Online Letters to the Editor

secreted into the proximal renal tubule, such that CLCR measures will generally exceed the true GFR. In this respect, assuming a GFR of 125 mL/min/1.73 m2 and 20% tubular creatinine secretion (4), a CLCR measure of 150 mL/min/1.73 m2 might be considered normal. In those with ARC on day 1, we observed a mean CLCR (95% CI) of 172 mL/min/1.73 m2 (164–181 mL/min/1.73 m2) (Supplemental Appendix A in [2]), suggesting augmented tubular secretion, an increase in filtration, or both. The assertion that this likely represents an increase in GFR is based on the association between augmented CLCR and suboptimal concentrations of β-lactams (5), and vancomycin (6), both of which are primarily cleared by glomerular filtration. The alternate suggestion that this may represent early occult chronic kidney disease is interesting, although the high prevalence of ARC observed would suggest otherwise. Rather we propose this as a transient phenomenon, linked with the underlying inflammatory state, as recently demonstrated by Shimamoto et al (7). As implied, ARC will greatly impact the pharmacokinetics of renally eliminated antibacterial agents, predisposing to subtherapeutic drug exposure. We agree that many factors, including an expanded volume of distribution, distorted protein binding, and altered drug clearance, may contribute to such variability in the critically ill. Therapeutic drug monitoring is therefore a useful tool to combat this heterogeneity. Unfortunately for many agents, such technology is unlikely to be widely available at the bedside for some time, such that ongoing research to identify clinical variables that may assist in optimizing drug exposure is warranted. Our study essentially serves to remind the clinician that an assessment of renal function should focus on more than simply identifying acute kidney injury. In scenarios where ARC is likely, consideration may be given to empirical dose escalation, particularly with less susceptible organisms, although we would rather suggest systematic study of such an approach in the critically ill. Dr. Udy is employed by Alfred Health and lectured for Pfizer Inc. (speakers fees, accommodation, and travel). His institution received grant support from the Royal Brisbane and Women’s Hospital Research Foundation (research scholarship and project grants) and The University of Queensland (project grants). Dr. Baptista received support for travel from Pfizer (European Congress 2013; Intensive Care Medicine). Dr. Lipman served as board member for the Bayer ESICM Advisory Board; consulted for Merk Sharp Dohme, Pfizer Australia, and AstraZeneca; received grant support from AstraZeneca; and lectured for AstraZeneca and Pfizer Australia Pty Ltd. The remaining authors have disclosed that they do not have any potential conflicts of interest. Andrew A. Udy, BHB, MBChB, FCICM, Burns, Trauma, and Critical Care Research Centre, The University of Queensland, Herston, QLD, Australia, and Department of Intensive Care and Hyperbaric Medicine, The Alfred Hospital, Prahran, VIC, Australia; João P. Baptista, MD, Serviço de Medicina Intensiva, Hospitais da Universidade de Coimbra, Coimbra,

Critical Care Medicine

Portugal; Noelle L. Lim, MBBS, MMed (Anaes), FAMS, Anaesthesia and Surgical Intensive Care, Changi General Hospital, Singapore; Gavin M. Joynt, MBBCh, FFA (Crit Care), FHKCA, FHKCA (IC), FHKAM (Anaesthesiology), FCICM, Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin NT, Hong Kong SAR; Paul Jarrett, DipHE (Nursing), Department of Intensive Care Medicine, Royal Brisbane and Womens Hospital, Herston, QLD, Australia; Robert J. Boots, MBBS, PhD, MMedSci, MHAIS, FRACP, FCICM, Burns, Trauma, and Critical Care Research Centre, The University of Queensland, Royal Brisbane and Womens Hospital, Herston, QLD, Australia, and Department of Intensive Care Medicine, Royal Brisbane and Womens Hospital, Herston, QLD, Australia; Jeffrey Lipman, MBBCh, DA, FFA, FFA (Crit Care), FCICM, MD, Burns, Trauma, and Critical Care Research Centre, The University of Queensland, Royal Brisbane and Womens Hospital, Herston, QLD, Australia, and Department of Intensive Care Medicine, Royal Brisbane and Womens Hospital, Herston, QLD, Australia

REFERENCES

1. Koeze J, Aardema H, van Meurs M, et al: Augmented Renal Clearance in Critically Ill: Advantage or Threat. Crit Care Med 2014; 42:e602 2. Udy AA, Baptista JP, Lim NL, et al: Augmented renal clearance in the ICU: Results of a multicenter observational study of renal function in critically ill patients with normal plasma creatinine concentrations. Crit Care Med 2014; 42:520–527 3. Udy AA, Morton FJ, Nguyen-Pham S, et al: A comparison of CKD-EPI estimated glomerular filtration rate and measured creatinine clearance in recently admitted critically ill patients with normal plasma creatinine concentrations. BMC Nephrol 2013; 14:250 4. Breyer MD, Qi Z: Better nephrology for mice–and man. Kidney Int 2010; 77:487–489 5. Udy AA, Varghese JM, Altukroni M, et al: Subtherapeutic initial β-lactam concentrations in select critically ill patients: Association between augmented renal clearance and low trough drug concentrations. Chest 2012; 142:30–39 6. Baptista JP, Sousa E, Martins PJ, et al: Augmented renal clearance in septic patients and implications for vancomycin optimisation. Int J Antimicrob Agents 2012; 39:420–423 7. Shimamoto Y, Fukuda T, Tanaka K, et al: Systemic inflammatory response syndrome criteria and vancomycin dose requirement in patients with sepsis. Intensive Care Med 2013; 39: 1247–1252 DOI: 10.1097/CCM.0000000000000465

