ArticlePDF AvailableLiterature Review

Abstract

Bromelain may be of interest to plastic surgeons because of its apparent ability to reduce pain, edema, inflammation, and platelet aggregation, as well as its ability to potentiate antibiotics, which may be beneficial in postoperative healing. Bromelain's reported efficacy in burn débridement and ischemia/reperfusion may also have positive applications in plastic surgery. Although bromelain is widely used and generally considered to be a safe substance, more randomized, controlled clinical trials are necessary to further elucidate its clinical potential.
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SAFETY & EFFICACY REPORT
Bromelain
Roger A. Orsini, M.D.
Plastic Surgery Educational
Foundation Technology
Assessment Committee
Easton, Md.
Summary: Bromelain may be of interest to plastic surgeons because of its
apparent ability to reduce pain, edema, inflammation, and platelet aggregation,
as well as its ability to potentiate antibiotics, which may be beneficial in post-
operative healing. Bromelain’s reported efficacy in burn de´bridement and
ischemia/reperfusion may also have positive applications in plastic surgery.
Although bromelain is widely used and generally considered to be a safe sub-
stance, more randomized, controlled clinical trials are necessary to further
elucidate its clinical potential. (Plast. Reconstr. Surg. 118: 1640, 2006.)
T
he pineapple plant, Ananas comosus, has
long been used for medicinal purposes. Na-
tive cultures used it as a digestive aid and as
a remedy for skin disorders.
1
A compound called
bromelain, which was found to be highly con-
centrated in mature pineapple stems,
2
has since
been linked to the medicinal properties. Re-
search on bromelain has been conducted for
decades in Europe and Asia, and in recent years,
it has been of interest in the United States.
3
Although most of the available information
comes from in vitro and animal studies or anec-
dotal evidence, rather than randomized, con-
trolled clinical trials, bromelain has been shown
to exhibit beneficial therapeutic effects while
maintaining low toxicity and producing few
harmful or undesired side effects.
4
In particular,
bromelain is reported to have antiinflammatory,
antiedematous, anticoagulant, and antimeta-
static properties, and has also been shown to
enhance antibiotic activity.
1,3,4
WHAT IS BROMELAIN?
Bromelain is a crude, aqueous extract derived
from pineapple stems and fruits. It is composed
primarily of sulfhydryl proteolytic enzymes that
have protein-digesting and milk-clotting proper-
ties. Although there has been some controversy
over the years as to whether the enzymes found in
the stem and fruit are distinguishable as separate
enzymes, current literature indicates that there
are four distinct proteases in pineapples; the two
major enzymes are now described as stem brome-
lain and fruit bromelain.4,5 Several additional com-
ponents have been found in bromelain, including
peroxidase, acid phosphatase, several protease in-
hibitors, and organically bound calcium,5but
their activities are not well understood. Some stud-
ies indicate that proteolytic enzymes are not solely
responsible for bromelain’s pharmacological ef-
fects. Thus, further research is needed to deter-
mine whether the other components contribute
to bromelain’s medicinal properties.
COMMERCIAL AVAILABILITY AND
RECOMMENDED USE
Bromelain is categorized as a food additive by
the U.S. Food and Drug Administration and is on
the list of substances generally recognized as safe.6
The commercially available product is most often
made from stem bromelain, whereby the extract is
removed from cooled pineapple juice through
centrifugation, ultrafiltration, and lyophilization4
and the remaining substance is made available to
the public in the form of a powder, cream, tablet,
or capsule. It is available in pure form or in mul-
tienzyme combinations (Debridase, Phlogenzym,
and Traumanase).
Bromelain appears to be most effective when
taken orally. In vitro studies have shown that low
doses of bromelain are readily degraded by pro-
tease inhibitors in blood plasma and that oral ad-
ministration may help bromelain retain its pro-
teolytic activity.7Theoretically, bromelain could
also be degraded in the digestive tract; however,
the glycosylated nature of bromelain4contributes
to its functional stability8and may also prevent
proteolytic degradation in the intestine.1It has
been suggested that bromelain be taken on an
empty stomach, as it can interact with certain types
of food.9
Recommended dosages of bromelain are avail-
able only through the scientific literature and vary
depending on clinical indication. Most studies
From Shore Aesthetic and Reconstruction Associates.
Received for publication June 28, 2006; accepted July 12,
2006.
