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Review

Drug dosage in continuous venoveno hemofiltration in critically ill children

Farahnak Assadi1,*,Fatemeh Ghane Shahrbaf2
1
Department of Pediatrics, Section of Nephrology, Rush University Medical Center, Chicago, 445 E. North Water Street, Chicago, Illinois, USA 60611, M.D
2
Department of Pediatrics, Section of Nephrology, Mashhad University of Medical Sciences, Dr. Shiekh Children’s Hospital, Mashahd, Iran
DOI: 10.2741/S446 Volume 8 Issue 1, pp.56-66
Published: 01 January 2016
*Corresponding Author(s):  
Farahnak Assadi
E-mail:  
fassadi@rush.edu
Abstract

The dosage of drugs in patients requiring continuous renal replacement therapy need to be adjusted based on a number of variables that that affect pharmacokinetics (PK) including patient weight, CRRT modality (convention, vs. diffusion), blood and/or effluent flow, hemofilter characteristics, physiochemical drug properties, volume of distribution, protein binding and half-life as well as residual renal function. There is a paucity of data on PK studies in children with acute kidney injury requiring CRRT. When possible, therapeutic drug monitoring should be utilized for those medications where serum drug concentrations can be obtained in a clinically relevant time frame. Also, a patient-centered team approach that includes an intensive care unit pharmacist is recommended to prevent medication-related errors and enhance safe and effective medication use is highly recommended. The aim of this article is to review the current guidelines for drug dosing in critically ill children who require continuous venovenous hemofiltration.

Key words

Continuous venovenous hemofiltration; acute kidney injury; Critically ill children; Drug dosing Adjustment, Review

2. Introduction

Acute kidney injury (AKI) is a common problem in pediatric patients and is associated with significant mortality and morbidity (1-4). It occurs in 5% of all hospitalized patients and up to 30% of critically ill patients (5,6). The morbidity and mortality rates are 40% and 60%, respectively in all patients admitted to the pediatric intensive care unit (7-10). The critically ill and hemodynamically unstable children with AKI are frequently treated with continuous renal replacement therapy (CRRT) (11-17). CRRT, unlike the traditional hemodialysis and peritoneal dialysis provides a slow and gentle fluid removal from body much like the native kidneys and removes inflammatory mediators of sepsis such as interleukin, TNF-alpha, and complement. CRRT also provides adequate nutritional support for the catabolic AKI patients a controlled desired fluid balance (18,19).

Many AKI patients receiving CRRT suffer from multiple organ dysfunctions and are also on various types of medications including antibiotics, anticonvulsants, anticoagulants, and cardiovascular agents. With the use of CRRT in the critically ill patients it is of the utmost importance to properly dose the multitude of drugs administered in these patients, especially those whose pharmacodynamic (PK) effects are difficult to measure.

Many guidelines for drug dosing during CRRT are extrapolated from experiences with adult chronic hemodialysis and there has been a relative paucity of data concerning PK and CRRT in pediatric patients (20). Drug properties such as protein binding, sieving coefficient, volume distribution (Vd), and half-life all influence the drug PK so dosing adjustments are variable (21,22). Drug doses used in adults cannot be directly applied to these children, as the CRRT dialysate prescription and pharmacokinetic are different in adults compared with children. The extent of drug removal is variable depending on the CRRT modality, convection or diffusion or both, patient body weight, blood flow, ultrafiltrate and dialysate flow rates, membrane size, drugs molecular weigh, Vd, protein binding, as well as residual renal function and non-renal drug clearance. Failure to correctly dose may result in either drug toxicity or treatment failure. In order to understand the optimal drug dosing for children receiving CRRT, one must understand the pattern of water and solutes transport through a semipermeable membrane by all forms of CRRT (23). The existing FDA guidance however, does not include a recommendation for PK studies in CRRT, and the studies are not required for getting approval, so currently, no regulatory incentive exists for pharmaceutical manufacturers to study PK in CRRT during drug development (24).

To date, there are mostly sporadic post-marketing studies that exist for less than 20 percent of currently marketed drugs. It is common place to most often extrapolate dosing recommendations from PK studies that used outdated CRRT technology, from studies in ESRD patients receiving intermittent hemodialysis and adult patients, each of which typically requires lower doses than higher intensity CRRT. For example, in a recently published retrospective study by Gist et al, the authors discuss the use of therapeutic drug monitoring for dose adjustment of milrinone in critically ill children, including some who required CRRT (25). They reported a large variability in milrinone concentrations, which were often outside the target a range, as well as large between patient variability suggesting that dosing regimens should be individualized in critically ill patients.

This review article provides recommended CVVH dosing adjustments for drugs commonly used in critically ill children.

