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 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
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
Surviving Sepsis Campaign: http://www.survivingsepsis.org. 2012. Background & Rationale
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
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. 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. 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 Surviving Sepsis Campaign was established to standardize the classification, diagnosis and treatment protocols
The latest recommendations were released in 2008
Surviving Sepsis Campaign: http://www.survivingsepsis.org. 2012. Background & Rationale
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. Background & Rationale
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
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 Design
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
Institutional review board approval Design
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. Design
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. Design Methods
Independent sample t-test analysis
Utilizing IBM Statistical Package for the Social Sciences (SPSS) software
Help from a statistically inclined colleague! Outcome Measures
Primary – Absolute APACHE-II at 72 hours – Net reduction in APACHE-II at 72 hours
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
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.
Results
Without Protocol (N=95) With Protocol (N=53)
Age (years) 68.2 65.1
Weight on Arrival (kg) 78.4 85.6
Temperature on Arrival (˚C) 37.6 37.9
Heart Rate on Arrival (bpm) 106 106
24 Hour Input (liters) 6.05 8.42
24 Hour Ouput (liters) 2.11 2.34
MAP at 24 Hours 82 84.7
Percentage Receiving Central Line 49.4% 98.1%
*Mortality 25.3% (24/95) 20.7% (11/53)
*Underpowered to detect mortality Results
Without Protocol With Protocol (N=95) (N=53) p Value
APACHE-II at Arrival 17.5 21.5 <0.00001
Absolute APACHE-II at 72 Hours 15.7 14.9 0.419
Net Reduction in APACHE at 72 1.8 6.5 <0.00001 Hours
ED Length of Stay (Hours) 4.51 3.51 0.002
ICU Length of Stay (Days) 7.2 6.1 0.296
Hospital Length of Stay (Days) 13.6 10.7 0.046
Input in first 6 Hours (liters) 1.62 2.23 0.002
Input in first 12 Hours (liters) 3.13 5.15 <0.00001 Results
Without Protocol With Protocol (N=95) (N=53) p Value
APACHE-II at Arrival 17.5 21.5 <0.00001
Absolute APACHE-II at 72 Hours 15.7 14.9 0.419
Net Reduction in APACHE at 72 1.8 6.5 <0.00001 Hours
ED Length of Stay (Hours) 4.51 3.51 0.002
ICU Length of Stay (Days) 7.2 6.1 0.296
Hospital Length of Stay (Days) 13.6 10.7 0.046
Input in First 6 Hours (liters) 1.62 2.23 0.002
Input in First 12 Hours (liters) 3.13 5.15 <0.00001 Results
Comparison in the Net Reduction of the APACHE-II Score at 72 Hours (p < 0.00001)
With Protcol (N=53) 6.5
Without Protocol (N=95) 1.8
0 1 2 3 4 5 6 7
APACHE-II Point Reduction Results
Comparison in ED Length of Stay (p = 0.002)
5
4 4.51 3 3.51 Hours 2
1
0 Without Protocol (N=95) With Protcol (N=53) Results
Comparison in Hospital Length of Stay (p = 0.046)
14
12 13.6
10 10.7 Hospital Days 8 6
4 2
0 Without Protocol (N=95) With Protcol (N=53) Results
Mean p 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 Results
Mean p 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 Time (Hours) 0 6 12 18 24
Temperature ˚C
No Protocol (N=95) 37.5 37.3 37.5 37.5 37.5
Protocol (N=53) 37.9 37.4 37.6 37.7 37.5
Heart Rate (bpm)
No Protocol (N=95) 106 98 97 94 95
Protocol (N=53) 106 96 93 91 93
Input (liters)
No Protocol (N=95) 0.00 1.67 3.13 4.70 6.05
Protocol (N=53) 0.00 2.23 5.15 6.96 8.42
Output (liters)
No Protocol (N=95) 0.00 0.42 1.01 1.56 2.10
Protocol (N=53) 0.00 0.36 0.96 1.60 2.34
MAP
No Protocol (N=95) 79.0 76.9 76.0 76.4 78.2
Protocol (N=53) 75.0 73.6 75.6 74.1 78.8 Time (Hours) 0 6 12 18 24
Temperature ˚C
No Protocol (N=95) 37.5 37.3 37.5 37.5 37.5
Protocol (N=53) 37.9 37.4 37.6 37.7 37.5
Heart Rate (bpm)
No Protocol (N=95) 106 98 97 94 95
Protocol (N=53) 106 96 93 91 93
Input (liters)
No Protocol (N=95) 0.00 1.67 3.13 4.70 6.05
Protocol (N=53) 0.00 2.23 5.15 6.96 8.42
Output (liters)
No Protocol (N=95) 0.00 0.42 1.01 1.56 2.10
Protocol (N=53) 0.00 0.36 0.96 1.60 2.34
MAP
No Protocol (N=95) 79.0 76.9 76.0 76.4 78.2
Protocol (N=53) 75.0 73.6 75.6 74.1 78.8 Conclusions
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 (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)
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 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) 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 Discussion and Considerations
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
Despite the out layers, hospital and emergency department length of stay were still found to be significantly reduced Discussion and Considerations
Underpowered to detect mortality between the two arms
Analysis of the entire population reflects what we already know: – 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) Discussion and 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
Discussion and Considerations
Can the principles learned from early goal directed therapy be executed in a small community based hospital and have meaningful outcomes? –YES !!!!!!!!!!!!!!!! Questions 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.
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.