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Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article

Background: Initiatives in perioperative care warrant robust cost-effectiveness analysis in a cost-constrained era when high-value care is a priority. A model of anesthesia-led early high-acuity postoperative care, advanced recovery room care (ARRC), has shown benefit in terms of hospital and patient outcomes, but its cost-effectiveness has not yet been formally determined., Methods: Data from a previously published single-center prospective cohort study of ARRC in medium-risk patients were used to generate a Markov model, which described patient transition between care locations, each with different characteristics and costs. The incremental cost-effectiveness ratio (ICER), using days at home (DAH) and hospital costs, was calculated for ARRC compared to usual ward care using deterministic and probabilistic sensitivity analysis., Results: The Markov model accurately described patient disposition after surgery. For each patient, ARRC provided 4.3 more DAH within the first 90 days after surgery and decreased overall hospital costs by $1081 per patient. Probabilistic sensitivity analysis revealed that ARRC had a 99.3% probability of increased DAH and a 77.4% probability that ARRC was dominant from the perspective of the hospital, with improved outcomes and decreased costs., Conclusions: Early high-acuity care for approximately 24 hours after surgery in medium-risk patients provides highly cost-effective improvements in outcomes when compared to usual ward care., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2023 International Anesthesia Research Society.)

Triiodothyronine (T3) concentrations in plasma decrease during acute illness and it is unclear if this contributes to disease. Clinical and laboratory studies of T3 supplementation in disease have revealed little or no effect. It is uncertain if short term supplementation of T3 has any discernible effect in a healthy animals. Observational study of intravenous T3 (1 µg/kg/h) for 24 h in a healthy sheep model receiving protocol-guided intensive care supports (T3 group, n=5). A total of 45 endpoints were measured including hemodynamic, respiratory, renal, hematological, metabolic and endocrine parameters. Data were compared with previously published studies of sheep subject to the same support protocol without administered T3 (No T3 group, n=5). Plasma free T3 concentrations were elevated 8-fold by the infusion (pmol/l at 24 h; T3 group 34.9±9.9 vs. No T3 group 4.4±0.3, P<0.01, reference range 1.6 to 6.8). There was no significant physiological response to administration of T3 over the study duration. Supplementation of intravenous T3 for 24 h has no physiological effect on relevant physiological endpoints in healthy sheep. Further research is required to understand if the lack of effect of short-term T3 may be related to kinetics of T3 cellular uptake, metabolism and action, or acute counterbalancing hormone resistance. This information may be helpful in design of clinical T3 supplementation trials., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2024, Spandidos Publications.)

Competing Interests: There are no conflicts of interest.

Objectives: This study aimed to evaluate the application of cost-effectiveness modeling to redesign of perioperative care pathways, from a hospital perspective., Methods: A Markov cost-effectiveness model of patient transition between care locations, each with different characteristics and cost, was developed. Inputs were derived from clinical trials piloting a preoperative call center and a postoperative medium-acuity care unit. The effect chosen was days at home (DAH) after surgery, reflecting quality of in-hospital care, acknowledged financially by fundholders, and relevant to consumers. Cost was from the hospital's perspective. A model cycle time of 4 hours for 30 days reflected relevant timelines and costs., Results: A Markov model was successfully created, accounting for the care locations in the 2 pathways as model states and accounting for consequences and costs. Cost-effectiveness analysis allowed the calculation of an incremental cost-effectiveness ratio comparing these pathways, providing a mean incremental cost-effectiveness ratio of -$427 per additional DAH, where incremental costs and DAH were -$644 and +1.51, respectively. Probabilistic sensitivity analysis suggested the new pathway had a 61% probability of reduced costs and a 74% probability of increased DAH and a 58% probability this pathway was dominant. Tornado analysis revealed the major contributor to increased costs as intensive care unit stay and the major contributor to decreased costs as ward stay. For the new pathway, the probability of transfer from ward to home and the probability of staying at home had the greatest impact on DAH., Conclusions: These data suggest Markov modeling may be a useful tool for the cost-effectiveness analysis of initiatives in perioperative care., (Copyright © 2021 ISPOR–The International Society for Pharmacoeconomics and Outcomes Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Population-based increases in ageing and medical co-morbidities are expected to substantially increase the incidence of expensive postoperative complications. This threatens the sustainability of essential surgical care, with negative impacts on patients' health and wellbeing., Recent Findings: Identification of key high-risk areas, and implementation of proven cost-effective strategies to manage both outcome and cost across the end-to-end journey of the surgical episode of care, is clearly feasible. However, good programme design and formal cost-effectiveness analysis is critical to identify, and implement, true high value change., Summary: Both outcome and cost need to be a high priority for both fundholders and clinicians in perioperative care, with the focus for both groups on delivering high-quality care, which in itself, is the key to good cost management., Competing Interests: Conflict of InterestThe author does not have any potential conflicts of interest to disclose., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021.)