3. Continuous venoveno hemofiltration (CVVH) principles

CVVH is one of the most commonly CRRT modalities used for the treatment of hemodynamically unstable patients complicated with AKI, fluid overload and septic in the intensive care unit setting (16, 23,26,27). Primary therapeutic goal of CVVH is water and solute removal across a semipermeable membrane to provide fluid balance as well as control of electrolyte balance. Continuous hemofiltration with the aid of a blood pump provides solute removal by convection (Figure 1). CVVH offers high volume ultrafiltration using replacement fluid, which can be administered pre-filter or post-filter. In post-dilution the drug clearance equals the ultrafiltration rate, while in pre-dilution the replacement fluid should be considered when calculating clearance. The pump guarantees adequate blood flow to maintain required ultrafiltration rates. Venous blood access is usually jugular or subclavian using a double lumen cannula (28,29).

Figure 1. CVVH extracorporeal circuit with the aid of a blood pump and using venous access.

Because unwanted solutes are removed by taking off plasma water, increased clearances are achieved by using higher ultrafiltration rate to remove more plasma water. Compared to CVVHD therapy, CVVH provides less efficient removal of solutes of small molecular weight (<350 Daltons), but more efficient removal of solutes of larger molecular weight (30).

4. Drug dosing adjustments during CVVH treatment

In general, drugs that are predominately removed by the normal kidneys require a dose reduction in patients with AKI (31). If CRRT is initiated, some of the drugs may be eliminated by CRRT (32-36). The extent of drug removal determines whether supplemental dosing is necessary during CRRT to avoid the drug under-dosing. Therefore, a dose adjustment is required to prevent under dosing of the medication or drug toxicity.

The impact of CRRT on drug removal is variable depending on the various techniques are used in the management of AKI, the blood flow, ultrafiltrate and dialysate flow rates, the filter, and the patients residual renal and non-renal drug clearance (37-41). Middle and large size solutes such as inflammatory mediators, myoglobin, and bilirubin can be removed more efficiently by CVVH than diffusion technique. The data suggest an early initiation of treatment and a minimum delivery dose of 25mL/Kg/h improve patient survival rate (42). Guidelines whether or not dose adjustment is required for children with AKI is provided in Table 1. The limitations of using these dosage guidelines for children include the population of neonates and infants who continue to undergo normal renal functional maturation until age two and the unreliability of a calculated GFR in the critically ill children.

