Title: High creatinine clearance in critically ill patients with community-acquired acute infectious meningitis

Transcription

1 Author's response to reviews Title: High creatinine clearance in critically ill patients with community-acquired acute infectious meningitis Authors: Alexandre Lautrette Thuy-Nga Phan Lemlih Ouchchane Ali AitHssain Vincent Tixier Anne-Elisabeth Heng Bertrand Souweine Version: 4 Date: 4 September 2012 Author's response to reviews: see over

2 The Editor in Chief BMC Nephrology Department of ICU and Nephrology Gabriel Montpied Teaching Hospital 54 rue Montalembert BP Clermont Ferrand Cedex 1 FRANCE Tuesday, September 4, 2012 Dear Sir, Please find enclosed the revised version of the BMC Nephrology manuscript entitled High creatinine clearance in critically ill patients with community-acquired acute infectious meningitis. We would like to thank the reviewers for their help in improving our manuscript. All the comments and suggestions have been taken into account and we have included pointby-point replies to the reviewers remarks. As the corresponding author, I remain at your disposal for any further information. Sincerely yours, Dr A Lautrette 1

3 We are grateful to the Reviewers for making constructive comments that have helped us to improve our manuscript. Replies to Reviewer Andrew Udy Thank-you for the opportunity to review this interesting work by Lautrette and colleagues. This report adds to the weight of growing literature describing the prevalence of augmented renal clearance (ARC) in subsets of critically ill patients. The data should be of interest to a wide variety of clinicians, least of which include infectious disease specialists and intensive care physicians. The clinical imperative to optimize antibacterial dosing in this group of patients is well established, although very limited conclusions can be drawn in reference to clinical outcomes and pharmacokinetic end-points from the data provided. Despite this, there appears to be a very clear signal that such patients are likely to manifest ARC, clearly warranting further investigation. Major Compulsory Revisions: 1) Can the authors provide clarification on how they have dealt with repeated measures in their analysis? Specifically, it is noted that a significant number of patients did not remain in the ICU for the full 7 days, suggesting that individual patients may have contributed differing numbers of measured creatinine clearances (CLCR) / mathematically derived estimates? We agree. If we take into account only one value per patient - the lowest measured creatinine clearances in patients with high CrCl, and the highest in patients without high CrCl - the best threshold for the Cockcroft-Gault formula to predict high CrCl is 101ml/min/1.73m² (sensitivity: 0.93, specificity: 0.82, AUC = 0.92±0.05), similar to the threshold reported in the original manuscript (101ml/min/1.73m² with sensitivity: 0.96, specificity: 0.75, AUC = 2

4 0.90±0.03). For the simplified MDRD equation, the best threshold was 103ml/min/1.73m² (sensitivity: 0.93, specificity: 0.77, AUC = 0.91±0.06) instead of 108ml/min/1.73m² (sensitivity: 0.91, specificity: 0.80, AUC = 0.88±0.03) in the original manuscript. The difference between these two thresholds is not clinically significant for a screening tool. 2) Is it appropriate to treat each measure as an independent event? This approach should be stated in the manuscript. See reply above. We treated each measure as an independent event. This point has been included in the Methods section (Statistical analysis): Each measure was treated as an independent event. 3) How was the patients height and weight measured (for calculation of BSA)? The patients height and weight were measured in a supine position on ICU admission with a tape measure and a Hill Rom bed (Medicraft, Marrickville NSW, Australia), respectively. This point is mentioned in the Methods section. 4) It is not clear at what time point (eg at ICU admission or at any subsequent point) some of the therapeutic variables were recorded. Eg. the requirement for mechanical ventilation? or Vasopressors? This point has been taken into account. In table 1, the data are presented with the time point at which they were recorded (on admission or during ICU stay). 3

5 5) Bland-Altman analysis is a key technique for the interpretation of diagnostic accuracy / tests. The details of this approach should be provided in the statistical analysis section, prior to reporting the results thereof later in the manuscript. We have added the sentence in Methods section (Statistical analysis): For comparisons between measurement methods, we built a Bland-Altman plot between differences and averages seeking possible biases and outliers. 6) Can the authors expand on why they have chosen a threshold value of > 140ml/min/1.73m2? The relevant literature would suggest a cut-off value of > 130ml/min/1.73m2 being associated with sub-therapeutic antibacterial drug concentrations? We agree with reviewer. However, there is no consensual definition of augmented renal clearance in the literature. Among the major papers in this field, three used a cut-off value > 130ml/min/1.73m² ((i) Baptista, Critical Care, 2011; (ii) Udy, Chest, 2011 and (iii) Baptista, Int J Antimicrob Agents 2012) and three others used thresholds >120 ml/min/1.73m² (Fuster- Lluch, Anaesth Intensive Care, 2008 and Minville, Critical Care, 2011); > 150 ml/min/1.73m² in females and > 160 ml/min/1.73m² in males (Udy, Anesth Analg, 2010). The high cut-off value used in our study leads to increased specificity in the diagnosis of augmented renal clearance. Minor Essential Revisions: Abstract, Results section Line 5 - suggest to change to "..with a negative likelihood ratio of 0.06." 4

