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A Random-Allocation Graded Dose–Response Study of Norepinephrine and Phenylephrine for Treating Hypotension During Spinal Anesthesia for Cesarean Delivery

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A Random-Allocation Graded Dose–Response Study of Norepinephrine and Phenylephrine for Treating Hypotension During Spinal Anesthesia for Cesarean Delivery A Random-allocation Graded Dose–Response Study of Norepinephrine and Phenylephrine for Treating Hypotension during Spinal Anesthesia for Cesarean Delivery Warwick D. Ngan Kee, M.D., F.A.N.Z.C.A., F.H.K.A.M. ABSTRACT Background: Norepinephrine has been investigated as a potential alterative to phenylephrine for maintaining blood pressure during spinal anesthesia for cesarean delivery with the advantage of less depression of maternal heart rate and cardiac output. Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/127/6/934/380248/20171200_0-00010.pdf by guest on 03 October 2021 However, the relative potencies of these two vasopressors have not been fully determined in this context. Methods: In a random-allocation, graded dose–response study, 180 healthy patients undergoing spinal anesthesia for elective cesarean delivery received a single bolus of norepinephrine in one of six different doses ranging from 4 to 12 µg or phenyl- ephrine in one of six different doses ranging from 60 to 200 µg to treat the first episode of hypotension. The magnitude of response was measured as the percentage of full restoration of systolic blood pressure to the baseline value. Dose–response analysis was performed using nonlinear regression to derive four-parameter logistic dose–response curves, which were com- pared to determine relative potency. Results: Data were analyzed for 180 patients. The estimated ED50 values (dose giving a 50% response) were norepinephrine 10 µg (95% CI, 6 to 17 µg) and phenylephrine 137 µg (95% CI, 79 to 236 µg). The estimated relative potency ratio for the two drugs was 13.1 µg (95% CI, 10.4 to 15.8 µg). Conclusions: Comparative dose–response analysis was completed for norepinephrine and phenylephrine given as a bolus to treat the first episode of hypotension in patients undergoing spinal anesthesia for cesarean delivery. The estimated dose equiva- lent to phenylephrine 100 µg was norepinephrine 8 µg (95% CI, 6 to 10 µg). These results may be useful to inform the design of future comparative studies. (ANESTHESIOLOGY 2017; 127:934-41) URRENTLY phenylephrine is established as a pre- C ferred first-line vasopressor for maintaining blood What We Already Know about This Topic pressure (BP) during spinal anesthesia for cesarean delivery.1 • Norepinephrine is suggested as an alternative to phenylephrine However, because phenylephrine at usual clinical doses is a for maintaining blood pressure during spinal anesthesia for cesarean delivery pure vasoconstrictor, its use is often associated with a reflex • Although a recent dose-finding study reported 6 µg decrease in heart rate (HR) and an associated decrease in norepinephrine bolus injection effective for the purpose, the cardiac output (CO).2 As a result, this has encouraged the relative potencies of these two vasopressors have not been fully determined investigation of alternative agents such as dilute norepineph- rine.3–5 Norepinephrine is similar to phenylephrine in being What This Article Tells Us That Is New a potent α-adrenergic agonist, but in addition norepineph- • In this random-allocation, graded dose–response study, the rine also possesses weak β-adrenergic agonist activity. The relative potencies of the vasopressors were assessed by the latter counteracts the reflex slowing of HR, which poten- proportion of full restoration of systolic blood pressure to the baseline in response to a bolus injection of one of six different tially may result in a more stable hemodynamic profile when doses of the vasopressors in 180 healthy patients undergoing norepinephrine is used to maintain BP during neuraxial spinal anesthesia for elective cesarean delivery anesthesia. • The estimated dose equivalent to phenylephrine 100 µg was norepinephrine 7.6 µg (95% CI, 6.3 to 9.6 µg) To determine the possible utility of norepinephrine as a suitable vasopressor in obstetric patients, comparison with the current standard, phenylephrine, is appropriate. of the relative potencies of norepinephrine and phenyleph- Although a number of such comparisons have been pub- rine in obstetric patients is required. Therefore, the author lished recently, the relative doses of norepinephrine and performed a random-allocation, graded dose–response study phenylephrine have varied.3–5 To facilitate accurate compari- of norepinephrine and phenylephrine. The aim of the study son and also to guide clinical administration, determination was to determine the relative potencies of these drugs when This article is featured in “This Month in Anesthesiology,” page 1A. This article has an audio podcast. Submitted for publication March 9, 2017. Accepted for publication August 10, 2017. From the Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China. Copyright © 2017, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved. Anesthesiology 2017; 127:934-41 Anesthesiology, V 127 • No 6 934 December 2017 Copyright © 2017, the American Society of Anesthesiologists,<zdoi;10.1097/ALN.0000000000001880> Inc. Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. PERIOPERATIVE MEDICINE given as a bolus to treat hypotension during spinal anesthesia episode of hypotension, the patient was given the study drug for cesarean delivery. as a rapid IV bolus via a three-way stopcock attached directly to the IV catheter, followed immediately by a 1-ml saline Materials and Methods flush. If a patient did not have an episode of hypotension This randomized, double-blinded study was approved by the before the time of uterine incision, she was excluded from Joint Chinese University of Hong Kong–New Territories East the study, and the randomization code was reused for the Cluster Clinical Research Ethics Committee (Shatin, Hong next consecutive patient enrolled. Kong, China) and was registered in the Chinese Clinical The study drugs were prepared by a research nurse who Trial Registry (registration No. ChiCTR-TRC-14005206). was not involved with patient management or study data All of the patients gave written informed consent to partici- collection. Block randomization was performed in groups of pate. The study was conducted in the operating rooms in the 12 using shuffled, opaque numbered envelopes. Each patient Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/127/6/934/380248/20171200_0-00010.pdf by guest on 03 October 2021 labor ward of a university-affiliated teaching hospital. received a single IV bolus of either norepinephrine at a dose Patients scheduled for routine elective cesarean delivery of 4, 5, 6, 8, 10, or 12 µg or phenylephrine at a dose of 60, under spinal anesthesia were enrolled. Inclusion criteria were 80, 100, 120, 160, or 200 µg. The doses of phenylephrine nonlaboring, normotensive parturients with term singleton were chosen to cover the approximate usual range of doses pregnancy with baseline systolic BP within the range 90 to used clinically, with dose sizes chosen so that their logarithms 140 mmHg. Exclusion criteria were American Society of were approximately evenly spaced, with doses rounded to Anesthesiologists physical status of 3 or higher, known fetal convenient sizes for ease of preparation. The doses of nor- abnormality, preexisting or pregnancy-induced hypertension, epinephrine were chosen to be approximately equivalent to known cardiovascular or cerebrovascular disease, thrombo- the doses of phenylephrine based on an estimated potency cytopenia, coagulopathy, any medical contraindication to ratio of 16:1 for norepinephrine:phenylephrine; this esti- spinal anesthesia, known allergy to phenylephrine or nor- mated ratio was our best approximation according to data epinephrine, weight less than 50 kg or greater than 100 kg, from a previous study.3 All of the study drugs were prepared height less than 140 cm or greater than 180 cm, inability or by a research nurse in identical 10-ml syringes that were refusal to give informed consent, and age less than 18 yr. each labeled study drug and were diluted to a total volume After routine fasting and antacid premedication, patients of 10 ml with saline. The investigator who administered the were transferred to the operating room and routine moni- study drug was blinded to the group allocation. toring was attached. BP was recorded noninvasively on the After injection of the study drug, the BP monitor cycle right arm using the standard monitor (Infinity C500, Dräger was stopped. BP measurement was restarted 60 s after the Medical AG & Co., Germany) set to cycle at 1-min inter- completion of injection of the study drug. The first BP vals. Baseline systolic BP and HR were determined as the measurement at that time was recorded and used to derive mean of three consecutive measurements with a difference response data. Response was defined according to the follow- of not more than 10%. A wide-bore intravenous catheter ing equation: (default size 16-gauge) was inserted under local anesthesia CB− in the left forearm or hand. Patients were then turned to Response = × 100% (1) AB− the right lateral position and, after skin disinfection and skin infiltration with lidocaine, a 25-gauge Whitacre spi- where A = baseline systolic BP, B = systolic BP at first episode nal needle was inserted via an introducer at the estimated of hypotension, and C = systolic BP of the measurement L3 to 4 or L4 to 5 vertebral interspace. Eleven milligrams started 60 s after injection of the study drug. The decision to hyperbaric bupivacaine 0.5% w/v and 15 µg fentanyl were assess BP response 60 s after vasopressor injection was based injected intrathecally, after which the patient was turned to on previous work that showed that the peak pressor effect of the supine position with left lateral tilt, and rapid intrave- phenylephrine occurred between 32 and 47 s after central nous (IV) cohydration up to 2 l was started using Plasma- venous injection.6 Lyte-A solution (Baxter Healthcare Corporation, USA) by After completion of the response measurement, the study fully opening the IV fluid-giving set with the bag suspended was terminated.
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