Naloxone is a pure mu-opioid antagonist with a high affinity for the receptor. It can reverse both the analgesic and respiratory effects of opioids[12]. Naloxone may be administered intravenously, intramuscularly, subcutaneously and via an endotracheal tube. The dosage of intravenous naloxone is 1 mcg/kg to 2 mcg/kg every 2-3 min with a maximum dose of 0.1 mg/kg, up to 2 mg. Because of its rapid removal from the brain, naloxone has a short duration of action and one dose typically only lasts for 30-45 min. The patient should be monitored for at least 2 h after administration of naloxone to ensure that resedation does not occur. Potential adverse reactions of naloxone include reversal of opioid withdrawal, nausea/vomiting, hypertension, tachycardia, pulmonary edema and cardiac dysrhythmias.

Flumazenil is a benzodiazepine antagonist that can safely reverse the sedative and respiratory effects caused by benzodiazepines[1]. It is a highly specific benzodiazepine receptor antagonist. The usual adult dose is 0.01 mg/kg, up to 1 mg. Its clinical duration of action is approximately 1 h[12]. However, its effects are reversible, so it is not recommended for routine use. Similar to naloxone, patients should be monitored for at least 2 h after administration of flumazenil to ensure that resedation does not occur. Potential adverse reactions of flumazenil include sweating, flushing, nausea/vomiting, hiccups, agitation, abnormal vision, paresthesia and seizures.

A significant decline in blood pressure from baseline should alert clinicians. Hypotension is defined as systolic blood pressure less than 90 mmHg which is due to a fall in either cardiac output or total peripheral resistance, lowering the patient’s mean arterial pressure[14]. Episodes of hypotension in clinical practice are most commonly associated with vasovagal events and are generally transient. However, they may become prolonged in the presence of central nervous system depressants[1]. Blood pressure is a reflection of cardiac output and total peripheral resistance and a fall in either or both will lower the patient’s mean arterial pressure. In general, a systolic blood pressure of 90 mmHg should sustain mean arterial blood pressure sufficiently to perfuse tissues in the recumbent patient. Blood pressure lower than this, combined with evidence of inadequate perfusion, requires intervention.

The evaluation of tissue perfusion is the most significant component of cardiovascular assessment. Hypotension encountered during sedation is usually attributed to either vasovagal episodes or the use of sedative and anesthetic agents that depress sympathetic outflow to the cardiovascular system. Benzodiazepines, such as midazolam and diazepam, have a mild vasodilator effect and usually produce a slight fall in arterial blood pressure, even in normal sedative doses. The combination use of a benzodiazepine and an opioid can profoundly drop blood pressure. Propofol has been shown to be safe and effective for sedation during endoscopic retrograde cholangiopancreatography, endoscopic ultrasonography and small bowel enteroscopy because these procedures require more time and patient co-operation[15-19].

Cardiovascular effects of propofol include decreases in cardiac output, systemic vascular resistance and arterial pressure. A fall in heart rate and/or cardiac stroke volume will also lower blood pressure. Additionally, more profound falls in blood pressure occur in a hypovolemic patient. Propofol has also been proven to reduce post-procedural hypoxemic events, which may be of significance in critically ill elderly patients[20,21] and sick pediatric patients[22,23]. Prevention of this complication is to take a relevant medical and drug history before the procedure with particular detail required regarding current antihypertensives, antianginal and antiarrhythmic therapy and the use of systemic corticosteroids. The use of volume supplementation might be beneficial and could therefore be recommended in order to avoid propofol-induced hypotension. Additionally, blood pressure and heart rate should be recorded before, during and after the endoscopic procedure.

Blood pressure continuously fluctuates due to the cyclic nature of the pumping action of the heart. The highest pressure occurs during ventricular contraction. The lowest pressure occurs during ventricular relaxation[24]. Generally, hypertension is defined as the systolic blood pressure greater than 160 mmHg. Sudden elevations of systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg are generally regarded as an acute hypertensive episode[25]. The causes of hypertension are background systemic hypertension, anxiety or pain, and a reflex pressure response from intubation of the esophagus. Generally, asymptomatic patients and patients without acute end-organ symptoms should not receive antihypertensive agents in the endoscopy unit.

