Association between maternal cardiac output and fetal acidaemia in Caesarean delivery under spinal anaesthesia with norepinephrine infusion: a retrospective cohort study

Editor—Maintaining uteroplacental blood flow during Caesarean delivery is pivotal for the safety of the fetus. The concept of anaesthetic management has been changed from treating to preventing maternal hypotension.1Kinsella 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.Anaesthesia. 2018; 73: 71-92Crossref PubMed Scopus (271) Google Scholar Norepinephrine prophylaxis is gaining popularity in clinical practice because of less bradycardia2Sharley A.M. Siddiqui N. Downey K. Ye X.Y. Guevara J. Carvalho J.C.A. Comparison of intermittent intravenous boluses of phenylephrine and norepinephrine to prevent and treat spinal-induced hypotension in Cesarean deliveries: randomized controlled trial.Anesth Analg. 2019; 129: 1312-1318Crossref PubMed Scopus (50) Google Scholar and higher maternal cardiac output3Ngan Kee W.D. Lee S.W.Y. Ng F.F. Tan P.E. Khaw K.S. Randomized double-blinded comparison of norepinephrine and phenylephrine for maintenance of blood pressure during spinal anesthesia for cesarean delivery.Anesthesiology. 2015; 122: 736-745Crossref PubMed Scopus (190) Google Scholar compared with phenylephrine prophylaxis. However, it is not clear whether maintaining cardiac output, as opposed to maintaining blood pressure, should be the goal of prophylactic vasoactive medication administration. Estimated continuous cardiac output monitoring (esCCO®, Nihon Kohden Corp., Tokyo, Japan) is a novel technology to measure cardiac output noninvasively.4Sugo Y. Ukawa T. Takeda S. Ishihara H. Kazama T. Takeda J. A novel continuous cardiac output monitor based on pulse wave transit time.Annu Int Conf IEEE Eng Med Biol Soc. 2010; 2010: 2853-2856PubMed Google Scholar It does not require application of special monitoring other than a disposable pulse oximetry. Pulse wave transit time is defined as the time difference between the R wave on the electrocardiogram and the rising point of the pulse wave on pulse oximetry. It negatively correlates with stroke volume, allowing continuous estimation of cardiac output. Its use has been validated in several clinical settings.5Terada T. Maemura Y. Yoshida A. Muto R. Ochiai R. Evaluation of the estimated continuous cardiac output monitoring systems in adults and children undergoing kidney transplant surgery: a pilot study.J Clin Monit Comput. 2014; 28: 95-99Crossref PubMed Scopus (9) Google Scholar, 6Terada T. Oiwa A. Maemura Y. Robert S. Kessoku S. Ochiai R. Comparison of the ability of two continuous cardiac output monitors to measure trends in cardiac output: estimated continuous cardiac output measured by modified pulse wave transit time and an arterial pulse contour-based cardiac output device.J Clin Monit Comput. 2016; 30: 621-627Crossref PubMed Scopus (16) Google Scholar, 7Suzuki T. Suzuki Y. Okuda J. et al.Cardiac output and stroke volume variation measured by the pulse wave transit time method: a comparison with an arterial pressure-based cardiac output system.J Clin Monit Comput. 2019; 33: 385-392Crossref PubMed Scopus (14) Google Scholar Hypothesising that continuous and noninvasive cardiac output monitoring is beneficial in obstetric patients, we changed our practice in 2020 and began routinely using noninvasive cardiac monitoring even though validation studies in obstetric patients were not available. However, because of the extra cost of the oximetry probe for measuring cardiac output using esCCO®, we planned to assess clinical outcomes using the primary outcome of umbilical arterial pH retrospectively. We hypothesised that decreased cardiac output is associated with compromised fetal acid–base balance when maintaining maternal arterial pressure appropriately. After local institutional review board approval (#2530), we conducted this retrospective study using data from January 1, 2020 to December 31, 2020. We included women who had elective Caesarean delivery using a standard spinal anaesthesia protocol with a fixed intrathecal dose of hyperbaric bupivacaine 12 mg, fentanyl 10 μg, and morphine 150 μg. The esCCO® was calibrated before positioning for the spinal anaesthesia, baseline values were confirmed and then measured every minute with arterial pressure until delivery. Patients were positioned with left uterine displacement, and we administered a prophylactic norepinephrine infusion at 2.5 μg min−1 and a colloid co-load of 500 ml of hydroxyethyl starch 6% to maintain maternal arterial pressure at least 90% of baseline, followed by