ORIGINAL ARTICLE

Comparison of Topical Anti-ischemic Agents

in the Salvage of Failing Random-Pattern
Skin Flaps in Rats
Richard E. Davis, MD; Jeffrey H. Wachholz, MD; David Jassir, MD; Chad A. Perlyn, BS; Mark H. Agrama, MD

Objective: To determine the efficacy of topical anti-
ischemic drug therapy in the salvage of failing, random-
pattern skin flaps.
Design: Prospective, randomized, placebo-controlled,
therapeutic trial.
Setting: Academic medical center.
Subjects: Sixty-one adult male Sprague-Dawley rats.
Intervention: Each experimental rat underwent a cau-
dally based random-pattern skin flap using the modified
McFarlane technique. Rats were randomized to 1 of 6 treat-
ment groups: topical nifedipine, topical trolamine salicy-
late, topical nitroglycerin, topical trolamine salicylate-
nitroglycerin combination, topical nifedipine-trolamine
salicylate-nitroglycerin combination, or inert carrier oint-
ment (control). Treatment was initiated immediately fol-
lowing flap closure and continued every 6 hours for 7 days.
At the end of the treatment period, animals were eutha-
nized and flap survival was determined for each one.
Results: Topical anti-ischemic drug therapy resulted in
a statistically significant reduction in ischemic flap ne-
crosis for each drug (or combination) tested relative to
the 44.2% mean necrosis observed in control animals.
Treatment with the combination of topical nitroglyc-
erin and topical trolamine salicylate resulted in the best
salvage response (25.2% mean necrosis) with a statisti-
cally significant improvement in flap survival relative to
both controls and nitroglycerin alone.
Conclusions: Topical anti-ischemic agents are effec-
tive in reducing ischemic necrosis of failing, random-
pattern skin flaps in the rat model. Although nitroglyc-
erin, trolamine salicylate, and nifedipine possess unique
pharmacologic mechanisms of action, each drug pro-
duced a statistically significant improvement in flap sur-
vival. The results of this study suggest that topical drug
therapy may play an important role in clinical salvage of
the failing skin flap. Further studies are needed to ex-
plore the potential of combination drug therapy.
Arch Facial Plast Surg. 1999;1:27-32

From the Division of Facial
Plastic and Reconstructive
Surgery, Department of
Otolaryngology, University of
Miami School of Medicine,
Miami, Fla.
B
ECAUSE OF thegrowingpreva-
lence of skin malignancy, re-
constructive surgeons are
confronted by an increasing
number of complex skin de-
fects. Most of these defects arise on the face
where cosmetic concerns are of prime im-
portance.Becauserandom-patternskinflaps
typically enjoy excellent color, texture, and
thickness match, they remain a valuable as-
set in facial reconstruction. Unfortunately,
the susceptibility of these flaps to ischemic
necrosis is difficult to predict owing to varia-
tions in flap design and intrinsic tissue vas-
cularity.1 As a consequence, unforeseen skin
flap necrosis remains a rare but serious com-
plication of facial reconstruction. A safe,
convenient, and cost-effective treatment for
failing skin flaps is currently needed.
As the pathophysiologic characteristics
of random-patternskinflap necrosis become
more clearly defined, pharmacologic treat-
ment of flap ischemia has become an area
of increasing interest.2,3 To date, numerous
pharmacologicalagentshavebeenexamined
for their ability to prevent or reverse skin flap
ischemia. These drugs include sympatho-
lytics, vasodilators, calcium channel block-
ers, hemorheologics, prostaglandin in-
hibitors, anticoagulants, glucocorticoids,
and free radical scavengers.1-6 Unfortu-
nately, few of these drugs have proven
unequivocally effective. Of those agents
with proven experimental efficacy, most
have been limited by undesirable adverse
effects, high cost, or restricted availabil-
ity. Moreover, to use many of these drugs,
extensive preoperative treatment or direct
vascular infusion is required, making their
use in postoperative ischemic flap sal-
vage either impractical or impossible. As
a consequence, the ideal agent for salvage
of the failing, random-pattern skin flap does
not currently exist.

ARCH FACIAL PLAST SURG/ VOL 1, JAN-MAR 1999

27

©1999 American Medical Association. All rights reserved.


