Download Novel Use of Clevidipine for Intraoperative Blood Pressure

Novel Use of Clevidipine for Intraoperative
Blood Pressure Management in Patients With
Pheochromocytoma
Eric J. Lindstrom, CRNA
Ahmed F. Attaallah, MD, PhD
Pheochromocytomas are rare tumors that produce
excessive epinephrine and norepinephrine, leading
to multiple manifestations of catecholamine surges.
Acute intraoperative hypertension during pheochromocytoma resection requires prompt control to avoid
major and potentially lethal cardiac and neurologic
complications. This article reports the planned and
successful use of clevidipine (Cleviprex) as the “sole
agent” for intraoperative blood pressure management
P
heochromocytoma is a rare tumor of the chromaffin tissue found in the adrenal glands
causing the release of excessive amounts of
norepinephrine and epinephrine.1 The common current practice is to medicate with oral
α-blockers preoperatively, followed by β-blockers if
needed. Intraoperative control of hypertension is usually
achieved with intravenous α-blockers or with sodium
nitroprusside.2-4 Phentolamine, one of the most commonly studied and used α-blockers in pheochromocytoma management, has intermittently been unavailable in
the US market. Current supplies are limited and soon will
become nonexistent. Because of the rebranding of sodium
nitroprusside, the cost has grown exponentially to nearly
10 times its previous value. The need for an effective,
readily available, and affordable drug is apparent.
Clevidipine butyrate (Cleviprex, The Medicines
Company, Parsippany, NJ) is a dihydropyridine l-type
calcium channel blocker that reduces arterial blood pressure by decreasing systemic vascular resistance. It has
been approved for intravenous treatment of essential and
perioperative hypertension. Because of rapid metabolism
by blood and extravascular ester hydrolysis, clevidipine
has a fast onset, brief duration of action, and a short halflife of approximately 1 minute.5
in 2 adult patients with a diagnosis of pheochromocytoma undergoing elective open adrenalectomy. Clevidipine effectively and promptly provided predictable
blood pressure control in both patients.
Keywords: Calcium channel blocker, catecholamine
surge, clevidipine, intraoperative hypertension, pheochromocytoma.
Two patients, a 43-year-old man (case 1) and a 37-yearold woman (case 2) with average body habitus, each
presented to our hospital with periodic episodes of hypertension, diaphoresis, and palpitations. Both patients
did not have any other remarkable medical history. The
diagnosis of pheochromocytoma was made based on
finding elevated plasma catecholamine levels and their
urine metabolite concentrations, along with the presence
of hypervascular adrenal masses on the patients’ computed tomographic angiograms.
Each patient was started on an oral regimen of prazosin hydrochloride (α-adrenergic blocker) and scheduled
for open adrenalectomy after 3 weeks but did not need
preoperative β-blockers. Before surgery neither patient
exhibited symptomatic orthostatic hypotension or a
marked difference between standing and supine blood
pressure.
In the surgical suite holding area, they were normotensive with baseline blood pressures of 115/70 and 140/80
mm Hg, and their heart rates were 75/min (case 1) and
82/min (case 2) in normal sinus rhythm. We planned
on using clevidipine as the primary agent to manage
intraoperative hypertension, with other antihypertensive
agents (nitroprusside sodium, nitroglycerin, magnesium
sulfate, and hydralazine) prepared as a backup. After
premedication with intravenous midazolam and before
each patient entered the operative suite, arterial access
was obtained. Propofol (2 mg/kg), remifentanil (1 µg/
kg), and vecuronium (0.1 mg/kg) boluses were used for
anesthesia induction, and a clevidipine infusion was initiated at a rate of 2 mg/h immediately thereafter. During
direct laryngoscopy and intubation, mild blood pressure
elevation was noted in both patients. A 1-mg intravenous
bolus of clevidipine resulted in prompt control of systolic
blood pressure from 170 to 130 mm Hg and from 185 to
140 mm Hg in less than 90 seconds.
