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NAMA : DINA FATIN NABILA

NIM : NH0222013
PRODI : S1 KEPERAWATAN
Author Tahun terbit Nama jurnal Judul Tujuan penelitian Metode
penelitian
Leopoldo C. Cancio 2021 Mary Ann Liebert, Inc. Topical Deepen understanding of A review of the
Antimicrobial burn treatment modalities historical
Agents For Burn not only from a technical literature on the
Wound Care: point of view, but also topical
History and from the point of view of antimicrobial
Current Status the clinical context in care of burn
which these modalities wounds was
are located originally performed
developed.
Hasil Kesimpulan
As our understanding The development of
of post-burn infection effective topical
evolved, and as new antimicrobial agents
products were for wound care was,
developed for the arguably, the single
prevention of post-burn most important
wound infection, major advance in the care of
advances in post-burn the burn patient. Still,
survival occurred. many gaps in our
Ultimately, ability to treat
improvements in complicated burn
anesthetic, surgical, wounds remain.
and critical care Fungal infection is an
management have unusual but daunting
permitted early challenge. Patients
excision and grafting of with impaired wound
the burn wound, healing and those with
decreasing but not advanced age or
eliminating the medical comorbidities
importance of topical may not benefit from
antimicrobial care, and early excision, and the
shifting much of the benefits of early
burden of wound excision may not be
infection prevention to available in austere or
the post-operative remote locations. For
period. these reasons, research
on optimal topical
treatment continues.
 Topical Antimicrobial Agents for Burn Wound Care:
History and Current Status

Leopoldo C. Cancio

Abstract

Background: Infection is the leading cause of death after thermal injury. Optimal prevention and treatment of
burn wound infection is enabled by an in-depth understanding of burn wound treatment modalities not only
from a technical standpoint, but also from the standpoint of the clinical context in which these modalities
were originally developed.
Methods: A review of the historical literature on the topical antimicrobial care of burn wounds was
performed. Results: As our understanding of post-burn infection evolved, and as new products were
developed for the prevention of post-burn wound infection, major advances in post-burn survival occurred.
Ultimately, improve- ments in anesthetic, surgical, and critical care management have permitted early
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excision and grafting of the burn wound, decreasing but not eliminating the importance of topical
antimicrobial care, and shifting much of the burden of wound infection prevention to the post-operative
period.
Conclusions: The development of effective topical antimicrobial agents for wound care was, arguably, the
single most important advance in the care of the burn patient. Still, many gaps in our ability to treat
complicated burn wounds remain. Fungal infection is an unusual but daunting challenge. Patients with
impaired wound healing and those with advanced age or medical comorbidities may not benefit from early
excision, and the benefits of early excision may not be available in austere or remote locations. For these
reasons, research on optimal topical treatment continues.

Keywords: antibiotic agents; antimicrobial agents; burns; infection; mafenide; silver

A
ccoRdINg To Basil A. Pruitt, Jr. (1930–2019), burns Antisepsis
should not be viewed as a unique phenomenon but rather
as the ‘‘universal trauma model’’ that exemplifies many of the The modern history of topical antimicrobial wound treat-
only.

body’s responses to injury, inflammation, and infection [1].
Indeed, the development of topical antimicrobial agents for
burn care is a microcosm of the larger campaign to understand
and treat surgical infections. The development by Pruitt and
colleagues of effective topical antimicrobial agents for the
prevention of invasive gram-negative burn wound infection
was the single most important step in the history of burn
care and led to important and sustained improvements in
post-burn mortality. This achievement was marked by the
introduction to the bedside of topical mafenide acetate
cream (Sulfamylon®, Mylan, Inc., Canonsburg, PA) in
January 1964 [2]. This pivotal event was grounded in years
of integrated laboratory and clinical research and was
followed by continued efforts to ad- dress the ever-changing
epidemiology of burn wound infection [3]. These efforts are
incomplete and continue to this day.
ment begins with the English surgeon Joseph Lister (1827–
1912), who recognized that micro-organisms, rather than
‘‘miasma,’’ were the cause of wound infection. In 1867 he
described ‘‘the antiseptic principle in the practice of surgery’’:
I arrived.at the conclusion that the essential cause of
sup- puration in wounds is decomposition, brought about
by the influence of the atmosphere upon blood or serum
retained within them, and, in the case of contused wounds,
upon por- tions of tissue destroyed by the violence of
the injury (.) When it had been shown by the researches
of Pasteur that the septic property of the atmosphere
depended not on the oxygen, or any gaseous constituent,
but on minute organisms sus- pending in it.it occurred
to me that decomposition in the injured part might be
avoided.by applying as a dressing some material
capable of destroying the life of the floating particles [4].

U.S. Army Institute of Surgical Research, Fort Sam Houston, Texas, USA.
3
 TOPICAL ANTIMICROBIAL AGENTS
For this purpose, he selected carbolic acid (phenol), be-
cause it was used in the town of Carlisle to reduce the
stench of sewage applied as a fertilizer to pasture land, with
the additional effect of preventing parasitic infections in the
cattle who grazed there [5]. Lister applied it topically to
compound fractures and abscess cavities, he used it to cleanse
the instruments and the surgeon’s gloved hands, and he had
an assistant spray it into the air during surgery [6]. Lister
avoided the ignominious fate of his Hungarian predeces-
sor, Ignaz Semmelweis (1818–1865), in part because of the
contemporaneous work of Louis Pasteur (1822–1895), and in
part because of his travels to communicate his findings to
surgical audiences in Europe and America. Thus, for exam-
ple, Lister was able to convert Henry Bigelow (1818–
1890), professor of surgery at Harvard University, from a
skeptic who referred to Lister as a practitioner of ‘‘medical
hocus- pocus’’ [6] to a devoted proponent:
But after two years’ experience, I have accepted the
new doctrine with most of its details. I have learned
that.the duty of the surgeon is to act as if all the particles
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made visible by a sunbeam were noxious, falling like snow-
flakes during every operation and every dressing.His aim
should be to destroy the actual intruders, and effectually to
exclude their thronging companions [7].
Even so, it is worth noting that Lister in later life discarded
the practice of spraying carbolic acid during surgery [8].
The onset of World War I challenged surgeons with in-
juries of unprecedented severity and number, caused by
machine-gun fire and artillery shells during trench warfare.
Massive wounds, contaminated field conditions, and delayed
evacuation led to a high rate of death from necrotizing
wound infections [9]. Under these circumstances, listerian
principles were questioned. Antiseptic solutions, applied to
the surface of a wound, were incapable of eradicating in-
fection from septic penetrating injuries. Rather, immunolo-
gist Almroth Wright (1861–1947) argued that hypertonic
saline (5%) dressings should be applied to septic wounds in
order to ‘‘attract water’’ from the depths of the wound, thus
producing an ‘‘outflowing current of water’’ and ‘‘drawing
into the tissues from the blood stream lymph inimical to
only.
microbial growth.’’ Thus, his idea was to enhance the body’s
own antimicrobial processes [10].
Meanwhile, French surgeon Alexis Carrel (1873–1944) and
English chemist Henry Drysdale Dakin (1880–1952) devel-
oped a refinement of the antiseptic technique. Dakin tested
a number of chemicals, settling on 0.5% sodium
hypochlorite solution, buffered with boric acid, as the agent
of choice. He described the antimicrobial properties of the
solution and as- serted that clinicians had found it non-
irritating to tissues [11]. Carrel tested the solution as one
component of what we would nowadays call a ‘‘bundle’’ of
care, which included a three- week training program for
physicians and nurses, wide incision and debridement of
wounds, implantation of tubes into the wound to permit the
instillation of the solution, frequent (every two to four
hours) infusion of the solution, bacterio- logic analysis of
wound contents, and delayed wound closure to correspond
with resolution of infection [12,13]. Devel- opment,
documentation, and popularization of the method was
accelerated by Carrel’s relationship with leading Bel- gian
surgeon Antoine Depage, at whose hospital at Com-
pie`gne Carrel oversaw an 80-bed ‘‘experimental
clinic’’
4
[14]. Carrel’s method was, however, subject to numerous
pitfalls requiring precision in its implementation, and was
logistically and technically demanding [15,16].
Antimicrobial Agents
The role of antisepsis in wound care began to be eclipsed
during the inter-war years by the development of antibacterial
drugs. Paul Ehrlich (1854–1915), the pioneering immunolo-
gist and biochemist, had discovered dyes that preferentially
stained tissues such as axons in living organisms and other
dyes that identified the different categories of granulocytes
(neutrophils, basophils, and eosinophils). Perhaps the same
concept could be used to target micro-organisms? Methy-
lene blue was only somewhat effective against malaria, and
trypan red against Trypanosoma equinum. Ehrlich et al.
[17] then turned to arsenicals, synthesizing and testing
approximately 1,000 compounds. Their compound 606,
arsphenamine (salvarsan), was found to be effective against
Treponema pallidum in a rabbit model of syphilis, the first
synthetic antibiotic.
Gerhard Domagk (1895–1964], a German pathologist
and bacteriologist, built on Ehrlich’s work, exploring the
antibacterial properties of various dyes at IG Farbenindus-
trie. He noted that, ‘‘For coccal infections, there have been
no reasonable effective chemotherapeutants known.’’ He
found that a red crystalline powder related to the azo dyes
and synthesized by others in 1932, Prontosil (4¢-sulfanamid-
2,4-diaminoazobenzene; Bayer AG, Leverkusen,
Germany), was curative when given subcutaneously or
orally in a lethal mouse model of intra-peritoneal
streptococcal infection. (In- terestingly, this drug was
effective only in vivo but not in vitro; this is because it is
what we now call a pro-drug and is metabolized to
sulfanilamide.) Also, Prontosil had differential efficacy
against different organisms; it was effective against
Streptococcus, somewhat against Staphylococcus, and not
at all against Pneumococcus. He referred to this selectivity
as ‘‘elektive Wirkung’’ [18].
After performing murine studies of streptococcal perito-
nitis similar to those done by Domagk [19], English physician
Leonard Colebrook (1883–1967), a student of Almroth
Wright, conducted an uncontrolled clinical trial of Prontosil
in puerperal sepsis in 1936. The use of Prontosil resulted in
a decrease in the death rate in this disease from 16.6%-
31.6% in previous years to 4.7% [20]. This stunning
advance her- alded the beginning of the age of antibiotic
agents.
Another inter-war development was growing interest in
improving the care of thermal injuries, but application of
the recent advances in microbiology and debridement was
de- layed by competing theories on burn pathophysiology.
The toxemia theory held that the eschar released a toxin
into the circulation. The identity and effects of this toxin
were ill- defined, which did not deter Davidson [21] from
writing in 1925 that the concept was ‘‘most strongly
supported.’’ Al- though some authors described the ‘‘early
and complete re- moval of the burned tissue,’’ Davidson
[21] proposed the use of tannic acid to precipitate proteins
and other ‘‘poisonous materials’’ in the burn wound. This
became a standard first aid treatment for burns through the
middle of World War II. On the other hand, Aldrich
claimed that tannic acid merely delayed the onset of
infection [22]. He, and others, performed bacteriologic
studies of burn wounds, demonstrating that
 TOPICAL ANTIMICROBIAL AGENTS 5

wound cultures became positive for streptococci beginning at

approximately the eighteenth hour post-burn [23,24]. Aldrich
[22] used a dye-based topical antimicrobial, gentian violet, to
prevent streptococcal infection. Later, he added acriviolet
and brilliant green to address gram-negative bacteria, thus
constituting ‘‘triple dye’’ therapy. He concluded ‘‘that the
conception of a burn as an infected surgical lesion is
correct, and that it is infection rather than the absorption of
a split protein which causes death’’ [23].
When the United Kingdom began experiencing large
numbers of burned aviators during the Battle of Britain in
1940, Archibald McIndoe assumed the care of these casual-
ties at the Queen Victoria Hospital in East Grinstead [25].
Among his numerous contributions to the nascent field of
burns was condemnation of tannic acid treatment. Not only
did it fail to prevent infection, but also ‘‘the hard inelastic
crust’’ led to ‘‘totally crippled hands and severe facial de-
formities with loss of vision’’ [26].
During 1940–1941, the U.S. government stood up two
organizations to support medical preparations for war: the
Advisory Committees to the Surgeon Generals of the Na-
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tional Research Council (NRC) and the Committee on

Medical Research. The NRC’s Subcommittee on Surgical
Infections funded eight U.S. civilian hospitals to establish
wound study units. The original project called for a multi-
center controlled study of sulfa drugs for the prevention of
infection in burn and non-burn wounds. These plans changed
after the attack on Pearl Harbor of December 1941 [27].
Approximately 60% of the more than 500 casualties at the FIG. 1. Use of a Flit gun to apply a topical agent to a
burn patient following the attack at Pearl Harbor, 1941.
naval hospital had burns, and their treatment varied widely. (Source: Getty Images.)
Despite McIndoe’s rejection of tannic acid, it was liberally
used there. For example, Flit guns (normally used to deliver
insecticide) were used to spray tannic acid onto wounds in vivo studies of efficacy in murine models, and clinical
(Fig. 1). Gentian violet or triple dye, with or without silver use in a handful of patients [33]. With this evidence in
nitrate, was also used. In some cases, sulfanilamide powder hand, Florey traveled to the United States in 1941 to gain
was mixed in with these substances. Sulfa drugs were also support for mass production and clinical trials. One such
given orally if infection was suspected [28]. clinical study was ready to go under the leadership of
I.S. Ravdin and Perrin H. Long visited Pearl Harbor after Champ Lyons at the Massachusetts General Hospital (
the attack to report back to the NRC on the medical response. MGH) at the time of the Cocoanut Grove Nightclub fire in
They derived an overly optimistic impression of the ‘‘in- November 1942 [30,34]. Topical treatment of these patients
calculable value of sulfonamide therapy,’’ both oral and at the MGH consisted of boric ointment strips and sterile
topical [29]. As a result, they recommended that, ‘‘You gauze under a pressure dressing. Intravenous sulfadiazine
only.

