An open-label randomized controlled clinical trial for comparison of continuous phenylephrine versus norepinephrine infusion in prevention of spinal hypotension during cesarean delivery

Accepted Manuscript Original article An open-label randomized controlled clinical trial for comparison of continuous phenylephrine versus norepinephrine infusion in prevention of spinal hypotension during cesarean delivery M.C. Vallejo, A.F. Attaallah, O.M. Elzamzamy, D.T. Cifarelli, A.L. Phelps, G.R. Hobbs, R.E. Shapiro, P. Ranganathan PII: DOI: Reference:

S0959-289X(16)30069-3 http://dx.doi.org/10.1016/j.ijoa.2016.08.005 YIJOA 2491

To appear in:

International Journal of Obstetric A nesthesia

Accepted Date:

21 August 2016

Please cite this article as: Vallejo, M.C., Attaallah, A.F., Elzamzamy, O.M., Cifarelli, D.T., Phelps, A.L., Hobbs, G.R., Shapiro, R.E., Ranganathan, P., An open-label randomized controlled clinical trial for comparison of continuous phenylephrine versus norepinephrine infusion in prevention of spinal hypotension during cesarean delivery, International Journal of Obstetric A nesthesia (2016), doi: http://dx.doi.org/10.1016/j.ijoa.2016.08.005

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IJOA 16-00063 ORIGINAL ARTICLE An open-label randomized controlled clinical trial for comparison of continuous phenylephrine versus norepinephrine infusion in prevention of spinal hypotension during cesarean delivery M. C. Vallejo,a A. F. Attaallah,a O. M. Elzamzamy,a D. T. Cifarelli,a A. L. Phelps,b G. R. Hobbs,a R. E. Shapiro,a P. Ranganathan a a

West Virginia University School of Medicine, Morgantown, WV, USA

b

Duquesne University School of Business, Pittsburgh, PA, USA

Short Title: Vasopressors for spinal hypotension during cesarean delivery

Correspondence to: Manuel C. Vallejo, MD, DMD, Professor, West Virginia University - School of Medicine - Department of Anesthesiology, 1 Medical Center Dr., PO Box 8255, Morgantown, WV. 26506, USA E-mail address: [email protected]

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ABSTRACT Background: During spinal anesthesia for cesarean delivery phenylephrine is the vasopressor of choice but can cause bradycardia. Norepinephrine has both β and α adrenergic activity suitable for maintaining blood pressure with less bradycardia. We hypothesized that norepinephrine would be superior to phenylephrine, requiring fewer rescue bolus interventions to maintain blood pressure. Methods: Eighty-five parturients having spinal anesthesia for elective cesarean delivery were randomized to Group P (phenylephrine 0.1 µg/kg/min) or Group N (norepinephrine 0.05 µg/kg/min) fixed-rate infusions. Rescue bolus interventions of phenylephrine 100 µg for hypotension, or ephedrine 5 mg for bradycardia with hypotension, were given as required to maintain systolic blood pressure. Maternal hemodynamic variables were measured noninvasively. Results: There was no difference between groups in the proportion of patients who required rescue vasopressor boluses (Group P: 65.8% [n=25] vs. Group N 48.8% [n=21], P=0.12). The proportion of patients who received ≥1 bolus of phenylephrine was similar between groups (Group P: 52.6% [n=20] vs. Group N 46.5% [n=20], P=0.58). However, more patients received ≥1 bolus of ephedrine in the phenylephrine group (Group P 23.7% [n=9] vs. Group N 2.3% [n=1], P<0.01). The incidence of emesis was greater in the phenylephrine group (Group P=26.3% vs. Group N=16.3%, P<0.001). Hemodynamic parameters including heart rate, the incidence of bradycardia, blood pressure, cardiac output, cardiac index, stroke volume, and systemic vascular resistance and neonatal outcome were similar between groups (all P<0.05). Conclusions: Norepinephrine fixed-rate infusion has efficacy for preventing hypotension and can be considered as an alternative to phenylephrine.