MATERIALS AND METHODS
Sixty-one adult male Sprague-Dawley rats (weigh-
ing 250-275 mg) were used as experimental sub-
jects in full accordance with the protocols estab-
lished by the Institutional Animal Care and Use
Committee (IACUC) at the University of Miami, in
Florida. Isoflurane inhalational anesthesia was se-
lected to approximate routine surgical conditions. An-
esthetic induction was achieved with 5% isoflurane
and subjects were maintained intraoperatively on a
1.5% isoflurane regimen administered through a snout
cone by spontaneous ventilation.
Following induction, animals were shaved, pre-
pared, and uniformly immobilized in the prone posi-
tion. Restrictive collars were then placed to prevent
unwanted ingestion of ointment during self-groom-
ing. After adequate depth of anesthesia was con-
firmed using the pinch flexion/withdrawal test, cau-
dally based, random-pattern skin flaps, each measuring
3 x 10 cm, were raised along the dorsal midline by sharp
dissection. Flaps were designed according to the Khouri
modification of the original McFarlane tech-
nique,33,34 and care was taken to elevate the pannicu-
lus carnosus with the overlying skin flap. After hemo-
stasis was secured with electrocautery, the flaps were
sutured in the native position using 4-0 interrupted
silk sutures (Ethicon Inc, Somerville, NJ). To pre-
vent postoperative flap cannibalization, all animals were
returned to solitary housing following emergence from
anesthesia. Subjects were allowed water and rat chow
ad libitum throughout the study period, and acetami-
nophen with codeine was added to the drinking wa-
ter for 5 days postoperatively.
Immediately following flap closure, each flap
pedicle was uniformly coated with topical carrier oint-
ment containing active drugs according to 1 of 6 ran-
domized treatment groups. The control group re-
ceived only inert (placebo) carrier ointment, while
the remaining groups received either nifedipine
(5 mg), trolamine salicylate (30 mg), nitroglycerin
(30 mg), trolamine salicylate-nitroglycerin combi-
nation (30 mg each), or trolamine salicylate-nitro-
glycerin-nifedipine combination (30 mg, 30 mg, 5 mg,
respectively). Care was taken to distribute ointment
evenly along the entire flap and dosing was repeated
every 6 hours for 7 days postoperatively.
At the conclusion of the study period, all of the
animals were euthanized by rapid carbon dioxide as-
phyxia in accordance with approved IACUC proto-
cols. Comparisons of flap survival were then deter-
mined for each cohort by calculating ratios of ischemic
to healthy flap tissue using the acetate weight tech-
nique previously described.35 Data were statistically
evaluated using 1-way analysis of variance (ANOVA)
to detect differences between treatment groups. Pair-
wise comparisons were performed at the 95% confi-
dence level using the least significant difference
criterion.
Although the mechanisms for random-pattern skin
flap ischemia have yet to be fully elucidated, surgically
induced adrenergic vasoconstriction is believed to play
ARCH FACIAL PLAST SURG/ VOL 1, JAN-MAR 1999
28
©1999 American Medical Association. All rights reserved.
a major role in the reduction of nutrient capillary blood
flow.2,7-9 Various pharmacologic agents that diminish sym-
pathetic tone or promote arteriolar smooth muscle re-
laxation have been shown to improve skin flap perfu-
sion and survival, lending support to this proposed
pathophysiologic mechanism.10 One such group of va-
soactive drugs is the calcium channel blockers. Nifed-
ipine is a clinically available calcium channel blocker be-
lieved to block adrenergically mediated vasoconstriction
by inhibiting calcium ion flux into vascular smooth muscle
cells.10 Other potential benefits of calcium channel block-
ers, such as inhibition of platelet activation and cell mem-
brane stabilization, may also contribute to improved skin
flap survival.10-12
To date, 3 animal studies using oral nifedipine have
demonstrated improvement in random-pattern skin flap
survival with postoperative drug administration.10,13,14 Pal
and coworkers13 noted a reduction in random-pattern skin
flap necrosis from 37% to 12% in rats given 0.3 to 0.5
mg/kg per day of postoperative oral nifedipine. Only a
slight additional benefit was observed when treatment
was initiated preoperatively. Similarly, Bailet and co-
