SEPSIS MANAGEMENTpresentation

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Sepsis syndrome managementDr Amit KochetaDNB TraineeDeptt. Of Anesthesia& Critical CareBMHRC : 

Sepsis syndrome managementDr Amit KochetaDNB TraineeDeptt. Of Anesthesia& Critical CareBMHRC

Sepsis : 

Sepsis Most common cause of death in ICU 750,000 cases/yr: Incidence increasing Mortality is 10% to 90%. Average 40% Average LOS 19 days /$22k cost <50% have a positive blood culture 50% need ICU, 17% need ventilator (D.Angus: Crit. Care Med: 2001:1303)

Increased Incidence of Sepsis : 

Increased Incidence of Sepsis Increase in number of aged Chronic illnesses ( DM, chronic renal failure) Increase in invasive procedures/catheters Increased use of antibiotics/resistance Immunosuppressed patients/steroids

SepsisDefinitions : 

SepsisDefinitions Based on ACCP/SCCM consensus panel Infection Inflammatory response to pathogen Classically Gram (-) rod Bacteremia Viable bacteria in blood

SepsisDefinitions : 

SepsisDefinitions SIRS Widespread inflammatory response in absence of documented infection Need 2 or more: Temp > 380C (100.40F) or < 360C (96.80F) Heart rate > 90 bpm Respiratory rate > 20 /min or PaCO2 < 32 mmHg WBC > 12,000 cells/mm3, < 4,000 cells/mm3, or > 10% immature (band) form

SepsisDefinitions : 

SepsisDefinitions Sepsis Systemic response to infection SIRS + infection( culture or gram stain of blood, sputum, urine or fluid positive Severe sepsis Sepsis and at least one sign of organ dysfunction - Area of mottled skin - Capillary refilling time ≥ 3 seconds - Urinary output < 0.5 ml/kg for at least 1hr or RRT - Abrupt change in mental status or abnormal EEG - Platelet counts < 100,000/ml or DIC - ALI/ARDS - Cardiac dysfunction on echocardiography

SepsisDefinitions : 

SepsisDefinitions Septic shock Sepsis + hypotension Systemic MAP < 60mmHg(<80mmHg if previous HTN) after 20-30ml/kg starch or 40-60ml/kg saline, or PCWP between 12-20mmHg Need for dopamine >5µg/kg/min or NA< 0.25µg/kg/min to maintain MAP above 60mmHg(80mmhg if HTN) ~ 40% of sepsis Hypotension/Refractory Shock Need for dopamine >15µg/kg/min or NA >0.25µg/kg/min to maintain MAP above 60mmHg

SepsisDefinitions : 

SepsisDefinitions MODS Primary MODS: early organ dysfunction Secondary MODS: later organ dysfunction Most common manifestations of severe MODS: - ARDS, acute renal failure, DIC Prevalence Rates SIRS – 60% Sepsis – 20% Severe sepsis/shock – 3% Estimated 751,000 cases of severe sepsis/septic shock in US each year Similar number of deaths as myocardial infarction 215,000 (9.3% of all deaths)

Sepsis: Defining a Disease Continuum : 

Sepsis: Defining a Disease Continuum A clinical response arisingfrom a nonspecific insult, including 2 of the following: Temperature 38oC or 36oC HR 90 beats/min Respirations 20/min WBC count 12,000/mm3 or 4,000/mm3 or >10% immature neutrophils SIRS = systemic inflammatory response syndrome. Bone et al. Chest. 1992;101:1644. SIRS with a presumed or confirmed infectious process Sepsis SIRS Infection Severe Sepsis

Sepsis: Defining a Disease Continuum : 

Sepsis: Defining a Disease Continuum Bone et al. Chest. 1992;101:1644; Wheeler and Bernard. N Engl J Med. 1999;340:207. Sepsis SIRS Infection Severe Sepsis Sepsis with 1 sign of organ failure Cardiovascular (refractory hypotension) Renal Respiratory Hepatic Hematologic CNS - Metabolic acidosis

The Proposed PIRO Model of Sepsis : 

O R I P The Proposed PIRO Model of Sepsis Levy M et al, Critical Care Medicine. 31(4):1250-1256, April 2003.

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PIRO system allows for integration of clinical ,translational and basic scientific discoveries and promises to more accurately predict outcomes and response to therapy for individual patients.

