Prevention of sufentanil-induced cough during induction of general anesthesia by low-dose esketamine

Abstract

Background

Sufentanil is commonly used to induce general anaesthesia due to its rapid onset of action, strong analgesic effect, long-lasting effect, and stable haemodynamics; however, it often induces cough, increasing the risk of anaesthesia. This study aimed to investigate the preventive effect of low-dose esketamine on sufentanil-induced cough.

Methods

This randomised, double-blind, placebo-controlled clinical study was conducted at the Air Force Medical Center between September 2023 and May 2024. A total of 100 adult patients (ASA of Anaesthesiologists class I–II) required general anaesthesia for elective surgery. The patients were randomly assigned to two groups: the esketamine group (Group E, n = 50), receiving 0.2 mg/kg esketamine intravenously, and the control group (Group C, n = 50), receiving an equal volume of normal saline. The incidence and severity of sufentanil-induced cough were assessed 1 min after administering of 0.5 μg/kg sufentanil intravenously. Heart rate (HR), mean arterial pressure (MAP), and adverse reactions were recorded at four time points: before esketamine administration (T0), 3 min after esketamine administration (T1), 1 min after endotracheal intubation (T2), and 3 min after endotracheal intubation (T3). The results were analyzed using appropriate statistical methods.

Results

A total of 100 eligible patients were screened, of which 99 participated in this study (1 patient refused to participate), 50 in Group E, and 49 in Group C. The incidence of cough in Group E (6.0%) was significantly lower than that in Group C (34.7%) (P < 0.001), and the severity of cough was also significantly milder than that in Group C (P = 0.038). The differences in the HR and MAP levels at T₀, T₁, T₂, and T₃ between the two groups were not statistically significant (P > 0.05). Two patients in Group C experienced chest wall stiffness, while no adverse reactions were observed in Group E. The difference in the incidence of adverse reactions between the two groups was not statistically significant (P > 0.05).

Conclusion

Low-dose esketamine (0.2 mg/kg) can significantly reduce the incidence of sufentanil-induced cough during the induction of general anaesthesia in patients, with a small impact on haemodynamics, no adverse reactions, and good safety.

Introduction

Sufentanil is commonly used to induce general anaesthesia because of its rapid onset of action, strong analgesic effect, long-lasting effect, and stable haemodynamics. However, it is often accompanied by a relatively high incidence of adverse reactions, such as cough, chest wall stiffness, and respiratory depression, with cough being the most common adverse reaction [1]. According to relevant literature reports, the incidence of sufentanil-induced cough can reach 15%–47.1% [2, 3]. Although this symptom can resolve spontaneously in most patients without special treatment, it increases the risk of anaesthesia to a certain extent and compromises the comfort of anaesthesia. In addition, cough may lead to changes in intra-abdominal pressure in patients with a full stomach, which further increases the risk of regurgitation and aspiration during the anaesthesia induction period and can even be life-threatening in severe cases [4]. To reduce sufentanil-induced cough, various methods have been adopted in clinical practice, such as the use of superior laryngeal nerve block, which, however, is difficult to operate and prone to cause puncture injury [5], and the use of intravenous dexmedetomidine, diazoxide, ketamine, etc., which have a certain effect, but the side effects of these drugs limit their clinical application, for example, likely to prolong the induction time and increase the occurrence of nausea and vomiting, delirium, and other adverse reactions [6]. Therefore, exploring new effective drugs to prevent sufentanil-induced cough during the induction stage of general anaesthesia is of great significance for reducing the risk of anaesthesia and improving the patient experience of surgery. Esketamine is a new intravenous anaesthetic drug with pharmacological effects similar to those of ketamine, but it has a higher clearance rate and lower incidence of adverse reactions [7]. Studies have shown that low-dose ketamine can reduce fentanyl-induced cough during the induction of anaesthesia [8], and esketamine, as the S-enantiomer of ketamine, has a 2- to 3-fold higher affinity than ketamine for glutamate through the N-methyl-D-aspartate (NMDA) receptor, that is, twice the potency of ketamine. Although previous studies have investigated the use of ketamine and its S-enantiomer esketamine for reducing opioid-induced cough, this study uniquely evaluates the effectiveness of an ultra-low dose (0.2 mg/kg) of esketamine in preventing sufentanil-induced cough. Unlike earlier research, which predominantly focused on higher doses or different clinical settings, our study specifically examined the preventive effect of esketamine in the context of routine anaesthesia induction, with a focus on minimising side effects such as haemodynamic instability. This study also compared the safety profile of esketamine with that of a saline placebo in a controlled, randomised, double-blind design, providing new evidence for clinical practice.

