Population Pharmacokinetic Study of Benzylpenicillin in Critically Unwell Adults.

Pharmacokinetics are highly variable in critical illness, and suboptimal antibiotic exposure is associated with treatment failure. Benzylpenicillin is a commonly used beta-lactam antibiotic, and pharmacokinetic data of its use in critically ill adults are lacking. We performed a pharmacokinetic study of critically unwell patients receiving benzylpenicillin, using data from the ABDose study. Population pharmacokinetic modelling was undertaken using NONMEM version 7.5, and simulations using the final model were undertaken to optimize the pharmacokinetic profile. We included 77 samples from 12 participants. A two-compartment structural model provided the best fit, with allometric weight scaling for all parameters and a creatinine covariate effect on clearance. Simulations (n = 10,000) demonstrated that 25% of simulated patients receiving 2.4 g 4-hourly failed to achieve a conservative target of 50% of the dosing interval with free drug above the clinical breakpoint MIC (2 mg/L). Simulations demonstrated that target attainment was improved with continuous or extended dosing. To our knowledge, this study represents the first full population PK analysis of benzylpenicillin in critically ill adults.

Mortality and readmission rates of patients discharged in-hours and out-of-hours from a British ICU over a 3-year period.

Excess in-hospital mortality following out-of-hours ICU discharge has been reported worldwide. From preliminary data, we observed that magnitude of difference may be reduced when patients discharged for end-of-life care or organ donation are excluded. We speculated that these patients may be disproportionately discharged out-of-hours, biasing results. We now compare in-hospital mortality and ICU readmission rates following discharge in-hours and out-of-hours over 3 years, excluding discharges for organ donation or end-of-life care. This single-centre retrospective study includes patients discharged alive following ICU admission between 01/07/2015-31/07/2018, excluding readmissions and discharges for end-of-life care/organ donation. A multiple logistic regression model was fitted to estimate adjusted odds ratio of death following out-of-hours versus in-hours discharge. Characteristics and outcomes for both groups were compared. 4678 patients were included. Patients discharged out-of-hours were older (62 vs 59 years, p < 0.001), with greater APACHE II scores (15.7 vs 14.4, p < 0.001), length of ICU stay (3.25 vs 3.00 days, p = 0.01) and delays to ICU discharge (736 vs 489 min, p < 0.001). No difference was observed in mortality (4.6% vs 3.7%, p = 0.25) or readmission rate (4.1% vs 4.2%, p = 0.85). In the multiple logistic regression model out-of-hours discharge was not associated with in-hospital mortality (OR = 1.017, 95% CI 0.682-1.518, p = 0.93). Our findings present a possible explanation for reported excess mortality following out-of-hours ICU discharge, related to inclusion of organ donation and end-of-life care patients in data sets rather than standards of care delivered out-of-hours. We are not aware of any other studies investigating the influence of this group on reported post-ICU mortality rates.

Real-world experience of SARS-CoV-2 antibody assays in UK healthcare workers.

BACKGROUND: The seroprevalence of antibodies to SARS-CoV-2 in healthcare workers is variable throughout the world. This study compares the use of two antibody assays among large cohorts of healthcare workers in southern England. METHODS: This cohort study includes data obtained from staff at Western Sussex Hospitals NHS Foundation Trust (WSHT) and Brighton and Sussex University Hospitals (BSUH) during voluntary antibody testing, using Abbott and Roche SARS-CoV-2 antibody assays at each Trust respectively. RESULTS: The observed seroprevalence level was 7.9% for the WSHT/Abbott cohort versus 13% for the BSUH/Roche cohort. Based on a previous positive PCR, we find that the false-negative rate of the Abbott and Roche assays were 60.2% and 19% respectively, implying sensitivity levels of 39.8% and 81%. Within these cohorts, seropositivity was most strongly associated with those of South Asian ethnicity, allied health professionals and male sex (p<0.0001). CONCLUSIONS: In this real-world study, neither antibody test performed to the specification level stated by the manufacturer. More rigorous testing of these and other assays in target populations is recommended prior to widespread usage if they are to provide data that might be useful to control the pandemic.

ß-Lactam antimicrobial pharmacokinetics and target attainment in critically ill patients aged 1 day to 90 years: the ABDose study.

