Incremental Dosing
Synergistic Effects
Onset of Action
Intravenous Access
Reversal Agents
Use of Supplemental Oxygen

Incremental dosing

The clinician can expect the range of individual patient response may be three- to fivefold for any particular sedative or analgesic agent.  Because of this variable response, the recommended procedure for a clinician attempting to achieve moderate sedation is to deliver an initial bolus based on knowledge of the pharmacokinetic profile of the agents used (i.e the factors such as concentration, time, volume, and elimination that influence the drug's plasma concentration) and clinical estimation of the necessary dose, then titrate the drug by incremental dosing based on the pharmacodynamic properties of the agents until the desired level of sedation is achieved.  Adequate time must elapse between doses to assess drug effect before subsequent dose administration.  When administering drugs via alternative routes (oral, rectal, intramuscular, etc.), the clinician should take into account the variations in amount of time needed for the drug’s peak effect to be reached for each method of administration. 

Training in the administration of moderate sedation should include opportunities for the trainee to observe an expert performing the administration of sedation followed by a period of mentor-supervised practice in selecting doses and performing patient assessment.

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Synergistic effects

Combining a sedative such as a benzodiazepine and an opioid can provide satisfactory moderate and deep sedation for most patients.  However, when determining a sedation regimen, it is important for the sedationist to keep in mind that combinations of drugs from different classes often have synergistic effects, which can increase the likelihood of adverse outcomes, including ventilatory depression and resultant hypoxemia.

Therefore, the administration of one drug can reduce the amount of a second in a different class that is needed to achieve the desired level of sedation. For example, the dose of either a benzodiazepine or propofol needed to perform an endoscopy will be substantially lower if even a small amount of narcotic is used concomitantly.  The understanding of this principle is critical to managing moderate sedation.

Fixed combinations of sedative and analgesic agents may not allow the individual components of sedation/analgesia to be appropriately titrated to meet individual requirements of the patient and procedure, while reducing the associated risks. Ideally, each component should be administered alone to achieve the desired effect (i.e., treating pain vs. treating procedural anxiety).  The likelihood that combinations of these medications will cause respiratory depression and resultant airway obstruction highlights the need to appropriately reduce the dose of each agent as well as the need to continually monitor respiratory function.

Onset of action

Another variable determining the effects of a sedation agent is the length of time between the IV injection, the onset of sedative action, and the peak effects of the drug. If additional doses of the drug are administered before the initial bolus peaks, the sedative effects may accumulate to the point where the patient moves into a deeper than desired level of sedation. 

Intravenous access

The intravenous administration of agents for moderate sedation increases the likelihood of satisfactory sedation compared with non-intravenous routes of delivery (oral, rectal, or intramuscular). When administering sedatives intravenously, venous access should be maintained until the patient is no longer at risk for cardiovascular or respiratory depression.

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Reversal agents

Specific antagonists are available for opioids and benzodiazepines.  Naloxone or flumazenil may be administered to improve spontaneous ventilatory efforts in patients who have received opioids or benzodiazepines, respectively. Although naloxone can reverse opioid-induced sedation and respiratory depression, it should be noted that the acute reversal of opioid-induced analgesia can result in pain, hypertension, tachycardia or pulmonary edema.  Flumazenil antagonizes benzodiazepine-induced sedation and ventilatory depression.  It is effective when the benzodiazepine was administered alone, as well as when the benzodiazepine was given in conjunction with an opioid.  The immediate availability of both drugs during moderate and deep sedation is associated with decreased risk of adverse outcomes. 

A patient-specific approach to the treatment of respiratory depression is advised. Transient hypoxemia can be treated with stimulation of the patient. Repeated or more prolonged episodes of hypoxemia can be treated with supplemental oxygen. In cases where severe hypoxemia is noted, support of the airway may be necessary. Using the head tilt or jaw thrust maneuvers can be helpful. Occasionally the use of bag-mask ventilation with the possible placement of an oropharyngeal or nasopharyngeal airway is necessary. In the case of severe hypoxemia and/or the use of the aforementioned airway management maneuvers, a reversal agent is strongly advised

Before, or concomitantly with pharmacological reversal, patients who become hypoxic or apneic during sedation/analgesia should:

• Be encouraged or stimulated to breathe deeply
• Receive supplemental oxygen
• Receive positive pressure ventilation if spontaneous ventilation is inadequate 

Patients should be observed for a long enough period to ensure that symptoms do not return once the effect of the antagonist dissipates.

Use of supplemental oxygen

Both the American Society of Anesthesiologists (ASA) and the American Society for Gastrointestinal Endoscopy (ASGE) endorse the use of supplemental oxygen. The ASA calls for oxygen supplementation to be considered during moderate sedation and administered during deep sedation. The use of oxygen is recommended for elderly patients and individuals who have an advanced ASA status. Oxygen delivery equipment should be routinely available whenever endoscopic sedation is being administered. However, controversy remains about the ability of supplemental oxygen to reduce the incidence of significant cardiopulmonary complications. Several studies have suggested that delivering supplemental oxygen may actually increase the rate of sedation-related events by delaying the detection of apnea and hypoxemia. (see Sedation Risks & Complications: Use of Supplemental Oxygen)

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American Society of Anesthesiologists Task Force on Sedation and Analgesia by Non-Anesthesiologists. Practice Guidelines for Sedation and Analgesia by Non-Anesthesiologists. Anesthesiology. 2002; 96(4):1004-17.

http://www.asahq.org/publicationsAndServices/sedation1017.pdf Accessed April 22, 2008.

Cohen, LB et al. AGA Institute Review of Endoscopic Sedation, Gastronenterology 2007;133:675-701.

Drossman DA, Shaheen NJ, Grimm IS, eds. Handbook of Gastroenterologic Procedure, 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2005:14

Rex DK. Moderate Sedation for Endoscopy: Sedation Regimens for Non-Anesthesiologists, Ailment Pharmacol Ther. 2006;24(2):163-171
http://www.medscape.com/viewarticle/537718  Accessed February 13, 2008.

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Last Updated December 5, 2008