workers10 showed a 25% reduction in ischemic flap ne-
crosis in the rodent model when nifedipine administra-
tion was begun intraoperatively by intraperitoneal
injection (0.75 mg/kg) and continued orally for 7 days
postoperatively with rat chow containing 3000-ppm nifed-
ipine.10 Pretreatment with oral nifedipine reduced ne-
crosis further to 50% of controls. Hypotension was not
reported in either experiment. Finally, Hira et al14 ob-
served improved flap survival from 56% in the control
group to 77% in animals treated with 1 mg/kg per day of
postoperative oral nifedipine. Interestingly, in the same
study, animals given much higher doses of oral nifed-
ipine (10 mg/kg per day) also demonstrated an im-
proved mean flap survival of 72%. The failure of this much
higher dose to produce systemic hypotension and flap
hypoperfusion is difficult to explain. Bailet and cowork-
ers10 have theorized that other pharmacological proper-
ties of nifedipine, such as platelet deactivation and cell
membrane stabilization, may have been responsible for
the beneficial effects of nifedipine at higher doses.
In contrast to these reports, 2 additional studies have
shown no beneficial effects of nifedipine on flap sur-
vival. Miller et al15 reported no improvement in random-
pattern skin flap survival using pigs treated postopera-
tively with 1.5 mg/kg of oral nifedipine. However, the
authors reported significant hypotension following nifed-
ipine administration and concluded that drug-related hy-
potension may have negated any beneficial effects on flap
survival. Similarly, Emery et al16 observed no improve-
ment in flap survival in rats treated with 2.5 mg/kg of oral
nifedipine. In their study, blood pressure monitoring was
conducted in only a single test animal, and although hy-
potension was not observed at the 2.5-mg/kg dose, this dose
has been previously shown to produce hypotension in nor-
motensive rats.17 Thus, unrecognized hypotension may
have also been a factor in this experiment. Moreover, Fu-
mas18 has suggested that vasoconstricting agents con-
tained within the drug vehicle (caffeine, theobromine, and
theophylline) may have further negated any beneficial ef-
fects of nifedipine on flap survival.
 From these data, it seems likely that nifedipine im-
proves ischemic random-pattern skin flap survival if thera-
peutic tissue levels can be achieved without significant
reductions in systemic blood pressure. Moreover, since
nifedipine is safe, widely available, and inexpensive, it
is potentially well suited to clinical use in ischemic flap
salvage.
Another commonly recognized vasoactive drug that re-
laxes smooth muscle tone in peripheral arteries and veins
is nitroglycerin.19 Nitroglycerin acts predominantly through
venous dilation and is commonly prescribed in the treatment
of angina pectoris due to coronary artery disease.19 The va-
sodilatory effect of nitroglycerin is believed to stem from the
releaseofprostacyclin,apotentendogenousvasodilatorfound
in vascular endothelium.20 In addition, nitroglycerin also ap-
pears to preferentially dilate spastic vessels within ischemic
tissue.21 Recent animal studies have shown a reduction in
random-pattern skin flap necrosis following treatment with
nitroglycerin, suggesting a beneficial effect on nutrient blood
flow.22-24 Like nifedipine, nitroglycerin is widely available,
inexpensive, and generally well tolerated, making it poten-
tially suitable for clinical use in flap salvage.
I
N ADDITION to adrenergic vasoconstriction, an-
other proposed mechanism for ischemic skin flap
necrosis is microvascular compromise result-
ing from platelet aggregation.2,3 Surgically in-
duced platelet aggregation is believed to stem
from release of thromboxane A2 (TXA2), a platelet-
derived prostaglandin that behaves as a potent vasocon-
strictor and promoter of platelet aggregation.2,25 Under
normal circumstances, TXA2 is held in check by its more
abundant antagonist, prostacyclin (PGI2), which is se-
lectively synthesized and released by vascular endothe-
lium. However, following surgical trauma there seems
to be an accelerated synthesis of TXA2 and a correspond-
ing reduction in PGI2 synthesis, both of which lead to
increased platelet aggregation.2,26
Trolamine salicylate (Aspercreme) is a topical anti-
