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Educated Hand Publishing LLC 
“The Science Behind the Art” 
Volume 7 - No. 2 2019 

 Anesthesia eJournal - Online
ISSN 2333-2611

Page 5

Use of Clevidipine as an Alternative to Nitroglycerin in Cardiac Surgery:  
 Case Report and Current Literature
Kate Cloud, DNP, CRNA
Monica Jenschke, PhD, CRNA

Affiliation:
School of Nurse Anesthesia at Texas Christian University

Funding/Conflict of Interest Disclosure: 
None

KEYWORDS: clevidipine, nitroglycerin, hypotension, anesthesia, perfusion

INTRODUCTION
This report summarizes a case of tachyphylaxis to nitroglycerin that occurred intraoperatively during cardiac surgery in a 
patient in whom therapeutic hypotension was being induced. The anesthesia providers were prepared with an ample supply 
of nitroglycerin and had other antihypertensive agents such as hydralazine, labetalol, and esmolol available in the operating 
room. However, the ideal medication for inducing therapeutic hypotension and most similar to nitroglycerin in its ability 
to create rapid-onset, transient hypotension, ie, clevidipine, was not readily available. The therapeutic hypotension had 
been requested by the surgeon for surgical optimization; thus, the patient experienced no harm despite the lack of expected 
response to nitroglycerin and delay in onset of therapeutic hypotension. However, the anesthesia providers recognized the 
need to avoid similar hemodynamic delays, particularly in less forgiving scenarios in which timing is crucial. 

Abstract
Cardiac surgery requires periods of therapeutic hypotension. Anesthesia providers often administer intravenous nitroglyc-
erin to accomplish these meticulous hemodynamic goals. However, patients can manifest adverse responses to nitro-
glycerin, such as decreased stroke volume; decreased cardiac output; decreased renal, splanchnic, and cerebral perfusion; 
and tolerance. This report summarizes a case of tachyphylaxis to nitroglycerin that occurred intraoperatively in a patient 
undergoing cardiac surgery in whom therapeutic hypotension was being induced. In situations such as this, an alternative 
medication is needed that is just as effective and safe. Clevidipine is currently the best choice for this because of its rapid 
onset and termination of action and specific arterial effects. Multiple studies have shown that clevidipine is as effective 
and safe as nitroglycerin. 

AEJ



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Volume 7 - No.2 2019 Page 6

CASE SUMMARY
A 70-year-old man presented for off-pump coronary artery 
bypass grafting (CABG) surgery. The patient was 170 cm tall, 
weighed 89 kg, had a body mass index of 31, and received a 
physical status indicator of 4. He denied any drug allergies. 
Aspirin 81 mg orally twice a day was his only home medication. 
However, his medical history included hypertension, coronary 
artery disease, angina with exertion, peripheral vascular 
disease, chronic obstructive pulmonary disease, osteoarthritis, 
degenerative disc disease, vertigo, and an asymptomatic infrarenal 
abdominal aortic aneurysm. The patient quit smoking 10 years 
ago, and reported alcohol consumption 3 times per week. 
A chest x-ray showed signs of mild emphysema, and the patient’s 
lungs were clear to auscultation bilaterally. A 2D echocardiogram 
revealed mild concentric hypertrophy of the patient’s heart, 
left ventricular diastolic dysfunction, and an ejection fraction 
of about 55%-65%. Heart tones were regular to auscultation. 
Preoperative laboratory results included a hemoglobin of 14 g/
dL, hematocrit of 44%, creatinine of 0.9 mg/dL, and potassium 
of 4.3 mEq/L. Airway assessment showed the patient to have 
full range of motion of his neck, interincisor distance of 3 cm, 
temporomandibular distance of 3 cm, and a Mallampati score of 
2.
General anesthesia was induced with midazolam 5 mg 
intravenous (IV), sufentanil 50 mcg IV, propofol 150 mg, and 
inhaled sevoflurane. The patient also received vecuronium 10 mg 
IV. The airway was secured with an 8-mm endotracheal tube. 
Acetaminophen 1000 mg and cefazolin 2 g were given as IV
infusions. A central venous introducer and pulmonary artery
catheter were placed. Transesophageal echocardiography (TEE)
was performed. The mediastinum was accessed via midline
sternotomy, and the surgeon began to harvest the internal
mammary artery and tack up the pericardium. When the heart
was manipulated for off-pump grafting, the pulmonary arterial
systolic pressure increased suddenly from 30 mm Hg to 80 mm
Hg. ST segment changes were noted per electrocardiogram, and
TEE revealed hypokinesis of the lateral wall of the heart.
The decision was made to abort the off-pump attempt at grafting
and to initiate cardiopulmonary bypass (CPB) to complete
the procedure. Nitroglycerin was administered in 40-80 mcg
intermittent IV boluses to maintain systolic blood pressure (BP)
at less than 100 mm Hg during placement of the aortic cannula.
Milrinone infusion was started at 0.375 mcg/kg/min. CPB was
initiated and mean arterial pressure was maintained at or greater
than 60 mm Hg. 
The grafts were completed, and the patient was weaned from
CPB. When it was time to remove the aortic cannula, the surgeon
requested a systolic BP less than 100 mm Hg. Nitroglycerin 200
mcg was given intravenously. The systolic BP changed from 147
mm Hg to 144 mm Hg. Nitroglycerin 400 mcg IV was given. 
The systolic BP then decreased to 131 mm Hg. Nitroglycerin
1400 mcg IV was given, and the systolic BP decreased to 120 mm
Hg. Minutes passed and the surgeon still waited to remove the
aortic cannula. Sufentanil 50 mcg IV and vecuronium 4 mg IV
were given at that point. Nitroglycerin was attempted again, in a
dose of 2000 mcg IV. The systolic BP remained at 124 mm Hg.
Another dose of nitroglycerin 2000 mcg IV was given, and the
systolic BP decreased to 111 mm Hg. Nitroglycerin 2000 mcg IV
was repeated, and the systolic BP decreased to 103 mm Hg. The

