Changing trends in the management of hypotension following spinal anesthesia in cesarean sectionJK Mitra1, J Roy2, P Bhattacharyya1, M Yunus1, NM Lyngdoh1
1 Department of Anesthesiology, Critical Care and Pain Medicine, NEIGRIHMS, Shillong, Meghalaya, India
2 Department of Obstetrics and Gynecology, College of Medicine and JNM Hospital, Kalyani, Nadia, West Bengal, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.113840
Source of Support: None, Conflict of Interest: None
Hypotension during cesarean section under spinal anesthesia remains a frequent scenario in obstetric practice. A number of factors play a role in altering the incidence and severity of hypotension. Counteracting aortocaval compression does not significantly prevent hypotension in most singleton pregnancies. Intravenous crystalloid pre-hydration is not very efficient. Thus, the focus has changed toward co-hydration and use of colloids. Among vasopressors, phenylephrine is now established as a first line drug, although there is limited data in high-risk patients. Though ephedrine crosses the placenta more than phenylephrine and can possibly cause alterations in the fetal physiology, it has not been shown to affect the fetal Apgar or neurobehavioral scores.
Keywords: Cesarean section, hypotension, spinal anesthesia
Spinal anesthesia is now the technique of choice for cesarean section.  It is frequently accompanied by hypotension, which may be defined in absolute terms as a systolic blood pressure (SBP) of 90 or 100 mmHg or in relative terms as a percentage (20% fall from baseline).  The incidence of hypotension can be as high as 70-80% when pharmacological prophylaxis is not used;  the severity depends on the height of the block, the position of the parturient, the volume status and whether it is elective or emergency cesarean section. Measures that decrease the risk of hypotension to varying degrees include intravenous administration of fluids, avoidance of aortocaval compression, and monitoring of blood pressure at frequent intervals after placement of regional anesthetic. If recognized and treated promptly, maternal hypotension may not be associated with maternal or neonatal morbidity.  The risk of hypotension and associated emetic symptoms correlate directly with the level of segmental sympathetic blockade.  The supine position significantly increases the incidence of hypotension. This can be reduced in parturients who remain in the sitting position for 3 min compared to parturients who are placed in the modified supine position immediately after induction of spinal anesthesia. 
Spinal anesthesia-induced hypotension is caused by an increase in venous capacitance because of sympathectomy causing venodilatation in the lower part of the body. The situation is further compounded in pregnancy by aortocaval compression. Hypotension caused by a reduction in systemic vascular resistance is physiologically compensated by an increase in cardiac output (CO). However, a high level of spinal block can inhibit the cardioaccelerator fibers leading to a fall in the heart rate, and hence the CO-thus, instead of a compensatory increase, CO usually decreases.  The combined effect of reduced CO and decreased systemic vascular resistance accounts for the high incidence of hypotension after spinal anesthesia in parturients.
Since, there is no auto regulation of the placental bed uterine blood flow is pressure dependent. As a consequence, prolonged maternal hypotension is detrimental to the fetus and is also frequently associated with maternal nausea and vomiting. Brief episodes of maternal hypotension can lower fetal Apgar scores, prolong fetal acidosis, and the time to sustained respiration. 
It is necessary to maintain left uterine displacement before and during cesarean section, regardless of the anesthetic technique.  In the supine position, the gravid uterus of the pregnant woman compresses the aorta and the inferior vena cava against the bodies of the lumbar vertebra. Compression of the inferior vena cava results in decreased venous return, which may decrease maternal CO and blood pressure. Combined with the aortic compression, it can lead to a compromised uteroplacental perfusion. Uterine displacement may be accomplished by placing a wedge of 12 cm height beneath the right buttock. Although widely used, this procedure is variably applied,  and does not completely prevent hypotension after spinal anesthesia. 
Recently, the physiology of maternal hypotension was revisited  and it has been found that hypotension induced by spinal anesthesia is caused mainly by peripheral vasodilatation and is not usually associated with a decrease in CO.
