present kritikus foundation & redding critical care medical group
TRANSCRIPT
Present
Kritikus Foundation & Redding Critical Care Medical
Group
ShockShock
If you come to the ED, with sepsis and a lactic acid > 4 and MAP > 100 ?
A. Your chances of survival are greater than if you are hypotensive
B. Your chances of survival are less than if you are hypotensive
C. Your chances of survival are the same as the group of hypotensive patients
D. All of the above
Michael W. Donnino, MD; Bryant Nguyen, MD;Gordon Jacobsen, PhD; Michael Tomlanovich, MD; Emanuel Rivers, MD.
Henry Ford Hospital, Detroit, MI
Cryptic Septic Shock: Cryptic Septic Shock: A Sub-Analysis of Early, A Sub-Analysis of Early, Goal-Directed TherapyGoal-Directed Therapy
Methods-Post-hoc Analysis RandomizationMethods-Post-hoc Analysis Randomization
• Patients were randomized to conventional care
- SaO2 > 92% and decreased work of breathing
- CVP between 8-12 with fluids
• Conventional care as above and central venous oximetry (ScvO2) > 70%
- Hb > 10
- Dobutamine
ResultsResults
Control
n=23
Protocol
n=25p value
MAP 116 mm Hg 117.6 mm Hg
APACHE Same Same
MODS Same Same
SAPS Same Same
ScvO2 45% 44%
ScvO2 at 6 hours 59% 76% < 0.05
Fluid Received Less Significantly more < 0.05
Mortality 70% 24% 0.002
SIRS: LA > 4 mmol/liter; MAP >100 mm Hg
A multi-disciplinary community A multi-disciplinary community hospital program for early and hospital program for early and rapid resuscitation of shock in rapid resuscitation of shock in
non-trauma patientsnon-trauma patients
Frank Sebat, MS, MDFrank Sebat, MS, MD
– Decrease LOC– Tachypnea– Cool or mottled
extremities
– Decrease urine output– Metabolic acidosis– Hypothermia
Shock is a syndrome of global inadequate tissue perfusion which can be manifested by
Why a Shock Why a Shock Program at Your Program at Your
Facility ?Facility ?
Why a Shock Program at Your Facility?Why a Shock Program at Your Facility?
• High mortality - 100% fatal if untreated
• 71% ICU mortality for septic shock 1975
• 56% day 28 mortality for septic shock (multi center trial in France, JAMA, 1995)
• 50% mortality of septic shock by recent studies
• A well defined syndrome which could lend itself to earlier identification of patient population
• Pathophysiology and sequelae are predictable facilitating standardization of treatment
• Large number of patients estimated to be approximately 900,000 / year in the US
Why a Shock Program at Your Facility?Why a Shock Program at Your Facility?
Why a Shock Program at Your Facility?Why a Shock Program at Your Facility?
• A standardized and systematic approach to shock will lead to: • Early Recognition
• Early Initiation of Best Practice
Improved Outcomes !
Background &Background &
Prior Experience Prior Experience
Medical Emergency TeamsMedical Emergency Teams
A Shock Team
In A General Hospital
Edward D. Frank, M.D. Department of Surgery Harvard Medical School
Published in Anesthesia and AnalgesiaNovember - December 1967
Portable Monitoring Equipment at BedsidePortable Monitoring Equipment at Bedside
Edward David Frank, MD
Flow Flow Sheet Sheet Used for Used for Shock Shock PatientsPatients
Confused, Shock Appearance
Cool, Moist
Blood Pressure
Heart Rate
Respiratory Rate
Temperature
Urinary Output
Fluid BalanceHCT
Cardiac Output
CVP
Arterial Blood Gases
Whole Blood Treatment
Pressor Drug IV
Cooling Blanket
Antibiotic Treatment
Time
Medical Emergency TeamMedical Emergency Team
A New Strategy To Identify and Intervene In High-risk PatientsA New Strategy To Identify and Intervene In High-risk Patients
460 Bed University Teaching Hospital Sydney, Australia
1990-1995, Lee, Bishop and Hillman
Published in Anesthesia and Intensive Care, 1995
Criteria for Calling METCriteria for Calling MET
All Cardiac and Respiratory Arrests
ACUTE CHANGES IN: VITAL SIGNS:
• AIRWAY • Threatened
• BREATHING • Respiratory rate <5 or >36
• CIRCULATION • Pulse <40 or >140, SBP <90 or >200
• NEUROLOGY• Sudden decrease LOC and repeated
or prolonged seizures
• OTHER • Any patient who does not fit the above criteria who you are seriously worried about
Call 666 and tell the operator where you are
Medical Emergency TeamMedical Emergency TeamSydney, Australia Sydney, Australia
• 522 emergency calls in one year period• 28% were cardiac arrests• 71% were as follows:
– Decreased level of consciousness 42% – Hypotension 27%– Hypertension 2%– RR 12% – Pulse 10%– Other 7%
Effects of a MET on Reduction of Effects of a MET on Reduction of Unexpected Cardiac ArrestsUnexpected Cardiac ArrestsMichael D. Buist, BMJ 2002Michael D. Buist, BMJ 2002
• 19,317 patients in 1996 compared to 22,847 patients in 1999 in Dandenong Hospital, Australia
• Unexpected cardiac arrests- 3.77/1000 admissions vs. 2.05 /1000 admissions
• After adjustment for severity of illness a 50% reduction in incidences of cardiac arrest
• 29% reduction in mortality
MET Decrease Incidence of Cardiac ArrestMET Decrease Incidence of Cardiac Arrest
• OBJECTIVE: To determine the effect on cardiac arrests and overall hospital mortality of an intensive care-based medical emergency team.
