The Addition of Phenylephrine Contributes to the Development of Transient Neurologic Symptoms after Spinal Anesthesia with 0.5% Tetracaine 

With institutional review board approval and written informed consent, we studied 160 patients classified as American Society of Anesthesiologists physical status I or II who were scheduled for elective surgery on a lower limb or perineum. Patients with a history of back pain, coagulation abnormality, or neurologic disease were excluded. Some demographic and intraoperative data collected from the subset of supine patients in the present study were included in a subsequent study of spinal anesthesia. [21]

Premedication consisted of atropine (0.005–0.01 mg/kg) and hydroxyzine (0.5–1 mg/kg) given intramuscularly approximately 1 h before anesthesia. Intraoperative monitoring included noninvasive blood pressure and heart rate monitoring, electrocardiography, and pulse oximetry. After an intravenous infusion of acetated Ringer's solution was initiated at a rate of 10 ml [center dot] kg sup -1 [center dot] h sup -1, patients were placed in the lateral decubitus position. The lumbar area was cleansed with an iodine-containing solution, wiped dry, and then approximately 2 ml of a 1% lidocaine solution was infiltrated for local anesthesia of the skin and the subcutaneous tissue using a 25-gauge needle. Under sterile conditions, the lumbar puncture was performed at the L3-L4 interspace with a 25-gauge Quincke needle (Top Corporation, Tokyo, Japan) using the midline approach.

A sequential sampling strategy was used to assign patients to receive one of four anesthetic solutions such that every fourth patient was assigned to each group. Patients were excluded from the study if subarachnoid puncture could not be accomplished at the initial interspace, cerebral spinal fluid flow obtained with initial puncture was suboptimal, bleeding through the needle occurred, or paresthesia was encountered. In the event of exclusion, the next patient was assigned to receive the same anesthetic solution that the excluded patient would have received. Group assignment and drug preparation were performed by an investigator who did not provide care or collect outcome data.

After obtaining a free reflux of cerebrospinal fluid, the test solution (2–3 ml, calculated based on patient height) was administered at a rate of approximately 0.1 ml/s with the bevel of the needle oriented toward the dependent side. To reconfirm correct needle placement after injection of study solution, approximately 0.1 ml cerebrospinal fluid was aspirated and reinjected.

Group I received 0.5% tetracaine in 7.5% glucose; group II received 0.5% tetracaine in 0.75% glucose; group III received 0.5% tetracaine in 7.5% glucose with 0.125% phenylephrine; and group IV received 0.5% tetracaine in 0.75% glucose with 0.125% phenylephrine. The solutions were prepared immediately before injection by dissolving 20 mg crystalline tetracaine hydrochloride (Kyorin Pharmaceutical, Tokyo, Japan) in a combined solution of 3 ml 10% or 1% glucose (Otsuka Pharmaceutical, Naruto, Japan) and 1 ml sterile water (Otsuka Pharmaceutical) or 0.5% phenylephrine (Kowa, Nagoya, Japan). Table 1lists the physical characteristics of the solutions.

Patients were immediately placed supine and remained level for at least 30 min after injection and before surgery started. The extent of sensory blockade was assessed bilaterally by pinprick using a 23-gauge needle, and the degree of motor blockade was evaluated by a modified Bromage scale [22] ranging from 0 to 4, where 0 = able to move hip, knee, ankle, toes; 1 = unable to move hip, able to move knee, ankle, and toes; 2 = unable to move hip and knee, able to move ankle and toes; 3 = unable to move hip, knee and ankle, able to move toes; and, 4 = unable to move hip, knee, ankle, and toes. Measurements were taken by an investigator blinded to the local anesthetic solution injected, at 5-min intervals for 30 min, and then at 30-min intervals until two-segment regression was achieved. Hypotension was treated by intravenous administration of ephedrine if systolic arterial pressure decreased by more than 25% from baseline, or symptoms such as nausea or dizziness were reported.

