Introduction

Caesarean section is one of the most performed major surgeries in obstetric practice, which now a day is significantly increased compared to last decades. For example, the cesarean rate in America and Australia includes 26.1% of all deliveries¹.

Over the decade, tendencies to use regional anesthesia to do cesarean surgery are increased to reduce the complications of mortality of mothers compared to general anesthesia ², although such anesthesia can also bring some complications such as hypotension while a surgical operation is the most common complication. The pressure on the Inferior vena cava (IVC) in the pregnant uterus can cause decreased intravenous return and ultimately, hypotension in the mother, which is called sleep-related hypotension syndrome³. On the other hand, Spinal anesthesia is the preferred anesthetic method for elective cesarean section in obstetric anesthesia practice. Cesarean sections (C.S.) normally require an anesthetic block at T4 level, so hypotension is reported in up to 80% of spinal anesthesia cases⁴.

Other complications caused by spinal anesthesia include headache, nausea and vomiting, urinary retention, postoperative pain, and postoperative shivering^5,6. As anesthesia in CS is needed to the level of dermatomes T4-T6 and as the majority of roots of sympathetic nerves are inactivated to this level, it is most likely to have hypotension after spinal anesthesia. This is less likely in low-level anesthesia⁷. Although 70 years have passed from the time that four cases of cardiac arrest following undiagnosed hypotension in CS under spinal anesthesia (1930), still no effective method is proposed to meet the problem. Therefore, the ideal vasopressor to reduce the hypotension caused by spinal anesthesia for CS is the subject of this study. The drug should maintain the maternal blood pressure and placental perfusion with the least negative effects on the fetus^8-10.

Ephedrine as a non-catecholamine sympathetic compound, not only has mainly indirect adrenergic receptor activity through the release of norepinephrine, but also exerts weak direct effects, and its sympathomimetic properties, which in turn occur due to its stimulating action on α-, β1-, and β2-adrenergic. This explains the comparatively slow onset and long duration of action. Ephedrine typically increases heart rate and contractility by cardiac β1-adrenergic receptor stimulation. Ephedrine elimination half-life is two and a half hours, and 70-80% of its compound are excreted from the urine with no change. Ephedrine can enhance intravenous blood pressure and has positive (+) inotrope effects. As it never reduces the uterine blood flow, it has been applied in some studies as a vasopressor to treat the hypotension of pregnant women. The stimulating effects of ephedrine on β1 receptor causing increased cardiac output has made the drug a suitable way to treat mid-hypotension, which comes with a heart rate drop. However, there is more evidence showing that ephedrine causes decreased pH in the fetus¹¹.

However, the mechanism of the action of epinephrine is non-selective stimulation of sympathetic alpha and beta receptors^12,13. Epinephrine is a sympathomimetic drug, which has high affinity for α1-, β 1- and β2-adrenergic receptors, β2-effects predominate at low doses, while α1-effects are more significant at higher doses. Epinephrine relaxes the bronchus smooth muscles cells through the stimulation of β2-adrenergic receptor and contracts the bronchial arteries through the alpha-adrenergic receptors. As a result, it can eliminate bronchospasm, congestion, and bloating. Epinephrine can affect the alpha-adrenergic receptors of the skin and membranes and causes arterial contraction and ultimately, reduces intake of regional anesthesia drug and increases its effect. Epinephrine as a cardiac stimulant affects the beta receptors in the heart and causes positive inotropic and chronotropic effects. By this, epinephrine increase cardiac output, increases the myocardia oxygen intake, contractile force, and decreases cardiac adequacy. On the other hand, epinephrine increases blood pressure¹⁴.

In multiple studies, epinephrine has been investigated as a vasopressor to treat hypotension as a result of local anesthesia and spinal anesthesia and its useful effects have been confirmed. Moreover, the long-lasting effect of Lidocaine is due to addition of epinephrine^15,16. According to the significance of the issue of reducing the complications including bradycardia and hypotension caused by spinal anesthesia in the women under elective CS with its suitable treatment; this study aimed to investigate the effects of intravenous epinephrine and ephedrine for management of hypotension and bradycardia caused by spinal anesthesia of elective CS patients in Kamali Hospital, Karaj in 2020-21.

