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| ORIGINAL ARTICLE |
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| Year : 2023 | Volume
: 2
| Issue : 1 | Page : 37-43 |
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Effects of prophylactic bolus of norepinephrine versus phenylephrine on maternal and fetal outcome during caesarean section under subarachnoid block: A randomized study
Anjeleena Kumar Gupta1, Shweta Sinha2, Anjali Gera1, Ashwin Marwaha1, Jayashree Sood1
1 Institute of Anaesthesiology, Pain and Perioperative Medicine, Sir Ganga Ram Hospital, New Delhi, India
2 Department of Anaesthesia and Critical Care, Institute of Liver and Biliary Sciences, New Delhi, India
| Date of Submission | 03-Feb-2023 |
| Date of Decision | 28-Mar-2023 |
| Date of Acceptance | 04-Apr-2023 |
| Date of Web Publication | 25-May-2023 |
Correspondence Address:
Dr. Anjeleena Kumar Gupta
Institute of Anaesthesiology, Pain and Perioperative Medicine, Sir Ganga Ram Hospital, New Delhi - 110 060
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/jica.jica_4_23
Background: Vasopressors are the mainstay of treatment of subarachnoid block-induced hypotension (SAIH). The literature is ambiguous regarding the choice of vasopressor, the strategy of administration, and their potency ratio for proper comparison. A prophylactic bolus dosing is the preferred mode of administration for obstetric anesthesia. Thus, we undertook a study to assess the efficacy of norepinephrine (NE) and phenylephrine (PE) in preventing SAIH and compare their effects on maternal and fetal outcomes. Materials and Methods: A randomized, double-blind clinical study was conducted on 240 parturients planned for elective cesarean section under subarachnoid block (SAB). They were allocated to receive a prophylactic bolus dose of either NE 4 μg or PE 50 μg immediately after the SAB. The incidence of maternal hypotension (primary outcome); heart rate (HR), reactive hypertension, intraoperative nausea or vomiting, neonatal APGAR score, umbilical umblical cord blood pH, and the need for active neonatal resuscitation (secondary outcomes) was compared between the groups. Results: The incidence of hypotension was comparable between the groups (P = 0.42). The mean HR was significantly higher in the NE group at 2 min (83.9 ± 9.2 vs. 80.6 ± 9.3 bpm, P = 0.005), 3 min (84.4 ± 8.8 vs. 79.3 ± 11.1 bpm, P < 0.001) and 4 min (85.0 ± 9.9 vs. 79.6 ± 12.6 bpm, P < 0.001). Rest of the maternal and fetal outcomes were similar in both the groups. Conclusion: Based on the relative potency ratio of 12.5, the effect of an intermittent prophylactic bolus dose of NE is comparable to that of PE in preventing SAIH.
Keywords: Cesarean section, hypotension, norepinephrine, obstetric, phenylephrine, spinal anesthesia, subarachnoid block, vasopressors
How to cite this article:
Gupta AK, Sinha S, Gera A, Marwaha A, Sood J. Effects of prophylactic bolus of norepinephrine versus phenylephrine on maternal and fetal outcome during caesarean section under subarachnoid block: A randomized study. J Ind Coll Anesth 2023;2:37-43 |
How to cite this URL:
Gupta AK, Sinha S, Gera A, Marwaha A, Sood J. Effects of prophylactic bolus of norepinephrine versus phenylephrine on maternal and fetal outcome during caesarean section under subarachnoid block: A randomized study. J Ind Coll Anesth [serial online] 2023 [cited 2023 Jun 8];2:37-43. Available from: https://www.jicajournal.in//text.asp?2023/2/1/37/377600 |
| Introduction | |  |
Hypotension following subarachnoid block (SAB) is a common side effect with an incidence of up to 71%.[1] It is associated with adverse maternal outcomes such as nausea, vomiting, dizziness, and rarely cardiovascular collapse. It has the potential to cause a decrease in uteroplacental blood flow which raises concerns about fetal acidosis, hypoxia, and postnatal neurological injury. Transient severe hypotension is not as deleterious as the sustained duration (>4 min) of hypotension which has been associated with neurobehavioural changes in neonates.[2] Sympatholysis has been accepted as the main etiology of hypotension, therefore, vasopressors are the mainstay of treatment. Phenylephrine (PE), α1 adrenergic receptor agonist without β-adrenergic activity, is considered the gold standard drug to prevent subarachnoid block-induced hypotension (SAIH) but is associated with reflex bradycardia and the resultant decrease in cardiac output (CO).[3] Preservation of maternal heart rate (HR) is of paramount importance. Recently, norepinephrine (NE), a potent α1 adrenergic receptor agonist with β-agonistic activity, has been proposed as an alternative to PE. NE is considered better in terms of HR control, however, its use in obstetric practice is limited. There is controversy not only in the choice of vasopressors but also in the strategy of administration and potency ratio of the drugs for proper comparison in clinical studies. Theoretically, the prophylactic strategy is considered better compared to the reactive strategy; wherein the incidence and degree of hypotension should be lower.