The transmuscular quadratus lumborum (TQL) block is one of the recently evolved myofascial blocks utilised in abdominal surgery. It involves injecting local anaesthetic into the fascial plane anterior to the thoracolumbar fascia. This block has previously been described with a transverse oblique paramedian approach at the L2 level in the sitting position. We describe a TQL block at the same level in the lateral position using a transverse posterolateral approach to provide analgesia for patients undergoing abdominal surgery. We elaborate on these two approaches of TQL block at the L2 level, in relation to the anatomy, sonoanatomy and technical aspects.

Background: The "Analgesia Nociception Index" (ANI; MetroDoloris Medical Systems, Lille, France) is a proposed noninvasive guide to analgesia derived from an electrocardiogram trace. ANI is scaled from 0 to 100; with previous studies suggesting that values ≥50 can indicate adequate analgesia. This clinical trial was designed to investigate the effect of intraoperative ANI-guided fentanyl administration on postoperative pain, under anesthetic conditions optimized for ANI functioning., Methods: Fifty patients aged 18 to 75 years undergoing lumbar discectomy or laminectomy were studied. Participants were randomly allocated to receive intraoperative fentanyl guided either by the anesthesiologist's standard clinical practice (control group) or by maintaining ANI ≥50 with boluses of fentanyl at 5-minute intervals (ANI group). A standardized anesthetic regimen (sevoflurane, rocuronium, and nonopioid analgesia) was utilized for both groups. The primary outcome was Numerical Rating Scale pain scores recorded from 0 to 90 minutes of recovery room stay. Secondary outcomes included those in the recovery room period (total fentanyl administration, nausea, vomiting, shivering, airway obstruction, respiratory depression, sedation, emergence time, and time spent in the recovery room) and in the intraoperative period (total fentanyl administration, intraoperative-predicted fentanyl effect-site concentrations over time [CeFent], the correlation between ANI and predicted CeFent and the incidence of movement). Statistical analysis was performed with 2-tailed Student t tests, χ tests, ordinal logistic generalized estimating equation models, and linear mixed-effects models. Bonferroni corrections for multiple comparisons were made for primary and secondary outcomes., Results: Over the recovery room period (0-90 minutes) Numerical Rating Scale pain scores were on average 1.3 units lower in ANI group compared to the control group (95% confidence interval [CI], -0.4 to 2.4; P= .01). Patients in the ANI group additionally had 64% lower recovery room total fentanyl administration (95% CI, -12% to 85%; P= .44, unadjusted P= .026), 82% lower nausea scores (95% CI, -19% to 96%; P= .43, unadjusted P= .03), and a reduced incidence of shivering (ANI 4%, control 27%, P= .80, unadjusted P= .047) compared to the control group. Intraoperatively, ANI group patients had on average 27% higher predicted CeFent levels during the highly nociceptive periods of intubation and first incision (5-30 minutes) compared with control group patients (95% CI, 3%-57%; P= .51, unadjusted P= .03). For a 1-unit decrease in ANI scores, predicted CeFent on average increased by an estimated 1.98% in the ANI group (95% CI, 1.7%-2.26%; P< .0001) and 1.08% in the control group (95% CI, 0.76%-1.39%; P< .0001). This correlation was significantly different between groups (0.9%, 95% CI, 0.5%-1.3%; P< .0001). Recovery room vomiting, airway obstruction, respiratory depression, sedation, emergence time, time spent in the recovery room as well as total intraoperative fentanyl administration, hypnotic parameters, and incidence of intraoperative movement were not different between groups., Conclusions: Patients receiving intraoperative ANI-guided fentanyl administration during sevoflurane anesthesia for lumbar discectomy and laminectomy demonstrated decreased pain in the recovery room, likely as a result of more objective intraoperative fentanyl administration.

