|Year : 2014 | Volume
| Issue : 3 | Page : 544-551
|Outcome of patients with acute kidney injury in severe sepsis and septic shock treated with early goal-directed therapy in an intensive care unit
Wasim Ahmed1, Javed I Memon1, Rifat Rehmani2, Abdulmajeed Al Juhaiman1
1 Department of Medicine, King Abdul Aziz Medical City, National Guard Health Affairs, Al Ahsa, Saudi Arabia
2 Department of Emergency Medicine, King Abdul Aziz Medical City, National Guard Health Affairs, Al Ahsa, Saudi Arabia
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|Date of Web Publication||9-May-2014|
| Abstract|| |
Acute kidney injury (AKI) in the intensive care unit (ICU) is commonly caused by severe sepsis and septic shock. There is limited data regarding the incidence and outcomes of patients developing AKI treated with early goal-directed therapy (EGDT). Our aim was to observe the incidence and outcomes of patients with AKI in severe sepsis and septic shock, treated with EGDT as compared with historic controls. Study subjects included all adults admitted to the ICU with a diagnosis of severe sepsis and septic shock prior to (historic controls) and after introduction of EGDT (intervention group). Two groups were compared for incidence of AKI, length of ICU and hospital stay, incidence and requirement for renal replacement therapy, serum creatinine at discharge, maximum RIFLE (Risk, injury, failure, loss, end stage) in each group and 28-day mortality. Two groups were well matched for age, sex, (April 16, 2014) and acute physiological and chronic health evaluation (APACHE) II scores. We found no significant difference in the incidence of AKI (51% vs. 46%). There was no statistical difference in any of the above outcomes, including 28-day mortality in historic controls versus patients treated with EGDT. Septic AKI is a complex syndrome. The incidence and outcomes have not improved despite advances in sepsis management and EGDT. Very early detection of septic AKI and targeted therapies may improve outcomes.
|How to cite this article:|
Ahmed W, Memon JI, Rehmani R, Al Juhaiman A. Outcome of patients with acute kidney injury in severe sepsis and septic shock treated with early goal-directed therapy in an intensive care unit. Saudi J Kidney Dis Transpl 2014;25:544-51
|How to cite this URL:|
Ahmed W, Memon JI, Rehmani R, Al Juhaiman A. Outcome of patients with acute kidney injury in severe sepsis and septic shock treated with early goal-directed therapy in an intensive care unit. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2020 Jan 20];25:544-51. Available from: http://www.sjkdt.org/text.asp?2014/25/3/544/132171
| Introduction|| |
Sepsis is a severe and dysregulated response to infection, and is characterized by end organ dysfunction distant from the primary site of infection. Development of acute kidney injury (AKI) during sepsis increases patient morbidity and predicts mortality, is associated with increased length of intensive care unit (ICU) stay and hence consumes considerable health care resources.  AKI is a frequent and serious complication of sepsis in ICU patients, particularly in the elderly. Sepsis and septic shock accounts for half of the AKI cases in the ICU.  Septic AKI occurs between 15% and 20% of all ICU admissions, and the incidence has been reported to be as high as 60%. , Its mortality varies with the severity of AKI and ranges from 20% to 60%.  Septic AKI epidemiology and prognosis have remained high throughout the last ten years, and our understanding of the pathophysiology of septic AKI has remained limited. 
The pathophysiology of septic AKI is not completely understood. However, it is considered to be different from non-septic AKI and therefore requires a different approach to management.  Conventional opinion suggests that pathogenesis of septic AKI relies on hemodynamic factors (hypoperfusion, intra-renal re-distribution of blood flow leading to pre-renal azotemia) and/or damage to tubular cells that can be secondary to hypoperfusion or to toxin/ inflammation associated with sepsis leading to acute tubular necrosis and resulting in reversable loss of glomerular filtration.  Although initially reversible, persistent renal ischemia and the concentration of filtered nephrotoxins in the renal tubules results in acute tubular necrosis (ATN), which causes sustained renal impairment, cell death and delayed renal recovery that requires tissue regeneration. ,, Vigorous fluid administration in this setting is therefore aimed at reversing renal ischemia and diluting nephrotoxins, to either avert the onset of ATN or to prevent recurrent injury that might compromise renal recovery. 
Delays in antibiotic administration of more than 6 h and longer duration of hypotension after diagnosis of septic shock are associated with higher mortality and incidence of AKI.  Early effective administration of antibiotics after diagnosis of hypotension in septic shock has shown improved survival in experimental and clinical studies. 