crystalloid infusion. When systolic arterial pressure was <100 mm Hg or mean arterial pressure <70 mmHg,8Mazda Y. Terui K. Tamura K. Tanaka M. Does maternal mean arterial pressure predict fetal acidemia better than systolic blood pressure during spinal anesthesia for cesarean delivery?.J Saitama Med Univ. 2016; 42: 131-137Google Scholar hypotension was treated with a 5–15 μg bolus of norepinephrine or 50–100 μg bolus of phenylephrine i.v. at the discretion of the attending anaesthesiologists, and norepinephrine infusion was incrementally increased up to 5.0 μg min−1. Although the anaesthesiologists were not blinded to the cardiac output assessment, they titrated the vasopressors based on arterial pressure, not cardiac output. Umbilical arterial cord blood was obtained using the double-clamp technique immediately after placental delivery. As there was no consensus on appropriate maternal cardiac output for maintaining uteroplacental blood flow, we defined the low cardiac output group (Low CO) as >25% of cumulative time with cardiac output <80% of baseline from spinal anaesthesia to delivery. Umbilical artery pH was compared in women with low cardiac output and women who maintained cardiac output within their normal baseline range. During the study period, 125 women were eligible and analysed, which was 44% of our annual elective Caesarean deliveries. The low cardiac output group had a lower average cardiac index in the interval from induction of anaesthesia until delivery, but there were no differences in other haemodynamic variables. There was no difference between groups in the umbilical artery pH, the primary outcome (difference in means, 0.0092; 95% confidence interval −0.0071 to 0.0255). The base excess was lower in the low cardiac output group (Table 1). Vasopressors before delivery were also comparable between the groups.Table 1Patient characteristics, haemodynaics and umbilical arterial gas analysis.Low COn=26Normal COn=99Standard differenceAge, yr32.8 (5.6)34.9 (4.7)0.925Hight, cm157.9 (5.6)157.9 (6.0)0Weight, kg68.6 (12.3)62.5 (9.3)−1.856Gestational age, week36.4 (0.9)36.6 (1.3)0.191Nulliparous, n (%)9 (35%)22 (22%)−0.291ASA physical status, 2/3, n6/2084/151.589HDP, n(%)1 (4%)9 (9%)0.204Diabetes mellitus, n (%)3 (12%)12 (12%)0Baseline: SBP, mm Hg124 ± 15121± 18−0.739MAP, mm Hg97 ± 994 ± 15−0.866HR, bpm94 ± 1388 ± 15−1.604CI, L·min−1·m−24.23 ± 0.724.00 ± 0.75−0.268A-D average: SBP, mm Hg117 ± 8118 ± 110.324MAP, mm Hg87 ± 787 ± 90HR, bpm77 ± 1082 ± 131.474CI, L·min−1·m−23.27 ± 0.583.83 ± 0.690.703Anesthesia-to-delivery time, min23.3 ± 4.924.2 ± 5.70.391Total surgical time, min56 ± 1561 ± 181.231Total fluid intake, mL1,265 ± 3131,370 ± 1217.128Colloid, mL961 ± 207987 ± 2991.635EBL including amniotic fluid, mL1,149 ± 5951,162 ± 5070.554Norepinephrine until delivery, μg80.0 ± 49.089.4 ± 54.61.306Phenylephrine until delivery, μg40.4 ± 131.226.8 ± 103.1−1.257UA pH7.32 ± 0.047.33 ± 0.030.053UA pCO2, mm Hg45.4 ± 7.945.0 ± 5.4−0.155UA pO2, mm Hg25.0 ± 9.124.9 ± 5.8−0.037UA HCO3−, mEq·L−123.6 ± 3.424.3 ± 3.30.382UA BE, mEq·L−1-2.66 ± 1.7-1.81 ± 1.61.152UA lactate, mmol·L−12.02 ± 0.731.80 ± 0.47−0.284ASA: American Society of Anesthesiologists, BE: base excess, CI: cardiac index, CO: cardiac output, HDP: hyptertensive disorders of pregnancy, HR: heart rate, MAP: mean arterial pressure, SBP: systolic blood pressure, UA: umbilical artery. Open table in a new tab ASA: American Society of Anesthesiologists, BE: base excess, CI: cardiac index, CO: cardiac output, HDP: hyptertensive disorders of pregnancy, HR: heart rate, MAP: mean arterial pressure, SBP: systolic blood pressure, UA: umbilical artery. Our retrospective cohort study shows that the Low CO group did not have lower fetal umbilical arterial pH, although the base excess was significantly lower in the Low CO group. Arterial pressure is not necessarily correlated with organ blood flow. Most noninvasive blood pressure measurements apply oscillometric methods and calculate systolic and diastolic blood pressures from the peak amplitude of arterial pulsation by an algorithm. Thus, arterial pressure measurements might not detect low uteroplacental perfusion. Recent international consensus guidelines recommend that clinicians pay more attention to both arterial pressure and cardiac output.1Kinsella 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.Anaesthesia. 