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Anesth Analg 2002;95:751-756 © 2002 International Anesthesia Research Society
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Abstract |
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In a double-blinded, placebo-controlled, randomized study, we evaluated the effect of prophylactic IM phenylephrine at doses of 1.5 and 3 mg on hyperbaric tetracaine spinal anesthesia-induced hypotension in 90 normotensive and hypertensive patients aged >65 yr undergoing surgery for hip fracture. Thirty normotensive patients received 1.5 or 3 mg of phenylephrine IM (N/P-1.5 and N/P-3.0 groups; n = 15 in each), whereas controls received saline (N/C group; n = 15), and 45 hypertensive patients were treated in a similar manner (H/P-1.5, H/P-3.0, and H/C groups; n = 15 in each). All groups had a peak sensory block height of T9, with a range of T8 to T10. The incidence of hypotension (>25% decrease in mean arterial blood pressure [MAP] from baseline) was significantly lower in the patients who received phenylephrine 1.5 or 3 mg than in the controls, both in the normotensive and hypertensive groups (P < 0.01). The N/P-3.0 and N/P-1.5 groups and the H/P-3.0 group had significantly lower percentage reductions in MAP (P < 0.05) and required significantly smaller doses of rescue IV ephedrine (P < 0.05) than did the N/C group or the H/C group. The H/P-1.5 group also required significantly less rescue IV ephedrine (P < 0.05), although it was not sufficient to significantly attenuate the percentage decrease in MAP compared with that in the H/C group. Bradycardia (heart rate <50 bpm) as an adverse effect after IM administration of phenylephrine was not observed in any of the groups. Hypertension (MAP >20% increase from baseline) after medication occurred in the N/P-3.0 and H/P-3.0 groups, but not in the N/P-1.5 and H/P-1.5 groups. We conclude that prophylactic IM injection of 1.5 mg of phenylephrine is a safe (defined as the inhibition of bradycardia and hypertension) and effective means of reducing the incidence of hypotension associated with spinal anesthesia in normotensive and hypertensive elderly patients.
IMPLICATIONS: We evaluated the efficacy and safety of small-dose IM phenylephrine for prophylaxis against spinal anesthesia-induced hypotension in normotensive and hypertensive elderly patients. Phenylephrine 1.5 mg IM was effective for reducing the incidence of hypotension and avoided adverse effects.
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Introduction |
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Spinal anesthesia is often used for traumatic hip fracture surgery, a procedure largely restricted to the geriatric population. The most common complication of this anesthetic technique is hypotension (1,2), with a particularly frequent incidence in the elderly (3–5). This problem is a particularly important issue in elderly patients with cardiovascular disease such as hypertension, because their risk of ischemia secondary to hypotension is thus increased (6).
It is common practice to give IV fluids before and during spinal anesthesia to prevent hypotension. In elderly patients, however, fluid preloading is not always effective (3,7). Hypotension during spinal anesthesia results primarily from blockade of the sympathetic nervous system, which causes decreases in systemic vascular resistance and cardiac output. However, volume loading does not prevent the decrease in systemic vascular resistance caused by spinal anesthesia but, in fact, causes further decreases (8,9). Additionally, the attenuated physiological reserve in elderly patients appears to make them less able to increase cardiac output in response to volume loading.
An alternative approach suggested by a number of recent authors is the use of an IM depot injection of a vasopressor. However, the best vasopressor to avoid the heart rate (HR) and blood pressure sequelae of spinal anesthesia remains a controversial topic among anesthesiologists. The use of IM ephedrine, a mixed 
- and ß-adrenergic agonist, prophylactically given with moderate preloading to prevent bradycardia caused by spinal anesthesia-induced sympathetic block, has been reported for elderly patients (7,10,11). However, the prophylactic use of ephedrine has been criticized because of the associated frequent incidence of severe hypertension and tachycardia (12–14).
Phenylephrine, a pure -adrenergic agonist whose action is expected to counteract the decrease in systemic vascular resistance induced by spinal anesthesia without increasing the HR, has been found to be effective when given IM. However, there has been little study on the use of -agonists for the prevention of hypotension in elderly patients undergoing spinal anesthesia.
The aim of this study was to determine the efficacy and safety of IM phenylephrine against spinal anesthesia-induced hypotension, i.e., to clarify whether hypotension after spinal anesthesia and hypertension and bradycardia as adverse events of the study medication were prevented in hypertensive and normotensive elderly patients scheduled for surgical repair of hip fracture.
