Sepsis

DEFINITION OF TERMS• BACTEREMIA: bacteria in blood, evidence with (+) blood culture

• SEPTICEMIA: presence of microbes or their toxins in blood

• SIRS - ANY Two or more of the following: 1. Temperature

◦ 1.1.Fever → oral T >38ʼC

◦ 1.2.Hypothermia <36ʼ

2. Respiratory Rate◦ 2.1.Tachypnea >24cpm

3. Tachycardia >90bpm 4. WBC

◦ 4.1.Leukocytosis >12,000/uL

◦ 4.2.Leukopenia <4,000/uL

◦ 4.3. >10%band cells

◦ 4.4. May have non-infectious etiology

• SEPSIS: SIRS + proven microbial etiology

Harrison’ s Internal Medicine 18th edition1

SEPSIS

GROUP 1

Camacho, Hans Robert C. Francisco, Rimmon Pineda, Francis Ivan G. Yang, Sheryl Ray B. Zagada, Timothy M.

SEPSIS

Sepsis

• SEPSIS + severe distant organ dysfunction = SEVERE SEPSIS•SEVERE SEPSIS + Hypoperfusion/Hypotension = SEPTIC SHOCK

• Sepsis often reversible• Septic shock usually succumb

SEPTIC SHOCK >1hr not respond to fluid resuscitation or pressor administration = REFRACTORY SEPTIC SHOCK

Dysfunction of more than one organ, requiring

Intervention to maintain Homeostasis = MODS

- according to National Institute of Health define as an illness in which the body has a severe response to microbial infections.

Harrison’ s Internal Medicine 18th edition

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Severe sepsis can be a response to any class of microorganism

Microbial invasion in the blood stream –

not ESSENTIAL , since local inflammation can also illicit organ dysfunction and hypotension.

ETIOLOGY


Blood cultures are positive:◦ 20–40% of Severe sepsis cases◦40–70% of septic shock cases

Of cases with positive blood cultures, ◦40% -gram-positive bacteria, ◦35% t - gram-negative bacteria,◦11 % - Polymicrobial◦7% - fungi ◦<5% - classic pathogens

•(-) blood culture patients: the etiologic agent is often established by culture or microscopic examination of infected material from a local site

ETIOLOGY


The septic response is a contributing factor in >200,000 deaths per year in the United States.

The incidence of severe sepsis and septic shock has increased over the past 20 years

The annual number of cases is now >700,000 (~3 per 1000 population).

Epidemiology of sepsis: an update. (2001)National Center for Biotechnology Informationhttp://www.ncbi.nlm.nih.gov/pubmed/11445744

EPIDEMIOLOGY

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EPIDEMIOLOGY

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EPIDEMIOLOGY

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Patients hospitalized for septicemia or sepsis were more severely ill than patients hospitalized for another diagnosis.

Patients hospitalized for septicemia or sepsis stayed longer than other inpatients.

Patients hospitalized for septicemia or sepsis were more than eight times as likely to die during their hospitalization.

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11th National Convention on Statistics (NCS), 2010NEWBORN DEATHS IN THE PHILIPPINESAurora T. Reolalas* and Ma. Goretti M. Novilla

Chief, Vital Statistics DivisionNational Statistics Office9

Neonatal Sepsis in the PhilippinesGram-negative organisms

comprised the majority of the neonatal infections, with Pseudomonas and Burkholderia being the most prevalent.

PIDSP Journal 2011 Vol 12 No.2 ETIOLOGY OF NEONATAL SEPSIS IN FIVE URBAN HOSPITALS IN THE PHILIPPINESCopyright ® 2011

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LBP

Bacteria

LPS Phagocyte

CD 14

Toxin Recognition by the Host

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LBPBacteria

LPS Phagocyte

CD 14

LPS

MD-2

TLR-4

TLR4 – transmembrane protein, transmits the LPS recognition signal to the interior of the cell, where signal transduction and gene transcription pathways promote the production and/or secretion of numerous molecules that mediate the inflammatory response

LPS

MD-2Extracellular protein which binds the lipid A moiety of LPS

Toxin Recognition by the Host

Signaling complex

Mandell Principles of Infectious Disease

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Inflammatory Mediators

TNF alpha ◦Potent mediator of the subsequent

inflammatory response◦Stimulates muscle breakdown and

cachexia, mediates coagulation activation, enhances expression of adhesion molecules, prostaglandin E2 & PAF

• IL-1– Released in response to inflammation– Endogenous pyrogen

• IL-6– Increasingly expressed during stress as

in septic shock.– Promote intravascular coagulation

• Other Interleukins, Cytokines and Chemokines increased capillary permeability and blood flow, infiltration of neutrophils, and pain.

