Oral Oncology 83 (2018) 154–157

Contents lists available at ScienceDirect

Oral Oncology
journal homepage: www.elsevier.com/locate/oraloncology

Perioperative considerations in free flap surgery: A review of pressors and T

anticoagulation
⁎
Mark K. Wax , James Azzi
Oregon Health and Sciences University, Department of Otolaryngology-HNS, United States

A R T I C LE I N FO A B S T R A C T

Keywords: Given the high stakes for microvascular reconstruction, the majority of reconstructive surgeons have developed
Microvascular reconstruction paradigms for pre, intra, and postoperative management that have proven to result in individual high success
Vassopressor rates. Much has been done to identify and avoid perioperative factors that could potentially increase flap failure
Anticoagulation rates. Two example of this practice has been the generalized use of anticoagulation in free tissue transfer and the
Reconstruction
prohibition against vasopressor use in patients that are undergoing free tissue transfer. This manuscript will
Head and neck cancer
discuss these issues.

Introduction composite defect. Multiple surgical procedures or multiple attempts at

The head and neck plays a critical role in multiple homeostatic
processes. Many of these are noticeable in everyday social interaction.
From a physiologic perspective: eating, drinking, articulation, swal-
lowing, and the ability to maintain weight are dependent on intact
anatomy and function of the head and neck structures. Any procedure
that interferes with the anatomy and thus the physiologic processes will
have a debilitating effect on the patient. Whether it is psychological, a
cosmetic deformity or a physiological dysfunction, these issues need to
be addressed. Thus reconstruction following composite tissue loss is
required to allow for adequate rehabilitation of the patient. This tissue
loss may be the result of a composite tissue loss from an oncologic
procedure, trauma, osteoradionecrosis, or less commonly infection. The
best method of reconstructing composite tissue loss from any etiology is
with a composite tissue replacement. Free tissue transfer allows the
harvesting of multiple tissue components from one part of the body that
is similar to the tissue that has been lost in the head and neck region.
Over the last decade the use of free tissue transfer has become the
optimal method for allowing maximal rehabilitation with restoration of
functional outcomes.
The success rate of microvascular reconstruction in the head and
neck is typically greater than 95% in experienced author’s hands [1].
The use of vascularized non treated tissue allows for an improved
functional result, superior aesthetic outcomes and improved quality of
life [2–5]. Hospital stays can range from as little as a few days to a week
or longer depending on medical comorbidities [6]. Unfortunately there
is a small subset of patients in which free tissue transfer is unsuccessful.
In these cases the entire composite tissue is lost resulting in a large
salvage, lead to prolonged morbidity with increased hospital cost and
length of stay with poorer functional outcomes.
Given these high stakes for microvascular reconstruction, the ma-
jority of reconstructive surgeons have developed paradigms for pre,
intra, and postoperative management that have proven to result in in-
dividual high success rates [2,6]. Much has been done to identify and
avoid perioperative factors that could potentially increase flap failure
rates. Two example of this practice has been the generalized use of
anticoagulation in free tissue transfer and the prohibition against va-
sopressor use in patients that are undergoing free tissue transfer.
Anticoagulation in free tissue transfer
Patients requiring free tissue transfer, most often for cancer related
defects, are at risk for clotting events postoperatively. A survey of re-
constructive surgeons demonstrated that 97% of them used some form
of anticoagulation when performing free tissue transfer [7]. In regards
to the type of anticoagulation used in free flap management, practices
and opinions differ [1]. This stems from both clotting and bleeding
having the potential to compromise a free flap, by thrombosis or he-
matoma respectively. Common sense would also dictate that each pa-
tient must be approached individually, as with those cases where
stopping anticoagulation could be life-threatening due to serious heart
disease or another comorbidity. This has led to significant controversy
and a wide variation in postoperative anticoagulation protocols from
surgeon to surgeon [7,8]. The perfect balance remains unclear [6].
Many flap anticoagulation protocols exist with no consensus on
which is best [7,8]. Part of the difficulty in determining this more

