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Lung-protective mechanical ventilation does not protect against acute kidney injury in patients without lung injury at onset of mechanical ventilation
Journal of Critical Care (2012) 27, 261–267
Lung-protective mechanical ventilation does not protect against acute kidney injury in patients without lung injury at onset of mechanical ventilation☆,☆☆,★ Bart Cortjens MSc a , Annick A.N.M. Royakkers MD b , Rogier M. Determann MD, PhD c , Jeroen D.E. van Suijlen PhD d , Stephan S. Kamphuis PhD d , Jannetje Foppen d , Anita de Boer a , Cathrien.W. Wieland PhD a , Peter E. Spronk MD, PhD e , Marcus J. Schultz MD, PhD, FCCP a , Catherine S.C. Bouman MD, PhD c,⁎ a
Laboratory of Experimental Intensive Care and Anesthesiology (LEICA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands b Department of Anesthesiology, Tergooi Hospitals, Blaricum, The Netherlands c Department of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands d Laboratory of Clinical Chemistry, Gelre Hospitals, Apeldoorn, The Netherlands e Department of Intensive Care, Gelre Hospitals, Apeldoorn, The Netherlands
Keywords: Acute kidney injury; Ventilator-associated lung injury; Lung-protective mechanical ventilation; Cystatin C; Neutrophil gelatinase– associated lipocalin (NGAL)
Abstract Introduction: Preclinical and clinical studies suggest that mechanical ventilation contributes to the development of acute kidney injury (AKI), particularly in the setting of lung-injurious ventilator strategies. Objective: To determine whether ventilator settings in critically ill patients without acute lung injury (ALI) at onset of mechanical ventilation affect the development of AKI. Design, Setting, and Patients: Secondary analysis of a randomized controlled trial (N = 150), comparing conventional tidal volume (VT, 10 mL/kg) with low tidal volume (VT, 6 mL/kg) mechanical ventilation in critically ill patients without ALI at randomization. During the first 5 days of mechanical ventilation, the RIFLE class was determined daily, whereas neutrophil gelatinase–associated lipocalin and cystatin C levels were measured in plasma collected on days 0, 2, and 4. Results: Eighty-six patients had no AKI at inclusion, and 18 patients (21%) subsequently developed AKI, but without significant difference between ventilation strategies. (Cumulative hazard, 0.26 vs 0.23; P =
Abbreviations: AKI, acute kidney injury; ALI, acute lung injury; ARDS, acute respiratory distress syndrome; CyC, cystatin C; GFR, glomerular filtration rate; ICU, intensive care unit; IQR, interquartile range; NGAL, neutrophil gelatinase–associated lipocalin; RIFLE, Risk, Injury, Failure, Loss of kidney function, End-stage kidney disease; VALI, ventilator-associated lung injury; VT, tidal volume. ☆
Competing interests: The authors declare that they have no competing interests. The authors had no sponsored funding for this study. ★ Trial registration: Netherlands Trial Register Identifier NTR151. ⁎ Corresponding author. Tel.: +31 20 5662509. E-mail addresses: [email protected] (B. Cortjens), [email protected] (A.A.N.M. Royakkers), [email protected] (R.M. Determann), [email protected] (J.D.E. van Suijlen), [email protected] (J. Foppen), [email protected] (A. de Boer), [email protected] (C.W. Wieland), [email protected] (P.E. Spronk), [email protected] (M.J. Schultz), [email protected] (C.S.C. Bouman). ☆☆
0883-9441/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.jcrc.2011.05.005
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B. Cortjens et al. .88.) The courses of neutrophil gelatinase–associated lipocalin and cystatin C plasma levels did not differ significantly between randomization groups. Conclusion: In the present study in critically patients without ALI at onset of mechanical ventilation, lower tidal volume ventilation did not reduce the development or worsening of AKI compared with conventional tidal volume ventilation. © 2012 Elsevier Inc. All rights reserved.
1. Introduction Mechanical ventilation is an indispensable tool in the treatment of critically ill patients. Although frequently lifesaving, it may worsen preexisting lung injury and even cause lung injury, frequently referred to as ventilator-associated lung injury (VALI) [1,2]. Mechanical ventilation also plays a role in the development of multiple organ failure, including acute kidney injury (AKI) [3-5]. Several effects may be involved in the latter process, including hemodynamic and neurohormonal effects of positive pressure ventilation and effects on arterial blood gasses [6]. Emerging data further suggest that biotrauma plays an important role in the development of AKI secondary to mechanical ventilation, via spillover of lung-borne inflammatory mediators into the systemic circulation [3,7-10]. The development of AKI is a major complication which independently increases morbidity and mortality [11,12]. The mortality of acute lung injury (ALI) combined with AKI approaches 80% [13]. Recently, attention has focused on the interaction of the lung and the kidney in the setting of ALI and ventilation strategies. Preclinical models of ALI and lung-injurious mechanical ventilation demonstrated changes in inflammatory mediators, apoptosis, and function in the kidney, and these changes were attenuated during lung-protective mechanical ventilation [3,7,14,15]. In patients with ALI lung-protective mechanical ventilation, using lower tidal volumes not only decreased the development of VALI, but also resulted in lower rates of renal failure [2,10]. Recently, lung-protective mechanical ventilation using lower tidal volumes was shown to reduce the development of VALI in a randomized controlled trial of patients without ALI at the onset of mechanical ventilation [16]. We wondered whether protective ventilation strategy also attenuated the development or progression of AKI in these patients. We hypothesized that lung-protective mechanical ventilation using lower tidal volumes in critically ill patients, without ALI at onset of mechanical ventilation, reduces injury to the kidney as assessed by traditional AKI markers (serum creatinine and urine output) and 2 novel AKI markers, cystatin C (CyC) and neutrophil gelatinase–associated lipocalin (NGAL), in plasma [17].
