Hypotension commonly occurs in parturients undergoing cesarean delivery under spinal anesthesia. This leads to maternal and neonatal adverse outcomes, including maternal nausea and vomiting and fetal acidosis, and might even lead to cardiovascular collapse if not treated. Arterial dilatation and reduction in systemic vascular resistance are the major contributors to spinal-induced hypotension. Therefore, strategies aimed at expanding the intravascular volume with fluid loading or increasing venous return with lower extremities mechanical compression and lateral tilt have had limited effectiveness in the management of spinal-induced hypotension. Vasopressors are therefore the mainstay for the prophylaxis and treatment of spinal-induced hypotension. Phenylephrine is associated with improved neonatal acid-base status and a lower risk of maternal nausea and vomiting compared with ephedrine and is now considered the vasopressor of choice in obstetric patients. This review discusses the various strategies for managing spinal-induced hypotension with a particular emphasis on the optimal use of vasopressors.
Spinal anesthesia is often the modality of choice for cesarean delivery. It is an effective anesthetic that avoids the risks of general anesthesia in parturients with potentially difficult airways. However, a reliable spinal block has predictable undesirable consequences including maternal hypotension leading to nausea and vomiting, decreased uteroplacental blood flow, and fetal acidosis. In South Africa, more than half the anesthetic deaths in 2011–2013 were related to spinal hypotension . Much research over the last 20 years has improved the management of these adverse sequelae of spinal anesthesia, and yet they remain a persistent challenge to the anesthesia provider. The incidence of hypotension depends on the definition used and on the dose of intrathecal local anesthetics administered . Klohr et al. reported that 15 different definitions of hypotension were used in the literature . With the most commonly used definition of a 20% drop from baseline blood pressure, an incidence of 70–80% is reported .
Over the last two decades, considerable changes have occurred in the management of spinal-induced hypotension in the parturient. This review summarizes various strategies that have been investigated over the years including fluid loading, vasopressors, and other methods such as mechanical lower extremity compression, positioning, and 5HT 3 receptor antagonists. In addition, we discuss the mechanisms of hypotension and suggest areas for further study.
Mechanisms of spinal-induced hypotension
Aortocaval compression was first indicted as a cause for maternal hypotension over 50 years ago. Described in 1957, the theory poses that the gravid uterus compressing the great vessels against the lumbar vertebral bodies impedes the return of blood from the vena cava, resulting in decreased cardiac output . Compression of the aorta also impedes perfusion to the uteroplacental unit. Alternately, an early study from the 1940s suggested that 16–20% of blood volume can be redistributed after spinal blockade to the lower extremities, contributing to its hypotensive effect . Both mechanisms were thought to result in a reduction in central venous pressure, leading to a reduction in cardiac output and resulting in hypotension. Therefore, the mainstay of therapy included strategies such as increasing venous pressure with fluid loading, enhancing venous return with leg wrapping, and avoiding aortocaval compression with left uterine displacement. However, as will be discussed in this review, those strategies were only minimally effective, which challenged the notion that a reduction in cardiac output secondary to those mechanisms is the major factor leading to spinal-induced hypotension. In fact, recent studies assessing hemodynamic parameters have shown that cardiac output, heart rate, and stroke volume increase in the first 15 min following the initiation of spinal anesthesia . Concomitantly, a significant decrease in systemic vascular resistance occurs , highlighting the fact that loss of arteriolar tone is likely the main mechanism leading to hypotension . Therefore, vasopressors are currently identified as the mainstay for the management of spinal-induced hypotension.