Relationship Of Infection, SIRS, Sepsis Severe Sepsis and Septic Shock : 

Bone et al. Chest 1992;101:1644 Relationship Of Infection, SIRS, Sepsis Severe Sepsis and Septic Shock

Mortality Increases in Septic Shock Patients : 

Mortality Incidence Balk, R.A. Crit Care Clin 2000;337:52 Mortality Increases in Septic Shock Patients Approximately 200,000 patients including 70,000 Medicare patients have septic shock annually

Causes : 

Causes Infection of chest, abdomen, genitourinary system & primary blood stream cause more than 80% of cases of sepsis. Incidence of gram –ve sepsis has diminished over the years to 25%-30%. Gram+ve &polymicrobial infection account for 30-50% & 25% of cases respectively. MDR bacteria&fungi-25% Viruses&parasite-2-4% Culture –ve in about 30%of cases mainly in patients with community acquired sepsis who are treated with antibiotics before admission. D.Annane et al Lancet Jan 2005

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Estimated Frequency Gram+ve bacteria 30-50% MSSA 14-24% MRSA 5-11% Streptococcus pnemonia 9-12% Enterococcus 3-13% Anaerobes 1-2% Gram-ve bacteria 25-30% E.coli 9-27% Psedomonas aeruginosa 8-15% Klebsiella pnemonia 2-7% Haemophillus influenza 2-10% Anaerobes 3-7%

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Fungus Candida albicans 1-3% Other Candida 1-2% Yeast 1% Parasite 1-3% Viruses 2-4% D,Annana et al LANCET JAN 2005

Epidemiology of severe sepsis in IndiaS Todi, S Chatterjee and M BhattacharyyaCritical Care 2007, 11(Suppl 2):P65 : 

Epidemiology of severe sepsis in IndiaS Todi, S Chatterjee and M BhattacharyyaCritical Care 2007, 11(Suppl 2):P65 Introduction A multicentre, prospective, observational study was conducted in 12 intensive therapy units (ITUs) in India from June 2006 to November 2006 to determine the incidence and outcome of severe sepsis among adult patients.    Methodsll patients admitted to ITUs were screened daily for SIRS, organ dysfunction and severe sepsis. Patients with severe sepsis were further studied.  ConclusionSepsis was common in Indian ITUs and had predominant medical populations. ITU mortality was higher compared with western literature. Gram-positive infections were less common although the incidence of parasitic and viral infections were higher than in the West.

Pathophysiology of Severe Sepsis : 

Pathophysiology of Severe Sepsis

Severe Sepsis: The Final Common Pathway : 

Severe Sepsis: The Final Common Pathway Endothelial Dysfunction and Microvascular Thrombosis Hypoperfusion/Ischemia Acute Organ Dysfunction (Severe Sepsis) Death

Pathophysiology of Severe Sepsis : 

3/18/2010 Endothelium Pathophysiology of Severe Sepsis Organisms

Systemic Activation of Inflammation in Sepsis : 

Systemic Activation of Inflammation in Sepsis Chart adapted from: van Deventer SJ et al. Blood. 1990;76:2520-6.

Cytokines Kinetics : 

Cytokines Kinetics

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Biochemical markers Several biochemical markers present in blood, including serum procalcitonin (PCT) , C-reactive protein (CRP) and Triggering Receptor Expressed on Myeloid cells (TREM)have been proposed to be useful in this distinction.

Slide 27: 

Lobo SM, Lobo FR, Bota DP, et al.: C-reactive protein levels correlate with mortality and organ failure in critically ill patients. Chest 2003, 123:2043–2049.

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Du B, Pan J, Chen D, et al.: Serum procalcitonin and interleukin- 6 levels May help to differentiate systemic inflammatory response of infectious and noninfectious origin Chin Med J (Engl) 2003, 116:538–542.

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Luzzani A, Polati E, Dorizzi R, et al.: Comparison of procalcitonin and C-reactive protein as markers of sepsis Crit Care Med 2003, 31:1737–1741. Serum procalcitonin was a better marker of infection than CRP

PCT as a tool to guide Antimicrobial Therapy. : 

PCT as a tool to guide Antimicrobial Therapy. PCT Level Less than .1ng/ml-absence of infection. .1 to.25ng/ml-bacterial infection unlikelly and use of antibiotic-discouraged. .25 to.5ng/ml -indicate possible bacterial infection,initiate antimicrobial therapy. More than .5ng/ml-suggestive of presence of bacterial infection and antibiotic treatment is strongly recommended. Muller B et al(2000).Calcitonin precursors are reliable markers of sepsis in a MICU .Crit Care Med 28:977-983

