Comparison of Intravenous Nalbuphine and Paracetamol on Maternal Hemodynamic Status, Neonatal APGAR Score, and Postoperative Pain given before Induction of General Anesthesia for Elective Cesarean Section.

BACKGROUND: Stress response to endotracheal intubation and surgery is associated with exaggerated hemodynamic response and an increase in catecholamine levels which is deleterious to both the mother and fetus. We aimed to compare the effects of intravenous nalbuphine and paracetamol on maternal hemodynamic status, neonatal APGAR score, and postoperative pain using the visual analog scale for elective cesarean section under general anesthesia. STUDY
DESIGN: This was a prospective, randomized, double-blinded clinical study.
MATERIALS AND METHODS: Sixty full-term pregnant patients, belonging to the American Society of Anaesthesiologist physical status Classes I and II, scheduled for elective cesarean section under general anesthesia were enrolled for the study. The patients were randomly allocated into two groups of 30 patients each to receive paracetamol (15 mg.kg- 1) in Group Pand nalbuphine (0.2 mg.kg-1) in Group N before induction of general anesthesia. Maternal heart rate, blood pressure, and oxygen saturation were recorded before infusion of study drugs, after induction, after intubation, and during surgery across all periods. APGAR score of neonates was recorded by a pediatrician. Time to reach visual analogue score-1 was recorded.
RESULTS: Significant attenuation of maternal hemodynamic response was observed with nalbuphine compared to the paracetamol group (P < 0.05). The time to achieve visual analogue score-1 in the postoperative period was higher in the nalbuphine group. APGAR score at 1 min was significant between the groups and at 5 min, nonsignificant difference was observed (P > 0.05).
CONCLUSION: Nalbuphine and paracetamol are effective in perioperative hemodynamic stability of mother and APGAR score of neonates. However, nalbuphine had better hemodynamic stability as compared to paracetamol with a comparable APGAR score at 5 min. Copyright:

INTRODUCTION

Nowadays, the central neuraxial blockade is the preferred technique for cesarean section. But, there are various conditions which are absolute indications for general anesthesia for cesarean sections like maternal refusal to the central neuraxial blockade, inadequate effect of a regional block, the urgency of cesarean section, allergic to local anesthetics and other contraindications to regional blocks like patients having coagulopathy and some other systemic disorders like cardiac brain, spinal cord and spine related problems.[1] Analgesia, amnesia, muscle relaxation, and the abolition of autonomic reflexes with the maintenance of homeostasis are the main components of balanced anesthesia.

Opioids are the analgesics of choice used during general anesthesia to achieve good anesthesia outcomes.[2] However, due to fear of the development of neonatal respiratory depression, these are not instituted before the delivery of the baby. During general anesthesia for cesarean, stimulation of sympathetic nervous system and catecholamine release occurs during endotracheal intubation which leads to an increase in blood pressure and heart rate (HR)[3] and may result in fatal arrhythmia and intracranial hemorrhage.[4] These effects are further aggravated by painful surgical stimuli and lead to altered homeostasis. Catecholamines, released due to stress response of endotracheal intubation and painful surgical stimulation, may lead to uterine vasoconstriction and decreased uteroplacental blood circulation and adversely affect the outcome of neonates.[5] Hence, prevention of stress response during intubation and surgical stimulation decreases the level of catecholamine and will be beneficial for mother and newborn.

Opioids have been used to minimize these responses to endotracheal intubation[6] and surgical stimulation under general anesthesia. However, due to fear of neonatal respiratory depression, these drugs are not routinely administered until the baby is delivered.[7] However, opioids such as alfentanil are being used in pregnancies with severe cardiac disease or hypertensive disorders of pregnancy to minimize the pressure response to intubation.[8] Other drugs being used for this purpose are lignocaine, magnesium sulfate, and β-blockers like esmolol and labetalol, but they lack analgesic properties.

Hence, there is a constant need for drugs having property to obtund the sympathetic response to endotracheal intubation and optimal analgesia for the perioperative period to avoid any untoward stress effect on the mother and neonate. Keeping all these things in mind, we aimed to compare the effect of nalbuphine and paracetamol given before the induction of general anesthesia for a cesarean section on the maternal stress response, neonatal outcome, and postoperative analgesia. Nalbuphine is a highly lipid-soluble agonist–antagonist opioid, potent analgesic, and having short duration of action and rapid clearance compared with other opioids and is less likely to cause side effects such as respiratory depression, excessive sedation, pruritus, and urinary retention.[910] Paracetamol has a well-established safety and analgesic profile[11] and is safe during pregnancy.[12] It acts at both central and peripheral points of the pain pathway, by direct inhibition of N-methyl-D-aspartate receptors and inhibition of the cyclooxygenase 2 pathway.