aortic cannula was then removed without complications. Seven 
minutes had passed since the surgeon’s initial request for systolic 
BP less than 100 mm Hg. The surgical site was closed and the 
patient was transported to the intensive care unit with stable vital 
signs.
DISCUSSION
The patient’s lack of hemodynamic response to IV nitroglycerin 
during this case was unexpected. It was also unprecedented, as 
the patient had responded to the nitroglycerin earlier in the case. 
By definition, this was a case of tachyphylaxis: rapidly developed 
desensitization to the therapeutic effects of the medication. 
Nitroglycerin tolerance was ruled out, because tolerance would 
have required development over a longer period of time during 
which nitrates were administered consistently. Fortunately, the 
surgeon’s request for a decrease in BP was a matter of surgical 
optimization rather than a matter of life or death for the patient. 
However, IV nitroglycerin is a drug that anesthesia providers 
rely on during episodes of hemodynamic crisis in the operating 
room. Failure of hemodynamic response to nitroglycerin, coupled 
with lack of an alternative antihypertensive readily available 
could be detrimental to the patient. Therefore, an alternative 
antihypertensive should be chosen before initiation of the surgical 
procedure and should be readily available throughout the case. 
While there are many options for IV antihypertensive therapy, 
current literature reports many benefits to the use of clevidipine. 
Clevidipine has fast onset and termination of action times similar 
to those of nitroglycerin that make it an appealing alternative 
therapy. A literature search was conducted through the Embase 
(Elsevier), Medline (National Library of Medicine), and Web 
of Science databases using the terms nitroglycerin, clevidipine, 
tolerance, tachyphylaxis, and mechanism of action.
CURRENT LITERATURE
Nitroglycerin is an organic nitrate that can be administered 
sublingually or intravenously. It causes dilation of peripheral veins 
and large coronary arteries. These mechanisms yield decreased 
venous return and preload, decreased myocardial wall tension, 
decreased myocardial oxygen demand, and improved myocardial 
oxygen supply. Nitroglycerin does not cause dilation of small 
coronary vessels, which helps to prevent coronary steal syndrome. 
Nitroglycerin also causes a slight decrease in platelet aggregation. 
These characteristics make nitroglycerin ideal for the treatment of 
patients with coronary artery disease. 
Intraoperatively, IV nitroglycerin can be used for rapid yet 
meticulous BP management. It acts within seconds after 
administration, and the medication effects last only 3 to 5 
minutes, allowing for the quick changes in BP that are often 
required in vascular surgeries. In CABG procedures that use 
cardiopulmonary bypass, 2 specific moments require a normal but 
low systolic BP to prevent dissection or bleeding from the aorta: 
1) aortic cannulation and 2) removal of the aortic cannula. These 
procedures occur at the very beginning and the very end of CPB, 
respectively. Anesthesia providers routinely use nitroglycerin
at these times to adjust the BP to the surgeon’s requested level. 
Although this technique is effective for most patients, some 
patients have tolerance to organic nitrates such as nitroglycerin. 

