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Year : 2015  |  Volume : 8  |  Issue : 3  |  Page : 424-428

Norepinephrine versus ephedrine for the prevention of spinal anesthesia-induced hypotension in coronary artery disease patients undergoing knee arthroscopy

Department of Anaesthesiology and Intensive Care, Ain-Shams University, Cairo, Egypt

Date of Submission04-Apr-2015
Date of Acceptance03-May-2015
Date of Web Publication29-Jul-2015

Correspondence Address:
Dalia M El Fawy
Department of Anaesthesiology and Intensive Care, Ain-Shams University, Cairo
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1687-7934.161723

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Spinal anesthesia, a popular technique used for lower limb surgery in coronary artery disease patients, could be associated with hypotension, which could be managed with colloids, vasopressor, ephedrine, or norepinephrine (NE).
The aim of this study was to assess the efficacy and safety of bolus administration of NE versus ephedrine for the maintenance of systolic blood pressure during spinal anesthesia in coronary artery disease patients undergoing knee arthroscopy.
Patients and methods
A randomized, controlled, double-blinded study was carried out on 100 ASA II or III coronary artery disease patients undergoing knee arthroscopy. The patients were divided into two groups of 50 patients each: the ephedrine group (group EPH) and the norepinephrine group (group NE). When hypotension occurred, group EPH received 5 mg of ephedrine and group NE received 5 μg of NE. Systolic blood pressure and heart rate were recorded at 0, 5, 10, 15, 30, and 60 min, and side effects of both drugs were also recorded.
Efficacy was found in 20 (40%) patients of group EPH and in 40 (80%) patients of group NE. The results were highly significant (P < 0.0001). Tachycardia was significantly higher (P < 0.0001) in group EPH. The incidence of hypotension, hypertension, and bradycardia was not significantly different between the two groups.
NE is more effective compared with ephedrine in the maintenance of systolic blood pressure with reduction in heart rate, which is useful in coronary artery disease patients undergoing knee arthroscopy under spinal anesthesia in whom tachycardia is undesirable.

Keywords: coronary artery disease, ephedrine, hypotension, knee arthroscopy, norepinephrine, spinal anesthesia

How to cite this article:
El Shafei MM, El Gendy HA, El Fawy DM. Norepinephrine versus ephedrine for the prevention of spinal anesthesia-induced hypotension in coronary artery disease patients undergoing knee arthroscopy. Ain-Shams J Anaesthesiol 2015;8:424-8

How to cite this URL:
El Shafei MM, El Gendy HA, El Fawy DM. Norepinephrine versus ephedrine for the prevention of spinal anesthesia-induced hypotension in coronary artery disease patients undergoing knee arthroscopy. Ain-Shams J Anaesthesiol [serial online] 2015 [cited 2022 Nov 27];8:424-8. Available from:

  Introduction Top

Spinal anesthesia is used as a safe method in cardiac patients because of hemodynamic benefits, compared with general anesthesia, such as minimum decrease in myocardial contractility and only modest decreases in blood pressure and cardiac output [1] . Ischemic heart disease is an independent risk factor for perioperative morbidity and mortality in patients undergoing noncardiac surgery [2] . Perioperative hypotension after neuroaxial block is common requiring the administration of vasoactive drugs [3] . Ephedrine, the most commonly used vasoactive agent, increases arterial pressure by direct and indirect activations of a and b adrenoreceptors and has the disadvantage of causing tachycardia because of its strong affinity to β1 receptors [4] . Norepinephrine (NE) is a direct-acting sympathomimetic producing profound α-adrenergic receptor activity and is approved in maintaining the systemic vascular tone and managing perioperative hypotension [5],[6] . Physiologically, direct actions of β1-adrenergic stimulation of NE may increase heart rate (HR), but HR is maintained because of an overall neutral state due to reflex bradycardia by α-adrenergic stimulation, which may be advantageous in cardiac patients in whom tachycardia is undesirable [6] . We planned this study to compare the safety and efficacy of NE with ephedrine for the prevention of spinal anesthesia-induced hypotension in coronary artery disease patients undergoing knee arthroscopy.