Management strategies
Low-dose spinal anesthesia
The risk of hypotension is related to the dose of intrathecal bupivacaine. Several authors have reported that low-dose spinal anesthesia for cesarean delivery, using doses of 5–7 mg intrathecal bupivacaine, results in a smaller degree of sympathectomy, vasodilation, and hemodynamic changes, including hypotension . Although a smaller dose of intrathecal bupivacaine reduces the risk of hypotension and the ensuing nausea and vomiting, it increases the need for intraoperative analgesic supplementation . It also results in a shorter duration of block and a slower speed of onset . The combined-spinal epidural (CSE) technique, which provides the option to augment the block with the epidural catheter if needed, should therefore be used if a low-dose spinal anesthesia is planned. This allows the administration of epidural local anesthetics to supplement or prolong a block produced by a low intrathecal bupivacaine dose if needed. Roofthooft and Van de Velde recommend prophylactic epidural top-ups if uterus is not closed at 45 min after low-dose spinal injection to prevent breakthrough pain . Some researchers also deliberately administer a low spinal dose with the expectation of extending the block with epidural local anesthetics, a technique that is often described as low-dose sequential CSE technique . Alternatively, the level of the block after low-dose spinal anesthesia can be extended in a cephalad direction with normal saline administered epidurally shortly after spinal injection, a technique that has been labeled epidural volume extension or epidural volume expansion . The mechanism of this action is most likely from the compression of the subarachnoid space, which results in rostral spread of the local anesthetic in the intrathecal space. The reliability of this technique has, however, been challenged. Furthermore, the optimal intrathecal dose, epidural solution volume, and timing for supplementation remain unclear .
Positioning
Numerous studies investigated the impact of patient’s position on the risk of spinal-induced hypotension. A Cochrane review found no difference in the risk of hypotension between left lateral tilt, right lateral tilt, a right lumbar pelvic wedge, and head down tilt when compared with the supine position. The review also found no impact of the degree of lateral tilt on the risk of hypotension. However, the risk of hypotension was lower with left lateral tilt than with right lateral tilt and with manual displacement than with left lateral tilt. There were no statistically significant differences in maternal heart rate, Apgar scores, or neonatal acid-base status when comparing different positions. However, the risk of hypotension remains high with all positions, and additional measures are clearly needed.
Mechanical lower extremity compression/elevation
Mechanical compression of the lower extremities has been studied as a mechanism to improve the venous return to central circulation. Various mechanical compression devices or strategies including leg elevation, hip flexion, elastic compression bandages, thromboembolic deterrent stockings, and sequential compression devices have demonstrated mixed results . A Cochrane review including seven trials with 399 women reported that lower limb compression was more effective in preventing hypotension than control (RR 0.69, 95% CI 0.53 to 0.90); however, the studies were small with methodological limitations . Most recently, a study in Norway compared the effect of low-dose phenylephrine infusion (0.25 μg/kg bolus followed by an infusion at 0.25 μg/kg/min) with lower extremity compression and with placebo on blood pressure in women undergoing cesarean delivery under spinal anesthesia . They found that use of phenylephrine was superior to compression, but compression of the lower extremities was associated with a smaller decrease in mean arterial pressure compared with no intervention. Interestingly, the reduction in systemic vascular resistance was only countered by phenylephrine and not leg wrapping, suggesting that arterial vasodilation played the predominant role in spinal-induced hypotension, whereas enhancing venous return was only minimally effective.
Fluid therapy
Historically, fluid therapy has been the traditional approach for managing spinal-induced hypotension with the goal of expanding the intravascular volume. Studies have examined type of fluid (crystalloid vs. colloid), timing of fluid administration (preload prior to block vs. coload during and after block replacement), and optimal fluid volumes. For several decades, preloading with a crystalloid bolus was the mainstay of therapy. However, several studies have demonstrated that preloading is not an efficacious strategy . It is believed that because of short intravascular half-life, the fluid is quickly redistributed out of the intravascular space before any spinal-induced hemodynamic changes occur. Furthermore, atrial natriuretic peptide release with subsequent vasodilatation may contribute to the limited effectiveness of this approach . Therefore, it was theorized that it may be more effective to coload with crystalloid fluid during and immediately following spinal block to effectively increase intravascular volume at the time of vasodilation following sympathetic block . This coloading technique was examined by Dyer et al. in 2004, who found that it resulted in a significant reduction in ephedrine requirements when compared with preloading . However, a meta-analysis completed in 2010 by Banerjee et al., which included eight randomized controlled trials (518 total patients) including the previously mentioned trial by Dyer et al. and compared preloading to coloading, found that there was no statistically significant difference in the incidence of hypotension between the two fluid-loading strategies .