Extracorporeal Membrane Oxygenation: Is High Volume Better or Worse for the Patients? To the Editor:

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n a recent issue of Critical Care Medicine, Freeman et al (1) conclude that the mortality of patients who need extracorporeal membrane oxygenation (ECMO) has a reverse relationship with the center’s volume of cases. One cannot argue that ECMO cannulation is a risky procedure and an experienced practitioner is expected to have better results than an inexperienced one. However, this variable is not reported in the article. All the included patients were already placed on ECMO. www.ccmjournal.org

e603

Online Letters to the Editor

So what is determining the ECMO mortality after the cannulation which the authors are measuring? It is the reversibility of the underlying disease and operational ECMO mortality. Operational ECMO mortality is attributed to catastrophic oxygenator failure, uncontrolled bleeding, circuit thrombosis, accidental decannulation, etc. Although operational ECMO mortality occurs and may be indeed underreported, the literature and the overall consensus support that it is not a common problem (2). Most commonly the operational problems lead to treatable complications. Thus, the mortality associated with the reversibility of the underlying disease course is the main variable influencing the total ECMO mortality. Associating mortality due to the natural course of the disease with the center’s volume is conceptually difficult. The decision to place a patient on ECMO includes a strong subjective component. In cases of respiratory failure, one commonly measured variable is the oxygenation index. However, the oxygenation index depends on the mean airway pressure, which depends on the type of ventilation selected by the practitioner. It would have been interesting to have a measure of the severity of the patients’ conditions before they were placed on ECMO, but, unfortunately, such data are not provided in the article. Therefore, improvement of the mortality odds (0.75 for the high-volume centers) has to be attributed either to different natural courses of disease in those centers or to a massive prevalence of lethal complications in the low-volume centers. A more likely assumption is that the high-volume centers are placing some patients on ECMO with less strict criteria than the low-volume centers. Do such patients have better or worst prognosis while on ECMO? The question cannot be answered because the data are not provided. An interesting observation in the article is that the mortality rate of patients with hypoplastic left heart syndrome stage 1 palliation was the same regardless the center volume. One might have expected that treating such complex patients (often requiring cardiac cannulation) in institutions prone to complications would lead to a worse prognosis. In contrast, the mortality rate of a less demanding condition, that is, respiratory syncytial virus–induced respiratory failure, which requires the simpler venovenous cannulation, was significantly better at high-volume centers. Is this a clue that the low-volume centers have more vigorous criteria for placing patients on ECMO? The authors conclude “that a minimum ECMO volume may be required to maximize ECMO program performance and achieve better survival.” Perhaps, such a statement is true, but it is not supported by the data presented. In addition, overzealous placement on ECMO can be equally injurious for the patients. Dr. Spentzas conceptualized, designed, drafted, and approved the final manuscript as submitted. The author has disclosed that he does not have any potential conflicts of interest. Thomas Spentzas, MD, MS, Department of Pediatrics, Division of Critical Care, LeBonheur Children’s Hospital, University of Tennessee, Memphis, TN e604

www.ccmjournal.org

REFERENCES

1. Freeman CL, Bennett TD, Casper TC, et al: Pediatric and Neonatal Extracorporeal Membrane Oxygenation: Does Center Volume Impact Mortality? Crit Care Med 2014; 42:512–519 2. ECLS Registry Report International Summary, 2013. Available at: http://www.elso.org. Accessed March 4, 2014 DOI: 10.1097/CCM.0000000000000393

The author replies:

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thank Spentzas (1) for his comments and the opportunity to address his observations and questions regarding our work. An obvious limitation of our study was that we only evaluated subjects treated with extracorporeal membrane oxygenation (ECMO). We were not able to capture all patients at risk for severe organ failure that might lead to consideration of ECMO nor those who died without a trial of ECMO. Neither detailed physiologic information nor clinical decision-making information were available for analysis. ECMO mortality can be attributable to the use of ECMO in patients with disease processes that do not reverse within the time frame of reliable ECMO support or from complications of acute care which may be related to pre-ECMO care or complications of ECMO. Determining when to deploy ECMO support is indeed a difficult decision that relies heavily on the individual practitioner. A degree of subjectivity certainly exists. We cannot know how provider-specific decision making impacts ECMO candidacy. It is conceivable that larger programs may be more consistent in consideration of clinical features and candidacy for ECMO. Many ECMO centers have both guidelines and a process for multiple critical care providers to consider individual patients who are defined as borderline or are outside the usual center candidate guidelines. It may be that small-volume centers are reluctant to use ECMO and reserve it for more severely ill patients. An alternative speculation is that larger centers with greater ECMO experience identify patients with reversible disease more accurately and reserve ECMO for patients with greater potential to benefit from it. The assumption that small-volume centers are potentially reserving ECMO for the “more severely ill” may be true and we cannot exclude that possibility. However, we also cannot exclude the contrary assertion that larger centers have “sicker” patients on average or alternatively the neutral hypothesis that ECMO inclusion criteria are similar across center volume. Because we do not know what fraction of children at each center is “at risk” for severe organ failure, we cannot make conclusive statements regarding patient selection and center size. However, a prior study by Bucher et al (2), utilizing the Pediatric Health Information System database to assess inhospital mortality for infants with congenital diaphragmatic hernia, found similar ECMO use across centers but better survival among medium- and high-volume surgical centers as compared with low-volume centers. Similarly, higher institutional surgical volume was associated with lower mortality among patients with single-ventricle heart disease (3). August 2014 • Volume 42 • Number 8

Extracorporeal membrane oxygenation: is high volume better or worse for the patients?

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