Vasopressors for Cesarean Spinal Hypotension

The optimal choice of vasopressor drugs for managing hypotension during neuraxial anaesthesia for Caesarean delivery is unclear. Although phenylephrine was recently recommended as a consensus choice, direct comparison of phenylephrine with vasopressors used in other healthcare settings is largely lacking. Therefore, we assessed this indirectly by collating data from relevant studies in this comprehensive network meta-analysis. Here, we provide the possible rank orders for these vasopressor agents in relation to clinically important fetal and maternal outcomes. RCTs were independently searched in MEDLINE, Web of Science, Embase, The Cochrane Central Register of Controlled Trials, and clinicaltrials.gov (updated January 31, 2019). The primary outcome assessed was umbilical arterial base excess. Secondary fetal outcomes were umbilical arterial pH and Pco2. Maternal outcomes were incidences of nausea, vomiting, and bradycardia. We included 52 RCTs with a total of 4126 patients. Our Bayesian network meta-analysis showed the likelihood that norepinephrine, metaraminol, and mephentermine had the lowest probability of adversely affecting the fetal acid-base status as assessed by their effect on umbilical arterial base excess (probability rank order: norepinephrine > mephentermine > metaraminol > phenylephrine > ephedrine). This rank order largely held true for umbilical arterial pH and Pco2. With the exception of maternal bradycardia, ephedrine had the highest probability of being the worst agent for all assessed outcomes. Because of the inherent imprecision when collating direct/indirect comparisons, the rank orders suggested are possibilities rather than absolute ranks. Our analysis suggests the possibility that norepinephrine and metaraminol are less likely than phenylephrine to be associated with adverse fetal acid-base status during Caesarean delivery. Our results, therefore, lay the scientific foundation for focused trials to enable direct comparisons between these agents and phenylephrine.

During spinal anesthesia for cesarean delivery, phenylephrine can cause reflexive decreases in maternal heart rate and cardiac output. Norepinephrine has weak β-adrenergic receptor agonist activity in addition to potent α-adrenergic receptor activity and therefore may be suitable for maintaining blood pressure with less negative effects on heart rate and cardiac output compared with phenylephrine. In a randomized, double-blinded study, 104 healthy patients having cesarean delivery under spinal anesthesia were randomized to have systolic blood pressure maintained with a computer-controlled infusion of norepinephrine 5 μg/ml or phenylephrine 100 μg/ml. The primary outcome compared was cardiac output. Blood pressure heart rate and neonatal outcome were also compared. Normalized cardiac output 5 min after induction was greater in the norepinephrine group versus the phenylephrine group (median 102.7% [interquartile range, 94.3 to 116.7%] versus 93.8% [85.0 to 103.1%], P = 0.004, median difference 9.8%, 95% CI of difference between medians 2.8 to 16.1%). From induction until uterine incision, for norepinephrine versus phenylephrine, systolic blood pressure and stroke volume were similar, heart rate and cardiac output were greater, systemic vascular resistance was lower, and the incidence of bradycardia was smaller. Neonatal outcome was similar between groups. When given by computer-controlled infusion during spinal anesthesia for cesarean delivery, norepinephrine was effective for maintaining blood pressure and was associated with greater heart rate and cardiac output compared with phenylephrine. Further work would be of interest to confirm the safety and efficacy of norepinephrine as a vasopressor in obstetric patients.

Hypotension remains one of the most researched subjects in obstetric anaesthesia. The purpose of this study is to review the most recent published articles on the use of vasopressors during spinal anaesthesia for caesarean section. Despite continued research indicating advantages of phenylephrine over ephedrine, practitioners in some countries continue to favour ephedrine. Recent research has continued to compare the two drugs with some work emerging on high-risk patients. Concern about reflexive bradycardia during phenylephrine use has led to consideration of alternatives. Norepinephrine which has mild β-adrenergic activity has been shown to have equivalent pressor activity but with less depressant effect on heart rate and cardiac output versus phenylephrine. Research continues to focus on methods of vasopressor administration. Prophylactic infusions of phenylephrine have been shown to be effective and may require less physician intervention compared with intermittent boluses. Automated computer-controlled systems have been further investigated using multiple agents and continuous noninvasive blood pressure monitoring. Evidence continues to support phenylephrine as the first-line vasopressor in obstetrics. However, recent research is emerging to suggest that low-dose norepinephrine may be a better alternative. Prophylactic infusions are effective and automated systems have potential for the future.

