Hypotension After Spinal Anesthesia for Cesarean

Home , Cafedrine, Theodrenaline

Department of Anesthesiol- b www.co-anesthesiology.com b € unster and € usseldorf, Germany. 2020, 33:291–298 € usseldorf, Germany € unster, M € usseldorf, D , and Manuel Wenk Interestingly, increased susceptibility for hypo- During late pregnancy, compression of the infe- b Department of Anesthesiology, Intensive Care and Pain Medicine, a Tel: +49 211 4092300;e-mail: fax: [email protected] +49 211 4092037; Curr Opin Anesthesiol DOI:10.1097/ACO.0000000000000848 University Hospital M tensive events following neuraxial sympathetic block occurs as a result of gestation-induced cardiovascular and mechanic alterations in hemodynamics. rior vena cava bytion the could gravid cause uterus asubsequent in sudden supine fall decrease posi- in in preload cardiac and output. However, MRI Intensive Care and PainKreuzbergstraße Medicine, 79, Florence 40489 – D Nightingale – Hospital, ogy, Intensive CareHospital D and Pain Medicine,Correspondence to Florence Manuel Wenk, MD, – Department of Nightingale Anesthesiology, – ¨pel , Lisa To a Christina Massoth 2020 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. ß cesarean section, fluid therapy, hypotension, spinal anesthesia, vasopressors identified so far. Currentfor literature adequate discusses fluid the therapy efficacyphenylephrine and of over various low-dose ephedrine vasopressor spinal because regimens.discussed anesthesia, of Present as timing decreased guidelines a and umbilical favor probable solutions corddata the superior pH is use alternative values, limited. of with while Alternative regardmethods norepinephrine pharmacological to may is approaches, maternal be such bradycardia, taken as although into 5HT3-receptor supporting consideration antagonistsSummary to and further physical improve hemodynamicCurrent stability. evidence favors avasopressor combined support approach to of address low-doseis maternal spinal associated spinal-induced anesthesia, with hypotension. adequate relevantly Asfrom fluid impaired none obstetric therapy maternal of practice. and and the Rapid fetalshould available crystalloid outcomes, be vasopressors co-loading none preferred is of because of them of equivalent should a efficacyKeywords be more as abandoned favorable compared risk with profile. colloids and Purpose of review Hypotension during cesarean sectionassociated remains with a adverse frequent maternal complication and of fetal spinalRecent events. anesthesia findings and is Despite ongoing research, no single measure for sufficient treatment of spinal-induced hypotension was iatrogenic sympathectomy Hypotension after spinal anesthesiasection: for how cesarean to approach the PINION It is well known that iatrogenic sympathetic URRENT O C found bradycardia, vasodilation,cardiovascular collapse. and a potential with a reductionlevels of of spinal preload distributionand may decrease and cause of afterload. bradycardia strokeating volume High by sympathetic blocking cardiac acceler- ventricular filling fibers. may Decreasedtors also right trigger in mechanorecep- Bezold–Jarisch the reflex, cardiac associated with wall, sudden resulting pro- in vasovagal butions up to Th4 are requiredand for parturients operative delivery show anthe increased effects susceptibility of to local anesthetics. block causes arterialleads and to venous vasodilation a and decreased systemic vascular resistance INTRODUCTION Spinal anesthesia is thenique most for frequently elective cesarean used section tech- world, in the provided developed forMinimizing about side 78% ofsomewhat effects be procedures of challenging [1]. as neuraxial cephalad block block distri- may 0952-7907 Copyright

REVIEW

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lower during normal pregnancies in comparison to KEY POINTS the nonpregnant state [4,5]. This emphasizes that Spinal-induced hypotension is a frequent complication maintenance of maternal hemodynamics in the during cesarean section and can most effectively be status quo is already relying on incomplete compen- addressed by a multimodal approach. sation. A further reduction in peripheral vascular resistance, as through spinal anesthesia-induced Amongst various regimens and methods, current iatrogenic sympathectomy, could easily exceed evidence favors the combination of low-dose spinal anesthesia, high-flow crystalloid co-loading, and compensatory capacities, eventually causing a sig- vasopressor administration. nificant hemodynamic