SEPSIS THE SERIAL KILLER

DR.MAGDY KHAMES ALY

CRITICAL CARE MEDICINE

ZMH AL BATAYEH

INTRODUCTION• SEPSIS and the multiorgan failure that often

accompanies the systemic inflammatory response syndrome (SIRS) is a leading cause of mortality in the intensive care unit. Over 750,000 patients develop sepsis annually in the United States accounting for about 10% of all intensive care unit (ICU) admissions

• In UAE no solid statistics but roughly about 7% died from infectious diseases in 2013 according to

http://global-health.healthgrove.com/l/314/United-Arab-Emirates

DEFINITIONS

SEPSIS:

Life-threatening acute organ dysfunction caused by a dysregulated host response to infection. Organ dysfunction: acute change in SOFA score ≥ 2 points from infection.

SEPTIC SHOCK:

Sepsis with hypotension requiring vasopressors to maintain MAP ≥ 65 mmHg and having a serum lactate level > 2mmol/dL despite adequate volume resuscitation.

• Further refinements in sepsis terminology may be possible when rapid diagnostic techniques become available to assess the immune status of septic patients. Functional genomics and proteomics may assist in characterizing septic patients in the future.

PATHOGENESIS• MICROBIAL FACTORS:

• Bacterial endotoxin and other bacterial components:

Bacterial endotoxin, or lipopolysaccharide (LPS) in the circulation

provokes a vigorous systemic inflammatory response. Humans are especially susceptible to the profound immunostimulant properties of endotoxin; even minute doses may be lethal.

bacterial lipoteichoic acid, lipopeptides and even sequences of bacterial and viral DNA can be detected by the immune system and activate innate immune responses.

PATHOGENESIS• MICROBIAL FACTORS:

• Bacterial superantigens

Bacterial superantigens comprise a diverse group of protein-based exotoxins from streptococci, staphylococci, and other pathogens that all share the capacity to bind to specific sites on major histocompatibility class II molecules on antigen presenting cells and activate large numbers of CD4+ T cells, bypassing the usual mechanism of antigen processing and presentation.

PATHOGENESIS

• MICROBIAL FACTORS:

• Other microbial mediators

Translocation of microbial components such as bacterial endotoxin occurs from the GI tract to the circulation during periods of severe stress and hypoperfusion of the GI mucosa. Bacterial endotoxin and perhaps other gut-derived microbial mediators might play a pathogenic role in the ongoing inflammatory process after systemic hypotension produced by infectious or noninfectious insults.

PATHOGENESIS• HOST-DERIVED MEDIATORS:

• Cytokines

Inflammatory cytokines play a pivotal role in sepsis pathogenesis. The major proinflammatory cytokines, TNF-α and IL-1β, induce their hemodynamic and metabolic effects in concert with an expanding group of host-derived inflammatory mediators that work in a coordinated fashion to produce the systemic inflammatory response.

The cytokine system functions as a network of communication signals between neutrophils, monocytes, macrophages, and endothelial cells.

The endocrine-like effect of systemic cytokine and chemokine release drives the inflammatory process and causes coagulation activation throughout the body.

PATHOGENESIS

• HOST-DERIVED MEDIATORS:

• CD4+ T helper cells

• The coagulation system

Activation of the coagulation cascade and generation of a consumptive coagulopathy and diffuse microthrombi are well-recognized events in sepsis.

• Neutrophil–endothelial cell interactions

Activated neutrophils degranulate, exposing endothelial surfaces and surrounding structures to reactive oxygen intermediates, nitric oxide, and a variety of proteases. This process contributes not only to microbial clearance but also to diffuse endothelial injury in the setting of systemic inflammation.

PATHOGENESIS

• HOST-DERIVED MEDIATORS:

• Nitric oxide

• Nitric oxide is the major endothelial-derived relaxing factor that initiates the vasodilation and systemic hypotension observed in septic shock. Nitric oxide activates guanylate cyclase, which increases cyclic guanosine monophosphate levels inside vascular smooth muscle cells. This results in systemic vasodilation and decreased vascular resistance. Excessive and prolonged release of nitric oxide results in generalized vasodilatation and systemic hypotension. In the presence of superoxide anion, nitric oxide leads to the formation of peroxynitrite and highly cytotoxic molecules, such as hydroxyl radicals and nitrosyl chloride, which then initiate lipid peroxidation and cause irreversible cellular damage.