Table 1. Pediatric drug dosage adjustments during continuous venovenous hemofiltration*
Drug categoryProtein binding(%)SCVd L/kgT1/2 hNormal dose (GFR 100)Dose in CVVH<1-2L/h GFR<15-30 References 21,28,29,60
Analgesic
 Acetaminophen20-500.930.2-.42-35mg/kg iv q8hNo change
 Acetylsalicylic>99500.250.810mg/kg q4-6hNo change
 Codeine7NA3-630.5-1mg/kg q6h75% dose reduction
 Ibuprofen90-99NA0.141.8.5-10mg/kg q6hNo change
 Ketorolac>99NA0.1-.350.25-1mg/kg q6hNo change
 Fentanyl80-850.292.4.2.6.1-5mcg/kg q6h75% dose reduction
 Meperidine60-85NA2.4.110.5-2mg/kg infusion75% dose reduction
 Methadone60-90NA4.5.8-490.5mg/kg q6h0.5mg/kg q24h
 Morphine20-350.653.3.2.5.0.05-.2mg/kg iv q2-4h75% dose reduction
Antimicrobials
 Aciclovir9-330.850.72-310mg/kg iv q8hNormal dose iv q24h
 Amikacina<200.950.2-.71.6.-2.5.20mg/kg(max 1.5.g) iv q24h10mg/kg iv q24h
 Amoxicillin15-200.851.3.5-205-15mg/kg iv q8hNo change
 Amphotericin liposomal90NA0.1-.46-103-5mg/kg iv q24hNo change
 Ampicillin17-200.80.321-1.8.50mg/kg iv q8hNo change
 Azithromycin10-50NANA6-85mg/kg q12No change
 Atrreonam50-60NA0.25280-120mg/kg q8hNo change
 Benzylpenicillin60NA0.3-.40.5-1.2.25-50mg/kg iv in q8hNo change
 Cefaclor20-50NA0.24-.35110-20mg/kg iv q12hNo change
 Cefazolin70-86NA0.13-.22250-100mg/kg iv q8h505 dose reduction
 Cefotaxime40NA0.31.5.50mg/kg iv q8-12hNo change
 Ceftazidine<10NA0.2-.4125mg/kg iv q8hNo change
 Ceftriaxone85-950.660.35880mg/kg(max 2g) iv q24hNo change
 Cefuroxime330.660.191.5.25-50mg/kg iv q8h25-50mg/kg iv q12-24h
 Cidofovir<10NA0.315-255mg/kg iv q 1-2 weeks2mg/kg iv q 1-2 weeks
 Ciprofloxacin20-400.72-34-510mg/kg(max 400mg) iv q12h25% reduction q 12h
 Clindamycin>900.40.6-1.2.2-35-10mg/kg(max 1.2.g) iv q6hNo change
 Co-amoxiclave (amoxicillin+clavulanic acid)17-30NA0.2-.40.930mg/kg(max 1.2.g) iv q8h50% dose reduction
 Co-trimoxazole (trimethoprim+sulfamethoxazole)50-66NA0.3-2.2.5.5.-1740-60mh/kg ivq12h50% dose reduction
 Erythromycin70-950.30.6-1.2.212.5.-25mg/kg iv q6hNo change
 Flucloxacillin95NA0.132-325-100mg/kg iv q8hNo change
 Fluconazole12NA0.6-1.2.15-206-12mg/kg iv q 72hNo change
 Ganciclovir1-20.840.4-.83-285mg/kg iv q 12h50% dose reduction
 Gentamicina1-300.950.2-.51-37mg/kg iv q 24h4mg/kg iv q24h
 Imipenem13-2110.51-1.3.15mg/kg(max 500mg) iv q6h25% dose reduction
 Isoniazid10-15NANA2.8.10-15mg/kg q12-24hNo change
 Ketakonazole85-99NA2-483-6mg/kg q24hNo change
 Levofloxacin25-380.8NANA5-10mg/kg q24hNo change
 Meropenem2NA0.41.5.-2.3.10-20mg/kg iv q8hNo change
 Metronidazole<20, 81.1.6-127.5.mg/kg(max 500mg) iv q8hNo change
 Nafcillin900.20.35115-50mg/kg iv q4-6hNo change
 Olfaxacillin20-30NANANA15mg/kg iv q12hNo change
 Piperacillin20-30NA0.20.7200mg/kg q4h200mg/kg q8h
 Rifampicin800.20.661-3.8.10mg/kg(max 500mg) iv q12hNo change
 Streptomycin34NANA5-820-40mg/kg iv q24h7.5.mg/kg q24h
 Ticarcillin45-65NA0.221.1.80mg/kg(max 3.2.g) q 8hNo change
 Tobramycin44-501.6.1.6.1160mg/kg iv q12h50% dose reduction
 Vancomycina55NA0.4-0.75.6.15mg/kg iv q8h10mg/kg iv q 12h
Anticoagulants
 Heparinb95<0.11210-25U/kg/hNo change
 Warfarin>900.020.05500.5-8mg q24hNo change
Anticonvulsives
 Carbamazepine75-90740.251.3.5-10mg/kg q12h75% dose reduction
 Phenobarbital30-500.60.8803-7mg/kg q24h10mg/kg q 6-8h
 Phenytoin80-900.10.6203-7mg/kg q8hNo change
 Valporic acid80-930.10.2-19-1610-30mg/kg q12hNo change
Antihistamines
 Cimetidine190.8124-8mg/kg q12h50% dose reduction
 Diphenhydramine78NA3-65-111mg/kg q4-6hNo change
 Famotidine15-20NA1-1.5.2-40.5mg/kg q12hNo change
 Terbutaline25NA1.6.5.7.0.1-.4mg/kg/min iv infusionNo change
Antihypertensive agents
 Amlodipine93NA21400.05-.17mg/kg q24hNo change
 Capropril30NA1.5.1.5.0.1-.5mg/kg q6-8h75% dose reduction
 Clonidine20-400.72.1.82.5.-5mcg/kg q12hNo change
 Enalapril<500.51.7.110.1mg/kg q12h75% dose reduction
 Hydralazine85-900.15mg/kg q8h
 Isradipine950.131.5.1, 05-.2mg/kg q8hNo change
 Labetalol500.4-3mg/h iv infusionNo change
 Lisinopril25NANA5-60.1mg/kg q12-24h0.50% dose reduction
 Nifedipine95%0.081.2.2.8.0.25-.5mg/kg q6-8hNo change
 Prazosin950.030.62.9.0.2-1mg/kg q12hNo change
 Propranolol60-900.074.3.3.5.0.1-1mg/kg q6hNo change
Cardiovascular agents
 Amiodarone960.0361N/A5-10mg/kg q 24hNo change
 Atenolol<510.4361-2mg/kg q24hNo change
 Atropine14-220.52.9.2-40.5-1mg q5-30minNo change
 Digoxin20-550.86.5.40250mcg q24h62.5.mcg q24h
 DobutamineNANA0.222-20mcg/kg/min iv infusionNo change
 DopamineNANANA5.5.2-20mcg/kg/min iv infusionNo change
 EpinephrineN/ANA<.1<.10.01-1mcg/kg/min iv infusionNo change
 Milrinone70NA0.382.3.0.25-.75mcg/kg/min iv infusion0.33mcg/kg/min iv infusion
 Procanimide15-20NA1.7.-2.5.3-420-80mcg/kg/min iv infusionNo change
 Verapamil900.134.3.51-2mg/kg q8hNo change
Miscellaneous
 Aminophylline400.47NA402mg/kg q8hNo change
 Cytoxanc130.830.787.5.Follow protocol50-75% dose reduction
 Cyclosporinea, c960.131Follow protocolNo change
 Dexamethasone680.32131-4mg q6hNo change
 Hydrocortisone70-90NA0.4-.71.7.1-5-10mg/kg q6hNo change
 Insulin980.95<.10.30.5-10U/hNo change
 Mycophenolate97NA918-16600mg/m2q12hNo change
Sirolimus92NA20601mg/m2q24hNo change
*Subsequent doses should be based on the estimated ultrafiltration capacity of the CVVH. CVVH=continuous venovenous hemofiltration; SC=seiving coefficient(fraction); Vd=volume distribution; t1/2=half-time; GFR=glomerular filtration rat; iv=Intravenous; NA=not available; aLevels need to be checked daily; bDose need to be adjusted according to APPT measured q12-24h; cAccording to protocol

