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Humberto M. Guiot, MD, FACP

Infectious Disease
UPR School of Medicine


To discuss the definition of sepsis

To differentiate between bacteremia, systemic
inflammatory response syndrome (SIRS), severe
sepsis, septic shock, and multi-organ
dysfunction syndrome
To establish strategies for management and
treatment of patients in sepsis


A 69-year-old is brought to the emergency by his son

because of hypoactivity and drowsiness.
On physical examination, temperature is 40.1C, heart
rate is 132 bpm, respiratory rate is 32/min, and blood
pressure is 76/34 mmHg. The patient looks critically ill
and lethargic. Pulse oxymetry reveals an oxygen
saturation of 78%.


What is the
differential diagnosis?


SIRS systemic inflammatory response syndrome to a

variety of severe clinical insults, most commonly
infectious, but also non infectious

pancreatitis, ischemia, multiple trauma, and tissue injury,

hemorrhagic shock, immune-mediated organ injury, and
exogenous administration of inflammatory mediators (tumor
necrosis factor or other cytokines).

2 or more of the following:

T > 38 C or <36 C
HR > 90 beats/min
RR > 20 breaths/min or pCO2 < 32 mmHg
WBC >12,000 cells/mm3, <4,000 cells/mm3, or >10% bands


Sepsis SIRS to an infection.

Severe sepsis Sepsis associated to an organ
dysfunction, perfusion abnormalities (lactic acidosis,
oliguria, AMS), or hypotension (systolic BP <90
Septic shock Sepsis and hypotension despite adequate
fluid resuscitation.
MODS (multiorgan dysfunction syndrome) Altered
organ function in an acutely ill patient.
Bacteremia presence of viable bacteria in the blood


The patient is immediately intubated and placed on

mechanical ventilation with 100% oxygen. Lungs show
bilateral fine expiratory ronchi. The extremities are cold
and clammy with evidence of cyanosis.
The patient has a history of type-2 diabetes mellitus and
benign prostatic hypertrophy. According to the son, he
was recently complaining of urinary hesitance, dribbling,
and suprapubic abdominal pain.
Immediate fluid challenge with 2L of 0.9% saline
solution is started
After 30 minutes, blood pressure is 82/50 mmHg




WBC 23,000 cells/mcL

Hct 17.2 g/dL
PTL 80,000 cells/mcL
pH 7.180
pCO2 56.7 mmHg
pO2 67.8 mmHg
HCO3 13.2 mEq/L


BUN 98 mg/dL
Creat 5.4 mg/dL


What is the
precise diagnosis now?

Sepsis and Septic Shock

13th leading cause of death in U.S.

500,000 episodes each year
35% mortality
30-50% culture-positive blood

Factors Associated with

Highest Mortality

Respiratory > abdominal > urinary

Nosocomial infection
Hypotension, anuria
Isolation of enterococci or fungi
Gram-negative bacteremia
Body temperature lower than 38C
Age greater than 40
Underlying illness: cirrhosis or malignancy

Predisposing Underlying

Heart disease-rheumatic or congenital

Intraabdominal sepsis
Septic abortion or pelvic infection
Intravenous drug abuse

Most Common Etiologies

Gram-negative bacilli

E. coli
Klebsiella pneumonia

Gram-positive cocci
Gram-negative anaerobes

Organisms Responsible for Septic

Shock in Relation to Host Factors



Encapsulated organisms
Pneumococcus spp.,
Haemophilus influenzae,
Neisseria meningtidis,
canimorsus Babesiosis
Vibrio, Yersinia, and
Salmonella spp., other
Gram-negative rods (GNRs),
encapsulated organisms
Klebsiella spp.,



Mucormycosis and Pseudomonas ssp.

(malignant external otitis), Escherichia
Tuberculosis, fungi, herpes virus


Enteric GNR, Pseudomonas,

Aspergillus, Candida, and Mucor spp.,
Staphylococcus aureus


Listeria, Salmonella, and Mycobacteria

spp., herpes virus group (herpes simplex
virus, cytomegalovirus, varicella zoster

The patient persists on mechanical ventilation
with 100% FiO2.
No urine output has been reported.
V/S: BP: 88/56 mmHg; HR: 122/min; RR:
28/min; T: 34 degrees
A thermal blanket is placed and the nephrologist
is consulted


What is the most

appropriate next step?

Surviving Sepsis Campaign

International initiative:
To reduce mortality rate
To improve standards of care
To secure adequate funding

Initial Resuscitation

Begin as soon as the sepsis syndrome is recognized.

CVP 8-12 mmHg
Mean Arterial Pressure > 65 mmHg
Urine output >0.5mL/kg / hr
Central venous pressure venous oxygen saturation

If not achieved with fluid resuscitation (CVP 8-12 mm HG)

during first 6 hours, then transfuse PRBC (to achieve HCT >
30%) or admister vasopressors

Fluid Resuscitation

Natural or artificial colloids (Dextran, gelatin) or

crystalloids (NSS, D5W, Lactate)
No evidence to support one over the other
Resuscitation with crystalloids requires more fluid
(because Vd is much larger)

Fluid challenge (500 1000 cc over 30 min) in

patients with suspected hypovolemia


When fluid resuscitation fails to restore BP and organ perfusion

To sustain life and maintain perfusion in life-threatening
hypotension even during fluid challenge
First choice vasopressor: norepinephrine and dopamine
(through central catheter)

Both are preferred over epinephrine

Norepinephrine is more potent than dopamine and may be more

Vasopressin for refractory shock despite adequate resuscitation

and high dose conventional vasopressors

Inotropic Therapy

Dobutamine may be used to increase cardiac

If used during low blood pressure, it should be
combined with vasopressor therapy


V/S are now: BP: 92/61 mmHg; HR: 102/min; RR:

22/min; T: 36 degrees
B/C: positive for GNB in 2 hours
U/A: turbid urine with sediments. WBC are TNTC,
many bacteria, positive nitrites, positive leukoesterase
Abdominopelvic CT scan shows an enlarged prostate.
There is bilateral obstructive ureterolithiasis with
hydronephrosis and prominent perinephric fat stranding
suggestive of bilateral pyelonephritis.

