Annick A. N. M. Royakkers

Ventilation with lower tidal volumes as compared with conventional tidal volumes for patients without acute lung injury: a preventive randomized controlled trial

IntroductionRecent cohort studies have identified the use of large tidal volumes as a major risk factor for development of lung injury in mechanically ventilated patients without acute lung injury (ALI). We compared the effect of conventional with lower tidal volumes on pulmonary inflammation and development of lung injury in critically ill patients without ALI at the onset of mechanical ventilation.MethodsWe performed a randomized controlled nonblinded preventive trial comparing mechanical ventilation with tidal volumes of 10 ml versus 6 ml per kilogram of predicted body weight in critically ill patients without ALI at the onset of mechanical ventilation. The primary end point was cytokine levels in bronchoalveolar lavage fluid and plasma during mechanical ventilation. The secondary end point was the development of lung injury, as determined by consensus criteria for ALI, duration of mechanical ventilation, and mortality.ResultsOne hundred fifty patients (74 conventional versus 76 lower tidal volume) were enrolled and analyzed. No differences were observed in lavage fluid cytokine levels at baseline between the randomization groups. Plasma interleukin-6 (IL-6) levels decreased significantly more strongly in the lower-tidal-volume group ((from 51 (20 to 182) ng/ml to 11 (5 to 20) ng/ml versus 50 (21 to 122) ng/ml to 21 (20 to 77) ng/ml; P = 0.01)). The trial was stopped prematurely for safety reasons because the development of lung injury was higher in the conventional tidal-volume group as compared with the lower tidal-volume group (13.5% versus 2.6%; P = 0.01). Univariate analysis showed statistical relations between baseline lung-injury score, randomization group, level of positive end-expiratory pressure (PEEP), the number of transfused blood products, the presence of a risk factor for ALI, and baseline IL-6 lavage fluid levels and the development of lung injury. Multivariate analysis revealed the randomization group and the level of PEEP as independent predictors of the development of lung injury.ConclusionsMechanical ventilation with conventional tidal volumes is associated with sustained cytokine production, as measured in plasma. Our data suggest that mechanical ventilation with conventional tidal volumes contributes to the development of lung injury in patients without ALI at the onset of mechanical ventilation.Trial registrationISRCTN82533884

Plasma levels of surfactant protein D and KL-6 for evaluation of lung injury in critically ill mechanically ventilated patients

BackgroundPreventing ventilator-associated lung injury (VALI) has become pivotal in mechanical ventilation of patients with acute lung injury (ALI) or its more severe form, acute respiratory distress syndrome (ARDS). In the present study we investigated whether plasma levels of lung-specific biological markers can be used to evaluate lung injury in patients with ALI/ARDS and patients without lung injury at onset of mechanical ventilation.MethodsPlasma levels of surfactant protein D (SP-D), Clara Cell protein (CC16), KL-6 and soluble receptor for advanced glycation end-products (sRAGE) were measured in plasma samples obtained from 36 patients - 16 patients who were intubated and mechanically ventilated because of ALI/ARDS and 20 patients without lung injury at the onset of mechanical ventilation and during conduct of the study. Patients were ventilated with either a lung-protective strategy using lower tidal volumes or a potentially injurious strategy using conventional tidal volumes. Levels of biological markers were measured retrospectively at baseline and after 2 days of mechanical ventilation.ResultsPlasma levels of CC16 and KL-6 were higher in ALI/ARDS patients at baseline as compared to patients without lung injury. SP-D and sRAGE levels were not significantly different between these patients. In ALI/ARDS patients, SP-D and KL-6 levels increased over time, which was attenuated by lung-protective mechanical ventilation using lower tidal volumes (P = 0.02 for both biological markers). In these patients, with either ventilation strategy no changes over time were observed for plasma levels of CC16 and sRAGE. In patients without lung injury, no changes of plasma levels of any of the measured biological markers were observed.ConclusionPlasma levels of SP-D and KL-6 rise with potentially injurious ventilator settings, and thus may serve as biological markers of VALI in patients with ALI/ARDS.

Serum cystatin C-A useful endogenous marker of renal function in intensive care unit patients at risk for or with acute renal failure?

