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Wound Management Presenter: Susan Thompson, DO Christiana Care Health Systems Delaware, USA Authors: Susan Thompson, DO; Nicole Y. Ottens, DO; Donald J. Sefcik, DO, MBA

Wound Management Presenter: Susan Thompson, DO

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Case One A 22 year-old male presents with wounds involving his right hand. He was involved in an altercation at a bar. He grabbed a knife during an attempted stabbing. He has incisions on the palmar aspect of his index, long and ring fingers. - What do you need to consider?

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Page 1: Wound Management Presenter: Susan Thompson, DO

Wound ManagementPresenter: Susan Thompson, DOChristiana Care Health SystemsDelaware, USA

Authors: Susan Thompson, DO; Nicole Y. Ottens, DO; Donald J. Sefcik, DO, MBA

Page 2: Wound Management Presenter: Susan Thompson, DO

Case One

A 22 year-old male presents with wounds involving his right hand. He was involved in an altercation at a bar. He grabbed a knife during an attempted stabbing. He has incisions on the palmar aspect of his index, long and ring fingers.

- What do you need to consider?

Page 3: Wound Management Presenter: Susan Thompson, DO

Case Two

A 42 year-old female presents with a wound on her left forearm. While carrying a letter-opener, she was running to answer a telephone at work and tripped. She stabbed herself.

- What do you need to consider?

Page 4: Wound Management Presenter: Susan Thompson, DO

Case Three

A 9 year-old female presents with a wound above her left eye sustained during a bicycle accident.

- What do you need to consider?

Page 5: Wound Management Presenter: Susan Thompson, DO

Case Four

A 14 year-old male presents with a wound to the right thigh. He was bitten by the family pet.

- What do you need to consider?

Page 6: Wound Management Presenter: Susan Thompson, DO

Introduction

• Open wound injury comprises a significant component of emergency department (ED) workload.

• Three major causes are falls up to 1 meter; contact with cutting or piercing objects; or having been struck or collided with.

• Most are unintentional and only 3% are due to assault.– 12% - injuries to face, head and upper neck.– 62% - injuries to upper extremities.

• 88% of all wound presentations to the ED are repaired and the patient is discharged to home.

– Almost 50% referred to general practitioners and specialists for review.

• This lecture will cover those wounds that are suitable for repair in the ED.

Page 7: Wound Management Presenter: Susan Thompson, DO

Types of Wounds• Abrasion

– Forcible avulsion of skin• Laceration

– Simple – usually the result of shearing forces– Avulsion – usually the result of tension forces– Stellate – usually the result of compressive forces

• Puncture– Wound is deeper than it is wide– Difficult to explore

• Bite

Page 8: Wound Management Presenter: Susan Thompson, DO

Wound Care Principles

• Inspection• Preparation• Anesthesia• Closure• Dressings/immobilization• Prophylaxis• Follow-up

Page 9: Wound Management Presenter: Susan Thompson, DO

Clinical Presentation

• Initial assessment will direct plan of care for the patient and the wound– What are the injured structures?– How many wounds are present and % of

surface area involved?– What is the likely mode of repair?– Will repair need to be delayed for any reason?– What are the likely complications?

Page 10: Wound Management Presenter: Susan Thompson, DO

Clinical Presentation

• Important factors of the History:– Time and mechanism of injury– Any pre-hospital intervention– Likelihood of foreign bodies– Tetanus immunization status– PMHx (immunocompromised, diabetes)– Allergies to local anesthetics, antibiotics, etc.– Current medications (warfarin, cytotoxics)

Page 11: Wound Management Presenter: Susan Thompson, DO

Wound Inspection

• Is the wound life threatening?• Is it an acute or chronic wound?• What was the timing of the injury?• What was the nature of the injury?