PATHOGENESIS

• HOST-DERIVED MEDIATORS:

• Late host-derived mediators:

Macrophage migration inhibitory factor is a late mediator that activates immune cells, upregulates TLR4 expression, and contributes to lethal septic shock. This corticosteroid-regulated mediator promotes inflammation and has become a target for therapeutic agents in sepsis. The nuclear protein high-mobility group box–1 protein is released into the extracellular space with cell injury and necrosis and also participates in late-onset inflammatory phase of septic shock.

ORGAN DYSFUNCTION

• CAUSES:

• Inadequate tissue blood supply and repeated episodes of ischemia-reperfusion

• Failure of the microcirculation to support tissue maintenance may result from capillary bed hypoperfusion, blood flow redistribution within vascular beds, functional arteriovenous shunting, blood flow obstruction from microthrombi, platelet or white blood cell aggregates, or abnormal red blood cell deformability.

• Nitric oxide, reactive oxygen intermediates, inflammatory cytokines, and apoptosis inducers may directly damage endothelial surfaces.

• Endothelial swelling shifts intravascular fluid into extravascular and intracellular spaces, mechanically obstructing capillary lumens and further limiting microvascular blood flow.

• Myocardial performance and pulmonary function also diminish over the course of septic shock and may contribute to the development of MODS.

PATHOGENESIS

PATHOGENESIS

APPROACH TO SEPSIS

• “Hectic fever [meaning sepsis] at its inception is difficult to recognize but easy to treat; left unattended, it becomes easy to recognize but difficult to treat.” Machiavelli 1505

• Fully developed septic shock is a readily apparent clinical syndrome that is seldom confused with other pathologic states. However, the early phases of septic shock may be quite subtle even in carefully monitored patients. Although fever is characteristic, hypothermia may occur and connotes a poor prognosis.

• Early recognition of sepsis and septic shock risk factor is a challenge

SOFA

• The updated international guidelines use the Sequential [Sepsis-Related] Organ Failure Assessment Score to define sepsis (SOFA).

Laboratory criteria included in the SOFA focus on the presence of:

• Coagulopathy

• Hepatic dysfunction

• And/or renal dysfunction.

Other nonspecific laboratory criteria, such as peripheral white blood cell count can aid in the general diagnosis of infection but are no longer used to define sepsis or septic shock.

SOFA

QSOFA

• qSOFA & SOFA are mortality predictors, not tests for sepsis

• The SOFA score is an illness-severity score

SIRS VS SOFA AND QSOFA• Although qSOFA may be valuable in predicting sepsis-

related mortality, it performed poorly as a screening tool for identifying sepsis in the ED.

• As the time to meet qSOFA criteria was significantly longer than for SIRS, relying on qSOFA alone may delay initiation of evidence-based interventions known to

improve sepsis-related outcomes.

• SIRS might indeed be too sensitive to diagnose sepsis, and as such, it would be better to exclude SIRS from the sepsis diagnostic criteria entirely. It should be emphasized, however, that removal of SIRS from the diagnostic criteria does not equate the end of SIRS as a concept.

• Comparison with SIRS

• In the data set used to retrospectively validated the Sepsis 3 criteria:

• In ICU patients with suspected infection, SOFA (AUROC = 0.74; 95% CI, 0.73-0.76) was superior to SIRS (AUROC = 0.64; 95% CI, 0.62-0.66) for predicting hospital mortality

• In patients outside of the ICU, SOFA (AUROC = 0.79; 95% CI, 0.78-0.80) or change in SOFA score (AUROC = 0.79; 95% CI, 0.78-0.79) was similar to that with SIRS (AUROC = 0.76; 95% CI, 0.75-0.77) for predicting hospital mortality

• Therefore, SIRS is indeed not yet dead, but it will remain permanently

NEEDED ESPCIALY IN ED

Acute phase reactants/biomarkers

• C-reactive protein (CRP):

-CRP is helpful when normal but is not specific for infection when elevated. CRP can be elevated for days following surgery and will also be elevated in rheumatologic and neoplastic illnesses.

-Very high CRP levels (> 85 mg/L) is useful in distinguishing infection from non-infectious causes of acute systemic inflammation.

• Serum procalcitonin (PCT):

-PCT is an FDA approved test to aid in the risk assessment of patients with sepsis. A recent meta-analysis of studies examining confirms the value of PCT to distinguish sepsis for noninfectious causes of systemic inflammation. Levels of PCT more than 2 ng/mL is the best cutoff value in the early diagnosis of bacterial sepsis.

Management of septic shock

• The management of a patient with septic shock begins with prompt recognition of the condition and the rapid administration of appropriate antibiotic therapy as well as source control of infection.