Septic Shock Specific Organ Responses : 

Septic Shock Specific Organ Responses Regional circulation Altered blood flow Microcirculation Development of microthrombi Decreased functional capillaries Abnormal O2 utilization Increased microvascular permeability

Septic Shock Specific Organ Responses : 

Septic Shock Specific Organ Responses Systemic circulation Arterial & venous dilation SVR & PAWP Central circulation Systolic dysfunction ( LVEF & RVEF) Diastolic dysfunction ( compliance) Loss of ventricular compliance CVP & PAWP overestimate preload

SepsisSpecific Organ Responses : 

SepsisSpecific Organ Responses Lung: V/Q mismatch Hypoxemia Increased microvascular permeability Interstitial/alveolar edema ARDS

SepsisSpecific Organ Responses : 

SepsisSpecific Organ Responses Gastrointestinal: Impaired GI motility Bacterial translocation >> MODS Stress-ulcer GI bleeding Hepatic dysfunction

SepsisSpecific Organ Responses : 

SepsisSpecific Organ Responses Kidney: Altered renal function ATN/ acute renal failure Increases mortality rate Neurologic: Encephalopathy Peripheral polyneuropathy 68% - 100%

SepsisSpecific Organ Responses : 

SepsisSpecific Organ Responses Hematologic: Leukocytosis/leukopenia Thrombocytopenia Coagulopathy DIC ~ 15% - 20%

Metabolic Alterations in Sepsis : 

Metabolic Alterations in Sepsis

Failure of the Immune System : 

Failure of the Immune System Loss of delayed hypersensitivity Inability to clear infection Predisposition to nosocomial pneumonia Decreased Th1 cytokines without an increase in Th2 cytokines Trauma and burn patients have increased levels of IL-10

Slide 39: 

Predictors of Mortality: PROWESS Placebo Group Absolute or Relative Thrombocytopenia Risk Measures Standard Therapy Mortality (%) Renal Dysfunction 41 APACHE II Score > 25 49 36 >2 Organ Dysfunctions 34 Ventilator Use 33 Vasopressor Use 32 Lactic Acidosis 42 37 50 45 40 35 30 25 20 15 10 5 APACHE II Q4 APACHE II Q3

“High Risk” versus “Low Risk” Populations : 

“High Risk” versus “Low Risk” Populations

Septic Shock of Early or Late Onset-Does It Matter? Oscar Roman-Marchant, MD; Carlos E. A. Orellana-Jimenez, MD; : 

Septic Shock of Early or Late Onset-Does It Matter? Oscar Roman-Marchant, MD; Carlos E. A. Orellana-Jimenez, MD; Study objectives: To determine possible differences in morbidity and mortality between early and late onset of septic shock in ICU patients. Setting: Thirty-one–bed, mixed, medicosurgical ICU in a university hospital. Patients: All 65 patients who acquired septic shock after admission to the ICU between February 1999 and April 2000. Conclusions: Septic shock is more severe when of early onset, as reflected by more severe organ dysfunction, greater lactic acidosis, and higher vasopressor requirements, yet the outcome is better, as reflected by a shorter duration of the shock episode, shorter ICU stay, and slightly lower mortality rates. These differences may influence clinical trials of therapeutic agents for sepsis, and should be taken into account when analyzing the results Chest. 2004;126:173-178

Slide 42: 

Dellinger RP, Carlet JM, Masur H, et al. for the Surviving Sepsis Campaign Management Guidelines Committee. Crit Care Med 2004; 32:858-873. Surviving Sepsis CampaignGuidelines for Management of Severe Sepsis and Septic Shock

Background : 

Background The Surviving Sepsis Campaign’s mission is to increase awareness and improve outcome in severe sepsis Guidelines developed by a group of international experts representing 11 organizations Developed under unrestricted industry educational grants Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

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American Association of Critical-Care Nurses American College of Chest Physicians American College of Emergency Physicians American Thoracic Society Australian and New Zealand Intensive Care Society European Society of Clinical Microbiology and Infectious Diseases European Society of Intensive Care Medicine European Respiratory Society International Sepsis Forum Society of Critical Care Medicine Surgical Infection Society Sponsoring Organizations Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

Slide 45: 

Grading of Recommendations Supported by at least two level I investigations Supported by one level I investigation Supported by level II investigations only Supported by at least one level III investigation Support by level IV or V evidence Grading System Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

Slide 46: 

