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ORIGINAL ARTICLE
Year : 2017  |  Volume : 7  |  Issue : 2  |  Page : 69-74

Effect of ondansetron in attenuation of post-spinal hypotension in caesarean section: A comparison of two different doses with placebo


Department of Anaesthesia, Dr. L.H.Hiranandani Hospital, Mumbai, Maharashtra, India

Date of Web Publication7-Nov-2017

Correspondence Address:
Meenoti P Potdar
Dr. Lakhumal Hiranand Hiranandani Hospital, Department of Anaesthesia, Hillside Avenue, Hiranandani Gardens, Powai, Mumbai - 400 076, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joacc.JOACC_7_16

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  Abstract 

Context: Spinal anaesthesia (SA) is the preferred anaesthesia for Caesarean section. Hypotension and bradycardia are the most common side effects caused by sympathetic blockade with a parasympathetic overdrive, aortocaval compression, and the Bezold Jarisch reflex (BJR) which is mediated by serotonin (5 HT3) receptors. Ondansetron is a 5HT3 antagonist commonly used as an anti-emetic. The present study evaluated the effects of two different doses of ondansetron on the haemodynamic changes associated with SA for Caesarean section and the advantage of higher dose over the other. Aims: To study the effect of ondansetron in two different doses on the haemodynamic changes associated with spinal blocks. To compare the need of vasopressors if required and the incidence of nausea and vomiting with the two different doses of ondansetron in comparison with placebo in these patients. Settings and Design: Prospective, comparative, randomized, double-blinded placebo controlled study. Materials and Methods: After hospital ethics clearance 180 parturients undergoing Caesarean section were randomly divided into 3 groups before administration of SA. Group C received 10 ml of normal saline. Group F received 4 mg ondansetron with 8 ml normal saline. Group E received 8 mg ondansetron with 6 ml normal saline. All the patients were monitored for haemodynamics, vasopressor requirement and side effects and the results were compared. Three groups were compared using one-way analysis of variance with Tukey's multiple comparison post hoc test; the results were considered significant when P < 0.05. Adverse events were analysed with Chi-square test and was significant at P < 0.01. Results: The change in the heart rate (HR) was not significant statistically. The fall of systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) was statistically significant at all time intervals intraoperatively after administration of SA (P value <0.001) when compared to pre-operative values. The fall of SBP when compared between groups was significant after administration of SA, 111.92 ± 17.36 mmHg for Group C, group F was 122.16 ± 18.68 mm Hg and group E was119.29 ± 16.88 mmHg (P value = 0.04). The incidence of hypotension in patients was lesser in the group that received ondansetron, Group C (6, 14), Group F (3, 4) and Group E (1, 6) after administration of SA and at 5 minutes after administration of SA (P value = 0.03) but comparable between the ondansetron groups. Conclusions: Intravenous ondansetron reduced the incidence of hypotension, nausea and vomiting after administration of SA but there was no added advantage of 8 mg ondansetron over 4 mg.

Keywords: 5 HT3 receptors, Bezold Jarisch reflex, ondansetron, spinal hypotension


How to cite this article:
Potdar MP, Kamat LL, Jha TR, Talnikar AS, Mahevi ZM, Save MP. Effect of ondansetron in attenuation of post-spinal hypotension in caesarean section: A comparison of two different doses with placebo. J Obstet Anaesth Crit Care 2017;7:69-74

How to cite this URL:
Potdar MP, Kamat LL, Jha TR, Talnikar AS, Mahevi ZM, Save MP. Effect of ondansetron in attenuation of post-spinal hypotension in caesarean section: A comparison of two different doses with placebo. J Obstet Anaesth Crit Care [serial online] 2017 [cited 2017 Nov 22];7:69-74. Available from: http://www.joacc.com/text.asp?2017/7/2/69/217779


  Introduction Top


Spinal anaesthesia (SA) is the preferred anaesthesia technique for Caesarean section. Hypotension and bradycardia are the most common side effects encountered and are more pronounced in pregnant patients, the incidence being as high as 52.6% and 2.5% in normal patients.[1] The occurrence of hypotension can be dangerous as it compromises placental circulation and can have a detrimental effect on the foetus.

