CytoSorb mentioned in the new product section (page 122) of the International Journal of Intensive Care.

1. WINTER 2011 | VOLUME 18 | NUMBER 4
INTERNATIONAL JOURNAL OF
INTENSIVE CARE
Estimating
unmeasured ions
in extracellular fluid
Current surgical The correct Role of novel
strategies to antibiotic doses biomarkers in acute
prevent renal failure for septic shock kidney injury

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3. CONTENTS WINTER 2011
INTERNATIONAL JOURNAL OF
INTENSIVE CARE COVER PHOTOGRAPH
Editor Dr J Denis Edwards
Sub Editor Catherine Booth Blood sample being pipetted into a sample
Art Editor Bettina Brüx bottle. Blood samples are used to evaluate
Illustrator Marion Tasker
Advertisement Manager Robert Sloan oxygen levels and search for contaminating
Editorial Director Guy Wallis organisms and toxins in the blood. During
Editorial Advisory Board
critical illness, anionic species may leak from
Professor Rinaldo Bellomo, Melbourne, Australia the intracellular environment to the
Dr Martina Brückmann, Mannheim, Germany extracellular fluid.
Professor Pierre Carli, Paris, France
Dr Daniel De Backer, Brussels, Belgium
Professor Guillermo Gutierrez, Washington DC, USA
Dr Klaus Hankeln, Bremen, Germany
Professor Hiroyuki Hirasawa, Chiba, Japan
Professor Claus-Georg Krenn, Vienna, Austria © Tek Image/Science Photo Library
Professor H Matsuda, Tokyo, Japan
Professor Paolo Pelosi, Varese, Italy
Professor Azriel Perel, Tel Aviv, Israel
Dr Kees Polderman, Amsterdam, The Netherlands
Dr Jerome Pugin, Geneva, Switzerland REVIEW
Professor Konrad Reinhart, Jena, Germany Surgical and intensive care strategies to prevent renal failure
Dr Thomas Stewart, Toronto, Canada Acute kidney injury (AKI) refers to a sudden decline in kidney function causing disturbances in fluid, electrolyte,
Dr Robert Tasker, Cambridge, UK and acid–base balance. Its occurrence in surgical and critically ill patients is common and it is associated with
Dr Antonio Torres, Barcelona, Spain a substantial increase in morbidity and mortality. In this review, N Brienza, MT Giglio and L Dalfino discuss the
Professor Jean-Louis Vincent, Brussels, Belgium
epidemiology and prevention of AKI. Currently, excellent supportive care and avoidance of clinical conditions
Dr Julia Wendon, London, UK
Dr Duncan Wyncoll, London, UK
known to cause or worsen AKI remain the cornerstones of management. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Publishing Director Ashley Wallis COVER FEATURE
Significance and estimation of unmeasured ions in extracellular fluid – a brief review
The International Journal of Intensive Care is
During critical illness, anionic species may leak from the intracellular environment to the extracellular fluid.
indexed in EMBASE/Excerpta Medica and in the
Cumulative Index to Nursing and Allied Health
While these ions may not directly contribute to mortality, they do reflect underlying pathology and their ultimate
Literature (CINAHL). It is published quarterly and disappearance from the extracellular fluid is associated with a return to health. In this review, CM Anstey focuses
circulated on a controlled basis to practitioners on the physiological rationale behind measurements in the extracellular fluid and on the shortfalls of the current
who specialise in critical and emergency care, models for detecting unmeasured ions. A new parameter is introduced. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
coronary and neonatal care. All others are invited
to subscribe.
Europe Overseas
REVIEW
Individuals: GBP 50 (€ 60) GBP 65 (USD100) The diagnostic role of novel biomarkers in acute kidney injury in critically ill patients
Institutions: GBP105 (€130) GBP135 (USD210) Acute kidney injury (AKI) is a common and serious condition, in particular in critically ill patients. In this review,
N Lameire first discusses the drawbacks of serum creatinine and oliguria in the early diagnosis of AKI, and then
Advertising Department reviews novel biomarkers – specifically serum cystatin C and plasma and urine neutrophil gelatinase-associated
Tel/Fax: +44 (0)20 8882 7199
E-mail: r.sloan@greycoatpublishing.co.uk
lipocalin – that may allow the early detection, risk stratification and prognostication of patients with AKI. . . . . . . . . . 118
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misleading data, opinions or statements.

5. COMMENT
Antibiotics in patients with
septic shock: are we using the Fabio Taccone MD
right doses?
strated that β-lactams have a slow continuous kill
S
epsis is one of the most common reasons for required for difficult-to-treat pathogens such as
admission to an intensive care unit (ICU), characteristic that is almost entirely related to the Pseudomonas aeruginosa, Enterobacter and
and results in high morbidity and mortali- time during which serum concentrations exceed Klebsiella species or MRSA, suggesting again that
ty.1 In this setting, antibiotic treatment of critical- the MIC (T > MIC) for the infecting organism.6,7 these represent the target pathogens for which β-
ly ill patients remains a significant challenge. An The PK parameter that better drives the efficacy lactam dose adjustment is necessary to improve
early and appropriate antimicrobial therapy is of aminoglycosides is the ratio between the max- blood drug concentrations. In view of these
mandatory in the management of septic patients; imal concentrations obtained after an intra- results, broad-spectrum β-lactams should be
however, an antibiotic is appropriate not only venous administration (Cmax) and the MIC. A administered in doses larger than suggested for
because it is active in vitro against the isolated Cmax/MIC ratio between 8 and 10 has been report- non-septic patients. According to PK modelling,
pathogens, but also because the selected regimen ed to be the major determinant for optimal continuous or extended β-lactam infusions are
optimizes the killing drug activity.2 There are two antibacterial activity and clinical response.8,9 For required to optimize pathogen exposure to bac-
major reasons why ICU patients are exposed to vancomycin, the area under the serum concen- tericidal concentrations of these drugs.3 However,
subtherapeutic antibiotic concentrations during tration time curve (AUC) is generally calculated clinical data that have shown better outcomes
sepsis. First, antimicrobial dosages used in sepsis to determine the adequacy of drug levels. As it using this strategy are only from retrospective
are derived from pharmacokinetic (PK) data may be difficult to obtain multiple serum van- studies in critically ill populations of patients with
obtained from healthy volunteers or less severely comycin concentrations to determine the AUC, pneumonia.18,19 Further studies are needed to
ill patients, without taking into account the PK trough concentration (Cmin) monitoring has been assess the influence of continuous infusion (CI)
changes that occur during sepsis, which reduce the recommended as the most accurate and practical strategy on morbidity and mortality, especially in
efficacy of antibiotics. In sepsis, increased cardiac method to adjust vancomycin regimens. A Cmin patients with sepsis and infections caused by mul-
output associated with increased capillary leakage above 15 µg/mL should be achieved to optimize tidrug-resistant pathogens.
