Maternal hemodynamics during labor epidural analgesia with and without adrenaline: a secondary analysis of a randomized trial

Background: Pregnancy in general and labor in particular is associated with changes in maternal hemodynamic parameters such as increased cardiac output and heart rate, with peaks during uterine contractions. Adrenaline may be added to labor epidural solutions to enhance efficiency, but the hemodynamic fluctuations may increase. The aim of this study was to compare the hemodynamic changes of epidural drug solution with or without adrenaline 2 µg.ml -1 and to provide pilot data for a larger study. Methods: Forty-one nulliparous laboring women requesting epidural analgesia were randomized to epidural solution of bupivacaine 1mg.ml -1 , fentanyl 2 µg.ml -1 with or without adrenaline 2 µg.ml -1 . The participants were monitored with the Nexfin CC continuous non-invasive blood pressure and cardiac output monitor. The primary outcomes were changes in peak systolic blood pressure and cardiac output at uterine contraction within 30 minutes after epidural activation. The effect of adrenaline was tested statistically by a linear mixed effects model of the outcome variables’ dependency on time, adrenaline and their interaction. Results: The addition of adrenaline to the solution had no statistically significant effect on the temporal changes in peak systolic blood pressure (mean change 0.23 mmHg.min -1 95% CI [-0.17; 0.64] p=0.26), peak cardiac output (mean change 0.0029 l.min -1 .min -1 95 % CI [-0.026; 0.032] 0.84), or heart rate (mean change 0.015 beats.min -1 .min -1 95 % CI [-0.25; 0.28] p=0.91).

with increased cardiac output, accompanied by a marked increase in blood pressure. [3,4] The pain, anxiety and stress associated with labor are associated with increased catecholamine levels, including adrenaline. [5] Epidural analgesia, an effective treatment of labor pain, is shown to decrease plasma levels of adrenaline in the mother. [6,7] Adrenaline is used as an additive in the epidural mixture, with the intent of producing local vasoconstriction in the epidural space [8], thus reducing the systemic uptake of the epidural solution and thereby enhance the effect of the epidural analgesia. Opponents of this use, claim that the addition of adrenaline may have systemic sympathomimetic effects, raising blood pressure and cardiac output, which may be unfortunate in selected patients with pre-eclampsia and certain heart conditions. [8] In fact, early works of JJ Bonica and colleagues on healthy male volunteers showed an initial rise in systolic blood pressure and cardiac output when adrenaline was added to a dense epidural block. [9] However, little is known about the possible effects of epidural labor analgesia with respect to attenuated hemodynamic changes during labor. The aim of this study was to compare the hemodynamic changes and variability during labor with epidural analgesia with and without the addition of adrenaline 2 µg.ml − 1 to the solution and to provide pilot data for a further study.

Methods
This study was a secondary explorative analysis of data from another randomized clinical trial analyzing serum fentanyl levels in parturients randomized into epidural analgesia with and without the addition of adrenaline 2 µg.ml − 1 to the solution. [10] The study was approved by the regional ethics committee (REK Sør-Øst, ID number 2012/32, approved March 2012) and the Norwegian medicines agency, registered at clinicaltrials.gov (NCT00685672), and conducted according to Good Clinical Practice guidelines. The reporting in this manuscript adheres to the CONSORT guidelines. [11] All participants gave oral and written informed consent. The study design was a randomized controlled trial with two parallel groups. The parturients, the investigators, all personnel treating the participants and assessing the outcomes were blinded to the intervention. A multi orifice epidural catheter (PERIFIX, B-Braun, Melsungen, Germany) was inserted 5 cm in the epidural space at L1-2 or L2-3 by an 18 gauge Tuohy needle using the loss of resistance technique with saline, with the patient in the sitting position. The skin was anesthetized using lidocaine 10 mg.ml − 1 without adrenaline.
The patients were randomized to receive either an epidural solution of bupivacaine 1 mg.ml − 1 and fentanyl 2 µg.ml − 1 (control group) or bupivacaine 1 mg.ml − 1 , fentanyl 2 µg.ml − 1 and adrenaline 2 µg.ml − 1 (adrenaline group ). The blinded test drug solution bags were manufactured by the Hospital Pharmacy at Oslo University Hospital -Rikshospitalet according to the randomization list. The randomization list was created by a researcher who did not take active part in the study (see acknowledgements), using a list of random numbers. [12] Test drug bags were marked with general information of the study, the constituents -including information about containing adrenaline or placeboand study number. After epidural catheter placement, 5 mL of the solution was injected as a test-dose. If no signs of vascular or intrathecal catheter placement were found, an Before epidural catheter placement, blood pressure was measured once at the arm using an automated oscillometric blood pressure monitor (ProCare 100, GE Medical Systems Information Technologies, Inc., Milwaukee, Wisconsin) between contractions. In addition, the patient was connected to a Nexfin CC® monitor (BMEYE B.B., Amsterdam, The Netherlands). The Nexfin CC is a non-invasive continuous blood pressure and cardiac output monitor using the volume clamp method for measuring blood pressure [13,14], transforming it to a brachial blood pressure waveform. The cardiac output is estimated by the pulse contour method. [15] The Nexfin has been validated for blood pressure measurements in pregnant women, [16] and for cardiac output in cardiac surgical patients. [17,18] The monitor was calibrated to the patient's height, pre-delivery weight, age and sex. The patients were monitored for 60 minutes after epidural activation. A marker for 'time = 0' was created in the Nexfin CC monitor when the second starting bolus was given.
Fluids and/or vasopressors were given at clinical indications (fetal or maternal), no mandatory pre-or co-loading of fluids were given according to general departmental procedure.
All patients were monitored using cardiotocography, with use of ST-segment analysis at 6 the discretion of the attending midwife or obstetrician according to standard procedure.

