Population pharmacokinetics of fluconazole in critically ill patients receiving extracorporeal membrane oxygenation and continuous renal replacement therapy: an ASAP ECMO study.

This multicenter study describes the population pharmacokinetics (PK) of fluconazole in critically ill patients receiving concomitant extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) and includes an evaluation of different fluconazole dosing regimens for achievement of target exposure associated with maximal efficacy. Serial blood samples were obtained from critically ill patients on ECMO and CRRT receiving fluconazole. Total fluconazole concentrations were measured in plasma using a validated chromatographic assay. A population PK model was developed and Monte Carlo dosing simulations were performed using Pmetrics in R. The probability of target attainment (PTA) of various dosing regimens to achieve fluconazole area under the curve to minimal inhibitory concentration ratio (AUC0-24/MIC) >100 was estimated. Eight critically ill patients receiving concomitant ECMO and CRRT were included. A two-compartment model including total body weight as a covariate on clearance adequately described the data. The mean (±standard deviation, SD) clearance and volume of distribution were 2.87 ± 0.63 L/h and 15.90 ± 13.29 L, respectively. Dosing simulations showed that current guidelines (initial loading dose of 12 mg/kg then 6 mg/kg q24h) achieved >90% of PTA for a MIC up to 1 mg/L. None of the tested dosing regimens achieved 90% of PTA for MIC above 2 mg/L. Current fluconazole dosing regimen guidelines achieved >90% PTA only for Candida species with MIC <1 mg/L and thus should be only used for Candida-documented infections in critically ill patients receiving concomitant ECMO and CRRT. Total body weight should be considered for fluconazole dose.

Antimicrobial Exposures in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation.

Rationale: Data suggest that altered antimicrobial concentrations are likely during extracorporeal membrane oxygenation (ECMO). Objectives: The primary aim of this analysis was to describe the pharmacokinetics (PKs) of antimicrobials in critically ill adult patients receiving ECMO. Our secondary aim was to determine whether current antimicrobial dosing regimens achieve effective and safe exposure. Methods: This study was a prospective, open-labeled, PK study in six ICUs in Australia, New Zealand, South Korea, and Switzerland. Serial blood samples were collected over a single dosing interval during ECMO for 11 antimicrobials. PK parameters were estimated using noncompartmental methods. Adequacy of antimicrobial dosing regimens were evaluated using predefined concentration exposures associated with maximal clinical outcomes and minimal toxicity risks. Measurements and Main Results: We included 993 blood samples from 85 patients. The mean age was 44.7 ± 14.4 years, and 61.2% were male. Thirty-eight patients (44.7%) were receiving renal replacement therapy during the first PK sampling. Large variations (coefficient of variation of ⩾30%) in antimicrobial concentrations were seen leading to more than fivefold variations in all PK parameters across all study antimicrobials. Overall, 70 (56.5%) concentration profiles achieved the predefined target concentration and exposure range. Target attainment rates were not significantly different between modes of ECMO and renal replacement therapy. Poor target attainment was observed across the most frequently used antimicrobials for ECMO recipients, including for oseltamivir (33.3%), piperacillin (44.4%), and vancomycin (27.3%). Conclusions: Antimicrobial PKs were highly variable in critically ill patients receiving ECMO, leading to poor target attainment rates. Clinical trial registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612000559819).

Population Pharmacokinetics of Vancomycin in Critically Ill Adult Patients Receiving Extracorporeal Membrane Oxygenation (an ASAP ECMO Study).

