Monday, October 10, 2011

Lorazepam

I want to rehash some basic information that toxicologist Dan Anderson provided during his testimony last week about lorazepam. Though he stated he could not determine whether or not the elevated blood level of lorazepam was from oral or IV administration, he was clear in stating there were no tablets in the stomach and the level of lorazepam was high, but not toxic. The defense's argument that Michael took eight 2 mg tablets of lorazepam then quickly gave himself propofol and then died... instantly... actually died instantly with Anderson's testimony. That is the point I want to bring home in this blog.

First, here is some numbers for lorazepam (Ativan) for oral vs. intramuscular (IM) vs. intravenous (IV) administration:

Oral: onset of action--~30 minutes; time to peak (drug concentration)--~ 2 hours
Intramuscular: onset of action--~20-30 minutes; time to peak (drug concentration)--~1-3 hours
Intravenous: onset of action--~5-20 minutes; time to peak (drug concentration)--~10-20 minutes


Peak time for amnesic effects for oral is 60 to 90 minutes.
Peak time for amnesic effects for intravenous is 15 to 20 minutes.

The maximum recommended dose for insomnia is 4 mg--ORAL only unless a patient is NPO (nothing by mouth) in the hospital--then IV may be used.

All methods above have effects that last approximately 6-8 hours. Oral lorazepam is slightly less potent than intramuscular and intravenous (90% bioavailablity). Bioavailability of 90% means that an oral dose is roughly 90% as effective as an IM or IV dose. Or, think of it as taking a 1 mg tablet and 0.9 mg of that tablet being "active" lorazepam.

An IV 4-mg dose provides an initial concentration of approximately 70 ng/mL.
An oral 2 mg dose provides an initial concentration of approximately 20 ng/mL.

Michael's blood level was around 160-170 ng/mL. Therapeutic levels are listed as 50-240 ng/mL (most sources state therapeutic can be as low as 10 ng/mL and anything over 300 ng/mL is toxic). As you can see from this data, it is impossible that Michael was given only 2 mg of IV lorazepam twice by Murray, especially not with the last 2 mg dose being at about 5:30 a.m. This blood level does not tell us how the drug was administered but given it takes some time for an oral dose to get distributed into the body (see the times above) it is impossible this blood level was the result of oral administration within minutes of death. There were two 10 mL vials of lorazepam used (these vials were either 20 mg or 40 mg each, depending on the concentration which I do not know at this time but will hopefully know soon). Murray admits to giving IV lorazepam and was there at the house--why would Michael need to take anything oral or even IV with Murray there? There was no reason, to make it simple.

Doses of 8 mg to 10 mg of intravenous lorazepam (2 to 2-1/2 times the maximum recommended dosage) will produce loss of lid reflexes within 15 minutes. I simply found this interesting though it may not relate to this case. However, it tells us how sedated one can become on doses similar to that in Michael's body. Tolerance or not, 10 mg should have had some effect on him, especially if Murray is being honest and said he slept fine the night before on benzodiazepines only. There is no such thing as physical withdrawal of propofol so Murray's claim that the benzodiazepines did not work the next day because of "propofol withdrawal" is fallacious based on the lack of physical withdrawal of propofol and the inability to build a tolerance to benzodiazepines within a day, too. Once again, Murray is lying.

So how did the lorazepam end up in the stomach?

There is a process some drugs undergo called "ion trapping":

http://en.wikipedia.org/wiki/Ion_trapping

Simply put, some drugs that are basic or alkaline (pH greater than 7) tend to go to acidic places in the body. The pH of the stomach is typically around 1-2 which means it is very acidic. Thus, it is natural for some lorazepam to essentially leech from the blood and into the stomach. I like to think of this as "opposites attract"--if something is basic it will look for an acidic environment--if it is acidic it will look for an alkaline or basic environment (ex. the bladder can be an alkaline environment if the urine is basic). Anderson explained this in very simple terms and also explained that given the amount found in the stomach, though four times the amount found in the blood, it amounted to 1/40th of a tablet of lorazepam. This is not equal to oral ingestion of lorazepam tablets.

