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Ischemic and diabetic wounds of the lower extremityAdvances in patient-centered surgical careSantema, T.B.

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O2

CHAPTER 2Systemic wound care: A meta-review of Cochrane systematic reviews

D.T. UbbinkT.B. SantemaR.M. Stoekenbroek

Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands

Surgical Technology International 2014



22

Chapter 2

ABSTrACT

Wound care is a classic example of a surgical realm with a great variation in care. The diversity in wounds and wound treatments, the limited amount of convincing evidence, and the diverging opinions among doctors and nurses involved in wound care contribute to this undesirable variation in care. For chronic wounds, such as arterial or venous ulcers, pressure sores, and diabetic foot ulcers, but also for acute wounds after surgery or trauma, international and national guidelines provide recommendations on diagnostic procedures and treatment options, but rely mostly on expert opinion. We present the available evidence from Cochrane systematic reviews for the systemic treatment (i.e., not prevention) of patients with wounds, as opposed to topical wound treatments.

This evidence shows: ‒ Venous ulcers: High-compression therapy is the classic and evidence-based treatment

for treating venous ulcers. Oral pentoxifylline promotes ulcer healing with and without compression therapy. Oral zinc is not effective to heal venous ulcers.

‒ Acute wounds: Recombinant human growth hormone accelerates healing of large burn wounds and donor sites, while high-carbohydrate feeding might reduce the risk of pneumonia. Linezolid is more effective than vancomycin for treating skin and soft tissue infections. Hyperbaric oxygen may help heal crush wounds and skin grafts. Therapeutic touch does not heal acute wounds.

‒ Pressure sores: Air-fluidized and some low-tech devices appear effective for treating existing pressure ulcers. Oral zinc, protein, or vitamin C supplements seem ineffective. Also, evidence is lacking on the effectiveness of repositioning regimes as a treatment option.

‒ Diabetic ulcers: Hyperbaric oxygen therapy and pressure-relieving devices may improve healing rates.

‒ Arterial ulcers: Prostanoids and spinal cord stimulation may be effective in healing ischemic ulcers.

Thus, fortunately, some high-level evidence exists for various local and systemic interventions in wound care. Caregivers should be aware of, and apply, the strongest evidence available. Only when all stakeholders (patients, physicians, wound care nurses, but also manufacturers and buyers) implement this available evidence will optimum quality of care for patients with wounds be ensured.



Systemic wound care: A meta-review of Cochrane systematic reviews

23

2

INTroduCTIoN

Worldwide, many patients suffer from wounds. These may have various causes, generally divided into acute (i.e., after trauma or surgery) or chronic (i.e., due to arterial or venous insufficiency, pressure, or diabetes). Wound care has become a costly industry, given the large numbers of patients with wounds in the various care settings, and the many different medical and nursing specialists involved. Apart from this variety, a huge arsenal of treatment options exists. These comprise either local dressing materials or topical agents or systemic interventions that focus on improving the general condition of the patient or ameliorating the wound condition in order to support wound healing.

Furthermore, inter-observer variation exists as to the classification of wounds and subsequent choice of therapies.1, 2 This variation in care is understandable, as it concerns different wound types in different stages of wound healing. Hence, diverging interventions may be indicated, even for apparently similar wounds. However, unwarranted (geographic) variation in care also exists,3 which is mainly ascribed to differences in disease burden and socioeconomic factors, and suggests waste of health care resources. In the realm of wound care this variation is fostered by the wide range in wound care products available on the market and the many different care professionals involved, each having their own preferences and experience. In addition, there is a lack of convincing evidence on the treatment options in wound care as compared with other areas of medicine,4 which hampers a uniform wound care policy.

The Cochrane collaboration offers the highest-quality systematic reviews of best available evidence for effectiveness of treatments in the hierarchy of study designs.5 The vast majority of these systematic reviews on wound care address the local application of dressings or topical agents. The evidence on other, nonlocal treatment options seems relatively scarce. Nevertheless, if useful evidence is available, this should be known by those involved in wound care in order to provide high-quality care. Hence, this paper summarizes the available high-level evidence from Cochrane systematic reviews on systemic treatment options for any type of wound.

meThodS

This meta-review was conducted along the MARQ checklist.6 For this meta-review, all pertinent Cochrane systematic reviews (CSRs) on systemic wound care were included. “Systemic treatment” was defined as therapeutic interventions that are not limited, or applied directly, to the wound and affect the whole patient. Eligible reviews should deal with the treatment of open wounds of any type and etiology. Reviews on treatment for surgically closed wounds were excluded, as well as preventive interventions (e.g., antibiotic prophylaxis).



24

Chapter 2

All CSRs on systemic wound treatments in the Cochrane Database of Systematic Reviews up to January 2014, as published by the Cochrane Wounds Group or the Peripheral Vascular Disease Group, were retrieved and screened. We refrained from a formal internal validity judgment because all CSRs undergo clinical and methodological scrutiny.

Data extraction was performed by the three investigators using a predefined data extraction form comprising trial characteristics and outcomes. Significant relative risks or odds ratios were also presented as number needed to treat (NNT) or number needed to harm (NNH) with their 95% confidence intervals (CIs) in order to better illustrate the clinical relevance of the results.

To classify the strength of evidence of effect we graded each treatment comparison and outcome by taking into account the numbers of trials and participants included, consistency of results, and potential for pooling the results.7 In case of apparent methodological flaws or contradicting results in the individual trials we downgraded the level of evidence of the intervention studied. The resulting five levels of evidence are shown in Table 1.

Table 1. Definition of categories used to grade the strength of evidence of effectiveness.