The causes of hypotension after administration of SA block in a parturient are numerous but the main causes are sympathetic blockade with a parasympathetic overdrive, aortocaval compression caused by the gravid uterus and the Bezold Jarisch reflex (BJR).[2] Of these, the first two causes are unavoidable, however BJR, which causes the most profound drop in blood pressure and heart rate, can be attenuated. The BJR is mediated by serotonin (5 HT3) receptors, and it has been found that the administration of 5HT3 antagonist can attenuate the BJR.[3] Ondansetron is a 5HT3 antagonist used commonly for the prevention of nausea and vomiting, and it also reduces the incidence of hypotension after SA.[4] The present study was conducted to evaluate the effect of ondansetron on SA and whether increasing the dose of ondansetron reduces the incidence and severity of hypotension.


  Patients and Methods Top


This study was conducted after obtaining ethical committee clearance and written informed consent from 180 parturients from January 2013 to January 2014. Our study included all term (>38 weeks) singleton parturients, ASA 2, undergoing elective Caesarean section. The patients with ASA 2 or more with other comorbidities such as pregnancy induced hypertension (PIH), uncontrolled diabetes, SA converted to general anaesthesia, allergy to ondansetron or local anaesthetic, contraindication to regional anaesthesia and on medications which acts on the 5HT3 receptors were excluded from the study.

Patients were randomly divided into three groups. Group F received 4 mg ondansetron with 8 ml normal saline, group E received 8 mg ondansetron with 6 ml normal saline and Group C received 10 ml normal saline.

Initially, a pilot study of 45 cases in each group was done and sample size was calculated considering the incidence of hypotension after administration of SA between the groups. With the assumption of alpha as 0.05, standard deviation as 15 and maximum difference between the means of 3 groups as 9, a sample size of 55 was adequate. Hence, we decided to select a study group of 60 per group.

Randomisation was done by block randomisation using a block of 6. Chits were labelled as F1, F2, E1, E2, C1 and C2. Thirty such blocks were made. The recovery room nurse was asked to pick up a chit and the patient was allocated to the respective group.

After obtaining consent from the patient, an intravenous line was secured and the patients were preloaded with 500 ml Ringer lactate. Demographics such as maternal age, height, weight, gestational age and baseline parameters such as heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) and oxygen saturation (O2 saturation) were noted.

Depending on the group, study solution was administered to the patient 5 minutes before giving SA. The solution was administered by the investigator and subsequent monitoring was done by an anaesthesiologist not involved in the study.

SA was administered under aseptic precautions to the patients in the sitting position at the L3-L4 level using a 26-G Quincke needle with 12 mg of 0.5% hyperbaric bupivacaine and 60 mcg buprenorphine. The patient was made supine and oxygen was given at 2 L/min through a nasal cannula. The sensory level of SA was assessed using a cold swab, and motor blockade was assessed with Modified Bromage scale.

Haemodynamic parameters such as HR, SBP, DBP, MAP, and O2 saturation were recorded before injecting the study drug, then just before administering the SA, at spinal block, 5 minutes after administration of SA, and at an interval of 5 minutes thereafter till the end of the surgery. Incidence of nausea or vomiting, hypotension, volume of intravenous fluid infused, need for use of vasopressor ephedrine, urine output, blood loss during surgery and the APGAR score of the baby were also noted.