Keywords: Cesarean delivery, Spinal anesthesia, Phenylephrine, Norepinephrine

Introduction Spinal anesthesia is the anesthetic technique of choice for elective cesarean delivery (CD); however, it results in maternal hypotension in most women if not actively prevented.1-3 The incidence without prophylactic management during CD under spinal anesthesia can be in excess of 80%.2 If left untreated, maternal hypotension can lead to serious sequelae including nausea,

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emesis, cardiovascular instability, decreased uteroplacental blood flow, and fetal acidosis.3 To avoid maternal hypotension and blood pressure variability, the current standard is to administer a continuous phenylephrine infusion to limit the change from baseline.4-6 Prophylactic continuous infusion with rescue bolus dosing is more effective for hemodynamic stability than relying on rescue dosing alone, with the advantage of limiting clinician workload and increasing maternal comfort.7 Compared with ephedrine, phenylephrine is associated with less neonatal acidosis while maintaining uteroplacental blood flow.8 However, it has also been shown that phenylephrine can have clinically significant side effects such as a baroreceptor-mediated bradycardia with a consequent decrease in cardiac output (CO).9-11 A recent study showed that norepinephrine was also effective for maintaining blood pressure in obstetric patients;12 its use was associated with greater heart rate (HR) and CO compared with phenylephrine, but further studies confirming its safety and efficacy in this setting were recommended.12 The aim of this study was to compare prophylactic intravenous infusions of phenylephrine and norepinephrine infusions during CD under spinal anesthesia. We tested the hypothesis that a fixed-rate norepinephrine infusion would be superior to a fixed-rate phenylephrine infusion. The primary endpoint was reduction in the number and total dose of intraoperative provideradministered rescue bolus interventions needed to maintain systolic blood pressure (SBP).

Methods The local West Virginia University Institutional Review Board (IRB) approved this study and informed verbal and written consents were obtained from all study patients. The study was registered with the U.S. National Institutes of Health National Clinical Trials (trial registry number: NCT02354833). We conducted a prospective, observational, randomized, open labeled trial on parturients scheduled for elective CD under spinal anesthesia. Inclusion criteria were: American Society of Anesthesiologists physical status class <3, singleton gestation >36 weeks, scheduled elective CD under spinal anesthesia, fasting >6 h. Exclusion criteria were: cardiovascular disease, pregnancy-related hypertensive disease, preeclampsia, eclampsia, the use of cardiac medication or medication for blood pressure control, multiple gestation, gestational diabetes requiring insulin, documented history of postoperative nausea and vomiting, previous gastric bypass surgery, history of chronic opioid use (chronic pain syndrome), body mass index (BMI) >40 kg/m2, emergency CD for maternal and/or fetal distress,

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suspicion of abnormal placentation, history of seizures, progressive neurologic disease. Patients were randomized using a computer generated table to one of two treatment groups (Group P: phenylephrine 100 µg/mL infused at 0.1 µg/kg/min or Group N: norepinephrine infused at 0.05 µg/kg/min) to maintain SBP within 100–120% of baseline during standardized spinal anesthesia. Baseline SBP and HR were recorded as the mean of three consecutive preoperative measurements taken 5 min apart one hour before arrival in the operating room. All patients had a peripheral intravenous catheter placed in the upper extremity and received Lactated Ringers solution 500 mL over 15 min in their hospital room by the labor and delivery nurse as per our hospital protocol. Study group assignments were concealed in opaque envelopes and were revealed to the anesthesia providers upon entering the operating room. The study infusion medication was started at the same time cerebrospinal fluid was obtained, immediately before injection of spinal medications. Vasopressor infusions were administered through small-bore tubing connected directly to the peripheral intravenous catheter. A standardized spinal anesthetic consisting of hyperbaric bupivacaine 12–15 mg, preservative-free morphine 0.2 mg and fentanyl 20 µg was administered in the sitting position at the L3–4 or L4–5 vertebral interspace. After intrathecal injection, patients were placed in the supine position and the table tilted 15° to provide left uterine displacement. The spinal sensory level was tested bilaterally by pinprick to ensure a T4 dermatomal level before surgical incision. A rescue bolus of phenylephrine 100 µg was administered by the anesthesia care provider whenever SBP decreased below 100% of baseline. Hypotension was defined as the requirement for a rescue bolus intervention. Hypertensive episodes (SBP >120% of baseline) were treated with infusion cessation, and the infusion was restarted when the SBP decreased below the upper limit of the target range (120% of baseline SBP value). Bradycardia (HR <60 beats/min) was treated by stopping the infusion and if accompanied by hypotension, a rescue bolus of ephedrine 5 mg was given. Study variables included SBP, diastolic blood pressure (DBP), HR, CO, cardiac index (CI), stroke volume (SV), systemic vascular resistance (SVR), number and type of provider interventions for maintaining blood pressure, Apgar scores < 7 at 1 and 5 min, umbilical cord blood gases if clinically indicated as part of routine care, and intraoperative maternal nausea and emesis. Nausea was defined as a subjectively unpleasant sensation associated with awareness of the urge to vomit and emesis was defined as rhythmic contractions of the abdominal muscles

