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The effect of transdermal nitroglycerine on intrathecal fentanyl with bupivacaine for postoperative analgesia following gynaecological surgery.

Fentanyl is a potent, short-acting, synthetic, lipophilic spinal opioid. It is commonly used as an adjunct to intrathecal local anaesthesia but is limited by dose-dependent adverse effects (1,2). A key strategy in maintaining analgesic effectiveness while reducing the incidence of adverse effects of neuraxial opioids is to potentiate and/or prolong their antinociceptive effect by the addition of adjuncts. The opioid analgesic effect is mediated in part through activation of inhibitory descending pain pathways, involving nitric oxide (NO) through the NO-cGMP signal transduction system (3).

Nitric oxide is a central neurotransmitter (4,5). It is widely accepted that NO occupies a key position in the antinociceptive and tolerance-inducing action of opioids and in the endogenous mediation of pain. In vitro studies show that opioids inhibit activation of adenyl cyclase (6) and also stimulate the formation of cGMP (7). This L-arginine/NO/cGMP pathway plays an important role in spinal nociception (8,9). Hence, it is logical that a NO generator nitroglycerine patch might potentiate the spinal analgesic effect of an opioid.

NO interacts synergistically with morphine after intravenous or spinal administration through the activation of this pathway (8,10-12). The primary objective of this study was to determine whether a combination of transdermal nitroglycerine (a source of exogenous NO) would enhance the analgesic efficacy of intrathecal fentanyl in patients undergoing abdominal hysterectomy. We also investigated whether such a combination had secondary haemodynamic effects and side-effects. There have been several attempts to clarify the role of NO in pain sensitivity and the interaction of NO with opioids, particularly related to the role of NO in opioid analgesia and withdrawal, but the results are inconsistent (13-15). There is a paucity of work involving human subjects. Although the interaction of nitroglycerine with sufentanil and oral morphine has been studied previously, to the best of our knowledge the combination of intrathecal fentanyl and transdermal nitroglycerine has not been studied before.

METHODS

The Ethical Committee of Rajasthan University of Health Sciences, Jaipur approved this prospective, randomised, placebo-controlled, double-blind study protocol. After obtaining informed consent, a detailed physical examination of the patient was done the day before the proposed surgery. Patients of ASA grade I or II, aged 30 to 50 years, weighing 45 to 65 kg and scheduled for elective total abdominal hysterectomy, with or without bilateral salpingo-oophorectomy, were included in the study. Patients with a contraindication to spinal anaesthesia or major neurological, cardiovascular, metabolic, respiratory, renal disease or coagulation abnormalities were excluded.

The principles of simple random sampling were applied. Patients were randomised by computer into one of four groups, consisting of 30 subjects in each. In the holding room, the concept of a visual analogue scale (VAS), which consisted of a 100 mm line with zero equalling 'no pain at all' and 100 equalling 'the worst possible pain' was introduced to the patient. All patients were hydrated with 10 ml/kg Ringer's lactate solution preoperatively and premedicated with 1 mg midazolam intravenously (IV). Patients were positioned in the left lateral decubitus position for spinal anaesthesia which was performed using a 25 gauge Quincke needle at the L3 - L4 interspace. A total drug volume of 3.5 ml was injected and the patient was positioned supine with a 15[degrees] head-down tilt. Patients in the bupivacaine group (group B) received 3 ml bupivacaine 0.5% plus saline 0.5 ml and a placebo patch. The bupivacaine nitroglycerine group (group B-N) received 3 ml bupivacaine 0.5% plus saline 0.5 ml and a nitroglycerine patch (5 mg/24 h). The fentanyl group (group F) received bupivacaine 0.5% 3 ml plus fentanyl 25 [micro]g and a placebo patch. The fentanyl nitroglycerine group (group F-N) received 3 ml bupivacaine 0.5% plus fentanyl 25 [micro]g and a nitroglycerine patch (5 mg/24 h).

