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Nephrol Dial Transplant (2013) 28: 2723–2728 doi: 10.1093/ndt/gft086 Polar Views in Nephrology Con: Dialy- and continuous renal replacement (CRRT) trauma during renal replacement therapy: still under-recognized but on the way to better diagnostic understanding and prevention 1 Internist-Nephrologist-Intensivist Universitair Ziekenhuis Brussel, Patrick M. Honoré1, Vrije Universitieit Brussel, Brussels, Belgium, Rita Jacobs2, 2 Intensive Care Dept, Universitair Ziekenhuis Brussel, Vrije 3 Olivier Joannes-Boyau , Universiteit Brussel, Brussels, Belgium, 3 Haut Leveque University Hospital of Bordeaux, University of 2 Elisabeth De Waele , Bordeaux 2, Pessac, France and Viola Van Gorp2, Willem Boer 4 Department of Anaesthesiology and Critical Care Medicine, 4 Ziekenhuis Oost-Limburg, Genk, Belgium and Herbert D. Spapen2 Keywords: AKI, antibiotic dosing, CRRT-trauma, dialytrauma Correspondence and offprint requests to: Patrick Honoré; E-mail: [email protected], [email protected] replacement (CRRT) trauma’—to underscore the importance of applying CRRT with the least possible harm to the patient [1, 2]. Basically, they suggested to counterbalance CRRT trauma by anticipating inherent CRRT-related and -induced abnormalities. As such, they intended to avoid that overdone apprehension for CRRT-trauma in haemodynamically compromised patients might incite clinicians to opt for intermittent haemodialysis (IHD) as a less hazardous procedure. This would definitely go against the pooled results from the ATN [3] and RENAL [4] trials, showing that IHD in haemodynamically unstable patients with acute kidney injury (AKI) increased the risk of remaining dialysis dependence by 50%! Although other factors might have contributed to the observed worse renal recovery in IHD (e.g. the later start of treatment and the suspicion of more baseline structural kidney changes in the IHD patient group of the ATN study [3]), key opinion leaders actually recommend CRRT as the treatment of choice in this population [5]. Nevertheless, the use of CRRT in critically ill patients not only implies a rigorous knowledge of its technical applications and pitfalls, but also a better recognition, understanding, evaluation and finally prevention of any possible associated CRRT trauma. A B S T R AC T Dialy- and continuous renal replacement (CRRT) trauma are still un(der)recognized conditions that may be encountered during blood purification therapy. This particular form of trauma requires timely identification, a better understanding of pathophysiology and a definition of at-risk groups to prevent or correct any associated unwarranted effects. Among others, progress in the knowledge of antimicrobial pharmacokinetic/pharmacodynamic (PK/PD) behaviour during CRRT to obtain more efficient antimicrobial therapy with less sideeffects is one key example of limiting CRRT trauma. Optimal anticipation and prevention of CRRT trauma will preserve the safe use of CRRT in haemodynamically unstable critically ill patients with acute kidney injury (AKI), especially in septic patients who are at the greatest risk. ‘ D I A LY T R A U M A ’ A N D ‘ C R R T T R A U M A ’ : W H AT ’ S I N A N A M E ? Maynar-Moliner et al. recently proposed the concept of ‘dialytrauma’—and in a broader sense ‘continuous renal © The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. 2723 the discussions are still ongoing, the ‘Kidney Disease Improving Global Outcomes’ guidelines currently propose a dose of 25 mL/kg/h regardless of whether septic AKI is present or not [10]. The use of a uniform dose of 25 mL/kg/h might help to reduce the incidence of CRRT trauma. P O L A R V I E W S I N N E P H R O LO G Y C R R T T R A U M A : P AT H O P H Y S I O LO G Y A N D P O P U L AT I O N AT R I S K A key issue regarding CRRT trauma is that non-selective transport of molecules through membranes not only eliminates toxins from the plasma but, depending on the operational characteristics, inevitably also normal blood constituents and even some valuable substances. CRRT studies in intensive care unit (ICU) patients emphasize the positive correlation between haemofiltration dose and the frequency and magnitude of such losses, all of them being potentially harmful if not timely recognized and corrected [3–5]. CRRT trauma encompasses acid–base disorders, but also loss of heat, electrolytes, carbohydrates, nitrogen, watersoluble vitamins, trace elements and ( particularly antimicrobial) drugs [1, 2]. Instead