cannot withhold from these patients the benefit of the sul-
fonamide drugs,’’ and the use of the controls in the eight-
center civilian study became optional. The results of that
study ultimately were less sanguine and found no clear ad-
vantage to sulfa drugs. Referring to staphylococci and
gram- negative organisms in the burn wounds, Frank
Meleney concluded: ‘‘Something must be sought which
will be ef- fective at halting the growth of these organisms
in the presence of the dead and damaged tissue of burns’’
[27]. Furthermore, the wound study units found that
‘‘tanned burns showed a high incidence of infection,’’
leading to a recommendation in October 1942 that
procurement of tannic acid be discontinued [30].
The limitations of tannic acid and of sulfa drugs gave
impetus to the development of penicillin. Alexander Fleming
discovered penicillin in 1929, tested it in vitro, and suggested
that it could serve as an ‘‘efficient antiseptic’’ when
applied topically onto or injected into infected wounds [31].
Eleven years later, the Oxford team of Chain and Florey
[32] and others succeeded in producing enough penicillin
to permit
was given pro- phylactically, and penicillin as a treatment to
13 patients with clinical signs of infection, albeit at doses
subsequently rec- ognized as subtherapeutic [34].
As penicillin production ramped up, it was first studied in
U.S. combat casualties by Lyons (now an active duty Army
officer) at Bushnell General Hospital, Brigham City, Utah,
and then at Halloran General Hospital, Staten Island, New
York [35]. It was then distributed to British and U.S. hos-
pitals in the Mediterranean theater. Lyons reported from
that theater in 1944 that the proper role of antibiotic agents
was as an adjunct to, not as a substitute for, surgical man-
agement. Furthermore, he rejected the listerian concept
of topical antisepsis: ‘‘Experience in wound management
justifies the abandonment of local use of any chemical agent
in a wound’’ [36]. Despite that caveat, the extraordinary
collaboration among military, commercial, academic, and
government entities that delivered this new drug to the
battlefield is certainly one of the most important achieve-
ments of the war, and prepared the way for further post-war
antibiotic development [37].
 TOPICAL ANTIMICROBIAL AGENTS 6

Topical Antimicrobial Agents tridium perfringens [48]; the Germans issued it to their troops
for topical and oral use on the Eastern Front in 1941, and more
The exposure method

In January 1947, Edwin Pulaski moved from the

Halloran General Hospital (where early clinical studies of
penicillin had been conducted during World War II) to
Brooke General Hospital, Fort Sam Houston, Texas, to
establish a new sur- gical research unit (SRU; later the U.S.
Army Institute of Surgical Research [ISR]). This unit’s
mission was ‘‘evalua- tion and interpretation of new
antibiotics, chemotherapeutic agents and surgical technics’’
[38]. Patients admitted to this unit included not only those
with burns, but also those with a variety of infected
wounds. After 1949, the unit focused in- creasingly on
burns in anticipation of possible nuclear war. Pulaski
traveled to Birmingham, United Kingdom, to learn about
topical treatment with penicillin cream from Colebrook, but
ultimately adopted the ‘‘exposure method’’ from A.B.
Wallace at Edinburgh, who claimed that allowing burns to
dry out prevented infection and enhanced healing [39–42].
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Results of the exposure technique at the SRU were less

encouraging. Careful documentation of clinical and
microbiologic data in burn patients at the SRU showed that
during 1953–1963, there was a continued high prevalence of
bacteremia as the cause of death, and a gradual shift in the
causative organism from Sta- phylococcus aureus to
Pseudomonas. Control of Staphylo- coccus aureus was
attributed to the successful use of penicillin derivatives. On
the other hand, intravenous antibiotic agents were
ineffective at controlling Pseudomonas wound infection or
bacteremia. Furthermore, 90% of ‘‘burn wound sepsis’’
cases in 1963 had burn wound cultures positive for large
amounts of Pseudomonas.
Two divergent approaches were proposed to address this
problem. On the one hand, SRU surgeons noted that half of
septicemic patients during 1950–1954 had been treated
with the exposure method, and half with occlusive
dressings. Thus, the method of topical treatment did not
seem to mat- ter—particularly in larger burns. This
‘‘focuses attention on the need for wound closure at the
earliest possible time.’’ But the ‘‘heroic’’ decision to
only.

‘‘excise eschars boldly in stages during the immediate post-

burn period is difficult to make.’’ On the other hand, they
developed a model of invasive Pseudomonas aeruginosa
burn wound infection in rats, in which they proved the
wound origin of fatal post-burn sep- ticemia [43]. The
failure of systemic antibiotics to prevent or treat these
infections was explained by the avascular nature of the eschar
[44].

Mafenide

An answer to this problem was suggested by Janice Men-

delson, an Army surgeon doing research on blast injury in
goats. Fortuitously, a supply of mafenide hydrochloride
(Sul- famylon or marfanil; p-
aminomethylbenzenesulfonamide) seized from the Germans
during World War II was discovered in an Army warehouse
in Maryland [45]. This antibiotic had been synthesized in the
United States but abandoned because of a report of low
efficacy against streptococci [46]. (The murine model used
to test efficacy was intra-peritoneal injection of
Streptococcus pyogenes, followed by oral treatment [47].)
However, it was shown to have better activity against Clos-
TOPICAL ANTIMICROBIAL AGENTS 7
widely in 1943, mainly in order to prevent gas gangrene
[49]. Mendelson and Lindsay [50] demonstrated its
efficacy when applied topically (by spray) in a goat model
of undebrided blast injury complicated by a (naturally
occurring) Clostridium perfringens infection and related
these findings to the SRU group. At the SRU, Robert
Lindberg and Arthur D. Mason, Jr. (1928–2013) applied
Sulfamylon in the form of a cream in the rat burn wound
infection model. When applied either imme- diately or at
24 hours post-burn, the treatment produced a 100% survival
rate. Even as late as 72 hours post-burn, there was a
mortality effect [44]. This dramatic finding motivated
imme- diate translation to burn patients in January 1964
(Fig. 2) [2]. The results were similarly dramatic: a reduction
in burn wound sepsis as the cause of death from 59%
(during 1962–1963) to 10% (during 1964–1966) [2].
Despite its structural similarity to sulfanilamide, mafe-
nide’s mechanism of action is different. Unlike sulfa
drugs, mafenide does not act on bacteria to inhibit the
folate pre- cursor, para-aminobenzoic acid (PABA).
Furthermore, PABA does not inactivate mafenide, which
is important be- cause PABA may be present in large
quantities in wounds. Unlike silver preparations, it readily
diffuses through the avascular eschar, or through
avascular tissues such as carti- lage [51]. The latter
property makes it ideal for prevention of chondritis in
patients with ear burns. On the other hand, this means that
it needs to be re-applied twice daily to maintain an effective
concentration in the wound [51]. Once absorbed
systemically, it is metabolized rapidly to an inactive
metab- olite, p-carboxybenzenesulphonamide, a
compound with no antibacterial activity [52]. However,
this metabolite is a carbonic anhydrase inhibitor. Thus,
some patients with ex- tensive burns receiving twice-daily
Sulfamylon cream treat- ment may develop metabolic
acidosis and compensatory respiratory alkalosis [53].

Silver compounds and dressings

While SRU researchers were evaluating mafenide in the

early 1960s, Carl Moyer and colleagues performed studies of
silver nitrate (AgNO3) aqueous solution for topical burn
wound treatment. Silver nitrate had been used at concen-
trations of 5%–10% as a tanning agent and had
been

FIG. 2. Col. John Moncrief watches Maj. Basil A.

Pruitt, Jr. apply Sulfamylon burn cream to a patient, 1969.
(Source:
U.S. Army Institute of Surgical Research.)
 TOPICAL ANTIMICROBIAL AGENTS 8

discarded. Here, however, a 0.5% solution was used. This Spartanburg, SC).
was based on personal experience by one of the authors
with this solution in the treatment of problem wounds such
as necrotizing fasciitis. They observed that a 0.5% solution,
but not a 1% solution, was safe from the standpoint of not
im- peding epithelialization. They presented a case series,
dem- onstrating a reduction in wound colonization with
pathogens like Pseudomonoas aeruginosa and
Staphylococcus aureus. The primary indication of efficacy
was a reduction in mor- tality, from a predicted 41% to an
observed 14% [54].
Moyer et al. [54] emphasized the importance of using a
thick gauze dressing and of keeping the dressing moist con-
tinuously. That is, as the water evaporates from the
dressing, the concentration of AgNO3 remaining at the
wound surface was thought to increase past the safe level.
The cause of death while receiving AgNO3 was related to
electrolyte abnor- malities. As a hypotonic solution, silver
nitrate ‘‘leeches’’ electrolytes across the wound surface.
This can cause life- threatening levels of hyponatremia,
hypokalemia, and hy- pocalcemia, mandating frequent
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laboratory determinations (at least every six hours). Also,

use of this solution can cause hypothermia caused by
evaporation [54]. The primary limi- tation of AgNO3 is its
inability, unlike mafenide, to penetrate the eschar.
However, this limitation does not apply in the treatment of
superficial injuries, or of non-burn desquamating skin
diseases such as toxic epidermal necrolysis syndrome; the
latter is the primary indication for its use at the U.S. Army
Burn Center at this time.
The technical challenges associated with the use of silver
nitrate led Fox to develop silver sulfadiazine (SSD), a com-
plex of silver nitrate and the antibiotic sulfadiazine. When
mixed with chloride-containing fluids on the surface of a burn
wound, this complex releases the silver cation. In scalded
mice with otherwise lethal Pseudomonas aeruginosa
wound infections, SSD appeared to reduce mortality
compared to both silver nitrate and mafenide [55]. The
primary mechanism of action of SSD relates to the silver,
rather than to the sul- fadiazine. In contrast to silver nitrate
solution, release of silver from the silver sulfadiazine
complex is slow and steady [56]. Sometimes, SSD is
only.

associated with leukopenia, which re- solves within a few

days despite continuation of therapy [57]. The first silver
textiles used as dressings in the modern era were made
from nylon and were originally intended to serve as flexible
electric shields or radar reflectors [58]. Deitch et al.
[59] demonstrated in vitro efficacy of silver nylon against
Pseudomonas aeruginosa, Stapylococcus aureus, and Can-
dida albicans. Chu and McManus [58] at the ISR embarked
on a multiyear study of silver nylon dressings in rat models.
Interestingly, they demonstrated greater efficacy when the
dressing was connected, as an anode, to a weak direct
current source, causing increased release of silver cations
onto the wound. Under these conditions, silver nylon was
as effective as SSD [60]. Today, silver nylon is used
extensively in burn care, especially in superficial burns and in
clean, deeper burns of limited extent [61]. A variety of other
silver dressings have been developed, to include those made
with nanocrystalline silver (Acticoat, Smith+Nephew, Fort
Worth, TX) [62], soft silicone combined with foam
(Mepilex Ag®, Molnlycke, Gothenburg, Sweden) [63],
moisture-retentive spun fibers of sodium carboxymethyl-
cellulose (Aquacel Ag, ConvaTec, Oklahoma City, OK)
[64], and ceramic silver (Milliken As- sist, Milliken,
TOPICAL ANTIMICROBIAL AGENTS 9
The mechanism of action of silver is ‘‘oligodynamic,’’ interleukin (IL)-1b and IL-10 and chemokines GRO-KC
meaning that small amounts (parts per million) of silver and
are required for efficacy. Elemental silver is biologically
inert; only the cation (Ag+) is antimicrobial. Proposed
mechanisms of action include: (1) blocking the microbial
electron transport chain; (2) rupturing the cell membrane or
wall; (3) binding to and damaging bacterial DNA
(vulnerable because of its lo- cation in the cytoplasm);
and (4) destroying the cell by silver free radicals.
Antimicrobial resistance to silver is uncommon, thus, the
mechanism of action is likely multifactorial, such that
evolution of multiple resistance strategies would be re-
quired. A disadvantage of silver therapy is the fact that
silver cations can be precipitated on the wound surface by
anions such as chloride. This means that the effective
concentration in vivo is many times higher than that in
aqueous solutions. It also means that silver, unlike
mafenide, does not penetrate deeply into a wound.
Systemic silver toxicity (argyria) is extremely rare in burn
care [65]. An advantage of silver over mafenide is that the
former has some antifungal activity, particularly against
yeasts, whereas the latter has none.