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with or without expulsion of gastric contents from the mouth (i.e. including retching). Intravenous ondansetron 4 mg was administered after delivery of the baby to all patients. Hemodynamic variables were continuously recorded using the Nexfin® non-invasive hemodynamic monitor (Edwards Lifesciences Corp, Irvine, CA, USA). This was used according to guidelines provide by the manufacturer. A finger cuff was applied to the mid-phalanx of the middle finger and an appropriate arterial waveform was obtained. An acceptable waveform was characterized by a high-quality shape, amplitude, and a visible dicrotic notch. Hemodynamic variables were analyzed at nine defined intervals throughout the procedure (baseline, infusion start, spinal insertion, left uterine displacement, surgical incision, delivery, oxytocin start, fascial closure, procedure end). The study ended when patient care was transferred to the labor and delivery nurse postoperatively.

Statistical Analysis Ohpasanon et al. reported a 65% incidence of hypotension after spinal anesthesia in cesarean delivery without a phenylephrine infusion.13 A local pilot study was conducted on 20 parturients who were given a continuous infusion of phenylephrine for elective CD under spinal anesthesia where 35% of the patients experienced maternal hypotension treated by at least one bolus intervention. Based on this information, power analysis indicated that 35 patients were required per group to detect a reduction to 10% in the incidence of hypotension (patients requiring one or more rescue boluses) at the 0.05 significance level with 80% power. To allow for parturients who may not complete the study, we planned to enroll a total of 85 patients. The primary endpoint was the number and total dose of rescue bolus interventions needed to maintain SBP. A two-sample Z-test was used to determine a significant difference in the proportion of patients in each group requiring at least one bolus dose intervention. Demographic data and duration of infusion were compared using a two-sided t-test between groups. Gravidity and parity were compared using the Mann-Whitney U test. Ephedrine total dose and phenylephrine total dose were also compared between groups using the Mann-Whitney U test because the skewed distributions did not meet the required assumptions for the t-test. Differences in the incidence of nausea, emesis, bradycardia, number of rescue bolus interventions of ephedrine and phenylephrine, and Apgar scores <7 at 1 and 5 min were compared between groups using the chi-square test. Multivariate analysis of variance (MANOVA) was used to

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detect significant differences in the repeated hemodynamic parameters to measure trends over time for each measured variable. MANOVA accommodates for the multivariate, dependent responses by combining each numerical variable as a single vector of responses. P <0.05 was considered statistically significant. Data analysis was performed using Excel 2013 (Microsoft Corporation, Redmond, WA, USA) and JMP software from SAS (SAS Institute Inc., Cary, NC, USA).