Anesthesia was maintained with sevoflurane (1.5%2%) and a continuous infusion of remifentanil (0.05-1
µg/kg/min) to achieve bispectral index values between
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40 and 50. Blood pressure variations were managed by
adjusting the rate of clevidipine infusions (2 mg/h to 12
mg/h; note: maximum recommended infusion6 rate is
16 mg/h). Multiple episodes of hypertension occurred
during the surgical manipulations of the pheochromocytoma mass, with the highest systolic blood pressures
being 240 and 210 mm Hg. Intravenous clevidipine
boluses (1 mg for each bolus) were administered, and the
continuous infusion was increased to 12 mg/h, achieving
prompt blood pressure control within 2 minutes, after
which the infusion rate was reduced. The first patient
required 3 clevidipine boluses, and our second patient
needed 4 boluses at 10 to 15 minutes apart. We noticed a
dose-related increase in heart rate to a maximum of 100/
min to 120/min in both patients, with the higher rates
of clevidipine infusion. This increase was managed by
intermittent boluses of esmolol (20-40 mg each). Both
patients were given 3 boluses of esmolol to achieve a
slower heart rate of 80/min.
Once the adrenal veins were ligated, resulting in
termination of high serum levels of catecholamines, all
hypertensive episodes ceased and the clevidipine infusions were stopped. No refractory postresection hypotension was observed after pheochromocytoma removal in
either case, and vasopressor infusions were not needed.
Both patients were successfully extubated in the operating room at the conclusion of their procedures. They
remained hemodynamically stable, and both were discharged to home on postoperative day 1.
Discussion
Pheochromocytomas present a perioperative hemodynamic challenge.7 These tumors originate from chromaffin cells and usually exist in the adrenal gland.
Catecholamine-secreting masses may be extra-adrenal
(sympathetic chain, mediastinum, heart, and urinary
bladder) in about 10% of cases and are called paragangliomas. The incidence of pheochromocytomas and
paragangliomas is about 1 in 2,000.1,8 The clinical presentation is usually with nonspecific symptoms such as
headache, sweating, and palpitations.9,10 Norepinephrine
and epinephrine release surges from these tumors can
lead to major and potentially fatal cardiovascular and
neurologic complications.11-13
Although there is no consensus regarding the preferred
medications for preoperative blood pressure control in
patients with pheochromocytoma, phenoxybenzamine
(a noncompetitive, nonselective α-adrenergic blocking
agent) is usually prescribed for 2 weeks to allow for spontaneous intravascular volume expansion. Subsequently,
careful initiation and titration of β-adrenergic blockers may be needed to treat any associated tachycardias
after adequate α-blockade. The Table lists medications
that have been used for the management of intraoperative hypertensive crisis, including sodium nitroprusside,
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nicardipine, clevidipine, labetalol, esmolol, nitroglycerin, phentolamine, hydralazine, magnesium sulfate,
and fenoldopam.3,4,14,15 Because of various manufacturing and regulatory factors affecting the pharmaceutical
industry, drug shortages continue to rise dramatically.
Many of these drugs have been intermittently unavailable or are no longer available because of suspended
production.17 Health care professionals are increasingly
concerned about the effects that shortages have on their
patients with acute or emergent conditions. This leads
to a dire need for therapeutically equivalent alternatives that are safe and preferably have comparable costs.
Pheochromocytoma and acute hypertensive crisis are
prime examples.