Our study aimed to describe the population pharmacokinetics (PK) of vancomycin in critically ill patients receiving extracorporeal membrane oxygenation (ECMO), including those receiving concomitant renal replacement therapy (RRT). Dosing simulations were used to recommend maximally effective and safe dosing regimens. Serial vancomycin plasma concentrations were measured and analyzed using a population PK approach on Pmetrics. The final model was used to identify dosing regimens that achieved target exposures of area under the curve (AUC0-24) of 400-700 mg · h/liter at steady state. Twenty-two patients were enrolled, of which 11 patients received concomitant RRT. In the non-RRT patients, the median creatinine clearance (CrCL) was 75 ml/min and the mean daily dose of vancomycin was 25.5 mg/kg. Vancomycin was well described in a two-compartment model with CrCL, the presence of RRT, and total body weight found as significant predictors of clearance and central volume of distribution (Vc). The mean vancomycin renal clearance and Vc were 3.20 liters/h and 29.7 liters respectively, while the clearance for patients on RRT was 0.15 liters/h. ECMO variables did not improve the final covariate model. We found that recommended dosing regimens for critically ill adult patients not on ECMO can be safely and effectively used in those on ECMO. Loading doses of at least 25 mg/kg followed by maintenance doses of 12.5-20 mg/kg every 12 h are associated with a 97-98% probability of efficacy and 11-12% probability of toxicity, in patients with normal renal function. Therapeutic drug monitoring along with reductions in dosing are warranted for patients with renal impairment and those with concomitant RRT. (This study is registered with the Australian New Zealand Clinical Trials Registry [ANZCTR] under number ACTRN12612000559819.).

Evaluation of medical emergency team medication management practices in acute hospitals: A multicentre study.

BACKGROUND: Medical emergency teams use medications to rescue deteriorating patients. Medication management is the system of steps and processes, including prescribing, distribution, administration, and monitoring, to achieve the best outcomes from medication use. Systems or standards for medication management by medical emergency teams have not been defined. OBJECTIVES: The aim of the study was to propose potential solutions to improve medical emergency team medication management by evaluating medication supply and related medication management practices during medical emergency team activations and understanding clinicians' perceptions about medical emergency team medication management in acute hospitals. METHODS: A prospective multicentre audit of intensive care unit-equipped hospitals in Victoria, Australia, was conducted. After advertisement and invitation via scheduled email newsletters to hospitals, a representative of the medical emergency team from each hospital self-administered an online audit tool during December 2019 and January 2020. Audit data were analysed descriptively, and perceptions were analysed using content analysis. RESULTS: Responses were received from 32 of the 44 (72.7%) eligible hospitals. At 17 of the 32 (53.1%) hospitals, arrest trolleys provided medications for medical emergency team activations, in addition to arrest calls. At 15 of the 32 (46.9%) hospitals, separate, dedicated medical emergency team medication supplies were used to care for deteriorating patients. Dedicated medical emergency team supplies contained a median of 20 (range = 8-37) medications, predominantly cardiovascular (median = 8, mode = 7, range = 4-16) and neurological medications (median and mode = 6, range = 0-11). Variation was observed in all storage and other supply-related medication management practices studied. The four most frequent categories of clinicians' perceptions described systematic challenges with availability of the right medication in the right place at the right time. CONCLUSIONS: Current supply and related medication management practices and clinicians' perceptions demonstrated further development is necessary for medication management to meet the needs of medical emergency team clinicians and their patients.

Population Pharmacokinetics of Piperacillin and Tazobactam in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation: an ASAP ECMO Study.

Our study aimed to describe the population pharmacokinetics (PK) of piperacillin and tazobactam in patients on extracorporeal membrane oxygenation (ECMO), with and without renal replacement therapy (RRT). We also aimed to use dosing simulations to identify the optimal dosing strategy for these patient groups. Serial piperacillin and tazobactam plasma concentrations were measured with data analyzed using a population PK approach that included staged testing of patient and treatment covariates. Dosing simulations were conducted to identify the optimal dosing strategy that achieved piperacillin target exposures of 50% and 100% fraction of time free drug concentration is above MIC (%fT>MIC) and toxic exposures of greater than 360 mg/liter. The tazobactam target of percentage of time free concentrations of >2 mg/liter was also assessed. Twenty-seven patients were enrolled, of which 14 patients were receiving concurrent RRT. Piperacillin and tazobactam were both adequately described by two-compartment models, with body mass index, creatinine clearance, and RRT as significant predictors of PK. There were no substantial differences between observed PK parameters and published parameters from non-ECMO patients. Based on dosing simulations, a 4.5-g every 6 hours regimen administered over 4 hours achieves high probabilities of efficacy at a piperacillin MIC of 16 mg/liter while exposing patients to a <3% probability of toxic concentrations. In patients receiving ECMO and RRT, a frequency reduction to every 12 hours dosing lowers the probability of toxic concentrations, although this remains at 7 to 9%. In ECMO patients, piperacillin and tazobactam should be dosed in line with standard recommendations for the critically ill.