Critically ill patients are at high risk for developing acute renal failure (ARF). The prevention of ARF is of outmost importance in order to improve the increased morbidity and mortality associated with ARF. Unfortunately, there is lack of adequate endogenous markers that can identify renal dysfunction early - this hampers timely application of measures to prevent further renal damage. The use of exogenous markers of renal function is not only time-consuming but also expensive, and therefore can not be used on a regular basis in the intensive care unit. Both the presently used endogenous and exogenous markers are not reliable during continuous renal replacement therapy (CRRT) because these markers are removed by the therapy itself impeding early detection of recovering of renal function. Cystatin C has been proposed as an alternative endogenous marker of renal function for more than 15 years. In this manuscript we review the literature on the role of cystatin C as marker for renal function, focusing on the critically ill patient. Serum cystatin C concentrations have been found to relate to renal impairment and suggest that cystatin C is more sensitive to detect mild decreases in GFR. Cystatin C could be an important tool both to recognize early renal dysfunction and to identify renal recovery while on CRRT in the critically ill patient, however, we are in need of more studies.

Correlation of biomarkers for parasite burden and immune activation with acute kidney injury in severe falciparum malaria

BackgroundAcute kidney injury (AKI) complicating severe Plasmodium falciparum malaria occurs in up to 40% of adult patients. The case fatality rate reaches 75% in the absence of renal replacement therapy (RRT). The precise pathophysiology of AKI in falciparum malaria remains unclear. Histopathology shows acute tubular necrosis with localization of host monocytes and parasitized red blood cells in the microvasculature. This study explored the relationship of plasma soluble urokinase-type plasminogen activator receptor (suPAR), as a proxy-measure of mononuclear cell activation, and plasma P. falciparum histidine rich protein 2 (Pf HRP2), as a measure of sequestered parasite burden, with AKI in severe malaria.MethodsAdmission plasma suPAR and Pf HRP2 concentrations were assessed in Bangladeshi adults with severe falciparum malaria (n = 137). Patients were stratified according to AKI severity based on admission creatinine clearance.ResultsA total of 106 (77%) patients had AKI; 32 (23%), 42 (31%) and 32 (23%) were classified into ‘mild, ‘moderate’ and ‘severe’ AKI groups, respectively. Plasma suPAR and Pf HRP2 concentrations increased with AKI severity (test-for-trend P <0.0001) and correlated with other markers of renal dysfunction. Admission plasma suPAR and Pf HRP2 concentrations were higher in patients who later required RRT (P <0.0001 and P = 0.0004, respectively). In a multivariate analysis, both increasing suPAR and Pf HRP2 were independently associated with increasing urine neutrophil gelatinase-associated lipocalin concentration, a marker of acute tubular necrosis (β = 16.54 (95% CI 6.36-26.71) and β = 0.07 (0.02-0.11), respectively).ConclusionsBoth sequestered parasite burden and immune activation contribute to the pathogenesis of AKI in severe falciparum malaria.

Laboratory prediction of the requirement for renal replacement in acute falciparum malaria

BackgroundAcute renal failure is a common complication of severe malaria in adults, and without renal replacement therapy (RRT), it carries a poor prognosis. Even when RRT is available, delaying its initiation may increase mortality. Earlier identification of patients who will need RRT may improve outcomes.MethodProspectively collected data from two intervention studies in adults with severe malaria were analysed focusing on laboratory features on presentation and their association with a later requirement for RRT. In particular, laboratory indices of acute tubular necrosis (ATN) and acute kidney injury (AKI) that are used in other settings were examined.ResultsData from 163 patients were available for analysis. Whether or not the patients should have received RRT (a retrospective assessment determined by three independent reviewers) was used as the reference. Forty-three (26.4%) patients met criteria for dialysis, but only 19 (44.2%) were able to receive this intervention due to the limited availability of RRT. Patients with impaired renal function on admission (creatinine clearance < 60 ml/min) (n = 84) had their laboratory indices of ATN/AKI analysed. The plasma creatinine level had the greatest area under the ROC curve (AUC): 0.83 (95% confidence interval 0.74-0.92), significantly better than the AUCs for, urinary sodium level, the urea to creatinine ratio (UCR), the fractional excretion of urea (FeUN) and the urinary neutrophil gelatinase-associated lipocalcin (NGAL) level. The AUC for plasma creatinine was also greater than the AUC for blood urea nitrogen level, the fractional excretion of sodium (FeNa), the renal failure index (RFI), the urinary osmolality, the urine to plasma creatinine ratio (UPCR) and the creatinine clearance, although the difference for these variables did not reach statistical significance.ConclusionsIn adult patients with severe malaria and impaired renal function on admission, none of the evaluated laboratory indices was superior to the plasma creatinine level when used to predict a later requirement for renal replacement therapy.

Lung-protective mechanical ventilation does not protect against acute kidney injury in patients without lung injury at onset of mechanical ventilation

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 (V(T), 10 mL/kg) with low tidal volume (V(T), 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 = .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.

