Abbreviations:

EA — epidural analgesia;

PCEA — patient-controlled epidural analgesia;

PCEA + CEI — patient-controlled epidural analgesia + continuous epidural analgesia);

PIEB — programmed intermittent epidural bolus;

PIEB + PCEA — programmed intermittent epidural bolus + patient-controlled epidural analgesia;

VAS — visual analogue scale;

LA — local anesthetic;

UOO — uterine os opening;

BMI — body mass index;

CVS — cardiovascular system;

SD — standard deviation;

SVR — systemic vascular resistance;

CO — cardiac output

Since the time of the ancestor Eve, all childbirth was painful according to the program accompanied her expulsion from paradise. This pain is considered one of the strongest that a woman has to experience throughout her life. Extensive development of epidural analgesia made it possible to facilitate childbirth. At the same time, this process caused a completely understandable desire in doctors to objectify the results of numerous options of this “magic” manipulation. Of course, sarcastic definition “pain is when it hurts” was no longer suitable for assessing the quality of pain relief. Nevertheless, introduction of various pain assessment scales no longer meets the challenges of researchers who want to understand deep mechanisms of epidural analgesia although these scales were useful in everyday clinical practice. Of course, numerous studies of stress hormones make a great contribution to evaluation of effectiveness of pain relief [1 — 3]. We assumed that analysis of N-terminal prohormone of brain natriuretic peptide type B (NT-proBNP) will allow us to evaluate the effectiveness of various modes of labor epidural analgesia and their role in regulating tension of compensatory cardiovascular mechanisms in a woman directly responding to pain syndrome and effectiveness of analgesia.

The purpose was to assess the levels of serum NT-proBNP depending on epidural analgesia technique in labor.

Material and methods

A prospective single-center randomized comparative clinical study was devoted to efficacy of various epidural analgesia modes in spontaneous labor on dynamics of NT-proBNP. The Ethics Committee of the Moscow Regional Research Institute of Obstetrics and Gynecology approved the study (protocol No. 85 dated April 19, 2016). We used the envelope method for randomization of patients. All women in labor were recruited into study groups as soon as they signed an informed consent. Six hundred and fifty-seven women in labor underwent long-term epidural analgesia between June 2018 and October 2019. The cohort study included 175 ones.

Inclusion criteria:

—spontaneous labor;

—programmed labor;

—regular labor activity;

—age 18 — 42 years;

—BMI 16 — 39.99 kg/m2;

—gestational age 37 — 41 weeks;

—parity: the 1^st, 2nd, 3^rd childbirth;

—ASA grade I—III;

—need for uterotonics;

—duration of labor stage 1: 4 — 12 hours;

—duration of labor stage II: 30 min — 2 hours.

Exclusion criteria:

—severe preeclampsia;

—absolute contraindications for vaginal delivery;

—spontaneous childbirth with antenatal death, fetal malformations, multiple pregnancy;

—spontaneous childbirth with uterine scar;

—deviations from the protocol (conversion to another variant of anesthesia);

—non-compliance with inclusion criteria;

—incorrect documentation.

Non-inclusion criteria:

—drug anesthesia of spontaneous childbirth (parenteral injection of narcotic analgesics);

—inhalation analgesia with sevoflurane for pain relief in spontaneous labor.

Overall characteristics of patients are presented in Table 1.

Table 1. Characteristics of study patients

The main criterion for EA onset of labor was stable labor activity (regular contractions of sufficient strength, every 2—3 minutes) regardless degree of uterine os opening. We used both early (UOO up to 4 cm) and late EA (UOO over 4 cm). After insertion of epidural catheter (L₂—L₃, L₃—L₄), the necessary concentrations of local anesthetic were injected into epidural space using certain infusion mode (PCEA, PCEA + CEI, PCEA + PIEB) and the Mini Rythmic Evolution infusion pump (Mikrel S.A., Greece). Parturient women were instructed to work with infusion pump. PCEA bolus was given whenever the patient had a VAS pain score > 40. The bolus delivery rate was 100 ml/h. In case of PIEB, the minimum time between automatic bolus (PIEB) and PCEA bolus was limited by lockout interval. Levobupivacaine was used as a local amide type anesthetic in the following concentrations: 2.5 mg/ml, 1.25 mg/ml, 0.625 mg/ml.

All parturient women were divided into 5 groups depending on injection mode and concentration of levobupivacaine:

—group 1 — manual boluses on demand (every 80-90 min) (levobupivacaine 0.25% — 10.0 ml);

—group 2 — PCEA, levobupivacaine 0.125% — 10.0 ml; lockout interval — 30 min;

—group 3 — PCEA + CEI; PCEA (levobupivacaine 0.125% — 10.0 ml — 30 min) + CEI (levobupivacaine 0.125% — 10.0 ml/hour);

—group 4 — loading dose: manual bolus of levobupivacaine 0.125% — 10.0 ml, then PCEA (0.0625% — 10.0 ml — 20 min) + CEI (0.0625% — 15 ml/hour) [4];

—group 5 — loading dose: manual bolus of levobupivacaine 0.125% — 10.0 ml, then PIEB (0.0625% — 9.0 ml — 45') + PCEA (0.0625% — 10.0 ml — 10 min) [4].

