Division of Critical Care Medicine
University of Alberta

43 y/o woman presented to E.R. with decreased LOC and hypotension
Unwell at home for 5 days with cough, sputum, fever, chills
History of heavy smoking and ETOH abuse
Acutely ill, cyanosed, drowsy, resps 50/min, BP
70/40mmHg, HR 140/min, temp 39.5°C,
ABGs 56/29/7.28, Lactate 6
Hgb 150, Platelets 84, WBC 3.3 with 55% band forms
INR 1.9, PTT 63
Na 129, K 4.3, Cl 85, HCO3 16 BS 19.7
Urea 15 mmol/l, creatinine 137  mol/l
CXR Dense LLL and patchy RLL consolidation, ECG sinus tachycardia

Intubated and ventilated FiO
2
1.0, Vt 450 mls, PEEP 10, Paw 35
Sedated with fentanyl by IV infusion and intermittent lorazepam IV prn
IV fluid resuscitation
0.9% NaCl 3 litres over 3 hours
IV ceftriaxone and azithromycin
Central line inserted.
Norepinephrine infusion at 10 mcg/kg/min
Vasopressin infusion 0.03 u/min
Hydrocortisone 50 mg IV q 6H
Insulin protocol started
LP not performed because of coagulopathy
Activated protein C commenced 24  g/kg/hr

Hour 4
ABGs:
CVP:
Central venous gases
Fluid loaded:
Hour 5
CVP
Central venous gases
Inotropic support
More fluid
Hour 6
CVP
Central venous gases
Vent change:
ABGs:
IV NaHCO
3
86/39/7.21
8 mmHg
PcvO
2
29, ScvO2 56
RL 1 litre over 1 hour
12 mmHg
PcvO
2
31 mmHg, SvO2 62%
Dobutamine infusion 5  g/kg/min
Pentaspan 1 l over 1 hour and RL 250 mls/hr
14 mmHg
PcvO2 36 mmHg, SvO2 67%
Vt 400, PEEP 15, Paw 34
153/56/7.14
pH maintained > 7.25







Day 2 S. pneumoniae isolated from blood, sputum
Day 3 Step sensitive to Penicillin. Pt switched to Pen G
RL decreased to 125 cc/hr
Hemodynamically stabilized. Norepinephrine and vasopressin weaned off day 5. Hydrocortisone weaned off by day 8.
Slow improvement in oxygenation.
Pt successfully weaned from ventilator over next 72 hours

Transferred to medical unit after 2 weeks in ICU








Sepsis/septic shock definitions
Antibiotic management
Resuscitation

Resuscitation goals



Time

CV parameters
Fluid management

Crystalloid vs. colloid
Vasopressor management
“Low-dose” corticosteroid therapy
Microvascular circulation
Control of sepsis cascade
Intensive glycemic control

Severe Sepsis: Comparative
Incidence and Mortality
Mortality Incidence
300
250
200
150
100
50
0
AIDS Breast
Cancer
1st MI Severe
Sepsis
250000
200000
150000
100000
50000
0
AIDS Breast
Cancer
AMI Severe
Sepsis


ACCP/SCCM Consensus Definitions
Infection


Inflammatory response to microorganisms, or
Invasion of normally sterile tissues

Severe Sepsis


Sepsis
Organ dysfunction

Septic shock


Sepsis
Hypotension despite fluid resuscitation

Systemic
Inflammatory
Response
Syndrome
(SIRS)

Systemic response to a variety of processes

Sepsis


Infection plus
 2 SIRS criteria

Multiple Organ
Dysfunction
Syndrome
(MODS)


Altered organ function in an acutely ill patient
Homeostasis cannot be maintained without intervention

Sepsis: Defining a disease continuum
Infection/Trauma
SIRS
Sepsis Severe Sepsis
A clinical inflammatory response arising from a nonspecific insult, including  2 of the following:




Temperature  38 o C or
 36 o C
HR  90 beats/min
WBC count  12
000/mm 3 or
 4000/mm 3 , or
>10% immature neutrophils
Respirations  20/min