Drug dosing can be calculated from the knowledge of the PK parameters of a drug including the drug distribution, elimination within the body and the desired drug concentration in plasma (43). In the case of patients with AKI being treated with CRRT, clearance will depend on a combination of CRRT clearance, residual renal function and non-renal clearance. Both the volume of distribution and the non-renal clearance may be changed by AKI and critical illness In general, drug dosing during CRRT should follow the following pharmacokinetic parameters (44-50).

4.1. Volume of distribution

The dose administered divided by the final plasma concentration of drug yields a number with units of volume, called the “volume of distribution.”

Vd (L/Kg) = loading dose (mg/Kg)/concentration (mg/L). Loading dose (LD) mg/kg = Vd × serum concentration (mg/dL)

Fluid overload and extracellular fluid volume expansion increase volumes of distribution for hydrophilic drugs, such as aminoglycosides. In contrast, extracellular volume contraction decreases volume of distribution for hydrophilic drugs.

4.2. Protein binding

Pb describes the bound fraction of drug but also determines free fraction of drug available for pharmacological action. It is the single major determinant of clearance in patients on CRRT at a given rate, because only the unbound fraction is available to be filtered. Pb is decreased in patients with nephrotic syndrome and increases during albumin administration. Other factors that may affect pb in the critically ill children include pH, heparin therapy, hyperbilirubinemia, uremia, blood free acid concentration and presence of drugs that are competitive displacers (51-53).

4.3. Sieving coefficient

SC is the ratio of drug concentration on the filtrate side of the membrane to drug concentration in the blood passing through the filter. The SC vales can vary from zero for drugs that cant not be filtered to one for drugs, which are freely filtered. The major determinant of the SC is the proportion of the plasma protein binding, because the drug that is bound to plasma protein is not available for filtration.

4.4. Plasma clearance

In consideration of drug Cl, metabolism of the drug is usually significant and sometimes dominates elimination of drug from plasma. The drug may also be secreted in bile and eliminated in stool. Drug Cl (mL/min) = Volume (mL)/Time (min); where Cl=describes clearance of drug (volume) from the body per unit time in min. Drug clearance decreases in patients with oliguric AKI.

4.5. Maintenance dose

MD/mcg = CL (mL/min) x serum concentration (mcg/mL) x dosing interval (min)

Half-life (t1/2) =0.6.93 x ke hours-1,

where (t1/2) is the time in hours that it takes for the serum concentration of a drug to be reduced by 50% and ke hours-1 =Vd (L) x CL (mL)/min. (t1/2) increases in oliguric AKI and shock syndromes.

5. CRRT Impact on PK parameters

Prescription variables that may affect PK include patient seize, organ function, volume status, physiochemical drug properties, CRRT modality (convective vs. diffusive clearance routes), blood and/or dialysate flow and solute clearance, and hemofilter characteristics (54-56).

