1. Obstructive Sleep Apnea Perioperative Implications From Mechanisms to Risk Modification Satya Krishna Ramachandran MD FRCA Assistant Professor of Anesthesiology University of Michigan Medical School, Ann Arbor rsatyak@med.umich.edu

2. Disclosures Paid scientific advisory consultant –Galleon Pharmaceuticals –Merck, Sharp & Dohme Funding –PSA with MSD for 2014 –MiCHR CTSA PGP UL1TR000433 for 2014 The material of this talk is independent of these disclosures This is a confidential Quality Improvement and Assurance/peer review document of the University of Michigan Hospitals and Health Centers. Unauthorized disclosure or duplication is absolutely prohibited. This document is protected from disclosure pursuant to the provisions of MCL 333.20175; MCL 333.21515; MCL 331.531; MCL 331.533 or such other statutes that may be applicable

3. Goals & Objectives To describe the relationship between OSA and early postoperative respiratory failure To review mechanisms of unanticipated early postoperative respiratory failure To critically evaluate methods of risk- modification of early postoperative respiratory failure

4. Obstructive Sleep Apnea and Respiratory Failure

5. Evidence in the surgical population Retrospective studies: associations – Gupta – more complications, ICU admissions – Hwang – more morbidity – Memtsoudis – independent increase in morbidity – Mokhlesi – Increased respiratory failure Prospective evidence: associations – Chung – more postoperative desaturation episodes – Gali – more morbidity with postoperative episodic desat. Sudden death – case reports Gupta. Mayo Clin Proc. 2001;76:897-905 Hwang. Chest. 2008;133:1128-34 Memtsoudis. Anesth Analg. 2011;112:113-21 Gali B. Anesthesiology 2009;110:869-77 Ostermeier. Anesth Analg. 1997;85:452-60

6. AHI and outcome Gami. N Engl J Med. 2005;352:1206-14.

7. Nocturnal pattern in sudden death Gami. N Engl J Med. 2005;352:1206-14.

8. Severity of OSA and nocturnal variation in sudden death Gami. N Engl J Med. 2005;352:1206-14.

9. If they are prone to sudden death during sleep, is the risk of postoperative sudden death increased in patients with OSA?

10. Nocturnal Variation In Outcome Of ARE Ramachandran SK. J Clin Anesth 2011;23:207-13 Postoperative ARE from RM database 35 cases – 5 deaths / 6 years History or known risk factors for OSA present in ~40% cases

11. Mechanisms of Perioperative AE? Hypoxia Sympathetic activation Cardiovascular variability Inflammation Comorbid disease Chemoceptor hypersensitivity Somers et al. Circulation. 2008;118:1080-1111

12. Mechanisms of Perioperative AE? Hypoxia Sympathetic activation Cardiovascular variability Inflammation Comorbid disease Chemoceptor hypersensitivity

13. Hypoxia and Arrhythmia/Conduction Nocturnal ventricular arrhythmias – Min SpO 2 <60% – AHI >65.hr -1 QRS prolongation – Min SpO 2 <90% – AHI >30.hr -1 Heart Block – Min SpO 2 <90% – Obesity Sheppard. Chest. 1985 Sep;88(3):335-40 Valencia-Flores. Obes Res. 2000 May;8(3):262-9. Ramachandran – unpublished data

14. Mechanisms of Perioperative AE? Hypoxia Sympathetic activation Cardiovascular variability Inflammation Comorbid disease Chemoceptor hypersensitivity

15. MSNA and OSA Somers et al. J Clin Invest. 1995;96:1897-904

16. MSNA and Sleep Stage Somers et al. J Clin Invest. 1995;96:1897-904

17. MSNA In Awake State Somers et al. J Clin Invest. 1995;96:1897-904

18. Mechanisms of Perioperative AE? Hypoxia Sympathetic activation Cardiovascular variability Inflammation Comorbid disease Chemoceptor hypersensitivity

19. Cardiovascular variability Narkiewicz et al. Circulation. 1998;98:1071-1077

20. Intrathoracic Pressure Changes Repeated Mueller maneuvers during OSA – Intrathoracic pressures approach -65 mmHg ?Increased risk of postoperative pulmonary edema Increased transmural gradient across atria and ventricles – Increased wall stress and afterload – Diastolic dysfunction – Atrial remodeling

21. Mechanisms of Perioperative AE? Hypoxia Sympathetic activation Cardiovascular variability Inflammation Comorbid disease Chemoceptor hypersensitivity

