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ORIGINAL ARTICLE
Year : 2023 | Volume
: 13
| Issue : 1 | Page : 80-86
Comparison of norepinephrine bolus versus infusion for prevention of post-spinal hypotension in parturients with preeclampsia undergoing cesarean section
Renu Wakhloo, Ritu Devi, Megha Gandotra, Vishal Kant
Department of Anaesthesia and Critical Care, Government Medical College, Bakshi Nagar, Jammu, India
Correspondence Address:
Dr. Megha Gandotra
6D/92 Upper Shiv Nagar, Jammu - 180 005
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/JOACC.JOACC_55_22
Background: Currently, spinal anesthesia for cesarean section is the anesthetic technique of choice for women with preeclampsia in the absence of contraindications to neuraxial anesthesia. Recently, norepinephrine has been introduced for prevention and treatment of hypotension associated with spinal anesthesia; however, only a couple of studies have compared norepinephrine infusion and bolus. Aims: This study aims to compare primarily the efficacy and safety of norepinephrine bolus given therapeutically and norepinephrine infusion given prophylactically for management of hypotension and effects on other hemodynamic parameters in parturients with preeclampsia undergoing cesarean section under spinal anesthesia and secondarily to determine the effects of study drugs on neonatal Apgar score and arterial blood gas analysis of neonatal blood. Methods: In this prospective randomized study, 100 singleton full-term pregnant females of ASA grade II, aged 18–35 years, diagnosed with preeclampsia (controlled on single antihypertensive drug with BP ≤140/90), scheduled for elective cesarean section under spinal anesthesia were randomly divided into two groups. Group A: Received therapeutic norepinephrine bolus (4 μg) only when hypotension (fall in SBP to ≤20% of baseline) was detected after spinal anesthesia. Group B: Received prophylactic intravenous norepinephrine infusion (4 μg/min) immediately after induction of spinal anesthesia. Results: Heart rate, systolic, diastolic, and mean blood pressure had statistically significant difference at 3,4,5,6,7,8,9, and 10 mins of surgery. Number of episodes of hypotension and number of norepinephrine boluses used in Group A were higher and statistically significant (p-value < 0.001) than Group B. Apgar score at 1 and 5 minutes as well as umbilical artery parameters in two groups was comparable and statistically insignificant (p-value 0.301 for Apgar at 1 min and P value 0.562 for Apgar at 5 mins). Conclusion: Although both norepinephrine bolus and infusion doses are an effective way to treat spinal anesthesia-related hypotension in patients with preeclampsia undergoing cesarean section with comparable maternal and fetal side effects, infusion dose of norepinephrine is better in maintaining hemodynamics of parturients with insignificant changes in neonatal outcomes.
Keywords: Hypotension, infusion, norepinephrine, preeclampsia, pregnancy, spinal anesthesia
Maternal hypotension, an unwanted sequelae of spinal anesthesia if left untreated, can result in adverse effects for both mother and neonate. The incidence of post-spinal hypotension in cesarean section is up to 71%.[1] When severe and sustained, hypotension can impair uterine and intervillous blood flow, impair fetal oxygenation, and ultimately results in fetal acidosis and neonatal depression.[2] Fetal acid base status has been used as surrogate marker for neonatal well being and has been found to correlate positively with the degree and duration of hypotension.[3]
Preeclampsia is defined as the onset of hypertension [systolic blood pressure (SBP)>140 mmHg or diastolic blood pressure (DBP) >90 mmHg] after 20 weeks of gestation associated with or without proteinuria greater than 300 mg in 24 hours.[4] Of special concern in preeclamptic due to its pathophysiology is the compromised fetoplacental circulation and risk of hypoperfusion. Although hypotension is less frequent in preeclamptics, the need for prompt prevention and management of post-spinal hypotension is deemed necessary. Thus, the effective prevention and treatment of maternal hypotension is of great clinical significance.
