Pneumonia and septic shock - Division of Critical Care

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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 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

Discussion points

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

Sepsis: Defining a disease continuum

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

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:

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

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

Bacterial Pneumonia

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)

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;345:1368-

77.

Rivers E et al.

NEJM

2001;345:1368-

77.

Analysis

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

EGDT Outcomes

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

Conclusions

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

BP

CVP

Urine output

ScvO2

Hgb pH

Lactate

Resuscitation goals

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

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

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

Improved hemodynamic stability

Differentially reduced inflammation without significant immunosuppression

Vasopressor therapy in septic shock

To restore systemic vascular resistance towards normal and allow tissue and organ perfusion

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

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 (0.9-

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.

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 Systole

Images used with permission from Joseph E. Parrillo, MD

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 ( 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)

Why?

Low perfusion pressure

Low cardiac output

Microthrombosis

Microvascular events in severe sepsis

Sepsis

 Coagulation

 Fibrinolysis

Endothelial injury

 Inflammation

Microthrombosis

Organ failure Digital ischemia

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 NNT

• All patients 6% 16

APACHE II score

≥ 25 13% 8

N Eng J Med 2001;344:699-709.

ENHANCE Trial

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

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

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)

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

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)

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

Summary

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

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