For the purpose of our study hypotension was defined as a fall in SBP <90 mmHg and bradycardia was defined as HR <50 beats per minute. Any incidence of hypotension was promptly treated with rapid fluid infusion of 100 ml of Ringer lactate and if required titrated doses of intravenous ephedrine in aliquots of 12 mg. Further haemodynamics recording of the patient after ephedrine were excluded from evaluation, but patients were not excluded from the study. Bradycardia was treated with inj. atropine 0.6 mg intravenously. Metoclopramide 10 mg was given for any incidence of nausea or vomiting. The patients who had inadequate analgesia after 10 minutes of SA or had to be converted to general anaesthesia were excluded from the study.

Statistical analysis

The data were managed by Microsoft excel spreadsheet. Demographics are described using mean and standard deviation. Demographics and general information such as count, average and percentage for various parameters with all permutations and combinations were calculated in Microsoft excel. Three groups were compared using one-way analysis of variance (ANOVA) with Tukey's multiple comparison post hoc test for various parameters. Data was considered significant with P < 0.05. The adverse events were analysed using Chi-square test and statistical significance was observed at P < 0.01. All specific graphs were drawn and statistical analysis was done using Minitab 16.


  Results Top


One hundred and eighty patients were included in our study, of which 3 were excluded one in each group due to inadequate anaesthesia and conversion to general anaesthesia. The demographics for the three groups were comparable as shown in [Table 1].
Table 1: Comparison of demographic data

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The mean HR pre-operatively in group C was 91.79 ± 15.46 mins, in group F was 87.59 ± 16.33 mins and in group E was 89.84 ± 14.11mins. The HR after administration of the study drug was 94 ± 18.84 mins in group C, 91.31 ± 18.34 mins in group F and 89.12 ± 17.81 mins in group E [Figure 1]a. The difference of HR from preoperative to post administration of ondansetron was significant in group F (P value = 0.05). The HR immediately after administration of SA was 95.15 ± 19.24 mins in group C, 89.82 ± 19.84 mins in group F and 92.25 ± 17.50 mins in group E. The change in the HR was significant in group E (P value = 0.04).
Figure 1: (a) Comparison of mean heart rate; (b) Comparison of systolic blood pressure (SBP) between the three groups; (c) Comparison of diastolic blood pressure (DBP); (d) Comparison of mean arterial pressure (MAP)

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The change in the HR intra-operatively 5 minutes after administration of SA were comparable to pre-operative values till 40 minutes, but later differences were statistically significant in Group E and F (P value < 0.05).

The change in HR at different intervals among the three groups were comparable.

The mean SBP preoperatively in group C was 127.85 ± 16.64 mm of Hg, in group F was 130.71 ± 14.72 mm of Hg and in group E was 130.75 ± 16.06 mm of Hg. The SBP after administration of the study drug was 126.23 ± 17.05 mm of Hg in group C, 128.82 ± 16.56 mm of Hg in group F and 130.57 ± 13.72 mm of Hg in group E, and these changes are comparable to preoperative levels. There was a significant fall in SBP [Figure 1]b in all the three groups after administration of SA and at all time intervals intraoperatively (P value < 0.001). The SBP in group C after administration of SA was 111.92 ± 17.36 mmHg, group F was 122.16 ± 18.68 mmHg and group E was119.29 ± 16.88 mmHg. This difference immediately after SA was statistically significant (P value = 0.04). Similarly at 5 minutes and 10 minutes in group C the SBP was 107.82 ± 15.78, 103.64 ± 24.12 mmHg, group F 114.71 ± 19.08, 108.45 ± 14.02 mmHg and group E 109.43 ± 21.44, 101.67 ± 37.96 mmHg, respectively. This difference was statistically significant for group C and Group F (P value of 0.005 and 0.03, respectively) but not for group E.

