Sepsis A41.9

Sepsis (SIRS+infection; SIRS= systemic inflammatory response syndrome) is a complex (misdirected) systemic inflammatory host response to an infection (usually bacteria, more rarely fungi, parasites or viruses) in which pathogens enter the bloodstream from a focus, continuously or periodically.

The terms "sepsis, severe sepsis and septic shock" define a disease continuum that is defined by a combination of vital parameters, laboratory values, hemodynamic data and organ functions (Martin GS et al. 2003).

As a fatal consequence of sepsis, life-threatening (multi)organ failure can occur due to a malfunctioning immune response of the host to the infection and its inability to limit the infection.

Depending on the clinical severity, a septic process is classified as follows:

• Sepis: Life-threatening infection in which pathogens are continuously or intermittently introduced into the bloodstream.
• Severe sepsis (in addition to bacteremia) is accompanied by symptoms of organ failure.
• Septic shock: Persistent drop in blood pressure despite sufficient fluid intake

Basically, the following terms must be distinguished in the environment of septic processes:

• Bacteremia (also called bloodstream infection, refers to the infiltration of bacteria into the bloodstream. In contrast to sepsis, bacteria can be detected in the blood culture, but the patient does not show any clinical signs of sepsis. Analogous to bacteremia, the terms fungemia, parasitemia and viremia are used.
• Septicopyemia (refers to the colonisation of bacteria in various organs caused by haematogenous scattering of the pathogens in the course of severe sepsis, resulting in the formation of multiple centres of inflammation (abscesses).
• SIRS: SIRS stands for "Systemic Inflammatory Response Syndrome". This is a clinical picture that is similar to sepsis. In contrast to sepsis, an infection is not detectable here.

Almost 15% of patients in intensive care units have severe sepsis, two thirds of them have septic shock.

The adjusted hospital rate in Germany is 335 sepsis cases per 100 000 inhabitants. Annual increase in sepsis cases in Germany 5.7 %. Septic shock occurs in 110 out of 100,000 people per year. The percentage of particularly severe sepsis cases has increased from 27 % to 41 % in the period 2007 to 2013.

General symptoms: Chills, fever, warm and dry skin, hyperventilation, later developing shock symptoms with:

anxiety, restlessness, tachypnea, dyspnea, cool damp and marbled skin, later clouding of consciousness, tachycardia>100/min, drop in blood pressure:<100mmHG systolic, significant edema, positive fluid balance (>20mg/kgkgKG over 24h), hyperglycaemia (plasma glucose >140mg/dl or 7.7mM/l) without diabetes.

Shock index: pulse rate/systolic blood pressure >1

Inflammation parameters
:- leukocytosis, left-shift or leukopenia-
CRP/procalcitonin increased (> 2 x above normal)

Hemodynamic parameters
:- RP < 90 or MAP < 70 mm Hg- HI (
heart index) < 3.5 l/min/m²- SvO2 <
70

Organ dysfunction
:- Hypoxemia paO2/FiO2 < 300 mm Hg- Oliguria
< 0.5 ml/kg/h-creatinine increase
> 0.5 mg/dl- Coagulation disorder
INR > 1.5- Platelets
< 105,000/µl- Paralytic
ileus, bilirubin > 4 mg/dl

Perfusion parameters
:- Metabolic acidosis -
Capillary perfusion or marbled skin

Blood collection: BB (leukocytosis >12.000/ul), INR, PTT, fibrinogen, ATIII, FSP, creatinine, Na+, K+, lactate (lactatemia >1mmol/l), CKMB, GOT, lipase or alpha amylase, CRP (>2SD above norm), procalcitonin (>2SD above norm: PCT has a higher diagnostic precision than CRP and is detectable earlier after the infectious stimulus), blood cultures (before antibiotic therapy at least 3 decreases from different blood cultures), blood cultures (before antibiotic therapy at least 3 decreases from different blood cultures). Localizations within 10 min. (positive in approx. 50% of cases)

Diagnosis: Sepsis and severe sepsis:

I Evidence of infection must be provided by microbiologic evidence (e.g., bacteremia) or by clinical criteria.