and peripheral effusions induces a larger volume drug activity against Gram-positive bacteria such For aminoglycosides, Cmax is determined by
of distribution (Vd), which may decrease plasma as methicillin-resistant Staphylococcus aureus the administered dose and the Vd.3 The Vd of
levels of antibiotic. This hyperdynamic state can (MRSA) and Enterococcus species.10 aminoglycosides is largely increased in critically
also increase renal blood flow and creatinine clear- Studies on serum concentrations of broad- ill patients when compared with healthy volun-
ance, resulting in elevated antibiotic elimination. spectrum β-lactams, including cefepime, cef- teers and patients with mild infections, suggest-
In addition, organ (i.e., renal or hepatic) dysfunc- tazidime and piperacillin, have reported that drug ing that higher than recommended doses of these
tion can alter drug metabolism and clearance, levels were insufficient to treat less susceptible drugs should be administered to achieve optimal
leading to drug accumulation and possible side strains in patients with severe infections.11–13 On Cmax.20 In a recent study, a loading dose of 25
effects.3 Second, infections, especially when the other hand, serum drug concentrations of mg/kg amikacin was necessary to achieve opti-
acquired in the ICU, are often caused by more meropenem were adequate in most studies in crit- mal Cmax concentrations in a prospective cohort
resistant pathogens, which require higher drug ically ill patients, including patients with bacter- of septic patients with multiple organ failure.21
concentrations to be killed.4 aemia and ventilator-associated pneumonia.14,15 Simulation with a standard regimen (15 mg/kg)
To treat these pathogens, the combination of Furthermore, these reports excluded severely ill of amikacin resulted in insufficient peak con-
broad-spectrum β-lactams with aminoglycosides patients with septic shock and those with multi- centrations in more than 90% of patients, thus
and/or glycopeptides (especially vancomycin) is ple organ failure, limiting the generalizability of confirming the need to increase the dosing of
recommended.5 However, these drugs, which are the results to other populations of critically ill aminoglycosides to optimize Cmax in septic
hydrophilic compounds, have a small Vd (limit- patients. In a prospective multicentre study, patients. In another study, an even higher
ed to extracellular fluids) and are more likely to serum levels obtained after the first dose of amikacin regimen (30 mg/kg) was required to
be excreted unchanged by the kidney. Thus, PK piperacillin–tazobactam, ceftazidime or cefepime obtain adequate Cmax levels in septic patients.22
alterations occurring in sepsis may profoundly were insufficient to empirically treat less suscep- Assuming the three to four-fold factor for con-
affect drug concentrations and modification of tible pathogens in the early phase of severe sepsis verting doses of amikacin to gentamicin and
the drug regimen should be considered. and septic shock.16 Only meropenem achieved an tobramycin, higher doses (8–9 mg/kg) were sug-
Using PK principles, different strategies are adequate serum concentration in 75% of treated gested to optimize the efficacy of these two drugs
used to improve antibiotic concentrations in rela- patients. In another recent prospective study, in patients with septic shock.23,24
tion to the minimal inhibitory concentration monitoring of β-lactams levels was routinely Higher than recommended doses (15 mg/kg
(MIC) of the pathogen to the drug. The MIC rep- applied in the management of 236 critically ill every 12 hours) of vancomycin have been pro-
resents the threshold of antibiotic levels resulting patients; dose increases were required in 50% of posed to optimize drug concentrations in
in inhibition of bacterial growth under standard patients during the early phase of infection ther- patients with septic shock or with trauma and
conditions.3 Experimental studies have demon- apy.17 Dose increases were more frequently MRSA pneumonia.25,26 As alternative, a CI
WINTER 2011 | INTERNATIONAL JOURNAL OF INTENSIVE CARE 93

6. COMMENT
17. Roberts JA, Ulldemolins M, Roberts MS, et al. Therapeutic drug
administration (15 mg/kg loading dose followed critically ill patients to detect underdosing, which
monitoring of beta-lactams in critically ill patients: proof of con-
by 30 mg/kg/day) has been proposed to optimize is frequent in the early phase of therapy, and avoid cept. Int J Antimicrob Agents 2010; 36: 332–339.
the effectiveness of vancomycin.3 However, the overdosing and associated side effects, including 18. Lodise TP Jr, Lomaestro B, Drusano GL. Piperacillin-tazobac-
question whether intermittent dosing or CI is neurological disturbances and renal failure. Other tam for Pseudomonas aeruginosa infection: clinical implications
better to improve vancomycin efficacy remains conditions found in ICU patients, such as the use of an extended-infusion dosing strategy. Clin Infect Dis 2007;
unanswered. Wysocki et al. compared CI and of continuous renal replacement therapy, obesity, 44: 357–363.
intermittent dosing of vancomycin in 160 burns or liver cirrhosis, may also alter the PKs of 19. Lorente L, Jimenez A, Palmero S, et al. Comparison of clinical
cure rates in adults with ventilator-associated pneumonia treat-
patients with severe MRSA infection and found antibiotics and should be considered for drug reg-
ed with intravenous ceftazidime administered by continuous or
no significant differences in clinical efficacy.27 imen adjustments. Systematic clinical PK/phar- intermittent infusion: a retrospective, nonrandomized, open-
However, a faster time to achieve target drug con- macodynamic studies are required to evaluate the label, historical chart review. Clin Ther 2007; 29: 2433–2439.
centrations, lower daily dose and reduced thera- beneficial effects of these dosing strategies on the 20. Marik PE, Havlik I, Monteagudo FS, et al. The pharmacokinetic
py costs were reported for the CI strategy. Rello outcomes for septic patients. of amikacin in critically ill adult and paediatric patients: com-
et al. suggested clinical superiority of vancomycin parison of once-versus twice-daily dosing regimens. J
CI in a subgroup of patients with ventilator-asso- REFERENCES Antimicrob Chemother 1991; 27(Suppl. C): 81–89.