Subjects and methods

Study population

This study was a randomized, double-blind, placebo-controlled clinical study, which was approved by the Ethics Committee of Air Force Medical Center (2022-115-YJ01), and the written informed consent was signed by all patients. The protocol was registered at Chinese Clinical Trial Registry (No.: ChiCTR2200061894). A total of 100 patients admitted to the Air Force Medical Center between September 2023 and May 2024 who required elective surgery under general anaesthesia were selected. The patients were classified as Class I-II according to the American Society of Anesthesiologists (ASA) classification, aged 18–65 years, and weighing 40–80 kg. Exclusion criteria were as follows: body weight exceeding the ideal body weight by more than 20%, hepatic and renal function impairment, increased intracranial or intra-abdominal pressure and intraocular pressure before surgery, combined asthma or upper respiratory tract infection, uncontrolled hypertension or hyperthyroidism, combined gastroesophageal reflux or cardiovascular disease, and long-term use of angiotensin-converting enzyme inhibitors, antidepressants, bronchodilators, or steroids. The 100 patients with ASA Class I–II were randomly assigned to two groups: the esketamine group (Group E, n = 50) and the control group (Group C, n = 50). Randomisation was conducted using a computer-generated randomisation sequence to ensure allocation concealment. The sequence was prepared by an independent statistician who was not involved in patient care or data analysis. Group assignments were placed in sealed opaque envelopes that were opened sequentially by an independent nurse immediately before administering the allocated intervention. This ensured strict adherence to the randomisation protocol and prevented selection bias.

Anesthesia methods

All patients were fasted for 6 h and abstained from drinking for 2 h before the operation, vital signs such as blood pressure and heart rate (HR) were routinely monitored, and intravenous access was established. Before anesthesia induction, patients in the esketamine group (Group E) received 0.2 mg/kg esketamine (diluted to 3 mL) via intravenous push injection within 5 s. Patients in the control group received 3 mL of normal saline via intravenous push injection within 5 s. At 1 min after completion of the injection, patients in both groups were given 0.5 μg/kg sufentanil via intravenous push injection within 5 s. At 1 min after the completion of sufentanil injection, the number of patients experiencing cough and the severity of cough in the two groups were observed. The severity of cough was graded as follows: no cough, 0 times; mild, 1–2 times; moderate, 3–4 times; and severe, ≥ 5 times. At 1 min after completion of sufentanil injection, midazolam 0.03 mg/kg, etomidate 0.3 mg/kg, and rocuronium bromide 0.6 mg/kg were given intravenously in sequence, regardless of whether the patient experienced cough or not. Anaesthesia maintenance: intravenous pumping of propofol at 4–8 mg/(kg·h) and remifentanil at 0.2–0.3 μg/(kg·min), and inhalation of sevoflurane at 0.5%–1%; the doses of the anaesthetic drugs might be adjusted, and vasoactive drugs might be used during the surgery according to the patient’s HR and blood pressure. In both groups, blood pressure and HR were maintained at ± 20% by adjusting the intravenous fluid infusion and using vasoactive drugs preoperatively. Intravenous anaesthetics were stopped at the end of the operation, and the tracheal tube was removed after TOFT4/T1 > 0.9 by train of four monitoring, and the patient was awakened. After removal of the tracheal tube, the patient was sent to the anaesthesia recovery room for further observation for 30 min and then sent back to the ward after meeting the criteria for leaving the anaesthesia recovery room. After surgery, all patients used patient-controlled intravenous analgesia (PCIA) (sufentanil 2 μg/kg diluted with normal saline to 120 ml, background dose: 2 mL/h, top-up dose: 1.5 mL, lockout interval: 15 min). The combination of propofol infusion and sevoflurane inhalation for the maintenance of anaesthesia provides the advantages of both agents. Propofol, administered via continuous infusion, ensures a stable and adjustable anaesthesia depth with quick recovery and limited residual effects after surgery. Sevoflurane, a volatile anaesthetic, complements propofol by offering additional control over the depth of anaesthesia and allowing rapid adjustment in cases of haemodynamic instability. This balanced approach helps maintain stable haemodynamics, reduces the total dose of each agent required, and can lead to smoother recovery. Combining these agents takes advantage of their synergistic effects, while minimising the side effects associated with higher doses of a single anaesthetic.

