Sepsis, Severe Sepsis & Septic Shock

Sepsis, Severe Sepsis & Septic Shock
Meral SÖNMEZOĞLU, Prof Yeditepe University Hospital Infectious Diseases Department 1

Overview Differentiation between Septic Shock in relation to other conditions in current code, Sepsis, and Severe Sepsis Disease Epidemiology, Incidence and Mortality Inadequacy of Current Diagnostic Codes Proposed Modifications and Clarification Discussion 2

KEY POINTS Severe sepsis and septic shock have high prevalence and mortality. Treatment is time-sensitive and depends on early identification and risk-stratification. Treatment must include antibiotics and targeted therapies designed to optimize oxygen delivery. Adherence to a treatment algorithm decreases mortality 3

Systemic Inflammatory Response
At least 2 of 4 ( abnormal temp or leukocytes count is a must) Core temp >38.5 or <36 Tachycardia: HR >2 sd above Normal for age or bradycardia <10% for age Tachypnea: RR >2 sd for age or mechanical ventilation for acute process Leukocyte elevated or depressed for age or >10% immature neutrophils 5

Definitions Infection: Suspected or proven caused by any pathogen Or clinical syndrome associated with high probability of infection Sepsis: SIRS in the presence of or as a result of suspected of proven infection 6

Definitions Sepsis is defined as the presence (probable or documented) of infection together with systemic manifestations of infection. Severe sepsis is defined as sepsis plus sepsis-induced organ dysfunction or tissue hypoperfusion 7

Definitions Severe Sepsis: sepsis + one Septic shock
Cardiovascular dysfunction ARDS OR 2 or more other organ dysfunctions Septic shock Sepsis and cardiovascular organ dysfunction 8

Definitions Septic shock
Sepsis and cardiovascular organ dysfunction Septic shock is defined as sepsis-induced hypotension persisting despite adequate fluid resuscitation. Sepsis-induced tissue hypoperfusion is defined as infection-induced hypotension, elevated lactate, or oliguria 9

SIRS = Systemic Inflammatory Response Syndrome
Sepsis: Defining a Disease Continuum Infection/ Trauma SIRS Sepsis Severe Sepsis A clinical response arising from 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 with a presumed or confirmed infectious process SIRS = Systemic Inflammatory Response Syndrome Adapted from: Bone RC, et al. Chest 1992;101:1644 Opal SM, et al. Crit Care Med 2000;28:S81 10

Sepsis: Defining a Disease Continuum
Infection/ Trauma SIRS Sepsis Severe Sepsis Sepsis with 1 sign of organ failure Cardiovascular (refractory hypotension) Renal Respiratory Hepatic Hematologic CNS Metabolic acidosis Shock Bone et al. Chest 1992;101:1644; Wheeler and Bernard. N Engl J Med 1999;340:207 11

(Systemic Inflammatory Response Syndrome) Two or more of:
SIRS (Systemic Inflammatory Response Syndrome) Two or more of: Temperature >38°C or <36°C Heart rate >90/min Respiratory rate >20/min or Paco2 <32 mm Hg (4.3 kPa) White blood cell count >12 000/mm3 or <4000/mm3 or >10% immature bands From Bone et al 12

Key concepts Sepsis is the primary cause of death from infection, especially if not recognized and treated promptly. Its recognition mandates urgent attention. Sepsis is a syndrome shaped by pathogen factors and host factors (eg, sex, race and other genetic determinants, age, comorbidities, environment) with characteristics that evolve over time. differentiates sepsis from infection is an aberrant or dysregulated host response and the presence of organ dysfunction. 13

Sepsis Sepsis-induced organ dysfunction may be occult; therefore, its presence should be considered in any patient presenting with infection. Conversely, unrecognized infection may be the cause of new-onset organ dysfunction. Any unexplained organ dysfunction should thus raise the possibility of underlying infection. The clinical and biological phenotype of sepsis can be modified by preexisting acute illness, long-standing comorbidities, medication, and interventions. 14

