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Janković SM, Mirković N, Stojadinović D, Lukić S. Using validated model informed precision dosing for dose adjustment: superior evidence needed for efficacy and safety. Expert Opin Drug Metab Toxicol 2025:1-10. [PMID: 40323636 DOI: 10.1080/17425255.2025.2501128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Accepted: 04/29/2025] [Indexed: 05/08/2025]
Abstract
INTRODUCTION Modelinformed precision dosing (MIPD) allows determining the optimal dosage regimen and its correction based on the target plasma/serum concentrations of the drug. MIPD software must go through a validation and clinical study of its effectiveness and safety before being used in clinical practice. AREAS COVERED This narrative literature review provides insight into what is known to date about efficacy and safety trials of MIPD concept. Relevant publications were searched for in the PubMed database, without time or language constraints. EXPERT OPINION The application of MIPD in clinical practice logically and theoretically has great potential to improve the treatment of patients by leading to optimal exposure of target tissues to drugs, while achieving full effect and minimizing toxicity. Greater implementation of MIPD in clinical practice is hindered by the fact that the beneficial effects of MIPD on treatment outcomes and reduction of drug toxicity have been proven through clinical studies only for a small number of drugs. It is necessary to conduct well-designed clinical studies of the effects of MIPD, with sufficient statistical power, to prove the benefits of MIPD administration and to justify the costs of implementation in clinical practice.
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Affiliation(s)
| | - Nikola Mirković
- Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | | | - Snežana Lukić
- Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
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Balik M, Sedivy J, Waldauf P, Kolar M, Smejkalova V, Pachl J. Can Bioimpedance Determine the Volume of Distribution of Antibiotics in Sepsis? Anaesth Intensive Care 2019; 33:345-50. [PMID: 15973917 DOI: 10.1177/0310057x0503300310] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The relationship between the volume of distribution, assessed according to the two-compartmental pharmacokinetic model, and extracellular water estimated by bioimpedance was studied in mechanically ventilated patients with sepsis and capillary leak. A prospective observational study was performed in a twenty-bed general intensive care unit in the university hospital. Patients received either vancomycin (n=16) or netilmicin (n=12) for more than 48 hours. Those with ascites, pleural effusion, on renal replacement therapy or with haemodynamic instability were excluded. Serum concentrations of drugs were taken for pharmacokinetic analysis before, 1 hour and 4 hours after the 30 minute infusion. Bioimpedance measurement was performed at the time of the third sampling. The protocol was repeated after 24 hours. Fluid balance during the 24 hour interval was recorded. Extracellular water was increased and represented 45.6 to 46.6% of total body water. Fluid balance correlated with the change of extracellular water (r=0.82, P<0.0001) and total body water (r=0.74, P<0.0001). Volumes of distribution of vancomycin (0.677±0.339 l/kg) and netilmicin (0.505±0.172 l/kg) were increased compared to normal values. A correlation was demonstrated between volume of distribution (Vdarea) of vancomycin and extra cellular water/total body ratio (r=0.70, P<0.0001). The central compartment distribution volume (V1) of netilmicin correlated with extracellular water/total body water ratio (r=0.60, P<0.003). Serum concentrations above the recommended therapeutic range were detected in 81.2% of patients on vancomycin and in 50% of patients on netilmicin. Increased volumes of distribution can be estimated by the bioimpedance measurements but are not associated with requirements for higher dosage of the glycopeptide or aminoglycoside antibiotics.
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Affiliation(s)
- M Balik
- Department of Anaesthesia, University Hospital Kralovske Vinohrady, Srobarova, Prague, Czech Republic
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Abstract
Although aminoglycosides remain an essential part of therapy of severe gram-negative infections in critically ill patients, the use of extended-interval aminoglycoside dosing (EIAD) in this population is highly controversial. The rationale for EIAD is based on major pharmacodynamic characteristics of the aminoglycosides, which include concentration-dependent bactericidal effects, postantibiotic effect, and adaptive resistance. Alterations in the pharmacokinetics of aminoglycosides in the critically ill have been well documented, including changes in both drug distribution and elimination. These pharmacokinetic alterations may prevent critically ill patients from realizing the potential benefits of EIAD by reducing serum concentrations achieved by recommended EIAD regimens and may perhaps place patients at risk of therapeutic failure. Although numerous studies of EIAD have been conducted, there is a lack of data specifically concerning the efficacy and safety of EIAD in the critically ill. The most appropriate methods for monitoring EIAD in this population are also not clearly established. There are thus many questions regarding the suitability of EIAD in the critically ill. This article briefly reviews the rationale for EIAD and data related to the pharmacokinetics, efficacy, safety, and clinical monitoring of EIAD in critically ill patients. Considerations and recommendations for use of EIAD in the critically ill are provided.
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Affiliation(s)
- Douglas N. Fish
- Department of Pharmacy Practice, University of Colorado School of Pharmacy, Department of Pharmacy, University of Colorado Hospital, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Campus Box C- 238, Denver, CO 80262,
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Boyer A, Clouzeau B, M’zali F, Kann M, Gruson-Vescovali D. Comment utiliser les aminosides en réanimation. MEDECINE INTENSIVE REANIMATION 2015. [DOI: 10.1007/s13546-015-1067-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Zarzavadjian Le Bian A, Costi R, Sbai-Idrissi MS, Smadja C. Liver resection and metabolic disorders: An undescribed mechanism leading to postoperative mortality. World J Gastroenterol 2014; 20:14455-14462. [PMID: 25339832 PMCID: PMC4202374 DOI: 10.3748/wjg.v20.i39.14455] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2014] [Revised: 03/18/2014] [Accepted: 06/17/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the mechanism leading to perioperative mortality in patients undergoing major liver resection and presenting with metabolic disorders.
