Gastrointestinal endoscopy is a common procedure for prevention, diagnosis, and treatment of a variety of symptoms and diseases of the stomach and lower digestive tract. Sedation or anesthesia is an important means to increase comfort and decrease anxiety, discomfort and pain during the endoscopic maneuver [9]. Propofol is a satisfactory intravenous anesthetic due to its short half-life, fast emergence from anesthesia, and low incidence of nausea and vomiting. It is widely used in outpatient gastrointestinal endoscopic procedures for sedation and/ or anesthesia without increasing cardiopulmonary adverse events compared to conventional agents [10]. It has a very narrow therapeutic window, which can easily progress from moderate to deep sedation or general anesthesia without a reversal agent [11]. Thus, anesthetists must be meticulous for the side effects of propofol, including injection pain, hypotension, bradycardia, and low SpO2 [12]. In our study, the administration of intravenous propofol combined with fentanyl, as the anesthetic agent, resulted in a high incidence of low SpO2 (34.5%). Despite the respiration-assisted techniques and airway management available to ensure patients’ safety, decreasing the incidence of low SpO2 without affecting the quality of anesthesia is of interest to clinicians [13]. Intravenous propofol is routinely combined with a small dose of fentanyl and/or midazolam to assist in sedation and analgesia during colonoscopies on the grounds of its short analgesic effects [14,15,16]. Fentanyl, a synthetic opioid analgesic, has good analgesic effects at small doses. It is fast-acting and results in fewer low SpO2. Fentanyl is often administered in outpatient painless colonoscopy in combination with propofol to reduce propofol consumption, promote emergence and abridge theater stay. Unfortunately, both propofol and fentanyl may result in low SpO2. Thus, the combined application may render patients at increased risk of low SpO2. On the contrary, doxapram, a fast and short-acting respiratory stimulant, may reduce the incidence of low SpO2 from propofol and fentanyl [17], and is frequently applicable to low SpO2 due to anesthesia or central inhibition [18]. Moreover, doxapram can also serve as an analeptic after general anesthesia, such as sevoflurane inhalation [19].
Our results revealed that SpO2 was significantly increased at 1, 2, and 3 min subsequent to propofol injection in the group treated with doxapram compared to the saline-treated group. We also observed a decreased incidence of low SpO2, oxygen inhalation with a face mask and jaw lifting in the group treated with doxapram compared to the saline-treated group. These outcomes may be related to the effect of respiratory stimulation of doxapram and its action duration. Doxapram can reflexively stimulate the respiratory center via chemical receptors in the carotid body at low doses. At large doses, however, doxapram directly stimulates the respiratory center in the medulla oblongata [20]. S. Kruszynski et al. [21] attributed that part of the stimulatory effects of doxapram to the direct input on brainstem centers with differential effects on the rhythm generating kernel (PreBötzinger Complex) and the downstream motor output. Propofol acts as an agonist of γ-aminobutyric acid (GABA) receptor. GABAB activates the channel of K+ on postsynaptic membrane and leads to hyperpolarization of the latter. Doxapram blocks the K+ channel on postsynaptic membrane via Ca2+-dependent K+ conductance [22]. We speculated that this action might be one of the mechanisms underlying doxapram antagonizing the side effect of propofol. Our study demonstrated that doxapram could effectively alleviate the occurrence of low SpO2 during gastrointestinal endoscopy, thus providing improved safety of patients.
Despite the alleviation of low SpO2 by doxapram, precautions should be taken against the side effects whereby. Doxapram may induce headache, dyspnea, arrhythmia, diarrhea, nausea, vomiting, chest pain, and hypertension, etc., among which arrhythmia, dyspnea and hypertension are the most relevant and severe side effects. Notwithstanding the absence of adverse effects as arrhythmia, dyspnea and hypertension in this study, our small sample size did not suffice to reach a compelling conclusion for a risk-benefit balance of doxapram. Consequently, larger trials are required in order to verify the definite role of doxapram during general anesthesia for gastrointestinal endoscopy.
The development of hypotension and bradycardia in anesthesia is probably attributable to the effects of vascular dilation and myocardial inhibition by propofol on the gamma-aminobutyric acid receptors and the atrial muscarinic cholinergic receptors [23]. Doxapram causes transient tachycardia (1 min after injection), which may be related to the stimulation of catecholamine release via β1-receptor stimulation. In our study, even in the event of hypotension and bradycardia, doxapram may not have adequately exerted its reversive effects largely due to the relatively low dosage.
Doxapram is occasionally applied to promote emergence from volatile anesthesia, such as sevoflurane [19]. Our findings demonstrated that regardless of doxapram administration, all the 110 patients were discharged with a modified Aldrete–Kroulik index > 9 within 30 min, which indicated that doxapram did not affect the time required for emergence from anesthesia. We speculated that the inefficacy on emergence timing was due to the doxapram administered at the commencement rather than the denouement of anesthesia, as in the study by HL Wang et al. using total intravenous anesthesia with dexmedetomidine, propofol and remifentanil [24].
There are some limitations in our study. First, our results would have been more accurate provided that propofol delivery had been guided by the monitoring of anesthetic depth, as with a bispectral index for instance. Despite the same dose of doxapram we adopted for each patient, questions still remained as to whether the dose should be administered as per body weight. Second, we did not monitor ETCO2 as an element of respiratory depression and moreover we did not increase the flow rate of oxygen prior to application of face mask/jaw lifting or ventilation with constant flow rate for each patient, either. Furthermore, we did not employ SpO2/FiO2 ratio to evaluate respiratory depression, and we did not monitor for postoperative pulmonary complications for the patients in PACU. Nonetheless, with respect to the care of outpatients, early safe discharge from PACU is of importance for the improved medical efficiency and the medical care system at large, thus awaiting more profound investigations as to whether doxapram could decrease the emergence time in scenario of PACU.