1. 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
Harrison’ s Internal Medicine 18th edition
SEPS
IS
GROUP 1
Camacho, Hans Robert C.
Francisco, Rimmon
Pineda, Francis Ivan G.
Yang, Sheryl Ray B.
Zagada, Timothy M.
SEPSIS
2. 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
3. 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
Harrison’ s
Internal Medicine 18th editio
4. 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
Harrison’ s Internal Medicine 18th edition
5. 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 Information
http://www.ncbi.nlm.nih.gov/pubmed/11445744
EPIDEMIOLOGY
8. 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.
9. 11th National Convention on Statistics (NCS), 2010
NEWBORN DEATHS IN THE PHILIPPINES
Aurora T. Reolalas* and Ma. Goretti M. Novilla
Chief, Vital Statistics Division
National Statistics Office
10. Neonatal Sepsis in the
Philippines
Gram-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 PHILIPPINES
Copyright ® 2011
12. LBPBacteria
LP
S Phagocyte
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
LP
S
MD-2
Extracellular protein
which binds the lipid
A moiety of LPS
Toxin Recognition by the
Host
Signaling complex
Mandell Principles of Infectious
13. 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
Mandell Principles of Infectious
14. Microbial killing
The 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.
Mandell Principles of Infectious
15. Control Mechanisms
Local 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 IM
16.
17. CLINICAL MANIFESTATION
Patients 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
Harrison’ s Internal Medicine 18th edition
18. 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
Harrison’ s Internal Medicine 18th edition
19. 1. Cardiopulmonary Complications
◦ Acute respiratory distress syndrome
◦ Hypotension
◦ Decrease Myocardial function
II. Renal Complications
o Oliguira
o Azotemia
o Proteinuria
o Nonspecific casts
MAJOR COMPLICATIONS
20. 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
Harrison’ s Internal Medicine 18th edition
21. LEUKOCYTOSIS with
a left shift
Thrombocytopenia
Hyperbilirubinemia
Proteinuria
Neutrophils - 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
Harrison’ s Internal Medicine 18th edition
22. 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
Harrison’ s Internal Medicine 18th edition
23. 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
24. 36% normal temperature
40% normal respiratory rate
10% normal pulse rate
33% normal WBC count
Systemic responses of uninfected patien
with other conditions are similar to those
characteristic of sepsis
DIAGNOSIS
Harrison’ s Internal Medicine 18th edition
25. 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
Harrison’ s Internal Medicine 18th edition
26. 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.
Harrison’ s Internal Medicine 18th edition
Treatment:
27. 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
Antimicrobial Agents
28. 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
Antimicrobial Agents
29. 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
Harrison’ s Internal Medicine 18th edition
30. 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:
31. 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:
32. "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
33. 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 isHarrison’ s Internal Medicine 18th edition
34. General Support
Nutritional 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 theHarrison’ s Internal Medicine 18th edition
Treatment:
35. Other Measures
Endotoxin-neutralizing proteins,
inhibitors of COX or nitric oxide synthase,
anticoagulants,
polyclonal immunoglobulins,
glucocorticoids, and
antagonists to TNF-, IL-1, PAF, and
bradykinin.
Harrison’ s Internal Medicine 18th edition
Treatment:
36. 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.
Harrison’ s Internal Medicine 18th edition
37. 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.
Harrison’ s Internal Medicine 18th edition
38. "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.
Harrison’ s Internal Medicine 18th edition
39. Harrison’ s Internal Medicine 18th edition
Prevention
Limit 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
Hinweis der Redaktion
• Severe sepsis may have hypotension/hypoperfusion (ABP = <90mmHg or <40mmHg of the patients normal BP for at least 1 hour despite of resucitation.If hypotension canʼt be corrected with fluid infusion = SEPTIC SHOCK = = poor prognosis
The respiratory distress ofnewborn was the leading cause of early neonatal deaths in Regions I, IVA, V, X and ARMMfor both periods 2006 and 2007, while bacterial sepsis of newborn was the leading cause ofdeaths in NCR and Region VI for both periods also.
