Surviving Sepsis Campaign Updated

Guidelines for 2012

Surviving Sepsis Campaign

Surviving Sepsis Campaign—a collaboration of the European Society of Intensive Care Medicine (ESICM), the International Sepsis Forum (ISF), and the Society of Critical Care Medicine

In 2012, it has published an updated version of the International Guidelines for Management of Severe Sepsis and Septic Shock originally published in 2004 and last updated in 2008

Guide to Recommendations’ Strengths and Supporting Evidence

1 = strong recommendation;

2 = weak recommendation or suggestion;

A = good evidence from randomized trials;

B = moderate strength evidence from small randomized trial(s) or multiple good observational trials;

C = weak or absent evidence, mostly driven by consensus opinion

Definition

Sepsis is defined as the presence (or presumed presence) of an infection accompanied by evidence of systemic inflammatory response syndrome (SIRS).

SIRS is defined as the presence of 2 or more of the following:

(1) temperature greater than 38°C (100.4°F) or less than 36°C (96.8°F)

(2) pulse rate greater than 90 beats/min

(3) respiratory rate greater than 20 breaths/min (or PaCO2 less than 32 mmHg)

(4) WBC count greater than 12,000/mm3 or less than 4,000/mm3, or greater than 10% immature band forms.

Definitions

Severe sepsis is defined as the presence of sepsis and early organ dysfunction or hypoperfusion with lactic acidosis.

Septic shock is defined as the presence of sepsis and refractory hypotension

Incidence of sepsis

Sepsis is the 10th leading cause of death in the United States overall

Sepsis is the leading causes of admission to intensive care units (around 50%)

The annualized incidence of sepsis is increasing by 8%. The incidence of severe sepsis is increasing greatest in older adults and the nonwhite population

Prognosis

More than half of all septic patients develop severe sepsis and a quarter develop septic shock; thus, 10% to 15% of all patients admitted to ICUs develop septic shock

Published mortality rates for sepsis range from 28% to 56%

Management of sepsis

Early haemodynamic resuscitation (early goal-directed therapy “EGDT” (resuscitation bundle RB))

Antimicrobial therapy

Source control

Low tidal volume mechanical ventilation

Role of steroids?

Drotrecogin alfa??

Early haemodynamic optimization(resuscitation bundle)

In 2001, a trial of early hemodynamic resuscitation to normal physiologic parameters, or early goal-directed therapy, was conducted in ED patients with severe sepsis/septic shock and revealed a significant mortality reduction.

Early goal-directed therapy is an algorithmic approach to hemodynamic optimization and resolution of global tissue hypoxia within the first 6 hours of disease presentation

Early haemodynamic optimization(resuscitation bundle)

Specifically, patients are treated by

(1) fluid resuscitation with either crystalloid or colloid to achieve a central venous pressure goal of 8 to 12 mm Hg,

(2) vasoactive agents to achieve a mean arterial pressure goal of 65 to 90 mm Hg

(3) blood transfusion to a hematocrit level greater than 30%,

(4) inotrope therapy

(5) intubation, sedation, and paralysis

as necessary to achieve a ScvO2 of greater than 70%

Early haemodynamic optimization(resuscitation bundle)

During the first 6 hours in the ED, the early goal-directed therapy group had significantly greater amount of fluid therapy than the control group (5.0 versus 3.5 L, respectively), RBC transfusion (64.1% versus 18.5%, respectively), and inotrope (ie, dobutamine) administration (13.7% versus 0.8%, respectively).

The primary outcome variable, inhospitalmortality rate, was 46.5% in the control group versus 30.5% in the early goal-directed therapy group

Early haemodynamic optimization(resuscitation bundle)

Subsequent studies over one decade

Validated the RB and its elements

Provided evidence that this therapy modulates inflammation and decrease organ failure progression

Showed that this approach consistently saves 1 out of every 6 lives presenting with severe sepsis/septic shock

Current guidelines continue to recommend EGDT pending the results of numerous ongoing trials

Components of EGDT (resuscitation bundle)

Haemodynamic monitoring

Volume therapy

Vasoactive agents

Increasing oxygen carrying capacity

Inotropic therapy

Decreasing oxygen consumption

Haemodynamic monitoring

Optimal titration of fluids and vasoactive therapy is performed more objectively with invasive monitoring

Central venous access allows measurement of central venous pressure and ScvO

Surviving Sepsis: New monitoring recommendations

Using normalization of lactate levels as an alternate goal in EGDT for severe sepsis, if central venous oxygenation monitoring is not available (Grade 2C).

