Terra Sigillata

Judging from the press inquiries I’ve had since 5 am EDT today, expect today’s focus in the Michael Jackson case to be on the anesthetic drug, propofol (Diprivan®).

Last evening, California nutritionist and registered nurse Ms Cherilyn Lee gave an interview to Campbell Brown on CNN (and this AP exclusive report) describing Michael Jackson’s repeated requests of her for the intravenous sedative drug for his insomnia. She wisely rejected his requests, instead providing him with a vitamin and mineral “energy” injection called Myers’ cocktail.

However, four days before Jackson’s death she reported a frantic phone call from a Jackson staffer to her that led her to believe he had somehow procured the drug or something like it:

While in Florida on June 21, Lee was contacted by a member of Jackson’s staff.
“He called and was very frantic and said, `Michael needs to see you right away.’ I said, ‘What’s wrong?’ And I could hear Michael in the background …, ‘One side of my body is hot, it’s hot, and one side of my body is cold. It’s very cold,'” Lee said.
“I said, `Tell him he needs to go the hospital. I don’t know what’s going on, but he needs to go to the hospital … right away.”

“At that point, I knew that somebody had given him something that hit the central nervous system,” she said, adding, “He was in trouble Sunday and he was crying out.”

[. . .]

“I don’t know what happened there. The only thing I can say is he was adamant about this drug [Diprivan],” Lee said.

In the photo of Ms Lee that accompanies the AP report and the video interview now at ABC News, she looks terrifically distraught and was obviously very concerned about Mr Jackson. My thoughts go out to her as I suspect she is second-guessing what she might have done differently to help him.

What is Diprivan (propofol) and how is it normally used safely?

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Diprivan is the trade name for propofol (PROPE-uh-fawl), a product of AstraZeneca whose healthcare professionals website on the drug is currently closed. Estimated US annual sales of Diprivan are $375-400 million USD.

Propofol has a deceptively simple chemical structure and is known chemically as 2,6-diisopropylphenol. Its formulation in the Diprivan injectable product is as an emulsion with egg phospholipids. This imparts a white appearance that is responsible for its colloquial term amongst health professionals, “milk of amnesia.”

It is a widely-used intravenous anesthetic used primarily for outpatient surgical procedures owing to its very rapid onset of action, sometimes as fast as 30 sec, and rapid recovery. It is also used for inpatient procedures such as intubations, in conjunction with longer-acting anesthetics, and in painful procedures such as changing burn dressings.

Propofol has a remarkably good safety record given its widespread use. The average human intravenous dose is 2 to 2.5 mg per kg body weight while the intravenous LD50 (dose that is lethal to 50% of a population) in mice is 50 mg/kg. When used alone, or in combinations with the opioid analgesic fentanyl, it produces a “dissociative analgesia” that is very rarely fatal. Hence, its safety is one of the reasons it is used for outpatient surgery, together with its rapid onset and quick recovery. However, the prescribing information for Diprivan notes specifically that the dose should be reduced when the drug is used together with opioids (such as meperidine or fentanyl) or other sedatives such as benzodiazepines.

Note added: Later today, KevinMD (Dr Kevin Pho) further emphasized 1) there is no scientific basis for its unapproved indication in insomnia and that 2) propofol should never be found in a home. He goes on to say:

That is some serious malpractice, bordering on criminal, if any doctor had indeed injected Jackson with Diprivan simply to help him sleep.

While it is indeed a sedative, it has been reported to produce euphoria (the pleasant feelings of well-being most often associated with morphine and other opioids) in some people who have procured it for the purposes of clandestine use.

The potential risk is from “propofol-related infusion syndrome” – it can produce an elevation in body temperature that is usually not fatal (not “true” malignant hyperthermia as with the rare but fatal side effect of some inhaled anesthetics) but can trigger muscle breakdown called rhabdomyolysis, a rare but devastating side effect that can also occur with statin cholesterol-lowering drugs.

An excellent and timely review of propofol-related infusion syndrome was published in the May issue of Pharmacotherapy by Dr Stephanie Mallow-Corbett and colleagues from the University of Houston College of Pharmacy. The article is reprinted at Medscape (available with free registration). Most notable in this review is that while the syndrome is rare, it is fatal in 64% of cases when it does occur.

