SEPSIS DEFINITIONSRECOGNITIONINTERVENTIONS

THOMAS R. NUGENT, MDDIRECTOR CRITICAL CARE OUR LADY OF LOURDES CAMDEN DIVISION

Definition by American College of Chest Physicians/Society of Critical Care Medicine

3. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference, Levy MM et al., Crit. Care Med. 2003, 31(4): 1250-1256)

Diagnostic Criteria for Sepsis, Severe Sepsis, and Septic Shock.

Systemic Inflammatory Response Syndrome

• Temp < 36 ° C or > 38.3 ° C• HR > 90• RR > 20 or PCO2 < 32• WBC < 4K or > 12K or bands > 10%

Systemic Inflammatory Response Syndrome

• Temp < 36 ° C or > 38.3 ° C• HR > 90• RR > 20 or PCO2 < 32• WBC < 4K or > 12K or bands > 10%

SepsisSepsisSepsisSIRSSIRSSIRS Severe SepsisSevere SepsisSevere Sepsis Septic ShockSeptic ShockSeptic ShockSeptic Shock

Bone et al. Chest 1992;101:1644

SepsisSepsisSIRS Severe Sepsis Septic ShockSeptic Shock

Bone et al. Chest 1992;101:1644

SIRS with InfectionSIRS with Infection

SepsisSIRS Severe SepsisSevere Sepsis Septic ShockSeptic Shock

Bone et al. Chest 1992;101:1644

Sepsis plus Organ Dysfunction• Elevated Creatinine (>2)• Elevated INR (DIC)• Altered Mental Status (GCS <12)• Elevated Lactate (>4)• Hypotension that responds to

fluid

Sepsis plus Organ Dysfunction• Elevated Creatinine (>2)• Elevated INR (DIC)• Altered Mental Status (GCS <12)• Elevated Lactate (>4)• Hypotension that responds to

fluid

SepsisSIRS Severe Sepsis Septic ShockSeptic Shock

Bone et al. Chest 1992;101:1644

Severe Sepsis and Hypotension• Hypotension that does NOT

respond to fluid (500 cc bolus)

Severe Sepsis and Hypotension• Hypotension that does NOT

respond to fluid (500 cc bolus)

Early Goal-Directed Therapy in the Treatment of

Severe Sepsis and Septic Shock

Rivers E. N Engl J Med 2001;345:1368-77.

Early Goal Directed Therapy

• Early goal-directed therapy (EGDT) is a hemodynamic optimization protocol that is proven to reduce mortality in cases of severe sepsis/septic shock.

• Early goal-directed therapy (EGDT) was proposed by Rivers et al in 2001. This protocol advocates aggressive treatment commencing in the emergency department to achieve certain hemodynamic goals.

• This achieved a 16% absolute risk reduction for in-hospital mortality. (4)

4. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al. Early goal directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-77.

SURVIVING SEPSIS CARE BUNDLES

SURVIVING SEPSIS CARE BUNDLES

TO BE COMPLETED WITHIN 3 HOURS

1.Measure Lactate Levels2.Obtain Blood Cultures prior to administration

of Antibiotics.3.Administer broad spectrum Antibiotics4.Administer 30ml/kg Crystalloid for low BP or

lactate level – 4

TO BE COMPLETED WITHIN 6 HOURS

5. Apply Vasopressors (for hypotension that does not respond to the initial fluid resuscitation) to maintain a MAP > 65.

6. In the event of persistent hypotension despite volume resuscitation (septic Shock) Or

initial lactate being > 4 - Measure CVP & CVP saturation(ScvO2)

7. Remeasure Lactate levels if the initial lactate was elevated.

MAP = Diastolic BP + (Systolic BP – Diastolic BP)

3

Date of download: 9/5/2014Copyright © 2014 American Medical

Association. All rights reserved.

From: Mortality Related to Severe Sepsis and Septic Shock Among Critically Ill Patients in Australia and New Zealand, 2000-2012JAMA. 2014;311(13):1308-1316. doi:10.1001/jama.2014.2637

Characteristics and Outcomes in Severe Sepsis

Figure Legend:

Date of download: 9/5/2014Copyright © 2014 American Medical

Association. All rights reserved.

JAMA. 2014;311(13):1308-1316. doi:10.1001/jama.2014.2637

Mean Annual Mortality in Patients With Severe SepsisError bars indicate 95% CI.

