Emulsion Formulation Reduces Propofol's Dose Requirements and Enhances Safety

Background Propofol, a highly lipophilic anesthetic, is formulated in a lipid emulsion for intravenous use. Propofol has brisk onset and offset of effect after rapid administration and retains rapid offset characteristics after long-term administration. The authors tried to determine whether the emulsion vehicle is requisite for propofol's evanescent effect-time profile. Methods The time course of sedation and electroencephalographic (EEG) effect after propofol administration was measured in three studies in rats instrumented. In study 1, propofol was infused in either emulsion or lipid-free vehicle (n = 12), in a repeated measures cross-over design. In study 2, propofol in lipid-free vehicle was infused with or without simultaneous infusion of drug-free lipid emulsion (n = 6) in a repeated measures cross-over design. In study 3, propofol was infused in either emulsion (n = 5) or lipid-free vehicle (n = 5) to EEG burst suppression. Results In study 1, relative to the emulsion formulation, propofol administered at equivalent doses in lipid-free vehicle resulted in a longer time to effect onset (1.4 +/- 0.2 vs. 0.5 +/- 0.1 min, EEG) and a trend for delayed anesthetic recovery (26.8 +/- 9.4 vs. 17 +/- 3.5 min, EEG; 26.1 +/- 8.8 vs. 16.8 +/- 3.3 min, sleep). In study 2, coadministration of drug-free emulsion with propofol did not alter the time course of effect. In study 3, more than twice the dose of propofol was required to achieve EEG burst suppression with the lipid-free formulation. Two animals died after administration of propofol to EEG burst suppression with the lipid-free formulation; no deaths occurred in the emulsion group. Conclusion The incorporation of propofol in emulsion reduces dose requirements and produces rapid onset and recovery of anesthetic effect.

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Performance Evaluation Tests for Environmental Research (Peter): Evaluation of 114 Measures

Perceptual and Motor Skills ◽

10.2466/pms.1986.63.2.683 ◽

1986 ◽

Vol 63 (2) ◽

pp. 683-708 ◽

Cited By ~ 60

Author(s):

Alvah C. Bittner ◽

Robert C. Carter ◽

Robert S. Kennedy ◽

Mary M. Harbeson ◽

Michele Krause

Keyword(s):

Performance Evaluation ◽

Repeated Measures ◽

Time Course ◽

Environmental Studies ◽

Acceptable Level ◽

Environmental Research ◽

Human Capabilities ◽

Task Definition ◽

And Task

The goal of the Performance Evaluation Tests for Environmental Research (PETER) Program was to identify a set of measures of human capabilities for use in the study of environmental and other time-course effects. 114 measures studied in the PETER Program were evaluated and categorized into four groups based upon task stability and task definition. The Recommended category contained 30 measures that clearly obtained total stabilization and had an acceptable level of reliability efficiency. The Acceptable-But-Redundant category contained 15 measures. The 37 measures in the Marginal category, which included an inordinate number of slope and other derived measures, usually had desirable features which were outweighed by faults. The 32 measures in the Unacceptable category had either differential instability or weak reliability efficiency. It is our opinion that the 30 measures in the Recommended category should be given first consideration for environmental research applications. Further, it is recommended that information pertaining to preexperimental practice requirements and stabilized reliabilities should be utilized in repeated-measures environmental studies.

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Limb weakness

Oxford Cases in Medicine and Surgery ◽

10.1093/oso/9780198716228.003.0032 ◽

2015 ◽

Author(s):

Hugo Farne ◽

Edward Norris-Cervetto ◽

James Warbrick-Smith

Keyword(s):