Background: Accurate identification of patients at risk of early postoperative deterioration allows needs-based allocation of patients to appropriate levels of care. This study aimed to record the incidence of early postoperative deterioration and identify factors predictive of at-risk patients. Doing so may assist future evidence-based perioperative planning and allocation of patients to high-acuity facilities., Methods: With ethical approval, data from elective non-cardiac surgical patients were collected between May and August 2013. Patient and surgical factors potentially related to postoperative deterioration were collected from preoperative assessment records. Data on deterioration in the postanaesthesia care unit (PACU), and on the wards were collected prospectively for a period of 72 h postoperatively. Patient factors, surgical factors and PACU events were compared with ward events using binomial logistic regression analysis., Results: Of the 747 patients, postoperative deterioration was common both in PACU (155 (20.1%) patients) and on the wards (125 (16.7%)). Common ward events included hypotension (64 (8.2%)) and desaturation (59 (6.2%)). A rapid response team call occurred for 33 (4.4%) patients and an unplanned ICU admission for seven (0.9%) patients. A history of atrial fibrillation and chronic liver disease, duration of surgery and excessive sedation in PACU, among others, were strongly associated with subsequent ward deterioration. However, measures of surgical complexity were not., Conclusions: Patient factors, duration of surgery and events in PACU can be predictive of subsequent early postoperative ward clinical deterioration. Such information may aid appropriate perioperative decision-making with respect to postoperative utilization of high-acuity facilities., (© 2017 Royal Australasian College of Surgeons.)

Background: A clear surgical field is critical during endoscopic sinus surgery (ESS). Hypotensive anesthesia and cardiac output (CO) may optimize the surgical field; however, evidence of their effect on bleeding and cerebral blood flow is conflicting. The aim of this study was to evaluate the effect of blood pressure (BP) and CO on intraoperative bleeding and middle cerebral artery blood flow velocity (Vmca ) during ESS., Methods: This was a prospective randomized controlled trial. Patients undergoing ESS for chronic rhinosinusitis at a tertiary institution in 2013 were randomized to receive BP manipulation using target-controlled noradrenaline infusion during surgery to either their left or right sinuses. The contralateral side in each patient served as control. Bleeding was scored using a 0 to 10 point bleeding assessment scale (BAS, 0-10) and Vmca was measured using transcranial Doppler ultrasonography every 10 minutes or when surgically opportune, and time-matched with BP and CO. Data was analyzed using Bland-Altman methods., Results: A total of 105 time points were collected across a mean arterial pressure (MAP) range of 32 to 118 mmHg. Significant correlations were demonstrated between MAP and Vmca (r = 0.7, p < 0.0001), MAP and BAS (r = 0.50, p < 0.0001), CO and Vmca (r = 0.57, p < 0.0001), and CO and BAS (r = 0.42, p < 0.0001). The best surgical fields were seen at 40 to 59 mmHg MAP. However, MAP below 60 mmHg produced >50% reduction in Vmca in more than 10% of time points., Conclusion: Balancing surgical visibility with organ perfusion remains a challenge. The results of this study show that moderate hypotension significantly improves the surgical field; however reducing BP below 60 mmHg may risk cerebral hypoperfusion., (© 2016 ARS-AAOA, LLC.)

Objectives: Triiodothyronine concentration in plasma decreases during septic shock and may contribute to multiple organ dysfunction. We sought to determine the safety and efficacy of administering triiodothyronine, with and without hydrocortisone, in a model of septic shock., Design: Randomized blinded placebo-controlled trial., Setting: Preclinical research laboratory., Subjects: Thirty-two sheep rendered septic with IV Escherichia coli and receiving protocol-guided sedation, ventilation, IV fluids, and norepinephrine infusion., Interventions: Two hours following induction of sepsis, 32 sheep received a 24-hour IV infusion of 1) placebo + placebo, 2) triiodothyronine + placebo, 3) hydrocortisone + placebo, or 4) triiodothyronine + hydrocortisone., Measurements and Main Results: Primary outcome was the total amount of norepinephrine required to maintain a target mean arterial pressure; secondary outcomes included hemodynamic and metabolic indices. Plasma triiodothyronine levels increased to supraphysiological concentrations with hormonal therapy. Following 24 hours of study drug infusion, the amount of norepinephrine required was no different between the study groups (mean ± SD μg/kg; placebo + placebo group 208 ± 392; triiodothyronine + placebo group 501 ± 370; hydrocortisone + placebo group 167 ± 286; triiodothyronine + hydrocortisone group 466 ± 495; p = 0.20). There was no significant treatment effect on any hemodynamic variable, metabolic parameter, or measure of organ function., Conclusions: A 24-hour infusion of triiodothyronine, with or without hydrocortisone, in an ovine model of septic shock did not markedly alter norepinephrine requirement or any other physiological parameter.

