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INTRODUCTION
Sepsis is the main cause of the development of acute kidney
injury in critical ill patients in intensive care units
(sepsis-induced acute kidney injury - SI-AKI) (responsible for
20-50% of cases of acute kidney injury in these patients) [1-2]. The
mortality rate of patients with septic shock and acute kidney injury
is high and amounts to 50-80% [3]. Epidemiological studies show that
200000 patients die annually in the United States due to sepsis [4].
Critical ill patients in intensive care units with severe sepsis,
septic shock and acute kidney failure require prolonged
hospitalization, renal replacement therapy (RRT), increased
treatment costs and have a high risk of insufficiency of other
organs/systems and adverse outcomes. These patients require team
approach, enhanced cooperation between anesthesiologists,
infectologists and nephrologists. Early detection of sepsis and
acute kidney injury, coupled with early target therapy, use of
antibiotics and initiation of appropriate supportive therapy can
correct the outcome of critical ill patients in intensive care units
[5].
Definition of sepsis
Bacteraemia is defined as the presence of bacteria in the blood of
patients. The patient's response to a bacterial infection (systemic
inflammatory response syndrome -SIRS) is defined as the presence of
≥ 2 of the following criteria: body temperature >38,0OC or <36,0OC,
heart rate>90 beats per minute, breathing frequency> 20 respirations
in minute or partial pressure of carbon dioxide - pCO2<32 mmHg, the
number of white blood cells>12 x 109/L or <4 x 109/L or the normal
number of white blood cells with>10% immature cell forms. Sepsis is
defined as the systemic inflammatory response syndrome to proven
infection caused by the bacteria, and severe sepsis as a sepsis
associated with organ function disorder - SOFA score ≥ 2 (sequential
organ failure assessment - SOFA). Severe sepsis progresses to septic
shock, which is defined as a persistent hypotension that does not
repair after resuscitation of volume with 0.9% NaCl solution of
crystalloid at a dose of 40-60 ml/kg of body mass in the first hour,
requiring the use of vasopressor norepinephrine in a dose> 5
μg/kg/min to maintain a mean arterial blood pressure–MAP ≥ 65 mmHg,
associated with clinical data for hypoperfusion (serum lactate
concentration greater than 2 mmol/l) and organ function disorder
(SOFA score ≥ 2). Refractory septic shock is defined as the need for
norepinephrine at a dose> 15 μg/kg/min in order to achieve the
target value of MAP≥65 mmHg. In intensive care units, for detecting
patients with suspected infection or proven infection and adverse
outcome, a quick SOFA score (qSOFA) is used. Patients with qSOFA ≥
2have the risk of prolonged hospital treatment and adverse outcome
(altered state of consciousness: the Glasgow Coma Scale - GCS <15,
breathing frequency ≥22 respirations per minute, serum lactate
concentration greater than 2 mmol/l. In patients with sepsis, with
qSOFA score ≥ 2, a standard SOFA score should be made to detect
organ function disorders [6]. Renal injury exists if serum
creatinine concentration increases by more than 44.2 μmol/l or 0.5
mg/dl compared to basal value, and urine output decreases below 0.5
ml/kg/h. A ratio of partial pressure of arterial oxygen to the
fraction of inspired oxygen - PaO2/FiO2 ratio <300 indicates a lung
function disorder, and GCSless than 15 for brain function disorder
[6-7].
Definition of acute kidney injury
For the definition and assessment of the severity of acute kidney
injury, clasifications RIFLE 2004(Risk, Injury, Failure, Loss,
End-stage), as well as AKIN 2007(Acute Kidney Injury Network) and
KDIGO 2012(Kidney Disease Improving Global Outcomes) are used. Based
on the AKIN classification, acute kidney injury stage 1 is defined
as an increase in serum creatinine by ≥ 26.5 μmol/l (≥0.3 mg/dl) or
as an increase in serum creatinine concentration ≥ 1.5times compared
to basal creatinine in the serum in the previous 48 hours and/or as
a urine output less than 0.5 ml/kg/h for at least 6h. Based on the
KDIGO classification, stage 1 of acute kidney injury is present in
those patients who have a serum creatinine concentration of 1.5-1.9
times compared to basal, and urine output less than 0.5 ml/kg for
6-12h. The stage 2 of acute kidney injury is characterized by an
increase in serum creatinine concentration of 2-2.9 times compared
to basal and/or urine output less than 0.5 ml/kg/h for ≥12 h. The
third stage of KDIGO classification of acute kidney injuries
indicated either by increased serum creatinine concentration ≥3
times within seven days, or increase in serum creatinine≥354μmol/l
(≥4 mg/dl), with an acute increase of 0.5 mg/dL or initiation of
RRT, and/or urine output<0.3 ml/kg/h for 24h, or anuria for >12h
[8].
INSUFFICIENCY OF ORGANS AND SYSTEMS IN SEPSIS
Acute damage and kidney impairment in sepsis
Pathophysiological mechanisms of the development of acute kidney
injury in patients with sepsis may be hemodynamic and
non-hemodynamic. Hemodynamic patho-physiological mechanisms include:
hypoperfusion of the kidneys, increased intra-abdominal pressure,
increased central venous pressure and blood stasis in the venous
system of the kidneys. In the last decade, new non-hemodynamic
pathophysiological mechanisms of the development of acute kidney
injury in patients with sepsis have been discovered: the increased
systemic and local responses of the host immune system to infection,
increased production and secretion of proinflammatory mediators,
"cytokine storm" (disturbance of the balance of proinflammatory and
antiinflammatory cytokines in favour of proinflammatory),
endothelial dysfunction of the kidney microvasculature, infiltration
of renal parenchyma with immune system cells (monocytes /
macrophages, neutrophils / leukocytes), activation of epithelial
cells of proximal tubules through activation of Toll-like receptors
- TLRs and oxidative stress (disorder of equilibrium of oxidative
and antioxidative system in favour of oxidative) [9-11].