AKI affects both distribution and elimination of many drugs (57-63). CRRT also impacts on PK parameters in many ways. Replacement fluids may affect drug removal by influencing the drug concentration within the filter (15). Usual circuit priming volume ~100-150mL can increase Vd. Tubing and membrane filter bind drug and increases Vd. The use of higher blood flow rate (>3-5mL/Kg/min) can also lead to increased CL. The use of higher ultrafiltration rate ~ filter replacement fluid rate (>35-40mL/Kg/h or 2.5. L/m2/h) also lead to increased Cl.

The correct drug dosing should consider not only the extracorporeal drug removal, type of filter membrane but also residual renal and non-renal clearance and drug molecular weight, protein binding information and volume of distribution to avoid medications error. The ideal drug to be removed by CVVH that requires a dose adjustment has: a low protein binding, a low volume of distribution, and a low non-renal clearance.

Depending on the drug, it may be more appropriate to shorten the dosing interval or to increase the dose. Example, in oliguric AKI patients a very small single daily dose of aminoglycosides can be used to achieve peak concentrations and to avoid toxic side effects. After CRRT initiation, it is recommended to increase the single daily dose to achieve peak levels while lowering aminoglycosides levels to low trough concentration and avoiding the risk of side effects. In contrast, the bactericidal effect of β-lactam antibiotics (penicillins and cephalosporines) correlates with constant plasma levels above the minimal inhibitory concentrations of the bacteria and side effects may occur if high peak concentrations are reached with use of high single doses. In these drugs it may be useful to shorten the dosing intervals instead of increasing the individual dose (Table 1).

All β-lactams are small size (molecular weight <800 Daltons) have volume distributions >0.3. L/kg and protein bounding fraction <10% except for oxacillllin and ceftriaxone are not clinically significant. They undergo significant extracorporeal clearance during CVVH (45-50).

Meropenem, and aminoglycosides also have pharmacokinetic properties such as low molecular weight, small volume of distribution and negligible protein binding. They are easily filtered due to its low molecular eight, low volume of distribution and low protein binding. In contrast, quinolones (ciprofloxacin and levofloxacin) with molecular weight about 370 Daltons, volume of distribution 1.2.-1.8. L/kg and protein binding of 25-50% are less liable to clearance by CVVH (48-50).

Glycopeptides (vancomycin) has a large molecular weigh nearly 1550 Daltons with volume distribution of 0.3.8 L/kg and protein binding of 30% (57). The normal function kidneys clear about 70% of the drug. The clearance rates of vancomycin in patients on CAVVH are compatible with clearance in patients with GFR >50 mL/min.

As a general rule, because of the presence of a positive fluid balance in the early stages of AKI, the dosing regimen for many drugs, especially antimicrobial agents, should be initiated at normal or near-normal recommended dosage. In general, a loading dose that will achieve the target serum concentrations based on the expected volume of distribution should be given and no adjustments need to be made for residual renal function.

When possible, therapeutic drug monitoring should be utilized for those medications where serum drug concentrations can be obtained in a clinically relevant time frame. A patient-centered team approach that includes an ICU pharmacist is recommended to prevent medication-related errors and enhance safe and effective medication use is highly recommended. Clinical pharmacist provides excellent services including collecting patient data, estimating creatinine clearance and advising the physician to adjust medication dosages based on the creatinine clearance.

6. Summary and perspective

Drug dosing must be adjusted in children receiving CVVH due to its effects on drug PK. Drug properties such as protein binding, sieving coefficient, volume distribution, and half-life all influence the drug PK so dosing adjustments are variable. Both the volume of distribution and half-life of several drugs are markedly increased in the presence of AKI and thus larger loading doses may need to be administered to achieve the target serum concentrations. Therapeutic drug monitoring should be utilized for those medications where blood drug concentrations can be obtained in a clinically relevant time frame.

Abbereviations: CVVH, Continuous venoveno hemofiltration; PK, Pharmacokinetics; AKI, Acute kidney injury

References

    1. C. Garist, Z. Favia, Z. Ricci, M. Averardi, S. Picardo, D.N.Cruz.: Acute kidney injury in the pediatric population. Contrib Nephrol 165,345-356 (2010)

    2. G.M.,Barletta, T.F., Bunchman.: Acute renal failure in children and infants. Curr Opin Cri Care 10,499-505 (2004)

    3. M.E. Norman, F. Assadi: A prospective study of acute renal failure in the newborn infant, Pediatrics1979; 63,475-79 (1979)

    4. D.M.Williams, S.S. Sreedhar, J.J. Mickell, J.C. Chan: Acute kidney failure: a pediatric experience over 20 years. Arch Pediatr Adolesc Med 156,893–900 (2002)

    5. S.M. Bagshaw: Epidemiology of renal recovery after acute renal failure. Curr Opin Crit Care 12,544-5, (2006)

    6. S.S. Waikar, K.D. Liu, G.M. Chertow: Diagnosis, epidemiology and outcomes of acute kidney injury. Clin J Am Soc Nephrol 3,844-861 (2008)