  Patients and methods Top

After the protocol was approved by our institution review board (IRB) and patients gave informed written consent, 100 patients with American Society of Anesthesiologists (ASA) physical status II or III, between 40 and 60 years of age, who had known coronary artery disease were included in our study to receive spinal anesthesia for knee arthroscopy in Ain Shams University Hospitals during the period from January 2014 to January 2015. In this randomized, parallel, prospective, double-blinded study, patients were randomized - by using a computer generated randomization list and opening sequentially numbered opaque envelopes immediately before entering the operating room - into one of the two groups: the ephedrine group (group EPH, n = 50) and the norepinephrine group (group NE, n = 50). Patients with recent deterioration in their medical status, such as unstable angina, severe congestive heart failure, and malignant arrhythmia, presence of coagulation or hematological disorders, patients with contraindication to regional anesthesia, uncontrolled hypertension, impaired renal functions, impaired liver functions, rheumatoid arthritis, psychiatric diseases, pre-existing neurological disease, infection at site of injection, and past history of reaction to study drugs were excluded.

On arrival to the operating room an intravenous access was established using an 18-G intravenous cannula, and patients were preloaded with 5 ml/kg Ringer acetate 15-20 min before the administration of spinal anesthesia [7] . Patients were monitored using standard monitoring including continuous ECG, noninvasive arterial blood pressure, and continuous pulse oximetry, and ST segment analyzer (Datex Ohmeda, Switzerland) was used during surgery. Oxygen at 5 l/min was given through a facemask during surgery.

Patients were made to lie in the lateral decubitus position, and under complete aseptic conditions local skin infiltration was carried out using 2 ml of lidocaine 2%, followed by dural puncture with the midline approach at the L3-L4 interspace using a 25-G Whitacre spinal needle (Vygon, UK). After free cerebrospinal fluid flow had been observed, 2.5 ml hyperbaric 0.5% bupivacaine (Marcaine Spinal Heavy; Astra, Sweden) was injected slowly over 10 s through the needle [8] . Thereafter, patients were immediately turned to supine position. The sensory and motor block was evaluated by sense of coldness and the modified Bromage scale (0 = no motor block, 1 = inability to raise extended leg, 2 = inability to flex the knee and 3 = inability to flex the ankle and foot), respectively [9],[10] .

The anesthetist who performed the spinal anesthesia left the operating room, and another one blinded to the group was responsible for monitoring and collecting patients' vital data. All medications were prepared by the pharmacy staff who were not participating in the study. The complications related to anesthesia, such as hypotension, bradycardia, and vasopressor need, and blood units required were recorded. Hypotension was defined as a systolic blood pressure (SBP) less than 90 mmHg, or a decrease of more than 20% from the baseline mean arterial pressure (blood pressure before induction of anesthesia) at the first 30 min after spinal anesthesia. The hypotension episodes were treated with a loading dose of 5 ml/kg Ringer acetate over 10 min and an intravenous bolus of ephedrine 5 mg, with a maximum bolus dose of 10 mg or NE (5 μg).

Data (HR, SBP) were recorded before spinal anesthesia with the patient in the supine position, and every 5 min after induction of spinal anesthesia until the level of sensory block was stabilized between T5 and T10 and SBP was maintained around 90% of baseline value (~15-20 min after hyperbaric 0.5% bupivacaine administration), and after NE or ephedrine administration. If this level increased above T5 during the experimentation, patients were excluded from the study.

A prolonged hypotension was defined as SBP less than 90 mmHg, or a decrease of more than 20% from the baseline SBP for more than 10 min, despite treatment. An SBP greater than 120% of baseline was considered hypertension. Tachycardia was defined as a rise in HR of more than 20% from the baseline HR and bradycardia as a fall to less than 50 beats/min.