Objectives/hypothesis: Hypotensive anesthesia is often used in endoscopic sinus surgery (ESS) to improve surgical visibility; however, its safety and efficacy in this role are yet to be justified. This study aimed to evaluate the effect of hypotensive anesthesia on both real-time middle cerebral artery blood flow velocity (Vmca) and the severity of surgical bleeding in patients undergoing ESS., Study Design: Prospective, observational cohort study., Methods: Thirty-two patients undergoing hypotensive anesthesia for ESS at a single tertiary institution during February 2011 to July 2012 were recruited for the study. Transcranial Doppler ultrasonography measured periodic Vmca, which were time-matched for hemodynamic and respiratory factors. One-minute video segments corresponding with each Vmca reading were randomized and distributed to two blinded observers for bleeding assessment., Results: Three hundred and fifty-six data time points were recorded for systolic, diastolic, and mean arterial blood pressure (MAP), pulse rate, respiratory rate, end-tidal carbon dioxide concentration, Vmca, and bleeding assessment score (BAS). A direct relationship exists between MAP and Vmca (r = 0.77, P < .0001) as well as MAP and BAS (r = 0.36, P < .0001). MAP levels above 60 mm Hg maintained at least 50% of baseline Vmca flow in almost 90% of all time points., Conclusions: Hypotensive anesthesia is an effective method of controlling intraoperative bleeding during endoscopic sinus surgery; however the effect is clinically small in low MAP ranges. In otherwise healthy patients undergoing ESS with general anesthesia, reducing MAP to below 60 mm Hg may increase the risk of cerebral ischemia., (© 2014 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Tramadol is an atypical centrally acting analgesic agent available as both oral and parenteral preparations. For patients who are unable to take tramadol orally, the subcutaneous route of administration offers an easy alternative to intravenous or intramuscular routes. This study aimed to characterise the absorption pharmacokinetics of a single subcutaneous dose of tramadol in severely ill patients and in healthy subjects., Methods/design: Blood samples (5 ml) taken at intervals from 2 minutes to 24 hours after a subcutaneous dose of tramadol (50 mg) in 15 patients (13 male, two female) and eight healthy male subjects were assayed using high performance liquid chromatography. Pharmacokinetic parameters were derived using a non-compartmental approach., Results: There were no statistically significant differences between the two groups in the following parameters (mean ± SD): maximum venous concentration 0.44 ± 0.18 (patients) vs. 0.47 ± 0.13 (healthy volunteers) mcg/ml (p = 0.67); area under the plasma concentration-time curve 177 ± 109 (patients) vs. 175 ± 75 (healthy volunteers) mcg/ml*min (p = 0.96); time to maximum venous concentration 23.3 ± 2 (patients) vs. 20.6 ± 18.8 (healthy volunteers) minutes (p = 0.73) and mean residence time 463 ± 233 (patients) vs. 466 ± 224 (healthy volunteers) minutes (p = 0.97)., Conclusions: The similar time to maximum venous concentration and mean residence time suggest similar absorption rates between the two groups. These results indicate that the same dosing regimens for subcutaneous tramadol administration may therefore be used in both healthy subjects and severely ill patients., Trial Registration: ACTRN12611001018909.

