) 

25 from 24 keep 1-158 (158)
B-2 

EMBASE December 2005 

1 Glycosaminoglycans/ (8239) 

2 exp Heparin/ (56642) 

3 heparin, therapeutic/ (0) 

4 anticoagulant$.mp. (44490) 

5 fibrinolytic agent$.mp. (10502) 

6 glucosaminoglycan$.mp. (131) 

7 heparin.mp. (74395) 

8 (heparinic acid or alpha-heparin or alpha heparin or liquaemin or sodium heparin).mp. 

[mp=title, abstract, subject headings, heading word, drug trade name, original title, device 

manufacturer, drug manufacturer name] (281) 

9 or/1-8 (115664) 

10 or/2-3,7-8 (74395) 

11 (Alpha Heparin or Ammonium Heparinate or Benzalkonium or Heparin or Clarin or 

Contusol or Disebrin or Eleparon or Elheparin or Elheparon or Endogenous Heparin or 

Epiheparin or Gag 98 or Hepalean or Heparinate Sodium or Heparine or Heparine Novo or 

Heparinic Acid or Heparin Lock Flush or Heparin Monosulfate or Heparin Ointment or Heparin 

Potassium or Heparin Sodium or Heparin Sulfate or Heparin Sulfuric Acid or Heparitin 

Monosulfate or Hepcon or Hep Lock or Hepsal or Lipo Hepin or Lipohepin or Liquaemin or 

Liquaemin or Sodium Liquemin or Menaven or Monoparin or Mucoitin Polysulfate or Mucoitin 

Polysulfate Ester or Mucoitin Sodium Polysulfate or Multiparin or Noparin or Panheparin or 

Panhepin or Panheprin or Praecivenin or Pularin or Sodium Heparin or Thrombareduct or 

Thromboliquin or Thromboliquine or Thrombophlogat or Thrombophob or Thrombophob Gel or 

Thrombosamine or Thrombosamine Heparin or Thrombosamine Heparine or Thrombo Vetren or 

Unfractionated Heparin or Vetren or Vister).mp. [mp=title, abstract, subject headings, heading 

word, drug trade name, original title, device manufacturer, drug manufacturer name] (77001) 

12 2 or 3 or 7 or 8 or 11 (77001) 

13 exp burn/ or exp chemical injury/ (21157) 

14 (burn or burns or scald$ or thermal injur$).mp. (27192) 

15 13 or 14 (29169) 

16 12 and 15 (245) 

17 animal/ or (animal/ and human/) (15813) 

18 animals/ not (humans/ and animals/) (12812) 

19 16 not 18 (245) 

20 limit 19 to (editorial or erratum or letter or note or "review") (59) 

21 19 not 20 (186) 

22 from 21 keep 1-186 (186) 

CINAHL December 2005 

1 Glycosaminoglycans/ (41) 

2 exp Heparin/ (1872) 

3 heparin, therapeutic/ (0) 

4 anticoagulant$.mp. (1997)

5 fibrinolytic agent$.mp. (823) 
B-3 

6 glucosaminoglycan$.mp. (2) 

7 heparin.mp. (2304) 

8 (heparinic acid or alpha-heparin or alpha heparin or liquaemin or sodium heparin).mp. 

[mp=title, subject heading word, abstract, instrumentation] (16) 

9 or/1-8 (4465) 

10 or/2-3,7-8 (2306) 

11 (Alpha Heparin or Ammonium Heparinate or Benzalkonium or Heparin or Clarin or 

Contusol or Disebrin or Eleparon or Elheparin or Elheparon or Endogenous Heparin or 

Epiheparin or Gag 98 or Hepalean or Heparinate Sodium or Heparine or Heparine Novo or 

Heparinic Acid or Heparin Lock Flush or Heparin Monosulfate or Heparin Ointment or Heparin 

Potassium or Heparin Sodium or Heparin Sulfate or Heparin Sulfuric Acid or Heparitin 

Monosulfate or Hepcon or Hep Lock or Hepsal or Lipo Hepin or Lipohepin or Liquaemin or 

Liquaemin or Sodium Liquemin or Menaven or Monoparin or Mucoitin Polysulfate or Mucoitin 

Polysulfate Ester or Mucoitin Sodium Polysulfate or Multiparin or Noparin or Panheparin or 

Panhepin or Panheprin or Praecivenin or Pularin or Sodium Heparin or Thrombareduct or 

Thromboliquin or Thromboliquine or Thrombophlogat or Thrombophob or Thrombophob Gel or 

Thrombosamine or Thrombosamine Heparin or Thrombosamine Heparine or Thrombo Vetren or 

Unfractionated Heparin or Vetren or Vister).mp. [mp=title, subject heading word, abstract, 

instrumentation] (2329) 

12 2 or 3 or 7 or 8 or 11 (2331) 

13 exp burn/ or exp chemical injury/ (5156) 

14 (burn or burns or scald$ or thermal injur$).mp. (5878) 

15 13 or 14 (6313) 

16 12 and 15 (12) 

17 animal/ or (animal/ and human/) (630) 

18 animals/ not (humans/ and animals/) (630) 

19 16 not 18 (12) 

20 limit 19 to (editorial or erratum or letter or note or "review") [Limit not valid in: CINAHL; 

records were retained] (3) 

21 19 not 20 (9) 

22 from 21 keep 1-9 (9)

EBM Reviews - Cochrane Central Register of Controlled Trials December 2005 

1 Glycosaminoglycans/ (171) 

2 exp Heparin/ (2686) 

3 heparin, therapeutic/ (0) 

4 anticoagulant$.mp. (2762) 

5 fibrinolytic agent$.mp. (1185) 

6 glucosaminoglycan$.mp. (8) 

7 heparin.mp. (5293) 

8 (heparinic acid or alpha-heparin or alpha heparin or liquaemin or sodium heparin).mp. 