Studies have shown that colloid solutions may offer advantages over crystalloid solutions in reducing spinal-induced hypotension . In a recent meta-analysis, Ripolles et al. found that the use of colloids, given either as a preload or a coload, is associated with significantly reduced rates of hypotension when compared with crystalloids . It is believed that colloids are better retained within the intravascular space, allowing for increased and sustained intravascular volume expansion compared to crystalloids . As expected, there is no difference between preloading and coloading strategies using colloids with regard to their efficacy in reducing the risk of spinal-induced hypotension . However, the use of dextran- and gelatin-containing colloid solutions is associated with a risk of allergic reaction, although the risk is greatly reduced with the use of hydroxyethyl starch (HES) . Nevertheless, there are safety concerns with the use of HES because previous studies linked colloids to renal failure and mortality in the critically ill ; however, there is little evidence of similar adverse events in cesarean delivery patients.
To date, no studies have found that fluid administration alone eliminates hypotension, despite demonstrating increases in cardiac output with fluid loading . Although fluid loading expands the intravascular space, the incidence of hypotension remains high. This is further evidence that arterial dilation may contribute more significantly to hypotension, and thus, a need for vasopressor therapy is evident.
Vasopressors
Given the limited efficacy of fluid-loading strategies, vasopressors have emerged as the preferred therapy for spinal-induced hypotension. After spinal anesthesia, there is a fall in the mean arterial pressure and a marked reduction in systemic vascular resistance despite increase in cardiac output, heart rate, and stroke volume in the first 15 min after induction of spinal anesthesia , even after fluid therapy . Therefore, constriction of the arterial vessels is the optimal strategy to manage spinal-induced hypotension.
Animal studies
For several decades, ephedrine was the drug of choice to treat spinal-induced hypotension. This preference was based on several animal studies that investigated the effect of ephedrine, an indirect α and β agonist, and pure α agonists such as phenylephrine on the vasoconstriction of the uterine vascular bed. For instance, Greiss reported that although phenylephrine and norepinephrine corrected hypotension associated with spinal anesthesia in pregnant sheep, they caused significant uterine vessel vasoconstriction to negate the impact of increased blood pressure on uterine blood flow . James also investigated the impact of administration of ephedrine and mephentermine (α and β agonists) and methoxamine (pure α agonist) in 14 pregnant ewes that received a general anesthetic followed by a spinal anesthetic. They reported that although all three vasopressors were effective in correcting hypotension induced by spinal anesthesia, uterine blood flow was significantly higher with ephedrine and mephentermine than with methoxamine . Ralston administered ephedrine, mephentermine, methoxamine, and metaraminol to 16 nonanesthetized ewes and reported no reduction in uterine blood flow with ephedrine when the blood pressure was increased by 50%; however, the uterine blood flow was reduced by 45% and 62% with methoxamine and metaraminol, respectively .
Human studies
On the basis of data from animal studies, ephedrine was considered the vasopressor of choice in obstetric patients. However, there are some limitations associated with the use of ephedrine. It has a relatively slow onset of action, and repeated administration can be associated with tachyphylaxis . Furthermore, because the response to spinal anesthesia includes an initial increased heart rate and cardiac output, a beta-adrenergic agonist may not be the ideal therapeutic choice. The efficacy of IV ephedrine for prophylaxis against hypotension is also limited. Ngan Kee found that although a 30-mg dose of ephedrine given 1 min after spinal anesthesia was more effective than 10- or 20-mg doses (incidence of hypotension 35%, 95%, and 85% respectively), it was associated with a high incidence of reactive hypertension (45%), with no difference in the incidence of maternal nausea, vomiting, or neonatal acid-base status between the groups .
Neonatal outcomes
In the 1980s and 1990s, researchers revisited the use of direct α agonists, mainly phenylephrine, for the management of spinal-induced hypotension in humans. Those studies focused on neonatal outcomes, mainly neonatal acid-base status and Apgar scores. Multiple studies reported that phenylephrine and other α agonists could be safely used in this patient population. Interestingly, neonatal acid-base status was better with phenylephrine than with ephedrine. A meta-analysis of seven of those studies published in 2002 reported no difference between the two vasopressors in the incidence of hypotension but found lower umbilical artery pH with ephedrine than with phenylephrine [mean difference (95% CI) = 0.03 (0.02–0.04)] . A more recent meta-analysis also reported a five-fold increase in the risk of fetal acidosis (defined as pH <7.2) and larger base deficit [mean difference (95% CI) = −1.17 (−2.01, −0.33) with ephedrine than with phenylephrine . Notably, however, Apgar scores were not different with ephedrine compared to those with phenylephrine. Ngan Kee investigated the etiology of fetal acidosis associated with ephedrine administration . Women undergoing elective cesarean delivery were randomized to receive a prophylactic ephedrine or phenylephrine infusion titrated to maintain blood pressure at baseline. The authors found that ephedrine crossed the placenta to a much greater extent than phenylephrine, as indicated by a higher median umbilical venous/maternal arterial plasma concentration (1.13 vs. 0.17). Both arterial and venous umbilical pH were lower, PCO 2 was higher, and concentrations of lactate, glucose, epinephrine, and norepinephrine were greater with ephedrine than with phenylephrine, secondary to metabolic effects of fetal β adrenergic stimulation. Similar findings were also reported in previous studies .