Large randomized trials with clear-cut results; low risk of false-positive (alpha) error or false-negative (beta) error Small randomized trials with uncertain results; moderate-to-high risk of false-positive (alpha) and/or false-negative (beta) error Nonrandomized, contemporaneous controls Nonrandomized, historical controls and expert opinion Case series, uncontrolled studies, and expert opinion Grading of Evidence Grading System Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

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Initial Resuscitation Diagnosis Antibiotic therapy Source Control Fluid therapy Vasopressors Inotropic Therapy Steroids Recombinant Human Activated Protein C (rhAPC) [drotrecogin alfa (activated)] Blood Product Administration Mechanical Ventilation Sedation, Analgesia, and Neuromuscular Blockade in Sepsis Glucose Control Renal Replacement Bicarbonate Therapy Deep Vein Thrombosis Prophylaxis Stress Ulcer Prophylaxis Limitation of Support I DAS FVI S GDM RBS BLS Index Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

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Early goal-directed therapy !!!

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Central Venous Pressure 8-12 mm Hg (12-15 in ventilator pts) Mean arterial pressure > 65 mm Hg Urine output > 0.5 mL/kg/hr ScvO2 or SvO2 ≥ 70%; if not achieved with fluid resuscitation during first 6 hours: - Transfuse PRBC to hematocrit > 30% and/or - Administer dobutamine (max 20 mcg/kg/min) to goal Resuscitation should begin as soon as severe sepsis or sepsis induced tissue hypoperfusion is recognized Elevated Serum lactate identifies tissue hypoperfusion in patients at risk who are not hypotensive Goals of therapy within first 6 hours are Grade B Rivers E. N Engl J Med 2001;345:1368-77. Initial Resuscitation Dellinger, et. al. Crit Care Med 2004, 32: 858-873. -

Early Goal-Directed Therapyfor Septic Shock : 

Early Goal-Directed Therapyfor Septic Shock RCT, n = 263 Septic shock unresp to 20 ml/kg crystalloid or lactate > 4 Rx (all patients receive CVP and SvO2 monitor Traditional: CVP -12, vasopressors for SBP < 90 mm HG, keep UOP > 0.5 ml/kg/hr Investigation: As above + RBC for HCT < 30 and SvO2 < 70, if fails add dobutamine to dose of 20 ug/kg/min Rivers et al NEJM 2001;345:1368

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Rivers et al NEJM 2001;345:1368

EGDT - Outcome : 

EGDT - Outcome Key difference was in sudden CV collapse not MOSF Rivers et al NEJM 345:1368:2001

Slide 53: 

Before the initiation of antimicrobial therapy, at least two blood cultures should be obtained At least one drawn percutaneously At least one drawn through each vascular access device if inserted longer than 48 hours Other cultures such as urine, cerebrospinal fluid, wounds, respiratory secretions or other body fluids should be obtained as the clinical situation dictates Other diagnostic studies such as imaging and sampling should be performed promptly to determine the source and causative organism of the infection may be limited by patient stability Weinstein MP. Rev Infect Dis 1983;5:35-53Blot F. J Clin Microbiol 1999; 36: 105-109. Grade D Grade E Diagnosis Dellinger, et. al. Crit Care Med 2004, 32: 858-873. Grade D

Slide 54: 

Start intravenous antibiotic therapy within the first hour of recognition of severe sepsis after obtaining appropriate cultures Empirical choice of antimicrobials should include one or more drugs with activity against likely pathogens, both bacterial or fungal Penetrate presumed source of infection Guided by susceptibility patterns in the community and hospital Continue broad spectrum therapy until the causative organism and its susceptibilities are defined Kreger BE. Am J Med 1980;68:344-355. Ibrahim EH. Chest 2000;118:146-155. Hatala R. Ann Intern Med 1996;124-717-725. Antibiotic Therapy Grade E Grade D Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

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Reassess after 48-72 hours to narrow the spectrum of antibiotic therapy Duration of therapy should typically be 7-10 days and guided by clinical response Some experts prefer combination therapy for Pseudomonas infections or neutropenic patients Stop antimicrobials promptly if clinical syndrome is determined to be noninfectious Antibiotic Therapy Grade E Grade E Grade E Grade E Dellinger, et. al. Crit Care Med 2004, 32: 858-873. Ali MZ. Clin Infect Dis 1997;24:796-809

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THE EARLIEST , THE BETTER

Duration of hypotention before initiation of effective antimicrobial theraphy is the critical determinant of survival in humam septic shock : 

