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
(N=95)
With Protocol
(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
Hours
1.8
6.5
<0.00001
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
(N=95)
With Protocol
(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
Hours
1.8
6.5
<0.00001
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)
6.5
With Protcol (N=53)
1.8
Without Protocol (N=95)
0
1
2
3
4
APACHE-II Point Reduction
5
6
7
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
No Mortality (N=113)
63.4
<0.001
APACHE-II at 72
Mortality (N=35)
20.4
No Mortality (N=113)
13.8
<0.001
ED Length of Stay (Hours)
Mortality (N=35)
4.2
No Mortality (N=113)
4.1
0.98
ICU Length of Stay (Days)
Mortality (N=35)
8.9
No Mortality (N=113)
6.2
0.11
Hospital Length of Stay (Days)
Mortality (N=35)
14.9
No Mortality (N=113)
11.9
0.19
Results
Mean
p Value
Age (Years)
Mortality (N=35)
76.4
No Mortality (N=113)
63.4
<0.001
APACHE-II at 72
Mortality (N=35)
20.4
No Mortality (N=113)
13.8
<0.001
ED Length of Stay (Hours)
Mortality (N=35)
4.2
No Mortality (N=113)
4.1
0.98
ICU Length of Stay (Days)
Mortality (N=35)
8.9
No Mortality (N=113)
6.2
0.11
Hospital Length of Stay (Days)
Mortality (N=35)
14.9
No Mortality (N=113)
11.9
0.19
Time (Hours)
0
6
12
18
24
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
No Protocol (N=95)
106
98
97
94
95
Protocol (N=53)
106
96
93
91
93
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
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
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
Temperature ˚C
Heart Rate (bpm)
Input (liters)
Output (liters)
MAP
Time (Hours)
0
6
12
18
24
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
No Protocol (N=95)
106
98
97
94
95
Protocol (N=53)
106
96
93
91
93
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
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
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
Temperature ˚C
Heart Rate (bpm)
Input (liters)
Output (liters)
MAP
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 nonsignificance

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.