Materials and method

This study is a double-blind clinical trial. The studied population consists of the CS cases with hypotension and/or bradycardia, who were elective CS cases hospitalized in Kamali Hospital, Karaj in 2020-21. The sample size consisted of 126 people (63 people per group), obtained using G-power software (comparing two mean values in 2 groups) and concerning the type one error, 5% and power of 80% (beta=20%) and equal standard deviation of both groups (SD=2) for the blood pressure of patients. The inclusion criteria were, elective CS candidate, consent to participate in the study, no prohibition for spinal anesthesia, no background of hypertension or cardiovascular disease, lack of allergy to medication, pregnant women in the age range of 20-40 attended in ASA2 class, and gestational age of 36-40 weeks. Exclusion criteria included lack of consent to participate in the study, a contraindication for spinal anesthesia, or blood pressure more than 140/90mm, and diagnosis of placenta diseases. The conscious consent letter was obtained from the patients, and the Ethics Committee of Alborz University of Medical Sciences provided the ethics code and the permission of using intravenous epinephrine and ephedrine. Variables assessed included demographic such as age, education, and body mass index (BMI); and clinical variables included blood pressure, heart rate. In addition, we measured clinical variables such as Apgar, and laboratory variables such as VBG results. Samples were selected using convenience sampling and were divided into two intervention and control groups randomly using randomizing software. The first group received intravenous epinephrine and the second group received intravenous ephedrine. Before beginning the anesthesia process and surgery, the patients were monitored in terms of blood pressure and heart rate. Also, before the infusion of the anesthesia drug, they received 500 cc ringer serum. In sitting position, the anesthesia was applied in L3-L4 or L4-L5 region by spinal needle No. 25 and 15mg hyperbaric Marcain Spinal Heavy anesthesia equivalent to 3cc of 0.5% Marcain in the subarachnoid space by one anesthesiologist and trying once. Patients basal blood pressure and heart rate were measure before anesthesia, and every 2 minutes and up to 20 min, and then every 5 min up to 45min after infusion of an anesthesia drug. The pH ratio and Apgar were also measured for the fetus. In the ephedrine group, after beginning spinal anesthesia, blood pressure dropped more than 20%, and systolic blood pressure was reduced to less than 100 mmHg. 10mg intravenous ephedrine was prescribed until the time that systolic blood pressure of the mother was above 100 mmHg¹⁷. In the epinephrine group, based on the study conducted in 1997, the blood pressure drop was more than 20% and systolic blood pressure was below 100 mmHg and a 4µg bolus epinephrine was applied until systolic blood pressure of mother reached above 100 mmHg¹⁸.

Data we expressed as mean ± SD, and analyzed using independent t-test, Chi-squared, and Mann Whitney test. Data were considered significant at p<0,05.

Results

According to (Table 1), the mean value and SD of pH (p=0.374) and PO₂ (p=0.198) showed no significant statistical difference between the two groups. Mean and SD of PCO₂ (p=0.001) between two groups based on independent t-test showed significant statistical difference. Also, the mean and SD of HCO₃ (p=0.004) showed significant difference between the two groups based on the Mann-Whitney test, and yet both groups are at a high level in the ephedrine group .

According to (Table 2), the frequency distribution of Apgar showed no significant difference between the two groups in the first minute based on the Chi-squared test (p=0.204). Besides, Apgar in the fifth minute was ten on ten in all items in two groups.

According to (Table 3), based on the independent t-test, the mean value of diastolic blood pressure that was the same in early minutes (p>0.05) was increased significantly from the eighth minute in the majority of cases in the ephedrine group compared to the epinephrine group.

As shown in Table 4, based on the independent t-test, the mean value of systolic blood pressure, which was the same in two groups in early minutes (p>0.05), was significantly increased during minutes 8-16 in the ephedrine group compared to epinephrine group (p<0.05). However, they showed no significant difference in the rest of the time evaluated (p>0.05).