Duration of hypotention before initiation of effective antimicrobial theraphy is the critical determinant of survival in humam septic shock Objective: To determine the prevalence and impact on mortality of delays in initiation of effective antimicrobial therapy from initial onset of recurrent/persistent hypotension of septic shock. Design: A retrospective cohort study performed between July 1989 and June 2004. Setting: Fourteen intensive care units (four medical, four surgical, six mixed medical/surgical) and ten hospitals (four academic, six community) in Canada and the United States. Patients: Medical records of 2,731 adult patients with septic shock. Interventions: None. Conclusions: Effective antimicrobial administration within the first hour of documented hypotension was associated with increased survival to hospital discharge in adult patients with septic shock. Despite a progressive increase in mortality rate with increasing delays, only 50% of septic shock patients received effective antimicrobial therapy within 6 hrs of documented hypotension Kumar,Anand et al Crit Care Med Vol 34(6)June2006

Slide 58: 

Evaluate patients for focus of infection amenable to source control measures Drainage of an abscess or local focus of infection Debridement of infected necrotic tissue Removal of a potentially infected Device Definitive control of a source of ongoing microbial contamination Source control methods must weigh benefits and risks of the specific intervention Jimenez MF. Intensive Care Med 2001;27:S49-S62. Bufalari A. Acta Chir Belg 1996;96:197-200. Source Control (The D gang) Grade E Grade E Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

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Once a focus of infection has been identified, source control should be implemented as soon as possible following initial resuscitation Especially important for patients with necrotizing soft tissue infection or intestinal ischemia If intravascular access devices are suspected to be the source of infection, remove them promptly after establishing other vascular access Moss RL. J Pediatr Surg 1996;31:1142-1146. CDC. MMWR 2002;51:1-29. Source Control (cont) Grade E Grade E Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

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Fluid resuscitation may consist of natural or artificial colloids or crystalloids No evidenced-based support for one type of fluid over another Crystalloids have a much larger volume of distribution compared to colloids Crystalloid resuscitation requires more fluid to achieve the same endpoints as colloid Crystalloids result in more edema Choi PTL. Crit Care Med 1999;27:200-210. Cook D. Ann Intern Med 2001;135:205-208. Schierhout G. BMJ 1998;316:961-964. Fluid Therapy: Choice of Fluid Grade C Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

SAFE (Saline v Albumin Fluid Evaluation) : 

SAFE (Saline v Albumin Fluid Evaluation) • Aim: To compare the effects of two resuscitation fluids (4% human albumin or saline) on 28 day all cause mortality in critically ill patients requiring intravascular volume resuscitation • Double blind randomised controlled trial-7,000 patients from 16 ICUs in Australia and New Zealand over 18 months -Severe sepsis, trauma and ARDS Relative risk of death for patients assigned albumin versus saline: With severe sepsis 0.87, without severe sepsis 1.05 P=0.059 (Test for common relative risk)

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Fluid challenge in patients with suspected hypovolemia may be given 500 - 1000 mL of crystalloids over 30 mins 300 - 500 mL of colloids over 30 mins Repeat based on response and tolerance Input is typically greater than output due to venodilation and capillary leak Most patients require continuing aggressive fluid resuscitation during the first 24 hours of management Fluid Therapy: Fluid Challenge Grade E Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

Slide 63: 

Initiate vasopressor therapy if appropriate fluid challenge fails to restore adequate blood pressure and organ perfusion Vasopressor therapy should also be used transiently in the face of life-threatening hypotension, even when fluid challenge is in progress Either norepinephrine or dopamine are first line agents to correct hypotension in septic shock Norepinephrine is more potent than dopamine and may be more effective at reversing hypotension in septic shock patients Dopamine may be particularly useful in patients with compromised systolic function but causes more tachycardia and may be more arrhythmogenic LeDoux D. Crit Care Med 2000;28:2729-2732. Regnier B. Intensive Care Med 1977;3:47-53. Martin C. Chest 1993;103:1826-1831. Martin C. Crit Care Med 2000;28:2758-2765. DeBacker D. Crit Care Med 2003;31:1659-1667. Hollenberg SM. Crit Care Med 1999; 27: 639-660. Vasopressors Grade E Grade D Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

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Low dose dopamine should not be used for renal protection in severe sepsis An arterial catheter should be placed as soon as practical in all patients requiring vasopressors Arterial catheters provide more accurate and reproducible measurement of arterial pressure in shock states when compared to using a cuff Vasopressin may be considered in refractory shock patients that are refractory to fluid resuscitation and high dose vasopressors Infusion rate of 0.01-0.04 units/min in adults Vasopressors (cont) Grade B Grade E Grade E Dellinger, et. al. Crit Care Med 2004, 32: 858-873. Hollenberg SM. Crit Care Med 1999; 27:639-660. Bellomo R. Lancet 2000; 356: 2139-2143. Kellum J. Crti Care Med 2001; 29: 1526-1531.