Cerium

In 1977, Monafo, who with Moyer had described the use

of silver nitrate, treated patients with a combination of
cerium nitrate and SSD. Cerium is a rare-earth metal of
low toxicity. Monafo originally stated that cerium is an
antimicrobial, al- though subsequent studies have not
substantiated that claim [66]. Rather, cerium nitrate
results in a firm eschar that pro- tects against bacterial
ingress [67]. The eschar is tightly ad- herent without a
tendency to spontaneously separate from the burn wound
for at least six weeks [68,69]. Cerium also ap- pears to
exert a beneficial effect on host immune function. In
animal studies, cerium nitrate treatments decrease local
and systemic inflammation [70,71], limit burn wound
progression [72], and restore the helper-to-suppressor T-cell
ratio [73,74]. Moreover, cerium nitrate plus silver
sulfadiazine treatment— but not mafenide, silver nitrate, or
silver sulfadiazine alone— mitigates cell-mediated
immunity suppression in a mouse model [75].
It is not clear why cerium nitrate has these immune
benefits. Martin Allgo¨wer (1917–2007), a Swiss surgeon
best known as the co-inventor of the AO system for
internal fixation of frac- tures, proposed (in a manner
reminiscent of the toxemia theory), that burn wounds release
lipid-protein complexes (‘‘pernicious effectors’’) that cause
immunosuppression and systemic illness. Allgo¨wer and
colleagues stated that cerium nitrate binds to these
complexes and mitigates these effects. Other authors
demon- strated superficial connective tissue calcification
[69], which may result from cerium displacing calcium from
pyrophosphate to allow calcium to deposit, analogous to
the pyrophosphate- calcium interaction within cancellous
or cortical bone [67]. At the ISR, Kai Leung and
colleagues have shown in the Walker-Mason full-thickness
scald-burn model that cerium nitrate solution (40 mM)
treatment, as compared to a control solution, reduces
circulating levels of pro-inflammatory damage-associated
molecular patterns (DAMPs) such as high-mobility group
box protein 1 (HMGB1), hyaluronan, and xanthine
oxidase (XDH) on post-burn day one. On post- burn day
seven, circulating DAMP levels were on average halved
by cerium nitrate treatment, as were levels of cytokines
 TOPICAL ANTIMICROBIAL AGENTS
MIP-1a in wound tissue [70]. At present, cerium nitrate
with SSD is available in several countries as Flammacerium
(Derma UK Limited, Newcastle upon Tyne, UK), and has
received orphan drug status in the United States (it is not
yet Food and Drug Administration-approved).
Honey
Recently, there has been growing interest in the
antimicrobial properties of honey. Honey has been used since
ancient times as a topical antimicrobial and has been
proposed as an alterna- tive under austere or battlefield
conditions [76]. Medical-grade honey is now available
throughout the world. The mechanism of action of honey as
an antimicrobial is multifactorial. Honey is hyperosmolar
and has a low pH. Most honeys, because of the action of
glucose oxidase, produce hydrogen peroxide when diluted
with water. Some honeys contain specific antibacterial
agents. For example, manuka honey (from the flowers of
the Leptospermum tree of New Zealand) contains
methylglyoxal, an alpha-oxoaldehyde that reacts with DNA,
Downloaded by 36.72.68.103 from www.liebertpub.com at 11/17/22. For personal use
RNA, and proteins. This variety of honey has a broad range of
antibacterial activity, low mammalian toxicity [77], and (to
date) low likelihood of inducing resistance [78]. Honey also
shows promise as an an- tifungal agent [79]. A recent
Cochrane Review found that the studies of honey for burns
treatment are of low or very low quality. The studies are
also difficult to interpret because the comparator treatment
is often one that is not widely used [80]. Despite the
limitations of these studies, we now commonly use medical
honey and honey dressings, particularly in the care of
problem wounds.
Clinical Experience and Conclusions
A review of burn patient data from 1950–1999 permitted
analysis of the effects of topical mafenide and SSD on sur-
vival at the ISR Burn Center (Fig. 3) [81]. The introduction of
mafenide into burn care in 1964 resulted in a decrease in age-
and burn-size-adjusted mortality risk. This was followed by
an increase in mortality in the latter half of the 1960s, as
resistant strains of Providencia stuartii and Enterobacter
only.
FIG. 3. Age- and burn-size adjusted log-odds of mortality
following thermal injury at the U.S. Army Institute of Sur-
gical Research (U.S. Army Burn Center), 1950–1999
(Source Reference [81].)
10
cloacae appeared, and sepsis became more common [82].
In 1973, SSD was introduced, and improved control of
sepsis and mortality were gradually achieved. Briefly,
SSD was used as the sole antimicrobial agent; later, it was
alternated every 12 hours with mafenide (a practice called
alternating agents). Throughout this period, typical burn
treatment was as follows. Daily hydrotherapy and topical
antimicrobial care were performed until the burns either
healed or the eschar separated. Then, cadaver allografts
were applied, and finally autografting was performed.
Starting in 1978 and following the pioneering work on the
tangential excision by Janzekovic [83], excision of extensive
burns was introduced. A new burn unit was built, and better
isolation procedures were instituted in 1983 [84], resulting
in further improvements in mortality. The role and relative
importance of topical antimicrobial agents in burn care has
since evolved. Today, patients with smaller burns are
readily treated with silver dressings or with synthetic
bilaminar skin substitutes (Biobrane®, Smith+Nephew;
Permeaderm, Milliken). The latter have been shown to
hasten healing in comparison with SSD [85]. Total-body
excision of patients with large burns is com- pleted as
soon as possible from a physiological standpoint, often
within days of injury [86]. Usually, these wounds are
immediately closed with autograft, or where insufficient donor
sites are available, a combination of widely meshed
autograft covered with an allograft overlay. Under these
conditions, topical antimicrobial treatment is a temporizing
intervention. The major problem becomes the care of the
post-operative wound while it heals, and the prevention or
early detection and treatment of post-operative infections. In
this regard, fungal wound infections remain a particular
menace which indepen- dently increase post-burn mortality
[87], and for which no
good preventative measures exist.
On the other hand, some patients are not candidates for
early excision and grafting. These include those with con-
comitant medical diseases or advanced age. Other patients
may live in countries where modern surgical techniques are
not readily available. In a mass-casualty or military setting,
rapid excision may be logistically impossible. In the
military setting, we continue to recommend the use of
alternating agents (mafenide and SSD) for the treatment of
unexcised wounds [88]. Furthermore, Flammacerium or
other cerium- based treatments may be applicable as well.
In conclusion, effective management of the burn wound, to
include pre- vention of infection and successful wound
closure, remain the keys to survival in burn patients [89].
Acknowledgments
The author gratefully thanks Mr. Glen E. Gueller,
Records and Knowledge Manager (retired), and Ms. Susan
Reyna, Library Assistant, both of the Information
Management Di- vision, U.S. Army Institute of Surgical
Research.
Funding Information
The author reports no funding for this work.
Author Disclosure Statement
The opinions or assertions contained herein are the
private views of the author, and are not to be construed as
official or as reflecting the views of the Department of the
TOPICAL ANTIMICROBIAL AGENTS 11
Army or the Department of Defense.
 TOPICAL ANTIMICROBIAL AGENTS 12

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Address correspondence to:
Dr. Leopoldo C. Cancio
U.S. Army Burn Center
U.S. Army Institute of Surgical Research
3698 Chambers Pass
JBSA Fort Sam Houston, TX 78234-6315
USA
E-mail: Leopoldo.c.cancio.civ@mail.mil
TOPICAL ANTIMICROBIAL AGENTS 15

SINTESIS GRID
NAMA : DINA FATIN NABILA
NIM : NH0222013
PRODI : S1 KEPERAWATAN B
Metode
Author Tahun terbit Nama jurnal Judul Tujuan penelitian penelitian
Daan T. Van 2021 Elsevier Ltd Adherence to the The primary aim was This was a
Yperen, et all emergency to determine to what retrospective,
management of extent referral and multicenter
severe burns referral admission of burn cohort study
criteria in burn patients to a hospital
patients admitted to with or without a
a hospital with or burn center was in
without a specialized line with the EMSB
burn center referral criteria
Hasil Kesimpulan
A total of 1790 The overall adherence
patients were to the referral criteria of
included, of whom patients presented to a
951 patients were non-burn center was
primarily presented fairly high. However,
to anon-burncenter. approximately 25% was
Ofthese patients, not transferred to a burn
666 (70.0%) were center while meeting
managed according the criteria. Most
to the referral improvement for
criteria; 263 (27.7%) individual criteria can
were appropriately be achieved in patients
not referred, 403 with electrical and
(42.4%) were chemical burns
TOPICAL ANTIMICROBIAL AGENTS 16

appropriately
referred. Twenty
(2.1%) were
overtransferred, and
265 (27.9%)
undertransferred. In
1213 patients treated
at a burn center
1119 (92.3%) met
the referral criteria.
Adherence was
lowest for electrical
(N = 4; 14.3%) and
chemical burns (N =
16; 42.1%), and was
highest in ‘children
5% total body
surface area (TBSA)
burned’ (N = 109;
83.2%).
TOPICAL ANTIMICROBIAL AGENTS 17

b U R n s 4 7 ( 2 0 2 1 ) 1 8 1 0 —1 8 1 7

Available online at www.sciencedirect.com

ScienceDirect

jo ur n al ho m epag e: w ww.els evier.c o m/lo c

Adherence to the emergency management of

severe burns referral criteria in burn patients
admitted to a hospital with or without a
specialized burn center

Daan T. Van Yperen a,b, Esther M.M. Van Lieshout a,*,

Leendert H.T. Nugteren a, A. Cornelis Plaisier a, Michael H.J. Verhofstad a,
Cornelis H. Van der Vlies a,b, Burns study group 1
a
Trauma Research Unit, Department of Surgery, Erasmus MC, University Medical Center Rotterdam, P.O.
Box 2040, 3000 CA Rotterdam, The Netherlands

b
Burn Center, Maasstad Hospital, P.O. Box 9100, 3079 DZ Rotterdam, The Netherlands

A R T I C L E I N F O
AB S T R A C T

Article history: Background: The primary aim was to determine to what extent referral and
admission of burn patients to a hospital with or without a burn center was in line
Accepted 16 February
2021 with the EMSB referral criteria. Methods: This was a retrospective, multicenter
cohort study. Burn patients admitted from 2014 to 2018 to a hospital in the
Southwest Netherland trauma region and Network Emergency Care Brabant were
included in this study. Outcome measures were the adherence to the EMSB referral
criteria.
Keywords:
Results: A total of 1790 patients were included, of whom 951 patients were primarily
Burns presented to a non-burn center. Of these patients, 666 (70.0%) were managed
according to the referral criteria; 263 (27.7%) were appropriately not referred, 403
Guideline
(42.4%) were appropriately
adherence
Referral criteria referred. Twenty (2.1%) were overtransferred, and 265 (27.9%) undertransferred. In
1213 patients treated at a burn center 1119 (92.3%) met the referral criteria.
Adherence was lowest for electrical (N = 4; 14.3%) and chemical burns (N = 16;
42.1%), and was highest in ‘children

≥5% total body surface area (TBSA) burned’ (N = 109; 83.2%).

Conclusion: The overall adherence to the referral criteria of patients presented to a

non-burn center was fairly high. However, approximately 25% was not transferred
to a burn center while meeting the criteria. Most improvement for individual
criteria can be achieved in patients with electrical and chemical burns.

© 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the
CC BY
TOPICAL ANTIMICROBIAL AGENTS 18

license
(http://creativecommo
ns.org/licenses/by/4.0/)
.

* Corresponding author.

E-mail address: e.vanlieshout@erasmusmc.nl (E.M.M. Van Lieshout).

1

The Burns study group are listed in Appendix A.