of doing a classic listing and description of all constituents of CRRT trauma which have been already described in detail in previous papers including our recent review [1, 2], we decide to choose those constituents that are most important (as antibiotics losses) and also because they are the subject of discussion among the world of critical care nephrology. Therefore, an emphasis has been made on the constituents of CRRT-trauma related to the type of therapy, dose, continuous mode, provision of care by an intensivist or nephrologist, pharmacokinetics characteristics of ICU population and operational properties of membrane hydraulics when modifying the provision of dose. Septic patients are a specific high-risk group for CRRTtrauma as they generally receive higher CRRT dose and longer treatment duration, often have depleted macro- and micronutrient stores and face a worsening of the septic process when antimicrobials become underdosed [1, 2]. ANTIBIOTIC DOSING IN CRRT: ARE I N T E N S I V I S T S R E A L LY S O B A D LY INFORMED? Extracorporeal plasma clearance effectively replaces the lost ‘natural’ renal clearance. Consequently, drugs which are potentially and/or significantly removed by haemofiltration should be identified. Dose adaptation is based on correct knowledge of the pharmacokinetic/pharmacodynamic (PK/ PD) behaviour of the drug. Crucial factors that determine PK/PD of antimicrobial agents during renal replacement therapy include protein binding, volume of distribution and proportional renal clearance [11]. Antimicrobial dosing is relatively well standardized in AKI treated by IHD, but extrapolating these dose recommendations to continuous plasma clearance will lead to underdosing and thus significant CRRT trauma. However, the practice of estimating and adapting the dose of a drug in CRRT on its PK/PD-derived parameters for IHD has become obsolete! Indeed, the last decade has witnessed an explosion of publications on PK/PD-derived antimicrobial dosing in CRRT. The pioneering work of various research teams [11–16] allowed the creation, refinement and optimation of the guidelines for the bedside clinician. Another important aspect that has contributed to improved infection treatment in critically ill patients with AKI is the increasing role of ICU nephrologists highly acquainted with CRRT programmes [17–20]. In most European university and tertiary care hospitals, an ICU nephrologist takes responsibility for coordinating CRRT policy, which includes steering the technique within the delicate confines of antimicrobial dosing and complex forms of mechanical ventilation (e.g. permissive hypercapnic ventilation) [21]. Finally, practice patterns in the management of AKI associated with critical illness have changed considerably since the last survey published in 2006 [22]. In summary, a considerable effort has been made to improve the ‘quality’ of CRRT in critically ill patients. In this context, some important issues (e.g. antibiotic adsorption during CRRT with highly adsorptive membranes) have been remarkably neglected and definitely need more in-depth study [23]. C R R T D O S I N G I N I C U P AT I E N T S W I T H A K I : AN ONGOING STORY Based on the results of two large randomized studies, including more than 3000 patients [3, 4], the CRRT dose for treatment of non-septic AKI was reduced to 25 mL/kg/h. Aggregated data from both the trials incontestably demonstrated the superiority of CRRT to IHD in haemodynamically compromised AKI patients regarding renal recovery [5]. As septic patients with AKI were not specifically studied, the recommended dose in this population remained fixed at 35 mL/kg/h [6, 7]. Additional information on CRRT dosing in septic patients with AKI awaits publication of the recently completed prospective randomized IVOIRE (hIgh VOlume in Intensive caRE) study which compared CRRT doses of 35 and 70 mL/kg/h [8]. It must be acknowledged that measures that either prevent or reduce expected side-effects of a useful or necessary technique are relatively easily implemented in the intensive care setting [9]. Therefore, instead of upfront replacing CRRT by IHD, clinicians first should focus on prevention, diagnosis and adequate treatment of CRRT-trauma. A practical problemsolving guide for safe use of CRRT in haemodynamically unstable ICU patients with AKI is herein a prerequisite. While H Y P O P H O S P H ATA E M I A — A Q U A L I T Y I N D I C AT O R O F I C U C A R E R AT H E R T H A N THE ‘COAL MINE CANARY’ FOR CRRT TRAUMA