To ensure that the study remained double-blind, both patients and medical staff involved in the administration of the drugs, as well as those assessing the outcomes, were blinded to the group assignments. The esketamine and saline solutions were prepared and labelled by an independent pharmacist who was not involved in patient care or data analysis. The syringes containing the solutions were identical in appearance and volume and were administered by a separate anaesthesiologist who was unaware of the content of the syringes.

Observation indicators

The primary outcome measure of this study was the incidence and severity of sufentanil-induced cough, assessed at 1 minute after the completion of sufentanil injection. The severity of cough was graded based on the number of coughs, as follows: no cough (0 times), mild (1–2 times), moderate (3–4 times, lasting < 5 s), and severe (≥ 5 times, lasting ≥ 5 s). The secondary outcome measures included: (1) haemodynamic stability, assessed by comparing HR and MAP levels at four time points: before intravenous push injection of esketamine (T₀), 3 minutes after esketamine injection (T₁), 1 minute after endotracheal intubation (T₂), and 3 minutes after endotracheal intubation (T₃). (2) Adverse reactions such as chest wall stiffness and other complications were recorded throughout the study period.

Sample size calculation method

According to relevant literature, the clinical incidence of sufentanil-induced cough during anesthesia induction is about 35% [9], and the use of esketamine intervention can reduce the incidence of such cough to about 10%. Assuming α = 0.05 and β = 0.20, it can be calculated according to the formula of sample size estimation for comparing two independent samples: $n = 2\frac{{(u_{\alpha } + u_{\beta } )^{2} p(1 - p)}}{{(p_{1} - p_{2} )^{2} }}$ that n ≈ 43, and taking into account a dropout rate of 10%, n was taken as 50. Therefore, 50 subjects were included in each group, for a total of 100 subjects.

Statistical methods

The data to be analysed were imported into SPSS27.0 software. Measurement data were presented as mean ± standard deviation to describe the central tendency and dispersion of the data, an independent sample t-test was used for inter-group comparison, repeated data ANOVA was used for intra-group comparison, count data were presented as the number of subjects (%) to describe the distribution of the data, and the chi-square test was used for comparison. The results were considered statistically significant at P < 0.05.

Results

Demographics

The study was conducted between September 2023 and May 2024. A total of 100 eligible patients passed screening, of which 99 patients participated in this study (1 patient refused to participate), and the flow chart is shown in Fig. 1. Group E consisted of 29 males and 21 females and with a mean age was (38.60 ± 13.71) years, and Group C consisted of 31 males and 18 females and with a mean age was (37.02 ± 11.92) years. There was no statistically significant difference in the general information of the patients between the two groups, such as sex and age (P > 0.05), as shown in Table 1. The primary outcome measure of this study was the incidence of sufentanil-induced cough. The secondary outcome measures included the severity of cough, hemodynamic parameters (heart rate and mean arterial pressure), and the occurrence of adverse reactions. These outcomes were selected to evaluate the efficacy and safety of low-dose esketamine in preventing sufentanil-induced cough during general anesthesia induction.

