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Spinal anesthesia-induced hypotension: is it more than just a pesky nuisance?

      Related article, page 747.
      Spinal anesthesia (using cocaine) was first described by August Bier in 1899 in Germany, and the first cesarean delivery with spinal anesthesia was likely performed in North American in 1901
      • Carter J.
      • Macarthur A.
      Spinal anaesthesia for Caesarean section.
      or 1902.
      • Gogarten W.
      • Van Aken H.
      A century of regional analgesia in obstetrics.
      However, early after its introduction to surgical anesthesia, hypotension was recognized as a significant clinical problem.
      • Gray H.T.
      • Parsons L.
      Blood pressure variations associated with lumbar puncture and induction of spinal anesthesia.
      The “danger” of spinal anesthesia was summarized by Franken
      • Franken H.
      Warum ist die lumbalanaesthesie beim Kaiserschnitt besonders gefährlich?.
      in a 1934 observational study of 2088 spinal anesthetics performed for cesarean delivery—he reported 1 death for every 139 procedures, which even in 1934 was considered unacceptably high. The use of spinal anesthesia in obstetrics likely peaked in the United States in the 1950s when it was used for both vaginal and cesarean delivery anesthesia.
      • Morgan P.
      Spinal anaesthesia in obstetrics.
      By the early 1960s, methods of continuous epidural anesthesia were being introduced, and spinal anesthesia in obstetrics fell out of favor because of its high incidence of adverse maternal effects, including hypotension, inability to prolong anesthesia and analgesia, and postdural puncture (“spinal”) headache.
      • Gogarten W.
      • Van Aken H.
      A century of regional analgesia in obstetrics.
      ,
      • Morgan P.
      Spinal anaesthesia in obstetrics.
      However, starting in the early 1990s, spinal anesthesia experienced a resurgence in obstetrical anesthesia practice. New small-bore, disposable, pencil-point spinal needles significantly decreased the incidence of spinal headache, new drugs were available, and clinicians had a better appreciation of the hemodynamic consequences of spinal anesthesia. Maternal death was reported in both general
      • Hawkins J.L.
      • Koonin L.M.
      • Palmer S.K.
      • Gibbs C.P.
      Anesthesia-related deaths during obstetric delivery in the United States, 1979-1990.
      and epidural
      • Albright G.A.
      Cardiac arrest following regional anesthesia with etidocaine or bupivacaine.
      anesthesia, and by the late 1990s, it was well recognized that general anesthesia was associated with a higher anesthesia-related maternal mortality rate than neuraxial (spinal or epidural) anesthesia.
      • Hawkins J.L.
      • Koonin L.M.
      • Palmer S.K.
      • Gibbs C.P.
      Anesthesia-related deaths during obstetric delivery in the United States, 1979-1990.
      Anesthesiologists have long recognized that uteroplacental perfusion is not autoregulated and is therefore directly dependent on maternal blood pressure. Because of the resurgence of spinal anesthesia in the past several decades, there has been an explosion of research on the prevention and treatment of spinal anesthesia-induced hypotension. In the current issue of the American Journal of Obstetrics & Gynecology, Knigin et al
      • Knigin D.
      • Avidan A.
      • Weiniger C.
      The effect of spinal hypotension and anesthesia-to-delivery time interval on neonatal outcomes in planned cesarean delivery.
      reported the results of a single-center, retrospective observational study (data are from 2007 to 2017) in which they investigated factors associated with neonatal acidosis (defined as umbilical artery pH of ≤7.1 or base deficit of ≥12 mEq/L) in women undergoing planned cesarean delivery with spinal anesthesia. Sustained hypotension and a prolonged anesthesia-to-delivery interval were both associated with fetal acidosis (overall incidence, 2.6%).
      The finding of an association between hypotension and fetal acidosis is not new or surprising. Crawford recognized as early as 1966 that spinal anesthesia was associated with a greater degree of fetal acidosis than general anesthesia.
      • Crawford J.S.
      A comparison of spinal analgesia and general anesthesia for elective cesarean section.
      Depending on the definition of hypotension (and how one defines “baseline”), the incidence of hypotension in women undergoing cesarean delivery with spinal anesthesia reaches 100%.