Page 12: Wound Management Presenter: Susan Thompson, DO

Initial Evaluation

• General exam– A, B, C’s– Vital signs– Brief head-to-toe examination– Remove any clothing that may restrict

examination– Remove constricting rings or other jewelry

Page 13: Wound Management Presenter: Susan Thompson, DO

Initial Examination

• Focused local examination– Size and depth of wound– Gross muscle and tendon function

• Full range of motion testing– Nervovascular status – Initial cleansing for adequate visualization

• This step often requires anesthesia• Rule out deep soft tissue injuries

– Tendons– Ligaments– Joint capsules– Neurovascular structures– Fascia/compartments

Page 14: Wound Management Presenter: Susan Thompson, DO

Wound inspection

Tendon injuries•An injury to the tendon at the base of a wound may not be apparent in all positions of the limb or body part

– The tendon may only be visible when the limb is the position it was at the time of injury

– Marked pain with a particular movement of the muscle/tendon may be a clue to the underlying injury and the presence of a tendon injury

Page 15: Wound Management Presenter: Susan Thompson, DO

Wound Inspection

Muscle injuries•Note any loss of function

– Again, may need analgesia

•Determine if fascia is compromised

Page 16: Wound Management Presenter: Susan Thompson, DO

Wound Inspection

Foreign bodies (FB)– Depending on mechanism of injury

• Penetrating objects (GSW)• Shattered glass• Soil, twigs, leaves• Shrapnel• Broken off needles, etc.

– Penetrating FB’s do not always remain local– Consider the course of the FB and the

possible structures damaged

Page 17: Wound Management Presenter: Susan Thompson, DO

Wound Inspection

Identifying foreign bodies – Direct visualization and removal– Radiographs

• Radio-opaque FB’s such as gravel, metal, pencil lead, glass >2mm1

• Place a radio-opaque marker over the wound to assist with location of the FB

– Ultrasound• Detect radio-lucent objects larger than 2.5mm• Gas in an open wound makes US less

sensitive1 Lammers R. Foreign bodies in wounds. In: Singer AJ, Hollander JE, eds. Lacerations and acute wounds: an evidence based guide. Philadelphia: FA Davis, 2003;147

Page 18: Wound Management Presenter: Susan Thompson, DO

Wound Inspection

Look for associated injuries•Imaging

– Radiographs• Possible underlying fractures• Suspicion of joint involvement• Radio-opaque FB

– Ultrasound• Fluid, hematomas in tissues• Vascular structure injuries• Radio-lucent FB

Page 19: Wound Management Presenter: Susan Thompson, DO

Other Considerations

• Rabies Risk• Tetanus risk

• Unknown tetanus status• “Dirty” wound

• Subsequent infection

Page 20: Wound Management Presenter: Susan Thompson, DO

Tetanus Considerations

• Clostridium tetani– Anaerobic bacterium– Present in soil and animal feces– 3-21 day incubation period– Bacteria produces toxin in the wound – Toxin causes severe muscle spasm and

contraction, convulsions– Death occurs commonly from respiratory

failure, rhabdomyolysis and renal failure

Page 21: Wound Management Presenter: Susan Thompson, DO

Tetanus ConsiderationsWounds that are prone to Tetanus

•Compound fractures

•Deep penetrating wounds

•Wounds containing foreign bodies

•Crush injuries or wounds with extensive tissue damage, burns

•Wounds contaminated with soil or horse manure

•Wound cleansing delayed more than 3-6 hours

Patients that are prone to Tetanus

•Elderly2

• Persons >60 y/o are at a six-fold increased risk of acquiring tetanus than those at any younger age

• Having 2 or more prior doses of tetanus toxoid puts one at lower risk for death from tetanus

• Tetanus antibody levels decline with age, and only 28% of the population >70 have protective levels

2 National Health and Medical Research Council, the Australian Immunization Handbook, 9 th Edn. Canberra: NHMRC, 2008

Page 22: Wound Management Presenter: Susan Thompson, DO

Tetanus Management

Vaccination History

(CDT) Td Type of Wound DTP, DT or tetanus toxoid

Tetanus immuno-globulin

3 doses or more

<5y since last dose

All wounds No No

5-10y since last dose

Clean minor wounds No

All other wounds Yes No

>10y since last dose

All wounds Yes No

Uncertain Clean minor wounds Yes No

Less than 3 doses

All other wounds Yes Yes

DTP: diptheria, tetanus, pertussis for children before the 8th birthdayDT: child diptheria tetanus (CDT) if pertussis is contraindicatedTd: adult diptheria tetanus (ADT) for children after their 8th birthday

1 Lammers R., Foreign bodies in wounds. In: Singer, AJ, Hollander, JE, Lacerations and acute wounds: an evidence-based guide. 2009