2. Methods 2.1. Study design and setting The present study was conducted as part of a randomized controlled trial studying the effects of lung-protective
mechanical ventilation on pulmonary inflammation, and the development of VALI in patients without ALI at onset of mechanical ventilation [16]. The study was conducted at the intensive care units of one academic and one regional teaching hospital in the Netherlands. The protocol was approved by the medical ethics committees of both hospitals (MEC 04/195), and written informed consent was obtained from the patient or closest relatives before entry in the study. All procedures were done in compliance with the Helsinki declaration. Consecutively admitted critically ill patients who did not meet the North American-European Consensus Conference criteria for ALI [18] and needed mechanical ventilation for an anticipated duration of more than 72 hours were randomized to mechanical ventilation with lower tidal volumes (6 mL/kg of predicted body weight) or conventional tidal volumes (10 mL/kg of predicted body weight). Patients were randomized within 36 hours after onset of mechanical ventilation. Exclusion criteria were age of 18 years or younger, participation in other clinical trials, pregnancy, increased uncontrollable intracranial pressure, severe chronic obstructive pulmonary disease (defined as a forced expiratory volume in 1 second to forced vital capacity ratio of b0.64 and daily medication), severe restrictive pulmonary disease (evidence of chronic interstitial infiltration on chest radiograph), use of immunosuppressive agents (100 mg hydrocortisone per day was allowed), pulmonary thromboembolism, previous pneumectomy or lobectomy, and previous randomization in the same study.
2.2. Clinical and laboratory data collection For each patient, we collected the baseline demographic data. The hourly urine output and serum creatinine on days 0, 1, 2, 3, and 4 were retrieved from our electronic Patient Data Management System (PDMS metavision, iMD soft, Sassenheim, The Netherlands). All the patients were scored daily for development of ALI using the North American-European Consensus Conference criteria [18].
2.3. Assessment of acute kidney injury The patients were scored daily for AKI using the creatinine and urine output criteria of the RIFLE (Risk, Injury, Failure, Loss of kidney function, End-stage kidney disease) classification system [19]. For all patients, we estimated baseline serum creatinine by solving the Modification of Diet in Renal Disease Study equation [20]. The lowest value of intensive care unit
Lung-protective mechanical ventilation against kidney injury (ICU) admission and estimated serum creatinine was used as baseline for the RIFLE criteria. If serum creatinine at ICU admission was higher than the estimated value, we searched for a recent premorbid serum creatinine to represent the baseline. If premorbid serum creatinine was unknown, the estimated value was used as baseline. In addition, we measured NGAL as a marker of active kidney damage [21,22] and CyC as a measure of kidney function [23].
2.4. Sampling and measurement of cystatin C and NGAL We used plasma samples taken on days 0, 2, and 4 and stored at −80°C. CyC was measured batchwise by particleenhanced immunonephelometry (BN Prospec System, Siemens, Germany); NGAL was measured by means of an ELISA (R&D Systems, Abingdon, UK). The detection limits were 0.05 mg/L for CyC and 312 pg/mL for NGAL. Intraassay variation was 1.7% for CyC and 13.4% for NGAL.
2.5. Statistical analysis Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS Inc, Chicago, Ill). Results are presented as mean ± SD, or as median and interquartile range. Results between groups were compared using the Student's t test, Mann-Whitney U test, χ2 test, Fisher exact test, and log-rank test where appropriate. The difference in AKI progression between groups was assessed using Kaplan-Meier cumulative hazards estimates. We used a 95% confidence interval to determine significance.
3. Results 3.1. Patients All 150 patients of the original study were included in the secondary analysis; 76 patients were randomized into the lung-protective mechanical ventilation group and 74 patients in the conventional mechanical ventilation group. The baseline characteristics of these 2 groups are shown in Table 1. Twelve patients developed VALI: 10 patients in the conventional mechanical ventilation group and 2 patients in the lung-protective mechanical ventilation group (P = .01). Vasopressor use, transfusion of blood products, and cumulative fluid balance before randomization were not significantly different between the 2 groups (Table 1).
3.2. Developing or worsening of AKI Fig. 1 shows the distribution of AKI in the 2 randomization groups. Development or worsening of AKI was seen in 39 (26%) patients; however, the difference in AKI
263 Table 1
Baseline characteristics
Age (years) Male (%) Comorbidities Diabetes mellitus Hypertension CKD APACHE-II SOFA Primary diagnosis Cardiac arrest Neurological disease Sepsis Pneumonia Trauma Pancreatitis Medical other Cardiopulmonary surgery Other surgery Plasma cystatin C (mg/L) Plasma NGAL (mg/L) Serum creatinine (μmol/L) Data before randomization Mechanical ventilation (h) Tidal volume (mL/kg) Blood transfusiona (%) Blood products a Vasopressor use Cumulative fluid balance (L) 28-day mortality (%)
Conventional tidal volume (n = 74)
Lower tidal volume (n = 76)
58 (17) 50 (68)
63 (15) 49 (64)
8 18 1 20 (8) 8 (4)
13 18 1 21 (7) 7 (3)
22 24
32 15
7 1 12 – 5 1
4 4 10 1 5 3
P value .06 .69 .60
.93 .19 .60
2 2 0.739 (0.54-1.25) 0.734 (0.59-1.23) 1.00 134 (100-205)
149 (81-242)
.86
69 (52-121)
75 (55-126)
.80
20 (9)
18 (9)
.25
8.2 (0.4)
8.4 (0.6)
.31
26 (35)
20 (26)
.40
0 (0-2) 25 (34) 1.77 (0.33-3.50)
0 (0-1) 27 (36) 1.71 (0.63-2.88)
.25 .86 .64
23 (31)
24 (32)
.94
Values are mean ± SD, median and interquartile range, or number of patients and %. APACHE-II indicates Acute Physiology and Chronic Health Evaluation-II; SOFA, Sequential Organ Failure Assessment; CKD, chronic kidney disease; NGAL, neutrophil gelatinase–associated lipocalin; AKI, acute kidney injury. a Red cells and fresh frozen plasma.