Data extraction and preparation
Data was stored in the Nexfin device as proprietary .csd, .xml and .idx files. The data were extracted using the FrameInspector ® software (v 2.3.0.2, BMEYE B.B, Amsterdam, The Netherlands), and beat-to-beat data were converted to Microsoft Office Excel 2010 ® (Microsoft, Redmond, WA, USA) format, and then imported to MATLAB® version R2015b (MathWorks, Natick, MA). In MATLAB, the data were first cleared of artifact readings using an algorithm previously published [19], which uses the deviation from the median of surrounding measurements in combination with appropriately selected threshold values for each parameter (cardiac output: 5, heart rate: 25, Systolic blood pressure: 50, MAP: 50, Diastolic blood pressure:50, SVR: 400). Tracings for all patients were manually inspected to ensure correctness of artifact clearance. Secondly, the beat-to-beat measurements were transformed to median values with a frame of 50 measurements and 50% overlap between frames to acquire a smoother curve. This step was also manually inspected to ensure that the median values represented the original data. Finally, the peak at each contraction was found using the findpeaks() function in MATLAB, using a minimum criterion for the peak prominence (how much the peak stands out due to its intrinsic height and its location relative to other peaks), adjusted manually for each recording (2-10 mmHg for blood pressure peaks and 0.1-0.7 L.min − 1 for cardiac output).
These peak values were used as the primary outcome and as dependent variables in the final analysis. Figure 2 gives an example of data from a representative case.

Statistical analysis
The primary outcomes in this secondary analysis were changes in cardiac output and systolic blood pressure related to contractions. The hypothesis was that the change over time in these hemodynamic outcomes following epidural activation is different between the two study groups (with and without adrenaline). The temporal development of cardiac output and systolic blood pressure was first inspected visually within the 30 minutes window following epidural activation by plotting these variables against time. Because no particular curve or phase transition could be identified in the data, a linear approach was assumed for statistical analysis. A linear mixed-effects (LME) model was employed for testing this hypothesis based on the interaction effect between time (the time at the identified peaks of the respective variable, from epidural activation to 30 minutes later) and adrenaline (binary variable for study group with or without adrenaline in the bolus).
With systolic blood pressure and cardiac output as the dependent variable in different Secondary outcomes included changes in heart rate, pain scores after epidural activation, neonatal outcomes (Apgar scores at one and five minutes, umbilical venous base excess), and obstetric outcomes (length of labor after epidural, cesarean delivery, mechanical assisted delivery). The statistical assessments for these outcomes were previously reported. [10] Temporal changes in the outcome variables were also assessed for both groups merged, employing the LME model without the adrenaline and time-adrenaline interaction terms. Heart rate values were converted to median values for every five minutes, and thereafter used as the dependent variable in in the abovementioned linear mixed effects model.
The LME analysis was conducted in MATLAB using the fitlme() function from the Statistics and Machine Learning Toolbox. All other statistical calculations were performed in SPSS ® version 24 (IBM, Chicago, IL). A significance level of 5% was used.
At trial conception, there was to our knowledge no data describing continuous hemodynamic changes during labor with the use of epidural in general and no data on the use of epidural adrenaline in particular precluding a reliable power calculation. Based on data from this explorative study a statistical power calculation will define size requirement in a future trial.