https://doi.org/10.1016/j.burns.2021.02.023

0305-4179/© 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons. org/licenses/by/4.0/).
 TOPICAL ANTIMICROBIAL AGENTS
b U R n s 4 7 ( 2 0 2 1 ) 1 8 1 0 —1 8 1 7
1. Introduction
Because burn injuries can have major physical and psycho-
logical impact, it is important to refer patients with complex
burns to a specialized burn center [1]. In order to assist
clinicians in identifying patients that may warrant transfer
to a facility that has special expertise in the treatment
and rehabilitation of more extensive burn-related injuries,
referral criteria have been implemented. Burns associations
that have implemented referral criteria include the
American Burn Association [2], the National Health Services
in the UK [3], the Australian & New Zealand Burn
Association [4], and the European Burns Association. In the
Netherlands, the Dutch Burn Foundation has adopted the
Emergency Managements of Severe Burns (EMSB) referral
criteria [5]. Although these criteria have been used for
more than two decades, no information is available about
their adherence when referring patients from a non-burn
center to a burn center or vice versa. Previous studies only
investigated adherence rates to local or national criteria. In
the United Kingdom, 25% and 74% of the patients presented
to a general or pediatric emergency department
respectively, were not transferred to a burn center while
meeting at least one of the referral criteria as designed by the
British Burn Association [6,7]. In the United States, 48% and
54% of the patients treated at non-burn centers were
inappropriately not transferred to a burn center [8,9]. One
study assessed the accuracy of burn size estimation in
pediatric patients, according to the EMSB referral criteria,
and found that 20% was referred without meeting the referral
criteria regarding burn size [10]. Currently, no studies have
been conducted regarding the adherence to all EMSB
referral
criteria.
The primary aim of this study was to determine to what
extent referral and admission of burn patients to a hospital
with or without a burn center was adherent to the EMSB
referral criteria as used in the Netherlands. Referral can be
primary by the prehospital health care provider or
secondary from a non-burn center to a burn center. The
secondary aim was to determine whether adherence is
related to the number of criteria present.
2. Material and methods
Study design & setting
In the Netherlands, clinical health care is provided by
120 hospitals. All hospitals have to participate in a regional
trauma network, the so called Trauma Regions. Each region
has a governmentally assigned (Level 1) trauma center.
Three non-trauma centers have been assigned as a
supraregional burn center by the government in order to
provide advanced burn care and to improve patient outcomes.
Prehospital care is provided by independent, governmentally
organized ambu- lance services on a regional level.
Depending on the suspected injuries and physiological
status, a trauma patient is referred to the closest hospital, a
19
1811
(Van Yperen et al.; unpublished data). More than half of these
patients are treated at a specialized burn center [11].
This was a retrospective multicenter cohort study. Poten-
tial participants were selected from two trauma regions:
Southwest Netherland Trauma Region and Network Emer-
gency Care Brabant. All 22 hospitals, including one specialized
burn center, two level 1 trauma centers, one specialized eye
hospital, and 18 general hospitals, participated. Potential
participants were identified from the Dutch National Trauma
Registry (NTR). This registry collects data of trauma patients
admitted or transferred to a hospital within 48 h after their
injury. Data were collected from patient’s hospital records.
These records were reviewed by DTVY, LHTN, and ACP. This
study was exempted by the Medical Research Ethics
Commit- tee Erasmus MC (Rotterdam, the Netherlands;
registration number MEC-2019-0144).
2.2. Participants
All patients admitted to a hospital in the abovementioned
trauma regions, with burns or inhalation trauma that
occurred between January 1, 2014 and December 31, 2018,
were eligible for inclusion. Eligible patients were identified
by searching the NTR for patients with a registered
Abbreviated Injury Scores (AIS) for burns or inhalation
trauma (Table A.1). Patients were excluded when informa-
tion from their medical records in order to determine the
adherence to the EMSB referral criteria was missing.
Furthermore, patients were excluded when they were
transferred from one burn center to another, or when they
were transferred to a specialized hospital without a burn
center (e.g., a level 1 trauma center). These patients were
transferred because of other reasons, overruling the EMSB
criteria. For example, transferring a patient from one burn
center to another because of a shortage of ICU beds, or
transferring a severely burn child to a specialized children’s
hospital, because local arrangements prescribe to do so.
Depending on the hospital admission location, patients were
allocated to three groups: (1) patients primarily presented
to and treated at a non-burn center (non-burn center), (2)
patients primarily presented to a non-burn center and
transferred to a burn center for treatment (transferred),
and (3) patients primarily presented to and treated at a burn
regional trauma center or a supra- regional burn center.
Approximately 1000 patients undergo acute hospital
admission for burn related injuries each year
 TOPICAL ANTIMICROBIAL AGENTS 20
center (burn center). For patients treated at a burn center, a
distinction was made between patients directly presented
(by e.g. the emergency services or general practitioner), and
patients transferred from other, non-burn center, hospitals.

Outcome measures and data collection

The primary outcome measure was the adherence to the

Dutch EMSB referral criteria (Table 1). For all patients, the
location of hospital admission (non-burn center or burn
center) and whether they were transferred from a non-burn
center to a burn center was registered. For each patient, the
presence of each referral criterion and whether a burn
center was consulted for treatment advice was registered.
Patients who were not transferred to a burn center and had
none of the referral criteria, and patients who were
transferred to a burn center and met at least one of the
criteria, were considered as
 TOPICAL ANTIMICROBIAL AGENTS 21
1812 b U R n s 4 7 ( 2 0 2 1 ) 1 8 1 0 —1 8 1 7

Table 1 – Emergency Management of Severe Burns referral criteria; adjusted for Dutch hospitals [17].
Burns 10% or more TBSA in adults
Burns 5% or more TBSA in children (<16 year)
Full Thickness burns 5% or more TBSA
Burns of functional areas — face, hands, feet, genitals, perineum, or large joints (i.e., shoulder, elbow, knee, and
ankle) Circumferential burns of the neck, chest, or extremities
Electrical burns (high voltage) including lightning
strikes Chemical burns
Burns with suspected associated inhalation injury
Any burn patient with associated trauma or (pre-existing) medical condition that may affect treatment and recovery, or could increase mortality
Burns at the extremes of age — young children (<1 year) and the elderly (≥75 years)
Non-accidental burns
Burns for which the burn mechanism is uncertain in combination with uncertainty about the competence/equipment of the hospital for
these types of injuries
Burn wound that show insufficient signs of healing within two weeks

TBSA, total body surface area.

adherent to the criteria. Patients not transferred while meeting

the criteria were considered as undertransferred, and trans- 3. Results
ferred patient who did not meet the referral criteria as
overtransferred. Patient selection

Statistical analysis
Data were analyzed using the Statistical Package for the
Social Sciences (SPSS) version 25.0 (SPSS, Chicago, Ill., USA).
Normality of continuous data was tested with the Shapiro
—Wilk test. Missing values were not replaced by imputation.
Data were reported following the ‘Strengthening the Reporting
of Observational studies in Epidemiology’ (STROBE)
guidelines.
For continuous data, median and quartiles (non-normal
distribution) or mean and standard deviation (SD; normal
distribution) were reported. For categorical data, number and
frequencies were reported. No statistical comparison was
made between the groups.
Descriptive statistics were used to report the outcome
measures. Overall adherence to the referral criteria was
determined by plotting the presence of a referral criterion
against the admission location. The number and rate of (in)
appropriately admitted and (in)appropriately transferred
patients will be calculated, for both the whole set of criteria
combined as for the individual criteria. No statistical compari-
son was made between groups.
A total of 1807 patients were treated at a hospital from the
study region and registered in the NTR. For the analysis,
17 patients were excluded; 10 were transferred from a burn
center to another burn center and seven were transferred to
a specialized non-burn center. A total of 1790 patients were
included in this study (Fig. 1).
Fig. 2 provides an overview of the admission locations of the
included patients. A total of 951 (43.9%) patients were
primarily presented to a non-burn center. Of them, 35 (3.7%)
were transferred to a burn center outside the study region, 14
(1.5%) to the outpatient clinic of the assigned burn center in
the study region, and 374 (39.3%) were clinically admitted
to the burn center in the study region. Of the patients
primarily presented to a non-burn center, 528 (55.5%)
patients also received their final treatment at a non-burn
center.
A total of 1213 patients were treated at a burn center, of
whom 514 (42.4%) were directly presented there. Three
hundred seventy-four (30.8%) patients were transferred from
a non-burn center within the study region, and 325 (26.8%)
patients were transferred from a non-burn center outside
the study region that did not participate in this study.
TOPICAL ANTIMICROBIAL AGENTS 22

Fig. 1 – Study flow chart.

 TOPICAL ANTIMICROBIAL AGENTS 23
b U R n s 4 7 ( 2 0 2 1 ) 1 8 1 0 —1 8 1 7 1813

Fig. 2 – Admission location of the included patients.

Presence of the EMSB referral criteria

doubt about the burn mechanism or the hospital’s treatment
facilities, only one (33.3%) patient was appropriately treated,
Of the 951 patients presented to a non-burn center, 668
however, this criterion occurred in only three patients.
(70.2%) met the referral criteria. Of the 528 patients who
Furthermore, of the 38 patients with chemical burns, 16
received their treatment at a non-burn center, 265 (50.2%)
(42.1%) patients were appropriately transferred. All non-
met at least one of the referral criteria. Of the 423 patients
transferred patients with electrical burns (n = 24) or chemical
transferred, 403 (95.3%) patients met at least one of the
burns (n = 22) had burn wounds with a median TBSA burned of
criteria (Fig. 3A). Both groups mainly had burns located at
0.5% (P25—P75 0,1—0,5%) and 1% (P25—P75 1—2%), respectively.
functional body areas.
They were admitted for a median of 2 (P25—P75 2—2%) and 2%
Of the 1213 patients admitted to a burn center, 1119
(P25—P75 2—4%) days, respectively. In all other criteria, an
(92.3%) met at least one of the referral criteria. Of the 514
adherence rate of more than 50% was found. The highest
patients who were directly presented to a burn center, 457
adherence rate was observed for the criterion ‘≥5% total body
(88.9%) met one or more criteria and of the 699 patients who
surface area (TBSA) burned in children’ (N = 109; 83%).
were transferred, 662 (94.7%) met one or more criteria (Fig.
Fig. 4B shows adherence in patients with any of the referral
3B). These two groups mainly had burns located at
criteria (overall) as well as in patients with different
functional body areas.
numbers of criteria. This figure shows that the adherence to
the referral criteria was lower in patients with ≥1 criterion
Adherence to the EMSB referral criteria
than in the total
group; 60.3% versus 70.0%. The adherence rate was higher in
Fig. 4A shows that, of the 951 patients primarily presented to a
patients with two or more criteria (69.3%) and with three or
non-burn center, 666 (70.0%) patients were managed
more criteria (80.9%), but was lower in patients with for or
according to the referral criteria. Two hundred sixty-three
more criteria present.
(27.7%) of these patients were appropriately not transferred
and 403
(42.4%) patients were appropriately transferred to a burn
center. Of the 285 (30.0%) patients who were not managed 2 (P25—P75 1—2) days.
according to referral criteria, 20 (2.1%) were transferred while For each individual criterion the adherence rate was
not meeting any of the criteria and were deemed as over- determined (Fig. 4A). The lowest adherence rate was found in
transferred. The remaining 265 (27.9%) were not transferred patients with electrical burns. Only four (14.3%) of these
while meeting at least one of the criteria, and were deemed patients were appropriately transferred. In case there was any
as undertransferred. In 101 (38.1%) of these patients a burn
center was consulted for treatment advice. Consensus for not
referring was reached, and none of the patients underwent
transfer or further consultation at a later stage. In the majority
of patients, the burn wounds of these 101 patients was
caused by flames (n = 52), scalds (n = 33), or chemical burns
(n = 11). Seven of the 101 patients had inhalation
trauma, and all
101 had burn wounds, with a median TBSA of 4% (P25—P75 1
—6%). They were discharged after a median hospital stay of
 TOPICAL ANTIMICROBIAL AGENTS 24
4. Discussion

The aim of this study was to determine the adherence to the

EMSB referral criteria in burn patients treated at a hospital
with or without a specialized burn center, and to determine
whether specific criteria were followed less or more
strictly. The main findings were that, the overall adherence
to the referral criteria was 70.0% for patients presented to a
non-burn center. Two hundred sixty-three (27.7%) of these
patients were appropriately not transferred and 403 (42.4%)
were appropri- ately transferred to a burn center. Of all
patients admitted to a burn center, 92.3% were adherent to
the criteria. Adherence
was lowest for electrical burns and chemical burns, and
highest for ‘≥5% TBSA burned in children’.
Only a few previousstudies have investigated the
adherence
to referral criteria in burn patients. Differences in study
design, referralcriteriaapplicable, outcomemeasures,
anddefinition of adherence complicates comparison
between studies. The highest adherence rates were found
in a burn centers in
 TOPICAL ANTIMICROBIAL AGENTS 25
1814 b U R n s 4 7 ( 2 0 2 1 ) 1 8 1 0 —1 8 1 7

Fig. 3 – The number of patients who met the referral criteria.

This figure shows the number and percentage of patients who met with the referral criteria, for patients primarily presented
to non-burn centers (A) and patients treated at a burn center (B).
 TOPICAL ANTIMICROBIAL AGENTS 26
b U R n s 4 7 ( 2 0 2 1 ) 1 8 1 0 —1 8 1 7 1815

Fig. 4 – The adherence to the EMSB referral criteria. This

figure shows the adherence of patients with any the referral criteria (overall) and with each individual criterion (A), and the
adherence in patients with different numbers of criteria (B).
‘+’ Indicates that a burn center was consulted.