Understanding how medications contribute to clinical deterioration and are used in rapid response systems: A comprehensive scoping review.

BACKGROUND: In hospitals, rapid response systems (RRSs) identify patients who deteriorate and provide critical care at their bedsides to stabilise and escalate care. Medications, including oral and parenteral pharmaceutical preparations, are the most common intervention for hospitalised patients and the most common cause of harm. This connection between clinical deterioration and medication safety is poorly understood. OBJECTIVES: To inform improvements in prevention and management of clinical deterioration, this review aimed to examine how medications contributed to clinical deterioration and how medications were used in RRSs. REVIEW METHODS: A scoping review was undertaken of medication data reported in studies of clinical deterioration or RRSs in diverse hospital settings between 2005 and 2017. Bibliographic database searches used permutations of "rapid response system," "medical emergency team," and keyword searching with medication-related terms. Independent selection, quality assessment, and data extraction informed mapping against four medication themes: causes of deterioration, predictors of deterioration, RRS use, and management. RESULTS: Thirty articles were reviewed. Quality was low: limited by small samples, observational, single-centre designs and few primary medication-related outcomes. Adverse drug reactions and potentially preventable medication errors, involving sedatives, analgesics, and cardiovascular agents, contributed to clinical deterioration. While sparsely reported, outcomes included death and escalation of care. In children, administration of antibiotics or nebulised medications appeared to predict subsequent deterioration. Cardiovascular medications, sedatives, and analgesics commonly were used to manage deterioration but further detail was lacking. Despite reported potential for patient harm, evaluation of medication management systems was limited. CONCLUSIONS: Medications contributed to potentially preventable clinical deterioration, with considerable harm, and were common interventions for its management. When assessing deteriorating patients or caring for patients who require escalation to critical care, clinicians should consider medication errors and adverse reactions. Studies with more specific medication-related, patient-centred end points could reduce medication-related deterioration and refine RRS medication use and management.

Medication-related Medical Emergency Team activations: a case review study of frequency and preventability.

OBJECTIVES: Despite recognition of clinical deterioration and medication-related harm as patient safety risks, the frequency of medication-related Rapid Response System activations is undefined. We aimed to estimate the incidence and preventability of medication-related Medical Emergency Team (MET) activations and describe the associated adverse medication events. METHODS: A case review study of consecutive MET activations at two acute, academic teaching hospitals in Melbourne, Australia with mature Rapid Response Systems was conducted. All MET activations during a 3-week study period were assessed for a medication cause including identification of the contributing adverse medication event and its preventability, using validated tools and recognised classification systems. RESULTS: There were 9439 admissions and 628 MET activations during the study period. Of these, 146 (23.2%) MET activations were medication related: an incidence of 15.5 medication-related MET activation per 1000 admissions. Medication-related MET activations occurred a median of 46.6 hours earlier (IQR 22-165) in an admission than non-medication-related activations (p=0.001). Furthermore, this group also had more repeat MET activations during their admission (p=0.021, OR=1.68, 95% CI 1.09 to 2.59). A total of 92 of 146 (63%) medication-related MET activations were potentially preventable. Tachycardia due to omission of beta-blocking agents (10.9%, n=10 of 92) and hypotension due to cumulative toxicity (9.8%, n=9 of 92) or inappropriate use (10.9%, n=10 of 92) of antihypertensives were the most common adverse medication events leading to potentially preventable medication-related MET activations. CONCLUSIONS: Medications contributed to almost a quarter of MET activations, often early in a patient's admission. One in seven MET activations were due to potentially preventable adverse medication events. The most common of these were omission of beta-blockers and clinically inappropriate antihypertensive use. Strategies to prevent these events would increase patient safety and reduce burden on the MET.