Efficacy was taken as maintenance of SBP within 20% of the baseline during the first 5 min after a single bolus administration of the drug under study. In the norepinephrine group (group NE), 1 ml of NE (5 μg) (Levophed Hospira Inc., Brussels, Belgium) [11] was injected repeatedly until SBP returned to baseline value. If bradycardia (HR <50/min) developed, 0.3 mg intravenous atropine was given and was repeated if required. In the ephedrine group (group EPH), 2.5 mg/ml of ephedrine (Ephedrine Sterop, Brussels, Belgium), with a maximum of 10 mg, was injected as a single bolus. This dose was chosen based on previous studies [12],[13] . SBP was measured every minute for 5 min after the administration of the vasopressor for 15 min after spinal anesthesia. The aim of this study was to assess the efficacy (primary outcome) and side effects (secondary outcome) of bolus ephedrine versus bolus NE for the prevention of spinal anesthesia-induced hypotension in coronary artery disease patients undergoing knee arthroscopy.

Statistical analysis

IBM SPSS statistics (V. 22.0, 2013; IBM Corp., New York, USA) was used for data analysis. Data were expressed as mean ± SD for quantitative parametric measures in addition to both number and percentage for categorized data. Comparison between two independent means for parametric data was made using the Student t-test. Comparison between two dependent means for parametric data was made using the paired t-test. The χ2 -test was used to study the association between two variables or comparison between two independent groups as regards the categorized data. The probability of error at 0.05 was considered significant, whereas that at 0.01 and 0.001 was considered highly significant.

Sample size calculation

A total of 43 patients would be required in each group to achieve an a error of 5% and a β error of 1%. Thus, 45 patients in each group was considered sufficient for such data types.

  Results Top

A total of 108 ischemic heart disease patients of ASA physical status II or III scheduled for lower limb surgery were assessed for randomization. Eight patients were excluded: three patients refused regional anesthesia, two patients had signs of infection of sacral area, two patients had abnormal coagulation profile, and one patient had sensory level above T5. In all, 100 patients were included in the study, and there were no significant differences between the two groups with respect to their age, sex, and duration of surgery [Table 1].
Table 1: Patient characteristics

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The efficacy to maintain the SBP within 20% of the baseline during the first 5 min after a single bolus administration of the drug under study was statistically significant in group NE (P < 0.0001). On giving a bolus dose of ephedrine (5 mg) to maintain the SBP within 20% of the baseline, there was a significant tachycardia compared with a bolus dose of NE (5 μg) (P < 0.0001) [Table 2]. HR recorded at 5, 10, and 15 min following a bolus dose of ephedrine was significantly higher compared with group NE (P < 0.001). SBP recorded at baseline, 5, 10, 15, 30, and 60 min after spinal anesthesia, HR recorded at baseline, 30, and 60 min after spinal anesthesia, incidence of hypotension, hypertension, and bradycardia were not significantly different between the two groups [Table 3]. There were no recorded cases of failed spinal anesthesia, nausea, vomiting, or shivering.
Table 2: Intraoperative data

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Table 3: Hemodynamic parameters

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  Discussion Top

Sympathetic nervous system activity increases in patients with coronary artery disease; therefore, these patients after spinal anesthesia could be at risk of greater decreases in systemic vascular resistance (SVR) and blood pressure [14],[15] .

Preloading with crystalloids before spinal block might be practically ineffective because of secretion of natriuretic peptide, leading to peripheral vasodilatation and extravagation of fluid to the third space [16] . Co-loading seems to be more effective as the increase in intravascular volume induced by co-loading coincides with the time of maximal vasodilatation effect of spinal anesthesia, thus reducing the incidence of hypotension [17] . A major meta-analysis study involving eight studies and a total of 518 patients found that the incidence of hypotension was similar during comparison of preload and co-load [18] .