Results Patient recruitment and flow are shown in Fig. 1. The study enrolled 85 patients from August 2014 through August 2015. Thirty-eight women were enrolled in the phenylephrine group and none were excluded. Forty-three women were enrolled in the norepinephrine group; however, four patients were excluded (two because of monitoring equipment failure, and two who had emergency CD). The enrollment difference between groups was due to each patient being randomly assigned to one of two groups without restriction to an equal sample size. All patients had successful spinal anesthesia with an adequate bilateral sensory level to T4; no patient required supplemental intravenous opioids for intraoperative pain. No differences were noted between groups with respect to demographic data (age, BMI, gravidity, parity and gestation). There were no differences between the two groups in infusion duration, incidence of bradycardia, or incidence of nausea but the incidence of emesis was greater in the phenylephrine group (Group P=26.3% vs. Group N=16.3%, P<0.001), (Table 1). The proportion of patients who required rescue boluses of phenylephrine (given for SBP
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There were no differences between groups in the proportion of Apgar scores <7 at 1 min and 5 min, or in umbilical venous cord blood gases (Table 2). One patient in Group P and two in Group N required infusion cessation because of hypertension; only one of whom in group P became bradycardic. Regarding the measured non-invasive hemodynamic parameters, there were no differences in MANOVA modeling, treating the repeated outcome measures as multivariate sample of means or when followed by separate testing at each of recorded separate intervals (HR: P=0.17, CO: P=0.5, CI: P=0.84, SV P=0.5, SBP: P=0.25, DBP: P=0.15, and SVR: P=0.54), (Fig. 3).

Discussion Our results confirm our clinical impression that a fixed-rate infusion norepinephrine is effective for maintaining maternal blood pressure in elective CD under spinal anesthesia. When a norepinephrine infusion was used, the number of required rescue boluses of ephedrine was decreased and fewer patients had emesis compared with a phenylephrine infusion. A recent study by Ngan Kee et al. compared both drugs for cesarean delivery.12 Our study was different in that whereas the previous investigators used a computer-controlled closed-loop feedback system to administer and titrate the vasopressors with CO as the primary outcome, we used a fixed-rate infusion with the number of rescue boluses required as the primary outcome. Another difference was that we aimed to maintain maternal blood pressure within 100–120% of baseline value and intervened whenever SBP decreased below 100% of baseline, and as a result much larger doses would be expected to be used. Previously Ngan Kee et al.6 determined that when maternal blood pressure was maintained within 80%, 90% or 100% of baseline using a phenylephrine infusion, patients in the 100% baseline group had better maternal and neonatal outcomes. Phenylephrine is effective at increasing SVR but a high infusion dose can cause a significant reduction of up to 20% in both maternal HR and CO.9-12 Norepinephrine has weak βadrenergic receptor agonist activity in addition to its α-adrenergic receptor activity and therefore may be a more suitable option for maintaining maternal blood pressure with less negative effects on HR and CO compared with phenylephrine.12,14 However, contrary to previous findings of greater HR and CO in the norepinephrine group by Ngan Kee et al.12 we did not find significant