Below is a snapshot of Anderson's math in which he derived his amount of propofol in the stomach:



There we have it--Michael did not die from the ingestion of lorazepam tablets, be it 1 or 8 tablets. One question that lingers is--where are the syringes used to give lorazepam and midazolam? I have always assumed Murray may have reused the syringes he had and the leftover amount of benzodiazepines were eradicated with reuse of the syringe for propofol administration or too low to detect after reuse. I would also think it is possible he tossed them in the garbage or possibly tossed them in the fireplace that was on in the master bedroom--a fireplace on in late June, mind you. Investigators did not search the house very well or close it off so that leaves the pursuit of justice with a lot of gaping holes.

To tie all this together, propofol begins to work in less than a minute and depending on the dose, wears off in usually less than 15 minutes even for large doses. Regardless of the method of administration, lorazepam takes at least 5 or so minutes, minimum, to begin working. That means the administration of these drugs, if given around the same time, should never be at peaks "together" unless lorazepam is already at a high level (which would likely indicate sedation) when propofol is administered. That would indicate someone other than the person sedated would have to administer propofol for both of these drugs to be at such high levels in the body, with the lorazepam being administered first since it takes longer to become active. For there to be additive effects, which were mentioned in the autopsy report, the lorazepam should have been having an effect on the patient (sedation, possibly breathing problems, etc.). People do not typically die from benzodiazepine overdoses but giving lorazepam with propofol in a setting with no airway or respiratory assistance--you are basically asking for someone to stop breathing and die.

In closing, here is a warning that is quiet visible to anyone who reads about lorazepam:

AIRWAY OBSTRUCTION MAY OCCUR IN HEAVILY SEDATED PATIENTS. INTRAVENOUS LORAZEPAM AT ANY DOSE, WHEN GIVEN EITHER ALONE OR IN COMBINATION WITH OTHER DRUGS ADMINISTERED DURING ANESTHESIA, MAY PRODUCE HEAVY SEDATION; THEREFORE, EQUIPMENT NECESSARY TO MAINTAIN A PATENT AIRWAY AND TO SUPPORT RESPIRATION/VENTILATION SHOULD BE AVAILABLE.

On June 25th, 2009 Conrad Murray had nothing with him to treat airway obstruction in Michael while he anesthetized him as a way to treat insomnia and though Murray had an ambu-bag he refused to use it, opting for mouth-to-mouth, one-handed, in the bed CPR. He did not even have a pulse oximeter on Michael. How could someone entrusted to take care of someone be so damn careless for another person's life?

14 comments:

  1. I really appreciate these easy-to-digest summaries. I'm a novice when it comes to medical/drug related issues, so I'm glad that there's someone to help break it all down! :)

    But regarding the fireplace in the bedroom: La Toya actually wrote in her new book, "Starting Over," that not-long-after Michael died, she asked Paris about his final days. La Toya said that Paris told her Michael would always sit in front of the fireplace with blankets on . . . that even then, he was always cold to the touch, and complained of never being able to get warm, etc.

    So we do know that MJ was often using the fireplace to get warm, despite it being June in California.

    He might have just left it on (perhaps on purpose or by forgetfulness), and it stayed on, since no one else was allowed in that room to notice, etc. . . .

    Oh, and btw . . . I've heard many people state that propofol isn't addictive, but a writer at LawMDConsultant.com claims that propofol abuse and addiction are well known facts. He also cited about six medical articles on the subject of abuse/addiction, in regards to propofol: http://lawmedconsultant.com/2532/propofol-explained-factual-expert-answers-on-jackson-case

    I was wondering, what are your thoughts on propofol addiction? I'm not sure what's what, honestly. o_o

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  2. Everyone keeps saying he would have woke up when the propofol wore off, with all those other drugs in him, he could well be out of it when it did!?

