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Print version ISSN 0034-7094
Rev. Bras. Anestesiol. vol.59 no.1 Campinas Jan./Feb. 2009
Ephedrine versus phenylephrine: prevention of hypotension during spinal block for cesarean section and effects on the fetus*
Efedrina versus fenilefrina: prevención de hipotensión arterial durante anestesia raquidea para cesárea y efectos sobre el feto
Edno Magalhães, TSA, M.D.I; Catia Sousa Govêia, TSA, M.D.II; Luís Cláudio de Araújo Ladeira, TSA, M.D.II; Bruno Góis Nascimento, M.D.III; Sérgio Murilo Cavalcante Kluthcouski, M.D.III
dos Centros de Anestesiologia e de Clínicas Cirúrgicas do Hospital
Universitário de Brasília; Responsável pelo CET/SBA do
Centro de Anestesiologia da UnB
IIMédico Assistente do Hospital Universitário de Brasília; Co-Responsável pelo CET/SBA do Centro de Anestesiologia da UnB
IIIME3 do CET/SBA Centro de Anestesiologia da UnB
OBJECTIVES: Hypotension during spinal block for cesarean section is secondary
to the sympathetic blockade and aorto-caval compression by the uterus and it
can be deleterious to both the fetus and the mother. Ephedrine and phenylephrine
improve venous return after sympathetic blockade during the spinal block. The
objective of this study was to compare the efficacy of ephedrine and phenylephrine
in the prevention and treatment of maternal hypotension during spinal block
and to evaluate their side effects and fetal changes.
METHODS: Sixty patients undergoing spinal block with bupivacaine and sufentanil for cesarean section were randomly divided in two groups to receive prophylactic ephedrine (Group E, n = 30, dose = 10 mg) or phenylephrine (Group P, n = 30, dose = 80 µg). Hypotension (blood pressure equal or lower than 80% of baseline values) was treated with bolus administration of the vasoconstrictor at 50% of the initial dose. The incidence of hypotension, reactive hypertension, bradycardia, and vomiting, and Apgar scores on the 1st and 5th minutes, and blood gases of the umbilical cord blood were evaluated.
RESULTS: The mean dose of ephedrine used was 14.8 ± 3.8 mg and of phenylephrine was 186.7 ± 52.9 µg. Demographic parameters and the incidence of vomiting, bradycardia, and reactive hypertension were similar in both groups. Hypotension had an incidence of 70% in Group E and 93% in Group P (p < 0.05). The mean arterial pH of the umbilical cord blood and the Apgar score in the 1st minute were lower in Group E (p < 0.05). Differences in the Apgar score in the 5th minute were not observed.
CONCLUSIONS: Ephedrine was more effective than phenylephrine in the prevention of hypotension. Both drugs had similar incidence of side effects. Fetal repercussions were less frequent with phenylephrine and were transitory with the use of ephedrine.
Key Words: ANESTHESIA, Obstetrics; COMPLICATIONS: hypotension; DRUGS: ephedrine, phenylephrine; SURGERY, Obstetrics: cesarean section.
Y OBJETIVOS: La hipotensión arterial durante la anestesia raquídea
para cesárea se debe al bloqueo simpático y a la compresión
aortocava por el útero y puede ocasionar efectos malignos para el feto
y su madre. La efedrina y fenilefrina mejoran el retorno venoso después
del bloqueo simpático durante la anestesia raquídea. El objetivo
de este estudio fue comparar la eficacia de la efedrina y de la fenilefrina
en prevenir y tratar la hipotensión arterial materna durante la anestesia
raquídea y evaluar así sus efectos colaterales y las alteraciones
MÉTODO: Sesenta pacientes, sometidas a la anestesia raquídea con bupivacaína y sufentanil para cesárea, se dividieron aleatoriamente en dos grupos para recibir, profilácticamente, efedrina (Grupo E, n = 30, dosis = 10mg) o fenilefrina (Grupo F, n = 30, dosis = 80 µg). Hipotensión arterial (presión arterial menor o igual a un 80% de la medida basal) fue tratada con bolo de vasoconstrictor con un 50% de la dosis inicial. Se evaluaron: incidencia de hipotensión arterial, hipertensión arterial reactiva, bradicardia y vómitos, puntuación de Apgar en el 1° y 5° minutos y gasometría del cordón umbilical.
RESULTADOS: La dosis promedio de efedrina fue 14,8 mg (± 3,8) y 186,7 µg (± 52,9) de fenilefrina. Los grupos fueron similares en cuanto a los parámetros demográficos y a la incidencia de vómitos, bradicardia e hipertensión arterial reactiva. La incidencia de hipotensión arterial fue de un 70% en el Grupo E y un 93% en el Grupo F (p < 0,05). El pH arterial promedio del cordón umbilical y el puntaje de Apgar en el 1° minuto fueron menores en el grupo E (p < 0,05). No se registró diferencia en el puntaje del 5° minuto.