AND ANTIBIOTIC UNDERDOSING! Several authors consider hypophosphataemia, the incidence of which ranges between 10.9% and 66%, as a warning sign to re-evaluate drug dosing during CRRT [1–4, 6]. The clinical effect of hypophosphataemia remains unclear, yet phosphorus is involved in many vital processes such as tissue 2724 P.M. Honoré et al. I S T H E L AC K O F S U R V I VA L D I F F E R E N C E B E T W E E N H I G H - A N D LO W - D O S E C R R T D U E T O E X C E S S I V E A N T I M I C R O B I A L R E M O VA L O R T O I N A D E Q U AT E C Y T O K I N E CLEARANCE? C R R T I S N O T A ‘ H U R D L E ’ F O R A D E Q U AT E A N T I M I C R O B I A L D O S I N G B U T R AT H E R A ‘ S H I E L D ’ A L LO W I N G H I G H E R A N T I M I C R O B I A L D O S I N G AT L E S S TOXICITY RISK Recent literature suggested that the observed lack of survival difference between high- and low-dose CRRT might be explained by the inclusion of a proportionally larger number of septic patients [29]. However, other factors must be taken into account. Whether sepsis is present or not, higher dosed CRRT has consistently been shown to remove significantly more small-sized molecules such as ions, creatinine and many antibiotics [3, 4, 26]. In contrast, middle- and largesized molecules, including many relevant inflammatory cytokines, tend to adhere to the dialysis membrane and are not removed. With ongoing CRRT, a protein ‘cake’ is gradually formed on the inner part of the membrane obviating passage of these molecules. For a given patient’s weight, it can be assumed that higher CRRT doses are associated with less optimal filtration fraction and thus more filter constraints and shear forces. Consequently, protein precipitation and concomitant decrease in cytokine removal occur more rapidly resulting in a more pronounced decline in biological, haemodynamic and eventually survival benefit. In other words, the ‘reduced effectiveness’ of high-dose when compared with standard-dose CRRT in septic AKI patients should not be imputed only on enhanced loss of antibiotics but also on a relative decrease of convective elimination of inflammatory middle- and large-sized pivotal mediators of Several studies underpin the potential risk of antimicrobial underdosing during CRRT treatment which further increases CRRT trauma [29]. As discussed earlier, the integration of motivated ICU physicians with solid nephro- and pharmacological background in conjunction with an avalanche of recently published PK/PD data has yielded robust guidelines for bedside antimicrobial dosing in CRRT. Moreover, CRRT allowed the administration of substantially higher doses of antibiotics with a narrow dose-toxicity margin, such as the loading dose of amikacin (up to 30–35 mg/kg !) [11, 13, 34] and the maintenance dose of colistin [35]. CRRT also completely blunted the dreaded nephrotoxic effect caused by accumulation of the sulfobutylether β-cyclodextrin solvent during high-dose voriconazole treatment [11, 36]. Thus, a CRRT ‘paradox’ exists as the technique may promote antimicrobial underdosing, while at the same time permitting the use of higher antibiotic doses at less risk for side-effects [20]. CONCLUSIONS Dialy- and CRRT trauma are undeniably linked to renal replacement therapy including IHD and CRRT. CRRT fulfils a 2725 Dialy- and CRRT trauma during renal replacement therapy P O L A R V I E W S I N N E P H R O LO G Y the septic inflammatory cascade. Importantly, it has been learnt from the recent meta-analyses comparing high- and low-CRRT doses [30, 31] and data from one IVOIRE substudy [32] that almost doubling the CRRT dose did not simply cause a proportional mathematical increase in mediator removal (not achieving a doubling of the mediator removal but much less), in particular when heparin was used. A way to counter this enhanced membrane ‘clogging’ in high-dosed patients is to double blood flow to keep the filtration fraction <20%. However, this would require the insertion of two catheters and the running of two machines at the same time which is logistically impossible and will enhance bleeding and infection risk. Citrate strikingly reduces the rate of membrane clogging. Albeit still hypothetical, citrate anticoagulation may be an attractive alternative for heparin in that it allows easier and earlier passage of middle- and large-sized molecules during high-dose CRRT [32, 33]. Thus, haemodynamic and outcome results of previous large trials [3, 4, 8] could be different when repeated with citrate as an anticoagulant [32, 33]. Tolwani et al. [26] already ‘tested’ such a citrate effect, but these investigators delivered 65% of high-dose CRRT in diffusion mode which precludes removal of mediators with a molecular weight >5000 Da. In other words, the lack of survival difference between high- and low-dose CRRT is not only or simply a matter of CRRT trauma magnitude (severity of antibiotics underdosing) but it does imply other factors such as mediator convective clearance effectiveness. support, enzyme function, oxygen transport and energy transfer. In addition, a prospective study in medical ICU patients revealed an association between hypophosphataemia and failure to wean from mechanical ventilation [24]. Troyanov et al. [25] reported that adding phosphorus to substitution fluids could safely and adequately compensate undesirable losses. Moreover, in the large CRRT studies [3, 4, 8, 26], hypophosphataemia did not emerge as a surrogate marker of significant antimicrobial underdosing. In analogy with hypernatraemia [27], it indicates rather a lower quality of ICU care related to insufficient preventive measures. Accordingly, phosphorus should be checked at least twice daily during CRRT and substituted when needed. Not only the dose but also the duration of CRRT does affect phosphate levels. Ratanarat et al. [28] demonstrated that phosphate transfer during an IHD session was little more than half of the one observed during a 24-h CRRT treatment, despite a 4-fold higher clearance. This underlines the role of phosphate redistribution in relation to the duration of the used technique. In analogy, removal of many antibiotics also depends on both dose and duration of renal replacement treatment. Taken together, hypophosphataemia is an important determinant of CRRT trauma, but preventing or correcting this deficiency does not at all influence antimicrobial dosing. Other markers to assess antibiotic dosing during CRRT should be employed (e.g. direct measurement of antibiotic plasma levels). P O L A R V I E W S I N N E P H R O LO G Y 7. Honore PM, Jacobs R, Joannes-Boyau O et al. Septic AKI in ICU patients. Diagnosis, pathophysiology, and treatment type, dosing, and timing: a comprehensive review of recent and future developments. Ann Intensive Care 2011; 1: 32 8. Joannes-Boyau O, Honoré PM, Bagshaw SM et al. The IVOIRE Study: description of the methodology and the design used. Electronic Supplemental Material. Intensive Care Med 2013; Second Revised Submission. 9. Munoz-Price LS, Dezfulian C, Wyckoff M et al. Effectiveness of stepwise interventions targeted to decrease central catheterassociated bloodstream infections. Crit Care Med 2012; 40: 1464–1469 10. Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract 2012; 120: 179–184 11. Honore PM, Jacobs R, Spapen HD. Use of antifungal drugs during continuous hemofiltration therapies. Annu Updat Intensive Care Emerg Med 2012; 337–347 12. Roberts DM, Roberts JA, Roberts MS et al. Variability of antibiotic concentrations in critically ill patients receiving continuous renal replacement therapy: a multicentre pharmacokinetic study. Crit Care Med 2012; 40: 1523–1528 13. Taccone FS, de Backer D, Laterre PF et al. Pharmacokinetics of a loading dose of amikacin in septic patients undergoing continuous renal replacement therapy. Int J Antimicrob Agents 2011; 37: 531–535 14. Spapen HD, Janssen van Doorn K, Diltoer M et al. Retrospective evaluation of possible renal toxicity associated with continuous infusion of vancomycin in critically ill patients. Ann Intensive Care 2011; 1: 26 15. Jamal JA, Economou CJ, Lipman J et al. Improving antibiotic dosing in special situations in the ICU: burns, renal replacement therapy and extracorporeal membrane oxygenation. Curr Opin Crit Care 2012; 18: 460–471 16. Choi G, Gomersall CD, Tian Q et al. Principles of antibacterial dosing in continuous renal replacement therapy. Crit Care Med 2009; 37: 2268–2282 17. Vincent JL. Critical care nephrology: a multidisciplinary approach. Contrib Nephrol 2007; 156: 24–31 18. Honoré PM, Joannes-Boyau O, Gressens B. CRRT technology and logistics: is there a role for a medical emergency team in CRRT? Contrib Nephrol 2007; 156: 354–364 19. De Becker W. Starting up a continuous renal replacement therapy program on ICU. Contrib Nephrol 2007; 156: 185–190 20. Yee J. Newphrologist: the intensive care kidney specialist. Adv Chronic Kidney Dis 2013; 20: 1–3 21. Cerdá J, Tolwani AJ, Warnock DG. Critical care nephrology: management of acid–base disorders with CRRT. Kidney