All groups were comparable in age, gestational age, methods of labor induction and timing of EA (Table 2).

Table 2. Characteristics of patients in all groups

Study endpoints

NT-proBNP was analyzed before anesthesia, 1 hour later and after complete UOO. Considering difficult blood plasma sampling in parturient women, we analyzed NT-proBNP nly in 50% of patients in each group (n=18).

Statistical analysis

We used mean and median of each variable, standard deviation, first and third quartiles, minimum and maximum values to study pooled trends, within-group variability and between-group differences. The vast majority of variables were characterized by abnormal distribution. Therefore, the Kruskal-Wallis test was used to compare all groups at each stage of the study. Post-hoc analysis was performed using the Nemenyi test only for those variables whose distributions reached significant between-group difference in the Kruskal-Wallis test. The Friedman test for dependent samples was used for within-group comparison of variables between various stages. Differences were significant at p-value < 0.05. Statistical processing was carried out using the Statistics 12.0 software and the R environment.

Results

Analysis of NT-proBNP during childbirth made it possible to study within- and between-group changes of this parameter.

Within-group analysis of NT-proBNP changes

Mean within-group trends and variability of NT-proBNP were in reference intervals throughout the study (Table 3, Fig. 1, 2) [5]. NT-proBNP distribution significantly deviated from the normal law. Therefore, we used medians and interquartile ranges to assess variability of this variable. However, means and standard deviations were also calculated and considered for comparative analysis of sample distributions at all stages of the study in all groups. The results for all 5 groups are presented in Table 3 and Fig. 1.

Table 3. Within-group variability of NT-proBNP

Fig. 1. Mean and medians of NT-proBNP in all groups throughout the entire follow-up period.

Fig. 2. Serum NT-proBNP throughout the entire follow-up period in all groups.

Mean values and medians of serum NT-proBNP throughout the entire follow-up period are summarized in Fig. 1.

In the 1^st group (manual bolus of levobupivacaine 2.5 mg/ml), median of NT-proBNP significantly increased throughout the entire follow-up period (Table 3, Fig. 2A). There were significant differences in distributions of values at different stages (p<0.0001).

Similar changes of NT-proBNP were observed in the 2nd group (PCEA, levobupivacaine 1.25 mg/ml). However, the increase delta was somewhat smaller (Table 3, Fig. 2B). Differences in distributions at different stages were also significant (p<0.0001).

In the 4^th group (CEI+PCEA, levobupivacaine 0.625 mg/ml), mean level of NT-proBNP also increased throughout the entire follow-up period. However, this increment in 1 hour after anesthesia was not as significant as in the two previous groups. Increment at the point of complete UOO was very significant (p<0.0001) (Table 3, Fig. 2C).

Similar changes of mean NT-proBNP were observed in the 3^rd (CEI+PCEA, levobupivacaine 1.25 mg/ml) and 5^th groups (PIEB+PCEA, levobupivacaine 0.625 mg/ml). One hour after anesthesia onset, decrease of mean serum NT-proBNP was observed. Complete UOO was followed by significant augmentation of this value (Table 3, Fig. 2D, E). All these changes were significant (p<0.0001 in the 3^rd group and p=0.0008 in the 5^th group, respectively).

Between-group analysis of serum NT-proBNP

Mean trends and variability of NT-proBNP were also within the reference intervals throughout the study in all groups (Table 4, Fig. 3).

Table 4. Between-group variability of NT-proBNP

Fig. 3. Between-group comparison of serum NT-proBNP at each stage of the study.

Before anesthesia (a), 1 hour after anesthesia (b), and labor stage II (c).

The highest baseline mean level of NT-proBNP was observed in the 1^st and 5^th groups, the lowest — in the 2nd group (Table 4, Fig. 3A). However, distributions had similar interquartile intervals and ranges (p=0.728).

We observed multidirectional changes of this indicator in an hour after anesthesia onset. Mean serum NT-proBNP increased in the 1^st, 2nd and 4^th groups and decreased below the baseline level in the 3^rd and 5^th groups (Table 4, Fig. 3C). Mean serum NT-proBNP was the highest in the 1^st and 4^th groups and the lowest and almost equal in the 2nd, 3^rd and 5^th groups. In the 5^th group, mean levels of NT-proBNP were compactly located near the median and significantly lower than in all other groups. Between-group differences of distributions were significant at this stage (0.002). Differences of medians were also significant (p=0.018).

By the stage of complete UOO, mean NT-proBNP significantly increased in all groups. The most significant increment was typical for the 1^st, 2nd and 3^rd groups while increase was less obvious in the 4^th and 5^th groups (Table 4, Fig. 3C). Distributions of NT-proBNP levels were not significantly different at this stage (p=0.704).

Conclusion

Combined techniques of epidural analgesia together with a low concentration of local anesthetic prevent hemodynamic decompensation in parturients as labor progresses to the end.

The authors declare no conflicts of interest.