inflammatory analgesic hydrolyzed to salicylic acid, a
potent inhibitor of prostaglandin synthesis. 27,28 Like
other aspirin-containing compounds, trolamine salicy-
late is an irreversible inhibitor of platelet aggregation.
Because experimental results using either nonspecific
TXA2 inhibitors or selective TXA2 antagonists have
shown improvements in random-pattern skin flap sur-
vival,1,2,26,29,30 trolamine salicylate may also prove effica-
cious in the salvage of failing random-pattern skin flaps.
Like both nifedipine and nitroglycerin, trolamine salicy-
late is readily available, inexpensive, and generally well
tolerated.
In an effort to enhance the target tissue response, re-
duce systemic adverse effects (such as hypotension), and
avoid cumbersome intravascular drug delivery systems, we
chose to evaluate the efficacy of anti-ischemic agents ad-
ministered through topical application. Topical drug therapy
enjoys several potential advantages over oral or intravas-
cular methods of drug delivery. Foremost among these ad-
vantages is the direct targeting of ischemic tissue. Direct
application of anti-ischemic drugs to the target tissue op-
timizes local drug concentrations while minimizing sys-
ARCH FACIAL PLAST SURG/ VOL 1, JAN-MAR 1999
29
©1999 American Medical Association. All rights reserved.
temic drug distribution. Hypotension or other adverse ef-
fects produced by systemic drug distribution are thus
reduced or avoided. Previous studies of salicylate levels fol-
lowing topical application of trolamine salicylate have con-
firmed intra-articular drug levels comparable to those
achieved with oral aspirin administration, while serum lev-
els remained hundreds of times lower.31 Studies using the
adrenergic blocking agents phentolamine and phenoxy-
benzamine applied in a high-dose topical paste to random-
pattern skin flaps in rats have shown increased postopera-
tive flap survival relative to treatment with intramuscular
injection.32 Despite the topical application of doses con-
siderably higher than that recommended for parenteral
use, animal mortality was not observed, suggesting that
the normally potent adverse effects of phentolamine or
phenoxybenzamine were significantly reduced by topi-
cal application. Animal experiments with topical nitro-
glycerin ointment have also demonstrated augmented
random-pattern skin flap survival.22,23 Rohrich and co-
workers22 observed statistically significant improve-
ments in flap survival using 2% nitroglycerin ointment
applied to skin flaps raised in both the rat and pig. Again,
no lethal adverse effects were reported despite compar-
atively large topical doses. Similarly, Blomain et al23 stud-
ied random-pattern skin flap necrosis in pigs treated post-
operatively for 4 days with 2% nitroglycerin ointment.
Survival improved to 125% of controls in dorsally based
flaps and 176% of controls in ventrally based flaps, and
no lethal adverse effects of drug therapy were reported.
Based on these studies, it appears that direct tissue tar-
geting through topical drug application may improve is-
chemic flap survival while simultaneously minimizing
dose-limiting adverse effects. Topical drug delivery also
appears to be particularly well suited to skin flap ische-
mia where flap hypoperfusion often prevents effective in-
travascular drug distribution, particularly in the pres-
ence of co-existing hypotension.
In addition to improving the therapeutic ratio,
topical drug administration is also convenient, cost-
effective, and noninvasive. Because of its simplicity,
topical administration is well suited to outpatient use,
and drug administration may continue without inter-
ruption despite impaired or restricted oral intake. Fi-
nally, because nitroglycerin and trolamine salicylate are
commercially available as topical ointments, and be-
cause nifedipine is largely lipophilic, all 3 drugs are
likely to achieve therapeutic tissue levels via topical ap-
plication.
The purpose of this study is to establish the effi-
cacy of anti-ischemic agents when administered through
the transdermal route. The 3 drugs selected for this study,
nitroglycerin, trolamine salicylate, and nifedipine, have
widely differing mechanisms of action, and each drug has
either a theoretical or proven potential for the salvage of
ischemic random-pattern skin flaps. We have chosen to