The enhanced and uncontrolled response of the host immune system to
infection plays an important role in the development of acute kidney
injury. Microorganisms and their products/molecular structures -
pathogen-associated molecular patterns (PAMPs), such as
lipopolysaccharide, lipoteichoic acid, flagellin, DNA of the
bacteria are recognized by toll receptors [receptors that recognize
molecular structures - pattern recognizing receptors (PRRs) on the
surface of the immune system cells in the peripheral blood
(monocytes/leukocytes)]. Activation of these receptors activates the
cascade of signals that activate the transcription factors [(nuclear
factor kappa B (NFkB), activator protein 1 (AP-1), interferon
regulatory factor 3 (IRF3)], all of which results in increased
formation and release of proinflammatory cytokines. TLRs are
essential for the enhanced activation of the innate immune system of
the host to infection caused by bacteria. The immune response of the
host can be enhanced by molecules/molecular structures released from
necrotic host cells - damage-associated molecular patterns - DAMPs,
such as chromatin-associated protein high mobility group box 1 -
HMGB1 and heat shockproteins - HSP, histones and oxidatively altered
lipoproteins - oxLDL. DAMPs molecules/molecular structures bind to
TLR2/TLR4 on the surface of the cells of the innate immune system of
the host in the peripheral blood (monocytes/leukocytes) and also
stimulate the formation and release of proinflammatory mediators.
The recognition of these endogenous molecules/molecular structures
results in the development of "sterile inflammation", which
contributes to the increased and uncontrolled response of the innate
immune system of the host to the bacterial infection (a vicious
circle develops). A key role in the development of acute kidney
injury in patients with sepsis has the activation of epithelial
cells of proximal tubules by PAPMs and DAMPs molecules/molecular
structures. PAMPs and DAMPs molecules/molecular structures are
filtered into glomeruli, reach to the lumen of proximal tubules,
bind to and activate the toll-like receptors (TLR2/TLR4) expressed
on the luminal surface of epithelial cells of proximal tubules.
Previous studies have shown that the highest significance in the
induction of acute kidney damage in patients with sepsis has the
pathway of HMGB1-TLR4 signals (response of the local immune system
of the kidney). Stimulated epithelial cells of proximal tubules
increase the production and secretion of proinflammatory cytokines
(the response of the local immune system of the kidney enhances the
response of the systemic immune system to the bacterial infection: a
vicious circle develops) [9-11]. Released proinflammatory cytokines
from activated epithelial cells of proximal tubules and infiltrative
cells (monocytes/macrophages, leukocytes) induce endothelial
dysfunction, disorder of microcirculation of the kidney (peritubular
capillary network), ischemia of epithelial cells of proximal
tubules, oxidative stress, mitochondrial function disorder (reduced
ATP production) and stop the growth of epithelial cells of proximal
tubules in the G1 phase of mitosis. Two key factors involved in the
stopping of growth of proximal epithelial cells are insulin-like
growth factor binding protein 7 (IGFBP7) and tissue inhibitor of
metalloproteinase 2 (TIMP-2). The results of the research performed
so far show that the stopping of growth of epithelial cells of the
proximal tubules plays a significant role in the development of
acute kidney damage induced by sepsis [12-13]. Detection and clear
definition of pathophysiological mechanisms of the development of
acute kidney damage in patients with sepsis provides the possibility
of developing new strategies for the treatment/protection of
epithelial cells of proximal tubules [9-13].
Acute damage and function disorder of the heart in sepsis
Sepsis is an enhanced and uncontrolled response of the immune system
of the host to infection, which results in acute damage and
disorders of the function of several organs/system of organs,
including sepsis-induced cardiomyopathy - SICM. Cardiomyopathy
induced by sepsis is defined as an ejection fraction of the left
ventricle less than 50% or as a reduction in the ejection fraction
≥10% of the basal ejection fraction and the recovery of myocardial
function in two weeks. Pathophysiological mechanisms of acute damage
and function disorder of the heart in sepsis can be: hemodynamic
(reduced blood flow through coronary arteries, myocardial ischemia,
coronary microcirculation disorder and nonhemodynamic (inflammation
and infiltration of the myocardial interstitiumby cells of innate
immune system), oxidative stress, nitric oxide - NO, endothelial
dysfunction, apoptosis and necrosis of cardiomyocytes. In sepsis,
microorganisms release PAMPs molecules, such as lipopolysaccharide,
lipoteichoic acid, flagellin, and DNA/RNA. These molecules/molecular
structures are bound to specific receptors PRRs, such as TLRs on the
surface of the cells of innate immune system of the host in the
peripheral blood, but also on the surface of the cardiomyocytes.
Receptors that recognize molecular structures - PRRs play a key role
in enhancing the immune response of the host to the infection.