Levels of evidence of effect Criteria

1. Strong evidence of effect Significant results in favor of new treatment, based on pooled data of trials totaling over 100 patients

2. Strong evidence of no effect Significant results in favor of control treatment or non-significant differences, based on pooled data of studies totaling over 100 patients

3. Limited evidence of effect Significant results in favor of new treatment, based on one or more large (over 100 patients) but unpoolable studies, or pooled results from small studies totaling less than 100 patients

4. Limited evidence of no effect Significant results in favor of control treatment or non-significant difference, based on one or more large (over 100 patients) but unpoolable studies, or pooled results from small studies totaling less than 100 patients

5. Neither strong nor limited evidence of effect

No large or poolable trials available.

reSuLTS

The Cochrane library eventually yielded a total of 24 suitable reviews. The selection process and final number of included reviews are detailed in figure 1. The included reviews were categorized and are presented here based on wound type. Some CSRs reported on more than one ulcer type. Thus, 9 reviews on venous ulcers, 6 on acute wounds, 4 on pressure sores, 3 on diabetic ulcers, and 4




25

2

on arterial ulcers were available for analysis. Tables 2a through 2e show the review characteristics, Tables 3a through 3e present the outcomes of the reviews.

venous ulcersNine CSRs assessed systemic treatment options for venous ulcers (Tables 2a and 3a).8–16 Eight of them included trials conducted in a hospital setting. The CSR by Weller et al. included trials that were performed in a community setting.15

‒ Compression therapy is a classic treatment that is frequently used. Available evidence shows that using high-compression stockings improves wound healing more than short stretch bandages, and 4-layer bandages are more effective on wound healing than multi-layer short-stretch bandages.

‒ Besides compression therapy, oral pentoxifylline was found to significantly enhance venous

figure 1. Selection process of Cochrane systematic reviews for the meta-review. Two of the 24 reviews selected for the meta-review contained trials on more than one wound type.

1

Cochrane Systematic reviews in Cochrane Wounds Group

N = 103

Excluded titles:* Local- or preventive treatment: N = 80* No venous, acute, pressure, diabetic or arterial wounds included: N = 4

Venous woundsN = 9

Reviews on acute wounds

N = 6Reviews on

pressure ulcersN = 4

Reviews on arterial ulcersN = 4

Reviews on diabetic ulcersN = 3

Reviews for meta-reviewN = 24

Cochrane Systematic reviews on Critical Limb Ischemia in Peripheral Vascular Disease Group

N = 13

Excluded titles:* No venous, acute, pressure, diabetic or

arterial wounds included: N = 10



26

Chapter 2

ulcer healing as compared with placebo or no treatment with an NNT of 4 (95% CI 3 to 6). It is effective with and without compression therapy. However, more adverse events (mainly gastrointestinal disturbances) were reported in the pentoxifylline group (RR 1.56; 95% CI 1.10 to 2.22; NNH 14, 95% CI 7 to 38).

Other therapies investigated in CSRs showed no or limited effectiveness: ‒ No evidence was found for the effectiveness of hyperbaric oxygen for treating venous ulcers,

based on only one small trial (comparing 16 patients). ‒ Intermittent pneumatic compression (IPC) seemed more effective than no compression,

based on the results of one single trial. However, this finding seems not compatible with daily practice, in which ambulant compression therapy is the standard. The review concluded that ICP as an adjunct to compression therapy does not promote ulcer healing compared with compression therapy alone. In this review, one trial was excluded from the meta-analysis because of heterogeneity, but found an increased ulcer healing rate in the IPC group compared with compression therapy alone (RR 11.4, 95% CI 1.6 to 8.2). If using IPC, rapid IPC may heal more ulcers than slow IPC does.

‒ There is no current CSR evidence on the effectiveness of the routine use of systemic antibiotics to treat venous ulcers. Only levamisole compared favorably to placebo with respect to wound healing rate.

‒ No trials were found on the treatment of venous ulcers with endovenous thermal ablation. ‒ Flavonoid-containing compounds (both micronized purified flavonoid fraction [MPFF] and

hydroxyethylrutosides) seem to improve venous ulcer healing more than placebo when pooling the results. Yet, because of high risk of bias in studies that support this result, this should be interpreted with caution. In contrast, one unpublished study of good quality and low risk of bias reported no significant benefit of MPFF on ulcer healing (RR 0.94, 95% CI 0.73 to 1.22). Flavonoids are usually given orally, but can be administered topically or intravenously.

‒ One review about interventions to help people adhere to compression therapy contained two randomized clinical trials (RCTs), one about the Leg Club, a community-based clinic, and the other about the Lively Legs program, a self-management program. Both interventions did not seem to have any effect on wound healing in people with venous ulcers, while both trials were at high risk of bias.

‒ Oral zinc sulphate, when compared with placebo, has no effect on ulcer healing based on the pooled results of four small trials that included venous ulcers.

Acute woundsFive of the 6 CSRs on this topic contained trials on burns or skin infections in a hospital setting,17–22 while one CSR on the effectiveness of therapeutic touch comprised 4 trials,22 all performed in healthy volunteers (Tables 2b and 3b).




27

2

Tabl

e 2a

. Cha

ract

erist

ics o

f inc

lude

d Co

chra

ne s

yste

mat

ic re

view

s on

ven

ous

ulce

rs.