Ultrasound evaluation of uteroplacental perfusion
Because of concerns about uteroplacental vasoconstriction with α agonists, a few studies evaluated changes in uterine artery pulsatility index, a measure of vascular resistance, associated with the administration of ephedrine and α agonists. Alahuhta et al. reported an increase in uterine and arcuate artery pulsatility index with phenylephrine compared to that with ephedrine. There was no change in fetal umbilical artery pulsatility in either group, and there was a decrease in fetal renal arteries pulsatility index with phenylephrine . In contrast, Ngan Kee found no difference in uterine artery pulsatility index measured for 10 min after spinal anesthesia in women receiving ephedrine or metaraminol infusions titrated for hemodynamic management during cesarean delivery . Similar findings were reported by Hall et al. who measured uterine artery pulsatility index for 15 min after spinal placement and treated spinal-induced hypotension with boluses of ephedrine 5 mg or phenylephrine 100 μg .
Intraoperative nausea and vomiting
Studies comparing phenylephrine with ephedrine have reported a lower incidence of intraoperative nausea and vomiting with phenylephrine administration than with ephedrine. This was the case when the vasopressors were used to treat established hypotension and in studies where the vasopressor infusion was initiated prophylactically . This could be related to the more rapid onset of action of a phenylephrine bolus than an ephedrine bolus, leading to quicker correction of hypotension . When using a prophylactic infusion, the increased risk of intraoperative nausea and vomiting with ephedrine might be related to the reflex increase in vagal tone following reduction of preload in the presence of β adrenergic stimulation, whereas phenylephrine might reduce this risk by producing more effective venoconstriction and therefore better maintaining preload .
Optimization of phenylephrine administration
Because phenylephrine was associated with improved neonatal acid-base status and increased intraoperative maternal comfort compared with ephedrine, research started to focus on optimizing the administration of this vasopressor for the management of spinal-induced hypotension. Because of its rapid onset and short half-life, phenylephrine seemed to be an ideal agent for the titration of treatment and prophylaxis of spinal-induced hypotension.
Prophylactic versus rescue administration of phenylephrine
Ngan Kee compared a fixed-rate prophylactic phenylephrine infusion regimen (100 μg/min initiated after spinal anesthetic placement and maintained for 3 min, then switched off for systolic blood pressure >100% of baseline) with a 100 μg phenylephrine bolus given for the treatment of hypotension defined as a systolic blood pressure <80% of baseline . The incidence (23% vs. 88%), frequency, and magnitude of hypotension were significantly lower in the phenylephrine infusion group. Intraoperative nausea and vomiting were also numerically less frequent with the prophylactic phenylephrine infusion (4% vs. 21%), with no difference in umbilical cord gases or Apgar scores between the groups. Similarly, Das Neves reported a lower incidence of hypotension (18% vs. 85%) and intraoperative nausea (10% vs. 40%) when comparing a prophylactic phenylephrine infusion (0.15 μg/kg/min) with 50 μg phenylephrine boluses to treat a 20% drop in blood pressure . Allen also found a higher incidence of predelivery hypotension in patients who received 100 μg phenylephrine boluses for the treatment of established hypotension than in those who received a fixed-rate phenylephrine infusion of 25, 50, 75, or 100 μg/min (80% vs. 30%, 15%, 11%, and 0%, respectively). There was, however, no difference in the incidence of intraoperative nausea and vomiting, umbilical cord gases, or Apgar scores . Using a variable-rate phenylephrine infusion initiated at 0.75 μg/kg/min, Siddik-Sayyid found a lower incidence of hypotension (20% vs. 90%) and of intraoperative nausea and vomiting (10% vs. 44%) compared to treatment of established hypotension with 100 μg phenylephrine boluses, with no difference in umbilical cord gases or Apgar scores between the groups . The incidence of reactive hypertension was, however, higher with prophylactic infusions in all those studies.