BACKGROUND: The pharmacokinetics of ß-lactam antibiotics in critical illness remain poorly characterized, particularly in neonates, children and the elderly. We undertook a pharmacokinetic study of commonly used ß-lactam antibiotics in critically ill patients of all ages. The aims were to produce a whole-life ß-lactam pharmacokinetic model and describe the extent to which standard doses achieve pharmacokinetic/pharmacodynamic targets associated with clinical cure. PATIENTS AND METHODS: A total of 212 critically ill participants with an age range from 1 day (gestational age 24 weeks) to 90 years were recruited from a UK hospital, providing 1339 pharmacokinetic samples. Population pharmacokinetic analysis was undertaken using non-linear mixed-effects modelling (NONMEM) for each drug. Pooled data were used to estimate maturation and decline of ß-lactam pharmacokinetics throughout life. RESULTS: Pharmacokinetic models for eight drugs were described, including what is thought to be the first benzylpenicillin model in critically ill adults. We estimate that 50% of adult ß-lactam clearance is achieved by 43 weeks post-menstrual age (chronological plus gestational age). Fifty percent of decline from peak adult clearance occurs by 71 years. Paediatric participants were significantly less likely than adults to achieve pharmacokinetic/pharmacodynamic targets with standard antibiotic doses (P < 0.01). CONCLUSIONS: We believe this to be the first prospective whole-life antibiotic pharmacokinetic study in the critically ill. The study provides further evidence that standard antibiotic doses fail to achieve pharmacokinetic/pharmacodynamic targets associated with clinical success in adults, children and neonates. Maturation and decline parameters estimated from this study could be adopted as a standard for future prospective studies.

Von Willebrand factor (vWF): marker of endothelial damage and thrombotic risk in COVID-19?

BACKGROUND: COVID-19 infection is characterised, among other features, by a prothrombotic state with high rate of venous thromboembolism (VTE), D-dimer, and fibrinogen levels. Clinical observations have also highlighted that these patients have elevated von Willebrand factor (vWF) and factor VIIIc. METHODS: 24 consecutive COVID-19 positive patients were selected from the intensive care unit (ICU) or the high acuity ward of Brighton and Sussex University Hospitals NHS Trust. RESULTS: The rate of VTE was 25% and mortality rate was 16.7%. Fibrinogen and D-Dimers were elevated, 7.9 (1.6) g/L and 2.4 (2.02) ug/ml respectively. Factor VIIIc and von vWF antigen levels were both extremely elevated at 279 (148) u/dL and 350 (131) % respectively, which are comparable to levels seen in ICU patients with severe sepsis. vWF levels were significantly higher in patients that died (p=0.017) and showed a positive correlation with age. There was a statistically significant association between COVID-19 disease and non-O blood group (p=0.02); 80% (4/5) of COVID-19 patients with VTE were blood group A. CONCLUSION: Very high levels of vWF and factor VIIIc are common in COVID-19 patients, comparable to levels in severely septic non-COVID ICU patients. This could contribute to the hypercoagulable state and increased VTE rate in COVID-19. Further studies are needed to evaluate the use of vWF for stratifying thrombotic risk in COVID-19 and to determine if elevated vWF is contributing to disease pathogenesis.

Scaling beta-lactam antimicrobial pharmacokinetics from early life to old age.

AIMS: Beta-lactam dose optimization in critical care is a current priority. We aimed to review the pharmacokinetics (PK) of three commonly used beta-lactams (amoxicillin ± clavulanate, piperacillin-tazobactam and meropenem) to compare PK parameters reported in critically and noncritically ill neonates, children and adults, and to investigate whether allometric and maturation scaling principles could be applied to describe changes in PK parameters through life. METHODS: A systematic review of PK studies of the three drugs was undertaken using MEDLINE and EMBASE. PK parameters and summary statistics were extracted and scaled using allometric principles to 70 kg individual for comparison. Pooled data were used to model clearance maturation and decline using a sigmoidal (Hill) function. RESULTS: A total of 130 papers were identified. Age ranged from 29 weeks to 82 years and weight from 0.9-200 kg. PK parameters from critically ill populations were reported with wider confidence intervals than those in healthy volunteers, indicating greater PK variability in critical illness. The standard allometric size and sigmoidal maturation model adequately described increasing clearance in neonates, and a sigmoidal model was also used to describe decline in older age. Adult weight-adjusted clearance was achieved at approximately 2 years postmenstrual age. Changes in volume of distribution were well described by the standard allometric model, although amoxicillin data suggested a relatively higher volume of distribution in neonates. CONCLUSIONS: Critical illness is associated with greater PK variability than in healthy volunteers. The maturation models presented will be useful for optimizing beta-lactam dosing, although a prospective, age-inclusive study is warranted for external validation.

An analysis of emergency tracheal intubations in critically ill patients by critical care trainees.

