Despite many advantages, spinal anesthesia often is followed by undesirable decreases in blood pressure, for which the ideal treatment remains controversial. Because spinal anesthesia-induced sympathectomy and management with a pure alpha-adrenergic agonist can separately lead to bradycardia, the authors hypothesized that epinephrine, a mixed alpha- and beta-adrenergic agonist, would more effectively restore arterial blood pressure and cardiac output after spinal anesthesia than phenylephrine, a pure alpha-adrenergic agonist.
Using a prospective, double-blind, randomized, cross-over study design, 13 patients received sequential infusions of epinephrine and phenylephrine to manage hypotension after hyperbaric tetracaine (10 mg) spinal anesthesia. Blood pressure, heart rate, and stroke volume (measured by Doppler echocardiography using the transmitral time-velocity integral) were recorded at baseline, 5 min after injection of tetracaine, and before and after management of hypotension with epinephrine and phenylephrine. Cardiac output was calculated by multiplying stroke volume x heart rate.
Five min after placement of a hyperbaric tetracaine spinal anesthesia, significant decrease in systolic (from 143 +/- 6 mmHg to 125 +/- 5 mmHg; P < 0.001), diastolic (from 81 +/- 3 to 71 +/- 3; P < 0.001), and mean (from 102 +/- 4 to 89 +/- 3; P < 0.001) arterial pressures occurred. Heart rate (75 +/- 4 beats/min to 76 +/- 4 beat/min; P = 0.9), stroke volume (115 +/- 17 to 113 +/- 13; P = 0.9), and cardiac output (8.0 +/- 1 l/m to 8.0 +/- 1l/m; P = 0.8) did not change significantly after spinal anesthesia. Phenylephrine was effective at restoring systolic blood pressure after spinal anesthesia (120 +/- 6 mmHg to 144 +/- 5 mmHg; P < 0.001) but was associated with a decrease in heart rate from 80 +/- 5 beats/min to 60 +/- 4 beats/min (P < 0.001) and in cardiac output from 8.6 +/- 0.7 l/m to 6.2 +/- 0.7 l/m (P < 0.003). Epinephrine was effective at restoring systolic blood pressure after spinal anesthesia (119 +/- 5 mmHg to 139 +/- 6 mmHg; P < 0.001) and was associated with an increase in stroke volume from 114 +/- 12 ml to 142 +/- 17 (P < 0.001) and cardiac output from 7.8 +/- 0.6 l/m to 10.8 +/- 1.1 l/m (P < 0.001).
Epinephrine management of tetracaine spinal-induced hypotension increases heart rate and cardiac output and restores systolic arterial pressure but does not restore mean and diastolic blood pressure. Phenylephrine management of tetracaine spinal-induced hypotension decreases heart rate and cardiac output while restoring systolic, mean, and diastolic blood pressure.
Spinal anesthesia is used commonly for surgery on the lower abdomen and lower extremities. Despite many benefits, spinal anesthesia may be accompanied by hypotension, bradycardia, and in a few patients, cardiac arrest.  The best drug to reverse the heart rate and blood pressure sequelae of spinal anesthesia remains a controversial topic among anesthesiologists. The objective of this study was to test our hypothesis that epinephrine, a mixed alpha- and beta-adrenergic agonist, would more completely and effectively restore baseline cardiovascular conditions after spinal anesthesia than than phenylephrine, a pure alpha-adrenergic agonist.
Material and Methods
After review and approval of our study by the Clinical Research Practices Committee, informed consent was obtained from 14 patients scheduled for elective surgery for which tetracaine spinal anesthesia would be appropriate. Patients were excluded if they exhibited any of the following during the preoperative assessment: anticoagulation, symptomatic coronary artery disease, cardiac valvular regurgitation or stenosis, pregnancy, or unwillingness to have a spinal anesthetic. Patients also were excluded if satisfactory images of the mitral valve could not be obtained during preoperative screening.