On postoperative day one, but more than 24 h after surgery, patients were interviewed concerning transient neurologic symptoms by an investigator unaware of the local anesthetic solution injected. These symptoms were defined as pain or dysesthesia in the legs or buttocks starting within 24 h of, but after recovery from, spinal anesthesia. Localized back pain at the site of injection was, by definition, excluded. When a symptom was noted, a sensory and motor examination was performed, and the examination was repeated on a daily basis until the symptoms resolved.

Results are expressed as means +/- SD or median and 10th and 90th percentiles. Continuous variables were compared using one-way or two-way analysis of variance and the Student-Newman-Keuls test. The height of sensory block and the degree of motor block were compared using the Kruskal-Wallis test and the Student-Newman-Keuls test. Chi-squared analysis, with the Bon-ferroni correction if necessary, was used to compare the incidence of transient neurologic symptoms across study groups. P < 0.05 was considered significant.

One-hundred eighty-three patients gave consent. Twenty-three were excluded before they could receive anesthetic (patients 7, 4, 4, and 8 from groups I, II, III, and IV, respectively), resulting in a study population of 160 patients. Excluded were nine patients who required multiple attempts to achieve dural puncture, nine who experienced a paresthesia, and five in whom bleeding from the spinal needle occurred. Patient demographics, the dose of tetracaine administered, and surgical procedures performed did not differ significantly among the four study groups (Table 2and Table 3).

All of the anesthetic solutions produced satisfactory anesthesia, including appropriate motor block for the proposed surgery. However, solutions in 7.5% glucose produced significantly more extensive block than did those in 0.75% glucose, whereas peak dermatomal levels to pinprick did not change with the addition of phenylephrine (Table 4). All the study solutions were associated with similar maximum reduction in both systolic blood pressure and heart rate. However, there was a statistically significant increase in the use of ephedrine in patients receiving the higher concentration of glucose. The time for two-segment regression was prolonged significantly with phenylephrine. There were no differences among groups in duration of surgery, the number of procedures performed with the patient in the lithotomy position, or the number of operations involving the knee.

Transient neurologic symptoms were observed in 10 patients (12.5%) receiving phenylephrine, 6 in group III (7.5% glucose) and 4 in group IV (0.75% glucose), but in only one patient (1.3%) receiving spinal anesthesia without phenylephrine. The difference in the incidence of transient neurologic symptoms between groups with and without phenylephrine was statistically significant (P = 0.012); in contrast, there was no significant difference in the incidence between groups receiving 7.5% glucose and 0.75% glucose (Table 5). Perioperative clinical and hemodynamic characteristics in patients given phenylephrine did not differ between those with and without transient neurologic symptoms (Table 6).

Pain was characterized as dull, aching, or burning and was bilateral in all but one patient in group III and in one patient in group IV. Dysesthesia was reported by one patient in group III and one patient in group IV, and both of these patients also reported pain (Table 5). In one additional patient in group IV, unilateral buttock and leg pain was associated with ipsilateral hypesthesia in the region of S3; this persisted for 3 days, 2 days beyond resolution of the pain. None of the patients appeared distressed or disabled by these symptoms. None had evidence of bowel or bladder dysfunction or abnormal muscle-tendon reflexes. Symptoms resolved within 5 days in all patients except one in group III whose pain lasted for 13 days.

These results show that transient neurologic symptoms may occur after spinal anesthesia with tetracaine and that adding phenylephrine to the anesthetic solution increases the incidence of these symptoms. The results also support previous data indicating that the concentration of glucose in the anesthetic solution does not affect the occurrence of this complication. [14]