INTRODUCTION: We evaluated intensive care medicine trainees' practice of emergency intubations in the United Kingdom. METHODS: Retrospective analysis of 881 in-hospital emergency intubations over a three-year period using an online trainee logbook. RESULTS: Emergency intubations out-of-hours were less frequent than in-hours, both on weekdays and weekends. Complications occurred in 9% of cases, with no association with time of day/day of week (p = 0.860). Complications were associated with higher Cormack and Lehane grades (p=0.004) and number of intubation attempts (p < 0.001), but not American Society of Anesthesiologist grade. Capnography usage was ≥99% in all locations except in wards (85%; p = 0.001). Ward patients were the oldest (p < 0.001), had higher American Society of Anesthesiologist grades (p < 0.001) and lowest Glasgow Coma Scale (p < 0.001). CONCLUSIONS: Complications of intubations are associated with higher Cormack and Lehane grades and number of attempts, but not time of day/day of week. The uptake of capnography is reassuring, although there is scope for improvement on the ward.

Continuous Infusion of Low-Dose Iohexol Measures Changing Glomerular Filtration Rate in Critically Ill Patients.

OBJECTIVE: Measurement of changing glomerular filtration rate in acute kidney injury remains problematic. We have previously used a continuous infusion of low-dose Iohexol to measure glomerular filtration rate in stable subjects and postulate that changes greater than 10.3% in critically ill patients indicate acute kidney injury. Our objective is to explore the extent to which continuous infusion of low-dose Iohexol can be a measure of changing glomerular filtration rate during acute kidney injury. DESIGN: Clinical observational exploratory study. SETTING: Adult ICU. PATIENTS: Three patient groups were recruited: nephrectomy group: predictable onset of acute kidney injury and outcome (n = 10); surgery group: predictable onset of acute kidney injury, unpredictable outcome (n = 11); and acute kidney injury group: unpredictable onset of acute kidney injury and outcome (n = 13). INTERVENTIONS: Continuous infusion of low-dose Iohexol was administered for 24-80 hours. Plasma (ClP) and renal (ClR) Iohexol clearances were measured at timed intervals. MEASUREMENTS AND MAIN RESULTS: Kidney Disease: Improved Global Outcomes acute kidney injury criteria were fulfilled in 22 patients (nephrectomy = 5, surgery = 4, and acute kidney injury = 13); continuous infusion of low-dose Iohexol demonstrated acute kidney injury in 29 patients (nephrectomy = 10, surgery = 8, acute kidney injury = 11). Dynamic changes in glomerular filtration rate were tracked in all patients. In the nephrectomy group, ClR decreased by an expected 50% (50.8% ± 11.0%). Agreement between ClP and ClR improved with increasing duration of infusion: bias of ClP versus ClR at 48 hours was -0.1 ± 3.6 mL/min/1.73 m (limits of agreement: -7.2 to 7.1 mL/min/1.73 m). Coefficient of variation of laboratory sample analysis was 2.4%. CONCLUSIONS: Continuous infusion of low-dose Iohexol is accurate and precise when measuring glomerular filtration rate and tracks changes in patients with differing risks of acute kidney injury. Continuous infusion of low-dose Iohexol may provide a useful standard against which to test novel biomarkers for the diagnosis of acute kidney injury.

Do statins prevent acute kidney injury?

INTRODUCTION: Statins were introduced as lipid-lowering agents with a specific action to decrease plasma cholesterol concentrations and they have led to significant reductions in cardiovascular morbidity and mortality. Since their introduction, they have been found to have highly pleiotropic effects and potential use in many medical conditions well beyond cardiovascular disease alone. With their widespread and increasing use, adverse effects have also become apparent and it is suggested from the interrogation of observational data from large datasets that an early complication of statin use may be acute kidney injury (AKI). AREAS COVERED: This review explores the evidence relating to statins and the risks of AKI. The pathophysiology of AKI is considered and the statins are compared and contrasted. Statins have also been attributed with reno-protective effects and the literature relating to these circumstances are reviewed. EXPERT OPINION: The question of whether statins cause AKI remains unresolved. Evidence suggests that statins may both protect or harm kidneys acutely and that risk varies with the condition and the dose and type of statin used. However, any current adverse data should not deter prescription of statins in patients where there is clear evidence for either primary or secondary prevention of cardiovascular events.

Validation of a continuous infusion of low dose Iohexol to measure glomerular filtration rate: randomised clinical trial.