Infection/Trauma
SIRS
Sepsis Severe Sepsis
SIRS with a presumed or confirmed infectious process

Sepsis: Defining a disease continuum
Infection/Trauma
SIRS
Sepsis Severe Sepsis
Sepsis with  1 sign of organ failure







Cardiovascular
Renal
Respiratory
Hepatic
Hematologic
CNS
Unexplained metabolic acidosis
Shock
Refractory hypotension

Relationship of SIRS, Sepsis, and
Infection
PANCREATITIS
BACTEREMIA
INFECTION
FUNGEMIA
PARASITEMIA
SEPSIS
VIREMIA
OTHER
POST-PUMP SYNDROME
SIRS
TRAUMA
OTHER
BURNS
The ACCP/SCCM consensus Conference Committee, Chest 1992;101:1644-55 .

Sites of confirmed or presumed infection in severe sepsis
Endocarditis
Other
CNS
0.6%
10.8%
0.8%
Wound/soft tissue
6.6%
Device-related
2.2%
Respiratory
44.0%
Abdominal
8.6%
Genitourinary
9.1%
Bacteremia, site unspecified
17.3%
Angus DC, et al. Crit Care Med 2001

In-hospital mortality for sepsis

Incidence of sepsis by causative organism

Compared with the general ICU population, the septic shock subset has:






Older patients
Higher proportion of patients with severe comorbidities, immune deficiency, and a higher proportion of surgical patients.
Lung is the primary source of infection
Decrease in urosepsis
Pseudomonas and Staphylococcus resistant to methicillin-related septic shock have dramatically increased with time, to reach a worrying proportion of 20-25% of cases in 2000.
Likely from intensive antibiotic use in ICUs.

Inflammation
Pro-coagulant state Inhibition of fibrinolysis

Pathogenesis of Shock
Infectious triggers
Cytokine and inflammatory mediator cascade
Cardiac dysfunction and microvascular injury
Hypotension and shock

CARS
SIRS
Antiinflammatory
(endogenous)
Organ
Injury
Time
RECOVERY

Risk factors for mortality in pneumonia
Factors Odds ratio
Previous hospitalization
7.99
95%
Confidence
Interval
1.49-42.70
COPD 9.18
1.69-49.82
Multilobar disease
Inappropriate antibiotic
14.29
2.40-85.00
27.35
NCCLS 2002
1.82-410.16

Death Rate in the United States
Medicare patients >65 yrs in US
100
80
60
40
20
0
2 h 4 h 6 h 8 h 10 h
Time Until Antibiotic Therapy (h)
1.2
1.0
0.8
0.6
2 h 4 h 6 h 8 h 10 h
Hours Within Which Antibiotics Were
Administered
Mortality increased for each hour delay
Mortality at 30 days was reduced significantly if antibiotics administered within 8 hrs

Harbarth et al. Am J Med 2003;115:529
Lenercept trial-904 patients with severe sepsis
468 documented bacteremia (52%)
Patients
28 day mortality
Appropriate antibiotic therapy
693 (77%)
24%
Inappropriate antibiotic therapy
211 (27%)
39%*
MacArthur et al. Clin Infect Dis 2004; 38:284
MONARCS trial - Monoclonal Anti-TNF
Appropriate antibiotic therapy
Inappropriate antibiotic therapy
Patients 2396 (91%) 237 (9%)
28 day mortality 33% 43%*
*p<0.001

Delay in Initiation of Effective
Antibiotics

Septic Shock – Impact of time of Antibiotic
Administration

An Injury Paradigm of Sepsis and
Septic Shock
Antimicrobial therapy
Cellular dysfunction/tissue injury
Inflammatory response
Toxic burden
Infectious load
TIME

An Injury Paradigm of Sepsis and
Septic Shock earlier antimicrobial therapy
Cellular dysfunction/tissue injury
Inflammatory response
Toxic burden
Infectious load
TIME

An Injury Paradigm of Sepsis and
Septic Shock more intense antimicrobial therapy
Cellular dysfunction/tissue injury
Inflammatory response
Toxic burden
Infectious load
TIME