evaluate the efficacy of topical anti-ischemic therapy in
the setting of postoperative flap salvage using an animal
model. The model selected in this study has been previ-
ously standardized to produce consistent levels of ische-
mic flap necrosis in untreated (control) animals and serves
as a statistically valid method for assessing the preven-
tion of surgically induced ischemic flap changes.33
 NTG NTG+TS+Nifed
31.63 26.22
Schematic representation of mean percentage of random-pattern skin flap necrosis (percentage) for each experimental group. NTG indicates nitroglycerin; TS,
trolamine salicylate; and Nifed, nifedipine. For each group, P = .05.
RESULTS
Sixty-one animals were enrolled in the study and 59
animals were available for data collection at the conclu-
sion of the study period. Two animals died intraopera-
tively from anesthetic overdose. Postmortem examina-
tion of all animals revealed no evidence of hematoma or
seroma formation.
The mean percentage of flap necrosis was com-
pared for each treatment group. Control animals treated
with inert petrolatum ointment exhibited the highest per-
centage of flap necrosis (mean = 44.1% ± 1.6% SE). By
comparison, all animals treated with topical anti-
ischemic agents exhibited a statistically significant re-
duction in ischemic flap necrosis at the 95% confidence
level (Figure). Treatment with topical nitroglycerin pro-
duced the weakest salvage response with 31.6% ± 3.1%
flap necrosis. However, relative to control animals, this
reduction in flap necrosis was statistically significant
(P,.05). Similarly, in comparison to control subjects, both
topical nifedipine and topical trolamine salicylate dem-
onstrated an improved salvage response with 26.2% ±
1.5% and 26.2% ± 2.5% flap necrosis, respectively
(P,.05). However, the trend toward reduction in flap ne-
crosis relative to nitroglycerin was not statistically sig-
nificant. Combining all 3 agents failed to improve the
salvage response relative to any single agent alone, al-
though the salvage response of 26.2% ± 1.5% flap necro-
sis was statistically significant relative to the control group
(P,.05). Overall, the best salvage response was pro-
duced from the combination of topical nitroglycerin and
topical trolamine salicylate with 25.2% ± 1.9% flap ne-
crosis. This reduction in flap necrosis was statistically sig-
nificant relative to both the control group (P,.05) and
the nitroglycerin treatment group (P,.05). In contrast,
this combination failed to produce a statistically signifi-
cant improvement over either the nifedipine or the tro-
lamine salicylate treatment groups.
COMMENT
Because ischemic necrosis is difficult to predict, unfore-
seen flap loss remains a serious complication of random-
pattern skin flap surgery. Although the incidence of flap
ARCH FACIAL PLAST SURG/ VOL 1, JAN-MAR 1999
©1999 American Medical Association. All rights reserved.
Nifed TS NTG+TS Control
26.21 26.16 25.16 44.15
failure remains comparatively low, the morbidity asso-
ciated with flap necrosis has fueled the search for an ef-
fective drug therapy. To date, there is no ideal drug therapy
for random-pattern skin flap necrosis.
Although some drugs have demonstrated experi-
mental reductions in ischemic flap necrosis, these ben-
efits have usually been offset by systemic adverse ef-
fects, high cost, or poor availability. In addition,
administration of many of these agents requires lengthy
pretreatment dosing schemes or invasive drug delivery
systems for therapeutic success, limiting their effective-
ness in the treatment of unexpected flap ischemia or acute
skin trauma.
Moreover, since most random-pattern skin flap pro-
cedures are not associated with flap ischemia, it is diffi-
cult to justify the routine use of anti-ischemic prophy-
laxis for low-risk patients, particularly if drug therapy is
associated with increased cost or significant adverse ef-
fects. Consequently, a safe, inexpensive salvage drug is
currently needed.
To be most effective, the ideal salvage drug would
need to prevent tissue necrosis even when drug admin-
istration was withheld pending the development of early
ischemic signs or symptoms. Ideally, such a drug would
also be well tolerated, cost-effective, readily available, and
suitable for outpatient administration. Because such a sal-
