i wonder about the reason why murray became distracted when he was calling anding:
i first assumed mj must have woken up and murray became distracted when he realized this, that he rushed to his side to give him a propofol bolus and administered the bolus too fast.
but another idea hit me: is it possible mj had stopped breathing (or had subdued breathing) because of lorazepam?
maybe murray realized mj was not breathing (or his breathing was subdued) when he was calling anding and he rushed to mj's side to inject flumazenil to counter the lorazepam effect. only when the antidote began to show effect and mj was waking up ("mumbling and coughing") did he give the propofol bolus. but he was nervous and rushed the bolus
if this was true it would be even more damning, but probably hard to prove
question:
- how likely is it that mj (who had a damaged lung, s. autopsy report for findings) would have stopped breathing or had subdued breathing with the lorazepam blood values found at time of death?
- at the same time, how likely is it mj would have woken up with these lorazepam blood values? (maybe he had developed tolerance?)
could people with medical knowledge give some input, thanks
lorazepam blood levels found in body were over 0.160ug/ml, from tox report:
[positive toxicological findings, pg. 50 in pdf]
Lorazepam heart blood: 0.162 ug/ml
Lorazepam femoral blood: 0.169 ug/ml
about flumazenil, the tox expert said at prelim they don't have an extraction method for it, that's why it was only detected at tubing.
from sprocket’s notes, witness lintemoot (tox expert):
http://sprocket-trials.blogspot.com/2011/01/dr-conrad-murray-prelim-day-5-part-ii.html
[Prelim: Day 5 Part II - Mon, Jan 10 2011 - #19 JAIME LINTEMOOT - Cross by Flanagan]
...
The D tube had drugs in it? Yes.
The D tube had lydocaine propofol and flazaxidal?
You can’t analyze for flazadnil in a blood sample? We don’t have an extraction method. (futher explanation).
So you can’t test for flazadnil in the body? We don’t have a method for it.
i wonder what the problem was, we don't have lintemoot's explanation. - it's strange, because i found a reference on antidotes which says it
is possible to detect flumazenil, read here:
http://www.inchem.org/documents/antidote/antidote/ant01.htm#SubSectionNumber:3.5.1
3. FLUMAZENIL
[…]
3.5.2 Quantification of the antidote in biological samples
The determination of flumazenil in plasma by gas-liquid chromatography (GLC) with nitrogen phosphorus detection is a sensitive and specific method, the detection limit being 3 ng/ml (Abernethy et al., 1983). An ethyl acetate extraction (neutral pH) of 0.1-3 ml plasma is used for sample preparation. When methylclonazepam is used as an internal standard, the graph is linear for plasma concentrations up to 200 ng/ml. The retention time for flumazenil is 3.96 min.
High-performance liquid chromatography (HPLC) with UV detection at 254 nm is a sensitive method for determination in urine or plasma, the detection limit being about 10 ng/ml (Timm & Zell, 1983; Bun et al., 1989). When the n-propyl ester analogue is used as an internal standard, the graph is linear for plasma concentrations up to 320 ng/ml.
murray said in his police interview he had administered flumazenil when he "found" mj not breathing, from search warrant:
[Pg 19 of 32]
Upon his return, Murray noticed that Jackson was no longer breathing. Murray began single man CPR at once, Murray also administered .2mg of Flumanezil to Jackson and called Jackson's personal assistant, Michael Amir Williams, with his cellular telephone for help.
__
here's some info from online sources about lorazepam blood values, dosage, precautions:
according to drugs.com the daily lorazepam dose should usually be 2-6mg, a dose of 4mg would correspond to initial blood level of 0.070ug/ml:
http://www.drugs.com/pro/lorazepam.html
The usual range is 2 to 6 mg/day given in divided doses, the largest dose being taken before bedtime, but the daily dosage may vary from 1 to 10 mg/day.