firs

t au

thor

Year

of l

ast

upda

te#

of r

CTs

Tota

l #

patie

nts

Wou

nd ty

peIn

terv

entio

nC

ompa

rison

Prim

ary

outc

ome

para

met

er(s

)fo

llow

-up

dura

tion

veN

ou

S u

LCer

S

Jull

2012

1286

4Ve

nous

ulce

rsPe

ntox

ifyllin

e (w

ith a

nd

with

out c

ompr

essio

n th

erap

y)Pl

aceb

o or

no

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men

tHe

aling

or s

igni

fican

t im

prov

emen

t and

ad

vers

e ef

fect

s

6 w

eeks

to

6 m

onth

s

Kran

ke20

121

16Ve

nous

ulce

rsHB

OT

Sham

trea

tmen

tPr

opor

tion

of u

lcers

he

aled

18 w

eeks

Nelso

n20

117

367

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us u

lcers

IPC

Sham

or n

o IP

CPr

opor

tion

of u

lcers

he

aled

3 m

onth

s to

18

0 da

ys

O’M

eara

2012

4843

21Ve

nous

ulce

rsCo

mpr

essio

n th

erap

yNo

com

pres

sion

or d

iffere

nt ty

pe

of c

ompr

essio

n

Prop

ortio

n of

hea

led

ulce

rs a

nd ti

me

to

com

plet

e he

aling

2 m

onth

s to

1

year

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3Ve

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stem

ic an

tibio

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anda

rd c

are

or

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ebo

Prop

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ks

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uel

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00

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al ab

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cer h

ealin

g

Scall

on20

139

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R or

MPF

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are

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6

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132

151

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Inte

rven

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for h

elpin

g pe

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atm

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Hom

e vis

its b

y nu

rse

or u

sual

care

Prop

ortio

n of

pa

rticip

ants

with

ulce

rs

heale

d

24 w

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18 m

onth

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inso

n20

124

on

veno

us

ulce

rs

183

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us o

r arte

rial le

g ul

cers

>

4 w

eeks

; iso

lated

foot

ulce

rs

wer

e ex

clude

d (o

nly

stud

ies

inve

stig

atin

g ve

nous

ulce

rs a

re

repo

rted)

Ora

l zin

c su

lpha

tePl

aceb

oPr

opor

tion

of h

ealed

ul

cers

4 w

eeks

to

4 m

onth

s

HBO

T: h

yper

baric

oxy

gen

ther

apy,

IPC:

inte

rmitt

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neum

atic

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pres

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HR:

hyd

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ethy

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F: m

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purifi

ed fl

avon

oid

fract

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28

Chapter 2

‒ In patients with at least 10% total body surface area (TBSA) burns, high-carbohydrate, low-fat enteral feeds significantly reduced the incidence of pneumonia (NNT 2.5; 95% CI 1.7 to 4.5). In large burn wounds (>40% TSBA), recombinant human growth hormone accelerates wound healing.

‒ For skin and soft tissue infections, linezolid performed better than vancomycin in terms of clinical cure (NNT 18.5, 95% CI 11.4 to 52.6) and microbiological cure (NNT 15.9, 95% CI 9.8 to 40.5).

‒ Hyperbaric oxygen therapy (HBOT) was found to be effective in burn wounds covered with skin grafts to achieve complete graft survival as compared to sham-HBOT (NNT 2.4, 95% CI 1.5 to 5.9), dexamethasone, and heparin. HBOT was also effective in crush wounds to achieve complete healing (NNT 2.6, 95% CI 1.6 to 7.4) and to reduce tissue necrosis (NNT 2.6, 95% CI 1.6 to 7.4).

‒ No RCTs were available on the treatment of phosphorus burns.

Pressure sores Various treatment options for pressure sores were studied in hospitals, elderly care, and nursing home settings (Tables 2c and 3c). Available evidence from four CSRs showed no effectiveness of enteral or parenteral nutrition (i.e., zinc or protein suppletion) or nutritional supplements (i.e., vitamin C) as treatment modalities for pressure ulcers.23–26 The same was true for repositioning regimes, on which no trials were found. While no conclusive evidence was found to suggest that low-pressure or alternating-pressure supports, profiling beds, or sheepskins were more effective than other surfaces, limited evidence was available for the effectiveness of air-fluidized and some low-tech devices in the treatment of existing pressure ulcers.

diabetic ulcersThree different treatment options for diabetic ulcers were addressed in three CSRs:9, 27, 28 hyperbaric oxygen therapy, granulocyte-colony stimulating factor and pressure-relieving interventions (Tables 2d and 3d).

‒ Adding HBOT to usual care appeared to increase the healing of diabetic ulcers after 6 weeks (NNT 8.2, 95% CI 4.9 to 26.3). This beneficial effect was no longer significant in the long term, nor did HBOT significantly decrease eventual amputation rates.

‒ G-CSF is given by daily injections during the acute phase of the infection, in doses based on neutrophil counts. However, evidence is lacking that G-CSF might cure diabetic foot infections or improve ulcer healing. Therefore, G-CSF is not recommended in the treatment of relatively mild infections. On the other hand, G-CSF may be considered in limb-threatening infections as the available evidence suggests that G-CSF has a beneficial effect on amputation rates (NNT 8.9, 95% CI 4.7 to 80). The high cost of this treatment needs to be taken into consideration.




29

2

Tabl

e 2b

. Cha

ract

erist

ics o

f inc

lude

d Co

chra

ne s

yste

mat

ic re

view

s on

acu

te w

ound

s.

firs

t aut

hor

Year

of l

ast

upda

te#

of r

CTs

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l #

patie

nts

Wou

nd ty

peIn

terv

entio

nC

ompa

rison

Prim

ary

outc

ome

para

met

er(s

)fo

llow

-up

dura

tion

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ou

Nd

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ouni

2012

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us b

urns

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y tre

atm

ent

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h, ti

me

to

com

plet

e w

ound

he

aling

or p

ropo

rtion

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derv

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rse

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cts

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ters

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nts

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ter T

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, low

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rimen

tal f

ull t

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perie

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t

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tic to

uch;

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nd d

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r an

tibac

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l was

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ack

for 1

0 m

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uscle

relax

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n fo

r 15

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ded

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ery

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30

Chapter 2Ta

ble

2c. C

hara

cter

istics

of i

nclu

ded

Coch

rane

sys

tem

atic

revie

ws

on p

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ure

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thor

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date

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r

CTs

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l #

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PreS

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essu

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rface

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ir- o

r wat

er-fi

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mat

tress

es, o

verla

ys, b

eds,

cu

shio

ns, s

heep

skin

s)