Date of download: 9/5/2014Copyright © 2014 American Medical

Association. All rights reserved.

From: Mortality Related to Severe Sepsis and Septic Shock Among Critically Ill Patients in Australia and New Zealand, 2000-2012

JAMA. 2014;311(13):1308-1316. doi:10.1001/jama.2014.2637

Mortality Rate Among Severe Sepsis Patients Overall and Within Subgroups in 2000 and 2012a

ScvO2 and blood transfusion• Scvo2 – central venous oxygen saturation –

reflects tissue perfusion

ScvO2 and blood transfusion

• In the instance of the central venous oxygen saturation (ScvO2) was still below 70% after adequate fluid and vasopressors, packed red cell transfusion will be given if the hematocrit <30%.

• Add Dobutamine if ScvO2 remains below 70% and Hct > 30%

Lactate Clearance vs Central Venous Oxygen Saturation as Goals of Early

Sepsis Therapy

JAMA, February 24, 2010—Vol 303, No. 8 739

• Compares fluid and vasopressor resuscitation guided by lactate clearance or central venous oxygen saturation

Lactate vs ScvO2• 150 pts in ED assigned with severe sepsis or septic

shock to one of two groups of resuscitation protocols• The ScvO2 group was resuscitated to normalize CVP,

mean BP, and ScvO2 > 70%• The lactate clearance group was resuscitated to

normalize CVP, mean BP and lactate clearance of at least 10% over at least 2 hours

• Study protocol was continued until all goals were achieved or for up to 6 hours.

Cardiac filling pressures are not appropriate to predict hemodynamic

response to volume challengeOsman, David; Ridel, Christophe; Ray, Patrick; Monnet, Xavier; Anguel, Nadia; Richard,

Christian; Teboul, Jean-LouisCritical Care Medicine. 35(1):64-68, January 2007.

doi: 10.1097/01.CCM.0000249851.94101.4F

• A total of 150 volume challenges in 96 patients were reviewed to investigate whether CVP or Pulmonary wedge pressure provided an accurate assessment of volume stasis

Figure 3

Figure 3. Individual values (open circles) and mean ± sd (closed circles) of pre-infusion pulmonary artery occlusion pressure (PAOP) (both expressed in millimeters of mercury) in responders (R) and nonresponders (NR).

Copyright © 2014 Critical Care Medicine. Published by Lippincott Williams & Wilkins. 28

Cardiac filling pressures are not appropriate to predict hemodynamic response to volume challengeOsman, David; Ridel, Christophe; Ray, Patrick; Monnet, Xavier; Anguel, Nadia; Richard, Christian; Teboul, Jean-LouisCritical Care Medicine. 35(1):64-68, January 2007.doi: 10.1097/01.CCM.0000249851.94101.4F

Figure 2

Figure 2. Individual values (open circles) and mean ± sd (closed circles) of pre-infusion central venous pressure (CVP) (both expressed in millimeters of mercury) in responders (R) and nonresponders (NR).

Copyright © 2014 Critical Care Medicine. Published by Lippincott Williams & Wilkins.

29

Cardiac filling pressures are not appropriate to predict hemodynamic response to volume challengeOsman, David; Ridel, Christophe; Ray, Patrick; Monnet, Xavier; Anguel, Nadia; Richard, Christian; Teboul, Jean-LouisCritical Care Medicine. 35(1):64-68, January 2007.doi: 10.1097/01.CCM.0000249851.94101.4F

Cardiac filling pressures are not appropriate to predict hemodynamic response to volume

challenge

• A central venous pressure of <8 mm Hg and a pulmonary artery occlusion pressure of <12 mm Hg predicted volume responsiveness with a positive predictive value of only 47% and 54%, respectively.

• Combination of central venous pressure and pulmonary artery occlusion pressure was considered, the degree of prediction of volume responsiveness was not improved.

Cardiac filling pressures are not appropriate to predict hemodynamic response to volume

challenge

• Conclusion: Our study demonstrates that cardiac filling pressures are poor predictors of fluid responsiveness in septic patients.

• Therefore, their use as targets for volume resuscitation must be discouraged, at least after the early phase of sepsis has concluded. (Crit Care Med 2007; 35:64–68)

The ProCESS Investigators. N Engl J Med 2014;370:1683-1693

• Do we need to follow strict protocols for resuscitation with ScvO2, CVP, etc?

• Patients met 2 SIRS criteria and had SBP <90 or lactate >4 mmol after receiving 20 cc/ kg bolus or 1 liter of fluid over 30 minutes.

• Also pts who required vasopressors to maintain SBP>90 after fluid challenge were eligible

• Random assignment of patients, in 1:1:1 ratio to (1) protocol-based EGDT, (2)protocol standard therapy, (3) or usual care

The ProCESS Investigators. N Engl J Med 2014;370:1683-1693

• (1)EDGT group followed Rivers trial with CVP and ScvO2 to guide fluid resuscitation, vasopressors and blood transfusion

• (2) Protocol-based group had 6 hour resuscitation instructions peripheral IV, fluids and vasopressors to reach SBP and HR goals with hourly assessment

• (3) Physician lead interventions without any protocol

Screening, Randomization, and Follow-up.

The ProCESS Investigators. N Engl J Med 2014;370:1683-1693

Cumulative Mortality.

The ProCESS Investigators. N Engl J Med 2014;370:1683-1693

Outcomes.

The ProCESS Investigators. N Engl J Med 2014;370:1683-1693

Study Overview

• In this study, two protocols for the care of patients with septic shock were compared with usual care with respect to 60-day mortality and other outcomes.

• There were no significant differences in outcome.

The ProCESS Investigators. N Engl J Med 2014;370:1683-1693

Conclusions• In a multicenter trial conducted in the

tertiary care setting, protocol-based resuscitation of patients in whom septic shock was diagnosed in the emergency department did not improve outcomes.

Other interesting studies regarding sepsis

management

From JAMA:

Association Between a Chloride-Liberal vs Chloride-Restrictive Intravenous Fluid Administration Strategy and Kidney Injury in Critically Ill Adults

Date of download: 9/6/2014Copyright © 2014 American Medical

Association. All rights reserved.

From: Association Between a Chloride-Liberal vs Chloride-Restrictive Intravenous Fluid Administration Strategy and Kidney Injury in Critically Ill Adults

JAMA. 2012;308(15):1566-1572. doi:10.1001/jama.2012.13356

Stage 2 or 3 defined according to the Kidney Disease: Improving Global Outcomes clinical practice guideline.

Early Administration of Hydrocortisone Replacement After the Advent of Septic Shock:

Impact on Survival and Immune Response

Sepsis Study GroupCritical Care Medicine. 42(7):1651-1657, July 2014.

Figure 1

Figure 1. Study flowchart. Patient recruitment and classification in groups of early and late intiation of hydrocortisone. PBMCs = peripheral blood mononuclear cells, TNF-α = tumor necrosis factor-α.

Copyright © 2014 Critical Care Medicine. Published by Lippincott Williams & Wilkins. 44

Early Administration of Hydrocortisone Replacement After the Advent of Septic Shock: Impact on Survival and Immune Response*Katsenos, Chrysostomos S.; Antonopoulou, Anastasia N.; Apostolidou, Efterpi N.; Ioakeimidou, Aikaterini; Kalpakou, Georgia Th.; Papanikolaou, Metaxia N.; Pistiki, Aikaterini C.; Mpalla, Margarita C.; Paraschos, Michael D.; Patrani, Maria A.; Pratikaki, Maria E.; Retsas, Theodoros A.; Savva, Athina A.; Vassiliagkou, Spyridoula D.; Lekkou, Alexandra A.; Dimopoulou, Ioanna; Routsi, Christina; Mandragos, Konstantinos E.; on behalf of the Hellenic Sepsis Study GroupCritical Care Medicine. 42(7):1651-1657, July 2014.doi: 10.1097/CCM.0000000000000318

•

Figure 3

Figure 3. Impact of early initiation of hydrocortisone on the total time on vasopressors. Using quartile analysis, two groups of patients were defined: those with early initiation of hydrocortisone treatment (i.e., < 9 hr from start of vasopressors, n = 46) and those with late initiation of hydrocortisone treatment (i.e., > 9 hr from start of vasopressors, n = 124). Statistical comparisons between early- and late-initiation groups are shown.