Sepsis Specific infections may result in local organ dysfunction without generating a dysregulated systemic host response. Severity of organ dysfunction has been assessed with various scoring systems that quantify abnormalities according to clinical findings, laboratory data, or therapeutic interventions 15

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)
Mervyn Singer, MD, FRCP1; Clifford S. Deutschman, MD, MS2; Christopher Warren Seymour, MD, MSc3 JAMA. 2016;315(8): 16

Copyright © 2016 American Medical Association. All rights reserved.
From: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8): doi: /jama Table Title: Sequential [Sepsis-Related] Organ Failure Assessment Scorea Copyright © 2016 American Medical Association. All rights reserved.

From: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8): doi: /jama Table Title: Terminology and International Classification of Diseases Coding Copyright © 2016 American Medical Association. All rights reserved.

From: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8): doi: /jama Figure Legend: Operationalization of Clinical Criteria Identifying Patients With Sepsis and Septic ShockThe baseline Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score should be assumed to be zero unless the patient is known to have preexisting (acute or chronic) organ dysfunction before the onset of infection. qSOFA indicates quick SOFA; MAP, mean arterial pressure. Copyright © 2016 American Medical Association. All rights reserved.

Relationship Of Infection, SIRS, Sepsis Severe Sepsis and Septic Shock
PANCREATITIS SEPSIS SEVERE SEPSIS BURNS SEPTIC SHOCK This conceptual framework shows the interrelationships between infection, non-infectious disorders, SIRS, sepsis and severe sepsis. Components of the process not discussed on the following slides include: Infection: a microbial phenomenon characterized by an inflammatory response to the presence of microorganisms or the invasion of normally sterile host tissue by those organisms Bacteremia: the presence of viable bacteria in the bloodstream Septic shock: sepsis-induced hypotension despite adequate fluid resuscitation along with the presence of perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria or an acute alteration in mental status Multiple organ dysfunction syndrome (MODS): presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992;101: Opal SM, Thijs L, Cavaillon JM, et al. Relationships between coagulation and inflammatory processes. Crit Care Med 2000;28:S81-2. TRAUMA OTHER 22 Bone et al. Chest 1992;101:1644 Draft. For internal use only. Confidential, Eli Lilly and Company, 2001.

Inflamatory Cascade * Cytokines
Chemotaxis Complement Superoxide Radicals Lysosomal Enzymes Gram- negative Bacteria/ Endotoxin System Neutrophil Accumulation Capillary Leak Neutrophils Adhesion Molecules Hypotension, ARDS, DIC, Multiple Organ Failure, Death Fever Monocytic Cells Cytokines Metabolic Changes Hormonal Changes* TNF-a, IL-1, IL-6, IL-8, etc. Lipid Mediators Vasodilation Nitric Oxide Clotting Abnormalities Endothelial Cells Bradykinin Tissue Factor = inhibited by rBPI in vivo or in vitro = not investigated Coagulation System * 23

SEPSIS MEDIATORS Table 1. Pathways and Mediators of Sepsis, Potential Treatments, and Results of Randomized, Controlled Trials (RCTs). 24 Russell J. N Engl J Med 2006;355: Draft. For internal use only. Confidential, Eli Lilly and Company, 2001.

Sepsis ! Septic Shock Severe Sepsis t. SepsisT. 25

Mortality Increases in Septic Shock Patients
Incidence Mortality 7-17% Sepsis 400,000 20-53% Severe Sepsis 300,000 Septic Shock 53-63% Approximately 200,000 patients including 70,000 Medicare patients have septic shock annually Balk, R.A. Crit Care Clin 2000;337:52 26

Septic Shock is Unique within 785.59
Unspecified Shock 7% Other Shock 62% Details 10,100 Population Mortality Length Of Stay Cost With infection * 70,900 51% 17.1 $30,300 Without infection 17,700 52% 8.9 $17,400 45,200 88,600 785.51 Cardiogenic Shock 31% * Represents Septic Shock Patients ICD-9-CM code 785.5X Population Septic Shock patients have a longer length of stay and a higher cost than other patients within 27