II SIRS (systemic inflammatory response syndrome). SIRS refers to a misdirected inflammatory response of the organism and includes the following symptoms:

• Fever (≥38°C) or hypothermia (≤36°C) confirmed by rectal or intravascular or -vesical measurement, tachycardia (heart rate ≥90 /min),

• Tachypnea (rate ≥20/min) o. Hyperventilation (PaCO2 ≤4.3 kPa/ ≤33 mmHg),

• Leukocytosis (≥12000/mm3) or leukopenia (≤4000/mm3), or ≥10% immature neutrophil granulocytes on differential blood count

• (At least 2 SIRS criteria must be met to define sepsis).

III Organ dysfunction.

• Symptoms of acute encephalopathy (impaired vigilance, disorientation, agitation, delirium)

• Relative or absolute thrombocytopenia (drop in platelets of more than 30% within 24 hours or platelet count ≤100,000/mm3. Thrombocytopenia due to acute bleeding or immunologic causes must be excluded).

• Arterial hypoxemia (PaO2 ≤10 kPa; ≤75 mmHg) on room air or a PaO2/FiO2 ratio of ≤33 kPa; ≤250 mmHg) on oxygen administration. Manifest cardiac or pulmonary disease must be excluded as a cause of hypoxemia.

• Renal dysfunction: A diuresis of ≤0.5 ml/kg/h for at least 2 hours despite adequate volume substitution and/or an increase in serum creatinine >2× above the locally usual reference range. Metabolic acidosis: base excess ≤-5 mmol/l or a lactate concentration >1.5× above the locally usual reference range (for the definition of severe sepsis, at least 1 criterion of III must be met in addition to criteria I+II).

Sepsis = I+II

Severe sepsis = I+II+III

Diagnosis (Septic Shock):

• Persistent drop in blood pressure despite adequate fluid intake as a result of microorganism-induced release of vasoactive mediators (assuming arterial hypotension cannot be explained by other causes).
• Vasopressor administration required to maintain mean arterial pressure ≥65 mm Hg in persistent hypotension.
• Serum lactate >2 mmol/l (>18 mg/dl) despite adequate volume substitution.
• Predisposing factors: immune deficiency, immunosuppressive therapy of all types, previous major surgery, extensive burns, extensive wounds (e.g., decubitus wounds), superinfected ulcer curis, long-standing bladder or indwelling catheters, severe general illness (e.g., diabetes mellitus, tumor disease, liver cirrhosis, AIDS), advanced age. Hospital mortality exceeds 40%.

During the diagnostic procedure, suitable material is obtained for microbiological examination. In addition, collection of 2or >2blood cultures is performed by percutaneous puncture (use aerobic and anaerobic bottle). This will also involve collecting a blood sample from each vascular access site that has been in place for longer than 48 hours. Blood samples are collected as soon as possible before starting antimicrobial therapy. Additionally, diagnostic imaging is performed without delaying the start of therapy.

Multiple organ dysfunctions (reversible) or multiple organ failure (irreversible)

• Acute renal failure: Suspension of urine production until anuria
• Lung: Acute lung injury (PaO2/FiO2<250 without pneumonia as source of infection; PaO2/FiO2<200 with pneumonia as source of infection)
• Thrombocytopenia: Platelets <100.000/ul
• Coagulation system: INR >1.5; aPTT>60sec.
• Heart failure due to reduced coronary perfusion
• Gastrointestinal damage and hepatic dysfunction (bilirubin >2mg/dl) due to reduced perfusion of the splanchnic area
• Cerebral damage due to reduced cerebrovascular perfusion
• Fulminant forms of sepsis: Toxic shoc-syndrome (TSS); Landouzy sepsis, meningococcal sepsis - Waterhouse Friedrichsen syndrome;

In the context of severe sepsis or septic shock, therapy is provided on three levels: a causal therapy aimed at remediating the focus of infection, an antimicrobial treatment according to guidelines. Early intravenously calculated therapy, which at best begins within the first hour after diagnosis of severe sepsis or septic shock at the latest.

