|Year : 2020 | Volume
| Issue : 2 | Page : 111-117
Prophylactic co-administration of two different bolus doses of norepinephrine in spinal-induced hypotension during caesarean section: A prospective randomized double-blinded study
Savita Choudhary, Rakesh Dagar, Lalita Jeenger, Anil K Bhiwal, Swapnil Tuteja, Sunanda Gupta
Department of Anesthesiology and Critical Care, Geetanjali Medical College, Udaipur, Rajasthan, India
|Date of Submission||18-May-2020|
|Date of Acceptance||12-Jul-2020|
|Date of Web Publication||20-Aug-2020|
Dr. Savita Choudhary
Department of Anesthesiology and Critical Care, Geetanjali Medical College, Udaipur, Rajasthan
Source of Support: None, Conflict of Interest: None
Background: Vasopressors for prophylaxis and treatment of spinal hypotension have grown in popularity in recent years. Norepinephrine is now emerging as one of the feasible options for prevention as well as management of spinal-induced hypotension in caesarean section (CS). The aim of our study was to compare the efficacy of two different doses of norepinephrine as prophylaxis for spinal-induced hypotension during CS. Material and Methods: Total 110 patients were recruited in this prospective randomized double-blind study from December 2017 to June 2019. After fulfilling the inclusion and exclusion criteria, this study was conducted on 90 patients undergoing elective CS under spinal anesthesia, who were assigned into three groups of 30 patients each. Group N6received norepinephrine 6 μg as an intravenous bolus, group N4received norepinephrine 4 μg, and group C received normal saline simultaneously with subarachnoid block. Incidence of hypotension, requirement of rescue doses of norepinephrine, time of first rescue dose, hemodynamic parameters, adverse effects, and neonatal complications were assessed, compared and analyzed. Results: The incidence of post spinal hypotension was 63.33% in group N6, 80% in group N4, and 83.33% in group C (p = 0.155). Total rescue dose requirement of norepinephrine was significantly less in group N6(8.21 ± 2.97 μg) as compared to N4(9.00 ± 3.06 μg) and control group (11.00 ± 4.57 μg).(p = 0.011). The median time to first rescue dose requirement of norepinephrine was significantly delayed in group N6(6[8–4.5] min) and group N4(4[9–2.5] min) as compared to control group (4[5–2] min) (p = 0.004). Conclusion: Prophylactic intravenous bolus dose of 6 μg norepinephrine when co-administered with spinal anesthesia was found to be more effective than 4 μg norepinephrine in terms of decreasing total rescue dose requirement of vasopressor and delaying the time to first rescue dose, without significant change in the incidence of hypotension.
Keywords: Caesarean section, prophylactic norepinephrine, spinal-induced hypotension
|How to cite this article:|
Choudhary S, Dagar R, Jeenger L, Bhiwal AK, Tuteja S, Gupta S. Prophylactic co-administration of two different bolus doses of norepinephrine in spinal-induced hypotension during caesarean section: A prospective randomized double-blinded study. J Obstet Anaesth Crit Care 2020;10:111-7
|How to cite this URL:|
Choudhary S, Dagar R, Jeenger L, Bhiwal AK, Tuteja S, Gupta S. Prophylactic co-administration of two different bolus doses of norepinephrine in spinal-induced hypotension during caesarean section: A prospective randomized double-blinded study. J Obstet Anaesth Crit Care [serial online] 2020 [cited 2020 Dec 2];10:111-7. Available from: https://www.joacc.com/text.asp?2020/10/2/111/292740
| Introduction|| |
Maternal hypotension is one of the most common complications with 70–80% incidence during caesarean deliveries under spinal anesthesia. Intraoperative hypotension is usually defined as a mean arterial pressure (MAP) <25% of patient's baseline value although recent recommendations advocate maintaining maternal blood pressure closer to 100% of baseline, to avert and minimize associated complications such as nausea, vomiting, decreased consciousness in mother, and uteroplacental insufficiency, acidosis, and impaired oxygenation in fetus. Major strategies utilized to correct hypotension include intravascular volume expansion with fluid preload, using different vasopressors and lateral positioning of the uterus, but in spite of all these maneuvres, hypotension is still inevitable., In recent years, emphasis has changed towards early administration and liberal use of vasopressors, which directly counter the sympathetic block derangements. Prophylactic administration of vasopressors including mephentermine, ephedrine, phenylephrine, infusion of angiotensin-2, and atrial natriuretic peptide has been proved to be beneficial. Despite being one of the most researched topic in obstetric anesthesia, still many controversies are associated regarding the choice and use of vasopressors.