Severe Sepsis: A Significant Healthcare Challenge
Major cause of morbidity and mortality worldwide Leading cause of death in noncoronary ICU (US)* 11th leading cause of death overall (US) †§ 1 About 1,000,000 cases of severe sepsis in US annually‡ 2 In the US, about patients die of severe sepsis daily 3 *Sands KE et al. JAMA. 1997;278:234-40; †Based on data for septicemia. §Murphy SL. National Vital Statistics Reports. ‡Angus DC et al. Crit Care Med (In Press); reflects hospital-wide cases of severe sepsis as defined by infection in the presence of organ failure.

Sepsis Epidemiology: Effect of the Aging Population

Severe Sepsis: Comparison With Other Major Diseases
Incidence of Severe Sepsis Mortality of Severe Sepsis Cases/100,000 Deaths/Year AIDS* Colon Breast CHF† Severe Sepsis‡ AIDS* Breast Cancer§ AMI† Severe Sepsis‡ Cancer§ †National Center for Health Statistics, §American Cancer Society, *American Heart Association ‡Angus DC et al. Crit Care Med. 2001

Mortality of Sepsis over Time
Proportion of Patients with Sepsis Who Died

Epidemiology Incidence of Sepsis Mortality of Sepsis [1993-2001]...a
75% increase in... severe sepsis... Mortality of Sepsis [ ]...a 17% reduction in mortality. Brun-Buisson, C., Meshaka, P., Pinton, P., Vallet, B., EPISEPSIS Study Group. (2004). EPISEPSIS: a reappraisal of the epidemiology and outcome of severe sepsis in French intensive care units. Intensive Care Medicine, 30(4), 580–588. Harrison, D. A., Welch, C. A., & Eddleston, J. M. (2006). The epidemiology of severe sepsis in England, Wales and Northern Ireland, 1996 to 2004: secondary analysis of a high quality clinical database, the ICNARC Case Mix Programme Database. Critical Care, 10(2), R42. Martin, G. S., Mannino, D. M., Eaton, S., & Moss, M. (2003). The epidemiology of sepsis in the United States from 1979 through New England Journal of Medicine, 348(16), 1546–1554.

Evolution of Sepsis care
Established Core Rx: Source Control More Antibiotics Faster Resuscitation Better Supportive Care Established Core Rx: Source Control Antibiotics Resuscitation Supportive Care Mortality In general the process of care has improved Steroids No Steroids Endotoxin Antagonists LPS/LPS receptor antagonist anti-TNF NSAIDs Nitric Oxide Synthase Inhibitors Tissue Factor Pathway Inhibitors anti-TLR4 Xigris Tight Glycemic Control Immunonutrition Steroids Loose Glycemic Control Immunonutrition? ?Not Steroids ? No Xigris Steroids

Economics of Sepsis Severe Sepsis Nosocomial Sepsis $22,000 per case
US annual cost $16.7 Billion Nosocomial Sepsis increased LOS - ICU 8 days, Hosp 24 days $40,890 per case Angus CCM, 2001 Pittet JAMA, 1994

Time Sensitive Interventions
“Door to PCI” Focus on the timely return of blood flow to the affected areas of the heart. (percutanous coronary intervention) AMI “Time is Brain” The sooner that treatment begins, the better are one’s chances of survival without disability. Stroke “The Golden Hour” Requires immediate response and medical care “on the scene.” Patients typically transferred to a qualified trauma center for care. Trauma

Trauma vs. Sepsis Patient Care Where we spend our efforts

Severe Sepsis vs. Current Care Priorities
U.S. Incidence # of Deaths Mortality Rate AMI (1) 900,000 225,000 25% Stroke (2) 700,000 163,500 23% Trauma (3) (Motor Vehicle) 2.9 million (injuries) 42,643 1.5% Severe Sepsis (4) 751,000 215,000 29% Source: (1) Ryan TJ, et al. ACC/AHA Guidelines for management of patients with AMI. JACC. 1996; 28: (2) American Heart Association. Heart Disease and Stroke Statistics – 2005 Update. Available at: (3) National Highway Traffic Safety Administration. Traffic Safety Facts 2003: A Compilation of Motor Vehicle Crash Data from the Fatality Analysis Reporting System and the General Estimates System. Available at (4) Angus DC et al. Crit Care Med 2001;29(7):