The drug combinations were prepared by one anaesthetist while the second anaesthetist, who was blinded to the drug selection, administered the drug intrathecally and observed the patient intraand postoperatively. The patients were blinded throughout the study. All patients received supplementary oxygen at 4 l/min via a Ventimask.

The transdermal patch was applied on the thorax, in a non-anaesthetised area, 20 minutes after the spinal injection and haemodynamic stabilisation. The nitroglycerine patch (Nitroderm TTS; Novartis Pharma) had a total nitroglycerine content of 25 mg per patch and delivered nitroglycerine at 20 to 25 [micro]g/[cm.sup.2]/h (i.e. 5 mg over 24 hours). The drug releasing surface area of the patch was 10 [cm.sup.2]. The placebo patch was prepared by the same anaesthesist who prepared the intrathecal drug combinations. It was an adhesive patch similar in shape and size to that of the nitroglycerine patch (surface area 10 [cm.sup.2]). To further reduce observation bias, all the patches were covered with white opaque paper.

The cephalad spread of sensory block and the degree of motor block of the lower limbs were recorded every minute. The level of sensory block was assessed using a 22 gauge needle and recorded as loss of sensation to pinprick, checking in a caudal to cephalic direction. Motor block was recorded according to the Bromage scale (Table 1). Blood pressure was monitored non-invasively every five minutes throughout surgery and heart rate via electrocardiogram and oxyhaemoglobin saturation (pulse oximetry) monitored continuously. A decrease in mean arterial pressure greater than 15% below the pre-anaesthetic baseline value was treated with incremental doses of ephedrine 4 mg IV. A decrease in heart rate below 50 beats per/minute was treated with incremental doses of atropine 0.3 mg IV.

Postoperative assessments included pain VAS at two hours and at the time of giving the rescue analgesia, and adverse effects (haemodynamic changes, respiratory depression, shivering, nausea, vomiting, pruritus and headache) over 24 hours. The duration of effective analgesia was defined as the time from intrathecal drug administration to the patient's first request for rescue analgesic. This constituted the primary end-point of the study, though the patients were kept under observation for a total period of 24 hours to rule out any adverse effects due to the study drugs. Patients were allowed rescue analgesics on demand. Intramuscular diclofenac 75 mg was given as rescue analgesic. The duration of motor block was defined as the time of attainment of Bromage grade IV block (onset) until reversal to Bromage grade II.

Statistical analysis

The sample size was based on experimental data. After reviewing the previous studies, it was decided that a 20% of difference should be the minimum detectable difference of means in all four groups. The standard deviation of residual was also kept the same (20% of average duration of all four groups). We hypothesised that use of intrathecal fentanyl would increase the time to first rescue analgesic by 20% in the population studied and that use of a transdermal nitroglycerine patch would increase the time to first rescue analgesic by more than 100% compared with the control group. The alpha value was 0.05 and the power (1-[Beta]) of the study was 0.80. Thus, the calculated sample size for each group was 23 patients. To preserve the designing effect it was decided to include 30 patients in each group.

Statistical analysis was performed with SPSS, version 15.0, for Windows statistical software package (SPSS inc., Chicago, IL, USA). The normality of the data distributions was evaluated using the Shapiro-Wilk test. Categorical data, i.e. ASA grade, type of surgery and the incidence of adverse events (hypotension, bradycardia, respiratory depression, shivering, nausea, pruritus and headache) are presented as numbers (percent) and were compared among groups using chi-square test. P <0.05 was considered statistically significant. Groups were compared for demographic data (age, weight), duration of surgery, time for two segment regression, VAS score, total duration of motor block and analgesia by analysis of variance and t-test. Probability was considered to be significant if less than 0.05. Data are represented as mean and standard deviation.