Systemic and Urinary Neutrophil Gelatinase-Associated Lipocalins Are Poor Predictors of Acute Kidney Injury in Unselected Critically Ill Patients

Background. Neutrophil gelatinase-associated lipocalin (NGAL) in serum and urine have been suggested as potential early predictive biological markers of acute kidney injury (AKI) in selected critically ill patients. Methods. We performed a secondary analysis of a multicenter prospective observational cohort study of unselected critically ill patients. Results. The analysis included 140 patients, including 57 patients who did not develop AKI, 31 patients who developed AKI, and 52 patients with AKI on admission to the ICU. Levels of sNGAL and uNGAL on non-AKI days were significantly lower compared to levels of sNGAL on RIFLERISK days, RIFLEINJURY days, and RIFLEFAILURE days. The AUC of sNGAL for predicting AKI was low: 0.45 (95% confidence interval (CI) 0.27–0.63) and 0.53 (CI 0.38–0.67), 2 days and 1 day before development of AKI, respectively. The AUC of uNGAL for predicting AKI was also low: 0.48 (CI 0.33–0.62) and 0.48 (CI 0.33–0.62), 2 days and 1 day before development of AKI, respectively. AUC of sNGAL and uNGAL for the prediction of renal replacement therapy requirement was 0.47 (CI 0.37–0.58) and 0.26 (CI 0.03–0.50). Conclusions. In unselected critically ill patients, sNGAL and uNGAL are poor predictors of AKI or RRT.

Serum levels of N-terminal proB-type natriuretic peptide in mechanically ventilated critically ill patients--relation to tidal volume size and development of acute respiratory distress syndrome.

BackgroundSerum levels of N–terminal proB–type natriuretic peptide (NT–proBNP) are elevated in patients acute respiratory distress syndrome (ARDS). Recent studies showed a lower incidence of acute cor pulmonale in ARDS patients ventilated with lower tidal volumes. Consequently, serum levels of NT–proBNP may be lower in these patients.We investigated the relation between serum levels of NT–proBNP and tidal volumes in critically ill patients without ARDS at the onset of mechanical ventilation.MethodsSecondary analysis of a randomized controlled trial of lower versus conventional tidal volumes in patients without ARDS. NT–pro BNP were measured in stored serum samples. Serial serum levels of NT–pro BNP were analyzed controlling for acute kidney injury, cumulative fluid balance and presence of brain injury. The primary outcome was the effect of tidal volume size on serum levels of NT–proBNP. Secondary outcome was the association with development of ARDS.ResultsSamples from 150 patients were analyzed. No relation was found between serum levels of NT–pro BNP and tidal volume size. However, NT-proBNP levels were increasing in patients who developed ARDS. In addition, higher levels were observed in patients with acute kidney injury, and in patients with a more positive cumulative fluid balance.ConclusionSerum levels of NT–proBNP are independent of tidal volume size, but are increasing in patients who develop ARDS.

Bronchoalveolar Activation of Coagulation and Inhibition of Fibrinolysis during Ventilator-Associated Lung Injury

Background and Objective. Bronchoalveolar coagulopathy is a characteristic feature of pulmonary inflammation. We compared bronchoalveolar and systemic levels of coagulation in patients who did and patients who did not develop ventilator-associated lung injury (VALI). Methods. Secondary analysis of a randomized controlled trial evaluating the effect of lower tidal volumes versus conventional tidal volumes in patients without acute lung injury or acute respiratory distress syndrome at the onset of mechanical ventilation. Results. Ten patients with VALI and 10 random control patients without lung injury during the course of mechanical ventilation, but all ventilated with conventional tidal volumes, were compared. Patients who developed VALI showed both bronchoalveolar activation of coagulation (increase in thrombin–antithrombin complex levels P < 0.001 versus baseline) and inhibition of fibrinolysis (decline in plasminogen activator activity P < 0.001 versus baseline). The later seemed to be dependent on higher levels of plasminogen activator inhibitor type 1 (P = 0.001 versus baseline). Patients who developed VALI also showed elevated systemic thrombin-antithrombin complex levels and decreased systemic plasminogen activator activity levels. Conclusions. VALI is characterized by bronchoalveolar coagulopathy. Systemic and bronchoalveolar coagulopathy at the onset of mechanical ventilation may be a risk factor for developing VALI in patients ventilated with conventional tidal volumes.

