Evaluation of antihypotensive techniques for cesarean section under spinal anesthesia: Rapid crystalloid hydration versus intravenous ephedrine.

BACKGROUND: Spinal anesthesia is a preferred technique over general anesthesia for cesarean delivery. It avoids maternal airway related complications, aspiration and neonatal depression. However hypotension following spinal anesthesia can lead to decrease in uterine blood flow and neonatal hypoxia. AIMS: We aimed to evaluate the efficacy of 15 mL.kg- 1of crystalloid preloading versus prophylactic intravenous bolus of 10 mg ephedrine as an antihypotensive measure for cesarean section.
METHODS: A prospective randomized double blind study was conducted in hundred ASA grade I/II parturient undergoing cesarean section, allocated to group P (n=50) who received preloading with ringer lactate 15 mL.kg- 1 over 20 minutes before spinal anesthesia and group E (n=50) received intravenous bolus of 10mg ephedrine within one minute of spinal anesthesia with 10mg of hyperbaric bupivacaine 0.5% at L2-3/L3-4 level. They were monitored for incidences of hypotension, need of rescue doses of ephedrine, Apgar score and adverse events. Appropriate statistical tests were applied and P < 0.05 was considered as significant.
RESULTS: Incidence of hypotension within 20 minutes of spinal anesthesia was significantly less in group E (28%) as compared to group P (58%) and need of rescue doses were more in group P. Adverse events like nausea vomiting and shivering were less in group E. Apgar score were better in group E than in group P delivered babies.
CONCLUSION: Prophylactic intravenous bolus of 10mg ephedrine with spinal injection is more effective in maintaining maternal hemodynamic stability and better neonatal outcome as compared to crystalloid preloading during cesarean delivery.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Spinal anesthesia (SA) is a preferred technique for cesarean delivery for its distinct advantages over general anesthesia (GA) such as avoidance of airway-related complications, aspiration, neonatal depression with anesthetic agents, and ability of mother to enjoy the birth experience of her baby. Parturient at term are susceptible for hypotension, especially in the supine position and with sympathetic blockade of SA; there is a decrease in systemic vascular resistance (SVR) causing a reduction in venous return, cardiac output, and dependent uterine blood flow. Various prophylactic measures are described such as traditional preloading or coloading with crystalloids/colloids to combat with vasodilatation or use of vasopressors to maintain vasoconstriction.[1234] On the review of clinical researches, it is observed that preloading helps to combat vasodilatation and decrease the incidence of hypotension immediately following SA, but due to conflicting results on the benefit of preloading, a concept of coloading with crystalloids has been found more safer and appropriate physiologically as it coincides with the period of spinal hypotension. However, a meta-analysis involving eight studies on 518 patients observed a similar incidence of hypotension and nausea/vomiting when compared preloading with coloading of crystalloids. Moreover, the efficacy of pre/co-loading of colloids was found similar to crystalloids in the prevention of postspinal hypotension so also the incidence of the requirement of rescue doses of vasopressors.[2] Since vasodilatation is the primary cause of spinal hypotension, it seems logical to use vasopressor like ephedrine which stimulates both α and β adrenoreceptors to maintain normal cardiac output and uterine blood flow. There are ample studies for the use of pre/co-loading, timing of its administration, use of vasopressors, or combination of preload with vasopressors as prophylaxis to prevent hypotension. Currently, ephedrine or phenylephrine is used prophylactically or in rescue doses by intravenous (i.v.)/intramuscular route to control postspinal hypotension during cesarean section but with inconsistent results.[5678910]

Ephedrine has been studied in different doses from 0.25 to 0.5 mg/kg as prophylaxis to prevent hypotension.[27] On comparison of three doses of 10, 20, and 30 mg of ephedrine, Ngan Kee et al. found the favorable vasoconstrictive effects with less detrimental effect on uteroplacental blood flow.[11] Lee et al. suggested larger doses >14 mg do not completely eliminate hypotension but causes reactive hypertension.[12]

Based on various studies,[234101112] we chosen a dose of 10 mg ephedrine bolus as prophylaxis and aimed to compare with the traditional crystalloid preloading of 15 mL/kg ringer lactate for hemodynamic stability in the mother as the primary outcome and neonatal effects in terms of Apgar score and cord blood pH values as the secondary outcome.

METHODS

In this study, 115 parturient were enrolled for cesarean section during January 2012–December 2014. After exclusion of 15 patients who did not meet the selection criteria, one hundred parturient of the American Society of Anesthesiologists grades I/II undergoing cesarean section under SA were included in the prospective, randomized, double-blind study [Figure 1]. The Ethical Committee approval and written informed consent were obtained. Patients having pregnancy induced hypertension, known neurological/cardiorespiratory diseases, or contraindications for SA were excluded from the study groups.

