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ANALGESIA

The Effects of Intravenous Granisetron on the Sensory and Motor Blockade Produced by Intrathecal Bupivacaine

From the Department of Anesthesia, Faculty of Medicine, King Faisal University, Saudi Arabia.

Address correspondence and reprint requests to Dr. Hany A. Mowafi, Anesthesiology Department, King Fahd University Hospital, PO Box 40081, Al-Khobar 31952, Saudi Arabia. Address e-mail to hany_mowafi{at}hotmail.com.

Abstract

BACKGROUND: We hypothesized that pretreatment with IV granisetron would affect the sensory and motor components of spinal blockade through 5-HT₃ receptor blockade.

METHODS: Forty unpremedicated patients scheduled for elective knee arthroscopy under spinal anesthesia were randomly allocated to receive either IV granisetron 1 mg (granisetron group) or saline (control group) on arrival to the operating room. Two and half milliliters (12.5 mg) of hyperbaric bupivacaine 0.5% was injected intrathecally. Regression of the sensory level and motor blockade, and the hemodynamic changes were evaluated.

RESULTS: There were no significant differences between the two groups in the maximum cephalad spread of sensory block or the time to maximum sensory level. Compared with the control group, patients who received granisetron had significantly faster sensory regression times by two segments (69.8 ± 25.5 min vs 88.0 ± 27.8 min, P = 0.036), to segment T12 (105.5 ± 25.1 min vs 127.0 ± 30.5 min, P = 0.019) and to segment S1 (162.8 ± 41.1 min vs 189.8 ± 39.8 min, P = 0.041), respectively. In contrast, motor block did not differ between the two groups at any study time. No significant differences were detected between the two study groups in the hemodynamic data.

CONCLUSION: We concluded that IV granisetron facilitated a faster recovery of sensory block after bupivacaine subarachnoid anesthesia.

Granisetron is a highly selective 5-hydroxytryptamine3 (5-HT₃) receptor antagonist.1 It is not metabolized by the cytochrome P450 (CYP) 2D6 pathway and, therefore, is associated with less variation in patient response due to factors such as pharmacogenomic differences.2 It is a potent antiemetic, administered to prevent or treat perioperative or chemotherapy and radiotherapy-induced nausea and/or vomiting.3

The 5-HT₃ binding sites are abundant at the spinal level.4 These receptors are located in the superficial laminae and substantia gelatinosa of the spinal cord.5 Although the spinal serotonergic mechanisms in pain modulation are complex, several studies have confirmed the role of 5-HT₃ receptors in antinociception.6–8 In rats, intrathecal injection of the selective 5-HT₃ receptor agonist, 2-methyl-serotonin, revealed an antinociceptive activity. This effect was antagonized by the selective 5-HT₃ receptor antagonists.9 In humans, the cerebrospinal fluid serotonin levels increased three-fold after spinal bupivacaine administration.10 In addition, ondansetron antagonized the sensory blockade of spinal lidocaine.11

The aim of this study was to examine the effects of granisetron on the sensory and motor block resulting from subarachnoid anesthesia using hyperbaric bupivacaine.

METHODS

After local research committee approval and an informed written patient consent, 40 adult patients of ASA I–II, scheduled for elective knee arthroscopy under spinal anesthesia, were included in this study. No sedative or analgesic premedication was given. Exclusion criteria were patients with difficulty in communicating, chronic pain, neurological diseases, and those receiving opioids, -2 agonists, calcium channel blockers, drugs that act on serotonin receptors or affect the level of serotonin, in addition to any contraindication to spinal anesthesia.

Patients were randomly allocated using an online research randomizer (http://www.randomizer.org) into two equal groups (20 patients each) to receive either granisetron (granisetron group) or saline (control group). The granisetron group received IV 1 mg granisetron (Kytril, Roche) on arrival to the operating room. The control group received an equal volume of 0.9% normal saline solution IV at the same time. Drugs were administered by an anesthesiologist who did not participate in the study. In the operating room, standard intraoperative monitoring included 3-lead electrocardiogram, plethysmographic pulse oximeter, and noninvasive arterial blood pressure using a Datex-Ohmeda S/5, ADU machine. Ten milliliters per kilogram of lactated Ringer's solution was infused 20 min before the beginning of spinal anesthesia, and infusion was continued at 5 mL · kg^–1 · h^–1 after spinal injection until the end of surgery. Oxygen 3 L/min via nasal cannula was administered during anesthesia and surgery.

Spinal anesthesia was performed with the patient in the sitting position using the midline approach at the L3–4 intervertebral space, with a 25-gauge Quincke needle. After a free flow of cerebrospinal fluid was obtained, 2.5 mL hyperbaric bupivacaine 0.5% (Marcaine®, AstraZeneca, Södertälje, Sweden) was injected without barbotage in approximately 15 s, with the bevel of the needle oriented the cephalad. After injection, patients were placed in the supine position and maintained in this position until the end of the study. All spinal blocks were performed by the same consultant anesthesiologist.

In the operating room and in the recovery room, an anesthesiologist who was unaware of the patient's group assignment recorded the following variables:

• Mean arterial blood pressure and heart rate every 5 min during surgery, then every 15 min until the end of the study.
  
• Cephalad sensory level by loss of pinprick sensation bilaterally at the midclavicular line using a short-beveled 25-gauge needle, every 2 minutes until the sensory block remained at the same level at two consecutive times and was recorded as maximal sensory block. Thereafter, the patients were evaluated every 15 min until sensory level regression to S1.
  