Causes for Delays







Failure to recognize that hypotension represents septic shock
Effect of inappropriate antibiotic initiation
Failure to appreciate risk of resistant organisms in certain scenarios (e.g. immunocompromised vs immunosuppressed; pre-shock antimicrobial use)
Transfer from ER before antibiotics given
Failure to use “stat” orders
No specified order with multiple drug regimens
Administrative/logistic delays (nursing/pharmacy/ ward clerk)

Delays in Source Control in Septic Shock
8
6
4
2
0
14
12
10
3-
5.
99
6-
11.99
12-
23.99
>24
Time (hrs)



Stabilization?
Convenience?

1.
2.
3.
Hit the organism
Hit the organism early
Hit the organism hard
* Get in the ring

Rivers E et al.
NEJM
2001;345:1368-
77.

Rivers E et al.
NEJM
2001;345:1368-
77.



Major therapeutic difference between groups


3 litres more crystalloid in first 6 hours
No difference in fluid balance over 72 hrs
Other differences


Use of packed rbcs
Use of dobutamine

Standard therapy
(N=133)
Early goal directed therapy
(N=130)
In-hospital mortality
All patients
Severe sepsis
Septic shock
Sepsis syndrome
59 (46.5%)
19 (30.0%)
40 (56.8%)
44 (45.4%)
38 (30.5%)
9 (14.9%)
29 (42.3%)
35 (35.1%)
P value
0.009
0.06
0.04
0.07
28 Day mortality
60 Day mortality
61 (49.2%)
70 (56.9%)
40 (33.3%)
50 (44.3%)
0.01
0.03
Sudden CV collapse
NNT=16
12/117
(10.3%) failure
Rivers E et al. N Eng J Med 2001;345:1368-77
.
0.02
0.27






Early goal directed therapy in management of severe sepsis/septic shock can result in dramatically improved outcome
Early aggressive resuscitation ameliorates later multiple organ dysfunction
Outcome determined in first 6 hours for many patients
Fluid resuscitation critical
NNT 16


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
BP
CVP
Urine output
ScvO2
Hgb pH
Lactate


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
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


BP MAP>65 mmHg/SBP>90 mmHg
CVP 8-12 mmHg
Urine output 0.5-1 ml/kg/hr
ScvO2
Hgb pH
Lactate
>70%
>70-100 g/L
>7.30
<4
However time frame is likely as important as absolute goals!!

Impact of medical emergency team on unexpected cardiac arrests
Percentage reduction: 66.6%
35
30
25
20
15
10
5
0
Cardiac arrests
Bellomo R et al. Crit Care Med 2004;32:916-921.
P=0.0003
Control
MET

30
25
20
15
10
5
0
Impact of Medical Emergency Team on ARF requiring Renal Replacement Therapy
27
2 p<0.001
Control
MET

Corticosteroids for septic shock

Outcomes with corticosteroids in septic shock
NNT=8


Adrenal insufficiency common in patients with septic shock

ACTH stimulation test ideal

No absolute diagnostic random serum cortisol level

Random serum cortisol level < 690 nmol/l in a highly stressed patient is useful diagnostic threshold for diagnosis of adrenal insufficiency


“Low dose” hydrocortisone (HC 50 mg q 6H) :

Inhibited NOx formation

Reduced vasopressor requirements

Improved hemodynamic stability

Differentially reduced inflammation without significant immunosuppression


To restore systemic vascular resistance towards normal and allow tissue and organ perfusion



Dopamine
Norepinephrine
Vasopressin


Forget about low-dose dopamine

Perhaps forget about dopamine entirely!!!

Should we titrate to SBP or MAP

What target BP?

Other?