Study Design: Multicenter, randomized, double-blind, placebo-controlled trial., Objective: To examine the safety and efficacy of three different doses of the tumor necrosis factor alpha (TNF-α) inhibitor etanercept versus placebo for the treatment of symptomatic lumbar disc herniation (LDH)., Summary of Background Data: TNF-α is considered to be a major cause of radicular leg pain associated with symptomatic LDH. Systemic administration of TNF-α inhibitors for sciatica has indicated a trend toward efficacy., Methods: Forty-nine subjects aged between 18 and 70 years, with persistent lumbosacral radicular pain secondary to LDH, and an average leg pain intensity of 5/10 or more were randomized to 1 of 4 groups: 0.5-mg, 2.5-mg, 12.5-mg etanercept, or placebo. Subjects received 2 transforaminal epidural injections, 2 weeks apart, and were assessed for efficacy up to 26 weeks after the second injection. The primary outcome measure was the change in mean daily worst leg pain (WLP). Secondary outcomes included average leg pain, worst back pain, average back pain, in-clinic pain, Oswestry Disability Index, patient global impression of change, and tolerability., Results: Forty-three of the 49 randomized patients completed the study. Patients receiving 0.5-mg etanercept showed a clinically and statistically significant (P< 0.1) reduction in mean daily WLP compared with the placebo cohort from 2 to 26 weeks for both the per protocol population (-5.13 vs. -1.95; P= 0.066) and the intention-to-treat population (-4.40 vs. -1.84; P= 0.058). Fifty percent of these subjects reported a 100% reduction in WLP 4 weeks post-treatment compared with 0% of subjects in the placebo cohort. Improvements in all secondary outcomes were also observed in the 0.5-mg etanercept cohort. The overall incidence of adverse events was similar in placebo and all etanercept cohorts., Conclusion: Two transforaminal injections of etanercept provided clinically significant reductions in mean daily WLP and worst back pain compared with placebo for subjects with symptomatic LDH. Epidural etanercept may offer patients with sciatica a safe and effective nonoperative treatment.

Background and Objectives: The objective of this study was to assess the pharmacokinetics, sensory/motor effects, and safety of epidurally administered liposome bupivacaine versus bupivacaine HCl in healthy volunteers., Methods: Thirty subjects were randomized to receive liposome bupivacaine 89, 155, or 266 mg, or bupivacaine HCl 50 mg in a double-blind fashion. Occurrence/duration of motor blockade, pinprick/cold sensitivity, and plasma bupivacaine levels were assessed for 96 hours after study drug administration. Tolerability parameters were also assessed., Results: All doses of liposome bupivacaine resulted in greater area under the curve and a longer time to observed maximum plasma concentration and terminal elimination half-life than bupivacaine HCl 50 mg. Mean maximum plasma concentration with liposome bupivacaine 89 and 155 mg (but not 266 mg) was statistically significantly lower than with bupivacaine HCl 50 mg (P < 0.001). Median duration of motor blockade with liposome bupivacaine 266 mg was 1 hour versus 2.8 hours for bupivacaine HCl. Of subjects who received liposome bupivacaine 266 mg, 29% (2/7) were unable to ambulate at 4 hours postdose versus 67% (4/6) of those receiving bupivacaine HCl. Median durations of pinprick/cold sensitivity loss were 36 and 69 hours, respectively, in the liposome bupivacaine 266-mg group versus 12 hours for both pinprick and cold in the bupivacaine HCl group. Liposome bupivacaine was well tolerated; the most common adverse event in all treatment groups was injection site pain, which resolved within 30 days for most subjects., Conclusions: Epidurally administered liposome bupivacaine 266 mg resulted in a longer duration of sensory blockade than liposome bupivacaine 89 or 155 mg or bupivacaine HCl 50 mg. Duration of motor blockade was shorter with liposome bupivacaine 266 mg versus bupivacaine HCl.

Background and Objective: Pain relief using intermittent subcutaneous injections of an opioid (e.g. morphine) avoids the need for venous access and does not require complex or expensive pumps and devices. Although data on the pharmacokinetics of subcutaneous morphine exist, there are no comparable data for fentanyl in healthy volunteers. Therefore, the aim of this study was to characterize the pharmacokinetics of 200 microg fentanyl administered as a single bolus dose via the subcutaneous route in healthy opioid-naive volunteers., Methods: Nine healthy male volunteers were given 200 microg of subcutaneous fentanyl for more than 30 s. Opioid effects were blocked by administration of naltrexone. Venous blood samples taken at intervals from 5 min to 10 h after the dose were assayed using a liquid chromatography-mass spectrometry method. Pharmacokinetic data were analysed using a noncompartmental analysis approach., Results: After subcutaneous bolus dose administration, the median maximum concentration of fentanyl was 0.55 ng ml(-1) (range 0.28-0.87 ng ml(-1)), reached at a median time of 15 min (range 10-30 min). The terminal half-life was 10.00 h (range 5.48-16.37 h)., Conclusion: Absorption of subcutaneous fentanyl was relatively rapid and similar to the rate of absorption previously reported for subcutaneous morphine; the terminal half-life for fentanyl was substantially longer (10 h) than that of morphine (2.1 h), and blood concentrations were no more variable than that after administration by other nonintravenous routes.