• DESIGN AND SETTING: Prospective before-and-after trial in a tertiary referral hospital.
• PATIENTS: Consecutive patients admitted to hospital during a 4-month "before" period (May-August 1999) (n = 21 090) and a 4-month intervention period (November 2000 -February 2001) (n = 20 921).
Buist MD, Moore GE, Bernard SA, et al. Effects of a medical emergency team on reduction of incidence of and mortality from unexpected cardiac arrests in hospital: preliminary study. BMJ 2002; 324:387-390
MET ResultsMET Results
• Hospital deaths– 302 before– 222 intervention period (RRR: 26%; P = 0.004)
• Cardiac Arrests– 63 before – 22 intervention period (RRR: 65%; P < 0.001)
• Deaths Due to Cardiac Arrests– 37 before– 16 intervention period (RRR: 56%; P = 0.005)
• Survivors of cardiac arrest ICU/hospital bed days– 163 / 1533 before– 33 / 159 (RRR: 80-88%; P < 0.001)
How to Implement a Shock Program at Your FacilityHow to Implement a Shock Program at Your Facility
EducationEducation EducationEducation Education Education
EducationEducation
• To the Emergency Medical System (pre hospital)
• All nursing units within the hospital / nursing supervisors
• Intensivists, surgeons, interventional radiologists, anesthelogists, and medical staff at large
• Mock shock alerts
• Shock binders and criteria posted in all units
EducationEducation
• On Going Education to Nursing Units As Needed• Critical Care Research Coordinator
– Responds to all shock alerts– Reviews care / protocol adherence– Assists in data collection and analysis
• Medical Director – Oversees program development, implementation, data analysis and
process improvement
• Inservice Education• Research Assistant (secretarial / data entry)
Examples of Examples of Education Education PresentedPresented
Types of ShockTypes of Shock
• Hypovolemic Due to low circulating blood volume. Result of GI bleed, severe dehydration.
• Obstructive Result of pulmonary embolism, cardiac tamponade, tension pneumothorax or other causes of obstructed blood flow.
• Cardiogenic Due to muscle, valve or rhythm problem causing significant drop in cardiac output.
Types of ShockTypes of Shock
• Septic or Distributive Result of an infection, pancreatitis or other sources of tissue injury releasing mediators that decrease vascular tone dropping blood pressure to critical levels.
• Anaphylactic A reaction to drug or environmental agent resulting in vasodilation (similar to sepsis) resulting in critically low blood pressure, usually with respiratory involvement (bronchospasm).
Hemodynamics Of ShockHemodynamics Of Shock
BP = CO X SVR (HR x SV)
Hemodynamics Of ShockHemodynamics Of Shock
SVR =BP
CO x 60
COMPONENTS OF BPStroke Volume
Aortic Elasticity
Aortic Valve
Arteriolar Resistance
}S}S}S}S
}D
MAP = HR x SV x SVRMAP = HR x SV x SVR
TissueTissue
DecreasedPreload
i.e., GI Bleed
Hypovolemic ShockHypovolemic Shock
or BP = BP = CO X CO X SVR SVR
EndotoxinPancreatitisAnaphylaxis
Septic / Distributive ShockSeptic / Distributive Shock
BP = CO x SVRor
A.M.I. Valve Failure
P.E.Tamponade
Cardiogenic / Obstructive ShockCardiogenic / Obstructive Shock
NL BP = CO x SVRor
Leads to
cardiogenic
shock
ALLALLALLALL SHOCKSHOCKSHOCKSHOCK
FLOW
MAP60 120
Coronary Artery Blood FlowCoronary Artery Blood Flow
Target BP
Shock Leads ToShock Leads To
Over time Code Blue
• Decreased mentation
• Decreased cardiac performance
– Leading to decreased respiratory compensation
Comparisons Between Ward and Intensive Care Unit Comparisons Between Ward and Intensive Care Unit (ICU) Patients with Septic Shock (ICU) Patients with Septic Shock Critical Care Medicine 1998Critical Care Medicine 1998
U of Iowa Ward (n=10) ICU (n=31)
Median APACHE II18.5 (range 10-38) (mean 20 + 9)
24 (range 5-39) (mean 23 + 10)
Median min to ICU transfer
67 (range 10-360) (mean 148 + 140)
0
>1 hr time to inotropic support
89% (8/9) 43% (13/30)
Median time (min) to first IV bolus
27 (range 0-675) (mean 100 + 206)
15 (range 0-1145) (mean 12 + 251)
Death 70% (7) 39% (12)
Recognition of ShockRecognition of Shock
Frequently obvious, but can be subtle
• Anxiety stupor
• Cool extremities, but absent in early sepsis syndrome
Recognition of ShockRecognition of Shock
Frequently obvious, but can be subtle
• Tachypnea or tachycardia almostalways present, but non specific
• Hypotension--frequently, but not always
• Oliguria--takes time to assess
How Do We Recognize Shock Sooner?How Do We Recognize Shock Sooner?