Schwartz Principles of Surgery


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Microbial killingThe major inherited mechanisms for killing

microbes in the blood are soluble molecules: ◦ the mannose-binding lectin & C-reactive protein

(CRP) pathways for activating complement◦ the alternative complement pathway ◦antibacterial proteins (such as bactericidal

permeability-increasing protein [BPI])◦natural IgM antibodies.

Increased capillary permeability allows these molecules to diffuse into tissues where there is local inflammation.


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Control MechanismsLocal Control Mechanisms Intracellular factors

(e.g., suppressor of cytokine signaling 3 and IL-1 receptor associated kinase 3)

Molecules derived from essential polyunsaturated fatty acids (lipoxins, resolvins, and protectins)

Enzymatic inactivation of microbial signal molecules (e.g., LPS)

Systemic Control Mechanisms

• LPS-binding protein• Glucocorticoids• Epinephrine • Prostaglandin E2 • IL-10, and C-reactive

protein • IL-1 receptor

antagonist. • soluble TNF receptors • protease inhibitors or

antioxidants; • Hepcidin Harrison’s Principle of IM15

CLINICAL MANIFESTATIONPatients usually manifests symptoms and signs

related to primary infection.

Manifestations of Systemic Inflammatory Response

Evidence of shock

(-) fever: most common in neonates, elderly patients and in persons with uremia or alcoholism


Hyperventilation Encephalopathy Hypotension DIC, acrocyanosis, ischemic necrosis of

peripheral tissues (e.g., digits)• Skin: hemorrhagic lesions, bullae, cellulitis.

Skin lesions may suggest specific pathogens—e.g., petechiae and purpura with Neisseria meningitidis, ecthyma gangrenosum with Pseudomonas aeruginosa.

• Gastrointestinal• Hypoxemia

CLINICAL MANIFESTATION


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1. Cardiopulmonary Complications

◦Acute respiratory distress syndrome◦Hypotension◦Decrease Myocardial function

II. Renal ComplicationsoOliguiraoAzotemiao Proteinuriao Nonspecific casts

MAJOR COMPLICATIONS

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III. Coagulopathy• Thrombocytopenia in 10-30%• Platelet usually very low

<50,000/uL in px with DIC

IV. Neurological Complications• DDX: Guillain-Barre

syndrome, metabolic disturbance, toxin activity

MAJOR COMPLICATIONS


LEUKOCYTOSIS with a left shift

ThrombocytopeniaHyperbilirubinemi

aProteinuriaNeutrophils - may

contain toxic granulations, Dohle bodies or cytoplasmic vacuoles

Early sepsis: hyperventilation respiratory alkalosis

Respiratory muscle fatigue & accum. of lactate metabolic acidosis

ABG: hypoxemia (initially correctable with supplemental oxygen)

LABORATORY FINDINGS


CXR: normal or may show evidence of underlying pneumonia, volume overload, or the diffuse infiltrates of ARDS

ECG: sinus tachycardia & nonspecific ST-T wave abnormalities

Diabetic patients: ◦ develops

hyperglycemia◦ Severe infection

diabetic ketoacidosis (may exacerbate hypotension)

◦ Serum albumin - initially within normal range, declines as sepsis continues

LABORATORY FINDINGS


NO specific diagnostic test Diagnostically sensitive

findings: Fever or hypothermia Tachypnea Tachycardia Leukocytosis or

leukopenia

Acutely altered mental status

Thrombocytopenia

Elevated blood lactate level

hypotension

DIAGNOSIS

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36% normal temperature40% normal respiratory rate10% normal pulse rate33% normal WBC count

Systemic responses of uninfected patients with other conditions are similar to those characteristic of sepsis

DIAGNOSIS


Definitive etiologic diagnosis ◦ requires isolation of the microorganism from blood

or a local site of infection

Culture: At least 2 blood samples (10mL each)◦ should be obtained (from different venipuncture

sites)

Gram (-) bacteremia ◦ typically low grade (10 organism/mL of blood),

prolonged incubation may be necessary

S. aureus grows more rapidly – detectable in blood within 48 hours


Antimicrobial Agents

Given after blood and other relevant sites have been cultured.

major determinant of outcome: ◦interval between hypotension and the administration antimicrobial chemotherapy

◦a delay of 1 h is associated with lower survival rates.