Concern that transient neurologic symptoms might follow uncomplicated single-injection spinal anesthesia arose when Schneider et al. [6] reported four cases of lower extremity pain or dysesthesia associated with the use of 5% lidocaine in 7.5% dextrose. Several studies have since shown that this complication commonly occurs when lidocaine is used for spinal anesthesia: In a prospective surveillance study by Hampl et al., [12] lower extremity pain was reported by 37% of patients receiving hyperbaric 5% lidocaine. Similarly, a surveillance study by Tarkkila et al. [13] found a lower (10%), but still substantial, incidence of this complication associated with this anesthetic solution. In a follow-up randomized study, Hampl et al. [14] again found a high incidence (32%) of symptoms, equivalent when 5% lidocaine was administered with either 7.5% or 2.7% glucose. In a subsequent randomized study, Pollock et al. [15] reported symptoms in 16% of patients receiving either 5% hyperbaric lidocaine with epinephrine or 2% isobaric lidocaine, whereas more recently, Hampl et al. [16] reported 32% and 40% incidences, respectively, with equivalent hyperbaric solutions of 5% and 2% lidocaine.

In our study, only 1.3% of patients receiving tetracaine without phenylephrine reported transient neurologic symptoms. This low incidence suggests that, like bupivacaine, tetracaine is less likely to produce symptoms than is lidocaine. However, because tetracaine and lidocaine were not directly compared, this perception clearly requires confirmation.

As previously shown, [23] phenylephrine, a potent alpha-adrenergic agonist, increased the duration of tetracaine spinal anesthesia. Prolongation of spinal anesthesia is likely due to decreased uptake of tetracaine secondary to phenylephrine-induced vasoconstriction. Thus one possible explanation for the increased incidence of transient neurologic symptoms with phenylephrine is an increase in the effective exposure to anesthetic. Alternatively, vasoconstriction, per se, might increase the occurrence of symptoms by inducing localized ischemia.

Potentiation of transient neurologic symptoms by a vasoconstrictor may not occur with other commonly used local anesthetics. Injected intrathecally, tetracaine produces a significant increase in spinal cord blood flow, an effect that can be prevented or reversed by epinephrine. [20] Vasodilation is less prominent with lidocaine, [24] and bupivacaine induces vasoconstriction. [25] Predictably, vasoconstrictors appear to be less effective at prolonging lidocaine spinal anesthesia than tetracaine spinal anesthesia [23,26,27]; their effect on bupivacaine spinal anesthesia remains controversial and is, at best, minimal. [28]

Some clinical data suggest that adding epinephrine does not increase transient neurologic symptoms induced by lidocaine: In a recent study, [15] the incidence of back pain with radiation was the same whether lidocaine was administered with or without this agent. However, nonequivalent solutions were used, with the epinephrine group receiving hyperbaric 5% lidocaine with glucose and the other group receiving a glucose-free isobaric solution of 2% lidocaine. In addition, the apparent discrepancy between the results of the present study and these previous data may merely reflect differences in effect between epinephrine and phenylephrine. The reported lack of potentiation of lidocaine-induced transient neurologic symptoms by epinephrine also conflicts with preliminary animal data demonstrating that concurrent administration of epinephrine enhances sensory deficits resulting from intrathecal administration of lidocaine. [29] However, it has not been established that anesthetic-induced sensory impairment or histologic damage share a common mechanism with transient pain and dysesthesia.

The results of the present study do not preclude that transient neurologic symptoms may be produced by phenylephrine alone. Because this was a clinical study, it would not have been appropriate to include a control group receiving only phenylephrine. Of note, in rats, intrathecal epinephrine potentiates lidocaine-induced sensory deficit but produces neither sensory impairment nor morphologic damage when administered without anesthetic. [29] However, the use of a different anesthetic and vasoconstrictor, and uncertainty regarding the commonality of mechanism, warrant caution when extrapolating from these data to transient clinical effects.

There are many possible causes for the neurologic symptoms after spinal anesthesia that we observed in this study. One important cause, mechanical trauma, can be largely eliminated because patients who experienced paresthesia required multiple attempts at dural puncture, or in whom bleeding developed, were excluded from study. Most other causes, such as global ischemia, infection, and immunologic reaction, also can be excluded based on clinical circumstances and the results of the study. Unrelated factors or indirect effects, such as prolonged pressure points or ligamentous laxity secondary to muscular relaxation, could result in transient myofascial pain. [30] However, the association with particular anesthetic solutions suggest that a direct effect of the anesthetic solution is likely. Regardless of the cause, the clinical course of patients in whom neurologic symptoms developed in the present study is similar to that previously reported with lidocaine, [6–16] implying a common mechanism.

