Transcript Pneumonia and septic shock - Division of Critical Care

Severe Sepsis /
Septic Shock
Division of Critical Care Medicine
University of Alberta
Case summary
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 FiO2 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
86/39/7.21
8 mmHg
PcvO2 29, ScvO2 56
Fluid loaded:
RL 1 litre over 1 hour
Hour 5
CVP
Central venous gases
12 mmHg
PcvO2 31 mmHg, SvO2 62%
Inotropic support
More fluid
Dobutamine infusion 5g/kg/min
Pentaspan 1 l over 1 hour and RL 250
mls/hr
Hour 6
CVP
Central venous gases
14 mmHg
PcvO2 36 mmHg, SvO2 67%
Vent change:
ABGs:
IV NaHCO3
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
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RL decreased to 125 cc/hr
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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
Discussion points
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Sepsis/septic shock definitions
Antibiotic management
Resuscitation

Resuscitation goals
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Fluid management


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Time
CV parameters
Crystalloid vs. colloid
Vasopressor management
“Low-dose” corticosteroid therapy
Microvascular circulation
Control of sepsis cascade
Intensive glycemic control
Severe Sepsis: Comparative
Incidence and Mortality
Incidence
Mortality
300
250000
200000
200
Deaths/Year
Cases/100,000
250
150
100
150000
100000
50000
50
0
0
AIDS
Breast
Cancer
1st MI
Severe
Sepsis
AIDS
Breast
Cancer
AMI
Severe
Sepsis
ACCP/SCCM Consensus Definitions

Infection



Systemic
Inflammatory
Response
Syndrome
(SIRS)


Inflammatory response to
microorganisms, or
Invasion of normally
sterile tissues
Systemic response to a
variety of processes
Sepsis


Infection plus
2 SIRS criteria

Severe Sepsis



Septic shock



Sepsis
Organ dysfunction
Sepsis
Hypotension despite fluid
resuscitation
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
A clinical inflammatory
response arising from a
nonspecific insult,
including 2 of the
following:




Temperature 38oC or
36oC
HR 90 beats/min
WBC count 12
000/mm3 or
4000/mm3, or
>10% immature
neutrophils
Respirations 20/min
Sepsis
Severe Sepsis
Sepsis: Defining a disease
continuum
Infection/Trauma
SIRS
Sepsis
SIRS with a
presumed or
confirmed
infectious
process
Severe Sepsis
Sepsis: Defining a disease
continuum
Infection/Trauma
Sepsis
SIRS
Severe Sepsis
Sepsis with 1 sign of
organ failure
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
Cardiovascular
Renal
Respiratory
Hepatic
Hematologic
CNS
Unexplained metabolic
acidosis
Shock
Refractory
hypotension
Relationship of SIRS, Sepsis, and
Infection
PANCREATITIS
BACTEREMIA
POST-PUMP SYNDROME
INFECTION
SIRS
FUNGEMIA
TRAUMA
SEPSIS
PARASITEMIA
BURNS
VIREMIA
OTHER
OTHER
The ACCP/SCCM consensus Conference Committee, Chest 1992;101:1644-55.
Sites of confirmed or presumed
infection in severe sepsis
CNS
0.8%
Other
10.8%
Endocarditis
0.6%
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
Incidence of sepsis in USA
1979-2000
In-hospital mortality for sepsis
Incidence of sepsis by causative organism
Compared with the general ICU
population, the septic shock subset
has:
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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.
Pathophysiology of Shock in
Sepsis
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
The Dynamic Nature of Sepsis
CARS
SIRS
Antiinflammatory
(endogenous)
Organ
Injury
Time
RECOVERY
Risk factors for mortality in pneumonia
Factors
Odds ratio
95%
Confidence
Interval
Previous
hospitalization
7.99
1.49-42.70
COPD
9.18
1.69-49.82
Multilobar
disease
14.29
2.40-85.00
Inappropriate
antibiotic
27.35
1.82-410.16
NCCLS 2002
Bacterial Pneumonia
Death Rate in the United States
100
80
60
40
20
0
2h
4h
6h
8h
10 h
Time Until Antibiotic Therapy (h)
Adjusted Odds of
30 Day Mortality (95% CI)
Percent of Patients
Medicare patients >65 yrs in US
1.2
1.0
0.8
0.6
2h
4h
6h
8h
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
Inappropriate
antibiotic therapy
693 (77%)
211 (27%)
24%
39%*
MacArthur et al. Clin Infect Dis 2004; 38:284
MONARCS trial - Monoclonal Anti-TNF
Patients
28 day mortality
Appropriate
antibiotic therapy
Inappropriate
antibiotic therapy
2396 (91%)
237 (9%)
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
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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
Odds Ratio of Death
(95% Confidence Interval)
14
12
10
8
6
4
2
0
4
>2
9
.9
23
12
99
.
11
6-
9
9
5.
3-
Time (hrs)
Source Control Delays


Stabilization?
Convenience?
Eliminate Infection
1.
2.
3.
Hit the organism
Hit the organism early
Hit the organism hard
* Get in the ring
Resuscitation
Rivers E et al.
NEJM
2001;345:136877.
Rivers E et al.
NEJM
2001;345:136877.
Analysis