We undertook a study to assess the efficacy of prophylactic equipotent bolus dose of NE and PE in the prevention of induced maternal hypotension and compare their effects on maternal HR, intraoperative nausea or vomiting, and neonatal outcome in healthy parturients scheduled for cesarean section under SAB.
| Materials and Methods | | |
This randomized double-blinded parallel clinical study was conducted after approval from Institutional Ethics Committee (EC/01/19/1470) and registered under Clinical Study Registry, India (CTRI/2019/05/019426). The study was conducted in accordance with the Helsinki Declaration of 2013. Written informed consent was taken from 240 parturients that were enrolled in the study from June 2019 to December 2020. Inclusion criteria were term pregnancy (≥37 weeks) planned for cesarean section, age >18 years, American Society of Anaesthesiologists physical status I/II, weight >50 kg or <90 kg, height >150 cm or <170 cm and singleton pregnancy. Exclusion criteria were preeclampsia, hemoglobin <8 g/dL, resting HR >120 beats/min (bpm), history of cardiovascular (hypertension, arrhythmia, cardiomyopathy, ischemic, and valvular heart disease) or cerebrovascular disease, renal impairment (serum creatinine >1.2 mg/dl), platelet count <1 lakh, International Normalized Ratio >1.5 or previously known fetal abnormality (syndromic issues, small for gestational age).
Parturients were randomized using randomization codes generated using an online random number generator (URL: stattrek.com/statistics/random-numbergenerator.aspx) to ensure equal numbers in each group. One code for each parturient was placed in a sealed, opaque, consecutively numbered envelope by the investigator who was not involved in the conduct of the study. Parturients were assigned into two groups to receive prophylactic bolus dose of either NE 4 μg (NE group) or PE 50 μg (PE group).
The study drugs were prepared using 800 μg NE base (0.8 mL) or 10 mg PE (1 mL), each diluted in 100 mL 0.9% normal saline to give a concentration of 8 μg/mL (NE) or 100 μg/mL (PE). The potency ratio of the study drugs was kept at 12.5 (50 μg PE vs. 4 μg NE) based on a random allocation, graded dose-response study by Ngan Kee, and comparative study by Wang et al.[4],[5] To maintain blinding, the study drug solutions were prepared in identical 5 mL syringes by the individual who was not involved in parturient monitoring. The study drug syringe labeled as test drug was handed to the attending anaesthesiologist who took 0.5 mL of the drug solution in 1 mL syringe to give it as a bolus dose (NE 4 μg/PE 50 μg) each time. Both the drugs being transparent were similar in appearance, hence the observer was also blinded to the administration of the study drug.
Standard anesthetic care; fasting (8 h), antacid premedication was provided according to institutional standards. Baseline noninvasive blood pressure (NIBP) was defined as the mean of 3 consecutive readings at 1 min interval after a brief resting period. A lower alarm limit for systolic blood pressure (SBP) was set at a value <80% of baseline. Standard co-loading was done with balanced salt solution through a 20 G intravenous (IV) cannula.
SAB was administered under full aseptic precautions in the sitting position. After local anesthetic infiltration (2 mL lidocaine 1% w/v), a 27G pencil point spinal needle was introduced at L2–3 or L3–4 vertebral interspace. After a free flow of cerebrospinal fluid; a mixture of 20 μg fentanyl along with 9 mg hyperbaric bupivacaine (0.5%) was injected into the subarachnoid space. The Parturient was returned to a supine position with a 15° left lateral tilt of the operating table until delivery of the baby. The height of neuraxial blockade was assessed using a spirit swab for loss of cold sensation 2 min after SAB and thereafter, at 2 min intervals till the block height of T5 dermatome was achieved. The time taken from SAB to the achievement of T5 dermatome (T1), to the skin incision (T2) and to the delivery of the baby (T3) was recorded. In the event of SAB failure, the surgery was conducted under general anesthesia, and the parturient was excluded from the study.