Sim

ilar p

ress

ure-

relie

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ort s

urfa

ces

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rs h

ealed

, tim

e to

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, wou

nd s

ize (o

nly

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lts o

f ulce

r hea

ling

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show

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7 da

ys to

18

mon

ths

McG

inni

s20

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pres

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sus

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i.e.,

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ays

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(tw

ice a

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.d.:

tres

in d

iem (t

hrice

a d

ay)




31

2

Tabl

e 2d

. Cha

ract

erist

ics o

f inc

lude

d Co

chra

ne s

yste

mat

ic re

view

s on

diab

etic

ulce

rs.

firs

t au

thor

Year

of

last

up

date

# of

r

CTs

Tota

l #

patie

nts

Wou

nd ty

peIn

terv

entio

nC

ompa

rison

Prim

ary

outc

ome

para

met

er(s

)fo

llow

-up

dura

tion

dIA

BeTI

C u

LCer

S

Cruc

iani

2013

516

7Pa

tient

s w

ith d

iabet

ic fo

ot in

fect

ions

G-C

SF +

st

anda

rd

treat

men

t

Care

as

usua

l / p

laceb

oRe

solu

tion

of in

fect

ion,

impr

ovem

ent

of in

fect

ion,

ulce

rs h

ealin

g, s

urgi

cal

proc

edur

es, (

any)

ampu

tatio

n ra

tes

Not s

pecifi

ed in

re

view

Kran

ke20

127

369

Chro

nic

ulce

rs (a

s de

fined

by

stud

y au

thor

s) a

ssoc

iated

w

ith d

iabet

es

HBO

TCa

re a

s us

ual /

sha

m

treat

men

tPr

opor

tion

of h

ealed

ulce

rs,

prop

ortio

n of

majo

r am

puta

tions

4 w

eeks

to 2

2 m

onth

s

Lew

is20

1314

709

Ulce

rs o

f any

sev

erity

in

diab

etic

patie

nts

Exte

rnal

or

surg

ical

pres

sure

relie

f

Anot

her e

xter

nal p

ress

ure

–reli

evin

g in

terv

entio

n,

or n

o pr

essu

re-re

lievin

g in

terv

entio

n

Tim

e to

com

plet

e he

aling

, hea

ling

rate

s (o

nly

resu

lts o

f hea

ling

rate

s ar

e sh

own)

30 d

ays

to

2 ye

ars

G-C

SF: g

ranu

locy

te-c

olon

y st

imul

atin

g fa

ctor

, HBO

T: h

yper

baric

oxy

gen

ther

apy



32

Chapter 2

‒ Non-removable pressure-relieving devices, such as the total contact cast, are more effective than removable devices in promoting the healing of plantar diabetic ulcers (NNT 7.2, 95% CI 4.0 to 36.6). However, contraindications and disadvantages, such as postural instability and the inability to regularly check the ulcer, need to be taken into account. Removable devices and felt may be considered in case of contraindications or if nonremovable devices have been unsuccessful.

Arterial ulcersFour of the identified CSRs on critical limb ischemia, including arterial ulcers, reported on ulcer healing (Tables 2e and 3e).16, 29–31

‒ There is no evidence to support the use of oral zinc sulphate in the treatment of arterial leg ulcers, as the CSR contained only one small trial of poor methodological quality.

‒ Treatment with prostanoids may improve the healing of arterial leg ulcers. However, available evidence is inconclusive because of clinical heterogeneity. Moreover, the optimal drug from the prostanoid-family remains to be established, and the clinical usefulness is limited by the necessity of intravenous administration, often for more than one week.

‒ Some evidence suggests that spinal cord stimulation may improve wound healing in patients with arterial ulcers and non-reconstructable limb ischemia. Transcutaneous oxygen tension may be useful in selecting appropriate patients. However, the cost-effectiveness needs to be established and the risk of implantation failure and complications should be taken into consideration.

‒ A CSR on subintimal angioplasty identified no RCTs.

dISCuSSIoN

Several Cochrane systematic reviews offer convincing evidence on the effectiveness or ineffectiveness of systemic treatments of various wound types, which is useful for clinical practice and should be applied to ensure a high quality of care. However, many other reviews show a striking lack of convincing evidence from randomized trials on various commonly applied systemic treatment modalities, while existing trials are all too often flawed by several sources of bias and heterogeneity. For future research in wound care, standards for proper conduct and reporting of such trials are available.32, 33

For the treatment of venous leg ulcers compression therapy is currently the gold standard, while various forms of compression are widely used. Because of differences in preference for specific bandages or stockings,34 local expertise may affect the effectiveness of these treatments, and this should be taken into consideration when choosing a specific type of compression therapy. Furthermore, the potential




33

2

Tabl

e 2e

. Cha

ract

erist

ics o

f inc

lude

d Co

chra

ne s

yste

mat

ic re

view

s on

arte

rial u

lcers

.

firs

t au

thor

Year

of

last

up

date

# of

rC

TsTo

tal #

pa

tient

sW

ound

type

Inte

rven

tion

Com

paris

onPr

imar

y ou

tcom

e pa

ram

eter

(s)

follo

w-u

p du

ratio

n

ArTe

rIA

L u

LCer

S

Chan

g20

130

0Ch

roni

c lo

wer

limb

ische

mia

Subi

ntim

al an

giop

lasty,

with

or

with

out s

tent

Alte

rnat

ive m

odali

ties

Ruffo

lo20

108

RCTs

re

porte

d on

ul

cer h

ealin

g

1132

Critic

al lim

b isc

hem

ia w

ithou

t cha

nce

of re

scue

or

reco

nstru

ctive

inte

rven

tion

(onl

y st

udies

inve

stig

atin

g ul

cer

heali

ng a

re re

porte

d)

