present kritikus foundation & redding critical care medical group

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



• 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.


• 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


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


• 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

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


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 with ≥ 1 sign of organ failure– Cardiovascular (refractory hypotension)– Renal– Respiratory– Hepatic– Hematologic– CNS– Unexplained metabolic acidosis

ShockShock



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 <


• 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




• Sepsis with ≥ 1 sign of organ failure– Cardiovascular (refractory hypotension)– Renal– Respiratory– Hepatic– Hematologic– CNS– Unexplained metabolic acidosis

ShockShock



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

present kritikus foundation & redding critical care medical group

Documents

shock program

shock appearancecool

shock patientsconfused

mortality of septic

rapid resuscitation

mi cryptic septic shock

dandenong hospital

intensive care