Copyright ©2006 by the American Society of Plastic Surgeons
DOI: 10.1097/01.prs.0000242503.50548.ee
www.PRSJournal.com1640
suggest 500 to 1500 mg/day taken in divided
doses. Bromelain’s activity is measured in gelatin-
digesting units, milk-clotting units, Federation In-
ternationale Pharmaceutiques units, or Rorer
units, and many manufactures sell bromelain
products that are standardized to 2000 gelatin-
digesting units in 500-mg tablets.9
THERAPEUTIC BENEFITS AND
MECHANISMS OF ACTION
Bromelain may be of particular interest in
plastic surgery because of its apparent antiedema-
tous, anti-inflammatory, and anticoagulation
properties. Additional evidence suggests that bro-
melain may be beneficial in pain reduction,
wound healing, burn de´bridement, and ischemia/
reperfusion. It may even be an effective adjuvant
to antibiotic therapy. The various mechanisms in-
volved in these processes are just beginning to be
understood.
Pain
Bromelain may be effective at reducing pain.
In early studies, patients who were treated with
bromelain experienced statistically significant de-
creases in pain associated with mediolateral
episiotomy10 and in pain response to bradykinin
that was topically applied to open blisters.11 In a
more recent study of mild acute knee pain in
healthy adults, bromelain was shown to have a
dose-dependent effect on the reduction of phys-
ical symptoms and improvement of general
well-being.12 However, bromelain was not effective
and was no better than standard treatment, pla-
cebo, or control in reducing pain associated with
delayed-onset muscle soreness.13
Edema
Several studies have shown bromelain’s anti-
edematous properties. In a double-blind, placebo-
controlled study, bromelain was shown to reduce
edema and ecchymoses in patients who experi-
enced surgical (e.g., rhinoplasty) or nonsurgical
trauma to the face. The investigator suggested that
the resolution of edema and ecchymoses in the
bromelain-treated subjects required one-third to
one-half fewer days than would have been ex-
pected if these same patients had received placebo
instead of active treatment.14 In a study of isch-
emia/reperfusion injury in rabbits, Neumayer et
al. observed reduced interstitial edema in rabbits
treated with Phlogenzym (MUCOS Pharma
GmbH & Co., Geretsried, Germany), a combina-
tion of bromelain, trypsin, and rutin, compared
with rabbits that were not treated.15
Inflammation
There is evidence that bromelain acts as an
anti-inflammatory agent. In a rat model of knee
joint acute inflammation, inflammatory exudates
from bromelain-treated rats had reduced concen-
trations of prostaglandin E2and substance P, two
key mediators of the immune response.16 Another
mechanism of action relates to bromelain’s ability
to alter leukocyte expression of cell surface mol-
ecules. Hale et al. found that bromelain removes
several types of cell surface molecules, thereby
decreasing leukocyte adhesion and activation, ul-
timately resulting in decreased inflammation.7
Recent studies suggest that bromelain may be
beneficial in treating inflammatory diseases. In a
mouse model of inflammatory bowel disease, bro-
melain was found to decrease the clinical and
histological severity of spontaneous colitis and co-
lonic inflammation. While the proteolytic activity
of bromelain seemed to be related to the reduc-
tion in inflammatory bowel disease symptoms, the
exact mechanisms of action have yet to be
determined.17 Secor et al. found that systemic bro-
melain treatment reduced the inflammatory pro-
cess in a mouse model of allergic airway disease.18
In addition, anecdotal evidence suggests that bro-
melain may be effective in treating mild ulcerative
colitis. A 67-year-old woman and a 60-year-old
woman, both with ulcerative colitis, reported im-
proved conditions after self-treatment with bro-
melain. In both cases, improvement of disease was
confirmed by endoscopic examination.19
Wound Healing
Bromelain may have beneficial effects in soft-
tissue wound healing. In a double-blind, con-
trolled clinical trial investigating the effects of bro-
melain on episiotomy wounds, Howat and Lewis
reported faster rates of reduction of edema and
bruising in subjects who received bromelain treat-
ment compared with subjects who received
placebo.20 The authors noted, however, that none
of the results reached statistical significance. In a
study of wound healing in healthy adults, an oral
nutritional supplement containing bromelain,
other proteases, vitamins, and minerals was shown
to decrease the soft-tissue would-healing time
when administered during the early phase of
wound healing. However, it is important to note