The Surviving Sepsis Campaign
25% Reduction In Sepsis Mortality within next 5 yrs = ~ 50,000 people in the United States each year. = ~ 1,100,000 individuals worldwide each year. Angus DC, et al. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Critical Care Medicine. Jul 2001;29(7):

Cardiovascular Dysfunction
Despite administration of isotonic intravenous fluid bolus ≥40 mL/kg in 1 hr Hypotension: BP <5th % or <2 sd OR Need for vasoactive drug to maintain BP (dopamine >5 mcg/kg/min or dob, epi, or norepi at any dose) OR Two of the following Unexplained metabolic acidosis: Base deficit >5.0 mEq/L Arterial lactate: >2 times upper limit of normal Oliguria: Urine output <0.5 mL/kg/hr Capillary refill: >5 secs Core to peripheral temperature gap >3°C 39

Respiratory Dysfunction
PaO2 /Fio2 <300 in absence of cyanotic heart disease or preexisting lung disease OR PaCo2 >65 or 20 mm Hg over baseline Paco2 OR Need or >50% Fio2 to maintain saturation ≥92% OR Need for non-elective invasive or non-invasive mechanical ventilation 40

Neurologic Dysfunction
Glasgow Coma Score ≤11 OR Acute change in mental status with a decrease in Glasgow Coma Score ≥3 points from abnormal baseline 41

Hematologic Dysfunction
Platelet count <80,000/mm or a decline of 50% in platelet count from highest value recorded over the past 3 days INR >2 42

Renal Dysfunction Serum creatinine ≥2 times upper limit of
normal for age or 2-fold increase in baseline creatinine 43

Hepatic Dysfunction Total bilirubin ≥4 mg/dL (not applicable for
newborn) OR ALT 2 times upper limit of normal for age 44

Mortality and SIRS 45

Mortality

Conclusion Septic shock has distinct characteristics that support the creation of a unique code (785.52) Septic shock should be linked to severe sepsis Modification of current SIRS coding will better represent the clinical presentation of the sepsis syndrome 995.51, sepsis Modification to “code also” list in 48

Deficiencies of 1991 Consensus Conference
Limitations inherent in these definitions: Incomplete agreement as to what defines “Systemic Response" Inflammation only? Organ/System failures not defined Except hypotension (SBP <90 mmHg or >40 mmHg decline from baseline; need for vasopressor support) "Dear SIRS, I do not like you" Jean Louis Vincent

2001 Sepsis Definitions Conference
Current definitions will remain unchanged However, will accept the uncertainty of definitions SIRS expanded to signs and symptoms Chills Alteration in temperature Tachypnea Change in mental status Tachycardia Altered WBC, Bandemia Thrombocytopenia Decreased perfusion: mottling, poor capillary refill Increased blood sugar Petichiae/Purpura 50

2001 Sepsis Definitions Conference
PIRO staging system proposed Predisposition: Genetics, Chronic illness Insult: Infection, Injury, Ischemia Response: Physiologic, Mediators, Markers Organ Dysfunction: Outcome, Organ dysfunction 51 To be published 2002 (Verbal communication Mitchell Levy, SCCM 2002)

Pathophysiology of Sepsis

Disorder Due to Uncontrolled Inflammation? Increased inflamatory mediators like IL-1, TNF, IL-6. Based on animal studies. In a study in children with meningococcemia, TNF levels directly correlated with mortality. Clinical trials involving TNF anagonist, antiendotoxin antibodies, IL-1 receptor antagonists, cortocosteroids failed to show any benefits. Patients with RA treated with TNF antagonist develop infectious complications.

