Download Dialy- and continuous renal replacement (CRRT)

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.
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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
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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
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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
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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
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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
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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
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2. Schwenger V, Weigand MA, Hoffmann O et al. Sustained low
efficiency dialysis using a single-pass batch system in acute
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3. Kielstein JT, Burkhardt O. Dosing of antibiotics in critically ill
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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
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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
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Hypernatremia in the intensive care unit: an indicator of quality
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antibiotics in continuous renal replacement therapies (CRRT).
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and meta-analysis. Crit Care Med 2010; 38: 1360–1369
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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,
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33. Honoré PM, Jacobs R, Boer W et al. New insights regarding
rationale, therapeutic target and dose of hemofiltration and
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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
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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
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in ICUs in Mainland China. Crit Care Med 2013; 41: 84–92.
6. Clajus C, Kuhn-Velten WN, Schmidt JJ et al. Cotrimoxazole
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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.
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