• Motor block every 2 min until maximal motor blockade, then every 15 min until complete motor recovery, on a previously described modified Bromage scale12 as follows: 0 = able to move hip, knee, ankle, and 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, or toes.
  

A 30% decrease in systolic blood pressure below baseline was treated with 5–10 mg IV ephedrine, and decrease of the heart rate <45 bpm with 0.5 mg IV atropine.

From the recorded variables, we assessed the following time intervals, defined as time elapsed from spinal injection to:

1. Maximum sensory block
   
2. Regression of sensory level by two dermatomes
   
3. Regression of sensory level to T12
   
4. Regression of sensory level to S1
   
5. Maximum motor block
   
6. Motor recovery by one level
   
7. Complete motor recovery (modified Bromage scale = 0)
   

Sample size was selected to detect a mean difference of 25% in the duration of block between the two groups with type I error of 0.05 and type II error of 0.20. Power analysis was based on the study of hospital data for intrathecal bupivacaine, which revealed duration of block around 150–180 min and standard deviation (sd) 20%–25% of the duration of block. Data were tested for normal distribution using the Kolmogorov–Smirnov test. Continuous data, expressed as the mean ± sd, were compared using the unpaired Student's t-test. Discrete data (such as sensory levels) are expressed as the median with range and were compared using the Mann–Whitney U test. Fisher's exact test was used to compare ordinal data. P < 0.05 was considered significant. Analysis was performed using Statistica software version 6.0 for windows (Statsoft, Inc., Tulsa, OK).

RESULTS

There were no significant differences between the two groups with regard to age, weight, height, gender, and duration of surgery (Table 1).

The maximum cephalad spread of sensory block was similar (P = 0.13), since it was T4.5 (range, T2–8) in the control group and T5 (range, T3–9) in the granisetron group. The time course of spinal block in both groups is summarized in Table 2, which shows that patients who received granisetron had significantly faster sensory regression times by two segments, to segment T12 and to segment S1.

There were no significant differences between the two groups in hemodynamic variables. One patient in each group required 10 mg of ephedrine to treat hypotension. Atropine was never given, and neither anesthetic failure nor complications related to spinal anesthesia were observed.

DISCUSSION

The important finding in this study is that IV granisetron administration before spinal bupivacaine results in a faster recovery of the sensory blockade. On the contrary, the offset of motor blockade was similar in both groups.

Our results agree with those of Fassoulaki et al., who reported that systemic ondansetron, a 5-HT₃ antagonist, caused a faster regression of the sensory block after spinal lidocaine.11 In addition, continuous IV administration of ondansetron and tramadol decreased its analgesic potency on postoperative pain.13 In rats, intrathecal injection of serotonin antagonists significantly reduced the nociceptive threshold to both inflammatory and thermal pain.14 No previous study examined the concomitant administration of IV granisetron and spinal bupivacaine in humans.

Granisetron, in contrast to ondansetron, which acts on mixed receptors, strongly and selectively binds to the 5-HT₃ receptors with minimal or no affinity for other 5-HT receptors, or dopaminergic, adrenergic, histaminic, and opioid receptors.15 Additionally, it has minimal adverse effects and possible drug interactions.1,3

The potential mechanisms for our observation are not clear. However, electrophysiologic and behavioral studies in animals have clarified the antinociceptive mechanisms of the descending serotonergic system at the spinal cord level.6,16 It directly hyperpolarizes the membrane of substantia gelatinosa neurons, inhibits the excitatory transmitter, glutamate, release from A and C afferent fibers presynaptically and increases the inhibitory transmitters release including -aminobutyric acid and glycine from the interneurons.16

The role of 5-HT₃ receptors in pain modulation is conflicting, as they could mediate excitatory and inhibitory effects, depending on variables such as the concentration of 5-HT or the state (sensitized/desensitized) of the spinal cord.17 On the contrary, peripheral 5-HT₃ receptors that mediate a component of inflammatory pain may be effectively inhibited through the local administration of granisetron and tropisetron.18–20

Collection of the sensory and motor regression data at 15-min intervals is a limitation of our methodology. However, more frequent recording might have caused further disturbances to the surgery and patient comfort. The dose of granisetron used in our study was 1 mg as recommended by the Food and Drug Administration and the prescribing information of the drug for treatment of postoperative nausea and vomiting (PONV). Moreover, Fujii and Tanaka found that the minimal effective dose of granisetron for treatment of PONV in women after breast surgery was 20 µg/kg body weight in a prospective, randomized, double-blind, placebo-controlled study.21 Although most studies have demonstrated granisetron's efficacy at 1 mg dose for prophylaxis of PONV, other researchers showed that substantially lower doses (0.1–0.35 mg) of granisetron have been effectively used as a prophylaxis and/or treatment of PONV.22,2 The effect of lower doses of granisetron on the sensory level regression time after spinal bupivacaine remains unknown.

This study raises several concerns that need to be further investigated. Should the dose of bupivacaine for spinal anesthesia be adjusted whenever granisetron is concomitantly used? The potential for granisetron to reverse perioperative analgesia also requires further investigation. In addition, other studies are required to determine whether patients with intractable pain who are treated by granisetron demonstrate resistance to neuraxial analgesia.

In conclusion, IV administration of granisetron, in a dose of 1 mg, before intrathecal bupivacaine results in a faster recovery of sensory block in adult patients.

Footnotes

Accepted for publication November 29, 2007.

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