6 Line 6/7 - suggest to change to ".. with a negative likelihood ratio of 0.11" Abstract, Conclusions section Recommend changing this to suggest that the mathematical formulae may be useful as a "screening" tool to identify high ClCr. A surrogate would suggest it can be used in place of, which given the lack of accuracy of these estimates at higher ClCr, is not the case. We have rephrased the sentence: The estimated methods of CrCl could be used as a screening tool to identify high ClCr. Background section, 2nd paragraph, line 2 - "postoperatives" is not a word. Suggest change to " in the post-operative setting" or similar Results section, 1st paragraph, line 4 - suggest change "fungi" to "fungal" Discussion section, 1st paragraph, line 2 - suggest using the term "screened for" rather than predicted (see earlier comments), given that the authors focus on a lower limit value, below which ARC is going to be unlikely. Discussion section, 3rd paragraph, line 21 - suggest using "screening tool" rather than "surrogate" (see earlier comments) We have rephrased the sentence: Our findings are in agreement with previously published data and suggest that the estimated methods of CrCl could be used as a screening tool to diagnose high ClCr with a 101 ml/min/1.73m² threshold for Cockcroft-Gault formula and a 108 ml/min/1.73m² threshold for simplified MDRD equation. 5

7 Replies to Reviewer Jean-Philippe Haymann A Lautrette et al report in their work the high incidence of hyperfiltration in a series of 32 patients hospitalized for meningitis within the seven first day of ICU admission. They furthermore assess threshold value for cockcroft and MDRD equations to assess hyperfiltration in a daily practice. To my view, the authors have adequately answer previous reviewers concerns. There is however mainly two limitations in this study : 1) the measurement of creatinine clearance that do not allow a discrimination between a high GFR and/or tubular creatinine secretion We agree with the reviewer. Tubular secretion of creatinine increases with decreasing GFR (G Vervoort et al.: Assessment of glomerular filtration rate in healthy subjects and normoalbuminuric diabetic patients: validity of a new MDRD prediction equation. Nephrol Dial Transplant (2002) 17: ). As shown in Figure 1 of this article, when GFR is high, tubular creatinine secretion is very low. Thus, this suggests that the augmented creatinine clearance observed in our patients is related to augmented GFR rather than to augmented tubular creatinine secretion. 2) The creatinine measurement using the Jaffe method instead of enzymatic method We agree with the reviewer. Between January 2006 and December 2009, the biochemistry laboratory of our hospital used the compensated Jaffe method (we have added this point in the Methods section) to measure creatinine, like 80% of biochemistry laboratories in France (French report of the Haute Autorité de Santé on Évaluation du débit de filtration glomérulaire, et du dosage de la créatininémie dans le diagnostic de la maladie rénale chronique chez l adulte, December 2011). The enzymatic method is more accurate in 6

8 measuring creatinine than the Jaffe method. However, the error of measurement with the compensated Jaffe method is lower than 2µmol/L when serum creatinine is < 76µmol/L ( (i) Delanghe JR et al.: Trueness verification of actual creatinine assays in the European market demonstrates a disappointing variability that needs substantial improvement. An international study in the framework of the EC4 creatinine standardization working group. Clin Chem Lab Med 2008; 46(9): ; (ii) Miller WG et al.: Creatinine measurement: state of the art in accuracy and interlaboratory harmonization. Arch Pathol Lab Med 2005; 129(3): ). We think that the error in creatinine measurement with the compensated Jaffe method did not have any impact on our results. Despite these limitations, these findings lay the stress on the requirement to adapt the posology of some antibiotics in these circumstances. Discretionary Revisions: As serum creatinine was performed using a Jaffe method, 24 hours creatinine clearance is underestimated compared to enzymatic creatinine method. It would be however interesting to have an idea of the magnitude of (24 hours) creatinine clearance increase: what is the mean percentage of creatinine clearance increase in the population experiencing hyperfiltration (ratio between Clcr max and ClCr at discharge)? A ratio above 100% would suggest a very likely tubular secretion at play (in part...). As the reviewer suggested we determined the ratio between CrCl max and CrCl at discharge in 14 of 15 patients with high CrCl during the first 7 days in the ICU (one patient had renal failure requiring dialysis at ICU discharge). All patients had a ratio above 100%. The mean 7

9 ratio was 183% +/- 58. We do not know if this can be considered as a strong argument for tubular secretion. 8