Early goal-directed therapy (EGDT) using sepsis bundles in patients with severe sepsis and septic shock has shown that early interventions can reduce morbidity and mortality in this group of patients.  However, this land-mark study did not look specifically at AKI. Surviving sepsis campaign using sepsis bundles and EGDT has well-defined goals to be achieved within 6 h of diagnosis of severe sepsis and septic shock, including fluid and antibiotic administration.  The benefits of EGDT in survival of patients with severe sepsis and septic shock appear to arise from early recognition, protocol-directed resuscitation and restoration of a balance between oxygen delivery and oxygen demand by means of SvO 2 (mixed venous oxygen) monitoring. However, there is limited data on the incidence and outcomes of septic AKI in patients treated with EGDT. The aim of our study was to look at the incidence and outcomes of septic AKI in patients who received EGDT versus patients who were managed conventionally.
| Materials and Methods|| |
Study population and methods
The King Abdul Aziz Hospital (KAH), Ministry of National Guard, is a 260-bed, tertiary care hospital. The ICU at KAH has ten beds and accepts both medical and surgical patients. EGDT using sepsis bundles was introduced at the KAH ICU in July 2009 to improve the management of patients with severe sepsis and septic shock. Our EGDT goals include administration of bolus of intravenous fluids (IV) at 20 mL/kg, intravenous antibiotics (within 1 h of diagnosis from the ward and within 3 h from the emergency department), blood cultures taken prior to antibiotics, measurement of serum lactate, target central venous pressure (CVP) between 8 and 12, target mixed venous oxygen saturation (SvO 2 ) above 70% and mean arterial pressure (MAP) of above 65 mm Hg.
Patients admitted during 15 months prior to the introduction of this protocol served as historic controls, whereas patients admitted during the ensuing 15 months after the EGDT protocol were termed as the intervention group. Inclusion criteria included adults (above the age of 14 years, as per the hospital policy) admitted to the ICU, referred from either the emergency room or wards, with a diagnosis of severe sepsis and septic shock. Exclusion criteria included age below 14 years, AKI due to non-sepsis causes, pregnancy, trauma, acute stroke, acute coronary syndrome, acute pulmonary edema, active hemorrhage, drug overdose and patients with a "do not resuscitate" decision. Data were collected from the ICU charts and medical records for historic controls and prospectively for the intervention group. Severe sepsis and septic shock were defined as per the American College of Chest Physicians and the Society of Critical Care Medicine (ACCP/ SCCM) Consensus Conference Committee.  AKI was defined as per the RIFLE (Risk, injury, failure, loss, end stage) criteria determined by either urine output or rise of serum creatinine.  Patients were categorized to one of the first three RIFLE criteria by the end of the first 24 h of ICU admission and the maximum RIFLE achieved while in ICU. The first 24 h was chosen as the maximum intervention in the EGDT that would be carried out during this period. The two groups were compared for incidence of AKI, length of ICU and hospital stay, incidence and requirement for renal replacement therapy, serum creatinine at discharge, RIFLE at 24 h and maximum RIFLE in each group and 28-day mortality.
Institutional Review Board approval was obtained from the King Abdullah International Medical Research Center.
Data were collected on patient demographics, acute physiological and chronic health evaluation (APACHE) II score and comorbidities (diabetes, hypertension, chronic obstructive pulmonary disease, congestive heart failure, previous stroke, malignancy and transplantation). In addition, data were collected for the goals of EGDT to check compliance to the sepsis bundles.
| Statistical Analysis|| |
The data were entered into a personal computer and Statistical Package for Social Sciences (SPSS, version 17.0, Chicago, IL, USA) was used for data analysis. Descriptive statistics included frequencies and percentages for categorical variables and means, standard deviations and confidence intervals (CIs) for continuous variables. The continuous variables during the two study periods were compared by the t test, while the χ2 test was used to analyze categorical variables during the two study periods. A two-sided P-value of <0.05 was considered statistically significant.
| Results|| |
One hundred and ninety-nine patients' data were analyzed. There were 84 patients in the historic control group and 115 patients in the intervention group. Baseline demographics of the whole study population are given in [Table 1]. Mean age of the patients of the whole group was 68.2 ± 19.8 years in the control and 65.6 ± 18.8 years (P = 0.35) in the intervention group. There were 53.5% males in the historic control group versus 50% in the intervention group. The mean APACHE score was 20.6 ± 7.7 vs. 20 ± 6.0 (P = 0.50) in controls vs. intervention groups, respectively. There was no significant difference in the distribution of severe sepsis and septic shock and (April 16, 2014) of the two groups of patients at baseline.
