Urosepsis A41.9

Already Hippokrates described in the year 400 b.o.c. a fever, which is caused by a rotting matter. Around 1000 A.D. Ibn Sina described this as "rotting of the blood". After Koch and Pasteur established microbiology around 1860, the era of endotoxin research began at the end of the 19th century. In 1847, Ignaz Semmelweis introduced hand disinfection with chlorinated water and was thus able to reduce infant mortality immensely. (Werdan 2005). When Sir Alexander Fleming discovered penicillin in 1928 and first described it in 1929, the therapeutic era of antibiotics began in the 1940s (Schulz 2016).

Sepsis was redefined in 2016 as a life-threatening organ dysfunction caused by an inadequate host response to infection (Sepsis- 3- Definition) (Singer 2016). Urosepsis is an acutely life-threatening organ dysfunction that occurs in the urogenital tract due to the transfer of endotoxin-producing microorganisms into the bloodstream (Vater 2019 / Sökeland 2007). As the disease progresses, abscesses can also settle in other organs (Keller 2007).

Urosepsis is divided into uncomplicated and complicated urosepsis. In complicated sepsis, there are additional functional and/or structural abnormalities of the urogenital tract, such as obstructive nephrolithiasis, prostate hyperplasia, etc. (Klumm 2019). Urosepsis can develop into septic shock. One speaks of a "septic shock" if the following combination is present in addition to sepsis:

• Serum lactate > 2 mmol / l (= 18 mg / dl) plus
• despite adequate volume, persistent hypotension requires constant administration of vasopressors to maintain a mean arterial pressure of ≥ 65 mm Hg

The lethality rate here is > 40 % (Brunkhorst 2020).

Despite all the progress made, sepsis is still the most common cause of death in intensive care units and causes almost as many deaths as acute myocardial infarction (Werdan 2005). The incidence of sepsis is 335 / 100,000 inhabitants per year. Of these, about 12 % suffer from septic shock (Herold 2020). Septitides occur more frequently in men than in women (Dreger 2015). Figures specifically for urosepsis are not available.

Urosepsis is one of the 3 major causes of sepsis (pulmonary about 47%, intra-abdominal about 29%, urogenital about 12% [Herold 2020]).

Favouring factorsfor urosepsis are:

• Urinary outflow obstructions due to, for example:
  • Prostate hypertrophy
  • nephrolithiasis
  • neurogenic bladder emptying disorders (Klumm 2019)
• inflammatory changes such as:
  • Urinary tract infection (especially frequent with permanent catheterization)
  • Pyelonephritis
  • Prostatitis
  • epididymidis (Klumm 2019)
• advanced age
• malignant tumours
• diabetes mellitus
• immunosuppression (Klumm 2019)
• liver cirrhosis (Sökeland 2007)
• renal insufficiency (Haferkamp 2008)

In up to 65%, instrumental procedures in the urinary tract with existing pyelonephritis can lead to sepsis. (Herold 2020). In community-acquired sepsis, the following germs are predominantly found:

• Escherichia coli (in about 70%).
• Klebsial
• Proteus
• Pseudomonas (Schapps 2008)

In nosocomial infections:

• Proteus spp. (species pluralis)
• Klebsiella spp.
• Serratia
• rarely Staphylococci or gram-positive germs (Haverkamp 2008)

Recently, ESBL (extended-spectrum beta-lactamase) formers have increasingly been found as pathogens of urosepsis, where, on the other hand, carbapenemase-forming Enterobacteriaceae are increasingly rare (Pletz 2018).

The penetration of bacteria or their toxins into the bloodstream leads to a release of interleukin and tumor necrosis factor alpha, which, among other things, causes an activation of:

• histamine
• Bradykinin
• Prostaglandin
• Leucotrienes

These destroy the endothelial barrier in the area of the vessels so that intravascular fluid can leak into the interstitium.

Coagulation processes occur in the damaged capillaries, which can lead to disseminated intravascular coagulation (DIC) with both thrombus formation and an increased bleeding tendency.

The cardiac output is normal to slightly increased with low central venous oxygen saturation.

In order to maintain sufficient perfusion pressure, cardiac output is increased up to the maximum contractility of the heart muscle. However, the systemic vascular resistance continues to decrease, resulting in diastolic hypotension and ultimately myocardial failure.