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Methods |
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This study was approved by our hospital’s ethics committee and conducted after obtaining written informed consent from the subjects. The subjects included 90 normotensive and hypertensive patients (n = 45 each) aged older than 65 yr (ASA physical status I–II) scheduled to undergo open surgical repair of a hip fracture under spinal anesthesia. Patients with anticoagulation, symptomatic coronary artery disease, cardiac valvular regurgitation or stenosis, and neuromuscular disorders and those who were not willing to undergo spinal anesthesia were excluded.
Hypertension was diagnosed if systolic arterial blood pressure (SAP) was >160 mm Hg, diastolic arterial blood pressure was >95 mm Hg, or both on admission (in accordance with the definition by the World Health Organization). A well controlled hypertensive patient was also classified in the hypertensive group, even if such a patient had not met the abovementioned hypertension criteria.
All of the hypertensive patients had been receiving calcium channel blockers and ß-adrenergic blockers and received their medication 6 h before the induction of anesthesia. Normotensive and hypertensive patients were randomized by a sealed-envelope technique into one of the following 6 groups: (a) a group in which patients without hypertension received 3 mg of IM phenylephrine (N/P-3.0 group); (b) a group in which patients without hypertension received 1.5 mg of IM phenylephrine (N/P-1.5 group); (c) a control group in which patients without hypertension received 0.9% saline solution (N/C group); (d) a group in which patients with hypertension received 3 mg of IM phenylephrine (H/P-3.0 group); (e) a group in which patients with hypertension received 1.5 mg of IM phenylephrine (H/P-1.5 group); and (f) a control group in which patients with hypertension received 0.9% saline solution (H/C group). All medication with phenylephrine was made up to 2 mL with 0.9% saline and was administered by a nurse not involved in the care of the patient. All patients were managed by an anesthesiologist who was blinded to the identity of the study medication.
Patients received no premedication. Before spinal anesthesia, each patient received a rapid infusion of 8 mL/kg of acetated Ringer’s solution. Standard monitoring included continuous electrocardiography and pulse oximetry. Noninvasive arterial pressure (SAP, diastolic arterial pressure, and mean arterial blood pressure [MAP]) and HR measurements were recorded at 1-min intervals for 20 min after the induction of anesthesia and every 5 min thereafter by using an automated noninvasive oscillometer (BSM-3000; Colin Co., Tokyo, Japan). The baseline MAP and HR were determined from the average of three consecutive readings taken after the infusion of fluids. Lumbar puncture was performed in the lateral position by using a 25-gauge Quincke point needle (Top Co., Tokyo, Japan) positioned midline at the L3-4 vertebral interspace. Eight milligrams of tetracaine diluted in an equal volume (2 mL) of 10% dextrose was injected over 10 s in every patient. After completion of injection, the patients were immediately returned to the supine position, and the IM injection of the study medication was given into the lateral aspect of the thigh of the nontraumatized leg. After anesthesia, a preload of 4 mL/kg of acetated Ringer’s solution was given over 20 min, and a maintenance infusion of the same crystalloid solution was then run at a rate of 4 mL · kg-1 · h-1 throughout surgery. Block height was assessed with pinprick testing at 5 and 20 min after blockade.
Hypotension was defined as SAP of <90 mm Hg or a decrease of more than 25% from the baseline MAP. Patients who met either criterion were treated with rescue IV bolus doses of ephedrine 5–10 mg until both SAP and MAP had increased above the threshold levels. Treatment with IV atropine or ephedrine was given if bradycardia (defined as HR <50 bpm) occurred after the study medication. Hypertension (defined as a >20% increase in MAP from the baseline) after the study medication was treated with IV nicardipine. In addition to the loading dose of IV fluids, patients received additional acetated Ringer’s solution as deemed necessary. The percentage changes in MAP and HR were calculated from the difference between the baseline and the lowest recorded MAP and HR, respectively. No additional sedative medications were given during the operation.
A power analysis was performed by assuming an incidence of hypotension of 70% in the control group (3–5) and had revealed that a sample size of 15 patients in each group would have an 80% power to detect a 35% reduction in the incidence of hypotension, with a Type I error probability of 0.05. Data are presented as means ± SD. Statistical analysis was performed on a Macintosh computer (Apple Computer, Inc., Cupertino, CA) using the software package StatView 4.02 (Abacus Concepts, Inc., Berkeley, CA). Patient characteristics, hemodynamic data, and the timing and doses of ephedrine required were compared by using analysis of variance with Fisher’s protected least significant differences post hoc test. The sensory levels of the block were treated as nonparametric data and were compared by using the Kruskal-Wallis test. The incidences of hypotension and hypertension were compared by using the 
2 test or Fisher’s exact test, as appropriate. A value of P < 0.05 was considered statistically significant.