For patients at risk for fungal infection as a source for severe sepsis, checking one of the newer assays for invasive candidiasis such as 1,3-beta-D-glucan, mannan, or anti-mannan ELISA antibody testing (Grade 2B/C).

When no infection can be found, consider using a low procalcitonin level as a supportive tool for the decision to stop antibiotics (Grade 2C).

Volume therapy

The first parameter to target in hemodynamic optimization is intravascular volume with the use of fluid therapy targeting a central venous pressure of 8 to 12 mm Hg.

No outcome benefit has been demonstrated in using colloids compared to crystalloids with respect to mortality or hospital length of stay.

However, in one investigation a trend to improved survival with the use of colloid (albumin) in sepsis was observed

Surviving Sepsis: New Fluid Resuscitation Recommendations

They gave a strong 1A recommendation for the use of crystalloids like normal saline as the initial fluid resuscitation for people with severe sepsis

Incremental fluid boluses should be continued as long as patients continue to improve haemodynamically (Grade 1C).

They weakly recommended adding albumin to initial fluid resuscitation with crystalloid for severe sepsis and septic shock (Grade 2B).

Vasoactive agents

Vasopressors should be administered when hypotension is persistent or mean arterial blood pressure less than 65 mm Hg, regardless of the central venous pressure, because in the presence of hypotension, organ perfusion cannot be maintained with fluids alone.

Norepinephrine may be more effective in correcting hypotension in septic shock while avoiding the potential tachycardia induced by dopamine

In the patient with refractory hypotension, vasopressin deficiency should be considered

Surviving Sepsis: New Recommendations for Vasopressors

Authors strongly recommend norepinephrine as the first choice for vasopressor therapy (Grade 1B). Vasopressin 0.03 units / minute is an alternative to norepinephrine, or may be added to it (Grade 2A).

When a second agent is needed, epinephrine is their weakly-recommended vasopressor choice (Grade 2B).

Dopamine was only recommended in highly selected patients whose risk for arrhythmias was felt to be very low and who had a low heart rate and/or cardiac output (Grade 2C).

Increasing Oxygen Carrying Capacity

After mean arterial pressure has been optimized, patients with inadequate oxygen delivery reflected by ScvO2 less than 70%, elevated lactate, and hematocrit less than 30% should receive a transfusion of packed RBCs to achieve a hematocrit level greater than 30%.

Inotropic therapy

After adequate volume, mean arterial pressure, and hematocrit goals are met and ScvO2 is persistently less than 70%, dobutamine to improve contractility, in a dosage of 2.5 to 20 µg/kg/minute, titrated to achieve ScvO2 greater than 70%, is recommended.

Because the vasodilatory effect of dobutaminecould worsen hypotension, it should be used in combination with vasopressors for patients with persistent hypotension.

Surviving Sepsis: New Recommendations for inotropic therapy

Dobutamine is strongly recommended (by itself or in addition to a vasopressor) for patients with:

1. cardiac dysfunction as evidenced by high filling pressures and low cardiac output, or

2. clinical signs of hypoperfusion after achievement of restoration of blood pressure with effective volume resuscitation (Grade 1C).