South-Africa (namely 93.4%) [12] and the USA (88% adherence burn center in the USA only 70% of the children met the
for adults) [8]. Despite assumed differences in the (supra) referral criteria[13]. Fromtheir data,
regional organization of general trauma and burn care, these itseemslikeclinicaljudgementhas
adherence rates are comparable with the results of the current
study (92.3%). Nevertheless, of all patients admitted to a
 TOPICAL ANTIMICROBIAL AGENTS 27
overruled the referral criteria, since 860 out of 1274 (67.5%)
had 10% TBSA burned. In the national burn center in
Denmark, 70% of all the patients were appropriately referred
[14]. Differences in referralcriteriaand organization of
hospitalcare may explain this difference. The Danish study
used European criteria, which include 1% full thickness or 3%
partial thickness burns as criteria, whereas the EMSB uses 5%
full thickness burns as
 TOPICAL ANTIMICROBIAL AGENTS 28
1816 b U R n s 4 7 ( 2 0 2 1 ) 1 8 1 0 —1 8 1 7

criterion. Other studies investigated the adherence rate of

was based on information from patient’s medical records
patientspresented to a non-burncenter. Davis et al. reportedfor
and not restricted to information from a database.
the USA that 54.0% of the patients were not referred while
A limitation of this study is the retrospective study
meeting one of the referral criteria [9]. This percentage is
design. Inherent to such a design is that some data were
higher than the 30% in the current study, which may be
incomplete. In some cases this complicated the interpreta-
explained by differences in referral criteria, distance to a burn
tion of the adherence to the referral criteria. In a few cases it
center, in taking family preference into account, and insurance
was also not possible to retrieve data about consulting a
status. Rose et al. found that only 17.4% of the pediatric
burn center. It is unclear from the patient files if the
patients were appropriatelyreferred to a burn unit thatwas
treating
locatedwithinthe same hospital [7]. A clear reason for this low
physicians decided not to transfer the patient because of
percentage compared with the adherence rate of 50.2% found
arguments or ‘forgot’ to do so, e.g., due to limited knowledge
in the current study cannot be given. However, Rose et al.
of the referral criteria. As far as cases in which the treating
mention as possible
physician considered advanced care as absent, the most
reason for their large underreferral that many patients had
likely reasons would be limited burn injury severity,
small (<5%), superficial partial-thickness burns, and that
sufficient expertise and facilities at the non-burn center,
(84%) of these patients were brought back to follow-up within
misinterpretation of the EMSB referral criteria (especially
the ED
for inhalation trauma), the patient being moribund, or the
without specialist input.
decision was made after consulting a burn center. In
Furthermore, 265 (27.9%) patients primarily presented to a
particular when deviating from the referral criteria insight
non-burn center were not referred although they met the
into the reason would have been interesting information.
referral criteria. Most improvement in adherence rate for
Furthermore, interpreting the presence of inhalation injury
individual criteria could be achieved in patients with chemical
was difficult in this study because information about
and electrical burns, and to a lesser extent in patients with
confirming the diagnosis was lacking. Finally, the current
inhalation injury and burns located at functional areas. Given
study does not provide details about the functional con-
the relatively low prevalence of especially chemical and
sequences of patients with referral criteria who were not
electrical burns, the effect on improved adherence for the
transferred to a burn center. Results of the prospective study
criteria on overall adherence will be limited. Currently, the
mentioned above might provide relevant information re-
clinical consequences of underreferring patient with any of
garding this topic [15].
these injuries remains unclear. Rose et al. reported no
The results of this study can help in improving the
significant increased morbidity in the underreferred
referral patterns of burn patients presented at non-burn
patients on a short-term [7]. However, they did not investigate
center hospitals. Not all of the referral criteria are rigid and
the long- term consequences, nor did they evaluate
some must be interpreted while taking clinical assessment
individual criteria. Baartmans et al. reported that 20% of the
of a patient into consideration. Whether or not amending
pediatric burns center patients were incorrectly referred
certain referral criteria or educating physicians at the non-
regarding burn size, resulted into 16% unnecessary fluid
burn centers will improve the adherence rate requires
resuscitations [10]. For criteria with proven clinical
additional research. The adjusted criteria should be more
consequences, improved awareness is of benefit in order to
capable of identifying patients in need of specialized care.
increase the adherence rate. Criteria with limited or no
clinical consequence may benefit from adjust- ment or can
even be omitted. Results from an ongoing
prospective cohort study investigating treatment and out-
come of burn patients in hospitals without burn center included whom are described in detail. With approximately
might provide relevant information regarding this topic
[15].
In 38% of the undertransferred patients, a burn center
was consulted. Although the distance between burn centers
and non-burn center hospitals in the Netherlands is
relatively small, consultation by telephone provides a good
alternative for referring a patient to a burn center. In
particular patients with minor burns can be primarily
treated at a non-burn center hospital with the support of a
specialized burn center. A nationwide network of burn
telemedicine may help optimizing burn care provided at a
non-burn center [16].

4.1. Strengths, limitations, and implications

A strength of this study is the large number of patients

 TOPICAL ANTIMICROBIAL AGENTS 29
5. Conclusion Highest adherence rate was found in ‘children with ≥5%
TBSA burned’, and most improvement in adherence rate can
The overall adherence of patients presented to a non-burn be achieved in patients with electrical and chemical burns.
center was fairly high. However, still more than a quarter
of patients was not transferred while meeting the criteria. In
Declaration of interest
only the minority of these patients a burn center was
consulted for treatment advice. Of the patients admitted to
None.
a burn center, nearly all patients met the referral criteria.
1800 patients included, this study is one of the largest studies
performed regarding this topic. This study also clearly Author’s contribution
described where a patient was treated, and whether (not)
transferring a patient was adherent with the referral criteria. The study was developed by DTVY, EMMVL, MHJV, CHVDV,
Furthermore, adherence to the referral criteria in this study and MEVB. Data was collected by DTVY, LHTN, and ACP. DTVY
 TOPICAL ANTIMICROBIAL AGENTS
b U R n s 4 7 ( 2 0 2 1 ) 1 8 1 0 —1 8 1 7
and EMMVL performed data analysis and drafted the manu-
script. DTVY, EMMVL, MHJV, CHVDV, MEVB, DB, AYMVPC,
PARDR, DDH, MG, WAJJM, TMALK, KWWL, LMSJP, ANR, MS,
LVDS, BJMT, AHVDV, FCVE, PVVE, BJP, DIV, MW critically
revised the manuscript and approved the final version to be
submitted.
This research received a specific grant from the Dutch
Burns Foundation (Beverwijk, the Netherlands; reference
number WO/16.110). The funder of the study had no role in
study design, data collection, data analysis, data interpreta-
tion, or writing of the report.
Appendix A.
Doeke Boersma MD PhD, Department of Surgery, Jeroen Bosch
Hospital, ‘s-Hertogenbosch, the Netherlands.
Anne Y.M.V.P. Cardon MD, Department of Surgery, Zorg-
Saam Zeeuws-Vlaanderen, Terneuzen, the Netherlands.
Piet A.R. De Rijcke MD, Department of Surgery, IJsselland
Hospital, Capelle aan den IJssel, the Netherlands.
Dennis Den Hartog MD PhD, Trauma Research Unit
Department of Surgery, Erasmus MC, University Medical
Center Rotterdam, Rotterdam, the Netherlands.
Marc Guijt MD, Department of Surgery, Elkerliek Hospital,
Helmond, the Netherlands.
Wilbert A.J.J.M. Haagh, MD, Department of Surgery, St.
Anna Hospital, Geldrop, the Netherlands.
Taco M.A.L Klem MD PhD, Department of Surgery,
Franciscus Gasthuis&Vlietland, Rotterdam, the Netherlands.
Koen W.W. Lansink MD PhD, Department of Surgery,
Elisabeth-TweeSteden Hospital, Tilburg, the Netherlands.
Lodewijk M.S.J. Poelhekke MD, Department of Surgery,
Maasziekenhuis Pantein, Beugen, the Netherlands.
Bas J. Punt MD PhD, Department of Surgery, Albert
Schweitzer Hospital, Dordrecht, the Netherlands.
Akkie N. Ringburg, MD PhD, Department of Surgery,
Ikazia Hospital, Rotterdam, the Netherlands.
Maarten Staarink MD, Department of Surgery, Van Weel-
Bethesda Hospital, Dirksland, the Netherlands.
Bastiaan J.M. Thomeer, MD PhD, Department of Surgery,
Bernhoven, Uden, the Netherlands
Margriet E. Van Baar MSc PhD, Association of Dutch Burn
Centers, Burn Center Maasstad Hospital, Rotterdam, the
Netherlands.
Leon Van de Schoot MD, Department of Surgery, Beatrix
Hospital/Rivas, Gorinchem, the Netherlands.
Alexander H. Van der Veen MD PhD, Department of Surgery,
Catharina Hospital, Eindhoven, the Netherlands.
Percy V. Van Eerten MD, Department of Surgery, Má xima
Medisch Centrum, Veldhoven, the Netherlands.
Floortje C. Van Eijck MD PhD, Department of Surgery, Bravis
Hospital, Roosendaal, the Netherlands.
Dagmar I. Vos MD PhD, Department of Surgery, Amphia
Hospital, Breda, the Netherlands.
Marco Waleboer MD, Department of Surgery, Admiraal
De Ruyter Hospital, Goes, the Netherlands.
30
1817
Appendix B. Supplementary data
Supplementary material related to this article can be found, in
the online version, at
doi:https://doi.org/10.1016/j.burns.2021. 02.023.
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TOPICAL ANTIMICROBIAL AGENTS 32

SINTESIS GIRD
NAMA : DINA FATIN NABILA
NIM : NH0222013
PRODI : S1 KEPERAWATAN B
Author Tahun terbit Nama jurnal Judul Tujuan penelitian Metode
penelitian
Hikmat Hadoush, et 2021 Systematic Reviews in Non-Pharmacological This study aimed to Only
all Pharmacy Management of Burn- systematically review randomized
related Pain and the recent literature controlled trials
Distress in Children: regarding the efficacy (RCTs) or RCT
A Systematic Review of the non- crossovers that
and Meta-Analysis pharmacological had a no-
Study interventions to treatment control
control pain comparison were
perception and eligible for
distress in children inclusion in the
undergoing painful analyses
burn management
procedures.
Hasil Kesimpulan
Out of 244 studies Distraction and VR
found, 15 trials met are effective non
the inclusion criteria pharmacological
for further review interventions
with non- in reducing the pain
pharmacological perception and
interventions that distress in children
included distraction during painful burn
(n=8), VR (n=5), management
hypnosis (n=1), and procedures
TOPICAL ANTIMICROBIAL AGENTS 33

massage therapy
(n=1). However, 13
trials out of 15 were
included in the meta-
analysis with 685
participants. Meta-
analysis
showed large effects
of distraction
intervention on self-
reported pain (SMD -
1.64, 95% CI -3.16, -
0.12), observer-
reported pain (SMD -
3.02, 95% CI -5.85, -
0.19), and behavioral
distress (SMD -2.82,
95% CI -5.50, -0.14).
Besides, distraction
intervention showed
moderate effects on
self-reported distress
(SMD-0.33, 95% CI -
0.58, -0.08), and no
effect on behavioral
pain (SMD -1.06,
95% CI -2.44, 0.31).
On the other hand,
VR reported a large
effect on self-reported
pain (SMD 1.41, 95%
CI -2.52, -0.30), a
TOPICAL ANTIMICROBIAL AGENTS 34

moderate effect on
observer-reported
pain (SMD -0.56,
95% CI -0.90, -0.22),
and no effect on the
behavioral pain (SMD
-0.48, 95% CI -1.04,
0.08). Overall, the
quality of derived
evidence was
downgraded due to
study limitations,
inconsistency, and
imprecision
TOPICAL ANTIMICROBIAL AGENTS 35

Sys Rev Pharm 2021;12(3):423-438

A multifaceted review journal in the field of pharmacy

Non-Pharmacological Management of Burn-

related Pain and Distress in Children: A
Systematic Review and Meta-Analysis Study
Hikmat Hadoush1, Salam Alruz2, Manal Kassab3, Anit N Roy4
1
Associate Professor, Department of Rehabilitation Sciences, Faculty of Applied
Medical Sciences at Jordan University of Science and Technology. Irbid, Jordan.
2
Department of Rehabilitation Sciences, Faculty of Applied Medical Sciences at Jordan University
of Science and Technology. Irbid, Jordan.
3
Associate Professor, Department of Maternal and Child Health, Faculty of Nursing at Jordan
University of Science and Technology. Irbid, Jordan.
Associate (Clinical Fellow) in Nursing at the University of Technology, Sydney, Australia.
4
Kerala University of Health Sciences, Kerala, India

behavioral pain (SMD - 0.48, 95% CI -1.04, 0.08). Overall,

ABSTRACT
Introduction: Pain and distress during burn-related painful
procedures are common. Various non-pharmacological
interventions are used to control pain and distress during
burn-related painful procedures. Hereby, this study aimed
to systematically review the recent literature regarding the
efficacy of the non- pharmacological interventions to
control pain perception and distress in children undergoing
painful burn management procedures.
the quality of derived evidence was downgraded due to
study limitations, inconsistency, and imprecision.
Conclusion: Distraction and VR are effective non-
pharmacological interventions in reducing the pain
perception and distress in children during painful burn
management procedures.

Methods: the data sources were Cochrane Central Register

of Controlled Trials, CINAHL, MEDLINE, and Science

Direct databases were searched through 1989-2020. Data

extraction was performed by two independent researchers.

Selection criteria: Participants included children from

birth to nineteen years.

Only randomized controlled trials

(RCTs) or RCT crossovers that had a no-treatment control

comparison were eligible for inclusion in the analyses.

Data analysis: The risk of bias was assessed using the

Cochrane risk-of-bias tool for randomized trials. Review

Manager 5.4 software was used to calculate standardized

mean differences (SMDs) with 95% confidence intervals
(CIs).

Results: Out of 244 studies found, 15 trials met the inclusion

criteria for further review with non-pharmacological
interventions that included distraction (n=8), VR (n=5),
hypnosis (n=1), and massage therapy (n=1). However, 13
trials out of

15 were included in the meta-analysis with 685 participants.