MATERIALS AND METHODS

After obtaining approval of the institutional ethics committee (749/UPUMS/DEAN/2019-20/E. C. NO: 12/2018) and written and informed consent from the patients, a randomized double-blind clinical trial was conducted at the department of anesthesiology of a tertiary care center during December 2018–June 2019. Sixty full-term pregnant patients in the age group of 18–40 years, belonging to the American Society of Anesthesiologist (ASA) physical status classes I and II, body mass index (BMI) 18–29 kg.m −2, posted for elective cesarean section under general anesthesia were enrolled in the study. Patients of ASA physical status Classes III and IV, hypersensitivity or allergy to any of the study drug to be used, BMI > 30 kg.m − 2, multiple gestations, having fetal distress, hypertensive disorder of pregnancy, preexisting cardiopulmonary disease, severe hepatic and renal insufficiency, and any medication likely to alter HR like monoamine oxidase inhibitor and affecting autonomic nervous system were excluded from the study. The preanesthetic checkup was done which included detailed history, general physical and systemic examination, and laboratory investigations. On the morning of surgery, all patients received 150 mg ranitidine and 10 mg metoclopramide 2 h before the induction of general anesthesia. In the operation theater, uterine displacement was achieved by tilting the table left side by 15° to avoid aortocaval compression syndrome due to gravid uterus. Standard monitoring devices such as electrocardiography, noninvasive blood pressure (NIBP), and pulse oximetry were attached and baseline values of HR, mean arterial pressure (MAP), oxygen saturation (SPO2), and respiratory rate were recorded. Intravenous access was secured with 18 G intravenous (i.v.) cannula and lactated ringer's solution was infused at 10–20 ml.kg − 1 in all patients. All patients were preoxygenated with 100% O2 for 3 min and the study drug was administered randomly to one of the two study groups:

Group P (n = 30): Received paracetamol 15 mg.kg − 1 body weight in 100 ml NS and infused over 5 min.

Group N (n = 30): Received nalbuphine 0.2 mg.kg − 1 body weight in 100 ml NS and infused over 5 min.

Drugs were prepared by the anesthesia technician and the identity of the solution was not revealed to the patient and anesthetist who was recording the data.

The study drug (either solution Group P or Group N) was infused and completed 1 min before the induction of general anesthesia. All patients were induced with injection thiopentone 5 mg.kg − 1 body weight and relaxed with injection succinylcholine 1.5 mg.kg − 1 body weight to facilitate endotracheal intubation. Following endotracheal intubation, anesthesia was maintained with 0.7% isoflurane in 50% nitrous oxide with 50% oxygen mixture and atracurium 0.5 mg.kg − 1 was administered as a muscle relaxant.

Monitoring of vitals including systolic blood pressure, diastolic blood pressure, MAP, HR (beats.min −1), SpO2, and EtCO2 (end tidal carbon dioxide) was recorded before and after infusion of either solution, after intubation at 0, 1, 5, 10, 15, and 30 min, just after extubation, and at visual analogue score-1 (VAS-1).

Time to achieve VAS-1 was recorded using visual analog scale [Figure 1] to know the requirement of rescue analgesia for postoperative pain. The induction-delivery time (I-D) and uterine incision-delivery time (U-D) were recorded. After delivery of the baby, 5 international unit (IU) of the oxytocin was administered slowly and oxytocin infusion of 10 IU in 500 ml RL was started in both the groups to sustain uterine contraction. Intraoperatively, if any patient has increased HR and NIBP both by >20% from the baseline despite maintaining an adequate depth of anesthesia, fentanyl in the dose 1 μg.kg − 1 was given and that patient was excluded from the study. After completion of the surgery, residual neuromuscular blockade was reversed using neostigmine and glycopyrrolate. After the extubation, the patient was shifted to the recovery room. The data collection and monitoring of study parameters were done by an anesthetist who was blind to the study. Neonatal APGAR scores at 1 and 5 min after delivery were recorded by the pediatrician.