NIBP and HR were recorded every 1 min from SAB till the time of delivery of the baby then every 5 min till the end of surgery. Immediately after SAB, before the start of surgery, prophylactic bolus of the study drug was given IV and flushed with 2 mL balanced salt solution on flow.
Immediately after the delivery of the baby, umbilical venous cord blood sample was collected from the placental end and sent in ice immediately for blood gas analysis (RAPIDLAB 1265, SIEMENS). APGAR scores at 1 and 5 min as assessed by the attending neonatologist were recorded. The neonates were resuscitated as per the Neonatal Resuscitation Program guidelines 2015 in the event of any such need.[6] The requirement of active neonatal resuscitation in terms of positive pressure ventilation, chest compression, or medication (epinephrine) was recorded.
Hypotension was defined as SBP <80% of the baseline value.[1] In the event of hypotension, the parturient received the first rescue bolus dose of the study drug (0.5 mL) as per the assigned group. If hypotension persisted, then the second rescue bolus drug was repeated after 1 min. If the hypotension persisted even after the third rescue bolus administration, an alternative rescue vasopressor, mephentermine 6 mg IV bolus was given followed by bolus fluid administration (250 mL aliquots). Once the NIBP reached baseline value, hypotension was considered as treated. If hypotension occurred again after being treated then it was considered a second episode for which rescue boluses of the study drug were given similarly as for the first episode of hypotension. The number of episodes of hypotension was recorded. The total dose of vasopressor and IV fluid given were also recorded.
If the parturient developed reactive hypertension (SBP >120% of baseline value),[7] a note was made, and IV lignocaine (1 mg/kg) was administered. Bradycardia was defined as HR <50 bpm. If bradycardia was associated with hypotension, IV atropine (0.3 mg) was administered.
The primary objective of the study was to compare the effects of study drugs on the incidence of maternal hypotension and the secondary objective was to compare maternal HR, incidence of reactive hypertension, intraoperative nausea or vomiting, neonatal APGAR score, umbilical cord blood pH and the need for active neonatal resuscitation.
Statistical analysis
Our primary outcome measurement was the incidence of maternal hypotension following SAB. Sample size calculation was based on testing the difference between the incidence of hypotension with respect to NE and PE with a prophylactic infusion of the two vasopressor drugs whose expected values have been reported as 17%–23% respectively.[8],[9] Required sample size for testing the expected difference at a significance level of 5% and with the statistical power of 80% was 697 for each group. Since our study was time bound, therefore, the proposed study was pursued as a pilot study with a smaller sample size of 120 cases in each group.
Data preparation was done using MS EXCEL and statistical analysis was done with Statistical Package for Social Sciences SPSS statistical package (version 20.0; SPSS Inc., Chicago, IL, USA). Continuous variables were presented as mean ± standard deviation or median (interquartile range). Qualitative variables such as incidence of hypotension, bradycardia, nausea/vomiting, and need for neonatal resuscitation were expressed as frequencies or percentages and the comparison/association between the groups was done using the Chi-square test or Fisher's Exact test as appropriate.
Quantitative variables such as APGAR score, umbilical cord blood pH, number of episodes of hypotension were compared using Unpaired Student's t-test or Mann–Whitney U-test depending upon the distribution. For all statistical tests, a P < 0.05 was taken to indicate a significant difference. An intention-to-treat analysis was done.
| Results | | |
Three hundred and eighty-six parturients were assessed for eligibility, and after exclusion 240 parturients were randomized into two groups [Figure 1].