In one patient, pain was associated with hypesthesia which, to our knowledge, has not been reported before. Although this finding raises suspicion that this patient's pain may have been neuropathic, it is possible that hypesthesia and pain resulted from independent mechanisms. Regardless of whether this was related to pain, the relevant question is whether this sensory abnormality represents prolonged functional block or injury, and whether it is related to technique, the anesthetic, the specific combination of agents (tetracaine and phenylephrine), or to an unrelated factor. Thus whether hypes-thesia represents a distinguishing feature of an isolated case or a link between transient neurologic symptoms and the persistent deficits associated with higher doses of anesthetic is not known.

The present study used a systematic sampling strategy. Although less rigorous than randomization, we found no difference in characteristics among the four groups (Table 2and Table 3). More importantly, the investigator who administered the anesthetic, conducted the interviews, and collected the data was unaware of the sampling regimen and the patient's group assignment.

The finding in the present study that patient position did not affect the occurrence of symptoms is surprising. This conflicts with current hypotheses and the common perception that the lithotomy position predisposes patients to development of radicular symptoms. In the initial report by Schneider et al., [6] all four patients were in the lithotomy position, leading the authors to postulate that stretch on the cauda equina reduced blood flow, increasing the vulnerability of these nerves to anesthetic toxicity. Recent preliminary data from an epidemiologic study appear to support the concept that the lithotomy position increases the potential for transient neurologic symptoms. [31]

That stretch on a nerve might contribute to transient toxicity also has been used to explain a higher incidence of transient symptoms observed among patients receiving intrathecal lidocaine for knee arthroscopy (13%) than among those receiving this anesthetic for hernia repair (5%)[15]: For knee surgery, patients were positioned supine with the nonoperative leg straight at the hip and flexed 90 degrees at the knee while the operated leg was manipulated as needed to facilitate surgery; herniorrhaphy was performed with the patient in standard supine horizontal position.

One possible explanation for the lack of effect of patient position is that the present protocol required patients to be studied supine for at least 30 min, which may have negated the effect of subsequent surgical positioning. Alternatively, these discrepant findings might have resulted from use of a different anesthetic solution.

Two concentrations of glucose were used in the present study. The higher concentration was associated with a slightly higher incidence of symptoms, but this difference was not statistically significant. Although it is possible that this lack of significance reflects lack of statistical power, the present results are consistent with previous clinical data suggesting that the concentration of glucose and the osmolarity of the anesthetic solution are unimportant in the development of transient neurologic symptoms. [14] These results also are consistent with animal data demonstrating that the addition of 7.5% glucose does not alter the neurotoxic potential of intrathecally administered 5% lidocaine. [32] But, again, the relation between transient clinical symptoms and neurotoxic damage has not been established.

Our study shows that phenylephrine prolongs the duration of tetracaine spinal anesthesia and increases the incidence of transient neurologic symptoms. Our results also appear to confirm and extend previous data suggesting that the glucose concentration and osmolarity of the anesthetic solution do not affect the potential for these symptoms; however, they do not confirm the importance of patient positioning. These findings suggest that phenylephrine perhaps should not be used to extend the duration of tetracaine spinal anesthesia. Additional studies are needed to determine whether other vasoconstrictors (e.g., epinephrine) increase the risk for neurologic symptoms associated with tetracaine spinal anesthesia.

The authors thank Dr. Karl Hampl for many helpful discussions, and Winifred von Ehrenburg, M.A., for editorial advice.

*FDA Safety Alert: Cauda equina syndrome associated with use of small-bore catheters in continuous spinal anesthesia. Washington, DC, Food and Drug Administration, May 29, 1992.