• Learn the manifestations
• Have a high index of suspicion
• Once the question of shock is raised, go through the drill, i.e., Hx, exam, lab, repeat observation
Burden of proof on the caregiver i.e., prove to yourself the patient is not in shock!
C.N.S. Manifestations of ShockC.N.S. Manifestations of Shock
Lethargy / Stupor
Coma
Apathy
Anxiety
Skin Manifestations of Shock: Livedo reticularisSkin Manifestations of Shock: Livedo reticularis
Cardiac Manifestations of ShockCardiac Manifestations of Shock
Dysrhythmias
Myocardial ischemia, chest pain
Myocardial depression
ALL SHOCK LEADS TO ALL SHOCK LEADS TO CARDIOGENIC SHOCKCARDIOGENIC SHOCK
Abdominal Manifestations of ShockAbdominal Manifestations of Shock
Our window to the abdomen1st Hour/Kidney Oliguria
Ileus1st 24 Hours/Bowel
ATN, increasing LFTs24-72 Hours
leading to multi organ failure
Ischemic bowel, acalculus cholecystitisDay 3-21 occult abdominal problems
Acid accumulation in the body
BE < -5 meq/LLactic Acid > 2.0 meq/L
Metabolic Manifestations of ShockMetabolic Manifestations of Shock
Coagulation Manifestations of ShockCoagulation Manifestations of Shock
• Decreasing platelet count
– Endothelial injury with consumption in lung, liver, bowel
– DIC
• Increasing protime
– Decrease synthesis of coagulation factor by the liver
– Increase consumption of clotting factors
Inclusion Criteria Inclusion Criteria For Calling A Shock AlertFor Calling A Shock Alert
SBP < 90, MAP < 60 with one or more….or
with three or more………………………. and not corrected with one liter rapidly infused crystalloid:
1. Temperature < 36° C 4. Cool extremities or or 96.8 ° F skin mottling
2. RR > 20 bpm 5. Oliguria < 30 cc/hour
3. Altered mental status 6. Lactic Acid > 2.0 or BE < -5 mmol/L
Hypotension
Normotensionof the
following}
Exclusion Criteria Exclusion Criteria For Calling A Shock AlertFor Calling A Shock Alert
• Trauma as cause of shock
• Acute MI as cause of shock
• Patients who are not candidates for ACLS treatment
• Patients already receiving ACLS therapy
SHOCKSHOCK SHOCKSHOCK CALLCALL
ALERTALERT
TreatmentTreatment
Treatment Goals for Shock ResuscitationTreatment Goals for Shock Resuscitation
• Decrease work of breathing (early intubation) • MAP > 70
– Aggressive volume resuscitation (CVP > 12)– Levophed
• UO > .5 ml/kg/hr
• ScvO2 > 70 (Rivers) SvO2 > 60– SaO2 > 93%
– Transfuse HCT > 30– Dobutamine
Weil MH; Shubin H. JAMA 1969 Jan 13
Standardized Best Practice:Standardized Best Practice:V. I. P.P. S. Approach to Bedside Management of ShockV. I. P.P. S. Approach to Bedside Management of Shock
S
ressors / Pump
harmacy
entilation/oxygenation
pecific
nfusion of VOL
PI
P
V
Treatment - V. I. P. P. S. ApproachTreatment - V. I. P. P. S. Approach
entilation / oxygenation– Supplemental Oxygen
– Early Intubation
– Adequate Hemoglobin
Prospective Study of the Treatment of Prospective Study of the Treatment of Septic ShockSeptic Shock
The Lancet, June 3, 1978113 patients over 3 years
1975 1976 1977
Mechanical Vent 51% 69% 70%
Started Early* 0% 3% 20%
Mortality 71% 54% 47%
*Started in anticipation of deterioration in pulmonary gas-exchange
Treatment - V. I. P. P. S. ApproachTreatment - V. I. P. P. S. Approach
nfusion of VOL• 2 16 ga IVs
• Central line
• Up to two liters of Crystalloid
• 500 cc of Colloid up to 1,000 cc
• Packed red blood cells for Hgb < 9, < 10 for sepsis