impairment. It, therefore, comes as no surprise, that arterial As neither ephedrine nor noradrenaline or hypotension is one of the most frequent complica- phenylephrine are associated with worse fetal tions of spinal anesthesia for cesarean section and outcomes, application of any substance may be considered on a case-by-case decision. appears to significantly overshoot as compared with the nonpregnant patient. Regarding the lack of an accepted definition of hypotension per se, incidences of hypotensive events during cesarean section vary remarkably, measurements of blood flow demonstrated a 220% depending on which definition is applied. A meta- flow increase in the vena azygos in supine position, analysis of 63 studies reported a decrease of 80% mitigating the reduction in stroke volume and baseline alone or combined with systolic pressures explaining why a majority of more than 90% below 100 mmHg as most frequently used defini- remains unaffected of supine hypotensive syn- tions. However, among 15 differing definitions, the drome [2&]. Symptomatic women, in contrast, were spectrum of maternal hypotensive events ranged found to have significantly reduced flow rates in the between 7.4 and 74.1% [6]. vena azygos compared with asymptomatic women Nausea and vomiting are common and indica- in MRI phase contrast images [0.15 (95% CI 0.30 tive symptoms of maternal hypotension. Several to 0.01) l/min], but with a comparable increase in hypotheses to its pathophysiology have been out- heart rate and a lack of any further compensatory lined, including the occurrence of gastrointestinal mechanisms [3&]. ischemia because of a reduced splanchnic perfusion More importantly – but lesser known – is the triggering a release of pro-emetic substances, such fact that a physiologic reduction of systemic vascu- as serotonin [7], as well as cerebral hypoperfusion lar resistance and its consequences provide a far causing ischemia of the vomiting center in the brain more decisive determinant for the occurrence and stem [8]. treatment of spinal-induced hypotension. Untreated hypotension may ultimately result in Peripheral arterial vasodilation already occurs loss of consciousness and aspiration and is not only during early pregnancy because of increased levels a serious maternal risk factor but also a cause of fetal of prostaglandins, progesterone, and estrogen. The adverse events. circulating peptide hormone relaxin and – espe- Due to missing vascular autoregulation, mater- cially in uterine vessels – increased levels of nitric nal hypotension promotes decreases in uteroplacen- oxide, as a promoter of improved uterine perfusion, tal blood flow, resulting in fetal hypoxia, acidosis are strong vasodilatory mediators. Resulting relative and low Apgar scores, correlated with severity and arterial underfilling stimulates the renin–angioten- duration of hypotensive events. sin–aldosterone system, thus leading to renal Approaches to maintain maternal blood pres- sodium and water retention, promoting expansion sure during cesarean delivery are an issue of of plasma volume and total body water. unabated interest for more than 60 years [9]. Along Dilutional anemia stimulates a permanent with increasing popularity of neuraxial anesthesia increase in heart rate, while atrial stretch because techniques in obstetrics, a plethora of studies on of volume overload is not only associated with an different substances, approaches, and regimens has elevated stroke volume but also induces remodeling been published since. processes in the cardiac wall and a further release Key issues are not only the choice of the most of natriuretic peptides, which have additional vaso- appropriate substance but also timing (prophylaxis dilatory effects. versus treatment) and method of administration However, elevation of plasma volume and car- (bolus versus continuous administration). On that diac output are not sufficient to counterbalance the account, this review highlights current recommen- decrease in vascular resistance, which may reach up dations against the background of most recent evi- to 40%, as mean arterial pressures are constantly dence (Fig. 1).

FIGURE 1. Flowchart: gradual management of hypotension during cesarean section, starting with preventive measures prior to induction of spinal anesthesia. Precede to next step of algorithm if hypotension persists. Consider suggested vasopressor regimens as equally appropriate with regard to aforementioned conditions. IVCS, inferior vena cava syndrome; sbp, systolic blood pressure.