Figure 1

Flow chart of patients included in the study

Following a thorough preanesthetic evaluation and operation theater preparation, all patients received injection ranitidine 50 mg and metoclopramide 10 mg i.v. They were assigned to two groups by computer-generated random numbers. Continuous monitoring started with heart rate (HR), systolic blood pressure (SBP), oxygen saturation (SpO2), temperature, and urine output. Patients in Group P (n = 50) received ringer lactate infusion 15 mL/kg over 15–30 min and in Group E (n = 50) received bolus dose of 10 mg of ephedrine i.v. within 1 min of SA. Under aseptic precautions with 25-guage Quincke's lumbar puncture needle, SA was given in left lateral position at L2–L3/L3–L4 space and 2 mL (10 mg) of heavy 0.5% bupivacaine was injected over 20 s.

Patients were given supine position with 15° leftward tilt. Another anesthetist who was blinded to the study groups observed the patient further. Sensory anesthesia was observed by pinprick method. Surgery started after the attainment of sensory block up to T5/T6 level. Intraoperatively, crystalloids were infused at 10 mL/kg/h. Oxytocin 20 units in 500 mL of crystalloid were given after delivery of the baby. Oxygen supplementation was given with oxygen mask done with 3–4 L of flow until 30 min postoperative period. SBP, HR, and SpO2 recorded at baseline, 1, 5, 10, 15 min, and later every 30 min until 4 h postoperative period. Time of induction of SA to delivery of the baby (I-D), uterine incision to delivery of the baby (U-D), and total duration of surgical procedure were noted. After the delivery of the baby, Apgar score was assessed and noted at 1 and 5 min. The umbilical cord arterial blood gas analysis was done for pH estimation.

Any adverse events in hemodynamic parameters, nausea, vomiting, and chest discomfort were noted and managed accordingly. Hypotension when SBP was <20% of baseline was managed with 5 mg of ephedrine bolus i.v. bradycardia when HR was <20% of baseline was treated with 0.6 mg of atropine i.v. The number of rescue doses of ephedrine required was noted. Any episode of hypertension or tachycardia of >20% of baseline value was noted.

Statistical analysis

The prospective power analysis showed that a sample size of forty patients per study group would have 80% power at the 5% level of significance to detect a difference of 30% in the incidence of hypotension in the study groups. Thus, we included fifty patients in each group. Data were collected, tabulated, coded, and then analyzed with SPSS® computer software-IBM SPSS Statistics version 22.0. SPSS South Asia Pvt. Ltd. Banglore (Karnataka, India) Statistical analyses were performed with GraphPad quickcal software. Numerical variables (demographical variables, surgical time, HR, SBP, and umbilical cord blood pH) were presented as mean ± standard deviation and Z-test was used wherever appropriate for between-group comparisons. Upper sensory level attained was compared with Mann–Whitney U-test.

Categorical variables (number of rescue doses in percent of patient, Apgar scores, incidences of hypertension, tachycardia, nausea, vomiting, shivering, headache, and backache) of the study groups were presented as frequency and percent, and Chi-square test or Fisher exact test was used for comparisons as appropriate. A difference with significance level of P < 0.05 was considered statistically significant (S) and P < 0.01 as highly significant (HS) and P > 0.05 as insignificant (NS).

RESULTS

In this double-blind, prospective, randomized study, one hundred patients undergoing cesarean section were allotted to two groups; Group P (n = 50) received preload with 15 mL/kg of ringer lactate and Group E (n = 50) received 10 mg of ephedrine within 1 min of induction of SA. The demographic profile is mentioned in Table 1. The two groups were comparable for age, weight, height, duration of surgical procedure, time from induction to delivery of the baby (I-D), and surgical incision (U-D) to delivery of the baby. The upper level of sensory block was T5–T6 in both the groups and no patient required supplementation with GA. After delivery of the baby, i.v. midazolam 1–2 mg was given for anxiolysis. The umbilical cord arterial blood pH values were lower in Group E delivered babies, however the difference with pH of Group P delivered babies was NS (P > 0.05).