RESULTS

A total of 150 patients were assessed for eligibility. Of these, 24 patients did not fulfill the study criteria and were excluded, thus 126 patients were enrolled in the study. Six patients were excluded because of failed/partial spinal block, leaving a protocol-compliant sample size of 120. All groups were comparable with respect to age, gender, weight, ASA status, type of surgery and duration of surgery (Table 2). The sensory distribution of bupivacaine-induced spinal block was not changed by fentanyl and the level of loss of pinprick did not differ between groups at 5 (P=0.16) or 10 minutes (P=0.20) (Table 3).

The time interval from intrathecal injection to two-segment regression was prolonged in the study groups compared with the control group (Table 3). Two-segment regression in group F-N was 132.87 [+ or -]31.20 minutes and was significantly longer than groups B (P=0.0001), B-N (P=0.0013) and F (P=0.001).

A significantly longer duration of effective analgesia in F-N group was observed compared with other groups (P <0.001) (Table 3). The mean duration of effective analgesia in group F-N was 363.53[+ or -]34.09 minutes versus 249.3[+ or -]31.06 minutes in group F (P=0.000). VAS scores at two hours and at the time of giving rescue analgesia are shown in Table 4. The average VAS pain score at the time of giving rescue analgesic medication was similar among groups.

The mean arterial blood pressure trends are shown in Figure 1. There were no significant differences between groups regarding the incidence of perioperative adverse effects (Table 5). There was no significant difference between groups in the number of patients experiencing episodes of bradycardia (P=0.35) or hypotension (P=0.72). In both groups receiving fentanyl, two patients from each reported pruritus (P=0.56). One patient from group F and two patients from group B-N reported postoperative headache (P=0.73).

DISCUSSION

The results of our study showed an almost twofold increase (249 minutes) in postoperative analgesia from intrathecal bupivacaine and fentanyl (compared with 126 minutes when bupivacaine was given alone) and was in accordance with findings in the literature (16,17). Biswas et al (16) reported analgesia of 248 minutes in a bupivacaine plus fentanyl group compared with 150 minutes in a bupivacaine group among patients undergoing elective caesarean section. Khanna et al (17) similarly reported an increase in the total duration of analgesia among patients undergoing hip replacement DHS surgery.

More significantly, our study demonstrated enhancement of the antinociceptive effect of intrathecal fentanyl by transdermal nitroglycerine. Although 5 mg of transdermal nitroglycerine alone did not result in postoperative analgesia, it enhanced the analgesic effect of intrathecal fentanyl. The bupivacaine and nitroglycerine group reported total effective analgesia for 139 minutes whereas the combination of bupivacaine, fentanyl and nitroglycerine resulted in 364 minutes of postoperative analgesia, a threefold increase. These results confirm those of Lauretti et al (18) who reported 785 minutes of postoperative analgesia after arthroscopy and meniscectomy using sufentanil with bupivacaine and nitroglycerine. In their study also, there was no prolongation of analgesia when nitroglycerine was used with bupivacaine alone.

Our study found no clinically important difference in the haemodynamic parameters and adverse effects among the four groups. Similarly, Lauretti et al (18) reported no increase in adverse effects compared with their control group when using intrathecal opioid with transdermal nitroglycerine.

The exact mechanism of action of NO induced prolongation of the postoperative analgesic effect of fentanyl is not known. The following explanations are possible but need to be proven in future studies. In vitro investigations have demonstrated that morphine increases cGMP production (7). Further, it has been reported that the NO-cGMP pathway may be involved in the antinociception induced by morphine in the central nervous system (8,10,11,19). Guanylate cyclase activity in the brain is markedly stimulated by NO, generated from L-arginine or provided through an exogenous source20 as in the present study, through transdermal nitroglycerine. The possible involvement of this arginine-NO-cGMP pathway in the supraspinal mechanism of central analgesia is supported in the literature (20).

