Clevidipine Controls Intraoperative Blood Pressure In an Adolescent with Renal Failure

Abstract

In pediatric-aged patients, various factors may result in perioperative hypertension including renal failure or insufficiency, volume overload, or other factors that activate the sympathetic nervous system including pain and agitation. Perioperative blood pressure control may be even more difficult to achieve and maintain in patients with pre-existing hypertension. We present a 16-year-old adolescent with renal failure and hypertension who presented for anesthetic care during placement of a peritoneal dialysis catheter. Perioperative blood pressure control was achieved with the administration of clevidipine, an ultra-short acting calcium channel antagonist of the dihydropyridine class. Its role in the perioperative control of blood pressure is discussed.

INTRODUCTION

Various factors may result in perioperative hypertension in the pediatric-aged patient including renal failure or insufficiency, volume overload, or other factors that activate the sympathetic nervous system including pain and agitation. Perioperative blood pressure (BP) control may be even more difficult in patients with preexisting hypertension.¹ Even with an adequate depth of anesthesia, hemodynamic responses accompanied by hypertension may occur with these responses being exaggerated in patients with pre-existing hypertension.^1,2 During the perioperative period, there are several options for rapid BP control including the intravenous administration of sodium nitroprusside, labetolol, nicardipine, and hydralazine.³ Clevidipine (Cleviprex, The Medicines Company, Parsippany, NJ) is an ultra-short-acting, intravenous calcium channel antagonist that belongs to the dihydropyridine class. It undergoes rapid metabolism by non-specific blood and tissue esterases with a half-life of 1–3 minutes.⁴ Initial reports in the adult population have demonstrated an efficacy that parallels that of sodium nitroprusside, but with an improved adverse effect profile.^5–7 To date, there are no reports of its use in infants, children or adolescents. We present our experience with the perioperative control of blood pressure in an adolescent with renal failure and hypertension who required intraoperative care for placement of a peritoneal dialysis catheter.

CASE REPORT

Review of this patient's medical records and presentation of this information as a case report were approved by the Institutional Review Board of the University of Missouri. The patient was a 16-year-old (57 kg) with a history of hemolytic uremic syndrome at 14 months of age. Initially, he required temporary peritoneal dialysis, but had recovered adequate renal function and was not dialysis dependent. He presented to our institution with decreased urine output, edema, and hypertension. Initial evaluation revealed a markedly elevated blood urea nitrogen (BUN) and serum creatinine. Intermittent hemodialysis was instituted through a percutaneous dialysis catheter that was placed in the right femoral vein. With hemodialysis, his weight had decreased to its baseline value and there were no signs of peripheral edema. His current antihypertensive therapy included oral amlodipine (5 mg every morning) and labetolol (180 mg every 12 hours). With this regimen, his BP had ranged from 130–150/85–100 mmHg (mean arterial pressure or MAP of 110–117 mmHg).

The morning of surgery, the patient arrived in the preoperative holding area and had not received his morning antihypertensive medications as surgery was scheduled prior to their administration time of 9 AM. His BP was 162/108 mmHg (MAP 127 mmHg). His physical examination was otherwise unremarkable. Laboratory evaluation revealed a hemoglobin of 8.8 gm/dL, hematocrit of 25%, and a platelet count of 153,000/mm³. The BUN was 53 mg/dL and the serum creatinine was 7.2 mg/dL. The serum electrolytes were within normal limits.

He was premedicated with intravenous midazolam (2 mg) and transported to the operating room, where routine monitors were placed. The initial BP in the operating room was 158/107 mmHg (MAP 124 mmHg) with a heart rate (HR) of 88 beats/minute. Clevidipine was started at 1 μg/kg/min. Within 3–4 minutes of administration there was a reduction in BP to 117/66 (MAP 83 mmHg) and no change in HR (86 beats/minute). He was preoxygenated with 100% oxygen followed by anesthetic induction with lidocaine (60 mg), propofol (100 mg), fentanyl (100 μg), and sevoflurane (inspired concentration of 2–4%). Endotracheal intubation was facilitated by cisatracurium (8 mg). Following endotracheal intubation, his BP was 124/79 mmHg (MAP 94 mmHg) and the HR was 90 beats/minute. The clevidipine infusion was decreased to 0.5 μg/kg/min.