Meta-analysis showed large effects of distraction
intervention on self-reported pain (SMD - 1.64, 95% CI -
3.16, -0.12), observer-reported pain (SMD -3.02, 95% CI -
5.85, - 0.19), and behavioral distress (SMD -2.82, 95% CI -
5.50, -0.14). Besides, distraction intervention showed
moderate effects on self-reported distress (SMD

-0.33, 95% CI -0.58, -0.08), and no effect on behavioral pain

(SMD -1.06, 95% CI - 2.44, 0.31). On the other hand, VR
reported a large effect on self-reported pain (SMD 1.41, 95%
CI -2.52, -0.30), a moderate effect on observer-reported
pain (SMD -0.56, 95% CI -0.90, -0.22), and no effect on the

35 Systematic Reviews in Pharmacy Vol 12, Issue 03, Mar-Apr

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TOPICAL ANTIMICROBIAL AGENTS 36

Hikmat Hadoush

Keywords: Burn, Pain, Distress, Children, Non- Associate Professor, Department of Rehabilitation
pharmacological interventions. Sciences, Faculty of Applied Medical Sciences at
Jordan University of Science and Technology. Irbid,
Jordan.
Correspondence:

INTRODUCTION
perception, memory, and the emotional
A burn is a tissue damage injury linked to
status of patients. (5, 7) Besides, it could
severe pain and distress (1). Children and
contribute to diminished social skills,
adolescents are considered at high risk to
increased fear, and sleep disorders (5, 8).
be admitted to the hospitals and
Non-pharmacological pain relief
emergency departments due to burning
interventions are used as
accidents (2). Pain perception in burns is
complementary and alternative
linked to two sources, the continuous
interventions to control pain and
background pain of the injured tissues
distress in children and adolescents
and the procedural pain experienced
during medical procedures. Such non-
during burn management procedures (3).
pharmacological interventions include
Besides procedural pain, children
distraction, virtual reality (VR), hypnosis
experience procedural distress as a
therapy, and massage therapy, which are
negative reaction to the medical
all considered as noninvasive, easily
procedures, this could include anxiety,
assessable, with little training needed,
fear, or stress emotions (4). While
suiting most ages. (9, 10) The
background pain is routinely managed
mechanism of such nonpharmacological
with medications, procedural pain is more
intervention in reducing pain is assumed
complicated and requires advanced
as a result of mindset shifting or
analgesia for adequate pain control (5, 6).
modifying the pain-related cognitive and
Undertreated or poorly managed pain has
perception pathway.(6)
adverse effects in the short and long-term,
To the best of our knowledge, there is no
as well as has a negative impact on the
recent meta- analysis study that
healing process, child development and
evaluates the potential therapeutic
behavior, pain
effects of the non-pharmacological
interventions on burn-

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 Non-Pharmacological Management of Burn-related Pain and Distress in Children: A
Systematic Review and Meta-Analysis Study
related pain and distress in children undergoing painful
burn management procedures. Hereby, this study aimed
to evaluate the effect of non-pharmacological
interventions including distraction, VR, hypnosis, and
massage therapy on controlling pain and distress
outcomes in children aged up to 18 years, and who
undergoing or experienced painful procedures during
burning management.
METHODS
Search Strategy
The following four electronic databases were searched
for relevant trials published between January 1989 and
June 2020. A systematic literature review was performed
in the Cochrane Central Register of Controlled Trials (88
Studies retrieved), MEDLINE (83 Studies retrieved),
Science Direct (40 studies retrieved), and CINAHL(33
Studies retrieved), using the following search terms:
(Burn) AND (wound dressing OR dressing change OR
physiotherapy OR hydrotherapy OR painful procedure)
AND (cognitive OR behavior OR distract OR hypnosis OR
audiovisual OR game OR music OR breathing exercises
OR massage OR virtual OR VR) AND (pain OR distress OR
discomfort OR fear OR anxiety). Also, a search was
conducted through clinical trial registries, conference
proceedings, and reference lists of Randomized
Controlled Trials (RCTs).
Searches were limited to studies conducted in humans
and published in English for which a full text was
available. We included RCTs and randomized cross-over
trials that were conducted for the non-pharmacological
management of procedural burn-related pain and
distress in children aged up to 18 years. Studies eligible
for inclusion including studies where pediatric patients
with burns and undergoing painful burn management
procedures. Studies with participants out of the targeted
age group, reviewing and meta-analysis studies, studies
with abstract only were excluded.
Two authors (S.A and M.K) extracted the data
independently and assessed the quality of trials. To
extract the data, a designed standard form was used.
Extracted data included (study design, sample size,
participants’ characteristics, interventions, comparisons,
and outcome measures). For any missing data, the
authors of the studies were contacted. Any questions
regarding the inclusion of the studies in the meta-analysis
were brought for further discussion to both investigators.
Types of participants
Participants included all young children aged day 1 to 18
years old and were undergoing painful burn management
procedures either in outpatient or inpatient settings.
Given that research in the area of burn pain management
began in the late 1980s, we selected a broad mandate
of ’procedural pain’ rather than any particular type of
procedure including dressing changes, hydrotherapy,
physiotherapy, positioning, or occupational therapy
procedures.
Types of interventions
All included studies examined the effect of at least one
non-pharmacological intervention in the intervention
group compared with at least one comparator group or
control group including (standard care, no treatment
control, or another non-pharmacological method). As
most non-pharmacological interventions are combined
with some doses of pharmacological medications, a
decision was made to include studies with combined
37 Systematic Reviews in Pharmacy
treatment as long that all the study groups received the
same pharmacological intervention.
As that non-pharmacological interventions include a
variety of delivering methods, techniques, and devices,
the review classified interventions under specific
categories based on their mechanism of effect and/or a
distinct used strategy. Accordingly, one of the following
non-pharmacological categories were included:
distraction, VR, hypnosis therapy, and massage therapy.
Types of outcome measures
Pain intensity and distress were selected as primary
outcomes. Six pain and distress outcomes including self-
reported pain, observer-reported pain, pain behavioral
measures, distress self-reported, distress observer-
reported, and distress behavioral measures were
extracted separately under a condition of the assessed
outcomes were measured a validated self-reported
measure, observer-reported measures (i.e. caregivers,
nurses, researcher), or behavioral measurement scales
displayed by children/adolescents. Secondary outcomes
include any adverse events as reported and measured by
the authors of all included studies.
In terms of the temporal outcome’s assessment, data
from the outcomes assessed during the burn painful
management procedures were used and included in the
meta-analysis. Besides, if outcomes were not assessed
during the procedure, the data of the closest point of
assessment to the completion of the procedure was used.
However, if the outcomes were assessed at both points,
during and at the end of the procedure, only data of
outcomes assessed during the procedure was included. In
addition, in studies that reported outcomes on multiple
procedures, only outcomes assessed on the first
procedure were included.
Data analysis
Using Review Manager 5.4 (RevMan 5.4), the outcomes
from each study were compared using a fixed- or
randomeffect model according to the heterogeneity of all
included studies. (11) If the insistency index (I 2) was > 50
(indicating high heterogeneity), the random-effects
model was used to interpret the results. Otherwise, the
fixedeffects model was used. Significance was set at an
alpha of 0.05.
Risk of bias assessment
To assess the risk of bias in individual studies, the 'Risk of
bias' tool in Review Manager 5.4 (RevMan 5.4) (11) was
used. For each study the following types of bias were
assessed: random sequence generation (selection bias),
allocation concealment (selection bias), blinding of
participants and personnel (performance bias), blinding
of outcome assessment (detection bias), and incomplete
outcome data (attrition bias), and selective reporting
(reporting bias), and other sources of bias (other bias).
Besides, the risk of bias graph and risk of bias summary
would be created.
Measures of treatment effects
As the outcome measures represented with continuous
data of means and standard deviations, means, and
standard deviations were entered in the Cochrane
Collaboration freeware RevMan 5.4. As multiple
measurement scales were used to assess the same
outcome, standardized mean differences (SMDs) with
95% confidence intervals were calculated, SMDs allows
for the combination of measures taken using different
measurement tools.
The following criteria were used to interpret the effect
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sizes, SMDs of (0.2) represents a small effect,
(0.5)