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Results |
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Fifteen patients were studied in each group, and all patients completed the study. Demographic characteristics, baseline hemodynamic data, and dermatomal sensory levels are presented in Table 1. The six groups were similar in age, weight, height, ASA status, sex distribution, level of sensory block at 20 min, and baseline hemodynamic variables.
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The incidence of hypotension is shown in Table 2. In both normotensive and hypertensive groups, the incidence of hypotension in both groups of patients given 3 mg of phenylephrine (N/P-3.0 and H/P-3.0 groups) and 1.5 mg of phenylephrine (N/P-1.5 and H/P-1.5 groups) was significantly less frequent than that in the control patients (N/C and H/C groups, respectively) (P < 0.01).
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In normotensive groups, the patients who received 1.5 mg of phenylephrine (N/P-1.5 group) and 3.0 mg of phenylephrine (N/P-3.0 group) had significantly smaller percentage reductions in MAP compared with that in the control patients (N/C group) (P = 0.0012 and 0.0003, respectively) (Fig. 1). These two groups also required significantly smaller doses of rescue IV ephedrine (P < 0.0001 in both) (Fig. 2). In the hypertensive groups, the percentage reduction in MAP was significantly smaller in H/P-3.0 patients than in H/C patients (P = 0.038) (Fig. 1), and the H/P-3.0 group also required a significantly smaller dose of rescue IV ephedrine than did the H/C group (P = 0.0046) (Fig. 2). The H/P-1.5 group also had a significantly smaller ephedrine dose requirement than did the H/C group (P = 0.0156), but the percentage reductions in MAP in the two groups were similar (Figs. 1 and 2). The times to first requirement for rescue IV ephedrine in all four groups were similar.
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P < 0.001 in the N/P-3.0 group compared with the N/C group. N or H/P-1.5 or 3.0 = normotensive or hypertensive group receiving phenylephrine 1.5 or 3 mg IM; N or H/C = normotensive or hypertensive group receiving 0.9% saline (control).
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The percentage decreases in HR (Fig. 1) in the three subgroups of the normotensive and hypertensive groups were not significantly different. The lowest HR value in all groups was >50 bpm, and no patient in any group developed bradycardia and required medication after spinal anesthesia (Table 2).
One patient in the N/P-3.0 group and two patients in the H/P-3.0 group required nicardipine because of hypertension after the study medication (Table 2). No patient in the other groups developed hypertension requiring treatment after the study medication.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Prophylactic IM injections of phenylephrine at doses of 3 and 1.5 mg reduced the incidence of hypotension after hyperbaric tetracaine spinal anesthesia in normotensive and hypertensive elderly patients. In normotensive groups, both doses decreased the severity of hypotension and the required dose of rescue IV ephedrine. In the hypertensive groups, 3 mg of phenylephrine decreased both the severity of hypotension and the required dose of rescue ephedrine, and 1.5 mg of phenylephrine reduced the ephedrine requirement but failed to obtund the hypotensive response. In both normotensive and hypertensive patients, 1.5 mg of phenylephrine did not cause hypertension, whereas 3 mg of phenylephrine did.
To improve hemodynamic consequences secondary to spinal anesthesia, we tested the prophylactic use of IM phenylephrine in this study because it has been observed that volume expansion alone is not consistently effective in attenuating spinal anesthesia-induced hypotension, and may even be harmful in elderly patients with cardiovascular complications (3,7–9); moreover, IM application of vasopressor maintains its effect for more than 60 minutes (11). In addition, Critchley et al. (8) and Critchley and Conway (9) found that an infusion of metaraminol, an -adrenergic agonist, was significantly better than ephedrine in maintaining SAP and did not require IV fluids during spinal anesthesia, unlike ephedrine. Data on -adrenergic agonists via the IM route are, however, limited because there have been few studies on the IM use of -agonists for the prevention of hypotension during spinal anesthesia in the elderly. Thus, the purpose of our study was to evaluate the efficacy and safety of the use of IM injection of phenylephrine for spinal anesthesia-induced hypotension and also to determine the optimal dose of phenylephrine given via this route.
The elderly population in Japan is increasing. These patients often have concomitant medical problems, and the functional capacity of organs decreases with aging. Therefore, spinal anesthesia, which is often preferred for its minimal effect on mental status, minimal decrease in myocardial contractility, and protection against thromboembolic complications (15,16), can be an ideal anesthetic technique. However, spinal anesthesia is accompanied by the risk of potential complications, the main one being hypotension. The elderly have increased resting sympathetic nervous system activity and associated increased norepinephrine release from nerve terminals (17,18). Hemodynamic instability after spinal anesthesia, therefore, might be exaggerated in the elderly because of larger decreases in systemic vascular resistance. Moreover, morbidity and mortality rates in elderly patients with hypertension might be more frequent than those in elderly patients without hypertension because of the marked intraoperative hemodynamic lability (19).
