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Urosepsis: Definition, Diagnosis, and Treatment

Definition of Urosepsis

Urosepsis is a life-threatening clinical syndrome in which complex physiological and biochemical changes to an infection of the urinary tract or male genitals lead to organ dysfunction (Singer u.a., 2016) EAU Guidelines Urological Infections

Development of Sepsis Definitions:

The understanding of sepsis is subject to constant evolution. The previous definitions of sepsis (post hoc referred to as "sepsis-1" and "sepsis-2") accounted for an excessive inflammatory response ("cytokine storm") for the pathogenesis. Recent studies confirm the importance of induced host response and organ dysfunction. This paradigm shift was essential for revising the current definition of sepsis (Weis et al., 2017).

Classic Sepsis Definition ("Sepsis-2" 2001)

Sepsis is a life-threatening systemic inflammatory response reaction (SIRS, see below) to a confirmed or suspected bacterial infection (Hotchkiss et al., 2003).

Systemic inflammatory response syndrome (SIRS):

SIRS is an inflammatory response affecting the whole organism due to significant infection or damage to the organism. SIRS is present, if two or more of the following criteria are met:

• Tachykardia: heart rate > 90/min
• Tachypnea: high respiratory rate > 20/min or
  hyperventilation (pCO₂ < 33 mmHg)
• Fever (> 38℃) or
  hypothermia (< 36℃)
• Leucopenia (< 4000/μl) or
  leucocytosis (> 12000/μl) or left shift with > 10% immature neutrophile granulocytes

Severe sepsis:

Severe Sepsis is the presence of sepsis criteria with at least one sign of acute organ dysfunction:

• Encephalopathy: limited vigilance, disorientation, restlessness, delirium.
• Thrombocytopenia: within 24 h, drop in platelets by more than 30% or platelet count < 100000/μl (no acute bleeding or immune system disease)
• Hypotension (systolic blood pressure < 90 mmHg or mean arterial blood pressure < 70 mmHg for at least one hour despite adequate fluid resuscitation without other causes for shock. This corresponds to the definition of septic shock.
• Hypoxia: PaO₂ < 75 mmHg without explaining cardiac or pulmonary diseases
• Acute renal failure: diuresis < 0.5 ml/kg body weight per hour for at least two hours despite adequate fluid resuscitation or increased serum creatinine by double the reference range
• Metabolic acidosis: BE < -5 mmol

Current Sepsis Definition ("Sepsis-3" 2017)

Sepsis is defined as a life-threatening organ dysfunction caused by an inadequate host response to an infection. Since the new definition includes organ dysfunction, every sepsis now fulfills the old term "severe sepsis" criteria. With the new definition of sepsis, a quick sepsis-related organ failure assessment score was introduced for everyday clinical practice (quick-SOFA, qSOFA) that allows early and rapid identification of patients with infections that are at increased risk of organ failure and mortality (Singer et al., 2016):

• Glasgow Coma Scale of ≤14
• Respiratory rate ≥22/min
• Hypotension with systolic arterial blood pressure < 90 mmHg

The presence of 2–3 qSOFA criteria indicates a severe course of infection with an increased risk of mortality and is a good predictor of the need for intensive care (Weis et al., 2017). A more accurate determination of the organ dysfunction and, thus, of the prognosis can be determined with the aid of the SOFA score, which is more complex and requires numerous serum parameters for the calculation.

Epidemiology of Sepsis

The incidence of severe sepsis is 3/1000. The mortality of sepsis amounts to 20%. Urosepsis has a better prognosis than other forms of sepsis, probably because of the possibility of effective causal therapy.

Etiology and Pathogenesis of Sepsis

Etiology of Urosepsis

Bacterial Infections of the Urogenital Tract:

Pyelonephritis, renal abscess, infected hydronephrosis, bacterial prostatitis, epididymitis, Fournier gangrene.
Responsible bacterial organisms: E. coli, Klebsiella, Enterobacter, Serratia, Proteus, Pseudomonas, Enterococcus.

Other Causes of Sepsis (Differential Diagnosis)

Cardial infections:

Endocarditis. The bacterial spectrum is diverse: Streptococcus viridans, Enterococcus, Staphylococcus, Pseudomonas, Candida.

Respiratory infections:

Pneumonia, pleural empyema, mediastinitis, lung abscess. Bacterial spectrum: Pneumococcus, Staphylococcus, anaerobes in case of aspiration, enterobacteria, tuberculosis, Candida, Aspergillus.

Infections of the digestive tract:

Peritonitis, liver abscess, cholecystitis, cholangitis, necrotizing pancreatitis. Bacterial spectrum: E. coli, Enterobacter, Salmonella, Campylobacter, anaerobes, Enterococcus, Staphylococcus, Candida.

Infections of the ENT tract:

Tonsillitis, oral cavity floor phlegmone. Bacterial spectrum: Streptococcus pyogenes, Staph. aureus.

Infections of the CNS:

Meningococcal meningitis (sometimes with Waterhouse-Friedrichsen syndrome).

Dermal infections:

Erysipel, impetigo, dermal abscess. Bacterial spectrum: Streptococcus, Staphylococcus.

Nosocomial infections:

Catheter-associated infections (central venous catheter, bladder catheter), implants, wound infection, pneumonia. Diverse bacterial spectrum.

Pathogenesis of Urosepsis

Immune system response:

Patients with sepsis present with an initial excessive immune response, followed by immunosuppression. Causes for the transition from hyperinflammation to immunosuppression are the depletion of proinflammatory cytokines, lymphocyte apoptosis, and the formation of anergy. Several genetic risk factors that influence the immune system are known, which increase the case fatality rate of sepsis.

