Evaluating the effects of a global pandemic on the operation of an investigational drug service.

PURPOSE: This study is an analysis of the changes to workload and operations of UNC Health's investigational drug service (IDS) brought about by the coronavirus disease 2019 (COVID-19) pandemic. METHODS: Workload statistics were collected and analyzed for trend changes to illustrate operational changes necessitated by the COVID-19 pandemic within the IDS pharmacy at UNC Health. RESULTS: Multiple workload metrics declined at the beginning of the COVID-19 pandemic, followed by an increase in the metrics for many categories as the pandemic continued. Notably, monthly inventory added initially decreased by 37.5%, later leveling off but showing increased variability. Fills dispensed and monitoring visits both decreased by 34.5% from the first quarter (Q1) to Q2 of 2020. Both metrics returned to or slightly exceeded prepandemic levels by the end of the study period in March 2021. Patient enrollment decreased 76% from February to May 2020 before dramatically increasing in Q3 of 2020 and Q1 of 2021 with the initiation of COVID-19 vaccine studies. The average time to study startup increased for trials not related to COVID-19 and decreased for COVID-19-related trials. There has been no major impact on the number of open protocols throughout the course of the pandemic. CONCLUSION: Despite initial decreases in workload following the start of the COVID-19 pandemic, IDS operations returned to and, in some cases, exceeded prepandemic levels.

Leptin treatment prevents impaired hypoglycemic counterregulation induced by exposure to severe caloric restriction or exposure to recurrent hypoglycemia.

Hypoglycemia-associated autonomic failure (HAAF) is a maladaptive failure in glucose counterregulation in persons with diabetes (PWD) that is caused by recurrent exposure to hypoglycemia. The adipokine leptin is known to regulate glucose homeostasis, and leptin levels fall following exposure to recurrent hypoglycemia. Yet, little is known regarding how reduced leptin levels influence glucose counterregulation, or if low leptin levels are involved in the development of HAAF. The purpose of this study was to determine the effect of hypoleptinemia on the neuroendocrine responses to hypoglycemia. We utilized two separate experimental paradigms known to induce a hypoleptinemic state: 60% caloric restriction (CR) in mice and three days of recurrent hypoglycemia (3dRH) in rats. A sub-set of animals were also treated with leptin (0.5-1.0 µg/g) during the CR or 3dRH periods. Neuroendocrine responses to hypoglycemia were assessed 60 min following an IP insulin injection on the terminal day of the paradigms. CR mice displayed defects in hypoglycemic counterregulation, indicated by significantly lower glucagon levels relative to controls, 13.5 pmol/L (SD 10.7) versus 64.7 pmol/L (SD 45) (p = 0.002). 3dRH rats displayed reduced epinephrine levels relative to controls, 1900 pg/mL (SD 1052) versus 3670 pg/mL (SD 780) (p = 0.030). Remarkably, leptin treatment during either paradigm completely reversed this effect by normalizing glucagon levels in CR mice, 78.0 pmol/L (SD 47.3) (p = 0.764), and epinephrine levels in 3dRH rats, 2910 pg/mL (SD 1680) (p = 0.522). These findings suggest that hypoleptinemia may be a key signaling event driving the development of HAAF and that leptin treatment may prevent the development of HAAF in PWD.

Consuming a ketogenic diet leads to altered hypoglycemic counter-regulation in mice.

Ketogenic diets (KDs) are becoming increasingly popular for the treatment of diabetes, yet they are associated with increased frequency of hypoglycemia. Here we report that mice fed a KD display blunted glucagon release to hypoglycemia and neuroglucopenia, suggesting that consuming a KD may increase the risk for iatrogenic hypoglycemia.

Quality of electronic records documenting adverse drug reactions within a hospital setting: identification of discrepancies and information completeness.