Of hypes and hopes: N-acetylcysteine and cystatin C

Of Hypes and Hopes: N-Acetylcysteine and Cystatin C There are several gold-standard methods for determining glomerular filtration rate (GFR), including the inulin clearance and radionuclide clearance techniques. Unfortunately, these techniques are expensive and laborious and therefore not routinely used in clinical practice. Systemic creatinine concentrations and clearance of creatinine on the basis of 24-hour urine collections are frequently used alternative indicators of GFR. However, systemic creatinine concentrations are affected by muscle mass [1] and diet [2] and vary with age and sex [3]. Of importance, as systemic creatinine concentrations rise, tubular secretion increases, leading to overestimation of GFR in patients with moderate to severe decreases in renal function [4]. More accurate and practical indicators, preferably an endogenous marker of GFR, are needed. In the AJR, Poletti et al. [5] studied the effect of IV administration of N-acetylcysteine (NAC) on systemic creatinine and cystatin C concentrations in patients with renal insufficiency who underwent emergency contrastenhanced CT. Patients were randomized to two groups. In the first group, in addition to hydration, patients received NAC. Patients in the second group received hydration only. A 25% or greater increase in systemic creatinine concentration was found in nine of 43 patients in the control group and in two of 44 patients in the NAC group (p = 0.026). However, a 25% or greater increase in systemic cystatin C concentration was found in nine of 40 patients in the control group and in seven of 41 patients in the NAC group (p = 0.59). The authors correctly conclude that although NAC appears protective against contrast-induced nephrotoxicity when using systemic creatinine concentrations to assess renal function, no effect is found when serum cystatin C concentrations are used. The authors deserve compliments for their efforts. This study extends a previous study by Hoffmann et al. [6]. In this study, volunteers with normal renal function who did not receive contrast medium received NAC. Surrogate markers of renal function, including systemic creatinine and cystatin C concentrations were measured immediately before and 4 and 48 hours after administration of NAC. There was a significant decrease in the mean systemic creatinine concentration (p < 0.05). The cystatin C concentrations, however, did not change significantly. Thus, it may be that NAC has a direct effect on the systemic creatinine concentration, whereas it has no effect on preventing contrast-induced nephrotoxicity [6, 7]. Several reports now suggest cystatin C to be a reliable marker of GFR [8]. The study of Poletti et al. [5] adds to this suggestion. Before the protective effects of any agent against contrast material–induced nephrotoxicity are considered, the direct effects thereof on creatinine levels should be assessed. In addition, future trials regarding protective measures against contrast-induced nephrotoxicity should preferentially be measured directly—or at least additional markers of the renal function (such as cystatin C concentrations) have to be assessed. Marcus J. Schultz Academic Medical Center, University of Amsterdam Amsterdam, The Netherlands Annick A. N. M. Royakkers Tergooi Hospitals Blaricum, The Netherlands Catherine S. C. Bouman Academic Medical Center, University of Amsterdam Amsterdam, The Netherlands References 1. Perrone RD, Madias NE, Levey AS. Serum creatinine as an index of renal function: new insights into old concepts. Clin Chem 1992; 38:1933–1953 2. Jacobsen FK, Christensen CK, Mogensen CE, Heilskov NS. Evaluation of kidney function after meals. Lancet 1980; 1:319 3. James GD, Sealey JE, Alderman M, et al. A longitudinal study of urinary creatinine and creatinine clearance in normal subjects: race, sex, and age differences. Am J Hypertens 1988; 1:124–131 4. Levey AS, Berg RL, Gassman JJ, Hall PM, Walker WG. Creatinine filtration, secretion and excretion during progressive renal disease: Modification of Diet in Renal Disease (MDRD) Study Group. Kidney Int Suppl 1989; 27:S73–S80 5. Poletti PA, Saudan P, Platon A, et al. IV N-acetylcysteine and emergency CT: use of serum creatinine and cystatin C as markers of radiocontrast nephrotoxicity. AJR 2007; 189:687–692 6. Hoffmann U, Fischereder M, Kruger B, Drobnik W, Kramer BK. The value of N-acetylcysteine in the prevention of radiocontrast agent–induced nephropathy seems questionable. J Am Soc Nephrol 2004; 15:407–410 7. Hoffmann U, Banas B, Fischereder M, Kramer BK. N-acetylcysteine in the prevention of radiocontrastinduced nephropathy: clinical trials and end points. Kidney Blood Press Res 2004; 27:161–166 8. Royakkers AA, van Suijlen JD, Hofstra LS, et al. Serum cystatin C: a useful endogenous marker of renal function in intensive care unit patients at risk for or with acute renal failure? Curr Med Chem 2007; 14:2314–2317