Pathogenesis of Sepsis

Failure of Immune System to Eliminate Microorganism? Shift from inflammatory (ThI) to antiinflammatory response (Th2). Anergy. Apotosis of B cells, T cells, Dendritic cells. Loss of macrophage expression of MHC Class I and co-stimulatory molecules. Immunosuppressive effect of apoptotic cells.

Pathogenesis of Sepsis

Inflammatory Responses to Sepsis
Figure 1. Inflammatory Responses to Sepsis. Sepsis initiates a brisk inflammatory response that directly and indirectly causes widespread tissue injury. Shown here are key components of this process and their interactions at the level of the microvasculature of a representative vital organ. Gram-positive and gram-negative bacteria, viruses, and fungi have unique cell-wall molecules called pathogen-associated molecular patterns that bind to pattern-recognition receptors (toll-like receptors [TLRs]) on the surface of immune cells. The lipopolysaccharide of gram-negative bacilli binds to lipopolysaccharide-binding protein, CD14 complex. The peptidoglycan of gram-positive bacteria and the lipopolysaccharide of gram-negative bacteria bind to TLR-2 and TLR-4, respectively. Binding of TLR-2 and TLR-4 activates intracellular signal-transduction pathways that lead to the activation of cytosolic nuclear factor {kappa}B (NF-{kappa}B). Activated NF-{kappa}B moves from the cytoplasm to the nucleus, binds to transcription initiation sites, and increases the transcription of cytokines such as tumor necrosis factor {alpha} (TNF-{alpha}), interleukin-1beta, and interleukin-10. TNF-{alpha} and interleukin-1beta are proinflammatory cytokines that activate the adaptive immune response but also cause both direct and indirect host injury. Interleukin-10 is an antiinflammatory cytokine that inactivates macrophages and has other antiinflammatory effects. Sepsis increases the activity of inducible nitric oxide synthase (iNOS), which increases the synthesis of nitric oxide (NO), a potent vasodilator. Cytokines activate endothelial cells by up-regulating adhesion receptors and injure endothelial cells by inducing neutrophils, monocytes, macrophages, and platelets to bind to endothelial cells. These effector cells release mediators such as proteases, oxidants, prostaglandins, and leukotrienes. Key functions of the endothelium are selective permeability, vasoregulation, and provision of an anticoagulant surface. Proteases, oxidants, prostaglandins, and leukotrienes injure endothelial cells, leading to increased permeability, further vasodilation, and alteration of the procoagulant-anticoagulant balance. Cytokines also activate the coagulation cascade. Russell J. N Engl J Med 2006;355: 59 Draft. For internal use only. Confidential, Eli Lilly and Company, 2001.

Procoagulant Response in Sepsis
Figure 2. Procoagulant Response in Sepsis. Sepsis initiates coagulation by activating endothelium to increase the expression of tissue factor. Activation of the coagulation cascade, and especially factors Va and VIIIa, leads to the formation of thrombin-{alpha}, which converts fibrinogen to fibrin. Fibrin binds to platelets, which in turn adhere to endothelial cells, forming microvascular thrombi. Microvascular thrombi amplify injury through the release of mediators and by microvascular obstruction, which causes distal ischemia and tissue hypoxia. Normally, natural anticoagulants (protein C and protein S), antithrombin III, and tissue factor-pathway inhibitor (TFPI) dampen coagulation, enhance fibrinolysis, and remove microthrombi. Thrombin-{alpha} binds to thrombomodulin on endothelial cells, which dramatically increases activation of protein C to activated protein C. Protein C forms a complex with its cofactor protein S. Activated protein C proteolytically inactivates factors Va and VIIIa and decreases the synthesis of plasminogen-activator inhibitor 1 (PAI-1). In contrast, sepsis increases the synthesis of PAI-1. Sepsis also decreases the levels of protein C, protein S, antithrombin III, and TFPI. Lipopolysaccharide and tumor necrosis factor {alpha} (TNF-{alpha}) decrease the synthesis of thrombomodulin and endothelial protein C receptor (EPCR), thus decreasing the activation of protein C. Sepsis further disrupts the protein C pathway because sepsis also decreases the expression of EPCR, which amplifies the deleterious effects of the sepsis-induced decrease in levels of protein C. Lipopolysaccharide and TNF-{alpha} also increase PAI-1 levels so that fibrinolysis is inhibited. The clinical consequences of the changes in coagulation caused by sepsis are increased levels of markers of disseminated intravascular coagulation and widespread organ dysfunction. t-PA denotes tissue plasminogen activator. Russell J. N Engl J Med 2006;355: 60 Draft. For internal use only. Confidential, Eli Lilly and Company, 2001.