Pros

tano

ids

Plac

ebo

or o

ther

ph

arm

acol

ogica

l co

ntro

l tre

atm

ent

Mor

tality

, res

t-pain

relie

f and

lim

b sa

lvage

(not

limite

d to

pa

tient

s w

ith w

ound

s). W

ound

he

aling

is a

sec

onda

ry o

utco

me

3 w

eeks

to

4 ye

ars

Ubbi

nk20

132

RCTs

re

porte

d on

ul

cer h

ealin

g

72No

n-re

cons

truct

able

chro

nic

critic

al lim

b isc

hem

ia (o

nly

stud

ies in

vest

igat

ing

ulce

r he

aling

are

repo

rted)

Spin

al co

rd

stim

ulat

ion

Cons

erva

tive

treat

men

t (i.e

. non

-su

rgica

l tre

atm

ent a

nd

loca

l wou

nd c

are)

Lim

b sa

lvage

(not

limite

d to

pa

tient

s w

ith w

ound

s). W

ound

he

aling

is a

sec

onda

ry o

utco

me

1 to

2

year

s

Wilk

inso

n20

121

RCTs

on

arte

rial u

lcers

30Ve

nous

or a

rteria

l leg

ulce

rs

>4 w

eeks

; iso

lated

foot

ulce

rs

wer

e ex

clude

d (o

nly

stud

ies

inve

stig

atin

g ar

teria

l ulce

rs a

re

repo

rted)

Ora

l zin

c su

lpha

tePl

aceb

o or

no

inte

rven

tion

Num

ber o

f ulce

rs h

ealed

, tim

e to

hea

ling

and

rate

of h

ealin

g1

year



34

Chapter 2Ta

ble

3a. R

esul

ts fr

om th

e 9

Coch

rane

sys

tem

atic

revie

ws

on v

enou

s ul

cers

.

firs

t au

thor

Prim

ary

outc

ome(

s)r

r*(9

5% C

I)r

isk

of b

ias

Leve

l of

evid

ence

rec

omm

enda

tion

Jull

Com

plet

e ul

cer h

ealin

g or

sig

nific

ant

impr

ovem

ent

‒O

vera

ll ‒W

ith c

ompr

essio

n th

erap

y ‒W

ithou

t com

pres

sion

ther

apy

1.70

(1.3

0 to

2.2

4)1.

56 (1

.14

to 2

.13)

2.25

(1.4

9 to

3.3

9)

Mod

erat

e1

Pent

oxify

lline

is an

effe

ctive

adj

unct

to c

ompr

essio

n ba

ndag

ing

or w

ithou

t com

pres

sion

ther

apy

for t

reat

ing

veno

us u

lcers

Kran

kePr

opor

tion

of u

lcers

hea

led a

t 18

wee

ks

5.00

(0.2

8 to

90.

18)

Mod

erat

e5

No c

onclu

sions

can

be

mad

e on

the

effe

ctive

ness

of H

BOT

base

d on

onl

y 1

small

trial

Nelso

nCo

mpl

ete

ulce

r hea

ling

‒IP

C +

com

pres

sion

vs c

ompr

essio

n alo

ne ‒IC

P vs

no

com

pres

sion

‒Fa

st IP

C vs

slo

w IP

C

1.09

(0.9

1 to

1.3

0)2.

27 (1

.30

to 3

.97)

1.41

(1.1

1 to

1.7

9)

Mod

erat

e2 5 5

IPC

with

com

pres

sion

ther

apy

does

not

pro

mot

e he

aling

co

mpa

red

with

com

pres

sion

ther

apy

alone

IPC

with

dre

ssin

g m

ay in

crea

se h

ealin

g co

mpa

red

with

dre

ssin

g alo

neRa

pid

IPC

may

pro

mot

e ul

cer h

ealin

g m

ore

than

slo

w IP

C

O’M

eara

Tim

e to

ulce

r hea

ling

‒4-

layer

ban

dage

vs

mul

ti-lay

er s

hort-

stre

tch

band

age

Com

plet

e ul

cer h

ealin

g ‒Hi

gh-c

ompr

essio

n st

ockin

gs v

s sh

ort-s

tretc

h ba

ndag

e

Com

plet

e he

aling

at 3

mon

ths

‒Tw

o-co

mpo

nent

sys

tem

vs

four

-laye

r ban

dage

Com

plet

e ul

cer h

ealin

g ‒Si

ngle-

com

pone

nt c

ompr

essio

n vs

mul

ti-co

mpo

nent

com

pres

sion

(unp

ooled

stu

dies

)

HR 1

.47

(1.2

0 to

1.8

1)

1.66

(1.0

7 to

2.5

8)

RR 0

.83

(0.6

6 to

1.0

5)

RRs

rang

e fro

m 0

.29

(0.0

8 to

1.0

5) to

1.2

9 (0

.62

to 2

.65)

Mos

t tria

ls un

clear

to

high

1 1 2 3 3 5

Patie

nts

rece

iving

the

4LB

heal

fast

er th

an th

ose

alloc

ated

the

SSB

Mor

e pa

tient

s he

al on

hig

h-co

mpr

essio

n st

ockin

g sy

stem

s th

an

with

the

SSB

Two-

com

pone

nt b

anda

ge s

yste

ms

appe

ar to

per

form

as

well

as

the

4LB

Mul

ti-co

mpo

nent

sys

tem

s m

ay b

e m

ore

effe

ctive

than

sin

gle-

com

pone

nt s

yste

ms

Mul

ti-co

mpo

nent

sys

tem

s co

ntain

ing

an e

lastic

ban

dage

ap

pear

to b

e m

ore

effe

ctive

than

thos

e co

mpo

sed

main

ly of

in

elast

ic co

nstit

uent

sCo

mpr

essio

n m

ay in

crea

se u

lcer h

ealin

g m

ore

than

no

com

pres

sion




35

2

Com

plet

e ul

cer h

ealin

g ‒3

com

pone

nts

inclu

ding

elas

tic b

anda

ge v

s 3

co

mpo

nent

s in

cludi

ng in

elast

ic ba

ndag

e

Com

plet

e ul

cer h

ealin

g ‒Co

mpr

essio

n vs

no

com

pres

sion

(unp

ooled

st

udies

)