Autonomic control of the heart rate will respond to demands placed on the patient and may be initiated via several baroreceptor-mediated reflexes[20]. Electrocardiogram (ECG) is also a useful monitor for heart rate and a better assessment of heart rhythm. Continuous ECG monitoring is recommended for a high risk patient with relevant cardiac history. Cardiac arrhythmias are frequently observed during GIE procedures. Fortunately, most of them are not clinically significant.

In healthy patients, a heart rate of up to 120 beats/min will usually allow adequate filling. Sinus tachycardia can be caused by a patient’s anxiety or be related to pain, a compensatory mechanism in patients who are hypotensive as a result of either dehydration or blood loss, and following intravenous anticholinergic drugs such as buscopan. Heart rate < 50 beats/min in healthy patients may allow for more time in diastole, but ventricular filling becomes maximized[24]. Sinus bradycardia is most frequently seen in patients who are taking beta blockers. It can also be induced by vagal stimulation, which occurs at the time of intubation of the esophagus or the stretching of the sigmoid mesentery during colonoscopy or flexible sigmoidoscopy.

Myocardial infarction occurs either during or in the few days after endoscopic procedures with or without sedation. A proportion of these are undoubtedly causally related to the endoscopic procedure. The causes of angina or myocardial infarction are two factors: increased myocardial oxygen demand and reduced myocardial perfusion[26].

Increased myocardial oxygen demand is due to an increase in the mean arterial blood pressure and heart rate. This can cause angina in patients with ischemic heart disease or occult symptomless myocardial ischemia. Additionally, marked hypertension and/or tachycardia increase myocardial oxygen consumption. On the other hand, hypotension and/or bradycardia reduce myocardial perfusion. Stress-induced myocardial ischemia can occur even in patients with or without clinically significant coronary disease[27]. This myocardial ischemia is related to the activation of the sympathetic nervous system, resulting in hemodynamic changes causing an increase in cardiac demand.

Prevention or minimization of myocardial ischemia/infarction during GIE procedure: (1) pre-oxygenation in at risk patients and give continuous supplemental oxygen; (2) give patients their normal anti-hypertensive and/or antianginal therapy right up to the time of the endoscopy; (3) angina developing during an endoscopy is usually best managed by giving sublingual nitroglycerine, oxygen supplementation and discontinuing the examination; and (4) if angina or myocardial infarction is suspected during or following an endoscopy, arrange an ECG to exclude an myocardial infarction.

A higher dose of benzodiazepine and/or opioid and the greater the percentage benzodiazepine and/or opioid receptor occupancy in the central nervous system, the greater is the degree of depression of consciousness. Intravenous benzodiazepines such as midazolam and diazepam can cause respiratory depression. Intravenous opioids, such as meperidine and fentanyl, occupy opioid receptor sites within the brain and brainstem and can similarly cause respiratory depression[26]. Drug induced hypoventilation may cause both hypoxemia and carbon dioxide retention.

Pulse oximetry is a very useful indicator of oxygenation but not ventilation. However, when supplemental oxygen is used, the fall in SpO₂ may be significantly delayed for between 30-90 s, so continuous capnography monitoring is recommended in patients being deeply sedated with propofol[1]. As for over-sedation, loss of verbal contact due to a reduced conscious level may be the first sign of impending respiratory depression. Reduction in SpO₂ on pulse oximetry is a good indicator but it can be a late sign of respiratory depression. Increased PaCO₂ is the most sensitive early warning of respiratory depression[28]. However, several controlled randomized studies showed a beneficial effect of capnography regarding some surrogate parameters of patients, such as the occurrence of hypoxemia detected by pulse oximetry, but a clear effect on patient outcome has not been demonstrated. Therefore, most national guidelines do not recommend its routine use currently.