The activation of descending pain pathways involves the participation of NO and the mechanism of action is likely to include activation of second messengers such as cyclic guanosine monophosphate (cGMP). The NO-cGMP signal transduction system contributes to sensitisation of wide dynamic range spinothalamic tract neurons located in the deep dorsal horn. This sensitisation decreases the response of wide-dynamic-range neurons in the superficial dorsal horn and high-threshold cells in the superficial or deep layers to mechanical stimulation by intradermal nociceptive stimuli (21).

In another study, a transdermal nitroglycerine patch prolonged the duration of effective analgesia of intrathecal bupivacaine (15 mg) and neostigmine (5 [micro]g) (to 550 minutes) in patients undergoing vaginoplasty (22). Kaur et al (23) reported an increase in total analgesia in patients undergoing infraumbilical surgery using intrathecal bupivacaine and neostigmine with

transdermal nitroglycerine. The connection of these results with our study is that opioids produce analgesia by direct effects as well as by activating neural pathways that release non-opioid neurotransmitters. Opioids cause noradrenaline and acetylcholine release in the spinal cord by a naloxone-sensitive mechanism (24). Other studies suggest that these neurotransmitters are linked such that spinally released noradrenaline directly stimulates acetylcholine release by actions on [alpha.sub.2]-adrenoceptors. (25) Acetylcholine stimulates NO synthesis in the spinal cord (26) and this synthesis is necessary for the expression of analgesia secondary to the cholinomimetic agents (27), such as spinal neostigmine.

Intrathecal or epidural fentanyl acts mainly on neurons with opioid receptors in lamina III of the dorsal horn and laminae V and VII, producing a segmental antinociceptive effect (28). Recent studies showed that neurons containing nitric oxide synthase and located in laminae I through III of the dorsal horn (29) probably function as interneurons modulating sensory processing (30) in the spinal cord. These histological investigations support an antinociceptive interaction between fentanyl and NO.

To conclude, our study suggests that transdermal nitroglycerine alone does not show analgesic potential but that it enhances the analgesic effect of intrathecal fentanyl. The underlying mechanism of this augmentation has not been defined and needs further investigation. We provide further clinical evidence to validate the hypothesis that exogenous or endogenous NO contributes to a modulatory system of opioid function.

Accepted for publication on September 17, 2009.

REFERENCES

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(2.) Belzarena SD. Clinical effects of intrathecally administered fentanyl in patients undergoing cesarean section. Anesth Analg 1992; 74:653-657.

(3.) Zhuo M, Meller ST, Gebhart GF. Endogenous NO is required for tonic cholinergic inhibition of spinal mechanical transmission. Pain 1993; 54:71-78.

(4.) Dawson TM, Dawson VL, Snyder SH. A novel neuronal messenger molecule in brain: the free radical, NO. Ann Neurol 1992; 32:297-311.

(5.) Snyder SH. NO: first in a new class of neurotransmitters. Science 1992; 257:494-496.

(6.) Ronai AZ, Szekrly J. Opiate Peptides. CRC Press, Florida 1982; 1.

(7.) Minneman KP, Iversen LL. Enkephalin and opiate narcotics increase cyclic GMP accumulation in slices of rat neostriatum. Nature 1976; 262:313-314.

(8.) Duarte IDG, dos Santos IR, Lorenzetti B, Ferreira SH. Analgesia by direct antagonism of nociceptor sensitization involves the arginine-NO-cGMP pathway. Eur J Pharmacol 1992; 217:225-227.

(9.) Yamamoto T, Shimoyama N, Mizuguchi T. NO synthase inhibitor blocks spinal sensitization induced by formalin injection into the rat paw. Anesth Analg 1993; 77:886-890.

(10.) Duarte ID, Ferreira SH. The molecular mechanism of central analgesia induced by morphine or carbachol and the L-argininenitric oxide-cGMP pathway. Eur J Pharmacol 1992; 221:171-174.