From

0.9

4 (0

.69

to

1.27

) to

1.90

(1.2

2 to

2.9

5)

RRs

rang

e fro

m 1

.18

(0.9

6 to

1.4

7) to

4.0

(1

.35

to 1

1.82

)

O’M

eara

Com

plet

e ul

cer h

ealin

g ‒SC

vs

syst

emic

antib

iotic

s

- Af

ter 2

0 da

ys

- La

ter,

unsp

ecifie

d tim

e po

int

‒Le

vam

isole

vs p

laceb

o ‒Ci

profl

oxac

in v

s SC

or p

laceb

o ‒Ci

profl

oxac

in v

s tri

met

hopr

im ‒Tr

imet

hopr

im v

s pl

aceb

o

0.62

(0.2

2 to

1.7

2)0.

91 (0

.55

to 1

.25)

1.31

(1.0

6 to

1.6

2)1.

74 (0

.57

to 5

.30)

1.54

(0.4

6 to

5.0

9)0.

92 (0

.23

to 3

.63)

Uncle

ar4 5

Ther

e is

no e

viden

ce fo

r the

effe

ctive

ness

of r

outin

e us

e of

an

tibio

tics

to p

rom

ote

veno

us w

ound

hea

ling

Leva

miso

le sh

owed

a b

enefi

t in

term

s of

hea

ling

com

pare

d w

ith

plac

ebo

Sam

uel

No ra

ndom

ized

trials

exis

t tha

t ass

ess

the

effe

cts

of

endo

veno

us th

erm

al ab

latio

n on

the

heali

ng ra

tes

of v

enou

s ul

cers

Scall

onCo

mpl

ete

ulce

r hea

ling

‒M

PFF

‒HR

1.

36 (1

.07

to 1

.74)

1.70

(1.2

4 to

2.3

4)

Uncle

ar1

At p

rese

nt, t

here

is s

ome

evid

ence

of t

he b

enefi

cial e

ffect

s of

fla

vono

ids

for v

enou

s leg

ulce

rs fr

om tr

ials

that

wer

e po

orly

repo

rted

and

had

an u

nclea

r risk

of b

ias

Well

erCo

mpl

ete

ulce

r hea

ling

afte

r 6 m

onth

s ‒Le

g Cl

ub v

s nu

rse

visits

Com

plet

e ul

cer h

ealin

g af

ter 1

8 m

onth

s ‒Li

vely

Legs

vs

usua

l car

e

1.55

(0.8

1 to

2.9

3)

1.24

(0.9

3 to

1.6

7)

High

5cA

com

mun

ity b

ased

nur

sing

clini

c (L

eg C

lub)

or c

ouns

eling

pr

ogra

m (L

ively

Legs

) may

not

impr

ove

heali

ng ra

tes

Wilk

inso

nCo

mpl

ete

ulce

r hea

ling

1.22

(0.8

8 to

1.6

8)Un

clear

to

high

2O

ral z

inc

sulp

hate

doe

s no

t app

ear t

o aid

the

heali

ng o

f ven

ous

leg u

lcers

CI: c

onfid

ence

inte

rval,

RR:

relat

ive ri

sk, H

R: h

azar

d ra

tio, H

BOT:

hyp

erba

ric o

xyge

n th

erap

y, IP

C: In

term

itten

t pne

umat

ic co

mpr

essio

n, M

PFF:

micr

onize

d pu

rified

flavo

noid

frac

tion,

HR:

hy

drox

yeth

ylrut

osid

es, 4

LB: 4

-laye

r ban

dage

, SC:

sta

ndar

d ca

re, S

SB: s

hort-

stre

tch

band

age

*If n

ot o

ther

wise

spe

cified



36

Chapter 2Ta

ble

3b. R

esul

ts fr

om th

e 6

Coch

rane

sys

tem

atic

revie

ws

on a

cute

wou

nds.

firs

t aut

hor

Prim

ary

outc

ome(

s)r

r*(

95%

CI)

ris

k of

bia

sLe

vel o

f ev

iden

cer

ecom

men

datio

n

O’M

athú

naCo

mpl

etely

hea

led w

ound

s10

.3 (0

.12

to 8

.60)

Mod

erat

e to

hig

h2

Ther

e is

no ro

bust

evid

ence

that

TT

prom

otes

he

aling

of a

cute

wou

nds

Barq

ouni

No ra

ndom

ized

trials

exis

t tha

t ass

ess

the

effe

cts

of s

yste

mic

ther

apies

on

phos

phor

us b

urns

Mas

ters

Pneu

mon

ia (O

R)

Mor

tality

(OR)

Da

ys o

n ve

ntila

tor (

MD

in d

ays)

0.12

(0.0

4 to

0.3

9)0.

36 (0

.11

to 1

.15)

3.30

(0.8

0 to

5.8

0)

Mod

erat

e to

hig

h3

High

-car

bohy

drat

e, lo

w-fa

t ent

eral

feed

s in

pat

ients

w

ith a

t lea

st 1

0% T

BSA

burn

s m

ight

redu

ce

incid

ence

of p

neum

onia

com

pare

d w

ith u

se o

f a

low

-car

bohy

drat

e, h

igh-

fat d

iet

Bree

derv

eldHe

aling

tim

e bu

rns

for a

dults

(MD

in d

ays)

He

aling

tim

e do

nor s

ite fo

r adu

lts: (

MD

in d

ays)

He

aling

tim

e do

nor s

ite fo

r chi

ldre

n: M

D in

day

s)

Mor

tality

9.07

(4.3

7 to

13.