Treatment - V. I. P. P. S. ApproachTreatment - V. I. P. P. S. Approach
• MAP < 60 – With Dopamine or Levophed for Cardiogenic Shock
– Levophed for Septic Shock
• Treat dysrhythmia
• Rule out tamponade, ischemia, PE, or valvular abnormality
ressors / Pump
Treatment - V. I. P. P.S. ApproachTreatment - V. I. P. P.S. Approach
harmacy• Antibiotics, Activated Protein C, Hydrocortisone for pressor dependent sepsis
• Albuterol, steroids, H1 and H2 blockers for anaphylaxis
• Dobutamine / Nipride for cardiogenic shock, MAP > 60
• Thrombolytics for PE
• Other
Treatment - V. I. P. P.S. ApproachTreatment - V. I. P. P.S. Approach
pecific• Endoscopy for upper GI bleed
• O.R. for ruptured Abdominal Aortic Aneurysm or perforated viscus
• Pericardiocentesis for tamponade
• Activated protein C for toxic shock
Shock Screening CriteriaHypotension SBP<90, MAP< 60 and one or more of the following:
Normotension with three or more of the following:
- Anxiety, apathy, agitation, coma or lethargy - Respirations > 20 bpm - Lactic acid > 2.0 or BE < -5 mmol/L- Cool extremities or skin mottling - Oliguria < 30 cc/hour - Temperature < 36oC
Screening Criteria still met andExclusion Criteria do not apply
CALL SHOCK ALERTNotify Primary MD
Shock team, cart, lab panel,
and ICU bed activated
Initiate 500 cc Fluid Increments(2) 16 gauge IV or central line
Up to 2000 cc per protocol
Respiratory SupportSaO2 > 92
Decrease work of breathingEarly intubation
Goals:- MAP > 70 - UO > 30 Cc/hr- Decreased work - Improve skin or
of breathing peripheral perfusion
Goals Not Met:Continue Fluid Challenge Protocol
Start Dopamine or Levophed MAP < 70Add Dobutamine if MAP > 70
Rapid TransferICU or OR
Septic Shock andAntibiotic Protocols
Cardiogenic ShockProtocol
Anaphylactic ShockProtocol
PATIENT IN SHOCK
Hypovolemic ShockTransfusion and Coag
Factor Protocols
Goals not met or increase in pressor requirement or deteriorating oxygenationIntubate and place ScvO2 catheter for hypovolemic or septic shock
Consider PA catheter for cardiogenic shockAdditional Goals:
- ScvO2 > 70 SvO2 > 60 - Cardiac IndexSaO2 > 92 > 2.7 (cardiogenic)Transfuse to Hb 10 > 3.0 (hypovolemic)Dobutamine > 4.5 (septic and anaphylactic)
Fluid Bolus1000 cc for ER patients250 cc for floor patients
Exclusion Criteria- Trauma as cause of shock- Acute MI as cause of shock- Patients who are not
candidates for aggressivetreatment by advanced directive,or pre-existing diagnosis
- Patients in critical care unitsalready receiving ACLS therapy
Goals for Shock ResuscitationGoals for Shock Resuscitation
• Decrease work of breathing (early intubation)
• Aggressive volume resuscitation, CVP >12
• MAP > 70 (Levophed)
• UO > .5 ml/kg/hr
• SvO2 > 60 (Rivers ScvO2 >70)
– SaO2 > 93%
– HCT > 30
– Dobutamine, CI > 2.5 (cardiogenic) , > 2.7 hypovolemic, > 3.0 septic or anaphylactic SvO2 supersedes CI
Early Goal Directed Therapy in the Treatment of Early Goal Directed Therapy in the Treatment of Severe Sepsis and Septic ShockSevere Sepsis and Septic ShockEmanuel Rivers MD et al, NEJM November 2001
Between 7 and 72hours of therapy
ControlN = 130
TreatmentN = 133
SvO2 65.3 70.4
LA 3.9 3.0
Base deficit/pH 5.1 (pH 7.4) 2.0 (pH 7.36)
Apache II / organ failure 19.5 (p <.001) 13
Hospital Mortality 46.5 30.7 (p =.009)
Hemodynamic OptimizationHemodynamic OptimizationKern and Shoemaker, CC Medicine, 2002, Vol 30
Hemodynamic OptimizationHemodynamic OptimizationKern and Shoemaker, CC Medicine, 2002, Vol 30
