1. Assessment of Outcomes in Septic Shock and Severe Sepsis Patients with Early Critical Care Intervention A Case Comparison Study Kenmore Mercy Hospital, Buffalo, NY Matthew Missert DO Gopichand Pendurti MBBS Thomas Brewer DO

2. Background & Rationale Severe sepsis and septic shock are characterized by a systemic inflammatory state secondary to an infectious cause with evidence of end-organ damage or hemodynamic instability Severe sepsis and septic shock are characterized by a systemic inflammatory state secondary to an infectious cause with evidence of end-organ damage or hemodynamic instability In the United States there are an estimated 215,000 deaths annually as a result of severe sepsis and septic shock In the United States there are an estimated 215,000 deaths annually as a result of severe sepsis and septic shock In the past, despite heroic measures septic shock and severe sepsis have carried a staggering mortality rate of 40 to 50 percent In the past, despite heroic measures septic shock and severe sepsis have carried a staggering mortality rate of 40 to 50 percent Surviving Sepsis Campaign: http://www.survivingsepsis.org. 2012.http://www.survivingsepsis.org

3. Background & Rationale Shapiro N, Howell MD, Talmor D. Implementation and Outcomes of the Multiple Urgent Sepsis Therapies (MUST) Protocol. Critical Care Medicine. 2006. 34(4), 1025-32. Newer methods of treatment such as those described by Rivers et. al. (Early Goal-directed Therapy) have demonstrated a 28-day reduction in mortality from Newer methods of treatment such as those described by Rivers et. al. (Early Goal-directed Therapy) have demonstrated a 28-day reduction in mortality from 49.2 to 33.3 percent Comparable results have been observed with similar protocols placing emphasis on urgency and appropriateness of treatment Comparable results have been observed with similar protocols placing emphasis on urgency and appropriateness of treatment

4. Background & Rationale Rivers E, Nguyen B, Havstad S, et al. Early Goal-directed Therapy in the Treatment of Severe Sepsis and Septic Shock. New England Journal of Medicine. 2001; 345(19), 1368-1377.

5. Background & Rationale The Society of Critical Care Medicine in conjunction with the European Society of Intensive Care Medicine have established recommendations for the management of severe sepsis and septic shock The Society of Critical Care Medicine in conjunction with the European Society of Intensive Care Medicine have established recommendations for the management of severe sepsis and septic shock The Surviving Sepsis Campaign was established to standardize the classification, diagnosis and treatment protocols The Surviving Sepsis Campaign was established to standardize the classification, diagnosis and treatment protocols The latest recommendations were released in The latest recommendations were released in 2008 Surviving Sepsis Campaign: http://www.survivingsepsis.org. 2012.http://www.survivingsepsis.org

6. Background & Rationale In summary, the Surviving Sepsis Campaign resuscitation bundle recommends the following be completed within the first 6 hours of diagnosis: In summary, the Surviving Sepsis Campaign resuscitation bundle recommends the following be completed within the first 6 hours of diagnosis: 1.ICU admission 2.Measurement of serum lactate within the first hour 3.Fluid resuscitation to achieve a CVP of ≥ 8 mmHg (≥ 12 mmHg in mechanically ventilated patients) 4.Maintenance of MAP ≥ 65 with the use of vasopressors if needed 5.Obtain blood cultures prior to the administration of antibiotics 6.Administer broad spectrum antibiotics within the first 3 hours of ED admission and within the first 1 hour of non-ED admission 7.Achieve a central venous oxygen saturation (ScvO2) > 70% OR a mixed central venous oxygen saturation M(SvO2) > 65% Surviving Sepsis Campaign: http://www.survivingsepsis.org. 2012.http://www.survivingsepsis.org