1. Vincent JL, Sakr Y, Sprung C, et al. Sepsis in European inten- 21. Taccone FS, Laterre PF, Spapen H et al. Revisiting the loading
ciated pneumonia due to MRSA.28 Nevertheless, sive care units: results of the SOAP study. Crit Care Med 2006; dose of amikacin for patients with severe sepsis and septic
data on the optimal regimen of vancomycin 34: 344–353. shock. Crit Care 2010; 14: R53.
when given by CI in patients with sepsis are 2. Khollef MH. Inadequate antimicrobial treatment: an important 22. Gálvez R, Luengo C, Cornejo R, et al. Higher than recommend-
scarce. Using a Monte Carlo simulation, higher determinant of outcome for hospitalized patients. Clin Infect Dis ed amikacin loading doses achieve pharmacokinetic targets
than recommended loading (35 mg/kg) and daily 2000; 31(Suppl. 4): S131–S138. without associated toxicity. Int J Antimicrob Agents 2011; 38:
3. Roberts JA, Lipman J. Pharmacokinetic issues for antibiotics in 146–151.
(30–40 mg/kg if normal renal function) doses of
the critically ill patients. Crit Care Med 2009; 37: 840–851. 23. Rea RS, Capitano B, Bies R, et al. Suboptimal aminoglycoside
CI vancomycin have been suggested to rapidly dosing in critically ill patients. Ther Drug Monit 2008; 30:
4. Van Eldere J. Multicentre surveillance of Pseudomonas aerug-
achieve therapeutic serum concentrations in the inosa susceptibility patterns in nosocomial infections. J 674–681.
early phase of sepsis.29 However, this strategy Antimicrob Chemother 2003; 51: 347–352. 24. Buijk SE, Mouton JW, Gyssens IC, et al. Experience with a once-
needs to be prospectively validated and its impact 5. Dellinger P, Levy M, Carlet J, et al. Surviving sepsis campaign: daily dosing program of aminoglycosides in critically ill patients.
on drug-related toxicity further determined. international guidelines for management of severe sepsis and Intensive Care Med 2002; 28: 936–942.
If higher than recommended doses for all of septic shock. Crit Care Med 2008; 36: 296–327. 25. Vázquez M, Fagiolino P, Boronat A, et al. Therapeutic drug mon-
6. Andes D, Craig WA. In vivo activities of amoxicillin and amoxi- itoring of vancomycin in severe sepsis and septic shock. Int J
these antibiotics should be considered when treat-
cillin–clavulanate against Streptococcus pneumoniae: applica- Clin Pharmacol Ther 2008; 46: 140–145.
ing patients with severe sepsis and septic shock, tion to breakpoint determinations. Antimicrob Agents 26. Patanwala AE, Norris CJ, Nix DE, et al. Vancomycin dosing for
routine drug monitoring is also required to avoid Chemother 1998; 42: 2375–2379. pneumonia in critically ill trauma patients. J Trauma 2009; 67:
overdosing with related toxicity. In 10% of ICU 7. Mouton JW, Punt N. Use of the t > MIC to choose between dif- 802–804.
patients with renal dysfunction receiving cefepime, ferent dosing regimens of beta-lactam antibiotics. J Antimicrob 27. Wysocki M, Delatour F, Faurisson F, et al. Continuous versus
serum drug accumulation occurred despite dosage Chemother 2001; 47: 500–501. intermittent infusion of vancomycin in severe staphylococcal
8. Moore RD, Lietman PS, Smith CR. Clinical response to aminogly- infections: prospective multicenter randomized study.
adjustments and resulted in non-convulsive
coside therapy: importance of the ratio of peak concentration to Antimicrob Agents Chemother 2001; 45: 2460–7.
seizures, disappearing after drug discontinua- minimal inhibitory concentration. J Infect Dis 1987; 155: 93–99. 28. Rello J, Sole-Violan J, Sa-Borges M, et al. Pneumonia caused
tion.30 Roberts et al. reported that a β-lactams dose 9. Kashuba AD, Nafziger AN, Drusano GL, Bertino JS Jr. Optimizing by methicillin-resistant Staphylococcus aureus treated with gly-
reduction was applied in 24% of ICU patients when aminoglycoside therapy for nosocomial pneumonia caused by copeptides. Crit Care Med 2005; 33: 1983–1987.
monitoring was routinely performed.17 Potential Gram-negative bacteria. Antimicrob Agents Chemother 1999; 29. Roberts JA, Taccone FS, Udy AA, et al. Vancomycin dosing in
renal, vestibular and neuromuscular toxicity can 43: 623–629. critically ill patients – robust methods for improved continuous
10. Rybak MJ, Lomaestro BM, Rotschafer JC, et al. Vancomycin ther- infusion regimens. Antimicrob Agents Chemother 2011; 55:
occur in the early or late phases of aminoglycoside
apeutic guidelines: a summary of consensus recommendations 2704–2709.
therapy, with a wide spectrum of severity.17 The 30. Chapuis TM, Giannoni E, Majcherczyk PA, et al. Prospective
from the infectious diseases Society of America, the American
risk of renal dysfunction increases with concomi- Society of Health-System Pharmacists, and the Society of monitoring of cefepime in intensive care unit adult patients. Crit
tant hypovolaemia, pre-existing renal disease, Infectious Diseases Pharmacists. Clin Infect Dis 2009; 49: 325–7. Care 2010; 14: R51.
nephrotoxics and advanced age. Cumulative dose, 11. Ambrose PG, Owens RC Jr, Garvey MJ, et al. Pharmacodynamic 31. Rybak MJ, Abate BJ, Kang SL, et al. Prospective evaluation of
especially where there are persistent elevated considerations in the treatment of moderate to severe pseu- the effect of an aminoglycoside dosing regimen on rates of
trough concentrations, is also associated with an domonal infections with cefepime. J Antimicrob Chemother observed nephrotoxicity and ototoxicity. Antimicrob Agents
2002; 49: 445–453. Chemother 1999; 43: 1549–1555
increased risk of renal toxicity so that Cmin moni-
12. Ikawa K, Morikawa N, Hayato S, et al. Pharmacokinetic and 32. Vandecasteele SJ, De Vriese AS. Recent changes in vancomycin
toring is advocated to minimize drug side effects.31 pharmacodynamic profiling of cefepime in plasma and peri- use in renal failure. Kidney Int 2010; 77: 760–764. ■
Finally, toxicity may occur when increasing the toneal fluid of abdominal surgery patients. Int J Antimicrob
dose of vancomycin, and some studies have shown Agents 2007; 30: 270–273.
that drug levels above 28 µg/mL are associated with 13. Roberts JA, Kirkpatrick CM, Roberts MS, et al. First-dose and
a greater risk of renal dysfunction, especially if other steady-state population pharmacokinetics and pharmacody-
namics of piperacillin by continuous or intermittent dosing in
potential nephrotoxics, such as aminoglycosides or
critically ill patients with sepsis. Int J Antimicrob Agents 2010;
amphotericin, are co-administered.32 Although a 35: 156–163.