Demographic profile, baseline laboratory and hemodynamic parameters, and surgical times were comparable between the two groups [Table 1]. There was no difference in the comorbid conditions (gestational diabetes, hypothyroidism, and bronchial asthma) in the study population. | Table 1: Demographic profile, surgical times, baseline laboratory, and hemodynamic parameters (n=120)
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Changes in SBP and HR are depicted in [Figure 2]. SBP remained similar at all time points between the groups (P > 0.05). The incidence of hypotension was lower in NE group (59.1%) as compared to that in the PE group (64.1%) as given in [Table 2]. The difference was not statistically significant (P = 0.42). The time to first rescue bolus dose of vasopressor was comparable between the groups (NE: 5.88 ± 3.1 min, PE: 5.7 ± 2.9 min; P = 0.3). There was no incidence of reactive hypertension in either group. | Figure 2: Serial changes in SBP (a) and maternal HR (b). Data are expressed as mean ± SD, number (n) NE: Norepinephrine group, PE:Phenylephrine group, SBP:Systolic blood pressure, HR: Heart rate, SD: Standard deviation
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The mean HR was significantly higher in the NE group at 2 min (83.9 ± 9.2 vs. 80.6 ± 9.3 bpm; P = 0.005), 3 min (84.4 ± 8.8 vs. 79.3 ± 11.1 bpm; P < 0.001) and 4 min (85.0 ± 9.9 vs. 79.6 ± 12.6 bpm; P < 0.001). At all other time points, the difference was not statistically significant. HR <60 bpm was experienced by 6 parturients in the NE and 7 parturients in the PE group. One parturient in either group had HR <50 bpm requiring treatment with atropine.
The incidence of nausea was 5% (6/120) and 6.7% (8/120) in NE and PE groups respectively which was not statistically significant (P = 0.78). None of the parturients experienced vomiting during the study.
APGAR scores at 1 and 5 min were not different between the groups. None of the neonates had an APGAR score <8 and none required active neonatal resuscitation. Umbilical cord blood gas analysis was comparable between the two groups. There was no difference in cord blood pH, lactate, bicarbonate, and base deficit between the groups [Table 3]. None of the neonates had umblical cord blood pH.
| Discussion | | |
This is one of the largest studies on the use of prophylactic vasopressors for the prevention of SAIH during cesarean section. This study indicates that prophylactic bolus of NE and PE are equally effective in maintaining maternal blood pressure with higher HR in the NE group. Both the drugs are associated with favorable maternal and fetal outcomes.
Strict exclusion criteria were used to have a uniform study group and to minimize confounding factors. The subjects were comparable with regard to demographic and clinical variables which allowed proper comparison. Only, few studies have used potency ratio, based on the available literature and preliminary dose-finding studies.[7],[10],[11],[12],[13],[14],[15] Potency ratio of 12.5 (50 μg PE vs. 4 μg NE) was used for an accurate estimation of the effectiveness of NE.
Maternal hemodynamics are consistent and predictable following SAB. Decrease in systemic vascular resistance results in a drop in SBP and a compensatory rise in HR to maintain the CO.[16],[17] Current standard of α-agonist (PE) increases SBP but is associated with a reflex reduction in HR, thus a decrease in the CO.[3] HR measurement is thus, a direct reflection of CO. NE effectively treats hypotension and preserves CO by countering reflex bradycardia by α1 stimulation. Maintenance of CO is the primary objective of vasopressor use in SAIH since it determines the adequacy of uteroplacental blood flow and fetal well-being. NE has been used for sick patients as a first-line agent for hypotension in intensive care unit settings. Therefore, its use in obstetric patients where treatment of abrupt and transient changes in hemodynamics after SAB is required should be justifiable. Pure α-agonists cause reduced regional and organ blood flow but whether this concern can be translated to the obstetric population is debatable.[18]
Our study results show no statistically significant difference between the groups in terms of SBP at any time point (P > 0.05) and are in concurrence with other studies.[7],[10],[13] The standardized SBP in the study by Wang et al. was 97.1 ± 8.0 mmHg in the NE group and 95.0 ± 6.8 mmHg in the PE group (P = 0.17).[13] Similarly, the study using a prophylactic bolus of 50 μg PE and 10 μg NE to prevent SAIH, found no difference in SBP at any time point (P > 0.05).[7] This might be the result of the potent α-blocking properties of both the study drugs.
In our study, 59.1% of parturients (71/120) in the NE group and 64.1% (77/120) in the PE group had episodes of hypotension requiring rescue bolus of the same study drug. However, it did not achieve statistical significance (P = 0.42). Three boluses to counteract an episode of hypotension were required for two parturients in the NE group but none in the PE group. Two parturients in each group experienced a second episode of hypotension requiring vasopressor boluses. Puthenveettil et al. used a reactive strategy of bolus vasopressor (NE/PE) administration showing that the mean number of boluses of vasopressor was higher in PE group (2.28 ± 1.06 vs. 1.40 ± 0.57).[19] The requirement of rescue boluses is expected as the duration of action of these drugs is short.
