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*Intensive Care Unit and Renal Unit, Ghent University Hospital, Gent, Belgium.
Correspondence to Dr. Eric Hoste, Intensive Care Unit, 2K12-C, Ghent University Hospital, De Pintelaan 185, 9000 Gent, Belgium. Phone: 32-9-240-27-75; Fax: 32-9-240-49-95;
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Abstract |
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Introduction |
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Analysis of a well-described subgroup of ICU patients (e.g., patients after cardiac surgery or sepsis patients) can reveal more precise information concerning the epidemiology and risk factors for development of ARF.
Sepsis is a common condition with an annual death toll in the United States comparable to that of acute myocardial infarction (30). Sepsis is also a well-known risk factor for the development of ARF, and 35 to 50% of ARF cases in the ICU can be attributed to sepsis (2,12,20,23 ). Mortality in this subgroup of patients is considerably higher than in other subgroups of ARF (2,20,23 ).
Despite these considerations, there are to the best of our knowledge hardly any data concerning risk factors associated with the development of ARF in patients with sepsis. Our own group found in 1993 that sepsis patients who developed ARF had more associated organ failure, more need for vasoactive therapy, and had a lower central venous pressure (CVP), despite more aggressive fluid therapy, compared with sepsis patients without ARF (31).
The aim of this study was to evaluate the incidence of ARF in critically ill patients with sepsis admitted in a surgical ICU and to identify predisposing factors leading to this condition. In addition, we evaluated the impact of the development of ARF and other organ dysfunctions during the ICU stay on outcome of this sepsis population.
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Materials and Methods |
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Data Collection
The study was designed as a retrospective cohort study. One of the authors (EH) reviewed the complete electronic ICU patient database for patients admitted during the study period. Patient files with a diagnosis of sepsis were retrieved and the individual files of each selected patient were subsequently screened to determine whether sepsis criteria were indeed fulfilled and whether there were no exclusion criteria. For every sepsis patient, two data nurses registered a set of physiologic and laboratory parameters during the first 14 d of the septic episode or when the ICU stay was shorter than 14 d, until ICU discharge or demise. For every parameter, the most abnormal value per day was registered. Need for organ support (vasoactive therapy, mechanical ventilation, and renal replacement therapy [RRT]) was scored for the whole ICU observation period. APACHE II score and predicted mortality were calculated on data collected during the first 24 h of admission (33). Additionally, the APACHE II score and the sepsis-related organ failure assessment score (SOFA) (34) were calculated daily during sepsis to evaluate the evolution of associated organ dysfunction and severity of illness. Both scores were calculated twice: once in the classical way, and once with omission of the points for renal dysfunction.
ARF was arbitrarily defined as a rise from normal creatinine (upper limit 1.0 mg/dl) to at least a serum creatinine 
2 mg/dl.
Cardiovascular dysfunction was defined as the need for vasoactive medication (epinephrine, norepinephrine, vasopressin, dopamine when administered in a dose > 5 µg/kg per min, or dobutamine), pulmonary dysfunction as need for mechanical ventilation, coagulation abnormalities when platelet count was < 150 x 103/mm3, and liver dysfunction when serum bilirubin was > 2 mg/dl.
Volume balance was calculated by subtracting urinary volume, gastric residue, and fluid loss from drains from the total volume of fluids infused (colloids, crystalloids, and dextrose).
Patient Management
All patients were treated according to an existing protocol for hemodynamic management. A minimum mean arterial pressure (MAP) of 65 to 75 mmHg was pursued; when MAP was lower, adequate fluid resuscitation was checked by means of central venous pressure or pulmonary artery occlusion pressure and corrected by crystalloid or colloid infusions. Therapy with vasoactive medication was initiated when the MAP remained < 65 mmHg. Pulmonary artery catheterization using a semi-continuous cardiac output catheter and monitor (Vigilance; Baxter Healthcare Corporation, McGaw Park, IL), was performed when the patient remained oliguric despite adequate fluid resuscitation and/or when there was need for additional vasoactive therapy. RRT was instituted in patients with acute renal failure fulfilling at least one of the following criteria: urea > 200 mg/dl; fluid overload and oligo-anuria (< 400 ml/d); bicarbonate < 15 mEq/L; or potassium > 6.0 mmol/L. The indication for RRT was independently made by the attending renal consultant, who was not involved in this analysis.