CORRESPONDENCE TO:
slower onset of nephrotoxicity was observed in 14. Kitzes-Cohen R, Farin D, Piva G, et al. Pharmacokinetics and Fabio Silvio Taccone MD
patients receiving vancomycin by CI,27 the impact pharmacodynamics of meropenem in critically ill patients. Int J Department of Intensive Care
of higher than recommended CI regimens on renal Antimicrob Agents 2002; 19: 105–110. Hôpital Erasme, Université Libre de
function has not been evaluated. 15. de Stoppelaar F, Stolk L, van Tiel F, et al. Meropenem pharma- Bruxelles (ULB)
In conclusion, high or CI regimens of antibiotics cokinetics and pharmacodynamics in patients with ventilator- Route de Lennik, 808
associated pneumonia. J Antimicrob Chemother 2000; 46:
are necessary to rapidly achieve therapeutic drug 1070 Brussels
150–151.
levels for difficult-to-treat pathogens in patients 16. Taccone FS, Laterre PF, Durgernier T et al. Insufficient b-lac- Belgium
with severe sepsis and septic shock. Monitoring tam concentrations in the early phase of severe sepsis and sep- E-mail: ftaccone@ulb.ac.be
serum antibiotic concentrations is important in tic shock. Crit Care 2010; 14: R126.
94 INTERNATIONAL JOURNAL OF INTENSIVE CARE | WINTER 2011

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8. CLINICAL NEWS From the cutting edge of research
Interactive video games aid
ICU patient recovery
Interactive video games appear to safely enhance games included boxing, bowling and use of the Kho noted. “Our next step is to study what physical
physical therapy for patients in intensive care units, balance board, which were chosen to improve the therapy goals best benefit from video games.”
new US research suggests.1 patients’ stamina and balance.
1. Kho ME, Damluji A, Zanni JM, Needham DM. Feasibility and
“Patients admitted to our medical intensive care “As always, patient safety was a top priority … observed safety of interactive video games for physical reha-
unit are very sick and, despite early physical thera- when properly selected and supervised by experi- bilitation in the intensive care unit: a case series. J Crit Care
py, still experience problems with muscle weak- enced ICU physical therapists, patients enjoyed the 2011; Epub Sept 26: DOI:10.1016/j.jcrc.2011.08.017.
ness, balance and coordination as they recover,” challenge of the video games and welcomed the
said lead researcher Dr Michelle E. Kho of Johns change from their physical therapy routines,” said
Hopkins University. “Our study suggests that inter- study author Dr Dale M. Needham.
active video games may be a helpful addition.” The video game therapy activities are short in dura-
© Paul Rapson/Science Photo Library
Over a one-year period, the researchers identi- tion, which is ideal for severely deconditioned patients,
fied a select group of 22 critically ill adult patients Dr Needham said. They are also very low cost com-
who received video games as part of routine physi- pared to most ICU medical equipment, he added.
cal therapy. They were mostly males aged 32 to 64 More research is needed into whether the video
years old. game therapy helps patients to improve their abili-
The 42, 20-minute physical therapy sessions ties to do tasks that are most important to then, the
included use of the Nintendo Wii and Wii Fit video researchers caution.
games under supervision of a physical therapist. “Our study had limitations because the patients were
Almost half the sessions included patients who not randomly selected, the video game sessions were The Nintendo Wii: a safe addition to physical therapy
were mechanically ventilated. The most common infrequent and the number of patients was small,” in the ICU.
Timing crucial for family Calorific intake essential
for ICU patients
consent in organ donation The amount of calories that intensive care patients
receive is essential for improving their chances of
recovery, according to Canadian research.1
The time at which organ donation in brain dead lected retrospectively from 228 patients declared Patients who receive more calories while in inten-
donors is first discussed with family members could brain dead between 1987 and 2009 in the Erasmus sive care have lower mortality rates than those who
affect whether or not they consent to donation, MC University Medical Centre. receive less of their daily-prescribed calories, con-
according to a Dutch study. The Donor Register was introduced in the clude the researchers.
Discussing the issue of donation with relatives of Netherlands in 1998, which increased patient-con- “Our finding is significant as there have been a
victims of catastrophic brain injury earlier on in the sent rates more than seven-fold, from 5.7% to 41%, number of previous studies in the area of critical
process may have a negative effect on the consent the researchers found. care nutrition that have produced conflicting clinical
rate, the authors conclude. They also observed that over the past 15 years recommendations and policy implications,” said
In the study, the researchers analysed data col- there was a decline in donation after brain death study lead author Dr Daren Heyland of Queen’s
from 89% to 58%; in contrast, donation after circu- University and Kingston General Hospital. “Since
latory death increased from 11% to 42%. caloric delivery is essential for improving the
The timing of discussion about organ donation chances of these critically ill patients, it’s vital that
with relatives changed after 1998 from first being we know what the optimal level is.”
mentioned after the completion of all tests, to after The research team examined the records of 7872
© Klaus Guldbrandsen/Science Photo Library
determination of loss of consciousness and the mechanically ventilated, artificially fed patients in
absence of brainstem reflexes but before completion 352 ICUs in 33 countries. They found that patients
of confirmatory tests. receiving at least two-thirds of their prescribed calo-
Lead author Dr Erwin Kompanje said, “It is unclear rie intake had reduced mortality rates when com-
whether the observed shift contributed to the high pared with patients receiving less than one-third of
refusal rate in the Netherlands and the increase in their prescribed calorie intake. The optimal caloric
family refusal in our hospital after 1998 … it is pos- intake was identified to be about 80 to 85% of total
sible that this may have a counterproductive effect.” prescribed calorie intake.