SPINAL ANESTHESIA supplementation [RR 3.76 (95% CI 2.38–5.92)]. Contemporary practice of obstetric spinal anesthe- However, the analysis included several varying sia implies the application of a reduced dosage of approaches of anesthetic combinations with fenta- local anesthetic in comparison with nonobstetric nyl, ranging from 10 up to 50 mg and differing doses practice as severity of hypotension is correlated with of morphine in some studies [10]. Therefore, ade- total administered amount of local anesthetic. quate dosages of opioid adjuvants are paramount A systematic review on low-dose vs. conven- when using small amounts of local anesthetics. A tional dose spinal anesthesia for cesarean section, recent randomized controlled trial compared 5 vs. defining low dose at an amount of 8 mg or less of 7.5 mg bupivacaine in combination with 25 mg fen- bupivacaine, reported a reduced risk of hypotension tanyl, respectively and reported 7.5 mg to be feasible [risk ratio (RR) 0.78, 95% confidence interval (95% and superior for adequate anesthesia quality and CI) 0.65–0.93] and nausea and vomiting [RR 0.71 sufficient surgical conditions compared with the (95% CI 0.55–0.93)] accordingly but also an inferi- lower dosage. No difference with regard to the inci- ority of lower doses with regard to required analgesic dence of hypotension was found between both

0952-7907 Copyright ß 2020 Wolters Kluwer Health, Inc. All rights reserved. www.co-anesthesiology.com 293 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. Obstetric and gynecological anesthesia groups, though (P ¼ 0.751; x2 ¼ 0.101, df ¼ 1) [11&]. section, they reported significantly higher umbilical Consequently, reduction of local anesthetics is lim- cord pH values in women treated with phenyleph- ited not only by a decreasing quality of anesthesia rine [weighted mean difference 0.03 (95% CI 0.02– but also because of a ceiling effect with regard to 0.04)] [15]. Although historically ephedrine was hypotensive events. favored because of observations from animal studies The implementation of a combined spinal-epi- where it was found to cause less uteroplacental dural technique (CSE) allows for a reduction or even vasoconstriction [16], measurements of plasma con- waiver of intrathecal administered local anesthetics centrations in maternal and venous umbilical blood and provides a sufficient anesthesia for cesarean revealed a greater placental transfer for ephedrine section. A recent Cochrane-Analysis comparing than for phenylephrine (median umbilical venous/ CSE and spinal anesthesia for cesarean section maternal arterial plasma concentration ratio 1.13 vs. reported no certain differences with regard to the 0.17). Additionally, ephedrine was found to be nei- quality of analgesia and additional analgesic ther associated with true fetal acidosis defined at pH requirements (average RR 1.25, 95% CI 0.19–8.43; less than 7.2 in the analysis of Lee et al. [RR 0.78 seven studies) but indicated that a CSE technique (95% CI 0.16–3.92)] nor with any apparent differ- may be superior to reduce the incidence of hypo- ences in APGAR scores after 1 min [RR 0.77 (95% CI tension requiring treatment in comparison to low- 0.17–3.51)] and 5 min [RR 1.00 (95% CI 0.21–4.83)] dose spinal anesthesia (average RR 0.59, 95% CI [15]. 0.38–0.93; four studies, 336 women). Evidence is Further, based on associated increased umbilical limited; however, because of the quality and sample levels of lactate, glucose, and catecholamines, it has size of included trials [12&]. been suggested, that ephedrine not only undergoes less early metabolism in the fetus but also has direct effects on fetal adrenoceptors, causing related met- VASOPRESSORS abolic stimulation [17]. The significance of vasopressors for the treatment of The current Cochrane review on prevention of maternal hypotension is probably reflected by the hypotension during spinal anesthesia for cesarean unchanged high level of interest as a research issue section showed no clear evidence for a higher risk of in obstetric anesthesia, focusing on varying substan- fetal acidosis [incidence with phenylephrine 11/ ces and administration regimens. In this regard, 1000 vs. ephedrine 10 (1–131)/1000; average RR ephedrine and phenylephrine are currently the 0.89 (95% CI 0.07–12.00); three studies (175 babies) most extensively investigated substances featuring with low-quality evidence] [18]. also long-term experience in application. In