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represents a medium effect, and (0.8) represents a large
effect as recommended by Cohen 1988 (12) Besides, to
assess heterogeneity in meta-analysis, I2 statistical test
was calculated as recommended by Higgins & Thompson.
(13) Each category of the non-pharmacological
interventions was assessed. Within each category, each
outcome of the six primary outcomes was assessed
separately. It is important to note that studies of
intervention groups that include variations of the same
non-pharmacological intervention such as two different
types of virtual reality, were combined to create a single
pair-wise comparison. Also, in the case of multiple
control groups, the condition that most clearly isolates
the active effect of the intervention condition was
selected.
The quality of evidence was assessed using a customized
quality of evidence method based on the grading of
recommendation, assessment, development, and
evaluation (GRADE) approach. The evidence of the
included randomized trials begins as high-quality
evidence and could be downgraded to moderate, low, and
very low levels based on the following factors: risk of bias,
inconsistency, and imprecision. The quality of evidence
was downgraded by one level (-1) in the presence of the
following: serious limitation to study quality (risk of bias),
moderate heterogeneity > 45% (inconsistency), or
analysis based on < 400 sample size of group of analysis
(imprecision). The quality of evidence was downgraded
by two levels (-2) in the presence of the following:
considerable heterogeneity > 90% (inconsistency), or
analysis based on < 100 sample size of group of analysis
(imprecision).
RESULTS
Results of the search.
Utilizing the search criteria, 247 studies were retrieved
for review. Out of them, 158 studies were excluded based
on the protocol's inclusion and exclusion criteria. Then,
the remained 89 studies went for full-text review. Out of
them, 36 studies were removed as they were duplicated
articles, and we ended with 53 studies. Then, 38 studies
were excluded due to several reasons including not a
randomized controlled trial, or reported assignment that
was not truly random (n=4, 14-17), participants older
than included age range (n= 20,(18-37), no painful burn-
related procedures (n=3,(38-40), the intervention was
not primarily non-pharmacological (n=1,(41), outcomes
not related to pain or distress (n=4, 42-45), participants
condition not related to burn painful procedures (n=2,(46,
47), and missing data necessary for pooling (n=4, 48-51).
As a result, we ended with 15 studies (52-66) that were
included in the metaanalysis. More details and
descriptions of the screening process are presented in the
study flow diagram (Figure 1).
Characteristics of included studies
In this review, the 15 studies (52-66) that were included
in the meta-analysis had two to four study arms. Thirteen
studies (53-64, 66) used RCT design, and 2 studies (52,
65) used a cross-over randomized design. Trials were
conducted in a variety of settings, including hospital
inpatients and hospital outpatient clinics.
Most of the burn-related painful procedures were wound
care and during the dressing changes (n=13, 53-59, 61-
66), other painful procedures were during the
hydrotherapy sessions (n=2, 52, 60). Eight studies (n=8)
included distraction intervention (54, 55, 57-60, 62, 63),
five studies included virtual reality interventions (52, 53,
39 Systematic Reviews in Pharmacy
56, 65, 66), one study included hypnosis (61), and one
study included massage therapy.(64)
Ages of participating ranged from day one to 18 years old.
Six studies (n=6, 54, 55, 61, 62, 65, 66) included children
ranging from early childhood up to 18 years old. Four
studies (n=4, 52, 57, 63, 64) focused exclusively on
children in early childhood (i.e. zero to five years old),
while another 3 studies (56, 58-60) focused on middle
childhood (i.e. 5 to 12 years old), and one study (53)
focused exclusively on adolescents (11 to 17 years old).
The characteristics of the included studies are
summarized in (Table 1).
Risk of bias assessment
In terms of risk of bias evaluation, there were 6 types of
bias have been evaluated: 1) selection bias, 2)
performance bias, 3) detection bias, 4) attrition bias, 5)
reporting bias, and 6) miscellaneous bias (Figure 2 &
Figure 3). In terms of selection bias, the randomization
method and allocation concealment procedures were
evaluated, where a low risk of selection bias was reported
for 13 studies (52-60, 62, 63, 66) that used clear
strategies for generating random sequences with enough
documentation of the method used. Only 2 studies (61, 64)
were found to have an unclear risk of selection bias as
they did not specify the method of randomization. In
terms of concealment procedures, 7 studies (52-55, 58,
60, 62) were rated at low risk of bias as they used
appropriate allocation concealment methods with
enough documentation of the process used. Six studies
(56, 57, 59, 61, 63, 66) were rated at unclear risk of bias
as they did not provide details about allocation methods.
Only two (64, 65) studies did not mention applying
allocation concealment and were rated at high risk.
In terms of performance bias, which evaluates the
patients and intervention blindness, the nature of the
intervention made the blindness of participants and
personnel inapplicable in most of the studies, hereby they
were rated at high risk of bias. In terms of detection bias
that evaluates the blinding of outcomes assessment, 8
studies (54, 56, 58-60, 63, 65, 66) were rated at high risk
as they did not use independent assessors, or their
assessors were blind to the administered intervention.
However, 5 studies (52, 57, 61, 62, 64) were at low risk of
bias as the outcome assessors were blinded to the
intervention groups, and the remained 2 studies (53, 55)
have unclear risk.
In terms of attrition bias, which evaluate the incomplete
outcome data, most of the studies (n=11(52-55, 57-60, 62,
63, 65) were at low risk of attrition bias as they reported
sufficiently all outcomes related to the study, did not
report any dropouts and reported managing the missing
data using “intention-to-treat analysis” method. However,
3 studies (56, 64, 66) had an unclear risk because of an
unclear number of analyzed participants, and 1 study (61)
was rated at high risk due to unexplained dropouts.
In terms of reporting bias, which evaluates the selective
reporting bias, 6 studies (53, 54, 56, 59, 61, 62) were at
high risk of selective reporting bias due to their selective
outcome measures reporting. However, 5 studies (52, 55,
58, 60, 63) were at low risk of selective reporting bias as
they reported clearly all details regarding the primary
and secondary outcomes. Whereas the remained 4
studies (57, 64-66) were at unclear risk of selective
reporting bias since there was not enough information to
judge.
In terms of other miscellaneous bias, 6 studies (52, 53, 57,
59, 60, 66) were clear of other types of bias sources,
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whereas 6 studies (54, 55, 58, 61, 64, 65) reported high
risk due to small sample sizes, applying no power
analysis, or have concerns regarding measurement tools
validity and reliability and questionable differences in
pain levels between groups pre-intervention. Besides, 3
studies did not provide enough information to be judged
properly (56,
62, 63). Again, the “risk of bias graph and summary” are
presented in detail for all included studies in (Figure 2
and Figure 3).
Effects of Non-pharmacological interventions
1) Distraction
Eight studies (54, 55, 57-60, 62, 63) assessed the efficacy
of distraction for reducing children's burn-related
procedural pain and distress. Different distraction
interventions were used that included video games on
computers (n=2, 57, 58), interactive games on computer
tablet (n= 1, 60), live music distraction (n= 1, 62),
combination or selection of animation, music, and videos
on a medical screen (n=1, 63), and interactive stories or
games on a handheld electronic device (n=3,(54, 55, 59).
Out of these studies assessing distraction, painful
procedures included wound care and dressing changes
(n=7, 54, 55, 57-59, 62, 63) and hydrotherapy (n=1, 60).
Across distraction-related studies, distraction efficacy
was assessed in children aged from day 1 to 13 years old,
in which 6 studies (54, 55, 58-60, 63) included children
aged from day 1 to 13 years old, and 2 studies (57, 63)
exclusively included children of early childhood (1-6
years old). No adverse events were recorded for
distraction intervention.
In terms of pain, 5 studies (54, 55, 58-60) with 245
participants (intervention group = 130) revealed a large
effect of distraction on self-reported pain (SMD -1.64,
95% CI -3.16 to -0.12, Z = 2.11, P = 0.04). These studies
displayed substantial heterogeneity (I 2: 96%) (Figure 4).
Three studies (54, 55, 60) with 130 participants
(intervention group =
75) revealed a large effect of distraction on observer-
reported pain (SMD -3.02, 95% CI -5.85 to -0.19, Z = 2.09,
P substantial heterogeneity reported (I 2 = 62%) (Figure 11).
= 0.04). These studies displayed high heterogeneity. (I 2 =
97%) (Figure 5). Besides, 4 studies (57, 58, 62, 63) with
307 participants (intervention group = 157) revealed no
effect of distraction on behavioral pain measures (SMD
1.06, 95% CI -2.445 to 0.31, Z =1.51, P = 0.13). These
studies also presented high heterogeneity (I2 = 96%)
(Figure
6).
In terms of distress, 3 studies (58, 59, 62) with 250
participants (intervention group = 126) revealed a
moderate effect of distraction on self-reported distress
(SMD -0.33, 95% CI -0.58 to -0.08, Z = 2.61, P = 0.009).
Importantly, these studies displayed zero heterogeneity
(I2: 0%) (Figure 7). Besides, 3 studies (54, 55, 62) with
253 participants (intervention group = 131) revealed a
large effect of distraction on behavioral measures of
distress (SMD -2.82, 95% CI -0.63 to 0.04, Z = 2.06, P =
0.04). These studies displayed high heterogeneity (I2:
98%) (Figure 8).
The quality of evidence for distraction is very low for all
pain outcomes including self-reported pain,
observerreported pain, and behavioral measures of pain.
For that, we have very little confidence in the effect
estimates. The quality of evidence was low for self-
reported distress and very low for behavioral measures
of distress. Therefore, further research is likely to have an
40 Systematic Reviews in Pharmacy
important impact on the confidence in the estimated
effects and could lead to a change in these estimates.
Obvious reasons for downgrading the quality of the
evidence include serious limitations in the studies
(frequent unclear and high risk of bias), high
inconsistency represented by considerable heterogeneity,
and small numbers of included participants per group in
all meta-analyses (imprecision). The details of assessing
the quality of evidence are presented in (Table 2).
2) Virtua Reality
Five studies (n=5, (52, 53, 56, 65, 66) assessed the
efficacy of virtual reality (VR) for reducing children's
burn-related procedural pain. Different VR devices were
used that included VR videogames through a head-
mounted display (n=3, 53, 65, 66), augmented hand-held
VR system (n=1,(56), and projector-based hybrid VR (n=1,
52). Out of these 5 studies assessing VR, painful
procedures included wound care and dressing changes
(n=4,(53, 56, 65, 66) and hydrotherapy (n=1, (52)
Across the five VR-related studies, VR efficacy was
assessed in children aged from day 1 to 18 years old, in
which 3 studies (56, 65, 66) included children aged from
day 1 to 18 years old, single study (52) exclusively
included children of early childhood (1-6 years old), and
another single study (53) exclusively included
adolescents (11-17 years old). No adverse events were
recorded for VR intervention.
In terms of pain, 4 studies (53, 56, 65, 66) with 162
participants (intervention group = 80) revealed a large
effect of VR on self-reported pain (SMD -1.41, 95% CI -
2.52 to -0.30, Z = 2.48, P ˂ 0.00001). Substantial
heterogeneity was reported (I2 = 89%) (Figure 9). Three
studies (n=3, (52, 53, 66) with 141 participants
(intervention group = 71) revealed a moderate effect of
VR on observer-reported pain (SMD -0.56, 95% CI -0.90
to -0.22, Z = 3.24, P = 0.001).
These studies displayed zero heterogeneity (I2 = 0%)
(Figure 10). Three studies (52, 53, 66) with 141
participants (intervention group = 71) revealed no
evidence of effect of VR for behavioral pain measures
(SMD -0.48, 95% CI 1.04 to 0.08, Z= 1.67, P = 0.09) with
In terms of distress, only a single study (52) assessed the
effects of VR in children aged between 6 months and 7
years undergoing a painful hydrotherapy dressing
procedure on the observer reported distress. Given only
this single study, we cannot run a meta-analysis and no
conclusions are available about the efficacy of VR on
distress outcomes. No adverse events were recorded.
The quality of evidence for VR is low for self-reported
pain, and this suggests a little confidence in the effect
estimate. Moreover, very low quality of evidence is
reported for observer-reported pain and behavioral
measures of pain, and further research is expected to
have an important impact on the estimate of these effects.
Obvious reasons for downgrading the quality of the
evidence include serious limitations in the studies
(frequent unclear and high risk of bias), high
inconsistency represented by considerable heterogeneity,
and small numbers of included participants per group in
all meta-analyses (imprecision). The details of assessing
the quality of evidence are presented in (Table 2). 3)
Hypnosis
Only one study (61) assessed the effects of hypnosis in
children aged between 3 and 12 years undergoing a
dressing change procedure. This study included a
behavioral measure of distress and pain measures. Given
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only this single study, we cannot run a meta-analysis and of emotional response or experienced discomfort, fear,
no conclusions are available about the efficacy of this
treatment. No adverse events were recorded.
4) Massage Therapy

Only one study (64) assessed the effects of massage

therapy in children aged between 1 and 4 years,
undergoing a dressing change procedure. This study
included outcomes of observer-reported pain and
behavioral measures of distress. However, given only this
single study, we cannot run a meta-analysis and no
conclusions are available about this treatment efficacy.
No adverse events were recorded.

DISCUSSION
To the best of our knowledge, this is the first
comprehensive review with a meta-analysis result that
explored the potential therapeutic effects of the non-
pharmacological interventions on pain and distress in
children and adolescents undergoing painful burn
management procedures.
Summary of main results

The overall findings of this review are summarized

succinctly in Table 2 with the explanation of the numbers
presented in Table 1. This review represents the results
of 15 studies comprising 685 participants of children and
adolescents. The results of this review indicate the
efficacy of distraction on pain and distress based on a
very low to the low quality of evidence and efficacy of
virtual reality on pain based on a very low to the low
quality of evidence. Regarding other interventions of
hypnosis and massage therapy, no conclusions were
available. Due to low and very low quality of evidence, a
little confidence is applied to these effect estimates, and
most likely that future upcoming research could identify
different findings.
In terms of distraction, a positive large effect was found
on self-reported and observer reported pain, moderate
effect on self-distress, and large effect on behavioral
measures of distress. However, distraction showed no
effect on behavioral measures of pain, and that could be
due to the small sample size and a limited number of
studies, and most likely that with the presence of
additional work in the future these results would change.
An important point to mention is that there was a wide
range of types of distraction used, therefore it is unclear if
the type of distraction could influence the efficacy, and it
is unknown if some types of distraction have a superior
effect compared to other types.
In terms of virtual reality, a large effect of virtual reality
was found on self-reported pain and a moderate effect on
observer-reported pain. However, VR showed no effect
on behavioral measures of pain. Again, both positive and
negative results could tremendously change when more
studies with larger sample sizes are available. It should
be noted that distress outcome was lacking in studies
examined virtual reality. Only one study (52) included
distress outcome (observer-reported distress).
In the light of the given results, the evidence is more
focused on procedural pain outcome and lesser focus was
noticed on procedural distress, however, it is known that
procedural distress is positively related to
uncooperativeness during treatment procedures and
experienced pain.(67) Besides, reducing child distress
could make the painful procedure more tolerable and
therefore the non-pharmacological interventions may
have a more positive effect.(4) Moreover, the assessment

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and stress emotions is a recommended core issues and limitations should be addressed.
outcome measure in clinical trials of pediatric Although the highest quality of evidence could not be
acute pain.(68) realistic in the use of non-pharmacological interventions,
As the literature was lacking for studies due to the obvious nature of treatment that is impossible
examining the effect of hypnosis and massage to be blinded in the research, future studies should work
therapy on children and adolescents with burns, on improving the quality through blinded outcome
we were not able to evaluate their effectiveness, assessments. In addition, ensuring adequate allocation
and this highlights the urgent need for future concealment, registering the clinical trials to minimize
research examining the potential therapeutic selective reporting, and the use of larger sample sizes
effect of hypnosis and massage interventions. The
same argument was reported by Provençal et al.,
2018, who conducted a systematic review and
meta-analysis including six-RCTs and highlighted
that studies examining the effects of hypnosis are
scarce. (69) Also, no studies were published about
massage therapy for burn- related procedural
pain in patients with burns since the year of 2001.
(64)
Overall completeness and applicability of evidence

The evidence presented by this review is

applicable to the efficacy of non-pharmacological
interventions for burnrelated pain and distress in
children and adolescents. Included studies
examined different interventions, but more focus
was on distraction and virtual reality methods.
The trials include both inpatient and outpatient
settings, variable children's ages, and painful
burn-related procedures. For that, the
applicability of the findings of this review is based
on the clinical condition and the studied
populations.
The included studies focused more on studying
the intervention in the middle childhood age
range, while younger children and adolescents
were less studied. This could affect the
generalizability of the review results and the
trustworthiness of the interpretations and effect
estimates. For example, the study conducted by
Kipping et al.,2012 (53) has examined the effect of
a VR intervention and included only adolescents
between 11 and 17 years, for that, the results of
this study are only applicable to the specific
population studied and generalizing its effect to
other populations is questionable.
Moreover, some painful procedures that come
from the rehabilitation treatment sessions (i.e.,
stretching exercises) were not studied, although
these procedures are very painful and stressful.
(70) Also, the results indicate an obvious need to
include more non- pharmacological interventions
such as hypnosis therapy, massage therapy, and
breathing exercises in future research, as these
interventions were poorly studied in the
literature.
Quality of the evidence

Performed meta-analyses showed low to a very

low quality of evidence, the low quality was
directly linked to multiple reasons, including
frequent studies limitation in the methodological
quality or bias including selection bias, detecting
bias, performance bias, and other bias sources
including small sample sizes. Besides, the high
heterogeneity in most of the meta-analyses, and
imprecision or a low number of participants in
almost all meta-analyses. To present more quality
evidence in future research, the above-mentioned