CONCLUSIONES: La efedrina fue más efectiva que la fenilefrina en la prevención de la hipotensión arterial. Los dos fármacos presentaron una incidencia similar de efectos colaterales. Las repercusiones fetales fueron menos frecuentes con el uso de la fenilefrina y apenas transitorias con el uso de la efedrina.
Hypotension during spinal block for cesarean section is secondary to the sympathetic blockade and it can be harmful to both the fetus and mother. Among the deleterious effects one can mention a reduction in uterine and placental blood flow, disruption of fetal oxygenation and fetal acidosis, and maternal symptoms of reduced cardiac output, such as nausea, vomiting, and altered level of consciousness 1.
The incidence of hypotension after spinal block for cesarean section can be as high as 80% 2-4 if prophylactic measures, such as prior hydration, moving the uterus to the left side, and vasopressors, are not instituted 5,6.
Ephedrine is a non-catecholamine sympathomimetic agent that stimulates alpha and beta adrenergic receptors direct and predominantly indirectly, producing its effects by releasing norepinephrine from nerve endings in the autonomous nervous system. Traditionally it is the vasopressor of choice in obstetric anesthesia despite the lack of confirmation of its superiority over other vasopressors 7,8. The intercurrences of epinephrine include maternal supraventricular tachycardia, tachyphylaxis, and fetal acidosis. Prior studies reported that the increase in blood pressure caused by ephedrine is related to preservation of uterine and placental blood flow, especially due to its beta-adrenergic action 9,10. However, other authors have suggested that ephedrine can reduce umbilical cord pH without affecting Apgar scores 4,11.
Phenylephrine is considered a pure α1-adrenergic agonist. It promotes dose-dependent vasoconstriction, which is more pronounced in the venous than in the arterial bed, improving venous return after the sympathetic blockade during spinal block. Studies have shown that phenylephrine maintain uterine and placental blood flow and higher umbilical cord blood pH than ephedrine, having similar efficacy in controlling hypotension but with a lower risk of fetal acidosis 5,12,13.
The present study hypothesized that the pharmacologic profile of phenylephrine regarding the vitality of the newborn is superior to that of ephedrine in the treatment of hypotension during cesarean section under spinal block. The objective of this study was to compare the efficacy of phenylephrine and ephedrine in the prevention and treatment of intraoperative maternal hypotension, evaluate the side effects of this therapy, and to study fetal changes using Apgar scores and arterial and venous umbilical cord blood gases.
After approval by the Ethics on Research Committee (CEP, from the Portuguese) in humans of the University of Brasília and signing of the informed consent, 60 women were selected for this randomized, double blind, prospective study.
Inclusion criteria were as follows: physical status ASA I or II, term pregnancy of a single fetus, and indication for cesarean section. Exclusion criteria were refusal to participate in the study, patients younger than 18 years, preexisting or pregnancy-induced systemic hypertension, and presence of cardiovascular or cerebrovascular diseases, fetal abnormalities, history of allergy to the drugs used in the study, and contraindications to spinal block.
Monitoring included continuous electrocardiogram, non-invasive blood pressure, and pulse oximetry. Patients were placed in dorsal decubitus for a few minutes and blood pressure and heart rate were recorded every three minutes for three times to obtain mean baseline levels. With the patient in left lateral decubitus, spinal puncture was done with a 25 ´ 3.5 Quincke needle between L2-L3 or L3-L4 and a solution containing 10 mg of 0.5% hyperbaric bupivacaine and 3 µg of sufentanil was administered. Afterwards, with the patient in dorsal decubitus, a Crawford wedge was placed under her right hip to obtain left uterine displacement. Immediately after the subarachnoid injection and before the incision of the uterus, an infusion of two liters of Ringer's lactate was initiated, followed by a slow infusion.
Patients were randomly divided into two groups using sequential, sealed envelopes with random numbers generated previously by a computer. The result of the allocation was ignored by both the patients and the physicians responsible for collecting and analyzing the study parameters. The determination of sample size was based on prior studies 12,13. Groups were composed of 30 patients each and denominated Group E (ephedrine) and Group P (phenylephrine). Patients in Group E received a prophylactic intravenous bolus of 10 mg of ephedrine immediately after the subarachnoid block and patients in Group P received a prophylactic intravenous bolus of 80 µg of phenylephrine. The syringes with the study drugs were prepared by a physician who was not involved in the collection of the data and analysis of the results.