Figure 1

Visual analog scale

Sample size

The sample size required for the study was determined based on the 95% confidence interval, study power of 80%, the standard deviation for visual analog scale (VAS) 1.1 in nalbuphine group and 1.4 in paracetamol group, standard error of 1, and referring to previous similar studies, a total of 60 patients were required (30 patients per group).

Statistical analysis

All the data were compiled systematically and analyzed using mean, standard deviation, and cross-tabulations. The statistical analysis of quantitative data (mean ± standard deviation) between the groups was done by unpaired Student's t-test. To find the significance in categorical data, a Chi-square test was used. All the statistical calculations were done through IBM SPSS Statistics for Windows, Version 24.0. (Armonk, NY: IBM Corp.). P < 0.05 was considered significant.

RESULTS

Sixty full-term pregnant patients requiring general anesthesia for cesarean section were recruited for the study and none was excluded as shown in Consort chart [Figure 2]. Both the groups were comparable in terms of age, BMI, and ASA physical status classification, I-D time, and U-D time [Table 1]. Heart rate (HR) in both the groups was comparable (P > 0.05) in the preoperative period, after the administration of the study drugs, and during induction of general anesthesia. A statistically significant difference in HR between the two groups was recorded just after intubation (0 min) and at 1, 5, 10, 15, and 30 min of intubation and at visual analogue score-1. The mean value of the HR was lower in the nalbuphine group during surgery compared to the paracetamol group [Table 2]. MAP in both the groups was comparable in the preoperative period and after the administration of study drugs and induction of general anesthesia. A statistically significant difference in MAP between the groups was recorded just after intubation (0 min) and at 1, 5, 10, 15, and 30 min of intubation and at visual analogue score-1. The mean value of MAP was lower in the nalbuphine group compared to the paracetamol group during surgery and till the attainment of visual analogue score-1 [Table 3]. Oxygen saturation was comparable between the groups at baseline and remained nonsignificant in the perioperative period across the time (P > 0.05) [Table 4]. APGAR scores after 1 min of delivery in Group Pand Group N were 9.03 ± 0.81 and 6.96 ± 0.92, respectively, and the difference was statically significant (P < 0.05), but APGAR scores at 5 min for Group Pand Group N were 9.86 ± 0.35 and 9.60 ± 0.50, respectively, and the difference was observed to be nonsignificant (P > 0.05) [Table 5]. Time to achieve VAS-1 in the postoperative period in the nalbuphine group (60.33 ± 6.07 min) was significantly higher as compared to paracetamol (40.76 ± 7.37 min) group (P = 0.001) [Table 6].

Figure 2

Consort diagram

Table 1

Maternal Demographic Profile in Both Groups (n=30)

Study group	Mean±SD		T	P
	Group P	Group N
Age (years)	25.53±4.78	24.73±3.45	0.74	0.46*
BMI (kg/m2)	22.46±1.48	22.43±1.51	0.06	0.95*
I-D (min)	16.3±3.4	15.6±3.8	0.75	0.45*
U-D (s)	81±31	84±33	0.36	0.72*
ASA (I/II)	26/4	27/3	χ2=0.1617, P=0.687*

*Nonsignificant (P>0.05), n=Number of patients in each group, SD=Standard deviation, BMI=Body mass index, ASA=American Society of Anesthesiologist

Table 2

Comparison of maternal heart rate variations in both groups (n=30)

HR (beats.min−1)	Mean±SD		t	P
	Group P	Group N
Baseline	81.17±9.33	82.90±12.24	0.62	0.54*
After administration of the study drug	82.10±8.23	81.77±11.73	0.64	0.53*
After induction	83.70±10.31	83.90±10.17	0.76	0.94*
After intubation
0 min	99.40±6.65	93.87±10.07	2.511	0.015**
1 min	97.93±6.62	92.97±8.45	2.536	0.014**
5 min	96.16±8.13	91.67±7.36	2.246	0.03**
10 min	93.66±8.09	89.00±6.63	2.44	0.018**
15 min	90.33±7.84	85.50±7.34	2.465	0.017**
30 min	89.20±8.28	84.63±7.72	2.209	0.03**
Extubation	97.30±8.16	91.63±7.73	2.76	0.008**
HR at VAS-1 (in postoperative period)	96.56±9.71	92.33±4.83	2.138	0.037**

**Significant (P<0.05), *Nonsignificant (P>0.05), n=number of patients in each group, VAS=Visual analogue score, HR=Heart rate, SD=Standard deviation

Table 3

Comparison of maternal mean arterial pressure in both groups (n=30)