Phenylephrine has been recommended as first-line vasopressor during cesarean section. However, its use is associated with decrease in heart rate and cardiac output.[5],[6] Similarly, ephedrine has been associated with adverse outcomes like supraventricular tachycardia, reactive hypertension, and fetal academia.[7]
Norepinephrine is a potent α adrenergic agonist with weak β adrenergic agonist properties which counteracts the baroreceptor response to the α-effect. It is postulated that norepinephrine might therefore be an effective vasopressor for maintaining blood pressure (BP) during spinal anesthesia in parturients with less tendency to decrease heart rate (HR) and cardiac output compared with phenylephrine.[8]
Norepinephrine has been used as both intravenous bolus and continuous infusion for prevention and treatment of post-spinal hypotension,[9],[10] but studies comparing norepinephrine bolus and norepinephrine infusion in preeclamptics are scarce.
MethodologyAfter approval from the Ethical Committee of the institute (No. IEC/GMC/2021/692) and after obtaining informed written consent, this prospective randomized double-blind study was undertaken in the Department of Anesthesiology And Intensive Care of a tertiary care hospital for the duration of one year.
Inclusion criteria
A total of 100 singleton full-term pregnant females of ASA grade II, aged 18–35 years, weight 60–80 kgs, height 130–180 cms, diagnosed with preeclampsia (controlled on single antihypertensive drug with BP ≤140/90, with 24 hour proteinuria ≥300 mg or ≥1+ in dipstick (at the time of diagnosis), scheduled for elective caesarean section under spinal anesthesia were included in the study.
Exclusion criteria
Any parturient falling in the category of allergy to study medications, ASA grade III and IV, contraindications to spinal anesthesia, pregnancy with diagnosis of chronic hypertension, comorbidity with diabetes mellitus, abnormal thyroid function tests, cardiovascular disorders, neurological disorders and psychiatric illness, severe preeclampsia and co-morbid with one or more of the following abnormalities: thrombocytopenia, cerebral or visual disturbances, pulmonary edema, liver function impairment, impairment of renal function, and impaired coagulation profile, were excluded from the study.
Patient groups
Patient group allocation to the study was done by an investigator not directly linked to the study using computer-generated random numbers for an even distribution of 50 patients to each of the two groups. An anesthesia resident not involved in the patient management prepared the study drugs and started the study infusion dose rates according to the instructions given. Determination of sample size was done using GPOWER software (Version 3.0.10), according to which the least number of patients required in each group with 80% power, 5% significance level, and an effect size of 0.505 is 50.
Group A: Pregnant females co-loaded with crystalloid (10 ml/kg) received intravenous norepinephrine bolus (4 μg) only when hypotension was detected after giving subarachnoid block.
Group B: Pregnant females co-loaded with crystalloid (10 ml/kg) received intravenous norepinephrine infusion (4 μg/min) started after giving spinal anesthesia.
Norepinephrine bolus: Norepinephrine 40 μg diluted to 10 ml with 0.9% normal saline in 10 ml syringe prepared as final concentration of 4 μg/ml.
Norepinephrine infusion: Norepinephrine infusion was prepared in 50 ml syringe using 48 ml of 0.9% normal saline and norepinephrine 1 ampoule (2 mg) prepared to be 40 μg/ml and was delivered using a syringe pump as per study infusion dose rate.
Routine preoperative evaluation was undertaken and patients assessed. The patients were kept fasted for 8 hours preoperatively and given Inj. pantoprazole 40 mg IV 30 minutes before surgery. After receiving in the operating room, patients were positioned in supine position with left uterine displacement (LUD). Two large peripheral veins were cannulated using 18 gauge cannula to establish vascular access. Baseline hemodynamic parameters recorded were HR, electrocardiogram, pulse oximetry, and noninvasive blood pressure (NIBP). Spinal anesthesia was performed in L3-L4 or L4-L5 intervertebral space using 25 gauge Quincke's needle with parturient in sitting position under all aseptic precautions. After obtaining free flow of cerebrospinal fluid, 2.0 ml (10 mg) of 0.5% hyperbaric bupivacaine and fentanyl 0.3 ml (15 μg) was given. Simultaneously, co-loading was started with Ringer's Lactate solution 10 ml/kg. Oxygen was administered at a rate of 5-6 L/min by ventimask to all patients till the delivery of the baby. Successful sensory block was defined as block reaching T4 dermatomal level which was assessed by loss of sensation to pin prick. Time to achieve motor level was defined as time when Modified Bromage Scale 3 was achieved.
