Respiratory depression due to an overdose of sedatives is the most common adverse event during sedation.10) All patients undergoing procedural sedation should be monitored for hypoxemia or desaturation by pulse oximetry.11) Because pulse oximetry measures arterial oxygen saturation, the detection of compromised respiratory activity can be delayed, especially if patients are receiving supplemental oxygen. For early detection of hypoventilation, monitoring exhaled carbon dioxide tension is superior than pulse oximetry.12) Early detection enables rapid interventions to relieve respiratory depression, including adjustment of drug dosing and the depth of sedation, patient stimulation, maneuvers for airway patency, assisted ventilation and supplemental oxygen. Indeed, capnography monitoring was demonstrated to reduce respiratory complication and improve patient safety during procedural sedation with benzodiazepines and opioids.13) The sedation provider should also observe vigilantly for qualitative clinical signs, such as movement of chest wall, suprasternal, intercostal, and subcostal retraction, gasping for air, and stridor.

For sedation during cardiovascular procedures, non-invasive blood pressure, heart rate and electrocardiography monitoring is recommended. Invasive blood pressure monitoring is occasionally required for the patients with advanced cardiovascular dysfunction.

The depth of sedation should be monitored throughout the procedure. Patient may be uncomfortable with light sedation, whereas deep sedation has greater impact on cardiopulmonary function. Thus, the margin of safety for deeper level of sedation may be narrow, especially in patients with impaired cardiopulmonary function. The dose of sedatives and analgesics are carefully titrated according to the depth of sedation as most of sedation-related complications are associated with unintended deeper level of sedation. The sedation provider can monitor the depth of sedation by periodical verbal stimulation as well as other clinical signs. However, some clinicians advocate processed, digitalized form of electroencephalogram-derived monitor to monitor the level of consciousness.

The bispectral index (BIS; Aspect Medical Systems, Norwood, MA, USA) is the one of the most popular monitors of processed electroencephalogram. It receives electroencephalogram signal via a single patch sensor attached on the forehead, analyzes and processes the signal into a single number, ranging 0 (isoelectric electroencephalographic activity) to 100. A BIS value between 90 and 100 indicates fully awaken status, a value between 70 and 90 represents light to moderate sedation. A BIS value of 60 to 70 indicates superficial anesthesia, and a value between 40 and 60 is regarded as an appropriate value for general anesthesia. Monitoring with BIS is continuous and more convenient than assessment of clinical signs alone, however, for relatively short procedures, addition of BIS monitoring seems to provide little benefit over conventional assessment of clinical signs. In a study comparing the BIS monitoring with clinical assessment, awareness, propofol requirement, desaturation and need for hemodynamic and respiratory support were all similar between the study groups in patients undergoing bronchoscopy.14) Moreover, the correlation between the BIS and the assessed sedation level was very weak.15) In contrast, procedures which take long time or require moderate to deep sedation may benefit from the BIS monitoring.16)17)18)

Midazolam is a benzodiazepine with a rapid onset (1 to 5 minutes) and short duration of action (Table 2). It is the most commonly used agent for short procedures requiring light to moderate sedation. It confers anxiolysis and antegrade amnesia. Because it has no analgesic property, it is usually used in combination with opioids. It blunts central respiratory drive response to hypercapnia or hypoxia.19) The respiratory depressant effect is dose-dependent and might be increased with rapid intravenous bolus administration. A reduced dose is recommended for old age and patients with impaired cardiopulmonary function. Midazolam is thought to have minimal effect in terms of hemodynamic deterioration.20) Midazolam has negligible direct myocardial depressive effect and modest decrease in blood pressure can occur due to mild vasodilation and sympatholytic effect. However, both respiratory and cardiovascular effects are synergistic when midazolam is used in combination of other sedatives and analgesics, for example opioids, leading to severe respiratory depression and hypotension greater than expected by the effect of each drug.21) Midazolam is metabolized in liver, and the main metabolite, which possesses sedative activity, is rapidly cleared via kidney. Thus, in patients with liver cirrhosis or renal impairment, midazolam administration can result in profound sedation for longer duration.22)23)

Midazolam may induce agitation, restlessness, aggressiveness or hallucinations.24) This paradoxical disinhibitory reactions develop within several minutes after intravenous administration following transient sedation. It is reported to occur in <1% of midazolam administrations and thought to be associated with loss of cortical resistance and reduced serotonin control.25) Patient with alcohol abuse or psychologic disturbances are at increased risk of paradoxical reactions. The paradoxical reactions may be attenuated with flumazenil or haloperidol.26)27)

Propofol is a sedative-hypnotic agent with no analgesic effect. It has rapid onset (<1 minute) and relatively short context-sensitive half-time, which enables smooth and quick recovery even after prolonged continuous infusion (Table 2). Propofol has little paradoxical excitatory effect and low incidence of nausea and vomiting.28) These favorable pharmacokinetic and pharmacodynamics profile made it one of the most popular intravenous agents in modern anesthetic practice.