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differences in HR, CO, CI, SV, and SVR between the two study groups. This may be related to the doses used. Furthermore, these measurements were not defined study outcomes and therefore a type II statistical error is a possibility. Also worth noting, Ngan Kee et al.12 compared norepinephrine with phenylephrine according to an estimate of a potency ratio of 20:1, which was the ratio used in previous clinical comparisons.15-17 The potency ratio used in our study was 2:1. In the doses used in our study, we did not find a difference in the incidence of bradycardia between groups. The true potency ratio in this setting remains uncertain; using variable titrated rate infusions could decrease the issue of potency ratio, although a potency ratio between two drugs that differ in effect can be problematic to define. Stewart et al.11 conducted a randomized double-blind study on women scheduled for elective CD with differing phenylephrine infusions at 25 µg/min, 50 µg/min or 100 µg/min. They demonstrated that all three infusion regimens maintained maternal blood pressure equally, and recommended that infusion rates of phenylephrine insufficient to cause bradycardia should be used.11 Most studies show that phenylephrine doses in the range on 0.25–1.0 µg/kg/min are clinically sufficient. In our study, a substantial portion of the vasopressor used was actually in phenylephrine bolus form, which may be an explanation of why few differences between groups were seen. We also chose the lowest phenylephrine infusion rate clinically used (0.1 µg/kg/min) and demonstrated a lower incidence of bradycardia while maintaining comparable HR, BP, CO, CI, SV, and SVR between the two study groups. We found a greater use of ephedrine bolus interventions in the phenylephrine group, but not in the ephedrine total dose, which resulted in a lower incidence of bradycardia in the phenylephrine group (13.2% vs. 18.6%, P=0.71). However, a large proportion of our findings may be due to the difference in potency between the two drug solutions tested, rather than differences in the drugs themselves. Our patients received intrathecal preservative free morphine 0.2 mg and fentanyl 20 µg for postoperative analgesia. High rates of nausea and vomiting have been reported with this technique.18 While the blood pressure was maintained at 100–120% of baseline, our reported rates of nausea and emesis could perhaps be attributed in part to the use of these medications and the definitions used to report them in our study. The external noninvasive hemodynamic monitoring system (Nexfin) has been validated in pregnant patients.19 It was shown that intraoperative CO measurement using Nexfin has a strong correlation (94% concordance) with CO measured by esophageal Doppler.20 A number of recent

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articles have shown inaccuracies in agreement in measured hemodynamic variables with noninvasive devices compared with invasive devices,21,22 however the Nexfin can provide a reasonable estimate of CO, blood pressure, pulse pressure variation, SV variation, and be used to adequately reflect hemodynamic alterations.23-25 We used a fixed-rate infusion which is different from other protocols that have utilized variable rate infusions with additional boluses if needed. Another limitation is that the fixed-rate infusion of phenylephrine was low (about 8 µg/min in an 80 kg woman) which is lower than most current regimens. We found a high incidence of nausea and emesis in both groups, which presumably could be due to the low study phenylephrine infusion rate. Another limitation was that this study was unblinded (open-label) which could have led to bias. This, however, was minimized in that all data were recorded independently by a research assistant minimizing the provider’s ability to influence results. In our study, hypotension was defined as the requirement for rescue bolus intervention and ephedrine was administered when bradycardia was accompanied by hypotension, which can result in a discrepancy in rescue bolus treatment. The open-label aspect was incorporated as a local IRB requirement to assure best patient safety practices owing to research on a vulnerable patient population. The IRB considers pregnant patients, prisoners, and the pediatric population to be vulnerable populations and incorporated this requirement to ensure the attending anesthesiologists were aware of the drug used, in order to safeguard the patient’s best interest and potential effects especially on the fetus. In summary, norepinephrine fixed-rate infusion has efficacy for preventing hypotension and can be considered as an alternative to phenylephrine. Future research is needed to assess the safety of norepinephrine, its potency compared to phenylephrine, its use in the parturient with other comorbidities, and to determine the optimal infusion rate and dosing strategy for maintaining maternal hemodynamics under spinal anesthesia for CD.

Disclosure This study received no external funding and the authors have no conflicts of interest to declare.

References

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1.

Datta S, Alper MH, Ostheimer GW, Weiss JB. Method of ephedrine administration and nausea and hypotension during spinal anesthesia for cesarean section. Anesthesiology. 1982;56: 68-70.

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Saravanan S, Kocarev M, Wilson RC, Watkins E, Columb MO, Lyons G. Equivalent dose of ephedrine and phenylephrine in the prevention of post-spinal hypotension in caesarean section. Br J Anaesth 2006; 96:95–9.

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Macarthur A, Riley ET. Obstetric anesthesia controversies: vasopressor choice for postspinal hypotension during cesarean delivery. Int Anesthesiol Clin 2007; 45:115–32.

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Cooper DW, Carpenter M, Mowbray P, Desira WR, Ryall DM, Kokri MS. Fetal and maternal effects of phenylephrine and ephedrine during spinal anesthesia for cesarean delivery. Anesthesiology 2002; 97:1582–90.