Overview of Overview of Patient Patient Enrollment and Enrollment and Hemodynamic Hemodynamic SupportSupport
Kaplan-Meier Estimates of Mortality and Kaplan-Meier Estimates of Mortality and Causes of In-Hospital DeathCauses of In-Hospital Death
TreatmentsTreatmentsAdministeredAdministered
Continued Continued Implementation of the Implementation of the
Shock ProgramShock Program
Mock Shock Alerts with the Shock TeamMock Shock Alerts with the Shock Team
• Prehospital EMS
• ER physician and
nurse
• Intensivists and ICU
nurse
• Nursing supervisor
• Respiratory therapy
• Clinical laboratory
• Social and Pastoral
services
• Radiology
• EKG
• Pharmacy
Mock Shock Alerts IncludeMock Shock Alerts Include
called by any health care professional in field, ER, and all hospital nursing units (based on inclusion and exclusion criteria) activates: • The Shock Team
• Shock Alert Protocols
• Shock Cart • Shock Bed in ICU (available at all times)
– Hypovolemic – Cardiogenic/Obstructive– Septic – Anaphylactic
“Shock Alert”
Key Points of Shock ProgramKey Points of Shock Program
• Early recognition:
• Rapid response by Shock Team
• Early / Aggressive treatment
• Rapid transfer to ICU or O.R.
• Application of Best Practice
““Shock Alert”Shock Alert”
Study MethodsStudy Methods
• Control Group were patients who came into Redding Medical Center between 1998 and June 2000 who qualified by inclusion / exclusion criteria
• Intensive education and implementation of protocols and mock shock alerts during June 2000
• Treatment Group were all patients who qualified by inclusion/exclusion criteria starting July 1, 2000
ResultsResults
Identification of Patients in ShockIdentification of Patients in Shock
• Control 86 /20,976 or 1/244 Admissions
• Protocol 103/9,120 or 1/89 Admissions
•p < 0.001Increased the identification of shock
by a factor of 300%
Sensitivity & Specificity of Shock AlertsSensitivity & Specificity of Shock Alerts
100%
83%
17%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Shock Alert Criteria Met /In Shock
Alert Called In Shock Alert Called In NotInShock
Shock Alert Criteria Met Alert Called Alert Called
In Shock In Shock Not In Shock
3:27
5:46
3:37
4:28
6:04
2:482:35
0:49
2:472:58
3:23
2:352:43
4:19
3:22
2:25
1:57
1:00
2:00
3:00
4:00
5:00
6:00
7:00
Shock Alert IntensivistArrival***
ICU/ORAdmit**
2L Fluid*** Central Line PA Cath* Antibiotics Pressors TrachealIntubation
Shock: Time To Treatment IntervalsShock: Time To Treatment IntervalsTime zerozero is when signs & symptoms of shock could have
been first recognized determined by retrospective review
* P = < .1** P = < .05*** P = < .001
0
Control
Treatment
medians control na / 0:15 2:00 / 0:50 2:47 / 1:30 3:52 / 1:45 1:53 / 1:40 3:50 / 2:10 3:59 / 3:10 1:52 / 2:00 1:33 / 1:33 protocol
Relative Reduction= 28.5% **
Absolute Reduction = 11.6% **
APS & APACHE ScoresAPS & APACHE Scores
**P = < 0.05
Control
Treatment
60.5
72.6
61.5
40.7
74.7
29.1
0
10
20
30
40
50
60
70
80
90
APS APACHE III Actual Mortality
Types of ShockTypes of Shock
5%
13%
38%42%
2%0%
10%
42%
48%
1%
0%
10%
20%
30%
40%
50%
60%
Anaphylatic Cardiogenic Hypovolemic Septic Other
Control
Treatment
Mortality by Shock TypeMortality by Shock Type
p value 0.56 0.16 0.0534 0.67
0%
36% 36%
50% 50%
30%26%
33%
0%0%
0%
10%
20%
30%
40%
50%
60%
Anaphylactic Cardiogenic Hypovolemic Septic Other
Control
Treatment
