JPPT Clinical Investigation A Prospective, Open-Label Trial of Clevidipine for Controlled Hypotension During Posterior Spinal Fusion Hiromi Kako, MD,1,2 Andrew Gable, BA,1 David Martin, MD,1,2 Allan Beebe, MD,3 Arlyne Thung, MD,1,2 Walter Samora, MD,3 Jan Klamar, MD,3 Tarun Bhalla, MD,1,2 and Joseph D. Tobias, MD1,2,4 1 Department of Anesthesiology & Pain Medicine, Nationwide Children’s Hospital, Columbus, Ohio, 2Department of Anesthesiology & Pain Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, 3Departments of Orthopedic Surgery and 4Pediatrics, Nationwide Children’s Hospital and the Ohio State University Wexner Medical Center, Columbus, Ohio
OBJECTIVES: Controlled hypotension is one means to limit or avoid the need for allogeneic blood products. Clevidipine is a short-acting, intravenous calcium channel antagonist with a half-life of 1 to 3 minutes due to rapid metabolism by non-specific blood and tissue esterases. To date, there are no prospective evaluations with clevidipine in the pediatric population. We prospectively evaluated the dosing requirements, efficacy, and safety of clevidipine for ontrolled hypotension during spinal surgery for neuromuscular scoliosis in the pediatric population. METHODS: Patients undergoing posterior spinal fusion for neuromuscular scoliosis were eligible for inclusion. The study was an open label, observational study. Maintenance anesthesia included desflurane titrated to maintain a bispectral index at 40 to 60 and a remifentanil infusion. Motor and somatosensory evoked potentials were monitored intraoperatively. When the mean arterial pressure (MAP) was ≥ 65 mmHg despite remifentanil at 0.3 mcg/kg/min, clevidipine was added to maintain the MAP at 55 to 65 mmHg. Clevidipine was initiated at 0.25 to 1 mcg/kg/min and titrated up in increments of 0.25 to 1 mcg/kg/min every 3 to 5 minutes to achieve the desired MAP. RESULTS: The study cohort included 45 patients. Fifteen patients (33.3%) did not require a clevidipine infusion to maintain the desired MAP range, leaving 30 patients including 13 males and 17 females for analysis. These patients ranged in age from 7.9 to 17.4 years (mean ± SD: 13.7 ± 2.2 years) and in weight from 18.9 to 78.1 kg (mean ± SD: 43.4 ± 14.2 kg). Intraoperatively, the clevidipine infusion was stopped in 6 patients as the surgeon expressed concerns regarding spinal cord perfusion and requested a higher MAP than the study protocol allowed. The data until that point were included for analysis. The target MAP was initially achieved at a mean time of 8.9 minutes. Sixteen of the 30 patients (53.3%) achieved the target MAP within 5 minutes. Heart rate (HR) increased from a baseline of 83 ± 16 to 86 ± 15 beats per minute (mean ± SD) (p=0.04) with the administration of clevidipine. No patient had a HR increase ≥ 20 beats per minute or required the administration of a β-adrenergic antagonist. The duration of the clevidipine administration varied from 8 to 527 minutes (mean ± SD: 160 ± 123 minutes). The maintenance infusion rate of clevidipine varied from 0.25 to 5.0 mcg/kg/min (mean ± SD: 1.4 ± 1.1 mcg/kg/min). Clevidipine was paused a total of 43 times in the 30 cases. In 18 of the 30 patients (60%), the clevidipine infusion was temporarily paused more than once due to a MAP < 55 mmHg. A fluid bolus was administered to only 1 patient to treat the low MAP. No patient required the administration of a vasoactive agent for hypotension. When the clevidipine infusion was discontinued as controlled hypotension was no longer required, the MAP returned to baseline or ≥ 65 mmHg within 10 minutes in 12 of the 30 patients (40%). CONCLUSIONS: Clevidipine can be used to provide controlled hypotension during posterior spinal fusion. The response of the MAP, both the onset and duration of action, were rapid. Although titration of the infusion with occasional pauses of administration may be needed, excessive hypotension was not noted. INDEX TERMS: clevidipine, controlled, hypotension, orthopedic surgery, spinal fusion J Pediatr Pharmacol Ther 2015;20(1):54–60
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J Pediatr Pharmacol Ther 2015 Vol. 20 No. 1 • www.jppt.org
JPPT
Clevidipine for Controlled Hypotension
INTRODUCTION
METHODS