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Ngan Kee WD, Khaw KS, Ng FF, Lee BB. Prophylactic phenylephrine infusion for preventing hypotension during spinal anesthesia for cesarean delivery. Anesth Analg 2004; 98: 815-21.

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Ngan Kee WD, Khaw KS, Ng FF. Comparison of phenylephrine infusion regimens for maintaining maternal blood pressure during spinal anaesthesia for caesarean section. Br J Anaesth 2004; 92: 469-74.

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Siddik-Sayyid SM, Taha SK, Kanazi GE, Aouad MT. A randomized controlled trial of variable rate phenylephrine infusion with rescue phenylephrine boluses versus rescue boluses alone on physician interventions during spinal anesthesia for elective cesarean delivery. Anesth Analg 2014; 118: 611-8.

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Lee A, Ngan Kee WD, 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. Anesth Analg 2002; 94: 920-6.

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Dyer RA, Reed AR, van Dyk D, et al. Hemodynamic effects of ephedrine, phenylephrine, and the coadministration of phenylephrine with oxytocin during spinal anesthesia for elective cesarean delivery. Anesthesiology 2009; 111:753–65.

10. Langesaeter E, Rosseland LA, Stubhaug A. Continuous invasive blood pressure and cardiac output monitoring during cesarean delivery: a randomized, double-blind comparison of lowdose versus high-dose spinal anesthesia with intravenous phenylephrine or placebo infusion. Anesthesiology 2008; 109: 856–63.

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11. Stewart A, Fernando R, McDonald S, Hignett R, Jones T, Columb M. The dose-dependent effects of phenylephrine for elective cesarean delivery under spinal anesthesia. Anesth Analg 2010; 111: 1230-7. 12. Ngan Kee WD, Lee SW, Ng FF, Tan PE, Khaw KS. Randomized double-blinded comparison of norepinephrine and phenylephrine for maintenance of blood pressure during spinal anesthesia for cesarean delivery. Anesthesiology 2015; 122: 736-45. 13. Ohpasanon P, Chinachoti T, Sriswasdi P, Srichu S. Prospective study of hypotension after spinal anaesthesia for cesarean section at Siriraj hospital: Incidence and risk factors, part 2. J Med Assoc Thai 2008; 91: 675-80. 14. Hoyme M, Scheungraber C, Reinhart K, Schummer W. Comparison of norepinephrine and cafedrine/theodrenaline regimens for maintaining maternal blood pressure during spinal anaesthesia for caesarean section. Obstetrics & Gynecology: An International Journal 2015; Article ID 714966, DOI: 10.5171/2015.714966 http://www.ibimapublishing.com/journals/GYNE/2015/714966/714966.pdf 15. Sjöberg T, Norgren L, Andersson KE, Steen S. Comparative effects of the α-adrenoceptor agonists noradrenaline, phenylephrine and clonidine in the human saphenous vein in vivo and in vitro. Acta Physiol Scand 1989; 136: 463–71. 16. Goertz AW, Lindner KH, Seefelder C, Schirmer U, Beyer M, Georgieff M. Effect of phenylephrine bolus administration on global left ventricular function in patients with coronary artery disease and patients with valvular aortic stenosis. Anesthesiology 1993; 78: 834-41. 17. Goertz AW, Seeling W, Heinrich H, Lindner KH, Rockemann MG, Georgieff M. Effect of phenylephrine bolus administration on left ventricular function during high thoracic and lumbar epidural anesthesia combined with general anesthesia. Anesth Analg 1993; 76: 541-5. 18. Nortcliffe SA, Shah J, Buggy DJ. Prevention of postoperative nausea and vomiting after spinal morphine for Caesarean section: comparison of cyclizine, dexamethasone and placebo. Br J Anaesth 2003; 90: 665-70. 19. Akkermans J, Diepeveen M, Ganzevoort W, van Montfrans GA, Westerhof BE, Wolf H. Continuous non-invasive blood pressure monitoring, a validation study of Nexfin in a pregnant population. Hypertens Pregnancy 2009; 28: 230-42.