DAMPs, molecules/molecular structures which are released from
damaged cardiomyocytes, recognize and bind TLRs on the surface of
cardiomyocytes (TLR2/TLR4), stimulate increased formation and
release of proinflammatory cytokines (endothelial dysfunction,
increased permeability of small blood vessels of myocardial
interstitum, infiltration of myocardial interstitium with
inflammatory cells, negative inotropic effect of proinflammatory
mediators, cardiomyocyte mitochondrial function disorders, oxidative
stress, apoptosis and necrosis of cardiomyocytes). All of this
results in left ventricular dilatation with normal or low filling
pressure, development of systolic heart failure (left
ventricularejection fraction - LVEF< 50%) with normal or elevated
stroke volume and cardiac index and with possible development of
critical reduction in tissue perfusion(septic shock) [14]. Early
application of antibiotics and surgical removal of the focus (early
control of the site of infection) are crucial for the optimal
treatment of patients with sepsis (they reduce the production of
PAMPs molecules from bacteria). Optimization of the status of
volemia and cardiac function is achieved by the use of crystalloid
solution, norepinephrine, and in patients with cardiac index (CI)
<2.2 l/min/m2 administration of levosimendan is indicated (increases
the sensitivity of the myofibrils to calcium, improves left
ventricular relaxation in the diastolic phase, does not increase the
use of oxygen by cardiomyocytes and does not cause heart rhythm
disturbances) [14-15].
Acute damage and disorder of function of the liver in sepsis
The incidence of acute damage and disorder of function of the liver
in patients with sepsis ranges from 30-50%. In patients with sepsis,
two types of liver damage can develop: hypoxic hepatitis (HH), and
sepsis induced cholestasis (SIC). HH occurs as a consequence of
septic shock due to reduced hepatic perfusion and decreased oxygen
utilization by hepatocytes (due to the action of inflammatory
mediators and endotoxins) and is characterized by centrilobular
necrosis (CLN), a significant transient increase in aminotransferase
concentration in the serum in the absence of another possible cause
of necrosis of the liver cells. Clinically, it can also be
demonstrated by acute liver failure. Another important
pathophysiological mechanism of liver damage in patients with sepsis
is cholestasis. The disorder of the bile salts transport occurs as a
result of the reduced activity of the bile salt export pump (BSEP),
which is located on the canalicular side of the liver cells. The
decrease in activity is due to hypoperfusion, hypoxia, and disorder
of mitochondrial function of the liver cells: lack of ATP. SIC is
clinically manifested as a progressive increase in serum bilirubin
concentrations (increase in total bilirubin at the expense of
conjugated bilirubin) and jaundice. Due to intrahepatic cholestasis,
decreased flow and bile inflow to the lumen of the gastrointestinal
tract, there is an atrophy of the mucous membrane of the intestine,
loss of bacteriostatic action, increased bacterial translocation and
increased serum concentrations of endotoxins in these patients
(enhancement of the systemic immune response of the host to
bacterial infection) [16-17]. An important role in acute liver
damage also has the enhanced response of the systemic and local
immune system in the liver of the host to bacterial infection.
PAMPS/DAMPs molecules/molecular structures, which bind to specific
receptors - PRRs on the surface of the innate immune system cells
(monocytes, leukocytes), but also toTLRs (TLR2-TLR6) of the liver
and Kupffer cells, have a key role in the enhanced response of the
immune system of the host and induction of the gene for the
synthesis of proinflammatory cytokines, apoptosis and necrosis of
the liver cells (acute liver failure, acutisation of chronic liver
failure) [18]. The basic principles of treating acute liver damage
in sepsis are early goal-directed therapy - EGDT, volume
resuscitation, early antibiotic administration, infection site
control, vasopressor support, and restoration of liver perfusion.
Medicaments that have the potential to induce cholestasis and
hepatocellular damage should be excluded [16-18]. An important role
in the treatment of these patients also have thedifferent albumin
dialysis modalities [16-18].
Acute damage and disorder of the function of the lung in sepsis
Acute respiratory distress syndrome (ARDS) is defined as an acute
condition characterized by severe hypoxia, bilateral pulmonary
infiltrates, and absence of evidence of cardiogenic pulmonary edema.
An important role in the development of acute damage and lung
function disorders (acute respiratory distress syndrome,
non-cardiogenic pulmonary edema) has a reinforced and uncontrolled
response of the systemic and local immune system to the bacterial
infection. PAMPs and DAMPs molecules/molecular structures bind to
TLRs on the surface of the innate immune system cells in the
peripheral blood (monocytes/leukocytes), as well as on the surface
of the epithelial and endothelial cells of the alveolo-capillary
membrane of the lungs. After binding to TLRs on the target cells
(HMGB1-TLR4), the transcription factor NFkB is activated, and the
proinflammatory cytokines are increasingly produced and released.
These mediators allow the accumulation of neutrophils and T-cells,
apoptosis of epithelial and endothelial lung cells, and the
development of non-cardiogenic pulmonary edema. The disease develops
12-48h after the initial event, and is clinically manifested with a
feeling of choking and severe hypoxia. The diagnosis of ARDS is
based on four criteria: rapid onset, bilateral infiltrates on the
chest radiograph, normal cardiac function (pulmonary capillary wedge
pressure - PCWP) and PaO2/FiO2 ratio less than or equal to 200 [19].
These patients are advised to lung protective ventilation strategy -
LPVS, with low respiratory volume (tidal volume of 6 ml/kg of ideal
body weight), whereby end-inspiratory plateau pressure should be
less than 30 cmH2O using the lowest positive end-expiratory pressure
(PEEP = 5-10 cmH2O) by which the satisfactory oxygenation is
achieved (PaO22 = 55-80 mmHg or SaHbO2 = 88 -90%) [20-21]. In severe
form of ARDS (severe hypoxemia:PaO2/FiO2<80 mmHg, uncompensated
hypercapnia: pH<7.2), the therapy for extracorporeal carbon dioxide
removal - ECCO2R is indicated[22].
Acute damage and disorder of the function of the brain in sepsis
Sepsis-associated encephalopathy (SAE) is defined as a diffused
brain function disorder that arises as a result of an increased and
uncontrolled response of the host immune system to infection in the
absence of a direct central nervous system infection. In the
development of acute damage and brain function disorders, in
patients with sepsis there are included three pathophysiologic
pathways: the neuron/nerve pathway (activation of the afferent
nerves, such as vagus and trigeminal nerves), the humoral pathway
(cytokines in circulation) and the pathway of altered blood-brain
barrier (BBB). All three pathophysiologic pathways activate the
microglial cells of the brain (the first detected change in SAE).