8)

3.15

(1.5

4 to

4.7

5)1.

70 (0

.87

to 2

.53)

0.

53 (0

.22

to 1

.29)

Low

or u

nclea

r1

Usin

g rh

GH

in p

eopl

e w

ith la

rge

burn

s (>

40%

TB

SA) c

ould

resu

lt in

mor

e ra

pid

heali

ng o

f th

e bu

rn w

ound

and

don

or s

ites

in a

dults

and

ch

ildre

n, a

nd in

redu

ced

lengt

h of

hos

pita

l sta

y, w

ithou

t inc

reas

ed m

orta

lity o

r sca

rring

, but

with

an

incr

ease

d ris

k of

hyp

ergl

ycem

ia

Yue

Clin

ical c

ure

micr

obio

logi

cal c

ure

Mor

tality

1.09

(1.0

3 to

1.1

9)1.

08 (1

.01

to 1

.16)

1.44

(0.7

5 to

2.8

0)

Low

to h

igh

1Li

nezo

lid s

eem

s to

be

mor

e ef

fect

ive th

an

vanc

omyc

in fo

r tre

atin

g pe

ople

with

skin

& s

oft

tissu

e in

fect

ions

Eske

sCo

mpl

ete

graf

t sur

vival

Crus

h w

ound

s he

aled

Tiss

ue n

ecro

sis

Com

plet

e gr

aft s

urviv

al (vs

. dex

amet

haso

ne)

(vs. h

epar

in)

3.50

( 1.

35 to

9.1

1)1.

70 (1

.11

to 2

.61)

0.13

(0.0

2 to

0.9

0)

1.14

(0.9

5 to

1.3

8)

1.21

(0.9

9 to

1.4

9)

Uncle

ar o

r hig

h3

HBO

T m

ay im

prov

e th

e ou

tcom

es o

f skin

gra

fting

an

d tra

uma

CI: c

onfid

ence

inte

rval,

HBO

T: h

yper

baric

oxy

gen

ther

apy,

MD:

mea

n di

ffere

nce,

rhG

H: re

com

bina

nt h

uman

gro

wth

hor

mon

e, R

R: ri

sk ra

tio, O

R: o

dds

ratio

, TT:

ther

apeu

tic to

uch,

TB

SA: t

otal

body

sur

face

are

a*If

not

oth

erw

ise s

pecifi

ed




37

2

Tabl

e 3c

. Res

ults

from

the

4 in

clude

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rs

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effe

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r hea

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pres

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of th

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el

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reNo

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xist t

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fect

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posit

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atien

ts o

n th

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aling

rate

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MD:

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ther

wise

spe

cified



38

Chapter 2

Table 3d. Results from the 3 included Cochrane systematic reviews on diabetic ulcers.

first author Primary outcome(s) rr (95% CI) risk of bias

Level of evidence recommendation

Cruciani Improvement of infectionSurgical proceduresAny amputation

1.40 ( 1.06 to 1.85)0.38 (0.21 to 0.70)0.41 (0.18 to 0.95)

Moderate or unknown (high risk of detection bias)

2 Little reason to use G-CSF in mild infections. G-CSF might decrease amputation rates in limb-threatening infections

Kranke Proportion of healed ulcers6 weeks (end of treatment)6 months1 yearMajor amputation rates

5.20 (1.25 to 21.7)1.70 ( 0.90 to 3.20)9.53 (0.44 to 207.8)0.36 (0.11 to 1.18)

Moderate to high

5 HBOT may improve healing rates on the short-term. No definite conclusions can be drawn regarding longer-term healing and amputation rates

Lewis Complete healingNon-removable vs. removable deviceNon-removable cast vs. temporary therapeutic shoe

1.17 (1.01 to 1.36)

1.41 (0.93 to 2.14)

Moderate (high risk of detection bias)

1

4

Non-removable devices more effectively heal diabetic ulcers than removable devices. Contra-indications should be acknowledged

CI: confidence interval, HBOT: hyperbaric oxygen therapy, G-CSF: granulocyte-colony stimulating, RR: risk ratio

Table 3e. Results from the 4 included Cochrane systematic reviews on arterial ulcers.

first author

Primary outcome(s) rr*(95% CI) risk of bias

Level of evidence recommendation

Chang No RCTs comparing subintimal angioplasty with other modalities were identified

Ruffolo Ulcer healing 1.54 (1.22 to 1.96) Unclear to moderate

1 Prostanoids might improve wound healing, although heterogeneity precludes firm conclusions

Ubbink Ulcer healing (RD)

-0.54 (-0.73 to -0.35) Unclear 3 Some evidence of a beneficial effect of SCS on ulcer healing

Wilkinson Ulcer healing 1.14 (0.89 to 1.47) Unclear 4 No evidence to support the use of oral zinc sulphate in patients with arterial leg ulcers

CI: confidence interval, RD: risk difference, RR: relative risk, SCS: spinal cord stimulation*If not otherwise specified

benefit of compression therapy may be underestimated because of lack of compliance. However, current interventions to enhance adherence have not been proven to be effective. In addition to compression therapy, pentoxifylline may provide additional benefit on wound healing. Despite the strong evidence available, pentoxifylline is, strikingly, not yet frequently used in clinical practice.

For acute wound care after trauma or surgery a recent Dutch guideline has been published addressing wound cleansing and disinfection, wound dressing materials, treatment of wound pain,




39

2

patient instructions, and organization of care.35 In contrast, systemic wound treatments do not receive much attention. Currently available evidence from this meta-review offers some additional systemic treatment options for burns and ischemic or infected wounds.