1. Indomethacin has been used to manage raised intracranial pressure (ICP) in humans during neuroanaesthesia and neurosurgery. Indomethacin causes cerebral vasoconstriction and reduces cerebral blood flow (CBF) and, therefore, ICP. 2. The systemic kinetics, cerebral kinetics and cerebral dynamics of indomethacin (0.2 mg/kg) were measured and modelled using a population approach. Data were collected using an instrumented sheep preparation with raised ICP and under either isoflurane or propofol anaesthesia to parallel the clinical use of indomethacin in neurosurgery. 3. The systemic kinetics of indomethacin could be described by a two-compartment model, with small distribution volumes and a clearance of 0.68 L/min. The cerebral kinetics of indomethacin could be described using a model with a cerebral distribution volume between 5 and 8 mL and a loss term of 3.3 mL/min, the latter probably representing slow diffusion across the blood-brain barrier. 4. The changes in CBF lagged behind the blood concentrations of indomethacin. Indirect response models with turnover times of 1.70-4.08 min were generally better able to describe the effect of indomethacin on CBF than effect compartment models. 5. There was a non-linear concentration-effect relationship, with the maximum possible reduction in CBF being to 73-74% of baseline. 6. The data and model support the concept of indomethacin having limited uptake into the brain, with its effect on CBF being the result of its action on the endothelium, where it indirectly modifies the turnover of a compound regulating vascular tone.

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.

Background: The potential benefit of propofol dose regimens that use physiologic pharmacokinetic modeling to target the brain has been demonstrated in animals, but no data are available on the rate of propofol distribution to the brain in humans. This study measured the brain uptake of propofol in humans and the simultaneous effects on electroencephalography, cerebral blood flow velocity (V(mca)), and cerebral oxygen extraction., Methods: Seven subjects had arterial and jugular bulb catheters placed before induction. Electroencephalography and V(mca) were recorded during induction with propofol while blood samples were taken from both catheters for later propofol analysis. Brain uptake of propofol was calculated using mass balance principles, with effect compartment modeling used to quantitate the rate of uptake., Results: Bispectral index (electroencephalogram) values decreased to a minimum value of approximately 4 at around 7 min from the onset of propofol administration and then slowly recovered. This was accompanied by decreases in V(mca), reaching a minimum value of approximately 40% of baseline. Cerebral oxygen extraction did not change, suggesting parallel changes in cerebral metabolism. There was slow equilibrium of propofol between the blood and the brain (t(1/2keo) of 6.5 min), with a close relation between brain concentrations and bispectral index, although with considerable interpatient variability. The majority of the decreases in V(mca), and presumably cerebral metabolism, corresponded with bispectral index values reaching 40-50 and the onset of burst suppression., Conclusion: Description of brain distribution of propofol will allow development of physiologic pharmacokinetic models for propofol and evaluation of dose regimens that target the brain.

Purpose of Review: The timing and magnitude of drug onset can be influenced by factors in the chain of drug delivery from the site of administration to the site of effect. This review examines recent evidence regarding the contribution and significance of these factors., Recent Findings: It is apparent that drug formulations and mixtures can play a significant role in drug onset. An extension of this is the effect of coadministration of drugs, which can influence drug effect both by altering the physiology underlying drug delivery and by an effect at the target organ. Of the physiological variables, cardiac output and its distribution are clearly important. Cardiac output is a significant source of variability in drug response, and indeed has been successfully incorporated into pharmacokinetic models. The pattern of cardiac output distribution is also relevant. In particular, the blood flow to target organs will influence both the timing and magnitude of the effect of some anaesthetic drugs. In addition, the role of the lung in affecting drug distribution may be important for some drugs. At the site or organ of effect itself, variability in drug distribution, drug-receptor interactions, and the influence of other drugs, can all impact on the profile of drug onset., Summary: Factors in the chain of drug delivery have been demonstrated to affect the nature of drug onset, and can account for some of the observed variability in response. The significance to dosing guidelines and strategies, and to predictions of variability in response, remains to be explored.