Q: How should the

infection be treated?


Cultures are to be obtained before antimicrobials are

At least 2 B/C (one peripherally and one through
central catheter)
Culture of other sites (CSF, urine, wounds, respiratory
Imaging studies and sampling of likely sources of
infection should be performed, but some patients may
be too unstable.

Antibiotic Therapy

Started within 1 hour of recognition

One or more drugs with activity against the
most likely pathogens and that penetrate the
presumed source of sepsis
Guided by susceptibility pattern
Use of procalcitonin (or similar markers) to
assist clinicians in the discontinuation of
Re-assess after 48-72 hours with the aim of
narrowing spectrum

Antibiotic Therapy

Duration: 7-10 days and guided by clinical

response (longer courses in MRSA, some fungal
and viral infections in immunodeficiencies,
patients with slow clinical response, etc)
Combination therapy against Pseudomonas and
Acinetobacter and in neutropenic patients
Stop antibiotics if clinical syndrome is
determined not to be infectious

Antibiotic Therapy


Intra-abdominal infection

(Piperacilllin/tazobactam, higher general

cephalosporin or carbapenem) aminoglycoside
(Piperacilllin/tazobactam, higher general
cephalosporin or carbapenem) aminoglycoside


(Cefepime, meropenem or impinem) PLUS

(aminoglycoside or quinolones) (vancomycin or

Antibiotic Therapy

CNS infection

Skin infection

Vancomycin PLUS (ceftriaxone or cefotaxime or

cefepime or meropenem) ampicillin acyclovir
(linezolid or vancomycin)
(piperacillin/tazobactam or cephalosporins or


depending on organism

Source control

Evaluate the presence of a focus of infection amenable for

source control measures within 12 hours, if feasible

Source control with the least physiological effect

Percutaneous rather than surgical drainage, for example

Source control as soon as possible following initial resuscitation

Drainage of abscess
Debridement of infected necrotic tissue
Removal of infected device

GI perforation
Intestinal ischemia

Promptly remove infected central lines/intravascular devices


The patient was administered meropenem and

On the following day, the patient undergoes
Urologic Surgeon performs a bilateral double-J catheter


What other
strategies are
recommended in the
treatment of sepsis?


IV Hydrocortisone (200-300 mg/day) is recommended for 7 days in patients

with septic shock requiring vasopressors

Three or four divided doses or continuous infusion

Rationale: a trial showed shock reversal and reduction in mortality in patients

with relative adrenal insufficiency (post-adrenocorticotropic hormone cortisol
increase <9 mcg/dL)
ACTH test to identify responders (>9mcg/dL increase in cortisol). No
steroids for responders, as these patients do not have relative adrenal
Taper steroids after resolution of shock
Other authorities taper doses of corticosteroids at the end of therapy
No high dose hydrocortisone (>300 mg/day)
No shock = no steroids
Dexamethasone does not interfere with ACTH test

Activated Protein C

Recombinant human activated protein C

(rhAPC or drotrecogin alfa, Xigris) was
recommended in patients at high risk of death
(APACHE II>25, sepsis-induced MOF, septic
shock, or sepsis-induced ARDS) with no
absolute contraindication (mostly related to
bleeding or risk of bleeding).
Withdrawn from the US Market on October
2011 due to failure to show survival benefit

Blood Product Administration

After initial resuscitation

PRBC transfusion for Hb < 7 g/dL to a target of 7-9 g/dL

Erythropoetin is not recommended as specific treatment of
anemia associated to severe sepsis
No FFP in the absence of bleeding or planned procedure
Antithrombin administration is not recommended for the
treatment of severe sepsis and shock
Platelet transfusion

5,000-30,000 + risk of bleeding
>50,000 for surgery of invasive procedure

Glucose Control

BS < 150 mg/dL

Studies have used continuous infusion of insulin and
Best results with BS between 80-110 mg/dL
Glucose should be monitored frequently after
initiation of the protocol (every 30-60 mins) and on
a regular basis (every 4 hours) once BS has been

Nutrition protocol with preferential use of

enteric route

DVT Prophylaxis

Severe sepsis patients should receive prophylaxis

with low-dose unfractionated heparin or

In patients who have contraindications for heparin

use, mechanical prophylactic device (compression
stockings, intermittent compression device) is

Stress Ulcer Prophylaxis

Should be given to all patients with severe sepsis

H2 receptor blockers are more efficacious than

PPIs have not been assessed in a direct comparison

with H2 receptor antagonists


72 hours after admission:

Vasopressors could be discontinued

Creat is now 1.5 mg/dL and dialysis is put on hold
FiO2 has been decreased to 40%
Final B/C and U/C report: MDS E. coli
WBC are 11,000 cells/mcL while PTL count is 140,000


What is the most

appropriate next step?


What would be
done if the course had
been different?

Consideration for Limitation of Support

Advance care planning (communication of likely

outcomes and realistic goals) should be
discussed with patients and relatives.
Decisions for less aggressive support or
withdrawal of support may be in the patients
best interest.


Surviving Sepsis Campaign: International

Guidelines for the Management of Severe Sepsis
and Septic Shock. Crit Care Med. 2013; 41:
Surviving Sepsis Campaign: Guidelines for the
Management of Severe Sepsis and Septic
Shock. Crit Care Med. 2004; 32: 858-873.
Gorbach SL. Infectious Diseases, 3rd edition.