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  3. Hi Gigi! Hope you're OK. I've been away for quite some time and just saw this: http://tinyurl.com/3to8crg

    What kind of people can do this over and over again to a person? This is so outrageous!!!
    Hugz

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  4. I will comment here shortly but wanted to warn people that the link above that Skeptikos posted is the photo from the autopsy. I do not want anyone to click on it not knowing what it is--and by no means want to promote it, either. I see the need for the jury to see it--it shows someone who was thin--but healthy--but it is very painful to see especially when one is not expecting it. I really wish the public had never had access to this--as they did not have access to Caylee Marie's skull. It just makes me so sick that people still fail to realize this man was human, he had a heart, a heavy heart that hurt often. He may not be here anymore but it still hurts to think this hurts him in some way.

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  5. I just wanted to comment real quick on something--today we learned that one of the tablets in the lorazepam vial from April 28th, 2009 was split. I just found that highly interesting in someone who supposedly allowed a doctor to drug him along with his will (and someone who supposedly took 8 tablets on June 25th, yeah right)...

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  6. Hey Anon,
    Yes, LaToya stated that in her book. I also know that Michael was "cold natured" as in, he seemed to be cold rather than hot most of the time. It is possible that the fireplace was left on 24-7 but that does seem a bit odd, especially if the room was not used for so many hours in the day. Given Murray was the only one upstairs--who knows if he went in there and did stuff or not...

    As for propofol being addictive, there are a few reported cases of abuse--I would rather use the term abuse over addiction. By all means, there is not really an epidemic of propofol abuse occurring though it is an easy abuse to hide. In most of these cases of abuse, there may be some psychological component for the use but as far as a physical need for the drug--there is none. There is no withdrawal, no tolerance built to it over time. In ICU settings we do not see tolerance or withdrawal, either. So basically, these people who abuse propofol, it is a mind over matter issue. In this situation, I really believe Michael thought this medication was safe for sleep and he had no hidden reasons for using it, like euphoria. I am not sure who told him it was safe for sleep, but they must have been really convincing. Given Murray's charisma I am sure he could pull off having Michael believe it can be used for sleep all on his own or with Michael's inquiring about it. Michael desperately wanted to be able to sleep to get through this tour. Tours tore him up--he was very honest about that...

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  7. Nikki, such a straightforward explanation for us layperson types. Not to belabor that autopsy photo, my opinion is that the prosecution showed this to demonstrate clearly Michael's height, 5'9", weight 136 and normal BMI, in refutation of all the junknews out there that he was "frail". According to the ME Rogers, these are all within normal limits. Michael was not skeletal as some have said and Walgren wanted visual clarification for the jury. Michael went from a healthy 50 year old man per ME Rogers to dead the next day. I also wish the media would report that FACT that on May 10, 2009, Michael WAS Murray's patient; media implies that Murray found Michael this way (slurring speech) when it is obvious Murray was recording Michael after Murray's own "treatment".

    What is your current opinion of Nurse Cherilynn Lee's role (sometimes called Dr. Lee "who also treated the Lakers"), and do you think she will be called to testify; she was the first person after Michael's death to go on TV saying he had asked her for prop months earlier.

    Using Anon as Blogger isn't working well.
    Thank you.
    June

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  8. I'm sorry about posting that link, but I was so mad about it. Just wanted to know why was this possible. There's no ethics anymore. What a shame, poor soul, can't RIP.

    Concerning: «Michael desperately wanted to be able to sleep to get through this tour. Tours tore him up--he was very honest about that...»
    Yes, I agree. But still don't know if he knew all the consequences of those drugs. Still think he was poisoned. How could he take those meds on his own?

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  9. @ Anonymous: All the more reason to "check Michael's level of sedation," as the sleep specialist, Dr. Kamangar & the anesthesiologist, Dr. Steinberg, stated.

    YES, that means you HAVE to wake the patient to make sure they are sleeping naturally or if they are still unconscious due to an adverse affect of the drug.

    @ gatorgirl277: I noticed that, too - about the 1/2 pill in the bottle. What "ADDICT" takes 1/2 of anything??! Never mind the prescription was filled, I believe, back in late April - was it? 30 pills, 9 1/2 left! WOW! What an addict (tongue in cheek/ROLLING eyes!)

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