      • Cyna A.M.
      • Andrew M.
      • Emmett R.S.
      • Middleton P.
      • Simmons S.W.
      Techniques for preventing hypotension during spinal anaesthesia for caesarean section.
      Helpfully, the advent of noninvasive cardiac output monitoring in the past 2 decades has allowed more nuanced assessment of the cardiovascular changes associated with midthoracic spinal anesthesia. It is now well understood that the primary mechanism of hypotension is a profound decrease in systemic vascular resistance owing to dilation of the arteriolar resistance vessels.
      • Dyer R.A.
      • Reed A.R.
      • van Dyk D.
      • et al.
      Hemodynamic effects of ephedrine, phenylephrine, and the coadministration of phenylephrine with oxytocin during spinal anesthesia for elective cesarean delivery.
      A compensatory increase in cardiac output and heart rate is the result.
      Along with a better understanding of the hemodynamic changes associated with spinal anesthesia, the last 2 decades has brought a sea change in the prevention and treatment of spinal hypotension. Historically, ephedrine, an indirect-acting drug with both alpha- and beta-adrenergic agonist effects, was the vasopressor of choice. Initial studies performed in the 1970s in instrumented gravid ewes suggested that ephedrine maintained uterine blood flow, whereas direct alpha-adrenergic agonists decreased flow.
      • Ralston D.H.
      • Shnider S.M.
      • DeLorimier A.A.
      Effects of equipotent ephedrine, metaraminol, mephentermine, and methoxamine on uterine blood flow in the pregnant ewe.
      Subsequently however, randomized controlled trials (RCTs) in humans comparing ephedrine with phenylephrine (a direct-acting alpha-adrenergic agonist) showed that neonates whose mothers received phenylephrine had higher umbilical artery pH and lower base deficit than neonates whose mothers received ephedrine, although both drugs successfully treated hypotension.
      • Lee A.
      • Ngan Kee W.D.
      • Gin T.
      A quantitative, systematic review of randomized controlled trials of ephedrine versus phenylephrine for the management of hypotension during spinal anesthesia for cesarean delivery.
      Further study showed that ephedrine crosses the placenta at a higher rate and undergoes less early metabolism or redistribution in the fetus than phenylephrine.
      • Ngan Kee W.D.
      • Khaw K.S.
      • Tan P.E.
      • Ng F.F.
      • Karmakar M.K.
      Placental transfer and fetal metabolic effects of phenylephrine and ephedrine during spinal anesthesia for cesarean delivery.
      Associated increases in umbilical artery lactate and pCO2 suggest that the mechanism of fetal acidosis associated with ephedrine may be because of ephedrine stimulation of fetal metabolism.
      Spinal anesthesia-induced hypotension in the setting of cesarean delivery has been variably defined, but most studies have used the definition of a 20% or 30% decrease in baseline systolic blood pressure or systolic blood pressure of <100 mm Hg,
      • Kinsella S.M.
      • Carvalho B.
      • Dyer R.A.
      • et al.
      International consensus statement on the management of hypotension with vasopressors during caesarean section under spinal anaesthesia.
      and anesthesiologists have used these thresholds to determine when to treat hypotension. However, further study has suggested that maternal and neonatal outcomes are better if maternal blood pressure is maintained close to the baseline. In a RCT using phenylephrine, the management strategy of treating blood pressure whenever it dropped below baseline was compared to the strategy of treating blood pressure whenever it dropped below 80% of baseline. Umbilical artery pH was higher, and the incidence of maternal nausea and vomiting was lower in women whose blood pressure was maintained near baseline.
      • Ngan Kee W.D.
      • Khaw K.S.
      • Ng F.F.
      Comparison of phenylephrine infusion regimens for maintaining maternal blood pressure during spinal anaesthesia for caesarean section.
      This study, along with others, supports the practice of preventing hypotension with prophylactic phenylephrine administration rather than waiting for the inevitable hypotension to occur and then treating it.
      • Allen T.K.
      • George R.B.
      • White W.D.
      • Muir H.A.
      • Habib A.S.
      A double-blind, placebo-controlled trial of four fixed rate infusion regimens of phenylephrine for hemodynamic support during spinal anesthesia for cesarean delivery.