Activated microglial cells of the brain enhance the production and
secretion of nitric oxide, cytokines and free radicals – the
reactive oxygen species(ROS), all of which results in the activation
of endothelial cells and an increased BBB permeability (vicious
circle), disorder of functions of microcirculation of the brain,
reduced cholinergic function and altered neurotransmission,
mitochondrial function disorder and brain cell apoptosis,
development of acute damage and disorder of the function of the
brain (encephalopathy associated with sepsis). Precipitating factors
include metabolic disorders and use of medicaments. The main
clinical features of acute encephalopathy caused by sepsis are:
altered state of consciousness, cognitive disorder, cramping attacks
and coma. The diagnosis of acute damage and disorder of the function
of the brain is based on neurological examination and neurological
tests, such as electroencephalography, transcranial Doppler
ultrasound, computed tomography and nuclear magnetic resonance.
Treatment of SAE consists of the application of early target
therapy, early administration of antibiotics, optimal control of the
site of infection and precipitating factors (metabolic disorders,
use of medicaments) [23].
Acute damage and disorder of coagulation in sepsis
Disseminated intravascular coagulopathy occurs in 35% of patients
with severe sepsis (sepsis-induced disseminated intravascular
coagulation - SI-DIC). An initial step in the development of DIC in
patients with sepsis is the increased accumulation of tissue factor
(TF) on the surface of endothelial cells of small blood vessels. As
part of the enhanced response of the immune system of the host to
bacterial infection, PAMPs molecules/molecular structures of the
bacteria (lipopolysaccharide, peptidoglycan) activate TLRs
(TLR2/TLR4) on the surface of the immune system cells in the
peripheral blood (monocytes, neutrophils). Activated neutrophils
enhance the production and secretion of extracellular fibers
consisting of DNA and numerous bactericidal proteins such
asneutrophil extracellular traps (NETs), which are deposited on the
surface of endothelial cells and initiate the process of
immunotrombosis. Further, DAMPs such as HMGB1 and histones, release
from the activated immune system cells and damaged tissue cells.
These molecules activate TLRs on the surface of the endothelial
cells, reduce the release of thrombomodulin (TM, anticoagulant
effect), increase TF concentration (procoagulant effect), increase
the formation and release of proinflammatory cytokines ("sterile
inflammation"), stimulate platelet aggregation, lead to blood clots
formation in small blood vessels and the development of DIC. TM is
an endothelial anticoagulant factor: it stimulates the formation of
activated protein C (APC), binds to HMGB1 and promotes its
degradation by thrombin,so it prevents/blocks the binding of HMGB1
to the receptor for advanced glycation end products (RAGE) on the
surface of endothelial cells. The TM/APC system plays a significant
role in maintaining homeostasis of thrombosis and haemostasis, and
in maintaining vascular integrity (prevents the development of DIC
in patients with severe sepsis) [24-26]. Four clinical forms of DIC
syndrome are distinguished: an asymptomatic form, a form with
positive results without bleeding and/or thrombosis, a form with
increased bleeding and a clinical form with increased thrombosis.
The use of recombinant human APC (rhAPC)is associated with a high
risk of bleeding. In clinical practice, for the treatment of DIC in
patients with severe sepsis, antithrombin III is used (a loading
dose of 6,000 IU/30 minutes followed by a continuous i.v. infusion
of 6,000 IU/day for 4 days), rhAPC (administered in the form of a
continuous i.v. infusion of 24 μg/kg/h for 96h) and recombinant
human soluble thrombomodulin (rTM). rTM is applied in patients with
SI-DIC accompanied with one or morOorgan dysfunctions, wherein a
value of the international normalized ratio (INR) is more than 1.4,
at a dose of 0.06 mg/kg/day for six days (i.v. infusion over 30
minutes/day, for six consecutive days) [24-27].
DIAGNOSIS
Indicators of sepsis
The number of leukocytes and serum C-reactive protein concentrations
represent the "gold standard" for diagnosing the infection.
Procalcitonin (PCT) concentration in serum is used to diagnose
sepsis, make a decision for the use of antibiotics, and monitoring
of the response to the applied antibiotic. The normal serum PCT
concentration is less than 0.05 ng/ml (by some authors less than 0.1
ng/ml). The serum PCT concentration below 0.5 ng/ml indicates local
infection and inflammation, with a small risk of progression and
severe sepsis (the concentration of PCT should be repeatedly checked
over the interval of 6-24h). Sepsis is possible if the serum PCT
concentration is 0.5-1.9 ng/ml (grey zone), and serum PCT
concentration ≥ 2 ng/ml indicates sepsis. It considers that PCT
elevation to 10 ng/ml indicates a severe sepsis, while level higher
than 10 ng/ml is associated with the development of septic shock. In
patients whose serum PCT concentration is ≥ 2 ng/ml, therapy with
antibiotics should be initiated immediately. The use of antibiotics
should be discontinued when the concentration of PCT in the serum
drops below 0.5 ng/ml [28-29].
Indicators of acute damage and disorder of function of the
kidnies
In the last decade, a greater number of new indicators of acute
kidney injury have been detected (indicators more sensitive compared
to serum creatinine levels): urinary neutrophil
gelatinase-associated lipocalin (uNGAL), urinary kidney injury
molecule (uKIM-1), a liver-type fatty acid binding protein (L-FABP),
urinary IL 18, TIMP-2, IGFBP-7 and cystatin C. The concentration of
uNGAL> 150 ng/ml two hours after the initial event indicates the
development of AKI. Significant role in the early detection of AKI
have the growth factors of proximal tubule epithelial cells: TIMP-2
and IGFBP-7. The combination of TIMP-2 and IGFBP-7 in the urine
showed good diagnostic performance in the early detection of the
risk of developing acute renal failure within 12 hours.