vage agent would obviate the need for global prophy-
laxis or expensive flap delay procedures, it would also
be well suited for use in acute skin trauma. Currently,
the ideal salvage drug does not exist.
To date, drug therapy for the salvage of failing skin
flaps has focused largely on systemic and sometimes in-
vasive routes of drug delivery. Although these ap-
proaches have occasionally met with experimental suc-
cess, dose-limiting adverse effects from systemic drug
distribution have often been an obstacle to satisfactory
flap salvage. Ironically, the adverse effect most fre-
quently encountered, systemic hypotension, likely serves
to increase ischemic tissue loss by further reducing per-
fusion pressure in the already compromised skin flap.
Consequently, many potentially efficacious drugs, in-
cluding sympatholytics, vasodilators, and calcium chan-
nel blockers, have likely been rendered ineffective in flap
salvage as a consequence of systemic drug distribution.
30
 In an effort to circumvent the problem of systemic
drug distribution, we chose to evaluate the efficacy of
flap salvage using topical drug administration. Topical
anti-ischemic therapy offers numerous advantages over
conventional oral or parenteral therapy, the foremost of
which is the ability to achieve therapeutic target tissue
levels without significant systemic drug distribution. In
spite of drug levels far in excess of recommended par-
enteral or oral doses, results of initial investigations us-
ing topical salvage agents have shown reductions in tis-
sue necrosis without dose-limiting systemic adverse
effects.22,23,32 In contrast to oral or parenteral adminis-
tration, topical drug therapy may also continue uninter-
rupted despite postoperative nausea, oral intake restric-
tions, or patient discharge, making them ideal for
postoperative ambulatory use.
In this study we chose to evaluate 3 different topi-
cal drugs, each with the potential to prevent or reverse
ischemic injury in the failing, random-pattern skin flap.
The results of this study suggest that all 3 drugs are ef-
fective in reducing impending ischemic tissue loss when
applied topically to the target tissue. Using a carefully stan-
dardized animal model, topical nifedipine and topical tro-
lamine salicylate therapy improved survival from 56% in
control animals to 74% in treated animals. This reduc-
tion in ischemic necrosis was observed without the
need for pretreatment or systemic drug delivery. More-
over, the magnitude of tissue salvage observed follow-
ing topical nifedipine administration compares favor-
ably with studies using oral drug administration. To our
knowledge, this is also the first published report of sta-
tistically significant flap salvage using a topically ap-
plied platelet inhibitor (trolamine salicylate). Although
topical nitroglycerin demonstrated the weakest salvage
response (68% flap survival), these results are similar in
magnitude to those previously reported by Rohrich and
coworkers22 or Blomain et al23 and serve to confirm the
efficacy of topical nitroglycerin in ischemic flap salvage.
As with previous experimental studies of topical anti-
ischemic agents, we also observed no visible evidence of
adverse effects, suggesting that systemic effects of topi-
cal drug therapy were negligible. Unlike many drugs
previously evaluated in flap salvage, the drugs used in
this study are widely available, inexpensive, and well
tolerated. Based on the results of this preliminary ani-
mal study, topical drug therapy may eventually provide
an effective clinical means for the salvage of failing ran-
dom-pattern skin flaps.
It is worth emphasizing that this study did not con-
firm a true salvage drug response because drug therapy
was initiated prior to clinical signs of tissue ischemia.
Rather, these data suggest only that trolamine salicy-
late, nifedipine, and nitroglycerin are effective for in-
creasing tissue tolerance to surgical ischemia. Whether
topical drug therapy would augment flap survival if treat-
ment were withheld pending the onset of visible signs
of flap ischemia was not assessed in this study. How-
ever, because both nitroglycerin and nifedipine presum-
ably improve impaired nutrient blood flow through va-
sodilation, these drugs may also have efficacy as legitimate
salvage drugs. Further studies will be necessary to de-
