Pharmacokinetic-pharmacodynamic modelling of the cardiovascular effects of drugs – method development and application to magnesium in sheep

BACKGROUND: There have been few reports of pharmacokinetic models that have been linked to models of the cardiovascular system. Such models could predict the cardiovascular effects of a drug under a variety of circumstances. Limiting factors may be the lack of a suitably simple cardiovascular model, the difficulty in managing extensive cardiovascular data sets, and the lack of physiologically based pharmacokinetic models that can account for blood flow changes that may be caused by a drug. An approach for addressing these limitations is proposed, and illustrated using data on the cardiovascular effects of magnesium given intravenously to sheep. The cardiovascular model was based on compartments for venous and arterial blood. Blood flowed from arterial to venous compartments via a passive flow through a systemic vascular resistance. Blood flowed from venous to arterial via a pump (the heart-lung system), the pumping rate was governed by the venous pressure (Frank-Starling mechanism). Heart rate was controlled via the difference between arterial blood pressure and a set point (Baroreceptor control). Constraints were made to pressure-volume relationships, pressure-stroke volume relationships, and physical limits were imposed to produce plausible cardiac function curves and baseline cardiovascular variables. "Cardiovascular radar plots" were developed for concisely displaying the cardiovascular status. A recirculatory kinetic model of magnesium was developed that could account for the large changes in cardiac output caused by this drug. Arterial concentrations predicted by the kinetic model were linked to the systemic vascular resistance and venous compliance terms of the cardiovascular model. The kinetic-dynamic model based on a training data set (30 mmol over 2 min) was used to predict the results for a separate validation data set (30 mmol over 5 min). RESULTS: The kinetic-dynamic model was able to describe the training data set. A recirculatory kinetic model was a good description of the acute kinetics of magnesium in sheep. The volume of distribution of magnesium in the lungs was 0.89 L, and in the body was 4.02 L. A permeability term (0.59 L min(-1)) described the distribution of magnesium into a deeper (probably intracellular) compartment. The final kinetic-dynamic model was able to predict the validation data set. The mean prediction error for the arterial magnesium concentrations, cardiac output and mean arterial blood pressure for the validation data set were 0.02, 3.0 and 6.1%, respectively. CONCLUSION: The combination of a recirculatory model and a simple two-compartment cardiovascular model was able to describe and predict the kinetics and cardiovascular effects of magnesium in sheep

A call centre and extended checklist for pre-screening elective surgical patients – a pilot study

BACKGROUND: Novel approaches to preoperative assessment and management before elective surgery are warranted to ensure that a sustainable high quality service is provided. The benefits of a call centre incorporating an extended preoperative electronic checklist and phone follow-up as an alternative to a clinic attendance were examined. METHODS: This was a pilot study of a new method of patient assessment in patients scheduled for elective non-cardiac surgery and who attended a conventional preoperative clinic. A call centre assessment, using a Computer-assisted Health Assessment by Telephone (CHAT), paper review by an anaesthetist, and a follow-up phone call if the anaesthetist wished more information, preceded the conventional preoperative clinic. Summaries from the call centre and clinic assessments were independently produced. The times spent by call centre staff were recorded. The 'procedural anaesthetist' (who provided anaesthesia for each patient's actual surgery/procedure) documented an opinion on whether the call centre assessment alone would have been sufficient to bypass the preoperative clinic if the patient were hypothetically undergoing laparoscopic cholecystectomy. This opinion was also sought from a panel of four senior anaesthetists, based on patient summaries from both the call centre and preoperative clinic, but expanded to three hypothetical operations of different complexity – cataract removal, laparoscopic cholecystectomy, and total hip replacement. RESULTS: Call centre assessment followed by clinic attendance was studied in 193 patients. The mean time for CHAT was 19.8 (SD 7.5) minutes and, after review of CHAT summaries, anaesthetists telephoned 45.6% of cases for follow-up information. The mean time spent by anaesthetists on summary review and phone calls was 3.8 (SD 3.9) minutes. Procedural anaesthetists considered 89% of the patients under their care suitable to have bypassed the preoperative clinic if they were to have undergone cholecystectomy. The panel of senior anaesthetists judged 95-97% of patients suitable to have bypassed preoperative clinic for cataract surgery, 81-85% for cholecystectomy and 79-82% for hip replacement. CONCLUSIONS: A call centre to pre-screen elective surgical patients might substantially reduce patient numbers attending preoperative anaesthetic assessment clinics. Further studies to assess the quality of such an approach are indicated. TRIAL REGISTRATION: ANZCTR ACTRN12614000199617.Guy Ludbrook, Richard Seglenieks, Shona Osborn, and Cliff Gran

International comparison of cosmetic outcomes of breast conserving surgery and radiation therapy for women with ductal carcinoma in situ of the breast

Purpose: To assess the cosmetic impact of breast conserving surgery (BCS), whole breast irradiation (WBI) fractionation and tumour bed boost (TBB) use in a phase III trial for women with ductal carcinoma in situ (DCIS) of the breast. Materials and methods: Baseline and 3-year cosmesis were assessed using the European Organization for Research and Treatment of Cancer (EORTC) Cosmetic Rating System and digital images in a randomised trial of non-low risk DCIS treated with postoperative WBI +/- TBB. Baseline cosmesis was assessed for four geographic clusters of treating centres. Cosmetic failure was a global score of fair or poor. Cosmetic deterioration was a score change from excellent or good at baseline to fair or poor at three years. Odds ratios for cosmetic deterioration by WBI dose-fractionation and TBB use were calculated for both scoring systems. Results: 1608 women were enrolled from 11 countries between 2007 and 2014. 85-90% had excellent or good baseline cosmesis independent of geography or assessment method. TBB (16 Gy in 8 fractions) was associated with a >2-fold risk of cosmetic deterioration (p

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

The cerebral pharmacokinetics and pharmacodynamics of propofol in sheep / Guy Lawrence Ludbrook.

Bibliography: p. 207-236.236 p. : ill. ; 30 cm.This thesis examines the systemic and cerebral pharmacokinetics and pharmacodynamics of propofol following rapid administration, using regional pharmacokinetic techniques in a sheep preparation. New methods for measurement of cerebral blood flow, cerebral metabolic rate and depth of anaesthesia are developed and validated. The final studies show that distribution of propofol to the brain is dependent on cardiac output.Thesis (Ph.D.)--University of Adelaide, Dept. of Anaesthesia and Intensive Care, 1997

Propofol infusion for the difficult airway: Reply

Publisher's copy made available with the permission of the publisher© 1997 Australian Society of AnaesthetistsG. Ludbroo