Stanford R. Plavin MD Vice Chairperson Board Certified Anesthesiologist and Patient Safety Advocate

Preventing Colorectal Cancer.org Established to preserve the tradition of safe, comfortable, and quality based-medicine while advocating for the development of new methods to provide this endpoint but not at the risk of a patient’s well being Mission is to educate the public and key stakeholders about the opportunities to reduce the incidence of CRC through maintaining screening and care options for patients and their clinicians

Sedasys NCT SAFETY and effectiveness of a Computer-Assisted Personalized Sedation (CAPS) Device for propofol delivery during endoscopy Primary outcome: Area under the curve for oxygen desaturation Secondary outcome: Duration of deep sedation/general anesthesia Additional endpoints: Patient satisfaction, clinician satisfaction, recovery time Done with Physician/RN teams

Study design and indication Funded by Ethicon-Endo (exclusively?) No Blinding of Investigators; were there other designs not used? Appears not to be done with appropriate personnel for treating AE, SRAE, and continuum of sedation per ASA statement on Safe use of propofol and current FDA guidelines Change in design from original data presented; why did that occur? Why was ARM(Automated Response Monitoring) used throughout study, but excluded from any reporting? Using off label approach with propofol; Is this a common practice? Especially when using experimental device. Why was AUC used as primary endpoint? Difficult design.

Sedation Facts Difficulty assessing depth of sedation and endpoints MOAA/S (see appendix) scores of 1 and 2 (?3) can represent Deep Sedation and thus not moderate sedation as indicated Apnea: Loss of spontaneous ventilation occurred very frequently in both arms of the study, obvious concern given the variability of propofol. ARM in initial data represents 14/24 patients lost responsiveness: greater depth of sedation, NO Purposeful response, concerning as to why not shown? 7/24 patients had apnea (29.16%): No spontaneous ventilation Study of 1000 patients done in a patient population that is standardized as well as excludes many other patients with various co-morbidities that represent a vast subset of our population.

FDA ruling on Propofol Labeling is clear cut and has been UNsuccessfully challenged Emphasis made on patient safety Fospropofol has MAC label and their endpoints for MOAS/S were comparable in design for moderate sedation Variability of pharmacokinetics and pharmacodynamics has been shown in numerous studies TCI studies with propofol have shown variety of responses and levels of sedation with similar dosing Role of FDA is to advance technology but not without safety mechanisms in place

Adverse events Study acknowledges adverse events: what are they? Percentages of adverse events were comparable in both arms of the study; is there a design flaw? Why was AUC (area under curve) chosen as an endpoint? Any attempts made to simulate propofol in order to try and blind the investigators? Deep sedation/gen anesthesia occurred and in a case lasted up to 16 minutes. How was that patient managed?

Area under the Curve? Equal to the probability that classifier will rank a randomly chosen positive instance higher than a regularly chosen negative one. Not a traditional method of Biometric and Statistical Analysis. Pulse oximetry readings of less than 90% are a later signal of hypoventilation and apnea which tends to lag direct clinical signs and symptoms; it is a great tool but does not replace skilled and appropriate vigilance Ethicon Endo website: “It (device) automatically detects and responds to signs of over sedation (Oxygen desaturations and low respiratory rate/apnea) by stopping or reducing delivery of propofol, increasing oxygen delivery and automatically instructing patients to take a deep breath” Why wasn’t apnea data included in the study reports as an outcome measure? If patients are apneic and unconscious: then?

Device and Delivery Concerns Studied with a medication that we all acknowledge has very dynamic characteristics, no reversal agent, and has been ruled upon numerous times in many arenas. Our concern is that the temptation to sedating in a more timely manner may cause catastrophic outcomes if this device is not monitored with the proper and skilled personnel. Technology should be advanced but not for the sake of bypassing the standards and safety measures already in place. The machine uses all the parameters that acknowledge it is delivering a General Anesthetic; yet promotes light to moderate sedation, seems to be a disconnect.

Propofol sedation for Endoscopy Ethicon Endo has tremendous resources and foresight and does seem to acknowledge the need for improved sedation options for endoscopy. The GI societies should also formally acknowledge that there is an improved and preferred method of sedation for endoscopy What the FDA’s role is to protect and serve the American public PCC.org applauds the goal of promoting improved sedation methods with propofol in order to improve access and increase screening for CRC. We do not endorse the methodology being used to circumvent FDA labeling and rulings in order to accomplish this goal.

Thoughts in summary “ This new technology represents an exciting breakthrough in the use of computers to properly administer and monitor sedation in patients undergoing a variety of procedures,” said Daniel Pambianco, M.D., Charlottesville Medical Research and lead study author. “ When used with a TRAINED ANESTHESIOLOGIST, this device may help manage the potential risks associated with sedation and ensure that each patient is cared for based on THEIR own needs. Medical News Today, May 22,2006

Stanford R. Plavin MD

Appendix Modified Observer’s Assessment of Alertness/Sedation (OAA/S) Scale ResponsivenessSCORE Responds readily to name spoken in normal tone 5(Alert) Lethargic response to name spoken in normal tone 4 Responds only after name is called loudly and/or repeatedly 3 Responds only after mild prodding or shaking 2 Responds only after painful trapezius squeeze 1 Does not respond to painful trapezius squeeze 0

Resources and References PCC.org library of articles Patient Safety Advisory : Pennsylvania Patient Safety Authority Diprivan: Propofol, Package insert and labeling Pediatrics 2004;114;e74-76: Conscious Sedation of Children with propofol Is anything but conscious Practice Guidelines for Sedation and Analgesia by Non- Anesthesiologists: Anesthesiology, V96, NO.4, April 2002 Efficiency in Endoscopy Centers: Gastrointestinal Endoscopy: Vol. 64, Issue 5, Nov ASA and AANA: Statement on Safe use of propofol, 2004 Moderate Sedation for Endoscopy: Sedation Regimens for Non- Anesthesiologists, D.K. Rex, 7/12/2006

Resources and References Automated Responsiveness Test (ART) Predicts loss of consciousness and Adverse Physiologic responses during propofol Conscious Sedation: Anesthesiology, V.94, No.4 April 2001 USPTO 78/283422: Sedasys: Johnson and Johnson: 005: pharmaceutical preparations for use in sedation, namely, anesthetics for surgical use: 010: medical device for use in surgical sedation procedures, namely, anesthetic delivery device, infusion pump, and parts there of. Feasibility Assessment of a Sedation delivery System to Administer propofol: Anesthesiology 2006, 105: A1586 Sedation facts.org: funded by an educational grant from Ethicon Endo-Surgery, Inc. Sedation and Analgesia for GI endoscopy: Gastrointestinal Endoscopy 2006; 63: On Computers, nurses, and propofol: further evidence for the Jury. Gastrointestinal Endoscopy 2008; 68: