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What To Do Before The Subspecialist Arrives: Septic

Shock

Ruth M. Divinagracia, M.D.

Clinical Associate Professor College of Medicine and Philippine General Hospital

University of the Philippines

Attending Physician Makati Medical Center

Saint Luke’s Medical Center Global City

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Septic Shock • Acute organ dysfunction secondary to infection

(sepsis) associated with hypotension not reversed by fluid resuscitation

• Severe sepsis accounts for 9.3% of all deaths in

the US (Angus et al Crit Care Med 2001: 29) • Septic shock, the most severe manifestation of

sepsis, occurs in 2 to 20% of inpatients (Matot et al Int Care Med 2001:27)

• Overall mortality for severe sepsis is 30% and 50% for septic shock (Annane et AJRCCM 2003:168) and kills approximately 1400 people worldwide daily

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Epidemiology of Sepsis in the US

NEJM 2002; 347:966-67

Septic

shock

(severe sepsis

plus refractory

hypotension)

200,000 cases

Severe sepsis

(sepsis plus organ failure)

300,000 cases

Sepsis

(systemic inflammatory response syndrome plus evidence of infection)

400,000 cases

Crude mortality

Number of deaths annually

45%

20%

15%

90,000

60,000

60,000

Total: 210,000

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Sepsis and Septic Shock Defined SEPSIS

• (+) infection (proven of suspected) plus the presence of SIRS (on the basis of ≥ 2 of the following):

• Increased HR > 90/min • Increased RR > 20 or PaCO2 less than 32 or use of MV • Increased temperature > 38C or decreased temperature < 36C • Increased WBC (>12,000) or decreased WBC (<4000) or >90% immature forms • Hyperglycemia, elevated CRP and procalcitonin

Levy et al Crit Care Med 2003;31:1250-56

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Sepsis and Septic Shock Defined SEVERE SEPSIS

•Sepsis with organ dysfunction • hypotension (SBP < 90 mm Hg, MAP < 70)

• hypoxemia (Pa02/FiO2 300)

• oliguria (< 0.5 ml/kg x 2 hours despite fluids)

• metabolic acidosis / lactic acidosis • thrombocytopenia, coagulopathy • obtundation

SEPTIC SHOCK Severe sepsis with hypotension despite ADEQUATE fluid resuscitation

Levy et al Crit Care Med 2003;31:1250-56

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Surviving Sepsis Campaign • Launched in 2002 to improve diagnosis, survival

and management of patients with sepsis • Spearheaded by

• European Society of Intensive Care Medicine • International Sepsis Forum • Society of Critical Care Medicine

• In 2008, the Surviving Sepsis Campaign

International Guidelines were published in the journal Critical Care Medicine™

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Management of Septic Shock: Initial Resuscitation (first 6 hours)

Goal: must be achieved within 6 hours of identification of severe sepsis, do not delay

pending ICU admission • Quickly assess patient for possible infection +

SIRS • Measure serum lactate*, obtain blood cultures

prior antibiotic administration; central line placement for CVP monitoring and adequate access

Dellinger et al Surviving Sepsis Campaign: Crit Care Med 2008; 36: 296-327

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Diagnosis • Obtain appropriate cultures prior to antibiotic therapy but this should NOT delay initiation of antimicrobials • Obtain TWO or more blood cultures (a MUST!)

• One blood culture from each vascular access in place > 48 hours

• Perform imaging studies promptly and sample any source of infection if safe to do so Dellinger et al Surviving Sepsis Campaign: Crit Care Med

2008; 36: 296-327

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Antibiotic Therapy • Begin IV antibiotics as early as possible and within the first hour of recognizing sepsis/septic shock • BROAD-spectrum: one or more agents against likely pathogens and with good tissue penetration • Consider combination therapy if Pseudomas infection likely • SKIN TESTING should not delay therapy, commer-

cially able skin testing for antibiotics aside from penicillin are NOT too reliable; ask for drug history

Dellinger et al Surviving Sepsis Campaign: Crit Care Med 2008; 36: 296-327

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Management of Septic Shock: Initial Resuscitation (first 6 hours) – the

Rivers Protocol • Goal-directed therapy in severe sepsis and septic shock involves interventions to achieve optimum preload, afterload, and contractility to balance O2 delivery and O2 demand • Resuscitation goals:

• CVP 8-12 mm Hg and MAP ≥ 65 mm Hg • Urine output ≥ 0.5 ml/kg/hr • Central venous O2 at ≥ 70% or mixed venous 65%

Rivers et al NEJM 2001;345:1368-77)

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Management of Septic Shock: Initial Resuscitation (first 6 hours)

• In the event of hypotension and/or serum lactate > 4 mmol/L • Deliver an initial minimum of 20 ml/kg of

crystalloid or equivalent over 30 minutes (1000 ml of crystalloids or 300-500 ml of

colloids) • Monitor for hemodynamic response

• Rate of fluid administration should be reduced if cardiac filling pressure increases without concurrent hemodynamic improvement

Rivers et al NEJM 2001;345:1368-77)

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Management of Septic Shock: Initial Resuscitation (first 6 hours)

• Apply vasopressors for hypotension not responding to initial fluid resuscitation to maintain mean arterial (MAP) > 65 mm Hg

• Achieve a CVP of 8 mm Hg ( 12 mm Hg ≥ if

with MV) • Achieve a central venous Oxygen saturation

of (ScvO2) ≥ 70% or mixed venous O2 sat (SVO2) ≥ 65%

Rivers et al NEJM 2001;345:1368-77)

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Initial Fluid Resuscitation: The Rivers Protocol

Supplemental oxygen endotracheal

intubation and mechanical ventilation

Central venous and arterial catherization

Sedation, paralysis

(if intubated), or both

CVP

MAP

ScvO2

Hospital admission

ScvO2

Goals

achieved

Crystalloid

Colloid

Vasoactive agents

Transfusion of red cells

until hematocrit > 30%

Inotropic agents

< 8 mmHg

< 65 mmHg

> 90 mmHg

< 70% > 70%

< 70%

Yes

No

> 65 and < 90 mmHg

8-12 mmHg

Rivers et al NEJM 2001;345:1368-77)

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Table 3. Kaplan-Meier Estimate's of Mortality and Causes of Hospital Death*

Variable Standard

Therapy

Early

Goal-Directed

Therapy

(N = 130)

Relative Risk

(95% Cl)

P Value

No. (%)

In-hospital mortality

All patients

Patients with severe sepsis

Patients with septic shock

Patients with 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)

0.58 (0.38-0.87)

0.46 (0.21-1.03)

0.60 (0.36-0.98)

0.66 (0.42-1.04)

0.009

0.06

0.04

0.07

28-day mortality 61 (49.2) 40 (33.3) 0.58 (0.39-0.87) 0.01

60-day mortality 70 (56.9) 50 (44.3) 0.67 (0.46-0.96) 0.03

Causes of in-hospital death

Sudden cardiovascular collapse

Multi-organ failure

25/199 (21.0)

26/119 (21.8)

12/17 (10.3)

19/117 (16.2)

--

--

0.02

0.27

Kaplan- Meier Estimates of Mortality and Causes of In-Hospital Death: Early Goal - Directed Therapy

Rivers et al NEJM 2001;345:1368-77)

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Vasopressor Therapy • Use to maintain MAP ≥ mm Hg if hypotension persist despite fluid therapy • Norepinephrine or Dopamine centrally administered are the vasopressors of choice

•Recent data (Becker et al NEJM 2010;362:779-89) favor NE over Dopamine due to greater adverse

events with Dopamine)

• Epinephrine, Phenylephrine or vasopressin should NOT be administered as initial vasopressor in SS • Low-dose Dopamine should NOT be used for renal protection Dellinger et al Surviving Sepsis Campaign: Crit Care Med 2008; 36: 296-327

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Table 2. Mortality Rates.*

Time period Dopamine Norepinephrine Odds Ratio

(95% Cl)

P Value

Percent mortality

During stay in intensive

care unit

50.2 45.9 1.19 (0.98 – 1.44) 0.07

During hospital stay 59.4 56.6 1.12 (0.92 – 1.37) 0.24

At 28 days 52.5 48.5 1.17 (0.97 – 1.42) 0.10

At 6 months 63.8 62.9 1.06 (0.86 – 1.31) 0.71

At 12 months 65.9 63 1.15 (0.91 – 1.46) 0.34

Vasopressor Therapy: Norepinephrine versus Dopamine

(Becker et al NEJM 2010;362:779-89), “Comparison of Dopamine and Norepinephrine in the Treatment of Shock” n= 1679, SS=1044

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0.5 1.0 1.5

Type of shock

Hypovolemic

Cardiogenic

Septic

All patients

Hazard Ration (95% Cl)

Norepinephrine Better

Dopamine Better

Vasopressor Therapy: Norepinephrine versus Dopamine (N=1044 septic shock)

Forrest Plot for Predefined Subgroup Analysis According to Type of Shock

P value for interaction = 0.87 Cardiogenic shock = 280 Hypovelemic shock=263

(Becker et al NEJM 2010;362:779-89)

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Inotropic Therapy/Bicarbonate Therapy

• Use dobutamine in patients with myocardial dysfunction as supported by elevated cardiac filling pressures and low cardiac output • Do NOT increased cardiac index to predetermined SUPRANORMAL levels • Bicarbonate should NOT be used hypoperfusion- induced lactic acidosis

Dellinger et al Surviving Sepsis Campaign: Crit Care Med 2008; 36: 296-327

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Steroids for Septic Shock? : Rationale for Physiologic Dose

• Relative adrenal insufficiency may be present in up to 50% of patients with septic shock ( Annane et al 2000: 283) • Systemic inflammation may lead to glucocorticoid

receptor resistance (Molijn et al J Clin Endocrinol Metab 1995; 80)

• Patients with septic shock who had a reduced response to corticotropin (increase in plasma cortisol < 9 µg per deciliter) were likely to die (Rothwell et al Lancet 1991: 337)

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Probability of Survival of Patients with Septic Shock: Annane Study 2002

Placebo vs Steroids

Annane D et al JAMA 2002; 288: 862-871; N=300, 19 ICU’s

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Kaplan-Meier Curves for Survival at 28 Days CORTICUS Study: Steroids vs Placebo

Sprung et al NEJM 2008; 358: 111-124 CORTICUS Study N=251

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CORTICUS Study: Placebo vs Steroids in Septic Shock

Kaplan-Meier Curve for The Time to Reversal of Shock

Sprung et al NEJM 2008; 358: 111-124

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Steroid Therapy

Dellinger et al Surviving Sepsis Campaign: Crit Care Med 2008; 36: 296-327

• Steroid therapy should be considered for adult septic shock when hypotension persists despite fluid resuscitation and vasopressors • ACTH stimulation test nor serum cortisol level are not recommended to identify the subset of adults with septic shock who should receive steroids • Hydrocortisone is the steroid of choice at a dose of 50 mg IV q6

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Mechanical Ventilation of Sepsis-Induced ALI/ARDS

• Up to 42% of patients with severe sepsis will develop ALI/ARDS (Hudson et al Chest 1999; 116: 74S-82S) • Severe sepsis is the most common nonpulmonary cause of ARDS • Biggest breakthrough in ARDS Care: Low tidal volume ventilation strategy has been shown to decrease mortality in patients with ALI/ARDS

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ARDS Network: Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal

Volumes for ALI and ARDS

Study Design: Comparison of clinical outcomes – mortality and ventilator free days – in patients ventilated at 12 ml/kg and a plateau pressure of 50 cm or less versus 6 ml/kg and a plateau pressure of 30 cm or less Outcomes: Mortality and ventilator-free days from Day 1 to 28 Results: Trial was stopped after the enrollment of 861 patients because mortality was lower in the low-tidal volume group (31% vs 39.8%, P=0.007. Ventilator free days was 12 ± 11 vs 10 ±11, P=0.007, again favoring the low-tidal volume group

The ARDS Network NEJM 2000; 342: 1301-1308

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Probability of Survival and being Discharged Home after Randomization: Low Tidal Volume vs

Traditional Tidal Volume

The ARDS Network NEJM 2000; 342: 1301-1308

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Low Tidal Volume Ventilation Strategy in Patients with ARDS

Mortality Among Patients with Pulmonary versus Nonpulmonary Risk Factors for ALI/ARDS: Efficacy of the Low VT Ventilation Strategy

Clinical risk factor

Low VT Ventilation* 6 ml/kg (n = 473)

Traditional VT Ventilation 12 ml/kg (n

= 429)

All Patients† (n = 902)

Pulmonary 32% 76 / 234

40% 89 / 220

36% 165 / 454

Non pulmonary

29% 70 / 239

40% 84 / 209

34% 154 / 448

Eisner et al AJRCCM 2001

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Management of Patients with ARDS

• Ventilate with “ lung protective strategy” – VT of 6 ml/kg, Pplat target of ≤ 30 cm H20, non-toxic FiO2 with more modest PaO2 goal of pO2 of at least 55 mm Hg or SpO2 of at least 88% • Use of PEEP to improvement recruitment, to prevent

alveolar trauma and to decrease FiO2 requirement • Use of CVC (instead of PAC) • “Conservative” fluid management strategy (keep patient on

the “dry” side!) in patients who have no evidence of tissue hypoperfusion after initial fluid resuscitation ARDSnet Publications, 2000, 2005

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Septic Shock: The Critical First 6 Hours • Appropriate and prompt diagnosis of severe

sepsis and septic shock • Early-Goal Directed Therapy (1C)

• Blood Cultures before antibiotic therapy, other cultures as needed (1C)

• Administration of antibiotics within 1 hour of diagnosis of septic shock (1B)

• Vasopressor preference for norepinephrine and dopamine (1C)

• Low tidal volume, limitation of plateau pressure and the use of PEEP in ALI/ARDS (1B)

• Use of stress dose steroids with hydrocortisone as choice should be considered (2C)

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