DOI: https://doi.org/10.21203/rs.3.rs-1667379/v1
Backgroud: Postoperative nausea and vomiting (PONV) is one of the most common complication after thyroid surgery under general anesthesia. Propofol-based total intravenous anesthesia (TIVA) has been documented to prevent PONV in patients undergoing thyroid surgery. Penehyclidine, an anticholinergic agent with an elimination half-life over 10 hours, is widely used as premedication to reduce glandular secretion. This study was to explore the preventative effects of penehyclidine with propofol based TIVA to single-TIVA on PONV in patients undergoing thyroid surgery.
Methods: A total of 100 patients scheduled for thyroid surgery were randomly assigned into penehyclidine group or TIVA group. Propofol was used for TIVA in all patients. There were no patients who received premedication. Patients were administrated with 5ml of normal saline or 0.5mg of penehyclidin soon after anesthesia induction. The incidence of nausea and vomiting, severity of nausea, the requirement of rescue antiemetics, and adverse effects were investigated during the first 24 hours in 2 time periods (0-2 h and 2-24 h).
Results: The overall PONV incidence during the 24 h after surgery was significantly lower in the penehyclidine group compared with the TIVA group (12% vs 36%, P < 0.005). Besides, the incidence of nausea and vomiting were significantly lower in the penehyclidine group compared with the TIVA group at 2-24 h after surgery. However, there was no significant difference between the two groups at 0-2 h after surgery.
Conclusions: Penehyclidine with propofol based TIVA was more effective in PONV than TIVA, especially 2-24 h after thyroid surgery.
Trial registration: https://www.chictr.org.cn/edit.aspx?pid=132463&htm=4 (Ref: ChiCTR2100050278, the full date of first registration: 25/08/2021).
The thyroid is located near the esophagus and trachea. Within the proximity are relatively important blood vessels and nerves, including the internal jugular artery and vein, recurrent laryngeal nerve, and superior laryngeal nerve. Therefore, patients are prone to various complications after thyroid surgery, among which postoperative nausea and vomiting (PONV) is the most common complication. The occurrence of PONV in thyroid surgery is associated with many risk factors. The common risk factors include female, nonsmokers, PONV or motion sickness history, and the use of opioids. PONV increases the risk of aspiration of gastric contents, suture dehiscence, postoperative bleeding, and airway obstruction by hematoma, which may affect the surgical treatment and postoperative recovery time. The incidence of PONV after thyroid surgery is reported to be 60–80% when no prophylactic antiemetic is administered [1, 2].
Propofol-based total intravenous anesthesia (TIVA) has been documented to prevent PONV after various surgeries [1]. Besides, TIVA was recommend by recent guidelines recommend as an equivalent intervention to one single antiemetic in preventing PONV [2]. But the use of TIVA with a single-drug pharmacological prophylaxis such as 5-HT3 antagonists did not decrease PONV sufficiently across previous study [3].
Many drugs have been tried for prevention of PONV, and anticholinergics has been shown to be effective in this regard [4–6]. The recommended anticholinergic agent to prevent PONV is transdermal scopolamine patch [7, 8]. Other anticholinergic drugs for preventing PONV, such as glycopyrrolate and atropine, have been shown to be ineffective [9].
Currently, the effect of penehyclidine, a new anticholinergic agent with a long elimination half-life, has been proved to mitigate PONV in patients after strabismus surgery[10]. However, no data is used on penehyclidine as an antiemetic against PONV in patients undergoing thyroid surgery receiving TIVA. This study was to compare the preventative effects of penehyclidine with propofol based TIVA to single-TIVA on PONV in patients undergong thyroid surgery.