Fig. 1

Flowchart of the participants enrollment

Table 1 Comparison of general information between the two groups

Comparison of the incidence and severity of cough between the two groups

The primary outcome measure of this study was the incidence of sufentanil-induced cough. The results demonstrated that the incidence of cough in patients in Group E (6.0%) was significantly lower than that in Group C (34.7%), with a statistically significant difference (P < 0.001). The secondary outcome measure included the severity grading of cough, which was also significantly lower in Group E compared to Group C (P = 0.038). These findings suggest that low-dose esketamine is effective in reducing both the incidence and severity of sufentanil-induced cough during general anesthesia induction, detailed data are presented in Table 2.

Table 2 Comparison of incidence and severity of cough between the two groups [n (%)]

Comparison of HR levels at different time points between the two groups

The results showed no statistically significant differences in HR levels between the esketamine group (Group E) and the control group (Group C) at T₀, T₁, T₂, and T₃ (P > 0.05). However, the interaction between time and HR levels exhibited a statistically significant difference (P < 0.05) between the two groups, indicating the potential influence of esketamine on HR changes over time. Detailed results are presented in Table 3.

Table 3 Comparison of HR levels at different time points between the two groups (bpm, $\overline{x} \pm s$)

Comparison of MAP levels at different time points between the two groups

The results showed no statistically significant differences in MAP levels between the esketamine group (Group E) and the control group (Group C) at T₀, T₁, T₂, and T₃ (P > 0.05). However, the interaction between time and MAP levels exhibited a statistically significant difference (P < 0.05) between the two groups, suggesting that esketamine may have an impact on MAP trends over time, detailed data are presented in Table 4.

Table 4 Comparison of MAP levels at different time points between the two groups (mmHg, $\overline{x} \pm s$)

Comparison of adverse reactions in the two groups

The results indicated that two patients in the control group (Group C) experienced chest wall stiffness, while no adverse reactions were observed in the esketamine group (Group E). Although the difference in the incidence of adverse reactions between the two groups was not statistically significant (P > 0.05), the absence of adverse reactions in Group E supports the safety profile of low dose esketamine in this clinical setting. Detailed data are summarized in Supplementary Material 1.

Discussion

The results of this study showed that the incidence of cough in Group E (6.0%) was significantly lower than that in Group C (34.7%), and the severity grading was also significantly lower in Group E, suggesting that low dose esketamine has a good preventive effect on sufentanil during the induction of general anesthesia.

Cough is a complex physiological response that is usually caused by changes in chemical or physical properties that irritate the trachea and bronchi. The mechanism of cough involves several physiological processes and neural pathways [10]. First, triggering of the cough reflex usually begins when an external stimulus comes into contact with the airway epithelium, such as a chemical irritant, dust, or allergen. These irritants lead to the transmission of nerve impulses by stimulating airway receptors, particularly the C-fibre terminals of the airway epithelium [11]. Next, these nerve impulses enter the medulla through the afferent fibres of the 5th cranial nerve (trigeminal). In the medulla, nerve impulses are further processed and regulated, which involves a complex neural network in the brainstem, particularly the medullary respiratory centre and brainstem cough centre [12]. Third, once nerve impulses are transmitted to the brainstem respiratory centre, they trigger a series of neural responses, including increases in the strength and frequency of contraction of the respiratory muscles, especially the diaphragm and intercostal muscles. This response leads to a rapid change in the gas volume in the lungs, which manifests as a cough [13]. Finally, the main purpose of the cough reflex is to clear irritants from the airway and to maintain airway patency. However, in some cases, this response can become hypersensitive or abnormally enhanced, leading to chronic cough or exacerbation of respiratory disease symptoms [14, 15].