METHODS: The link between Metabolic Syndrome and non-alcoholic fatty liver disease is currently demonstrated. Various metabolic disorders and the Metabolic Syndrome (the association of ≥ 3 metabolic disorders) have been recently described as a risk factor of perioperative mortality in major liver resection. Patients who passed away during perioperative course of major liver resection and presenting with the association of ≥ 2 metabolic disorders without any other known cause of liver disorders were reviewed.
RESULTS: From January 2001 to May 2010 in a tertiary centre, ten patients presenting with ≥ 2 metabolic disorders without any other known cause of liver disorders died during perioperative course of major liver resection. The same four-consecutive-steps sequence of events occurred, including jaundice. The analysis of this series suggested a rapidly deteriorating congestive liver resulting in an increased portal hypertension leading to hepatorenal syndrome and lately to multiorgan failure (mimicking septic collapse) as the mechanism leading to exitus. The acute portal hypertension is mainly related to the surgical procedure. The chronic portal hypertension is indeterminate. Patients with ≥ 2 metabolic disorders should be considered as potentially presenting with portal hypertension possibly evolving towards hepatorenal syndrome; thus, they should be considered as having a high perioperative risk and should be carefully evaluated before undergoing major liver resection.
CONCLUSION: As fibrosis was not present or marginal in liver specimens, the real cause of portal hypertension in patients with multiple metabolic disorders should be investigated with further studies.
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Thursky K. Use of computerized decision support systems to improve antibiotic prescribing. Expert Rev Anti Infect Ther 2014; 4:491-507. [PMID: 16771625 DOI: 10.1586/14787210.4.3.491] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
This decade will see the emergence of the electronic medical record, electronic prescribing and computerized decision support in the hospital setting. Current opinion from key infectious diseases bodies supports the use of computerized decision support systems as potentially useful tools in antibiotic stewardship programs. However, although antibiotic decision support systems appear beneficial for improving the quality of prescribing and reducing the costs of antibiotic prescribing, their overall cost-effectiveness, impact on patient outcome and antimicrobial resistance is much less certain. This review describes computerized decision support systems used to assist with antibiotic prescribing, the evidence for their effectiveness and the current and future roles.
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Affiliation(s)
- Karin Thursky
- Infectious Diseases Physician, Centre for Clinical Research Excellence in Infectious Diseases, Victorian Infectious Diseases Service, Royal Melbourne Hospital, Grattan Street, Parkville, Victoria, 3051, Australia.
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Personalized Drug Administrations Using Support Vector Machine. BIONANOSCIENCE 2013. [DOI: 10.1007/s12668-013-0103-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Gillaizeau F, Chan E, Trinquart L, Colombet I, Walton RT, Rège-Walther M, Burnand B, Durieux P. Computerized advice on drug dosage to improve prescribing practice. Cochrane Database Syst Rev 2013; 2013:CD002894. [PMID: 24218045 PMCID: PMC11393523 DOI: 10.1002/14651858.cd002894.pub3] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
BACKGROUND Maintaining therapeutic concentrations of drugs with a narrow therapeutic window is a complex task. Several computer systems have been designed to help doctors determine optimum drug dosage. Significant improvements in health care could be achieved if computer advice improved health outcomes and could be implemented in routine practice in a cost-effective fashion. This is an updated version of an earlier Cochrane systematic review, first published in 2001 and updated in 2008. OBJECTIVES To assess whether computerized advice on drug dosage has beneficial effects on patient outcomes compared with routine care (empiric dosing without computer assistance). SEARCH METHODS The following databases were searched from 1996 to January 2012: EPOC Group Specialized Register, Reference Manager; Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Ovid; EMBASE, Ovid; and CINAHL, EbscoHost. A "top up" search was conducted for the period January 2012 to January 2013; these results were screened by the authors and potentially relevant studies are listed in Studies Awaiting Classification. The review authors also searched reference lists of relevant studies and related reviews. SELECTION CRITERIA We included randomized controlled trials, non-randomized controlled trials, controlled before-and-after studies and interrupted time series analyses of computerized advice on drug dosage. The participants were healthcare professionals responsible for patient care. The outcomes were any objectively measured change in the health of patients resulting from computerized advice (such as therapeutic drug control, clinical improvement, adverse reactions). DATA COLLECTION AND ANALYSIS Two review authors independently extracted data and assessed study quality. We grouped the results from the included studies by drug used and the effect aimed at for aminoglycoside antibiotics, amitriptyline, anaesthetics, insulin, anticoagulants, ovarian stimulation, anti-rejection drugs and theophylline. We combined the effect sizes to give an overall effect for each subgroup of studies, using a random-effects model. We further grouped studies by type of outcome when appropriate (i.e. no evidence of heterogeneity). MAIN RESULTS Forty-six comparisons (from 42 trials) were included (as compared with 26 comparisons in the last update) including a wide range of drugs in inpatient and outpatient settings. All were randomized controlled trials except two studies. Interventions usually targeted doctors, although some studies attempted to influence