Hyperinflammation:

The presence of the bacteria induces an excessive immune response, which causes significant damage to the host organism. Although the responsible cytokines are partially known (TNF-α, interleukin 1 and 2, interferon-γ), clinical trials to block these cytokines have failed to improve the prognosis of sepsis.

Immunosuppression:

The following signs indicate immunosuppression: lack of delayed hypersensitivity reaction, limited ability to remove the infection and predisposition to nosocomial infections. Immunosuppression is associated with decreased secretion of proinflammatory cytokines in response to bacterial antigens (see below). Furthermore, anti-inflammatory cytokines are increasing (e.g., interleukin 4 and 10). The stimulation of the immune reaction with interferon-γ may lead to an improvement of the prognosis. Sepsis can begin immediately in this immunosuppressive state, this correlates with reduced symptoms (no fever) and a poor prognosis.

Cellular mechanisms of organ dysfunction:

Autopsy studies failed to identify microscopic changes in kidney, myocardial, or liver cells that could explain pronounced organ dysfunction with mortality. Cell dysfunction ("cell stunning or cell hibernating") is explained by the influence of the cytokines and metabolites of sepsis, which disturb the body cell's mitochondrial function and energy production. The following metabolic shutdown and organ dysfunction can largely recover after the survival of sepsis.

Signs and Symptoms of Urosepsis

Local symptoms:

Local symptoms depend on the underlying disease causing urosepsis (see above).

General symptoms of urosepsis:

Fever, chills, hyperventilation, tachycardia, and hypotension are the classic symptoms. Hypothermia indicates a poor prognosis. Furthermore, altered mental status, somnolence, oliguria, or anuria.

Diagnosis of Urosepsis

Vital signs:

Heart rate, blood pressure, respiratory rate, urine output, and vigilance are essential for assessing the prognosis and initiating intensive care measures.

Urine culture:

Collect urine culture before starting calculated antibiotic treatment, e.g., when inserting a bladder catheter, ureteral splint, or nephrostomy.

Blood cultures:

Collect blood cultures before starting calculated antibiotic treatment.

Further microbiological diagnosis:

Before starting a calculated antibiotic, depending on the suspected infection: sputum, stool, wound secretions, cerebrospinal fluid.

Laboratory tests:

Blood count, coagulation tests with AT III and fibrinogen, CRP, liver parameters, creatinine, blood gas analysis, procalcitonin as a marker for sepsis.

Imaging in Urosepsis:

Ultrasound of the urogenital organs, abdominal CT scan, and chest X-ray depending on the clinical situation.

Treatment of Urosepsis

Treatment of urosepsis is an emergency and requires immediate intensive care, empiric intravenous antibiotic treatment, and evaluation for a causal therapy.

Intensive Care Therapy:

Quick administration of oxygen and intravenous fluids to normalize blood pressure and oxygen saturation is essential for a good prognosis.

Oxygen and Fluid Management:

Begin with 30 ml/kg of fluid in adults in the first three hours. The aim is to create a balance between oxygen consumption and oxygen transport within six hours, shown by the normalization of central venous oxygen saturation, lactate concentration, base excess (BE), pH, and urine output.

Vasopressor therapy:

If fluids are insufficient to achieve a mean arterial blood pressure over 65 mmHg, administering vasoactive and positive inotropic substances such as noradrenaline or adrenaline is necessary.

Treatment of organ failure:

Mechanical ventilation and renal replacement procedures (hemofiltration) are often necessary.

Antibiotic treatment:

After obtaining blood cultures and cultures from other sites (see above), empiric intravenous antibiotic therapy should be started within one hour after diagnosis of sepsis: e.g., Amoxicillin/clavulanic acid combined with gentamicin, 3rd generation cephalosporins or reserve antibiotics such as imipenem or meropenem (depending on suspected resistance or severity of sepsis). Anaerobic infections are possible with peritonitis, wound infections, or Fournier gangrene and may require additional use of metronidazole. Antibiotic therapy is necessary for at least 7–14 days, depending on the clinical course.

Causal Treatment of Urosepsis

Numerous diseases causing urosepsis can be improved by surgical means. Depending on the cause, consider appropriate diagnostics in order not to overlook surgical options:

• Pyelonephritis: drain renal/pararenal abscesses, nephrectomy of a nonfunctioning kidney.
• Hydronephrosis: retrograde ureteral splint or percutaneous nephrostomy.
• Prostatitis: suprapubic catheter, drainage of abscesses.
• Fournier gangrene: radical excision of the necroses.
• Epididymitis: drain abscess and orchiectomy

References

G. Bonkat, R. Bartoletti, F. Bruyère, S. E. Geerlings, F. Wagenlehner, and B. Wullt, “EAU Guideline: Urological Infections.” [Online]. Available: https://uroweb.org/guidelines/urological-infections/

Hotchkiss und Karl 2003 HOTCHKISS, R. S. ; KARL, I. E.: The pathophysiology and treatment of sepsis.
In: N Engl J Med
348 (2003), Nr. 2, S. 138–50

Singer, M.; Deutschman, C. S.; Seymour, C. W.; Shankar-Hari, M.; Annane, D.; Bauer, M.; Bellomo, R.; Bernard, G. R.; Chiche, J.-D.; Coopersmith, C. M.; Hotchkiss, R. S.; Levy, M. M.; Marshall, J. C.; Martin, G. S.; Opal, S. M.; Rubenfeld, G. D.; van der Poll, T.; Vincent, J.-L. & Angus, D. C. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).
JAMA, 2016, 315, 801-810

  Deutsche Version: Definition und Ursachen der Urosepsis