Motor Neurons ◽

Time Course ◽

Internal Capsule ◽

Time Frame ◽

Rapid Onset ◽

Sudden Onset ◽

Limb Weakness ◽

Ischaemic Attack ◽

Definition Of ◽

Slow Growing

The definition of weakness is important, because many patients who self-describe a ‘weak limb’ will actually have a clumsy limb (ataxia), a numb limb (reduced sensation), or a limb that is too painful to move. The time course of the onset of the symptoms in general reflects the time course of the underlying pathology: • Sudden onset (seconds to minutes) usually implies either trauma (e.g. displaced vertebral fractures due to major trauma) or certain vascular insults (e.g. stroke, transient ischaemic attack (TIA)). • Subacute onset (hours to days) suggests a progressive demyelination (e.g. Guillain–Barre syndrome, multiple sclerosis) or a slowly expanding haematoma (e.g. subdural haematoma). • Chronic onset (weeks to months), is consistent with pathologies such as a slow-growing tumour or motor neuron disease (progressive degeneration of motor neurons). As only acute and subacute limb weakness will present acutely to generalists in hospital (chronic onset cases will most likely be referred to neurology from primary care), we have limited the chapter to these cases. Limb movement requires an intact pathway from the cerebral cortex, down the corona radiata, internal capsule, and pons, along the corticospinal tract of the spinal cord, out along a nerve root, and down a peripheral nerve to the neuromuscular junction and muscle itself. If a patient has limb weakness, there must be a lesion somewhere in this pathway. Figure 26.2 gives the differential diagnosis for limb weakness. Mr Walker has presented with rapid onset of left-sided arm weakness. Key clues in the history to elicit include: • Exact time of onset? This is critical in suspected strokes because the window of time in which to confirm the diagnosis and administer thrombolysis (if appropriate) is only 4.5 hours from onset of symptoms (after that, you risk doing more harm than good to the patient). If you suspect a stroke in a patient within that time frame, call the thrombolysis team immediately. In this case, all we can say is that the onset was at some point in the 7 hours between 11 p.m. (when he went to sleep) and 6 a.m. (when he woke up), so we cannot confidently say the onset was within 4.5 hours.

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TREATMENT OF AIDS-RELATED SYSTEMIC MYCOSES WITH A LIPID EMULSION FORMULATION OF AMPHOTERICIN B

AIDS ◽

10.1097/00002030-199411004-00086 ◽

1994 ◽

Vol 8 (Supplement 4) ◽

pp. S23

Author(s):

H A Leake ◽

R Nandwani ◽

M N Appleyard ◽

JPR Hartley

Keyword(s):

Amphotericin B ◽

Lipid Emulsion ◽

Emulsion Formulation

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Prediction of Human Pharmacokinetics of Bendamustine from Preclinical Species Pharmacokinetics Based on Normalizing Time Course Profiles

Drug Research ◽

10.1055/a-0640-8977 ◽

2018 ◽

Vol 69 (01) ◽

pp. 32-39 ◽

Cited By ~ 1

Author(s):

Nuggehally Srinivas ◽

Ravi Jairam ◽

Sadanand Mallurwar ◽

Suresh Sulochana ◽

Devaraj Chandrasekar ◽

...

Keyword(s):

Intravenous Infusion ◽

Time Course ◽

Animal Species ◽

Anticancer Agent ◽

Time Profile ◽

Lymphocytic Leukemia ◽

Human Pharmacokinetics ◽

Correction Factors ◽

Preclinical Pharmacokinetics ◽

Preclinical Species

AbstractBendamustine, an alkylating anticancer agent, is used to treat chronic lymphocytic leukemia by intravenous infusion alone or in combination. The work aimed to develop a method to predict time vs. concentration profile for humans based on preclinical pharmacokinetics using the assumption of superimposability of normalized time course profiles of animals and humans. Standard allometric equations with/without correction factors (CF) were also used in prediction. The Vss was predicted by simple allometry of 0.312W0.871 (r2=0.987), where W is body weight; predicted Vss (19.71 L) was similar to the reported value (20.10 L). However, CL prediction involved both simple and CF allometry. Best proximity CL (543 vs. 598 mL/min) was obtained with maximum life span correction (MLP) [2.46W1.215 (r2=0.988)]. Normalized curves were obtained by normalizing the time (with mean residence time) vs. concentration (with dose/Vss) in animal species. The concentration vs. time profile in humans after intravenous infusion was then simulated using normalized curve for each animal species and the values of CL and Vss were predicted for humans. In summary the findings indicate that normalized time course approach could predict the bendamustine human pharmacokinetics and such an approach could be prospectively applied for analog drugs of this class.

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The Effects of Intravenous Lipid Emulsion Therapy in the Prevention of Depressive Effects of Propofol on Cardiovascular and Respiratory Systems: An Experimental Animal Study

Medicina ◽

10.3390/medicina55010001 ◽

2018 ◽

Vol 55 (1) ◽

pp. 1 ◽

Cited By ~ 1

Author(s):

Fatih Doğanay ◽

Rohat Ak ◽

Halil Alışkan ◽

Serdar Abut ◽

Engin Sümer ◽

...