Treatment

Severe Sepsis/Septic Shock Goals
CVP 8 – 12 mmHg MAP  65 mmHg SBP > 90 mmHg SaO2  93% ScVO2 > 70%

Emergency Department and Intensive Care Unit
Sepsis Resuscitation Emergency Department and Intensive Care Unit

Sepsis Resuscitation Bundle
Serum lactate measured Blood cultures obtained prior to antibiotic administration From the time of presentation, broad-spectrum antibiotics administered: within 3 hours for ED admissions within 1 hour for non-ED ICU admissions In the event of hypotension and/or lactate > 4 mmol/L (36 mg/dl): Deliver an initial minimum of ml/kg of crystalloid (or colloid equivalent) Apply vasopressors for hypotension not responding to initial fluid resuscitation to maintain MAP > 65 mmHg In the event of persistent hypotension despite fluid resuscitation (septic shock) and/or lactate > 4 mmol/L (36 mg/dl): Achieve central venous pressure (CVP) of > 8 mmHg Achieve central venous oxygen saturation (ScvO2) of > 70% Information taken from Institute for Healthcare Improvement, Sepsis Module:

Bundle Completion and Outcome A 2-year Implementation Experience
Total Patients = 330 patients from Oct 2003 – Sept 2005 Bundle Not Completed = 253; Bundle Completed = 77 Mortality (p=0.003) Hospital LOS (p=0.22) Nguyen, Ann Emerg Med, ACEP Annual Meeting; and Crit Care Med, Critical Care Congress

Serum Lactate Hyperlactatemia is typically present in patients with severe sepsis or septic shock and may be secondary to anaerobic metabolism due to hypoperfusion. The prognostic value of raised blood lactate levels has been well established in septic shock patients, particularly if the high levels persist (that’s why we trend them). Obtaining serum lactate is essential to identifying tissue hypoperfusion in patients who are not yet hypotensive but who are at risk for septic shock. Information taken from Institute for Healthcare Improvement, Sepsis Module:

Blood cultures The incidence of sepsis and bacteremia in critically ill patients has been increasing in the past two decades. % of patients presenting with a clinical syndrome of severe sepsis or shock have positive blood cultures. Therefore, blood should be obtained for culture in any critically ill septic patient. Collecting blood cultures prior to antibiotic administration offers the best hope of identifying the organism that caused severe sepsis in an individual patient. Failure to check blood cultures prior to antibiotic infusion will perhaps affect the growth of any blood borne bacteria and prevent a culture from becoming positive later. Information taken from Institute for Healthcare Improvement, Sepsis Module:

Broad Spectrum Antibiotics
The balance of evidence unwaveringly suggests that early administration of appropriate antibiotics reduces mortality in patients with Gram-positive and Gram-negative bacteremias. Some of the evidence supporting early administration is based upon the assumption that patients who fail to receive appropriate antibiotics essentially represent a set of patients for whom delay has occurred in antibiotic delivery. Several studies have confirmed the mortality benefit associated with appropriate antimicrobials in patients with severe infections due to Gram-negative and Gram-positive bacteria. All patients should receive a full loading dose of each antimicrobial. However, patients with sepsis or septic shock often have abnormal renal or hepatic function and may have abnormal volumes of distribution due to aggressive fluid resuscitation. The ICU pharmacist should be consulted to ensure that serum concentrations are attained that maximize efficacy and minimize toxicity Information taken from Institute for Healthcare Improvement, Sepsis Module:

Antibiotics and Mortality
p = 0.006 p = 0.01 In addition, the major sources of infection in severe sepsis or shock are pneumonia and intra-abdominal infections and other sources generally account for < 5 percent of cases. The prevalence of pneumonia as a cause of sepsis lends support to the case for treating severe sepsis with early antibiotic administration. In a recent study of ventilator acquired pneumonia, patients with significant organ dysfunction who received antibiotics later had far greater ICU mortality: 37 percent vs. 7 percent, P=0.006; hospital mortality: 44 percent vs. 15 percent, P=0.01. Information taken from Institute for Healthcare Improvement, Sepsis Module:

Choice of Antibiotics If pseudomonas is an unlikely pathogen, combine
vancomycin with one of the following: Cephalosporin, 3rd or 4th generation (e.g., ceftriaxone, cefotaxime, or cefepime). Beta-lactam/beta-lactamase inhibitor (e.g., ampicillin-sulbactam). Fluroquinolones (eg., Levofloxacin, gatifloxacin, moxifloxacin.) If pseudomonas is suspected, combine vancomycin with two of the following : Antipseudomonal cephalosporin (e.g., cefepime, ceftazidime, or cefoperazone). Antipseudomonal carbapenem (eg, imipenem, meropenem). Antipseudomonal beta-lactam/beta-lactamase inhibitor (e.g., pipercillin-tazobactam,ticarcillin-clavulanate). Aminoglycoside (e.g., gentamicin, amikacin, tobramycin). Fluoroquinolone with good anti-pseudomonal activity (e.g., ciprofloxacin). Monobactam (e.g., aztreonam).

Fluid Resuscitation The Severe Sepsis Resuscitation Bundle calls for an initial administration of 20 – 30 ml/kg of crystalloid as a fluid challenge in cases of suspected hypovolemia or actual cases of serum lactate greater than 4 mmol/L (36 g/dl). A colloid equivalent is an acceptable alternative to crystalloid, and an equivalent dose generally ranges from 0.2 g/kg to 0.3 g/kg depending upon the colloid. Fluid resuscitation should be commenced as early as possible in the course of septic shock (even before intensive care unit admission). Requirements for fluid infusion are not easily determined so that repeated fluid challenges should be performed. The bundle does not restrict the amount and extent of an initial fluid challenge, but rather defines a minimum challenge. Subsequent actions in the bundle are undertaken only for hypotension not responding to fluid challenge or for an elevated lactate level as above. Information taken from Institute for Healthcare Improvement, Sepsis Module:

Vasopressor Support Adequate fluid resuscitation is a prerequisite for the successful and appropriate use of vasopressors in patients with septic shock. In general, the end points of fluid resuscitation are the same as those for the use of pharmacologic hemodynamic support, i.e. MAP > 65 mmHg. Sometimes, fluid resuscitation alone may suffice. When an appropriate fluid challenge fails to restore an adequate arterial pressure and organ perfusion, therapy with vasopressor agents should be started. Vasopressor therapy may also be required transiently to sustain life and maintain perfusion in the face of life-threatening hypotension, even when hypovolemia has not been resolved or when a fluid challenge is in progress Either norepinephrine or dopamine (through a central catheter as soon as placement is possible) is the first-choice vasopressor agent to correct hypotension in septic shock. Information taken from Institute for Healthcare Improvement, Sepsis Module:

Maintaining Hemodynamics
Goal-directed therapy represents an attempt to predefine resuscitation end-points to help clinicians at the bedside to resuscitate patients in septic shock. The end-points used vary according to the clinical study but attempt to adjust cardiac preload, contractility, and afterload to balance systemic oxygen delivery with demand. Two essential features of early goal directed therapy include: maintaining an adequate central venous pressure (CVP) to carryout other hemodynamic adjustments maximizing mixed or central venous oxygen saturation (ScVO2) Special patients: In mechanically ventilated patients, a higher target central venous pressure of 12–15 mmHg is recommended to account for the presence of positive end expiratory pressure and increases in intrathoracic pressure. Similar consideration to the above may be warranted in circumstances of increased abdominal pressure. Information taken from Institute for Healthcare Improvement, Sepsis Module:

Blood products When it’s used: if the ScVO2 remains < 70% despite adequate fluid resuscitation, consider transfusion to a hematocrit of 30%. How it works: Increases blood carrying capacity to the tissues. Dosing: Patient specific (however, 1 unit of PRBCs should increase the hematocrit by ~3%) Monitoring: Per routine

Sepsis Management Intensive Care Unit

Early Goal-directed therapy in the treatment of severe sepsis and septic shock
Rivers et al; NEJM 2001;345:1368

Early Recognition of Adult Patients with Severe Sepsis/Septic Shock
Two or more of the following: 1) Temp >38.3C(100.9F) or <36.0C(96.8F) 2) Heart Rate >90 3) Resp Rate >20 or PaCO2 <32 mmHg 4) WBC >12K, <4K or >10% Bands Suspected Infection NO NO YES Re-Assess Re-Assess YES Obtain Appropriate Cultures Check Lactate Sepsis Antibiotics & IVF Re-Assess SBP < 90 after Bolus NO Lactate > 4 mmol/L or Multi-Organ Dysfunction NO Lactate > 2 mmol/L or Organ Dysfunction NO YES YES YES Septic Shock Severe Sepsis High Risk Severe Sepsis Low Risk Antibiotics & IVF Re-check Lactate Early Intervention to Resolve Organ Hypoperfusion

Hemodynamic support and adjunctive therapy
87

Hemodynamic support and adjunctive therapy
88

Summary Sepsis may be obvious or subtle early
There is a high mortality and morbidity Have a high index of suspicion Know local organisms / susceptibilities Take appropriate cultures Treat early and aggressively Investigate early and aggressively Refer early and aggressively Be aware of new developments 91

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TUS 2013 Hangisi şiddetli sepsis için gerekli olan bulgudur?
bk 12000>, trombosit >, ateş 38.3, enfeksiyon odağı 105

TUS 2013 Hangisi şiddetli sepsis için gerekli olan bulgudur?
bk 12000>, trombosit >, ateş 38.3, enfeksiyon odağı 106

TUS 2013 Yağ infuzyonu yapılan hastada sepsis nedeni?
A) Malessezia furfur Fungal factors that contribute to infection include the size of the inoculum and factors that favor colonization and proliferation (eg, use of broad-spectrum antibiotics, postnatal steroids, histamine type-2 [H2] antagonists, parenteral nutrition, or lipid emulsions [Malassezia spp 107

TUS 2013 Septik şok tanısı konulan bir hastada, laktik asideminin düzeltilmesinde hücre membranındaki enzimlerin aktivitesini artırarak etki gösteren madde aşağıdakilerden hangisidir? A) Dopamin B) Dobutamin C) Arjinin vazopressin D) Epinefrin E) Kortizol 108

TUS 2013 Septik şok tanısı konulan bir hastada, laktik asideminin düzeltilmesinde hücre membranındaki enzimlerin aktivitesini artırarak etki gösteren madde aşağıdakilerden hangisidir? A) Dopamin B) Dobutamin C) Arjinin vazopressin D) Epinefrin E) Kortizol 109

TUS 2013 Aşağıdakilerden hangisi, septik şoktaki bir hastada temel tedavi olarak önerilmez? A) Sıvı resüsitasyonu B) Vazopressörler C) İnotropik tedavi D) Steroid tedavisi E) Bikarbonat tedavisi 110

TUS 2013 Aşağıdakilerden hangisi, septik şoktaki bir hastada temel tedavi olarak önerilmez? A) Sıvı resüsitasyonu B) Vazopressörler C) İnotropik tedavi D) Steroid tedavisi E) Bikarbonat tedavisi 111

TUS 2014 112

TUS 2014 113

Sepsis, Severe Sepsis & Septic Shock

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