(11.) Durate ID, Lorenzetti BB, Ferreira SH. Peripheral analgesia and activation of the nitric oxide-cyclic GMP pathway. Eur J Pharmacol 1990; 186:289-293.

(12.) Yamaguchi H, Naito H. Antinociceptive synergistic interaction between morphine and n omega-nitro 1-arginine methyl ester on thermal nociceptive tests in the rats. Can J Anaesth 1996; 43:975-981.

(13.) Majeed NH, Przewlocka B, Machelska H, Przewlocki R. Inhibition of nitric oxide synthase attenuates the development of morphine tolerance and dependence in mice. Neuropharmacology 1994; 33:189-192.

(14.) Pasternak GW, Kolesnikov YA, Babey AM. Perspectives on the N-methyl-D-aspartate/nitric oxide cascade and opioid tolerance. Neuropsychopharmacology 1995; 13:309-313.

(15.) Vaupel DB, Kimes AS, London ED. Nitric oxide synthase inhibitors. Preclinical studies of potential use for treatment of opioid withdrawal. Neuropsychopharmacology 1995; 13:315-322.

(16.) Biswas BN, Rudra A, Bose BK, Nath S, Chakrabarthy S, Bhattacharya S. Intrathecal fentanyl with bupivacaine for intraoperative and postoperative analgesia. Indian J Anaesth 2002; 46 (6):469-472.

(17.) Khanna MS, Singh IKJP. Comparative evaluation of bupivacaine plain versus bupivacaine with fentanyl in spinal anaesthesia in geriatric patients. Indian J Anaesth 2002; 46:199-203.

(18.) Lauretti GR, de Oliveira R, Reis MP, Mattos AL, Pereira NL. Transdermal nitroglycerine enhances spinal sufentanil postoperative analgesia following orthopedic surgery. Anesthesiology 1999; 90:734-739.

(19.) Ferreira SH, Duarte ID, Lorenzetti BB. The molecular mechanism of action of peripheral morphine analgesia: stimulation of the cGMP system via nitric oxide release. Eur J Pharmacol 1991; 201:121-122.

(20.) Moncada S, Palmer RMJ, Higgs EA. NO: physiology, pathophysiology and pharmacology. Pharmacol Rev 1991; 43:109-142.

(21.) Lin Q, Peng YB, Wu J, Willis WD. Involvement of cGMP in nociceptive processing by and sensitization of spinothalamic neurons in primates. J Neurosci 1997; 17:3293-3302.

(22.) Lauretti GR, Oliveira AP, Juliao MC, Reis MP, Pereira NL. Transdermal nitroglycerine enhances spinal neostigmine Postoperative analgesia following gynecological surgery. Anesthesiology 2000; 93:943-946.

(23.) Kaur G, Osahan N, Afza L. Effect of transdermal nitroglycerine patch on analgesia of low dose intrathecal neostigmine: an evaluation. J Anesth Clin Pharmacology 2007; 23:159-162.

(24.) Bouaziz H, Tong C, Yoon Y, Hood DD, Eisenach JC. Intravenous opioids stimulate norepinephrine and acetylcholine release in spinal cord dorsal horn. Systematic studies in sheep and an observation in a human. Anesthesiology 1996; 84:143-154.

(25.) Detweiler DJ, Eisenach JC, Tong C, Jackson C. A cholinergic interaction in alpha 2 adrenoceptor-mediated antinociception in sheep. J Pharmacol Exp Ther 1993; 265:536-542.

(26.) Xu Z, Tong C, Eisenach JC. Acetylcholine stimulates the release of nitric oxide from rat spinal cord. Anesthesiology 1996; 85:107-111.

(27.) Bouaziz H, Hewitt C, Eisenach JC. Subarachnoid neostigmine potentiation of alpha 2-adrenergic agonist analgesia. Dexmedetomidine versus Clonidine. Reg Anesth 1995; 20:121-127.