Population pharmacokinetics of ciprofloxacin in critically ill patients receiving extracorporeal membrane oxygenation (an ASAP ECMO study).

INTRODUCTION: This study aimed to describe the pharmacokinetics (PK) of ciprofloxacin in critically ill patients receiving ECMO and recommend a dosing regimen that provides adequate drug exposure. METHODS: Serial blood samples were taken from ECMO patients receiving ciprofloxacin. Total ciprofloxacin concentrations were measured by chromatographic assay and analysed using a population PK approach with Pmetrics®. Dosing simulations were performed to ascertain the probability of target attainment (PTA) represented by the area under the curve to minimum inhibitory concentration ratio (AUC0-24/MIC) ≥ 125. RESULTS: Eight patients were enrolled, of which three received concurrent continuous venovenous haemodiafiltration (CVVHDF). Ciprofloxacin was best described in a two-compartment model with total body weight and creatinine clearance (CrCL) included as significant predictors of PK. Patients not requiring renal replacement therapy generated a mean clearance of 11.08 L/h while patients receiving CVVHDF had a mean clearance of 1.51 L/h. Central and peripheral volume of distribution was 77.31 L and 90.71 L, respectively. ECMO variables were not found to be significant predictors of ciprofloxacin PK. Dosing simulations reported that a 400 mg 8 -hly regimen achieved > 72% PTA in all simulated patients with CrCL of 30 mL/min, 50 mL/min and 100 mL/min and total body weights of 60 kg and 100 kg at a MIC of 0.5 mg/L. CONCLUSION: Our study reports that established dosing recommendations for critically ill patients not on ECMO provides sufficient drug exposure for maximal ciprofloxacin activity for ECMO patients. In line with non-ECMO critically ill adult PK studies, higher doses and therapeutic drug monitoring may be required for critically ill adult patients on ECMO.

Population pharmacokinetics of cefepime in critically ill patients receiving extracorporeal membrane oxygenation (an ASAP ECMO study).

OBJECTIVES: This study aimed to describe the population pharmacokinetics (PK) of cefepime during extracorporeal membrane oxygenation (ECMO) and through dosing simulations, identify a maximally effective and safe dosing strategy. METHODS: Serial cefepime plasma concentrations were measured in patients on ECMO, and data were analysed using a population PK approach with Pmetrics®. Dosing simulations were used to identify the optimal dosing strategy that achieved target trough concentrations (Cmin) of 8-20 mg/L. Six patients were enrolled, of which one was receiving renal replacement therapy. Cefepime was best described in a two-compartment model, with total body weight and creatinine clearance (CrCL) as significant predictors of PK parameters. The mean clearance and central volume of distribution were 2.42 L/h and 15.09 L, respectively. RESULTS: Based on simulations, patients with CrCL of 120 mL/min receiving 1 g 8-hourly dosing achieved a 40-44% probability of efficacy (Cmin > 8 mg/L) and 1-6% toxicity (Cmin > 20 mg/L). Patients with CrCL 30 mL/min and 65 mL/min receiving 1 g 12-hourly dosing achieved an 84-92% and 46-53% probability of efficacy and 8-44% and 1-8% probability of toxicity, respectively. Simulations demonstrated a lower probability of efficacy and higher probability of toxicity with decreasing patient weight. CONCLUSION: This study reported reduced cefepime clearance in patients receiving ECMO, resulting in an increased risk of cefepime toxicity. To avoid drug accumulation, modified dosing regimens should be used in critically ill patients on ECMO. Clinicians should adopt therapeutic drug monitoring when treating less susceptible organisms and in patients with reduced renal clearance on ECMO.

An Observational Analysis of Medication Use During 5,727 Medical Emergency Team Activations at a Tertiary Referral Hospital.