AIM: Incomplete and incorrect documentation of adverse drug reactions (ADRs) can restrict prescribing choices resulting in suboptimal pharmaceutical care. This study aimed to examine the quality of information held within electronic systems in a hospital setting, to determine the preciseness of ADR documentation, and identify discrepancies where multiple electronic systems are utilised. METHOD: Over a four-week period, consecutive patients admitted to the general medical ward at the study hospital had their electronic profiles reviewed. Patient demographic information (de-identified), ADR history and discrepancies between information sources (as recorded in all electronic systems utilised at initial prescribing) were recorded and analysed. RESULTS: Over the four-week period, 332 patient profiles were reviewed, and over 1,200 alerts were identified and analysed (including duplicates of ADR reactions). Of these patients, 151 (45.5%) had at least one documented allergy or intolerance which generated 585 reactions, relating to 526 unique events. A further 151 (45.5%) were classified as having no known (drug) allergies or intolerances; however, 20 (15%) of these patients did have at least one allergy documented in at least one other electronic system. The remaining 30 (9%) patients were classified as having an unknown allergy status and of those nine had allergies documented in at least one other electronic system. Further, most systems contained information duplication, which had not been addressed during the admission process. CONCLUSION: ADR information was both imprecise and inaccurate, as multiple discrepancies between ADR information recorded in different electronic patient management systems were found to exist. Information sharing between systems needs to be prioritised in order to allow full, accurate and complete ADR information to be collected, stored and utilised; both to reduce current inadequacies and to allow optimal pharmaceutical care.

The role of the suspicious renal pharmacist in identifying unusual adverse drug reactions-why this is not a small problem.

Renal patients have a high incidence of adverse drug reactions due to both pharmacokinetic and pharmacodynamic changes and detecting these adverse drug reactions relies heavily on having a high index of suspicion-which seems to be invoked through experience, whether our own or that of our colleagues. Pharmacists must be vigilant about adverse drug reactions and it is vital that pharmacists continue to teach their colleagues about their experiences identifying less common adverse drug reactions and adverse drug reactions with unusual presentations in addition to simply reporting these adverse drug reactions.

Comparison of documentation of patient reported adverse drug reactions on both paper-based medication charts and electronic medication charts at a New Zealand hospital.

AIM: Known adverse drug reactions (ADRs) can have profound effects on disease states, as well as prescribing practice. Therefore, the correct and complete documentation of each individual patient's ADR history, upon hospital admission, is important in optimising that individual patient's pharmacotherapy. This study investigated the documentation of ADRs at a tertiary New Zealand hospital, on both paper-based medication charts and electronic medication charts to quantify both the number of ADRs patients self-report, as well as the differences between recording of that information in electronic and paper-based charting systems. METHOD: Following ethical approval, inpatient medication charts on the general medical ward (electronic prescribing), or the general surgical ward (paper-based medication charts) were viewed for documented ADRs-as reported by each patient on admission. Consecutive patient charts (and electronic clinical management system) were viewed until 50 patients from each ward, each with at least one documented ADR, (in any of the information sources) were obtained. Patient demographic information, ADR history and discrepancies between information sources were determined. RESULTS: In both wards 114 patients were reviewed in order to find 50 patients with documented ADRs. In the medical ward (electronic) 44 (90%) patients had discrepancies in ADR information between different information sources and in the surgical ward (paper) this occurred in 49 (98%) patients. CONCLUSION: A large number of patients self-report ADRs. Full documentation of patient reported ADRs is required to adequately inform future prescribing decisions. Discrepancies between ADR information recorded in different information systems exist, but information sharing between electronic and non-electronic sources could be prioritised in order to allow full and complete information to be collected, stored and utilised; and reduce the current inadequacies.

Drug related problems identified by community pharmacists on hospital discharge prescriptions in New Zealand.

BACKGROUND: There can be a lack of transfer of information between hospitals and community pharmacies following patient discharge, which puts patients at a high risk of suffering drug related problems (DRPs). Community pharmacy plays a vital role in identifying and solving these discharge DRPs and taking action before these DRPs can lead to patient harm. OBJECTIVE: To identify the types and quantities of DRPs that community pharmacies detect within a single district health board (DHB) in New Zealand. SETTING: One DHB in New Zealand that contains 50 community pharmacies, which receive discharge prescriptions from two local hospitals. METHOD: All community pharmacies in the DHB area (n = 50) were invited to participate in the 2 week study which involved documenting the number of hospital discharge prescriptions received, and then the number and type of DRPs identified and what interventions were required. MAIN OUTCOME MEASURE: The number and type of DRPs identified as a proportion of all discharge prescriptions received during the 2 week study period. RESULTS: Initially a total of 38 pharmacies agreed to participate in this study, however only 32 pharmacies provided data for the entire 2 week period. Over a 2 week period a total of 1,374 hospital discharge prescriptions were presented to these pharmacies. From these prescriptions 344 (25 %) required further action to be taken by the pharmacist. These 344 prescriptions consisted of a total of 396 individual DRPs. Actions classified as "Supply and/or Funding" accounted for 43 % (171), which represented the largest class of all actions required from hospital discharge prescriptions. This class consisted of "Special Authority" problems, medications not being available, non-subsidised items on the prescription and other supply/funding problems. "Errors" accounted for 38 % (151) which included errors of omission (20 %) and errors of commission (18 %). CONCLUSION: This study found a significant number of DRPs identified by community pharmacists on hospital discharge prescriptions. These included missing and incorrect information which required clarification with prescribers. Interventions need to be put in place to reduce the number of errors and improve clarity of hospital discharge prescriptions. Better information sharing and understanding of medications available in primary care will reduce the potential for DRPs.