However, most relevant to the Jackson case is that propofol can cause cardiac tachyarrhythmias (rhythmic disturbances at high heart rate), especially in people predisposed to cardiac problems.

As I wrote last week in my blog post on Demerol ® (meperidine), Jackson’s reported long-term use of this analgesic for back pain may have already primed him for cardiac problems due to the accumulation of a toxic metabolite, normeperidine. However – and please note – that while all of my pharmacology/toxicology discussion is based in science and medicine, any extrapolation to the Michael Jackson case and the cause of his death is speculation at this point. I only have access to the reports regarding his potential drug exposure that all of you do. Only time will tell what is the truth once the full autopsy and toxicology reports are released.

What is Myers’ Cocktail?

Myers’ Cocktail is a vitamin and mineral supplement concocted by the late Baltimore physician, Dr John Myers, that has now been popularized by alternative medicine physican, Dr Alan Gaby. According to the abstract for Gaby’s 2002 article in Alternative Medicine Review (2002; 7:389-403; full text PDF available free at time of posting) on the concotion:

Building on the work of the late John Myers, MD, the author has used an intravenous vitamin-and-mineral formula for the treatment of a wide range of clinical conditions. The modified “Myers’ cocktail,” which consists of magnesium, calcium, B vitamins, and vitamin C, has been found to be effective against acute asthma attacks, migraines, fatigue (including chronic fatigue syndrome), fibromyalgia, acute muscle spasm, upper respiratory tract infections, chronic sinusitis, seasonal allergic rhinitis, cardiovascular disease, and other disorders. This paper presents a rationale for the therapeutic use of intravenous nutrients, reviews the relevant published clinical research, describes the author’s clinical experiences, and discusses potential side effects and precautions.

While Myers actually recipe was never published, this is the formula that Gaby uses as published in his review:

2-5 mL of magnesium chloride hexahydrate 20% (assume w/v?)
1-3 mL of calcium gluconate 10%
1 mL of hydroxocobalamin 1,000 mcg/mL (one form of vitamin B12)
1 mL of pyridoxine hydrochloride 100 mg/mL (vitamin B6)
1 mL of dexpanthenol 250 mg/mL (vitamin B5)
1 mL of “B complex 100 (B complex)” (composition not defined in Gaby paper)
4-20 mL of Vitamin C 222 mg/mL (C)

Results of a recent trial of Myers’ Cocktail (termed intravenous micronutrient therapy, or IVMT) in patients with fibromyalgia were published in the Journal of Alternative and Complementary Medicine but concluded that there was no statistically significant difference in symptoms between placebo and IVMT.

Most relevant to the Jackson case is that the safety of Myers’ Cocktail is not yet clear. I am particularly concerned with the calcium composition of this intravenous brew; while not likely to be toxic on its own, if dosed as listed, I do have some concern if Mr Jackson already had pre-existing cardiac problems and/or was receiving drugs such as Demerol (meperidine) or Diprivan (propofol) which each pose a risk of cardiac toxicity.

So, while press reports will be focusing today on Diprivan (propofol), let us not forget to consider the potential contributions of this “natural, alternative” therapy in the sad case of his death.

Comments

  1. #1 Ciaria Jackson
    July 1, 2009

    I truly believe the Doctor and think that this drug was given to him on Sunday. I do not think he fully recovered from this. The Doctor would not risk her practice to do a interview and lie that is not true. I am sure there will be a lot of people capitalizing on Michael but she is not one of them. Leave this man alone and let him rest in peace all the talk about his kids not being his is a bunch of BS and when they grow up they will have to deal with it all. LEAVE THEM ALONE!!

  2. #2 Eliza
    July 1, 2009

    Gosh, enough already! His family is grieving and we all loved him very much. Let Michael rest in peace…let it be! What happened,happened. He is gone…forever! Love u always Michael, my heart bleeds for your family & children….all this negative publicity is making me sick. I loved Michael and always will…no matter what.

  3. #3 MS
    July 1, 2009

    The commenters trying to suppress the conversation as abhorrent or innappropriate are examples of the extent to which our culture would prefer to be in full blown denial and while he was a great musician, he carried the scars of humanity that are destrucive to others (innapppropriate sexual boundaries) and destructive to himself (longstanding, undisputed opioid addiction). Those who seek to memorialize only his “thriller” identity without acknowledging the shadow side of his personality only serve to perpetuatate the collective ignorance relating to these issues in our culture, and you will be blind to when addiction and sexual abuse arrive at your own doorstep, smelling like a rotten carcass.