fine their precise efficacy as salvage agents.
ARCH FACIAL PLAST SURG/ VOL 1, JAN-MAR 1999
31
©1999 American Medical Association. All rights reserved.
Because nifedipine, trolamine salicylate, and nitro-
glycerin presumably work by distinct pharmacological
mechanisms of action (ie, inhibition of calcium ion flux
into vascular smooth muscle, inhibition of TXA2 synthe-
sis, and stimulation of endothelial PGI2 release, respec-
tively), the results of this study support the notion that
the origin of random-pattern skin flap necrosis is com-
plex and multifactorial. Hence, combining drugs with dif-
fering mechanisms of action should theoretically result
in an additive or even synergistic salvage response. The
failure of combination drug therapy to produce such a
response in this study is difficult to explain. Perhaps the
absence of additive or synergistic drug interactions re-
flects a single common mechanism of action for the 3
drugs tested. Another possible explanation is that the com-
bination of 2 potent vasodilators may have negated any
beneficial effects of topical drug therapy through suble-
thal reductions in systemic blood pressure. Although the
combination of trolamine salicylate and nitroglycerin did
produce a statistically significant reduction in flap ne-
crosis relative to nitroglycerin alone, the response was
not statistically significant relative to trolamine salicy-
late alone, suggesting that the observed improvement may
have been from the isolated effect of trolamine salicy-
late. Because these 3 drugs are believed to work through
separate and complementary mechanisms, further study
using variations in drug dosages and drug combinations
will be necessary to assess the potential for improved flap
salvage through combined (synergistic) drug therapy.
CONCLUSIONS
The results of this animal investigation indicate that topi-
caldrugsalvageof ischemicrandom-patternskinflapsissafe,
efficacious, and potentially well suited to clinical applica-
tion. Further studies of this potential treatment modality are
needed to better define optimal drug doses, application in-
tervals, and drug combinations. Ultimately, topical anti-
ischemic drug therapy may provide a needed pharmacologic
rescue in the clinical management of failing skin flaps.
Accepted for publication September 22, 1998.
We wish to express our gratitude to Robert Duncan,
PhD, professor of epidemiology and biostatistics, for his as-
sistance with statistical data analysis.
Corresponding author: Richard E. Davis, MD, Uni-
versity of Miami Hospitals and Clinics, Suite 4027 (D-1),
1475 NW 12th Ave, Miami, FL 33136.
REFERENCES
1. Sloan GM, Reinsch JF. Flap physiology and the prediction of flap viability. Hand
Clin. 1985;1:609-619.
2. Pang CY, Forrest CR, Morris SF. Pharmacological augmentation of skin flap vi-
ability: a hypothesis to mimic the surgical delay phenomenon or a wishful thought.
Ann Plast Surg. 1989;22:293-306.
3. Nichter LS, Sobieski MW, Edgerton MT. Augmentation of critical skin flap sur-
vival following ibuprofen therapy. Ann Plast Surg. 1986;16:305-312.
4. Kerrigan CL, Daniel RK. Pharmacologic treatment of the failing skin flap. Plast
Reconstr Surg. 1982;70:541-548.
5. Pratt MF. Evaluation of random skin flap survival in a porcine model. Laryngo-
scope. 1996;106:700-712.
6. Davis RE, Cohen JI, Robinson JE, Urben SL, Cook TA. Ketorolac (Toradol) and
 acute random-pattern skin flap survival in rat. Arch Otolaryngol Head Neck Surg.
1995;121:673-677.
7. Kerrigan CL. Skin flap failure: pathophysiology. Plast Reconstr Surg. 1983;72:
766-774.
8. Cutting CB, Robson MC, Koss N. Dennervation supersensitivity and the delay
phenomenon. Plast Reconstr Surg. 1978;61:881-887.
9. Moore GK, Trachy RE, Cummings CW. The effect of alpha-adrenergic stimula-
tion and blockage of perfusion of myocutaneous flaps. Otolaryngol Head Neck
Surg. 1986;94:489-496.
10. Bailet JW, Hoffman LF, Trachy RE, Weymuller EA. The effect of nifedipine on skin
flap survival in rats. Laryngoscope. 1994;104:253-258.
11. Stein HJ, Fayman MS, Oosthuizen MMJ, Hinder RA. Verapamil improves sur-
vival of rat hyperemic island flaps. Surgery. 1989;106:617-623.
12. Malamet R, Wise RA, Ettinger WH, Wigely FM. Nifedipine in the treatment of
Raynaud’s phenomenon: evidence for inhibition of platelet activation. Am J Med.
1985;78:602-608.
