Original Research—Facial Plastic and Reconstructive Surgery
Otolaryngology–
Vasodilation by Verapamil-Nitroglycerin
Solution in Microvascular Surgery
Rahul Seth, MD1, Karam W. Badran, MD1,2, Elizabeth Cedars, MD1,
Karolina Plonowska, MD1, Tania Benjamin, MD1,
Satvir Saggi2, P. Daniel Knott, MD1, Chase M. Heaton, MD1, and
Keith E. Blackwell, MD2
Abstract
Objective. Papaverine is a topical vasodilator commonly used
during microvascular surgery to inhibit undesired vasocon-
striction. A previous national shortage of papaverine prompted
evaluation of an alternative, effective vasodilator. This study
aims to assess the experience of a solution of verapamil
and nitroglycerin (VG) as a potential alternative pharmaco-
logic vasodilator.
Study Design. Retrospective case series.
Setting. Two tertiary academic medical centers.
Subjects and Methods. Among 298 patients, 306 consecutive
free tissue transfers performed between 2014 and 2017 for
head and neck defect reconstruction utilized a VG solution.
Patient and flap characteristics, intraoperative patient and
flap complications, and postoperative complications were
reviewed. Diameter of the cervical recipient artery was
measured intraoperatively before and after topical applica-
tion of the VG solution in a subset of 43 patients (44 flaps).
Results. Flaps included fibula, radial forearm, subscapular
system, and anterolateral thigh. In total, 3 (0.98%) flaps
failed with varied etiology unrelated to the VG solution
(venous thrombosis, arterial anastomosis thrombosis, physi-
cal damage to the perforator). Specific to topical application
of the VG solution, the mean recipient artery diameter
increased from 2.1 to 3.1 mm, a 48% increase (P \ .01).
There were no intraoperative cardiac events or complica-
tions attributable to the VG solution.
Conclusion. We describe the use of a VG solution for phar-
macologic vasodilation during microvascular free tissue
transfer. Its use was associated with an acceptable incidence
of adverse events, none of which were directly attributable
to the VG solution. Apparent and sustained vasodilation was
demonstrated. The VG solution represents a safe and effica-
cious alternative to papaverine in microvascular surgery.
Keywords
free flap, head and neck reconstruction, microvascular sur-
gery, vasodilator, vasospasm, anastomosis, papaverine, vera-
pamil, nitroglycerin, antispasmodic
Head and Neck Surgery
2021, Vol. 164(1) 104–109
Ó American Academy of
Otolaryngology–Head and Neck
Surgery Foundation 2020
Reprints and permission:
sagepub.com/journalsPermissions.nav
DOI: 10.1177/0194599820937991
http://otojournal.org
Received January 26, 2020; accepted June 3, 2020.
F
ree tissue transfer has been used reliably for recon-
struction of head and neck defects since the 1970s.
With advances and standardization in technique,
microvascular success rates have risen to levels .95%.1,2 To
optimize perfusion of the transferred tissue, maintenance of
vessel patency is mandatory. Unanticipated intraoperative
arterial vasospasm, either proximal or distal to the anastomo-
sis site, can lead to tissue ischemia with reductions in blood
flow and/or perfusion pressure. Combating vasospasm is sus-
pected to improve flap viability with the use of a vasodilat-
ing agent.3
The application of a pharmacologic vasodilator is common
practice among reconstructive surgeons, with up to 94% of
microvascular surgeons utilizing some form of topical agent.4
Papaverine, the most commonly used vasodilator, is particu-
larly potent and has been shown to increase vessel diameter
by approximately 60% following application.3 During a
nationwide shortage of papaverine from 2012 to 2015, alterna-
tive vasodilators were sought.5
Originally reported for radial artery grafts during coron-
ary artery bypass surgery, the use of a mixture of verapamil
and nitroglycerin (VG) solution provided a synergistic dila-
tory effect with the benefits of quick onset and long duration
of action.6-9 Although well described in the cardiovascular
literature, use of a VG solution within the head and neck is
limited. Therefore, this study investigates the vasodilatory
1
Department of Otolaryngology–Head and Neck Surgery, University of
California–San Francisco, San Francisco, California, USA
2
Department of Otolaryngology–Head and Neck Surgery, University of
California–Los Angeles, Los Angeles, California, USA
This article was presented at the AAO-HNS Annual Meeting; October 27-
30, 2015; Dallas, Texas.