In recent years, sufentanil has been used in the induction of general anesthesia due to its rapid onset of action, strong analgesic effect, long-lasting effect, and stable hemodynamics [16, 17], but several studies have pointed out that the use of sufentanil during the induction of general anesthesia can increase the risk of cough [18, 19]. He et al. found that the dose of sufentanil administered centrally or peripherally affects the risk of opioid-induced cough [20]. Wang et al. found that opioids induced different risk levels of cough, but no cough induced by sufentanil was observed [21]. Zou et al. noted that the incidence of cough within 2 s of sufentanil injection was 32% [22].

Currently, the mechanism of sufentanil-induced cough remains unclear; however, it is thought to involve increased vagal nerve excitation due to the inhibitory effects of opioids on the efferent portion of the central sympathetic nerves. Additionally, stimulation of pulmonary vascular receptors or vagal C-fibre receptor-mediated pulmonary chemoreactivity has been implicated, with histamine released from lung mast cells potentially contributing to airway smooth muscle contraction and cough reflex activation. While sufentanil-induced cough is multifactorial, esketamine appears to inhibit this response through the modulation of the N-methyl-D-aspartate (NMDA) receptor. By blocking NMDA receptor activity in the central nervous system, esketamine likely alters the neural transmission pathways that regulate cough reflex sensitivity and reduces the hyperexcitability induced by sufentanil. Furthermore, the ability of esketamine to stabilise the airway smooth muscle tone may mitigate the sensitivity of airway receptors to external stimuli. This dual action of central neural modulation and peripheral smooth muscle stabilisation distinguishes esketamine from other agents. Recent findings suggest that the rapid onset and short duration of action of esketamine provide effective cough suppression without prolonging anaesthesia induction or introducing haemodynamic instability. This unique pharmacological profile underscores the potential use of esketamine as a targeted intervention for opioid-induced cough. Future cellular and molecular studies could elucidate additional pathways, such as the potential impact of esketamine on inflammatory mediators or vagal afferent fibres, further advancing our understanding of its mechanism of action [23, 24].

First, sufentanil may affect the neuromodulation of the respiratory system by acting on multiple pathways in the central and peripheral nervous systems. Its actions include high-affinity binding to μ-opioid receptors, which inhibit modulation of the cough reflex in the central nervous system. This inhibition may lead to the accumulation of irritants in the airway, triggering a cough response. Second, sufentanil may indirectly modulate the cough reflex by affecting the contractile state of airway smooth muscle. Studies have shown that sufentanil can relax airway smooth muscle by activating the K-ATP and other ion channels, leading to airway dilation. This state of airway dilatation may increase the sensitivity of airway receptors, making them more sensitive to stimuli, which in turn triggers the cough response. Third, sufentanil may alter the regulation of respiratory control through its action in the central nervous system. This alteration may result in changed or abnormal respiratory rhythms, which may in turn interfere with the normal regulation and execution of the cough reflex. A clinical study found that the main cause of cough induced by sufentanil (1 μg/kg) may be related to reduced thoracic wall compliance, which can lead to adduction of the vocal cords, thus inducing a transient and violent cough [25].

While previous studies have demonstrated the effectiveness of lower doses of sufentanil in suppressing cough, higher doses of sufentanil during anaesthesia induction may offer enhanced analgesia and a more stable haemodynamic profile, which are essential for maintaining intraoperative stability. However, these benefits must be weighed against the increased risk of adverse effects such as cough, chest wall rigidity, and respiratory depression. Higher doses of sufentanil may be preferred in cases where stronger analgesic effects are required, particularly during longer or more invasive surgeries. However, the increased risk of cough and other side effects may necessitate the concurrent use of preventive measures, such as low-dose esketamine, to minimize these complications. In clinical practice, the use of higher doses of sufentanil can provide prolonged analgesia, reducing the need for additional opioid administration during surgery. However, the risk of side effects such as cough should be managed through adjunctive therapies, as demonstrated in this study with the use of low dose esketamine.