⁎
Corresponding author.
E-mail address: waxm@ohsu.edu (M.K. Wax).

https://doi.org/10.1016/j.oraloncology.2018.06.025
Received 7 December 2017; Received in revised form 12 June 2018; Accepted 21 June 2018
1368-8375/ © 2018 Published by Elsevier Ltd.
M.K. Wax, J. Azzi
definitively is that randomized-controlled trials in human patients
could place some patients at higher risk for flap failure. Currently with
very low reported flap failure rates at most major academic medical
centers, the need to elucidate this definitively is arguably not an urgent
necessity. When thrombosis does occur it is most often in the first three
days post-operatively, presumably when vessel intimal damage is
greatest [1,10,11]. The majority of these are venous thrombi and if not
explored and corrected urgently can be devastating for the flap [9].
In a multicenter analysis of radial forearm flap survival, on multi-
variate logistic regression analysis, no anticoagulation regimen im-
proved flap survival or decreased the rate of flap-related complications
[8]. Despite this, the vast majority of surgeons report that they use
some type of anticoagulation prophylaxis to prevent anastomotic
thrombosis [1,7]. The most common medications include aspirin, he-
parin, and dextran. More recently statins have been discussed as an-
other theoretical agent [12,13].
Aspirin works as an anticoagulant by inhibiting cyclooxygenase
which decreases the amount of thromboxane A2 produced.
Thromboxane A2 has prothrombotic properties. It stimulates activation
of new platelets and increases aggregation. Aspirin use also has well-
known potential complications associated with its use, including gastric
bleeding [9]. When compared with other various anticoagulation re-
gimens, aspirin has not shown to have a greater impact on reducing the
incidence of flap loss or thrombotic complications [14].
Heparin binds antithrombin and inactivates multiple clotting fac-
tors. The primary risk of its administration is bleeding. It can be used
topically, systemically, or by subcutaneous injection. Animal studies
looking at topical use of heparin have shown a benefit in reducing
microvascular thrombosis [15–17]. On the other hand, a prospective,
clinical study did not show any difference in flap outcome with the use
of topical heparin [18]. Other topical agents have also been studied and
compared to heparin for intraoperative use. A blinded, randomized,
parallel group study looked at recombinant human tissue factor
pathway inhibitor as an antithrombotic additive to intraluminal irri-
gation solution. 622 patients undergoing free flaps were divided into
three groups. Overall there was equivalent efficacy in the groups of low
and high concentrations compared to standard heparinized irrigating
solution [19]. In addition, intraoperative use of systemic heparin had
no effect on thrombotic complication rate [16,20]. Postoperative sub-
cutaneous heparin, however, has shown to decrease the incidence of
microvascular thrombosis [18]. Other various retrospective studies
have looked at combinations of anticoagulants compared to single
agent regimens and found no significant differences in rate of compli-
cations, thrombosis, or flap failure [14,21–24]. The one exception is
dextran.
Dextran, an artificial colloid, is an intravascular volume expander
and works as an anticoagulant primarily by reducing platelet and ery-
throcyte aggregation. Some known complications include anaphylaxis,
renal injury, and pulmonary edema [9]. Two studies have shown no
benefit to dextran use, but rather have implied a potential harm. In a
prospective, randomized trial, dextran did not have an effect on flap
survival but increased the incidence of systemic complications com-
pared to aspirin [25]. In a retrospective review of 1351 free flaps,
dextran administration increased the rate of flap failure in high-risk
patients while not effecting flap survival compared to no antith-
rombotic prophylaxis [26].
Statins have been widely used in the management of hyperlipidemia
and for the prevention of coronary artery disease and stroke. They have
a relatively low side-effect profile. The most common being myalgia
and rhabdomyolysis. They work by inhibiting HMG-CoA reductase. This
leads to reductions in inflammation, thrombogenicity, and improved
vasodilation. They have also been shown to improve endothelial dys-
function. For these reasons they are theorized to have a potential
benefit in microvascular free flap surgery, although no studies to date