Corresponding Author:
Rahul Seth, MD, Division of Facial Plastic and Reconstructive Surgery,
Department of Otolaryngology–Head and Neck Surgery, University of
California–San Francisco, 2233 Post Street, Third Floor, San Francisco, CA
94115, USA.
Email: Rahul.Seth@ucsf.edu
Seth et al
Table 1. Verapamil and Nitroglycerin Solution: Neutral pH. a
Component Dose
Nitroglycerin, 0.4 mg/mL b 2.5 mg
Verapamil, 2.5 mg/mL 5 mg
Sodium bicarbonate, 8.4% 0.2 mEq
Heparin, 1000 U/mL 500 U
Lactated Ringer solution — 291
a
Adapted from He GW, Yang CQ. Use of verapamil and nitroglycerin solution in preparation of radial artery for coronary grafting. Ann Thorac Surg.
1996;61(2):610-614.
b
Drawn from nitroglycerin aliquot, 4 mg /10 mL.
effect of a VG topical application to arterial anastomoses
during head and neck microvascular reconstruction.
Methods
Retrospective review of patient records was approved by the
University of California–San Francisco’s Committee on
Human Research (14-13685). Medical records were reviewed
detailing intra- and postoperative data from 298 consecutive
patients undergoing free tissue transfer at the University of
California–San Francisco and the University of California–
Los Angeles.
Patient Characteristics
All patients had a VG solution applied topically to the arter-
ial adventitia on the recipient and donor vessels prior to and
following the anastomosis of arterial lumens with 9-0 nylon
suture. All patients had a minimum of 1-month follow-up to
assess postoperative outcomes. Data reviewed included opera-
tive notes, anesthesia records, discharge summaries, and post-
operative hospital and clinic notes. Variables collected included
age, sex, flap characteristics, choice of recipient cervical ves-
sels, intraoperative patient and flap complications, and post-
operative complications.
VG Solution
The VG solution was prepared according to the protocol
developed by He and Yang9 by combining 2 mL of verapa-
mil (2.5 mg/mL) with 6.25 mL of nitroglycerin (0.4 mg/
mL), 0.2 mL of sodium bicarbonate 8.4%, 500 U of heparin
(solution, 0.5 mL of 1000 U/mL), and 291 mL of lactated
Ringer solution, yielding approximately 300 mL of total
solution with a neutral pH (Table 1). The solution is com-
pounded by the pharmacy into a 500-mL non–polyvinyl
chloride bag.
Intraoperative Measurement and Statistical Analysis
Standard microsurgical techniques were used. The cervical
recipient artery was prepared with circumferential dissection
from surrounding tissues to facilitate vessel mobility for
microvascular anastomosis. Excess donor and recipient
artery adventitia was removed from both arterial lumens.
Prior to luminal anastomosis, in a subset of patients, recipi-
ent artery diameter was measured via background material
105
Volume, mL Final concentration
6.25 8.3 mcg/mL
2 16.7 mcg/mL
0.2 pH 7.4
0.5 1.6 U/mL
—
with 1-mm markings (prevasodilator measurement). Next,
approximately 5 mL of the VG solution was applied to the
arterial subadventitia with a Vistek 27-gauge anterior cham-
ber needle (Supplemental Video S1). Thirty minutes follow-
ing the administration of the VG solution, the arterial
diameter was again measured and recorded as ‘‘postvasodila-
tor measurement.’’ Arterial anastomosis was then performed
with circumferentially placed interrupted 9-0 nylon suture.
Statistical analysis was performed with JMP statistical
software (SAS Institute). A paired t test was used to compare
pre- and postvasodilator measurements. P \ .05 was consid-
ered statistically significant.
Results
The VG solution was utilized in 298 consecutive patients
(306 free tissue transfers) undergoing free tissue transfer for
head and neck surgical defects between July 2014 and
December 2017. Eight patients underwent 2 free tissue trans-
fers due to cancer recurrence (n = 2), subsequent osteoradio-
necrosis (n = 1), a second head and neck primary tumor (n =
1), wound breakdown or dehiscence (n = 1), previous flap
failure (n = 1), or large defect size (n = 2).
Flap characteristics and complications are outlined in
Table 2. The most common donor site for tissue transfer
was the fibula (n = 106), followed by radial forearm (n =
91), anterolateral thigh (ALT; n = 90), latissimus
(n = 16), gracilis (n = 2), and iliac (n = 1). The facial artery
was the most frequently used recipient artery (n = 237).
Ischemia time averaged 162 minutes (range, 60-420 min).