prescriptions by pharmacists and nurses. Drugs evaluated were anticoagulants, insulin, aminoglycoside antibiotics, theophylline, anti-rejection drugs, anaesthetic agents, antidepressants and gonadotropins. Although all studies used reliable outcome measures, their quality was generally low.This update found similar results to the previous update and managed to identify specific therapeutic areas where the computerized advice on drug dosage was beneficial compared with routine care:1. it increased target peak serum concentrations (standardized mean difference (SMD) 0.79, 95% CI 0.46 to 1.13) and the proportion of people with plasma drug concentrations within the therapeutic range after two days (pooled risk ratio (RR) 4.44, 95% CI 1.94 to 10.13) for aminoglycoside antibiotics;2. it led to a physiological parameter more often within the desired range for oral anticoagulants (SMD for percentage of time spent in target international normalized ratio +0.19, 95% CI 0.06 to 0.33) and insulin (SMD for percentage of time in target glucose range: +1.27, 95% CI 0.56 to 1.98);3. it decreased the time to achieve stabilization for oral anticoagulants (SMD -0.56, 95% CI -1.07 to -0.04);4. it decreased the thromboembolism events (rate ratio 0.68, 95% CI 0.49 to 0.94) and tended to decrease bleeding events for anticoagulants although the difference was not significant (rate ratio 0.81, 95% CI 0.60 to 1.08). It tended to decrease unwanted effects for aminoglycoside antibiotics (nephrotoxicity: RR 0.67, 95% CI 0.42 to 1.06) and anti-rejection drugs (cytomegalovirus infections: RR 0.90, 95% CI 0.58 to 1.40);5. it tended to reduce the length of time spent in the hospital although the difference was not significant (SMD -0.15, 95% CI -0.33 to 0.02) and to achieve comparable or better cost-effectiveness ratios than usual care;6. there was no evidence of differences in mortality or other clinical adverse events for insulin (hypoglycaemia), anaesthetic agents, anti-rejection drugs and antidepressants.For all outcomes, statistical heterogeneity quantified by I(2) statistics was moderate to high. AUTHORS' CONCLUSIONS This review update suggests that computerized advice for drug dosage has some benefits: it increases the serum concentrations for aminoglycoside antibiotics and improves the proportion of people for which the plasma drug is within the therapeutic range for aminoglycoside antibiotics.It leads to a physiological parameter more often within the desired range for oral anticoagulants and insulin. It decreases the time to achieve stabilization for oral anticoagulants. It tends to decrease unwanted effects for aminoglycoside antibiotics and anti-rejection drugs, and it significantly decreases thromboembolism events for anticoagulants. It tends to reduce the length of hospital stay compared with routine care while comparable or better cost-effectiveness ratios were achieved.However, there was no evidence that decision support had an effect on mortality or other clinical adverse events for insulin (hypoglycaemia), anaesthetic agents, anti-rejection drugs and antidepressants. In addition, there was no evidence to suggest that some decision support technical features (such as its integration into a computer physician order entry system) or aspects of organization of care (such as the setting) could optimize the effect of computerized advice.Taking into account the high risk of bias of, and high heterogeneity between, studies, these results must be interpreted with caution.
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Affiliation(s)
- Florence Gillaizeau
- French Cochrane Center, Hôpital Hôtel-Dieu, 1 place du Parvis Notre-Dame, Paris, France, 75004
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Boyer A, Gruson D, Bouchet S, Clouzeau B, Hoang-Nam B, Vargas F, Gilles H, Molimard M, Rogues AM, Moore N. Aminoglycosides in Septic Shock. Drug Saf 2013; 36:217-30. [DOI: 10.1007/s40264-013-0031-0] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Cox ZL, Nelsen CL, Waitman LR, McCoy JA, Peterson JF. Effects of clinical decision support on initial dosing and monitoring of tobramycin and amikacin. Am J Health Syst Pharm 2012; 68:624-32. [PMID: 21411805 DOI: 10.2146/ajhp100155] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
PURPOSE The impact of clinical decision support (CDS) on initial doses and intervals and pharmacokinetic outcomes of amikacin and tobramycin therapy was evaluated. METHODS A complex CDS advisor to provide guidance on initial dosing and monitoring of aminoglycoside orders, using both traditional-dosing and extended-interval-dosing strategies, was integrated into a computerized prescriber-order-entry (CPOE) system and compared with a control group whose aminoglycoside orders were closely monitored by pharmacists. The primary outcome measured was an initial dose within 10% of a dose calculated to be adherent to published dose guidelines. Secondary outcomes included a guideline-adherent interval, trough and peak concentrations in goal range, and rate of nephrotoxicity. RESULTS Of 216 patients studied, 97 were prescribed amikacin and 119 were prescribed tobramycin. The number of orders with initial doses consistent with reference standards increased from 40% in the preadvisor group to 80% in the postadvisor group (p < 0.001). Selection of the correct initial interval based on renal function increased from 63% to 87% (p < 0.001). The changes in the initial dosing and interval resulted in an increase of trough concentrations at goal (59% in the preadvisor group versus 89% in the postadvisor group, p = 0.0004). There was no significant difference in peak concentrations in the goal range or rate of nephrotoxicity. CONCLUSION An advisor for aminoglycoside dosing and monitoring integrated into a CPOE system significantly improved selection of initial doses and intervals and resulted in an improvement in the rate of trough serum drug concentrations at goal compared with standard provider dosing.
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Affiliation(s)
- Zachary L Cox
- Department of Pharmacy, Vanderbilt University Medical Center, Nashville, TN, USA.