Copyright © 2014 Critical Care Medicine. Published by Lippincott Williams & Wilkins. 45

Early Administration of Hydrocortisone Replacement After the Advent of Septic Shock: Impact on Survival and Immune Response*Katsenos, Chrysostomos S.; Antonopoulou, Anastasia N.; Apostolidou, Efterpi N.; Ioakeimidou, Aikaterini; Kalpakou, Georgia Th.; Papanikolaou, Metaxia N.; Pistiki, Aikaterini C.; Mpalla, Margarita C.; Paraschos, Michael D.; Patrani, Maria A.; Pratikaki, Maria E.; Retsas, Theodoros A.; Savva, Athina A.; Vassiliagkou, Spyridoula D.; Lekkou, Alexandra A.; Dimopoulou, Ioanna; Routsi, Christina; Mandragos, Konstantinos E.; on behalf of the Hellenic Sepsis Study GroupCritical Care Medicine. 42(7):1651-1657, July 2014.doi: 10.1097/CCM.0000000000000318

•

Dopamine vs Noradrenaline

11. Xu B, Oziemski P. Dopamine versus noradrenaline in septic shock AMJ 2011, 4, 10, 571-574

Dopamine Vs Noradrenaline• Bottomline

1. There is no significant mortality difference at 28 days in patients with septic shock treated with dopamine or noradrenaline.

2. Dopamine is associated with more arrhythmic events.

3. Noradrenaline might be preferred over dopamine asthe first line vasopressor to avoid cardiovascular adverse events.

4. The recent SOAP II study challenges the guidelinerecommendation that dopamine should be one of twofirst line vasopressor agents in septic shock.

11. Xu B, Oziemski P. Dopamine versus noradrenaline in septic shock AMJ 2011, 4, 10, 571-574

SEPSIS MANAGEMENT

• Most importantly– Recognize the signs of sepsis– Act quickly to administer broad spectrum

antibiotics and aggressively fluid resuscitate– Average fluid deficit is 6 liters in severe sepsis

Overview of Current concepts and standards regarding Critical Care

Management

Antibiotics Administration

– Administration of an antimicrobial effective for isolated or suspected pathogens within the first hour of documented hypotension was associated with a survival rate of 79.9%

– Each hour of delay in antimicrobial administration over the ensuing 6 hrs was associated with an average decrease in survival of 7.6%.(12)

– A longer duration to antimicrobial therapy was also associated an increase in incidence of AKI AND AKI was associated with significantly higher odds of death

– Surviving Sepsis 2008 :

“Begin IV antibiotics as early as possible and always within the first hour of recognizing severe sepsis and septic shock”

12 . Kumar et al, Intens Care Med 2009

Antibiotic Therapy• Begin IV Antibiotics as early as possible, & always

within the first hour of recognizing severe sepsis and septic shock. (Grade 1B)

• Broad-spectrum : one or more agents active against likely bacterial/ fungal pathogens & with good penetration into the presumed source. (Grade 1B)

• Duration of therapy typically limited to 7-10 days; longer if response is slow, undrainable foci of infection, or immunogenic deficiencies & neutropenic patients, or Bacteremia with S.Aureus. (Grade 2C)

• Antiviral initiated as early as possible in severe sepsis of viral origin.

Infection Prevention

• Oral chlorhexidine gluconate be used as a form of oropharyngeal decontamination to reduce the risk of ventilator-associated pneumonia in ICU patients. (Grade 2B)

• Dopamine as an alternative to NA is recommended only for patients with low risk of tachyarrhythmia & absolute or relative bradycardia.

• Phenylephrine is NOT recommended for septic shock except in (Grade 1C)

– NA associated serious arrhythmias– C.Output is known to be high but BP is low– As salvage therapy when combined vasopressor-inotrope

drugs & low dose vasopressin have all failed to achieve MAP.

• Do NOT use low dose dopamine for Renal Protection.(Grade 1A)

• All patients requiring Vasopressors should have an arterial catheter placed as soon as practical.

Ionotropic Therapy

• A trial of Dobutamine infusion of up to 20mcg/kg/min may be administered alone or added to vasopressor in presence of

–Myocardial dysfunction suggested by elevated cardiac filling pressures & low cardiac output, or

–Ongoing signs of hypoperfusion, despite achieving intravascular volume & adequate MAP. (Grade 1C)

Corticosteroids• Do NOT use IV Hydrocortisone to treat adult septic

shock if adequate fluid resuscitation & vasopressor therapy is able to restore hemodynamic stability. In case this is not achieved IV Hydrocortisone alone @ 200mg IV OD may be used.(Grade 2C)

• ACTH stimulation test is NOT to be used to identify adults with septic shock receiving Hydrocortisone.