Management of over-sedation is to stimulate the patient, both verbally and/or by light shaking, to wake up and take deep breaths. If the patient is not responding, then a benzodiazepine antagonist such as flumazenil and/or opioid antagonist such as naloxone may be required. The airway may need to be protected with chin lift, jaw thrust and, if necessary, airway or laryngeal mask[26].

Obstruction may result in hypoventilation and hypoxia. However, airway obstruction must be distinguished from respiratory depression. Hypoxia is common in patients undergoing an upper GIE procedure with or without sedation. Sedation significantly increases the incidence of desaturation and hypoxia. Supplementary nasal oxygen at 3 L/min in sedated patients abolishes desaturation and hypoxia. Upper airway obstruction may be attributed to anatomical structures or a foreign body[29]. Independent predictors of airway modifications include male sex, ASA class of III or higher, and increased body mass index[1].

Laryngospasm is a reflex closure or spasm of the glottic muscles, including the false and true vocal cords. It is more likely to occur during deep sedation. Laryngospasm occurs more frequently in adults who are smokers. Bronchospasm is a lower airway obstruction due to contraction or spasm of the bronchial smooth muscle. It may be a result of an anaphylactoid reaction or a consequence of a hyper-reactive airway in asthmatic patients[30]. Management of laryngospasm and bronchospasm depends on the severity and the cause.

Hypoxia may be a consequence of respiratory depression or airway obstruction. The incidence of hypoxia is 1.5% to 70%, which makes it the most common cardiorespiratory complication during endoscopy[31]. Hypoxemia can lead to several complications, depending on the severity of hypoxemic attack. The use of supplemental oxygen during a GIE procedure is routinely used by many endoscopists. However, oxygen supplementation will delay the detection of apnea and hypoxia[5]. Additionally, in patients given supplemental oxygen, saturation may be maintained in the progression of hypercapnia.

Multivariable logistic regressions revealed that independent risk factors for hypoxemia include high body mass index, hypertension, diabetes, gastrointestinal diseases, heart diseases and procedures that combined esophagogastroduodenoscopy (EGD) and colonoscopy[32]. Hypoxemia occurs typically within 5 min of medication administration or endoscope intubation and only one third of all apnea and abnormal ventilation events eventually lead to hypoxemia[31].

Aspiration of gastric contents into the lungs during a GIE procedure is relatively common. It may cause pneumonia and may result in death. Risk factors for aspiration are the elderly, over-sedated patients, patients with gastrointestinal bleeding, gastric stasis, gastric outlet obstruction, hepatic encephalopathy and a full stomach. Aspiration can also occur when a local anesthetic spray is used in combination with intravenous sedation[26].

Aspiration may be suspected when a patient starts coughing violently either during or soon after an endoscopic procedure and cyanosis may occur. The higher incidence of pulmonary aspiration is because of the better sensitivity of 2-[¹⁸F] fluoro-2-deoxy-D-glucose positron tomography. However, the low incidence of clinical events needing intervention may still reflect the safety of sedation used for the GIE procedure[33]. Treatments of pulmonary aspiration includes suction of fluids from oral cavity and throat, increasing the rate of supplemental oxygen, encouraging the patient to cough, chest film, antibiotics and physiotherapy.

Nausea and vomiting are common side effects of opioids. Additionally, the over distension of the stomach or colonic loop can produce nausea and vomiting after the endoscopic procedure. The prevention of this complication is to reassure the patient and to minimize the opioid dose. In severe cases, anti-emetic agents such as metoclopramide and ondansetron may be required[35].

Paradoxical reactions are characterized by combativeness, agitation, talkativeness, disorientation and tachycardia. This reaction frequently occurs with benzodiazepines, in particular midazolam and diazepam, and is more common in children[36]. Inadequate sedation or cerebral hypoxia may mimic paradoxical reactions. Early recognition of paradoxical reactions is imperative for proper management. The administration of a benzodiazepine antagonist such as flumazenil has been shown to be effective in managing paradoxical reactions with minimal side effects.