[mp=title, original title, abstract, mesh headings, heading words, keyword] (71) 

9 or/1-8 (7651) 

10 or/2-3,7-8 (5388) 
B-4 

11 (Alpha Heparin or Ammonium Heparinate or Benzalkonium or Heparin or Clarin or 

Contusol or Disebrin or Eleparon or Elheparin or Elheparon or Endogenous Heparin or 

Epiheparin or Gag 98 or Hepalean or Heparinate Sodium or Heparine or Heparine Novo or 

Heparinic Acid or Heparin Lock Flush or Heparin Monosulfate or Heparin Ointment or Heparin 

Potassium or Heparin Sodium or Heparin Sulfate or Heparin Sulfuric Acid or Heparitin 

Monosulfate or Hepcon or Hep Lock or Hepsal or Lipo Hepin or Lipohepin or Liquaemin or 

Liquaemin or Sodium Liquemin or Menaven or Monoparin or Mucoitin Polysulfate or Mucoitin 

Polysulfate Ester or Mucoitin Sodium Polysulfate or Multiparin or Noparin or Panheparin or 

Panhepin or Panheprin or Praecivenin or Pularin or Sodium Heparin or Thrombareduct or 

Thromboliquin or Thromboliquine or Thrombophlogat or Thrombophob or Thrombophob Gel or 

Thrombosamine or Thrombosamine Heparin or Thrombosamine Heparine or Thrombo Vetren or 

Unfractionated Heparin or Vetren or Vister).mp. [mp=title, original title, abstract, mesh 

headings, heading words, keyword] (5440) 

12 2 or 3 or 7 or 8 or 11 (5535)

13 exp burns/ (664) 

14 (burn or burns or scald$ or thermal injur$).mp. [mp=title, original title, abstract, mesh 

headings, heading words, keyword] (1175) 

15 13 or 14 (1257) 

16 12 and 15 (5) 

17 from 16 keep 1-5 (5) 

18 from 17 keep 1-5 (5) 

WOS (Web of Science) December 2005 

TS=((heparin* OR Benzalkonium or Clarin or Contusol or Disebrin or Eleparon or Elheparin or 

Elheparon or Epiheparin or Gag 98 or Hepalean or Heparitin Monosulfate or Hepcon or Hep 

Lock or Hepsal or Lipo Hepin or Lipohepin or Liquaemin or Liquaemin or Sodium Liquemin or 

Menaven or Monoparin or Mucoitin Polysulfate or Mucoitin Polysulfate Ester or Mucoitin 

Sodium Polysulfate or Multiparin or Noparin or Panheparin or Panhepin or Panheprin or 

Praecivenin or Pularin or Thrombareduct or Thromboliquin or Thromboliquine or 

Thrombophlogat or Thrombophob or Thrombophob Gel or Thrombosamine or Thrombo Vetren 

or Vetren or Vister) AND (burn or burns or scald* or thermal injur*)) 

BIOSIS December 2005 

TS=((heparin* OR Benzalkonium or Clarin or Contusol or Disebrin or Eleparon or Elheparin or 

Elheparon or Epiheparin or Gag 98 or Hepalean or Heparitin Monosulfate or Hepcon or Hep 

Lock or Hepsal or Lipo Hepin or Lipohepin or Liquaemin or Liquaemin or Sodium Liquemin or 

Menaven or Monoparin or Mucoitin Polysulfate or Mucoitin Polysulfate Ester or Mucoitin 

Sodium Polysulfate or Multiparin or Noparin or Panheparin or Panhepin or Panheprin or 

Praecivenin or Pularin or Thrombareduct or Thromboliquin or Thromboliquine or 

Thrombophlogat or Thrombophob or Thrombophob Gel or Thrombosamine or Thrombo Vetren 

or Vetren or Vister) AND (burn or burns or scald* or thermal injur*)) 
C-1 

Appendix C – List of Excluded Studies 

Agnelli G, Sonaglia F. Prevention of venous 

thromboembolism. Thromb Res 2000; 97(1):V49-V62 

Status: Excluded because no comparison group 

Akhtar M, Gang RK. Treatment of Burns with Topical 

Heparin - Study of Its Analgesic Effect. Chirurgia Plastica 

1979; 5(1):51-3 

Status: Excluded because no comparison group 

Aronson SB, Elliott JH, Moore TE Jr., et al. Pathogenetic 

approach to therapy of peripheral corneal inflammatory 

disease. Am J Ophthalmol 1970 Jul; 70(1):65-90 

Status: Excluded because no use of heparin in burns 

Askoseljavaara S, Alho A, Sundell B, et al. Heparin 

Improves and Alpha-Blocker Treatment Possibly Impairs 

Host-Resistance in Burns. Burns 1977; 4(2):140-2 

Status: Excluded because no use of heparin in burns 

Author(s) Unknown. Ophthalmic levocabastine for allergic 

conjunctivitis. Med Lett Drugs Ther 1994; 36(920):35-6 

Status: Excluded because no use of heparin in burns 

Bahm J. The fatal fight for upper limb preservation in 

severe electrical burns. Microsurgery 1997; 17(5):286-9 

Status: Excluded because no comparison group 

Ballinger WF, Wise L. Gastric mucus: quantitative and 

qualitative studies in humans and dogs. Br J Surg 1969 

Sep; 56(9):701-2 

Status: Excluded because no use of heparin in burns 

Barret JP, Desai MH, Herndon DN. Effects of 

tracheostomies on infection and airway complications in 

pediatric burn patients Burns 2000; 26(2):190-3. 