4%
10%
18%
68%
Discharge LocationDischarge Location
73%
5%
15%
7%
HOME
REHAB OTHER
SNF
CONTROL GROUPCONTROL GROUP TREATMENT GROUPTREATMENT GROUP
Educational Educational Attachment for Attachment for
Activated Protein CActivated Protein C
THE ROLE OFTHE ROLE OF
IN SEVERE SEPSIS & IN SEVERE SEPSIS & SEPTIC SHOCKSEPTIC SHOCK
ACTIVATED PROTEIN CACTIVATED PROTEIN C
Severe Sepsis: Comparison With Severe Sepsis: Comparison With Other Major DiseasesOther Major Diseases
0
50
100
150
200
250
300
AIDS* ColonCancer§
BreastCancer§
CHF† Severe Sepsis‡
Cas
es/1
00,0
00
Incidence of Severe Sepsis
0
50,000
100,000
150,000
200,000
250,000
Death
s/Y
ear
Mortality of Severe Sepsis
AIDS* SevereSepsis‡
AMI†Breast Cancer§
Sepsis: An Urgent Healthcare ChallengeSepsis: An Urgent Healthcare Challenge
More than 550 people lose More than 550 people lose their lives to severe sepsis their lives to severe sepsis
every day- every day-
215,000 per year215,000 per year
Sepsis: Defining a Disease ContinuumSepsis: Defining a Disease Continuum
• A systemic clinical response arising from an insult, including 2 of the following:– Temperature ≥38oC or ≤36oC– HR ≥90 beats/min– Respirations ≥20/min– WBC count ≥12,000/mm3 or
≤4,000/mm3 or >10% immature neutrophils
• SIRS with a presumed or confirmed infectious process
SepsisSepsisSIRSSIRSLocalized Localized InsultInsult
SevereSevere SepsisSepsis
Sepsis: Defining a Disease ContinuumSepsis: Defining a Disease Continuum
• Sepsis with ≥ 1 sign of organ failure– Cardiovascular (refractory hypotension)– Renal– Respiratory– Hepatic– Hematologic– CNS– Unexplained metabolic acidosis
ShockShock
SepsisSepsisSIRSSIRSLocalized Localized InsultInsult
SevereSevere SepsisSepsis
A New Understanding of Sepsis PathophysiologyA New Understanding of Sepsis Pathophysiology
Organ Failure
SepsisSepsis
CoagulationCoagulation Fibrinolysis Fibrinolysis
InflammationInflammationEndothelial Endothelial
InjuryInjury
DeathDeath
Activated Protein CActivated Protein CModulator of InflammationModulator of Inflammation
Antiinflammatory• Inhibits thrombin-
mediatedinflammatory activities
• Inhibits attachment of leukocytes to endothelium
Decrease inflammatory response
Activated Protein CActivated Protein CModulator of HomeostasisModulator of Homeostasis
Anticoagulant• Activated
Protein C inhibits factors V and VIII
Prevents coagulation from becoming generalized
Activated Protein CActivated Protein CMModulator of Fibrinolysisodulator of Fibrinolysis
Remove formed micro thrombin and maintain blood fluidity
Activated Protein C inhibits:
– PAI-1 Increases t-PA
– TAFI activation
Results: 28-Day All-cause MortalityResults: 28-Day All-cause Mortality
2-sided p-value
Adjusted relative risk reduction
Increase in odds of survival
Placebo
(n=840)
Drotrecogin alfa
(activated)
(n=850)
Primary analysis results
p=0.005
19.4%
38.1%35
30
25
20
15
10
5
0
30.8 %
24.7 %6.1%
absolute reduction in
mortality
Mo
rtal
ity
(%)
Mortality Reduction by Baseline APACHEII Mortality Reduction by Baseline APACHEII Scores in PROWESSScores in PROWESS
Overall Population n=1690
Absolute Reduction
Relative Risk Reduction
Overall Population 6% 19% (p= 0.005)
Baseline APACHE II Score* Quartiles 3 & 4 Quartiles 1 & 2
13%0%
29%1%
*Of measure used, the APACHE II score was most effective in classifying patients by risk of death and by likelihood of benefit from drotrecogin alfa (activated).