Korkuschko et al. (19), who performed one of the few studies on IM injection of phenylephrine, found that 0.15 mg/kg (up to 10 mg) of IM phenylephrine was safe for healthy volunteers, including elderly volunteers. In this study on the effects of 1.5 and 3 mg IM injection of phenylephrine on spinal hypotension, it was found that even 1.5 mg of IM phenylephrine significantly decreased the incidence of hypotension after spinal anesthesia in both normotensive and hypertensive elderly patients. One possible explanation for this result could be related to the low site of the sensory block level in our study. The incidence of hypotension during spinal anesthesia appears to be directly related to the level of sensory block (20–22). Carpenter et al. (21) suggested that a peak block height of T5 or higher confers a threefold increase in the odds of developing hypotension. In this study, the sensory block height was T9, with a range of T8 to T10. Thus, one of the most effective methods for preventing hypotension during spinal blockade is to avoid a high level of analgesia.
IM administration of 1.5 mg of phenylephrine, however, failed to attenuate the percentage reduction of MAP after spinal anesthesia in elderly patients with hypertension. In addition to the increase in sympathetic nervous system activity with aging, preexisting hypertension causes an exaggerated circulatory response to several forms of stress because of long-term persistent vascular hyperreactivity (19). Therefore, IM administration of 1.5 mg of phenylephrine would not have a sufficiently strong effect to attenuate severe hypotension after spinal anesthesia in hypertensive patients, although its action was sufficient to maintain the hemodynamic stability after spinal anesthesia in normotensive patients.
As for the occurrence of adverse events in the use of phenylephrine, Critchley and Conway (9) also pointed out that metaraminol was very potent and could cause hypertension because of prophylactic infusions. Thus, the administration of the minimal effective dose of phenylephrine is recommended for elderly patients. In fact, hypertension after the study medication occurred in 7% of the patients in the N/P-3.0 group and in 13% of the patients in the H/P-3.0 group in our study. Care should therefore be taken when administering 3 mg of phenylephrine IM, especially to elderly patients with hypertension.
The main reason there has been no study on the use of -adrenergic agonists for elderly patients undergoing spinal anesthesia is that spinal anesthesia-induced sympathectomy and management with -agonists can lead to bradycardia, which can be associated with decreased MAP and sudden cardiac arrest. Bradycardia during spinal anesthesia is believed to result from at least two causes: blockade of sympathetic cardioaccelerator fibers and decreased venous return to the heart. A high level of sensory blockade by spinal anesthesia causes both of these effects. However, decrease in preload has been reported to be the main cause of large decreases in HR (23,24). Therefore, severe bradycardia can develop during spinal anesthesia even when the sensory blockade level is below that necessary to produce complete sympathetic blockade. Carpenter et al. (21) observed that peak sensory block height causing the development of severe bradycardia was above T5; moreover, the use of phenylephrine for the treatment of spinal hypotension has been cautioned against because bradycardia can develop when the level of sensory block is above T7 (3). In our study, in addition to the low level of sensory block, crystalloid preloading of 12 mL/kg was performed, with 8 mL/kg of the preload given before and 4 mL/kg after intrathecal injection. The low level of block positioning and the moderate fluid preloading might have been the main factors counteracting the development of bradycardia. The total number of patients in this study, however, was too small to determine the safety against bradycardia or hypertension. Therefore, a large-scale study may be needed to confirm the safety of this approach.
The timing of IM injection of phenylephrine to achieve optimal efficacy is difficult to predict. The peak effect of IM injection of phenylephrine has been suggested by results of pharmacokinetic studies to be 10–15 minutes after administration (25). However, in our study, we found reductions in the incidence of spinal anesthesia-induced hypotension in all phenylephrine groups, with no difference in the times to first requirement for rescue IV ephedrine. Additionally, no hypertension was found after IM administration of phenylephrine, when a peak effect of phenylephrine would have been expected. This suggests that the IM administration of phenylephrine immediately after the induction of spinal anesthesia is not too late to achieve a beneficial effect.
In conclusion, we demonstrated that prophylactic injection of 1.5 mg of phenylephrine IM is a safe and effective means for reducing the incidence of hypotension associated with hyperbaric tetracaine spinal anesthesia during surgical repair of hip fracture in normotensive and hypertensive elderly patients.
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References |
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