Optimum dosing of phenylephrine boluses
Very few studies investigated the dosing of phenylephrine boluses for the management of spinal-induced hypotension. Using an up-down sequential allocation study design, Tanaka et al. found that the ED95 (95% CI) of a prophylactic phenylephrine bolus to prevent hypotension or nausea following spinal anesthesia with 12 mg bupivacaine was 159 (122, 371) μg . Moreover, George et al. determined that the ED90 (95% CI) of a phenylephrine bolus for treating established hypotension following spinal anesthesia with 12 mg hyperbaric bupivacaine was 147 (98, 222) μg . Although the two studies reported doses that are generally higher than those used in previous studies, it is worth noting that they investigated the first dose needed following spinal injection while the sympathectomy is evolving and did not investigate doses needed to manage hypotension after this initial stage.
Optimization of phenylephrine infusion regimens
With the improved outcomes reported with the use of prophylactic phenylephrine infusions compared to the use of phenylephrine boluses for the treatment of established hypotension, researchers looked at optimizing those prophylactic regimens. Ngan Kee investigated the impact of adding a fluid coload to the fixed rate phenylephrine infusion regimen of 100 μg/min (described above); and reported a reduction in the incidence of hypotension from 28% in the group receiving fluids at maintenance rate to 2% in the group receiving a 2-L lactated Ringer’s coload, with a concomitant decrease in phenylephrine consumption . The same group investigated the optimal blood pressure target when using their fixed rate 100 μg/min prophylactic phenylephrine infusion regimen . After running the infusion for 2 min following spinal placement, the infusion was maintained if systolic blood pressure was below 100%, 90%, or 80% of baseline but stopped if it exceeded those targets. There was a significant reduction in the incidence of intraoperative nausea or vomiting when blood pressure was maintained at 100% of baseline compared to the 90% and 80% targets (40% vs. 16% vs. 4%). Umbilical artery pH was also higher in the 100% group compared to the other two groups; however, the difference was small and likely not clinically relevant.
Closed-loop feedback control
A number of researchers investigated the use of closed loop feedback computer-controlled systems for vasopressor administration in the management of spinal-induced hypotension. Ngan Kee initially described the use of a simple on-off algorithm using a phenylephrine infusion of 100 μg/min . Subsequently, this group investigated a variable rate phenylephrine infusion regimen using a proportional algorithm that administered phenylephrine at rates ranging from 0 to 100 μg/min using a computer-controlled feedback system and compared it with their previously described on-off fixed regimen of 100 μg/min. A noninvasive blood pressure measurement was obtained every minute. The computer-controlled variable rate system was associated with fewer physician interventions needed to maintain blood pressure in the target range and resulted in slightly better blood pressure control but without difference in hypotension, reactive hypertension, or nausea and vomiting .
Sng et al. investigated a closed-loop automated system for the treatment of established hypotension using continuous noninvasive blood pressure monitoring and compared it with manual boluses. Their algorithm involved treating hypotension with either phenylephrine or ephedrine based on maternal heart rate: phenylephrine was used if the heart rate was >60 bpm (50 μg every 30 s in the automated group or 100 μg every minute in the manual group) and ephedrine if heart rate was <60 bpm (8 mg every 30 s in the automated group and 4 mg every minute in the manual group). The incidence of hypotension (35% vs. 59%) and intraoperative nausea (1% vs. 10%) was significantly lower in the automated group. Furthermore, the close-loop feedback control group was associated with more accurate blood pressure control than the manual boluses group .
Dose–response studies and impact on maternal hemodynamics
Allen et al. evaluated the number of physician interventions needed to maintain systolic blood pressure within 20% of baseline associated with the use of fixed rate phenylephrine infusion regimens of 25, 50, 75, and 100 μg/min . The number of physician interventions was lower in the 25 and 50 μg/min groups than in the 100 μg/min group. Reactive hypertension occurred less commonly with the lower infusion rates. The median absolute performance error, a measure of inaccuracy of blood pressure control, was also the lowest in the 50 μg/min group.