Clevidipine butyrate (Cleviprex; The Medicines
Company, Parsippany, NJ) is an intravenous ultrashortacting, third-generation dihydropyridine calcium channel
blocker that causes selective arterial vasodilation. This
leads to a predictable dose-dependent decrease in afterload and peripheral vascular resistance. Because of its
rapid metabolism by plasma esterases, the initial half-life
of clevidipine is about 1 minute and the terminal half-life
is 15 minutes with minimal accumulation.18 Clevidipine
is one of the few intravenous solutions that is prepared in
a lipid emulsion. Previously, because of infection risks,
once the stopper on the vial was punctured, the medication had a 4-hour limit until it is was required to be discarded. Recent preparations of the solution contain EDTA
(similar to propofol), allowing single-bottle infusions of
up to 12 hours in duration.6 This has greatly reduced the
cost of continuous infusions. However, it should be noted
that strict aseptic technique is imperative. Clevidipine is
contraindicated in patients who have impaired lipid metabolism, soy or egg allergies, or severe aortic stenosis.6
Clevidipine was approved in 2008 for the management of acute hypertension in various clinical scenarios.19-22 Results of clinical trials showed that clevidipine
was more effective in blood pressure control than nitroglycerin (P < .0006) and sodium nitroprusside (P < .003)
are and required fewer interventions than nicardipine did
to maintain the blood pressure within a narrower predetermined range.23,24 The tight hemodynamic control of
clevidipine can lead to decreased perioperative complications and increased survival.25 Although clevidipine has
not been formally studied for blood pressure control in
the setting of pheochromocytoma, its ideal pharmacologic antihypertensive characteristics make it an attractive option for hypertensive crisis management in these
cases.8,26 Clevidipine has a fast onset and short duration
of clinical effects because of rapid elimination that is independent of hepatic and renal clearance, thus providing
easy titration with precise hemodynamic control.27
Despite these facts, it seems that clevidipine remains
underused in the perioperative management of pheochromocytomas and paragangliomas. One author reported
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β-blocker
Venous and
arteriolar dilator
Nonselective
α-blocker
Arteriolar dilator
Esmolol
Nitroglycerin
Phentolamine
Hydralazine
5 min
15-30 min
10-30 min
1-2 min
2-5 min
1 min
5-10 min
2-4 min
5-15 min
Seconds
Onset
10 min
3-6 h
2-4 h
3-10 min
5-10 min
10-20 min
3-6 h
5-15 min
3-6 h
3 min
Duration
aCost values from McKesson Corp, 2015.16
bAvailability data from American Society of Health-System Pharmacists, 2015.17
(Adapted from and modified with permission from The Medical Letter.15)
0.1 μg/kg/min initially,
then 0.03-0.3 μg/kg/min
4-g loading dose over 20
min, then 2 g/h infusion
5-10 mg every 20-30 min
5-15 mg
5-100 µg/min
0.5-1 mg/kg over 1 min,
then 50-300 µg/kg/min
20 mg initially, then 20-80
mg every 10 min or 2
mg/min (300 mg max)
1-2 mg/h, doubling dose
at 90-sec intervals, up to
max 16 mg/h
5 mg/h increased by 2.5
mg/h every 5min up to
30 mg/h
0.25-10 µg/kg/min
Dosage
0.5 mg/mL—50 mL
0.5 mg/mL—100 mL
2.5 mg/mL—10 mL
40 mg/200 mL
50 mg/2 mL
10 mg/mL—10 mL
10 mg/mL—250 mL
20 mg/mL—250 mL
For patients with impaired renal
function
May increase the duration of a
neuromuscular blockade
May precipitate angina, myocardial
infarction; not used for aortic
dissection
10 mg/mL
1 g/2 mL
1 g/100 mL
2 g/50 mL
20 mg/mL
For patients with pheochromocy5 mg/2 mL
toma, cocaine intoxication, and MAO
interactions
For patients with cardiac ischemia or 5 mg/mL—10 mL
postoperative hypertension
50 mg/250-mL bottle
For patients with aortic dissection
or postoperative hypertension
Availabilityb
65.00
130.00
18.96
178.81
326.89
1.29
6.16
10.62
11.28
141.17
10.00
7.17
6.12
184.39
198.68
Recent national
shortage
Recent national
shortage
Recent national
shortage
Intermittently
unavailable
Recent national
shortage
Available
Recent national
shortage
Available
Recent national
shortage
606.53 Available
Wholesale Acquisition
Cost (US $)a
Not for patients with bronchospasm, 5 mg/mL—4-mL syringe 4.76
cardiogenic shock, heart block, or
5 mg/mL—20 mL
2.16
severe bradycardia
5 mg/mL—40 mL
4.32
Reflex tachycardia
Reflex tachycardia
Cyanide toxicity with prolonged
or too rapid infusion
Comments
Table. Commonly Used Intravenous Medications for the Management of Hypertensive Crisis
Dopamine (DA1)
agonist arteriolar dilator
β- and αadrenergic
blocker
Labetalol
Fenoldopam
Calcium channel
blocker
Clevidipine
Inhibits
catecholamine
release and
receptors
Calcium channel
blocker
Nicardipine
Magnesium
sulfate
Arteriolar and
venous dilator
Class
Sodium nitroprusside
Drug
the successful utilization of clevidipine to manage severe
and unexpected intraoperative hypertension caused by
an undiagnosed pheochromocytoma after failed control
by administering a variety of other medications.28 Only
one other published report described the planned use of
clevidipine in the elective resection of a catecholaminesecreting paraganglioma, in a pediatric patient.29 To our
knowledge, based on a literature search performed on
June 2, 2015, there were no published reports for the
planned use of clevidipine in the elective resection of
pheochromocytoma or paraganglioma tumor (known
diagnosis) in the adult population.