• Steroid therapy may be weaned when vasopressors are no longer required.

• Do NOT use corticosteroids to treat sepsis in the absence of shock.

Blood Product Administration• Transfuse Red Blood Cells when Hb decreases to < 7

& target a Hb of 7-9 in adults.(Grade 1B)

• Higher Hb level may be required in presence of myocardial ischemia, severe hypoxemia, or acute hemorrhage.

• Erythropoietin not recommended as a treatment of sepsis related severe anemia.(Grade 1B)

• FFP should only be used to correct clotting abnormalities in the presence of bleeding or planned invasive procedures. (Grade 2D)

• Antithrombin should not be used for the treatment of severe sepsis. (Grade 1B)

Mechanical ventilation in Sepsis induced ARDS

• Target a Tidal volume of 6ml/kg of predicted body wt.(vs. 12ml/kg). (Grade 1A)

• Plateau pressure should be measured in pts with ARDS & Target an initial upper limit pressure <30 cm H2o in a passively inflated lung.

• PEEP should be applied to avoid alveolar collapse at end expiration (atelectrauma). (Grade 1B)

• Higher rather than lower levels of PEEP should be used in sepsis associated ARDS. (Grade 2C)

Sedation, Analgesia & Neuromuscular Blocking Agents(NBMAs)

• Continuous or intermittent sedation should be minimized in mechanically ventilated sepsis pts targeting specific titration endpoints. (Grade 1B)

• NBMAs should be avoided if possible in septic pts without ARDS.(due to risk of prolonged NM blockade following discontinuation)

• If NMBAs are needed, either intermittent bolus as required or continuous infusion with Train of Four monitoring of the depth of blockade is advised. (Grade 1C)

• A short course of NMBA of NOT greater than 48hrs for pts with early sepsis induced ARDS & a PaO2/ FiO2 < 150 is advised.

Glucose Control• In patients with severe sepsis start insulin dosing when 2

consecutive blood sugar reading are > 180.• A protocolized approach should target an upper level of <

180 rather than a upper target blood glucose level of < 110. (Grade 1A)

• Blood glucose monitoring every 1-2 hrs until glucose values & insulin infusion rates are stable & thereafter every 4hrs. (Grade 1C)

• Use IV insulin in pts with severe sepsis.• Interpret with caution low glucose levels obtained with

point of care testing as these techniques may overestimate arterial blood or plasma glucose values

Renal Replacement Therapy& Bicarbonate

• CRRT & Intermittent HD are equivalent in Severe Sepsis and ARF. (Grade 2B)

• Use continuous therapies to facilitate management of fluid balance in hemodynamically unstable septic pts.

• Do NOT use Sodium Bicarbonate for the purpose of improving hemodynamics or reducing vasopressor requirements when treating hypo perfusion induced lactic acidemia with a pH>7.15 (Grade 2B)

DVT Prophylaxis• Pts with severe sepsis should receive daily

phamacoprophylaxis against VTE. (Grade 1B)

• Use once daily sc LMWH (vs BID dosing of UFH & vs TDS dosing of UFH). (Grade 1B)

• If CrCl <30 use Dalteparin. (Grade 1A)

• Whenever possible treat with a combination of pharmacological therapy & intermittent pneumatic compression.

• Where heparin is contraindicated (low platelets, severe coagulopathy, active bleeding or recent ICH) mechanical prophylactic treatment (compression stocking or devices) should be used.

Stress Ulcer Prophylaxis• Use H2 Blocker or Proton Pump Inhibitor in pts

who have bleeding risk factors. (Grade 1B)

• When stress ulcer prophylaxis is needed use PPI rather than H2 blockers(?).

• Pts without risk factors should not receive prophylaxis

Nutrition• Give oral or enteral feeding, as tolerated rather than

either complete fasting or only IV glucose within the first 48 hrs of diagnosing severe sepsis.

• Avoid mandatory full caloric feeding in the first week instead suggest low dose feeding (e.g. upto 500 calories per day) then advancing only as tolerated.

• Use IV glucose & Enteral Nutrition rather than TPN alone or Parenteral nutrition in conjugation with enteral feeding during the first 7 days of diagnosis.

• Use nutrition with no specific immunomodulating supplementation (rather than nutrition providing specific immunomodulating supplementation) in severe sepsis.