Existing pressure ulcers apparently do not benefit from pressure-relieving surfaces or nutritional supplements, as was confirmed by another systematic review.36 However, sheepskins and various mattresses and overlays for operation tables are evidence-based and commonly used to prevent pressure ulcers in the pre-sacral,37 heel, and other areas.38

Diabetic ulcers are a menace to all caregivers and patients involved. Current guidelines advise an approach from many angles, such as hyperglycemic control, proper off-loading, prompt treatment of local ischemia and infection, and patient education. The addition of a single intervention to standard care, as was described in most Cochrane reviews, may not result in a detectable improvement if other issues are not properly taken care of. Moreover, there are no dedicated randomized trials on the interventional (endovascular) treatment of diabetic foot ulcers,39 and it is still unclear what the contribution of new stent and drug-eluting technologies will have on the clinical outcome of diabetic feet.

HBOT showed some effectiveness for a range of acute and chronic, mainly ischemic, wound types. Similar findings were observed for diabetic ulcers in a meta-analysis by O’Reilly et al.40 However, the reliability of any of the pooled estimates is questionable because of substantial clinical heterogeneity and methodological shortcomings of the trials included in the review. The patient burden and the costs of repeated HBOT sessions are additional reasons why future well-conducted trials should elucidate its effectiveness and cost-effectiveness for various disorders. In such trials the patient population and interventions to be studied, as well as the outcomes and assessment moments should be clearly defined and clinically relevant.

Revascularization remains the cornerstone of the treatment of patients with critical limb ischemia, although its effectiveness in terms of wound healing was not reported separately in any CSR. However, some patients with ulcers primarily attributable to peripheral arterial disease are not suitable candidates (anymore) for vascular reconstruction. Some evidence indicates that spinal cord stimulation and parenterally administered prostanoids may improve wound healing in these patients. Consequently, current treatment guidelines recommend that these treatment modalities may be considered in patients in whom revascularization is not possible.41,42

Limitations of this studyWe limited ourselves to systemic interventions with respect to the treatment of wounds, rather than their prevention. For example, there is more high-level evidence from Cochrane reviews on the prevention of pressure ulcers or infection of mammalian bites.38, 43 Second, we also limited



40

Chapter 2

ourselves to Cochrane systematic reviews. Although other relevant systematic reviews do exist, the Cochrane reviews included here offer valuable insight in the highest level evidence currently available. Third, although the effectiveness of certain interventions may be clear from one or more randomized trials, their cost-effectiveness and effect on the patients’ quality of life are frequently neglected or underreported at best. Fourth, evidence-based wound care also involves taking into account the patients’ preferences in clinical decision-making on wound care. Particularly in the absence of convincing evidence, the patient’s preference should be involved.44

CoNCLuSIoN

In conclusion, the awareness and application by all stakeholders in wound care of the best available evidence, as presented in this meta-review, may contribute to higher-quality and more uniform care for patients suffering from wounds.




41

2

refereNCeS

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17. Barqouni L, Abu Shaaban N, Elessi K.Interventions for treating phosphorus burns. Cochrane Database Syst Rev 2012;3: CD008805.

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21. Yue J, Dong BR, Yang M, et al. Linezolid versus vancomycin for skin and soft tissue infections. Cochrane Database Syst Rev 2013;7:CD008056.

22. O’Mathúna DP, Ashford RL. Therapeutic touch for healing acute wounds. Cochrane Database Syst Rev 2012;6:CD002766.

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24. McGinnis E, Stubbs N. Pressure-relieving devices for treating heel pressure ulcers. Cochrane Database Syst Rev 2011;9:CD005485.

25. Moore ZEH, Cowman S. Repositioning for treating pressure ulcers. Cochrane Database Syst Rev 2012;9:CD006898.

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27. Cruciani M, Lipsky BA, Mengoli C, et al. Granulocyte-colony stimulating factors as adjunctive therapy for



42

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diabetic foot infections. Cochrane Database Syst Rev 2013 ;8:CD006810.

28. Lewis J, Lipp A. Pressure-relieving interventions for treating diabetic foot ulcers. Cochrane Database Syst Rev 2013;1:CD002302.

29. Chang ZH, Liu ZY. Subintimal angioplasty for chronic lower limb arterial occlusion. Cochrane Database Syst Rev 2013;3: CD009418.

30. Ruffolo AJ, Romano M, Ciapponi A. Prostanoids for critical limb ischaemia. Cochrane Database Syst Rev 2010;1:CD006544.

31. Ubbink DT, Vermeulen H. Spinal cord stimulation for non-reconstructable chronic critical leg ischaemia. Cochrane Database Syst Rev 2013;2:CD004001.

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33. Brölmann FE, Eskes AM, Sumpio BE, et al. Fundamentals of randomized clinical trials in wound care: reporting standards. Wound Repair Regen 2013;21(5):641–7.

34. Cullen GH, Phillips TJ. Clinician’s perspectives on the treatment of venous leg ulceration. Int Wound J 2009;6:367–78.

35. Guideline wound care. http://www.heelkunde.nl/uploads/o1/hI/o1hIRR2oR4QDojTm5pGjGA/Richtlijn-Wondzorgfinal. pdf. Last accessed Feb 3, 2014.

36. Reddy M, Gill SS, Kalkar SR, et al. Treatment of pressure ulcers: a systematic review. JAMA 2008;300(22):2647–62.

37. Mistiaen PJ, Jolley DJ, McGowan S, et al. A multilevel analysis of three randomised controlled trials of the Australian Medical Sheepskin in the prevention of sacral pressure ulcers. Med J Aust 2010;193(11–12):638–41.

38. McInnes E, Jammali-Blasi A, Bell-Syer SEM, et al. Support surfaces for pressure ulcer prevention. Cochrane Database Sys Rev 2011;4:CD001735.

39. Reekers JA. Interventional radiology in the diabetic lower extremity. Med Clin North Am 2013;97(5):835–45.

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Documents

UvA-DARE (Digital Academic Repository) Ischemic and ... · Wound care is a classic example of a surgical realm with a great variation in care. The diversity in wounds and wound treatments,