The study was approved by the Review Board of the First Affiliated Hospital with Nanjing Medical University (number 2019-SR-238) and the trial was registered at https://www.chictr.org.cn/edit.aspx?pid=132463&htm=4(Ref:ChiCTR2100050278,the full date of first registration: 25/08/2021). Written informed consent was obtained from all the subjects or their legal guardians. A total of 181 subjects, who were American Society of Anesthesiologist (ASA) physical status Ⅰ-Ⅱ and aged 24 ~ 64, scheduled for total thyroidectomy with central compartment node dissection years were screened. Exclusion criteria were body mass index of more than 30 kg/m2, smoking history, history of PONV or motion sickness, severe cardiopulmonary disease, history of hepatic or renal disease, medication with steroids, or cognitive impairment. The subjects requiring radical neck dissection were excluded because their operation time is longer than those of simple total thyroidectomy. All subjects were in a euthyroid state at the time of surgery. The same surgeon performed the thyroid surgery using similar techniques.
The patients were randomly allocated to the TIVA group or penehyclidine group by computer-generated randomization in a 1:1 ratio. All patients did not receive premedication before surgery. Each patient was monitored with electrocardiography, non-invasive blood pressure monitor, and pulse oximetry. General anesthesia was induced with propofol 1.5-2.5mg/kg and fentanyl 5µg/kg, and orotracheal intubation was performed after administration of cisatracurium 0.15mg/kg. Anaesthesia was maintained with propofol infusion at a rate of 60–200 µg·kg− 1·min− 1, and remifentanil infusion at a rate of 0.1–0.15 µg·kg− 1·min− 1 without the use of inhalational anaesthetics. Lactic Ringer's solution was infused at a rate of 10–15 ml/kg/h throughout the surgery. Mechanical ventilation was used with a tidal volume of 6–8 ml/kg and a frequency of 10–12 beats per minute to keep end tidal CO2 at 35–45 mmHg throughout the surgery.
The fresh gas was adjusted to 1 L oxygen to 1 L air with an oxygen concentration of about 60%. In the PACU, residual muscle relaxation was not antagonized by neostigmine and atropine.
The anesthesia nurse who prepared the drug/placebo mixtures according to the group assignment was not involved in this study. After anesthesia induction, 0.5 mg penehyclidine in 5 ml or an equal volume of 0.9% normal saline was administrated immediately in the penehyclidine and TIVA group, respectively.
A resident blinded to the treatment evaluated nausea and its severity, vomiting, postoperative pain, the requirement of rescue antiemetic, use of additional analgesics, and side effects at 2 and 24 h after surgery.
Patients were instructed before the operation. The intensity of nausea was based on a 10-point numerical rating scale (NRS: 0 = no nausea at all to 10 = the most severe nausea). The severity of nausea was described finally by NRS scores (mild 1–3, moderate 4–6, severe 7–10). The severity of pain was measured on a 10-point visual analog scale (VAS) (0 = no pain; 10 = most severe pain).
The patients who complained of severe nausea and/or vomiting were rescued by 3mg granisetron, and severe pain VAS score of more than 5 was treated with 40 mg of parecoxib.
The sample size was calculated based on the incidence of PONV (40%) with TIVA in the literature reviews [3, 11]. Assuming a 30% reduction in the incidence of PONV in penehyclidine group could be considered clinically significant. The value of α would be 0.05 with a power (1 – β) of 0.8. A total of 36 patients per group were required.
All values are expressed as mean ± standard deviation or percentage. Continuous variables were compared using the Student's t-test or Mann-Whitney U test according to the normality. Categorical variables were compared using the Chi-square test or Fischer’s exact test, as appropriate. Ranked data was compared using the Mann-Whitney U test. A P-value < 0.05 was considered statistically significant. SPSS software for Windows version 25.0 (IBM Corp., Armonk, NY, USA) was used.
A total of 181 patients were enrolled in this study and 100 patients completed the protocol between December 2019 and January 2021 (Fig. 1). The patient characteristics (including age, gender, body weight), operation data, and fentanyl consumption were statistically similar between two groups (Table 1).