The pharmacokinetic model of propofol is described as a 3-compartmental model which consists of central, peripheral (lean tissues) and deep (fat tissues) compartment.29) Following intravenous bolus administration, propofol is rapidly redistributed to a peripheral compartment, resulting in fast offset of its clinical effect (5–10 minutes). Because propofol is lipophilic, the fat compartment acts as a reservoir after prolonged infusion. Redistribution from the fat compartment may delay the offset of action especially in obese patient.30) Time required for decrease in plasma concentrations are also significantly longer in the elderly.29) Nonetheless, recovery after prolonged infusion is relatively quicker compared with other hypnotics such as midazolam, because the rate of metabolism and excretion is faster than the rate of redistribution. The context-sensitive half-time of propofol is 25 minutes after 3 hour-long infusion, whereas midazolam has a context-sensitive half-time of 70 minutes for a similar duration of infusion.31) Propofol is mainly metabolized in liver, and the metabolites, which have no hypnotic effect, are excreted via kidney.30)

Propofol is a potent respiratory depressant. An intravascular bolus administration may result in apnea. The dose, speed of injection and co-administered drugs, especially opioids, are associated with the incidence and duration of apnea.32) Propofol infusion at 100 µg/kg/min induces a 40% decrease in tidal volume and a 20% increase in respiratory rate.33) Propofol also induces cardiovascular depression, with a greater extent compared with other intravascular sedative agents.34) Even in healthy individual with no cardiovascular impairment, propofol produces 25% to 40% decrease in systemic blood pressure. In addition to vasodilatory effect, it also decreases cardiac output and stroke volume. These cardiovascular effects are associated with sympatholytic activity and whether propofol has direct myocardial depressive effect is still controversial.35) Notably, peak hemodynamic effect of propofol tends to follow behind the hypnotic effect.36) So profound hypotension may manifest a few minutes after the patients fall into deeper level of sedation.

The most frequent complaints in patients who receive propofol is pain at injection site, which can be managed with concomitant use of lidocaine at the start of injection.37)38) Propofol has no physical dependence, however, it may result in euphoria with sense of ‘general well-being’, predisposing a risk of addiction or abuse.39) Lipid-based formulation of propofol is susceptible to bacterial contamination and can induce life-threatening sepsis unless stored and handled appropriately in a sterile and aseptic manner.40)

Dexmedetomidine is an α-2 adrenergic receptor agonist which has anxiolytic, sedative and analgesic property (Table 2).41) Compared with clonidine, it is more selective and efficacious. It exerts sedative effect by binding to α-2 receptors in the locus coeruleus and analgesic effect by an action on α-2 receptors in spinal cord as well as locus coeruleus.42) Unlike other sedative drugs such as propofol and benzodiazepines, dexmedetomidine induces sedation through the endogenous sleep-promoting pathway.43) Thus, it produces a natural sleep-like patterns of the electroencephalogram, and patients receiving dexmedetomidine usually fall asleep when undisturbed, while they are easily arousable and cooperative. Dexmedetomidine has minimal respiratory depressive effect. Sedation with dexmedetomidine induces modest reduction in minute ventilation,44) however, ventilatory response to hypercapnia is unaffected even in deep sedation.45) Dexmedetomidine reduces the release of norepinephrine and sympathetic tone in the central nervous system, thus it can induce severe bradycardia.46)47) Transient hypertension can occur due to stimulation of peripheral α-2 receptors. Slow initial loading over 20 minutes may reduce the transient hypertension.48) In case of hypertension during initial loading, it is recommended to decrease subsequent continuous infusion rate. Hypotension can also occur, especially in old age, history of diabetes or hypertension, or with a large loading dose. Dexmedetomidine can be used alone or in combination with other sedatives/analgesics. Because dexmedetomidine exerts minimal respiratory depression, combined administration with other sedatives/analgesics provide excellent results without increased risk of respiratory complication.49)