Int 2012; 82: 9–18 22. Ricci Z, Ronco C, D’Amico G et al. Practice patterns in the management of acute renal failure in the critically ill patient: an international survey. Nephrol Dial Transplant 2006; 21: 690–696 23. Honore PM, Jacobs R, Spapen HD. Antibiotic adsorption on CRRT membranes. Relevance and impact on antibiotic dosing in critically ill patients. Annu Updat Intensive Care Emerg Med 2013; 33: 123–131 crucial role in the treatment of haemodynamically unstable, and, in particular septic, patients with smouldering or acute AKI. Efforts must thus be concentrated on prevention, timely anticipation, recognition and eventual correction of CRRTtrauma in this population. We recently described the concept of dialy trauma in detail and provided a checklist for bedside identification and prevention of this condition in ICU patients receiving CRRT [2]. Hypophosphataemia is not a marker of poor antimicrobial dosing in patients with septic AKI but rather an indicator of (shortcomings in) ICU quality. The observed inverse relationship between CRRT dose and survival is not solely explained by a higher incidence of sepsis and related PK/PD disturbances but may also result from inadequate or insufficient convective clearance of middle-and large-sized inflammatory mediators. Citrate anticoagulation may reverse this dose/survival relationship. Finally, CRRT is not an obstacle for adequate antimicrobial dosing but rather acts as a ‘shield’ that allows higher antimicrobial dosing at less toxicity risk. To date, the PK/PD behaviour of many antimicrobials during CRRT has been elucidated and dose recommendations are available. Criticalcare nephrology platforms embedded inside ICU departments further facilitate these anti-infective drug adaptation programmes. A better approach of dialy- and CRRT trauma will dramatically improve the quality of care for ICU patients treated by any form of renal replacement therapy. CRRT trauma prevention is not only dependent on the type of therapy, dose or provider of care (nephrologist versus intensivist), but represents a dedicated quality programme based on safety measures with proven outcome benefit [37]. Prospective studies on the effect of implementing preventive strategies on CRRT trauma and its presumed associated mortality are eagerly awaited. REFERENCES 1. Maynar-Moliner J, Sanchez-Izquierdo-Riera JA, Herrera-Gutierrez M. Renal support in critically ill patients with acute kidney injury. N Engl J Med 2008; 359: 1960–1962 2. Maynar-Moliner JM, Honore PM, Sanchez-Izquierdo JA et al. Handling RRT-related adverse effects in ICU patients: the Dialytrauma concept. Blood Purif 2012; 34: 177–185 3. Palevsky PM, Zhang JH, O’Connor TZ et al. Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med 2008; 359: 7–20 4. Bellomo R, Cass A, Cole L et al. Intensity of continuous renalreplacement therapy in critically ill patients. N Engl J Med 2009; 361: 1627–1638 5. Prowle JR, Bellomo R. Continuous renal replacement therapy: recent advances and future research. Nat Rev Nephrol 2010; 6: 521–529 6. Ronco C, Cruz D, Oudemans van Straaten H et al. Dialysis dose in acute kidney injury: no time for therapeutic nihilism—a critical appraisal of the Acute Renal Failure Trial Network study. Crit Care 2008; 12: 308 2726 P.M. Honoré et al. particular mode of RRT is no remedy, let alone a cure ReReTra. Quality of critical care varies as indicated by a recent large Chinese ICU study in which out of 864 patients undergoing ventilation only 40% had an arterial line [5]. In our view, hypophosphatemia is more than a reflection of poor quality. The Boy-Scout advice to check dosing of antimicrobial drugs at latest (or one more time) if hypophosphatemia ensues is not based on studies, it is directed to the 50% of units that do not assess the delivered dose of RRT [4]. The advice os also directed to those physicians who use antimicrobials for which we neither have valid and detailed dosing suggestions nor recent PK studies [3]. Our advice is directed to those not being able (or willing) to consult nephrologists, i.e. 40% of UK ICUs [4]. Hence we have to go a long way before discussing appropriate RRT and drug dose adjustments in AKI with a nephrologist becomes reality. Even then, we have no clue whether the dosing recommendations from the vinyl age, result in adequate drugs levels using todays RRT technology. TDM, if timely available at all, is limited to a few drugs only. For old generics like cotrimoxazole the ‘database’ for critically ill patients with AKI