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20. Chen G, Meng L, Alexander B, Tran NP, Kain ZN, Cannesson M. Comparison of noninvasive cardiac output measurements using the Nexfin monitoring device and the esophageal Doppler. J Clin Anesth 2012; 24: 275-83. 21. Blanié A, Soued M, Benhamou D, Mazoit JX, Duranteau J. A Comparison of Photoplethysmography versus esophageal Doppler for the assessment of cardiac index during major noncardiac surgery. Anesth Analg. 2016; 122:430-6. 22. Schramm P, Tzanova I, Gööck T, et al. Noninvasive hemodynamic measurements during neurosurgical procedures in sitting position. J Neurosurg Anesthesiol. 2016 Mar 18. [Epub ahead of print] 23. Ameloot K, Palmers PJ, Malbrain ML. The accuracy of noninvasive cardiac output and pressure measurements with finger cuff: a concise review. Curr Opin Crit Care. 2015; 21:232-9. 24. Balzer F, Habicher M, Sander M, et al. Comparison of the non-invasive Nexfin® monitor with conventional methods for the measurement of arterial blood pressure in moderate risk orthopaedic surgery patients. J Int Med Res. 2016 May 2. pii: 0300060516635383. [Epub ahead of print] 25. Stens J, Oeben J, Van Dusseldorp AA, Boer C. Non-invasive measurements of pulse pressure variation and stroke volume variation in anesthetized patients using the Nexfin blood pressure monitor. J Clin Monit Comput. 2015 Aug 29. [Epub ahead of print]

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IJOA 16-00063 Legends for Figures

Fig. 1 Study CONSORT diagram showing patient recruitment and flow

Fig. 2 Proportion of patients who received rescue boluses of phenylephrine for hypotension and/or ephedrine for bradycardia and hypotension. The upper panel shows the proportion of patients who received different numbers of boluses. The lower panel shows the proportion of patients who received either or both vasopressors (fields are not mutually exclusive). Group P = Phenylephrine, Group N = Norepinephrine. *P < 0.01), #P=0.03

Fig. 3 Hemodynamic parameters at the specific time periods of infusion start, spinal insert, supine with left uterine displacement and at delivery. Multiple analyses of variance for heart rate P=0.17, cardiac output P=0.5, cardiac index P=0.84, stroke volume P=0.5, systolic blood pressure P=0.25, diastolic blood pressure P=0.15, and systemic vascular resistance P=0.54. Group P: phenylephrine group. Group N: norepinephrine group.

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Fig. 1

Enrollment

Assessed for eligibility (n=85)

Excluded (n=0) • Not meeting inclusion criteria (n=0) • Declined to participate (n=0) • Other reasons (n=0)

Randomized (n=85)

Allocation Allocated to Group P - Phenylephrine (n=38)

Allocated to Group N - Norepinephrine (n=47)

• Received allocated intervention (n=38) • Did not receive allocated intervention (n=0)

• Received allocated intervention (n=45) • Did not receive allocated intervention (emergency caesarean deliveries) (n=2)

Follow-Up Lost to follow-up (n=0)

Lost to follow-up (n=0)

Discontinued intervention (n=0)

Discontinued intervention (monitoring equipment failure) (n=2)

Analysis Analysed (n=38)

Analysed (n=43)

• Excluded from analysis (n=0)

• Excluded from analysis (n=0)

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Bolus Requirements 70%

65.8%

60% 48.8%

50% 40%

31.6% 27.9%

30% 20%

13.2% 9.3%

10%

2.6%

0.0%

0%

Rescue Bolus (%)

> 1 Boluses Group P

> 2 Boluses

> 3 Boluses

Group N

Phenylephrine + Ephedrine Bolus Requirements 70%

65.8%

60% 50%

52.6% 48.8%

46.5%

40%

*

30%

23.7%

#

20%

10.5% 10%

2.3%

0.0%

0%

Rescue Bolus (%)