have looked at this specifically [13,27]. The majority of clinical data
comes from cohort studies looking at patients with hyperlipidemia and
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Oral Oncology 83 (2018) 154–157
other cardiovascular diseases [13,27]. Given the prevalence of cardio-
vascular disease in the Head and Neck cancer population it may be
beneficial to start patients that have indications on statins. Whether this
will be efficacious in reducing free flap morbidity is unknown.
Although data regarding the effect of the above mentioned agents is
generally inconclusive, after a thorough review of the existing pub-
lished evidence, Motakef et al. [28] made three definitive re-
commendations and provide the corresponding levels of evidence for
each. First, with a level of evidence 2b, they recommend aspirin 325 mg
or heparin 5000 units subcutaneously every day for antithrombotic
prophylaxis. Second, and also with a level of evidence 2b, they state
that there is no benefit to systemic heparin. Lastly, with a level of
evidence 1b, they advise against the use of dextran due to a strong link
with flap and systemic complications. Interestingly they acknowledge
that the data regarding anticoagulation is inconclusive. A key factor for
their conclusion is based on Chien et al.’s [29] review of their institu-
tional data of flap survival with a regime that utilized aspirin and
subcutaneous heparin in the post-operative setting. They demonstrated
that their survival was similar to other protocols in the literature. Thus
the basis for routine peri-operative anti coagulation is generally based
on very low level data. A further limitation of Motakef’s [28] study was
that the populations studied were not exclusively head and neck re-
constructions. Translating this information to the head and neck po-
pulation must be done carefully as there are differences between flaps
in this area and other body parts. Clearly more study is needed.
Two recent studies have focused on special situations. Rather than
standard anticoagulation protocols for prevention of thrombosis post-
operatively, Senchenkov et al. [30] addressed the use of anticoagulants
to manage thrombosis after it has occurred. They constructed an al-
gorithm to guide management in this situation using multiple antic-
oagulants. They performed a retrospective review of 395 free flaps and
focused on the 15 thrombotic complications, of which two were ulti-
mately lost due to arterial thrombosis. Upon return to the operating
room for a postoperative thrombosis, a stat heparin bolus was given and
optimized to therapeutic range. An intraflap injection of tPA was given
followed by emergent exploration with thrombectomy, intra-arterial
tPA injection, and vascular revision. Weight-based systemic heparin
was then continued for at least 5 days. Dextran was added in cases
where thrombus was considered extensive. All flaps with venous
thromboses were salvaged with this protocol with no reconstructive site
hematomas reported.
Nelson et al. [31] addressed specifically how patients with a pre-
operative history of hypercoagulability can be approached differently.
They performed a retrospective study comparing a historical cohort of
hypercoagulable patients with a newly designed and implemented
protocol for thrombosis prevention. They identified hypercoagulable
patients as those with a documented history of a blood clot or blood clot
event or had been told that they are at a high risk for a clot. The an-
ticoagulation protocol involved intraoperative administration of 5000
units subcutaneous heparin at induction, 2000 units IV heparin bolus
prior to anastomosis, and initiation of a continuous 500 units/hour IV
heparin infusion at the time of anastomosis. The heparin infusion was
titrated to a therapeutic level post-operatively while an inpatient, and
anticoagulation was transitioned to warfarin or enoxaparin and con-
tinued for one month. They looked at 32 flaps in 23 patients, 11 of
which received the novel anticoagulation protocol. Three thrombotic
events occurred in the control cohort and these flaps were lost. None of
the patients in the novel protocol cohort had any thrombotic events or
flap losses, but they were more likely to have had red blood cell
transfusion (72.6% vs. 16.7%), hematoma (26.7% vs. 0%), and lower
hemoglobin nadirs (6.9 vs. 8.9) post-operatively. Although this study
was of low power, it illustrates the ongoing attempt by microvascular
surgeons to balance prevention of thrombosis and bleeding complica-