  4. #4 Abel Pharmboy
    July 1, 2009

    @MS: I understand your point and appreciate your comments. I prefer to cite Michael Jackson’s sad death as a cautionary note: rather than reference “the shallow side of his personality,” I believe that we as a society need to address instead the denialism of prescription drug abuse as a legitimate disease with a biological predisposition. While Mr Jackson’s character flaws might be discussed, his self-admitted addiction to prescription opioids dating back to the Pepsi commercial injuries (1993 NYT article) was originally a result of the appropriate prescription of painkillers.

    Substance abuse is not a weakness or a character flaw. It is a disease that requires treatment and its victims deserve the same compassion as those with any other disorder of pathophysiological origin.

  5. #5 Barbara and Dominique Spruill
    July 1, 2009

    Everyone loved Michael and we all understand that money is the root of all evil, I truly hope that no one sought money over life. Michael was a great entertainer in every way and a person we all loved’ and he truly was a child of God. Don’t try to take his joy away, he is at peace and will forever be a part of our lives.

    Much Love

  6. #6 Roland Brancoonier
    July 1, 2009

    Propofol, Myers’ Cocktail, all the people with steep hyperbolic discounting curves want to know the answers right now! In a few weeks, MJ’s final autopsy results will be available and all will be revealed. Of course this will not stop the speculation by conspiracy theorists who will continue to posit violations of Occam’s razor ad infinitum.

  7. #7 Dan Smith
    July 1, 2009

    The more that is told, the stranger this gets. Mr. Jackson was even more mentally ill and chemically dependent than I could have imagined. I hope his various enablers, including but not limited to Ms. Lee, stand trial for their participation in his preventable death.

  8. #8 Catharine
    July 1, 2009

    It totally blows my mind that anyone would seek Propofol for recreation, although I suppose it is more accurate to say that Michael Jackson had an urgent need to self-medicate. Propofol is neither a benzo nor an opiate and it’s appropriately used for anesthesia not analgesia. And when you’re on propofol, you don’t exactly sleep. In fact, when we use it in the ICU to sedate ventilated patients, we always make sure the patient gets morphine (or something) in addition to propofol because propofol doesn’t cover pain. The poor guy must have been utterly desperate. (I’m so out of the pop culture loop I had no idea he had a drug problem.)

    I have seen propofol cause bradycardia. I have seen (more often) propofol cause hypotension. I have never seen propofol related infusion syndrome (and thank you for this very useful information). I have administered the drug thousands of times, usually in the form of a continuous infusion. For ICU nurses, propofol is the gold standard for sedating intubated patients. We almost never give demerol. In ten years I’ve given it once or twice for rigors.

    We like to call propofol “milk of amnesia.”

    I find it fascinating -and disturbing- that some of the commenters here don’t want to talk about it. It’s not about Michael Jackson being a pop star. Michael Jackson was a victim of addiction, which is a serious health problem (like depression) and, obviously, can be fatal. We need to talk about it.

  9. #9 John
    July 1, 2009

    Thanks for injecting some informed commentary into the speculation over Jackson’s death.

  10. #10 Texas Reader
    July 1, 2009

    TMZ is reporting this drug was found in his home.

  11. #11 Evan Burke
    July 2, 2009

    “Later today, KevinMD (Dr Kevin Pho) further emphasized 1) there is no scientific basis for its unapproved indication in insomnia”

    What Dr Kevin Pho said is correct, however this doesn’t change the fact that nearly every propofol addict started injecting to overcome persistent insomnia, according to directors of addiction treatment clinics, in an article published on Anesthesiology News back in May 2007.

    http://www.anesthesiologynews.com/index.asp?ses=ogst&section_id=1&show=dept&article_id=7579

  12. #12 daedalus2u
    July 2, 2009

    Looking at the whole paragraph

    “In his experience, Dr. Manejwala said, nearly every propofol addict started injecting to overcome persistent insomnia. That aspect of the medication fits neatly with the link both Drs. Manejwala and Earley have observed between propofol abuse and a history of trauma. “One of the hallmark symptoms of post-traumatic stress disorder [PTSD] is hyperarousal. Folks with PTSD want to block that out,” Dr. Manejwala said.”