that the efficacy of each component of the sup-
plement was not determined, and it is unknown if
Volume 118, Number 7 Bromelain
1641
the components had an additive or synergistic
effect.21
Platelet Aggregation
Several earlier studies have suggested that bro-
melain may be an effective anticoagulant. In vitro
and in vivo studies22,23 have shown bromelain to
reduce adenosine 5=-diphosphate–induced plate-
let aggregation by degrading fibrinogen. Brome-
lain was more effective at degrading purified fi-
brinogen rather than fibrinogen in plasma,
possibly because of the action of protease inhib-
itors in the plasma.23 In a more recent study, Gla¨-
ser and Hilberg report that bromelain decreased
adenosine 5=-diphosphate– and thrombin recep-
tor–activated peptide-6–induced platelet aggrega-
tion, most likely by altering fibrinogen receptors
and blocking the formation of fibrin.24
Antibiotics
Bromelain has been shown to enhance the
action of antibiotics. In an early study, bromelain
was found to increase tissue permeability to anti-
biotics, although the results were not statistically
significant.11 Tinozzi and Venegoni found a sta-
tistically significant increase in serum and tissue
levels of amoxicillin in subjects treated with the
antibiotic and bromelain.25 More recently, brome-
lain was shown to be effective at enhancing the
activity of antibiotics in children with sepsis. Sha-
hid et al. observed a statistically significant de-
crease in the number of days it took for fever to
subside and for the withdrawal of hemodynamic
support in the children who received Phlogenzym
with antibiotics compared with the children who
received antibiotic therapy alone.26
Burn De´bridement
Bromelain may be an effective alternative to
surgical escharotomy in patients with deep burns.
Results of in vitro and in vivo studies show that
bromelain preparations can effectively de´bride
full-thickness burns in pig skin in less than 24
hours. The preparations affected only burned skin
and resulted in minimal blood loss.27 Debridase
(Biotechnology General LTD, Kiryat Malchi, Is-
rael), a bromelain-derived preparation, has also
been shown to be an effective burn-de´briding
agent. In a preliminary study of 130 patients with
deep second- and third-degree burns, Rosenberg
et al. found that, in most cases, treatment with
Debridase resulted in complete de´bridement of
eschar after only one or two brief applications;
however, the investigators note that data were in-
complete for a large number of patients, and the
noncomparative nature of the study did not allow
for a comparison between Debridase and standard
of care.28 In a porcine model of burn-induced
compartment syndrome, circumferential limb
burns treated with Debridase exhibited a statisti-
cally significant reduction in intracompartmental
pressures compared with untreated burns, and
enzymatic digestion of burn eschar effectively
cleaned the wound area without damaging viable
tissue.29
Ischemia/Reperfusion
Neumayer et al. found that Phlogenzym had a
protective effect on skeletal muscle during isch-
emia/reperfusion studies in rabbits. The authors
suggest that bromelain’s ability to reduce platelet
and leukocyte aggregation may have reduced clot-
ting in the microvessels, thereby preventing the
no-reflow phenomenon.15
Toxicity and Side Effects
Bromelain has been shown to have low toxic-
ity. In several animal studies, the median lethal
dose during oral administration was greater than
10 g/kg. When bromelain was administered in-
travenously and intraperitoneally, the median le-
thal dose ranged from 20 to 35 mg/kg and from
36.7 to 85.2 mg/kg, respectively.1
Most studies of bromelain report a low inci-
dence of adverse effects. In a review of clinical
studies that investigated bromelain’s effect on os-
teoarthritis, no serious adverse events were re-
ported; however, there were some cases of gastro-
intestinal problems, headache, tiredness, dry
mouth, skin rash, and unspecified allergic reac-
tions. In these studies, bromelain was adminis-
tered at dosages ranging from 540 to 1890 mg/
day. Higher dosages of bromelain tended to have
higher incidences of adverse drug reactions com-
pared with standard treatment.30
Other investigators have reported isolated
cases of allergic reaction and exacerbation of
asthma symptoms as a result of occupational
exposure to bromelain.31–33 In most cases, ad-
verse reactions occurred after inhalation of bro-
melain; however, some patients experienced
gastrointestinal discomfort after peroral chal-
lenge with pineapple. The respiratory and gas-
trointestinal symptoms in these cases were
found to be the result of immunoglobulin E–me-
diated reactions to bromelain.