[TIMP-2]x[IGFBP-7] >0.3 (ng/mL)2/1000 was superior for risk
assessment of KDIGO stage 2 or 3 AKI when compared to simultaneously
measured plasma and urine NGAL, plasma cystatin C, urine IL-18,
KIM-1 and L-FABP [30-33].
Indicators of acute damage and disorder of the function of the
heart
Cardiac troponins (cTnT/cTnI) are used to detect damage of
myocardium caused by ischemia. An increase in troponin levels in
serum of ≥ 20% compared to baseline indicates ischemic damage of
cardiomyocytes, and values of ≥ 2 ng/ml indicate the development of
acute myocardial infarction [34]. For the diagnosis of disorder of
cardiac contractile function, natriuretic peptides (BNP, NT-proBNP)
are used. In patients with endogenous creatinine clearance greater
than 60 ml/min/1.73m2, heart failure exists if the serum BNP
concentration is greater than 100 ng/ml and the concentration of
NT-proBNP is greater than 400 pg/ml. If the endogenous creatinine
clearance is less than 60 ml/min/1.73m2, the heart failure is
indicated by a BNP concentration greater than 200 pg/ml, or
NT-proBNP greater than 1200 pg/ml [34].
Indicators of acute damage and disorder of the function of the
liver
The most significant indicators of early liver damage are
aminotransferases (ALT/AST), alkaline phosphatase (ALP), lactate
dehydrogenase (LDH), gammaglutamyl- transpeptidase (GGT), total
bilirubin, albumin, and parameters of the blood coagulation system.
For hepatocellular dysfunction, serum aminotransferases
concentrations are measured, while cholestatic liver damage is
defined by an increased concentration of ALP, conjugated bilirubin
and GGT [35]. In HH, serum bilirubin concentration is normal or
slightly increased, aminotransferase is increased up to 20 times
from the upper normal limit, LDH is also increased (LDH > 5000
IU/l), and the ALT/LDH ratio is less than 1.5. Acute damage to the
liver induced by medications (hepatocellular damage) indicates an
increase in ALT for ≥ 5 and the ratio ALT/ALP ≥ 5. Cholestasis in
patients with sepsis shows the total serum bilirubin concentration ≥
2 mg/dl (≥ 34 μmol/l) (increase of total bilirubin is at the expense
of conjugated bilirubin), increased ALP ≥ 2 times in relation to the
upper normal limit and ALT/ALP ratio ≤2 [35, 36].
Indicators of acute damage and disorders of the function of the
lung
For early detection of acute lung injury in sepsis, gas analysis
(pH, PaO2, PaCO2 and PaO2/FiO2 ratio, sometimes called the Carrico
index)are used. For the definition and classification of severity of
ARDS by PaO2/FiO2 ratio, the Berlin Classification is used. This
definition partitions patients into mild (PaO2/FiO2 200-300),
moderate(PaO2/FiO2 100-199), and severe ARDS (PaO2/FiO2<100) and no
longer includes the term ‘‘acute lung injury’’[37].
Indicators of acute damage and disorder of the function of the
brain
For early detection of acute damage and disorder of the function of
the brain, a neuron specific enolase - NSE and S100β protein are
used [38]. Studies have shown that S100β protein is a better
indicator of acute damage and brain function disorders compared to
NSE. The normal serum NSE concentration is ≤ 12.5 ng/ml, and the
serum protein S100β is less than 0.15 μg/l. On the development of
encephalopathy induced by sepsis indicate the NSE values> 24.15
ng/ml and S100β> 0.15 μg/l. Values of S100β ≥ 4 μg/l indicate a
severe form of ischemic brain damage [38].
Indicators of acute damage and disorders of the function of the
coagulation system
For early detection of DIC in patients with sepsis are used:
platelet count, prothrombin time (PT), INR, activated partial
thromboplastin time (aPTT), fibrin and fibrinogen-degradation
products (FDP), concentration of D-dimer, APC, and serum TM. PT
serves to evaluate the external pathway of activation of the
coagulation system, and aPTT to assess the activation of the
internal pathway of the coagulation system. Thrombocytopenia is an
indicator of platelet aggregation induced by fibrin. An important
role in homeostasis of thrombosis and hemostasis has a protein C
system/activated protein C. The normal concentration of activated
protein C in the serum is 1-3 ng/ml. Reduced platelet count (< 100 x
109/l), increased INR (≥ 1.2), prolonged PT (≥ 3s), decreased
fibrinogen (< 1 g/l), increased FDP (≥ 10 μg/ml), increased D-dimer
(> 1 ng/ml), decreased concentration of activated protein C (APC < 1
ng/ml) and SIRS score ≥ 3 indicate the development of DIC in
patients with severe sepsis [39].
