Vasopressor Choice for 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.

Spinal anaesthesia for caesarean section commonly causes maternal hypotension. This systematic review and network meta-analysis compared methods to prevent hypotension in women receiving spinal anaesthesia for caesarean section. We selected randomised controlled trials that compared an intervention to prevent hypotension with another intervention or inactive control by searching MEDLINE and Embase, Web of Science to December 2018. There was no language restriction. Two reviewers extracted data on trial characteristics, methods and outcomes. We assessed risk of bias for individual trials (Cochrane tool) and quality of evidence (GRADE checklist). We assessed 109 trials (8561 women) and 12 different methods that resulted in 30 direct comparisons. Methods ranked by OR (95%CI) from most effective to least effective were: metaraminol 0.11 (0.04-0.26); norepinephrine 0.13 (0.06-0.28); phenylephrine 0.18 (0.11-0.29); leg compression 0.25 (0.14-0.43); ephedrine 0.28 (0.18-0.43); colloid given before induction of anaesthesia 0.38 (0.24-0.61); angiotensin 2, 0.12 (0.02-0.75); colloid given after induction of anaesthesia 0.52 (0.30-0.90); mephentermine 0.09 (0.01-1.30); crystalloid given after induction of anaesthesia 0.78 (0.46-1.31); and crystalloid given before induction of anaesthesia 1.16 (0.76-1.79). Phenylephrine caused maternal bradycardia compared with control, OR (95%CI) 0.23 (0.07-0.79). Ephedrine lowered umbilical artery pH more than phenylephrine, standardised mean difference (95%CI) 0.78 (0.47-1.49). We conclude that vasopressors should be given to healthy women to prevent hypotension during caesarean section with spinal anaesthesia.

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.

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.

We conducted a systematic review of the literature reporting phenylephrine-induced changes in blood pressure, cardiac output, cerebral blood flow and cerebral tissue oxygen saturation as measured by near-infrared spectroscopy in humans. We used the proportion change of the group mean values reported by the original studies in our analysis. Phenylephrine elevates blood pressure whilst concurrently inducing a reduction in cardiac output. Furthermore, despite increasing cerebral blood flow, it decreases cerebral tissue oxygen saturation. The extent of phenylephrine's influence on cardiac output (r&#x2009;=&#x2009;-0.54 and p&#x2009;=&#x2009;0.09 in awake humans; r&#x2009;=&#x2009;-0.55 and p&#x2009;=&#x2009;0.007 in anaesthetised humans), cerebral blood flow (r&#x2009;=&#x2009;0.65 and p&#x2009;=&#x2009;0.002 in awake humans; r&#x2009;=&#x2009;0.80 and p&#x2009;=&#x2009;0.003 in anaesthetised humans) and cerebral tissue oxygen saturation (r&#x2009;=&#x2009;-0.72 and p&#x2009;=&#x2009;0.03 in awake humans; r&#x2009;=&#x2009;-0.24 and p&#x2009;=&#x2009;0.48 in anaesthetised humans) appears closely linked to the magnitude of phenylephrine-induced blood pressure changes. When comparing the effects of phenylephrine in awake and anaesthetised humans, we found no evidence of a significant difference in cardiac output, cerebral blood flow or cerebral tissue oxygen saturation. There was also no evidence of a significant difference in effect on systemic and cerebral circulations whether phenylephrine was given by bolus or infusion. We explore the underlying mechanisms driving the phenylephrine-induced cardiac output reduction, cerebral blood flow increase and cerebral tissue oxygen saturation decrease. Individualised treatment approaches, close monitoring and consideration of potential risks and benefits remain vital to the safe and effective use of phenylephrine in acute care.

Norepinephrine has been investigated as a potential alterative to phenylephrine for maintaining blood pressure during spinal anesthesia for cesarean delivery with the advantage of less depression of maternal heart rate and cardiac output. However, the relative potencies of these two vasopressors have not been fully determined in this context. In a random-allocation, graded dose-response study, 180 healthy patients undergoing spinal anesthesia for elective cesarean delivery received a single bolus of norepinephrine in one of six different doses ranging from 4 to 12 &#xb5;g or phenylephrine in one of six different doses ranging from 60 to 200 &#xb5;g to treat the first episode of hypotension. The magnitude of response was measured as the percentage of full restoration of systolic blood pressure to the baseline value. Dose-response analysis was performed using nonlinear regression to derive four-parameter logistic dose-response curves, which were compared to determine relative potency. Data were analyzed for 180 patients. The estimated ED50 values (dose giving a 50% response) were norepinephrine 10 &#xb5;g (95% CI, 6 to 17 &#xb5;g) and phenylephrine 137 &#xb5;g (95% CI, 79 to 236 &#xb5;g). The estimated relative potency ratio for the two drugs was 13.1 &#xb5;g (95% CI, 10.4 to 15.8 &#xb5;g). Comparative dose-response analysis was completed for norepinephrine and phenylephrine given as a bolus to treat the first episode of hypotension in patients undergoing spinal anesthesia for cesarean delivery. The estimated dose equivalent to phenylephrine 100 &#xb5;g was norepinephrine 8 &#xb5;g (95% CI, 6 to 10 &#xb5;g). These results may be useful to inform the design of future comparative studies.