Forty-three of the 84 (51%) and 53/115 (46%) patients developed AKI in the historic control and intervention groups, respectively. The mean age of these patients in the control group was 72.3 ± 16.4 years vs. 68 ± 15.4 years in the intervention group (P = 0.12). There were 58% males in the control group as compared with 50% in the intervention group (P = 0.39). The mean creatinine on admission to ICU was 255 ± 154 vs. 263 ± 131 μmol/L (P = 0.70). The mean APACHE II score was 22.5 ± 7.3 and 22.0 ± 6.6 in the historic control and intervention groups, respectively (P = 0.87). There was no statistical difference in the distribution of severe sepsis and septic shock in those who developed AKI. The intervention group had more diabetic patients (P = 0.014) as compared with controls, whereas the other comorbidities were equally distributed.
In terms of outcomes for patients who developed AKI in the two groups, there was no statistical difference in the mean serum creatinine at discharge from hospital (146 ± 77 vs. 135 ± 74 μmol/L, P = 0.84). There was no statistical difference in the number of patients requiring renal replacement therapy (RRT) in the two groups; however, those who required RRT remained on it longer in the intervention group (3 ± 1.7 vs. 7.0 ± 6.1, P = 0.02). Length of ICU stay was 11.7 ± 16.2 vs. 8.2 ± 7.9 days in the control and intervention groups, respectively (P = 0.07). There was no difference in the number of patients who were dialysis dependent at the time of discharge or death. There was no statistical difference in the 28-day mortality in the two groups (P = 0.67) [Table 3].
Compliance to six of seven elements of EGDT was significantly better in the intervention group [Table 2].
Patients who developed AKI as compared with those who did not in either group had longer ICU stay (9.8 ± 12.4 vs. 6.6 ± 6.5; P = 0.02) and higher mortality (42% vs. 19.5%; P = 0.001).
| Discussion|| |
In patients with severe sepsis and septic shock managed with EGDT, our study did not find any reduction in the incidence or improved outcomes of AKI as compared with historic controls.
Our control and intervention groups were well matched for age, sex, baseline renal functions, APACHE II scores and comorbidities. There was significant improvement in management as shown by our compliance to goals of EGDT in the intervention group. Mortality, length of ICU and hospital stay remained high in patients who develop AKI as compared with those who did not.
EGDT has shown reduction in morbidity and mortality in patients with severe sepsis and septic shock; however, data on the incidence and outcome of AKI treated with EGDT therapy is limited. In a retrospective analysis by Plataki et al, of the patients with septic shock treated with EGDT in a tertiary care hospital, the incidence of AKI remained very high (61%). In this study, AKI development was independently associated with delay in initiation of adequate antibiotics, intra-abdominal sepsis, blood product transfusion, use of angiotensin-converting enzyme inhibitor/angiotensin recaptor blocker and body mass index (kg/m 2 ). Higher baseline glomerular filtration rate and successful early goal-directed resuscitation were associated with a decreased risk of AKI. Hospital mortality was significantly greater in patients who developed AKI (49% versus 34%), and was comparable to our study (42% versus 19.5%). 
In the study by Lin et al, implementation of goal-directed therapy caused more rapid reversal of persistent shock (47 ± 22.8 vs. 65.4 ± 32.1 h, P = 0.006) and decrease of ICU (50% vs. 67.2%, P = 0.009) and in-hospital (53.7% vs. 71.6%, P = 0.006) mortality rates compared with non-goal-directed therapy. They found that the incidence of renal failure was less in the EGDT group versus standard treatment (38.9 vs. 55.2, P = 0.015). They concluded that rapid hemodynamic optimization caused by aggressive fluid resuscitation and less delayed vasopressor administration in the goal-directed therapy group may therefore prevent the development of major organ dysfunction, such as central nervous system and AKI.  However, this study does not give details as to how the AKI was diagnosed and other outcomes measures related to AKI, as described in detail in our study.