For insomnia due to anxiety or transient situational stress, a single daily dose of 2 to 4 mg may be given, usually at bedtime.
http://www.drugs.com/pro/lorazepam-injection.html
Intravenous: A 4-mg dose provides an initial concentration of approximately 70 ng/mL.
if a dose of 4mg produces blood levels of 0.070 ug/ml (= 70 ng/ml), blood levels of over 0.160 ug/ml could indicate murray gave a much higher dose than 4mg; to me it looks like he gave doses of 2-4mg over a period of several hours and blood levels were accumulating.
if lorazepam is given intravenously at higher doses or for prolonged periods of time patients should be ventilated according to references:
http://www.drugs.com/pro/lorazepam-injection.html
Respiratory Depression
The most important risk associated with the use of Lorazepam Injection in status epilepticus is respiratory depression. Accordingly, airway patency must be assured and respiration monitored closely. Ventilatory support should be given as required.
Status Epilepticus - Intravenous Injection
For the treatment of status epilepticus, the usual recommended dose of Lorazepam Injection is 4 mg given slowly (2 mg/min) for patients 18 years and older. If seizures cease, no additional Lorazepam Injection is required. If seizures continue or recur after a 10- to 15-minute observation period, an additional 4 mg intravenous dose may be slowly administered. Experience with further doses of lorazepam is very limited. The usual precautions in treating status epilepticus should be employed. An intravenous infusion should be started, vital signs should be monitored, an unobstructed airway should be maintained, and artificial ventilation equipment should be available.
Preanesthetic - Intravenous Injection
For the primary purpose of sedation and relief of anxiety, the usual recommended initial dose of lorazepam for intravenous injection is 2 mg total, or 0.02 mg/lb (0.044 mg/kg), whichever is smaller. This dose will suffice for sedating most adult patients and ordinarily should not be exceeded in patients over 50 years of age. In those patients in whom a greater likelihood of lack of recall for perioperative events would be beneficial, larger doses as high as 0.05 mg/kg up to a total of 4 mg may be administered
http://home.intekom.com/pharm/akromed/ativan-i.html
DOSAGE AND DIRECTIONS FOR USE
Intravenous injection should be made slowly and with repeated aspiration.
Partial airway obstruction may occur in heavily sedated patients. Intravenous ATIVAN (lorazepam), when given alone in greater than the recommended dose, or at the recommended dose and accompanied by other drugs used during the administration of anaesthesia, may produce heavy sedation;
therefore, equipment necessary to maintain a patent airway and to support respiration/ventilation should be available.
below is from a manual about sedation guidelines in the ICU - the manual says, during longtime sedation in ventilated patients, to achieve the target level of sedation (ramsay score 3) a dose of 8mg lorazepam is advised within first 2 hours, followed by 1mg doses hourly:
http://www.mc.vanderbilt.edu/surgery/trauma/Protocols/SedationAnalgesiaGuidelines.pdf
[pg. 6]
DOSING LORAZEPAM
ICU patients - to achieve Ramsay 3
dose mg/hr (age<60): 2 (bolus) 3 2 1 1 1 ...
at hour: 0 (bolus) 0 1 2 4 6 ...
These lorazepam doses correspond to an anticipated ramsay sedation score of 3. ramsay sedation scores indicate how deeply asleep a patient is:
http://www.mc.vanderbilt.edu/surgery/trauma/Protocols/SedationAnalgesiaGuidelines.pdf
[pg. 1]
Ramsay Scale
1 Anxious and agitated
2 Cooperative, tranquil, oriented
3 Responds only to verbal commands
4 Asleep with brisk response to light stimulation
5 Asleep without response to light stimulation
6 Non responsive
s. also:
http://en.wikipedia.org/wiki/Ramsay_Sedation_Scale
the ideal (target) sedation score is 3, it means a patient is asleep but can be easily awakened.
If we assume murray had given a lorazepam dose of at least 8-10mg within the last hours before tod, the above guidelines would indicate mj should have been asleep (unless he had developed tolerance?)