(28.) Nishio Y, Sinatra RS, Kitahata LM, Collins JG. Spinal cord distribution of 3H-morphine after intrathecal administration: relationship to analgesia. Anesth Analg 1989; 69:323-327.

(29.) Saito S, Kidd GJ, Trapp BD, Dawson TM, Bredt DS, Wilson DA et al. Rat spinal cord neurons contain nitric oxide synthase. Neuroscience 1994; 59:447-456.

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A. GARG *, F. AHMED [[dagger]], M. KHANDELWAL [[dagger]], V. CHAWLA *, A. P. VERMA [[double dagger]]

Department of Anaesthesia and Critical Care, Sawai Man Singh Medical College and Hospital, Jaipur, Rajasthan, India

* M.B., B.S., M.D., Resident.

[[dagger]] M.B., B.S, M.D., Associate Professor.

[[double dagger]] M.B., B.S., M.D., Consultant.

Address for correspondence: Dr Ashish Garg, 699 Frontier Colony, Adarsh Nagar, Jaipur-4 (Rajasthan), India.
Table 1
Bromage scale

Grade   Criteria                       Degree of block

I       Free movement of legs and      Nil (0%)
        feet

II      Just able to flex knees with   Partial (33%)
        free movement of feet

III     Unable to flex knees, but      Almost complete (66%)
        with free movement of feet

IV      Unable to move legs or feet    Complete (100%)

Anaesthesia and Intensive Care, Vol. 38, No. 2, March 2010

Table 2
Demographic profile of groups

                 Group B             Group B-N

Number of        30                  30
patients

ASA grade        18/12               15/15

Age, y           42.2 [+ or -] 7.9   42.2 [+ or -] 6.9

Weight, kg       56.8 [+ or -] 4.5   52.6 [+ or -] 9.5

Surgical time,   56.8 [+ or -] 7.7   59.2 [+ or -] 11.0
min

Type of
Surgery

TAH + BSO        21 (70%)            19 (63%)

TAH              9 (30%)             11 (37%)

                 Group F             Group F-N

Number of        30                  30
patients

ASA grade        20/10               17/13

Age, y           40.2 [+ or -] 6.0   42.5 [+ or -] 8.0

Weight, kg       56.8 [+ or -] 4.2   55.6 [+ or -] 6.5

Surgical time,   57.8 [+ or -] 9.1   59.0 [+ or -] 11.3
min

Type of
Surgery

TAH + BSO        21 (70%)            22 (73%)

TAH              9 (30%)             8 (27%)

Values are mean [+ or -] SD. ASA=American Society of Anaesthetists,
TAH=total abdominal hysterectomy, BSO=bilateral salpingo-oophorectomy.

Table 3
Characteristics of sensory and motor block

Sensory level (pinprick)                Group B

5 min *                                 [T.sub.9] ([T.sub.7]-[T.sub.9])

10 min *                                [T.sub.6] ([T.sub.5]-[T.sub.7])

Time for 2 segment regression (min)%    83.6 [+ or -] 21.2

Total duration of analgesia (min) (#)   125.9 [+ or -] 23.3

Onset of motor block [R] (min) *        9 [+ or -] 1.36

Total duration of motor block ($)       116.7 [+ or -] 10.9
(min)

Sensory level (pinprick)                Group B-N

5 min *                                 [T.sub.9] ([T.sub.7]-[T.sub.10])

10 min *                                [T.sub.6] ([T.sub.5]-[T.sub.7])

Time for 2 segment regression (min)%    88.9 [+ or -] 23.5

Total duration of analgesia (min) (#)   139.0 [+ or -] 18.6

Onset of motor block [R] (min) *        8.47 [+ or -] 1.20

Total duration of motor block ($)       118.4 [+ or -] 12.2
(min)

Sensory level (pinprick)                Group F

5 min *                                 [T.sub.9] ([T.sub.7]-[T.sub.9])

10 min *                                [T.sub.6] ([T.sub.5]-[T.sub.7])