Phenylephrine is often associated with a reflex bradycardia attributed to the baroreceptor-mediated response to the increased afterload. Bradycardia occurring in the setting of a phenylephrine infusion should not be treated with an anticholinergic agent or with ephedrine, unless it is accompanied by hypotension, otherwise significant hypertension may occur . Reducing the rate or stopping the phenylephrine infusion best manages such bradycardia .
Reactive hypertension also commonly occurs when a prophylactic phenylephrine infusion is used . Because phenylephrine has a short half-life, reducing the rate or stopping the phenylephrine infusion quickly eliminates this increase in blood pressure. Often the increase in cardiac afterload combined with bradycardia results in decreased cardiac output. However, some investigators have demonstrated that immediately following neuraxial placement, there is an increase in cardiac output . Therefore, although phenylephrine can decrease the cardiac output, it typically remains higher than baseline levels. Dyer examined the changes in heart rate and cardiac output for 150 s following the administration of an 80 μg phenylephrine bolus or a 10 mg ephedrine bolus for the treatment of spinal-induced hypotension . Peak blood pressure values were achieved significantly quicker following phenylephrine administration. There was a decrease in heart rate and cardiac output following phenylephrine administration, with values that were significantly lower than those obtained following ephedrine administration. However, cardiac output remained numerically higher than baseline cardiac output, which increased by 35% following spinal anesthesia and before vasopressor administration. The study suggested that heart rate changes could be used as a surrogate for cardiac output changes because changes in both those parameters were significantly correlated.
Stewart et al. investigated three fixed rate prophylactic phenylephrine infusion regimens (25, 50, and 100 μg/min) and reported time-dependent and dose-dependent reductions in heart rate and cardiac output, demonstrating greater depression of heart rate and cardiac output with the higher phenylephrine infusion regimen of 100 μg/min . The maximum decrease in cardiac output was 22%, 15%, and 8% in the 100, 50, and 25 μg/min groups, respectively. Stroke volume remained stable, indicating that cardiac output changes are secondary to changes in heart rate.
Some authors have suggested that uteroplacental blood flow is better correlated with cardiac output than with upper arm blood pressure measurements . Therefore, although studies in healthy parturients did not report any negative impact of this reduction in cardiac output with phenylephrine infusions on neonatal acid base status or Apgar scores, concern has been expressed that this reduction in cardiac output might have detrimental effects on an already compromised fetus such as in emergency situations with pre-existing fetal acidosis . Therefore, Stewart et al. suggested caution with the use of high- dose phenylephrine infusions sufficient to cause a reduction in heart rate .
A number of strategies have been investigated to reduce the bradycardia associated with the use of phenylephrine infusions. Ngan Kee et al. randomized women undergoing cesarean delivery under spinal anesthesia to receive pretreatment with glycopyrrolate 4 μg/kg or saline placebo and maintained blood pressure in both groups with a prophylactic phenylephrine infusion . They reported higher heart rate and cardiac output and lower phenylephrine consumption with glycopyrrolate pretreatment, with no difference in hypotension and an increased risk of reactive hypertension, greater inaccuracy of blood pressure control, and an increased risk of dry mouth. There was also no difference between the groups in neonatal outcomes or in the incidence of maternal nausea and vomiting. The same group of investigators examined the impact of mixing phenylephrine with ephedrine on neonatal and maternal outcomes. The study included prophylactic infusions of phenylephrine, ephedrine, or combinations of ephedrine and phenylephrine in a ratio of 25%, 50%, or 75% of either agent. The authors found that as the proportion of phenylephrine decreased and that of ephedrine increased, the heart rate increased along with increased hypotension, greater inaccuracy of blood pressure control, increased maternal nausea and vomiting, and lower neonatal umbilical artery pH . Those studies suggest that in healthy parturients with noncompromised fetuses, strategies to increase heart rate when using a prophylactic phenylephrine infusion did not translate into improved outcomes.