PREVENTION AND TREATMENT
Prevention of acute damage and disorders of the function of
the kidneys in sepsis
Preventing the development of AKI include EGDT, early
administration of antibiotics, and optimal control of the site of
infection. Early target therapy involves resuscitation of volume
using crystalloid solutions of 0.9% NaCl at a dose of 20-40 ml/kg
(2000 ml 0.9% NaCl sol. i.v. inf./60 minutes), during the first
three hours of the development of septic shock (along with
hemodynamic monitoring). Early target therapy should ensure
optimal/adequate hemodynamic stability of patients: central venous
pressure (CVP) of 8-12 mmHg, MAP ≥ 65 mmHg, urine output greater
than 0.5 ml/kg/h and central venous oxygen saturation (ScvO2) ≥ 70%
in the first 6 hours from the development of septic shock. New
recommendations indicate that targeted MAP in patients with septic
shock should be 80-85 mmHg (especially in patients who had high
arterial blood pressure before the development of septic shock). If
the target value of MAP is not achieved after resuscitation of
volume with crystalloid solutions, norepinephrine (first-line
vasopressor) is used, and in patients with CI < 2.2 l/min/m2,
inotropic therapy (dobutamine, levosimendan). If hypotension is
resistant to norepinephrine, vasopressin is administered at a dose
of 0.01-0.03 IU/min. Patients receiving norepinephrine at a dose of
5 μg/min can be added vasopressin at a dose of 0.01-0.03 IU/min. A
broad spectrum antibiotic (vancomycin, beta-lactam antibiotics)
should be administered within one hour from the development of
septic shock, with pre-sampling blood for the hemoculture. A loading
dose of vancomycin is 25-30 mg/kg, and it is applied for 7-10 days,
and the target vancomycin concentration is 15-20 mg/l. In addition
to the use of antibiotics, control of the site of infection is
important [40-47]. Early targeted therapy should ensure the
restoration of effective arterial volume and perfusion of vital
organs [46, 47].
Treatment of acute damage and disorders of function of the
kidneys caused by sepsis
Critical ill patients in intensive care units with sepsis (severe
sepsis/septic shock) and acute kidney injury require dialysis
treatment (according to medical indications). Intermittent
hemodialysis is a first-line therapeutic modality in hemodynamically
stable patients with acute kidney injury for the treatment of
hyperkalemia and life-threatening hypervolemia. Continuous dialysis
modalities are indicated in hemodynamically unstable patients with
acute kidney injuryassociated with severe sepsis/septic shock, as
well as in patients with acute kidney injury associated with acute
damage and impairment of the function of other organs (heart, brain,
liver, lung). In patients with sepsis and acute kidney injury, the
severity of AKI and the presence of absolute criteria for dialysis
treatment should be assessed: resistant hyperkalemia (K+> 6.5 mmol/l
with or without electrocardiographic changes), resistant
hypervolemia (furosemide resistant edema), severe metabolic acidosis
(pH of arterial blood ≤7.15), complications of high
azotemia(uremic encephalopathy, uremic pericarditis) [48, 49].
In the absence of absolute criteria, treatment with dialysis should
be started if severe AKIis diagnosed (stage AKIN3/KDIGO3), and in
patients with severe sepsis and rapid deterioration of renal
function treatment with dialysis should be initiated at stage 2
(AKIN2/KDIGO2) (modulation of response of the systemic and local
immune system of the host on infection, clearanceof inflammatory
mediators, PAMPs and DAMPs). Prior to making a decision to initiate
treatment with dialysis in patients with sepsis and mild/moderate
AKI (AKIN 1/2, KDIGO 1/2), treatment objectives should be
considered: the severity of the clinical condition of the patient,
renal functional reserve, the potential for complications, and
clinical conditions that adversely affect the function of the
kidneys. The clinical conditions that adversely affect the function
of the kidneys are intra-abdominal hypertension and mechanical
ventilation with positive ventilation pressure, and agentsthat have
toxic effect on kidney tubules are nephrotoxic antibiotics and
radiocontrast agents [50-52].
When indication for dialysis treatment is set, it is necessary to
choose the appropriate dialysis modality, define the dialysis
prescription (dialysis dose, duration, ultrafiltration, bleeding
risk, anticoagulation type), patient monitoring, monitoring of
extracorporeal circulation (ensuring survival of the hemodialysis
filters) and evaluate the dose of dialysis delivered (percentage of
delivered/achieved dose of dialysis in relation to the given
dialysis dose). Intermittent hemodialysis is used in hemodynamically
stable patients with hyperkalemia and hypervolemia that are
life-threatening for patients. Intermittent hemodialysis does not
affect the clearance of inflammatory mediators (proinflammatory
cytokines, antiinflammatory cytokines, PAMPs / DAMPs
molecules/molecular structures). The dose of individual treatment of
standard intermittent hemodialysis should be aimed to achieve Kt/V
index ≥ 1.20 [50-55]. Critically ill patients in intensive care
units with severe sepsis/septic shock that are hemodynamically
unstable with multiple organ systems failure, increased of serum
concentrations ofinflammatory mediators (serum IL-6 ≥ 1000 pg/ml),
increased catabolism and hypervolemia require treatment with
continuous modalities of dialysis: high-volume veno-venous
hemofiltration (HVHF), continuous veno-venous hemodialysis with high
cut-offmembranes (CVVHD-HCO), continuous veno-venous
hemodiafiltration (CVVHDF) with polymethylmethacrylate (PMMA) and
standard / modified acrylonitrile 69 surface-treated (AN69ST)
membrane hemofilters [50-56]. HVHFcan be used as continuous with an
ultrafiltration rate of 50-70 ml/kg/h (35-80 ml/kg/h) for 24 hours,
or as a pulsed high-volume hemofiltration with a rate of
ultrafiltration of 85-100 ml/kg/h (100-120 ml/kg/h) for 4-8 hours
and then it can be proceeded with a standard dose of 35 ml/kg/h
[50-56].HVHF significantly reduces the concentration of inflammatory
mediators and restores the balance of the proinflammatory and
anti-inflammatory response of the immune system of the host to the
bacterial infection [50-56]. CVVHD-HCO appear to achieve
greaterclearances of middle molecular weight solutes of 20-50 kDa
[inflammatory mediators: IL1b (18 kDa), IL-6 (21 kDa), IL-10 (37
kDa); procalcitonin (13 kDa); myoglobin (17 kDa); β2-microglobulin
(12 kDa); Cystatin C (13 kDa); kappa free light chains(25 kDa)] (the
pore diameter >0.01 μm, around double than a standard
high-fluxmembrane). In clinical practice, two HCO membranes are
used: polyarylethersulfone - septeX® and
polysulfone - Enhanced Middle Molecule Clearance - EMiC. CVVHD-HCO
is used in patients with severe sepsis/septic shock and acute kidney
damage (AKIN/KDIGO stage≥ 1) at a dose of 35 ml/kg/h for 24 hours
(increased risk of albumin loss (65 kDa) and blockers
ofanticoagulation: protein C (62 kDa), protein S (69 kDa),
antithrombin III (60 kDa) [57-59].
