In this retrospective cohort study, a single dose of chlorpheniramine administered before the induction of anesthesia did not attenuate EA in adult patients undergoing ureteroscopic stone surgery with desflurane anesthesia. In addition, 8 mg chlorpheniramine administered before the induction of anesthesia did not affect the requirement for desflurane during surgery or the changes in mean blood pressure and heart rate during emergence.
The etiology of EA is not known. EA has been reported more often in the context of the use of newer, short-acting halogenated compounds, such as desflurane and sevoflurane, than with the use of other inhaled anesthetics [15]. Proposed hypotheses for EA seen with desflurane use include rapid emergence with insufficient time to adjust to the strange environment, late recovery of cognitive function compared with other brain functions resulting in altered cognitive perception, increased pain sensation, and activation of the sympathetic nervous system [16].
Although the etiology of EA remains unknown, extended duration of surgery, CRBD, PONV, anticholinergics, type of surgery (e.g., otolaryngological and oral cavity surgeries), pain, and the presence of invasive devices (e.g., urinary catheter, tracheal tube, or chest tube) contributed to EA in adult patients undergoing general anesthesia [2]. Drugs that prevent EA include propofol, N-methyl-D-aspartate receptor antagonists (e.g., magnesium sulfate, ketamine, and tramadol), α2-adrenoreceptor agonists (clonidine and dexmedetomidine), and µ-opioid agonists (e.g., fentanyl and remifentanil); these drugs have sedative and/or analgesic effects in common [13].
Antihistamines are among the drugs used most commonly during the perioperative period [17], and some researchers have recommended routine prophylaxis with an antihistamine to prevent life-threatening histamine-related consequences after the induction of anesthesia [18]. Depending on their impacts on the central nervous system (CNS), H1 antihistamines are classified into first-generation sedating antihistamines and second-generation antihistamines that provide less or no sedation [6]. First-generation antihistamines act on central and peripheral H1 receptors, and second-generation antihistamines have high affinity and selectivity for peripheral H1 receptors [6]. Thus, second-generation antihistamines are less anticholinergic, with fewer adverse CNS effects, than are first-generation antihistamines, but no injectable formulation is available due to their low aqueous solubility [7]. Chlorpheniramine can be administered intravenously and can be used in patients who are scheduled to receive general anesthesia that requires fasting.
Chlorpheniramine is a first-generation H1 receptor antagonist (H1 antihistamine) and one of the most potent antiallergic agents in the alkylamine group; thus, it is commonly used to prevent or treat hypersensitivity and allergic reactions [8]. In addition, chlorpheniramine has sedating, antinociceptive, antiemetic, anti-inflammatory, and antimuscarinic effects [9, 19]. These effects are expected to have a positive influence on EA, but chlorpheniramine did not reduce EA in this study. Possible explanations are as follows. First, although chlorpheniramine provides a sedative effect by penetrating the blood–brain barrier and acting on central H1 receptors, it can impair cognitive and psychomotor performance, cause problems with coordination, and, paradoxically, cause excitability and restlessness, even at therapeutic doses [6]. These effects contribute to EA by further delaying the recovery of cognitive function after desflurane anesthesia. Second, previous studies have shown that anti-inflammatory and antimuscarinic agents (e.g., paracetamol, oxybutynin, tolterodine, glycopyrrolate, and butylscopolamine) reduce CRBD [20, 21], but the effects of chlorpheniramine on CRBD have not been verified. The antimuscarinic effects of chlorpheniramine are weak [7]; thus, this drug may not reduce CRBD. In addition, chlorpheniramine acts on serotoninergic and cholinergic receptors, which can cause adverse effects, such as dizziness, tinnitus, anxiety, blurred vision, problems with concentration, dry mouth, and difficulty urinating [22]. These adverse effects would act negatively on EA. Third, in this study, postoperative NRS scores for pain were low (medians = 1 and 2) in both groups, and only a few patients in the control group complained of PONV. These findings suggest that postoperative pain and PONV are not important risk factors for EA in patients undergoing ureteroscopic stone surgery. Consequently, the antinociceptive and antiemetic effects of chlorpheniramine do not appear to contribute to the attenuation of EA.
The incidence of EA in this study was lower than the 63.5% reported in patients with urinary catheters [3]. This difference may reflect the evaluation of EA only in patients undergoing ureteroscopic stone surgery, which causes less postoperative pain, in this study, whereas previous studies included patients undergoing various types of surgery known to be associated with high risks of EA, such as oral cavity, otolaryngological, and orthopedic and abdominal surgeries [2, 3]. In contrast, the incidence of EA in our study was more than double that of 9.8% reported in patients undergoing urological surgery [4]. However, not all patients in that study had urinary catheters, and some patients had surgery under general anesthesia comprising total intravenous anesthesia (TIVA) and/or induced with a supraglottic airway device [4]; TIVA is a protective factor against EA [23], and the use of a supraglottic airway device may have induced less EA than would the use of an endotracheal tube [24].
In a previous study, intravenous chlorpheniramine (8 mg) caused no significant hemodynamic change during anesthesia [17]. However, EA itself can cause hemodynamic changes (e.g., hypertension and tachycardia) by increasing the sympathetic tone during emergence [13]. In this study, the mean blood pressure and heart rate during emergence did not differ between groups, supporting the lack of a significant difference in EA between groups.
The effect of the difference in anesthesia depth according to differences in inhalation anesthetic concentrations on EA is controversial [25, 26]. In a randomized controlled trial, the difference in depth of sevoflurane anesthesia did not affect EA in pediatric patients [25], but the effect of desflurane dose on EA in adult patients was unclear. In this study, desflurane concentrations were adjusted under PSi monitoring in both groups, and the highest and lowest desflurane doses during anesthesia were comparable between groups. Thus, the effect of the difference in anesthesia depth on EA could be excluded.
This study has some limitations. First, all patients received 1–2 µg/kg fentanyl during the induction of anesthesia. In a meta-analysis of data from 3,172 children, fentanyl showed a prophylactic effect against desflurane-related EA [27]. Thus, fentanyl may have contributed to the reduction of EA in both groups in this study. Second, in this retrospective study, chlorpheniramine was not administered for preventing EA. The effect of the drugs on EA may vary depending on the dose and timing of administration [2]. Therefore, prospective studies are needed in which the dose and timing of chlorpheniramine were set to prevent EA.