MAP (mmHg)	Mean±SD		t	P
	Group P	Group N
Baseline	84.10±9.17	82.86±7.87	0.56	0.58
After administration of Study drug	82.63±8.60	81.13±6.58	0.76	0.45
After induction	67.86±9.34	76.56±7.60	0.14	0.89
After intubation
0 min	100.90±10.04	94.06±8.81	2.8	0.007**
1 min	81.50±9.32	90.13±7.19	2.96	0.004**
5 min	93.53±6.70	87.73±7.50	3.15	0.003**
10 min	90.70±7.43	85.26±8.53	2.62	0.011**
15 min	86.90±7.78	82.90±6.24	2.19	0.032**
30 min	86.63±7.05	82.56±6.00	2.41	0.019**
Extubation	96.43±9.75	90.93±7.73	2.42	0.02**
MAP at VAS-1 (in postoperative period)	93.46±7.30	89.36±5.93	2.28	0.026**

**Significant (P<0.05), n=Number of patients in each group, SD=Standard deviation, VAS=Visual analogue score, MAP=Mean arterial pressure

Table 4

Comparison of oxygen saturation variations in both groups (n=30)

SPO2 (%)	Mean±SD		t	p
	Group P	Group N
Baseline	99.96±0.18	99.90±0.30	1.03	0.31*
After administration of the study drug	99.76±0.50	99.86±0.43	0.82	0.41*
After induction	99.76±0.43	99.80±0.40	0.31	0.75*
After intubation
0 min	99.73±0.52	99.23±1.90	1.386	0.171*
1 min	99.76±0.43	99.53±0.62	1.677	0.099*
5 min	99.56±0.56	99.63±0.71	0.399	0.692*
10 min	99.56±0.68	99.70±0.53	0.845	0.402*
15 min	99.43±0.78	99.70±0.60	1.495	0.140*
30 min	99.83±0.37	99.53±0.73	1.997	0.056*
After extubation	99.83±0.37	99.56±0.68	1.878	0.065*

*Nonsignificant (P>0.05), SD=Standard deviation, n=Number of patients in each group, SPO2=Oxygen saturation

Table 5

Comparison of neonatal APGAR score in both groups (n=30)

APGAR score	Group P (n=30)	Group N (n=30)	T and P
At 1 min
3 or less	0	0
4-6	0	11
7-10	21	19
Mean±SD	9.03±0.81	6.96±0.92	8.521, 0.0001**
At 5 min
9-10	30	30
Mean±SD	9.76±0.30	9.60±0.50	0.428, 0.39*

**Significant (P<0.05), *Nonsignificant (P>0.05), n=number of patients in each group, SD=Standard deviation

Table 6

Time to achieve visual analogue score-1 in postoperative period in both groups (n=30)

	Mean±SD		T	P
	Group P	Group N
Time to achieve VAS 1 (min) postoperative period	40.76±7.37	60.33±6.07	11.22	0.001**

Sample t-test, **Significant (P<0.05) and P, n=Number of patients in each group, SD=Standard deviation, VAS=Visual analog score

DISCUSSION

Although regional anesthesia is the method of choice in the cesarean section, general anesthesia is administered in some situations such as fetal distress, coagulopathy, previous surgery of the spine, or mother's request.[13141516] The stress response to intubation and surgery with subsequent increase in catecholamines level has an adverse effect on the mother and may also adversely affect the fetus due to decreased uteroplacental blood flow.[17] There are many published controlled trials for the pharmacological modifications of the sympathetic response to laryngoscopy, tracheal intubation, and surgical stimulation including opioids, tenoxicam, ketorolac, lidocaine, and paracetamol.[18] The primary goal of the anesthesiologist is to minimize the stress response to intubation and surgery in the mother, with a minimal adverse effect on the fetus.[141516] Previously, paracetamol and nalbuphine had been studied separately for its effects on maternal hemodynamic variables, postoperative pain, and neonatal APGAR score during elective cesarean section. Nalbuphine was studied extensively in labor analgesia and was proved to be acceptable analgesics during delivery and its effect on neonates vary between studies, but its use as a premedication before induction of general anesthesia for cesarean section had not been studied. Hence, we planned a study to compare the effects of i.v. nalbuphine and paracetamol on maternal hemodynamic status, neonatal APGAR score Table 7, and postoperative pain, given before induction of general anesthesia for elective cesarean section.