Phenylephrine is recommended for the management of hypotension after spinal anaesthesia in women undergoing caesarean section. Noradrenaline, an adrenergic agonist with weak &#x3b2;-adrenergic activity, has been reported to have a more favourable haemodynamic profile than phenylephrine. However, there are concerns that noradrenaline may be associated with a higher risk of fetal acidosis, defined as an umbilical artery pH <&#xa0;7.20. We performed a systematic review of trials comparing noradrenaline with phenylephrine, concentrating on primary outcomes of fetal acidosis and maternal hypotension. We identified 13 randomised controlled trials including 2002 patients. Heterogeneity among the studies was high, and there were too few data to calculate a pooled effect estimate. Fetal acidosis was assessed in four studies that had a low risk of bias and a low risk of confounding, that is, studies which used a prophylactic vasopressor and where women received the allocated vasopressor only. There were no significant differences between these studies. No significant differences were observed for hypotension. Two trials found a significantly lower incidence of bradycardia when using noradrenaline. Cardiac output was significantly higher after noradrenaline in two of three studies. For other secondary outcomes including nausea, vomiting and Apgar scores at 1 and 5&#xa0;min, no studies found significant differences. The evidence so far is too limited to support an advantage of noradrenaline over phenylephrine. Concerns of a deleterious effect of noradrenaline on fetal blood gas status cannot currently be assuaged by the available data from randomised controlled studies.

Phenylephrine (PE) is currently the vasopressor of choice to prevent and treat spinal-induced hypotension at cesarean delivery (CD). However, its use is often associated with reflex bradycardia. Norepinephrine (NE) has been put forward as an alternative vasopressor during CD due to its ability to treat hypotension while maintaining heart rate (HR). Recent studies have focused on the role of NE used as an infusion with favorable results compared to PE. No studies have compared equipotent bolus doses of PE and NE at CD. We hypothesized that when used in equipotent doses as an intermittent bolus regimen to prevent and treat spinal-induced hypotension, NE would result in a reduction in the incidence of bradycardia compared to PE. This was a double-blind, randomized clinical trial of women undergoing elective CD under spinal anesthesia. Women were randomized to receive either PE 100 &#xb5;g or NE 6 &#xb5;g when the systolic blood pressure (SBP) was below baseline. In addition to the randomized treatment, ephedrine was given intravenously to both groups if the SBP was below baseline and the HR <60 bpm or if the SBP was <80% of baseline for 2 consecutive readings. The primary outcome was bradycardia (HR <50 bpm) in the predelivery period. Secondary outcomes included hypotension (SBP <80% of baseline), hypertension (SBP >120% of baseline), tachycardia (HR >120% of baseline), &#x2265;2 episodes of bradycardia, nausea, vomiting, umbilical artery and vein blood gases, and Apgar scores. One hundred twelve patients were randomized. The incidence of bradycardia was lower in the NE group compared to the PE group (10.7% vs 37.5%; P < .001; difference [95% confidence interval {CI}], -26.8% [-41.8% to -11.7%]), implying an estimated 71% relative reduction (95% CI, 35%-88%). The distribution of the number of bradycardia episodes was also different between the 2 groups (P = .007). Further testing showed that the patients in the PE group had a higher risk of multiple bradycardia episodes (&#x2265;2 episodes) compared to the NE group (19.6% for PE versus 3.6% for NE; P = .008). The proportion of patients requiring rescue boluses of ephedrine was lower in the NE group compared to the PE group (7.2% for NE versus 21.4% for PE; P < .03; difference [95% CI], -14.3% [-27.0% to -1.6%]). No differences were observed between the 2 groups in the incidence of other secondary outcomes. When used as an intermittent bolus regimen to prevent and treat spinal-induced hypotension during CD, NE resulted in a significant reduction in the incidence of bradycardia as compared to an equipotent bolus regimen of PE. We conclude that the hemodynamic profile offered by NE during CD is superior to that of PE due to less fluctuations in HR and possibly cardiac output.

Multiple studies have compared varying prophylactic and therapeutic doses of norepinephrine and phenylephrine given as either intermittent bolus or fixed-rate infusion to combat postspinal hypotension in patients undergoing cesarean section (CS). We conducted a systematic review to figure out the best alternative to treat postspinal hypotension. PubMed and Cochrane databases were extensively searched for eligible RCTs. A total of 15 studies were found eligible and analyzed for the incidence of maternal bradycardia as the primary outcome and other maternal adverse effects, fetal acidosis and Apgar scores at 1 and 5 min as the secondary outcome. Data was analyzed using Review Manager Version 5.3. software. There was no significant difference in the efficacy of norepinephrine and phenylephrine for managing postspinal hypotension (OR=1.15 [95% CI: 0.91-1.45], P=0.24, I2=0%,moderate quality) in parturients undergoing CS. Odds of incidence of maternal bradycardia decrease significantly by 61% with norepinephrine versus phenylephrine (OR=0.39 [95% CI: 0.31-0.49], P<0.00001, I2=27%, high quality evidence). Significant higher umbilical artery mean pH values were observed with NE versus PE (MD=0.0 [95% CI: 0.00 to 0.01], P=0.03), although not clinical relevant. However, no significant difference was found in the incidence of other maternal adverse effects and fetal outcomes. Comparable efficacy for management of postspinal hypotension, though, norepinephrine was found to cause less incidence of maternal bradycardia as compared to phenylephrine.