Fluid pre-loading was routinely used in up to 87% of cesarean section cases carried out under spinal anesthesia.  Rout et al.,  noted that the incidence of hypotension was reduced from 71% in patients without pre-hydration to 55% in patients who received crystalloid 20 ml/kg. However, a study by Park et al.,  showed that there were no differences in the indices of maternal hypotension or requirement of ephedrine when 10 ml-30 ml/kg of Ringer's Lactate was used for acute volume expansion before the induction of spinal anesthesia. Both the rate,  and volume,  of crystalloid pre-loading have been shown to be unimportant. Muzlifah and Choy observed that infusing 20 or 10 ml/kg of Ringer's Lactate before spinal anesthesia gave similar incidence of hypotension and nausea vomiting (12/40 and 5/40 vs. 11/40 and 6/40, respectively).  Ouerghi et al.,  using low-dose spinal anesthesia also reported no difference in the incidence of hypotension and ephedrine requirements in patients receiving 20 ml/kg of Ringer's Lactate pre-loading versus no fluid pre-loading. A number of studies with similar results of this kind have led to a reappraisal of the role of crystalloid pre-loading. ,
Gunusen et al.,  reported that a crystalloid co-load (1 L) combined with a low-dose ephedrine infusion (1.25 mg/min) was more effective in preventing moderate and severe hypotension than a fluid pre-load with crystalloid alone (20 ml/kg) or colloid alone (0.5 L of 4% gelatin solution). Williamson et al.,  compared the combination of crystalloid pre-load and co-load (10 ml/kg + 10 ml/kg) to a full crystalloid pre-load (20 ml/kg) in 87 patients. The total intravenous fluid requirements were significantly lower in the pre-loading plus co-loading group when compared to the conventional pre-loading group; vasopressor requirements also tended to be lower, but the decrease was not statistically significant.
A recent systematic review found that crystalloid was inconsistent in preventing hypotension and that colloid was significantly better for pre-loading.  Dahlgren et al.,  also compared crystalloid with colloids for pre-loading and found that the hypotension was significantly reduced after larger volumes of colloid infusion. In another study comparing pentastarch with crystalloid pre-loading, French et al.,  demonstrated a reduction in the incidence of hypotension in the colloid group (12.5% vs. 47.5%). In contrast to these studies all of which found colloid pre-load of benefit, Karinen et al.,  failed to find any reduction in the incidence of hypotension with colloid. Tamilselvan et al.,  used the Doppler flow technique for serial maternal CO measurements at 5 min intervals in 60 patients. They were assigned to any of three groups and received 1.5 l crystalloid, 0.5 l of 6% hydroxyethyl starch (HES) or 1 l of 6% HES pre-load 30 min before induction of spinal anesthesia. Vasopressors were used only if hypotension occurred (defined as SBP less than 80 mmHg). The increase in CO after pre-load was greater with HES and more so in the HES 1 l group. No difference was detected in the incidence of hypotension (which remained high in all three groups) or mean vasopressor requirement.
Carvalho et al.,  compared 500 ml 6% hetastarch administered as a pre-load or co-load and reported no differences in prophylactic requirements for vasopressors, important maternal hemodynamic or neonatal outcome values. They concluded that hetastarch co-loading was as effective as pre-loading for the prevention of hypotension. Teoh and Sia,  reported a significant increase in maternal CO for the first 5 min after spinal anesthesia when 15 ml/kg of 6% tetrastarch was given quickly as a pre-load in combination with prophylactic phenylephrine boluses. However, there were no significant differences between pre-load and co-load groups in terms of incidence of hypotension, nausea, vomiting, pre-delivery phenylephrine requirements, and neonatal outcomes. Therefore, the authors advocated the use of a modest pre-load or co-load along with phenylephrine for the maintenance of SBP close to the baseline value. Siddik-Sayyid et al.,  performed a large (n=178), double-blind study comparing 500 ml 6% HES pre-loading with 500 ml 6% HES co-loading. There were no significant difference between groups in incidence of hypotension (68 vs. 75%, respectively), severity of hypotension (defined as SBP less than 80 mmHg) (16 vs. 22%) or vasopressor requirements. The authors concluded that both modalities of HES loading were inefficient as single interventions.
Weeks et al.,  questioned the use of colloids in the prevention of hypotension, in view of the cost, possibility of anaphylactic reactions and the risk of excessive volume expansion causing pulmonary edema. It is postulated that a parturient pre-operatively susceptible to the supine position would benefit the most from colloid pre-loading.  Encouragingly, a recent study demonstrated that thromboelastographic parameters remained within or very close to the normal range after preloading with 500 ml 6% HES (130/0.4),  and it has been found that the incidence and severity of allergic reactions with HES compared with gelatins or dextrans is much lower in pregnant patients. 
Several recent studies that have compared pre-hydration versus co-hydration using crystalloids and colloids have shown that hemodynamic changes and vasopressor requirements are similar in both groups. Banerjee et al.,  performed a meta-analysis of eight studies (518 parturients) which compared pre-hydration with co-hydration using either crystalloid or colloid fluids. They found that the incidence of hypotension was similar (odds ratio 0.93, 95% confidence interval 0.54-1.6) in both the fluid groups and vasopressors may be required in a significant proportion of patients.
The ideal fluid for co-pre hydration is still a matter of debate. Colloid pre-loading is more reliable. At the same time, colloid co-loading appears equally effective if infused rapidly at the time of identification of cerebrospinal fluid. The amount of co-loading has varied from 500 ml to 1000 ml. ,, However, the practice of co-loading can replace a pre-load to shorten preparation time and to avoid any delay in performing spinal anesthesia. It needs repeated mention that both modalities are inefficient as single interventions and should be combined with timely and judicious use of vasopressors.  Crystalloid co-loading is a cheaper alternative, but it may be less efficacious. Moreover, a substantial volume needs to be infused to get the desired effect. Crystalloid pre-loading is clinically ineffective, and therefore is of no use.  The benefit of combining colloid pre-loading with crystalloid co-loading should be also investigated. Further studies comparing colloid-crystalloid combinations using either colloid pre-load with crystalloid co-load or crystalloid co-load with colloid co-load are required in the future as it may reduce the ultimate cost of therapy.
Ephedrine has been the drug of choice for more than 30 years in the treatment of maternal hypotension in obstetric spinal anesthesia when conservative measures fail. It has a good safety record, is readily available, and familiar to most anesthesiologists. Ephedrine is a sympathomimetic that has both a direct (alpha and beta receptor agonist) and indirect (release of norepinephrine from presynaptic nerve terminals) mechanism of action. Uterine blood flow, in particular was maintained more favorably with beta-agonists than with alpha-agonists.  A British survey in 2001 found that more than 95% of obstetric anesthetists in the United Kingdom used ephedrine as the sole vasopressor, with only 0.4% choosing phenylephrine.  Ephedrine has a slow onset of action making it difficult to titrate. Studies have investigated the role of prophylactic ephedrine in preventing maternal hypotension. Ngan Kee et al., found that a 30-mg bolus of ephedrine administered over 30 s following intrathecal injection did not completely eliminate maternal hypotension, nausea, vomiting and fetal acidosis.  Shearer et al., also reported a similar result. Thus, a single prophylactic dose is ineffective while its effectiveness depends on the dose and the rate of administration.  It must also be appreciated that ephedrine depresses the fetal acid-base status more than phenylephrine. Ephedrine crosses the placenta more readily than phenylephrine, and is associated with greater fetal concentrations of lactate, glucose and catecholamine's.  This appears to support the hypothesis that depression of fetal pH and metabolic effects secondary to stimulation of fetal beta-adrenergic receptors result in fetal base excess with the use of ephedrine. Recently, in a genotype study it has been found that the neonatal ADRB2 p.Arg16 genotype protects against ephedrine-induced fetal academia.  Ephedrine, with its long duration of action still has a role in obstetric anesthesia in preventing or treating spinal induced hypotension when given in an appropriate dose. The optimal method of administering ephedrine, (alone, or combined with other vasopressors) awaits future study.
Phenylephrine is a short-acting, potent vasoconstrictor that causes an increase in both systolic and diastolic blood pressure due to its alpha-2 agonist action. In normal pregnancy, the circulation is well filled and the venous tone is low. Spinal anesthesia further reduces venous tone, often unmasking the effects of caval compression, by blocking the compensatory sympathetic response. Increasing the venous tone with an α-agonist can; therefore, be effective at countering the effects of spinal anesthesia and caval compression.
Traditionally phenylephrine had been used as a second line vasoconstrictor in obstetrics because it was mistakenly thought to compromise uteroplacental circulation. In 1988, Ramanathan and Grant,  found that phenylephrine did not cause fetal acidosis when used to treat maternal hypotension. This may be because there is a significant placental reserve of oxygen, or that the relatively high doses of α agonists have little effect on placental blood flow because of differing placental anatomy and physiology.