    7. Goldstein SL, Acute kidney injury in children: prevention, treatment, and rehabilitation. Contrib Nephrol 174,163-72 (2011)

    8. H.E. Wang, P. Muntner, G.M. Chertow, D.G. Warnock: Acute kidney injury and mortality in hospitalized patients. Am J Nephrol 35,349-355 (2012)

    9. S.G. Coca, B.Yusuf, M.G. Shlipak, A.X. Garg, C.R. Parikh: Long-term risk of mortality and other adverse outcomes after acute kidney injury: a systematic review and meta-analysis. Am J Kidney Dis 53,961-973 (2009)

    10. S.L. Goldstein, P Devarajan: Acute kidney injury leads to pediatric patient mortality. Nat Rev Nephrol 6,393-4 (2010)

    11. F. Assadi: Treatment of acute renal failure in an infant by continuous arteriovenous hemodialysis. Pediatr Nephrol 2,230-232, (1988)

    12. S.L. Goldstein: Overview of pediatric renal replacement therapy in acute kidney injury. Semin Dial 22:180-84 (2009)

    13. S.L. Goldstein, M.J. Somers M.A., J.M. Baum, P.D. Symons, D.Brophy, D. Blowey, T.E. Bunchman, C. Baker, T. Mottes, N. McAfee, J. Barnett, G. Morrison, K. Rogers, J.D. Fortenberry: Pediatric patients with multi-organ dysfunction syndrome receiving continuous renal replacement therapy. Kidney Int 67,653-58 (2005)

    14. P.G. Metnitz, C.G. Krenn, H. Steltzer, T. Lang, J. Ploder, K. Lenz, J.R. Le Gall, W. Druml: Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients. Crit Care Med 30,2051–8 (2002)

    15. J.A. Kellum, D.C. Angus, J.P. Johnson, M. Leblanc, M. Griffin, N. Ramakrishnan, W.T. Linde-Zwirble: Continuous versus intermittent renal replacement therapy: a meta-analysis. Intensive Care Med. 28,29–37 (2002)

    16. T.E. Bunchman: Treatment of acute kidney injury in children: from conservative management to renal replacement therapy, Nat Clin Pract Nephrol 4,510-14 (2008)

    17. R, Gottlieb, F Assadi: Continued Renal Replacement therapy in Newborn Infants. In: Intensive Care of the Fetus and Neonate. Ed: Spitzer A.R., Mosby-Year Book, Inc., Philadelphia, PA, 1187-1191 (1995)

    18. B.R. McDonald, R.L. Mehta: Transmembrane flux of IL-1B and TNF in patients undergoing continuous arteriovenous hemodialysis (CAVHD). J Am Soc Nephrol. 1,368-71 (1990)

    19. W. Silvester: Mediator removal with CRRT: complement and cytokines.Am J Kidney Dis 30 (5 Suppl 4), S38–43 (1997)

    20. D.J Askenazi, S.L. Goldstein R. Koralkar, J. Fortenberry, M. Baum, R. Hackbarth, D. Blowey, T.E. Bunchman, P.D. Broph, J.Symons, A. Chua, F. Flores, M.J.Somers: Continuous renal replacement therapy for children under 10kg: a report from the prospective pediatric continuous renal replacement therapy registry. J Pediatr.162,587-92 (2013)

    21. J.T. Flynn: Choice of dialysis modality for management of pediatric acute renal failure. Pediatr Nephrol 17,61-69 (2002)

    22. Schetz M: Non-renal indications for continuous renal replacement therapy. Kidney Int Suppl 72,S88–94 (1999)

    23. S.L. Goldstein, T,D. Nolin: Lack of drug dosing guidelines for critically ill patients treceiving continuous renal replacement therapy. Clinical Pharmacology and Therapeutics. 96,159-61 (2014)

    24. T.D. Nolin, G.R.Aronoff, W.H. Fissell WH, L. Jain, R. Madabushi, K. Reynolds, L. Zhang, S.M. Huang, R. Mehrotra, M.F.Flessner, J.K. Leypoldt, J.W. Witcher, I. Zineh, P. Archdeacon P. Roy, P. Chaudhur, S.L., Goldstein: Pharmacokinetic assessment in patients receiving continuous RRT: perspectives from the kidney health initiative. Clin J Am Soc Nephrol 10, 159-64 (2015)

    25. K.M.Gist, T. Mizuno, S.L. Goldstein, A. Vinks: Retrospective evaluation of milrinone pharmacokinetics in children with kidney injury. Ther Drug Monit. Apr 9. (Epub ahead of print). (2015)