Norepinephrine has been heralded as a good alternative to phenylephrine, in spinal anesthesia-induced hypotension, because of its potent α adrenergic agonistic activity with intrinsic β adrenergic potential that results in theoretically, lesser incidence of maternal bradycardia and decreased cardiac output following spinal anesthesia. Norepinephrine has been used as both intravenous bolus as well as continuous infusion for prevention and treatment of post spinal hypotension.,, However, intermittent intravenous bolus doses may be a simpler, feasible, more acceptable method for routine practice in the low resource set up, where either infusion pumps are not available or there is limited availability. Norepinephrine is 16 times more potent than phenylephrine, and with an effective phenylephrine dose of approximately 100 μg, the ED90 for bolus dose of norepinephrine is calculated as 6 μg; while doses ranging from 4–10 μg have been reported to be effective.,,,,
Norepinephrine has mainly been used as continuous infusion, with very few studies using it as intermittent bolus dose, to control spinal-induced hypotension in caesarean section (CS). Thus, the present study was planned to compare two different intermittent bolus doses of norepinephrine in prevention of spinal-induced hypotension during CS.
| Material and Methods|| |
This prospective, randomized, double-blinded controlled study was conducted at a tertiary care teaching center from December 2017 to June 2019, after obtaining approval from the Institutional Review Board and Human Research Ethics Committee (approval number GU/HREC/EC/2017/1497 Dated December 12, 2017). Inclusion criteria included, nonlaboring women at term, aged 18–40 years with singleton pregnancy without any comorbid illness, ASA grade 1 undergoing elective caesarean delivery. Written informed consent was obtained from each participant. Exclusion criteria included parturients with contraindication to norepinephrine, hyperthyroidism, hypothyroidism, blood pressure >140/90 mmHg, pre-eclampsia, or any other co-morbid conditions like neurological, cerebrovascular, cardiovascular, renal, psychiatric disorders, or any fetal abnormalities. The patient and the anesthesiologist who monitored the patients were blinded to group allocation. Study drug was prepared by an anesthesiologist who was not involved in the study. The selected patients were subjected to a preanesthetic checkup prior to surgery. In the preoperative area, baseline blood pressure was measured in sitting position with a noninvasive blood pressure monitor. A peripheral 18-gauge i.v. cannula was inserted, and an infusion of Ringer Lactate was started at 10 ml/kg/h over 30 min. Simultaneously, all patients received i.v. ranitidine (1 mg/kg), inj metoclopramide (1–2 mg/kg). In the operating room, standard monitoring included pulse oximetry (SpO2), noninvasive BP and 5 lead electrocardiography with a multipara monitor (B-125, Wipro GE monitor). Randomization was performed using computer-generated random table, and the parturients were assigned to three groups (30 patients each in Group N4, Group N6, and Group C). Group N4 received norepinephrine 4 μg (3 ml) iv along with the subarachnoid block, group N6 received 6 μg (3 ml) of norepinephrine, while group C was given normal saline (3 ml) as placebo. The subarachnoid block was performed at L3-4 or L4-5 in a sitting position with 0.5% hyperbaric bupivacaine 2 ml (10 mg), using a 25 G Quincke spinal needle. Patients were then placed supine with a wedge under the right hip for left uterine displacement. Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), MAP, and oxygen saturation (SpO2) were recorded at baseline, at time of intrathecal drug administration and at 2-min intervals up to 20 min, followed by 5-min intervals for next 30 min or till the end of surgery.