Tetanus vaccination schedule for acute wound management1

Page 23: Wound Management Presenter: Susan Thompson, DO

General Principles

• Purposes of acute wound repair– Control Bleeding– Promote Healing– Decrease Risk of infection– Minimize scarring

Page 24: Wound Management Presenter: Susan Thompson, DO

General Principles

Wound-healing Mechanisms•Wounds never gain more than 80% of the strength of intact skin3

•Three phases of wound healing– Days 1-5, inflammatory phase

• No gain in strength of the wound– Days 5-14, fibroplasia and epithelialization

• Rapid increase in wound strength– Day 14 onwards, maturation

• Production, cross-linking and remodeling of collagen

3 Moy, RL, Lee A, Zalka A. Commonly used suturing techniques in skin surgery. American Family Physician 1991; 44:1625-1634.

Page 25: Wound Management Presenter: Susan Thompson, DO

General Principles

• Factors that affect the rate of wound healing– Technical factors of the repair– Anatomic factors

• Intrinsic blood supply, location over a joint

– Drugs• Steroids, cytotoxics, etc.

– Associated conditions and diseases• Diabetes, vitamin C, Zinc deficiency, etc.

– General nutritional state of the patient

Page 26: Wound Management Presenter: Susan Thompson, DO

General Principles

• When to Repair- Low Risk Wounds

• Primary Closure can be done- Extremity wounds can be closed within 6 hours- Torso wounds can be closed within 12 hours- Facial wounds can be closed within 24 hours

- High Risk Wounds• Primary closure may not be indicated• Delayed primary closure option• Wound may need to be allowed to heal by

secondary or tertiary intention

Page 27: Wound Management Presenter: Susan Thompson, DO

General Principles

• When to Consult/Refer– Neurovascular compromise– Tendon or Ligament involvement– Wound characteristics

• Wound size• Severe contamination• Open fractures• Amputations• Joint involvement

– History of prior wound dehiscence– Cosmetic concerns

• Skills of plastic surgeon required• Often this is a later referral and may not be done until healing

completion a year later

Page 28: Wound Management Presenter: Susan Thompson, DO

General Principles

• Indications for delayed closure– Puncture wounds

• Bacteria has been deposited deep into tissues and has high incidence of infection

• Thoroughly lavage and allow healing by secondary intention

– Wounds unable to be adequately debrided– Contaminated wounds more than 6 hours old– Too much tension in the wound, particularly

with crush injury

Page 29: Wound Management Presenter: Susan Thompson, DO

Wound PreparationMethods to minimize risk of infection

– Solution• Antiseptic solutions unnecessary4

• Sterile saline or tap water acceptable5

– Irrigation (“The solution to pollution is dilution”)

• Copious irrigation decreases infection risk• Sufficient pressure and volume are important• Various techniques have been described

– Debridement• Remove foreign bodies, necrotic and nonviable tissue

4 Dire DJ, Welch AP. A comparison of wound irrigation solution used in the Emergency Department. Annals of Emergency Medicine 1996; 19: 704.

5 Bansal BC, Weike PA, Perkins SD, Abramo TJ. Tap water irrigation of lacerations. American Journal of Emergency Medicine 2002; 20: 469.

Page 30: Wound Management Presenter: Susan Thompson, DO

Wound Preparation

• Essential to remove all contaminants, foreign bodies and devitalized tissue prior to closure

• Universal precautions• Be aware of latex allergy• Powder-free gloves6

– Powders, starches in the wound will delay healing and produce granulomas

6 Ellis H. Hazards from surgical gloves. Annals of the Royal College of Surgeons of England 2007; 79:161-163

Page 31: Wound Management Presenter: Susan Thompson, DO

Wound Preparation

• Hair can be removed by clipping 1-2cm above the skin with scissors

• Shaving with a razor is associated with an increased infection rate

• Scalp wounds closed without prior hair removal heal with no increase in infection7

7 Howell JM, Morgan JA,. Scalp lacerations repair without prior hair removal. American Journal of Emergency Medicine 1988; 6:7.