    26. S.K. Sethi, T.E. Bunchman, R. Raina, V. Kher: Unique considerations in renal replacement therapy in children: core curriculum. Am J Kidney Dis 63,329-45 (2014)

    27. W.R. Clark, B. Mueller, A. Kraus, W.L. Macias:. Extracorporeal therapy requirements for patients with acute renal failure. J Am Soc Neph 8,804–12 (1997)

    28. G.E.Cimochowski, E. Worley, W.E. Rutherford, J Sartin, J Blondin, H Harter: Superiority of the internal jugular over the subclavian access for temporary dialysis. Nephron 54,154–61 (1990)

    29. A.R.Webb, M.G.Mythen, D. Jacobson, IJ Mackie: Maintaining blood flow in the extracorporeal circuit. Intensive Care Med. 21,84–93 (1995)

    30. C. Ronco, R. Belomo, P. Homel, A. Brendolan, M. Dan, P. Piccinni, G. La Greca: Effects of different doses in continuous venovenous hemofiltration on outcomes of acute renal failure: a prospective randomizes trail. Lancet 356,26-30 (2000)

    31. G.R. Aronoff, W.M. Bennett, J. Berns, M.E. Brier, N. Kasabaker, B.A. Muelle, D.A. Pasko DA, W.A.Smoye: Drug prescribing in renal failure: dosing guidelines for adults and children, 5th ed. Philadelphia: American College of Physicians (2007)

    32. W.A.Veltri, A.M. Neu, B.A. Fivus, R.S. Parekh, S.L. Furth: Drug dosing during intermittent hemodialysis and continuous renal replacement therapy: special considerations in pediatric patients. Pediatr Drugs 6,45-65 (2004)

    33. G. Choi, C.D. Gomersall, Q. Tian, G.M. Joynt, R. Freebairn, J. Lipman: Principles of antibacterial dosing in continuous renal replacement therapy. Crit Care Med 37,2268-282 (2009)

    34. G. Choi, C.D. Gomersall, Q. Tian, G.M. Joynt, R. Freebairn, J. Lipman: Pricinpal of antibacterial dosing in continuous renal replacement therapy. Blood Purif. 30,195-12 (2010)

    35. M.D. Churchwell, B.A. Mueller: Drug dosing during continuous renal replacement therapy. Semin Dial 22,185-8 (2009)

    36. T.E. Bunchman: Medication errors and patient complications with continuous renal replacement therapy. Pediatr Nephrol 21,842-45 (2006)

    37. A.F Grootendorst, E.F.H. Van Bommel, B. Van Der Hoven, A.A. van Leengoed, A.L. van Osta: High-volume hemofiltration improves hemodynamics of endotoxin-induced shock in the pig. J Crit Car 7,67–75 (1992)

    38. A.H.Lau, N.O. Kronfol: Determinants of drug removal by continuous hemofiltration. Int J Artif Organs 17,373–78 (1994)

    39. M.C. Vos, H.H.Vincent, E.P.F. Yzerman, M. Vogel, J.W. Mouon: Drug clearance by continuous haemodiafiltration: Results with the AN-69 capillary haemofilter and recommended dose adjustment for seven antibiotics. Drug Invest 7:,315–22 (1994)

    40. B.L. Roder, BL, N. Frimodt-Moller, F. Espersen, S.N. Rasmussen: Dicloxacillin and flucloxacillin: Pharmacokinetics, protein binding and serum bactericidal titers in healthy subjects after oral administration. Infection 23,107–12 (1995)

    41. H.H. Vincent, M.C. Vos, E. Akcahuseyin, W.H. Goessens, W.A. van Duyl, M.A. Schalekamp, MA: Drug clearance by continuous haemodiafiltration: Analysis of sieving coefficients and mass transfer coefficients of diffusion. Bloo Purif. 11,99–07 (1993)

    42. KDIGO. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int. Suppl. 2, 1-138 (2012).

    43. U.F. Kroh, M. Dehne, K. Abed, K.D. Feussner, W. Hofmann, H. Lennartz: Drug dosage during continuous hemofiltration: Pharmacokinetics and practical implications. Contrib Nephrol 93,127–30 (1991)

    44. R.A. Subach, M.A.Marx: Drug dosing in acute renal failure: The role of renal replacement therapy in altering drug pharmacokinetics. Adv Renal Replace Ther 5,141–47 (1998)

    45. J. Böhler, J. Donauer, F. Keller: Pharmacokinetic principles during continuous renal replacement therapy: Drugs and dosage. Kidney Int 56,S24–S28 (1999)