1. de Groot YJ, Lingsma HF, van der Jagt M, et al. Remarkable
changes in the choice of timing to discuss organ donation with 1. Heyland D, Cahill N, Day AG. Optimal amount of calories for criti-
When to discuss organ donation with relatives is the relatives of a patient: a study in 228 organ donations in 20 cally ill patients: depends on how you slice the cake! Crit Care Med
crucial. years. Crit Care 2011; 15: R235. 2011; Epub June 23: DOI:10.1097/CCM.0b013e318226641d.
96 INTERNATIONAL JOURNAL OF INTENSIVE CARE | WINTER 2011

10. INDUSTRY NEWS An update on recent industry initiatives
Value of closed loop ventilation
recognised by major award
The winner of the Swiss Technology Award 2011 has created by Hamilton Medical, and as well as the clin- advanced lung protective strategies and patient adap-
been announced as the INTELLIVENT®-ASV introduced ical benefits, it has a positive impact on costs as well. tive modes. The device is the ideal choice for extreme
by Hamilton Medical. It is the first complete closed loop Costs in the ICU include labour, materials and also environments, where ICU ventilation is essential and
ventilation solution, that offers automated adjustment indirect costs from other departments. The impact of reliable data.
of oxygenation and ventilation. Today, conventional intelligent ventilators can be substantial as they can
mechanical ventilation still requires a great deal of reduce the time a patient spends on the ventilator by
expertise and the manual adjustment of ventilator set- reducing ventilator interractions by staff as well as pro-
tings. This can be challenging, as it is impossible for a viding innovative diagnostic tools.
respiratory clinician to be at the bedside all the time. The award was in recognition of only one aspect of
Now there is a solution to the problem as the device Hamilton Medical's programme of innovation. It does not
provides guidance when complex decisions are made. end at the hospital doors, but responds to the require-
Equally important it not only gives recommendations, ment for ready access to appropriate modes of therapy
but also adjusts ventilation settings automatically. The for ventilated patients outside the hospital environment.
INTELLIVENT-ASV even applies comprehensive lung The HAMILTON-T1 delivers a cost-effective solution
protective strategies automatically and reduces the risk that is appropriate for all patients from paediatric to
of operator errors while encouraging early weaning. adult. It is suitable for mobile ICU ambulances, heli- The Hamilton Medical team receives the Swiss
The device is based on innovative ASV technology copters and long distance jets. The device also includes Technology Award for 2011.
Compact monitor Medication data flies
over the airwaves
gives instant access
Medication errors remain a continuing hazard in hos-
pitals and there are a variety of products available to
address it. This creates the problem of how to choose
the most suitable infusion system for a particular appli-
A certain percentage of patients invariably have to the hospital information loop. This has meant greater cation. The latest system to make its appearance is
move around the hospital for a variety of reasons. mobility for patients and more time available for clin- the new Medfusion® 400 wireless syringe infusion
Monitoring is required during their transport or within ical and nursing procedures. pump with the PharmGuard® infusion management
the hospital, in a progressive care area or during super- software suite introduced by Smiths Medical. In com-
vised recovery from an acute event or surgical proce- mon with other infusion devices it is designed to help
dure. Recognising this need Philips has introduced the prevent errors. The difference is that at the same time
IntelliVue MX40 patient monitor. It is a wearable mon- it facilitates the forwarding and receipt of medication
itor which combines the benefit of the IntelliVue X2 and delivery information more efficiently. This is achieved
Philips Telemetry into a single, compact wearable via the wireless Ethernet connectivity.
monitor. The benefits it brings are considerable. It Financial and other considerations are making the
allows the clinician to better manage patient alerts and challenge of improved patient outcomes more difficult
is designed to support effective infection control. to achieve. The easy access to medication data can
There is easy access to such important data as ECG, help clinicians to make these improvements. This sys-
SpO2 and non-invasive blood pressure. Patient alerts tem with its wireless connectivity allows hospitals to
are highlighted at both the bedside and the central capture many types of infusion data and facilitates easy
monitoring station. The clinician is alerted to changes reporting for evidence based practice improvements.
in the patient conditions based on real-time surveil- It also smoothes the update of drug libraries and
lance. In total the monitor makes an important contri- improves both patient safety and clinical care by the
bution to a streamlined data flow. The Intellivue quick and easy update of pumps.
Information Centre is an integral part of the MX40 solu-
tion as it facilitates interfacing with the hospital EMR
(electronic medical record). PLEASE SEND YOUR NEWS ITEMS TO:
The development of the system was the result of a Guy Wallis
research initiative that took two different technologies Editorial Director
and combined them into a single innovative device that Alerts are highlighted at the bedside and the central g.wallis@greycoatpublishing.co.uk
could speed vital patient data around the key points of monitoring station as well.
98 INTERNATIONAL JOURNAL OF INTENSIVE CARE | WINTER 2011

12. REVIEW
Surgical and intensive care strategies
to prevent renal failure
Acute kidney injury (AKI) refers to a sudden decline in kidney meta-analysis established the usefulness of NGAL as a diag-
N Brienza MD, PhD,
function causing disturbances in fluid, electrolyte, and nostic and prognostic tool in cardiac surgical and critical-
MT Giglio MD,
L Dalfino MD,
acid–base balance due to a loss in small solute clearance and ly ill patients, as well as in patients with contrast-related
Emergency and Organ decreased glomerular filtration rate. Its occurrence in surgical renal damage, while no conclusions can be drawn for non-
Transplantation Department, and critically ill patients is common and it is associated with a cardiac surgical patients.8 In a large multicentre analysis,
Anesthesia and Intensive Care substantial increase in morbidity and mortality. Although the the same group confirmed that a positive NGAL finding
Unit, University of Bari, pathophysiology of AKI is complex, subsequent injury identified approximately 40% more AKI cases than creati-
Bari, Italy responses are likely to involve similar mechanisms. Major nine alone and that these patients were at greater risk of
contributors that precede renal injury are hypotension, death compared with control subjects.9 Very recent tri-
ischaemia/reperfusion, inflammation and toxins. Appropriate als10,11 suggest that a single NGAL measurement at ICU
and early identification of patients at risk for AKI provides an admission can predict later-onset AKI as well as ICU mor-
opportunity to prevent subsequent renal insults and impact tality, both alone or in combination with other AKI
overall intensive care unit morbidity and mortality; strategies biomarkers.