Keyword(s):

Blood Pressure ◽

Repeated Measures ◽

Lipid Emulsion ◽

Survival Duration ◽

Control Group ◽

Linear Mixed Effect Model ◽

Sprague Dawley ◽

Adult Rats ◽

Mixed Effect ◽

Intravenous Lipid Emulsion

Background and objectives: Although there are several hypotheses about the mechanism of action, intravenous lipid emulsion (ILE) therapy has been shown to be effective in the treatment of toxicities due to local anaesthetics and many lipophilic drugs. In this study, we had hypothesized that ILE therapy might also be effective in preventing mortality and cardiorespiratory depressant effects due to propofol intoxication. Materials and methods: Twenty-eight Sprague-Dawley adult rats were randomly divided into four groups. Saline was administered to the subjects in the control group. The second group was administered propofol (PP group); the third group was administered ILE (ILE group), and the fourth group was administered propofol and ILE therapy together (ILE+PP group). Systolic blood pressure (SBP), diastolic blood pressure (DBP), respiratory rate (RR), heart rate (HR), and mortality were recorded at 10 time-points during a period of 60 min. A repeated measures linear mixed-effect model with unstructured covariance was used to compare the groups. Results: In the PP group; SBP, DBP, RR, and HR levels declined steadily; and all rats in this group died after the 60-min period. In the ILE+PP group, the initially reduced SBP, DBP, RR, and HR scores increased close to the levels observed in the control group. The SBP, DBP, RR, and HR values in the PP group were significantly lower compared to the other groups (p < 0.01). The mortality rate was 100% (with survival duration of 60 min) for the PP group; however, it was 0% for the remaining three groups. Conclusions: Our results suggest that the untoward effects of propofol including hypotension, bradycardia, and respiratory depression might be prevented with ILE therapy.

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Does Prior Surgery Affect Total Ankle Complication and Failure Rates?

Foot & Ankle Orthopaedics ◽

10.1177/2473011420s00345 ◽

2020 ◽

Vol 5 (4) ◽

pp. 2473011420S0034

Author(s):

Luigi Manzi ◽

Federico Giuseppe Usuelli ◽

Alexander Caughman ◽

Christopher E. Gross

Keyword(s):

Functional Outcome ◽

Repeated Measures ◽

Functional Outcomes ◽

Time Course ◽

Temporal Evolution ◽

Consecutive Series ◽

Exact Test ◽

Time Points ◽

Significant Difference ◽

Pain Outcomes

Category: Ankle Arthritis; Ankle Introduction/Purpose: Given that most ankle replacements are post-traumatic in origin, it is important to investigate if prior interventions can affect a patient’s functional outcome or the possibility of having a complication. Prior surgeries create scar, incisions, and possible affect bone health that could interfere with healing. The purpose of the study is to assess the pain and functional temporal outcomes of patients with and without prior surgeries in the ipsilateral ankle. We hypothesize that those with a previous ipsilateral ankle procedure will not have an increased complication rate or worse functional outcomes. Methods: We retrospectively identified a consecutive series of 100 primary TARs with a prior procedure who were followed for a minimum of 3 years. The follow-up time points considered were 0, 6, 12, and 36 months. Outcomes were measured using AOFAS, VAS, SF12, and range of motion scores. The mean patient age was 56.5 +- 13.4 years. Sixty-four patients had previous interventions which included osteosynthesis (49), arthroscopy (11), hardware removal (25), arthrodesis (3), prosthesis (1), open fracture (9), and other open surgery (12). Within-group comparisons were performed using one-way repeated-measures ANOVA (1-w rANOVA), analyzing temporal course of clinical data (comparisons between different time points) between the groups. To compare the time course of clinical measures between the two groups, 2-w rANOVAs were performed. Data and statistical analysis were conducted using Matlab (MathWorks, Natick, MA). Results: For each type of intervention, every outcome was compared to test whether presurgery interventions have an influence on the temporal evolution of the outcomes. The two groups did not show any difference on the temporal evolution of the outcomes. The type of intervention did have a weak effect on outcomes. Treatment of previous open fractures was the only pre- surgical intervention that showed a statistically significant difference in temporal evolution of functional and pain outcomes between intervention and non-intervention groups. No significant correlations were found between all outcomes and the time between the last intervention and prosthesis. Using Fisher’s-exact test, there was not a significant association between the those who had previous surgery and those who did not and the rate of complication and revision (p =0.10). Conclusion: A pre-operative discussion should center on potential complications and predicted functional outcomes. The presence, type, and timing of an intervention prior to an ankle replacement does not strongly affect the temporal outcomes of pain and functional outcome scores. Furthermore, the complication or revision rate is not affected by prior surgeries.