High Risk Severe Sepsis Patients with High Risk Severe Sepsis Patients with Intra-Abdominal SurgeryIntra-Abdominal Surgery
Survival Time
Day 28 Mortality
PROWESS: Outcomes in Patients With Community PROWESS: Outcomes in Patients With Community Acquired PneumoniaAcquired Pneumonia
31.5%
22.8%
0%
10%
20%
30%
40%
50%
placebo Xigris
n=279
n=325
P=0.015
ARR = 8.7%
RRR = 27.8%
Presentation at Chest 2001 by PF Laterre
Overt DIC in Severe Sepsis Patients Treated with Recombinant Overt DIC in Severe Sepsis Patients Treated with Recombinant Human Activated Protein C a Subgroup AnalysisHuman Activated Protein C a Subgroup Analysis
APACHE IIControl (103)
XTreatment (118)
X+1
Relative risk reduction
Mortality 52.4% 30.5% 42%
Defined by at least 3 of the following :• The presence of petechiae or purpura fulminans
• Platelet count < 80,000 mm3 or a 50% decrease
• Prothrombin time > 21 seconds
• d-Dimer > 8 mg/L
• Protein C level < 40%
PROWESS ResultsPROWESS Results
• Number needed to treat in other trials to
• Save 1 life
• PROWESS 16
• TIMI-IIB (Abs reduction 2.5%) 40
• ISIS-2 (Strep vs placebo) 36
• GUSTO (TPA vs Strep) 100
• B-Blockers post MI 116
Cost of APCCost of APC
Illness Lives Saved Cost per Life Saved
Acute MI TPA vs. Streptokinase
1 in 100 $180,000
All patients with sepsis, Rx with APC 1 in 16 $107,000
Apache score > 25 Rx with APC 1 in 8 $53,000
Severe DIC with APC 1 in 5 $33,000
* Vasopressor requirement at study entry through day 1. Based on the Sequential Organ Failure Assessment (SOFA) score, low dose was defined as dopamine 6-15 µg/kg/min, epinephrine 0.1 µg/kg/min, or norepinephrine 0.1 µg/kg/min. High dose was defined as dopamine > 15 µg/kg/min, epinephrine > 0.1 µg/kg/min, or norepinephrine > 0.1 µg/kg/min. 1.Data on file, Eli Lilly and Company: 28-day mortality for standard therapy patients enrolled in PROWESS and EZZF clinical studies
Vasopressor as a Marker for Severe Sepsis with Vasopressor as a Marker for Severe Sepsis with a High-Risk of Death a High-Risk of Death
Low Dose to High DoseVasopressor
No Vasopressorto High DoseVasopressor
0
20
40
60
No Vasopressor
No Vasopressorto Low DoseVasopressor
Mo
rtal
ity
(%)
20%20%
3737%%
58%58%54%54%
ENHANCE ENHANCE
Study ResultsStudy Results
XigrisXigris
ENHANCE: Timing of Treatment in APACHE II ≥ 25 PatientsENHANCE: Timing of Treatment in APACHE II ≥ 25 Patients
0
20
40
60
Pa
tient
s (%
)
50% 50%
N=430 N=432
Drotrecogin alfa (activated)on Day One
Drotrecogin alfa (activated)
on Day Two or after
• 50% of patients received drotrecogin alfa (activated) on day one
• Average time from diagnosis of first organ dysfunction to drotrecogin alfa (activated) treatment was 25 hours
ENHANCE: Mortality of APACHE II ≥ 25 Patients ENHANCE: Mortality of APACHE II ≥ 25 Patients Based on Time to TreatmentBased on Time to Treatment
Day one*
• Average time from diagnosis of first organ dysfunction to start of drotrecogin alfa (activated) infusion was 25 hours
• 28 day mortality for ENHANCE (open-label trial)
Day Two**
0
20
40
60
Mo
rtal
ity
(%)
33%
41%
N=430 N=432
P=0.019
*Drotrecogin alfa (activated) infusion started ≤ 24 hrs.from onset of acute organ dysfunction**Drotrecogin alfa (activated )infusion started ≥ 24hrs. from onset of acute organ dysfunction
Retrospective Study Retrospective Study Results from Five Results from Five
Teaching HospitalsTeaching Hospitals
Retrospective Study DescriptionRetrospective Study Description
• Purpose: To understand how drotrecogin alfa (activated) was being used under “real world” conditions
• Retrospective case review of 274 patients treated with commercially available drotrecogin alfa (activated) between November 22, 2001 and December 31, 2002
• Five teaching hospitals were included
Retrospective Study: Retrospective Study: Timing of Drotrecogin alfa (activated) Treatment Timing of Drotrecogin alfa (activated) Treatment
Day Three,or after
0
20
40
60
Day One Day Two
Pati
ents
/Mort
alit
y (
%)
25%
42%
34%
*A post-marketing retrospective analysis of 274 patients with severe sepsis that received drotrecogin alfa (activated) at 5 large, teaching hospitals
33%40%
52%
N=114 N=93N=67
Retrospective Study: Organ Dysfunctions at Baseline and at Retrospective Study: Organ Dysfunctions at Baseline and at Initiation of Drotrecogin alfa (activated)Initiation of Drotrecogin alfa (activated)
Data on file, Eli Lilly and Company.
Day Threeor After
3.5
0
1.0
1.5
2.0
2.5
3.0
Nu
mb
er o
f O
rgan
Dys
fun
ctio
ns
(me
an)
Day One Day Two
2.7 2.7
2.4
3.1
1.8
2.9
At Baseline
At Drotrecogin alfa (activated) treatment
N=67 N=114 N=93
Day One Day One Day One
% Increase in Organ Dysfunction
0% 37% 56%
Retrospective Study*: Patient Characteristics at Time of Retrospective Study*: Patient Characteristics at Time of Drotrecogin alfa (activated) Infusion InitiationDrotrecogin alfa (activated) Infusion Initiation
Age (mean in years) 57
Mechanical Ventilation (%) 74
Vasopressor Support (%) 85
Data on file, Eli Lilly and Company.