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Vasopressin Relative deficiency in septic shock Initial high rise >300 pg/ml . Deplete after ~ 1h < 30pg/ml . Exogenous vasopressin increase BP . Decreases nitric oxide synthesis by decreasing expression of inducible NOS • Decreases cGMP signaling by NO . Reduces arterial vasodilatation and and pressor resistance • Synergistic with other pressors Sharshar T et al ccm 2003

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In patients with low cardiac output despite adequate fluid resuscitation, dobutamine may be used to increase cardiac output Should be combined with vasopressor therapy in the presence of hypotension It is not recommended to increase cardiac index to target an arbitrarily predefined elevated level Patients with severe sepsis failed to benefit from increasing oxygen delivery to supranormal levels by use of dobutamine Inotropic Therapy Grade E Grade A Gattinoni L. N Eng J Med 1995;333:1025-1032. Hayes MA. N Eng J Med 1994;330:1717-1722. Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

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Low dose steroids !!!

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Intravenous corticosteroids are recommended in patients with septic shock who require vasopressor therapy to maintain blood pressure Administer intravenous hydrocortisone 200-300 mg/day for 7 days in three or four divided doses or by continuous infusion Shown to reduce mortality rate in patients with relative adrenal insufficiency Steroids Grade C Annane, D. JAMA, 2002; 288 (7): 868 Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

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0 25 50 75 Placebo Corticoids Mortality (%) 63% 53% p = 0.02 + more rapid decrease of vasopressors + similar incidence of secondary infection and digestive hemorrhage Annane D, et al. JAMA 2002 229 patients with septic shock and adrenal failure Adrenal failure = < 9 µg/dL rise in plasma cortisol after a 250 μg ACTH bolus Hydrocortisone 4 x 50 mg IV/d + fludrocortisone 50 µg PO/d versus placebo, during 1 week

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Recombinant human Activated Protein C Indication Adult patients At least 2 organ failures (cardiovascular, respiratory, renal, hematological, metabolic acidosis) Treatment with drotrecogin alfa (activated) should begin as soon as possible once a patient has been identified as high risk for death.

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Present or recent (within 3 months) intracranial or intraspinal surgery, or severe head trauma Trauma with increased risk of life-threatening bleeding Presence of an epidural catheter Active internal or external bleeding Recent (within 3 months) hemorrhagic stroke Absolute contra-indications

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Severely depleted platelets (< 30,000 /mm³) * Therapeutic heparin therapy (> 15 IU/kg/hr) * Recent (within 6 weeks) gastrointestinal bleeding * Recent (within 3 months) ischemic stroke * Known bleeding diathesis * Chronic severe hepatic disease * Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location Relative contra-indications (increased risk of bleeding)

The Role of Activated Protein Cin Severe Sepsis : 

Endothelium The Role of Activated Protein Cin Severe Sepsis Organisms

Slide 74: 

rhAPC Dose = 24 μg/kg/h for 96 h,continuous IV Short half-life 90% steady state plasma concentration reached within 2 hrs of start infusion 90% elimination within 2 hrs of stop infusion No dose adjustment or titration needed, even in end-stage renal disease.

Prowess trial : 

Prowess trial Design Randomized, double-blind, placebo-controlled trial 11 countries comprising 164 participating departments Patient population – Severe Sepsis Presence of known or suspected infection At least 3 criteria for systemic inflammatory response syndrome (SIRS) Sepsis-induced dysfunction of at least 1 organ in 24 hours Study therapy 1:1 randomization to Drotrecogin Alfa (activated) 24 µg/kg/hr or placebo in 96 hours All patients received standard sepsis therapy

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PROWESSResults: 28-day overall mortality

ADDRESS TRAIL : 

ADDRESS TRAIL Randomized, double blind, placebo controlled trial in 2640 pts 96hrs infusion of rAPC @ 24µg/kg/hr in adult pts. with severe sepsis who were not at high risk of death Most pts have APACHE II <25 OR one organ failure 28days mortality was 18% in rAPC &17% in pts randomized to placebo group(RR:1.08, 95%CI:0.91-1.27)