All patients received their usual medications on the day of surgery. Sedative medications before spinal anesthesia were limited to 2 mg of midazolam and 100 micro gram of fentanyl intravenously. Fluid administration was limited to 3 ml/kg before spinal anesthesia. Patients were monitored with five-lead electrocardiograph (ECG), noninvasive blood pressure cuff (Dinamap (R), model 1846SX, Critikon, Inc., Tampa, FL, with a measurement every 2 min), continuous finger pulse oximetry, and skin temperature probe. Transthoracic echocardiographic measurements were made using a Hewlett Packard Sonos 1500 ultrasound system (Hewlett Packard, Andover, MA) and a 2.5-MHz handheld probe. Blood pressure (systolic, diastolic, and mean arterial pressure [MAP]), heart rate, and transmitral diastolic time-velocity integral were recorded at baseline, 5 min after spinal anesthesia, and before and after management of spinal anesthesia-induced hypotension with phenylephrine or epinephrine. Baseline values were obtained concurrently with the echocardiographic measurements; the time required for echocardiography preparations afforded us at least 5 min during which we observed the heart rate and blood pressure (at 1-min intervals). The recorded baseline heart rate and blood pressure measurements differed by less than 3% from the immediately preceding measurements.
After spinal anesthesia, when a 15% reduction in systolic arterial pressure was observed, treatment was initiated with a bolus of either epinephrine (4.0 micro gram) or phenylephrine (40.0 micro gram) followed by an infusion of either epinephrine (0.05 micro gram [center dot] kg sup -1 [center dot] min sup -1) or phenylephrine. (0.5 micro gram [center dot] kg sup -1 [center dot] min sup -1), respectively. If systolic blood pressure did not increase with the initial infusion, repeat bolus doses could be given and the infusion rate could be doubled until systolic blood pressure increased to the value measured before spinal anesthesia. Then, after measurements were completed, the infusion was discontinued. A 10-min washout period was used, and the second drug was given in a similar manner. The drugs were administered in a random order. Patients and physicians were blinded to the identity of the drugs. The drug infusions were prepared as follows: 10 mg of phenylephrine was dissolved in 250 cc normal saline (40 micro gram/ml), and 1.0 mg epinephrine was dissolved in 250 cc normal saline (4.0 micro gram/ml). Based on this preparation, bolus volumes and infusion volumes were similar for each drug.
Lumbar puncture was performed at either the L3-L4 or L4-L5 interspace using a midline approach. Ten mg of tetracaine diluted in an equal volume (1 ml) of 10% dextrose was injected in every patient. Drug injections were made with patients in a lateral decubitus position. Patients were turned supine immediately after drug injection. The peak upper dermatomal level of sensory anesthesia was assessed using response to pin prick.
The echocardiographic examination focused on measurement of the transmitral flow-velocity from the apical four-chamber window.  A single-lead ECG was monitored in the channel provided on the imaging system. The entire protocol was captured on super VHS videotape. Gain, filter, and depth settings were adjusted to optimize delineation of endocardial borders. Wherever possible, the scan sector was narrowed to increase frame rate. During all stages, standard two-dimensional images were obtained by American Society of Echocardiography  guidelines in the apical two- and four-chamber views. Particular care was taken using external (intercostal space, anterior axillary line) and internal (left ventricular outflow, papillary muscles) landmarks to ensure that comparable anatomic views were obtained between stages and that artifactual foreshortening of the left ventricular apex was avoided. These methods are similar to those used previously by other investigators.  Image-directed pulsed-wave Doppler tracings of mitral valve inflow were performed as previously described by Little et al.  and Kitzman et al.  Measurement of the mitral annular diameter and transmitral flow-velocity integral were performed offline using a Nova Microsonics (Allendale, NJ) calculation package. The mid-diastolic transverse diameter of the mitral annulus was measured from the second or third video frame after the initial maximal opening of the anterior leaflet. Measurements were taken from the inner edge of the lateral bright corner of the annulus to the inner edge of the medial corner just below the insertion of the mitral leaflets. Measurements from at least three cardiac cycles were averaged, and the cross-sectional area of the mitral annulus was derived from the equation pi r2, where r represents half the annular diameter. The annular diameter was measured at each time-point during the study. The spectral pulsed Doppler envelope was traced using the maximal velocity contour edge convention. The mitral inflow volume was determined by multiplying the area under the diastolic inflow curve (time-velocity integral) by the cross-sectional area of the mitral annulus. Curves from four to six cardiac cycles were digitized, and an average transmitral flow-velocity integral was calculated for each time-point. Stroke volume was calculated as:Equation 1
Cardiac output was calculated by multiplying the stroke volume by the average heart rate recorded during each measurement time. 