tions.
M.K. Wax, J. Azzi
Conclusion
Aside from special circumstance and, despite no good evidence to
justify the use of anticoagulation as prophylaxis against flap throm-
bosis, with literature that is mainly retrospective, underpowered and
even anecdotal, most surgeons still routinely use some form of anti-
coagulation. Perhaps this is due to the nature of free flap surgery being
a laborious endeavor and flap failure a devastating event. Even though
these events are relatively rare, they can remain in the immediate
memory of a microvascular surgeon and strongly influence his or her
practice patterns. It appears, that in the foreseeable future, antic-
oagulation in free tissue transfer will remain a source of significant
controversy in the field of microvascular surgery.
The author’s practice of perioperative anticoagulation has evolved
over the last 2 decades. Originally 5 days of dextran were utilized as this
was the protocol at the institution. The significant morbidity secondary
to prolonged used of dextran prompted a change to 2 days of dextran. A
continued observation of significant morbidity caused the abandon-
ment of dextran and the utilization of subcutaneous lovanox. A review
of flap outcomes in the literature suggesting that subcutaneous lovanox
did not have an effect on flap outcomes and the continued higher in-
cidence of hematoma’s in flap patients prompted the author to stop
Lovanox and utilize aspirin. This was re-examined and the consensus
was that no method no pharmacologic anticoagulation protocol needed
to be utilized. Thus patients were not given any anticoagulation treat-
ment directed at the free flap. Our institution did not routinely utilize
subcutaneous heparin for prophylaxis against DVT while performing a
number of prospective studies. Currently patients are receiving pro-
phylactic subcutaneous heparin as part of a DVT prevention protocol.
No medications are used specifically from a flap perspective.
Vasopressor usage
Much of the theoretical literature on vasopressor use in free tissue
transfer in humans has come from a limited number of observational
studies in animals. In an animal model vasopressor administration in-
creased cutaneous microcirculation in an amount proportional to the
change in mean arterial pressure in postsympathectomy tissue, whereas
flow in normal tissue was reduced [32,33]. Dobutamine has been
shown to significantly improve flap flow [34]. Prospective studies
comparing postoperative epinephrine, norepinephrine, dobutamine,
and dopexamine use demonstrated that both dobutamine and nor-
epinephrine improved free flap skin blood flow, with norepinephrine
yielding the greatest improvement [35,36].
Even with these results there exists dogma prohibiting the use of
vasopressors in microvascular surgical reconstruction. The belief that a
de-enervated flap pedicle becomes hypersensitive to vasoconstrictor
medication persists. The deleterious effects of a consistently low MAP
on perfusion is well accepted from a physiologic perspective, yet many
microvascular surgeons are unable to accept that the potential benefits
of providing adequate systemic perfusion pressure to the flap may
outweigh any potential changes in vascular tone of the flap pedicle. A
2012 survey [37] that included members of the American Society for
reconstructive microsurgery and the American Society of plastic sur-
gery that demonstrated that 94% of respondents felt fluid administra-
tion was the treatment of choice for hypotension. One limiting factor in
interpreting this data is that the data set was not unique to the head and
neck and in fact involved many body sites. Thus extrapolation to the
head and neck should be done carefully.
There are 2 methodologies of improving blood flow to the tissue:
fluid loading or vasopressor use. The morbidity of fluid overloading
patients is well known in the literature. Thus vasopressor use may in
fact be beneficial to patient outcomes. Studies in the literature ad-
dressing vasopressor usage in human free tissue transfer is very limited.
It turns out that vasopressor usage by anesthesia is much more common
than thought. Monroe et al. [38] in a retrospective fashion examined
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Oral Oncology 83 (2018) 154–157
patients to see who had been exposed to vasopressors during free tissue
transfer. They found a high incidence of vasopressor use (82%) and no
associated increase in flap failure rates. The retrospective nature of