consists of an embarrassing two patients for CVVHDF and one treated by EDD [6]. If another membrane/extracorporeal treatment such as ECMO is added, a treatment that is frequently associated with AKI [7], the studies on drug dosing are as rare as European countries without fiscal debt [8]. This inconvenient truth was the main reason to propose the hypophosphatemia-inadequate dosing duet. The awareness of ReReTra and methods to prevent its occurrence or to overcome its detrimental effects are one piece in the therapeutic puzzle that intensivists, pharmacologists, nutritional specialists, and intensophil nephrologists have to solve on a day-to-day basis. To tackle this task we have to demand tools to objectively asses ReReTra from device manufacturers and analytical chemistry companies (for TDM). Jan T. Kielstein REFERENCES 1. Kielstein JT, Schiffer M, Hafer C. Back to the future: extended dialysis for treatment of acute kidney injury in the intensive care unit. J Nephrol 2010; 23: 494–501. 2. Schwenger V, Weigand MA, Hoffmann O et al. Sustained low efficiency dialysis using a single-pass batch system in acute kidney injury—a randomized interventional trial: the REnal Replacement Therapy Study in Intensive Care Unit PatiEnts. Crit Care 2012; 16: R140. 3. Kielstein JT, Burkhardt O. Dosing of antibiotics in critically ill patients undergoing renal replacement therapy. Curr Pharm Biotechnol 2011: 12: 2015–9. 4. Jones SL, Devonald MA. How acute kidney injury is investigated and managed in UK intensive care units—a survey of current practice. Nephrol Dial Transplant 2013. OPPONENT’S COMMENTS Our intention was not to compare different RRTs and their specific influence on incidence and severity of ‘renal replacement trauma’ (ReReTra). Every mode of RRT has the potential to cause trauma, even though we feel that ED can combine the advantages and reduce ReReTra of both IHD and CRRT [1], a view recently confirmed [2]. Avoiding one 2727 Dialy- and CRRT trauma during renal replacement therapy P O L A R V I E W S I N N E P H R O LO G Y 24. Alsumrain MH, Jawad SA, Imran NB et al. Association of hypophosphatemia with failure-to-wean from mechanical ventilation. Ann Clin Lab Sci 2010; 40: 144–148 25. Troyanov S, Geadah D, Ghannoum M et al. Phosphate addition to hemodiafiltration solutions during continuous renal replacement therapy. Intensive Care Med 2004; 30: 1662–1665 26. Tolwani AJ, Campbell RC, Stofan BS et al. Standard versus high-dose CVVHDF for ICU-related acute renal failure. J Am Soc Nephrol 2008; 19: 1233–1238 27. Polderman KH, Schreuder WO, Strack van Schijndel RJ et al. Hypernatremia in the intensive care unit: an indicator of quality of care? Crit Care Med 1999; 27: 1105–1108 28. Ratanarat R, Brendolan A, Volker G et al. Phosphate kinetics during different dialysis modalities. Blood Purif 2005; 23: 83–90 29. Morabito S, Pistolesi V, Maggiore U et al. Pharmacokinetics of antibiotics in continuous renal replacement therapies (CRRT). G Ital Nefrol 2012; 29: 425–444 30. Van Wert R, Friedrich JO, Scales DC et al. High-dose renal replacement therapy for acute kidney injury: systematic review and meta-analysis. Crit Care Med 2010; 38: 1360–1369 31. Zhang Z, Xu X, Zhu H. Intensive- vs less-intensive-dose continuous renal replacement therapy for the intensive care unitrelated acute kidney injury: a meta-analysis and systematic review. J Crit Care 2010; 8: 595–600 32. Cantaluppi V, Medital D, Honoré PM et al. Biological effects of High Volume Hemofiltration (HVHF) on endothelial and tubular cell alterations by septic plasma. An IVOIRE Substudy. [Abstract ]16th International Conference on CRRT. San Diego, 22–25 Feb 2011 33. Honoré PM, Jacobs R, Boer W et al. New insights regarding rationale, therapeutic target and dose of hemofiltration and hybrid therapies in septic acute kidney injury. Blood Purif 2012; 33: 44–51 34. Taccone FS, Laterre PF, Spapen HD et al. Revisiting the loading dose of amikacin for patients with severe sepsis and septic shock. Crit Care 2010; 14: R53 35. Spapen H, Jacobs R, Van Gorp V et al. Renal and neurological side effects of colistin in critically ill patients. Ann Intensive Care 2011; 1: 14 36. Radej J, Krouzeckt A, Stehlik P et al. Pharmacokinetic evaluation of voriconazole treatment in critically ill patients undergoing continuous veno-venous hemofiltration. Ther Drug Monit 2011; 33: 393–397 37. Semel ME, Resch S, Haynes AB et al. Adopting a surgical safety checklist could save money and improve the quality of care in US Hospitals. Health Aff (Millwood) 2010; 29: 1593–1599 receiving continuous venovenous hemodialysis and/or extracorporeal membrane oxygenation. Pharmacotherapy 2012; 32: 1061–9. 