Sensory block was assessed using the pin prick technique, and motor block was assessed using the Modified Bromage score. Hypotension was defined as decrease in SBP to less than 90% of baseline value, and a fall of up to 10% of baseline was managed with rapid rescue boluses of norepinephrine (6 μg); HR <50 bpm was treated with i.v. atropine 0.6 mg. Intraoperative rigors, complaints of pain, and nausea/vomiting were treated with i.v. tramadol 25 mg, fentanyl 50 μg or i.v. promethazine 12.5 mg, respectively. All patients with sensory block lower than T6 at 20 min were considered as dropouts.
Maternal demographic data like age, weight, height, gestation week, time from spinal anesthesia to delivery, and duration of surgery were noted. Hemodynamic parameters (SBP, DBP, MAP, HR), SpO2 sensory, and motor block characteristics along with APGAR scores at 1 and 5 min were measured. Incidence of hypotension, total episodes of hypotension, hypertension, time of first rescue vasopressor (norepinephrine), and the total no of rescue doses with total doses were noted. Adverse effects like nausea, vomiting, bradycardia, shivering, and hypertension were recorded.
The aim of our study was to compare the efficacy of two different bolus doses of norepinephrine in prevention of spinal-induced hypotension during CS.
The primary outcome was to compare the incidence of hypotension and the requirement of intermittent rescue bolus doses of norepinephrine in all the three groups. The secondary outcome was to compare the incidence of bradycardia, nausea, vomiting, hypertension in the mother, and neonatal outcomes with APGAR scores at 1 and 5 min.
A sample size was calculated using software Epi Info™ 7 with the assumption of alpha error 5% (confidence level 95%) and beta error to be 10% (power of study to be 90%); a sample size of 26 patients in each group was sufficient to detect a 10% reduction in SBP among the groups. Considering the exclusions and to reject the null hypothesis, a total of 90 patients were considered for the study.
Data was presented as mean, standard deviation, median (range), or percent as appropriate. Statistical analysis was performed using SPSS (version 17, SPSS, Chicago, IL). Hemodynamic responses were analyzed by ANOVA (analysis of variation), demographic data were analyzed by one-way ANOVA, and Chi-square was used for adverse effects. Kruskal–Wallis H-test was used to analyze the data which was not normally distributed. P value less than 0.05 was considered significant.
| Results|| |
The study included 90 patients who were randomly allocated into three equal groups [Figure 1]. Demographic data and duration of surgery in all three groups were found comparable and nonsignificant (p > 0.05). APGAR score at 1 and 5 min was statistically nonsignificant between the groups (p > 0.05) [Table 1]. Baseline hemodynamic parameters (HR, SBP, DBP, and MAP) before spinal anesthesia were comparable in all the three groups (p > 0.05).
|Table 1: Comparison of demographic, obstetric data, and neonatal outcome in all three groups|
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Incidence of hypotension was 63.33% in group N6, while it was 83.33% in control group and 80% in group N4.(p = 0.155). Total rescue dose requirement of norepinephrine to maintain blood pressure near baseline was significantly low in group N6(8.21 ± 2.97 μg) and N4(9.00 ± 3.06 μg) as compared to the control group (11.00 ± 4.57 μg) (p = 0.011). The median time to first rescue dose requirement of norepinephrine was significantly delayed in group N6(6[8–4.5] min) and group N4(4[9–2.5] min) as compared to control group (4[5-2] min) (p = 0.004) [Table 2].
|Table 2: Comparison of incidence of hypotension and norepinephrine requirement between all the groups|
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A decrease in SBP from baseline was found in all the three groups, but the fall of SBP was significantly more in control group and group N4 at different time intervals (2, 4, 6 min) (p < 0.05). The fall in SBP was found highly significant, while comparing control group to group N6 at 2 and 4 mins (p = 0.001) [Figure 2].