Page 32: Wound Management Presenter: Susan Thompson, DO

Wound Anesthesia

• Proper cleansing and closure of wounds requires adequate anesthesia

• General anesthesia only occasionally indicated– Extensive or multiple wounds– Requiring lengthy debridement/scrubbing– When local infiltration would require more than

the safe dose of local anesthetic

Page 33: Wound Management Presenter: Susan Thompson, DO

Wound Anesthesia

Anesthetic Agent Examples– Procaine– Lidocaine – Bupivicaine – Each of these combined w/epinepherine

Anesthetic Techniques– Topical – Local infiltration– Regional / nerve blocks– Intra-articular anesthesia– Hematoma blocks– General anesthesia

Page 34: Wound Management Presenter: Susan Thompson, DO

Wound AnesthesiaAgents

– Lidocaine 1 or 2%• Onset: 2-5 minutes• Duration: 1-2 hours• Maximum dose: 4.5 mg/kg

– Bupivicaine 0.25 or 0.5%• Onset: 8-12 minutes• Duration: 4-8 hours• Maximum dose: 2 mg/kg

– Because of lack of clinical trials, bupivicaine not recommended for children <12, however it is commonly used without problems in children

8 McGhee DL. Anesthetic and analgesic techniques. Roberts and Hedges, Clinical Procedures in Emergency Medicine. 5th edn. 2010: 490-491

Page 35: Wound Management Presenter: Susan Thompson, DO

Wound Anesthesia

Agents•Addition of Epinepherine to local anesthetic

– Advantages• Provides hemostasis• Prolongs duration of action of the anesthetic agent• Slows absorption; allows increased dose• Increases level of blockade

– Disadvantages• Increased infection; impairs host defenses• Delays wound healing• Do not use in areas with terminal arteries• Toxicity – catecholamine reaction

Page 36: Wound Management Presenter: Susan Thompson, DO

Wound AnesthesiaTechniques•Topical application

– Helpful with pediatric patients, small wounds, and/or prior to injections of anesthetic agents

– Ingredients: • Lidocaine 4%, epinepherine bitartrate 0.1%, tetracaine

0.5%, sodium metabisulfate– Application instructions:

• Apply 1-3 ml to laceration with cotton swab• Secure remainder of dose using gauze

– Tape for 20-30 minutes• Do not exceed 4mg/kg of lidocaine (up to 280mg)

– Lidocaine 4% is 40 mg/ml (7ml = 280 mg)

Page 37: Wound Management Presenter: Susan Thompson, DO

Wound Anesthesia

Techniques•Local Infiltration

– Infiltration of agent around and into the wound– Considered quicker and safer than regional or general

anesthesia– Can provide local hemostasis– A relatively large dose of drug needed to anesthetize

certain wounds8

– Can distort the tissues

8 McGhee DL. Anesthetic and analgesic techniques. Roberts and Hedges, Clinical Procedures in Emergency Medicine. 5th edn. 2010: 490-491

Page 38: Wound Management Presenter: Susan Thompson, DO

Wound Anesthesia

Techniques•Regional nerve block

– Infiltration at a site proximal to the wound– Nerve exit site that innervates the wound area– Can anesthetize a large area with a small amount of

agent– Less distortion to the wound area– Less risk of infection– Depends on operator skill and comfort with procedure

Page 39: Wound Management Presenter: Susan Thompson, DO

Types of Wound Closure

Chemical Adhesives– Useful on small, linear, dry wounds under low tension– Topical antibacterial ointments can affect integrity– Non-toxic, however avoid getting into the eye

Wound Tape (Steri-strips)– Paper tape reinforced with rayon– Easy to apply, good with fragile skin– Most useful with small, linear, low tension, dry wounds– Adherence may be improved by the application of adhesive

adjuncts (tincture of benzoin)• Do not get into the wound, can be very painful and

potentiate infection– Tape and staples have lower rates of infection than closure

with conventional sutures

Page 40: Wound Management Presenter: Susan Thompson, DO

Types of Wound Closure

Staples– Rapidly and easily applied– Cause less tissue reactivity– On appropriately chosen wounds, cosmetic results

comparable to sutures– Must be removed with an appropriate device

Sutures– Multiple decisions regarding suture type, size and suturing

techniques need to be made– Provide more precision for delicate skin– Able to close multiple layers of tissue and complicated

wounds and lacerations

Page 41: Wound Management Presenter: Susan Thompson, DO

Suture Types

Absorbable•Maintain tensile strength for less than 60 days

– Polyglactin (Vicryl); polyglycolic acid (Dexon)Non-absorbable•Maintain tensile strength for longer than 60 days