|
Penehyclidine (n = 50) |
TIVA (n = 50) |
P value |
|
|---|---|---|---|
|
Age (yr) |
42.8 ± 9.6 |
43.6 ± 10.1 |
0.590 |
|
Gender (M/F) |
13/37 |
17/33 |
0.762 |
|
Body weight (kg) |
64.5 ± 11.2 |
65.3 ± 11.7 |
0.674 |
|
Body height (cm) |
165.3 ± 6.9 |
163.8 ± 7.5 |
0.473 |
|
Duration of surgery (min) |
76.6 ± 13.9 |
75.5 ± 15.5 |
0.171 |
|
Duration of anesthesia (min) |
95.9 ± 14.5 |
95.9 ± 16.7 |
0.104 |
|
Fentanyl consumption (mg) |
0.41 ± 0.05 |
0.42 ± 0.06 |
0.492 |
| TIVA: Propofol-based total intravenous anesthesia. Values are expressed as mean ± SD or ratio. There was no significant difference between two groups. | |||
The overall PONV incidence during the 24 h after surgery was significantly lower in the penehyclidine group compared with TIVA group (12% vs 36%, P = 0.005; Fig. 3). Besides, the incidence of nausea (10% vs. 32%, P = 0.007) and vomiting (4% vs. 24%, P = 0.009; Fig. 2) were significantly lower in the penehyclidine group compared with the TIVA group at 2–24 h after surgery. However, there was no significant difference between the penehyclidine and TIVA group at 0–2 h after surgery.
The overall PONV incidence 24 h after surgery, proportion of patients who required rescue antiemetic treatments, and severity of nausea were significantly lower in the penehyclidine group than in the TIVA group (6% vs. 24%, P = 0.025, Fig. 3; P = 0.001; Fig. 3).
There were no significant differences with total consumption of fentanyl, VAS pain score and the rescue analgesic requirement during the study period. There were also no significant differences in the incidences of dry mouth, headache and dizziness between the two groups (Table 2).
|
Penehyclidine (n = 50) |
TIVA (n = 50) |
P value |
|
|---|---|---|---|
|
Fentanyl consumption (mg) |
0.41 ± 0.05 |
0.42 ± 0.06 |
0.492 |
|
Pain score 0–2 h |
2.68 ± 0.96 |
2.66 ± 0.96 |
0.937 |
|
2–24 h |
1.48 ± 0.68 |
1.40 ± 0.70 |
0.563 |
|
Rescue analgesics |
4 (8) |
4(8) |
1.00 |
|
Dry mouth |
14(28) |
8(16) |
0.148 |
|
Headache |
9(18) |
8(16) |
0.790 |
|
Dizziness |
10(20) |
9(18) |
0.799 |
| TIVA: Propofol-based total intravenous anesthesia. Values are presented as mean ± SD or number (%) of patients. | |||
PONV is one of the most common complication and the most unpleasant aspect after thyroid surgery under general anesthesia. This complication can delay patient discharge from the hospital and increase the cost of care[12, 13]. Thyroid surgery, specifically is associated with a high incidence of PONV. The main cause of the high incidence of PONV after thyroid surgery is not thoroughly clear, but it is thought to result from the hyperextension of the neck and strong vagal stimulation [14]. Hyperextension of neck posture might lead to cerebral blood flow disorders which could cause central nausea and vomiting[15]. And strong vagal stimulation by surgical handling of neck structures might exacerbated the incidence of PONV [16, 17].
Muscarinic receptors are involved in PONV by various mechanisms [18, 19]. Golding et al. [20] reported that M3 and M5 acetylcholine receptors have been shown to reduce motion sickness, a risk factor of PONV. The vestibular system is densely packed with M1 receptors, and cholinergic transmission from the vestibular nuclei to the central nervous system centers and from the medullary reticular formation to the vomiting center is blocked by anticholinergics. Additionally, in thyroid surgery, surgical handling of neck structures strongly stimulates the vagus nerve in neck [21]. Anticholinergics have been shown to be effective to prevent PONV, and the recommended anticholinergic drug is scopolamine [7, 9]. Due to its short half-life, scopolamine is used as a transdermal patch before surgery.