For the 44 flaps that underwent pre- and post-VG solution
measurements, the prevasodilator diameter of the recipient
cervical vessel ranged from 1.5 to 3.0 mm, with a mean 6
SD of 2.1 6 0.3 mm (Figure 1). After application of VG
solution, the vessel size increased to 3.1 6 0.5 mm (range,
2-4.5 mm), yielding a statistically significant 48% increase
in arterial diameter (P \ .01; Figure 2). In all cases of
observed arterial vasospasm, the spasm was broken with
application of the VG solution.
There were no intraoperative cardiac events or physiolo-
gic changes attributable to VG solution application. A total
of 22 (7.2%) complications related to tissue transfer occurred
that required operative intervention. This included cervical
wound infection (n = 11, 3.6%), hematoma (n = 8, 2.6%),
106 Otolaryngology–Head and Neck Surgery 164(1)

Table 2. Free Flap Characteristics.

No. (%)

Total 306
Donor site
Anterolateral thigh 90 (29)
Fibula 106 (35)
Radial forearm 91 (30)
Latissimus 16 (5)
Iliac 1 (0.3)
Gracilis 2 (0.7)
Recipient artery
Facial 237 (77)
Superior thyroid 17 (5.5)
Superficial temporal 8 (2.6)
External carotid 19 (6.2) Figure 2. Postapplication of verapamil and nitroglycerin solution.
Transverse cervical 6 (2.0) Resolution of facial artery vasospasm with vasodilation. Note the
Lingual 18 (5.9) significant increase in vessel diameter and resolution vasospasm at
Internal mammary 1 (0.3) previous sites of focal narrowing.
Complications
Wound infection 11 (3.6)
Hematoma 8 (2.6) identified insult at the level of the artery. The second flap
Flap failure 3 (1.0) sustained evulsion and stretch injury to the perforators
during inset of a bulky ALT flap into the oral cavity. Upon
exploration, this flap had flow through the arterial anastomo-
sis and arterial pedicle but demonstrated a lack of blood
supply to the flap’s skin component. This flap was replaced
successfully with the contralateral ALT. The third failed
ALT flap was observed to be venous congested on post-
operative day 3 following reconstruction of an oral and phar-
yngeal defect. On exploration, thrombosis of the venous and
arterial anastomoses was identified. Despite attempts at sal-
vage with thrombectomy and thrombolysis, blood flow to
the flap could not be restored, and reconstruction with a
pedicled pectoralis myocutaneous flap was performed. The
final compromised flap was a fibula free flap for an oral
cavity defect that was found to have poor Doppler flow on
postoperative day 4. Surgical re-exploration identified a
thrombosis of the facial-peroneal artery anastomosis. The
fibula free flap was salvaged by excision of the thrombosed
segment and reanastomosis of the peroneal artery to the ipsi-
lateral terminal external carotid artery.
Figure 1. Preapplication of verapamil and nitroglycerin solution.
Facial artery demonstrating vasospasm and focal narrowing. Discussion
The intraoperative use of topical pharmacologic vasodilators
during microvascular surgery is routinely employed to offset
and flap loss (n = 3, 1.0%). Necessary interventions included arterial vasospasm and improve free tissue transfer success.
evacuation of hematoma and control of bleeding, washout Following our review of 306 free tissue transfers to the head
and debridement of the donor and/or recipient sites, and and neck, this combination of verapamil, nitroglycerin,
vessel exploration for flap compromise. heparin, and bicarbonate is identified as a safe alternative to
There were 4 compromised flaps, and of these 3 were papaverine and results in a significant increase (48%) of
ALT free flaps and were unable to be salvaged. The 3 flap vessel diameter via vasodilation.
