Pathophilia

Sources are now implicating propofol (Diprivan; sanofi-aventis) in Michael Jackson's death. TMZ reports that police recovered the anesthesia inducer at Jackson's rented home. And ABC News interviewed Jackson's nutritionist, Cherilyn Lee, who stated that the singer asked her for Diprivan, by trade name, 3 months ago. Jackson's alleged intention, bizarre as it may sound, was to be put to sleep at home under the guidance of an anesthesiologist.

In use for more than 2 decades, Diprivan is a rapidly acting (within 40 seconds) IV sedative-hypnotic that is FDA approved for the induction and maintenance of anesthesia and for sedation in an intensive care unit (in both cases, patients are mechanically ventilated). According to the prescribing information, the induction dosage for ICU sedation begins at 5 microg/kg/min and should be titrated (by increments of 5-10 microg/kg/min) to the desired clinical effect. Maintenance rates are generally 5-50 microg/kg/min or higher for adults.*

For anesthesia induction, the typical dosage is 40 mg every 10 seconds in healthy adults younger than 55 years of age; maintenance of anesthesia can be achieved by intermittent boluses of 20-50 mg. However, slow infusion or injection techniques are recommended to avoid apnea and hypotension. Diprivan dosages should be reduced in patients who have received large doses of narcotics.

Common adverse events with Diprivan use include bradycardia or other arrhythmias, hypotension, and apnea. Burning pain or stinging at the injection site, which is also common, may be reduced by preinjecting the vein with a 1% lidocaine solution (1 mL).

Subanesthetic doses of Diprivan may have the potential for abuse by inducing euphoria. Diprivan's abuse potential is particularly high among physicians who have access to the drug—namely, anesthesiologists. An e-mail survey in 2007 indicated that Diprivan abuse has increased substantially in academic anesthesia departments during the last 10 years. Among the 25 reported abusers in the survey, 16 (64%) were resident physicians. Seven (28%) abusers died; 6 of the deceased were resident physicians. In academic centers where abuse occurred, none had established pharmacy protocols to account for the drug (as is done routinely with opiate medications).

In 2008, an anesthesia nurse was convicted of killing a University of Florida student, with whom he was infatuated, by injecting her with propofol in her home. The victim's propofol blood level was 4.3 microg/mL. The expected propofol concentration after a bolus induction dose of 2.5 mg/kg (175 mg for a 70-kg man) is 1.3-6.8 microg/mL.

If a vial or vials of Diprivan were indeed recovered from Jackson's home, it seems almost certain that the medication was palmed by someone who had access, rather than formally prescribed.

Addendum: It also appears that Diprivan can be purchased through online pharmacies. For instance, drugdelivery.ca offers a 50-mL prefilled syringe for $122.99 USD. The completion of a patient questionnaire is necessary (along with payment); it is not clear that a valid prescription is required.

* So for a 70-kg man (~154 lbs), 0.35 mg/min would be administered for induction, and the maintenance dosage ranges from 0.35 to 3.5 mg/min. Vials of Diprivan contain 10 mg/mL and come in 20-, 50-, and 100-mL vials.

Image of Diprivan formulations from APP.

The 911 call for Michael Jackson revealed that the singer's hired physician, Conrad Murray, performed CPR (ie, chest compressions) on a bed. Because anybody who's familiar with CPR knows that the procedure should be performed on a hard flat surface (so that chest compressions can be effective), the doctor's resuscitation technique has been called into question.

Now Murray's criminal defense lawyer, Edward Chernoff, offers at least 2 explanations to "Good Morning America" for why the doctor performed chest compressions on a bed. Neither explanation is particularly satisfying. The first is that the bed was "firm," ostensibly serving as a hard, flat surface. The second is that Murray "braced Michael Jackson's back with his hand and compressed his chest with his other hand." This explanation obviously begs the question: If the bed was sufficiently firm, then why was it necessary to brace Jackson's back?