Status: Excluded because no use of heparin in burns 

Berkessy S. Letter: High-dosage heparin treatment of large 

burns. JAMA 1973 Dec 17; 226(12):1464 

Status: Excluded because no comparison group 

Boyce ST, Greenhalgh DG, Kagan RJ, et al. Skin anatomy 

and antigen expression after burn wound closure with 

composite grafts of cultured skin cells and biopolymers. 

Plast Reconstr Surg 1993 Apr; 91(4):632-41 

Status: Excluded because no use of heparin in burns 

Boyce ST, Goretsky MJ, Greenhalgh DG, et al. 

Comparative assessment of cultured skin substitutes and 

native skin autograft for treatment of full-thickness burns. 

Ann Surg 1995 Dec; 222(6):743-52 

Status: Excluded because no use of heparin in burns 

Braunstein KM, Dodds KA, Stewart G, et al. Heparin 

Cofactor Activity Following Thermal Injury. Am J Clin 

Pathol 1978; 70(4):632-6 

Status: Excluded because no use of heparin in burns 

Brean L, Bormioli M, Angela GC, et al. Coagulation 

disorders due to burns. Disseminated intravascular 

coagulation (DIC) and its possible prevention. Minerva 

Med 1975 Aug 29; 66(55):2729-42 

Status: Excluded because no comparison group 

Burkhardt H, Zellner PR, Moller I. Factor XIII deficiency 

in burns. Chirurg 1977 Aug; 48(8):520-3 

Status: Excluded because not retrievable 

Buyukcelik A, Akbulut H. Thromboembolism in patients 

with cancer. Turkish Journal of Haematology 2004; 

21(1):7-11 

Status: Excluded because no comparison group 

Cancio LC, Mozingo DW, Pruitt BA Jr. Strategies for 

diagnosing and treating asphyxiation and inhalation 

injuries: How to recognize warning signs and minimize 

morbidity/mortality risk. J Crit Illn 1997; 12(4):217-29 

Status: Excluded because no comparison group 

Cancio LC. Current concepts in the pathophysiology and 

treatment of inhalation injury. Trauma 2005; 7(1):19-35 

Status: Excluded because no use of heparin in burns 

Chen X-L, Sun Y-X, Hu D-L. An unusual case of volatile 

organic compounds explosion burns. Burns 2005; 

31(2):240-2 

Status: Excluded because no comparison group 

Clagett GP, Anderson FA Jr., Geerts W, et al. Prevention 

of venous thromboembolism. Chest 1998; 114(5 

Suppl):531S-60S 

Status: Excluded because no comparison group 

Cox CS. Heparin for smoke inhalation injury. Crit Care 

Med 2003; 31(4):1291 

Status: Excluded because no comparison group 

Criado PR, Ramos RDO, Criado RFJ, et al. Severe 

cutaneous adverse reactions to drugs - Relevant aspects to 

diagnosis and treatment - Part I: Anaphylaxis and 

anaphylactoid reactions, erythroderma and the clinical 

spectrum of Stevens-Johnson syndrome & toxic epidermal 

necrolysis (Lyell's disease). An Bras Dermatol 2004; 

79(4):471-88 

Status: Excluded because no use of heparin in burns 

Danielsson P, Nilsson L, Nettelblad H, et al. Is there a 

need for antithrombin III substitution early after burn 

injury? Burns 1997 Jun; 23(4):300-5 

Status: Excluded because no comparison group 

Davanzo F, Ruggeroni ML, Trojsi C, et al. A new therapy 

for hydrofluoric acid burns. Med Lav 1987; 78(4):333-6 

Status: Excluded because no comparison group 
C-2 

DeAngelis V, Matrisciano F. Use of acetyl-cysteine in 

corneal burns: Our experiences. Rass Int Clin Ter 1991; 

71(22):1035-7 

Status: Excluded because no comparison group 

Dellinger RP. Respiratory and critical care medicine: 

Preface. Sem Respir Crit Care Med 2001; 22(1):1-2 

Status: Excluded because no use of heparin in burns 

Demling R, Wolberg WH. Effect of heparin and cold 

immersion on burn edema. Surg Forum 1977; 28:29-30 

Status: Excluded because animal study 

Demling RH, Mazess R, Hanson J, et al. Effect of Heparin 

on Edema After 2nd-Degree and 3rd-Degree Burns. J Surg 

Res 1979; 26(1):27-32 

Status: Excluded because animal study 

Demling RH. The burn edema process: Current concepts. J 

Burn Care Rehabil 2005; 26(3):207-27 

Status: Excluded because no comparison group 

Di Stefano F, Giglio A, Vinci M, et al. Low molecular 

weight heparins for long-term therapy of peripheral 

vascular disease. Results of a controlled study. Curr Ther 

Res Clin Exp 1988; 44(1):1-10 

Status: Excluded because no use of heparin in burns 

Dougherty W, Waxman K. The complexities of managing 

severe burns with associated trauma. Surg Clin North Am 

1996; 76(4):923-58 

Status: Excluded because no comparison group 

Dunlavey ES. Topical antibiotics in dermatology for uses 

other than acne. Curr Probl Dermatol 2000; 12(5):216-21 

Status: Excluded because no use of heparin in burns 

Durango Gutierrez LF, Vargas GF. Management of the 

burnt patient. Iatreia 2004; 17(1):54-61 

Status: Excluded because no comparison group 

Ellis RJ, Cunningham MT, Cook JD. Laboratory heparin 

resistance in burn injury complicated by venous 

thrombosis. Burns 1999; 25(8):749-52 

Status: Excluded because no comparison group 

Eriksson E, Plymforshell K, Robson MC. Distant MicroCirculatory Changes After A Major Burn - Effects of 