CVVHDFwith PMMA membrane, which has the ability to adsorb the
inflammatory mediators (high capacity for cytokine adsorption), is
administered at a dose of 35 ml/kg/h, in the course of 24-72h and
provides significantly hemodynamic stability and homeostasis of the
host's systemic and local immune system responses to infection
(prevents the development of "cytokine storm"). When the
concentration of IL-6 decreases below 1000 pg/ml, treatment is
continued by standard CVVHDF with ultrafiltration of 35 ml/kg/h
[60-62]. The standard AN69ST membrane is highly permeable, and binds
heparin during the filling the extracorporeal circulation system
with heparinized saline solution (during the preparation of the
apparatus for the CVVHDF-AN69ST treatment), has a high adsorption
capacity for the inflammatory mediators (high adsorption capacity of
HMGB1 proteins) and exhibits anti-thrombogenic effects (also
referred to as an antithrombotic membrane, SepXiris®).
The modified AN69ST membrane is a surface-treated polyacrylonitrile
(AN69) hemofilter with a polyethyleneimine (PEI) layer, allowing for
incorporation of a heparin layer by priming the membrane in a
heparin-saline solution before CVVHDF, thereby significantlyreducing
local thrombogenesis when compared with the original AN69 membrane.
Also, heparin-primed AN69ST membranes are reportedly more
biocompatible with advantages in terms of inflammatory cytokine
adsorption.In patients with high risk of haemorrhage, venous
anticoagulation is not required, and in patients with normal
coagulation status for anticoagulation of extracorporeal
circulation, unfractionated heparin is used in a dose of 50% less
than the full dose [60-62]. Unfractionated heparin is used for
anticoagulation of the extracorporeal circulation as a bolus of
2,000-5,000 IU (30 IU/kg) in the arterial segment of extracorporeal
circulation after the blood-pump, and then continues with 5-10
IU/kg/h (target aPTT = 45-55s, 1.5-2 times in relation to the upper
normal limit in the blood sample before the filter).In patients with
increased risk of haemorrhage (platelet count less than 60 x 109/l,
aPTT> 60s, INR> 2), the following options are applied: dialysis
without heparin, pre-dilution method of HDF, standard or modified
AN69ST dialysis membrane, increased blood flow rate or regional
citrate anticoagulation [60-62]. In order to prevent the thrombosis
of the filter, it is necessary to monitor the "vital signs" of the
extracorporeal circulation: transmembrane pressure - TMP, pressure
in the extracorporeal circulation after the blood pump and before
the filter - Pin, pressure in the extracorporeal circulation segment
after the filter - Pv, pressure gradient - ΔP or "drop" pressure
(reduction of pressure that occurs when blood is passing through the
filter, calculated as ΔP = Pin - Pv). TMP> 250 mmHg, Pin> 200 mmHg
and ΔP> 26 mmHg indicate an increased risk of thrombosis of the
filter 63. For evaluation of the efficiency of AN69ST membrane,
serial measurement of urea concentration in effluent and blood of
patients - FUN/BUN (measurement at every 12h) is used. The filter is
effective if the FUN/BUN ratio is ≥ 0.8, and values less than 0.8
indicate the risk of thrombosis of the filter. For the assessment of
the dialysis dose of continuous renal replacement therapy, the ratio
of delivered and prescribed dose is calculated (intensity method).
CVVHDF is effective if the ratio of delivered and prescribed
dialysis is ≥ 80% (the effective treatment time should be ≥ 20h)
[64].
Recovery of renal function
The degree of recovery ofrenal function after acute damage affects
the long-term outcome of the kidney functions and patient’s
condition. One of the goals of treating patients with sepsis and
acute kidney injury is to achieve a maximum recovery of renal
function. Recovery of renal function in patients with acute kidney
injury may occur within the first seven days after initial kidney
damage (early recovery). Early recovery of renal function depends on
the severity of acute kidney injury, the duration of the acute
kidney injury episode, the patient's hemodynamic stability and the
functional reserve of the kidneys. Late recovery of renal function
can occur in the stage of acute kidney disease, within a time period
of 7-90 days after initial kidney injury [acute kidney disease
describes acute or subacute damage and/or loss of kidney function
for a duration of between 7 and 90 days after exposure to an acute
kidney injury initiating event]. Chronic kidney disease is defined
by the persistence of kidney disease for a period of >90 days [65,
66].