7. Background & Rationale On Kenmore Mercy Hospital implemented a modified sepsis bundle adapted from the University of Rochester Medical Center and Strong Memorial Hospital in concordance with the Surviving Sepsis Campaign On January 1st, 2011 Kenmore Mercy Hospital implemented a modified sepsis bundle adapted from the University of Rochester Medical Center and Strong Memorial Hospital in concordance with the Surviving Sepsis Campaign The modified sepsis bundle includes recommendations to have the ICU team notified and involved in patient care as soon as a patient with severe sepsis or septic shock has been identified in the emergency department The modified sepsis bundle includes recommendations to have the ICU team notified and involved in patient care as soon as a patient with severe sepsis or septic shock has been identified in the emergency department It was postulated that there would be an improvement in morbidity and length of stay in this select patient population at Kenmore Mercy Hospital after the implementation of 24-hour critical care coverage and the use of the modified sepsis bundle It was postulated that there would be an improvement in morbidity and length of stay in this select patient population at Kenmore Mercy Hospital after the implementation of 24-hour critical care coverage and the use of the modified sepsis bundle

8. Design A case-comparison retrospective analysis A case-comparison retrospective analysis Comparison of patients admitted with a diagnosis of severe sepsis and/or septic shock prior to and following the implementation of the protocol with 24 in-house critical care coverage Comparison of patients admitted with a diagnosis of severe sepsis and/or septic shock prior to and following the implementation of the protocol with 24 in-house critical care coverage Institutional review board approval Institutional review board approval

9. Design Inclusion criteria Inclusion criteria –The fulfillment of SIRS (systemic inflammatory response syndrome), AND –Identifiable source of infection, AND –A systolic blood pressure no greater than 90 mmHg on arrival or after a crystalloid-fluid challenge, OR –Blood lactate concentration ≥ 19.8 mg/dL (4 mmol/L), OR –Evidence of acute end-organ dysfunction Rivers E, Nguyen B, Havstad S, et al. Early Goal-directed Therapy in the Treatment of Severe Sepsis and Septic Shock. New England Journal of Medicine. 2001; 345(19), 1368-1377.

10. Design Exclusion criteria Exclusion criteria –age < 18 years –pregnancy –acute cerebral vascular accident (as a primary diagnosis) –acute coronary syndrome (as a primary diagnosis) –status asthmaticus –cardiac dysrhythmia (as a primary diagnosis) –contraindication to central venous catheterization –active gastrointestinal hemorrhage (as a primary diagnosis) –seizure on arrival –drug overdose –Do Not Resuscitate (DNR) order on arrival or within the first 72 hours of admission Rivers E, Nguyen B, Havstad S, et al. Early Goal-directed Therapy in the Treatment of Severe Sepsis and Septic Shock. New England Journal of Medicine. 2001; 345(19), 1368-1377.

11. Design

12. Methods Independent sample t-test analysis Independent sample t-test analysis Utilizing IBM Statistical Package for the Social Sciences (SPSS) software Utilizing IBM Statistical Package for the Social Sciences (SPSS) software Help from a statistically inclined colleague! Help from a statistically inclined colleague!

13. Outcome Measures Primary Primary –Absolute APACHE-II at 72 hours –Net reduction in APACHE-II at 72 hours Secondary Secondary –Hospital Length of Stay (days) –ICU Length of Stay (days) –Emergency Department Length of Stay (hours) –Volume infused in the first 6 and 12 hours –Volume infused over the first 24 hours –MAP at 24 hours

14. APACHE-II Score Knaus WA, Draper EA, Wagner DP, Zimmerman JE. 1985. "APACHE II: a severity of disease classification system". Critical Care Medicine 13 (10): 818–29.

15. Results Without Protocol (N=95)With Protocol (N=53) Age (years) 68.265.1 Weight on Arrival (kg) 78.485.6 Temperature on Arrival (˚C) 37.637.9 Heart Rate on Arrival (bpm) 106 24 Hour Input (liters) 6.058.42 24 Hour Ouput (liters) 2.112.34 MAP at 24 Hours 8284.7 Percentage Receiving Central Line 49.4%98.1% *Mortality 25.3% (24/95)20.7% (11/53) *Underpowered to detect mortality