Methyl Prednisolone, Dextran-40, Heparin and Normal 

Saline. Burns 1981; 7(3):158-61 

Status: Excluded because animal study 

Fecher AM, O'Mara MS, Goldfarb IW, et al. Analysis of 

deep vein thrombosis in burn patients. Burns 2004; 

30(6):591-3 

Status: Excluded because no comparison group 

Finta B, Haines DE. Catheter ablation therapy for atrial 

fibrillation. Cardiol Clin 2004; 22(1):127-45 

Status: Excluded because no use of heparin in burns 

Fitts CT, Cathcart RS, III, Artz CP, et al. Acute 

gastrointestinal tract ulceration: Cushing's ulcer, steroid 

ulcer, Curling's ulcer and stress ulcer. Am Surg 1971 Apr; 

37(4):218-23 

Status: Excluded because no comparison group 

Fortun J, Navas E. A critical approach to the pathogenesis, 

diagnosis, treatment and prevention of catheter-related 

bloodstream infections and nosocomial endocarditis. Clin 

Microbiol Infect 1999; 5(2 Suppl.):2S40-50 

Status: Excluded because no use of heparin in burns 

Geerts WH, Heit JA, Clagett GP, et al. Prevention of 

venous thromboembolism. Chest 2001; 119(1 

Suppl.):132S-75S 

Status: Excluded because no use of heparin in burns 

Gehrke CF, Penner JA, Niederhuber J, et al. Coagulation 

defects in burned patients. Surg Gynecol Obstet 1971 Oct; 

133(4):613-6 

Status: Excluded because no use of heparin in burns 

Geiger JP, Gielchinsky I. Acute pulmonary insufficiency. 

Treatment in Vietnam casualties. Arch Surg 1971 Apr; 

102(4):400-5 

Status: Excluded because no use of heparin in burns 

Georgieva SA, Kobzeva TV. Blood Heparin Activity in 

Patients with Burns. Khirurgiya 1982(4):21-3 

Status: Excluded because no comparison group 

Ghislain P-D, Roujeau J-C. Treatment of severe drug 

reactions: Stevens-Johnson syndrome, toxicepidermal 

necrolysis and hypersensitivity syndrome. Dermatol 

Online J 2002; 8(1):147-58 

Status: Excluded because no use of heparin in burns 

Goodwin MN Jr. Selected anatomic burn pathology review 

for clinicians and pathologists. Aviat Space Environ Med 

1989 Oct; 60(10 Pt 2):B39-B43 

Status: Excluded because no use of heparin in burns 

Gorman R, Gordan L, Zumberg M, et al. Successful use of 

argatroban as an anticoagulant in burn-related severe 

acquired antithrombin III deficiency after heparin failure. 

Thromb Haemost 2001; 86(6):1596-7 

Status: Excluded because no comparison group 

Grabosch A, Rokos H. Neopterin as parameter of cellmediated immunity response in thermally injured patients. 

Burns 1992; 18(2):113-6 

Status: Excluded because no comparison group 

Guimbretiere J, Lebeaupin R, Pannier M. Burns and 

Heparin-Therapy. Anesthesie Analgesie Reanimation 

1977; 34(6):1339-44 

Status: Excluded because no comparison group 
C-3 

Guimbretiere J. Unbalanced coagulation among burned 

patients. Convergences Medicales 1982; 1(4):289-97 

Status: Excluded because no comparison group 

Hainaut J, Guilbaud J, Dhennin C, et al. Quantitation of at 

Iii on Chromogenic Substrate - Prognosis of ThermalInjury with Heparin Treatment. Haemostasis 1982; 12(1-

2):74 

Status: Excluded because no comparison group 

Hansbrough JF, Boyce ST, Cooper ML, et al. Burn wound 

closure with cultured autologous keratinocytes and 

fibroblasts attached to a collagen-glycosaminoglycan 

substrate. JAMA 1989 Oct; 262(15):2125-30 

Status: Excluded because no comparison group 

Harriger MD, Warden GD, Greenhalgh DG, et al. 

Pigmentation and microanatomy of skin regenerated from 

composite grafts of cultured cells and biopolymers applied 

to full-thickness burn wounds. Transplantation 1995 Mar 

15; 59(5):702-7 

Status: Excluded because no use of heparin in burns 

Harrington DT, Mozingo DW, Cancio L, et al. Thermally 

injured patients are at significant risk for thromboembolic 

complications. Journal of Trauma-Injury Infection and 

Critical Care 2001; 50(3):495-9 

Status: Excluded because no use of heparin in burns 

Hatzifotis M, Williams A, Muller M, et al. Hydrofluoric 

acid burns. Burns 2004; 30(2):156-9 

Status: Excluded because no use of heparin in burns 

Hauben DJ, Mahler D, Neumann L. A burn formula in 

clinical practice. Ann R Coll Surg Engl 1981 Jul; 

63(4):293-4 

Status: Excluded because no use of heparin in burns 

Hawkins DB, Demeter MJ, Barnett TE. Caustic ingestion: 

Controversies in management. A review of 214 cases. 

