Download Sepsis review St Luc Hospital, September 2003 By Antonios Liolios

Sepsis review
St Luc Hospital, September 2003
By Antonios Liolios, MD
Introduction
Sepsis stems from the Greek word “σήψις”, which means “decomposition, decay”. It has
been observed and described since the dawn of medicine. A few landmark dates are
interesting: in 1752, John Pringle, a surgeon, first used the term “antiseptic”. Richard
Pfeiffer identified “endotoxin” in 1892 and in 1975, John Stenflo discovered protein C.
During the last several years, considerable advances have been made in the understanding
of the pathophysiology of sepsis.
Definition
It was early recognized that the symptoms and signs of sepsis may occur without an
infection. For this reason the concept of systemic inflammatory response syndrome
(SIRS) was created.
The classical criteria for SIRS and sepsis, proposed originally in 1992 and subsequently
validated in 1995 are the following 1,2
 SIRS (2 or more)
 Temperature > 38 C or < 36 C
 Heart rate > 90
 Respiratory rate > 20
 WBC . 12,000/microL or > 10 % bands
 Sepsis: SIRS + documented infection
 Severe sepsis: sepsis + organ dysfunction (hypotension or hypoperfusion –lactic
acidosis, oliguria, mental status changes)
 Septic shock: sepsis induced hypotension not responding to 500 cc IV fluid +
peripheral hypoperfusion
It is now evident that this definition is limited so another more comprehensive system,
the PIRO system was proposed. It is based on3
 Predisposition
 Predisposition to respond to therapy
 genetic comorbidities, environmental, social ie alcohol
 Infection
 Factors that may affect prognosis and likelihood of response to therapy
 identifiable infection source, severity,
localized-disseminated (eg
bacteraemia) organisms, appropriate/inappropriate initial antimicrobial
therapy
 Response
 stratification of response based on: biomarkers conventional laboratory
parameters eg WBC, procalcitonin, CRP, lactate
 Organ dysfunction
 number of organ dysfunctions specific organ dysfunctions magnitude of
each organ dysfunction
Although this system is more comprehensive it is still not the standard system for
defining sepsis. The older definition with the addition of more signs and symptoms is still
valid (see table)
Epidemiology
Sepsis represents a major health issue4. Severe sepsis has a mortality of almost 30% and
is responsible for 215,000 deaths each year in the USA. 750,000 cases of severe sepsis
occur in the US annually. In Europe 44.8% of ICU patients were found to be infected5. In
a European recent study, the overall frequency of septic shock was 8.2 per 100
admissions6. Mortality declined from 62.1% (in 1993) to 55.9 (in 2000). It appears that
the frequency of septic shock is increasing with more multiresistant strains worldwide
while its crude mortality rate is decreasing.
Pathophysiology
After an infectious insult, endothelial damage occurs with subsequent activation of
neutrophils. This causes increased vascular permeability with resulting tissue edema and
liberation of oxidants by the neutrophil. Tissue factor (TF) is expressed by monocytes
and the damaged vascular endothelium. Inflammatory cytokines, such as tumor necrosis
factor (TNF)-alpha and interleukin (IL)-1 and IL-6, are secreted by the monocytes.
Finally coagulation is activated with release of thrombin and the formation of the fibrin
clot. The purpose of this pathway is to “wall off” the infection. Immune system
overstimulation is not central. What has been recently recognized is that cytokines may
actually be beneficial in sepsis. The immune response is initiated by the innate immune
cells via the Toll Like Receptors (TLR). TLR 4 is part of a recognition complex for
bacterial lipopolysaccharide ansd it has been shown that modulation of tissue TLRs
during the early phases of polymicrobial sepsis correlates with mortality. Finally, nuclear
factor kappaB, a transcription factor involved in immediate early gene activation during
inflammation is activated and cytokines are released7. After the entrance of the infectious
agent the premorbid condition is crucial. The role of host genetic factors has been
recently elucidated: polymorphisms in TNF, interleukin-1, Fc, and Toll Like receptors 4
may influence the response to infection8,9. There is a definite potential for targeted
therapy of sepsis and septic shock based on genetic variability in the near future.
Inflammation promotes coagulation and coagulation induces inflammation by the release
of inflammatory cytokines. Coagulation factor Xa was found to produce a
proinflammatory response in endothelial cells and activated protein C (aPC) inhibits the
production of inflammatory cytokines. Finally, a deficiency of several coagulation factors
among which was antithrombin III and aPC has been demonstrated in severe septic shock
patients10. The following picture shows the response to sepsis of three hypothetical
patients11 and it illustrates how individual variation may play a significant role.
Symptoms and signs
Sepsis may have protean manifestations from many organs and systems as shown
before. It should be particularly suspected when there are
 Mental status changes – ANY KIND
 Confusion/delirium/compativeness

Your pleasant grandpa is now pulling his lines out
 Decreased responsiveness, pt is less perky
 Lethargy
 Tachypnea and/or tachycardia WITHOUT fever (yet)
 Hypothermia – remember RECTAL temperature
 Dropping (slightly initially) blood pressure – beware of RELATIVE changes