• Attention is simultaneously given to failing organs with institution of measures including fluid resuscitation, vasopressors, blood transfusions, and inotropic agents as needed to maximize oxygen delivery.

• Patients with ARDS are managed with low tidal volume ventilator strategies to minimize damage induced by overstretching the alveoli.

• Current sepsis bundles

• Sepsis bundles to be completed within the first 3-hour

- Measure lactate level

-Obtain blood cultures prior to administration of antibiotics

-Administer broad spectrum antibiotics

-Administer 30 mL/kg crystalloid for hypotension or lactate ≥4

• Sepsis bundles to be completed within the first 6-hour

-Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation) to maintain a MAP ≥65 mmHg

-When persistent hypotension after initial fluid administration (MAP <65 mmHg) or if initial lactate was ≥4 mmol/L, re-assess volume status and tissue perfusion (repeat focused exam, measure CVP or ScvO2, bedside cardiovascular ultrasound, dynamic assessment of fluid responsiveness)

• Re-measure lactate if initial lactate elevated

• Pitfalls of current sepsis bundles

• Measurement of ScvO2 no longer a first line goal therapy.

• Measurement of central venous pressure to assess volume status.

• Administration of large volume of crystalloid.

• Delayed administration of vasopressors.

• Static fluid status measurements (i.e. Central Venous Pressure) No longer recommended as lone guiding principles as they carry limited value for measuring fluid responsiveness

• 2017 guidelines recommend the use of dynamic variables over static variables to predict fluid responsiveness (ie passive leg raise, pulse pressure variation, stroke volume variation)

Hemodynamic Management of Patients with Septic Shock

• Hemodynamic management includes:

1. Making the diagnosis of septic shock (as one differential diagnosis of circulatory shock),

2. Assessing the hemodynamic status (volume status, fluid responsiveness, need for vasopressor, or inotropic agent) including the identification of therapeutic conflicts (e.g., intravascular hypovolemiain the presence of pulmonary fluid overload)

3. Guiding therapeutic interventions.

• The hemodynamic management of septic shock

patients remains a complex challenge. There are

no SSC guideline recommendations on the

hemodynamic management for the period

following the initial 6 hours of treatment in septic

shock. A consensus conference report of the

European Society of Intensive Care Medicine

(ESICM) can provide guidance on how to perform

hemodynamic monitoring in critically ill patients

with circulatory shock

SEPSIS BUNDLE VS EGDT

• Sepsis bundles after multicenter randomized clinical trials on EGDT:

Three recent multicenter randomized studies (ProCESS, ARISE and ProMISe) have shown that EGDT using ScvO2 did not reduce all-cause mortality.

• EGDT for Sepsis, Seen Through PRISM:

The PRISM analysis included a total of 3,723 patients at 138 hospitals in seven countries, with a subgroup analysis of the sickest patients included in the three trials.

PRISM AND EGDT

• Investigators found:

-90-day mortality was statistically identical for EGDT (24.9%) and usual care (25.4%)

-EGDT was associated with more ICU days (mean 5.3 days vs. 4.9 days) and vasoactive drug use (1.9 days vs. 1.6 days)

-There were higher costs with EGDT

-No benefit from EGDT for patients with worse septic shock (higher lactate levels, predicted mortality, or with combined hypotension and hyperlactatemia)

-PRISM's sickest one-third of patients by risk scoring had a 45% mortality in both the EGDT and usual care arms, and was 4x the size of the entire 2001 EGDT trial.

• Beyond the sepsis bundles, the prognosis of septic shock is

tightly linked to the earliness of both appropriate antibiotic therapy and early aggressive hemodynamic resuscitation.

• This includes administration of fluids and of vasopressors in order to target a MAP >65 mmHg, which remain the cornerstone of the management of septic shock patients. Nevertheless, the implementation of sepsis bundles results in a decrease in mortality and to better outcomes in septic shock patients. These benefits mainly depend on the compliance with the sepsis bundles, highlighting the importance of dedicated educational programs.

KEY POINTS• Early recognition of sepsis and patient at risk is the major

challenge

• Early administration of antibiotic and control of infection is the most important

• Early aggressive hemodynamic resuscitation also the main factor in improving patients outcome.

• Fluids vs vasopressors which one first or both together in aggressive hemodynamic resuscitation need more study to validate

• Amount of fluids given how much? How to assess?

• SIRS still needed, qSOFA not enough to assess SEPSIS in ED

• No single biomarker is enough to diagnose SEPSIS, combined biomarkers and developing score for diagnosis is needed