Determination of methylphenidate in Calliphorid larvae by liquid-liquid extraction and liquid chromatography mass spectrometry--forensic entomotoxicology using an in vivo rat brain model.

The aim of this study was to examine the potential forensic utilisation of blowfly larvae (Diptera: Calliphoridae) as an alternative toxicological specimen for the detection of the psychotropic model drug methylphenidate (MPH). MPH was extracted from biological matrices (rat brain, serum and Calliphorid larvae) by liquid-liquid extraction with recovery of >80%, and quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The LC-MS/MS assay was validated for entomotoxicological use and initially applied to male Sprague-Dawley rats (n=6) that were dosed with MPH (20mg/kg) ante-mortem. MPH could be detected in Calliphorid larvae (n=15) reared on the rat brains at 3.2±1.6 ng/g. Secondly, MPH-spiked porcine brain tissue (450 mg/kg) was used to investigate drug concentration in larvae over a period of 72 h. After larvae had feed for 60 h, MPH was detected at 19.8±1.4 µg/g in the feeding larvae and at 3.5±0.1 µg/g in the MPH-spiked porcine brain tissue. It could be advantageous to use Calliphorid larvae as an alternative toxicological specimen to detect alkaline labile drugs, such as MPH.

Access in New Zealand to antidotes for accidental and intentional drug poisonings.

INTRODUCTION: Access to antidotes for the treatment of drug poisonings can impact on morbidity and mortality. Treatment for drug poisonings usually occurs at the nearest emergency department; however, health professionals working in primary care are often the first point of contact for patients. As New Zealand has a small, diffuse population, and poisonings are a rare event, it can be difficult to anticipate what antidotes are required. AIM: The aim of the study was to determine what antidotes are frequently used and stocked in hospital pharmacies. METHODS: A survey was sent out to all 25 hospital pharmacies, excluding private and satellite hospitals. The survey contained questions about the stocking, and prior use, of over 30 antidotes. Also included were open-ended questions asking about reasons for not stocking antidotes and procedures for procuring antidotes in an emergency. RESULTS: Twenty out of 25 hospital pharmacies completed the survey. Most hospital pharmacies were found to stock large quantities of commonly used antidotes and low quantities of uncommonly used antidotes-but in sufficient quantity to treat one to two patients. A low number of poisonings was the most common reason cited for not stocking antidotes, followed by high cost. Most hospitals had clear guidelines for procuring and lending antidotes in an emergency. DISCUSSION: New Zealand hospital pharmacies stock adequate quantities of most antidotes, including antidotes that are expensive and rarely required, but which may be needed urgently. Hospital pharmacies also have clear procurement procedures for obtaining other antidotes in an emergency.

Assessment of markers of glycaemic control in diabetic patients with chronic kidney disease using continuous glucose monitoring.