To achieve blinding, a placebo infusion of normal saline using syringe pump was started in patients of Group A as soon as intrathecal block was performed. Further Group A received therapeutic intravenous norepinephrine bolus 4 μg slowly over 1 min any time the systolic blood pressure fell to ≤20% of baseline after initiating subarachnoid block. The bolus dose was repeated when adequate response was not achieved. Group B received prophylactic intravenous norepinephrine infusion (4 μg/min) as soon as subarachnoid block was performed. Any time the maternal SBP increased to >20% above baseline (defining hypertensive episode), the infusion was to be discontinued and BP reassessed in 1 minute. The infusion was resumed when blood pressure returned to its normal value. If at any time when SBP decreased to ≤20% of baseline, a rescue bolus of norepinephrine 4 μg (given over 1 min) was used.
After delivery of the baby, oxytocin was given as an initial bolus of 0.5 U over 5 sec followed by 40 mU/min infusion. The end point of study was till the delivery of the baby, though continuous monitoring was done till the completion of surgery. The total dose of norepinephrine in both the groups was calculated and recorded for comparison.
Primary and secondary outcomes
The primary outcome included incidence of post-spinal hypotension (SBP <20% of the baseline) throughout the observation period. The secondary outcome included the episodes of tachycardia (HR >120 beats/min); episodes of bradycardia (HR <60 beats/min); episodes of hypertension (SBP >20% of baseline); number of vasopressor boluses used; total dose of vasopressor used; maternal side effects including nausea, vomiting; neonatal Apgar score at 1 minute and five minutes; and umbilical blood gas analysis result.
Statistical methods
The recorded data was compiled and entered in a spreadsheet (Microsoft Excel) and then exported to data editor of SPSS Version 20.0 (SPSS Inc., Chicago, Illinois, USA). Continuous variables were expressed as Mean ± SD, and categorical variables were summarized as frequencies and percentages. Graphically, the data was presented by bar and pie diagrams. Student's independent t-test or Mann–Whitney U-test, whichever feasible, was employed for comparing continuous variables. Chi-square test or Fisher's exact test, whichever appropriate, was applied for comparing categorical variables. A P value of less than 0.05 was considered statistically significant. All P values were two tailed.
ResultsThe patient flow diagram illustrated in [Figure 1]a. In this study, demographic characteristics and surgical characteristics were comparable between the two groups [Table 1] and [Table 2]. Heart rate, systolic, diastolic, and mean blood pressure had statistically significant difference at 3, 4, 5, 6, 7, 8, 9, and 10 mins of intrathecal block between the two groups (p-value < 0.001). Group A had higher maternal heart rate and maintained lower systolic, diastolic, and mean BP as compared to Group B [Figure 1] and [Figure 2]. However after 10 mins, the difference between the two groups was statistically insignificant till the completion of surgery [Table 3].
Figure 2: Comparison based on intraoperative mean arterial pressure in two groupsNumber of episodes of hypotension in Group A was higher and statistically significant (p-value < 0.001) than Group B [Table 4]. In Group A, 38% patients had one episode of hypotension as against 6% patients in Group B, and 30% patients in Group A had two episodes of hypotension as against none of the patients in Group B. The number of norepinephrine rescue boluses used in Group A was statistically significant (p-value < 0.001) than Group B [Figure 4]. No norepinephrine bolus was used in 32% patients in Group A and 94% patients in Group B [Figure 5]. One bolus of rescue vasopressor was received in 28% patients in Group A versus 6% in Group B. Second dose of rescue vasopressor was received in 40% patients in Group A versus none in Group B.