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Time Course and Magnitude of Tolerance to the Ergogenic Effect of Caffeine on the Second Ventilatory Threshold

Life ◽

10.3390/life10120343 ◽

2020 ◽

Vol 10 (12) ◽

pp. 343

Author(s):

Carlos Ruiz-Moreno ◽

Beatriz Lara ◽

Jorge Gutiérrez-Hellín ◽

Jaime González-García ◽

Juan Del Coso

Keyword(s):

Heart Rate ◽

Aerobic Exercise ◽

Body Mass ◽

Repeated Measures ◽

Time Course ◽

Ventilatory Threshold ◽

Statistical Significance ◽

Ergogenic Effect ◽

Double Blind ◽

Main Effects

Pre-exercise caffeine ingestion has been shown to increase the workload at ventilatory threshold, suggesting an ergogenic effect of this stimulant on submaximal aerobic exercise. However, the time course of tolerance to the effect of caffeine on ventilatory threshold is unknown. This study aimed to determine the evolution of tolerance to the ergogenic effect of caffeine on the ventilatory threshold. Methods: Eleven participants (age 32.3 ± 4.9 yrs, height 171 ± 8 cm, body mass 66.6 ± 13.6 kg, VO2max = 48.0 ± 3.8 mL/kg/min) took part in a longitudinal, double-blind, placebo-controlled, randomized, crossover experimental design. Each participant took part in two identical treatments: in one treatment, participants ingested a capsule containing 3 mg of caffeine per kg of body mass per day (mg/kg/day) for twenty consecutive days; in the other treatment, participants ingested a capsule filled with a placebo for the same duration and frequency. During these treatments, participants performed a maximal ramp test on a cycle ergometer three times per week and the second ventilatory threshold (VT2) was assessed by using the ventilatory equivalents for oxygen and carbon dioxide. Results: A two-way ANOVA with repeated measures (substance × time) revealed statistically significant main effects of caffeine (p < 0.01) and time (p = 0.04) on the wattage obtained at VT2, although there was no interaction (p = 0.09). In comparison to the placebo, caffeine increased the workload at VT2 on days 1, 4, 6 and 15 of ingestion (p < 0.05). The size of the ergogenic effect of caffeine over the placebo on the workload at VT2 was progressively reduced with the duration of the treatment. In addition, there were main effects of caffeine (p = 0.03) and time (p = 0.16) on VO2 obtained at VT2, with no interaction (p = 0.49). Specifically, caffeine increased oxygen uptake at VT2 on days 1 and 4 (p < 0.05), with no other caffeine–placebo differences afterwards. For heart rate obtained at VT2, there was a main effect of substance (p < 0.01), while the overall effect of time (p = 0.13) and the interaction (p = 0.22) did not reach statistical significance. Heart rate at VT2 was higher with caffeine than with the placebo on days 1 and 4 (p < 0.05). The size of the effect of caffeine on VO2 and heart at VT2 tended to decline over time. Conclusion: Pre-exercise intake of 3 mg/kg/day of caffeine for twenty days enhanced the wattage obtained at VT2 during cycling ramp tests for ~15 days of ingestion, while there was a progressive attenuation of the size of the ergogenic effect of caffeine on this performance variable. Therefore, habituation to caffeine through daily ingestion may reduce the ergogenic effect of this stimulant on aerobic exercise of submaximal intensity.

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Time Course of Autonomic Symptoms in Postural Orthostatic Tachycardia Syndrome (POTS) Patients: Two-Year Follow-Up Results

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17165872 ◽

2020 ◽

Vol 17 (16) ◽

pp. 5872

Author(s):

Franca Dipaola ◽

Caterina Barberi ◽

Elena Castelnuovo ◽

Maura Minonzio ◽

Roberto Fornerone ◽

...