Time for 2 segment regression (min)%    126.4 [+ or -] 26.8

Total duration of analgesia (min) (#)   249.3 [+ or -] 31.1

Onset of motor block [R] (min) *        8.6 [+ or -] 1.16

Total duration of motor block ($)       122.9 [+ or -] 16.4
(min)

Sensory level (pinprick)                Group F-N

5 min *                                 [T.sub.9] ([T.sub.7]-[T.sub.9])

10 min *                                [T.sub.6] ([T.sub.5]-[T.sub.7])

Time for 2 segment regression (min)%    132.9 [+ or -] 31.2

Total duration of analgesia (min) (#)   363.5 [+ or -] 34.1

Onset of motor block [R] (min) *        8.5 [+ or -] 1.4

Total duration of motor block ($)       113.2 [+ or -] 7.3
(min)

* P >0.05, [R] Bromage Grade IV, ($) Return to Bromage Grade II, %
significant difference between groups B and F (P=0.0001), groups
B and F-N (P=0.0001), groups F and F-N (P=0.001), groups B-N and F
(P=0.0086), groups B-N and F-N (P=0.0013), (#) significant difference
between groups B and B-N (P=0.18), groups B and F (P=0.000), groups B
and F-N (P=0.000), groups F and F-N (P=0.000).

Table 4
Pain

                Group B               Group B-N

Time to         125.9 [+ or -] 23.3   3 139 [+ or -] 18.6
first rescue
analgesic
(min)

Pain score      29.5 [+ or -] 6.7     18.5 [+ or -] 7.2
(2 h) (#)

Pain score at   28.3 [+ or -] 6.7     28.7 [+ or -] 7.0
first rescue
analgesic

                Group F               Group F-N

Time to         249.3 [+ or -] 31.1   363.5 [+ or -] 34.1
first rescue
analgesic
(min)

Pain score      0.00                  0.00
(2 h) (#)

Pain score at   24.9 [+ or -] 5.1     26.8 [+ or -] 7.0
first rescue
analgesic

(#) Pain scores are 0-100 visual analogue scale.

Table 5
Characteristics of haemodynamic and incidence of side-effects
(intraoperative and early postoperative period)

                   Group B    Group       Group F    Group
                              B-N                    F-N

Hypotension (#)    2 (6.7%)   3 (10%)     3 (10%)    2 (6.7%)

Bradycardia *      3 (10%)    1 (3.3%)    0 (0%)     2 (6.7%)

Respiratory        0 (0%)     0 (0%)      0 (0%)     0 (0%)
depression (##)

Shivering          2 (6.7%)   4 (13.3%)   2 (6.7%)   3 (10%)

Nausea, vomiting   2 (3.3%)   0 (0%)      3 (10%)    2 (6.7%)

Pruritus           0 (0%)     0 (0%)      2 (6.7%)   2 (6.7%)

Headache           0 (0%)     2 (6.7%)    1 (3.3%)   0 (0%)

All P values non-significant. (#) Blood pressure reduction >20%
from baseline. * Heart rate <60 beats per/min, (##) respiratory rate
<9 breaths /min or oxygen saturation <90%.

Trends of blood pressure
(Mean of MAP at different time intervals in mmHg)

      Pre-op   1 min   5 min   10 min   15 min   30 min   60 min   120
                                                                   min
B     93       96      92      88       87       86       90       94
B-N   92       97      90      83       80       81       85       91
F     94       99      97      91       89       86       85       86
F-N   93       95      89      83       83       85       92       93

Figure 1: Changes in mean arterial blood pressure (MAP) over the first
two hours.


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Author:Garg, A.; Ahmed, F.; Khandelwal, M.; Chawla, V.; Verma, A.P.
Publication:Anaesthesia and Intensive Care
Article Type:Clinical report
Geographic Code:1USA
Date:Mar 1, 2010
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