contrast, another systematic review by Veeser et al. reported a significantly increased risk of umbilical cord pH values less than 7.2 associated with Ephedrine ephedrine. Noteworthy is, that only two of five Although ephedrine used to be the most widely included trials reported high incidences of fetal used vasopressor in obstetrics, previously applied acidosis (Ngan Kee et al. [22], 12/25 vs. 0/24; Cooper by 95% of providers as sole vasoconstrictor in 1999 et al., 20/50 vs. 1/48), whereas the other trials [13], it has now largely disappeared from current reported zero to one fetal acidosis in each group, recommendations. raising the question of external validity of these Ephedrine acts as a direct sympathomimetic at results. Interestingly, in both studies with results alpha and beta receptors and provides its mechanism of high incidences, ephedrine was continuously of action both directly at the receptor and indirectly administered, whereas the other trials investigated by an endogenous release of norepinephrine. bolus injections [19]. This might imply that not the The ‘International consensus statement on the administration of ephedrine per se increases the risk management of hypotension with vasopressors dur- of a true fetal acidosis and should be avoided, but the ing caesarean section under spinal anaesthesia’ pro- continuous administration that seems to be poses that ‘a-agonist drugs are the most appropriate potentially disadvantageous. agents to treat or prevent hypotension following spinal anaesthesia [...]’ and further that the highly selective alpha1-agonist phenylephrine ‘[...] is cur- Phenylephrine rently recommended because of the amount of sup- Despite the fact that phenylephrine is still favored as porting data’ [14]. This change of direction was the vasopressor of choice, its 15 min of fame seem to promoted by a meta-analysis of eight randomized have already expired and interests have turned controlled trials by Lee et al. in 2002. Comparing the towards alternative substances. The main disadvan- use of ephedrine and phenylephrine for cesarean tage of phenylephrine is its likeliness to cause

294 www.co-anesthesiology.com Volume 33 Number 3 June 2020 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. Hypotension after spinal anesthesia for c-section Massoth et al. occasional bradycardia, requiring for treatment with Norepinephrine a second vasopressor or anticholinergic substances Norepinephrine, a catecholamine with mainly as glycpyrrolate or atropine. The pooled incidence alpha and less beta agonistic activity, is probably of maternal bradycardia requiring intervention fol- the most extensively used vasopressor worldwide lowing the administration of phenylephrine reaches with the exception of obstetric anesthesia, even about 243/1000 [18] with an increasing likeliness in though it offers the theoretical advantage to be a a dose-dependent manner [50 mg/min 1/54 (0.5%) weak agonist at beta adrenergic receptors as well. vs. 100 mg/min 11/63 (17.4%)] [20]. To date, there is only little empirical data to There has been some controversy concerning support the use of norepinephrine in obstetrics. another potential disadvantage of phenylephrine: Although two randomized controlled trials two randomized controlled trials reported decreased independently reported lower incidences of brady- rostral spreads of spinal anesthesia in pregnancy cardia as compared with phenylephrine (Ngan Kee after use of phenylephrine compared with ephed- et al.: 18.4 vs. 55.8%, P < 0.001; Sharkey et al.: 10.9 rine. Lower levels by median of two dermatomes vs. 37.5%, P < 0.001) without relevant differences in were considered to be associated with a constriction fetal acid–base status [27,28], a recent study showed of epidural lumbar veins, resulting in a lower intra- controversial results. Mohta et al. [29] found no thecal pressure and lower spread of local anesthetics differences with regard to maternal bradycardia [21,22]. However, probably with regard to a differing (6.6 vs. 2.2%, P ¼ 0.1), but significantly decreased study design, other trials failed to identify any differ- fetal pH values in the norepinephrine group [7.29 ences in dosing requirements [23]. (SD 0.07) vs. 7.25 (SD 0.10), P ¼ 0.03], whereas inci- Addressing the question whether to prefer con- dences of true fetal acidosis did not differ between tinuous or repeated dosages, the current consensus the groups. statement encourages ‘the use of smart pumps and Assessing the relevance of the method of admin- double vasopressor [...]’ to achieve ‘greater cardio- istration, a double blinded randomized controlled vascular stability than [...] with physician-con- trial compared bolus administrations (5 mg) with a trolled infusion’ [14]. prophylactic manually adjusted continuous infu- A double-blinded randomized controlled trial, sions (0–5 mg/min). The continuous infusion was comparing a bolus regimen with an infusion regi- associated with improved maternal hemodynamic men of phenylephrine using a noninvasive cardiac stability but as well with remarkably higher total output measurement, found no differences with amount of norepinephrine administration (contin- regard to hemodynamic effects [mean maximum uous 61.0 (interquartile range 47.0–72.5) mg vs. change in cardiac output of bolus 1.87 (standard bolus 5.0 (interquartile range 0–18.1) mg, deviation; SD 1.68) l/min vs. infusion 1.9 (SD 1.46) l/ P < 0.001). Once again APGAR scores and umbilical min; P ¼ 0.94 (95% CI 0.84–0.78 l/min)], but a cord pH values were comparable in both groups [30]. higher total amount of vasopressors associated with These results were further confirmed by a recent the use of a fixed infusion regimen. In addition, in randomized dose-finding trial, assessing continuous both treatment arms, the total amounts of phenyl- infusions of 0.025, 0.05, and 0.075 mg/kg/min. Com- ephrine were remarkably high in this study [infu- parably, higher doses of norepinephrine were asso- sion 1740 mg (SD 613) vs. bolus 964 mg (SD 454), ciated with reduced incidences of hypotensive P < 0.001] [24]. events, but without effecting neonatal outcome, In contrast, another double-blinded randomized which did not differ between the three groups controlled trial comparing a prophylactic phenyl- & [31 ]. Both, continuous and intermittent adminis- ephrine infusion with rescue boluses and rescue trations of norepinephrine seem to be well tolerated boluses alone, reported significantly reduced inci- and effective and there are further indications that dences of hypotension in the prophylactic treatment norepinephrine may be superior for maternal and arm [8/40 (20%) vs. 35/39 (90%), P < 0.001] [25]. neonatal safety in parturients with preeclampsia Closed loop vasopressor systems, administering [32]. phenylephrine or ephedrine automatically, based on continuous blood pressure monitoring, were found to be associated with better maternal hemodynamic stability and a reduced incidence of nausea in Cafedrine/theodrenaline comparison to manual vasopressor bolus administra- Another rather old vasopressor might be preparing to tions in a randomized controlled trial [26]. However, appear as a potential new competitor in the obstetric as no differences with regard to fetal outcome were scene. The 20 : 1 combination of cafedrine/theodre- detectable, the expense and need for such devices in naline (Akrinor, ratiopharm GmbH, Ulm, Germany) clinical routine remains questionable. affecting alpha and beta adrenoceptors and hence

0952-7907 Copyright ß 2020 Wolters Kluwer Health, Inc. All rights reserved. www.co-anesthesiology.com 295 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. Obstetric and gynecological anesthesia raising mean arterial pressure and inotropy. How- effective measure to reduce the incidence of hypo- ever, approved for use only in Germany so far, pro- tension than a crystalloid preload, but the terms ‘co- spective studies investigating its effectiveness and loading’ and ‘rapid’ were not clearly defined. safety are lacking. Unpublished results of the recently Although most studies agreed that ‘co-loading’ completed ‘HYPOTENS’ study (NCT02893241), a starts with the positive identification of cerebrospi- prospective national multicenter trial comparing nal fluid/intrathecal administration at the latest cafedrine/theodrenaline (C/T) and ephedrine for with a total amount ranging between 15 and cesarean section, indicated a superiority of C/T with 20 ml/kg, the conception of rapid infusion diverged regard to maternal hemodynamic response and fetal widely. Some used a pressurized giving set, some acid base state. [33]. reported a duration for administration of 20 min, or However, as data on cafedrine/theodrenaline is at the ‘maximum possible rate’ or gave no informa- scarce and its use and spread still limited by national tion on it at all [18]. approval, the future role of this substance is