A recent randomized control trial examined the maternal and neonatal effects of maintaining maternal blood pressure within 80%, 90% or 100% of baseline levels using a phenylephrine infusion.  Using phenylephrine 100 mcg/ml infused at initial rates of 100 mcg/min, the investigators adjusted the dose depending upon whether blood pressure was kept within the assigned group's range. Women in the 100% baseline group had fewer episodes of nausea and vomiting and their neonatal mean umbilical arterial pH was higher. The authors concluded that hypotension was better controlled with a tight control of blood pressure using aggressive vasopressor administration. Another study by Stewart et al.,  examined three prophylactic infusion rates of phenylephrine (25, 50 and 100 mcg/min) during spinal anesthesia for caesarean delivery under spinal anesthesia. They found a dose-dependent decrease in CO. While the differences in systolic arterial pressures were small among the groups, the arterial pressures were most stable with 100 mcg/min with only 3 of 25 patients requiring an additional vasopressor compared to 10 out of 25 in the 25 mcg/min group. No patient had nausea in the 100 mcg/min group, whereas six of 25 had nausea in the 25 mcg/min group. Fetal pH was similar in all the groups. The authors concluded that CO is a better indicator of uterine perfusion than arterial pressure, and that a low HR with a normal arterial pressure is an indication to stop the phenylephrine infusion. However, uteroplacental perfusion is considered to be pressure dependent, and their study does not provide any evidence that the lower CO was associated with adverse fetal effects.
In human studies, ephedrine has been associated with a higher umbilical vein partial pressure of oxygen than phenylephrine. , With the infusion regimen that was used in both these studies, the median value of systolic arterial pressure was greater than the baseline in both groups, but more so with ephedrine.  A systematic review of seven RCTs comparing ephedrine with phenylephrine  concluded that phenylephrine was associated with higher umbilical artery (UA) pH values than ephedrine (although there was no difference in the incidence of fetal acidosis (UA pH <7.2) or in the number of cases with Apgar scores <7 at 1 and 5 min).The incidence of nausea in ephedrine treated mothers was 66% compared with 17% in the phenylephrine group.  It appears that ephedrine use is associated with lower pH and base excess in the neonate and there is a significantly higher risk for fetal acidosis with ephedrine than with phenylephrine. 
Combinations of phenylephrine and ephedrine given together in the same syringe have previously been advocated, although the optimal regimen has not been determined. Mercier et al., compared an ephedrine and phenylephrine infusion with an ephedrine infusion alone and found that the incidence of hypotension in the combination group was half of that in the ephedrine-alone group with a beneficial effect on UA pH.  However, in a randomized, double blinded trial comparing ephedrine, phenylephrine and ephedrine plus phenylepherine infusions, there was no decrease in the incidence of maternal nausea and vomiting or neonatal acidosis when the combination was used compared to phenylephrine alone.  The administration of vasopressor drugs by infusion as close to the time of induction of spinal anesthesia as possible appears to be the most helpful factor in reducing the incidence of hypotension. 
Phenylephrine is the current vasopressor of choice for the prevention of maternal hypotension and nausea.  Administration of phenylephrine as a prophylactic infusion is more effective in reducing the incidence of hypotension and nausea vomiting compared with bolus administration.  Bradycardia is usually seen with phenylephrine usage because of its well-known α-agonist properties. The incidence of tachycardia is significantly higher in the ephedrine group, possibly due to difficulty in accurate titration of ephedrine because of its initial slow response and longer duration of action. Thus, though both vasopressors reliably raise maternal blood pressure, drug-associated patients' discomfort due to tachycardia, bradycardia and intraoperative nausea, and vomiting should not be overlooked.
It is a mixed alpha and beta agonist can be used for spinal anesthesia induced hypotension. Ngan Kee et al., demonstrated that metaraminol was superior to ephedrine at maintaining both maternal blood pressure and fetal pH during spinal anesthesia for caesarean section. However, the doses of vasoconstrictors used in their study were large and the benefits may have been exaggerated. 
Angiotensin II, a potent vasoconstrictor with a short half-life, affects the uterine vasculature less than other vasoconstrictors. Hence, there are minimal adverse fetal effects. It has its limitations e.g. it can be given only through infusion, its effect is variable and it is expensive. However, Ramin et al., demonstrated benefit that angiotensin II compares favorably with ephedrine when assessing fetal pH after prophylactic infusions of these two drugs at cesarean section. 