Various techniques have been suggested as a means of limiting or avoiding the need for allogeneic blood transfusions during major orthopedic surgical procedures.1–6 Controlled hypotension is 1 technique that involves the use of pharmacological agents to lower the mean arterial pressure (MAP) to 50 to 65 mmHg.1,2,4–6 Despite the availability of several different agents to provide controlled hypotension including direct-acting vasodilators (sodium nitroprusside, nitroglycerin), calcium channel antagonists (nicardipine), β-adrenergic antagonists, ganglion blocking agents, and the inhalational anesthetic agents, none has gained universal use.4–6 Sodium nitroprusside can result in profound hypotension and is frequently associated with rebound tachycardia, which may require the addition of a second agent such as propranolol or esmolol. The calcium channel antagonist, nicardipine, which dilates primarily the arterial side of the vasculature, offers the advantage of less rebound tachycardia and a lower incidence of excessive hypotension.4,5,7–10 However, given its longer halflife, titration may be slower than a rapid-acting agent like sodium nitroprusside. Additionally, the duration of action is markedly longer thereby being problematic should inadvertent hypotension occur. Clevidipine (Cleviprex, The Medicines Company, Parsippany, NJ) is a short-acting, intravenous calcium channel antagonist with a half-life of 1 to 3 minutes due to rapid metabolism by non-specific blood and tissue esterases. It is currently approved by the Food and Drug Administration for the reduction of blood pressure (BP) in adults when oral therapy is not feasible or desirable. The majority of experience with this novel agent has been in the control of perioperative BP in adults.11,12 Preliminary data have also demonstrated the safety and efficacy of clevidipine in the pediatric population following cardiac surgery for congenital heart disease, as well as controlled hypotension during spinal surgery.13–15 To date, there are no prospective evaluations with the use of clevidipine in the pediatric population. The current study prospectively evaluates the dosing requirements, efficacy, and adverse effect profile of clevidipine for controlled hypotension during spinal surgery in the pediatric population.
This study was an open label, observational study in a single institution (Nationwide Children’s, Columbus, OH) to assess the effects of clevidipine to control BP and provide controlled hypotension during posterior spinal fusion. The study was approved by the Institutional Review Board of Nationwide Children’s, Columbus, Ohio (IRB12-00261), which waived requirements for informed consent due to the observational nature of the study, no significant change in our current practice, and no additional risk to the patient. The study was registered at ClinicalTrials.gov (NCT01645111). Patients less than 18 years of age undergoing posterior spinal fusion for neuromuscular scoliosis in which controlled hypotension was planned for the operative care were eligible for inclusion. Patients with idiopathic scoliosis were excluded from the current study because they were included in another ongoing study. There was no change in the standard and usual anesthetic care including premedication, anesthetic induction, intraoperative anesthetic management, and intraoperative monitoring. All patients were held nil per os according to guidelines of the American Society of Anesthesiologists (ASA). Premedication with oral or intravenous midazolam was administered based on the clinical needs of the patient. The patient was brought to the operating room and standard ASA monitors were applied. Anesthesia was induced with inhalational or intravenous agents based on the preference of the patient. Endotracheal intubation was facilitated with a single dose of rocuronium (0.3 mg-0.4 mg/kg). For each case, there were 2 large bore peripheral intravenous cannulae and an arterial cannula. Motor and somatosensory evoked potentials were monitored intraoperatively in all cases. Maintenance of anesthesia was based on our usual practice for these cases as has been previously reported.16 The technique included desflurane titrated to maintain a bispectral index at 40 to 60 and fentanyl 2 to 4 mcg/kg followed by a remifentanil infusion to maintain the MAP at 55 to 65 mmHg. Additional techniques to limit the need for allogeneic blood products included tranexamic acid and intraoperative blood salvage. If the MAP was ≥ 65 mmHg despite a remifentanil infusion at 0.3 mcg/kg/min, clevidipine was
J Pediatr Pharmacol Ther 2015 Vol. 20 No. 1 • www.jppt.org
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H Kako, et al
added to maintain the MAP at 55 to 65 mmHg. Clevidipine was initiated at 0.25 to 1 mcg/kg/min and titrated up in increments of 0.25 to 1 mcg/kg/ min every 3 to 5 minutes to achieve the desired MAP. Vital signs including heart rate (HR) and BP were recorded on the data sheet when clevidipine was started, at the time that the target MAP was achieved, and then at 30-minute increments thereafter. Primary end points for the study were time to achieve the target MAP, overall efficacy of clevidipine (percentage of patients in which successful controlled hypotension was achieved), and dose required to provide controlled hypotension. Adverse effects attributable to clevidipine including excessive hypotension, the need to pause the clevidipine infusion, the need to administer a vasoactive agent, or the need to give a fluid bolus were recorded as safety end points. As this was an open label trial, there was no comparator group. However, the baseline HR was compared to subsequent HRs using an analysis of variance with p