13. Pal S, Khazanchi RK, Moudgil K. An experimental study on the effect of nife-
dipine on ischaemic skin flap survival in rats. Br J Plast Surg. 1991;44:299-301.
14. Hira M, Tajima S, Sano S. Increased survival length of experimental flap by cal-
cium antagonist nifedipine. Ann Plast Surg. 1990;24:45-48.
15. Miller AP, Falcone RE, Nappi J, Redmon HA. The lack of effect of nifedipine on
failing skin flaps. J Dermatol Surg Oncol. 1985;11:612-614.
16. Emery FM, Kodey TR, Bomberger RA, McGregor DB. The effect of nifedipine on
skin flap survival. Plast Reconstr Surg. 1990;85:61-63.
17. Ishii H, Itoh K, Nose T. Different antihypertensive effects of nifedipine in conscious
experimental hypertensive and normotensive rats. Eur J Pharmacol. 1980;64:21.
18. Fumas H. The effect of nifedipine on skin flap survival. Plast Reconstr Surg. 1990;
86:1239.
19. Arky R, medical consultant. Physician’s Desk Reference. Montvale, NJ: Medical
Economics Data Production Co; 1998:1226.
20. Miller RR, Fennel WH, Young JB, et al. Differential systemic arterial and venous
actions and consequent cardiac effects of vasodilator drugs. Prog Cardiovasc
Dis. 1982;24:353.
21. Goldstein RE, Stinson EB, Scherer JL, et al. Intraoperative coronary occlusive
disease: nitroglycerin responsiveness and angiographic correlations. Circula-
tion. 1974;49:298-308.
22. Rohrich RJ, Cherry GW, Phil D, Spira M. Enhancement of skin flap survival uti-
lizing nitroglycerin ointment. Plast Reconstr Surg. 1984;73:943-948.
23. Blomain EW, Manders EK, Saggers G, et al. Topical nitroglycerin ointment en-
hances the survival of skin flaps. Surg Forum. 1982;33:594-595.
24. Gatti JE, Brousseau DA, Silverman DG, LaRossa D. Intravenous nitroglycerin as
a means of improving ischemic tissue hemodynamics and survival. Ann Plast
Surg. 1986;16:521-526.
25. Moncada S, Vane JR. Arachidonic acid metabolites and the interactions be-
tween platelets and blood vessel walls. N Engl J Med. 1979;300:1142-1147.
26. Sasaki GH, Pang CY. Experimental evidence for involvement of prostaglandins
in viability of acute skin flaps: effects on viability and mode of action. Plast Re-
constr Surg. 1981;67:335-340.
27. Myoflex Creme [product information pamphlet]. Fort Washington, Pa: Rorer Phar-
maceuticals; 1990.
28. Gilman AG, Rall TW, Nies AS, et al, eds. Goodman and Gilman’s The Pharma-
cologic Basis of Therapeutics, 8th ed. Elmsford, NY: Pergamon Press Inc; 1990.
29. Banic A, Kouris K, Rajacic N, Nazzal M, Al-Ghussain NM, Thulesius O. Effect of
ridogrel, a thromboxane receptor blocker and synthesis inhibitor on plasma and
red blood cell flow in an arterial skin flap in sheep. Scand J Plast Reconstr Hand
Surg. 1991;25:9-14.
30. Zachary LS, Heggers JP, Robson MC, Murphy RC. Combined prostacyclin and
thromboxane synthetase inhibitor UK 38485 in flap survival. Ann Plast Surg. 1986;
17:112-115.
31. Shamszad M, Perkal M, Golden EL, et al. Two double-blind comparisons of a
topically applied salicylate cream and orally ingested aspirin in the relief of chronic
musculoskeletal pain. Curr Ther Res. 1986;39:470-479.
32. Goshen J, Wexler MR, Peled IJ. The use of two alpha blocking agents, phenoxy-
benzamine and phentolamine, in ointment and injection form to improve skin
flap survival in rats. Ann Plast Surg. 985;15:431-435.
33. Khouri RK, Angel MF, Edstrom LE. Standardizing the dorsal rat flap. Plast Surg.
1986;37:590-591.
34. McFarlane RM, DeYoung G, Henry RA. The design of a pedicle flap in the rat to
study necrosis and its prevention. Plast Reconstr Surg. 1965;35:177-182.
35. Barton RM, Gilliand MD, Miller TA, Melissinos EG. The effect of 16,16-dimethyl
prostaglandin E2 on autogenous flap survival in rats. J Surg Res. 1981;30:
530-533.

Acknowledgment

Thanks to a generous grant from LifeCell Corporation, all fellows and

residents who are members of the American Academy of Facial Plastic and
Reconstructive Surgery will receive a 1-year subscription to the Archives of
Facial Plastic Surgery. LifeCell Corporation is dedicated to making valuable
educational resources available to physicians. We thank them for their
commitment and encouragement in our inaugural year.

Wayne F. Larrabee, Jr, MD

Editor

ARCH FACIAL PLAST SURG/ VOL 1, JAN-MAR 1999

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©1999 American Medical Association. All rights reserved.