Table 7

APGAR score

Sign	0 points	1 points	2 points
A=Activity (muscle tone)	Absent	Arms and legs flexed	Active Movements
P=Pulse	Absent	Below 100 bpm	Above 100 bpm
G=Grimace (reflex irritability)	No response	Grimace	Sneeze, cough, pulls away
A=Appearance (skin color)	Bluegray, pale all over	Normal, except for extremities	Normal over the entire body
R= Respiration	Absent	Slow, Irregular	Good, crying

In the present study, the increase in HR was less in the nalbuphine group compared to the paracetamol group during and after laryngoscopy and intubation and remained statistically significant during surgery at all periods. In line with our study, Amin et al.[9] observed significant attenuation of HR in the nalbuphine group compared to the control group given before induction of general anesthesia for cesarean section. In our study, the increase in MAP was significantly less in the nalbuphine group compared to the paracetamol group during laryngoscopy and intubation and persisted throughout the surgery. Another study was done by Ayatollahi et al.[19] for preoperative administration of i.v. paracetamol during lower segment cesarean section (LSCS) on hemodynamic variables relative to intubation, postoperative pain, and neonatal APGAR score and observed that paracetamol is effective in blunting the maternal stress response compared to the placebo group. Hossam I.E.A. Hasan[20] also reported that preemptive administration of paracetamol analgesic in LSCS is associated with better hemodynamic stability, especially before delivery of the baby (P < 0.001). This is in concordance with our study. However, paracetamol is less effective than nalbuphine in terms of maintaining hemodynamic stability. Solanki et al.[21] have conducted a comparative study between i.v. nalbuphine and tramadol in patients undergoing surgeries under regional or general anesthesia and concluded that nalbuphine is a better analgesic for the relief of moderate-to-severe postoperative pain and also provides good sedation, hemodynamic stability, and lower incidence of nausea and vomiting. Similarly, in our study, time to achieve VAS-1 in the postoperative period in the nalbuphine group was significantly higher as compared to the paracetamol group at all measuring periods. Another study done by Kumar et al.[22] on the effects of nalbuphine and tramadol in short surgical procedures and reported that nalbuphine is a better analgesic than tramadol and provides better relief of postoperative pain with good sedation, hemodynamic stability, and lower incidence of postoperative nausea and vomiting. In our study, the APGAR score was lower in the nalbuphine group at 1 min and was comparable at 5 min between the groups. This was probably a result of the rapid placental transfer of nalbuphine in neonates. This is in concordance to the study done by Amin et al.[9] who conducted a randomized double-blind study on maternal and neonatal effects of nalbuphine given immediately before induction of general anesthesia for elective cesarean section and observed significantly low APGAR score at 1 min in nalbuphine group than the control group (6.75 ± 2.3, 8.5 ± 0.74, respectively, P = 0.0002). All neonates at 5 min showed APGAR scores ranged between 9 and 10. Wilson et al.[23] also reported that nalbuphine used as a bolus for maternal analgesia during labor was associated with decreased APGAR and neonatal neurobehavioral scores compared to bolus meperidine, but others studies did not find any significant effect of nalbuphine on neonatal outcome.[2425] Another study was done by Nicolle et al.[26] who observed that nalbuphine placental transfer is high and its estimated half-life in the neonate is longer than in adult and two neonates had low APGAR score at 1 min and one of them had a score of 8, which improved spontaneously to 10 at 5 min and the other had score 3 and improved to 10 after resuscitation. Paracetamol is a safe drug during all stages of pregnancy and labor.[12] It belongs to an aniline analgesic class of drugs and is an active metabolite of phenacetin. Its chemical name is paraacetyl-amino-phenol. It has a well-established safety and analgesic profile. The main mechanism of action is inhibition of cyclo-oxygenase enzyme, which is responsible for the production of prostaglandins, an important mediator of inflammation and pain. The onset of action is within 5–10 min after the start of administration. Oral paracetamol is widely used as an over-the-counter nonopioid analgesic and antipyretic with few contraindications and lack significant drug interactions.[27]

CONCLUSION

From the present study, we concluded that nalbuphine and paracetamol reduce the maternal stress response related to intubation and surgery and maternal postoperative pain. Paracetamol reduces maternal stress response and postoperative pain and had normal neonatal APGAR score at 1 and 5 min, but nalbuphine provides better control on maternal stress response and postoperative pain except neonatal APGAR score at 1 min was lower, but APGAR score at 5 min was normal.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.