to prevent AKI are therefore of pivotal importance. Key
components of optimal prevention and management of the EPIDEMIOLOGY
intensive care unit patient with AKI include maintenance of Traditionally, AKI has been extensively studied in cardiac
renal perfusion and avoidance of precipitating factors. surgery, where it has a high occurrence (1–30%) and is
Whereas management of AKI remains limited primarily to highly predictive of other complications.12 In general sur-
supportive care, many potential therapies and interventions gical patients, AKI – defined as a creatinine increase of at
are on the horizon. For now, recognition of risk factors, least 2 mg/dL or need for dialysis – occurs in 1% of patients
excellent supportive care and avoidance of clinical conditions and is associated with an eight-fold increase in mortality,
known to cause or worsen AKI remain the cornerstones of independent of underlying comorbidities.13 Although
management of AKI. small as an absolute number, the rate of AKI is similar to
that of other ominous perioperative complications, such
as adverse cardiac events or venous thromboembolism.14
A
cute kidney injury (AKI) is a serious complication in
surgical and critical care patients, accounting for In patients admitted to the ICU after non-cardiac surgery,
18–47% of all hospital-acquired AKI,1,2 augmenting the AKI rate is 7.5% and AKI is an independent risk factor
hospitalisation costs3 and increasing mortality.4 for mortality at 6 months’ follow-up.15 More interesting-
Clinical manifestations of acute renal involvement range ly, the occurrence of postoperative AKI, independent of its
from short periods of oliguria to the need for renal replace- evolution, seems to affect outcomes.15 Knowing the exact
ment therapy (RRT). However, these manifestations have timing of kidney insult (i.e., surgery) would make preven-
different clinical impacts, since a common transient post- tion of postoperative kidney injury easier than in other set-
operative oliguria may not be synonymous of abnormal tings. However, one major problem is that we do not know
renal function but the appropriate response to hypoperfu- exactly which patients will really obtain a benefit. Whereas
sion of a kidney that is ‘doing its job’. The need for RRT,5 in cardiac surgery preoperative renal risk is carefully strat-
on the other hand, as well as subtle increases in serum cre- ified,12 this evaluation is lacking in non-cardiac surgery,
atinine, usually perceived as fluctuations within the ‘nor- although a specific risk index for AKI including congestive
mal range’,4 are both associated with increased mortality heart failure, emergency surgery or the complexity of
and morbidity. On the basis of glomerular filtration rate, surgery, mild or moderate chronic renal insufficiency and
creatinine level and urine output, the RIFLE (Risk, Injury, diabetes mellitus under therapy has recently been pro-
Failure, Loss and Endstage Kidney Disease) classification posed.13
defines three grades of increasing severity and two outcome AKI often complicates the course of critical illness and,
classes, all associated with increased hospital mortality.6 The although previously considered as a marker rather than a
AKI Network has modified RIFLE by adopting the term cause of adverse outcomes, it is independently associated
‘AKI’ to cover the entire spectrum of acute renal failure7 and with an increase in both morbidity and mortality.16 The
by including only three stages representing an increasing major causes of AKI in the ICU include renal hypoperfu-
degree of renal impairment, from small increases in creati- sion, sepsis/systemic inflammatory response syndrome and
nine to the need for RRT. direct nephrotoxicity, although in most cases the aetiology
However, the rise in creatinine lags behind the process is multifactorial.17,18 In a recent multicentre study, 42% of
leading to AKI, since it is revealed only after a substantial 33,375 septic patients developed concomitant AKI.19 Risk
fall in glomerular filtration rate has occurred. Therefore, factors for the development of septic AKI included age,
new biomarkers for AKI early diagnosis have been pro- comorbidities and a higher severity of illness. Since most of
posed with the aim of identifying an ongoing kidney insult these factors are not modifiable, AKI prevention should
before creatinine variation. The most promising is neu- mostly benefit from the avoidance of potential nephrotox-
trophil gelatinase-associated lipocalin (NGAL). A recent ic conditions and prompt recognition.
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13. STRATEGIES TO PREVENT RENAL FAILURE
PREVENTIVE STRATEGIES Haemodynamic optimisation
A major problem in AKI prevention is the lack of evidence- The kidney normally receives 20–25% of total cardiac
based strategies. In 2005, a systematic review did not find output. However, the medullary portion of the nephrons
any reliable evidence from the available literature to suggest is at risk of hypoperfusion because of low blood flow
that dopamine, diuretics, calcium-channel blockers or and high oxygen demand and extraction. In the perioper-
angiotensin-converting enzyme inhibitors can protect the ative setting, the increase in oxygen demand may put the
kidneys.20 Recent recommendations for the protection and kidney at further risk of hypoxia.30 Haemodynamic optimi-
prevention of AKI in ICU patients are all ‘negative’ 1A rec- sation or goal-directed therapy (GDT) is the perioperative
ommendations (strong recommendation with a high monitoring and manipulation of physiological haemody-
degree of evidence), and the few ‘positive’ clinical indica- namic parameters by means of fluids and inotropic drugs,
tions have been downgraded to suggestions with a low grade with the aim of achieving adequate oxygen delivery to
of evidence.21,22 cope with the increase in oxygen demand and prevent organ
failure.31
How many and which fluids? A recent meta-analysis demonstrated that GDT decreas-
Both relative and overt hypovolaemia are significant risk es the risk of postoperative renal impairment (Table 1).32
factors for the development of AKI. Consequently, timely Interestingly, this nephroprotective strategy was reported
fluid administration is a preventive measure that should be to be effective in high-risk surgical patients and when start-
effective through restoring the circulating volume and min- ed preoperatively to the first hours postoperatively.
