Sepsis. Communicable Diseases report- Internal Medicine

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

6. EPIDEMIOLOGY

7. 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

11. Bacteria
LP
S Phagocyte
Toxin Recognition by the
Host

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

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