Renal function reserve (RFR) describes the capacity of the kidney to
increase glomerular filtration rate (GFR) in response to
physiological or pathological stimuli. Kidney stress tests are used
for the evaluation of RFR (stress tests for the assessment of
glomerular and tubular kidney function). In patients with acute
kidney injury, a furosemide stress test is used to evaluate RFR. In
critical ill patients in intensive care units, with acute kidney
injury KDIGO stage 1 or stage 2, furosemide is applied intravenous
in a dose of 1-1.5 mg/kg (1.5 mg/kg in patients who had previously
received furosemide) and diuresis is monitored for the next two
hours. The response to furosemide is appropriate if the urine output
is ≥ 200 ml/2h. If an appropriate response is not achieved, this
indicates the progression of acute kidney injury, the transition of
acute kidney injury from KDIGO2 to KDIGO 3 stage (within 14 days)
and the need for dialysis treatment. Stress test with furosemide can
also be used to evaluate the end of treatment of AKI with continuous
dialysis modalities. After completing the treatment of a continuous
dialysis modality, diuresis is monitored during the period of
4h/first-four-period. A good response is defined as the urine
output> 400 ml/4h. After thefirst four-hour period, continuous
intravenous infusion of furosemide of 0.5 mg/kg/h is included for
4h. After 24 hours from the end of intravenous infusion of
furosemide, the diuresis is monitored in a new four-hour period and
compared with diuresis from the first four-hour period.Urine output
greater than 400 ml/4h and clearance of endogenous creatinine
calculated from the volume of urine collected over 4 hours greater
than 30 ml/min indicate the absence of need for further dialysis
treatment [66-69].
CONCLUSIONS
Sepsis is a common cause of developing acute kidney injury in
critical ill patients in intensive care units. A significant role in
the development of acute kidney injury in patients with sepsis
(severe sepsis/septic shock) has a reinforced and uncontrolled
response of the systemic and local immune system to the bacterial
infection. ("cytokine storm"). PAMP molecules/molecular structures
activate TLRs on the surface of the innate immune system cells
(monocytes and neutrophils) in systemic circulation. DAMP molecules
activate TLRs on the surface of the epithelial cells of proximal
tubules and stimulate the formation of proinflammatory mediators
("sterile inflammation"), which additionally enhances the response
of the immune system of the host (vicious circle). Early targeted
therapy, early antibiotic administration, and optimal control of the
site of infection have a key role in treating patients with sepsis.
CVVHDF with AN69ST membrane statistically significantly reduces the
concentration of inflammatory mediators as well as PAMP and DAMP
molecules in serum of patients with severe sepsis, septic shock and
acute kidney injury. It is administered at a dose of 35 ml/kg/h for
three consecutive days. When the concentration of IL-6 is reduced
below 1000 pg/ml, the treatment should continue with standard
CVVHDFin accordance with medical indications. The dialysis is
effective if the FUN/BUN ratio is ≥ 0.8 and the ratio of the
delivered and prescribed dose of dialysis ≥ 80%. Early sepsis
detection, enhanced co-operation of anesthesiologist, infectologist
and nephrologist, early target therapy, early antibiotic treatment
and early dialysis therapy (continuous veno-venous hemodiafiltration
with modified AN69ST membrane) provide a greater degree of recovery
of renal function and better outcome for patients with sepsis and
acute kidney injury.
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LIST OF ABBREVIATIONS
AKI - Acute Kidney Injury
AKIN - AKI Network
AN69ST - Polyacrylonitrile (surface treated)
AP-1 - Activator Protein 1
APC – Activated Protein C
ARDS - Acute Respiratory Distress Syndrome
BBB – Blood-Brain Barrier
BESP - Bile Salt Export Pump
CI – Cardiac Index
CLN - Centrilobular Cell Necrosis
CVVHDF - Continuous Veno-Venous Hemodiafiltration
CVVHD-HCO - Continuous Veno-Venous High - Cut-Off Hemodialysis
DAMPs - Damage-Associated Molecular Patterns
DIC - Disseminated Intravascular Coagulopathy
LVEF – Left Ventricular Ejection Fraction
ECCO2R - Extracorporeal Carbon Dioxide Removal
EGDT - Early Goal-Directed Therapy
GCS - Glasgow Coma Score
GFR – Glomerular Filtration Rate
HH - Hypoxic Hepatitis
HMGB1 - High-Mobility Group Box 1
HSP - Heat Shock Proteins
HVHF – High-Volume Hemofiltration
IGFBP-7 - Insulin-Like Growth Factor Binding Protein-7
INR – International Normalized Ratio
IRF3 - Interferon-Regular Factor 3
KDIGO - Kidney Disease Improving Global Outcomes
KIM-1 - Kidney Injury Molecule
L-FABP - Liver-type Fatty Acid-Binding Protein
LPVS – Lung Protective Ventilation Strategy
MAP - Mean Arterial Pressure
NETs – Neutrophil Extracellular Traps
NFkB - Nuclear Factor kB
NGAL - Neutrophil Gelatinase-Associated Lipocalin
PAMPs - Pathogen-Associated Molecular Patterns
PaO2/FiO2 - A ratio of partial pressure of arterial oxygen to the
fraction of inspired oxygen
PCT - Procalcitonin
PCWP - Pulmonary Capillary Wedge Pressure
PEEP – Positive End-Expiratory Pressure
PMMA - Polymethylmethacrylate
PRRs - Pattern Recognition Receptors
RAGE - Receptor for Advanced Glycation End products
RFR - Renal Function Reserve
RIFLE - Risk, Injury, Failure, Loss, End-stage
ROS – Reactive Oxygen Species
RRT - Renal Replacement Therapy
SAE – Sepsis Associated Encephalopathy
SI-AKI - Sepsis Induced Acute Kidney Injury
SIC - Sepsis Induced Cholestasis
SICM - Sepsis-Induced Cardiomyopathy
SIRS - Systemic Inflammatory Response Syndrome
SOFA - Sequential Organ Failure Assessment
TF – Tissue Factor
TIMP-2 - Tissue Inhibitor of Metalloproteinases-2
TLRs - Toll-Like Receptors
TM - Thrombomodulin
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