2018; 73: 71-92Crossref PubMed Scopus (271) Google Scholar The current trend shifting from phenylephrine to norepinephrine is driven by the clinical fact that norepinephrine is associated with higher cardiac output compared with phenylephrine because reflex bradycardia is avoided.3Ngan Kee W.D. Lee S.W.Y. Ng F.F. Tan P.E. Khaw K.S. Randomized double-blinded comparison of norepinephrine and phenylephrine for maintenance of blood pressure during spinal anesthesia for cesarean delivery.Anesthesiology. 2015; 122: 736-745Crossref PubMed Scopus (190) Google Scholar In our cohorts, the minimum heart rate was similar between groups, which means that stroke volume was compromised after spinal anaesthesia in the Low CO group. However, other haemodynamic parameters were comparable with appropriately maintained maternal arterial pressure as the baseline. We presumed that the lower cardiac output could be caused by high-dose norepinephrine for maintaining arterial pressure. As individual sensitivity to vasopressors differs from person to person, it might be related to norepinephrine effects on left ventricular afterload, resulting in reduced cardiac output.9Foulon P. De Backer D. The hemodynamic effects of norepinephrine: far more than an increase in blood pressure.Ann Transl Med. 2018; 6: S25Crossref PubMed Google Scholar Regarding cardiac output in Caesarean delivery, maintaining arterial pressure seems to be more critical than maintaining cardiac output based on previous studies comparing ephedrine (high cardiac output with low blood pressure) and phenylephrine (low cardiac output with high blood pressure).10Langesaeter E. Rosseland L.A. Stubhaug A. Continuous invasive blood pressure and cardiac output monitoring during cesarean delivery: a randomized, double-blind comparison of low-dose versus high-dose spinal anesthesia with intravenous phenylephrine or placebo infusion.Anesthesiology. 2008; 109: 856-863Crossref PubMed Scopus (194) Google Scholar,11Mon W. Stewart A. Fernando R. et al.Cardiac output changes with phenylephrine and ephedrine infusions during spinal anesthesia for cesarean section: a randomized, double-blind trial.J Clin Anesth. 2017; 37: 43-48Crossref PubMed Scopus (31) Google Scholar Currently, evidence does not suggest that maintaining cardiac output rather than arterial pressure improves neonatal outcomes. The esCCO® estimates cardiac output without applying any additional monitors, but it still requires additional cost by using a single-use pulse oximetry probe (5000 JPY). We decided against its routine use because we did not find clinical benefits in this study. The monitor should be considered for specific clinical situations, such as mothers with severe preeclampsia or with cardiac disease. This study has several limitations. Firstly, as a result of the retrospective analysis, our study cohort could have selection biases. As the esCCO® requires ∼5 min for calibration, some anaesthetists might have been reluctant to measure the cardiac output, especially when feeling production pressure for running the operating theatre efficiently. Selection bias might also have occurred because we only analysed cases with appropriate calibration before induction of anaesthesia. Even when we did calibrate the monitor in the operating theatre, some data were excluded because of the mechanical errors of our electric database system. In this retrospective study, we did not include emergency cases because it would be difficult to interpret the results. Hence, our results should not be applied in the emergency setting. Furthermore, we only analysed umbilical arterial blood gas, not venous blood gas parameters. This is our institutional standard practice and is the recommended practice in Japan. When drawing blood from the umbilical cord, it is easy to contaminate arterial and venous umbilical blood. Moreover, we found that base excess was significantly lower in the Low CO group, which might reflect decrease in uteroplacental perfusion; however, because of the lack of umbilical venous gas values, we could not confirm this. To overcome these limitations, a further prospective study should be considered. In conclusion, low cardiac output associated with administration of prophylactic norepinephrine was not associated with lower umbilical artery pH. Current evidence does not support routine measurement of maternal cardiac output for elective Caesarean delivery under spinal anaesthesia. Nihon Kohden Corporation (Tokyo, Japan) provided the clinical devices and measuring probes for the project without financial support to the authors. The authors would like to thank Katsuo Terui (Department of Obstetric Anesthesiology, Center for Maternal-Fetal and Neonatal Medicine, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan) for essential suggestions and dedicated support for the project.