imising drug-induced nephrotoxicity. In ICU patients, Moreover, targeting the optimisation to physiological val-
however, AKI commonly involves multiple mechanisms, ues of cardiac output revealed as much nephroprotection
including hypovolaemia and various types of shock. For as adopting supranormal goals of cardiac output. Because
example, sepsis and trauma can cause AKI through a com- of potential complications of fluid overload, myocardial
bination of renal hypoperfusion and the release of endoge- ischaemia and excessive use of catecholamine, which are not
nous nephrotoxins. Thus, correction of fluid deficit, while devoid of risks in terms of renal function,33 aggressive use
essential, will not always prevent renal failure. Moreover, it of fluids and catecholamines in an attempt to increase car-
is often difficult for clinicians to determine the amount of diac output to supranormal values can be avoided. Despite
fluids to administer to a given patient. From a kidney stand- the obvious limitations of all the meta-analysis regarding
point, on one side failure to prescribe adequate intravenous methodological differences among studies, publication bias
fluid can place a patient at risk of hypovolaemia, while on or suboptimal methodological quality of the studies, peri-
the other side excessive fluid infusion may promote third- operative GDT is, at the moment, the only evidence-based
space loss and intra-abdominal hypertension (IAH), a well- strategy able to reduce kidney injury in postoperative
known risk factor for AKI (see below). Currently, an patients. Moreover, evidence suggests that in surgical
individualised, timely fluid ‘replacement’ therapy by titrat- patients, perioperative GDT with epinephrine, dopexam-
ing volume to physiologic flow-related endpoints with ine or dobutamine may improve renal outcome,32,34 calling
appropriate monitoring23 may be a rational choice. for further trials to better clarify this issue.
The question of fluid infusion concerns not only the In patients with persistent hypotension despite volume
quantity of fluids, but also their quality. Aggressive crystal- optimisation, vasopressors are often employed to increase
loid resuscitation may increase intra-abdominal pressure mean arterial pressure and/or cardiac output, with the goal
and impair renal function, and colloids, while maintaining of ensuring optimal renal perfusion. In septic patients, nore-
the plasma volume more efficiently, may per se impair renal pinephrine has been traditionally used to increase blood
function. Recent randomised controlled trials (RCTs) have pressure with improvement of creatinine clearance.35 An
reported fewer marked changes in postoperative kidney RCT comparing dopamine with norepinephrine as the ini-
function with 6% hydroxyethyl starch (HES) 130/0.4 com- tial vasopressor in septic shock showed no significant dif-
pared with gelatine in both cardiac and vascular surgery ferences between groups with regard to renal function or
patients24,25 The most update-to-date evaluation of the rela- mortality, even if the use of norepinephrine was associated
tionship between colloids and kidney function shows that, with a lower incidence of arrhythmias.36 The results of
more than the quality, it is the mean colloid cumulative dose VASST (Vasopressin and Septic Shock Trial) suggest that,
that is associated with AKI.26 A recent Cochrane review stat- compared with norepinephrine, vasopressin may reduce
ed that colloids carry an increased risk of AKI in septic the progression to severe AKI only in a subgroup of patients
patients compared to non-septic surgical and trauma with less severe septic shock.37 The use of norepinephrine
patients.27 However, the small number of studies and the to improve renal oxygen delivery and renal oxygenation has
low event-rate claims for larger studies in non-septic set- been tested in other kinds of vasodilatory shock (i.e., post-
ting may have hampered the statistical power of these find- cardiac surgery patients) with convincing results.38
ings.
Recently, a pilot RCT performed in cardiac surgical Vasodilators
patients undergoing cardiopulmonary bypass suggested In recent years, a role for specific vasodilating drugs on kid-
that intravenous sodium bicarbonate is associated with a ney function has emerged. Fenoldopam mesylate is a selec-
lower incidence of acute renal dysfunction.28 This result tive DA-1 agonist that increases both medullary and cortical
warrants further investigation with adequately powered blood flow and reduces oxygen demand.39 A meta-analysis
RCTs and in other surgical settings. The benefit of sodium including 1,290 patients found that fenoldopam significant-
bicarbonate has been extensively studied in contrast- ly reduced the need for RRT and in-hospital mortality40 and
induced nephropathy, and recent inconclusive evidence a later review41 confirmed a beneficial effect in cardiac sur-
confirms a benefit of sodium bicarbonate over normal gical patients, but no conclusion can be drawn regarding
saline.29 non-cardiac surgery.
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14. STRATEGIES TO PREVENT RENAL FAILURE
Table 1. Subgroup analyses of pooled odds ratios of renal injury in perioperative haemodynamic goal-directed studies32
Treatment Control Q statistic Statistical
(n/N) (n/N) OR (95% CI) p-value p-value I2 (%) power (%)
High-quality RCTs (Jadad 102/1,741 150/1,699 0.66 (0.50–0.87) 0.003 0.75 0 99.7
score 3)
Renal injury according to 97/1,893 145/1,839 0.66 (0.50–0.86) 0.002 0.76 0 99.8
AKIN
Preoperative optimisation 94/1,347 117/1,289 0.70 (0.53–0.94) 0.02 0.41 0 75.6
Intraoperative or 21/770 58/814 0.47 (0.27–0.81) 0.006 0.80 0 100
postoperative optimisation
High-risk patients 102/1,393 158/998 0.64 (0.49–0.84) 0.001 0.53 0 99.8
Non-high-risk patients 13/724 17/686 0.69 (0.31–1.54) 0.37 0.61 0 19.1
Pulmonary artery catheter 103/1,640 151/1,629 0.62 (0.43–0.90 0.01 0.35 10.3 98
monitoring
Other monitoring devices 12/477 24/474 0.52 (0.25–1.07) 0.07 0.87 0 73
Fluids only 6/334 12/333 0.55 (0.20–1.47) 0.23 0.74 0 31
Fluids + inotropes 109/1,783 163/1,770 0.65 (0.50–0.85) 0.002 0.50 0 100
Fluids + dobutamine 12/511 42/518 0.36 (0.18–0.75) 0.006 0.57 0 100
Supranormal targets 30/354 55/353 0.49 (0.29–0.83) 0.008 0.54 0 98.2
Normal targets 85/1,763 120/1,750 0.70 (0.52–0.94) 0.02 0.71 0 94.5
AKIN = Acute Kidney Injury Network; CI = confidence interval; OR = odds ratio; RCT = randomised controlled trial
Atrial natriuretic peptide (ANP) is another ideal substance um by reperfusion (e.g., after haemorrhagic shock) or by
to counteract the initiation phase of AKI by causing vasodi- inflammatory mediators of injury (e.g., during sepsis/sys-
latation of the preglomerular artery, inhibition of the temic inflammatory response syndrome or major surgery)
renin–angiotensin axis and prostaglandin release.42 A recent associated with a positive fluid balance can lead to gut oede-
Cochrane review showed that low-dose ANP after major ma and IAH. IAH, by impairing systemic haemodynamics
surgery significantly reduced the requirement for RRT in and renal function, may foster a fluid-overload condition,
prevention studies, but not in treatment studies.43 However, leading to a vicious cycle that perpetuates IAH itself and renal
this result was mostly driven by the efficacy of low-dose ANP injury.47 Therefore, when IAH is present in an oliguric
in patients undergoing cardiovascular surgery. patient, intra-abdominal pressure should be monitored
carefully and crystalloid use should be avoided or limited.