If hypoperfusion and reduced renal blood flow were the major determinants in the development of AKI, then one would hope that with aggressive fluid resuscitation and maintained mean arterial pressure as suggested in the EGDT would prevent or at least shorten the duration of AKI. A small cohort study where renal blood flow was measured in patients with sepsis reported that renal blood flow was either preserved or increased in these patients.  Furthermore, studies of animal models of induced gram negative bacteremia and sepsis have shown renal vasodilatation and increased renal blood flow. Despite this increase in renal blood flow, creatinine clearance decreased significantly and serum creatinine increased approximately four fold. , These findings suggest that AKI, which occurs during sepsis, may actually be a hyperemic injury.
The reasons for lack of improved outcomes in our study could be multifactorial. This may be due to late presentation of patients or late recognition of severe sepsis and septic shock. However, it has been suggested that the prevention strategy is difficult to implement in sepsis because significant renal damage may already have occurred before the overt signs and symptoms of severe sepsis and septic shock appear.  According to the RIFLE criteria, AKI can be diagnosed by small changes in serum creatinine or acute reductions in urine output. Because of such sensitivity, the RIFLE criteria have enabled us to diagnose AKI in its relatively early stages. Nevertheless, when creatinine is rising and renal injury has been detected, some of the interventions may still lack efficacy because of the loss of an appropriate therapeutic window.  For this reason, an even earlier detection of renal injury before any functional abnormalities manifest may be required to deliver therapies at a sufficiently early time during the process of renal injury. One potential solution is the use of early biomarkers of renal injury.  Recently, molecules such as kidney injury molecule1 or neutrophil gelatinase-associated lipocalin (NGAL) demonstrated a good correlation with subsequent kidney damage and hence their potential in assisting not only with diagnosis but also with earlier therapeutic interventions.  The same molecule was observed to increase in the urine and plasma of children with AKI after cardiac surgery.  Increased levels of IL-18 predict deteriorating renal function approximately 24-48 h before the clinically significant AKI. 
There was no difference in patients' requirement of RRT in our two groups; however, the duration of RRT was significantly higher in the intervention group. EGDT involves liberal administration of intravenous fluids in an attempt to achieve target CVP. It is now increasingly recognized that positive fluid balances in the order of 5-10% of body weight are associated with worsening organ dysfunction in the critically ill, with no beneficial effects on renal function. In addition, these studies have shown an association between a positive fluid balance and an increased risk of AKI and non-recovery of renal function in AKI. , These studies have shown that a positive fluid balance was associated with increased mortality in patients who developed AKI.
An additional link between lung function and kidney injury was demonstrated in the randomized trial of conservative versus liberal fluid management in patients with established acute lung injury.  The conservative strategy resulted in fewer ventilator days and shorter ICU stays. There may be some concerns that this might compromise renal perfusion and cause or aggravate kidney injury. The conservative group did have higher levels of creatinine and urea; however, the trend was for dialysis treatments to be more common in the liberal strategy, suggesting that improved lung function and oxygenation was beneficial to the kidneys and other extrapulmonary organs.  Caution is now being advised on fluid management in these patients, and the advice is to avoid excessive positive balance.
While EGDT is the recommended protocol across many ICUs in the world and has shown significant improvement in outcomes of patients with severe sepsis and septic shock, the incidence and outcomes of AKI with EGDT remain largely unchanged. Despite extensive research and progress in this field, the under-lying pathology of septic AKI is not completely understood and the incidence as well as mortality of septic AKI remains unacceptably high.  Septic AKI is not a single disease but rather a syndrome comprising of multiple clinical conditions. The development of AKI is the consequence of complex interactions between the actual insult, hemodynamic instability and subsequent activation of inflammation and coagulation.  Contrary to the conventional view, recent experimental and clinical data argue against renal ischemia-reperfusion as a main mechanism for the development of AKI. Loss of renal function can occur without histological signs of tubular damage or even necrosis. 
Further research is needed to develop measures to recognize sepsis-induced AKI very early in the disease process, which can guide us to the most appropriate therapeutic interventions. This may improve outcomes in this group of critically ill patients with high morbidity and mortality.
Conflict of Interest: None
| Acknowledgments|| |
The authors would like to thank their colleagues from the King Abdullah International Medical Research Center, Dr Abdul Salaam for his input to the study design and Mr. Mohammad Al Arab for his help with data collection.
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Dr. Wasim Ahmed
Department of Medicine, King Abdul Aziz Hospital, Ministry of National Guard Health Affairs P.O. Box 2477, 31982 Al Ahsa
[Table 1], [Table 2], [Table 3]
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