Rescue P Bolus (%) Group P

Fig. 2

Rescue E Bolus (%) Group N

Both P + E Bolus (%)

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Fig 3

Heart Rate 120 90 bpm 60 30 0 Infusion Start

Spinal Insert Supine with Delivery LUD

Group P

Group N

Cardiac Output 10 8 6 L/min 4 2 0 Infusion Start

Spinal Insert Supine with Delivery LUD

Group P

Group N

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Cardiac Index 5 4 3 L/min/m2 2 1 0

Infusion Start

Spinal Insert

Group P

Supine with Delivery LUD

Group N

Stroke Volume 150 100 ml/beat 50 0

Infusion Start

Spinal Insert

Group P

Supine with LUD

Group N

Delivery

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Mean Systolic Blood Pressure 150 140 mmHg 130 120 110 Infusion Start

Spinal Insert

Group P

Supine with Delivery LUD

Group N

Mean Diastolic Blood Pressure 120 90 mmHg 60 30 0

Infusion Start

Spinal Insert

Group P

Supine with Delivery LUD

Group N

Systemic Vascular Resistance 1500 1000 dynes/sec/ cm5 500 0 Infusion Start Group P

Spinal Insert

Supine Delivery with LUD

Group N

Table 1 Demographic, vasopressor, maternal and fetal outcome data Phenylephrine Group (n=38)

Norepinephrine Group (n=43)

P value

29.1 ± 5.6 (27.3 to 30.8)

30.2 ± 6.8 (28.1 to 32.2)

0.43

Body mass index (kg/m )

33.6 ± 6.6 (31.5 to 35.7)

35.0 ± 7.0 (32.9 to 37.1)

0.34

Gravidity

3 [1-5]

2 [1-8]

0.14

Parity

1 [0-4]

1 [0-2]

0.08

Gestation (weeks)

37.6 ± 2.0 (37.0 to 38.3)

38.1 ± 1.6 (37.6 to 38.6)

0.27

Infusion duration (minutes)

69.2 ± 18.6 (63.3 to 75.1)

66.7 ± 21.6 (60.2 to 73.1)

0.57

Ephedrine total dose (mg)

0 [0-85]

0 [0-30]

0.10

Phenylephrine total dose (g)

50 [0-1000]

100 [0-700]

0.73

Incidence of bradycardia (%)

23.7% (10.2% to 37.2%)

18.6% (7.0% to 30.2%)

0.58

Nausea (%)

63.2% (47.9% to 78.5%)

51.2% (36.3% to 66.1%)

0.28

Emesis (%)

26.3% (12.3% to 40.3%)

16.3% (5.3% to 27.3%)

< 0.001

Age (years) 2

Median total rescue bolus dose

Data are mean  SD with 95% CI, median [range] or percentage with 95% CI for proportions. Rescue bolus interventions reflect number of interventions divided by number of time periods.

Table 2 Neonatal outcome Phenylephrine Group

Norepinephrine Group

(n=38)

P value

(n=43)

Apgar scores at 1 min <7

6

6

0.82

Apgar scores at 5 min <7

2

1

0.48

Umbilical venous blood gases

(n=5)

(n=7)

pH

7.30 [7.22-7.33]

7.27 [7.16-7.32]

0.42

PCO2 (mmHg)

54.0 [20.0-78.5)

24.0 [18.0-33.0]

0.32

PO2 (mmHg)

51.0 [43.0-58.0]

56.0 [46.0-73.0]

0.46

HCO3 (mEq/L)

23.0 [17.9-26.0]

20.3 [20.0-22.3]

0.56

Base excess (mEq/L)

4.3 [2.50-7.45]

4.3 [0.7-5.1]

0.74

Data are number or median [interquartile range]

21

IJOA 16-0063 Highlights •

Hypotension is common during spinal anesthesia for cesarean delivery

•

Fixed-rate infusions of norepinephrine vs phenylephrine were compared

•

Both regimens were effective with similar requirement for rescue boluses

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Norepinephrine can be considered as an alternative to phenylephrine