22. OSA and Inflammation Selective activation of inflammatory pathways – Hypoxemia – Sleep deprivation/fragmentation Increased levels in OSA – Cytokines, adhesion molecules, serum amyloid – C-reactive protein - ?obesity related – TNF May influence postoperative mortality and morbidity

23. Mechanisms of Perioperative AE? Hypoxia Sympathetic activation Cardiovascular variability Inflammation Comorbid disease Chemoceptor hypersensitivity

24. Unanticipated Postoperative Respiratory Failure Prediction model in 222,094 patients from the NSQIP dataset. Overall, 49.4% unanticipated tracheal intubations occurred within first three days after surgery. The incidence of unanticipated early postoperative intubation (UEPI) was 0.83-0.9% Ramachandran SK et al. Anesthesiology 2011;115:44-53

25. UEPI Independent Predictors Surgical Type Current Ethanol Use Current Smoker Dyspnea COPD Diabetes Mellitus Active Congestive Heart Failure Hypertension Requiring Medication Abnormal Liver Function Cancer Prolonged Hospitalization Recent Weight Loss Body Mass Index < 18.5 Or ≥ 40 Kg/m 2 Sepsis Ramachandran SK et al. Anesthesiology 2011;115:44-53

26. UEPI Independent Predictors Surgical Type Current Ethanol Use Current Smoker Dyspnea COPD Diabetes Mellitus Active Congestive Heart Failure Hypertension Requiring Medication Abnormal Liver Function Cancer Prolonged Hospitalization Recent Weight Loss Body Mass Index < 18.5 Or ≥ 40 Kg/m 2 Sepsis Ramachandran SK et al. Anesthesiology 2011;115:44-53

27. Mechanisms of Perioperative AE? Hypoxia Sympathetic activation Cardiovascular variability Inflammation Comorbid disease Chemoceptor hypersensitivity

28. OSA and chemoreceptor sensitivity Limited adult data Postoperative ARE outcomes unrelated to dose Opioid consumption lower in patients who died Ramachandran SK et al. J Clin Anesth 2011;23:207-13

29. Metabolic Disease and RD?

30. RISK MODIFICATION

31. Baseline Risk Reduction Strategies Preoperative CPAP Opioid sparing techniques – Regional anesthesia/analgesia – Non-opioid adjuncts – Minimal access surgery Continuous pulse oximetry monitoring Postoperative CPAP Expert Opinion

32. PREoperative CPAP No RCT guided evidence of perioperative benefit Possible mechanisms: – Less severe nocturnal desaturation – More dependable postoperative CPAP usage Challenges: – Majority of patients are undiagnosed – Adherence with therapy is low – Timely preoperative testing/fitting

33. Preop CPAP Benefit - MSNA, MAP Somers et al. J Clin Invest. 1995;96:1897-904

34. CPAP and QTc Dispersion Longitudinal 6-month study of CPAP 12-lead ECG data analysis Dursunoglu et al. Sleep Medicine 2007;8:478–483

35. Ryan et al. Thorax 2005;60:781–785 CPAP and Arrhythmia in CHF

36. Cessation of CPAP and MSNA Somers et al. J Clin Invest. 1995;96:1897-904

37. UM Model for Fast Track PSG

38. MSQC study Introduced a new concept – Preoperative PAP treatment for OSA – Implies diagnosis of OSA – Compliance generally ~50% MSQC nurse abstractors collect data from 56 hospitals in Michigan – Risk adjusted for surgery, comorbid conditions and intraoperative characteristics

39. Frequency Tables Entire Cohort Sleep ApneaFreq.(%) None32,14890.91 Untreated1,7695 Treated1,4464.09 Total35,363100 General Surgery Sleep ApneaFreq.(%) None20,87390.31 Untreated1,2265.3 Treated1,0134.38 Total23,112100

40. MSQC Analysis Entire Cohort Adjusted Odds Ratiop Value[95% Conf. Interval] Morbidity Sleep Apnea None1.00(ref) Untreated1.260.0081.06-1.50 Treated0.870.1150.72-1.04 Pulmonary Occurence Sleep Apnea None1.00(ref) Untreated1.140.3340.87-1.48 Treated0.600.0070.42-0.87 Mortality Sleep Apnea None1.00(ref) Untreated1.110.6920.66-1.86 Treated0.690.2370.37-1.28