The mechanism of action of mephentermine is similar to that of ephedrine. It is an α-as well as a β-adrenergic receptor agonist. It acts both directly and indirectly by releasing noradrenaline from storage sites.  It increases blood pressure mainly by augmenting CO.  The change in heart rate is variable depending on the degree of pre-existing vagal tone.  Being very similar to ephedrine, mephentermine would be expected to cross the placenta to a similar extent as ephedrine. However, not much information is available in the literature regarding its placental transfer and fetal metabolic effects. Mephentermine has been shown to be as effective and safe as ephedrine.  It is also equally effective when comparedto phenylephrine in preventing post-spinal hypotension in cesarean section. The cost-effectiveness of mephentermine justifies continued use of mephentermine in some developing countries, e.g., India, despite the availability of other vasopressors. 
Recent in-vitro work with human placenta studying the effects of vasopressors on the feto-placental circulation,  demonstrated that while ephedrine had a rapid pressor response, phenylephrine had a delayed response and there were no response to epinephrine, norepinephrine or any other drugs. The clinical significance of these observations is unclear.
There are very few reviews on invasive and non-invasive cardiac monitoring in obstetrics.  Minimally invasive CO monitoring demonstrated that hypotension is caused by a rapid reduction in systemic vascular resistance leading to a compensatory increase in HR and CO. Phenylephrine was found to rapidly reverse these changes.  A study by Robson et al.,  found that CO is a better indicator of uteroplacental blood flow than upper arm blood pressure measurement. However, the study did not assess uterine blood flow. In the study by Stewart et al.,  the reduction in CO was caused by a phenylephrine-induced decrease in venous return. However, stroke volume was unchanged as phenylephrine also caused a baroreceptor-mediated decrease in HR. 
Low dose local anesthetic agent
Studies of prevention and treatment of spinal anesthesia induced hypotension have shown that lowering the dose of local anesthetic improves maternal hemodynamic stability,  irrespective of what definition is used. However, such a strategy could compromise the adequacy of anesthesia, with the requirement for supplementary analgesia and possible neonatal consequences. Recent narrative reviews have addressed the controversy of spinal bupivacaine in LD. , Although useful, they are essentially theoretical and conclude with opinion-based recommendations. In addition, there are no operational cut-off points for the bupivacaine dose. Opioids may be used as adjuvants to neuraxial anesthesia to improve the quality of the block without producing a higher level of analgesia to pinprick.  Consequently, lower anesthetic doses cannot be recommended unless an epidural catheter is in place Combined Spinal Epidural (CSE) to rescue the block if anesthesia is inadequate before or during surgery. Low-dose CSE anesthesia may not be the optimal technique for all patients and institutions. 
Mechanical compression devices
Sequential compression devices (SCD) provide intermittent pressure in a sequential manner from the ankles upward. Studies in normal volunteers have shown that during the compression phase SCD can move approximately 125 ml of blood.  Although no studies have compared SCD blood volume recruitment in non-pregnant versus pregnant women, it is well-known that parturients at term have more blood trapped in the lower extremities, and spinal anesthesia induced vasodilatation will increase the pooling even more. Thus, theoretically, the SCD might move an even greater blood volume centrally in this patient population. In studies of SCD with high thigh sleeves there is reduced incidence and severity of hypotension after spinal anesthesia for caesarean section. 
Management of hypotension during ceserean section under spinal anesthesia continues to be controversial. Though most clinicians rely on non-invasive blood pressure monitoring, CO monitoring is a recent development and may prove useful in the near future. While fluid pre-load and left uterine displacements are frequently employed in an attempt to prevent this complication, a vasopressor is often required. Crystalloid pre-hydration seems to be of little use and the current focus is on timing of administration of fluids and the use of colloids. One may also choose a vasopressor. Ephedrine causes more depression of fetal acid-base status than phenylephrine, probably because ephedrine crosses the placenta more readily and has a direct metabolic effect on the fetus. However, it has a proven safety record in obstetrics. There is an abundance of evidence to suggest that phenylephrine is as good as ephedrine for maintaining blood pressure and a more liberal use of this drug is justified. Further work is required to determine the optimal therapy for hypotension in high-risk patients.