    There have been reports that MJ was abused as a child, and that for that reason he cut his father out of his will. PTSD does explain a lot of his behavior.

  13. #13 Candice
    July 2, 2009

    My partner suffered from Propofol Infusion Syndrome earlier this year, as a result of being infused with the drug for two and a half weeks to keep him in an induced coma after fracturing his skull. His symptoms were that of heart failure, renal failure (resulting in three days of dialysis) and acidic blood. He thankfully made a full recovery, but requires beta blockers due to the resulting tachycardiac arrythmia he experienced. Prior to the accident, my partner was a fit and healthy 33 year old man.

  14. #14 Richard Kaplan MD
    July 2, 2009

    Ms Lee is not telling the truth!
    She claims no knowlege of Ditrivan and had to look it up in the P D R !
    There is NO REFERENCE to the drug in the PDR!
    not generically or by manufacturer ( ASTRA ZENICA)
    RHK MD

  15. #15 Carman
    July 2, 2009

    @RHK MD: Um, that’s because it’s Diprivan, Doc. It’s there.

  16. #16 Tassie Devil
    July 2, 2009

    Propofol infusion syndrome is nasty, but you need to have been on an infusion for a minimum (from memory) of five days, without withdrawal periods. From the description MJ was using it for sleep periods, so this makes it less likely to be the cause. Propofol infusions for prolonged sedation have been pretty much stopped in the UK and other countries I have worked in for exactly this reason. I’m surprised that anyone could be kept on it for over two weeks as described above.

    Propofol does, however, cause apnoea – it is a significant side effect and why its use is restricted to highly trained individuals. It’s more likely he stopped breathing and no one noticed until his heart had stopped as well.

    Whoever prescribed this – and also whoever dispensed it, if it was obtained through the proper channels – needs to have their licence cancelled for good. No one prepared to do this should ever be allowed to work as a physician, nurse or pharmacist ever again.

  17. #17 thalarctos
    July 3, 2009

    Last evening, California nutritionist and registered nurse Ms Cherilyn Lee gave an interview to Campbell Brown on CNN (and this AP exclusive report) describing Michael Jackson’s repeated requests of her for the intravenous sedative drug for his insomnia.

    One thing I’ve been wondering about in this whole media feeding frenzy–this nurse, and also Deepak Chopra, have been making the rounds of the news channels, talking about what drugs Michael Jackson asked them to prescribe or obtain for him. From what little I understand about HIPAA, it seems to me that they’re violating patient confidentiality left and right. Or is it the case that, like privilege, it does not survive the client’s death?

    Just something I’ve been wondering about since this thing’s been going on. I’m certainly not including posts like yours in this description, Abel; as John said, we really appreciate your informed commentary on this case. I’ll continue to provide my own uninformed commentary as well, but since neither one of us was consulted by Jackson, that doesn’t sit anywhere nearly as badly with me as seeing his health-care providers all out talking to the media about what ought to be in his chart.

  18. #18 söve
    July 3, 2009

    Propofol does, söve however, cause apnoea – it is a significant side effect and why söve its use is restricted to highly söve trained individuals. It’s more söve likely he stopped breathing and no söve one noticed until his heart had stopped as well.

  19. #19 wojo
    July 3, 2009

    So if MJ really took this 2,6-diisopropyl phenol, what is the half-life of the drug in the blood (looks to be pretty short)?

    Will they (the feds and the police) try to detect the drug itself, or its metabolites in MJ’s blood?

    How does it all work?

  20. #20 A Jones
    July 4, 2009

    If the nurse was so damn concerned. Why did she not tell someone he was asking for the doggone drug? I don’t belive her. She is full of crap.

  21. #21 Jane
    July 7, 2009

    One would think that a patient receiving Propofol would be on a CPAP machine or some similar device to ensure that they could not stop breathing. Would he be alive today if he had that? (Of course, that’s assuming he died while under the influence of Propofol.)

    What about these rumors that he collapsed in front of his children? Do we even know what happened? Why did the doctor take 30 minutes to call anyone? The story of there being no working phone doesn’t jibe.