A mixed-model, double-repeated analysis of variance (ANOVA) model was used to determine differences between time-points and between treatment groups. Corrections were made for multiple comparisons using the Bonferroni technique as appropriate using Fisher's protected LSD approach. The SAS microcomputer program (SAS Institute, Cary, NC) was used for all analyses. Data are provided as raw data, mean +/- SEM, or as median and range. Statistical significance was set at an alpha level of 0.05.
Thirteen of 14 patients completed the study. One patient was excluded from the study because systolic blood pressure did not decrease by 15% after placement of the spinal anesthesia. Demographic data for these 13 patients, including age, weight, height, sex, American Society of Anesthesiologists classification, and preoperative antihypertensive medications are given in Table 1. Surgical procedures performed included five orthopedic, six urologic, and two gynecologic operations. All patients had satisfactory spinal anesthesia for their operative procedure. The extent of spinal anesthesia was measured by pinprick 10 min after injection of tetracaine and at 10-min intervals for 40 min. The median level of spinal analgesia (the highest value recorded during the anesthetic) was T7, with a range of T12-T4.
Five min after injection of tetracaine, significant decreases in systolic blood pressure, MAP, and diastolic blood pressure were observed. Systolic blood pressure decreased from 143 +/- 6 mmHg to 125 +/- 5 mmHg (P < 0.001); MAP decreased from 102 +/- 4 mmHg to 89 +/- 3 mmHg (P < 0.001); and diastolic blood pressure decreased from 81 +/- 3 to 71 +/- 3 (P < 0.001) before treatment. The lowest blood pressures were typically measured some time after initiation of drug therapy or during the drug washout period. Epinephrine and phenylephrine were effective at restoring systolic blood pressure to baseline, increasing systolic blood pressure from 119 +/- 6 mmHg to 139 +/- 6 mmHg (P < 0.001) and 120 +/- 6 to 144 +/- 5 mmHg (P < 0.001), respectively. Phenylephrine restored MAP from 82 +/- 4 to 100 +/- 4 mmHg (P < 0.001) and diastolic blood pressure from 63 +/- 4 to 77 +/- 3 (P < 0.001). Epinephrine had a statistically significant effect on MAP (84 +/- 4 to 90 +/- 4 mmHg; P = 0.04) but not on diastolic blood pressure (66 +/- 4 to 65 +/- 3; P = 0.07). Changes in systolic blood pressure, MAP, and diastolic blood pressure are shown in Figure 1, Figure 2, Figure 3.
Heart rate was unchanged after spinal anesthesia (P = 0.96) but decreased significantly from 80 +/- 5 to 60 +/- 4 beats/min with phenylephrine (P < 0.001). Epinephrine caused a modest increase in heart rate (74 +/- 4 to 80 +/- 4 beats/min: P = 0.02). Changes in heart rate are shown in Figure 4.
Stroke volume did not change significantly after spinal anesthesia (P = 0.9) or after treatment with phenylephrine (P = 0.8). In contrast, treatment with epinephrine caused a significant increase in stroke volume from 114.4 +/- 12 ml to 142 +/- 17 ml (P < 0.001;Figure 5).
Cardiac output was unchanged after spinal anesthesia (P = 0.59). Treatment with phenylephrine caused a significant decrease in cardiac output from 8.5 +/- 0.6 to 6.2 +/- 0.7 l/min (P < 0.003), whereas epinephrine caused a significant increase in cardiac output 7.8 +/- 0.6 to 10.8 +/- 1.1 l/min (P < 0.001;Figure 6).
The largest dosages of epinephrine and phenylephrine required to manage hypotension were 136 micro gram and 1,132 micro gram, respectively. The dosages of epinephrine and phenylephrine and number of infusion changes are shown in Table 2. Two patients required two additional boluses and two increases in infusion rates of epinephrine and phenylephrine to restore systolic blood pressure. Four patients in the epinephrine group and six patients in the phenylephrine group needed one additional bolus and one increase in infusion rate to restore systolic blood pressure. Six patients in the epinephrine group and five patients in the phenylephrine group needed no additional drug after the initial bolus and infusion to restore systolic blood pressure.
There were few arrhythmias at any time during the study. There were no significant differences between phenylephrine and epinephrine; moreover, there were no significant differences comparing arrhythmias recorded during spinal anesthesia, phenylephrine, or epinephrine with those recorded under baseline conditions (Table 3).