Metabolic control Specific medical treatments and surgical options should be
In 2001, an RCT in surgical ICU patients compared tight considered to decrease intra-abdominal pressure.48
blood glucose control with insulin (blood glucose 80–110
mg/dL) versus standard care (blood glucose 150–160 Drugs
mg/dL), demonstrating an improved survival rate and a The contribution of treatment-induced renal injury as a
41% reduction in AKI requiring RRT in the intensively con- preventable cause of AKI is frequently underestimated. In
trolled group.44 These positive findings have recently been severe AKI, nephrotoxic drugs are contributing factors in
questioned by the NICE-SUGAR trial,45 which included up to 19–25% of cases.2,49 In surgical and critically ill
surgical patients but was not limited to them. This trial patients, drug-induced AKI is mediated by inherent drug
found that a blood glucose target of 180 mg/dL or less result- nephrotoxic potential, disease states and impaired drug
ed in lower mortality than an intensive target of 81–108 pharmacokinetics, leading to overdosing.
mg/dL, with no effect on RRT. A recent meta-analysis, Drugs may exert a direct nephrotoxic effect by several
which included the NICE-SUGAR trial, tried to put the con- mechanisms. Most commonly, renally excreted drugs can
troversial results in a different perspective by analysing sub- exert direct toxic effects on renal tubules, inducing cellular
groups of mixed, medical and surgical ICU patients.46 The injury and death in acute tubular necrosis, or can induce
analysis concluded that a beneficial effect, if any, on mor- renal interstitium inflammation in acute interstitial nephri-
tality of this therapy may be restricted to patients in the sur- tis. Moreover, hypertonic solutions may cause osmotic
gical ICU. nephrosis and tubular obstruction by drug precipitation.
Drugs may also be indirectly nephrotoxic by impairing
Intra-abdominal hypertension intrarenal blood flow, thus making the kidneys vulnerable
Shock and IAH, by reducing abdominal perfusion pressure, to ischaemia and injury in low-flow states such as sepsis,
are the strongest independent predictors of AKI.47 ‘Third- volume depletion, major surgery, trauma and acute decom-
space’ losses from compromised bowel capillary endotheli- pensated heart failure.50
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16. STRATEGIES TO PREVENT RENAL FAILURE
Table 2. Primary pathogenetic mechanisms, specific clinical features and risk factors, preventive measures in high-risk patients and management of
drug-induced AKI22,26,50,51
Primary Drug Clinical features Specific risk factors AKI prevention in high-risk patients/management
mechanism Radiocontrast dye
Haemodynamically Radiocontrast dye Onset: 24 hours Advanced age, diabetes Address the issue of whether contrast exposure is
mediated mellitus, multiple mieloma, mandatory
nephrotic syndrome, Discontinue all other nephrotoxics if possible
haemodynamic instability
Use the smallest volume of iso-osmolar agents
High osmolality and/or high
volume ( twice the baseline Perform preprocedural hydration with crystalloid
GFR in mL) of radiocontrast dye solutions (sodium chloride or sodium bicarbonate
infused at 3 mL/kg/hr for 1 hour), plus high-dose NAC
Number of risk factors
(1,200 mg) administration, followed by postprocedural
hydration (1 mL/kg/hr for the subsequent 6 hours)
Monitor renal function at 24–72 hours
ACE inhibitors, Usually reversible upon Bilateral renal artery stenosis Consider drug requirement carefully
angiotensin-receptor discontinuation Discontinue if SCr >30% from baseline or
blockers hyperkalemia develops
NSAIDs, COX-2 Onset after a few doses Severe cardiovascular or Consider drug requirement carefully (prefer
inhibitors Usually oliguric hepatic failure acetominophen and/or narcotics)
Usually reversible upon Type (aspirin the least toxic, Begin with a low-dose of short half-lifes NSAIDs
discontinuation indomethacin the most toxic), (salycilates, sulindac)
dose and duration of therapy
Use half doses or avoid ketorolac, avoid indomethacin
Concomitant nephrotoxics Immediatly stop NSAID therapy
Correct volume depletion
Calcineurin inhibitors Onset: few weeks or Dose and serum levels Perform TDM
(cyclosporine, months
Concomitant nephrotoxics Avoid other nephrotoxins
tacrolimus)
Usually oliguric Perform dose reduction or drug discontinuation
Reversible after dose
reduction or
discontinuation
Acute tubular Aminoglycosides Onset: 5–10 days Advanced age Consider alternative antimicrobials
necrosis
Non-oliguric Type of aminoglycoside Use extended-interval dosing (i.e., once-daily dosing)
(streptomycin the least toxic,
From mild and rapidly Perform TDM, and titrate dose basing on trough levels
neomycin the most toxic)
reversible to severe and renal function
forms requiring RRT and Persistently high trough serum
Avoid concomitant nephrotoxins
a prolonged recovery levels
time Discontinue and choose alternative antimicrobials if
Frequency of administration, possible, when severe AKI ensues
Usually reversible upon large cumulative doses, long
early discontinuation and/or repeated courses of
therapy
Concomitant nephrotoxics
High-dose vancomicin Onset: 4–8 days Advanced age Perform TDM and titrate dose based on renal function
(daily dose 4 g or Usually reversible upon Obesity and ideal body weight
30 mg/kg, or target
discontinuation Discontinue and choose alternative antimicrobials if
trough concentrations High APACHE II score
possible, when severe AKI ensues
of 15–20 mg/L) Trough levels >15 mg/L
Duration of therapy
Concomitant aminoglycoside
therapy
Amphotericin B Frequency: 80% Hypokalemia Consider alternative antifungals
Usually oliguric Large single and cumulative Prefer lipid-based formulations
doses Perform sodium loading with intravenous hydration
Concomitant nephrotoxics before each dose
Prescribe prolonged infusion times and daily renal
function monitoring
Avoid concomitant nephrotoxins
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104 INTERNATIONAL JOURNAL OF INTENSIVE CARE | WINTER 2011