Severe Sepsis-Associated Mortality Increases with the Number of Dysfunctional Organs : 

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% One Two Three Four Five PROWESS Vincent Severe Sepsis-Associated Mortality Increases with the Number of Dysfunctional Organs mortality Number of organ failures

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Red blood transfusion should occur only when hemoglobin decreases to < 7 g/dL Once tissue hypoperfusion has resolved and in the absence of extenuating circumstances such as significant coronary artery disease, acute hemorrhage or lactic acidosis Target hemoglobin of 7 – 9 g/dL Erythropoietin is not recommended for specific treatment of anemia associated with severe sepsis Unless septic patients have other accepted reasons for administration of erythropoietin Routine use of fresh frozen plasma to correct laboratory clotting abnormalities in the absence of bleeding or planned invasive procedures is not recommended Blood Product Administration Grade B Grade B Grade E Corwin HL. JAMA 2002;288:2827-2835. Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

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It is not recommended to use antithrombin for the treatment of severe sepsis or septic shock High dose antithrombin in a phase III trial did not demonstrate a beneficial effect on 28-day mortality and was associated with increased risk of bleeding when administered with heparin Platelets should be administered when platelet counts are < 5000/mm3 regardless of apparent bleeding Platelet transfusion may be considered when counts are 5000 - 30,000/mm3 and there is a significant risk of bleeding Platelet counts  50,000/ mm3 are typically required for surgery or invasive procedures Blood Product Administration (cont) Grade B Grade E Warren BL. JAMA 2001;286:1869-1878. Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

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High tidal volumes, > 6 ml/kg, coupled with high plateau pressures, > 30 cm H2O, should be avoided Hypercapnia can be tolerated in patients with ALI/ARDS if required to minimize plateau pressures and tidal volumes A minimum amount of positive end expiratory pressure should be set to prevent lung collapse at end-expiration Mechanical Ventilation of Sepsis-Induced Acute Lung Injury (ALI)/ARDS ARDSNet. N Eng J Med 2000;342:1301-1308. Grade B Grade C Grade E Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

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Mortality* - Low vs Traditional Tidal Volume Low Tidal Volume Traditional Tidal Volume P=0.007 * death before discharge home and breathing without assistance Mechanical Ventilation of Sepsis-Induced Acute Lung Injury (ALI)/ARDS ARDSNet. N Eng J Med 2000;342:1301-1308.

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Prone position:It should be considered in ARDS Patients requiring potentially injurious levels of fio2 or plataeu pressure who are not at risk for adverse consequenceof position change. Grade E Unless contraindicated MV patients should be maintained semirecumbent with head of bed raised to 45 deg. to prevent VAP. Grade C. A Weaning protocol should be in place &MV patients should undergo a SBT to evaluate the ability to discontinue MV. Grade A

Multicentre Trail of Prolonged Prone Ventilation in Severe ARDS : 

Multicentre Trail of Prolonged Prone Ventilation in Severe ARDS 136 patients within 48 hrs of tracheal intubation for severe ARDS 60randamised to supine & 76 –prone ventilation. Continuous prone ventilation for 20hrs/day. Mortality 43%-prone 58%-supine Prone ventilation is feasible and safe and may reduce mortality in patients with severe ARDS when it is initiated early and applied for most of the day. Jordi Mancebo et al AJRCCM Mar 2006

Slide 85: 

Protocols should be used when sedation of critically ill mechanically ventilated patients is required The protocol should include the use of a sedation goal, measured by a standardized subjective sedation scale Intermittent bolus or continuous infusion sedation are recommended to predetermined end points With daily interruptions/lightening of continuous infusion sedation with awakening and retitration, if necessary Sedation, Analgesia, and Neuromuscular Blockade in Sepsis Brook AD. Crit Care Med 1999;27:2609-2615. Grade B Grade B Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

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If needed for more than the first hour of mechanical ventilation, either intermittent bolus as required or continuous infusion with monitoring of depth of block with train of four monitoring should be used Neuromuscular blockers should be avoided in the septic patient due to the risk of prolonged neuromuscular blockade Sedation, Analgesia, and Neuromuscular Blockade in Sepsis Grade E Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

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Following initial stabilization of patients with severe sepsis, maintain blood glucose to < 150 mg/dL Best results obtained when blood glucose was maintained between 80 and 110 mg/dL Glycemic control strategy should include a nutrition protocol with the preferential use of the enteral route Minimize the risk of hypoglycemia by providing a continuous supply of glucose substrate Accomplished by using 5% or 10% dextrose IV infusion and followed by initiation of feeding preferably by enteral route Glucose Control van den Berghe G. N Engl J Med 2001;345:1359-1367. Grade D Grade E Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

