Optimizing sepsis management in ED

Dr. Ahmed AlhubaishiEmergency R3

outlines

• Case for discussion• Definitions• Approach to septic Pts• Litreatures• Take home messages

case

• 51 y/o gentleman k/c/o HTN on atenolol• p/w several days of crampy abdominal pain,

nausea and loose stools• h/o fever with chills 2 wks earlier with mild rt

upper quadrant abdominal pain• 2 days back ,he was seen by his GP and

diagnosed to have G.E• He contineud to have abdominal pain,nausea and

mild diarrhoea + fever 40 C , chills/anorexia

• No known allergies• Not smoker or alcohol consumer• No h/o abdominal surgeries• He is from india, last visit was 1 yr ago• No : cough, chest pain, headache, neck

stiffness, sorethroat or urinary complaints

• Sick looking and pale• Awake and alert

– Vitals:– T 39.4 C– BP 70/40 mm Hg– PR 130 b/m– RR 26 b/m– O2 sat 97 % in R.A

• Mild jaundice, dry oropharynx

• Sick looking and pale• Awake and alert

– Vitals:– T 39.4 C– BP 70/40 mm Hg– PR 130 b/m– RR 26 b/m– O2 sat 97 % in R.A

• Mild jaundice, dry oropharynx

• No neck rigidity• CVS: tachycardic• Chest: clear• Abdomin: soft, decreased

B.S, epigastric and rt upper quadrant tenderness, no murphy’s or palsatile mass

• Limbs: cool and weak pulse, C.R > 3s

• Skin: pale , dry• Neuro: nad

• Cardiac monitor• Peripheral I.V lines• Blood taken for lab & c/s• Infusion of 1 L NS as bolus• ECG: s. tachycardia, 130

with nonspecific ST-T wave changes

• Portable CXR : no consolidation

• Cardiac monitor• Peripheral I.V lines• Blood taken for lab & c/s• Infusion of 1 L NS as bolus• ECG: s. tachycardia, 130

with nonspecific ST-T wave changes

• Portable CXR : no consolidation

• WBC : 2• Hematocrit : 29%• PLT: 81• Cr: 1.6 mg/dl[0.8-1.5]• T.bili : 2.9 [0.2-1.3]• AST: 84 [17-59]• ALT: 93[11-66]• ALP:205[38-126]• Trop: 0.18[0.00-0.09]

What is going on with the patient?

• What further you want?• How can we continue the care?

• The patient is in severe sepsis

Additional work-up

• Lactate 4.6• INR 1.3• Fibrinogen 516[189-

434]• ABG: ph 7.46, pco2 22,

po2 79, hco3 18 base excess -8.1

Additional work-up

• Lactate 4.6• INR 1.3• Fibrinogen 516[189-

434]• ABG: ph 7.46, pco2 22,

po2 79, hco3 18 base excess -8.1

• He received 5 L NS, no much improvement

• Norepi. Drip started• CVC and ScvO2 monitor

were placed• Emperic broad

spectrum antibiotics given

• Pt admitted to ICU

• Non-contrast CT abdomin: low attenuated fluid-filled areas in lt liver lobe

• CT abdomin with IV conrast: 4 cm multiloculated lt hepatic abscess

• Drained under Ct guidance by interventional radiologist

• The aspirated fluid sent for culture• A drain left in situ

• Blood & fluid c/s : strep constellatus [viridans]• Antibotics changed according to sensitivity• Patient was d/c after 10 days

sepsis

The Sepsis spectrum

A clinical response arising from a nonspecific insult, with 2 of the following: T >38oC or <36oC HR >90 beats/min RR >20/min WBC >12,000/mm3

or <4,000/mm3 or >10% bands

SIRS = systemic inflammatory

response syndrome

SIRS with a presumed or confirmed infectious process

Chest 1992;101:1644.

SepsisSIRSSevere Sepsis

SepticShock

Sepsis with organ failure

Refractoryhypotension

Sepsis complications

• Organ failure, respiratory, renal, hepatic, cardiovascular, coagulopathy/disseminated intravascular coagulation, neurologic failure

• Progression or development of new foci of infection despite antibiotic treatment (e.g. candidemia in a patient on prolonged antibiotic therapy for bacteremia)

• Bleeding diathesis • Reaction to antibiotics • Acute respiratory distress syndrome • Hyperglycemia

Management

• Early goal directed therapy • lung protective ventilation • broad spectrum antibiotics • possibly activated protein C

Early goal directed therapy

History of GDT• Shoemaker (1979)

– Determined haemodynamic and O2 transport values in surgical survivors

– Median values “goals” for high risk surgical patients– Mortality reduction 30% 4%!

• Subsequent studies - No survival benefit!• Hayes (1994): ICU patients

– 30 day mortality 34% (control) versus 54% (protocol)• European Consensus Conference (2000)

– Resuscitation to “supranormal values” harmful– Importance of “timely resuscitation” and “normal haemodynamic

values”

EGDT

• Rivers & colleagues [ rivers E,Nguyen B,havstad S,et al. early goal-directed therapyin the treatment of severe sepsis and

septic shock. N Engl J Med 2001 ]• RCT• Pts with severe sepsis and septic shock• Pt enrolled to either EGDT during the first 6

hrs or the standard therapy

Study Design• PRCT, partial blinding• Urban A&E: 9 bed unit• Inclusion criteria

– > 16yo– 2 SIRS criteria– SBP < 90mmHg after 20-30 ml/kg fluid bolus or serum lactate >

4mmol/L• Randomised to 6 hours EGDT or standard therapy• Clinicians subsequently blinded to care• Primary outcome measure

– In-hospital mortality• 72 hour serial:

– Resuscitation end-points– APACHE II scoring

• Crystalloids given to keep CVP at 8-12mmHg• Vasopressors added if MAP < 65 mmHg• PRBCs transfusion if ScvO2 [ central venous

oxygen saturation] < 70% to maintain hematocrit > 30%

• Conclusion : decreased mortality at 28 and 60 days & decreased duration of hospitalization

Key Results

• In-hospital mortality– 30.5% EGDT versus 46.5% control (p=0.009)

• 7-72hrs EGDT group significantly improved (p<0.02)– SVO2 (70% versus 65%)– Lactate concentration (3mmol versus 4mmol)– pH (7.4 versus 7.36)– Base deficit (2 versus 5.1)– Mean APACHE II scores (13 versus 15.9)

In-hospital mortality (all patients)

0

10

20

30

40

50

60 Standard therapy

EGDT

28-day mortality 60-day mortality

NNT to prevent 1 event (death) = 6 - 8

Mor

talit

y (%

)

The benefit mechanism of EGDT

• Unclear• But may include:– Reversal of tissue hypoxia– Decrease in inflammation and coagulation defects

• Russel JA. Drug therapy: managemnt of sepsis.N Engl J Med 2006

Litreture review

• EARLY MANAGEMENT :– first priority is stabilization of their airway and

breathing. – Next, perfusion to the peripheral tissues should be

restored – securing the airway and correcting hypoxemia.

Intubation and mechanical ventilation may be required

• Dellinger, RP, Levy, MM, Carlet, JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008

• Sessler, CN, Perry, JC, Varney, KL. Management of severe sepsis and septic shock. Curr Opin Crit Care 2004

Assess perfusion

• Hypotension is the most common indicator that perfusion is inadequate

• However, critical hypoperfusion can also occur in the absence of hypotension, especially during early sepsis

catheter

• (CVC) should be inserted in most patients with severe sepsis or septic shock

• In one clinical trial, treatment of septic shock guided by the ScvO2 reduced mortality

• Rivers, E, Nguyen, B, Havstad, S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001

Restore perfusion• early restoration of perfusion is necessary to

prevent or limit multiple organ dysfunction, as well as reduce mortality

• using IVFs, vasopressors, inotropes, and, possibly, red blood cell transfusions

• Recommendation: patients be managed with therapy aimed at achieving Scvo2 ≥70 percent within six hours of presentation (Grade 1B).

fluids• Recommendation:

– boluses of intravenous fluids as first-line therapy in patients who demonstrate impaired perfusion (Grade 1B).

– Fluid boluses are repeated until BP and tissue perfusion are acceptable

– These parameters should be assessed before and after each fluid bolus.

– There are no data to support preferential administration of crystalloid or colloid

• Hollenberg, SM, Ahrens, TS, Annane, D, et al. Practice parameters for hemodynamic support of sepsis in adult patients: 2004 update. Crit Care Med 2004;

• Choi, PT, Yip, G, Quinonez, LG, Cook, DJ. Crystalloids vs. colloids in fluid resuscitation: a systematic review. Crit Care Med 1999

Lactate clearance

• evaluated as a potential substitute for ScvO2 as the target of resuscitation

• Jones, AE, Shapiro, NI, Trzeciak, S, et al. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA 2010

– no difference in hospital mortality, length of stay, ventilator-free days, or incidence of multiorgan failure, suggesting that lactate clearance criteria may be an acceptable alternative to ScvO2 criteria.

• We prefer to target an ScvO2 ≥70 percent because it is the more extensively studied resuscitation goal, although a lactate clearance ≥10 percent appears to be a reasonable alternative if ScvO2 monitoring is unavailable

vassopressor

• second line agents in the treatment of severe sepsis and septic shock after fluids

• useful in patients who remain hypotensive despite adequate fluid resuscitation or who develop cardiogenic pulmonary edema

• prefer to use norepinephrine in most patients

• Reinhart, K, Bloos, F, Spies, C. Vasoactive drug therapy in sepsis. In: Clinical Trials for the treatment of sepsis, Sibbald, WJ, Vincent, JL (Eds), Springer Verlag, Berlin, 1995

• De Backer, D, Biston, P, Devriendt, J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med 2010

Inotropic therapy

• For patients who have myocardial dysfunction• if ScvO2 remains <70 percent after all of the

interventions been discussed • Dobutamine is the usual inotropic agent

• Bersten, AD, Hersch, M, Cheung, H, et al. The effect of various sympathomimetics on the regional circulations in hyperdynamic sepsis. Surgery 1992

Red blood cell transfusions

• EGDT aggressively utilizes red blood cell transfusions to raise the ScvO2

• 70 percent of patients in the EGDT group received transfusions, compared to 45 percent in the conventional therapy group

• Hébert, PC, Wells, G, Blajchman, MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999

Control of the septic focus

• Prompt identification and treatment of the site of infection are essential

• Sputum and urine ......for gram stain and culture

• Blood cultures• indwelling vascular access devices ... c/s and

removal

antibiotics

• should be administered immediately after appropriate cultures been obtained

• recommended: empiric broad spectrum antibiotics when a definite source of infection can not be identified (Grade 1B).

• early initiation of antibiotic therapy is associated with lower mortality

• Gaieski, DF, Mikkelsen, ME, Band, RA, et al. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. Crit Care Med 2010

• Kumar, A, Roberts, D, Wood, KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006:– time to initiation of appropriate antimicrobial therapy was the strongest predictor of

mortalit

• Safdar, N, Handelsman, J, Maki, DG. Does combination antimicrobial therapy reduce mortality in Gram-negative bacteraemia? A meta-analysis. Lancet Infect Dis 2004– several clinical trials and two meta-analyses have failed to demonstrate superior overall

efficacy of combination therapy compared to monotherapy with a third generation cephalosporin or a carbapenem

– recommend use of a single agent with proven efficacy and the least possible toxicity, except in patients who are either neutropenic or whose severe sepsis is due to a known or suspected Pseudomonas infection

Recombinant human activated protein C

• multicenter PROWESS trial supported the efficacy of rhAPC• Risk of intracranial bleeding-nonstatistically significant

Bernard, GR, Vincent, JL, Laterre, PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001

• ENHANCE trial also found that patients treated within 0 to 24 hours from their first sepsis-induced organ dysfunction had significantly lower mortality than those treated after 24 hours

Vincent, JL, Bernard, GR, Beale, R, et al. Drotrecogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE: further evidence for survival and safety and implications for early treatment. Crit Care Med 2005

Activated protein C

• 24 mic/kg/hr for 96 hrs• Reported to decrease mortality and to

ameliorate organ dysfunction in Pts with severe sepsis [ APACHE2 score > 25 or dysfunction 2 or more organs ]… decrease mortality by 13 %

• Not beneficial in low risk Pts• Ely EW, Laterre PF,Angus DC, et al. Drotrecogin alfa (activated)

administration across clinically important subgroup of Pts with severe sepsis. Crit Care Med 2003

corticosteroids

• Controversial• Theory of adrenal insufficiency• ??? Type, timing, dose, duration• Recent trial: hydrocort. Did not improve

survival or reverse the shock• Sprung CL, Annane D, Keh D, et al. hydrocort. Therapy for Pts with septic

shock. N Engl J Med 2008

corticosteroids• most likely to be beneficial to patients who have severe

septic shock (which we define as a SBP <90 mmHg for > 1 hour despite adequate fluid resuscitation and vasopressor administration), especially if begun within 8 hours of the onset of shock.

COIITSS Study Investigators, Annane, D, Cariou, A, et al. Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial. JAMA 2010

Minneci, PC, Deans, KJ, Eichacker, PQ, Natanson, C. The effects of steroids during sepsis depend on dose and severity of illness: an updated meta-analysis. Clin Microbiol Infect 2009

others

• Intensive insulin therapy placed critically ill Pts with sepsis at increase risk for serious adverse events related to hypoglycemia

• N Eng J Med 2008. 358:125• No evidence supports bicarbonate to treat lactic

acaedemia in sepsis esp. if pH > 7.15

Take home messages

• Early identification of septic pts is very important

• Early initiation of apprpriate management will decrease the mortality

• EGDT is the cornerstone of severe sepsis management

ECGC In Green Tea Is Powerful Medicine Against Severe Sepsis

THANK YOU

lactate

• Used as a biomarker for tissue oxygenation and perfusion

• Enhancing early identification of Pts with severe sepsis

• If > or equal to 4mmol/l , used as major criteria for EGDT

• For each 10% decraese in s.lactate ,mortality decrease by 11 %

• Nguyen HB,rivers EP,knoblichBP, et al.Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med 2004

• 29 % of infected Ptswith elevated lactate were normotensive- yet if lactate not cleared within 6 hrs, their mortality ----- 55 %

• Normal BP doesnot equate to effective end-organ perfusion

• When lactate is elevated, the Pt is in critical but potentially reversible situation [ O2 delivery is not meeting demand ]

• Nguyen HB,rivers EP,knoblichBP, et al.Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med 2004

Lung protective mechanical ventilation

• Use tidal volume 6cc/kg [ not 12cc/kg ]shown to decrease mortality rate from 40% to 31 %, to reduce organ dysfunction, to lower level of cytokines

• Ranieri VM, Suter PM,Tortorella C, et al. Effect of mechanical ventilation on inflammatry mediators in pts with ARDS : RCT. JAMA 1999