The main mechanism of hypotension after spinal block is a decrease in SVR, and loading of crystalloid alone may not be able to compensate the decrease in SVR. Decreases in cardiac output during spinal anesthesia are due to a shift in blood from the heart to peripheral arteries, but not due to decrease in cardiac contractility; therefore, the use of vasopressor injection is associated with an increase in cardiac output [19] . Although the most commonly used vasopressor for hypotension associated with spinal anesthesia is ephedrine, it may not be the drug of choice in this situation. It is not a potent vasopressor; therefore, ephedrine may not reliably reverse the decrease in SVR [20],[21] . Moreover, ephedrine treatment of hypotension increases HR and would be expected to be particularly deleterious in the patient with ischemic cardiac disease [22] . Epinephrine infusion during spinal anesthesia has been shown to restore systolic arterial pressure and increase cardiac output, but with no increase in diastolic or mean arterial pressure [23] .

Therefore, the ideal vasopressor should have a low cost, be readily available, have a fast onset of action, be reliable, and have favorable effects in HR, especially in patients with ischemic heart disease. Phenylephrine is considered the first drug of choice and its efficacy and safety have been thoroughly investigated. This is a synthetic noncatecholamine drug, but its function is similar to that of NE with direct action on the adrenergic receptor. It promotes vasoconstriction, especially arterial, by increasing SVR, and thereby increases preload [24] . From a theoretical point of view, NE should be an almost ideal drug to balance the hemodynamic compromise of spinal anesthesia, especially considering the short half-life of this vasopressor [11] .

This study evaluated the effect of low doses of intravenous ephedrine versus NE on HR and SBP on 100 ASA II or III coronary artery disease patients undergoing knee arthroscopy under spinal anesthesia. In our study, the two vasopressors were titrated to the same clinical endpoint. Despite this, the efficacy for maintaining SBP within 20% of baseline for the first 5 min was significantly better in the NE (80%) than in the ephedrine group (40%); HR was significantly higher (P = 0.00) at 5, 10, and 15 min in the EPH group than in the NE group. Despite achieving therapeutic equivalence, NE still produces a better hemodynamic stability compared with ephedrine by maintaining stable blood pressure and HR.

A recent review of randomized trials on the use of vasopressors with spinal anesthesia that analyzed seven studies [25],[26] concluded that clinical effects were similar between the two drugs in terms of prevention and treatment of hypotension. Ayorinde et al. [27] reported that 45 mg of ephedrine administered intramuscularly was clinically similar to phenylephrine 4 mg given by the same route, whereas Moran et al. [28] compared 5-10 mg boluses of ephedrine and 40-80 μg of phenylephrine, considering them equally effective. Ramanathan and Grant [29] studied the effect of different vasopressors in 127 healthy patients undergoing elective cesarean section under epidural anesthesia. They concluded that transient maternal hypotension does not affect neonatal acid-base status; both ephedrine and phenylephrine increase cardiac preload, and agent such as phenylephrine does not cause fetal acidosis, when used for treating maternal hypotension. Hall et al. [30] stated that, phenylephrine, when compared with ephedrine, causes significant increase (P < 0.001) in SBP during spinal anesthesia in patients undergoing elective cesarean section. Hoyme et al. [11] stated that both NE and akrinor (1 × 10−1 vial = 20 mg cafedrine and 1 mg theodrenaline act through b stimulation and consecutively through cyclic adenosine monophosphate) are suitable and potent drugs to counterbalance the hemodynamic effects of spinal anesthesia-associated sympathetic block. In healthy women the outcome is the same for the application of either drug. However, NE, through its pharmacological profile, represents the vasopressor that is associated with lower risks.

  Conclusion Top

NE is more effective compared with ephedrine in the maintenance of SBP with reduction in HR, which is useful in coronary artery disease patients undergoing knee arthroscopy under spinal anesthesia in whom tachycardia is undesirable.

  Acknowledgements Top

Conflicts of interest

None declared.

  References Top

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  [Table 1], [Table 2], [Table 3]

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