According to (Table 5), based on the independent t-test, the mean heart rate was the same in two groups in early minutes (p>0.05); although it was increased in the ephedrine group compared to epinephrine (p<0.05) in minutes 10, 25, 35, and 45. However, the two groups showed no significant difference in other times (p>0.05).

Discussion

Previous evidence provided by Chan et al. (1997), indicate that 64 women under CS whom received spinal anesthesia in a protocol of two groups of 20 ml serum per kg, or 0.25mg per kg ephedrine, have shown that 35% of participants in the ephedrine group and 65% in the serum group showed hypotension¹⁹. Similarly, Vercauteren et al. (2000), demonstrated that when 50 women of CS were exposed to spinal anesthesia in a protocol of two groups of 50 mg ephedrine or normal saline, the frequency of hypotension in the ephedrine group was equal to 8% and 42% in the normal saline group²⁰. Furthermore, Desalu et al. (2005), in 60 cesarean section case women received anesthesia in the frame of two groups of ephedrine and normal saline serum, found that 40% of participants in the ephedrine group and 70% in the normal saline group suffered from hypotension²¹. All this finding are consistent with the effectiveness of ephedrine observed in the present study.

Manuchehrian et al. (2011) demonstrated the effect of dosages of 10 and 20 mg intravenous ephedrine to prevent hypotension caused by spinal anesthesia in cesarean section, and the reduction was more evident by the dosage of 20 mg ephedrine²². In the present study, desirable effects of ephedrine to maintain the blood pressure was cleared from the eighth minute.

In the study conducted by Jabalameli et al. (2012), 150 cesarean section cases were placed in three groups of serum lactate, ephedrine, and combined group. The results showed that there was no difference between study groups²³; although the present study showed a significant difference between groups with no combined group.

In the study of Bouchnak et al. (2012), 60 cases of cesarean section were placed in two groups of receiving colloid and crystalloid. It was found that 40% of samples in the colloid group and 66% in the crystalloid group showed hypotension. Also, the number of complications in the newborns and ABG results showed no difference between the two groups²⁴. In the present study, no difference was observed between groups in terms of pH and PO2.

In the study of El-Mekawy et al. (2012), 90 cesarean section cases under spinal anesthesia were placed in three groups of ephedrine, Voluven, and lactated ringer. The results showed that the three groups were the same in terms of pH and PCO2 levels²⁵. However, in the present study, the pH of the two groups was the same, and PCO2 was significantly different between them.

Farsani et al. (2016) studied the effect of intravenous infusion of phenylephrine and ephedrine in the treatment of hypotension caused by spinal anesthesia in orthopedic surgical operations. The results showed that the prescription of phenylephrine in the treatment of hypotension caused by spinal anesthesia in orthopedic surgery of lower limbs is more suitable than ephedrine²⁶. However, the present study showed that ephedrine has better effects than epinephrine.

Conclusion

In general, according to the results obtained from this study, it could be found that ephedrine can increase blood pressure and heart rate more than epinephrine at the time of hypotension and bradycardia. Also, the blood pressure was the same between the two groups up to the eighth minute from the time of spinal anesthesia accomplishment. Hence, it could leave no desirable effect on the fetus, and Apgar and the VBG of the newborn were the same in both groups. Besides, the difference of pressure in both groups 8 minutes after spinal anesthesia was not significant, so that it had no undesirable maternal effects. Also, Tachycardia caused by ephedrine was not highly desirable in the ephedrine group compared to the epinephrine group. According to the findings, in addition to confirmation of using ephedrine in the management of hypotension and bradycardia caused by spinal anesthesia; the suggestion is the clinical use of intravenous epinephrine as an alternative with dosage more than the proposed dosage instead of ephedrine for management of hypotension and bradycardia caused by spinal anesthesia in cesarean sections (CS). Besides, it is recommended to conduct other studies with a larger sample size and higher dosage of epinephrine in form of comparative intervention concerning distorting factors.

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Notas de autor

Mashakbanafsheh@yahoo.com