Results
Forty-one patients were included in the study. Two patients were excluded due to malfunctioning epidural catheter (no pain relief after placement). Furthermore, three patients were excluded from analysis due to bad measurement quality, leaving 18 in the adrenaline group and 18 in the control group for analysis (Fig. 1).
Baseline data, including blood pressure between contractions were similar between groups, and are presented in Table 1. There were no significant differences in the temporal development in either systolic blood pressure (mean change 0.23 mmHg.min − 1 95% CI [-0.17; 0.64] p = 0.26) or cardiac output (mean change 0.0029 L.min − 1 per minute 95% CI [-0.026; 0.032 p = 0.84) at peak contractions between groups (Fig. 3, Table 2). Furthermore, there were no significant differences in temporal development of heart rate (mean change 0.015 beats.min − 1 per minute 95% CI [-0.25; 0.28] p = 0.24) between groups ( Table 2). There were no significant differences in neonatal outcomes at birth, including Apgar score and umbilical blood gas values (Table 3). There were no significant differences in obstetrical outcomes such as mode of delivery (p = 0.11) or length of labor after epidural placement (p = 0.54) ( Table 3). Pain scores at contraction after epidural activation declined similarly in both groups (Fig. 4).

Discussion
We found no significant differences in hemodynamic changes when adding adrenaline 2 µg.ml − 1 to the epidural solution. The initial dose of adrenaline was 10 + 10 µg, followed by an infusion of 10 µg.h − 1 . Theoretically, this dose, if quickly absorbed systemically would most likely have influenced heart rate, cardiac output and systolic blood pressure.
To put the statistical results into a clinical context, our data suggest that with 95% certainty, the true mean change in peak systolic blood pressure due to adrenaline is between − 1.7 and − 6.4 mmHg during a course of ten minutes. The corresponding values for peak cardiac output and heart rate were respectively − 0.26-0.32 L.min − 1 and − 2.5-2.8 beats.min − 1 . These values seem clinically insignificant when put in to the context of fairly large hemodynamic fluctuations occurring with uterine contractions.
As expected, the participants showed great hemodynamic fluctuations before epidural activation, as indicated by the baseline tracing on our example in Fig. 3. It is interesting to note that these fluctuations were not attenuated after epidural activation, even though our participants showed a marked decrease in pain scores. This is consistent with previously reported data from an observational study [4], and from a case report However, most of these studies used intermittent measurements, and did not include data of cardiac output and did not identify the peak values. The data presented in this article shows that there are large hemodynamic fluctuations during uterine contractions, emphasizing the need for a continuous measurement to fully identify and evaluate the peak of the hemodynamic strain. A future study should take this into consideration.
As described above, there was no reliable data for a proper power calculation to be performed, thus one of the goals of this secondary analysis was to provide data for a larger and more definitive trial. In order to design a trial which examines the potential effects of adrenaline on the peak systolic blood pressure during uterine contractions, we averaged the last three peak systolic values in the control group resulting in average values of 140 with a standard deviation of 20. If a minimal clinically relevant difference of 10 mmHg is considered and with a significance level of 5% and a power of 80%, a total sample size of approximately 125 is required. We observed a mean difference in peak systolic blood pressure of only 0.065 mmHg change per minute. Theoretically, based on these observations, a new RCT powered to test the potential effect of adrenaline after 20 minutes would have required more than 10,000 participants.
The Nexfin device is as mentioned above validated for blood pressure in pregnant women, but not for cardiac output. As noted by Hofhuizen et al, [18] the strength of the Nexfin system is in tracking changes in cardiac output rather than absolute values, which was the main goal of this study. None of the validation studies have been performed on laboring women with rapid changes in hemodynamic parameters and this limitation should be taken into account when interpreting the study results. However, heart rate is a reliable variable, closely related to CO, and was equal in both treatment groups.

Conclusions
In conclusion, in our study, the addition of adrenaline 2 2 µg.ml − 1 to bupivacaine 1 mg.ml      Supplementary Files