OBJECTIVES: Controlled hypotension is one means to limit or avoid the need for allogeneic blood products. Clevidipine is a short-acting, intravenous calcium channel antagonist with a half-life of 1 to 3 minutes due to rapid metabolism by non-specific blood and tissue esterases. To date, there are no prospective evaluations with clevidipine in the pediatric population. We prospectively evaluated the dosing requirements, efficacy, and safety of clevidipine for ontrolled hypotension during spinal surgery for neuromuscular scoliosis in the pediatric population. METHODS: Patients undergoing posterior spinal fusion for neuromuscular scoliosis were eligible for inclusion. The study was an open label, observational study. Maintenance anesthesia included desflurane titrated to maintain a bispectral index at 40 to 60 and a remifentanil infusion. Motor and somatosensory evoked potentials were monitored intraoperatively. When the mean arterial pressure (MAP) was ≥ 65 mmHg despite remifentanil at 0.3 mcg/kg/min, clevidipine was added to maintain the MAP at 55 to 65 mmHg. Clevidipine was initiated at 0.25 to 1 mcg/kg/min and titrated up in increments of 0.25 to 1 mcg/kg/min every 3 to 5 minutes to achieve the desired MAP. RESULTS: The study cohort included 45 patients. Fifteen patients (33.3%) did not require a clevidipine infusion to maintain the desired MAP range, leaving 30 patients including 13 males and 17 females for analysis. These patients ranged in age from 7.9 to 17.4 years (mean ± SD: 13.7 ± 2.2 years) and in weight from 18.9 to 78.1 kg (mean ± SD: 43.4 ± 14.2 kg). Intraoperatively, the clevidipine infusion was stopped in 6 patients as the surgeon expressed concerns regarding spinal cord perfusion and requested a higher MAP than the study protocol allowed. The data until that point were included for analysis. The target MAP was initially achieved at a mean time of 8.9 minutes. Sixteen of the 30 patients (53.3%) achieved the target MAP within 5 minutes. Heart rate (HR) increased from a baseline of 83 ± 16 to 86 ± 15 beats per minute (mean ± SD) (p=0.04) with the administration of clevidipine. No patient had a HR increase ≥ 20 beats per minute or required the administration of a β-adrenergic antagonist. The duration of the clevidipine administration varied from 8 to 527 minutes (mean ± SD: 160 ± 123 minutes). The maintenance infusion rate of clevidipine varied from 0.25 to 5.0 mcg/kg/min (mean ± SD: 1.4 ± 1.1 mcg/kg/min). Clevidipine was paused a total of 43 times in the 30 cases. In 18 of the 30 patients (60%), the clevidipine infusion was temporarily paused more than once due to a MAP < 55 mmHg. A fluid bolus was administered to only 1 patient to treat the low MAP. No patient required the administration of a vasoactive agent for hypotension. When the clevidipine infusion was discontinued as controlled hypotension was no longer required, the MAP returned to baseline or ≥ 65 mmHg within 10 minutes in 12 of the 30 patients (40%). CONCLUSIONS: Clevidipine can be used to provide controlled hypotension during posterior spinal fusion. The response of the MAP, both the onset and duration of action, were rapid. Although titration of the infusion with occasional pauses of administration may be needed, excessive hypotension was not noted. INDEX TERMS: clevidipine, controlled, hypotension, orthopedic surgery, spinal fusion J Pediatr Pharmacol Ther 2015;20(1):54–60
54
J Pediatr Pharmacol Ther 2015 Vol. 20 No. 1 • www.jppt.org
JPPT
Clevidipine for Controlled Hypotension
INTRODUCTION
METHODS
Various techniques have been suggested as a means of limiting or avoiding the need for allogeneic blood transfusions during major orthopedic surgical procedures.1–6 Controlled hypotension is 1 technique that involves the use of pharmacological agents to lower the mean arterial pressure (MAP) to 50 to 65 mmHg.1,2,4–6 Despite the availability of several different agents to provide controlled hypotension including direct-acting vasodilators (sodium nitroprusside, nitroglycerin), calcium channel antagonists (nicardipine), β-adrenergic antagonists, ganglion blocking agents, and the inhalational anesthetic agents, none has gained universal use.4–6 Sodium nitroprusside can result in profound hypotension and is frequently associated with rebound tachycardia, which may require the addition of a second agent such as propranolol or esmolol. The calcium channel antagonist, nicardipine, which