Dr White
Flanagan
Pharmaco dynamic model : variability
Effect site : concentration in the brain, not measurable in living humans; surrogate measures, using EEG.
Bispectral index study graph :
Y axis = vertical : EEG bispectral index 0 = dead , 100 = fully awake.
X axis = horizontal : level of sedation . 5 = fully awake, 1 not arousable.
Line shows a mean, or mathematical average, or model, dots show patients , dots show that patients reaction varies a lot. For a given level of sedation, the EEG bispectral index (effect on the brain) will vary
Shows a paper about a study of propofol and bispetral index, Was Principal Investigator . Shows a diagram , scale for EEG bispectral, is 40 = anethesized to 100 = awake, level of sedation 5 = fully awake to 1 , there is no line , just dots representing individual patients, shows the reaction vary a lot from a patient to another
shows study about relationship between bispectral index and effect site concentration value
shows a study : physilogical endpoints (= physiological changes such as apnea, eyelash reflects, verbal response) compared to EEG bispctral value. Variability 40 to 95 (shows great variability)
Endpoints compared to effect site concentration : 4 to 1 variability
back to dr Shafer's graph about the 2X2 mg lorazepam at 2 and 5am : is an accurate depication of an average patient. MJ had been taking oral lorazepam, you would expect residual levels of lorazepam from prior days. Objection by Walgren about the word «*oral*» , overruled, it's a matter of cross.
CM said he treated MJ with midazolam and lorazeapm : you would expect to find residual levels, but Dr White doesn't know how much given
Another graph from dr Shafer 2X2 mg midazolam 3 am and 7 30 am : same comments as previous graph. Midazolam has a shorter half life , quicker onset, popular for preoperative medication. This graph shows the blood at autopsy for lorazepam, not midazolam. Responsive to pain stimulus line is much higher, but midazolam is not an analgesic.
Actual blood concentration for midazolam in Autopsy Report was close to Shafer's model for midazolam.
Another graph , combining 2 X2mg midazolam and lorazepam , based on CMs interview, showing the concentration CM thought were in MJ's blood. The irrelevent resonsive to pain line is on the graph, much higher than the concentrations levels.
Dr Shafer didn't described the 25mg propofol over 3 to 5 mn in his report , it's the only thing from CMs inerview that Dr Shafer didn't include in his report, but did the simulation for the defense.
Showing the 25mg propofol over 3 to 5 mn simulation
Now showing another graph combining the 25mg propofol and 2 X2 mg lorazepam and midazolam ( still well below the response to pain line). It's a simulation done by dr Shafer , objection by Walgren , Shafer didn't do this one. He did both seperately, dr White combined them, . This doesn't depict a dangerous situation at all.
25 mg propofol over to 3 to 5 mn, would produce anxiety relief, a little sleepiness.
Study : efficacy of propofol compared to midazolam as an intrevenous premedication agent : the dose of propofol used in the study is the equivalent of 24 mg propofol used on MJ, that's minimal sedation.
Continum of depth sedation from minimal sedation (anxiolysis), moderate seation, deep sedation, general anesthesia . Shows relation of level of sedation and physiological effects (responsiveness, airway, obstruction, spontaneous ventiliation, cardio vascular fonction )
Minimal sedation as was provied by CM : would only produce only a little sleepiness, not produce the physiological effects described above.
Gack to graph with the 25mg propofol , midazolam, lorazepam : represents minimal sedation (except for the lorazepam concentration found at autopsy) .
Procedural sedation = conscious sedation = mac sedation = moderate sedation , origin of the terms are different, but they mean the same thing
Moderate sedation : verbal response, airway is unaffected , ventilation ok, cardiovascular function is ok.
Anesthesiolgists are trained in moderate sedation , for other doctors : most hospitals require that doctors who use conscious sedations are trained, in case they inadvertently sedate the patient into a deep sedation, and need to rescue the patient.
CM has a certification from Sunrise Hospital in Las Vegas for moderate sedation.
Shows CM certification for concious sedation : allows him to : evaluate the patient, adminster sedation, manage a compromised airway, provide adequate ventilation in case of apnea, rescue a patient from deeper sedation, monitor the petient to evaluate sedation
Showing Dr Shafer's graph with 40 mg lorazepam starting at midnigt, compared to 2 X 2 mg : simulation was modified cause MJ was still at Staples center at midnight. Shafer corrected it recently. The average patient would be dead, at the very least comatose for several hours, receiving 40mg over 5 hours. Shafer did that simulation because of the 10ml vial found at the house
Showing the modification , 9 doses of 4 mg each, starting at 1 30. Doesn't fit with the vial found. Made to fit with concentration. Last doses would have been given when he would still have been asleep.
Showing the graph with the 40mg lorazepam at midnight , 2X2 midazolam nd lorazepam.
Midazolam given by CM = what was found at autopsy.
Midazolam would have been given when MJ was highly sedated with lorazepam, it doesn't make sense.
Showing a computer model : lorzaepam concentration with a 2 mg lorzaepam bolus at 2 am, another dose at 5 am bolus, followed by an oral larger dose of 20mg (10 pills taken at the same time ) at 7 00. Assumes there was no residual lorazepam, but thinks there was
Showing another graph , same but with a residual level. Residual level for 10mg for 5 days; Same result with 16 mg oral lorazepam (8 pills) at 7 . could do aother simualtion with 3 or 4 pills at 4, other pills at 6
The quantity of lorazepam in stomach content was very low : dissulotion of the pill is 15 mn, then absorbstion halftime is 22 mn (some studies say 40 mn) : especially if MJ was drinking, it's normal that there was very little lorazepam found in the stomach.
This simulation is more reasonable , 40mg simulation is irrational.
The simulation with residual level is more realistic. MJ maybe didnt take the 8 pills all at once, maybe he took a few at one time, then later took more pills. We don't know at what time, how many pills were taken; could be some taken at 6 , some at 8.
it's speculation, but more reasoneble than 4 mg boluses every 30mns
the small amount of lorzaepem in the stomach is explained by absortion halflife
Lorazepam : 93% bioavailability.
Article by greenblack : is the equivalent of 1/300th of a pill in the stomach is consitent with your simulation ? Answer : You would not expect to find free lorazepam in the stomach if it was given IV
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