The mean DBP preoperatively in group C was 72.85 ± 14.70 mm of Hg, in group F was 78.12 ± 10.73 mm of Hg and in group E was 76.63 ± 11.62 mm of Hg. The DBP after administration of the study drug was comparable to pre-operative values, 75.10 ± 13.26 mm of Hg in group C, 76.53 ± 11.57 mm of Hg in group F and 76.20 ± 13.06 mm of Hg in group E. The DBP in group C after administration of SA was 66.74 ± 12.80 mmHg, group F was 70.10 ± 13.43 mmHg and group E was 68.88 ± 13.28 mmHg. There was a significant fall in DBP [Figure 1]c after administration of SA and intra-operatively at all time intervals as compared to pre-operative levels in all the groups (P value < 0.001). On comparison of DBP at 5 minutes after administration of SA between all three groups, there was a significant fall in group C (60.92 ± 11.17 mmHg) compared to group F (66.82 ± 13.22 mmHg) (P-value = 0.03) but not in group E (62.27 ± 13.55 mmHg).

The mean MAP preoperatively in group C was 98.28 ± 12.01mm of Hg, in group F was 99.31 ± 11.05 mm of Hg and in group E was 99.71 ± 12.08 mm of Hg. The MAP in group C after administration of the study drug was comparable with pre-operative levels, 95.67 ± 13.58 mmHg, group F was 97.04 ± 13.64 mmHg and group E was 99.27 ± 11.12 mmHg. There is a significant decrease in MAP intra-operatively [Figure 1]d in all the groups post SA administration and intra-operatively at all time intervals when compared to pre-operative levels (P value <0.001). The fall is significantly more immediately after administration of SA in Group C (83.97 ± 13.02 mmHg) as compared to group E (89.57 ± 13.99 mmHg) (P value = 0.001) but not for group F (90.02 ± 15.11 mmHg). Similarly, the fall in MAP is significant in group C (79.08 ± 15.31, 75.51 ± 17.93 mmHg) at 5 and 10 minutes post SA when compared to Group F (83.78 ± 17.47, 80.90 ± 11.09 mmHg) (P value = 0.02) but not in Group E (82.61 ± 14.75, 76.92 ± 11.46 mmHg), respectively.

The level of sensory block, motor block, blood loss, requirement of intravenous fluids, urine output and oxygen saturation were comparable in all the three groups.

The number of patient that needed ephedrine for hypotension (SBP < 90 mmHg) after administration of SA and at 5 minutes after administration of SA was significantly higher in Group C (6, 14) as compared to Group E (1, 6) and Group F (3, 4) (P value = 0.03) respectively. However, this difference was not statistically significant when we compared the need of ephedrine between group E and Group F [Figure 2].
Figure 2: Number of patients with hypotension after SA

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The incidence of nausea was lesser in Group E and Group F as compared to group C as shown in [Table 2].
Table 2: Incidence of side effects, height of block

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  Discussion Top


SA is commonly used for Caesarean sections because of advantages such as decreased blood loss, postoperative pain relief, use of lesser number of drugs and hence minimal foetal side effects. In pregnant patients, the venous return is decreased due to aortocaval compression.[5] SA further decreases the venous return due to sympathetic blockade causing a fall in blood pressure.[6] This decrease in blood pressure is sensed by the carotid baroreceptors which cause sympathetic activation as a compensatory response resulting in rapid contraction of the ventricles. The rapid contraction of under filled ventricles result in the activation of 5HT3 present in the left ventricle walls which causes profound hypotension, bradycardia and vasodilatation by vagal activation. This paradoxical reflex is known as BJR. Serotonin released from activated thrombocytes act on these receptors and stimulate BJR.[7]

Ondansetron is a 5HT3 antagonist routinely used pre-operatively before caesarean section to prevent nausea and vomiting in doses of 4 mg and 8 mg. We decided to conduct this study to assess the effects of 5HT3 antagonist to prevent hypotension after administration of SA and also to assess whether a higher dose of 8 mg had any additional benefit over 4 mg.

In the present study, 180 patients were included and divided into three groups. Three patients were excluded due to inadequate action of SA and conversion to general anaesthesia. Demographic data such as age, height and weight of the three groups were comparable, as shown in [Table 1].