These mediators include cytokines (in particular, tumor necrosis factor [TNF]; interleukin [IL]-1â, IL-12); chemokines (IL-8, macrophage inflammatory protein [MIP]-1á); lipid mediators (prostaglandins, leukotrienes); and others, and they result in the familiar elements of local inflammation: increased capil- lary permeability and blood flow, infiltration of neutrophils, and pain.In addition, local deposition of fibrin that is initiated by the expression of tissue factor on activated macrophages and endothelial cells helps wall off the infected tissue and provides an important impediment to bloodstream invasion.Although neutrophils circulate in the bloodstream, they carry out phagocytosis largely in tissue spaces, where they can attach to extracel- lular matrix, spread out, get traction, and ingest. Because phagocytes may regurgitate the contents of their lysosomes as they eat, limiting this activity to local tissues minimizes the release of digestive enzymes and oxidants into the circulating blood. The major inherited mecha- nisms for killing microbes in the blood are soluble molecules: the mannose-binding lectin and C-reactive protein (CRP) pathways for activating complement, the alternative complement pathway, antibac- terial proteins (such as bactericidal permeability-increasing protein [BPI]), and natural IgM antibodies. Increased capillary permeability allows these molecules to diffuse into tissues where there is local inflammation.
These mediators include cytokines (in particular, tumor necrosis factor [TNF]; interleukin [IL]-1â, IL-12); chemokines (IL-8, macrophage inflammatory protein [MIP]-1á); lipid mediators (prostaglandins, leukotrienes); and others, and they result in the familiar elements of local inflammation: increased capil- lary permeability and blood flow, infiltration of neutrophils, and pain.In addition, local deposition of fibrin that is initiated by the expression of tissue factor on activated macrophages and endothelial cells helps wall off the infected tissue and provides an important impediment to bloodstream invasion.Although neutrophils circulate in the bloodstream, they carry out phagocytosis largely in tissue spaces, where they can attach to extracel- lular matrix, spread out, get traction, and ingest. Because phagocytes may regurgitate the contents of their lysosomes as they eat, limiting this activity to local tissues minimizes the release of digestive enzymes and oxidants into the circulating blood. The major inherited mecha- nisms for killing microbes in the blood are soluble molecules: the mannose-binding lectin and C-reactive protein (CRP) pathways for activating complement, the alternative complement pathway, antibac- terial proteins (such as bactericidal permeability-increasing protein [BPI]), and natural IgM antibodies. Increased capillary permeability allows these molecules to diffuse into tissues where there is local inflammation.
Ex: Pneumonia ( cough, dypnea, productive sputum)Fever, chills, hypothermia, Hypotension, lactic acidemia, progressive organ system dysfunction. S/S rate differ from px to px• Different variations, too• Some sepsis are normo or hypothermic• Absence of fever MOST COMMON
Hyperventilation – earliest signEncephalopathy (disorientation, confusion)HypotensionDIC, acrocyanosis, ischemic necrosisof peripheral tissues (e.g., digits)• Skin: hemorrhagic lesions, bullae, cellulitis. Skin lesions may suggest specific pathogens—e.g., petechiae and purpura with Neisseria meningitidis, ecthymagangrenosum withPseudomonas aeruginosa.• Gastrointestinal: nausea, vomiting, diarrhea, ileus, cholestatic jaundice• Hypoxemia: ventilation-perfusion mismatchand increased alveolar capillary permeability with increased pulmonary water content
Acute respiratory distress syndrome VQ mismatch -> fall in arterial PO2 early in courseInc alveolar capillary permeability↓pulmonary water content↓decrease compliance and interferes with gas exchange(progressive diffuse pulmonary infiltratesand arterial hypoxemia (PaO2/FIO2 <200)) is ARD which develops in 50% of pts with severesepsis or septic shock.Hypotension: Normal or increased cardiac output and decreased systemicvascular resistance distinguish septic shock from cardiogenic or hypovolemicshock. a. generalized maldistribution of blood flow and blood volumeb. hypovolemia (dt diffuse capillary leakage of intravascular fluid)c. Dehydration from atecedentdse or insensible fluid losses, v/d, and polyuriaMyocardial function is depressed manifested with Decreased Ejection fraction• Increased end-diastolic and systolic ventricular volumes*CO normal even if decrease Ejection Fraction because of ventricular dilatation which permits normal strokevolumeRenal complications2) Renal Complications• Oliguira• Azotemia• Proteinuria• Nonspecific casts• Polyuric (Hypergly can exacerbate)• Most renal failure dt ATN induced by hypotension or capillary injury• Some may have glomerulonephritis, renal cortical necrosis or interstitial nephritis• Drug induced renal damage can complicate therapy
It is important, pending culture results, to initiate empirical antimicrobial therapy that is effective against both gram-positive and gram-negative bacteria (Table 265-3).
Removal or drainage of a focal source of infection is essential.
Despite aggressive management, many patients with severe sepsis or septic shock die. Numerous interventions have been tested for their ability to improve survival in patients with severe sepsis.