Chernoff goes on to state that Murray checked to determine that his compressions were producing "blood flow." In CPR, typically a second party will determine, by assessing the pulse (eg, the femoral pulse), if chest compressions are mechanically pumping the heart. This assessment can only be done, of course, while chest compressions are being administered. So if Murray was performing CPR with 2 hands, it'd be impossible for him to assess (by himself) the effectiveness of his compressions without an additional hand or two.

Then Chernoff relates that Murray, at some point, moved Jackson off the bed and continued CPR. At what time this action was performed is unknown; it logically took place after the 911 call. But, if Murray believed that his CPR technique was effective on the bed, then why did he later move Jackson onto the floor?

Last, Chernoff states that "it [Murray's CPR] went on for 25, 30 minutes"—suggesting that Murray attempted to revive Jackson on his own for quite some time, before attempting to call 911.

CPR = cardiopulmonary resuscitation. 

N.B.—Chernoff denies that Murray ever administered Demerol to Jackson. He states to GMA, "I can't go into any specifics about drugs that Michael Jackson might have taken the night before, by agreement. I can tell you this: Whatever was taken by Michael Jackson at any time wouldn't have caused his death."

Middlemarch (1994): If you can't get through the book (I'm talking to you, English majors), then watch the BBC mini-series—a highly faithful adaptation of George Eliot's novel (written by Andrew Davies of Pride and Prejudice fame).

Dorothea Brooke believes that life's purpose can be found in marriage to a fussy academic, the elderly Reverend Casabaun, while she cultivates a sympathic friendship with his disinherited cousin, the fetching Will Ladislaw (Rufus Sewell). The parallel lives of two other couples (the earnest Dr. Lydgate and his spoiled wife; a ne'er-do-well aristocrat and his long-suffering country sweetheart) are intertwined for the obligatory contrast and comparison.

Michael Jackson overdosed on Demerol (meperidine), according to numerous posts on the web, including those at TMZ—the go-to site for bottom-feeders of entertainment news. The web site also reports that Jackson received daily shots of the morphine analog, possibly for years, and that a physician who was at Jackson's home yesterday is "nowhere to be found." The physician possibly administered the dose, which must be given IM or IV.

According to other news sources, Brain Oxman, a Jackson family spokesperson and lawyer, and Liza Minnelli (no stranger to addiction) suggest that Jackson's abuse of prescription opiate medications is longstanding. The speed with which Jackson's speculated cause of death has been transmitted is evident in the fact that the news has already been incorporated into a Wikipedia entry for the drug.

While favored as a treatment for acute pain in the 1980s, Demerol has become considerably less popular among physicians as a short-term analgesic during the last 2 decades, largely because of its toxicity profile and abuse potential.

An autopsy on Jackson's body is to be performed today, with results expected this afternoon, reports MTV.com. Although some toxicology tests are reported to take weeks, measures of opiate medications can be obtained within a day, if not hours.

Delivering chemotherapy to brain tumors is particularly challenging because of the blood-brain barrier (BBB), the collection of tight junctions between endothelial cells in cerebral blood vessels. When intact, these protective junctions prevent the passage of a number of substances—including chemotherapeutic molecules—from the systemic circulation into the brain tumor bed. The key to effective, targeted therapy of brain tumors is to 1) selectively disrupt the BBB to allow the entry of cancer-killing drugs and then 2) reestablish the BBB so that chemotherapeutic agents are retained within the tumor bed.

Biomed engineers at Duke have constructed a prototype of an intravascular catheter, which can deliver BBB-busting hyperthermia* and provide real-time 3D imaging of brain tumors. The thin, flexible catheter is intended to be snaked through the internal jugular vein (which obviates the need for invasive cranial surgery) and manipulated into the dural venous sinuses. The investigators' proof-of-concept experiments, performed in dogs, was published in this month's issue of Ultrasonic Imaging.

The investigators concluded that their next-generation device must be smaller and more flexible than the prototype, to negotiate the curves of the cerebral vasculature. The long-term plan for the catheter is to obtain fluoroscopic-guided access to brain tumors through the venous sinuses, administer BBB-disrupting heat, which would then trigger the release of chemotherapeutic agents to the tumor bed.