Sahoo et al.[4] compared control group with 4 mg of ondansetron in 52 patients and found two instances of reduction of HR. They observed a significant reduction in MAP at 5 minutes, 6 minutes in the control group and significant reduction in MAP between 14 and 35 minutes only in the control group compared to pre-operative values. The incidence of decreases in SBP and MAP were reduced with the use of intravenous ondansetron 4 mg given 5 minutes before SA in parturients undergoing elective caesarean section.[4] In our study, we had a reduction of SBP, DBP and MAP after administration of SA at all time intervals intraoperatively as compared to the pre-operative levels (P< 0.001) unlike the findings of the above study. The change in HR was initially documented after administration of the study drug in Group F (P = 0.05) but not in Group E. After administration of SA this difference was seen in Group E (P = 0.04) but not in Group F. Thereafter, the change in HR was significant after 40 minutes in Group F and E (P< 0.05) but not in Group C.

When we compared the changes in the SBP between the three groups there was significant difference seen after administration of SA with the fall being the greatest in group C than group F and E (P = 0.04). At 5 and 10 minutes, the fall of SBP was significant for Group C and F but not for Group E (P value 0.005, 0.03, respectively). There was also a significant fall in DBP at 5 minutes (P = 0.03) and MAP at 5 and 10 minutes (P = 0.02) in Group C similar to the study by Sahoo et al.[4]

Similarly Owczuk et al. demonstrated higher systolic and mean blood pressure values in patients who were given 8 mg intravenous ondansetron before SA compared to patients in the placebo group.[8] The values of SBP, DBP and MAP are more in the study groups as compared with the control. Similarly, Rashad MM et al. studied the effects of intravenous ondansetron and granisetron haemodynamic changes post SA for caesarean section and found that the ondansetron group significantly had lesser fall of blood pressure as compared to granisetron or the placebo group.[9] Though in our study the reduction of BP in Group F and E after administration of SA were not consistent during the course of surgery except at 5 and 10 minutes after administration of SA.

The incidence of hypotension (SBP <90 mmHg) and use of ephedrine was also found to be lesser in the group that received ondansetron. Immediately after SA the incidence of hypotension was observed in 6 patients in Group C, 3 patients in Group F and 1 patient in group E. Five minutes after administration of SA the number of patients with hypotension were significantly more, 14 patients in Group C, 4 patients in Group F and 6 patients in Group E (P value 0.03). These findings are similar to study conducted by Sahoo et al. But when we compared the need for ephedrine between Group F and Group E they were comparable thus suggesting that 8 mg of ondansetron had no additional advantage over 4 mg.

The incidence of nausea was more in group C compared to E and F and the incidence of vomiting was lesser in group E as compared to F and C.

Ondansetron has been used in instances where there can be bradycardia or hypotension due to BJR. Hasanein R et al.[10] found that administration of 4 mg ondansetron can prevent the occurrence of hypotension due to BJR in patients undergoing surgery under inter-scalene block in sitting position.

Matrinek concluded that injection of 4 mg ondansetron intravenous with atropine 0.6 mg could revert asystole during SA.[11] In our study, we did not observe any instances of bradycardia.

Similarly, 5 HT3 antagonists such as granisteron have been used to reduce bradycardia and hypotension due to BJR. White et al. observed in a rabbit model that intravenous administration of the 5-HT3 antagonist granisetron 50 mcg/kg was efficacious in suppressing bradycardia and hypotension associated with the BJR.[12] Tsikouris et al. found that granisetron injection reduced the HR fluctuation and hypotension during head-up tilt table tests that are likely related to BJR.[13] However, Rashad MM et al. did not find similar effect with granisteron.[9]

In the present study, two doses of ondansetron 4 mg and 8 mg were used to evaluate any additional advantage of administering the higher dosage. The administration of pre-emptive ondansetron reduces the fall in SBP, DBP and MAP till 5 to 10 minutes after administration of SA but did not have this effect consistently throughout the intraoperative period. There was no statistically significant difference in HR, SBP, DBP, MAP and the need of ephedrine between group F and E. Only the incidence of vomiting was reduced with increasing dose of ondansetron from 8 mg to 4 mg.