    46. D. Kuang, A. Verbine, C. Ronco: Pharmacokinetics and antimicrobial dosing adjustment in critically ill patients during continuous renal replacement therapy. Clin Nephrol 67,267-84 (2007)

    47. M. Schetz M, P. Ferdinande, G. Van den Berghe, C. Verwaest, P. Lauwers: Pharmacokinetics of continuous renal replacement therapy. Intensive Care Med 21,612-20 (1995)

    48. J.M. Varghese, P. Jarrett, R.J Boots, C.M. Kirkpatrick, J. Lipman, J. Roberts J. Pharmacokinetics of piperacillin and tazobactam in plasma and subcutaneous interstitial fluid in critically ill patients receiving continuous venovenous haemodiafiltration. Int J Antimicrob Agents 43,343-8 (2014)

    49. S.R. Bauer, C. Salem, M.J. Jr. Connor, J. Groszek, M.E. Taylor, P. Wei, A.J. Tolwani, W.H. Fissell: Pharmacokinetics and pharmacodynamics of piperacillin-tazobactam in 42 patients treated with concomitant CRRT. Clin J Am Soc Nephrol 7,452-7 (2012)

    50. J.F. Bugge: Pharmacokinetics and drug dosing adjustments during continuous venovenous hemofiltration or hemodiafiltration in critically ill patients. Acta Anaesthesiol Scand 45,929-34 (2001)

    51. P.F. Gulyassy, T.A.Depner: Impaired binding of drugs and endogenous ligands in renal diseases. Am J Kidney Dis 2,578-601 (1983)

    52. P.J. McNamara, D. Lalka, M. Gibaldi: Endogenous accumulation products and serum protein binding in uremia. J Lab Clin Med 98,730-40. (1981)

    53. B. Suh B, W.A.Crai, A.C., England, R.L.Elliott: Effect of free fatty acids on protein binding of antimicrobial agents. The Journal of infectious diseases143, 609-16 (1981)

    54. B.A. Mueller, W.E. Smoyer: Challenges in developing evidence-based drug dosing guidelines for adults and children receiving renal replacement therapy. Clin. Pharmacol. Ther. 86, 479-482 (2009)

    55. B.J. Anderson, N.H. Holford: Mechanism-based concepts of size and maturity in pharmacokinetics. Annnul Rev pharmacol toxicol 48:303-32 (2008)

    56. B.J Anderson, N.H. Holford: Mechanistic basis of using body size and maturation to predict clearance in humans. Drug metabolism and pharmacokinetics 24,25-36 (2009)

    57. E. Carcelero, D. Soy: Antibiotic dose adjustment in the treatment of MRSA infections in patients with acute renal failure undergoing continuous renal replacement therapies. Enferm Infect Microbiol Clin 30, 249-56 (2012)

    58. R. Freebairn, J. Lipman: Principles of antibacterial dosing in continuous renal replacement therapy. Choi G, Gomersall CD, Tian Q, Joynt GM, Crit Care Med 37,2268-282 (2009)

    59. F. Keller, J. Böhler, D. Czock, D, Zeller, A.K.H. Mertz: Individualized drug dosage in patients treated with continuous hemofiltration. Kidney Int 56 (Suppl 72),S29–S31 (1996)

    60. A.M. Li AM, C.D. Gomersall, G. Choi G, Q. Tian, G.M. Joynt, J. Lipman: A systematic review of antibiotic dosing regimens for septic patients receiving continuous renal replacement therapy: do current studies supply sufficient data? J Antimicrob Chemother 64,929-37 (2009)

    61. C. Covajes C, S. Scolletta, L. Penaccini L, E. Ocampos-Martinez, A. Abdelhadii, M. Beumier, F. Jacobs, D. de Backer, J.L.Vincent, F.S.Taccone: Continuous infusion of vancomycin in septic patients receiving continuous renal replacement therapy. Int J Antimicrob Agents 261-10 (2013)

    62. M.J. Jr. Connor, C. Salem, S.R.Bauer, C.L. Hofmann, J. Groszek, R. Butler, S.R. Rehm, W.H. Fissell Therapeutic drug monitoring of piperacillin-tazobactam using spent dialysate effluent in patients receiving continuous venovenous hemodialysis. Antimicrob Agents Chemother 55,557-60 (2011)

    63. C.S. Bouman: Dosing of antimicrobial agents in critically-ill patients with acute kindey injury and continuous venvenous haemofiltration. Acta Clin Belg Suppl (2):356-70 (2007)

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Farahnak Assadi, Fatemeh Ghane Shahrbaf. Drug dosage in continuous venoveno hemofiltration in critically ill children. Frontiers in Bioscience-Scholar. 2016. 8(1); 56-66.