progression between the 2 ventilation strategies was not statistically significant (cumulative hazard estimate, respectively, 0.32 vs 0.32; P = .96) (Fig. 2). During the study period, there were no statistically significant differences between the 2 randomization groups for vasopressor use, number blood transfusions, or cumulative fluid balances (Table 2). Eighty-six patients had no AKI on day 0, and of
264
B. Cortjens et al. 6291 Patients admitted to ICU 347 Patients eligible for the study
195 Patients excluded 94 Had exclusion criterion 93 Refused to participate 8 Decision of intensivist
152 Patients randomized
76 Assigned to conventional tidal volume
76 Assigned to low tidal volume
1 Lost due to transfer to other hospital 1 Excluded due to ARDS diagnosis directly after randomization.
74 Included in analysis
76 Included in analysis
32 Had AKI at randomization 10 Had worsening of their AKI-score
32 Had AKI at randomization 11 Had worsening of their AKI-score
42 Had no AKI at randomization 9 Developed AKI de novo
44 Had no AKI at randomization 9 Developed AKI de novo
Fig. 1
Trial profile. AKI indicates acute kidney injury. Trial profile. AKI indicates acute kidney injury.
these patients 18 (21%) patients developed AKI; however, the difference between the 2 randomization groups was not statistically significant (cumulative hazard estimate, 0.26 vs 0.23; P = .88) (Fig. 2). Twelve patients developed VALI: 10 patients in the conventional mechanical ventilation group and 2 patients in the lung-protective mechanical ventilation group (P = .01). The development or worsening of AKI was not higher in these patients compared with the patients who
did not develop VALI (cumulative hazard estimate, respectively, 0.29 vs 0.24, P = .88).
3.3. Cystatin C and NGAL Cystatin C was measured in 270 plasma samples (1.81 ± 0.97 samples per patient), and NGAL was measured in 306
Fig. 2 Left panel: Cumulative hazard estimates graph on worsening in AKI score in all patients ventilated with conventional tidal volume (10 mL/kg predicted bodyweight, open circles) or lower tidal volumes (6 mL/kg predicted bodyweight, closed circles). Right panel: Cumulative hazard estimates graph on worsening in AKI score in patients without AKI at inclusion, ventilated with conventional (10 mL/kg predicted bodyweight) tidal volume (open circles) or low (6 mL/kg predicted bodyweight) tidal volumes (closed circles).
Lung-protective mechanical ventilation against kidney injury Table 2 Vasopressor use, blood products, and fluid balance during study period Conventional tidal volume group (n = 74) Vasopressor use (%) Day 0 27 (36) Day 2 18 (24) Day 4 6 (8) Blood products a (units) Day 0 0 (0-1) Day 2 0 (0-0) Day 4 0 (0-0) Fluid balance (L) Day 0 1.71 (0.63-2.88) Day 2 4.75 (2.67-6.69) Day 4 4.75 (0.80-8.21)
Lower tidal volume group (n = 76) 25 (33) 12 (16) 5 (7)
P value
.72 .51 .79
0 (0-2) 0 (0-0.5) 0 (0-0)
.25 .28 .51
1.77 (0.33-3.50) 4.76 (3.07-6.96) 6.20 (3.02-8.64)
.64 .50 .21
Values are median and interquartile range, or number of patients and %. a Red cells and/or plasma.
plasma samples (2.04 ± 0.89 samples per patient). Plasma levels of CyC and NGAL during mechanical ventilation were not significantly different between the LVT group and the CVT group (Fig. 3). The difference remained not significant after correction for AKI at onset (Fig. 4).
4. Discussion In this secondary analysis of a randomized controlled trial of mechanical ventilation with lower vs conventional tidal volumes in critically ill patients without ALI at the onset of mechanical ventilation, protective mechanical ventilation
265 with lower tidal volumes did not prevent development or progression of AKI compared to mechanical ventilation using conventional tidal volumes. Our findings are in contrast with 2 earlier clinical trials in which lung-protective mechanical ventilation reduced the development of AKI [2,10]. Several factors could explain the difference in results between our trial and other trials of lung-protective ventilation and AKI. First, we only included patients without ALI, whereas the ARDS Network Study [2] and the study by Ranieri et al [10] included patients with acute respiratory distress syndrome (ARDS), often combined with sepsis or pneumonia. Possibly, ventilator-induced injury to the kidney represents a multifactor process that may become more important in the presence of preexistent lung injury or infection [4]. Notably, the present study protocol mandated mechanical ventilation with a tidal volume of 6 mL/kg once VALI was diagnosed, thus attenuating further lung and kidney damage. A next possible explanation for the different results between our trial and earlier studies is the assessment of renal injury. The ARDS Network trial prospectively evaluated the number of days free of renal failure, defined as a serum creatinine level of more than 177 μmol/L, in 28 days [2]. Ranieri et al [10] retrospectively examined the occurrence of renal failure, using the criteria outlined by Knaus et al [24], within 72 hours of mechanical ventilation. In the present study, we applied the RIFLE classification system to assess the development or worsening of AKI within 5 days of mechanical ventilation [19]. The lack of a common reference point hampers comparison among studies. In addition to AKI as defined by the RIFLE classification system, we also looked at the longitudinal trend of systemic NGAL and CyC; however, neither of these 2 novel AKI markers was significantly different between the 2 randomization groups, suggesting that mechanical ventilation using conventional tidal
Fig. 3 Left panel: Plasma levels (median and interquartile range [IQR]) of NGAL in patients ventilated with conventional tidal volume (10 mL/kg predicted bodyweight, open circles) or low tidal volumes (6 mL/kg predicted bodyweight, closed circles). Right panel: Plasma levels (median and IQR) of cystatin C in patients ventilated with conventional tidal volume (10 mL/kg predicted bodyweight, open circles) or low tidal volumes (6 mL/kg predicted bodyweight, closed circles).
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B. Cortjens et al.
Fig. 4 Left panel: Plasma levels (median and IQR) of NGAL in patients without AKI at inclusion, ventilated with conventional tidal volume (10 mL/kg predicted bodyweight, open circles) or low tidal volumes (6 mL/kg predicted bodyweight, closed circles). Right panel: Plasma levels (median and IQR) of cystatin C in patients without AKI at inclusion, ventilated with conventional tidal volume (10 mL/kg predicted bodyweight, open circles) or low tidal volumes (6 mL/kg predicted bodyweight, closed circles).
volumes did not increase kidney damage. Small animal models of ALI and mechanical ventilation support the abovementioned hypothesis, although some of these studies applied tidal volumes not commonly used in clinical practice [3,7,14,15]. In mice, the combination of conventional mechanical ventilation (with tidal volumes of 10 mL/kg) and bacterial infection resulted in significantly greater serum creatinine concentrations compared with animals without bacterial infection [14]. Gurkan et al [3] established a murine model of VALI and demonstrated that a short period of mechanical ventilation with high tidal volumes (17 mL/kg) caused both increased pulmonary vascular permeability and hepatic and renal inflammation. This effect was dependent on presence of a localized pulmonary inflammatory stimulus (acid aspiration) and did not occur after mechanical ventilation of healthy mice [3]. Lower tidal volumes (6 mL/kg) after acid aspiration significantly attenuated lung injury, but also attenuated local cytokine expression in liver and kidney expression. In rabbits with acid aspiration lung injury, high tidal volume (15-17 mL/ kg) mechanical ventilation increased epithelial cell apoptosis in the kidney and led to increased concentrations of serum creatinine [7]. Hegeman et al [15] demonstrated that 4 hours of lung injurious mechanical ventilation of healthy mice induced endothelial activation, inflammatory mediator production, and the presence of granulocytes in distal organs. The authors proposed that, combined with other events, such as an endotoxin challenge, ventilatorinduced effects on the lungs and distal organs will be exacerbated and possibly underline the high incidence of organ failure in critically ill patients ventilated with high pressures and tidal volumes. Our trial was the first clinical study to investigate whether lung-protective mechanical ventilation with lower tidal volumes reduces the development of AKI in ICU patients without lung injury at the start of mechanical ventilation and
to combine traditional and novel markers for AKI; however, there are some limitations. The study protocol was designed to investigate the role of mechanical ventilation in the development of VALI in patients without lung injury at randomization, and in this post hoc analysis we retrospectively assessed the development and progression of AKI. We studied a specific group (no ALI at admission), which consisted mainly of patients with cardiac arrest and neurologic disorders, and therefore we cannot conclude that low tidal volume has no effect on development or worsening of AKI in a general ICU population. In addition, CyC and NGAL in plasma were determined on days 0, 2, and 4 and not daily. Therefore it is possible that we missed a peak on day 1 or 3. Nevertheless, the courses of NGAL and CyC in the 2 randomization groups are very similar, and therefore we believe that daily measurements would not have changed our conclusions. Finally, we did not measure urinary markers, although these markers may be more sensitive for the detection of kidney damage [25]. Systemic NGAL is a general marker of injury, whereas systemic CyC is a functional marker, and neither markers are specific for detection of kidney injury [26,27]. In contrast, urinary NGAL and CyC are specific markers of kidney injury and were shown to predict the development of severe AKI in selected patient groups [28-32].
5. Conclusions In this secondary analysis of a randomized controlled trial in critically ill patients without ALI at the beginning of mechanical ventilation, lung-protective mechanical ventilation significantly reduced the development of VALI, but not the development and/or worsening of AKI according to RIFLE and according to the plasma levels of NGAL and CyC.
Lung-protective mechanical ventilation against kidney injury
Acknowledgments We thank J.M. Binnekade for his assistance in the statistical analysis.
References [1] Amato MB, Barbas CS, Medeiros DM, et al. Effect of a protectiveventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998;338:347-54. [2] The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. New Engl J Med 2000;342:1301-8. [3] Gurkan OU, O'Donnell C, Brower R, et al. Differential effects of mechanical ventilatory strategy on lung injury and systemic organ inflammation in mice. Am J Physiol Lung Cell Mol Physiol 2003;285: L710-8. [4] Kuiper JW, Groeneveld AB, Slutsky AS, et al. Mechanical ventilation and acute renal failure. Crit Care Med 2005;33:1408-15. [5] Slutsky AS, Tremblay LN. Multiple system organ failure. Is mechanical ventilation a contributing factor? Am J Respir Crit Care Med 1998;157:1721-5. [6] Koyner JL, Murray PT. Mechanical ventilation and lung-kidney interactions. Clin J Am Soc Nephrol 2008;3:562-70. [7] Imai Y, Parodo J, Kajikawa O, et al. Injurious mechanical ventilation and end-organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome. JAMA 2003;289:2104-12. [8] Plotz FB, Slutsky AS, van Vught AJ, et al. Ventilator-induced lung injury and multiple system organ failure: a critical review of facts and hypotheses. Intensive Care Med 2004;30:1865-72. [9] Ranieri VM, Suter PM, Tortorella C, et al. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA 1999; 282:54-61. [10] Ranieri VM, Giunta F, Suter PM, et al. Mechanical ventilation as a mediator of multisystem organ failure in acute respiratory distress syndrome. JAMA 2000;284:43-4. [11] Hoste EA, Kellum JA. Acute kidney injury: epidemiology and diagnostic criteria. Curr Opin Crit Care 2006;12:531-7. [12] Joannidis M, Metnitz PG. Epidemiology and natural history of acute renal failure in the ICU. Crit Care Clin 2005;21:239-49. [13] Mehta RL, Pascual MT, Gruta CG, et al. Refining predictive models in critically ill patients with acute renal failure. J Am Soc Nephrol 2002;13:1350-7. [14] Dhanireddy S, Altemeier WA, Matute-Bello G, et al. Mechanical ventilation induces inflammation, lung injury, and extra-pulmonary organ dysfunction in experimental pneumonia. Lab Invest 2006;86: 790-9.
267 [15] Hegeman MA, Hennus MP, Heijnen CJ, et al. Ventilator-induced endothelial activation and inflammation in the lung and distal organs. Crit Care 2009;13:R182. [16] Determann RM, Royakkers A, Wolthuis EK, et al. Ventilation with lower tidal volumes as compared to conventional tidal volumes for patients without acute lung injury — a preventive randomized controlled trial. Crit Care 2010;14(1):R1. [17] Parikh CR, Devarajan P. New biomarkers of acute kidney injury. Crit Care Med 2008;36:S159-65. [18] Bernard GR, Artigas A, Brigham KL, et al. Report of the AmericanEuropean consensus conference on ARDS: definitions, mechanisms, relevant outcomes and clinical trial coordination. The Consensus Committee. Intensive Care Med 1994;20:225-32. [19] Bellomo R, Ronco C, Kellum JA, et al. Acute renal failure — definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004;8:R204-12. [20] Levey AS, Berg RL, Gassman JJ, et al. Creatinine filtration, secretion and excretion during progressive renal disease. Modification of Diet in Renal Disease (MDRD) Study Group. Kidney Int 1989;27:S73-80. [21] Cruz DN, de Cal M, Garzotto F, et al. Plasma neutrophil gelatinaseassociated lipocalin is an early biomarker for acute kidney injury in an adult ICU population. Intensive Care Med 2010;36:444-51. [22] Haase M, Bellomo R, Devarajan P, et al. Novel biomarkers early predict the severity of acute kidney injury after cardiac surgery in adults. Ann Thorac Surg 2009;88:124-30. [23] Herget-Rosenthal S, Marggraf G, Husing J, et al. Early detection of acute renal failure by serum cystatin C. Kidney Int 2004;66:1115-22. [24] Knaus WA, Draper EA, Wagner DP, et al. APACHE II: a severity of disease classification system. Crit Care Med 1985;13(10):818-29. [25] Koyner JL, Vaidya VS, Bennett MR, et al. Urinary biomarkers in the clinical prognosis and early detection of acute kidney injury. Clin J Am Soc Nephrol 2010;5:2154-65. [26] Bouman CS, Forni LG, Joannidis M. Biomarkers and acute kidney injury: dining with the Fisher King? Intensive Care Med 2010;36:381-4. [27] Wulkan R, den Hollander J, Berghout A. Cystatin C: unsuited to use as a marker of kidney function in the intensive care unit. Crit Care 2005;9:531-2. [28] Conti M, Moutereau S, Zater M, et al. Urinary cystatin C as a specific marker of tubular dysfunction. Clin Chem Lab Med 2006;44:288-91. [29] Herget-Rosenthal S, Poppen D, Husing J, et al. Prognostic value of tubular proteinuria and enzymuria in nonoliguric acute tubular necrosis. Clin Chem 2004;50:552-8. [30] Nejat M, Pickering JW, Walker RJ, et al. Urinary cystatin C is diagnostic of acute kidney injury and sepsis, and predicts mortality in the intensive care unit. Crit Care 2010;14:R85. [31] Wagener G, Jan M, Kim M, et al. Association between increases in urinary neutrophil gelatinase-associated lipocalin and acute renal dysfunction after adult cardiac surgery. Anesthesiology 2006;105:485-91. [32] Zappitelli M, Washburn KK, Arikan AA, et al. Urine neutrophil gelatinase-associated lipocalin is an early marker of acute kidney injury in critically ill children: a prospective cohort study. Crit Care 2007;11:R84.
Lung-protective mechanical ventilation does not protect against acute kidney injury in patients without lung injury at onset of mechanical ventilation☆,☆☆,★ Bart Cortjens MSc a , Annick A.N.M. Royakkers MD b , Rogier M. Determann MD, PhD c , Jeroen D.E. van Suijlen PhD d , Stephan S. Kamphuis PhD d , Jannetje Foppen d , Anita de Boer a , Cathrien.W. Wieland PhD a , Peter E. Spronk MD, PhD e , Marcus J. Schultz MD, PhD, FCCP a , Catherine S.C. Bouman MD, PhD c,⁎ a
Laboratory of Experimental Intensive Care and Anesthesiology (LEICA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands b Department of Anesthesiology, Tergooi Hospitals, Blaricum, The Netherlands c Department of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands d Laboratory of Clinical Chemistry, Gelre Hospitals, Apeldoorn, The Netherlands e Department of Intensive Care, Gelre Hospitals, Apeldoorn, The Netherlands
Keywords: Acute kidney injury; Ventilator-associated lung injury; Lung-protective mechanical ventilation; Cystatin C; Neutrophil gelatinase– associated lipocalin (NGAL)
Abstract Introduction: Preclinical and clinical studies suggest that mechanical ventilation contributes to the development of acute kidney injury (AKI), particularly in the setting of lung-injurious ventilator strategies. Objective: To determine whether ventilator settings in critically ill patients without acute lung injury (ALI) at onset of mechanical ventilation affect the development of AKI. Design, Setting, and Patients: Secondary analysis of a randomized controlled trial (N = 150), comparing conventional tidal volume (VT, 10 mL/kg) with low tidal volume (VT, 6 mL/kg) mechanical ventilation in critically ill patients without ALI at randomization. During the first 5 days of mechanical ventilation, the RIFLE class was determined daily, whereas neutrophil gelatinase–associated lipocalin and cystatin C levels were measured in plasma collected on days 0, 2, and 4. Results: Eighty-six patients had no AKI at inclusion, and 18 patients (21%) subsequently developed AKI, but without significant difference between ventilation strategies. (Cumulative hazard, 0.26 vs 0.23; P =
Abbreviations: AKI, acute kidney injury; ALI, acute lung injury; ARDS, acute respiratory distress syndrome; CyC, cystatin C; GFR, glomerular filtration rate; ICU, intensive care unit; IQR, interquartile range; NGAL, neutrophil gelatinase–associated lipocalin; RIFLE, Risk, Injury, Failure, Loss of kidney function, End-stage kidney disease; VALI, ventilator-associated lung injury; VT, tidal volume. ☆
Competing interests: The authors declare that they have no competing interests. The authors had no sponsored funding for this study. ★ Trial registration: Netherlands Trial Register Identifier NTR151. ⁎ Corresponding author. Tel.: +31 20 5662509. E-mail addresses: [email protected] (B. Cortjens), [email protected] (A.A.N.M. Royakkers), [email protected] (R.M. Determann), [email protected] (J.D.E. van Suijlen), [email protected] (J. Foppen), [email protected] (A. de Boer), [email protected] (C.W. Wieland), [email protected] (P.E. Spronk), [email protected] (M.J. Schultz), [email protected] (C.S.C. Bouman). ☆☆
0883-9441/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.jcrc.2011.05.005
262
B. Cortjens et al. .88.) The courses of neutrophil gelatinase–associated lipocalin and cystatin C plasma levels did not differ significantly between randomization groups. Conclusion: In the present study in critically patients without ALI at onset of mechanical ventilation, lower tidal volume ventilation did not reduce the development or worsening of AKI compared with conventional tidal volume ventilation. © 2012 Elsevier Inc. All rights reserved.