Laryngoscope 1980; 90(1):98-109 

Status: Excluded because no use of heparin in burns 

Hirsh J. Prevention of deep venous thrombosis. Br J Hosp 

Med 1981; 26(2):143-7 

Status: Excluded because no comparison group 

Hubsher J, Olshan AR, Schwartz AB, et al. Continuous 

arteriovenous hemofiltration for the treatment of anasarca 

and acute renal failure in severely burned patients. ASAIO 

Trans 1986 Jul; 32(1):401-4 

Status: Excluded because no comparison group 

Hurnikova M, Dostalova D. Continuous elimination 

methods in burn patients from the point of view of a nurse. 

Acta Chir Plast 2005; 47(2):55-7 

Status: Excluded because no comparison group 

Johansson SA. Platelets, coagulation factors and 5-

hydroxytryptamine in sensitization, anaphylaxis and burn 

injuries. Effect of heparin and possible relation to 

intravascular coagulation. Acta Med Scand Suppl 1967; 

471:1-30 

Status: Excluded because no comparison group 

Kereiakes DJ. The fire that burns within: C-reactive 

protein. Circulation 2003; 107(3):373-4 

Status: Excluded because no use of heparin in burns 

Kim K-J, Park Y-T, Yoo J-H, et al. Hydrofluoric acid 

burns. Exogenous Dermatology 2004; 3(1):12-8 

Status: Excluded because no comparison group 

Kinsella J, Rae CP. Smoke inhalation and airway injury. 

Baillieres Clinical Anaesthesiology 1997; 11(3):385-406 

Status: Excluded because no comparison group 

Konigova R. Commentary. Acta Chir Plast 1997; 39(1):36 

Status: Excluded because no use of heparin in burns 

Latenser BA, Iteld L. Smoke inhalation injury. Sem Respir 

Crit Care Med 2001; 22(1):13-22 

Status: Excluded because no use of heparin in burns 

Lawrence JC, Carney SA. Tangential excision of burns: 

studies on the metabolic activity of the recipient areas for 

skin grafts. Br J Plast Surg 1973 Apr; 26(2):93-100 

Status: Excluded because no use of heparin in burns 

Liljedahl SO, Frisk A, Wickman K. Successful treatment of 

Candida septicaemia in severely burned patients with a new 

antimycotic, clotrimazole (Bay b 5097). Injury 1972 Nov; 

4(2):157-63 

Status: Excluded because no use of heparin 

Lloyd JR. Thermal trauma: therapeutic achievements and 

investigative horizons. Surg Clin North Am 1977 Feb; 

57(1):121-38 

Status: Excluded because no use of heparin in burns 

Lunan HN. Topical treatment of the burn patient. Am J 

Hosp Pharm 1975 Jun; 32(6):599-605 

Status: Excluded because no use of heparin in burns 

Masaki F, Isao T, Aya Y, et al. Extensive thrombosis of 

the inferior vena cava and portal vein following electrical 

injury. Burns 2005; 31(5):660-4 

Status: Excluded because no comparison group 

Maxwell RA, Blanchard TR, Hickerson WB, et al. 

Management of an unusual thermal injury to the thigh. 

Journal of Trauma-Injury Infection & Critical Care 1999; 

46(5):976-7 

Status: Excluded because no comparison group 

Mayou BJ, Wee J, Girling M. Deep vein thrombosis in 

burns. Burns 1981; 7(6):438-40 

Status: Excluded because no comparison group 
C-4 

McAuliffe PF, Mozingo DW. Inhalation injury and 

ventilator management. Problems in General Surgery 

2003; 20(1):97-105 

Status: Excluded because no comparison group 

McCall JE, Cahill TJ. Respiratory care of the burn patient. 

Journal of Burn Care & Rehabilitation 2005; 26(3):200-6 

Status: Excluded because no comparison group 

Mcmanus WF, Eurenius K, Pruitt BA Jr. Disseminated 

intravascular coagulation in burned patients. J Trauma 

1973 May; 13(5):416-22 

Status: Excluded because no comparison group 

Miller SF. Blood platelets in severely injured burn patients. 

Burns 1999; 25(2):187 

Status: Excluded because no comparison group 

Monafo WW. Initial management of burns. N Engl J Med 

1996; 335(21):1581-6 

Status: Excluded because no use of heparin in burns 

Moore FD. Reflections on new treatments for burns--caveat 

legor. JAMA 1973 Jul 16; 225(3):294-5 

Status: Excluded because no comparison group 

Moore FD Jr. Therapeutic regulation of the complement 

system in acute injury states. Adv Immunol 1994; 56:267-

99 

Status: Excluded because no use of heparin in burns 

Munster AM. The early management of thermal burns. 

Surgery 1980 Jan; 87(1):29-40 

Status: Excluded because no use of heparin in burns 

Norman KE. Alternative treatments for disseminated 

intravascular coagulation. Drug News Perspect 2004; 

17(4):243-50 

Status: Excluded because no use of heparin in burns 

Ors S. Hand burn in severe Raynaud's phenomenon: Case 

report. Burns 2004; 30(3):272-5 

Status: Excluded because no comparison group 

Parks DA, Skinner KA, Skinner HB, et al. Multiple organ 

dysfunction syndrome: Role of xanthine oxidase and nitric 

oxide. Pathophysiology 1998; 5(1):49-66 

Status: Excluded because no use of heparin in burns 

Pastorova VE, Liapina LA, Tabakina TE. The indices of 

the function of the anticoagulation system and of the 

nonenzymatic fibrinolytic activity of the antithrombin IIIheparin-thrombin complex in the blood of children with 

burn and traumatic shock. Fiziol Cheloveka 1990 Mar; 

16(2):71-6 

Status: Excluded because no use of heparin in burns 

Purdue GF, Hunt JL. Pulmonary emboli in burned patients. 