  22. #22 Apple
    July 8, 2009

    Nurse Lee seemed convincing to me until Greta’s interview with her..something interesting happens. Greta asked the nurse regarding an IV and it’s place in the house in the last part of the interview on Part 3, in the last moments.
    The calm manner of Lee quickly changes. Her voice begins to shiver,she begins to scratch her face, perspires, and her eyes twitch at a rate unseen during the entire interview. She is clearly in a state of panic, and I can’t help but think that she has been busted. I think she is covering up for something.The investigators should be paying a close attention to this woman. Her nervous behavior was uncalled for, since she feels reluctant to even speak regarding the IV in the house. It may be that she is covering her tracks, and has come out as to not look like a suspect. This is the only time I’ve seen her in a state of panic.

  23. #23 Kim
    July 15, 2009

    I keep hearing that Diprivan is not for use for insomnia. Perhaps not in the US, but www:medicines.org.uk shows 3 “conditions” for Diprivan, anaesthesia, INSOMNIA, and sedation. See

    http://medguides.medicines.org.uk/document.aspx?name=Diprivan

    And, if you click on INSOMNIA, there are 5 different preparations for this “condition.”

    Is it possible insomnia is treated with Diprivan in the UK? If not, what does this website mean? If so, I’m not surprised MJ had experience with it…he did do some travel there.

    I agree with #22 regarding Cherilyn Lee. Further, if she was on the phone with an MJ staffer, begging for Diprivan, and she knew he was “in trouble” and needed to go to hospital, why didn’t she call 911? Not on the 21st, the 22nd, the 23rd, the 24th, not even on June 25th? And, MJ had begged her for Diprivan some 3 months prior? If this is appropriate behavior for any Registered Nurse, I hope their specialty is APATHY.

  24. #24 jason clark
    July 19, 2009

    yo michael jackson should have stayed black! He was afraid of his own skin. From 68 to 85, he was the shit! Then, he came back as a pale reflection of himself. Now, I hear reports of him being drugged into coma states. I don’t believe it, but if its true, why? Why would someone be so sick to self-destruct?
    wutever, let the man rest in peace.

  25. #25 Joan
    July 21, 2009

    Jason Clark I think if there is a “shit” that is you!!!! Who are you to judge or comment?

  26. #26 Taneesha
    July 25, 2009

    The nurse looks like a private lady who decided to come forward and speak on behalf of what she knew to assist in shedding light on the “whodunnit” we are witnessing weekly as the saga continues.

    Good for her for speaking up…Before she came to the forefront there was no clue as to the possible cause of death of MJ in terms of what to look for….

    I bet DIPRIVAN will be announced in the toxicology report

  27. #27 John Hurd
    August 6, 2009

    Just to set the record straight, Cherilyn Lee is more than
    an RN; she’s a nurse practitioner with an NP license in California.

    She also includes the initials P.A. after her name on her
    website, but the License Verification link at the California Board of Medical Examiners does NOT show her as
    having a physician assistant license, now or ever.

    I have asked the Medical Board to look into whether she is
    improperly implying to the public that she is a PA.
    Additionally, she got a distance-learning PhD in some kind
    of naturopathic medicine. An interesting person, certainly.

  28. #28 john
    January 14, 2010

    Our son was treated with high dose propofol for a fractured skull. he came done with acute renal failure and heart failure on the sixth day. he died the next day.from heart failure .He was 26 and very healthy before this. I belive the manufacturur is deficent in warning doctors of this effect.
    I also belive it happens much to often and the drug needs a black box warning.

  29. #29 June
    July 2, 2010

    Today is Friday, July 2, 2010, over 5 months since your last post and Cherilyn Lee’s place in all this is becoming more clear. Propofol was found in MJ’s house, no one knows the circumstances of how or why, and, then, five days after Michael’s death, Lee magically comes forward claiming he “begged” for propofol from her MONTHS EARLIER (depicting him a seeking the drug). She turned him down but gave him a Myers’ cocktail (or maybe more than one?). I didn’t know what a Myers’ cocktail was until recently and now know it’s dispensed through an IV. Perhaps this was why MJ’s body was riddled with IV insertion points. A comment in your article here warns against the use of “Myers cocktail” with concurrent use of propofol, of all things! In my opinon Ms. Lee was not truthful at all, hopefully the DA will reach this same conclusion. In my opinion, both she and Dr. Conrad Murray were (paid?) pawns of the higher ups who have been orchestrating Michael’s demise for years. With the passage of time and much research mostly by loyal MJ fans and justice seekers, the truth is being revealed. RIP MJ we still miss you mightily.

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