failures appeared unrelated to arterial spasm or other arterial Arterial spasm can be attributed to a multitude of factors,
etiology. One ALT flap failure suffered venous thrombosis including minor surgical manipulative trauma, pre- and intrao-
at the anastomosis to the external jugular vein. Despite perative medication administration, endogenous catecholamine
attempted salvage with reanastomosis of the vein to the release, systemic hormones, and local endothelium-derived
internal jugular vein, the flap ultimately failed. There was no factors.7,9,10 Overall, chemical and mechanical stimulation
Seth et al
of vessel wall receptors modulate membrane potentials and
calcium release, yielding vascular smooth muscle contrac-
tion. Excess, prolonged contraction, or vasospasm may ulti-
mately lead to reduced blood flow and perfusion pressure
to the graft and may increase risk of thrombus formation
due to a narrowed luminal diameter.4 Additionally, anasto-
mosis of smaller-caliber vessels can be technically challen-
ging with increased risk of detrimental vessel back-wall
incorporation during anastomosis.11 These factors may lead
to impaired or reduced flow through the vessel, vessel
thrombosis, and ultimately graft failure. Therefore, to coun-
ter these undesired results, the direct application of va-
sodilators to vessels undergoing anastomosis is common
practice.4
The vasodilatory effects of papaverine and VG solution
are similar and effect smooth muscle contraction. The intrao-
perative use of papaverine as a topical vasodilator was
reported as early as 1971 by Green on the internal mammary
artery.12 Its exact mechanism of action is not fully under-
stood, but it is theorized to relax blood vessels through mul-
tiple mechanisms. As a phosphodiesterase inhibitor, it is
thought to raise levels of cyclic guanosine 5#-monopho-
sphate (cGMP) in smooth muscle cells, and it may decrease
calcium influx or inhibit the release of intracellular calcium
stores. Therefore, when introduced to the vascular adventitia
at high concentrations, a vasodilatory effect is observed.7,8
Similarly, the mechanism of action of the VG solution is
multifactorial. Smooth muscle relaxation and vasodilation
following VG administration rely on transmembrane and
intracellular processes. Verapamil inhibits calcium influx at
L-type voltage-gated calcium channels to reduce smooth
muscle cell contraction.7,8 Nitroglycerin promotes nitric
oxide formation within myocytes, increasing the downstream
metabolism of guanosine triphosphate to cGMP. As a second
messenger, cGMP has several downstream effects within
vascular smooth muscle cells, including the activation of
potassium ion channels and reduction of inositol trispho-
sphate levels, to prevent calcium release from the sarcoplas-
mic reticulum. By limiting vasoconstriction through multiple
pathways, the VG solution is potent and has been shown to
abate the vasoconstrictive effects of epinephrine, angiotensin
II, prostaglandin F2, and phenylephrine.13-15
Following adventitial administration of VG, a clinically
significant increase in arterial vessel diameter was appre-
ciated (2.1 6 0.3 mm to 3.1 6 0.5 mm, D48%; P \ .01). A
papaverine comparison group was not performed in this
investigation. However, our results are similar to those by
Kerschner and Futran, demonstrating a 61% increase in
vessel diameter with the use of papaverine in a rodent
model.3 Among patients undergoing CABG, Formica et al
demonstrated that papaverine and VG significantly increased
blood flow rates in the left internal thoracic artery as com-
pared with control; however, no flow difference was found
between the agents.8
VG solution has been shown in multiple studies to allow
nearly 100% vessel relaxation in \5 minutes of application.9
This produced vasodilation that lasted at least 2 hours in an
107
experimental rat model15 and even up to 24 hours in an in
vitro model.9 In contrast, papaverine was demonstrated to
have an antispasmodic effect that takes approximately 15
minutes to reach full effect and lasts \1 hour.14-16
The toxicity profile of papaverine has been studied within
endothelial cells. While initially attributed to the acidity of
the solution (pH 4.4-4.8),8,9 use of papaverine not only impaired
endothelial-dependent vessel relaxation but also induced apopto-
sis in human and canine endothelial and smooth muscle cells of
the internal thoracic artery.17 Therefore, in contrast to the VG
solution, papaverine cannot be injected intravascularly due
to its endothelial cell toxicity. Given these concerns with
papaverine use, VG solution use is advocated within cardi-
ovascular surgery.13
In a recent publication, either lidocaine 2% or nicardipine
was used during the papaverine shortage for breast recon-
struction microvascular surgery. Both were found to break
vasospasm and were not associated with vascular complica-
tion.18 Nicardipine is a calcium channel blocker, similar to
verapamil, and there are no direct comparisons between
these as topical vasodilators. Our institutions chose not to
pursue lidocaine as a vasodilator because concerns are cited
throughout the literature attributed to potential induced
vasospasm and systemic toxicity. Vessel contraction was
induced with lidocaine 2% when applied topically to a rabbit
carotid artery.10 In a subsequent report, the same authors
reported that higher concentrations of lidocaine (20%) pro-
duced vasodilation similar to that of papaverine in rabbit car-
otid arteries.19 Other groups have similarly reported dose-
dependent vasoconstriction caused by lidocaine.20,21 Lidocaine
doses of 20% may lead to unwanted systemic toxicity, while
lidocaine 2% may lead to vasoconstriction. To avoid potential
toxicity of high-dose lidocaine and given its potential vasocon-
strictive properties, we concluded lidocaine to be an unaccepta-
ble potential substitute for papaverine.