16. Results Without Protocol (N=95) With Protocol (N=53)p Value APACHE-II at Arrival 17.521.5<0.00001 Absolute APACHE-II at 72 Hours 15.714.90.419 Net Reduction in APACHE at 72 Hours 1.86.5<0.00001 ED Length of Stay (Hours) 4.513.510.002 ICU Length of Stay (Days) 7.26.10.296 Hospital Length of Stay (Days) 13.610.70.046 Input in first 6 Hours (liters) 1.622.230.002 Input in first 12 Hours (liters) 3.135.15<0.00001

17. Results Without Protocol (N=95) With Protocol (N=53)p Value APACHE-II at Arrival 17.521.5<0.00001 Absolute APACHE-II at 72 Hours 15.714.90.419 Net Reduction in APACHE at 72 Hours 1.86.5<0.00001 ED Length of Stay (Hours) 4.513.510.002 ICU Length of Stay (Days) 7.26.10.296 Hospital Length of Stay (Days) 13.610.70.046 Input in First 6 Hours (liters) 1.622.230.002 Input in First 12 Hours (liters) 3.135.15<0.00001

18. Results

21. Meanp Value Age (Years) Mortality (N=35)76.4 <0.001 No Mortality (N=113)63.4 APACHE-II at 72 Mortality (N=35)20.4 <0.001 No Mortality (N=113)13.8 ED Length of Stay (Hours) Mortality (N=35)4.2 0.98 No Mortality (N=113)4.1 ICU Length of Stay (Days) Mortality (N=35)8.9 0.11 No Mortality (N=113)6.2 Hospital Length of Stay (Days) Mortality (N=35)14.9 0.19 No Mortality (N=113)11.9

22. Results Meanp Value Age (Years) Mortality (N=35)76.4 <0.001 No Mortality (N=113)63.4 APACHE-II at 72 Mortality (N=35)20.4 <0.001 No Mortality (N=113)13.8 ED Length of Stay (Hours) Mortality (N=35)4.2 0.98 No Mortality (N=113)4.1 ICU Length of Stay (Days) Mortality (N=35)8.9 0.11 No Mortality (N=113)6.2 Hospital Length of Stay (Days) Mortality (N=35)14.9 0.19 No Mortality (N=113)11.9

23. Time (Hours) 06121824 Temperature ˚C No Protocol (N=95)37.537.337.5 Protocol (N=53)37.937.437.637.737.5 Heart Rate (bpm) No Protocol (N=95)10698979495 Protocol (N=53)10696939193 Input (liters) No Protocol (N=95)0.001.673.134.706.05 Protocol (N=53)0.002.235.156.968.42 Output (liters) No Protocol (N=95)0.000.421.011.562.10 Protocol (N=53)0.000.360.961.602.34 MAP No Protocol (N=95)79.076.976.076.478.2 Protocol (N=53)75.073.675.674.178.8

24. Time (Hours) 06121824 Temperature ˚C No Protocol (N=95)37.537.337.5 Protocol (N=53)37.937.437.637.737.5 Heart Rate (bpm) No Protocol (N=95)10698979495 Protocol (N=53)10696939193 Input (liters) No Protocol (N=95)0.001.673.134.706.05 Protocol (N=53)0.002.235.156.968.42 Output (liters) No Protocol (N=95)0.000.421.011.562.10 Protocol (N=53)0.000.360.961.602.34 MAP No Protocol (N=95)79.076.976.076.478.2 Protocol (N=53)75.073.675.674.178.8

25. Conclusions The patients in the protocol arm had a significantly higher APACHE-II on arrival The patients in the protocol arm had a significantly higher APACHE-II on arrival (21.5 vs 17.5, p<0.00001) There was a significant difference in the net reduction in the APACHE-II score at 72 hours in the protocol arm but no significant difference in the absolute APACHE-II score at 72 hours (14.9 vs 15.7, p=0.419) There was a significant difference in the net reduction in the APACHE-II score at 72 hours in the protocol arm (6.5 vs 1.8, p<0.00001) but no significant difference in the absolute APACHE-II score at 72 hours (14.9 vs 15.7, p=0.419)