*A post-marketing retrospective analysis of 274 patients with severe sepsis that received drotrecogin alfa (activated) at 5 large, teaching hospitals
Retrospective Study: Retrospective Study: Patient Location Prior to ICU AdmissionPatient Location Prior to ICU Admission
Emergency Department 37%
Floor 32%
Post-op 16%
Other Hospital 13%
Other 2%
Total N = 274Data on file, Eli Lilly and Company.
Educational Educational Attachment for Attachment for ScvOScvO2 2 CatheterCatheter
Overview of Overview of Patient Patient Enrollment Enrollment and and Hemodynamic Hemodynamic SupportSupport
Goals for Shock ResuscitationGoals for Shock Resuscitation
• Decrease work of breathing (early intubation) • Aggressive volume resuscitation CVP 8-12• MAP > 70 (Levophed) • UO > .5ml/kg/hr
• ScvO2 > 70, SvO2 > 60
– SaO2 > 93%
– HCT > 30– Dobutamine, CI > 2.5 (cardiogenic) , > 2.7 hypovolemic,
> 3.0 septic or anaphylactic
Protocol Protocol forforEarly Early Goal-Goal-Directed Directed TherapyTherapy
Kaplan-Meier Estimates of Mortality and Kaplan-Meier Estimates of Mortality and Causes of In-Hospital DeathCauses of In-Hospital Death
TreatmentsTreatmentsAdministeredAdministered
Early Goal-Directed Therapy and the Edwards Early Goal-Directed Therapy and the Edwards
PreSepPreSepTMTM Central Venous Oximetry Catheter Central Venous Oximetry Catheter
PreSep Catheter Monitoring EssentialsPreSep Catheter Monitoring Essentials
• Arterial saturation
• Hemoglobin
• O2 consumption
– Temperature
– Muscle activity
• Cardiac output
SvOSvO22 / ScvO / ScvO22
If constant
ScvO2reflects cardiac
output}
Normal Oxygen Delivery and DemandNormal Oxygen Delivery and Demandhb=10 x 1.34 x 95% = 12.8hb=10 x 1.34 x 95% = 12.8
>92 % ~70 %
~25 % extraction
02c = 12.8/ml02c = 3.4/ml
02c = 9.4/ml
High Cardiac Output States or High Cardiac Output States or Tissue ShuntingTissue Shunting
>92 % ~77 %
<25 % extraction02c = 12.8/ml 02c =
10.3/ml02c = 2.5/ml
>92 % ~55 %
40% extraction
Inadequate Cardiac Output Resulting in Inadequate Cardiac Output Resulting in Inadequate Oxygen DeliveryInadequate Oxygen Delivery
02c = 12.5/ml02c = 7.4/ml
DELIVERY <
Sepsis: Defining a Disease ContinuumSepsis: Defining a Disease Continuum
• A systemic clinical response arising from an insult, including 2 of the following:– Temperature ≥38oC or ≤36oC– HR ≥90 beats/min– Respirations ≥20/min– WBC count ≥12,000/mm3 or
≤4,000/mm3 or >10% immature neutrophils
• SIRS with a presumed or confirmed infectious process
SepsisSepsisSIRSSIRSLocalized Localized InsultInsult
SevereSevere SepsisSepsis
Sepsis: Defining a Disease ContinuumSepsis: Defining a Disease Continuum
• Sepsis with ≥ 1 sign of organ failure– Cardiovascular (refractory hypotension)– Renal– Respiratory– Hepatic– Hematologic– CNS– Unexplained metabolic acidosis
ShockShock
SepsisSepsisSIRSSIRSLocalized Localized InsultInsult
SevereSevere SepsisSepsis
Oxygen ScvOOxygen ScvO22 5-10% above SvO 5-10% above SvO22
EGDT Case StudiesEGDT Case Studies
EGDT Early Treatment Strategies EGDT Early Treatment Strategies
Onset of Sepsis Syndrome
Location at Onset %
ICU 55
Emergency Department 12
Non-ICU Patient Care Unit 33
Excerpted from Sands et. al. JAMA 278:3 [237, Table 3]
Systems approach to early identification of sever sepsis and rapid initiation of goal directed treatment with ScvO2, antibiotics, hydrocortisone,
insulin, and Xigris decreases:
• The time to the initiation of therapy
• Time to hemodynamic optimization
• Organ failure
• Mortality
ConclusionConclusion