42 Systematic Reviews in Pharmacy Vol 12, Issue 03, Mar-Apr

2021
 Non-Pharmacological Management of Burn-related Pain and Distress in Children: A
Systematic Review and Meta-Analysis Study
that are based on power calculation are all applicable and
feasible procedures that would limit other sources of bias.
Finally, when the number of studies increased, the
presence of heterogeneity will be limited.
Overall agreements and disagreements with other reviews
This study would be the first comprehensive meta-
analysis that addresses this topic, hereby comparison
with other meta-analysis studies would be limited.
However, our findings still consistent with the results of
previous systematic reviews related to this pediatric burn
(71-76). For example, a previous systematic review (71)
that examined the potential effect of the psychosocial
interventions on burn-related painful management
procedures in children reported that distraction
interventions had a positive effect on pain, anxiety, and
stress symptoms, and they concluded that distraction and
virtual reality interventions showed efficacy in
controlling patients' pain and improving short-term
stress symptoms. However, the same systematic review
did not provide any quantitative synthesis of the results,
and the review emphasized the high need for additional
work to better support the current evidence and to
explore the effects of other non-pharmacological
interventions. Another systematic review (72) also
reported a positive effect of distraction on reducing
children's pain and distress symptoms during burn
dressing changes and needle procedures. Moreover,
additional three systematic reviews (73-75) reported a
positive effect of non-pharmacological interventions
including distraction, VR, and hypnosis on procedural
burn-pain relief in adults. Finally, a recent systematic
review and meta-analysis of non-pharmacological
interventions (76) found evidence supporting the efficacy
of distraction and hypnosis for reducing children's
needle-related pain and distress. They also reported a
low to a very low quality of overall evidence as a result of
methodological and reporting limitations across trials.
Limitations
This study assessed pain and distress outcomes in short
terms including the measures of one procedure for each
study and did not examine the effect of these
interventions on the overall recovery of patients and the
improvement of the function. Another important note is
that this study combined assessments of reported pain
and distress at different points during and after the
painful procedure, as some of the included studies
conducted outcomes assessments during the procedure
and other studies completed assessments after the
procedure. This variation in the timing of assessment in
the included studies could introduce bias. The used
approach of meta-analysis supports the validity of the
findings of this study and address the issue of small
sample sizes of included studies, however, the results
should be interpreted with caution because of the
obvious presence of methodological and statistical
variability between the studies. The analysis also shows
some heterogeneity, and many studies did not report
adverse reactions or determine if adverse reactions were
seen making it difficult to draw robust clinical
conclusions regarding adverse reactions.
CONCLUSION
This review supports the use of distraction to reduce pain
and distress, and the use of virtual reality to reduce pain
during painful burn management procedures. The
current evidence is most applicable in the middle-aged
children between 4 to 13 years old. These interventions
43 Systematic Reviews in Pharmacy
are recommended to be used during clinical practice
despite the low quality of the current evidence.
Future studies should emphasize targeting the gaps of the
existing literature. Interventions that showed efficacy
including distraction and virtual reality should be further
examined through studies with high quality. While other
interventions such as hypnosis and massage therapy are
lacking and have the priority to be addressed in future
work. Besides, targeting adolescents in future research is
recommended. Finally, procedural distress is a core
outcome measure that needs to be assessed and reported
for children and adolescents in future clinical trials.
ACKNOWLEDGMENTS
This study was supported by Jordan University of Science
and Technology (JUST) and European Union. This
manuscript is the academic outcome of a master student
who attended a program funded project by the Erasmus+
Programme of the European Union entitled
(Establishment of an interdisciplinary Clinical
rehabilitation sciences master program at JUST (JUST-
CRS). Project No: ‘573758- EPP-1-2016-1 JOEPPKA2-
CBHE-JP’).
CONFLICT OF INTREST
The authors have no conflict of interest to report.
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Table 1 Included studies summary table

Authors Age range (y/o)

(year) Gender (M/F)
(Reference) Design Painful procedure Study groups Outcome measures

Brown et al. RCT 2 4 - 13 y/o 60 Group I (intervention): Pain measure:

(2014) arms. M. 15 F. Ditto™: PP story before the procedure and interactive Self-reported: FPS-R.
(59) Dressing change stories/games during the procedure. Distress measure:
Group II (control): Self-reported: VAS-A.
Standard practice included the use of TV, videos,
books, toys, and parental soothing.

Burns-Nader et RCT 4 - 12 y/o 19 Group I (intervention): Pain measure:

al. (2017) 2 arms. M.11 F. Tablet distraction interactive games provided by a Self-reported: FACES
(60) Hydrotherapy child life specialist. scale.
Group II (control): Observer-reported:
Standard care including psychosocial support by a Nurse’s reports 0-5 scale.
child life specialist with no distraction. Distress measure:
Observer -reported:
CEMS scale.
Das et al. Cross-over 5 - 18 y/o 6 Condition I (intervention): Pain measure:
(2005) randomize M. 3 F. VR equipment constituted a laptop game, a head- Self-reported: Modified
(65) d Dressing change mounted display, and a tracking system with routine FACES scale.
pharmacological analgesia.
Condition II (control):
Only routine pharmacological analgesia.

Foertsch et al. RCT 3 - 12 y/o 12 Group I (intervention): Pain measure:

(1998) 2 arms. M. 11 F. Hypnosis familiar imagery treatment that focuses on Self-reported: FACES
(61) Dressing change childhood memory and experience. and VAS.
Group II (control): Distress measure:
Social support control treatment consists of Behavioral measures:
conversation and encouragement. OSBD.

Hernandez- RCT 1 - 4 y/o 19M. Group I (intervention): Pain measure:

Reif et al. 2 arms. 5 F. 15-minute massage therapy from a trained therapist Observer-reported:
(2001) Dressing change and routine pharmacological analgesia. Nurses’ Rating Scale.
(64) Group II (control): Distress measure:
Only routine pharmacological analgesia. Behavioral measures:
CHEOPS.

Hua et al. RCT 4 - 16 y/o 31 Group I (intervention): Pain measure:

(2015) 2 arms. M. 34 F. VR equipment constituted a laptop game, a head- Self-reported: FACES
(66) Dressing change mounted display, and a joystick to play the game. scale.
Group II (control): Observer-reported: VAS.
Standard distractions included the use of toys, TV, Behavioral measures:
books, and parental comforting. FLACC.

Kaheni et al. RCT 4- 6 y/o 45 Group I (intervention): Pain measure:

(2016) 2 arms. M. 35 F. Distraction using a video computer game on a Behavioral measures:
(57) Dressing change portable monitor. FLACC.
Group II (control):
The procedure was done with no intervention.

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Khadra et al. Cross-over 6 months - 7 y/o 45 Condition I (intervention): Pain measure:
(2020) randomize M. 35 F. Projector-Based Hybrid VR consisted of a screen Observer-reported:
(52) d Hydrotherapy with a wide-field view mounted at the end of NRS-obs.
the hydro-tank with standard pharmacological Behavioral measures:
analgesia. FLACC.
Condition II (control): Distress measure:
Only standard pharmacological analgesia. Behavioral measures:
OCCEBBECCO scale.

Kipping et al. RCT 11 - 17 y/o 28 Group I (intervention): Pain measure:

(2012) 2 arms. M. 24 F. Off-the-shelf VR system constituted a laptop game, a Self-reported: VAS.
(53) Dressing change head-mounted display, and joystick to play the Observer-reported: VAS.
game. Behavioral measures:
Group II (control): FLACC.
Standard distractions included TV, stories, music, or
no distraction based on choice.

Miller et al. RCT 3 - 10 y/o 47 Group I (intervention): Pain measure:

(2010) 4 arms. M. 33 F. Interactive distraction stories and games during the Self-reported: FACES scale.
(54) Dressing change procedure. Observer-reported: VAS.
Group II (intervention): Behavioral measures:
PP story pre-procedure and standard distraction FLACC.
during the procedure.
Group III: Video game distraction.
Group IV (control):
Standard distractions including toys, TV, nursing,
and caregiver interaction.

Miller et al. RCT 3 - 10 y/o 21 Group I (intervention): Pain measure:

(2011) 2 arms. M. 19 F. PP story pre-procedure and multi-modal distraction Self-reported:
(55) Dressing change during the procedure (either an interactive story or FACES scale.
game). Observer-reported: VAS.
Group II (control): Behavioral measures:
Standard distraction pre and during the procedure. FLACC.

Mott et al. RCT 3.5 - 14 y/o 30 Group I (intervention): Pain measure:

(2008) 2 arms. M. 12 F. Augmented VR used the hand-held system both Self-reported:
(56) Dressing change before and during the dressing change. FPS-R and VAS.
Group II (control): Behavioral measures:
Basic multi-dimensional cognitive techniques FLACC.
including attention- distraction, positive
reinforcement, relaxation, and an ageappropriate
video program.

Nilsson et al. RCT 5 - 12 y/o 21 Group I (intervention): Pain measure:

(2013) 3 arms. M. 19 F. Playing a game with Wii-remote (a remote control) Self-reported: CAS.
(58) Dressing change and a laptop. Behavioral measures:
Group II: FLACC Distress measure:
Lollipops distraction with varied colors. Self-reported: FAS.
Group III (control):
Standard care of conversation and encouragement.

Van der RCT 0 - 13 y/o 69 Group I (intervention): Pain measure:

Heijden et al. 2 arms. M. 66 F. Live music therapy by music therapists and Self-reported: FPS-R.
(2018) Dressing change standard care and pharmacological analgesia. Behavioral measures:
(62) Group II (control): COMFORT-B.
In standard care, the mother takes the child back to Distress measure:
the bed and try to calm the child down. Self-reported: FACES.
Behavioral measures:
OSBD-r.

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Zhang et al. RCT 1 - 3 y/o 19 Group I (intervention): Pain measure:
(2019) 2 arms. M. 33 F. Distractive play with a medical screen was used Behavioral measures:
(63) Dressing change for children during the dressing changes. MBPS.
Group II (control):
Only routine pharmacological analgesia.

Procedural Preparation (PP), Faces Pain Scale-Revised (FPS-R), Visual Analog Scale- Anxiety (VAS-A), Children’s emotional
manifestation scale (CEMS), Virtual Reality
(VR), Visual Analog Scale (VAS), Observational Scale of Behavioral Distress (OSBD), The Children’s Hospital of Eastern
Ontario Pain Scale (CHEOPS), Faces, Legs,
Activity, Cry and CONSOL ability scale (FLACC), Numerical Rating Scale-observational (NRS-obs), Behavioral Observational
Scale of Comfort Level for Child Burn
Victims (OCCEBBECCO), Colored Analogue Scale (CAS), The Facial Affective Scale (FAS), the COMFORT-behavioral
scale (COMFORT-B), Observational Scale of
Behavioral Distress revised (OSBD-r).

Table 2 Quality of evidence assessment table

Comparisons Outcomes No. of Quality Assessment for comparisons Quality
studies
Risk of bias Inconsistency Imprecision
Distraction Self-reported pain 5 Serious study Considerable Analysis based on < ● ○○○
limitations heterogeneity (I2) > 90% 400 participants per VERY LOW
group a, b, c

Observer-reported 3 Serious study Considerable Analysis based on < ● ○○○

pain limitations heterogeneity (I2) > 90% 100 participants per VERY LOW
group a, b, d

Behavioral 4 Serious study Considerable Analysis based on < ● ○○○

measures of pain limitations heterogeneity (I2) > 90% 400 participants per VERY LOW
group a, b, c

Self-reported 3 Serious study No heterogeneity Analysis based on < ●●○○

distress limitations 400 participants per LOW
group a, c

Behavioral 3 Serious study Considerable Analysis based on < ● ○○○

measures of limitations heterogeneity (I2) > 90% 400 participants per VERY LOW
distress group a, b, c

Virtual Self-reported pain 4 Serious study Moderate heterogeneity Analysis based on < ●●○○
Reality limitations (I2) > 45%. 100 participants per LOW
group a, d, e

Observer-reported 3 Serious study No heterogeneity Analysis based on < ● ○○○

pain limitations 100 participants per VERY LOW
group a, d

Behavioral 3 Serious study Moderate heterogeneity Analysis based on < ● ○○○

measures of pain limitations (I2) > 45%. 100 participants per VERY LOW
group a, d, e

a = Downgraded once for risk of bias: most trials had serious

study limitations. b = Downgraded twice for inconsistency:
considerable heterogeneity (I2 > 90%).
c = Downgraded once for imprecision: an analysis based on < 400
participants per group. d = Downgraded twice for imprecision: an
analysis based on < 100 participants per group. e = Downgraded once
for inconsistency: moderate heterogeneity (I2 > 45%).

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Figure captions/legends

Figure 1: Study flow diagram.

Figure 2: Risk of bias graph: review authors' judgments about each risk of bias item presented as percentages across all
included studies.
Figure 3: Risk of bias summary: review authors' judgments about each risk of bias item for each included study.
Figure 4: Forest plot of comparison: 1 Distraction, Outcome: 1 Self-reported pain.
Figure 5: Forest plot of comparison: 1 Distraction, Outcome: 2 Observer-reported pain.
Figure 6: Forest plot of comparison: 1 Distraction, Outcome: 3 Behavioral measures – Pain.
Figure 7: Forest plot of comparison: 1 Distraction, Outcome: 4 Self-reported distress.
Figure 8: Forest plot of comparison: 1 Distraction, Outcome: 4 Behavioral measures – Distress.
Figure 9: Forest plot of comparison: 2 Virtual Reality, Outcome: 1 Self-reported pain.
Figure 10: Forest plot of comparison: 2 Virtual Reality, Outcome: 2 Observer-reported pain.
Figure 11: Forest plot of comparison: 2 Virtual Reality, Outcome: 3 Behavioral measures – Pain.

Figure 1: Study flow diagram.

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Figure 2: Risk of bias graph: review authors' judgments about each risk of bias item presented as percentages across all included
studies.

Figure 3: Risk of bias summary: review authors' judgments about each risk of bias item for each included study.

Figure 4: Forest plot of comparison: 1 Distraction, Outcome: 1 Self-reported pain.

Figure 5: Forest plot of comparison: 1 Distraction, Outcome: 2 Observer-reported pain.

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Figure 6: Forest plot of comparison: 1 Distraction, Outcome: 3 Behavioral measures – Pain.

Figure 7: Forest plot of comparison: 1 Distraction, Outcome: 4 Self-reported distress.

Figure 8: Forest plot of comparison: 1 Distraction, Outcome: 4 Behavioral measures – Distress.

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Figure 9: Forest plot of comparison: 2 Virtual Reality, Outcome: 1 Self-reported pain.

Figure 10: Forest plot of comparison: 2 Virtual Reality, Outcome: 2 Observer-reported pain.

Figure 11: Forest plot of comparison: 2 Virtual Reality, Outcome: 3 Behavioral measures – Pain.

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