|Figure 2: Comparison of systolic blood pressure (SBP) in different groups at different time intervals|
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HR in all the three groups at different time intervals was found statistically nonsignificant from 0 till 30 min (p > 0.05), except at 10 min where it was found significant (p < 0.05). Comparison of HR between groups was found significant (p < 0.05), only at 4 and 6 min between group N6 vs group N4[Figure 3].
|Figure 3: Comparison of heart rate in different groups at different time intervals|
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The incidence of bradycardia was lower in group N6 but without any statistical significance. Other maternal complications like nausea/vomiting and shivering were also comparable in all the groups [Table 3].
| Discussion|| |
The results of present study showed nonsignificant change in the incidence of spinal-induced hypotension after co-administration of 6 and 4 μg doses of intravenous norepinephrine with spinal anesthesia. However, there is a significant decrease in the rescue dose requirement of vasopressor and also delay in the time to first rescue dose in group N6.
Many vasopressors have been extensively researched as prophylaxis for spinal hypotension. Previously, vasopressors were administered after the blood pressure started to decrease which led to an initial period of uncorrected hypotension leading to maternal and neonatal adverse effects. Recent studies have suggested that any reduction in blood pressure is undesirable and goal should be to maintain SBP at 100% of baseline with early and liberal use of vasopressors;,, thus, researchers have moved from a more reactive to a proactive approach. Maintaining stringent control of baseline blood pressure during spinal anesthesia for caesarean delivery has been found to have a beneficial effect on both mother and on the baby.
The incidence of post spinal hypotension has been reported to be approximately 60–80%., The present study also showed 63.33% incidence of hypotension in group N6 and 80% in group N4. The major causes, which lead to spinal induced hypotension, are sympathetic blockade with a parasympthatic overdrive and aortacaval compression caused by the gravid uterus. Studies,, have shown that norepinephrine had similar efficacy to phenylephrine for maintaining blood pressure during spinal anesthesia for CS in terms of maintenance of greater CO, suppressed venodilatation, augmented venous return to the heart with lesser reduction in hemodynamic variables. There is a reduction in the incidence of hypotension by virtue of its potent α and weak β intrinsic adrenergic potential.
Vasopressors have been used as continuous infusion as well as small intermittent bolus doses, as infusions provide a tighter blood pressure control with minimum interventions by anesthesiologist though the total dose of vasopressor utilized is higher without any observable maternal and neonatal side effects.,, The ED90 of an intermittent bolus of norepineprine is 6 μg; thus, we included two intermittent bolus doses (4 and 6 μg) to find the efficacy of norepinprine in maintaining the SBP at baseline values. Requirement of norepinephrine, when given as intermittent rescue bolus doses, was found to be significantly less in the proactive groups (N6 and N4) in our study. Time to first rescue dose requirement of norepinephrine was significantly higher in group N6. Requirement of vasopressor, in terms of total rescue doses, was also significantly less in group N6. Similarly, Onwochei et al., 2017 studied different norepinephrine doses (3, 4, 5, 6, and 7 μg) to maintain SBP at or above 80% of baseline during CS and found 6 μg dose to be the most effective and total requirement of bolus doses ranged from 6 to 78 μg.
In our study, SBP was maintained closer to the baseline at all time intervals in group N6; however, a fall in SBP was significantly more in control and N4 group at different time intervals (2–6 min; P < 0.05). Similarly Onwochei et al. found that SBP was better maintained in 83.3% of patients, who received 6 μg of norepinephrine as bolus dose. Vallejo et al. 2017 also observed that rescue vasopressor requirement was less in norepinephrine group vs phenylephrine (48.8% vs 65.8%; P = 0.12). Other authors have found statistically nonsignificant incidence of hypotension., This may be due to differing measurement indicators (SBP <80% vs SBP <90%) for hypotension that leads to significant variation in incidence among studies. The international consensus statement on the management of hypotension with vasopressors during CS under spinal anesthesia also suggests that the aim should be to maintain SBP at ≥90% of baseline obtained before spinal anesthesia and avoid a decrease to less than 80% of baseline.