- anyway, i don’t know how much this guideline can be applied to a not intubated patient who’s not in pain, intubation in itself can be hard to tolerate; could mean a not intubated patient needs lower doses to achieve same level of sedation.
i also found a study comparing lorazepam to midazolan in longtime sedation at ICUs (this also applies to intubated patients who are critically ill, so i’m not sure how these figures would relate to a patient who’s not intubated and not in pain).
one goal of the study was to estimate sedation scores for corresponding benzodiazepine blood levels, from the study:
http://www.ncbi.nlm.nih.gov/pubmed/11506097
A double-blind, randomized comparison of i.v. lorazepam versus midazolam for sedation of ICU patients via a pharmacologic model.
RESULTS: A two-compartment model best described the pharmacokinetics of both lorazepam and midazolam. The pharmacodynamic model predicted depth of sedation for both midazolam and lorazepam with 76% accuracy. The estimated sedative potency of lorazepam was twice that of midazolam. The predicted C50,ss (plasma benzodiazepine concentrations where P(Sedation > or = ss) = 50%) values for midazolam (sedation score [SS] > or = n, where n = a Ramsay Sedation Score of 2, 3, ... 6) were 68, 101, 208, 304, and 375 ng/ml. The corresponding predicted C50,ss values for lorazepam were 34, 51, 104, 152, and 188 ng/ml, respectively. Age, fentanyl administration, and the resolving effects of surgery and anesthesia were significant covariates of benzodiazepine sedation. The relative amnestic potency of lorazepam to midazolam was 4 (observed). The predicted emergence times from sedation after a 72-h benzodiazepine infusion for light (SS = 3) and deep (SS = 5) sedation in a typical patient were 3.6 and 14.9 h for midazolam infusions and 11.9 and 31.1 h for lorazepam infusions, respectively.
Full report available online as pdf:
http://www.consensus-conference.org/data/Upload/Consensus/1/pdf/824.pdf
the study says (in a 71 years old patient) a certain lorazepam level corresponds to a minimum sedation score with a likelyhood of 50%:
lorazepam level: 34 51 104 152 188 ng/ml
corresponding min. ramsay sedation score: 2 3 4 5 6
e.g. a lorazepam level of 50ng/ml corresponds to a ramsay sedation score of at least 3 with a likelyhood of 50%; while a level of 150ng/ml would indicate a sedation score of 5 or 6 (deep asleep) was reached with 50% likelihood (at age 71 yr).
in younger patients, levels need to be higher to achieve the same scores:
http://www.consensus-conference.org/data/Upload/Consensus/1/pdf/824.pdf
[pg.9]
Age was found to be a significant covariate of benzodiazepine sedation in the current study independent of its effects on pharmacokinetics. Older subjects required much lower benzodiazepine plasma concentrations to achieve comparable levels of sedation as compared with younger patients. This is consistent with the clinical observation that elderly patients appear to be more sensitive to the effects of benzodiazepines. Although most of the subjects in the current study were greater than 60 yr of age, there appeared to be an inverse linear relationship between age and C50,ss across the spectrum of sedation, with an 18% decrease in the benzodiazepine C50,ss value for each additional 10 yr of age. It is important not to extrapolate this result to much younger individuals, whose age is not reflected in the current study population. Otherwise, one might conclude that a 30-yr-old patient would require 3 x 18%, or 54%, higher benzodiazepine levels than a 60-yr-old individual to achieve similar levels of sedation.
lorazepam levels found in mj's blood were over 160 ng/ml (0.162 ug/ml resp. 0.169 ug/ml).
if we consider the age factor, this study would still indicate a patient with these blood values should have been asleep with a high likelyhood. (see fig. 5 in the study)
the study also says under lorazepam longtime sedation (by continuous infusion) there's a relatively high likelyhood a patient gets (too) deeply sedated at some points:
http://www.consensus-conference.org/data/Upload/Consensus/1/pdf/824.pdf
[pg.6]
During the maintenance period of sedation, subjects in the lorazepam group were optimally sedated (SS = 3 or 4) only 49% of the time versus 69% of the time for midazolam subjects (fig. 3).
Lorazepam subjects were more deeply sedated (i.e. SS = 5 or 6) more often (47%) than midazolam subjects (22%). These depth of sedation differences between lorazepam and midazolam subjects were statistically and clinically significant (P = 0.0001).