Reconstructive complications occurred at rates compara-
ble to rates reported in the literature.1,2 The flap failures
were reviewed to elucidate the underlying causes, as
described previously. In 2 cases, flap failure was unrelated
to arterial spasm or other arterial etiology and therefore
unrelated to VG solution application. In the flap failure with
arterial thrombus, incorporation of the vessel back wall at
the arterial anastomosis likely led to flap loss. Free flap com-
plications could not be attributed to the use of the VG solu-
tion. Therefore, we found the VG solution to be safe for use
in free flap surgery.
The demonstrated vasodilation and increased vessel dia-
meter, with a lack of related complications, support use of
VG solution in head and neck microvascular surgery as a
suitable substitute for papaverine. As free flap survival
remained unchanged with the switch to using VG solution
from papaverine (both with roughly 99% flap survival), our
institutions have shifted vasodilator preference from papa-
verine to VG solution, despite the returned production and
availability of papaverine.
At our institution, the cost of a 2-mL vial of papaverine is
$33.93, while the cost of 300 mL of VG solution is $47.53.
108
This amounts to a cost of $16.97/mL and $ 0.24/mL for
papaverine and VG, respectively. Although the cost per
milliliter is 70 times less for VG solution, \5 mL of vasodi-
lator solution is typically used in a case. Depending on the
amount of vasodilator used per case, VG may be a nearly
equivalent cost-efficient option or more. However, coordina-
tion with the pharmacy division is required for preparation
of the VG solution—specifically, an understanding of the
necessary lead time for pharmacology staff to compound and
deliver the solution to the operating room. At our institu-
tions, this logistic requires 30 minutes but ensures appropri-
ate and safe compounding.
There are several limitations of this study. First, the retro-
spective nature of these data precludes the ability to validate
safety and efficacy outcomes similar to well-designed pro-
spective clinical trials. Second, the lack of a control group or
equivalent limits the ability to directly compare the safety/
efficacy of VG and papaverine; however, given the very low
free flap failure rate of 1%, the study would require a very
large sample to differentiate outcomes between the pharma-
cotherapy groups. Additionally, based on the evidence in
support and benefit for use of vasodilatory solutions and the
standard practice of their use, it would not be ethical to com-
pare VG solution with a saline control in a patient popula-
tion. The previous shortage of papaverine precluded its use
for comparison in the study. Additionally, as there are no
human in vivo studies supporting its use, this study’s in vivo
microvascular demonstration of the effects of VG solution
already offers data beyond the evidence base for papaver-
ine’s application.
Conclusion
This study demonstrates the safety and efficacy of an intra-
adventitial application of a VG solution for vessel dilation
within microvascular surgery. Free tissue transfer with VG
resulted in a 48% (P \ .01) increase in vessel diameter. The
enhanced vessel caliber allows for more optimal surgical
anastomosis and a theoretical reduction in flow, limiting
vasospasm. The incidence of complications following free
tissue transfer in 306 head and neck reconstructive cases is
consistent with previously published series and unrelated to
the administration of the VG solution. Overall, VG is an
acceptable substitute or replacement for papaverine in micro-
vascular surgery.
Acknowledgment
We acknowledge Christine Ha, PharmD, at the Department of
Pharmacy, University of California–San Francisco, for her assis-
tance in providing compounding instructions and pharmaceutical
data for the VG solution.
Author Contributions
Rahul Seth, conception and design, analysis of data, drafting and
revision of work, final approval and accountability; Karam W.
Badran, data acquisition, revising manuscript, final approval and
accountability; Elizabeth Cedars, data acquisition and analysis,
drafting manuscript, final approval and accountability; Karolina
Otolaryngology–Head and Neck Surgery 164(1)
Plonowska, data acquisition, revising manuscript, final approval
and accountability; Tania Benjamin, data acquisition, revising
manuscript, final approval and accountability; Satvir Saggi, data
acquisition, revising manuscript, final approval and accountability;
P. Daniel Knott, design of the study, revising manuscript, final
approval and accountability; Chase M. Heaton, design of the
study, revising manuscript, final approval and accountability;
Keith E. Blackwell, design and conception of the study, revising
manuscript, final approval and accountability.
Disclosures
Competing interests: Rahul Seth, research grant from Bard Davol;
P. Daniel Knott, research grant from Bard Davol; Keith E. Blackwell,
consultant to Stryker.
Sponsorships: None.
Funding source: None.
Supplemental Material
Additional supporting information is available in the online version
of the article.
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