J Trauma 1988 Feb; 28(2):218-20 

Status: Excluded because no comparison group 

Ramasamy K, Gumaste VV. Corrosive ingestion in adults. 

J Clin Gastroenterol 2003; 37(2):119-24 

Status: Excluded because no use of heparin in burns 

Renard G, Hirsch M, Pouliquen Y. Sem and Tem Study of 

Heparin Injection in Anterior-Chamber After Experimental 

Alkali Burn of Cornea. Exp Eye Res 1977; 25(5):533-4 

Status: Excluded because animal study 

Rzany B, Mockenhaupt M, Hollander N, et al. StevensJohnson syndrome (SJS) and toxic epidermal necrolysis 

(TEN): Evaluation for drug risk based on sale numbers in 

defined daily doses (DDD). Example of the H2-antagonists. 

Pharmacoepidemiol Drug Saf 1995; 4(4):207-12 

Status: Excluded because no use of heparin in burns 

Sadik F. Burn injuries and their therapy. Pharmindex 1988; 

30(3):9-15 

Status: Excluded because no use of heparin in burns 

Saffle JR. What's new in general surgery: Burns and 

metabolism. J Am Coll Surg 2003; 196(2):267-89 

Status: Excluded because no comparison group 

Saliba MJ Jr. Heparin efficacy in burns. II. Human thermal 

burn treatment with large doses of topical and parenteral 

heparin. Aerosp Med 1970 Nov; 41(11):1302-6 

Status: Excluded because there is no comparison group 

Saliba MJ Jr, Dempsey WC, Kruggel JL. Large burns in 

humans. Treatment with heparin. JAMA 1973 Jul 16; 

225(3):-261 

Status: Excluded because there is no comparison group 

Saliba MJ Jr. The effects and uses of heparin in the care of 

burns that improves treatment and enhances the quality of 

life. Acta Chir Plast 1997; 39(1):13-6 

Status: Excluded because there is no comparison group 

Sevitt S, Innes D. Prothrombin-time and thrombotest in 

injured patients on prophylactic anticoagulant therapy. 

Lancet 1964 Jan 18; 283(7325):121-80 

Status: Excluded because no use of heparin in burns 

Sheridan R. Specific therapies for inhalation injury. Crit 

Care Med 2002; 30(3):718-9 

Status: Excluded because no use of heparin in burns 

Shetlar MR, Van Lier P, Hern DL, et al. Uronic acidcontaining polypeptides from the urine of burned patients. 

Proc Soc Exp Biol Med 1969 Dec; 132(3):999-1002 

Status: Excluded because no use of heparin in burns 

Shetlar MR, Shetlar CL, Chien SF, et al. The hypertrophic 

scar. Hexosamine containing components of burn scars. 

Proc Soc Exp Biol Med 1972 Feb; 139(2):544-7 

Status: Excluded because no use of heparin in burns 

Shook CD, MacMillan BG, Altemeier WA. Pulmonary 

complications of the burn patient. Arch Surg 1968 Aug; 
C-5 

97(2):215-24 

Status: Excluded because no comparison group 

Simon TL, Curreri PW, Harker LA. Kinetic 

characterization of hemostasis in thermal injury. J Lab Clin 

Med 1977 Apr; 89(4):702-11 

Status: Excluded because no use of heparin in burns 

Summerly R, Jefferson BM. Sulphated acid 

mucopolysaccharides in actinic elastosis. Br J Dermatol 

1969 Jan; 81(1):51-9 

Status: Excluded because no use of heparin in burns 

Thomas S, Humphries J, Fear-Price M. The role of moist 

wound healing in the management of meningococcal skin 

lesions: A case study. World Wide Wounds 1999 (June) 

Status: Excluded because no use of heparin in burns 

Traber DL, Traber LD. Airway blood flow changes and 

airway obstruction following lung injury. Arch Physiol 

Biochem 2003; 111(4):297-300 

Status: Excluded because animal study 

Tremblay R, Ethier J, Querin S, et al. Venovenous 

continuous renal replacement therapy for burned patients 

with acute renal failure. Burns 2000; 26(7):638-43 

Status: Excluded because no use of heparin in burns 

Triedman JK. So far, so good . . . J Cardiovasc 

Electrophysiol 2004; 15(3):284-5 

Status: Excluded because no comparison group 

Troshev K, Dimitrov R. Application of heparin in the local 

treatment of burns. Acta Chir Plast 2001; 43(4):143-4 

Status: Excluded because no comparison group 

Truong AT, Kowal-Vern A, Latenser BA. Aerosolized 

heparin does not improve pulmonary function in ventilated 

burn patients with < 50%TBSA. Crit Care Med 2001; 

29(12):A49 

Status: Excluded because no comparison group 

Vaglini M, Ammatuna M, Nava M. Regional perfusion at 

high temperature in treatment of stage IIIA-IIIAB 

melanoma patients. Tumori 1983; 69(6):585-8 

Status: Excluded because no use of heparin in burns 

Volcheck GW. Clinical evaluation and management of 

drug hypersensitivity. Immunol Allergy Clin North Am 

2004; 24(3):357-71 

Status: Excluded because no use of heparin in burns 

Wolf SE, Debroy M, Herndon DN. The cornerstones and 

directions of pediatric burn care. Pediatr Surg Int 1997; 