Treatment:

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A Single antimicrobial agent for treatment of known pathogens is adequate.

Combination antimicrobial therapy is NOT superior to monotherapy in treating Gram(-) bacteremia. EXCEPT in P.aeruginosa bacteremia where aminoglycoside monotherapy is less effective than combination of an aminoglycoside with an antipseudomonal -lactam agent.

antimicrobial therapy-at least 1 week;

Factors in duration of treatment:◦site of infection◦adequacy of surgical drainage, ◦underlying diseases◦susceptibility of the bacterial isolate(s) to

antimicrobials. Harrison’ s Internal Medicine 18th edition


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Factors in duration of treatment:

site of infection adequacy of surgical drainage, underlying diseases susceptibility of the bacterial isolate(s)

to antimicrobials.



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Clinical Condition Antimicrobial Regimens (Intravenous Therapy)

Immunocompetent adult The many acceptable regimens include (1) ceftriaxone (2 g q24h) or ticarcillin-clavulanate (3.1 g q4–6h) or piperacillin-tazobactam (3.375 g q4–6h); (2) imipenem-cilastatin (0.5 g q6h) or meropenem (1 g q8h) or cefepime (2 g q12h). Gentamicin or tobramycin (5–7 mg/kg q24h) may be addedto either regimen. If the patient is allergic to -lactam agents, use ciprofloxacin (400 mg q12h) or levofloxacin (500–750 mg q12h) plus clindamycin (600 mg q8h). If the institution or the community has a high prevalence of MRSA isolates, add vancomycin (15 mg/kg q12h) to each of the above regimens.

Neutropeniaa (<500 neutrophils/L)

Regimens include (1) imipenem-cilastatin (0.5 g q6h) ormeropenem (1 g q8h) or cefepime (2 g q8h); (2) ticarcillin-clavulanate (3.1 g q4h) or piperacillin-tazobactam (3.375 g q4h) plus tobramycin (5–7 mg/kg q24h). Vancomycin (15 mg/kg q12h) should be added if the patient has an infected vascular catheter, if staphylococci are suspected, if the patient has received quinolone prophylaxis, if the patient has received intensive chemotherapy that produces mucosal damage, if the institution has a high incidence of MRSA infections, or if there is a high prevalence of MRSA isolates in the community.

Splenectomy Cefotaxime (2 g q6–8h) or ceftriaxone (2 g q12h) should be used. If the local prevalence of cephalosporin-resistant pneumococci is high, add vancomycin. If the patient is allergic to -lactam drugs, vancomycin (15 mg/kg q12h) plus ciprofloxacin (400 mg q12h) or levofloxacin (750 mg q12h) or aztreonam (2 g q8h) should be used.

IV drug user Nafcillin or oxacillin (2 g q8h) plus gentamicin (5–7 mg/kg q24h). If the local prevalence of MRSA is high or if the patient is allergic to -lactam drugs, vancomycin (15 mg/kg q12h) with gentamicin should be used.

AIDS Cefepime (2 g q8h), ticarcillin-clavulanate (3.1 g q4h), or piperacillin-tazobactam (3.375 g q4h) plus tobramycin (5–7 mg/kg q24h) should be used. If the patient is allergic to -lactam drugs, ciprofloxacin (400 mg q12h) or levofloxacin (750 mg q12h) plus vancomycin (15 mg/kg q12h) plus tobramycin should be used.

Initial Antimicrobial Therapy for Severe Sepsis with No Obvious Source in Adults with Normal Renal Function


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Removal of the Source of Infection Indwelling IV cathethers should be removed and the

tip should be rolled over an agar plate for culture.