Several clinical trials have been conducted to reduce the incidence of sufentanil-induced cough using a number of different pretreatment medications. Esketamine is the S-enantiomer of ketamine and has similar pharmacokinetics to ketamine, but with twice the affinity for NMDA receptors, which means that a smaller dose of esketamine is required to achieve the same anaesthetic effect. Esketamine also has strong sedative and analgesic effects and milder adverse reactions [26, 27]. While the present study found no significant adverse reactions associated with low dose esketamine, it is noteworthy that other drugs used to prevent sufentanil could prolong the induction time and increase side effects such as nausea, vomiting, and delirium. Further research is necessary to comprehensively evaluate the safety profile of esketamine, specifically its potential to cause nausea, vomiting, or other central nervous system effects. Additionally, monitoring these adverse effects during clinical application is crucial, as they can impact patient recovery and overall experience. Future studies should concentrate on assessing these specific side effects to ensure a holistic understanding of the safety of esketamine compared with other interventions. The recommended dose of esketamine for anesthesia induction is 0.5 mg/kg, in some patients, this dose can cause increases in blood pressure and heart rate during surgery that require intervention. Therefore, the dose of esketamine for anaesthesia induction needs to be selected with caution [28]. In a study by Gao et al., 220 patients were enrolled and randomised to receive 0.15 mg/kg of esketamine or the same volume of normal saline, and the incidence and severity of cough within 1 min after sufentanil injection during the induction period were compared between the two groups. It was found that sufentanil could be reduced by pretreatment with a low dose of esketamine [29], which is in line with the findings of our current study. However, in this study, 0.2 mg/kg of esketamine was administered via intravenous push injection to observe its preventive effect on sufentanil-induced cough during the induction of general anesthesia, and the results showed that 0.2 mg/kg of esketamine also exhibited plausible preventive effect. The mechanism of this effect may be attributed to the regulatory effect on the central nervous system, which reduces the excitation of the cough response by sufentanil. By blocking the NMDA receptors, esketamine may reduce or alter the effects of sufentanil on respiratory control in the central nervous system, thereby reducing the incidence of cough. As a drug with a different molecular structure than sufentanil, esketamine may differ from sufentanil in its biological mechanism of action in the nervous system and airway, thereby affecting the mode of action of sufentanil in triggering cough response. This difference may help to reduce the incidences of adverse reactions, including cough, associated with the use of sufentanil [30, 31]. Meanwhile, the results of this study showed that there was no statistically significant difference in the HR and MAP levels at T₀, T₁, T₂, and T₃ between the two groups, which was consistent with the results of previous studies. This was probably because the sympathomimetic effect of esketamine could prevent the patient’s blood pressure from dropping drastically during the induction of anaesthesia, while cough occurring during the induction of anaesthesia could result in a transient but drastic increase in blood pressure as well as increases in heart rate and intracranial pressure.

This study has several limitations. Firstly, the sample size was relatively small, which may have introduced a statistical bias. Secondly, this study focused only on the immediate effects of low-dose esketamine during anesthesia induction and did not include long-term postoperative observations to evaluate the lasting effects of the intervention. Future research should incorporate extended follow-up periods to assess potential delayed adverse reactions, recovery profiles, and long-term impact of esketamine on patient outcomes. Additionally, the preventive effects of other esketamine doses should be analysed in larger and more diverse patient populations to provide a more comprehensive understanding of its clinical utility.

Conclusion

This study demonstrates that low-dose esketamine (0.2 mg/kg) is an effective and safe option for reducing the incidence and severity of sufentanil-induced cough during the induction of general anaesthesia. It has minimal impact on haemodynamics and does not cause significant adverse reactions, making it a reliable preventive measure in clinical practice.