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Sahota N, Lloyd R, Ramakrishna A, Mackay JA, Prorok JC, Weise-Kelly L, Navarro T, Wilczynski NL, Haynes RB. Computerized clinical decision support systems for acute care management: a decision-maker-researcher partnership systematic review of effects on process of care and patient outcomes. Implement Sci 2011; 6:91. [PMID: 21824385 PMCID: PMC3169487 DOI: 10.1186/1748-5908-6-91] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2011] [Accepted: 08/03/2011] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Acute medical care often demands timely, accurate decisions in complex situations. Computerized clinical decision support systems (CCDSSs) have many features that could help. However, as for any medical intervention, claims that CCDSSs improve care processes and patient outcomes need to be rigorously assessed. The objective of this review was to systematically review the effects of CCDSSs on process of care and patient outcomes for acute medical care. METHODS We conducted a decision-maker-researcher partnership systematic review. MEDLINE, EMBASE, Evidence-Based Medicine Reviews databases (Cochrane Database of Systematic Reviews, DARE, ACP Journal Club, and others), and the Inspec bibliographic database were searched to January 2010, in all languages, for randomized controlled trials (RCTs) of CCDSSs in all clinical areas. We included RCTs that evaluated the effect on process of care or patient outcomes of a CCDSS used for acute medical care compared with care provided without a CCDSS. A study was considered to have a positive effect (i.e., CCDSS showed improvement) if at least 50% of the relevant study outcomes were statistically significantly positive. RESULTS Thirty-six studies met our inclusion criteria for acute medical care. The CCDSS improved process of care in 63% (22/35) of studies, including 64% (9/14) of medication dosing assistants, 82% (9/11) of management assistants using alerts/reminders, 38% (3/8) of management assistants using guidelines/algorithms, and 67% (2/3) of diagnostic assistants. Twenty studies evaluated patient outcomes, of which three (15%) reported improvements, all of which were medication dosing assistants. CONCLUSION The majority of CCDSSs demonstrated improvements in process of care, but patient outcomes were less likely to be evaluated and far less likely to show positive results.
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Affiliation(s)
- Navdeep Sahota
- College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, Canada
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Nieuwlaat R, Connolly SJ, Mackay JA, Weise-Kelly L, Navarro T, Wilczynski NL, Haynes RB. Computerized clinical decision support systems for therapeutic drug monitoring and dosing: a decision-maker-researcher partnership systematic review. Implement Sci 2011; 6:90. [PMID: 21824384 PMCID: PMC3170236 DOI: 10.1186/1748-5908-6-90] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2011] [Accepted: 08/03/2011] [Indexed: 11/26/2022] Open
Abstract
Background Some drugs have a narrow therapeutic range and require monitoring and dose adjustments to optimize their efficacy and safety. Computerized clinical decision support systems (CCDSSs) may improve the net benefit of these drugs. The objective of this review was to determine if CCDSSs improve processes of care or patient outcomes for therapeutic drug monitoring and dosing. Methods We conducted a decision-maker-researcher partnership systematic review. Studies from our previous review were included, and new studies were sought until January 2010 in MEDLINE, EMBASE, Evidence-Based Medicine Reviews, and Inspec databases. Randomized controlled trials assessing the effect of a CCDSS on process of care or patient outcomes were selected by pairs of independent reviewers. A study was considered to have a positive effect (i.e., CCDSS showed improvement) if at least 50% of the relevant study outcomes were statistically significantly positive. Results Thirty-three randomized controlled trials were identified, assessing the effect of a CCDSS on management of vitamin K antagonists (14), insulin (6), theophylline/aminophylline (4), aminoglycosides (3), digoxin (2), lidocaine (1), or as part of a multifaceted approach (3). Cluster randomization was rarely used (18%) and CCDSSs were usually stand-alone systems (76%) primarily used by physicians (85%). Overall, 18 of 30 studies (60%) showed an improvement in the process of care and 4 of 19 (21%) an improvement in patient outcomes. All evaluable studies assessing insulin dosing for glycaemic control showed an improvement. In meta-analysis, CCDSSs for vitamin K antagonist dosing significantly improved time in therapeutic range. Conclusions CCDSSs have potential for improving process of care for therapeutic drug monitoring and dosing, specifically insulin and vitamin K antagonist dosing. However, studies were small and generally of modest quality, and effects on patient outcomes were uncertain, with no convincing benefit in the largest studies. At present, no firm recommendation for specific systems can be given. More potent CCDSSs need to be developed and should be evaluated by independent researchers using cluster randomization and primarily assess patient outcomes related to drug efficacy and safety.