Antibiotic therapy according to guidelines:

- Broad-spectrum antibiotic-
Evaluation of the antibiotic regimen-
Consideration of combination therapy for Pseudomonas; in neutropenic patients, combination therapy for a maximum of 3 to 5 days, followed by de-escalation depending on sensitivity-
Duration depends on the clinical response but is generally not more than 7 to 10 days

Infection focus and control:

respiratory tract (e.g. pneumonia, lung abscess
)intraabdominal (e.g. pancreatitis, cholecystitis, diverticulitis)
soft tissue (necrotising fasciitis)
foreign material (endoprostheses, osteosynthesis material, IUD)
urogenital tract (urinary catheter)
meningitis, brain abscess, endocarditis, vascular access, dental infections

Removal of vascular accesses in case of a potential catheter-associated infection, sono- or CT-guided puncture and drainage of abscesses, miracle opening and necrosectomy, removal of infected implants, amputation, in case of an acute abdomen laparotomy/laparoscopy.

A supportive therapy based on haemodynamic stabilization and airway management.

Hemodynamic stabilization:

Hemodynamic stabilization involves fluid/volume increase in hypotension and substitution of erythrocytes in severe anemia. The goals of fluid administration are
:ZVD 8 - 12 mm Hg, MAP > 65 mm Hg urinary excretion
> 0.5 ml/kg/central venous
o2 saturation > 70 % or mixed venous saturation > 65 %.

An adjunctive therapy:

- Control of blood glucose and acid-base status-
sedation/analgesia on demand -
platelet prophylaxis-
steroids (possibly in adult patients if hypotension does not improve despite volume administration and vasopression shows little improvement. No indication for septic shock)
- Recombinant activated protein C-
Ventilation in sepsis-induced ALI/ARDS-
Renal replacement therapy for renal failure

Intensive monitoring, transfer to an intensive care unit

O2 administration (initially 4-8l/min., then after BGA, if necessary intubation/ventilation

ZVK plant as soon as possible ZVD control

Volume replacement: as in hypovolemic shock (initial isotonic crystalline solutions such as Ringer's lactate or NaCl 0.9% 1000-2000ml as required (the benefit of colloidal solutions such as HAES 6% = hydroxyaethyl starch is controversial); acidosis compensation (controversial) with sodium bicarbonate (100mmol =100ml NaHCO3-8.4%) according to blood gas analysis (BGA), treatment of a consumption coagulopathy if necessary

Catecholamines: for RR<80mmHg: dopamine, dobutamine via perfusor. Early (especially with further reduced ZDV despite volume administration) Noradrenalin-Perfusor

Stress ulcer prophylaxis: with PPI or H2 antagonists

Immediate and complete remediation of the septic source of infection is the prerequisite for successful treatment of severe sepsis and septic shock. Insufficient focus sanitation is associated with increased mortality. It has been shown that the time between the onset of the septic symptoms and the initiation of sufficient measures to control the septic focus significantly determines the outcome of the patient. Surgical treatment of the foci can be achieved by the following measures, among others:

• removal of implants (catheters, vascular prostheses, osteosynthesis material, joint replacement
• Incision or CT-supported drainage of abscesses
• Miracle opening and necrosectomy, amputation and fasciotomy
• Treatment of peritonitis, anastomosis insufficiency and ileus by peritoneal lavage, drainage or enterostomy

The lethality rate for sepsis is 40 %, for septic shock up to 60 %.

The average treatment costs of sepsis are 27,467.92 euros per case. The total costs for the German healthcare system amount to approximately 7.7 billion euros.

qSOFA: Screening score for ambulance and emergency rooms: qSOFA: suspected infection + 2 of the following criteria:

• respiratory rate ≥ 22/min
• Changing the state of consciousness
• Systolic blood pressure ≤ 100mmHg

For early detection, the SIRS criteria must also be used, since qSOFA only has a sensitivity of 50-70%.

The interpretation of microbiological findings can be problematic in critically ill patients, since microorganisms are often detected that do not cause sepsis but only correspond to colonization.

Bacteremia (bacteremia = presence of microorganisms in the blood with/without clinical symptoms. The same applies to fungaemia, parasitaemia, viremia) is only found in an average of 30% of patients with severe sepsis or septic shock depending on antibiotic pre-treatment (Alberti C et al. 2002). Critically ill patients often show SIRS and multiple organ dysfunction, the causal relationship to infection cannot always be proven with certainty (Seymour CW et al. 2016).

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6. Seymour C et al (2016) Quick SOFA (qSOFA) JAMA 315:762-774
7. Seymour CW et al (2016) Assessment of Clinical Criteria for Sepsis: For the Third In