AIM: Due to altered red blood cell survival and erythropoietin therapy glycated haemoglobin (HbA1c) may not accurately reflect long-term glycaemic control in patients with diabetes and chronic kidney disease (CKD). Glycated albumin (GA) and fructosamine are alternative markers of glycaemia. The aim of this study was to investigate the accuracy of HbA1c, GA and fructosamine as indicators of glycaemic control using continuous glucose monitoring. METHODS: HbA1c, GA and fructosamine concentrations were measured in 25 subjects with diabetic nephropathy (CKD stages 4 and 5 (estimated glomerular filtration rate <30 mL/min per 1.73 m(2) )) matched with 25 subjects with diabetes and no evidence of nephropathy. Simultaneous real-time glucose concentrations were monitored by continuous glucose monitoring over 48 h. RESULTS: GA correlated significantly to mean glucose concentrations in patients with and without CKD (r = 0.54 vs 0.49, P < 0.05). A similar relationship was observed with fructosamine relative to glucose. A poor correlation between HbA1c and glucose was observed with CKD (r = 0.38, P = ns) but was significant in the non-CKD group (r = 0.66, P < 0.001). The GA/HbA1c ratio was significantly higher in diabetic patients with CKD compared with controls (2.5 ± 0.4 vs 2.2 ± 0.4, P < 0.05). HbA1c values were significantly lower in CKD patients, relative to non-CKD patients at comparable mean glucose concentrations. CONCLUSION: HbA1c significantly underestimates glycaemic control in patients with diabetes and CKD stages 4 and 5. In severe CKD, GA more accurately reflects glycaemic control compared with fructosamine and HbA1c and should be the preferred marker of glycaemic control.

Design of pharmacokinetic studies for latent covariates.

Latent covariates are covariates that are known to exist but are either observable but unavailable or unobservable at the time of the clinical study. Designs to account for latent covariates must incorporate both uncertainty in the prevalence of the covariate and the data-type of the covariate. The informativeness of the covariate will then depend on whether the covariate data is continuous, ordinal or nominal. In this work we consider designs for latent covariates that may either directly influence the parameter of interest, or indirectly via actions on an observable covariate which then influences the parameter of interest. We consider a motivating example based on the effect of a genetic polymorphism on the influence of a continuous covariate (age) on drug clearance (CL). The polymorphism could take the case of a haplotype with many variant alleles, or a copy number variation in genes with different phenotypic expressions which could be treated as continuous data, or as a bi- or tri-allelic single nucleotide polymorphism that could form either an ordinal or nominal covariate on drug CL. The aim of this study was to investigate designs for clinical studies for latent covariates that accommodate both unknown prevalence and unknown data-type. Initially, the informativeness of a covariate was explored using linear regression assuming the three data-types continuous, ordinal and nominal. The linear covariate model was then considered within a nonlinear mixed effects modelling framework. Two simulation scenarios were considered: (1) the influence of the latent covariate directly on the parameter of interest and (2) the influence of the latent covariate on an observable non-latent continuous covariate, which was assumed to follow a normal or stratified distribution, and the effect of this covariate on the parameter of interest. A power analysis for population PK modelling (1) where the latent covariate had direct influence on the parameter also showed similar behaviour to the linear regression solution. When the influence of the latent covariate was mediated via another observable non-latent continuous covariate, the power for the continuous model was highest but the power of the ordinal model was indistinguishable from that of the nominal model. Stratification of the observable non-latent continuous covariate did not appreciably change the power to identify the latent covariate from that when we assumed the observable covariate conformed to a normal distribution. It was found that parameter estimation is generally at least 1.5 to 7 fold more precise for continuous models than for categorical models.

Methanol and ethylene glycol acute poisonings - predictors of mortality.

CONTEXT: Methanol and ethylene glycol cause significant mortality post-ingestion. Predicting prognosis based on the biomarkers osmolal gap, anion gap and pH is beneficial. OBJECTIVE: To evaluate the relationship between biomarkers, measured post-methanol and ethylene glycol exposure, and clinical outcomes. METHODS: A review of the literature identified cases where methanol or ethylene glycol had been ingested and clinical outcomes were recorded. Biomarkers were extracted including osmolal gap, anion gap and pH, with clinical outcomes categorised as recovered, recovered with adverse sequelae and death. Biomarkers were analysed using the Mann-Whitney test for two samples; sensitivity and specificity were evaluated using receiver operating characteristic (ROC) curves. RESULTS: In total, 119 cases of methanol and 88 of ethylene glycol poisoning were identified; 21 methanol and 19 ethylene glycol patients died. For methanol ingestion the mean values, for survival compared to death, were 48 (range: 6-138) and 90 (range: 49-159) mOsm/kg water for osmolal gap (p=0.0052), 31 (range: 11-50) and 41 (range: 30-53) mmol/L for anion gap (p=0.0065) and 7.21 (range: 6.60-7.50) and 6.70 (range: 6.34-7.22) for arterial pH (p<0.0001). The area under the ROC curve was highest for arterial pH, 0.94 (95% CI: 0.89-0.99). For ethylene glycol, these were 49 (range: 0-189) and 79 (range: 25-184) mOsm/kg water for osmolal gap (p=0.050), 28 (range: 6-48) and 38 (range: 20-66) mmol/L for anion gap (p=0.0037) and 7.08 (range: 6.46-7.39) and 6.98 (range: 6.50-7.16) for pH (p=0.072), for survival compared to death. The area under the ROC curve was highest for anion gap, 0.73 (95% CI: 0.60-0.87). CONCLUSION: Post-methanol ingestion a large osmolal gap, anion gap and low pH (<7.22) were associated with increased mortality; and pH has the highest predictive value. Post-ethylene glycol ingestion, both osmolal gap and anion gap were associated with increased mortality.