* A temperature rise of approximately 5 degrees C.

Depiction of dural sinus system from Gray's Anatomy.

Thanks to vigilant laboratory testing (at least in part) for H1N1, the number of swine flu cases worldwide has increased by nearly 90% in the last 11 days.

The World Health Organization reports a total of 52,160 cases of H1N1 disease (up from 27,727) in 99 countries (up from 74), with a large bulk of new cases reported in the United States (3594) and Chile (1190). The number of deaths stands at 231 (up from 141), for an overall mortality rate of 0.44%.* Swine-flu-related deaths have now affected 11 countries.

Country	Cases	Deaths
Australia	2436	1
Costa Rica	149	1
Dominican Republic	93	1
Guatemala	208	1
United Kingdom	2506	1
Colombia	71	2
Chile	4315	4
Argentina	1010	7
Canada	5710	13
United States	21,449	87
Mexico	7624	113

* Which is slightly less than the previously calculated mortality rate of 0.5%. 

The Damned Don't Cry! (1950): A 40-something Joan Crawford still rocks a body as a ruthless, faux socialite. Nothing—and I mean nothing—detracts from Crawford, thanks mostly to a B-movie supporting cast. Still it's a brave star who's willing to receive an on-camera beating from one of those second-string actors.

When it debuted in 1991, Billy Bathgate—based on the novel by E. L. Doctorow—was generally faintly praised (Vincent Canby) or soundly panned (Roger Ebert). Perhaps the lukewarm reception had something to do with overblown expectations and rumors of production troubles on director Robert Benton's set. But the film is notably sustained by a young Loren Dean as the titular street kid. Dean (Mumford, "Bones"), who never quite developed the career that this movie would have forecasted, strikes a nice reactive-proactive balance as the protege of gangster Dutch Schulz (Dustin Hoffman) and the protector of his boss's mistress (Nicole Kidman).

While drugmakers create a vaccine against the currently pandemic swine-flu virus (H1N1 S-OIV 2009), neurologists are advised to monitor the safety of such inoculations, should they be implemented. The caution is founded on a higher-than-expected rate of Guillain-Barre syndrome (GBS) in vaccine recipients during the 1976 immunization campaign against swine flu, reports Neurology Today.

More than 30 years ago, soldiers at Fort Dix, New Jersey, experienced an outbreak of swine flu. Fearing a recurrence of the 1918 influenza epidemic, US government officials implemented a widespread vaccine campaign in which more than 40 million Americans were immunized. However, the drive was aborted after 3 months when reports of GBS in vaccinated individuals emerged. Although GBS surveillance data for the time period are sketchy, evidence suggests that vaccine recipients were significantly more likely to develop the condition within several weeks after inoculation.*

At present, leading neurologists do not anticipate a government-led vaccine campaign against H1N1 S-OIV 2009, given the low mortality rate (0.5%) of the current swine-flu pandemic and the historical risk of GBS with inoculation.

* The typical background rate of GBS is about 1.5 per 100,000 individuals.

After forecasting a swine flu pandemic for a good month or so, the World Health Organization (WHO) has now given the H1N1 virus official level 6 status. What this means is nothing particularly new: A pandemic occurs when a novel influenza virus causes several, simultaneous epidemics worldwide, according to WHO. In the case of H1N1, the virus is spreading in at least 2 regions, reports the BBC; specifically, rising numbers of cases are being observed in the United Kingdom, Australia, Japan, and Chile.

As of yesterday, 74 countries had reported a total of 27,727 cases of swine flu, the majority of which have occurred in Mexico and the United States. But the virus has caused only 141 deaths, for an overall mortality rate of about one half of 1%.

Country	Cases	Deaths	Mortality Rate, %
Mexico	5717	106	1.9
United States	13,217	27	0.2
Canada	2446	4	0.2
Chile	1694	2	0.1
Dominican Republic	91	1	1.1
Total	23,258	141	0.6

Swine flu in humans first emerged in Mexico last April; although Oxford scientists estimate that the H1N1 virus could have been transmitted from pigs to people as early as August of last year, writes the AP.