Most endoscopic procedures in the United States are performed using some form of sedation. Sedation offers significant benefits for both the patient and the endoscopist: the patient experiences less anxiety and discomfort and the endoscopist is able to perform a thorough examination with less risk of patient injury.

Despite the overall advantages, there are inherent problems with the currently available sedation regimens: 

• Sedation depth is not always easily titrated to varying levels of stimuli during GI procedure.
• A registered nurse or an anesthesia professional may be required to administer sedation.
• Effects of sedation may take longer to wear off than expected.
• An intravenous line is required to administer the agents.
• Some patients may react unpredictably to the drug used and become oversedated as a result. Conversely, other patients may not be sedated with standard regimens and may require an alternative approach.

In an effort to address these issues and to provide improved endoscopic sedation regimens, alternative pharmaceuticals and delivery methods are being explored.  Areas of interest include new agents such as fospropofol, as well as expanded applications for existing ones such as dexmedetomidine. On the technology side, a computer-assisted personalized sedation (CAPS) system, patient-controlled drug delivery systems (PCA/S) and target-controlled infusion (TCI)  are examples of innovative approaches to sedation that are on the horizon.  

Currently Under Review

The following drugs and technologies are currently under review by the US Food and Drug Administration (FDA). Although data is limited because of their investigational status, these agents and delivery methods represent promising trends for the future for endoscopic sedation.

Computer-assisted personalized sedation (CAPS)

The computer-assisted personalized sedation (CAPS) system is designed to help physician/nurse teams deliver minimal to moderate propofol sedation to patients during endoscopic procedures without an anesthesia provider.  The CAPS system continually monitors and records in real time pulse oximetry, ECG, capnography, non-invasive blood pressure and patient responsiveness. The platform continuously monitors for early signs of potentially adverse physiology and level of sedation, allowing physician/nurse teams to adjust the infusion in an appropriate fashion to a targeted level of sedation.  The system is also designed to react to signs of over-sedation by stopping or reducing delivery of propofol, increasing oxygen delivery and automatically instructing patients to take a deep breath. 

In two feasibility studies of CAPS involving 96 patients undergoing elective upper endoscopy and colonoscopy, patients remained minimally to moderately sedated throughout the procedure. For the majority of patients, recovery time was less than 1 minute and no serious adverse events occurred.  The nurses assisting in the procedures reported that the system was intuitive and user-friendly, and the built-in dosing limits and automated response algorithms allowed the team to be confident that an appropriate level of sedation was being maintained.  Results from one arm of this study were published in the September 2008 Gastrointestinal Endoscopy.  The report described two open label single-center studies of the CAPS device on a total of 48 patients undergoing either colonoscopy or EGD procedures and demonstrated that results were reproducible across two countries and two practice settings.

A subsequent multi-center prospective, randomized, controlled trial compared the safety and effectiveness of the CAPS system to physician-administered sedation regimens involving opioids and benzodiazepines in 1000 patients. Based on these investigations, the system was submitted to the U.S. FDA for premarket approval under the brand name, SEDASYS™ System. 

On May 28th, 2009, the Anesthesiology and Respiratory Therapy Devices Advisory Committee of the FDA voted 8 to 2 in favor of approval of the SEDASYS™ System. Provisional conditions of approval recommended by the Panel included that the SEDASYS™ System only be used in adult patients age 70 and under who are ASA I or II, a comprehensive training program, definition of the sedation delivery team, and a post-approval study. The final decision regarding approval of the device is forthcoming by the FDA.

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Fospropofol disodium

Fospropofol disodium, a water-soluble prodrug of propofol, has been studied for sedation for endoscopy without the presence of an anesthetist. Ideally, this agent would address some of the limitations associated with the use of propofol.  After injection of the prodrug, fospropofol is rapidly converted by the alkaline phosphatase enzyme into propofol. However, the resulting plasma concentrations of propofol exhibit a slower upwards slope, a lower peak, and a more extended plateau phase than with propofol emulsion. The water-soluble formulation helps avoid some of the problems seen with the lipid-based propofol including injection pain, potential hyperlipidemia with long-term administration, and a higher risk of bacteremia.  

At present, fospropofol has not been approved for marketing in the U.S. by the FDA.  Results from bronchoscopy and colonoscopy pivotal trials have shown it to safe and effective for sedation during these procedures.  In a randomized, double-blind, phase 3 trial of patients undergoing colonoscopy, sedation success and patient satisfaction was significantly higher in the patients receiving the 6.5mg/kg dose of fospropofol disodium.  The most common adverse reactions seen in the fospropofol groups were paresthesias and pruritus.  