The surgical procedure included placement of a peritoneal dialysis catheter, which was tunneled to the pre-sternal area, and repair of a right inguinal hernia, which was found during the procedure. Intraoperative maintenance anesthesia consisted of desflurane (expired concentration of 3–5% to maintain an adequate depth of anesthesia as judged by the bispectral index) and hydromorphone (0.2 mg). The clevidipine infusion was continued at 0.5 μg/kg/min and his systolic (100–115 mmHg) and diastolic (50–70 mmHg) (MAP 67–85 mmHg) blood pressures were controlled. During the surgical procedure the HR ranged from 75 to 90 beats/minute. Blood loss was less than 10 mL and fluid administered was 150 mL of normal saline. At the completion of the surgical procedure, the patient's trachea was extubated. His BP increased to 120–130/90–100 mmHg (MAP 100–110 mmHg) and the clevidipine infusion was increased to 1 μg/kg/min and then to 2 μg/kg/min on arrival in the post-anesthesia care unit (PACU) as his BP was 144/105 mmHg (MAP 118 mmHg). Within 3–5 minutes, his BP had decreased to 100–120/70–85 mmHg (MAP 80–97 mmHg).

In the PACU, his usual morning dose of amlodipine was administered and 30–45 minutes later, the clevidipine infusion was decreased in 0.25 μg/kg/min increments every 10 minutes until it was discontinued over 60 minutes. No further hypertension was noted. He was discharged to the inpatient ward and the remainder of his perioperative course was uneventful.

DISCUSSION

We found that clevidipine provided rapid and effective perioperative blood pressure control without causing adverse effects. Although the continuation of oral antihypertensive agents is generally suggested, our patient did not receive his usual morning doses, which were scheduled at a time after his arrival in the operating room; hence, his blood pressure was elevated upon arrival in the preoperative holding area. Given the need to proceed with his surgical procedure, we felt that the optimal path would be to use a rapidly acting intravenous agent to control his blood pressure perioperatively followed by the reinstitution of oral therapy at the completion of the procedure. Additionally, it is currently recommended that specific agents (e.g., angiotensin converting enzyme inhibitors; angiotensin receptor blocking agents) be held prior to surgery. This is important given the potential of these agents to cause profound intraoperative hypotension, which may be refractory to treatment with conventionally used α-adrenergic agonists such as phenylephrine.^8,9 Therefore, in several different scenarios, intravenous agents may be necessary for the perioperative control of blood pressure. Given that our patient's blood pressure had been under adequate control with his chronic oral medications, we felt that clevidipine could be used to achieve a normal blood pressure for age. In patients with chronic hypertension, the abrupt return of blood pressure to the normal range is not recommended given the potential to induce cerebral hypoperfusion in the setting of altered regulation of cerebral blood flow.

There are several potential options for the perioperative control of BP in the pediatric-aged patient. The most commonly used agents include sodium nitroprusside (SNP), labetolol, and nicardipine.³ SNP is a direct-acting, non-selective peripheral vasodilator that dilates resistance vessels to decrease systemic vascular resistance in addition to dilating capacitance vessels thereby also decreasing preload. It has a rapid onset of action (approximately 30 seconds) with a rapid peak hypotensive effect (within 2 minutes). These properties allow its easy titration by continuous intravenous infusion for the control of blood pressure. With the discontinuation of the infusion, there is a rapid return of blood pressure to baseline values generally within minutes. Despite its uniform efficacy in blood pressure control, its adverse effect profile may be problematic including the potential for excessive hypotension even when used within currently recommended dosing guidelines or even cardiovascular collapse should there be inadvertent overdosing, reflex tachycardia, activation of the sympathetic nervous system, rebound hypertension when the infusion is discontinued, tachyphylaxis with prolonged use, and potential issues regarding cyanide and thiocyanate toxicity especially in the setting of renal failure or insufficiency. The potential for hypotension mandates intra-arterial monitoring of blood pressure with its administration.