Major therapeutic difference between
groups
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3 litres more crystalloid in first 6 hours
No difference in fluid balance over 72 hrs
Other differences
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Use of packed rbcs
Use of dobutamine
EGDT Outcomes
Standard
therapy
(N=133)
Early goal
directed
therapy
(N=130)
P
value
All patients
59 (46.5%)
38 (30.5%)
0.009
Severe sepsis
19 (30.0%)
9 (14.9%)
0.06
Septic shock
40 (56.8%)
29 (42.3%)
0.04
Sepsis syndrome
44 (45.4%)
35 (35.1%)
0.07
28 Day mortality
61 (49.2%)
40 (33.3%)
0.01
60 Day mortality
70 (56.9%)
50 (44.3%)
0.03
Sudden CV collapse
NNT=16
25/119
(21%)
12/117
(10.3%)
0.02
In-hospital mortality
Multiple organ
26/119 (21.8%) 19/117
0.27
Rivers E et al. N Eng J Med 2001;345:1368-77.
failure
(16.2%)
Conclusions

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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
Resuscitation goals
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BP
CVP
Urine output
ScvO2
Hgb
pH
Lactate
Resuscitation goals
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BP
CVP
Urine output
ScvO2
Hgb
pH
Lactate
MAP>65 mmHg/SBP>90 mmHg
8-12 mmHg
0.5-1 ml/kg/hr
>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
P=0.0003
20
Control
MET
15
10
5
0
Cardiac arrests
Bellomo R et al. Crit Care Med 2004;32:916-921.
Impact of Medical Emergency Team on ARF
requiring Renal Replacement Therapy
27
p<0.001
Patients
30
25
20
Control
MET
15
10
5
2
0
Bellomo R et Events
al. Crit Care Med 2004;32:916-921.
They’re baaack!!
Corticosteroids for
septic shock
Outcomes with corticosteroids in
septic shock
NNT=8
Adrenal insufficiency during
septic shock

Adrenal insufficiency common in patients with septic
shock
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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
Hydrocortisone in septic shock

“Low dose” hydrocortisone (HC 50 mg q 6H) :

Inhibited NOx formation

Reduced vasopressor requirements
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Improved hemodynamic stability
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Differentially reduced inflammation without significant
immunosuppression
Vasopressor therapy in septic
shock

To restore systemic vascular
resistance towards normal and allow
tissue and organ perfusion
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Dopamine
Norepinephrine
Vasopressin
How should we use vasoactive
agents?

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
Flow rate (L / min)
Renal Blood Flow
1.0
0.1
GFR
0
50
75 100
150
MAP (mm Hg)
200
Vasopressin

Secreted under osmotic control to modify
permeability of renal collecting ducts to water (0.96.5 pmol/L) - V2 receptors

Secreted under baroreceptor control to modify BP (9-
187 pmol/L) - V1 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
Septic
Shock
(n=19)
Cardiogenic
Shock
(n=12)
22.7±2.2
AVP
(pg/ml)
3.1±0.4
Vasopressin Deficiency Contributes to the Vasodilation of Septic
Shock Landry DW et al. Circulation. 1997;95:1122-1125.
Rationale for use of Vasopressin in
septic shock

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
Vasopressin
• 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
Images used with permission from Joseph E. Parrillo, MD
Systole
Microcirculation in
severe sepsis
Time course of small vessel
perfusion
Sakr Y et al. Crit Care Med 2004; 32:1825-1831
Evolution of small vessel perfusion
between first (hatched) and last (white)
measurement
(*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)
Why?
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Low perfusion pressure
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Low cardiac output
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Microthrombosis
Microvascular events in severe
sepsis
Sepsis
 Coagulation
 Fibrinolysis
Endothelial
injury
 Inflammation
Microthrombosis
Digital ischemia
Organ failure
Death
Gangrene
Clinical impact of
microthrombosis
The sepsis cascade
Activated Protein C interrupts the
sepsis cascade
rAPC reduces microvascular thrombosis through
multiple mechanisms of action.
rAPC
Absolute mortality reduction
•All patients
6%
•APACHE II score ≥ 25 13%
NNT
16
8
N Eng J Med 2001;344:699-709.
ENHANCE Trial

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Large open label trial of rAPC in severe sepsis
Showed mortality improvement when rAPC
given within 24 hours of admission
ADDRESS Trial
• rAPC in septic patients with APACHE II
score <25
• Trial discontinued at interim analysis
because of lack of efficacy
APC Complication-Hemorrhage

Absolute contraindications:

Active internal bleeding

Recent (within 3 months) hemorrhagic stroke
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Trauma with an increased risk of life-threatening bleeding
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Presence of an epidural catheter
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Recent (within 2 months) intracranial or intraspinal surgery,
or severe head trauma
Intracranial neoplasm or mass lesion or evidence of cerebral
herniation
Relative contraindications

Platelet count < 30

PTT ≥ 100

INR ≥ 3
Intensive Insulin Therapy
Intensive insulin therapy
Insulin required
Median insulin dose IU/day
Inotropic/Vasopressor Tx
Morning blood glucose (mg/dl)
Standard therapy
(N=783)
Intensive
(N=785)
P Value
307 (39.2%)
33
586 (74.8%)
755 (98.7%)
71
574 (75%)
<0.001
<0.001
0.9
153+33
103+19
<0.001
Van den Berghe G et al. N Eng J Med 2001;345:1359-1367
Morbidity
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)
Intensive
(N=785)
P Value
63/783 (8.0%)
14/783 (1.8%)
49/243 (20.2%)
35/765 (4.6%)
13/765 (1.7%)
22/208 (10.6%)
<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
Summary
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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