Penehyclidine (2-hydroxyl-2-cyclopentyl-2-phenyl-ethoxy) is a new long-acting anticholinergic drug with anti-muscarinic and anti-nicotinic activities that has potent central and peripheral anticholinergic activities. It is widely used as a pharmacologic agent for organic phosphorus poisoning and preoperative medication, but its effect in PONV was unclear. Penehyclidine has greater selectivity for muscarinic 1(M1) and muscarinic 3 (M3) subtypes of acetylcholine receptors but no effect on muscarinic 2 (M2) subtype of acetylcholine receptors[22]. Its effect on PONV was expected given its mechanism of action. Previous reports showed that penehyclidine mitigated the incidence of PONV in patients after strabismus surgery[10] and gynecological laparoscopic surgery[23]. In our study, we also found that penehyclidine reduced PONV in patients undergoing thyroid surgery. In these surgeries, the draw reaction is a routine operation which may be related to the higher incidence of PONV.
The privious studies demonstrated that propofol prevent the incidence of PONV during the early 0–2 h postoperative period rather than late[3, 24],which is consistent with the results of our study. Our analysis shows that patients receiving TIVA had a higher incidence of PONV in the late postoperative phase, starting 2 h after surgery.
TIVA has been documented to prevent PONV after thyroid surgery. Apfel et al. [25]suggested that the risk factors between early PONV (< 2 h) and late PONV (2–24 h) are differ, inhalation or TIVA was not a risk factor of late PONV. A longer-acting antiemetic drug might be necessary to prevent late PONV after TIVA[24, 26]. Penehyclidine has a long elimination half-life (10.4 ± 1.22 h) which is longer than that of ondansetron (3.5 h) or granisetron (4.9 h) or ramosetron (9 h)[27, 28]. our study suggests that penehyclidine effectively reduced the late incidence of PONV (2–24 h) than early PONV (0–2 h) in patients after TIVA.
The main side effects of penehyclidine are dry mouth, headache and central anticholinergic syndrome. In the present investigation, none of the patients presented with central anticholine syndrome and there was no difference between groups in dry mouth, headache. These may possibly be explained by the limited dose of 0.5mg penehycline.
Potential risk factors contributing to PONV, such as etomidate and neostigmine were not administrated in in thyroid surgery. The gender of patients was mostly female, which was consistent with previous reports (female-to-male ratio 2–4:1) [29]. Besides, we strictly performed the randomization and double-blinded technique during the study.
A limitation of the current study should be noted. we anticipated that there would be about a 30% reduction between the two groups before our study. However, the actual reduction in overall PONV incidence was 24% (36% in TIVA group vs 12% in penehycline group, P = 0.005) during the 24 h after surgery. But the relative reduction rate of 30–40% in general PONV study is considered clinically relevant, the acquisition of a relative risk reduction of 67% in our study could be considered clinically significant [21, 30]. However, this operation was performed as a TIVA with propofol infusion. How high if using inhalational agents is unknown. Further studies are needed to research penehyclidine in more patients at more diverse surgical settings using different anesthetic techniques.
In conclusion, administration of penehyclidine after anesthesia induction based TIVA significantly reduces the incidence of PONV especially 2–24 h after thyroidectomy. Penehyclidine, a widely used preoperative anticholinergic agent, can be considered a as an effective anti-emetic protector in patients undergoing thyroid surgery.
PONV: postoperative nausea and vomiting; TIVA: Propofol-based total intravenous anesthesia; 5-HT3: 5-hydroxytryptamine.
Ethics approval and consent to participate
The research was carried out in accordance with relevant guidelines and regulations under ethics approval and consent to participate, and this study was approved by the Review Board of the First Affiliated Hospital with Nanjing Medical University (number 2019-SR-238). Written informed consent was got from all the subjects or their legal guardians.
Consent for publication
Not applicable
Availability of data and materials
The datasets are not publicly available due to the stipulations of ethics committee to protect individual privacy of patients but are available from the corresponding author on reasonable request.
Competing Interests
The authors declared that they have no competing interests.
Funding
Not applicable
Authors’ Contributions
JC contributed to study conception and design and drafted the article. TL, JS and RL contributed to clinical investigation and data collection. JC and TL contributed to statistical analysis.
Acknowledgements
Not applicable
Conflict of Interest statement
The authors declared that they have no competing interests.