– Silk• Good tensile strength• Increased infection rate and tissue reactivity

– Nylon (Ethilon; Dermalon); Polypropylene (Prolene; Surgilene)

• Good tensile strength• Less reactivity and infection• Require more knots to secure

Page 42: Wound Management Presenter: Susan Thompson, DO

Suture Size

Guidelines(the larger the number the smaller the diameter)

– Face: 5-0 or 6-0– Scalp: 4-0 or 5-0– Hands: 4-0 or 5-0– Trunk: 3-0 or 4-0– Feet: 3-0 or 4-0– High tension areas: 3-0 or 4-0

• Ex. over joints

Page 43: Wound Management Presenter: Susan Thompson, DO

Suturing Techniques

Overview– Goal is to align tissues vertically

• EVERT tissue margins• Minimize tension• Line up anatomical landmarks• If you don’t like a stitch, take it out

– Learn how to appropriately do instrument ties• First tie (throw) is a double loop• Second tie (throw) completes the first square

knot

Page 44: Wound Management Presenter: Susan Thompson, DO

Suturing Techniques

Subcutaneous layer closure– absorbable suture material necessary– Goal is to approximate the wound deeply– Work from the bottom to top– Suture knots should be at the bottom of the

wound

Page 45: Wound Management Presenter: Susan Thompson, DO

Suturing Techniques

Skin Closure– Simple interrupted

• Most commonly used• Each stitch placed individually• Place equal distance apart

– Distance varies by body part– 2-3mm on face; 5mm to 10mm on torso

• Close wound by repeatedly bisecting– Avoid the “dog ear”

Page 46: Wound Management Presenter: Susan Thompson, DO

Suturing Techniques

Skin Closure– Continuous (running)

• Begin at one end of wound and rather than cutting the suture after the knot is made, continue to loop through wound

• Advantage: fewer knots (weak points of stitches); even tension distribution

• Disadvantage: if suture breaks, entire run may unravel• No increase in wound strength with use of running

sutures9

9 McClean NR, Fyfe AH, Flint EF, et al. Comparison of skin closure using sontinuous and interrupted nylon sutures. British Journal of Sugery. 1999; 67: 633-635

Page 47: Wound Management Presenter: Susan Thompson, DO

Suturing Techniques

Skin Closure– Mattress

• Variations of interrupted stitches• Vertical mattress

– Used to evert edges with a natural tendency to roll inward

• Horizontal mattress– Redistributes tension on deeper wounds and everts

wound edges

Page 48: Wound Management Presenter: Susan Thompson, DO

Wound Follow-up

Prophylactic Antibiotics– Literature is controversial

• If initiated – the sooner the better– Ideally the first dose given intravenously prior to

wound closure

• Indications include:– Grossly contaminated wounds– Open fractures– Human and animal bite wounds– Immunocompromised patients– Patients with prostheses

Page 49: Wound Management Presenter: Susan Thompson, DO

Suture Removal

Scalp: 7-10 daysFace: 3-5 daysTrunk: 7-14 daysExtremities: 7-14 days

– Near joints• Flexor aspect: 7-10 days• Extensor aspect: 10-14 days

With immunocompromised patient consider delaying suture removal

Page 50: Wound Management Presenter: Susan Thompson, DO

Dressings

• Dressings and subsequent wound care are as important as the initial closure technique

• Nonadherent dressing and gauze wrap• Wound should remain moist • Should not be immersed or soaked• Initial dressing should ideally remain on until suture

removal– Change if its ability to absorb fluid is exceeded– If not possible, dressing may be removed 24 hours

after wound closure, bathed or showered and dabbed dry

• Contaminated wounds should be re-evaluated at 48 hours post-closure

Page 51: Wound Management Presenter: Susan Thompson, DO

Wound Follow-up

Information regarding follow-up– Discuss when wound should be examined next– Discuss signs and symptoms of infection– Discuss wound care

• Avoid wound immersion• Application of topical agents• Wound dressing changes if advised

– Advise when sutures/staples need to be removed– Remind the patient about scarring potential

• Keep healing skin out of direct sunlight

Page 52: Wound Management Presenter: Susan Thompson, DO

Complications

• Diabetes and peripheral vascular disease – greater risk of infection and poor wound healing in

wounds of the lower extremities.