Statistical Analyses
The data are expressed as median (interquartile range). The Mann-Whitney U test and 
2 test were used for univariate analysis. A stepwise forward logistic regression model was constructed on basis of demographic, hematologic, biochemical, hemodynamic, and ventilatory variables. Variables were selected for inclusion in the logistic regression model when the difference between ARF and non-ARF patients had a significance of 0.25 or less in bivariate analysis. When variables described more or less the same (e.g., pH and HCO3-), only the variable that was most significant in univariate analysis was included in the analysis. To assess the relationship between a continuous variable and the outcome and to subsequently analyze whether a continuous variable needed to be transformed or categorized, we used a smoothing scatter plot (Lowess of fit). Goodness-of-fit of the model was assessed with the Hosmer and Lemeshow test. Additionally, the model was evaluated using receiving operating characteristic curve analysis (ROC). ROC analysis gives a graphical representation of the sensitivity and 1-specificity of the studied model to predict either mortality or the development of acute renal failure. The discriminative power is maximal when the area under the curve is 1, and there is no discriminative power when the area under the curve is 0.5. Significance was accepted for a two-sided P value of < 0.05. The statistical software package SPSS 11.0.1 (SPSS Inc. Chicago, IL) was used.
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Results |
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Aminoglycosides were used in three (10.0%) and amphotericin B in another two (6.7%) patients who developed ARF. None of the patients who developed ARF were treated with vancomycin. The proportion of patients who were treated with these nephrotoxic drugs was not significantly different from the patients without ARF. Radio-contrast media were administered in four patients (13.3%) who developed ARF and in 19 patients (12.3%) who did not develop ARF; again, this was not significantly different.
The demographic characteristics of patients who did and those who did not develop ARF are described in Table 1. There was no difference in focus of infection between patients who developed ARF and those who did not.
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Risk Factors on the First Day of Sepsis for the Development of ARF
In Table 2, the parameters of patients who did and did not develop ARF on the first day of sepsis are illustrated. Sepsis patients who developed ARF had a lower mean arterial BP, despite a higher central venous pressure or pulmonary artery occlusion pressure, received more aggressive fluid loading, and were treated in a higher proportion with vasoactive medication. Although there was no difference in the need for ventilation between both groups, patients with ARF had a more pronounced impairment of gas exchange, as reflected by a lower PaO2/FIO2 ratio. Renal function was already impaired, and metabolic acidosis was already present on the first day of sepsis in patients who developed ARF. Patients who developed ARF had a somewhat lower hematocrit, possibly explained by the more positive fluid balance causing dilution.
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Discussion |
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ARF had an incidence of 16.2% in sepsis patients admitted to a surgical ICU. This was, not surprisingly, much higher than the incidence of ARF in patients after cardiac surgery (1.1 to 7.7%) (5,14 ) and was comparable to the incidence of ARF described in a general medical ICU population (16 to 24.7%) (24,35 ). In contrast to earlier reports ARF did not occur late in the clinical course of severe illness (1); ARF, as defined in the present study, appeared on average 3 d after the beginning of sepsis. One may speculate that this shift to early development (and the absence of a late peak in the incidence for ARF) is caused by improvements in the clinical care of these patients.
Patients who developed ARF were already early in the course of their disease and more severely ill compared with patients who did not develop ARF, as illustrated by the higher APACHE II score on admission and during the first week of sepsis and by the higher SOFA score from day 2 of sepsis on. The APACHE II and the SOFA score evaluate organ dysfunction, including renal dysfunction; it is therefore not surprising that patients with ARF had a higher score in these scoring methods. When renal dysfunction was not scored, there was for both scoring methods no significant difference between the two patient groups. ARF itself was therefore the main factor that discriminated severity of illness and organ dysfunction score.
The excess mortality in patients with ARF, over that predicted by the APACHE II score, is most probably an illustration of the failure of the APACHE II system to predict mortality accurately in subgroups of ICU patients.
In univariate analysis, the incidence of ARF was significantly higher in nonsurvivors. This was, however, entirely caused by the high mortality in ARF patients with need for RRT. ARF and need for RRT are so closely related to each other that multiple logistic regression analysis probably could not identify the independent contribution of each variable, a phenomenon known as multicollinearity. The need for RRT resulted in a 6 times increased odds for dismal outcome. This is an affirmation of data from the recent literature showing that patients who needed RRT had a significantly higher mortality compared with patient groups without need for RRT (2–4,11,17,18,20,22,35 ). It underlines the importance of further research regarding the optimal timing, dose, and mode of RRT. Furthermore, this highlights the importance of a logistic regression model for prediction of ARF. When the patients at risk for development of ARF can already be identified on the first day of sepsis, greater effort can be put in measures to prevent the evolution to ARF and need for RRT; this would also potentially result in a better outcome. One could argue, however, that the decision for starting RRT in patients with ARF is not always taken on objective grounds. In our patient population, the decision was taken by the consulting nephrologist, who has not been involved in the analysis of these data.