We did not detect any ST-segment changes consistent with ischemia during continuous two-lead ECG monitoring (lead II, V5) during the study. In addition, post hoc review of the transthoracic echocardiographic images revealed no new segmental wall motion abnormalities during the study.
There are many studies investigating the effects of volume loading and vasopressor therapy to manage hypotension after regional anesthesia. Interpretation of these studies is difficult because of the different patient populations used, i.e., obstetric and nonobstetric, and because of variable use of intravenous volume loading before the block. Some investigators have used drugs prophylactically; others have waited until hypotension appears. In addition, a variety of vasopressors, including ephedrine, [8–10] dopamine, [11,12] phenylephrine, [13–16] and epinephrine, [17,18] have been used with varying success. Measurement of cardiac output or stroke volume, which is key to determining the effects of spinal anesthesia and adrenergic agonists on oxygen delivery to tissue, usually has not been available. Therefore, it is not surprising that the conclusions from these investigations are sometimes contradictory and that no consensus as to the ideal agent (or class of agents) has emerged.
Our data show that epinephrine restored systolic blood pressure and increased heart rate and cardiac output after spinal anesthesia, but it did not restore MAP and diastolic blood pressure. Phenylephrine restored systolic, MAP, and diastolic blood pressure in all patients, but it decreased heart rate and cardiac output. Using the Doppler transmitral flow-velocity integral as an approximation of stroke volume, we observed that epinephrine significantly increased stroke volume, whereas phenylephrine had no effect on stroke volume. We recognize that an excessive increase in heart rate would almost never benefit the heart. Bradycardia generally favors myocardial oxygen supply (by increasing the duration of diastole) and minimizes oxygen demand (by reducing the relative amount of time spent in systole).
The results of our study are consistent with those reported previously, showing epinephrine to be effective at restoring blood pressure after lumbar epidural anesthesia. [17,19] Increased cardiac output with epinephrine after spinal anesthesia most likely resulted from a combination of increased heart rate, increased inotropic state, and decreases in systemic vascular resistance. The latter two effects most likely produced the significant increase in transmitral flow-velocity integral we observed. Our results differ from those observed by Thomas et al.,  comparing the efficacy of phenylephrine to that of ephedrine for managing hypotension produced by spinal anesthesia in pregnant women. These authors noted that phenylephrine restored blood pressure after spinal anesthesia, and despite causing significant bradycardia, it did not decrease cardiac output. There are a number of important differences between our study and that of Thomas et al., including patient age and volume preloading before spinal anesthesia, which may explain the different results observed.
Epinephrine did not significantly increase diastolic arterial pressure (P = 0.07) after spinal anesthesia, most likely reflecting the beta2-mediated peripheral vasodilating effects of epinephrine and our protocol design. We did not titrate epinephrine or phenylephrine to a MAP or diastolic arterial pressure end-point. We titrated each drug to a systolic blood pressure end-point to reflect our usual clinical practice. Phenylephrine and epinephrine restored systolic blood pressure under the conditions of our study. Good physiologic arguments could be made to use either diastolic blood pressure (reflecting coronary perfusion pressure) or MAP (better index of afterload changes); nevertheless, these are generally not used for drug titration in clinical practice. In addition, epinephrine caused a small but statistically significant increase in heart rate (mean, 6.0 beats/min; P = 0.02). An increase in heart rate without a significant increase in diastolic arterial pressure could be detrimental to patients with severe coronary artery disease. The combination of increasing myocardial oxygen demand without a commensurate increase in diastolic arterial pressure (the main contributor to MAP and a primary determinant of coronary blood flow) may result in myocardial ischemia in susceptible patients. Nevertheless, we did not observe myocardial ischemia or an increased incidence of ventricular ectopic beats during epinephrine infusions (Table 3).
No patient in our study suffered any adverse perioperative cardiovascular outcome; however, two patients required rescue therapy with epinephrine after the phenylephrine infusion (at the conclusion of the study) to manage severe bradycardia (heart rate < 45 beats/min in both patients). In one of the two patients, epinephrine was given when the patient's bradycardia failed to respond to 0.8 mg of intravenous atropine. No patient required any form of rescue therapy during or after epinephrine infusion.