• Prior mastectomy patients, or patients with chronic edema of the affected area– more likely to develop infection and poor wound

healing due to poor lymphatic and venous circulation.• Splenectomy, liver dysfunction, autoimmune

disease– poor healing.

• Smokers – impaired collagen production in healing wounds10

10 Jorgensen LN, Kallenhave F, Chrsitensen E, Siana JE, Less Collagen production in smokers. Surgery 1998; 123:450-455.

Page 53: Wound Management Presenter: Susan Thompson, DO

Summary - Essentials

1. Good cosmesis can be achieved in the Emergency Department with conservative treatment, thorough debridement, and accurate apposition of everted skin edges.

Page 54: Wound Management Presenter: Susan Thompson, DO

Summary - Essentials

2. Choose a suture that is monofilament, causes little tissue reactivity, and retains tensile strength until the strength of the healing wound is equal to that of the suture.

Page 55: Wound Management Presenter: Susan Thompson, DO

Summary - Essentials

3. Dirty, contaminated, open wounds should generally be cleansed, debrided and closed within 6 hours to minimize the chance of infection.

Page 56: Wound Management Presenter: Susan Thompson, DO

Summary - Essentials

4. Suspected tendon injuries require examination of the full range of movement of joints distal to the wound while observing the tendon in the base of the wound for breaches. This is often done under anesthesia

Page 57: Wound Management Presenter: Susan Thompson, DO

Summary - Essentials

5. The success of a tendon repair (as measured by function) related in large part to the postoperative care and therapy, not simply to the suture and wound closure

Page 58: Wound Management Presenter: Susan Thompson, DO

Summary - Essentials

6. Appropriate splinting and elevation of limb wounds at risk of infection takes precedence over antibiotics in the postoperative prevention of infection

Page 59: Wound Management Presenter: Susan Thompson, DO

Summary - Essentials

7. If prophylactic antibiotics are used, they should be given intravenously prior to wound closure to achieve adequate concentrations in the tissues and hematomasthat may collect. There is no need for antibiotics with simple lacerations not involving tendons, joints or nerves

Page 60: Wound Management Presenter: Susan Thompson, DO

Summary - Essentials

8. Wounds that breach body cavities, such as the peritoneum or joints, or involving flexor tendons, nerves and named arteries, should be referred to a specialist for consideration of repair and inpatient care

Page 61: Wound Management Presenter: Susan Thompson, DO

Summary - Essentials

9. Foreign bodies such as clay chemically impair wound healing

Page 62: Wound Management Presenter: Susan Thompson, DO

Summary - Essentials

10.Puncture wounds such as bites may be managed by either second-intention healing after thorough lavage, or better still by excisional debridement, lavage, antibiotics and atraumatic closure, if less than 24 hours old (preferably less than 6 hours)

Page 63: Wound Management Presenter: Susan Thompson, DO

References1. Lammers R. Foreign bodies in wounds. In: Singer AJ, Hollander JE, eds. Lacerations and

acute wounds: an evidence based guide. Philadelphia: FA Davis, 2003;1472. National Health and Medical Research Council, the Australian Immunization Handbook,

9th Edn. Canberra: NHMRC, 20083. Moy, RL, Lee A, Zalka A. Commonly used suturing techniques in skin surgery. American

Family Physician 1991; 44:1625-1634.4. Dire DJ, Welch AP. A comparison of wound irrigation solution used in the Emergency

Department. Annals of Emergency Medicine 1996; 19: 704.5. Bansal BC, Weike PA, Perkins SD, Abramo TJ. Tap water irrigation of lacerations.

American Journal of Emergency Medicine 2002; 20: 469.6. Ellis H. Hazards from surgical gloves. Annals of the Royal College of Surgeons of

England 2007; 79:161-1637. Howell JM, Morgan JA,. Scalp lacerations repair without prior hair removal. American

Journal of Emergency Medicine 1988; 6:7. 8. McGhee DL. Anesthetic and analgesic techniques. Roberts and Hedges, Clinical

Procedures in Emergency Medicine. 5th edn. 2010: 490-4919. McClean NR, Fyfe AH, Flint EF, et al. Comparison of skin closure using continuous and

interrupted nylon sutures. British Journal of Sugery. 1999; 67: 633-63510. Jorgensen LN, Kallenhave F, Chrsitensen E, Siana JE, Less Collagen production in

smokers. Surgery 1998; 123:450-455.