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Affiliation(s)
- Robby Nieuwlaat
- Population Health Research Institute, McMaster University, Hamilton General Hospital Campus, 237 Barton Street East, Hamilton, ON, Canada
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Durieux P, Trinquart L, Colombet I, Niès J, Walton R, Rajeswaran A, Rège Walther M, Harvey E, Burnand B. Computerized advice on drug dosage to improve prescribing practice. Cochrane Database Syst Rev 2008:CD002894. [PMID: 18646085 DOI: 10.1002/14651858.cd002894.pub2] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Maintaining therapeutic concentrations of drugs with a narrow therapeutic window is a complex task. Several computer systems have been designed to help doctors determine optimum drug dosage. Significant improvements in health care could be achieved if computer advice improved health outcomes and could be implemented in routine practice in a cost effective fashion. This is an updated version of an earlier Cochrane systematic review, by Walton et al, published in 2001. OBJECTIVES To assess whether computerised advice on drug dosage has beneficial effects on the process or outcome of health care. SEARCH STRATEGY We searched the Cochrane Effective Practice and Organisation of Care Group specialized register (June 1996 to December 2006), MEDLINE (1966 to December 2006), EMBASE (1980 to December 2006), hand searched the journal Therapeutic Drug Monitoring (1979 to March 2007) and the Journal of the American Medical Informatics Association (1996 to March 2007) as well as reference lists from primary articles. SELECTION CRITERIA Randomized controlled trials, controlled trials, controlled before and after studies and interrupted time series analyses of computerized advice on drug dosage were included. The participants were health professionals responsible for patient care. The outcomes were: any objectively measured change in the behaviour of the health care provider (such as changes in the dose of drug used); any change in the health of patients resulting from computerized advice (such as adverse reactions to drugs). DATA COLLECTION AND ANALYSIS Two reviewers independently extracted data and assessed study quality. MAIN RESULTS Twenty-six comparisons (23 articles) were included (as compared to fifteen comparisons in the original review) including a wide range of drugs in inpatient and outpatient settings. Interventions usually targeted doctors although some studies attempted to influence prescriptions by pharmacists and nurses. Although all studies used reliable outcome measures, their quality was generally low. Computerized advice for drug dosage gave significant benefits by:1.increasing the initial dose (standardised mean difference 1.12, 95% CI 0.33 to 1.92)2.increasing serum concentrations (standradised mean difference 1.12, 95% CI 0.43 to 1.82)3.reducing the time to therapeutic stabilisation (standardised mean difference -0.55, 95%CI -1.03 to -0.08)4.reducing the risk of toxic drug level (rate ratio 0.45, 95% CI 0.30 to 0.70)5.reducing the length of hospital stay (standardised mean difference -0.35, 95% CI -0.52 to -0.17). AUTHORS' CONCLUSIONS This review suggests that computerized advice for drug dosage has some benefits: it increased the initial dose of drug, increased serum drug concentrations and led to a more rapid therapeutic control. It also reduced the risk of toxic drug levels and the length of time spent in the hospital. However, it had no effect on adverse reactions. In addition, there was no evidence to suggest that some decision support technical features (such as its integration into a computer physician order entry system) or aspects of organization of care (such as the setting) could optimise the effect of computerised advice.
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Affiliation(s)
- Pierre Durieux
- Service de Santé Publique, Hôpital Cochin, 27 rue du Faubourg Saint Jacques, Paris, France, 75014.
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Abstract
Amikacin is an aminoglycoside commonly used to provide empirical double gram-negative treatment for febrile neutropenia and other suspected infections. Strategies of extended-interval and conventional dosing have been utilized extensively in the general medical population; however, data are lacking to support a dosing strategy in the hematology/oncology population. To evaluate amikacin-associated nephrotoxicity in an adult hematology/oncology population, a prospective, randomized, open-label trial was conducted at a university-affiliated medical center. Forty patients with a diagnosis consistent with a hematologic/oncologic disorder that required treatment with an aminoglycoside were randomized to either conventional or extended-interval amikacin. The occurrence of nephrotoxicity by means of an increase in serum creatinine and evaluation of efficacy via amikacin serum concentrations with respective pathogens were assessed. The occurrence of nephrotoxicity was similar between the conventional and extended-interval groups, at 10% and 5%, respectively (P = 1.00). Six patients in the conventional group had a positive culture, compared with none in the extended-interval group (P = 0.002). The occurrence of nephrotoxicity was similar between the two dosing regimens, but the distribution of risk factors was variable between the two groups. Efficacy could not be assessed.
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Adhikari N, Lapinsky SE. Medical informatics in the intensive care unit: overview of technology assessment. J Crit Care 2003; 18:41-7. [PMID: 12640613 DOI: 10.1053/jcrc.2003.yjcrc9] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Effective patient care in the intensive care unit (ICU) depends on the ability of clinicians to process large amounts of clinical and laboratory data. Recently, medical informatics applications have been developed to store and display patient information and assist clinical decision making. Despite the proliferation of these systems and their potential to improve patient care, there are no comprehensive health technology assessments incorporating considerations of safety, functionality, technical performance, clinical effectiveness, economics, and organizational implications. The objectives and methods of informatics evaluations depend on the type of application and the stage of development. Qualitative and quantitative nonrandomized evaluations of comprehensive information management systems like electronic medical records and picture archiving and communications systems should concentrate on technical and functional issues. Specific applications like clinical decision support systems and computerized patient care systems are designed to improve patient outcomes and clinical performance; randomized controlled trials (RCTs) to assess clinical effectiveness are important in their assessment. Although studies of these applications in the ICU setting are increasing, there are currently very few published randomized trials.
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Affiliation(s)
- Neill Adhikari
- Department of Critical Care Medicine, Sunnybrook and Women's College Health Sciences Centre, Toronto, Canada.