After antibiotic therapy, a new catheter should be replaced at a different site and Foley and drainage catherters should be replaced

Consider paranasal sinusitis in patients who have undergone nasal intubation.

In patients with abnormal CXR, a CT of the chest may identify parenchymal,mediastinal or pleural diseases.

In neutropenic patients, sites of tenderness and erythema must be carefully sought.

In sacral or ischial decubitus ulcers, exclude pelvic of soft tissue pus collections wit CT/MRI

In severe sepsis from the urinary tract, rule out urethereal obstruction, pernephric abcess and renall abcess by sonography or CT. Harrison’ s Internal Medicine 18th

edition

Treatment:

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Hemodynamic, Respiratory, and Metabolic Support

Primary goals ◦ restore adequate oxygen and substrate

delivery to the tissues.◦ improve tissue oxygen utilization and cellular

metabolism. Initial management of hypotension

• Administration of IV fluids (1-2L of NSS over 1-2 h)

Circulatory adequacy can be assessed by:◦ clinical parameters (mentation, urine output,

skin perfusion) ◦ measurements of oxygen delivery and

consumption. Harrison’ s Internal Medicine 18th

edition

Treatment:

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"early goal-directed therapy" (EGDT) • resuscitation based on maintenance of the

SvO2 at >70% was associated with significantly improved survival of patients

• The treatment algorithm ◦rapid administration of fluids, ◦antibiotics, and ◦vasopressor support; erythrocyte transfusion (to maintain the hematocrit above 30%); and

◦Dobutamine is administered if fluids, erythrocytes, and pressors did not result in an SvO2 of >70%. Harrison’ s Internal Medicine 18th

edition

Hemodynamic, Respiratory, and Metabolic Support

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Vasopressin ◦potent vasoconstrictor ◦Useful in vasodilatory shock and relative

resistance to other pressor hormones.

Ventilator therapy ◦For progressive hypoxemia, hypercapnia,

neurologic deterioration, or respiratory muscle failure.

Bicarbonates administered if severe metabolic acidosis <7.2ph

FFP and platelet transfusion in DIC if complicated by major bleeding.

In hypercatabolic patients and Acute renal failure, hemodialysis or hemofiltration is beneficial.


General SupportNutritional supplementation may reduce

the impact of protein hypercatabolism in patients with prolonged sepsis.

Prophylactic heparinization to prevent deep venous thrombosis for patients without active bleeding or coagulopathy.

Maintenance of blood glucose improved survival rates among patients who have undergone major surgery and received IV glucose.

Hypoglycemia was much more common in the intensive-insulin group.


Treatment:

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Other MeasuresEndotoxin-neutralizing proteins, inhibitors of COX or nitric oxide synthase, anticoagulants, polyclonal immunoglobulins, glucocorticoids, andantagonists to TNF-, IL-1, PAF, and bradykinin.


Treatment:

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Recombinant activated protein C (aPC) ◦Treatment of patients with severe

sepsis or septic shock. ◦The FDA approved aPC for use in adults

(>18 years of age) who meet the APACHE II criterion and have a low risk of hemorrhage-related side effects.

◦aPC is administered as a constant IV infusion of 24 g/kg per hour for 96 h.


should not be given to patients• platelet counts of <30,000/L • dysfunction of one organ system and

surgery within 30 days. Treatment with aPC should not be

started >24 h after the onset of severe sepsis, nor should it be used in the patient subsets—e.g., patients with pancreatitis or AIDS—that were excluded from the clinical trial.


"bundling" of multiple therapeutic maneuvers as the standard of care for severe sepsis.

The proposed resuscitation (6-h) bundle incorporates most of the elements discussed above for acute (EGDT) resuscitation.

The management (24-h) bundle includes three measures of uncertain or marginal benefit: ◦tight control of blood glucose,

administration of low-dose hydrocortisone, and treatment with aPC.



PreventionLimit the use of indwelling vascular and

bladder catheters

Reduce the incidence and duration of profound neutropenia (<500 neutrophils/L)

Aggressively treating localized nosocomial infections

Indiscriminate use of antimicrobial agents and glucocorticoids should be avoided, and optimal infection-control measures should be used

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Sepsis

Health & Medicine

Transcript of Sepsis