Norepinephrine has weak β adrenergic and potent α adrenergic receptor agonist activity that leads to decreased incidence of maternal bradycardia. Incidence of bradycardia (HR <50 bpm) in the present study was 3.33% in group N6, which is also corroborated by other authors.,,,,
Changes in hemodynamic parameters at different time intervals, in the present study, did not concur with findings in some other studies.,, This could be explained in terms of specific population, study design, sample size, anesthetic technique used, and also the allocation of the groups. Further factors that might affect blood pressure following the delivery of fetus such as use of uterotonics and blood loss during surgery could also affect the changes in hemodynamic parameters.
Vallejo et al. found lower incidence of nausea and vomiting in Group N (16.3%) when compared to GroupP(26.3%). Abdalla et al. found nausea and vomiting in control group (3.8%), while no patient in the NE group and vasopressin group had nausea. Similarly, in our study, the incidence of nausea and vomiting was low (p > 0.05). In contrast to our study, Ngan kee et al. found incidence of nausea and vomiting in norepinephrine group (6.1%) as compared to (3.8%) in phenylephrine group, which was statistically nonsignificant. Addition of preservative free morphine and fentanyl to intrathecal bupivacaine was associated with higher incidence of nausea and vomiting in few studies.,
Administration of norepinephrine via peripheral veins carries a potential concern for extravasation, local vasoconstriction, and tissue ischemia; though with administration of small intermittent doses as dilute solution, none of these adverse effects have been reported., Small intermittent doses (3–7 μg/ml) have been used thoroughly flushed with crystalloid IV fluids as opposed to more concentrated solutions (80–320 μg/ml) used for longer duration in ICU. This limits the concerns of any local tissue injury, which was also corroborated in our study. It is also established that a dilute solution of 6 μg/ml of norepinehrine has approximately the same vasoconstriction potential as phenylephrine 100 μg/ml, which has been routinely used and widely researched.
Similar to previous studies,,, no adverse neonatal outcome associated with norepinephrine was reported in our study. A double-blinded randomized controlled trial by Ngan kee et al., 2015 compared norepinephrine infusion (5 μg/ml @ 30 ml/h range 0–60 ml/h) with bolus dose of 5 μg norepinephrine and despite great variation in total dose administration, fetal outcome was found to be comparable. Fetal catecholamine levels have been shown to be greater with increased stress during delivery and fetal asphyxia,, with an inverse correlation between umbilical blood catecholamines concentration and PO2. Similar decrease in fetal stress with greater UVpH and the O2 content in norepinephrine group has been observed by Ngan Kee et al., which further corroborates the safety of norepinephrine on neonatal outcome.
This study has some limitations. Only two doses of the study drug were used, while a more wide range of doses can be compared in further studies as it could be more beneficial in deciding on the optimum dose. Hemodynamic measurements including estimation of the cardiac output could also be included for more accurate estimation of vasopressor requirement. Our findings cannot be extrapolated in laboring parturients, where the requirement of vasopressors may be lower or in emergency CD or with patients having co-morbid conditions like preeclampsia.
We suggest further research to determine the optimum bolus dose, safety of norepinephrine to maintain BP near baseline, and effect on uteroplacental flow in routine as well as obstetric patients with co-morbidities in larger study population.
| Conclusion|| |
In conclusion, prophylactic intravenous bolus dose of 6 μg norepinephrine when co-administered with spinal anesthesia was found to be more effective than 4 μg norepinephrine in terms of decreasing total rescue dose requirement of vasopressor and delaying the time to first rescue dose but without significant change in the incidence of hypotension and adverse effects in parturients undergoing CS under spinal anesthesia.
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Conflicts of interest
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]