their study did not allow them to identify the temporal relationship
between vasopressor administration and the microvascular portion of
the procedure. This information was confirmed by Hand et al. [39] who
reviewed a series of patients and while they did not examine con-
temporaneous timing of vasopressor administration, they also found
that only fluid administration had a deleterious effect on flap survival.
Looking at specific flaps utilized in head and neck reconstruction. Chan
et al. [40] reviewed 110 free jejunal flaps. They were able to demon-
strate that the intraoperative use of vasopressors was safe and did not
affect flap survival. The temporal relationship of usage was not well-
defined.
In order to examine whether temporal administration of vaso-
pressors had a deleterious effect on flap survival Monroe et al. [41]
went on to perform a prospective consecutive evaluation of 169 con-
secutive free tissue transfers. 74% of patients had vasopressors used
during surgery. Of these 74% had them administered within 2 h of the
microvascular anastomosis. There was no difference in flap survival or
morbidity among the group of patients that received vasopressors vs.
those that did not. When compared to a historical control group,
complications, infections, and medical comorbidities were equivalent.
The conclusion was that vasopressor use during critical portions of the
free tissue transfer did not adversely impact flap survival. Other authors
have also reported that temporal usage of Vasopressors around the time
of the anastomosis had no deleterious effect on flap survival or mor-
bidity.
For instance Fang et al. [42] reviewed 5671 free tissue transfers
involving multiple body sites. 85% of these require vasopressors at
some point during surgery. They examined vasopressor usage at various
time points during the procedure. While the majority of patients had
vasopressor use after induction and prior to critical microvascular
portions, a significant number were administered vasopressors prior to
anastomosis or in the post anastomotic phase. They demonstrated that
intraoperative use of any agents at any time during surgery was not
associated with increased overall pedicle compromise (3.2% vs 4.7%;
P = 0.074) or flap failure rates (1.6% vs 2.4%; P = 0.209). Patients
with extremity reconstructions did poorer overall as compared to other
sites.
A single prospective randomized trial was performed by Raittinen
et al. [43] They enrolled 27 patients in a randomized, controlled,
clinical trial using a radial forearm free flap for reconstruction. Patients
were allocated into one of three groups: dopamine, norepinephrine, and
control. The intervention groups received the vasoactive drug, aiming
to maintain the mean arterial pressure between 80 and 90 mmHg.
Normovolemia was maintained according to central venous pressure
measurements. Flap perfusion was monitored with continuous tissue
partial pressure of oxygen and microdialysate metabolite (lactate-to-
pyruvate ratio) measurements.
No adverse effects were observed, and postoperative recovery was
free of complications in all groups. Neither the lactate-to-pyruvate ratio
nor continuous tissue partial pressure of oxygen values differed sig-
nificantly between groups during the first 24 h of the vasoactive drug
infusion period or during the 72-hour follow-up.
They concluded that Norepinephrine and dopamine are safe and
effective vasopressors for use during the postoperative period following
head and neck cancer surgery with microvascular reconstruction
Systemic reviews of the literature have been unable to shed much
light on the effect of vasopressors. Motakeef et al. [28] confirmed that
high volumes of perioperative crystalloid administration increased
medical complications in flap patients. Given the deleterious effect of
fluid overload on patient morbidity, they suggested that vasopressors
maybe be preferable to fluids to maintain systemic blood pressure and
thus flap flow.
M.K. Wax, J. Azzi
Conclusion
Intraoperative vasopressor use in free flap surgery may not be as
harmful as previously feared. Contemporaneous use of vasopressors at
any stage of the procedure does not contribute to free tissue transfer
loss or postoperative morbidity. It may be that an improvement in
outcomes based on the ability to use less fluids to maintain systemic
pressure is a side benefit of vasopressor usage.
Conflict of interests
Dr Azzi and Dr Wax have no conflict of interests.
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