9. Kielstein JT, David S. Magnesium: the ‘earth cure’ of AKI? Nephrol Dial Transplant 2013; 28: 785–7. 10. Hetzel GR, Schmitz M, Wissing H et al. Regional citrate versus systemic heparin for anticoagulation in critically ill patients on continuous venovenous haemofiltration: a prospective randomized multicentre trial. Nephrol Dial Transplant 2011; 26: 232–9. 5. Du B, An Y, Kang Y et al. Characteristics of critically ill patients in ICUs in Mainland China. Crit Care Med 2013; 41: 84–92. 6. Clajus C, Kuhn-Velten WN, Schmidt JJ et al. Cotrimoxazole plasma levels, dialyzer clearance and total removal by extended dialysis in a patient with acute kidney injury: risk of underdosing using current dosing recommendations. BMC Pharmacol Toxicol 2013; 14: 19. 7. Kielstein JT, Heiden A, Beutel G et al. Renal function and survival in 200 patients undergoing ECMO therapy. Nephrol Dial Transplant 2012; 12: 15. 8. Eyler RF, Heung M, Pleva M et al. Pharmacokinetics of oseltamivir and oseltamivir carboxylate in critically ill patients Received for publication: 5.5.2012; Accepted in revised form: 2.3.2013 P O L A R V I E W S I N N E P H R O LO G Y Nephrol Dial Transplant (2013) 28: 2728–2733 doi: 10.1093/ndt/gft049 Pro: Renal replacement trauma or Paracelsus 2.0 Department of Nephrology and Hypertension, Medical School Jan T. Kielstein Hannover, 30625 Hannover, Germany and Sascha David Correspondence and offprint requests to: Jan T. Kielstein; E-mail: [email protected] Keywords: renal replacement therapy, acute kidney injury, sepsis, antibiotics, hypophosphatemia ‘Dosis sola facit venenum’—only dose determines the poison —is a famous phrase coined by the alchemist, physician and astrologer Paracelsus. Usually, this phrase applies to substances that can become toxic at a certain dose. It holds true for all known compounds even those generally associated with health and well-being like water or oxygen. Based on the landmark paper by Ronco, our idea as nephrologists and intensivists for the last decade was that an increase in renal replacement therapy (RRT) dose is beneficial in patients suffering from acute kidney injury (AKI) [1]. It was such an appealing hypothesis that even a discussion about it seemed utterly unnecessary. Non-adherence to this principle of cleaning things thoroughly has led to disastrous consequences, even if the subject is as trivial as a blue dress [2]. Despite the fact that recent prospective trials [3–5] could not confirm a benefit of higher RRT dose on patient survival, we still consider RRT dose escalation to be not beneficial at worst if it exceeds a certain range. Apart from hospital administrators hardly anyone would consider a high dose of RRT to be harmful. However, the Spanish physician Maynar-Moliner et al. [6] recently coined the term ‘Dialytrauma’ trying to integrate several complications of high-dose RRT in intensive care unit (ICU) patients. These consist of, but are not limited to, arterial hypotension (with need for vasopressors), metabolic (nutritional depletion, electrolyte disorders), haemorrhagic and infectious complications, hypothermia and maladapted drug doses—a mixture with potentially fatal consequences. This list (Table 1) of typical RRT-associated complications is probably true for any ICU population with AKI but seems to be of highest relevance for septic patients, i.e. the patient population that represents the highest percentage of AKI patients in the ICU today [7]. These patients might be highly susceptible to the ‘Dialytrauma’, especially if one looks at the aspect of drug dosing in those individuals who are critically dependent on appropriate serum levels of a given pharmaceutical compound. Indeed, one might find a rather simple but underappreciated explanation for the observed failure of increased RRT dose to improve survival in septic patients. Till today, the treatment of sepsis is mostly limited to supportive care, e.g. strategies like ‘early goal directed therapy’ [8]. The only true causative and therefore fundamental part of the treatment regimen of any septic individual is the anti-infectious medication. Most recommendations for dose adjustment of antibiotics in renal patients are derived from studies in CKD 5D patients on thriceweekly maintenance dialysis. Less data are available in AKI © The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. 2728