In the present study, HR in the NE group was significantly higher at 2, 3, and 4 min compared to the PE group (P < 0.05). NE with its mild β-adrenergic action maintains the HR better than the pure α-agonist PE. Wang et al. also showed a higher standardized HR (calculated by area under curve method) in the NE group compared to the PE group (P = 0.049).[13] Various other studies employing reactive bolus or prophylactic infusions have also shown similar results in terms of HR.[5],[7],[10]
Bradycardia is a well-known side effect of PE. In our study, the incidence of bradycardia was comparable between the two groups (5% in NE vs. 5.8% in PE), similar to that of Puthenveettil et al. (4% in NE vs. 20% in PE; P = 0.19).[19] Sharkey et al. reported a higher incidence of bradycardia (10.7% in NE vs. 37.5% in PE; P = 0.001) with an overall higher risk of multiple (≥2) episodes of bradycardia in the PE group.[14] This difference in result in our study can be explained by the different strategies of administration, the amount of drug administered and definition of bradycardia taken in the different studies. Significantly higher incidence of bradycardia has been observed in studies wherein 100 μg dose of PE was used as opposed to our study using 50 μg dose.[13],[14]
In this study, the incidence of nausea is comparable between the two groups; NE: 5% (6/120) and PE: 6.7% (8/120). No incidence of vomiting was observed in either group. Nausea and vomiting are related to decreasing CO leading to reduced splanchnic blood flow and cerebral hypoperfusion that stimulates the vomiting center in the brain stem. The incidence of nausea can be as high as 40% in absence of the use of prophylactic vasopressors as seen by Ashagrie et al.[20] Most recent studies show a lower incidence of nausea when prophylactic vasopressors are administered.[5],[7],[12]
The fetal outcome was favorable and comparable between the two groups. Mean APGAR scores at 1 and 5 min were more than 8.5 and none of the fetuses required active neonatal resuscitation. Umbilical cord blood analysis showed no incidence of fetal acidosis in either group. A meta-analysis by Xu et al. also showed no statistically significant difference between PE and NE in terms of incidence of fetal acidosis and APGAR score in the randomised controlled trials included.[21] This signifies that a brief decrease in CO due to PE does not translate into changes in acid-base balance or APGAR score.
In our study, only a small dose (4 μg) of NE was used to prevent SAIH which might be the reason for comparable HR and SBP between the two groups. However, this dose was effective in decreasing the incidence of hypotension after SAB with favorable neonatal outcomes.
Although most of the studies show the inferiority of PE in HR control and are associated with lower CO, none of the studies has shown any adverse effect on maternal or fetal outcomes. The reason might be the low sensitivity of the parameters measured and the selection of healthy parturients as in our study. Further studies on direct uteroplacental blood flow measurement and studies involving compromised fetuses will clarify the significance of the above findings.
There is a theoretical concern of the risk of tissue ischemia and necrosis secondary to extravasation with the use of vasopressors especially NE when given via peripheral veins. However, no adverse effect in this regard has been documented in recent studies using NE, similar to our study.[4],[8],[14],[22]
Intermittent bolus dosing is preferable in comparison to infusion, although the latter has been shown to better treat SAIH. Bolus dosing is the favorite medication paradigm for the anesthesiologist due to ease of administration and unavailability of infusion pumps in low-resource settings. The lower cost of NE compared to PE offers another advantage in such situations.
Our study has few limitations. First, we used HR as a surrogate marker for CO but did not measure CO directly with noninvasive CO monitor. Second, our study included healthy parturients with no cardiac comorbidities.
| Conclusion | | |
There is no significant difference between the two vasopressors, namely, NE and PE in the maintenance of SBP. The relative equivalent profile of NE and PE can be attributed to the adequately chosen relative potency of 12.5. However, NE was seen to have better HR control than PE. Whether better HR maintenance leads to better maternal or fetal outcomes is difficult to answer as the outcomes measures are probably too subjective to capture a small hemodynamic difference. Both the drugs were associated with favorable fetal outcome. Bolus NE can be used as a suitable alternative to PE to prevent SAIH. With regards to dosing, 4 μg dose of NE was found to be adequate to prevent SAIH. We believe that a higher dose may overshoot the patient's baseline BP and result in hypertension.
We recommend more studies to compare NE and PE in obstetric parturients with cardiac disorders, uteroplacental insufficiency, or morbidly obesity using CO monitoring and direct uterine artery blood flow measurements.
Acknowledgments
The author would like to acknowledge the contribution of Ms. Parul Chugh for her statistical help and Ms. Priya Yadav for her secretarial help.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]
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