Decreasing oxygen consumption

When ScvO2 remain less than 70% after the CVP, arterial BP and haematocrit have reached the target, oxygen consumption can be reduced through mechanical ventilation to decrease the work of breathing and redistribute blood flow to vital organs

Antimicrobial therapy

Administration of antibiotics within the time of ED care and as soon as possible once there is a reasonable suspicion of severe sepsis is likely to increase the chance of favourable outcome compared with later administration (Grade E)

Empirical regimens should be sufficiently broad, so there is little chance (less than 5%) that the offending pathogen will not be effectively covered

Empirical antibiotic combinations

Pneumonia: a respiratory quinolone (levofloxacin) plus vancomycin (or linezolid)

Bacterial meningitis: ceftriaxone or cefotaxime plus vancomycin

Urinary tract infections: β-lactam/β-lactamase inhibitor with antipseudomonasactivity (piperacillin/tazobactam) plus an aminoglycoside

Empirical antibiotic combinations

Intabdominal infections: piperacillin/tazobactam (or a carbopenem) plus an aminogycoside

Skin and soft tissue infection: clindamycin plus vancomycin (or linezolid)

Unknown source: meropenem (or piperacilline/tazobactam) plus an aminoglycoside (gentamicine)

Source control

Measures to eradicate the source of the infection is an integral component of therapy. This may include:

Abscess drainage

Debridement of devitalized infected tissue

Removal of infected prosthesis

Drotrecogin alfa (activated protein C)

In 2001, the FDA approved DrotAA for adult patients with severe sepsis and a high risk of death based on a subgroup analysis from the Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial.

Subsequent studies failed to show an efficacy benefit in patients with low disease severity—or even in patients with a high mortality risk

Drotrecogin alfa (activated protein C)

With similar concerns and sufficient doubt arising overseas, the European Medicines Agency called for a new trial to investigate whether DrotAAwould reduce mortality in patients with septic shock

PROWESS-SHOCK—a randomized, double-blind, placebo-controlled, multicenter trial of 1,697 patients

The researchers found no significant difference in efficacy between patients who received DrotAAand those who did not receive treatment. At 28 days, 26.4% of patients in the treatment arm and 24.2% of patients in the placebo arm had died.

Drotrecogin alfa (activated protein C)

These results, which prompted the removal of the drug from the market in October 2011, offer answers to questions about the use of DrotAA in severe sepsis that have persisted since its 2001 FDA approval

It might very well be that with early antimicrobial therapies, source control, and resuscitation, we interrupt the sepsis response and the coagulation abnormalities that follow, so there’s no longer a need for this drug

Systemic corticosteroids

Despite more than 5 decades of study and debate, the role of corticosteroid treatment in patients with severe sepsis and septic shock remains controversial

Systemic corticosteroids Annane’s practice-changing study published in 2002

showed that among 300 septic shock patients, those with a negative cosyntropin stimulation test (“non-responders”) randomized to 50 mg hydrocortisone IV q 6 hours had significantly improved 28-day mortality compared to placebo (53% vs. 68%).

CORTICUS (2008) then swung the pendulum back by showing no 28-day mortality benefit of steroids in 499 septic shock patients (39% vs. 36%) who were non-responders to cosyntropin. Steroids did reduce the time spent in shock (3.3 vs. 5.8 days), but steroid-treated patients had more superinfections and new episodes of sepsis

Systemic corticosteroids

Summing up, corticosteroids do improve blood pressure, but any beneficial effects on survival from septic shock remain hotly debated

Surviving Sepsis guidelines regarding corticosteroid therapy in severe sepsis

Unchanged from 2008, and continue to recommend: Hydrocortisone 300 mg / day or less in patients with

septic shock “only after it has been confirmed that their blood pressure is poorly responsive to fluid resuscitation and vasopressor therapy.” (Grade 2C:weak recommendation, low quality evidence)

No benefit of continuous vs. bolus infusions has been demonstrated

Adding fludrocortisone to hydrocortisone is associated with a higher infection rate, and shouldn’t be necessary as hydrocortisone has mineralocorticoid activity. Surviving Sepsis calls fludrocortisone an optional adjunctive treatment to hydrocortisone.

Surviving Sepsis guidelines regarding corticosteroid therapy in severe sepsis

Give hydrocortisone for 7 days, then wean it to prevent rebound hypotension and blood glucose lability.

Stick with the 300 mg / day dose: giving high-dose corticosteroids to people in septic shock is known to be harmful.