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Normoglycemia Van Den Berghe G, et al. N Engl JMed 2001 Surgical ICU ; 1548 patients Conventional (n=783) versus normoglycemic (n=765) normoglycemia = glycemia 80-110 mg/dL conventional = glycemia 180-200 mg/dL In both treatment groups : - mostly cardiac surgery (> 60%) - APACHE II = 9 (7-13)

Intensive Glucose Control Outcome : 

Intensive Glucose Control Outcome Van Den Berghe et al NEJM 2001;345:1359

Slide 90: 

Continuous hemofiltration offers easier management of fluid balance in hemodynamically unstable septic patients Renal Replacement Mehta RL. Kidney Int 2001;60:1154-1163 Kellum J. Intensive Care Med 2002;28:29-37. Grade B Continuous venovenous hemofiltration and intermittent hemodialysis are considered equivalent in acute renal failure (in the absence of hemodynamic instability) Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

Slide 91: 

No difference revealed in vasopressor requirements or hemodynamic variables between bicarbonate and normal saline for treating hypoperfusion-induced acidemia Effects of bicarbonate therapy at pH levels < 7.13 have not been studied Bicarbonate Therapy Cooper DJ. Ann Intern Med 1990;112:492-498. Mathieu D. Crit Care Med 1991;19:1352-1356. Grade C Bicarbonate is not recommended for the purpose of improving hemodynamics or reducing vasopressor requirements for the treatment of hypoperfusion induced lactic acidemia with pH  7.15 Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

Slide 92: 

Use a mechanical prophylactic device or intermittent compression in patients with contraindications to heparin Use a combination of pharmacological and mechanical therapy in very high risk patients (eg, severe sepsis and history of DVT) Belch JJ, Scott Med J 1981;26:115-117 Samama MM, N Engl J Med 1999;341:793-800 Deep Vein Thrombosis (DVT) Prophylaxis Grade A DVT prophylaxis with either low-dose unfractionated heparin or low molecular weight heparin should be used in severe sepsis patients Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

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H2 receptor blockers are more efficacious than sucralfate and are the preferred agents Proton pump inhibitors compared to H2 blockers have not been assessed Stress Ulcer Prophylaxis Bresalier RS et al. Am J Med 1987;83:110-116 Borrero et al. Am J Med 1985;79:62-64 Grade A Stress ulcer prophylaxis should be given to all patients with severe sepsis Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

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Decisions for less aggressive support or withdrawal of support may be in the patient’s best interest Consideration for Limitation of Support Grade E Advance care planning, including the communication of likely outcomes and realistic goals of treatment, should be discussed with patients and families Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

IMMUNONUTRITION : 

IMMUNONUTRITION Considering the beneficial effects and the absence of detrimental ones, the use of diets enriched with pharmaconutrients could be recommended in ICU patients requiring enteral feeding. Nevertheless, more investigation is needed in this field in order to find the more appropriate population of patients that can benefit from this nutritional therapy. Clin Nutr. 2003 Jun;22(3):221-33.

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PUTATIVE FUTURE TARGETS AND TREATMENTS

Future : 

Future Septic shock remains a major source of short term and long term morbidity and mortality and places a large burden on the health care system.The recent identification in people of molecules that sense microbial determinants has been an important step in understanding the molecular and cellular basis of sepsis. Characterisation of the links between inflamation, coagulation and the immune and neuroendocrine systems have led to international guidelines recommending the use of activated protein C and low dose steroid in the early management of septic shock.

Slide 99: 

New knowledge about apoptosis ,leucocyte reprogramming. epithelial dysfunction and factors involved in sepsis holds promise for the development of new therapeutic approaches. Although improvement of immediate survival is a key goal, physians are also becoming aware that specific rehabilitation program's and long term follow up are essential.

Sepsis Survivors…Multimodality : 

Sepsis Survivors…Multimodality Recognize early Remember essentials fluids antibiotics Ventilate Assess: severity of sepsis Consider Activated Protein C Sepsis

To Conclude : 

To Conclude Application of evidence-based approaches to treatment of infection, rapid and accurate shock resuscitation, adjuvant therapy, and comprehensive supportive care should continue to produce declining mortality rates. New knowledge of the pathogenesis of sepsis and shock will ideally translate into safe and effective novel agents for these important conditions

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THANK YOU

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