12(5-6):312-20 

Woodley DT. Covering wounds with cultured 

keratinocytes. JAMA 1989 Oct; 262(15):2140-1 

Status: Excluded because no use of heparin in burns 

Yannas IV, Burke JF, Warpehoski M, et al. Prompt, longterm functional replacement of skin. Trans Am Soc Artif 

Intern Organs 1981; 27:19-23 

Status: Excluded because no use of heparin in burns 

Yannas IV. What criteria should be used for designing 

artificial skin replacements and how well do the current 

grafting materials meet these criteria? J Trauma 1984 Sep; 

24(9 Suppl):S29-S39 

Status: Excluded because no use of heparin in burns 

Yogaratnam D, Smith BS, Angood PB, et al. Antifactor Xa 

levels in four patients with burn injuries who received 

enoxaparin to prevent venous thromboembolism. 

Pharmacotherapy 2004; 24(12):1793-9 

Status: Excluded because no comparison group 

Zamecnikova I, Tymonova J, Stetinsky J, et al. Critical and 

severe burn injury in children. Acta Chir Plast 2005; 

47(1):16-8 

Status: Excluded because no comparison group 
D-1 

Appendix D – Forms 

Title and Abstract Level 1 

2. In the title, keywords or abstract, are any of the following terms mentioned with 

respect to burns? 

Burns 

Thermal Injuries 

Scalds 

Smoke Inhalation 

Other burn related terms 

None of the above 

Can’t tell 

3. In the title, keywords or abstract, are any of the following terms mentioned with 

respect to heparin? 

Heparin/Heparine/Alpha Heparin/Anticoagulant 

Ammonium Heparinate/Benzalkonium 

Clarin/Contusol/Disebrin/Eleparon 

Elheparin/Elheparon/Gag 98/Noparin 

Hepcon/Hep Lock/Hepsal/Epiheparin 

Heparinate Sodium/Heparinic Acid/Fibrinolytic agent 

Lipo Hepin/Lipohepin/Hepalean/Panheparin 

Liquaemin/Sodium Liquemin/Multiparin 

Panhepin/Panheprin/Praecivenin/Pularin 

Menaven/Monoparin/Mucoitin Polysulfate 

Thromboliquin/Thromboliquine/Thrombareduct 

Thrombophlogat/Thrombophob/Thrombosamine 

Vetren/Vister/Thrombo Vetren/Glucosaminoglycan 

None of the above Î exclusion 

Can’t tell 

4. What language is the study published in? 

English 

1. Is there an abstract? 

Yes 

No 
D-2 

Other 

Can't tell 

Title and Abstract Level 2 

1. Is there a comparison group? 

Yes 

No 

Can't tell 

2. In this study, Heparin has been used to: 

treat burn injury 

prophylaxis of thrombosis in burn injury 

treat complications of burn injury 

none of the above (exclude) 

can't tell 

3. If excluded above, 

Should this paper be kept for background information? 

5. In this study, are the subjects 

humans 

animals ===> exclusion 

not applicable (i.e. lab studies, blood samples) ===> exclusion 

Can't tell 
D-3 

Yes 

No 

Full Text 

1. What is the targeted use of Heparin? 

Treatment of burns 

Complications 

Prophylaxis of thrombosis 

None of the above (EXCLUDE) 

2. What population does the study focus on 

adults 

children 

adults and children 

animals only (EXCLUDE) 

animals and humans 

can't tell 

3. What is the study design? 

Randomized trial 

Non-randomized trial 

Cohort study 

Case-control study 

Cross-sectional Study 

Case Report/Case Series (EXCLUDE) 

Non-comparative study (EXCLUDE) 

Animal study (EXCLUDE) 

Review (EXCLUDE) 
D-4 

Abstract only (EXCLUDE) 

4. What variables are presented? 

Length of Hospital Stay 

Mortality 

TBSA 

Length of follow-up 

Type of heparin used 

Dose of heparin 

Complications of 

heparin 

Other: (Specify) 

5. Language of paper 

English 

Not English (specify if known)

Data Abstraction 

Please write NR if any of the requested information is not reported.

1. Number of groups in this study. 

2 

3 

4 

5 

2. Year of Publication 

 
D-5 

3. Duration of Study 

 

4. Location of study 

USA 

Canada 

Germany 

Italy 

France 

Britain 

Netherlands 

China 

Africa 

Australia 

Latin 

America 

Russia 

Japan 

Poland 

Spain 

Bulgaria 

India 

Other 

Not Reported 

5. Funding Source 

Industry 

Government 
D-6 

Burns 
D-7 

Please write NR if any of the requested information is not reported.

1. Etiology of burn 

Flames 

Scald 

Chemical 

Contact 

Inhalation injury 

Electrical 

Combination 

Not reported 

2. Degree of burn 

First 

Second 

Third 

Not reported 

 

3. Total Body Surface Area of burn (Percentage) 
D-8 

Yes (Report page #) 

No 

4. Other descriptions of burns (extent, depth) 

 

5. List co-morbid conditions reported in the sample. 

 

6. Other Comments. 

 
D-9 

Heparin 

Please write NR if any of the requested information is not reported.