Owing to their strong analgesic efficacy, addition of opioids can ameliorate procedure-related discomfort. Opioids have no hypnotic effect, however, it can reduce the requirements of other hypnotics when used in combination. Because the risk of respiratory and cardiovascular depression increases synergistically with other sedatives, special attention is needed in patients receiving opioids in combination with propofol or midazolam. Remifentanil is an ultra-short acting synthetic opioid, which has gained popularity recently for conscious sedation during painful procedures.50) It has rapid onset and short context-sensitive half time regardless of the duration of infusion. Recovery is rapid even after prolonged infusion and not affected by hepatic or renal function.51) Initial loading dose is not necessary, and an infusion at 0.05–2 µg/kg/min provides sufficient analgesia for most procedures (Table 2). However, respiratory depression is not infrequent even at subtherapeutic doses. Like other opioids, remifentanil infusion occasionally induces chest wall rigidity which impairs ventilation.

Depending on the complexity of procedures, moderate sedation is feasible for most of cases, either with benzodiazepine, propofol, opioids or dexmedetomidine.52)53)54) However, in case of complex procedures, deep sedation or general anesthesia is occasionally required because the procedures can be lengthy and patient immobility is crucial for the induction and accurate mapping of the arrhythmogenic foci. In a trial comparing sedation versus general anesthesia for ablation of atrial fibrillation, general anesthesia was associated with shorter procedure time and higher arrhythmia-free rate.55) However, general anesthesia may predispose high incidence of esophageal injury, likely due to reduced esophageal motility and swallowing during general anesthesia.56) In addition, absence of feedback from patients might delay the detection of complications during the procedure.

There has been a concern that sedatives/anesthetics have a potential to suppress arrhythmia inducibility, interfering successful ablation of supraventricular tachyarrhythmia. Most of sedatives/anesthetics including volatile anesthetics, propofol, remifentanil and dexmedetomidine may slow cardiac conduction, exert sympatholytic effect and reduce the ability to elicit arrhythmia, especially in deep sedation with high doses.57)58)59) A combination of benzodiazepine and fentanyl is thought to have less impact on arrhythmia inducibility.60) However, a concrete evidence for superiority of any particular agent in regard to the ability to elicit arrhythmia and impact on success rate of the procedure is lacking so far, thus sedative strategy should be chosen upon a balance of patient comfort, preference and experience of sedation provider, and arrhythmia inducibility.

Electrical cardioversion is highly stimulating and requires deep sedation to alleviate patient discomfort. However, because the period of stimulation is brief, short-acting agents are recommended for rapid recovery. Either benzodiazepines, opioids, and propofol can be used.61)62) Propofol may have advantage in terms of quick onset and offset of sedation, ease of titration, less nausea and vomiting, whereas it is associated with more frequent episode of apnea and hypotension.63) Despite the theoretical advantage of propofol, benzodiazepines are widely used due to its practitioner familiarity and minimal hemodynamic effects.

The insertion of pacemakers and implantable cardiac defibrillators can be performed under minimal to moderate sedation. Tunneling of leads to a subcutaneous pocket needs adequate local anesthesia. Like electrical cardioversion, defibrillation threshold test requires deep sedation. Some patients with advanced heart failure may not be able to tolerate the supine position due to orthopnea and these patients are extremely sensitive to sedatives and opioids. Deep sedation in patients with advanced hear failure frequently results in hemodynamic deterioration due to reduced sympathetic tone. Moreover, retention of carbon dioxide may worsen pulmonary hypertension and lead to right ventricular failure.

The prevalence of peripheral artery disease and need for an appropriated sedation analgesia for percutaneous transluminal angioplasty is increasing.64) Patients undergoing percutaneous transluminal angioplasty are usually old and at increased risk of cardiovascular event. Peripheral artery disease provokes broad spectrums of pain, and ballooning may elicit significant ischemic pain. Thus, adequate pain control is crucial. Opioids alone may provide sufficient analgesia. Combination of opioids such as remifentanil with benzodiazepines or propofol may improve sedation experience, however, it can increase a risk of respiratory depression.65) Addition of dexmedetomidine can confer both sedation and analgesia while sparing the dose of opioids and preserving the respiratory function.66)