uncertain. Colloids vs. crystalloids When comparing crystalloids with colloids, the use OTHER PHARMACOLOGICAL of colloid solutions seems to offer at least a small INTERVENTIONS: 5- advantage in reducing the incidence of hypotension HYDROXYTRYPTAMINE-3 RECEPTOR [average RR 0.68 (95% CI 0.58–0.80); 28 studies ANTAGONISTS including 2105 women; very low-quality evidence] In addition to catecholamines and vasopressors, but different formulations, volumes, and adminis- 5HT3 antagonists have been discussed as further trations are limiting the comparability between pharmacological intervention to provide improved studies (I2 ¼ 85%, Tau2 ¼ 0.16) [18]. hemodynamic stability for spinal anesthesia. The The randomized controlled double blinded trial Bezold–Jarisch reflex is triggered by serotonin-sen- of Doherty et al. compared the effect of 1 l of a sitive chemoreceptors and mechanoreceptors and colloid and 1 l of a crystalloid co-load, administered potentially aggravating hypotension. Animal mod- at a flow rate of 200 ml/min via a 14 gauge intrave- els found 5HT3-antagonists to prevent the reflex nous catheter and assessed cardiac output measures response, and several clinical trials have addressed using suprasternal Doppler as outcome parameters. this issue since then [34]. As this approach was not associated with any overall A meta-analysis of 17 trials, including 1604 differences between the groups with regard to car- patients investigated prophylactic double-blind diac output variables and vasopressor requirements, administration of 5HT3 antagonists for spinal anes- it may be suggested that the administration of crys- thesia. Although no significant effects in nonobste- talloids as pressurized infusion with high flow rates tric cohorts were detectable, in patients undergoing may be equivalent to colloids [24]. cesarean section, the RR was 0.52 [95% CI 0.30– Additionally, colloids provide a less favorable 0.88, I2 ¼ 87% (number needed to treat 4)] [35]. side-effect profile and the benefits of their use have Analyses from a current Cochrane study, comparing to be outweighed against their inherent risk, studies with doses of 2, 4, 6, and 8 mg ondansetron although no conclusions with regard to long time with control, resulted in a superior effect of 4 mg safety can be made because of the small number ondansetron over higher or lower doses with a RR of of studies. 0.46 (95% CI 0.34–0.63, 5 studies including 277 women) [18]. LATERAL TILT POSITION Considering aortocaval compression in the supine VOLUME THERAPY position as an important contributing factor to Despite the fact that fluid administration alone is maternal hypotension, conducting cesarean section hardly sufficient to avoid maternal hypotension for in a 158 lateral tilt position can often be observed as the most part, it is nevertheless an important pillar common practice in clinical routine. Raised by sev- to mitigate the decrease in blood pressure and to eral authors in the 1970s, for example, Crawford reduce the total amount of vasopressors required. et al. [36], who reported a correlation of higher umbilical pH values in this position, left lateral tilt position has become one of the most persistent Preload vs. co-load dogmas in obstetric practice since and is still rec- Analyzing five studies with 384 parturients, a rapid ommended by the current international consensus crystalloid co-loading was found to be a more statement [14].

However, investigations of MRI measurements Conflicts of interest of the abdominal aorta and inferior vena cava in There are no conflicts of interest. supine and left lateral tilt position at 158,308 and 458 in full term parturients, revealed not only that aortic volumes did not differ among the tilt angles but also REFERENCES AND RECOMMENDED that inferior vena cava volume did not increase at READING 158. A left lateral tilt of at least 308 was necessary to Papers of particular interest, published within the annual period of review, have 8 been highlighted as: relieve the vena cava compression partially (15 : & of special interest 3.0 2.1 ml, 308: 11.5 8.6 ml, 458: 10.9 6.8 ml) && of outstanding interest [37]. Moreover, even the 158 angle is almost never 1. Traynor AJ, Aragon M, Ghosh D, et al. Obstetric Anesthesia Workforce achieved in clinical routine, as most practitioners Survey. Anesth Analg 2016; 122:1939–1946. tend to overestimate the set tilt [38]. In addition, 2. 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