Keyword(s):

Quality Of Life ◽

Repeated Measures ◽

Time Course ◽

Orthostatic Intolerance ◽

Occupational Status ◽

Postural Orthostatic Tachycardia Syndrome ◽

Autonomic Symptoms ◽

Post Hoc

Postural orthostatic tachycardia syndrome (POTS) is a multifactorial condition capable of chronically reducing the quality of life and the work ability of patients. The study aim was to assess the burden of autonomic symptoms in a cohort of POTS patients over 2 years. Patients’ clinical profiles were assessed by the 31-item Composite Autonomic Symptom Score questionnaire (COMPASS 31) and a visual analog scale (VAS). One-way ANOVA for repeated measures followed by Dunnett’s post-hoc test were used to compare symptoms at baseline and at 1 and 2 years. Out of 42 enrolled patients, 25 had a 1-year follow-up and 12 had a 2-year follow-up. At baseline, the reported burden of autonomic symptoms was high (overall COMPASS 31 = 49.9 ± 14.3 /100). Main complaints were related to orthostatic intolerance according to both COMPASS 31 and VAS. Fourteen patients were rendered inactive because of symptoms. At 1-year follow-up, a statistically significant improvement in pupillomotor function and overall score was detected by the COMPASS 31. These findings were confirmed at 2 years, together with a significant reduction in quality of life impairment, assessed by VAS. However, these improvements did not change patients’ occupational status. Awareness of POTS diagnosis, patient monitoring, and tailored therapies can help to improve patients’ condition.

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P001: Proof-of-principle in a large animal pilot: cardiac arrest may be associated with acute, transient coagulopathy that may drive post-cardiac arrest syndrome

CJEM ◽

10.1017/cem.2020.209 ◽

2020 ◽

Vol 22 (S1) ◽

pp. S64-S65

Author(s):

C. Yeh ◽

B. Camilotti ◽

H. Hanif ◽

R. Mohindra ◽

C. Sun ◽

...

Keyword(s):

Cardiac Arrest ◽

Repeated Measures ◽

Time Course ◽

Alpha Angle ◽

Clot Formation ◽

Lead Target ◽

Large Animal ◽

Early Medical Intervention ◽

Post Cardiac Arrest Syndrome ◽

Coagulation And Fibrinolysis

Introduction: Many cardiac arrest survivors die later due to hemorrhage or thromboembolism, thought to be caused by acquired coagulopathy in post-cardiac arrest syndrome (PCAS) from shock and reperfusion injury. Understanding PCAS is a priority identified by the AHA for the prevention of complications in cardiac arrest survivors. Shock dysregulates both coagulation and fibrinolysis. The key effector enzyme thrombin (Th), is responsible for both up- and down-regulating coagulation and fibrinolysis. Measuring early Th activity may allow for predicting PCAS coagulopathy, and early medical intervention in the ED. Therefore, we aimed to characterize the time-course profile of early coagulation using an established pig model of cardiac arrest. Methods: Yorkshire pigs were anaesthetised and intubated, had VF-arrest induced by pacing, and were resuscitated per ACLS. Rotational thromboelastometry (ROTEM) was performed on whole blood at four times: baseline, intra-arrest, post-arrest, and death, using the fibrin-based test with tissue factor to initiate clotting in the presence of a platelet inhibitor cytochalasin D (FIBTEM). Clot time (CT), clot formation time (CFT), alpha-angle during clot formation (Alpha), clot amplitude at 10 min (A10), maximum clot firmness (MCF), and maximum lysis as total percentage (ML%) were quantified. The primary outcome is the overall coagulation initiation measured by CFT, while secondary outcomes include ROTEM parameters reflecting Th activity. Parameters are compared over time in SPSS using repeated measures ANOVA and Bonferroni correction. Results: Pilot data from one experiment show that cardiac arrest causes immediate early changes to coagulation that subsequently normalized with ROSC (Figure 1). CFT was impaired immediately upon cardiac arrest (2.3-fold increase), normalized with ROSC, and impaired again at death when compared with baseline. Consistent with clotting impairment, A10, Alpha, and MCF were all reduced with cardiac arrest, normalized with ROSC, and impaired again at death. Conclusion: Higher initial indices of coagulopathy in patients with cardiac arrest appear to correlate with death and thromboembolism. In this pilot, CFT is acutely modified by cardiac arrest. Since CFT is affected by overall Th activity, early Th dysregulation may be a critical driver of coagulopathy. Th may therefore be a lead target that is modifiable in the emergency post-arrest setting to decrease morbidity and mortality from PCAS in cardiac arrest survivors.

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