Modeling red blood cell survival data.

Anaemia of chronic kidney disease (CKD) is a common complication in patients with renal impairment, especially in end-stage renal failure. As well as erythropoietin deficiency, decreased red blood cell survival is a contributing factor. However, it remains unclear which mechanism underlies the altered survival of red blood cells (RBCs). In this work a previously developed statistical model for RBC survival was applied to clinical data obtained from 14 patients with CKD undergoing hemodialysis as well as 14 healthy controls using radioactive chromium (5¹Cr) as random labelling method. A classical two-stage approach and a full population analysis were applied to estimate the key parameters controlling random destruction and senescence in the model. Estimating random destruction was preferred over estimating an accelerated senescence in both approaches and both groups as it provided the better fit to the data. Due to significant nonspecific random loss of the label from the cells that cannot be quantified directly only a relative RBC survival can be obtained from data using 5¹Cr as labelling method. Nevertheless, RBC survival was found to be significantly reduced in CKD patients compared to the controls with a relative reduction of 20-30% depending on the analysis method used.

Evaluation of red blood cell labelling methods based on a statistical model for red blood cell survival.

The aim of this work is to compare different labelling methods that are commonly used to estimate the lifespan of red blood cells (RBCs), e.g. in anaemia of renal failure, where the effect of treatment with erythropoietin depends on the lifespan of RBCs. A previously developed model for the survival time of RBCs that accounts for plausible physiological processes of RBC destruction was used to simulate ideal random and cohort labelling methods for RBCs, as well as the flaws associated with these methods (e.g. reuse of label and loss of the label from the surviving RBCs). Random labelling with radioactive chromium and cohort labelling using heavy nitrogen were considered. Blood sampling times were determined for RBC survival studies using both labelling methods by applying the theory of optimal design. It was assessed whether the underlying parameter values of the model are estimable from these studies, and the precision of the parameter estimates were calculated. In theory, parameter estimation would be possible for both types of ideal labelling methods without flaws. However, flaws associated with random labelling are significant and not all parameters controlling RBC survival in the model can be estimated with good precision. In contrast, cohort labelling shows good precision in the parameter estimates even in the presence of reuse and prolonged incorporation of the label. A model based analysis of RBC survival studies is recommended in future to account for limitations in methodology as well as likely causes of RBC destruction.

A dosing regimen for immediate N-acetylcysteine treatment for acute paracetamol overdose.

CONTEXT: Current treatment of paracetamol (acetaminophen) poisoning involves initiating a 3-phase N-acetylcysteine (NAC) infusion after comparing a plasma concentration, taken ≥ 4 h post-overdose, to a nomogram. This may result in dosing errors, a delay in treatment, or possibly more adverse effects - due to the use of a high dose rate for the first infusion when treatment is initiated. OBJECTIVE: Our aim was to investigate a novel dosing regimen for the immediate administration of NAC on admission at a lower infusion rate. METHODS: We used a published population pharmacokinetic model of NAC to simulate a scenario where a patient presents to the hospital 2 h post-overdose. The conventional regimen is commenced 6 h post-overdose when the 4-h plasma paracetamol concentration is available. We investigated an NAC infusion using a lower dosing rate initiated immediately on presentation. We determined a dosing rate that gave an area under the curve (AUC) of the concentration-time curve that was the same or greater than that from the conventional regimen on 90% of occasions. RESULTS: Lower dosing rates of NAC initiated immediately resulted in a similar exposure to NAC. An infusion of 110 mg/kg over the first 5 h (22 mg/kg/h) followed by the last two phases of the conventional regimen, or 200 mg/kg over 9 h (22.6 mg/kg/h) followed by the last phase of the conventional regimen could be used. CONCLUSION: The novel dosing regimen allowed immediate treatment of a patient using a lower dosing rate. This greatly simplifies the current dosing regimen and may reduce NAC adverse effects while ensuring the same amount of NAC is delivered.