Hence, we conclude that pre-emptive use of ondansetron 4 mg and 8 mg reduces the incidence of spinal hypotension, but the effect lasts only for the initial 5–10 minutes after administration of SA. Just increasing the dose of ondansetron from 4 mg to 8 mg does not benefit and decrease the incidence of hypotension.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Somboonviboon W, Kyokong K, Charulaxaman S, Narasethakamol A. Incidence and risk factors of hypotension and bradycardia after SA for Cesarean section. J Med Assoc Thai 2008;91:181-7.  Back to cited text no. 1
    
2.
Liu SS, McDonald SB. Current issues in SA. Anesthesiology 2001;94:888-906.  Back to cited text no. 2
    
3.
Yamano M, Kamato T, Nishida A, Ito H, Yuki H, Tsutsumi R, et al. Serotonin (5-HT) 3- receptor antagonism of 4, 5, 6, 7-tetrahydrobenzimidazole derivatives against 5-HT-induced bradycardia in anesthetized rats. Jpn J Pharmacol 1994;65:241-8.  Back to cited text no. 3
    
4.
Sahoo T, Sen Dasgupta C, Goswami A, Hazra A. Reduction in spinal-induced hypotension with ondansetron in parturients undergoing caesarean section: A double-blind randomised, placebo-controlled study. Int J Obstet Anesth 2012;21:24-8.  Back to cited text no. 4
    
5.
Clark SL, Cotton DB, Lee W, Hill T, Spillman T, Phelan J, et al. Central hemodynamic assessment of normal term pregnancy. Am J Obstet Gynecol 1989;161:1439-42.  Back to cited text no. 5
    
6.
Suresh MS, Segal BS, Preston RL, Fernando R, Mason CL. Anesthesia for Cesarean section. Schnider and Levinsons anesthesia for obstetrics. 5th ed. Wolters Kluwer Lippincott Williams and Wilkins. p. 174.  Back to cited text no. 6
    
7.
Warltier DC, Campagna JA, Carter C. Clinical relevance of the Bezold -Jarisch Reflex. Anesthesiology 2003;98:1250-60.  Back to cited text no. 7
    
8.
Owczuk R, Wenski W, Polak-Krzeminska A, Twardowski P, Arszulowicz R, Dylczyk-Sommer A, et al. Ondansetron given intravenously attenuates arterial blood pressure drop due to SA: A double-blind, placebo-controlled study. Reg Anesth Pain Med 2008;33:332-9.  Back to cited text no. 8
    
9.
Rashad MM, Farmawy MS. Effects of intravenous ondansetron and granisetron on hemodynamic changes and motor and sensory blockade induced by spinal anesthesia in parturients undergoing cesarean section. Egypt J Anaesth 2013;29:369-74.   Back to cited text no. 9
    
10.
Hasanein R, El-Sayed W. The effect of ondansetron in preventing the hypotensive bradycardic events during shoulder arthroscopy done under interscalene block in the sitting position. Egypt J Anaesth 2014;30:305-10.  Back to cited text no. 10
    
11.
Matrinek RM. Witnessed asystole during SA treated with atropine and ondansetron: A case report. Can J Anaesth 2004;51:226-30.  Back to cited text no. 11
    
12.
White CM, Chow MS, Fan C, Kluger J, Bazunga M. Efficacy of intravenous granisetron in suppressing the bradycardia and hypotension associated with a rabbit model of Bezold Jarisch reflex. J Clin Pharmacol 1998;38:172-7.  Back to cited text no. 12
    
13.
Tsikouris JP, Kluger J, Chow MS, White CM. Usefulness of intravenous granisetron for prevention of neurally mediated hypotension upon head upright tilt testing. Am J Cardiol 2000;85:1262-4.  Back to cited text no. 13
    


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