Table 1

Demographic parameters

The baseline mean HR and mean HR from 1 to 80 min period were NS different in both the groups (P > 0.05) [Figure 2]. No significant bradycardia was noted in both the groups when compared with the baseline HR. The incidence of hypotension from 1 to 20 min record of SBP in Group P was more than SBP in Group E patients (P = 0.001, HS), later there was no significant difference in SBP up to 80 min period when compared with patients in Group E (P > 0.05) [Figure 3]. There were no significant differences between both the groups as regards to maternal HR and reactive hypertension over 80 min period after SA (P > 0.05).

Figure 2

Heart rate variations in two groups

Figure 3

Systolic blood pressure variations in two groups

Table 2 depicts intraoperative events like a number of rescue doses of ephedrine where a single dose of 5 mg of ephedrine required in twenty (40%) patients in Group P and in 12 (24%) patients in Group E that was statistically NS (P = 0.087, >0.05). However, two rescue doses of ephedrine required in nine (18%) and two (4%) patients in Group P and E, respectively, that was significant statistically (P = 0.025, <0.05). Thus, the incidence of hypotension was more in preloaded Group P than in ephedrine Group E. Ten babies in Group P had Apgar score <7 at one and 5 min, eight out of them improved after thorough oropharyngeal suction and bag-mask ventilation, while two improved after endotracheal intubation with intermittent positive-pressure ventilation. The differences in Apgar score of neonates in two groups were statistically NS at 1 and 5 min. Within 1 h postoperative period, five (10%) patients in preload group and two (4%) in Group E had risen in SBP >20%, but the difference was NS statistically. A significant tachycardia of >20% of baseline HR occurred in Group P 2 (4%), however these events were transient and did not require any medication. No incidence of bradycardia was observed in both the groups postoperatively. In the preload Group P, 13 patients had nausea and two patients had vomiting, whereas five patients had nausea, and no patient had vomiting in ephedrine Group E, and thus the difference in the incidence of nausea/vomiting was significant P < 0.05. The incidence of shivering was 12 (24%) in Group P and 4 (8%) in Group E which was significantly less in patients who received prophylactic ephedrine (P = 0.023, <0.05). The incidences of headache and backache were NS in both the groups and responded well to i.v. fluids, analgesics, and rest.

Table 2

Intra- and post-operative events

DISCUSSION

The only major complication of neuraxial anesthesia in parturient undergoing cesarean section is precipitous hypotension in addition to the associated aortocaval compression and further if they are hypovolemic, it can be a contributing factor for cardiovascular collapse. Traditional fluid pre- or co-loading with or without vasopressors are the methods evolved over last few decades, but the use of prophylactic vasopressor is gaining popularity in the prevention of hypotension in cesarean delivery. Butwick et al. found in his review that i.v. crystalloid prehydration has poor efficacy, coloading with colloids is better, and pure α agonist phenylephrine is the preferred vasopressor to control hypotension.[13] Nagna Kee in his recent review observed the incidence of 71% of maternal hypotension following SA. The efficacy of fluid pre- or co-loading in the prevention of hypotension is questionable, and no fluid loading regime is 100% effective; in contrast, the use of prophylactic vasopressors has gained prominence for the control of hypotension by maintaining SVR, venous capacitance, and splanchnic venous tone, thus preventing fall in maternal cardiac output. Effects of aortocaval compression are also dependent on sympathetic vascular tone; hence, the current trend is toward the use of potent vasopressor such as phenylephrine to maintain BP, explains the relative ineffectiveness of i.v. hydration, and uterine displacement maneuvers.[14] An effective management of hypotension with phenylephrine infusion along with coloading of crystalloids is well established and found minimal episodes of hypotension, less nausea/vomiting with better cord blood pH, and no adverse fetal effects.[15]