Red blood cell survival in long-term dialysis patients.

BACKGROUND: Shortening of red blood cell (RBC) survival contributes to the anemia of chronic kidney disease. The toxic uremic environment accounts for the decreased RBC life span. The contribution of mechanical damage caused by hemodialysis to the shortened life span is unclear. Reductions up to 70% in RBC survival have been reported in uremic patients. To date, no accurate well-controlled RBC survival data exist in dialysis patients treated using different dialysis modalities and receiving erythropoiesis-stimulating agent (ESA) therapy. The aim of this study was to determine RBC survival in hemodialysis (HD) and peritoneal dialysis (PD) patients compared with healthy persons. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: 14 HD patients and 5 PD patients were recruited from the dialysis unit. Healthy volunteers (n = 14) age- and sex-matched to HD participants were included. All dialysis patients received either ESA therapy or regular iron supplementation. PREDICTOR: Dialysis patients versus age- and sex-matched healthy controls. OUTCOMES: RBC survival. MEASUREMENTS: RBC survival was determined using radioactive chromium labeling. RESULTS: More than 85% of dialysis patients were anemic (hemoglobin, 12.0 ± 1.1 g/dL); hemoglobin concentrations were not significantly different between HD and PD patients. Median RBC survival was significantly decreased by 20% in HD patients compared with healthy controls: 58.1 (25th-75th percentile, 54.6-71.2) versus 72.9 (25th-75th percentile, 63.4-87.8) days (P = 0.02). No difference was shown between the PD and HD groups: 55.3 (25th-75th percentile, 49.0-60.2) versus 58.1 (25th-75th percentile, 54.6-71.2) days (P = 0.2). LIMITATIONS: Label loss from RBCs associated with the chromium 51 labeling technique needs to be accounted for in the interpretation of RBC survival data. CONCLUSIONS: Despite current ESA therapy, decreased RBC survival contributes to chronic kidney disease-related anemia, although the reduction is less than previously reported. There does not appear to be net mechanical damage associated with HD therapy resulting in decreased RBC life span.

The pharmacokinetics of methanol in the presence of ethanol: a case study.

BACKGROUND AND OBJECTIVE: Methanol is a toxic alcohol that can cause significant morbidity and mortality in overdose, while ethanol is a readily available and effective antidote. Little is known about the pharmacokinetics of methanol in the presence of ethanol and vice versa. This paper explores the influence of methanol and ethanol on the pharmacokinetics of each other along with the effect of continuous venovenous haemodiafiltration (CVVHD) on alcohol removal. METHODS: Multiple plasma, urine and dialysate samples were collected from a 42-year-old male who ingested 166 g of methanol. Methanol and ethanol concentrations in both plasma and urine were assayed and the concentration-time data were modelled using nonlinear mixed-effects modelling software NONMEM® VI. Simulations were performed using the final model parameters in MATLAB® software where a variety of initial doses and ethanol infusions were assessed. RESULTS: The final model included a competitive metabolic interaction between methanol and ethanol as well as first-order elimination due to renal, CVVHD and an additional non-renal non-CVVHD mechanism. Simulations from the model show a loading dose of 28.4 g/70 kg of ethanol results in a target plasma concentration of 1 g/L. Due to the competitive interaction between methanol and ethanol, higher amounts of methanol require lower maintenance doses of ethanol but for longer. CVVHD was shown to increase the dose rate of ethanol required but to decrease the duration of the maintenance phase. CONCLUSION: A detailed understanding of the pharmacokinetics of methanol and ethanol in the presence of each other is required to accurately determine the doses of ethanol required to treat different methanol poisonings.

A statistical model for red blood cell survival.

A statistical model for the survival time of red blood cells (RBCs) with a continuous distribution of cell lifespans is presented. The underlying distribution of RBC lifespans is derived from a probability density function with a bathtub-shaped hazard curve, and accounts for death of RBCs due to senescence (age-dependent increasing hazard rate) and random destruction (constant hazard), as well as for death due to initial or delayed failures and neocytolysis (equivalent to early red cell mortality). The model yields survival times similar to those of previously published studies of RBC survival and is easily amenable to inclusion of drug effects and haemolytic disorders.