Labetolol is a competitive antagonist of the α₁, β₁, and β₂-adrenergic receptors. With intravenous administration, the initial blood pressure effects can be seen within 2–5 minutes with a peak effect at 5–15 minutes. However, it has a relatively prolonged duration of action of 2–4 hours. Adverse effects may also be seen related to blockade of the β-adrenergic receptors including bradycardia, heart block, and bronchospasm. Furthermore, it is contraindicated in patients with depressed left ventricular function.

Nicardipine is a calcium channel antagonist of the dihyropyridine group that vasodilates the systemic, cerebral and coronary vasculature with limited effects on myocardial contractility and stroke volume. Several case series have demonstrated that nicardipine is an effective agent for the control of blood pressure in infants and children in many clinical scenarios including the perioperative period.^3,10 Although its adverse effect profile, especially the risk of excessive hypotension, is limited; its duration of action may be prolonged following a continuous infusion.

Clevidipine is an ultra-shorting acting, intravenous calcium channel antagonist of the dihydropyridine class which is metabolized by non-specific blood and tissue esterases. When compared with placebo in a prospective, randomized trial of 152 adult cardiac surgery patients, clevidipine provided effective blood pressure control in 92.5% of patients compared to a failure rate of 82.7% in placebo-treated patients.⁵ Target blood pressure control (reduction of systolic blood pressure by ≥ 15%) was achieved at a median time of 6 minutes (95% confidence interval of 6–8 minutes). There was a modest increase in heart rate from a median baseline of 71 beats per minute to a maximum value of 84 beats per minute. There were no differences between clevidipine and placebo in regards to the adverse effect profile.

When comparing clevidipine with SNP, nitroglycerin or nicardipine in a randomized, prospective evaluation of the treatment of acute hypertension in adult cardiac surgery patients, Aronson et al. reported no difference in the incidence of stroke, myocardial infarction or renal dysfunction among the treatment groups.⁶ Blood pressure control was more effective with clevidipine when compared with nitroglycerin (p=0.0006) or SNP (p=0.003). When compared with SNP, mortality was lower in patients receiving clevidipine (p=0.04, p=NS compared to nicardipine or nitroglycerin). Prowroznyk et al. compared SNP with clevidipine for blood pressure control following coronary artery surgery and found an equal efficacy between the two agents.⁷ However, hemodynamic changes including tachycardia and decreases in stroke volume were less with clevidipine.

In our patient, we found that clevidipine in doses ranging from 0.5–2 μg/kg/minute effectively controlled perioperative blood pressure without excessive hypotension even during anesthetic induction. Given its short half-life, it can be rapidly titrated to achieve blood pressure control even during the perioperative period when changing levels of sympathetic stimulation related to pain or the surgical procedure may occur.

Our preliminary experience suggests that clevidipine may be an effective agent for the rapid control of blood pressure during hypertensive urgencies and emergencies. As with other calcium channel antagonists, there is a potential for adverse effects with clevidipine including excessive hypotension, effects on cardiac conduction, and negative inotropic effects. Should inadvertent hypotension occur, its short duration of action offers an additional advantage over nicardipine. The preliminary clinical data have demonstrated a limited effect on preload and cardiac output as well as only a mild increase in heart rate. Additionally, in an animal model of ischemic renal failure, it has been shown to preserve renal function.¹¹

Clevidipine is supplied in 50 or 100 mL vials in a concentration of 0.5 mg/mL. Because of solubility issues, it is provided in a lipid solution and is contraindicated in patients with allergy to eggs, egg products, soy beans or soy products as well as disorders of lipid metabolism. Although pricing varies according to region and supplier, the 100 mL vial is approximately $145. In the initial report in the adult populations, the dosing regimen included a starting dose of 0.4 μg/kg/min with the dose doubled every 90 seconds until the desired effect was achieved or up to a maximum dose of 8 μg/kg/min.⁶ However, the maximum end of the dosing range was allowed for only 2 hours. Given its efficacy in the adult population, future trials in pediatric-aged patients appear warranted. However, it must be recognized that clevidipine currently does not hold FDA-approval for use in the pediatric-aged patient.

ABBREVIATIONS

BP

blood pressure

BUN

blood urea nitrogen

HR

heart rate

PACU

post-anesthesia care unit

SNP

sodium nitroprusside