Ephedrine has been a drug of choice for hypotension in parturient. Its sympathomimetic stimulant activity on α and β adrenergic receptors causes positive ionotropic and chronotropic effects on the heart, maintains uterine blood flow, and relaxes uterine smooth muscles. However, its use should be avoided in patients with preeclampsia, thyrotoxicosis, and ischemic heart diseases for its hyper-reactivity. Efficacy and safety of 0.5 mg/kg i.v. ephedrine bolus along with 15 mL/kg of ringer's preloading have been studied by Kol et al. and found beneficial effects in prevention of hypotension, fewer rescue doses, less nausea/vomiting, and no adverse effects on a fetus with ephedrine bolus.[7] We chose commonly available ephedrine in a dose of 10 mg i.v. as bolus for the study and in the primary outcome, we too observed the fewer incidences of hypotension and need of rescue doses of ephedrine as observed in other studies by Carvalho et al. and Ngan Kee et al.[1011] As compared to 10 mg of ephedrine, higher doses of 20/30 mg were more associated with maternal hypertension and fetal acidosis was observed by Ngan Kee et al. and others.[31011] Higher doses of vasopressors can jeopardize the fetal well-being due to uteroplacental vasoconstriction and reduced blood flow. Siddiqui et al. compared the effects of 100 µg of phenylephrine with 6 mg of ephedrine bolus for the control of maternal hypotension after neuroaxial block in one hundred cesarean deliveries and found it effective, as well as noted no significant difference in Apgar scores at 1 and 5 min in the babies.[16] Chan et al. compared 20 mL/kg of crystalloid preloading versus 0.25 mg/kg of ephedrine for patients undergoing cesarean section under SA. He observed less incidence of hypotension, well-maintained umbilical arterial blood flow (measured by Doppler), and higher umbilical venous pH in group receiving ephedrine prophylaxis.[17] Ngan Kee et al. compared ephedrine in a dose of 5 mg/min with the traditional drug of choice metaraminol 0.25 mg/min and noted better control of maternal BP and higher umbilical arterial pH in patients receiving metaraminol infusion, but the Apgar scores were similar in both the groups.[18] In our study, as a secondary outcome, we also observed better Apgar score and no fetal acidosis when measured with pH estimation in patients receiving 10 mg of ephedrine bolus as observed by others.[7161718] However, studies also report the higher incidence of fetal acidosis with ephedrine. On meta-analysis of twenty trials to find fetal acidosis with the use of ephedrine and phenylephrine found a better control on hypotension with both the drugs but decreased the risk of fetal acidosis with phenylephrine prophylaxis. BE values on blood gas analysis of umbilical arterial blood were significantly lower for ephedrine than phenylephrine. PCO2 values did not differ in two groups, hence found no relation of pH depression with PCO2.[319] Although ephedrine has a propensity for tachyphylaxis with repeated doses and it crosses the placental barrier, it does not affect the fetal outcome.[19] The increased incidence of nausea and vomiting is observed under neuroaxial blockade because of reduced perfusion of the chemoreceptor trigger zone leading to hypoxia and its stimulation. We noted significantly the fewer incidences of nausea/vomiting in ephedrine group as observed by others.[71115] The incidence of shivering in ephedrine group was significantly lower than preload group in our study as observed by Chan et al.[17] Thus, SA is the most accepted technique for cesarean delivery for its rapid action and satisfactory sensory and motor blockade with minimal complications in mother and fetus than with GA.[20] Jabalameli et al. studied the efficacy of three combinations of crystalloid with colloid and i.v. 15 mg ephedrine bolus with crystalloid or colloid. There were good maternal hemodynamic stability and neonatal Apgar scores at 1 and 5 min which were similar in all the groups. However, the use of crystalloid preload with ephedrine bolus was found to be more effective in reducing the incidence of hypotension.[21] Bhardwaj et al. compared bolus dose (E = 5 mg, M = 0.5 mg, P = 30 µg) followed by infusion (E = 2.5 mg/min, M = 0.25 mg/min, P = 15 µg/min) with ephedrine, metaraminol, phenylephrine, respectively, and observed maternal hemodynamics, umbilical blood gases, and complications. They concluded that all the three vasopressors are effective for control of hypotension without adverse effects in mother and neonate.[22] Moslemi et al. compared the effects of prophylactic infusion of phenylephrine (450 µg) versus ephedrine (45 mg) in 250 mL of normal saline as infusion over 30 min before SA and observed good maternal hemodynamic stability with both the agents, however better 5 min Apgar score and less fetal acidosis were observed in babies of parturients who received phenylephrine infusion.[23] Certain limitations in our study show that we have included low-risk pregnancies for cesarean section. A comparative study in high-risk pregnancies is needed to ensure the safety of prophylactic use of ephedrine in those parturients. There is a need to consider the effects on uterine arterial pulsation index before and after ephedrine injection. In our study, we observed 1 and 5 min Apgar and umbilical arterial pH estimation, but more evaluation of other factors of fetal blood gas analysis such as PO2, PCO2, BE, and lactates are required. Considering the changing trends in the use of vasopressors with or without preloading further study is needed to compare the effects with other vasopressors such as phenylephrine or vasopressin-II for the smooth control of maternal BP and neonatal effects.

CONCLUSION

To conclude, our study also supports that prophylactic i.v. bolus of 10 mg of ephedrine is more effective than crystalloid preloading for the maintenance of maternal BP near baseline, less adverse effects such as nausea/vomiting, shivering, and better neonatal outcome following cesarean delivery in healthy parturient under SA.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.