St Luc Hospital, September 2003

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 mayactually 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 double-blind, 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.15Significant 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 (50- micro 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
• Could the pleural effusion be an empyema?
• Can the dilated kidney represent an obstructive pyelonephritis?
• Are the paranasal sinuses/teeth filled with pus?
• Is there any dead bowel in the abdomen?
• Is the ascites infected?
• Is the hematoma infected?
• Is the gallbladder infected?
• 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 HCO3-

 SvO2

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

1Rangel-Frausto MS, Pittet D, Costigan M, et al. The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. Jama 1995; 273:117-123

2American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992; 20:864-874

3Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003; 31:1250-1256

4Angus DC, Linde-Zwirble WT, Clermont G, et al. Cost-effectiveness of drotrecogin alfa (activated) in the treatment of severe sepsis. Crit Care Med 2003; 31:1-11

5Vincent JL, Bihari DJ, Suter PM, et al. The prevalence of nosocomial infection in intensive care units in Europe. Results of the European Prevalence of Infection in Intensive Care (EPIC) Study. EPIC International Advisory Committee. Jama 1995; 274:639-644

6Annane D, Aegerter P, Jars-Guincestre MC, et al. Current epidemiology of septic shock: the CUB-Rea Network. Am J Respir Crit Care Med 2003; 168:165-172

7Williams DL, Ha T, Li C, et al. Modulation of tissue Toll-like receptor 2 and 4 during the early phases of polymicrobial sepsis correlates with mortality. Crit Care Med 2003; 31:1808-1818

8Holmes CL, Russell JA, Walley KR. Genetic polymorphisms in sepsis and septic shock: role in prognosis and potential for therapy. Chest 2003; 124:1103-1115

9Mira JP, Cariou A, Grall F, et al. Association of TNF2, a TNF-alpha promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study. Jama 1999; 282:561-568

10Mavrommatis AC, Theodoridis T, Economou M, et al. Activation of the fibrinolytic system and utilization of the coagulation inhibitors in sepsis: comparison with severe sepsis and septic shock. Intensive Care Med 2001; 27:1853-1859

11Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003; 348:138-150

12Warren BL, Eid A, Singer P, et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. Jama 2001; 286:1869-1878

13Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368-1377

14van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001; 345:1359-1367

15Schiffl H, Lang SM, Fischer R. Daily hemodialysis and the outcome of acute renal failure. N Engl J Med 2002; 346:305-310

16Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. Jama 2002; 288:862-871