In May 2008, an FDA Advisory Panel voted 6-3 with one abstention to recommend approval of the drug by healthcare providers who are appropriately trained, for sedating adults undergoing various diagnostic and therapeutic procedures. The Panel noted that reversal agents for this drug do not exist, and raised the concern  in an 8-2 vote that they are not convinced this drug could be safely given by medical personnel without general anesthesia training.  The FDA announced a non-approvable decision in July 2008, which outlined deficiencies to be corrected in the pathway to potential approval of fospropofol disodium for use by appropriately trained physicians.

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Other Agents and Technologies

Although not currently under FDA review, other agents and delivery methods are being explored for use in gastrointestinal endoscopy.

Dexmedetomidine  

Dexmedetomidine received FDA approval in 1999 for use with intubated patients in the ICU. It is a relatively selective alpha2-adrenoceptor agonist that produces sedative, analgesic, anxiolytic, and sympatholytic effects.  Although the FDA approved labeling does not include sedation for GI endoscopy, certain qualities make dexmedetomidine attractive for short-term procedural sedation. Dexmedetomidine causes little respiratory depression while providing sedation, but can reduce blood pressure and heart rate at higher doses. In addition, patients sedated with the drug return to their baseline level of consciousness when stimulated.  The effects of dexmedetomidine can be reversed with the alpha2-adrenergic antagonist atipamezole.

A large double-blind placebo-controlled trial found that postsurgical patients requiring ventilation and sedation that received dexmedetomidine reported better pain relief with minimal side effects.  Results of studies using dexmedetomidine for gastrointestinal endoscopy are mixed. A randomized study involving 64 patients compared dexmedetomidine to either meperidine with midazolam or fentanyl on demand during elective colonoscopy. The study was terminated before the planned 90 patients had been enlisted because researchers observed a significantly larger decrease in heart rate during sedation among patients in the dexmedetomidine group.  However, a prospective, randomized study that compared dexmedetomidine with midazolam for sedation during upper endoscopy reported that dexmedetomidine provided as effective sedation as midazolam and resulted in fewer side effects and higher endoscopist satisfaction.

Nitrous Oxide

Nitrous oxide is an inhaled agent that produces analgesic and anxiolytic effects. Nitrous oxide may have potential value in endoscopic sedation because of its rapid onset of action and recovery time and excellent safety profile. However, more research including large scale trials in diverse patient populations are needed before it can be recommended for widespread use.

Ketamine

Ketamine is a rapid-acting general anesthetic drug with both analgesic and sedative characteristics.  Most of the studies to date on the use of ketamine for endoscopic sedation have focused on the pediatric population. Recent research, however, indicates that ketamine may have a role as an adjunct medication in patients who are difficult to sedate. Some patients receiving ketamine develop dysphoria such that routine use in the healthy patient undergoing endoscopy may not be ideal.

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Patient-Controlled Analgesia/Sedation (PCA/S)

Patient-controlled analgesia/sedation delivers pain medication via a computerized pump which the patient controls via a handheld button. The pump administers predetermined boluses of IV medication against a continuous background infusion. Several controlled trials using PCA/S with a combination of propofol and an opioid have shown the method to produce safe and effective sedation with a high degree of patient satisfaction.   In addition, patient recovery is faster because less total medication is used than with conventional sedation methods.  PCA/S may not be suitable for patients who do not have the willingness or capacity to comply with instructions. 

Target Controlled Infusion (TCI)

Another evolving technology currently used in Europe (but not yet commercially available in the United States) is target-controlled infusion (TCI). This delivery system administers IV agents via an infusion pump programmed to calculate and maintain the necessary infusion rate based on the pharmacokinetic model of a specific drug. The current TCI systems are known as "open-loop" systems because they operate using only a computer prediction of expected plasma concentration based on the drug profile. Unlike the PCA/S delivery method, there is no real-time feedback from the patient as to the actual effects of the drug concentration.

A refinement of the TCI system is a "closed-loop" administration method which incorporates feedback from real-time measures of sedation such as muscle relaxation into the computer-controlled algorithm for drug delivery. When using propofol, a closed-loop system has a potential advantage over an open-loop system of being able to provide a more precise level of sedation with a lower concentration of the drug. 

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Sources

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Bright E, Roseveare C, Dalgleish D, et al. Patient-controlled sedation for colonoscopy: a randomized trial comparing patient-controlled administration of propofol and alfentanil with physician-administered midazolam and pethidine. Endoscopy. 2003;35(8)683-7.

CAPS device for propofol sedation demonstrates nurse confidence and ease of use, EndoNurse, June 11, 2007. http://www.endonurse.com/hotnews/76h1115365792391.html  Accessed March 22, 2008.

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Ethicon Endo-Surgery submits application to FDA for approval of the Sedasys™ System the first computer-assisted personalized sedation system. Medical News Today. http://www.medicalnewstoday.com/articles/102180.php  Accessed April 20, 2008.

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Last Updated July 27, 2009