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Walton RT, Harvey E, Dovey S, Freemantle N. Computerised advice on drug dosage to improve prescribing practice. Cochrane Database Syst Rev 2001:CD002894. [PMID: 11279772 DOI: 10.1002/14651858.cd002894] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
BACKGROUND Maintaining therapeutic concentrations of toxic drugs is a complex task. Several computer systems have been designed to help doctors determine optimum drug dosage. Significant improvements in health could be achieved if computer advice was shown to be beneficial. OBJECTIVES To assess whether computer support for drug dosage benefits patients and hence whether it should be more widely available. SEARCH STRATEGY We searched the Cochrane Effective Practice and Organisation of Care Group specialised register (June 1996), MEDLINE (1966 to June 1996), EMBASE (1980 to June 1996), hand searched the journal Therapeutic Drug Monitoring (1979 to June 1996), reference lists of articles and contacted experts in the field. SELECTION CRITERIA Randomised trials, interrupted time series and controlled before and after studies of computerised advice on drug dosage. The participants were health professionals responsible for patient care. The outcomes were: any objectively measured change in the behaviour of the health care provider (such as changes in the dose of drug used); any change in the health of patients, resulting from computer support (such as adverse reactions to drugs). DATA COLLECTION AND ANALYSIS Two reviewers independently extracted data and assessed study quality. MAIN RESULTS Fifteen trials involving 1229 patients were included. The drugs studied were theophylline, warfarin, heparin, aminoglycosides, nitroprusside, lignocaine, oxytocin, fentanyl and midazolam. Interventions usually targeted doctors although some studies attempted to influence prescribing by pharmacists and nurses. All included studies took place on acute medical conditions in hospital settings. Although all studies used reliable outcome measures, sample size was often small and only two studies reported a sample size calculation. Computer support for drug dosage gave significant benefits reducing: 1. The time to achieve therapeutic control (standardised mean difference -0.44, 95% CI -0.70 to -0.17); 2. Toxic drug levels (risk difference -0.12, 95% CI -0.24 to -0.01); 3. Adverse reactions (risk difference -0.06, 95% CI -0.12 to 0.00); 4. Length of hospital stay (standardised mean difference -0.32, 95% CI -0.60 to -0.04). There was a tendency for computer support to result in higher doses of drugs, although this did not reach statistical significance. REVIEWER'S CONCLUSIONS This systematic review provides evidence to support the use of computer assistance in determining drug dosage. Further clinical trials are necessary to determine whether the benefits seen in specialist applications can be realised in general use.
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Affiliation(s)
- R T Walton
- University of Oxford Department of Public Health and Primary Care, Imperial Cancer Research Fund General Practice Research Group, Institute of Health Sciences, Old Road, Headington, Oxford, UK, OX3 7LF.
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17
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Abstract
AIMS To review the basis and optimal use of therapeutic drug monitoring of antimicrobial agents. METHODS Antimicrobial agents for which a reasonable case exists for therapeutic drug monitoring were reviewed under the following headings: pharmacokinetics, why monitor, therapeutic range, individualisation of therapy, sampling times, methods of analysis, interpretative problems and cost-effectiveness of monitoring. RESULTS There is a strong historical case for monitoring aminoglycosides. The recent move to once-daily dosing means that criteria for therapeutic drug monitoring need to be redefined. Vancomycin has been monitored routinely but many questions remain about the most appropriate approach to this. A case can be made for monitoring teicoplanin, flucytosine and itraconazole in certain circumstances. CONCLUSIONS The approach to monitoring aminoglycosides needs to be redefined in the light of once-daily dosing. It is premature to suggest that less stringent monitoring is necessary as toxicity remains a problem with these drugs. The ideal method of monitoring vancomycin remains to be defined although a reasonable case exists for measuring trough concentrations, mainly to ensure efficacy. Teicoplanin is monitored occasionally to ensure efficacy while flucytosine is monitored occasionally to avoid high concentrations associated with toxicity. Itraconazole has various pharmacokinetic problems and monitoring has been suggested to ensure that adequate concentrations are achieved.
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Affiliation(s)
- E J Begg
- Department of Clinical Pharmacology, Christchurch Hospital, New Zealand
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18
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Power BM, Forbes AM, van Heerden PV, Ilett KF. Pharmacokinetics of drugs used in critically ill adults. Clin Pharmacokinet 1998; 34:25-56. [PMID: 9474472 DOI: 10.2165/00003088-199834010-00002] [Citation(s) in RCA: 163] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Critically ill patients exhibit a range of organ dysfunctions and often require treatment with a variety of drugs including sedatives, analgesics, neuromuscular blockers, antimicrobials, inotropes and gastric acid suppressants. Understanding how organ dysfunction can alter the pharmacokinetics of drugs is a vital aspect of therapy in this patient group. Many drugs will need to be given intravenously because of gastrointestinal failure. For those occasions on which the oral route is possible, bioavailability may be altered by hypomotility, changes in gastrointestinal pH and enteral feeding. Hepatic and renal dysfunction are the primary determinants of drug clearance, and hence of steady-state drug concentrations, and of efficacy and toxicity in the individual patient. Oxidative metabolism is the main clearance mechanism for many drugs and there is increasing recognition of the importance of decreased activity of the hepatic cytochrome P450 system in critically ill patients. Renal failure is equally important with both filtration and secretion clearance mechanisms being required for the removal of parent drugs and their active metabolites. Changes in the steady-state volume of distribution are often secondary to renal failure and may lower the effective drug concentrations in the body. Failure of the central nervous system, muscle, the endothelial system and endocrine system may also affect the pharmacokinetics of specific drugs. Time-dependency of alterations in pharmacokinetic parameters is well documented for some drugs. Understanding the underlying pathophysiology in the critically ill and applying pharmacokinetic principles in selection of drug and dose regimen is, therefore, crucial to optimising the pharmacodynamic response and outcome.