Effects of Dopamine, Norepinephrine, and Epinephrine on the Splanchnic
Circulation in Septic Shock

NE improves survival in patients with severe sepsis
Days

Normal renal vascular autoregulation
Renal Blood Flow
1.0
0.1
GFR
0 50 75
100 150
MAP (mm Hg)
200





Secreted under osmotic control to modify permeability of renal collecting ducts to water (0.9-
6.5 pmol/L) - V
2 receptors
Secreted under baroreceptor control to modify BP (9-
187 pmol/L) - V
1 receptors
Rapid increase in vasopressin levels in early phase of hemorrhagic shock (>280 pmol/L)
Subsequent decrease in levels (30 pmol/L) due to depletion of posterior pituitary stores

Posterior Pituitary Vasopressin
Depletion in Shock
Normal Post shock

AVP
(pg/ml)
Septic
Shock
(n=19)
Cardiogenic
Shock
(n=12)
22.7
± 2.2
3.1
±0.4
Vasopressin Deficiency Contributes to the Vasodilation of Septic
Shock Landry DW et al. Circulation. 1997;95:1122-1125.


Low levels of vasopressin in patients with septic shock

Infusion of vasopressin to provide serum levels normally seen in shock provides significant improvement in BP even in patients refractory to NE and Epi

• Not a replacement for norepinephrine or dopamine as a first-line agent
• Consider in refractory shock despite high-dose conventional vasopressors
• If used, administer at 0.01-0.04 units/min in adults

Cardiac Dysfunction during Septic Shock
Diastole Systole
10 Days Post Shock
Diastole Systole
Images used with permission from Joseph E. Parrillo, MD

Sakr Y et al. Crit Care Med 2004; 32:1825-1831

Evolution of small vessel perfusion between first ( hatched ) and last ( measurement white )
(* p < .01 last vs. first
Sakr Y et al. Crit Care Med 2004; 32:1825-1831

Videomicroscopy of capillaries in a normal and septic patient with vasodilation. (approx 1 min)


Low perfusion pressure

Low cardiac output

Microthrombosis

Sepsis
 Coagulation
 Fibrinolysis
Endothelial injury
 Inflammation
Microthrombosis
Organ failure Digital ischemia
Death Gangrene

rAPC reduces microvascular thrombosis through multiple mechanisms of action.
rAPC

Absolute mortality reduction NNT
• All patients 6% 16
•
APACHE II score
≥ 25 13% 8
N Eng J Med 2001;344:699-709.



Large open label trial of rAPC in severe sepsis
Showed mortality improvement when rAPC given within 24 hours of admission
• rAPC in septic patients with APACHE II score <25
• Trial discontinued at interim analysis because of lack of efficacy



Absolute contraindications:
Active internal bleeding





Recent (within 3 months) hemorrhagic stroke
Recent (within 2 months) intracranial or intraspinal surgery, or severe head trauma
Trauma with an increased risk of life-threatening bleeding
Presence of an epidural catheter

Intracranial neoplasm or mass lesion or evidence of cerebral herniation
Relative contraindications

Platelet count < 30


PTT ≥ 100
INR ≥ 3

Insulin required
Median insulin dose IU/day
Inotropic/Vasopressor Tx
Morning blood glucose (mg/dl)
Standard therapy
(N=783)
307 (39.2%)
33
586 (74.8%)
153+33
Intensive
(N=785)
755 (98.7%)
71
574 (75%)
103+19
P Value
<0.001
<0.001
0.9
<0.001
Van den Berghe G et al. N Eng J Med 2001;345:1359-1367

Variable
Death in ICU
During first 5 days
After day 5
Cause of death
MOF with septic focus
MOF without septic focus
Standard therapy
(N=783)
63/783 (8.0%)
14/783 (1.8%)
49/243 (20.2%)
Intensive
(N=785)
35/765 (4.6%)
13/765 (1.7%)
22/208 (10.6%)
P Value
<0.04
0.9
0.005
33
18
8
14
Van den Berghe G et al. N Eng J Med 2001;345:1359-1367

Van den Berghe G et al. N Eng J Med 2001;345:1359-1367



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



Early diagnosis
Early appropriate antibiotic therapy and source control
Early aggressive goal directed resuscitation
Low dose corticosteroid therapy
Vasopressor therapy
Intensive glycemic control
Activated protein C