      Intravenous fluid loading before the induction of spinal anesthesia (“preload”) has been traditionally done to “fill the tank” made functionally empty by sympathetic blockade and acute vasodilation. Studies in the past several decades have demonstrated the flaw in this practice—the intravascular dwell time of crystalloid administered to a euvolemic patient (before the induction of anesthesia) is measured in minutes,
      • Brauer L.P.
      • Svensén C.H.
      • Hahn R.G.
      • Kilicturgay S.
      • Kramer G.C.
      • Prough D.S.
      Influence of rate and volume of infusion on the kinetics of 0.9% saline and 7.5% saline/6.0% dextran 70 in sheep.
      and preloading has been shown to be minimally effective. However, fluid administration is not without merit. In a trial in which patients were randomized to receive a phenylephrine infusion only or a phenylephrine infusion with a rapid fluid bolus initiated at the induction of spinal anesthesia (termed “coloading”), the incidence of hypotension was virtually zero in the phenylephrine with fluid coload group compared with a 28% incidence of hypotension in patients in the phenylephrine-only group.
      • Ngan Kee W.D.
      • Khaw K.S.
      • Ng F.F.
      • Lee B.B.
      Prophylactic phenylephrine infusion for preventing hypotension during spinal anesthesia for cesarean delivery.
      Thus, in any study of spinal hypotension, fluid management should be standardized or at least reported (timing, volume, and rate of administration).
      Where do we currently stand with blood pressure management? International consensus guidelines published in 2018 suggest that a vasopressor with potent alpha-adrenergic agonist activity should be used prophylactically to prevent hypotension with the aim of maintaining systolic blood pressure ≥90% of baseline.
      • Kinsella S.M.
      • Carvalho B.
      • Dyer R.A.
      • et al.
      International consensus statement on the management of hypotension with vasopressors during caesarean section under spinal anaesthesia.
      This is most easily accomplished with a titrated infusion (rather than bolus administration) of vasopressor and rapid intravenous administration of crystalloid (approximately 1 L) at the time of induction of anesthesia accompanied by frequent (every 1 minute) blood pressure measurements. Notably, no component of this management regime was used in the study by Knigin et al,
      • Knigin D.
      • Avidan A.
      • Weiniger C.
      The effect of spinal hypotension and anesthesia-to-delivery time interval on neonatal outcomes in planned cesarean delivery.
      alone or in combination. It is interesting to note that in patients whose hypotension was treated with phenylephrine, there was no association with neonatal acidosis (95% confidence interval of odds ratio included 1).
      • Knigin D.
      • Avidan A.
      • Weiniger C.
      The effect of spinal hypotension and anesthesia-to-delivery time interval on neonatal outcomes in planned cesarean delivery.
      In addition to the unsurprising finding that the extent and duration of predelivery maternal hypotension were associated with neonatal acidosis, Knigin et al
      • Knigin D.
      • Avidan A.
      • Weiniger C.
      The effect of spinal hypotension and anesthesia-to-delivery time interval on neonatal outcomes in planned cesarean delivery.
      reported that the anesthesia-delivery time interval was independently associated with acidosis. This association has also been reported by others.
      • Rimsza R.R.
      • Perez W.M.
      • Babbar S.
      • O’Brien M.
      • Vricella L.K.
      Time from neuraxial anesthesia placement to delivery is inversely proportional to umbilical arterial cord pH at scheduled cesarean delivery.
      Although investigators have suggested that this interval is potentially modifiable and shortening the interval may result in less neonatal acidosis, the question still remains as to the etiology of this association and whether prolonged (even mild) hypotension played a role in the study results.
      • Knigin D.
      • Avidan A.
      • Weiniger C.
      The effect of spinal hypotension and anesthesia-to-delivery time interval on neonatal outcomes in planned cesarean delivery.
      There are hard stops on the degree to which this interval is modifiable, and the intervals described in the Knigin et al
      • Knigin D.
      • Avidan A.
      • Weiniger C.
      The effect of spinal hypotension and anesthesia-to-delivery time interval on neonatal outcomes in planned cesarean delivery.
      study were not long (median anesthesia-to-delivery interval, 15 minutes; 90th percentile, 24 minutes). To my knowledge, no study has investigated this association in the setting of optimal blood pressure management (as described earlier).