1. Introduction Mechanical ventilation is an indispensable tool in the treatment of critically ill patients. Although frequently lifesaving, it may worsen preexisting lung injury and even cause lung injury, frequently referred to as ventilator-associated lung injury (VALI) [1,2]. Mechanical ventilation also plays a role in the development of multiple organ failure, including acute kidney injury (AKI) [3-5]. Several effects may be involved in the latter process, including hemodynamic and neurohormonal effects of positive pressure ventilation and effects on arterial blood gasses [6]. Emerging data further suggest that biotrauma plays an important role in the development of AKI secondary to mechanical ventilation, via spillover of lung-borne inflammatory mediators into the systemic circulation [3,7-10]. The development of AKI is a major complication which independently increases morbidity and mortality [11,12]. The mortality of acute lung injury (ALI) combined with AKI approaches 80% [13]. Recently, attention has focused on the interaction of the lung and the kidney in the setting of ALI and ventilation strategies. Preclinical models of ALI and lung-injurious mechanical ventilation demonstrated changes in inflammatory mediators, apoptosis, and function in the kidney, and these changes were attenuated during lung-protective mechanical ventilation [3,7,14,15]. In patients with ALI lung-protective mechanical ventilation, using lower tidal volumes not only decreased the development of VALI, but also resulted in lower rates of renal failure [2,10]. Recently, lung-protective mechanical ventilation using lower tidal volumes was shown to reduce the development of VALI in a randomized controlled trial of patients without ALI at the onset of mechanical ventilation [16]. We wondered whether protective ventilation strategy also attenuated the development or progression of AKI in these patients. We hypothesized that lung-protective mechanical ventilation using lower tidal volumes in critically ill patients, without ALI at onset of mechanical ventilation, reduces injury to the kidney as assessed by traditional AKI markers (serum creatinine and urine output) and 2 novel AKI markers, cystatin C (CyC) and neutrophil gelatinase–associated lipocalin (NGAL), in plasma [17].
2. Methods 2.1. Study design and setting The present study was conducted as part of a randomized controlled trial studying the effects of lung-protective
mechanical ventilation on pulmonary inflammation, and the development of VALI in patients without ALI at onset of mechanical ventilation [16]. The study was conducted at the intensive care units of one academic and one regional teaching hospital in the Netherlands. The protocol was approved by the medical ethics committees of both hospitals (MEC 04/195), and written informed consent was obtained from the patient or closest relatives before entry in the study. All procedures were done in compliance with the Helsinki declaration. Consecutively admitted critically ill patients who did not meet the North American-European Consensus Conference criteria for ALI [18] and needed mechanical ventilation for an anticipated duration of more than 72 hours were randomized to mechanical ventilation with lower tidal volumes (6 mL/kg of predicted body weight) or conventional tidal volumes (10 mL/kg of predicted body weight). Patients were randomized within 36 hours after onset of mechanical ventilation. Exclusion criteria were age of 18 years or younger, participation in other clinical trials, pregnancy, increased uncontrollable intracranial pressure, severe chronic obstructive pulmonary disease (defined as a forced expiratory volume in 1 second to forced vital capacity ratio of b0.64 and daily medication), severe restrictive pulmonary disease (evidence of chronic interstitial infiltration on chest radiograph), use of immunosuppressive agents (100 mg hydrocortisone per day was allowed), pulmonary thromboembolism, previous pneumectomy or lobectomy, and previous randomization in the same study.
2.2. Clinical and laboratory data collection For each patient, we collected the baseline demographic data. The hourly urine output and serum creatinine on days 0, 1, 2, 3, and 4 were retrieved from our electronic Patient Data Management System (PDMS metavision, iMD soft, Sassenheim, The Netherlands). All the patients were scored daily for development of ALI using the North American-European Consensus Conference criteria [18].
2.3. Assessment of acute kidney injury The patients were scored daily for AKI using the creatinine and urine output criteria of the RIFLE (Risk, Injury, Failure, Loss of kidney function, End-stage kidney disease) classification system [19]. For all patients, we estimated baseline serum creatinine by solving the Modification of Diet in Renal Disease Study equation [20]. The lowest value of intensive care unit
Lung-protective mechanical ventilation against kidney injury (ICU) admission and estimated serum creatinine was used as baseline for the RIFLE criteria. If serum creatinine at ICU admission was higher than the estimated value, we searched for a recent premorbid serum creatinine to represent the baseline. If premorbid serum creatinine was unknown, the estimated value was used as baseline. In addition, we measured NGAL as a marker of active kidney damage [21,22] and CyC as a measure of kidney function [23].
2.4. Sampling and measurement of cystatin C and NGAL We used plasma samples taken on days 0, 2, and 4 and stored at −80°C. CyC was measured batchwise by particleenhanced immunonephelometry (BN Prospec System, Siemens, Germany); NGAL was measured by means of an ELISA (R&D Systems, Abingdon, UK). The detection limits were 0.05 mg/L for CyC and 312 pg/mL for NGAL. Intraassay variation was 1.7% for CyC and 13.4% for NGAL.
2.5. Statistical analysis Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS Inc, Chicago, Ill). Results are presented as mean ± SD, or as median and interquartile range. Results between groups were compared using the Student's t test, Mann-Whitney U test, χ2 test, Fisher exact test, and log-rank test where appropriate. The difference in AKI progression between groups was assessed using Kaplan-Meier cumulative hazards estimates. We used a 95% confidence interval to determine significance.