Many anesthesiologists would argue that ephedrine would have been a better choice than epinephrine. We and others have observed that ephedrine, by virtue of its beta-adrenergic agonist properties, corrects the venous pooling after experimental spinal anesthesia and also corrects the hypotension.[8–10] However, had we used ephedrine in this study, it would have been necessary to always administer ephedrine last, unblinding the study, because its effects are longer-lasting than either phenylephrine or epinephrine and because its indirect effects from release of norepinephrine at nerve terminals may have altered the response to a subsequently administered agonist. We also recognize that in patients at high risk for ischemia, using a combined adrenergic agonist such as norepinephrine with greater alpha-adrenergic receptor activity (than epinephrine) may be warranted, but this hypothesis awaits testing.
There are other limitations to our study. Few patients were studied. We may have missed an occasional dysrhythmia or ischemic event by only monitoring the standard ECG leads (II, V5) and by continuously recording only a single ECG lead with the echocardiography machine. This ECG monitoring will not detect 100% of ischemic events. There were only two patients with sinus tachycardia (heart rate, maximum of 100 beats/min) during epinephrine treatment, and one of these patients had a heart rate of 119 beats/min before spinal anesthesia. The incidence of dysrhythmias may differ in other, less restricted patient populations.
Others may criticize us for infusing only 3 ml/kg of lactated Ringer's solution before spinal anesthesia. Larger volumes of intravenous fluid before spinal anesthesia could potentially have changed our results; however, we note that when Coe and Baranas compared patients who had received a larger volume before spinal anesthesia with those who had not, they observed an approximately 30% incidence of hypotension irrespective of volume loading. Additionally, volume loading during spinal anesthesia may put the elderly patient at risk for pulmonary edema and worsen postoperative urinary retention. Other authors have found prophylactic fluid loading to be of some value. Venn et al. found that patients receiving 1 l of crystalloid before spinal anesthesia had less of a drop in blood pressure when the level of anesthesia exceeded T6 than did patients who did not receive preoperative fluid therapy. It is possible that additional intravenous fluid administration could have augmented stroke volume during phenylephrine treatment, resulting in increases in cardiac output.
The clinician administering the spinal anesthesia was not prevented from observing the echocardiographic images during each study. Thus, our blinding was not complete. However, only 4 of 13 spinal anesthesias were provided by a clinician with any formal training in echocardiography; moreover, the frequency of data collection limited the clinicians' opportunities to monitor drug effects (and unblind the study) on the echocardiographic machine's display. Because the clinicians could not be blinded to heart rate (for safety and ethical reasons), each study was inevitably accompanied by speculation as to which drug was being administered at each time-point. Therefore, in the current analysis and conclusions, we have relied primarily on measurements only available from either echocardiography or objective monitoring techniques to compare epinephrine and phenylephrine.
We do not believe that echocardiographic measurements are required to safely infuse epinephrine or phenylephrine to correct hypotension after spinal anesthesia. We measured consistent, predictable responses to both drugs. In our study, adverse responses to phenylephrine resulted from bradycardia, a side effect that can be readily identified using the usual noninvasive monitoring devices available to clinicians when they perform spinal anesthesia. There may be some patients in whom bradycardia could be beneficial by decreasing myocardial oxygen consumption.
In summary, hyperbaric tetracaine spinal anesthesia caused a decrease in blood pressure with a variable effect on cardiac output. Phenylephrine was effective at restoring systolic, MAP, and diastolic blood pressure after spinal anesthesia, but it decreased heart rate and cardiac output. Epinephrine increased heart rate and cardiac output and restored systolic blood pressure after spinal anesthesia, but it did not restore MAP and diastolic blood pressure to prespinal levels. We reject our hypothesis that epinephrine more completely and effectively restores baseline conditions after spinal anesthesia than phenylephrine. The different responses observed with epinephrine and phenylephrine management suggest that these agents be selectively used to manage hypotension after spinal anesthesia based on the desired effect on heart rate, stroke volume, and diastolic arterial pressure. Use of phenylephrine decreased heart rate sufficiently in two patients to require therapy with first atropine and then epinephrine, whereas no patient required additional therapy after epinephrine treatment. Whether these pharmacologic differences between epinephrine and phenylephrine may result in outcome differences remains speculative.
The authors thank Dr. Thomas Downes, Kathy Stewart, RT, RDMS (sonographer), and Judy Bennett, RN (research nurse), for their assistance with this study.