INTRODUCTION: There is currently no accurate method of measuring glomerular filtration rate (GFR) during acute kidney injury (AKI). Knowledge of how much GFR varies in stable subjects is necessary before changes in GFR can be attributed to AKI. We have designed a method of continuous measurement of GFR intended as a research tool to time effects of AKI. The aims of this crossover trial were to establish accuracy and precision of a continuous infusion of low dose Iohexol (CILDI) and variation in GFR in stable volunteers over a range of estimated GFR (23-138 mL/min/1.73 m(2)). METHODS: We randomised 17 volunteers to GFR measurement by plasma clearance (PC) and renal clearance (RC) of either a single bolus of Iohexol (SBI; routine method), or of a continuous infusion of low dose Iohexol (CILDI; experimental method) at 0.5 mL/h for 12 h. GFR was measured by the alternative method after a washout period (4-28 days). Iohexol concentration was measured by high performance liquid chromatography/electrospray tandem mass spectrometry and time to steady state concentration (Css) determined. RESULTS: Mean PC was 76.7 ± 28.5 mL/min/1.73 m(2) (SBI), and 78.9 ± 28.6 mL/min/1.73 m(2) (CILDI), p = 0.82. No crossover effects occurred (p = 0.85). Correlation (r) between the methods was 0.98 (p < 0.0001). Bias was 2.2 mL/min/1.73 m(2) (limits of agreement -8.2 to 12.6 mL/min/1.73 m(2)) for CILDI. PC overestimated RC by 7.1 ± 7.3 mL/min/1.73 m(2). Mean intra-individual variation in GFR (CILDI) was 10.3% (p < 0.003). Mean ± SD Css was 172 ± 185 min. CONCLUSION: We hypothesise that changes in GFR >10.3% depict evolving AKI. If this were applicable to AKI, this is less than the 50% change in serum creatinine currently required to define AKI. CILDI is now ready for testing in patients with AKI. TRIAL REGISTRATION: This trial was registered with the European Union Clinical Trials Register ( https://www.clinicaltrialsregister.eu/ ), registration number: 2010-019933-89 .

Xenobiotic metabolism: the effect of acute kidney injury on non-renal drug clearance and hepatic drug metabolism.

Acute kidney injury (AKI) is a common complication of critical illness, and evidence is emerging that suggests AKI disrupts the function of other organs. It is a recognized phenomenon that patients with chronic kidney disease (CKD) have reduced hepatic metabolism of drugs, via the cytochrome P450 (CYP) enzyme group, and drug dosing guidelines in AKI are often extrapolated from data obtained from patients with CKD. This approach, however, is flawed because several confounding factors exist in AKI. The data from animal studies investigating the effects of AKI on CYP activity are conflicting, although the results of the majority do suggest that AKI impairs hepatic CYP activity. More recently, human study data have also demonstrated decreased CYP activity associated with AKI, in particular the CYP3A subtypes. Furthermore, preliminary data suggest that patients expressing the functional allele variant CYP3A5*1 may be protected from the deleterious effects of AKI when compared with patients homozygous for the variant CYP3A5*3, which codes for a non-functional protein. In conclusion, there is a need to individualize drug prescribing, particularly for the more sick and vulnerable patients, but this needs to be explored in greater depth.

The effects of acute renal failure on drug metabolism.

INTRODUCTION: Acute kidney injury (AKI) is common in all hospital admissions and affects 10% of acute admissions in hospital. It increases the risk of adverse events and mortality, although the precise reasons for this are still unclear. The impact of chronic kidney disease (CKD) on nonrenal drug clearance is increasingly apparent and is now considered an important factor by the Food and Drug Administration for drug dose recommendations in CKD. AREAS COVERED: This review explores the evidence of the impact of AKI on nonrenal drug metabolism. The review uses evidence from investigations of both CKD and AKI describing the manner of the inhibition and the most likely mediators of renohepatic crosstalk. The review also considers other forms of nonrenal clearance, including gut metabolism. Changes are related to critical illness in general, where appropriate. EXPERT OPINION: Renal and hepatic interactions are highly complex with increasing evidence for an important relationship between AKI and hepatic metabolism. Current recommended dosing regimens are inadequate for AKI patients and much greater understanding of the interaction between the kidney and liver is required. More extensive therapeutic drug monitoring may be required to optimize drug regimens.

Renohepatic crosstalk: does acute kidney injury cause liver dysfunction?

