Acute Kidney Injury As Indicator Of Septic Shock Biology Essay

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Sepsis results from an individual response to external infection, which begins with systemic inflammation initially, followed by coagulation abnormalities and finally deranged fibrinolysis.1 Systemic inflammatory response syndrome (SIRS) is expressed as fever or hypothermia, tachycardia, tachypnea which may be associated with leukocytosis or leucopenia. SIRS generates wide spread inflammatory reaction in body in response to external insult which is protective for an individual when its effects are restricted to pathogens, in other situations inflammatory reactions are deleterious when they are directed against normal tissues in addition to pathogens. SIRS can result from numerous conditions but termed as Sepsis, only when infection sets in and infective agent is detected. When sepsis causes one or more organ dysfunction, the syndrome is termed Multiple Organ Dysfunction Syndrome (MODS) or severe sepsis. Sepsis-induced hypotension which is refractory to fluid boluses is termed Septic shock. Hypothermia associated with septic shock indicates poor skin and splanchnic perfusion, is commonly associated with poor prognosis and high mortality rates of up to 30 to 40 %.14

Several serum biomarkers suggested having diagnostic or prognostic value in septic shock, but a definitive biomarker for routine clinical use is yet to be identified. One such marker is serum lactate which indicates marked hypoperfusion and tissue hypoxia in septic shock. Similarly serum Creatinine should also be considered as marker of decrease organ perfusion in sepsis and Acute Kidney Injury should be regarded as indicator of ongoing organ damage and likely possibility of onset of septic shock.

AKI is due to sudden and drastic reduction in kidney function (within 48 hours) characterized by absolute increase in serum Creatinine (>50% from baseline) or a reduction in urine output (oliguria of < 0.5 ml/kg/hour for > 6 hours).22 Renal hypoperfusion and ischemia during septic shock damages renal tubules leading to acute tubular necrosis (ATN) and have been demonstrated to be a common etiologic factor for AKI development during sepsis [4,5]. ATN was found to be a consistent histopathological finding in these patients, this would strongly suggest that ischemia and renal tubular cell necrosis are probably an important pathogenetic mechanism.[6,7]

Acute kidney injury have marked impact on the outcome of critically ill patients. Disease severity scores such as the Acute Physiology and Chronic Health Evaluation (APACHE II) and Sequential Organ Failure Assessment score (SOFA)[1,2] both have included renal dysfunction as predictor of morbidity and mortality; on the other hand liver dysfunction scores, coagulopathy, platelets and other vital organ functions are not much stressed in APACHE II scoring system. To establish a uniform definition of renal damage, RIFLE classification was formulated which characterizes Risk, Injury, Failure, Loss and End-stage Kidney (RIFLE) [11]. An important aspect of the RIFLE classification is that it grades the severity of acute kidney injury on the basis of changes in serum creatinine and urine output from the baseline condition.

Urine output is an important physiologic sign of body fluid status, and fluid imbalance is common in critically ill patients due to extravasation of fluid into extravascular space or due to third space losses and finally the renal dysfunction. This further suggest that reduced organ perfusion in septic shock plays a central role in development of AKI leading to reduced creatinine clearance and increased serum creatinine levels. In this study we compared increasing serum creatinine levels with plasma lactates and SOFA scores to detect onset of sepsis and septic shock and to test the hypothesis that ongoing acute kidney injury can indicate reduced organ perfusion and onset of septic shock in critically ill patients.

Patients and Methods:

This study was carried out to find a correlation between rising serum creatinine levels and onset of septic shock in 115 critically ill patients admitted in ICU and were managed following Surviving Sepsis guidelines.[14] Human ethical approval was taken by the institutional review board. Informed consents were obtained from control subjects and patients or their relatives. The control groups were the healthy relatives accompanying the patient. Total 90 controls were taken, among them 65 were males and 25 females with a mean (SD) age of 36.5 (8) years. Among patient group 67 were males and 48 females with mean (SD) age 37.5 (6) years. Patients included in our study had either of the following features: (1) Clinical evidence of infection; (2) Core temperature > 38°C or Core temperature < 35°C; (3) Heart beats > 100/min; (4) Respiratory rates >30 breaths/min or need for mechanical ventilation and (5) evidence of inadequate organ function or shock within 12 hours of enrollment. Patients excluded were: (1) patients older than 80 years; (2) cardiac failure (NYHA class III or IV); (3) liver insufficiency (Child C); (4) immunosuppression (positive HIV, HBs Ag virus serologic result, Cancer).