3. Results 3.1. Patients All 150 patients of the original study were included in the secondary analysis; 76 patients were randomized into the lung-protective mechanical ventilation group and 74 patients in the conventional mechanical ventilation group. The baseline characteristics of these 2 groups are shown in Table 1. Twelve patients developed VALI: 10 patients in the conventional mechanical ventilation group and 2 patients in the lung-protective mechanical ventilation group (P = .01). Vasopressor use, transfusion of blood products, and cumulative fluid balance before randomization were not significantly different between the 2 groups (Table 1).
3.2. Developing or worsening of AKI Fig. 1 shows the distribution of AKI in the 2 randomization groups. Development or worsening of AKI was seen in 39 (26%) patients; however, the difference in AKI
263 Table 1
Baseline characteristics
Age (years) Male (%) Comorbidities Diabetes mellitus Hypertension CKD APACHE-II SOFA Primary diagnosis Cardiac arrest Neurological disease Sepsis Pneumonia Trauma Pancreatitis Medical other Cardiopulmonary surgery Other surgery Plasma cystatin C (mg/L) Plasma NGAL (mg/L) Serum creatinine (μmol/L) Data before randomization Mechanical ventilation (h) Tidal volume (mL/kg) Blood transfusiona (%) Blood products a Vasopressor use Cumulative fluid balance (L) 28-day mortality (%)
Conventional tidal volume (n = 74)
Lower tidal volume (n = 76)
58 (17) 50 (68)
63 (15) 49 (64)
8 18 1 20 (8) 8 (4)
13 18 1 21 (7) 7 (3)
22 24
32 15
7 1 12 – 5 1
4 4 10 1 5 3
P value .06 .69 .60
.93 .19 .60
2 2 0.739 (0.54-1.25) 0.734 (0.59-1.23) 1.00 134 (100-205)
149 (81-242)
.86
69 (52-121)
75 (55-126)
.80
20 (9)
18 (9)
.25
8.2 (0.4)
8.4 (0.6)
.31
26 (35)
20 (26)
.40
0 (0-2) 25 (34) 1.77 (0.33-3.50)
0 (0-1) 27 (36) 1.71 (0.63-2.88)
.25 .86 .64
23 (31)
24 (32)
.94
Values are mean ± SD, median and interquartile range, or number of patients and %. APACHE-II indicates Acute Physiology and Chronic Health Evaluation-II; SOFA, Sequential Organ Failure Assessment; CKD, chronic kidney disease; NGAL, neutrophil gelatinase–associated lipocalin; AKI, acute kidney injury. a Red cells and fresh frozen plasma.
progression between the 2 ventilation strategies was not statistically significant (cumulative hazard estimate, respectively, 0.32 vs 0.32; P = .96) (Fig. 2). During the study period, there were no statistically significant differences between the 2 randomization groups for vasopressor use, number blood transfusions, or cumulative fluid balances (Table 2). Eighty-six patients had no AKI on day 0, and of
264
B. Cortjens et al. 6291 Patients admitted to ICU 347 Patients eligible for the study
195 Patients excluded 94 Had exclusion criterion 93 Refused to participate 8 Decision of intensivist
152 Patients randomized
76 Assigned to conventional tidal volume
76 Assigned to low tidal volume
1 Lost due to transfer to other hospital 1 Excluded due to ARDS diagnosis directly after randomization.
74 Included in analysis
76 Included in analysis
32 Had AKI at randomization 10 Had worsening of their AKI-score
32 Had AKI at randomization 11 Had worsening of their AKI-score
42 Had no AKI at randomization 9 Developed AKI de novo
44 Had no AKI at randomization 9 Developed AKI de novo
Fig. 1
Trial profile. AKI indicates acute kidney injury. Trial profile. AKI indicates acute kidney injury.
these patients 18 (21%) patients developed AKI; however, the difference between the 2 randomization groups was not statistically significant (cumulative hazard estimate, 0.26 vs 0.23; P = .88) (Fig. 2). Twelve patients developed VALI: 10 patients in the conventional mechanical ventilation group and 2 patients in the lung-protective mechanical ventilation group (P = .01). The development or worsening of AKI was not higher in these patients compared with the patients who
did not develop VALI (cumulative hazard estimate, respectively, 0.29 vs 0.24, P = .88).
3.3. Cystatin C and NGAL Cystatin C was measured in 270 plasma samples (1.81 ± 0.97 samples per patient), and NGAL was measured in 306
Fig. 2 Left panel: Cumulative hazard estimates graph on worsening in AKI score in all patients ventilated with conventional tidal volume (10 mL/kg predicted bodyweight, open circles) or lower tidal volumes (6 mL/kg predicted bodyweight, closed circles). Right panel: Cumulative hazard estimates graph on worsening in AKI score in patients without AKI at inclusion, ventilated with conventional (10 mL/kg predicted bodyweight) tidal volume (open circles) or low (6 mL/kg predicted bodyweight) tidal volumes (closed circles).
Lung-protective mechanical ventilation against kidney injury Table 2 Vasopressor use, blood products, and fluid balance during study period Conventional tidal volume group (n = 74) Vasopressor use (%) Day 0 27 (36) Day 2 18 (24) Day 4 6 (8) Blood products a (units) Day 0 0 (0-1) Day 2 0 (0-0) Day 4 0 (0-0) Fluid balance (L) Day 0 1.71 (0.63-2.88) Day 2 4.75 (2.67-6.69) Day 4 4.75 (0.80-8.21)
Lower tidal volume group (n = 76) 25 (33) 12 (16) 5 (7)
P value
.72 .51 .79
0 (0-2) 0 (0-0.5) 0 (0-0)
.25 .28 .51
1.77 (0.33-3.50) 4.76 (3.07-6.96) 6.20 (3.02-8.64)
.64 .50 .21
Values are median and interquartile range, or number of patients and %. a Red cells and/or plasma.
plasma samples (2.04 ± 0.89 samples per patient). Plasma levels of CyC and NGAL during mechanical ventilation were not significantly different between the LVT group and the CVT group (Fig. 3). The difference remained not significant after correction for AKI at onset (Fig. 4).