The opening of arteriovenous shunts impedes the oxygen supply. This leads to tissue hypoxia, an increase in lactate and acidosis (father 2019).

Urosepsis can occur at any age, even in infants (Beetz 2017). However, it predominantly occurs at an advanced age (mean age is 67 years)(Dreger 2015).

As this is a life-threatening clinical picture, the diagnosis should be made as early as possible. For this purpose, the so-called qSOFA score (quick Sequential [Sepsis-Related] Organ Failure Assessment [Singer 2016]) was developed:

• Glasgow Coma Scale < 15
• Respiratory frequency ≥ 22 / min
• Hypotension: RR systolic ≤ 100 mm Hg

1 point is awarded for each existing criterion.

At ≥ 2 points should be given for the infection focus. Hospital mortality is > 2 points up to 14 times higher than a score of < 2 points (father 2019). The term "SIRS" (systemic inflammatory response syndrome) criteria used for sepsis 1.2 is no longer used (Herold 2020).

The following symptoms may be present in urosepsis:

• fever with chills
• Nausea
• Vomiting
• Tachycardia
• Hypotension
• warm extremities in the early stages (due to the increased cardiac output) (Keller 2007)
• in later stages, cold extremities with livedo racemosa (due to vasoconstriction)
• Tachypnea
• clouding of consciousness
• Oliguria
• Anuria
• Signs of consumption coagulopathy through activation of coagulation and increased consumption of coagulation factors) (Sökeland 2007)

Before antibiotic treatment is started, blood cultures (during fever), urine cultures and, if necessary, wound swabs should be taken to determine the pathogen and resistance (Sökeland 2007). In up to 20% of cases, however, the cause of urosepsis remains unclear (Haverkamp 2008).

Medical history: In particular, questions about:

• Previous illnesses
• Dysuria
• nocturia
• haematuria
• known nephrolithiasis (Keller 2007)

Physical examination

• palpitation of the kidney
• swelling of a testis / labia
• rectal examination in case of suspected prostatitis (Haverkamp 2008)

Sonography Sonography is the method of first choice for diagnostics (Klumm 2019).

It can be used to identify any existing obstructions or dilatations of the kidney and the urinary tract (Schaps 2008) as well as localised infections (abscesses) of the kidneys, epididymis and prostate (Haverkamp 2008).

If an abscess is present, a sonographically controlled puncture can be performed (Dreger 2015).

Computer tomography: In case of ambiguous sonographic findings a CT is helpful.

Here, further details can be given on:

• Infections
• Stenosis etc. (Haverkamp 2008)

• Analysis of:
  • Blood cultures
  • Urine cultures
  • Abscess puncture
• Blood count:
  • Leukocytosis (at the beginning, changing into leukopenia in the further course)
  • often drop in thrombocytes
• Phosphate (often hypophosphatemia) (Hautmann 2014)
• antithrombin III
• Coagulation
• Blood gas analysis (Sökeland 2007)
• CRP
• Electrolytes
• Creatinine (Knuth 2006)
• Procalcitonin (PCT is considered the best evaluated inflammatory marker [Dreger 2015]).

A negative urine culture is not an exclusion criterion for urosepsis, as the source of infection may not be drained at all in the case of urinary outflow obstruction (Haverkamp 2008).

• Endotoxin shock (for gram-negative germs)
• Occurrence of a consumer coagulopathy in the context of endotoxin shock (Hautmann 2014)

Treatment should be interdisciplinary with urologists, microbiologists and intensive care physicians (Dreger 2015). It is divided into a causal (antimicrobial treatment and focus rehabilitation), supportive (e.g. fluid administration and circulation-stabilising drugs) and adjunctive therapy (corticoids, insulin etc.) (Wagenlehner 2016).

1. causal therapy: antibiotic treatment should be given as soon as possible, since a delay of 1 hour worsens the survival rate by an average of 7.6% (Dreger 2015).