Maternal hypotension was defined as a blood pressure equal or lower than 80% of baseline values and it was treated with a bolus of 50% of the initial dose of the vasopressor. Reactive hypertension was characterized as blood pressure 20% higher than baseline levels after the use of the vasopressor. Heart rate below 50 bpm characterized bradycardia, when accompanied by hypotension, and it was treated with 0.75 mg of atropine.
The level of sensitive blockade was evaluated every minute after the puncture, by painful stimuli with a needle, until the end of the procedure. Authorization for the surgical procedure was given only when the level of the blockade reached T5. The time from the blockade to the incision of the skin, incision of the uterus, and removal of the fetus were recorded.
The incidence of maternal hypotension, reactive hypertension, bradycardia, nausea and vomiting, and the total dose of vasopressor were also analyzed.
Apgar scores on the first and fifth minutes of all newborns were determined and a score below eight was considered low. Venous and arterial blood were drawn from the umbilical cord immediately after delivery for blood gases determination, and a pH below 7.2 was considered fetal acidosis.
The Student t test for continuous data, Mann-Whitney test for ordinal data, and Chi-square test for nominal data were used to analyze the results. A p < 0.05 was considered significant.
The mean age of patients in Group E was 27.2 years, and 26.5 years in Group P. The mean body mass index (BMI) was similar in both groups, as well as the weight. Patients had a mean gestational age of 39 weeks. Other demographic parameters and physical status did not show statistically significant differences (Table I).
The mean time from the spinal puncture to skin incision in Group E was 7.4 minutes and 6.9 minutes in Group P. The mean time to uterine incision was 12.7 and 12.8 in Groups E and P, respectively, and the mean time for delivery of the fetus was 13.8 and 14.2 minutes. Those parameters did not show statistically significant differences. In Group E the mean dose of vasopressor used was 14 mg and in Group P 186 µg. As for the sensitive blockade in most patients it reached T4 (Table II).
As for side effects, Group E had seven episodes of nausea and four of vomiting, while Group P had 10 episodes of nausea and six of vomiting. The incidence of reactive hypertension was similar: five episodes in Group E and four in Group P. Only one patient in Group P developed bradycardia, which was treated with atropine. Those differences were not statistically significant. In Group P, 28 patients (93%) developed hypotension and in Group E 21 (70%) patients developed this complication, and this difference was statistically significant (p < 0.05). The number of episodes of hypotension was significantly higher in Group P (80 episodes) than in Group E (29 episodes), p < 0.05 (Table III).
Group E had a higher proportion of newborns with Apgar scores in the first minute that were lower than 8 (27%) than group P (10%), and this difference was statistically significant (p < 0.05).
In Group E, eight newborns (27%) had Apgar scores in the first minute of seven, 17 (56%) had scores of eight, and five (17%) of nine. In Group P, three newborns (10%) had Apgar scores in the first minute of seven, fifteen (50%) of eight, eleven (37%) of nine, and one (3%) of 10.
Apgar scores in the fifth minute did not show differences between both groups. In Group E, two newborns (6%) had Apgar scores of eight, twenty (67%) had scores of nine, and eight (27%) of ten. In Group P, half of the newborns had Apgar scores in the fifth minute of nine and ten in the other half.
As for arterial and venous umbilical cord blood gases, mean pH showed statistically significant differences between both groups: 7.22 in Group E and 7.27 in Group P (p < 0.05). Table IV shows the mean blood gases levels.
The indication of regional block in obstetrics has gained acceptance due to the reduction in maternal and fetal morbidity and mortality 14. However, some studies have associated a greater incidence of fetal acidosis after spinal block, probably secondary to maternal hypotension or factors that modify uterine and placental blood flow 15,16.
Moving the uterus to the left and administering intravenous fluids have been used to reduce the severity of hypotension, but with limited efficacy. The administration of vasopressors is frequently necessary 17.
Historically, ephedrine has been the vasopressor of choice in obstetrics despite the uncertainty about its superiority 1,7,9. It was believed that ephedrine increases maternal blood pressure, therefore preserving uterine and placental blood flow due to its beta-adrenergic action, while pure alpha-agonist vasopressors were associated with a reduction in this blood flow 8,10. However, subsequent studies demonstrated that in the treatment of post-spinal block hypotension in cesarean sections ephedrine has similar efficacy, but it can occasionally promote fetal acidosis 18-20.
In the present study, parameters associated with post-spinal block hypotension were controlled to evaluate which drug would be more effective in the prevention of hypotension with fewer deleterious consequences to the fetus. Prior studies have presented different methodologies and questionable results regarding the ideal vasopressor, dose, and administration regimen, as well as the use of other techniques to control maternal blood pressure with minimal deleterious effects on the fetus 12,19,20.