Some authors have suggested that bromelain’s
anticoagulant properties could increase bleeding
Plastic and Reconstructive Surgery December 2006
1642
when it is taken in combination with other med-
ications, such as aspirin and warfarin.9,34
Despite the few reports of adverse events, bro-
melain is generally considered to be safe, but it is
important to note that most of the human studies
involving bromelain included adult subjects.
Thus, there is little information on the safety of
bromelain for children younger than 18 years of
age. In addition, little information is available on
the safety of bromelain when it is administered at
higher doses, when it is taken in combination with
other medications, or when it is taken long term.
FUTURE RESEARCH
Although bromelain has been studied for de-
cades in Europe and Asia and more recently in the
United States, most of the available literature de-
scribes results of in vitro or animal studies. Very
few randomized, controlled clinical trials have
been conducted. In order for bromelain to be
widely accepted as a therapeutic agent, more re-
search is needed. In particular, more trials are
needed to establish the efficacy and optimal dos-
age for each clinical indication. In addition, since
many bromelain preparations contain other en-
zymes and substances, more research is need to
identify bromelain’s contribution to the therapeu-
tic effects of these products.
CONCLUSIONS
The pineapple compound bromelain has long
been used for its medicinal properties. Although
the mechanisms of action are just beginning to be
understood, many studies have suggested that the
proteolytic component of bromelain is primarily
responsible for the pharmacological effects. Bro-
melain may be of interest to plastic surgeons be-
cause of its apparent ability to reduce pain, edema,
inflammation, and platelet aggregation, as well as
its ability to potentiate antibiotics, which may be
beneficial in postoperative healing. Bromelain’s
reported efficacy in burn de´bridement and isch-
emia/reperfusion may also have positive applica-
tions in plastic surgery. Although bromelain is
widely used and generally considered to be a safe
substance, more randomized, controlled clinical
trials are necessary to further elucidate its clinical
potential.
Roger A. Orsini, M.D.
Shore Aesthetic and Reconstruction Associates
505 Dutchmans Lane
Easton, Md. 21601-4302
raorsini@crosslink.net
ACKNOWLEDGMENT
The Plastic Surgery Educational Foundation Tech-
nology Assessment Committee would like to recognize
Jennifer Swanson of the American Society of Plastic Sur-
geons/Plastic Surgery Educational Foundation staff for
her work and support of this project.
DISCLOSURE
The author has no financial interest in any of the
products, devices, or drugs mentioned in this article.
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Plastic and Reconstructive Surgery December 2006
1644
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Bromelain, a standardized complex of proteases from the pineapple plant, is absorbed unchanged from the intestine of animals at a rate of 40%; in animal experiments it was found to have primarily anti-edema, antiinflammatory, and coagulation-inhibiting effects. These effects are due to an enhancement of the serum fibrinolytic activity and inhibition of the fibrinogen synthesis, as well as a direct degradation of fibrin and fibrinogen. Bromelain lowers kininogen and bradykinin serum and tissue levels and has an influence on prostaglandin synthesis, thus acting antiinflammatory. In in vitro and in animal studies, experimentally induced tumours could be inhibited by bromelain. Although many studies do not give extensive statistical data, the effects of bromelain in animal studies seem to be dose-dependent. Further investigations have to be carried out.
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Bromelains consist of a group of proteolytic enzymes of Bromeliaceae. They are commonly used in pharmaceutical industries, food production and in diagnostic laboratories. Bromelains are known to cause IgE-mediated reactions of both the immediate type and the 'late phase reaction of immediate type reaction' with predominantly respiratory symptoms. We report four cases of occupational allergy to bromelain in workers of a blood grouping laboratory. These observations prompted us to investigate the sensitization rate to bromelain in all workers of the particular diagnostic laboratory who had contact with bromelain. These results were compared with those obtained from healthy, randomly selected individuals without evident bromelain exposure. Our findings indicate that (i) bromelain is a strong sensitizer, (ii) sensitization usually occurs due to inhalation and not to ingestion, (iii) bromelain allergy is occupationally acquired, and adequate precautions are necessary. We can further state that (iv) skin testing with relatively pure allergens such as isolated proteases like bromelain may induce systemic reactions, even at very high dilutions.