41. Multivariate Analysis Entire Cohort Adjusted Odds Ratiop Value[95% Conf. Interval] Morbidity Sleep Apnea None1.00(ref) Untreated1.260.0081.06-1.50 Treated0.870.1150.72-1.04 Pulmonary Occurence Sleep Apnea None1.00(ref) Untreated1.140.3340.87-1.48 Treated0.600.0070.42-0.87 Mortality Sleep Apnea None1.00(ref) Untreated1.110.6920.66-1.86 Treated0.690.2370.37-1.28

42. Baseline Risk Reduction Strategies Preoperative CPAP Opioid sparing techniques – Regional anesthesia/analgesia – Non-opioid adjuncts – Minimal access surgery Continuous pulse oximetry monitoring Postoperative CPAP Expert Opinion

43. Baseline Risk Reduction Caveats Opioid sparing techniques – Reduce opioid consumption – May not modify respiratory risk Blake et al. Anesthes Int Care. 2009;37:720-725

44. Baseline Risk Reduction Strategies Preoperative CPAP Opioid sparing techniques – Regional anesthesia/analgesia – Non-opioid adjuncts – Minimal access surgery Postoperative CPAP Continuous pulse oximetry monitoring Expert Opinion

45. UM model for Postop CPAP

46. Risk Modification – Postop CPAP Robust evidence for early treatment of hypoxia – Randomized Controlled Trial of CPAP vs. O 2 – Major elective abdominal surgery CPAP associated with – lower intubation rate (1% vs 10%) – lower occurrence rate of pneumonia (2% vs 10%), infection (3% vs 10%), and sepsis (2% vs 9%). No RCT evidence of benefit of postoperative CPAP in OSA patients Squadrone V. JAMA 2005;293:589-595

47. Baseline Risk Reduction Strategies Preoperative CPAP Opioid sparing techniques – Regional anesthesia/analgesia – Non-opioid adjuncts – Minimal access surgery Postoperative CPAP Continuous pulse oximetry monitoring Expert Opinion

48. Postoperative Monitoring Overview Outcome studies – monitoring success is limited to recent, small single center studies, majority evidence points to no benefit. Limitations of current state of alarm technology Why universal monitoring may be a problem

49. Outcome Studies 3 tiers of monitoring conceptually: – Spot monitoring – Continuous bedside monitoring – Integrated monitoring /surveillance systems Largest studies are of bedside devices Majority of current evidence around IM/SS Direct comparative effectiveness trials are impossible in the current climate

51. Surveillance Systems

52. Unanswered Questions What were the monitoring signatures of “MET/RRT events”? What were the sensitivity and positive predictive value of the system? Did the treatment change the outcome?

53. Integrated Monitoring System An IMS (BioSign; OBS Medical, Carmel, Indiana) used heart rate, blood pressure, respiratory rate, and peripheral oxygen saturation by pulse oximetry to develop a single neural networked signal, or BioSign INDEX (BSI) Data were analyzed for cardiorespiratory instability according to BSI trigger value and local MET activation criteria.

54. Does IMS Prevent Instability?

55. Does IMS Reduce Frequency of Instability Events?

56. Does IMS Reduce Duration of Instability?

57. Unanswered Questions What were the monitoring signatures of “MET/RRT events”? What is the sensitivity and positive predictive value of IMS/SS? Did the treatment change the outcome?

58. What is the Sensitivity of EWS?

59. Unanswered Questions What were the monitoring signatures of “MET/RRT events”? What is the sensitivity and positive predictive value of IMS/SS? Did the treatment change the outcome? – NNT/NNP – NNH

60. Does Monitoring Change Outcomes? For outcome modification, two things need to happen: – The IMS event changes treatment – The treatment changes the outcome Neither was tested in Hravnak’s or Taenzer’s study Both studies used MET/RRT as escalation step

63. Are we monitoring the right patient at the right time?

64. Relationship Between Desaturation & Unanticipated Respiratory Failure

66. Can Monitoring Harm?

67. Summary It is possible to predict need for MET/RRT fairly accurately using advanced monitoring MET/RRT intervention does not change mortality risk Risk periods for desaturation and unplanned intubation are not congruent Postoperative monitoring is associated with increased technological intensification, alarm fatigue and risk of harm in CURRENT STATE

68. Future State of Monitoring Can only be effective in pathology that is responsive to treatment Shift away from threshold based event recognition Identification of “state change” from healthy to at-risk state Needs to address poor PPV and sensitivity

69. Conclusions OSA is associated with increased risk of early postoperative respiratory failure PREoperative CPAP is associated with significant physiological benefit – Compliant PAP therapy is associated with outcome benefit Postoperative monitoring is of unknown value in OSA patients