1. Heparin 

Type 

Dose (International Units)

Not Reported 

2. Number of subjects receiving Heparin. 

 

3. Number of subjects not receiving Heparin. 

 

4. Describe the method of administration of Heparin. 
D-10 

Topical (Cream and dressing impregnated with Heparin)

Subcutaneous 

Intravenous 

Infusion 

Aerosolized 

Combination 

Not Reported 

5. Describe the frequency at which Heparin was administered. 

 

6. Describe the length of time Heparin was administered? (i.e. # of days) 

 

7. Describe the time from injury that Heparin was first administered. 

 
D-11 

8. Did patients comply with the treatment? (Indicate number of patients) 

Yes 

No 

Not Applicable 

Not Reported 

9. Was there an inpatient/outpatient treatment component? 

Yes (describe) 

No 

10. Other Comments. 

 

Results 

Please write NR if any of the requested information is not reported. 

1. Results 

There are no results presented in this study. (STOP)

2. What type of outcome was described in this study? 
D-12 

Clinical 

Non-clinical 

Not Reported 

3. Did the authors identify one or more primary outcomes. If yes, then list. 

 

4. How were the outcomes defined? 
D-13 

Timing and need for surgical proceedure (i.e. grafting, 

debridement, fasciotomy) 

Quality of graft take (percentage) 

Pain (scale) 

Transfusion rate 

Mortality (prior to discharge from hospital) 

Length of stay: acute treatment (in hospital) 

Scarring (size, hypertrophic scarring) 

Decreased range of motion 

Respiratory measures ICU admission (length of intubation) 

Thromboses and emboli 

Complications (bleeding, infection...) 

Pruritis (Itching) 

Rehabilitation (follow-up of patient, re-grafting, 

reconstructive surgery) 

Quality of Life (scale) 

Psychiatric adjustment (post-traumatic stress disorder, 

anxiety and depression) 

Mortality (after discharge from hospital) 

Other 

N tR t d
D-14 
E-1 

Appendix E - Quality Assessment - Effective Public Health Practice Project 

Quality Assessment Tool 2003 

A Selection Bias 

1. Are the individuals selected to participate in the study likely to be 

representative of the target population? 

Very Likely 

Somewhat Likely 

Not Likely 

2. What percentage of selected individuals agreed to participate? 

80 - 100% Agreement 

60 - 79% Agreement 

Less than 60% Agreement

Not Reported 

Not Applicable 

3. Rate this section (see dictionary) 

Strong 

Moderate 

Weak 

B Allocation Bias 

4. Indicate the study design 

RCT (go to question 5) 

Quasi-Experimental (skip to question 8)

Case-Control (skip to question 8) 

Before/After study (skip to question 8) 

No Control Group (skip to question 8) 

Other (skip to question 8) 
E-2 

5. Is the method of random allocation stated? 

Yes 

No 

6. If the method of random allocation is stated, is it appropriate? 

Yes 

No 

7. Was the method of random allocation reported as concealed? 

Yes 

No 

8. Rate this section (see dictionary) 

Strong 

Moderate 

Weak 

C Confounders 

9. Prior to the intervention were there between group differences for important 

confounders reported in the paper? 

Yes 

No 

Can't tell 

10. Relevant confounders reported in the study. 

 

11. If there were differences between groups for important confounders, were 

they adequately managed in the analysis? 

Yes 

No 
E-3 

Not Applicable 

12. Were there important confounders not reported in the paper? 

Yes 

No 

13. Relevant confounders NOT reported in the study. 

 

14. Rate this section (see dictionary) 

Strong 

Moderate 

Weak 

D Blinding 

15. Was (were) the outcomes assessor(s) blinded to the intervention or 

exposure status of participants? 

Yes 

No 

Not Reported 

Not Applicable 

16. Rate this section (see dictionary) 

Strong 

Moderate 

Weak 

Not Applicable 

E Data Collection Methods 

17. Were data collection tools shown or are they known to be valid? 
E-4 

Yes 

No 

18. Were data collection tools shown or are they known to be reliable? 

Yes 

No 

19. Rate this section (see dictionary) 

Strong 

Moderate 

Weak 

F Withdrawals and Drop-outs 

20. Indicate the percentage of participants completing the study. (If the 

percentage differs by groups, record the lowest) 

80 - 100% 

60 - 79% 

Les than 60% 

Not Reported 

Not Applicable 

21. Rate this section (see dictionary) 

Strong 

Moderate 

Weak 

Not Applicable 

G Analysis 

22. Is there a sample size calculation or power calculation? 

Yes 
E-5 

Partially 

No 

23. Is there a statistically significant difference between groups? 

Yes 

No 

Not Reported 

24. Are the statistical methods appropriate? 

Yes 

No 

Not Reported 

25. Indicate the unit of allocation. 

Community 

Organization/Institution 

Group 

Provider 

Individual 

26. Indicate the unit of analysis. 

Community 

Organization/Institution 

Group 

Provider 

Individual 

27. If the unit of allocation and the unit of analysis are different, was the cluster 

analysis done? 

Yes 

No 
E-6 

Not Applicable 

28. Is the analysis performed by intervention allocation status (i.e. intention to 

treat) rather than the actual intervention received? 

Yes 

No 

Can't tell 

Not Applicable 

29. Comments 

 

H Intervention Integrity 

30. What percentage of participants received the allocated intervention or 

exposure of interest? 

80 - 100% 

60 - 79% 

Less than 60% 

Not Reported 

Not Applicable 

31. Was the consistency of the intervention measured? 

Yes 

No 

Not Reported 

Not Applicable 

32. Comments 
E-7