dilates primarily the arterial side of the vasculature, offers the advantage of less rebound tachycardia and a lower incidence of excessive hypotension.4,5,7–10 However, given its longer halflife, titration may be slower than a rapid-acting agent like sodium nitroprusside. Additionally, the duration of action is markedly longer thereby being problematic should inadvertent hypotension occur. Clevidipine (Cleviprex, The Medicines Company, Parsippany, NJ) is a short-acting, intravenous calcium channel antagonist with a half-life of 1 to 3 minutes due to rapid metabolism by non-specific blood and tissue esterases. It is currently approved by the Food and Drug Administration for the reduction of blood pressure (BP) in adults when oral therapy is not feasible or desirable. The majority of experience with this novel agent has been in the control of perioperative BP in adults.11,12 Preliminary data have also demonstrated the safety and efficacy of clevidipine in the pediatric population following cardiac surgery for congenital heart disease, as well as controlled hypotension during spinal surgery.13–15 To date, there are no prospective evaluations with the use of clevidipine in the pediatric population. The current study prospectively evaluates the dosing requirements, efficacy, and adverse effect profile of clevidipine for controlled hypotension during spinal surgery in the pediatric population.
This study was an open label, observational study in a single institution (Nationwide Children’s, Columbus, OH) to assess the effects of clevidipine to control BP and provide controlled hypotension during posterior spinal fusion. The study was approved by the Institutional Review Board of Nationwide Children’s, Columbus, Ohio (IRB12-00261), which waived requirements for informed consent due to the observational nature of the study, no significant change in our current practice, and no additional risk to the patient. The study was registered at ClinicalTrials.gov (NCT01645111). Patients less than 18 years of age undergoing posterior spinal fusion for neuromuscular scoliosis in which controlled hypotension was planned for the operative care were eligible for inclusion. Patients with idiopathic scoliosis were excluded from the current study because they were included in another ongoing study. There was no change in the standard and usual anesthetic care including premedication, anesthetic induction, intraoperative anesthetic management, and intraoperative monitoring. All patients were held nil per os according to guidelines of the American Society of Anesthesiologists (ASA). Premedication with oral or intravenous midazolam was administered based on the clinical needs of the patient. The patient was brought to the operating room and standard ASA monitors were applied. Anesthesia was induced with inhalational or intravenous agents based on the preference of the patient. Endotracheal intubation was facilitated with a single dose of rocuronium (0.3 mg-0.4 mg/kg). For each case, there were 2 large bore peripheral intravenous cannulae and an arterial cannula. Motor and somatosensory evoked potentials were monitored intraoperatively in all cases. Maintenance of anesthesia was based on our usual practice for these cases as has been previously reported.16 The technique included desflurane titrated to maintain a bispectral index at 40 to 60 and fentanyl 2 to 4 mcg/kg followed by a remifentanil infusion to maintain the MAP at 55 to 65 mmHg. Additional techniques to limit the need for allogeneic blood products included tranexamic acid and intraoperative blood salvage. If the MAP was ≥ 65 mmHg despite a remifentanil infusion at 0.3 mcg/kg/min, clevidipine was
J Pediatr Pharmacol Ther 2015 Vol. 20 No. 1 • www.jppt.org
55
JPPT
H Kako, et al
added to maintain the MAP at 55 to 65 mmHg. Clevidipine was initiated at 0.25 to 1 mcg/kg/min and titrated up in increments of 0.25 to 1 mcg/kg/ min every 3 to 5 minutes to achieve the desired MAP. Vital signs including heart rate (HR) and BP were recorded on the data sheet when clevidipine was started, at the time that the target MAP was achieved, and then at 30-minute increments thereafter. Primary end points for the study were time to achieve the target MAP, overall efficacy of clevidipine (percentage of patients in which successful controlled hypotension was achieved), and dose required to provide controlled hypotension. Adverse effects attributable to clevidipine including excessive hypotension, the need to pause the clevidipine infusion, the need to administer a vasoactive agent, or the need to give a fluid bolus were recorded as safety end points. As this was an open label trial, there was no comparator group. However, the baseline HR was compared to subsequent HRs using an analysis of variance with p