Total mean norepinephrine dose used in Group B was 27.5 ± 4.64 μg in range of 3.5–7.0 which was significantly higher than 5.6 ± 1.75 μg with a range of 24–40 used in Group A [Figure 4]. When compared, results were statistically significant with P value <0.05. Thus, Group B required a much higher total mean dose of norepinephrine as compared to Group A. Bradycardia was not observed in any patient in Group A as against 2% patients in Group B though the difference was statistically insignificant. Other common maternal side effects noted were nausea and vomiting. Nausea was observed in 10% patients in Group A as against 6% patients in Group B with statistically insignificant difference (p-value 0.712). Vomiting was observed in 6% patients in Group A and 4% patients in Group B with statistically insignificant difference (p-value 0.646).
Neonatal outcome was similar in both the groups. No newborn infant required tracheal intubation or admission to the neonatal intensive care unit (NICU) in the immediate post-delivery period. Apgar score at 1 and 5 minutes was more than 7 in both the groups. Umbilical artery parameters (pH, pC02, pO2, HCO3- and Lactate levels) were also comparable and statistically insignificant (p-value > 0.05) between the two groups [Table 5], [Figure 5].
Table 5: Comparison based on Apgar score at 1 and 5 minutes in two groups Discussion The aim of the study was to compare efficacy and safety of bolus norepinephrine versus infusion norepinephrine in preeclamptics undergoing LSCS under spinal anesthesia. Although hypotension is less frequent and easier to treat in patients with preeclampsia when compared with normotensive parturients, hypotension, during spinal anesthesia, is undesirable in the presence of fetoplacental hypoperfusion which theoretically is preexistent in preeclamptic patients as a part of their pathophysiology. Therefore, appropriate active intervention for spinal hypotension is necessary and may include fluid loading, lateral positioning, and the use of vasopressors. Before this study, only a couple of studies have been conducted to compare the two methods in preeclamptic patients.
One study by Wang X et al.[11] had explored the feasibility of norepinephrine in pregnant females with preeclampsia. In this study, they compared bolus dose of norepinephrine (4 μg), phenylephrine (50 μg), and ephedrine (4 mg) for treatment of maternal hypotension and found norepinephrine bolus dose having similar efficacy to phenylephrine but improved maternal and neonatal safety. We selected a dose of 4 μg for norepinephrine bolus in our study which was same as that used by Wang X et al.[11] due to limited literature of optimal dose in preeclamptic for rescuing post-spinal hypotension and good results with 4 μg dose reached by hit-and-trial method of adequate dose in pilot study.
In our study, both regimens were effective for decreasing the incidence of hypotension; however, infusion of norepinephrine 4 μg/min resulted in more stable blood pressure control compared with norepinephrine bolus group. There was significant reduction in the incidence of hypotension in norepinephrine infusion group compared to norepinephrine bolus group (6% versus 68%). Thus, infusion regimen was superior with higher number of patients maintaining blood pressure near baseline with statistically significantly low incidence of hypotension (p < 0.05). The results of our study are in accordance with Ngan Kee WD et al.[8] who also observed decreased incidence of hypotension in norepinephrine infusion group compared to control group (17% vs. 66%).
In our study, maternal heart rate in the norepinephrine infusion group remained near baseline after 3 minutes of subarachnoid injection than in the norepinephrine bolus group where heart rate was more than baseline and when compared, results were statistically significant till 10 minutes after spinal anesthesia (p < 0.05). The results of our study are in accordance with those of Ngan Kee WD et al.[8] who observed heart rate on average was lower over time in norepinephrine infusion group versus control group (p < 0.001).