To limit distortions, all patients were hydrated with 2,000 mL of Ringer's lactate, which was instituted after the spinal block since recent studies have demonstrated the inefficacious of prior hydration due to the fast redistribution 21. The uterus was moved to the left to reduce aortocaval compression, and the blockade was maintained on the same level in all patients.
Despite the care with the method employed, some factors can limit the interpretation of the study. The number of patients involved although greater than in some studies reported can be a bias since sample size was not calculated. The difference of time between the time the umbilical cord blood was drawn and the analysis of blood gases is another limitation. This difference might have altered the results of blood gases and possibly interfered with the results.
Prior studies have suggested that a bolus of 30 mg of intravenous ephedrine would be more effective in the prevention of hypotension, but with an increased incidence of reactive hypertension 22. In contrast, a prospective, observational study demonstrated that the intravenous administration of 15 to 20 mg of ephedrine reduced the incidence of maternal hypotension without increasing the incidence of reactive hypertension 20. A 2004 metaanalysis 19 concluded that doses above 14 mg of ephedrine did not reduce the incidence of maternal hypotension, but they caused reactive hypertension in the mother and a small reduction in umbilical cord blood pH. In the present study, a dose of 10 mg of ephedrine was considered to be effective and, at the same time, had little side effects.
As for phenylephrine, a recent study demonstrated that even high doses (above 2,000 µg) were not associated with deleterious effects on the fetus, as determined by the Apgar scores and umbilical cord blood gases 23. In the present study, the dose of 80 µg of phenylephrine was chosen based on a prior study that demonstrated that this was the effective dose when administered as an intravenous bolus, without severe side effects 12.
On evaluating the control of hypotension, several studies have demonstrated similar efficacy of ephedrine and phenylephrine on the prevention and treatment of this complication, both when used in bolus or continuous infusion 23,24. In the present study, for practical purposes, it was decided to administer the medication as a bolus. Phenylephrine showed lower efficacy on the prevention of hypotension than ephedrine, demonstrated by the number of patients who developed hypotension and the number of episodes in each group. This probably was secondary to the shorter duration of action of this vasopressor and the way it was administered, since it was administered as a bolus and prophylactically, only repeating the dose when the blood pressure was equal or lower than 80% of baseline levels, and fluctuations in its plasma concentrations could also have contributed. Although phenylephrine is less effective in controlling blood pressure, differences in the incidence of maternal side effects, such as nausea, vomiting, and changes in the level of consciousness, were not detected probably because the reduction in blood pressure was not severe.
A systematic revision of the factors associated with pH and base excess after spinal block for cesarean section concluded that the time between uterine incision and removal of the fetus was associated with low pH and base excess 24. However, in the present study, differences in the time between the installation of the blockade and removal of the fetus were not detected. We do not believe that gestational age and the weight of the newborn caused any interference with the evaluation, since those parameters were similar in both groups.
Prior studies reported changes in umbilical cord blood gases associated with the use of ephedrine, but without deleterious repercussions on the fetus, as demonstrated by the Apgar scores in the first and fifth minutes 18,19. Some authors have mentioned possible interferences of tachyphylaxis and changes in fetal metabolism due to the beta-adrenergic actions of ephedrine 18,19,24. Since it is a pure alpha-agonist, phenylephrine would not have the same effects. In the present study, despite the absence of numerical characterization of fetal acidosis, ephedrine was associated with a lower arterial pH than phenylephrine. This could suggest an influence in fetal metabolism, since venous pH did not show significant differences between both groups. Other possible etiology for this change in blood gases could be related to the change in uterine and placental blood flow. However, newborns in group E had low Apgar scores predominantly in the first minute, with a substantial improvement in the fifth minute, indicating transitory changes on the newborns, without medium- and long-term repercussions.
The results of the present study only give partial support to the hypothesis guiding this study, what could be justified by technical deficiencies of the method and the size of the study population. However, deleterious repercussions on the fetus, analyzed by the Apgar scores and blood gases, were less frequent with phenylephrine and only transitory with ephedrine.
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Correspondence to: Submitted em 13
de março de 2008 *
Received from CET/SBA do Centro de Anestesiologia do Hospital Universitário
de Brasília, Universidade de Brasília (UnB), Brasília,
Dr. Edno Magalhães
SQS 113, bloco C/406
70736-030 Brasília, DF
Accepted para publicação em 27 de outubro de 2008
Submitted em 13
de março de 2008
* Received from CET/SBA do Centro de Anestesiologia do Hospital Universitário de Brasília, Universidade de Brasília (UnB), Brasília, DF