26. Conclusions The use of a sepsis bundle and protocol significantly reduced the emergency department length of stay by 60 minutes (p=0.002) The use of a sepsis bundle and protocol significantly reduced the emergency department length of stay by 60 minutes (p=0.002) The use of a sepsis bundle and protocol significantly reduced the hospital length of stay by 2.9 days (p=0.046) The use of a sepsis bundle and protocol significantly reduced the hospital length of stay by 2.9 days (p=0.046) The fluid input for the first 6 & 12 hours was significantly greater in the protocol vs the no protocol arms (p=0.002 & p<0.00001, respectivley) The fluid input for the first 6 & 12 hours was significantly greater in the protocol vs the no protocol arms (p=0.002 & p<0.00001, respectivley)

27. Discussion and Considerations 19 of the 78 charts identified (24 percent) after the implementation of the sepsis bundle failed to follow the protocol These are missed opportunities to improve the patient’s APACHE-II and significantly reduce their ED & Hospital lengths of stay

28. Discussion and Considerations The data included out layers in both arms that may have actually skewed the results in favor non- significance The data included out layers in both arms that may have actually skewed the results in favor non- significance However, these were still included in the analysis in order to preserve the integrity of the data However, these were still included in the analysis in order to preserve the integrity of the data Despite the out layers, hospital and emergency department length of stay were still found to be significantly reduced Despite the out layers, hospital and emergency department length of stay were still found to be significantly reduced

29. Discussion and Considerations Underpowered to detect mortality between the two arms Underpowered to detect mortality between the two arms Analysis of the entire population reflects what we already know: Analysis of the entire population reflects what we already know: –The higher the APACHE-II, the greater the mortality –The higher the APACHE-II, the greater the mortality (20.4 vs. 13.8, p<0.001) –The older the patient, the greater the mortality (76.4 vs 63.4, p<0.001) APACHE-II has only been validated as a predictor of mortality at admission and not as a dynamic predictor of mortality. However, APACHE-II is routinely used in the literature as a severity of illness index in a dynamic fashion (see Rivers et al) APACHE-II has only been validated as a predictor of mortality at admission and not as a dynamic predictor of mortality. However, APACHE-II is routinely used in the literature as a severity of illness index in a dynamic fashion (see Rivers et al)

30. Discussion and Considerations Statistical considerations Statistical considerations –p-Value of < 0.00001 is not always a good thing –As in the case of the net reduction of the APACHE-II and APACHE-II at arrival having p<0.00001 –Can either mean the data is truly highly significant or there is the presence of a Type-I (alpha) error  e.g. Falsely rejecting the null hypothesis

31. Discussion and Considerations Can the principles learned from early goal directed therapy be executed in a small community based hospital and have meaningful outcomes? Can the principles learned from early goal directed therapy be executed in a small community based hospital and have meaningful outcomes? –YES !!!!!!!!!!!!!!!!

32. Questions

33. References 1. Schmidt GA, Mandel J, Parsons, PE, et al. Management of Severe Sepsis and Septic Shock in Adults. UpToDate®. February 3, 2010. 2. Shapiro N, Howell MD, Talmor D. Implementation and Outcomes of the Multiple Urgent Sepsis Therapies (MUST) Protocol. Critical Care Medicine. 2006. 34(4), 1025-32. 3. Dellinger RP, Levy, MM, Carlet JM, et. al. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2008. Critical Care Medicine. 2008. 4. The Surviving Sepsis Campaign: http://www.survivingsepsis.org. 2012. http://www.survivingsepsis.org 5. Rivers E, Nguyen B, Havstad S, et al. Early Goal-directed Therapy in the Treatment of Severe Sepsis and Septic Shock. New England Journal of Medicine. 2001; 345(19), 1368-1377. 6. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. 1985. "APACHE II: a severity of disease classification system". Critical Care Medicine 13 (10): 818–29. 7. Bryan-Brown CW, Dracup K. Procrastination is the Thief of Time: Surviving Guidelines. American Journal of Critical Care. 2004; 14(4), 287-289. 8. Talmore D, Greenberg D, Howell M et al. The Cost and Cost-effectiveness of an Integrated Sepsis Treatment Protocol. Critical Care Medicine. 2008; 36(4), 1168-1174.