Your hypertensive granny with a BP of 100/82 may very well be septic
 Rising blood sugar – increasing insulin requirements
Recent therapeutic advances
Coagulation
Based on the concept of acquired factor deficiency during sepsis, attempts have been
undertaken to replenish the missing factors: Various other agents have been used,
including recombinant soluble human thrombomodulin (ART-123), platelet activating
factor acetylhydrolase, recombinant form of tissue factor pathway inhibitor (Tifacogin),
monoclonal antibodies to the platelet GPIIb/IIIa receptor, Triflavin (an antiplatelet
peptide), plasminogen activator inhibitor-inhibitor (XR5118). None of these agents have
been proven to be efficacious so far.
AT and aPC were genetically engineered and administered to septic patients in 2 doubleblind, placebo-controlled, multicenter, phase 3 clinical trials. The first is the Kybersept
trial in which high doses of AT were given to patients with severe sepsis. An effect on
28-day mortality was not demonstrated and there was also an increased risk of
hemorrhage when AT was administered with heparin12.
In the PROWESS trial aPC was administered to severely septic patients. There was a
reduction in the relative risk of death of 19.4 percent (95 percent confidence interval, 6.6
to 30.5) and an absolute reduction in the risk of death of 6.1 percent (P=0.005). The
incidence of serious bleeding was higher in the aPC group than in the placebo group (3.5
percent vs. 2.0 percent, P=0.06)
Early Goal Directed Therapy Study
Essentially consisted of standard sepsis care plus the administration of blood transfusion
up to a hematocrit of 30% and dobutamine when the mixed venous saturation was below
70%13 within the first 6 hours after presentation. Significantly lower in-hospital, 28-day
and 60-day mortality was demonstrated. In-hospital mortality was 30.5 percent with early
goal-directed therapy, as compared with 46.5 percent in the standard group therapy (p =
0.009) decrease 16 %.
Intensive insulin therapy
In the study by van den Berghe et al, intensive insulin therapy reduced overall in-hospital
mortality by 34 %, bloodstream infections by 46 %, acute renal failure requiring dialysis
or hemofiltration by 41 %. 14The greatest reduction in mortality involved deaths due to
multiple-organ failure with a proven septic focus.
Kidney protection
The study by Schiffl et al compared daily hemodialysis to traditional every other day or
intermittent dialysis.15 Significant reduction in mortality (28 % for daily dialysis versus
46 % for alternate-day dialysis with p=0.01) was observed and increased morbidity
secondary to hypotension was not seen.
Steroids
The study by Annane et al was the first placebo-controlled, randomized, double-blind,
multicenter trial which demonstrated a decrease in mortality with the use of steroids. Low
dose hydrocortisone (50-mg intravenous bolus every 6 hours) and fludrocortisone (50micro g tablet once daily) were administered for 7 days to patients in septic shock. 73
deaths (63%) occurred in the placebo group as compared to 60 deaths (53%) in the
corticosteroid group (p =0.02). Vasopressor therapy was withdrawn within 28 days in 46
patients (40%) in the placebo group and in 65 patients (57%) in the corticosteroid group
(p=0.001)16
OVERALL RECOMMENDATIONS
Early identification
Early drainage/surgical intervention


Does the patient have a correctable source anywhere in his body?
Abscess
 Liver
 Brain
 Retroperitoneum
 Lung-mediastinum
o Could the pleural effusion be an empyema?
o Can the dilated kidney represent an obstructive pyelonephritis?
o Are the paranasal sinuses/teeth filled with pus?
o Is there any dead bowel in the abdomen?
o Is the ascites infected?
o Is the hematoma infected?
o Is the gallbladder infected?
o Has this organ perforated?
Prompt initiation of appropriate antibiotics

Broad spectrum antibiotics when in doubt and no clear source is evident
Early intubation, sedation

In the Emergency Department if possible!
Strictly timed goal-directed therapy
Rapid initiation of volume resuscitation







If possible in the Emergency Department!!
(CVP > 8 mm Hg, preferably > 12 mm Hg: crystalloids (6 - 10 L) or colloids (2 – 4 L) can be
used
If MAP < 65 mm Hg, addition of vasoactive agents: inotropes (if CO low) and/or pressors (if CO
is O.K.)
If SvO2 remains < 70% and the Hct is < 30% in the first 6 hours give RBCs
Dobutamine for cardiac output support.
Pressors of choice are norepinephrine or dopamine. Epinephrine (refractory shock) and
phenylephrine (tachyarrhythmias) are second-line drugs.
Consider adding vasopressin (starting at 0.01 to 0.04 u/min) if high-dose pressors are needed
AND vasodilatory shock is present
Standard measures
 aPC

24 microg/Kg/hr for 96 hours (4 days)
 Steroids

Hydrocortisone 50 mg IV every 6 hours for seven days
 Tight glycemic control by infusing insulin if necessary

Serum glucose around 80 – 110 mg/dL
 Renal support as needed

CVVH or hemodialysis for renal failure
 Close monitoring of end-organ function:






pH
Lactic acid levels
Anion gap / serum HCO3SvO2
Skin, fingers, toes: color, warmth, capillary filling
Adequate MAP
Additional measures
 head tilt for the ventilated patient
 sterile precautions during central venous catheter insertion
 hand washing
 stress ulcer prophylaxis
 low tidal volumes for acute lung injury
 TV 6-8 ml/Kg
 daily ventilator weaning trials
 sedation protocols
Future directions
 interleukin-12 reduced mortality from subsequent sepsis when administered after burn
injury
 antibodies against complement-activation product C5a decreased the frequency of
bacteremia, prevented apoptosis, and improved survival
 administration of antibodies against macrophage migration inhibitory factor protected
mice from peritonitis
 electrical stimulation of the vagus nerve protects against endotoxic shock
 ?genetic identification?
References
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