In addition to administering clevidipine as an intravenous infusion in our patients, we used clevidipine boluses
for the management of intraoperative hypertensive crisis.
This decision was based on reviewing the preliminary
results from a recent study (SPRINT) designed to evaluate the pharmacodynamics, as well as the efficacy and
safety, of the administration of 3 different bolus doses of
clevidipine (125, 250, and 500 µg) for the management
of blood pressure in cardiac surgical patients.30 With
clevidipine bolus injection, the blood pressure reduction
was generally rapid and the recovery to baseline was
fairly uniform. The maximum change in blood pressure
from baseline after a bolus dose of 500 µg was −22% (±
9%). The times until 5%, 10%, and 15% blood pressure
reduction were 0.8, 1.1, and 1.2 minutes, respectively,
with the onset of maximum reduction occurring around
2 minutes after the bolus injection. Time to recovery for
bolus dosing was approximately 50% faster than with a
clevidipine infusion. The times to 50% and 90% blood
pressure recovery after the administration were 2.9 and
6.8 minutes, respectively. The SPRINT study results
showed that rapid clevidipine administration as a small
intravenous bolus can be safely administered to acutely
decrease the systemic blood pressure. None of the patients experienced unintentional hypotension (systolic
blood pressure ≤ 85 mm Hg), and the change in heart rate
was 3.1/min (± 2.73/min).
During our intraoperative hemodynamic management
of both patients, we used esmolol boluses for heart
rate control. In patients with a hyperadrenergic state,
β-blockade alone is generally avoided to prevent unopposed α-adrenergic stimulation, which can lead to coronary vasoconstriction and further increases in hypertension.31 After ensuring adequate depth of anesthesia and
analgesia and after vasodilation had been achieved with a
short-acting direct vasodilator (as evidenced by a decrease
in blood pressure), esmolol was given to lower the heart
rate. Several case reports have shown that esmolol may be
the better choice in perioperative management of sympathetic surge because of its short duration of action.32
Based on our clinical experience, we suggest that
clevidipine can be considered a viable and effective alternative for use in patients with pheochromocytoma to the
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other commonly used agents in practice (eg, intravenous
α-blockers and nitroprusside sodium) during the perioperative period. Further prospective research studies are
required to clarify the efficacy, safety, and limitations
of clevidipine for perioperative hemodynamic management in adult and pediatric patients with catecholaminesecreting tumors.
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AUTHORS
Eric “Jake” Lindstrom, CRNA, is the interim chief and manager and the
clinical coordinator of anesthesiology at West Virginia University’s Ruby
Memorial Hospital, Morgantown, West Virginia. His primary areas of
interest are pediatric cardiac and adult anesthesia. He is a graduate of
Excela Health School of Anesthesia at La Roche College, Pittsburgh,
Pennsylvania.
Ahmed F. Attaallah, MD, PhD, graduated from the School of Medicine
at Cairo University, Cairo, Egypt, in 1994. He completed a residency
training program from 1996 to 1999 there and received his MS and PhD
degrees in 1999 and 2005, respectively. He also finished a research fellowship and another anesthesiology residency in 2005 at West Virginia
University, Morgantown, West Virginia, where he currently serves as an
associate professor. He is a diplomate of the American Board of Anesthesiology and a board-certified pediatric anesthesiologist.
DISCLOSURES
The authors have declared they have no financial relationships with any
commercial interest related to the content of this activity. The authors did
discuss off-label use within the article.
ACKNOWLEDGMENTS
The authors wish to acknowledge and extend their heartfelt gratitude to
Osama M. Elzamzamy, MD, research assistant, Department of Anesthesiology, West Virginia University, Morgantown, West Virginia, for his help
and participation in the preparation of this case report.
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