BACKGROUND: Medical emergency teams (METs) rescue deteriorating patients as the response arm of hospital rapid response systems. This study aimed to (1) investigate medication use during MET activations by describing the type, frequency and access sources of medications; and (2) assess associations between patient characteristics, MET activation criteria, and outcomes and MET medication use. METHODS: A single-center, retrospective study from a prospective database of MET activations in an Australian tertiary referral hospital was undertaken. Consecutive adult MET activations over a 12-month period were included. RESULTS: Across the study period, there were 5,727 MET activations with medications used at 33.5% (n = 1,920). Of 2,648 medications used, cardiac system agents (n = 944; 35.6%) were the most common category used, while intravenous electrolytes (n = 341; 12.9%) and opioid analgesics (n = 248; 9.4%).were the most frequently used medications. Most commonly, medications were sourced from ward stocks. High blood pressure, heart or respiratory rate, pain, and multiple activation criteria were associated with MET medication use (p < 0.001). Patients who required medications were less likely to remain on the ward, and immediate admission to the ICU was approximately doubled (odds ratio = 1.90; 95% confidence interval = 1.47-2.45). CONCLUSION: Medication use by the MET was common and associated with escalation to intensive care. A wide variety of medications, principally from ward stocks, were used with some predictability based on activation criteria. Local system improvements have demonstrated that by focusing on common MET syndromes and medications, further investigation can refine and improve medication use and management systems for deteriorating patients.

The frequency and nature of clinician identified medication-related rapid response system calls.

AIM: The contribution of adverse medication events to clinical deterioration is unknown. This study aimed to determine the frequency and nature of rapid response system (RRS) calls that clinicians perceived were medication-related using RRS quality arm data. METHODS: Analysis of routine data prospectively collected by clinicians responding to RRS calls in an Australian acute tertiary academic hospital. RESULTS: Between January 2013 and June 2017, 12,221 adult patients triggered the RRS for 25,906 medical emergency team (MET) and 512 code blue calls. Clinicians identified 433 medication-related RRS calls (1.6%) involving 406 patients (3.3%). These included 418 MET calls (1.3 medication-related MET calls per 1000 admissions) and 15 code blue calls (0.045 medication-related code blue calls per 1000 admissions). Medication-related calls occurred earlier in the admission (p = 0.002) and were more common for patients triggering multiple calls during the same admission (p < 0.001), compared to non-medication-related calls. Medication-related calls most commonly were triggered by low blood pressure (38.3%) and involved cardiovascular (43.0%) and nervous system medications (36.0%). Dose-related toxicity (n = 178) was the most frequent adverse medication event contributing to medication-related calls. CONCLUSION: One in 30 patients triggering a RRS call experienced medication-related clinical deterioration, most often due to dose related toxicity of cardiovascular system medications. The perceived frequency and potential preventability of this medication-related harm suggest further research is required to increase recognition of medication-related RRS calls by responding clinicians and to reduce the incidence.

Variability of intravenous medication preparation in Australian and New Zealand intensive care units.

RATIONALE, AIM AND OBJECTIVE: In Australia and New Zealand, there are no established standards for the final presentations of prepared intravenous medications in Intensive Care Units (ICUs). Variability has the potential to contribute to deficiencies in safety, efficiency and cost effectiveness. This study aimed to examine the variability in the preparation of intravenous medications in ICUs. METHODS: An electronic survey was distributed to critical care pharmacists in Australia and New Zealand via an established email group. The preparation of vasopressors, inotropes, sedation, analgesia, heparin, insulin and neuromuscular blockers were examined. Respondents were asked about initial presentation, final concentration prepared, who prepared and current safety practices used. Questions also addressed opinions and attitudes to safety practices and responsibility for leading change. RESULTS: Forty responses to the survey were received, representing 17% of ICUs in Australia and New Zealand. Significant variation in final concentration was observed for all infusions except insulin and esmolol. The final volumes varied significantly for all drugs. The majority of infusions were prepared by nursing staff with only a small number of pre-prepared presentations currently in use. Labelling was usually hand-written with some colour-coding. Most respondents identified safety and efficiency but not cost effectiveness as likely to be improved by the use of pre-prepared infusions. Most respondents felt 'government' or peak clinical bodies should lead practice standardization. CONCLUSION: Significant variation exists in the preparation of intravenous medications across ICUs in Australia and New Zealand. Nationally or regionally coordinated rationalization and standardization could improve safety and efficiency and potentially reduce the barrier of cost.