4. Discussion In this secondary analysis of a randomized controlled trial of mechanical ventilation with lower vs conventional tidal volumes in critically ill patients without ALI at the onset of mechanical ventilation, protective mechanical ventilation
265 with lower tidal volumes did not prevent development or progression of AKI compared to mechanical ventilation using conventional tidal volumes. Our findings are in contrast with 2 earlier clinical trials in which lung-protective mechanical ventilation reduced the development of AKI [2,10]. Several factors could explain the difference in results between our trial and other trials of lung-protective ventilation and AKI. First, we only included patients without ALI, whereas the ARDS Network Study [2] and the study by Ranieri et al [10] included patients with acute respiratory distress syndrome (ARDS), often combined with sepsis or pneumonia. Possibly, ventilator-induced injury to the kidney represents a multifactor process that may become more important in the presence of preexistent lung injury or infection [4]. Notably, the present study protocol mandated mechanical ventilation with a tidal volume of 6 mL/kg once VALI was diagnosed, thus attenuating further lung and kidney damage. A next possible explanation for the different results between our trial and earlier studies is the assessment of renal injury. The ARDS Network trial prospectively evaluated the number of days free of renal failure, defined as a serum creatinine level of more than 177 μmol/L, in 28 days [2]. Ranieri et al [10] retrospectively examined the occurrence of renal failure, using the criteria outlined by Knaus et al [24], within 72 hours of mechanical ventilation. In the present study, we applied the RIFLE classification system to assess the development or worsening of AKI within 5 days of mechanical ventilation [19]. The lack of a common reference point hampers comparison among studies. In addition to AKI as defined by the RIFLE classification system, we also looked at the longitudinal trend of systemic NGAL and CyC; however, neither of these 2 novel AKI markers was significantly different between the 2 randomization groups, suggesting that mechanical ventilation using conventional tidal
Fig. 3 Left panel: Plasma levels (median and interquartile range [IQR]) of NGAL in patients ventilated with conventional tidal volume (10 mL/kg predicted bodyweight, open circles) or low tidal volumes (6 mL/kg predicted bodyweight, closed circles). Right panel: Plasma levels (median and IQR) of cystatin C in patients ventilated with conventional tidal volume (10 mL/kg predicted bodyweight, open circles) or low tidal volumes (6 mL/kg predicted bodyweight, closed circles).
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B. Cortjens et al.
Fig. 4 Left panel: Plasma levels (median and IQR) of NGAL in patients without AKI at inclusion, ventilated with conventional tidal volume (10 mL/kg predicted bodyweight, open circles) or low tidal volumes (6 mL/kg predicted bodyweight, closed circles). Right panel: Plasma levels (median and IQR) of cystatin C in patients without AKI at inclusion, ventilated with conventional tidal volume (10 mL/kg predicted bodyweight, open circles) or low tidal volumes (6 mL/kg predicted bodyweight, closed circles).
volumes did not increase kidney damage. Small animal models of ALI and mechanical ventilation support the abovementioned hypothesis, although some of these studies applied tidal volumes not commonly used in clinical practice [3,7,14,15]. In mice, the combination of conventional mechanical ventilation (with tidal volumes of 10 mL/kg) and bacterial infection resulted in significantly greater serum creatinine concentrations compared with animals without bacterial infection [14]. Gurkan et al [3] established a murine model of VALI and demonstrated that a short period of mechanical ventilation with high tidal volumes (17 mL/kg) caused both increased pulmonary vascular permeability and hepatic and renal inflammation. This effect was dependent on presence of a localized pulmonary inflammatory stimulus (acid aspiration) and did not occur after mechanical ventilation of healthy mice [3]. Lower tidal volumes (6 mL/kg) after acid aspiration significantly attenuated lung injury, but also attenuated local cytokine expression in liver and kidney expression. In rabbits with acid aspiration lung injury, high tidal volume (15-17 mL/ kg) mechanical ventilation increased epithelial cell apoptosis in the kidney and led to increased concentrations of serum creatinine [7]. Hegeman et al [15] demonstrated that 4 hours of lung injurious mechanical ventilation of healthy mice induced endothelial activation, inflammatory mediator production, and the presence of granulocytes in distal organs. The authors proposed that, combined with other events, such as an endotoxin challenge, ventilatorinduced effects on the lungs and distal organs will be exacerbated and possibly underline the high incidence of organ failure in critically ill patients ventilated with high pressures and tidal volumes. Our trial was the first clinical study to investigate whether lung-protective mechanical ventilation with lower tidal volumes reduces the development of AKI in ICU patients without lung injury at the start of mechanical ventilation and
to combine traditional and novel markers for AKI; however, there are some limitations. The study protocol was designed to investigate the role of mechanical ventilation in the development of VALI in patients without lung injury at randomization, and in this post hoc analysis we retrospectively assessed the development and progression of AKI. We studied a specific group (no ALI at admission), which consisted mainly of patients with cardiac arrest and neurologic disorders, and therefore we cannot conclude that low tidal volume has no effect on development or worsening of AKI in a general ICU population. In addition, CyC and NGAL in plasma were determined on days 0, 2, and 4 and not daily. Therefore it is possible that we missed a peak on day 1 or 3. Nevertheless, the courses of NGAL and CyC in the 2 randomization groups are very similar, and therefore we believe that daily measurements would not have changed our conclusions. Finally, we did not measure urinary markers, although these markers may be more sensitive for the detection of kidney damage [25]. Systemic NGAL is a general marker of injury, whereas systemic CyC is a functional marker, and neither markers are specific for detection of kidney injury [26,27]. In contrast, urinary NGAL and CyC are specific markers of kidney injury and were shown to predict the development of severe AKI in selected patient groups [28-32].
5. Conclusions In this secondary analysis of a randomized controlled trial in critically ill patients without ALI at the beginning of mechanical ventilation, lung-protective mechanical ventilation significantly reduced the development of VALI, but not the development and/or worsening of AKI according to RIFLE and according to the plasma levels of NGAL and CyC.
Lung-protective mechanical ventilation against kidney injury
Acknowledgments We thank J.M. Binnekade for his assistance in the statistical analysis.
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