Demographic features like age, sex, primary site of infection, infective organisms and disease severity scores including Acute Physiology and Chronic Health Evaluation Scores (APACHE II) and Sequential Organ system Failure Assessment score (SOFA) were recorded for each patient's at the time of admission in ICU and subsequently. The plasma of these patients was tested for serum creatinine and lactates levels at the time of entry in ICU, then after every 24 hours till their stay in ICU. All the samples and information used in the study were coded and patient confidentiality was preserved according to the guidelines for studies of human subjects.

Blood sample collection: First blood sample was collected prior to start of antimicrobial, adrenergic, or steroid therapy. Blood samples were collected from central venous catheter (9 ml) into tubes containing 1ml trisodium citrate (TSC) upon admission of patient to ICU and subsequently. Plasma was separated by centrifuge at 13000 rpm for 15 min. The plasma was stored at -70°C for further analysis and repeated freeze thaw of samples was avoided in order to prevent degradation of plasma.

Statistical analysis:

All data were obtained in triplicate and results of calculations are reported as means and standard deviation up to two decimal points. The data were analyzed by Bartlett's test for nonparametric analysis of variance (ANOVA) with Newman-Keuls multiple comparison post-test. The relation between serum creatinine levels, plasma lactates and APACHE & SOFA score was tested by determining the Pearson correlation coefficient (r). A P-value of less than 0.05 was considered significant. All statistical analyses were performed with the Graph Pad InStat 5.0 demo program (Graph Pad Software, San Diego California, USA).

Results:

Among 115 patients admitted in ICU during the period April 2009 to May 2010, 45 patients were of SIRS, 39 patients were in sepsis and 31 patients in state of septic shock (Table 1). Sepsis was diagnosed on the basis of specific culture reports from various possible sites of infection, including blood culture report. Out of 115 patients studied there were 67 male patients and 48 females with a mean (SD) age of 37.5 (6) years.

Mean serum creatinine levels in healthy control group was 3.85 ± 1.99µM/L, ranging from 2.17 to 9.67µM/L (Figure1). In SIRS group, the mean plasma NO2-/NO3- levels were 64.01 ± 8.7µM/L, ranging from 40.73 to 82.56µM/L. The APACHE II and SOFA score correlated linearly with plasma NO2-/NO3- levels (r2=0.91, p<0.001 for APACHE & r2=0.87, p<0.001 for SOFA; Figure2) indicating high NO2-/NO3- levels with severity of inflammation. In sepsis patients mean NO2-/NO3- levels were 77.64 ± 1.25µM/L (range 64.34 to 95.53µM/L; Figure1). Pearson's coefficient showed linear correlation of plasma nitrate levels and sepsis severity scores (r2 = 0.76, p<0.001 for APACHE and r2 = 0.78, p<0.001 for SOFA; Figure2). The mean plasma nitrate levels in patients with septic shock (101.2 ± 12.68 µM/L; range 83.73 µM/L to 135.4 µM/L; Figure1) were significantly (P < 0.01) higher than those with sepsis (77.64 ± 1.25 µM/L), SIRS (64.01 ± 8.7 µM/L) and the control group (3.85 ± 1.99 µM/L).

Detection of metabolic acidosis in arterial blood gas analysis was evaluated further by blood lactate estimation (Figure 6). Blood lactate levels were increased in SIRS group (5.2 ± 1.1mmol/L) with range from 4.9 to 5.5mmol/L. Similarly blood lactate levels in sepsis (7.8 ± 1.2mmol/L) and septic shock group (9.5 ± 1.2mmol/L) was significantly high (95% CI in sepsis 7.4 to 8.2; shock 8.9 to 10.1mmol/L). In control group mean values were 0.93 ± 0.3mmol/L (95% CI 0.8 to 1.0).

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