In our study, there was statistically significant difference in SBP, DBP, and MAP after 3 minutes which lasted till 10 minutes after spinal anesthesia, where these parameters were higher in norepinephrine infusion group compared to norepinephrine bolus group. Our study results are in accordance with study by Hasanin AM et al.[10] in which they observed two higher dose norepinephrine infusion groups (the 0.050 μg/kg/min and the 0.075 μ/kg/min group) had higher systolic blood pressure and lower heart rate compared with the 0.025 μg/kg/min dose group. Results of norepinephrine infusion group (0.050 μ/kg/min) were comparable to our study norepinephrine infusion group, though we used fixed dose infusion (4 μg/min), as our eligibility criteria was patients in average weight range of 60–80 kgs. Similar results as in our study were also observed in study of Singh A et al.[12] who observed that norepinephrine infusion is an effective method to reduce incidence of hypotension during cesarean delivery under spinal anesthesia. They further observed that maternal bradycardia and hypertension were seen less frequently with noradrenaline infusion group.
In our study, percentage of patients receiving bolus rescue vasopressor was significantly higher in norepinephrine bolus rather than those in infusion group. The percentage of patients receiving 1 bolus of rescue vasopressor was 28% in norepinephrine bolus group versus 6% in norepinephrine infusion group, while a second dose of rescue vasopressor was required only in 40% patients in norepinephrine bolus group versus none of the patient in norepinephrine infusion group. This showed that when norepinephrine infusion was given, the requirement of rescue bolus vasopressor was decreased significantly as was seen by Puthenveettil N et al.[13] in their study. They found that number of boluses of vasopressor required to treat hypotension in norepinephrine bolus group was (1.40 ± 0.577), which was comparable to number of bolus (mean 1.08 norepinephrine bolus per patient) used in our study in norepinephrine bolus group to treat hypotension. In a similar study conducted by Wang X et al.[14] number of norepinephrine boluses used was 2-3 which was comparable to that used in Group A (norepinephrine bolus group) patients in our study although requirement of maximum of only two norepinephrine boluses was there in our study.
In our study, no episode of bradycardia was observed in norepinephrine bolus group, while one episode was observed in norepinephrine infusion group which was statistically insignificant (p-value = 1.000). The results of our study are in accordance with those of Ngan Kee WD et al.[8] who reported four episodes of bradycardia in each group, whereas Dong L et al.[15] and Wang X et al.[11] reported 2% and 3.6% incidence of bradycardia in norepinephrine bolus group in their respective studies.
In our study, none of the patient had any episode of tachycardia and hypertension possibly due to just adequate dose of norepinephrine we selected by hit and trial method in pilot study and going through the literature of studies with different doses of norepinephrine used. Similar results were also observed by Wang X et al.[11] who reported no incidence of hypertension although incidence of tachycardia was higher in their study (16%) compared to ours (0%). Chen D et al.[16] reported that patients who received the higher dose of norepinephrine (15 μg/kg/h) experienced more hypertension episodes than those who received 5 or 10 μg/kg/h norepinephrine (75% versus 41.4% and 36.6%, respectively). This difference could be attributed to higher infusion dose of norepinephrine used in their study.
Our results of neonatal outcome with regard to Apgar score and neonatal blood gas values were similar to results of Chen D et al.[16] study in which both the groups had statistically nonsignificant difference. Similar findings were also observed by Puthenveettil N et al.[13]and Dong L et al.[15] In our study, only one neonatal blood sample showed pH <7.20 that was 7.18 though Apgar score was more than 7 and results were statistically insignificant. Current evidence supports Apgar scores as a better predictor of neonatal outcome than measurement of umbilical artery pH (Casey BM et al.)[17]
The limitation of this study is that we did not compare effects of study drug norepinephrine on cardiac output of the parturients due to nonavailability of transthoracic echo. Another limitation is that effect of oxytocin on development of hypotension after birth of the baby has not been taken into account which could be a source of bias. Further studies are needed to optimize these limitations and increasing the accuracy of the study.
ConclusionThis study concluded that both norepinephrine bolus and infusion are an effective way to treat spinal anesthesia-related hypotension in patients with preeclampsia undergoing cesarean section with comparable maternal side effects and no adverse effects on neonatal outcomes. Furthermore, prophylactic infusion of norepinephrine is better in maintaining hemodynamics of parturients with significantly less number of episodes of hypotension compared to bolus administration of norepinephrine after the onset of hypotension.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
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