The mechanism of tolerance to organic nitrates is currently 



Anesthesia eJournal                         www.anesthesiaejournal.com
Volume 7 - No. 2 2019 Page 7

unspecified. Nitroglycerin undergoes complex biotransformation 
upon administration, making it difficult to identify a single source 
of tolerance. Nitroglycerin can be considered a prodrug; it is 
metabolized to yield nitric oxide (NO), the actual substance that 
stimulates smooth muscle cell relaxation. After administration of 
nitroglycerin or another organic nitrate, NO is formed in healthy 
vascular endothelium from L-arginine by endothelial nitric oxide 
synthase (eNOS). NO then activates soluble guanylyl cyclase 
(sGC), which increases levels of cyclic guanosine monophosphate 
(cGMP). cGMP has multiple effects that ultimately cause a 
decrease in intracellular calcium, which inhibits myosin activity, 
and thereby leads to vascular smooth muscle cell relaxation. 
This effect may appear clinically as decreased BP or improved 
myocardial oxygenation. 
However, if a patient is tolerant to organic nitrates, these expected 
effects will not occur. Tolerance to organic nitrates develops in the 
presence of nitrate therapy lasting 24 hours or longer. The result is 
a lack of response to subsequent doses of nitrates. This tolerance 
dissipates rapidly in the absence of organic nitrates and can 
therefore be avoided by daily pauses in nitrate therapy. 
In contrast, tachyphylaxis develops rapidly after initial 
administration of a drug. It may occur within minutes to 
hours of administration. A key characteristic of tachyphylaxis 
is diminishing response to the medication despite increased 
doses. Eventually, there may be no noticeable response to the 
medication. Tachyphylaxis after administration of intravenous 
nitroglycerin is rare, and the cause is unknown. It is possible 
that tachyphylaxis is caused by similar mechanisms proposed for 
tolerance to organic nitrates but in an accelerated timeframe. Or 
nitroglycerin tachyphylaxis may be due to something completely 
different. Regardless, tachyphylaxis is by nature unexpected. 
Therefore, the primary goal for anesthesia providers is to be 
prepared at all times with an alternative treatment for the patient, 
should the initial treatment fail. Current literature indicates that 
clevidipine is a good alternative in this situation.  
NEW TREATMENTS TO INDUCE HYPOTENSION
Clevidipine is a dihydropyridine, L-type, vasoselective calcium 
channel blocker. Due to this composition, clevidipine blocks 
intracellular calcium influx in arterial vasculature only, not in 

veins. Therefore, administration of clevidipine leads to decreased 
systemic vascular resistance, decreased BP, and increased stroke 
volume. These effects allow for a decrease in myocardial oxygen 
demand. Unlike nitroglycerin, venous beds are not dilated, and 
so venous return and preload remain constant, allowing for 
maintenance of cardiac output.
Clevidipine has a rapid onset and produces effects within 1 
minute. Termination of clevidipine action is also rapid. Plasma 
esterases hydrolyze clevidipine, and the effects are almost 
completely terminated within 5 minutes. The metabolites 
produced by ester hydrolysis are most likely excreted via biliary 
and intestinal tracts. Because metabolism remains independent 
from both renal and liver function, clevidipine can be 
administered to patients with renal or liver impairment. This ester 
hydrolysis metabolism is dependent on the temperature of the 
patient’s body, however. The deliberate hypothermia used during 
CPB reduces the metabolism of clevidipine to just half of the 
regular rate of metabolism.
Clevidipine is prepared as a lipid emulsion in soybean oil. At 
steady state, the volume of distribution is 0.6 L/kg. Clevidipine 
is also highly protein bound. It has been found to help reduce 
ischemia in renal, splanchnic, and myocardial tissues during 
reperfusion. No tolerance to clevidipine has been reported in the 
published literature to date.
SUMMARY
Overall, nitroglycerin and clevidipine have many similarities: 
protection against reperfusion injury, rapid onset and offset, and 
decreased BP. However, the mechanism of action of each of these 
drugs is distinct and is the basis of therapeutic decisions in the 
clinical setting. Of these 2 drugs, nitroglycerin administration is 
most likely to result in adverse hemodynamics or tolerance and 
lack of effectiveness. Therefore, while nitroglycerin is still useful 
during cardiovascular procedures, clevidipine must also be readily 
available.



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Volume 7 - No. 2 2019 Page 8

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