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Affiliation(s)
- B M Power
- Department of Intensive Care, Sir Charles Gairdner Hospital, Nedlands, Australia
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19
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Bressolle F, Gouby A, Martinez JM, Joubert P, Saissi G, Guillaud R, Gomeni R. Population pharmacokinetics of amikacin in critically ill patients. Antimicrob Agents Chemother 1996; 40:1682-9. [PMID: 8807062 PMCID: PMC163395 DOI: 10.1128/aac.40.7.1682] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
The pharmacokinetic parameters of amikacin were determined in a population of 20 adults and 36 pediatric patients admitted into an intensive care unit. Amikacin was administered by repeated intravenous infusion over 0.5 h (600 to 1,350 mg for adults; 70 to 1,500 mg for children). The number of administrations ranged from 2 to 17, and the number of samples collected from each patient ranged from 2 to 70. The population enrolled in the study had large variabilities in age (0.5 to 85 years), weight (6 to 95 kg), height (72 to 187 cm), creatinine clearance rate (18 to 110 ml/min), blood urea nitrogen concentration (1.5 to 15 mmol/liter), and total protein concentration (30 to 91 g/liter). The mean population parameters and their interindividual variabilities were obtained for an initial group of 44 patients (16 adults and 28 children). A two-compartment model was fitted to the population data by using the computer program P-PHARM. Model selection was guided by evaluation of the minimum objective function and the weighted residuals. The population analysis has been performed with the complete set of the collected data, including the individual serum amikacin concentration together with the individual estimate of the creatinine clearance values. The potential sources of variability in the population parameters were investigated by using patients' age, height, weight, creatinine clearance, blood urea nitrogen concentration, and total protein concentration as covariables. A test group of 12 additional patients (4 adults and 8 children) was used to evaluate the predictive performances of the population parameters. The individual pharmacokinetic parameters were computed by a Bayesian fitting procedure. From the resulting individualized values of the parameters, the concentrations of amikacin in the serum of the patients were calculated. To evaluate the performance of the Bayesian estimation, the experimental concentrations were compared with the predicted ones. The Bayesian approached developed in the study accurately predicts amikacin concentrations in serum and allows for the estimation of amikacin pharmacokinetics parameters, minimizing the risk of bias in the prediction. This was demonstrated in patients with both stable and unstable renal functions.
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Affiliation(s)
- F Bressolle
- Laboratoire de pharmacocinétique, Faculté de Pharmacie, Montpellier Cedex 01, France
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20
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Konrad F, Wagner R, Neumeister B, Rommel H, Georgieff M. Studies on drug monitoring in thrice and once daily treatment with aminoglycosides. Intensive Care Med 1993; 19:215-20. [PMID: 8366230 DOI: 10.1007/bf01694773] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
OBJECTIVES To investigate at what time the peak level should be determined under conventional thrice daily (t.i.d.) administration of the aminoglycoside netilmicin and to study its serum concentrations under once daily (od) treatment to define the required daily dose and to gain information about convenient drug monitoring. DESIGN The design of the study was a consecutive sample trial. SETTING The study took place in a university hospital. PATIENTS 41 intubated patients of a surgical ICU who received netilmicin as a short-term infusion over 30 min for life-threatening infections were included in the study. INTERVENTIONS In 21 patients netilmicin was administered t.i.d. The virtual peak levels which had been determined by pharmacokinetic dosage calculation were compared with the serum concentrations obtained directly after the administration as well as after 15, 30, 60 and 180 min. In 20 patients the netilmicin serum concentrations during od treatment were determined directly before and immediately after the application as well as 0.5, 1, 3, 7 and 12 h later. To achieve a virtual peak level of 25 mg/l and a trough level of 0.5 mg/l individual adjustment of the dosage based on pharmacokinetic calculations was performed. MEASUREMENTS AND RESULTS In t.i.d. treatment the serum concentration measured after 30 min was closest to the virtual peak level; therefore, this is the best time to determine the peak level. In od treatment the required daily dose was 7.86 mg/kg body weight (median) in patients with normal renal function. During od dosing the trough level was extremely important in drug monitoring, whereas determination of the high peak level was of doubtful value. CONCLUSIONS The peak level should be determined during t.i.d. administration at 30 min. In od treatment the initial daily dose should be 7 mg/kg body weight; in drug monitoring the trough level is very important.
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Affiliation(s)
- F Konrad
- Clinic for Anaesthesiology, University of Ulm, Germany
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21
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Lenert LA, Klostermann H, Coleman RW, Lurie J, Blaschke TF. Practical computer-assisted dosing for aminoglycoside antibiotics. Antimicrob Agents Chemother 1992; 36:1230-5. [PMID: 1416822 PMCID: PMC190323 DOI: 10.1128/aac.36.6.1230] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
In principle, computer-assisted individualization of antibiotic dosing offers the prospect of better patient outcomes through improved dosing precision. In practice, however, the expertise in pharmacokinetics required to operate these programs has precluded their use by most physicians and pharmacists. We developed a computer program for individualization of dosing of aminoglycoside antibiotics under conditions in which access to experts in pharmacokinetics is impractical. The program is accurate, yet it requires less effort for data collection than previous drug dosing programs did. The program generates advice on a broad spectrum of topics, including dose adjustment, interpretation of measured drug concentrations in blood, and recommendations for monitoring drug concentrations. We tested its performance by prospectively comparing it with a clinical pharmacokinetic consultation service in a series of 78 consecutive patients. There were no differences in accuracy or bias in the prediction of drug concentrations. The rate of agreement between the program's dosing recommendations and those of the consultation service was 67 percent. This rate of agreement is typical of interexpert variation. In a stratified set of 24 of the 41 instances with significant disagreement regarding the recommended dose, experts ranked the program's recommendations as highly as those of the consultation service (95% confidence interval for difference in rank, -0.30 less than chi less than 0.47). The results suggest that expert systems can be coupled with pharmacokinetic dosing programs to deliver high-quality clinical recommendations for administration of antimicrobial agents.