Renal function of patients who developed ARF was already impaired in the very early course of sepsis. It seems that a certain patient group was already predestined to develop ARF, despite the fact that the fluid balance was more positive. The fact that patients who developed ARF had more need for vasoactive therapy, despite greater volumes of fluid infused, can indicate that fluid therapy was insufficient. This can be explained by a more pronounced capillary leak syndrome resulting in intravascular hypovolemia and hemodynamic instability. These circulatory abnormalities could have led to tissue hypoxia and eventually to organ dysfunction. Following this line of reasoning, early and more aggressive fluid therapy and/or optimization of cardiac output by means of dobutamine can possibly restore imbalances in renal oxygen delivery and oxygen demand and development of ARF. This is in agreement with the observation that restoration of imbalances in oxygen delivery and demand, already on admission, in patients with sepsis leads to less organ dysfunction and better outcome (36). When comparable therapy is instituted later in the course of sepsis, no benefit regarding the reduction of organ dysfunction or mortality could be found (37,38 ).
The high incidence of ARF, despite volume therapy, could also lead to an alternative conclusion: volume repletion alone could not prevent ARF in all patients; therefore, additional therapeutic measures such as activated protein C might be necessary to reduce ARF, or other organ dysfunctions and mortality in patients with sepsis may be needed (39).
On the basis of the odds ratios from the logistic regression model, the risk for ARF can already be estimated on the first day of sepsis. The risk for development of ARF was increased 6 times when the pH was < 7.30, and 7.5 times when serum creatinine was > 1.0 mg/dl. This simple model might provide an elegant and easy-to-use bedside tool for the clinician on the basis of readily available parameters, but it is obvious that it needs further prospective confirmation in larger groups of patients, preferably recruited in a multicenter setting, before it can be recommended in daily practice.
A remarkable finding in the present study was that older age was not associated with development of ARF in sepsis, although common sense would suggest the opposite. The patient sample studied had relatively few patients of older age: the upper interquartile range was 67 yr in patients without ARF and 69.5 yr in patients with ARF. Therefore, it remains an open question whether another patient population with a wider age distribution would have altered the conclusion. Data in the literature are ambiguous on this point. Two community-based studies found that older age was associated with a higher incidence of ARF (11,40 ). In a general medical ICU population and in a population of patients undergoing myocardial revascularization, age was an independent factor associated with the development of ARF in multivariable analysis (14,24,35 ). On the other hand, older age was not included in another multivariable model for prediction of ARF after cardiac surgery (5) or in a model for a group of trauma patients (10). More recently, univariate analysis could also not reveal a difference in age between patients with and without ARF in a general ICU setting (18). An explanation for the fact that older age was not associated with ARF could be that in our septic patient population the impact of the underlying diseases leading to ARF (hemodynamic instability caused by sepsis, or trauma, or preexisting cardiovascular, pulmonary, and/or renal dysfunction) is so overwhelming compared with older age that it cannot be identified as an independent factor in multivariable analysis. Another explanation could be that older patients with more co-morbidity (e.g., higher baseline serum creatinine) were excluded from elective surgery and/or admission to the ICU, leading to a selection bias.
Mechanical ventilation probably exerts negative effects on renal function (41), and some studies found an association between mechanical ventilation and ARF (10,35 ). In our patient population, pulmonary failure was however not associated with an increased risk for ARF. The high proportion of patients needing mechanical ventilation, and the impact of other risk factors for development of ARF made it less likely that mechanical ventilation could be identified as an independent risk factor in this particular study population.
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Conclusions |
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One of six patients developed ARF early during the course of sepsis, and most of them needed RRT. ARF patients were already more severely ill on admission and on the first day of sepsis and had a higher mortality compared with sepsis patients who did not develop ARF; moreover, RRT was an independent risk factor for mortality.
On the basis of this database, an easy-to-use bedside tool for identification of patients at higher risk for ARF on day 1 of sepsis was developed.
Patients who developed ARF had already a higher serum creatinine, a lower urinary volume, and more need for vasoactive therapy on the first day of sepsis, despite a more positive fluid balance. To prevent ARF, restoration of hemodynamic status should therefore be started earlier and be applied more aggressively, and awareness on low and medium care wards should be raised to stimulate early transfer to the ICU and/or early aggressive treatment. Our findings add indirectly to the evidence that the timing of therapy is crucial in patients with sepsis. Alternatively, they also suggest that besides hemodynamic resuscitation, additional therapies will be needed to prevent the development of organ dysfunction in the course of sepsis. Finally, they also underline the potential importance of the developed risk stratification system for early detection of sepsis patients at risk for ARF.
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Acknowledgments |
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). CI, confidence interval; * P < 0.05; 
P < 0.001.