• initiate antibiotic treatment with e.g.:
  • Piperacillin / Tazobactam as monotherapy (Pletz 2018) e.g. Tazobac 3 x 4.5 g i. v. / d (Schuster 2000) or:
  • Cephalosporin of the 3rd generation in combination with an aminoglycoside e.g. Cefotaxim 3 x 2 g i. v. / d plus gentamicin 2 mg - 3 mg i. v. / kg KG / d (Pletz 2018 / Schuster 2000)
• after determination of pathogen or resistance, if necessary adjustment of the antibiotics

Antibiosis should normally be carried out for 7 - 10 days, as the risk of recurrence is high with shorter therapy duration.

In the case of Staphylococcus aureus bacteremia (SAH), some fungi, viruses and also in immunocompromised patients, an IV treatment lasting at least 14 days is recommended. In the case of complicated courses of SAH, an IV therapy lasting over 28 days is recommended (Herold 2020).

• Herd sanitation

In the case of an infected urinary stagnation kidney, this can be caused by

• ureteral splint or a
• percutaneous nephrostomy system. In a meta-analysis no superiority for either of the two methods could be found. Furthermore, these methods include:
• Abscess drainage
• Application of a transurethral bladder catheter for acute urinary retention or
• suprapubic bladder catheter for acute prostatitis, epididymidis etc. (Dreger 2015)
• Epididymectomy (Haverkamp 2008)

2. supportive therapy. Supportive treatment consists of:

• circulatory-stabilizing drugs such as:
  • Norepinephrine as a first-line treatment...
  • if necessary additionally vasopressin or epinephrine
• fluid therapy:
  • initial 30 ml / kg of crystalloids (Herold 2020), followed by fluid challenge (as long as there are signs of hypoperfusion, fluid administration is continued) (Brunkhorst 2020)
• blood transfusions
  • are recommended from an Hb value of < 7.0 g / dl
• Platelet transfusion
  • should only be done from a value of < 10,000 µl
• immunoglobulins:
  • the use of a dose should be avoided, as studies have shown no mortality reducing effect
• anticoagulants:
  • anticoagulant administration should also be avoided, as studies have not shown any definite positive results regarding survival rate
• bicarbonate:
  • bicarbonate administration is not recommended for patients with a pH of ≥ 7.15, as studies have shown no benefit in hypoperfusion-induced lactic acidemia in the context of sepsis
• invasive ventilation:
  • invasive ventilation is recommended for patients with ARDS from a VT ≤ 6ml / kg bw and for patients without ARDS with a VT of 6 - 8 ml / kg bw
• renal replacement therapy:
  • if acute renal failure occurs, continuous or intermittent renal replacement therapy is required (Brunkhorst 2020)

3. adjunctive therapy. Adjunctive treatment is carried out together with causal and supportive therapy (Dreger 2015).

• Glucocorticoids: A therapy with glucocorticoids is meanwhile controversial. The initially positive effects of high doses of corticoids in randomized studies showed in the CORTICUS study an increased mortality and the risk of superinfections by low-dose administration (Dreger 2015). According to current guidelines, treatment with glucocorticoids is now only recommended if hemodynamic stability cannot be achieved by fluid and vasopressor therapy. Dosage recommendation: Hydrocortisone 200 mg i. v. / d (Brunkhorst 2020)
• Insulin therapy: Blood sugar levels should initially be measured every 1 - 2 hours. Insulin therapy should be started when 2 consecutive measurements result in a blood sugar level of > 180 mg / dl. The target value is a blood sugar level of ≤ 180 mg / dl. (Brunkhorst 2020)
• Selenium application: An i. v. selenium administration can be considered (recommendation level C, evidence level Ia). However, the international guidelines do not recommend selenium administration. (Dreger 2015)

Mortality could be reduced from the original 56 % to up to 15 % with rapid and comprehensive treatment (Hautmann 2015).

In severe urosepsis, mortality is still between 20 % - 40 % even today. It is thus lower than in severe sepsis with 55.2%.

(Dreger 2015)

After sepsis, there can be late effects such as:

• CIP (critical illness polyneuropathy)
• CIM (critical illness myopathy)

Both have been known for more than 20 years and occur in > 70% of patients with septic shock.

In addition, there may be:

• persistent neurocognitive impairment (in about 17 %)
• post-traumatic stress (at approx. 44 %)
• Depression (at approx. 29 %) (Brunkhorst 2020)

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