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Affiliation(s)
- L A Lenert
- Division Clinical Pharmacology, Stanford University Medical Center, Stanford University, California 94305-5113
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22
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Edwards DJ. Therapeutic Drug Monitoring of Aminoglycosides and Vancomycin: Guidelines and Controversies. J Pharm Pract 1991. [DOI: 10.1177/089719009100400307] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- David J. Edwards
- Department of Pharmacy Practice, College of Pharmacy and Allied Health Professions, Wayne State University, Detroit, MI48202
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23
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Erdman SM, Rodvold KA, Pryka RD. An updated comparison of drug dosing methods. Part III: Aminoglycoside antibiotics. Clin Pharmacokinet 1991; 20:374-88. [PMID: 1908755 DOI: 10.2165/00003088-199120050-00003] [Citation(s) in RCA: 25] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Aminoglycoside antibiotics continue to be useful for the treatment of Gram-negative infections. Available dosing methods include predictive algorithms and nomograms, pharmacokinetics-based dosing methods, and methods that incorporate Bayesian forecasting. The individualised Sawchuk-Zaske and Bayesian methods have been extensively evaluated since the previous review in the Journal. Both methods continue to be rapid and accurate means of individualising dosage requirements for patients with diverse pharmacokinetic profiles. The predictive performance of the Bayesian method can be further enhanced when population-based parameters reflect the patient population being monitored. There are now several cost-effectiveness studies that demonstrate that pharmacokinetic dosing services for aminoglycosides result in cost savings, better therapeutic concentrations, fewer toxic serum concentrations, and shorter mean durations of hospital stay and aminoglycoside therapy. Further studies are needed for cost-effectiveness and comparison of various dosing methods in paediatric and neonatal patients.
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Affiliation(s)
- S M Erdman
- College of Pharmacy, University of Illinois, Chicago
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24
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Smith CL, Hampton EM. Using estimated creatinine clearance for individualizing drug therapy: a reassessment. DICP : THE ANNALS OF PHARMACOTHERAPY 1990; 24:1185-90. [PMID: 2089830 DOI: 10.1177/106002809002401209] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Estimates of renal function are frequently used to design individual dosing regimens. The accuracy of these estimates naturally influences their ability to predict certain pharmacokinetic parameters and appropriate drug dosages. Creatinine clearance is the most widely used estimate of renal function. Many formulas have been developed to provide a quick, relatively accurate prediction of creatinine clearance and, supposedly, the glomerular filtration rate (GFR). However, an understanding of the limitations associated with creatinine clearance estimations raises questions concerning their reliability as an aid in individualizing drug therapy. Many factors such as disease states, age, diet, analytical variations, and drug interactions affect the relationship between estimates and measures of creatinine clearance and GFR. As a result, creatinine clearance estimates using these formulas are often poor reflections of measured creatinine clearance or GFR. Also, studies comparing measured creatinine clearance with more accurate methods of assessing renal function (i.e., inulin) reveal errors that are often exaggerated as renal function declines. Therefore, estimated creatinine clearance is twice removed from the associated pharmacokinetic parameter. Despite these limitations, no other clinically relevant and convenient assessment of renal function is available. The authors recommend that the appropriate caveats be considered when using these tools clinically. For drugs with narrow therapeutic indices, estimates of creatinine clearance should only be used to establish initial dosing regimens, with subsequent therapy based on parameters generated from concentration determinations.
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Affiliation(s)
- C L Smith
- Section of Pharmacy Practice, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City 73190
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25
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van Dalen R, Vree TB. Pharmacokinetics of antibiotics in critically ill patients. Intensive Care Med 1990; 16 Suppl 3:S235-8. [PMID: 2289997 DOI: 10.1007/bf01709707] [Citation(s) in RCA: 65] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Differences in pharmacokinetic data of aminoglycosides, ceftazidime and ceftriaxone between intensive care patients and volunteers or patients who are less severely ill, are described. Similar differences are observed for midazolam. In severely ill patients with normal renal function a wide interpatient variability of aminoglycoside half-life (t1/2) and increased distribution volume (Vd) are observed. This results in inadequate serum levels. A pharmacokinetic approach of drug dosing, based on serum concentrations in individual patients, is advised. For ceftazidime and ceftriaxone similar changes of t1/2 and Vd are observed. Since protein binding is frequently reduced in severely ill patients, the influence of altered binding of highly bound drugs on Vd and drug clearance is discussed. As both may be increased by reduced protein binding, the change of t1/2 to be expected is unpredictable. Dosing regimens should be based on pharmacokinetic data derived from patients whose severity of disease is comparable to that of the patients to be treated.
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Affiliation(s)
- R van Dalen
- Department of Intensive Care, University Hospital St. Radboud, Nijmegen, The Netherlands
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