A more recent study, however, compared the use of norepinephrine, which possesses a weak β adrenergic effect in addition to the potent α agonistic effect, with phenylephrine, with the thought that the β activity of norepinephrine would promote less bradycardia with improvement in cardiac output. A computer-controlled infusion was used to maintain blood pressure using either phenylephrine starting at 100 μg/min or norepinephrine initiated at 5 μg/min . There was no difference in blood pressure or stroke volume between the groups, but cardiac output and heart rate were greater and systemic vascular resistance was lower in the norepinephrine group. The precision of blood pressure control was greater with norepinephrine, as suggested by the lower median absolute performance error . The authors suggested that the increase in cardiac output coupled with lower systemic vascular resistance might promote uteroplacental perfusion to a greater extent than phenylephrine. Interestingly, although there was no difference between the groups in umbilical artery pH, umbilical vein pH and umbilical vein oxygen content were greater with norpepinephrine, suggesting possible improved placental blood flow and oxygen delivery. However, the differences were very small and might not be clinically relevant.
Data from nonelective and high-risk pregnancies
Most of the studies investigating spinal-induced hypotension were performed in elective cesarean deliveries in healthy parturients, and it is not clear if results from those studies are also applicable to nonelective cases and high-risk pregnancies. In a study in women undergoing nonelective cesarean deliveries and receiving either ephedrine 10 mg or phenylephrine 100 μg boluses for the treatment of hypotension, there was no difference in neonatal acid-base status between the groups, but umbilical venous and arterial lactate concentrations and the incidence of nausea and/or vomiting were higher with ephedrine . Similarly, in a retrospective study of pre-eclamptic women receiving either ephedrine or phenylephrine for the treatment of spinal-induced hypotension, there was no difference in umbilical artery pH between the two groups . Two recent randomized controlled studies compared phenylephrine and ephedrine in women undergoing emergency cesarean delivery for fetal indications . One study administered the two agents as a prophylactic infusion , whereas the other study used rescue boluses for the treatment of established hypotension . There was no difference in neonatal acid-base status between those who received ephedrine or phenylephrine for blood pressure support , but the incidence of intraoperative nausea and vomiting and tachycardia was higher with ephedrine, whereas bradycardia was more common with phenylephrine .
Role of genetic polymorphisms
Because of wide variability in the incidence and severity of hypotension after spinal anesthesia, there has been growing interest in the possible impact of genetic predisposition. Landau et al. studied 170 healthy women with two different polymorphisms of β2 adrenoreceptors (ADRB2). All their study patients received the same spinal dose, and there was no difference in the incidence of hypotension. However, patients with certain variant genotypes of ADRB2 had a significantly smaller requirement of ephedrine to maintain blood pressure . The same group followed up this study on variant ADRB2 and response to phenylephrine, with the hypothesis that a significant difference should not exist with phenylephrine dose, which has a different mechanism of action. In this follow up study, they included 96 women and found that there was a statistically significant difference of 200 μg between 2 ADRB2 genotypes, which may not be as clinically relevant . Their work demonstrated that a genetic component of the ADRB2 genotype may contribute to a more severe hypotensive response after spinal anesthesia and varying responses to sympathomimetics.
Serotonin receptor antagonists
Several recent studies investigated the use of 5-hydroxytryptamine subtype-3 (5HT 3 ) receptor antagonists for prophylaxis against spinal-induced hypotension. The rationale for this approach is that the Bezold–Jarisch reflex is mediated by 5HT 3 receptors located on the vagus nerve and within the wall of the cardiac ventricles. Serotonin is released in response to systemic hypotension and can cause an increase in efferent vagal signaling and activates the Bezold–Jarisch reflex by binding to the 5HT 3 receptors, leading to bradycardia and hypotension .
A number of meta-analyses pooling studies that investigated the efficacy of 5HT 3 receptor antagonists in preventing spinal-induced hypotension have recently been published . Ondansetron was the most commonly investigated 5HT 3 receptor antagonist. The meta-analyses by Gao et al. and Heesen et al. suggested that 5HT 3 receptor antagonists reduced the incidence of hypotension, bradycardia, and need for vasopressors following spinal anesthesia in obstetric patients, but there was evidence of publication bias . Terkawi et al., however, used the GRADE system and suggested that the quality of the evidence was low to very low. Furthermore, using recently developed statistical techniques including small trial bias assessments, selection models, and trial sequential analyses, the authors failed to confirm that ondansetron reduced spinal-induced hypotension and bradycardia .
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