      Other questions regarding the management of spinal hypotension are currently being investigated. Almost all studies to date have included healthy, nonlaboring women undergoing planned cesarean delivery. We need to have a better understanding of whether the hemodynamic management goals differ for patients with comorbidities, including those with reduced placental reserve or those undergoing intrapartum delivery.
      • Higgins N.
      • Fitzgerald P.C.
      • van Dyk D.
      • et al.
      The effect of prophylactic phenylephrine and ephedrine infusions on umbilical artery blood pH in women with preeclampsia undergoing cesarean delivery with spinal anesthesia: a randomized, double-blind trial.
      Historically, systolic blood pressure has been used because it was easier to measure, but organ perfusion depends on mean arterial blood pressure, begging the question of whether we should focus blood pressure management on mean or on systolic blood pressure. Recently, norepinephrine has been proposed as an ideal vasopressor, as it may be associated with less maternal bradycardia than phenylephrine.
      • Singh P.M.
      • Singh N.P.
      • Reschke M.
      • Ngan Kee W.D.
      • Palanisamy A.
      • Monks D.T.
      Vasopressor drugs for the prevention and treatment of hypotension during neuraxial anaesthesia for caesarean delivery: a Bayesian network meta-analysis of fetal and maternal outcomes.
      Should the results of the Knigin et al
      • Knigin D.
      • Avidan A.
      • Weiniger C.
      The effect of spinal hypotension and anesthesia-to-delivery time interval on neonatal outcomes in planned cesarean delivery.
      study change our current preference for neuraxial anesthesia for cesarean delivery? The answer is definitively “no,” although anesthesiologists should pay meticulous attention to blood pressure management. The findings of Knigin et al
      • Knigin D.
      • Avidan A.
      • Weiniger C.
      The effect of spinal hypotension and anesthesia-to-delivery time interval on neonatal outcomes in planned cesarean delivery.
      bear confirmation in the modern era of blood pressure management. Small studies suggest that the incidence of neonatal acidosis is very low if blood pressure is maintained near the baseline.
      • Ngan Kee W.D.
      • Khaw K.S.
      • Ng F.F.
      Comparison of phenylephrine infusion regimens for maintaining maternal blood pressure during spinal anaesthesia for caesarean section.
      Accepting that spinal hypotension causes lower umbilical artery pH, we also need to ask whether these differences are worth fussing about in the context of other risks and benefits of alternative anesthetic techniques. Some cases of spinal hypotension are evitable unless we aim to maintain blood pressure higher than the baseline. The association between neonatal metabolic acidemia and longer-term complications (eg, neonatal encephalopathy, cerebral palsy) is weak.
      American College of Obstetricians and Gynecologist, American Academy of Pediatrics
      Neonatal encephalopathy and neurologic outcome.
      The finding in the Knigin et al
      • Knigin D.
      • Avidan A.
      • Weiniger C.
      The effect of spinal hypotension and anesthesia-to-delivery time interval on neonatal outcomes in planned cesarean delivery.
      study and others
      • Rimsza R.R.
      • Perez W.M.
      • Babbar S.
      • O’Brien M.
      • Vricella L.K.
      Time from neuraxial anesthesia placement to delivery is inversely proportional to umbilical arterial cord pH at scheduled cesarean delivery.
      that secondary neonatal outcomes (eg, low Apgar scores, transient tachypnea of the newborn, respiratory distress syndrome, intensive care unit admission) are not associated with hypotension suggests that a low incidence of isolated fetal acidosis may be low on our list of concerns. Our normal practice should be to induce spinal anesthesia and perform the necessary preparation (eg, urinary catheter insertion, skin decontamination, draping, time-out) efficiently and safely. We should not waste time, but neither should we rush and leave out important steps unless future research identifies a modifiable step that results in improved neonatal outcome without increased risk to the mother. Until these questions are answered and new findings suggest otherwise, we should not change current management.

      Acknowledgments

      The author thanks Alexander J. Butwick, MBBS, FRCA, MS, for his reading of the manuscript and suggestions.

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