The concept of hepatorenal syndrome is well recognized, although incompletely understood. The converse clinical problem of hepatic dysfunction in patients with acute kidney injury (AKI) is less well recognized yet may be a contributor to the high patient morbidity and mortality seen in this group. This review draws together the available evidence for AKI's effect on the liver from animal models, pharmacological studies and recent clinical data. It examines liver function beyond clinically used blood tests, to determine the effect of AKI on hepatic synthetic function, acute phase response and drug metabolism. Parallels are drawn with other organ crosstalk in AKI and with liver-kidney interactions in chronic kidney disease. Definition of the pathophysiology of renohepatic crosstalk may lead to improved management strategies for this vulnerable patient group.

Estimated glomerular filtration rate correlates poorly with four-hour creatinine clearance in critically ill patients with acute kidney injury.

Introduction. RIFLE and AKIN provide a standardised classification of acute kidney injury (AKI), but their categorical rather than continuous nature restricts their use to a research tool. A more accurate real-time description of renal function in AKI is needed, and some published data suggest that equations based on serum creatinine that estimate glomerular filtration rate (eGFR) can provide this. In addition, incorporating serum cystatin C concentration into estimates of GFR may improve their accuracy, but no eGFR equations are validated in critically ill patients with AKI. Aim. This study tests whether creatinine or cystatin-C-based eGFR equations, used in patients with CKD, offer an accurate representation of 4-hour creatinine clearance (4CrCl) in critically ill patients with AKI. Methods. Fifty-one critically ill patients with AKI were recruited. Thirty-seven met inclusion criteria, and the performance of eGFR equations was compared to 4CrCl. Results. eGFR equations were better than creatinine alone at predicting 4CrCl. Adding cystatin C to estimates did not improve the bias or add accuracy. The MDRD 7 eGFR had the best combination of correlation, bias, percentage error and accuracy. None were near acceptable standards quoted in patients with chronic kidney disease (CKD). Conclusions. eGFR equations are not sufficiently accurate for use in critically ill patients with AKI. Incorporating serum cystatin C does not improve estimates. eGFR should not be used to describe renal function in patients with AKI. Standards of accuracy for validating eGFR need to be set.

Clinical review: Biomarkers of acute kidney injury: where are we now?

The recognition that acute kidney injury (AKI) is a significant independent risk factor for morbidity and mortality has resulted in a substantial number of publications over the past 5 years or more. In no small part these have, to a degree, highlighted the inadequacy of conventional markers of renal insufficiency in the acute setting. Much effort has been invested in the identification of early, specific AKI markers in order to aid early diagnosis of AKI and hopefully improve outcome. The search for a 'biomarker' of AKI has seen early promise replaced by a degree of pessimism due to the lack of a clear candidate molecule and variability of results. We outline the major studies described to date as well as discuss potential reasons for the discrepancies observed and suggest that evolution of the field may result in success with ultimately an improvement in patient outcomes.

The interpretation of brain natriuretic peptide in critical care patients; will it ever be useful?

The measurement of B-type natriuretic peptide (BNP) is recommended for the diagnosis of decompensated heart failure, the prognosis of chronic heart failure is worse if BNP is increased and studies suggest that BNP is useful to guide therapy. A study by Di Somma and colleagues adds to the body of evidence showing that patients with a marked decrease in BNP concentrations during their hospital admission are less likely to be readmitted with a further adverse cardiac event than patients in whom BNP fails to decrease. However, the wider interpretation of BNP concentrations in critically ill patients with other conditions remains uncertain.

Using drug probes to monitor hepatic drug metabolism in critically ill patients: midazolam, a flawed but useful tool for clinical investigation of CYP3A activity?

IMPORTANCE OF THE FIELD: In the UK, acute kidney injury (AKI) occurs in 25% of patients admitted to intensive care. Outcome is worsened in the presence of AKI for reasons not easily explained. AKI unpredictably affects the pharmacokinetics and pharmacodynamics of drugs and dosing in patients with AKI is largely based on data from chronic kidney disease patients, but how appropriately is unknown. AREAS COVERED IN THIS REVIEW: Midazolam as a drug probe of CYP3A activity is reviewed, with discussion of its limitations and alternatives in critically ill patients. Pharmacogenetics of CYP3A enzymes and their significance are discussed and emerging evidence that AKI affects liver metabolism is reviewed. WHAT THE READER WILL GAIN: The aim is to give the reader insight into the complexities of in vivo research in critically ill patient with discussion of interaction between the kidney and liver. We explain the use of midazolam as a drug probe for the investigation of the effect of AKI on hepatic function. TAKE HOME MESSAGE: Critically ill patients are difficult to manage but methods are now available for investigation of complex interrelationships that complicate the care and management of these patients with the potential to improve safety, efficacy and outcome, particularly for drug administration.