If I was a cardiologist or a primary care physician or a neurologist I might love Plavix. As a neurosurgery resident I have a decidedly different view.

We know that anticoagulation therapy is associated with larger intracranial bleeds in trauma as well as worse outcomes. And we should have no doubt that antiplatelet therapy carries a similar risk. Indeed, Plavix is probably associated with worse outcomes in traumatic brain injury, although the data is scarcer for a drug like Plavix as compared to say warfarin.

Don’t get me wrong, cerebrally I know that the data supports its use whole heartedly. These are, typically, patients whom Plavix has helped save from further heart or brain attacks. The risk they face from such far outweighs the risk of an intracranial bleed. That said, it is hard to put aside what I see everyday; that is trauma patients with large bleeds associated with antiplatelet or anticoagulant use.

Well, Plavix, one of my largest scourges, is coming off patent.

The drug is set to lose its patent protection on Thursday. Faced with an expected influx of cheaper generic alternatives, Bristol-Myers Squibb, which sells Plavix in the United States under a partnership with Sanofi-Aventis, has said it no longer plans to actively promote the drug.

“This is one of the behemoth drugs that really defined the drug industry in the ’90s,” said Catherine J. Arnold, an analyst for Credit Suisse.

I’ll take comfort in the fact that the cheaper costs of generics typically does not actually lead to increased use of a drug. For me that would be a horror scenario. And I’ll keep telling myself that, despite my very limited view point, these are drugs that actually do far more good than harm.

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Background

Since Dawson demonstrated it in humans in 1946-1947 monitoring SSEPs during spinal surgery has become the norm rather than an exceptional available tool. It has spread from high risk deformity correction surgeries, such as scoliosis, to more mundane and typical procedures like fusions for trauma or degenerative disease.

Neuromonitoring during spinal surgery has become a huge industry and while population sized reports show a 50% decrease in neurological complications since monitoring came into wide use not all monitoring appears created equal and prospective studies trying to tease out the benefit of costly neuromonitoring have been inconclusive at best.

One of the newer additions to neuromonitoring is evoked EMG. And here is where the paper by Montes, et al out of the Hospital Ramon y Cajal in Madrid. In evoked EMG you stimulate something, usually the pedicle screw in spinal fusions, and see if the stimulation is conducted to neural tissue. The lower the level of stimulation required supposedly the closer the screw is to damaging a neural element (the spinal cord or a nerve, etc). One of the primary fears when placing these pedicle screws is placing the screw so that it is out of bone and in the spinal canal. It is a long held belief with EMG in neuromonitoring that stimulating the screw might give you evidence if you’ve broken through the bone medially. If the stimulation of the screw evoked a response at a low enough threshold then you removed the screw and replaced.

In an animal model the pediatric orthopedic practice in Spain wanted to see if there was a relationship between the stimulation needed to evoke a motor response in each screw and the integrity of the medial wall of the pedicle.

Design
Montes, et al used a porcine model. They placed a total of 18 viable screws in the thoracic columns of anesthetized pigs. The placed screws were measured and found 8mm from the spinal cord. With leads in the intercostal muscles the screws were stimulated in this position, 8mm from the cord with the medial pedicle bone intact, and the threshold at which stimulation of the muscle was achieved was recorded. The team then placed different materials in the canal, between the medial border of the pedicle (and the screw) and the dural sac. This organic material included bone, fat and muscle. With these interspersed tissues the EMG thresholds were again recorded. The team then removed the screws, took off some medial pedicle bone creating a “breach” and then replaced the screw so that it was 2mm from the spinal cord. EMG thresholds recorded the team then repeated the thresholds with fat, bone and muscle between the screw and the dural sac.

Results

The only association with the threshold for stimulation was the distance from the spinal cord.

The tissues between the screw made no difference. So whether the medial pedicle wall was intact or not had no effect at what stimulation there was a response in the muscle.

Discussion
It is true that other in vitro studies have shown that stimulation relates to the impedence from the screw to the neural elements (ie the tissues between the screw and the spinal cord) and the authors provide no answer for the discrepancy.

Taken alone these findings argue against somewhat the usefulness of evoked EMG in spinal fusion surgery in some ways. EMG cannot really give us a high sensitivty for breach of the pedicle cortex.

All EMG leaves us with is to have a very high tolerance for borderline thresholds on stimulation. The screws that should be replaced are those that have very, very low thresholds on EMG implying that they are touching or nearly touching neural elements. That in and of itself may still be of some use as its probably that proximity, more than the violation of the bone, that most puts patient at risk for injury (ie, even if there is no intervening tissue between the screw and the cord the fact that there’s some distance is safe in and of itself).

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One of the big things the use of social media in medicine is supposed to do is help diminish the information disparity between providers and patients. Although knowledge asymmetry is present in many fields perhaps nowhere is it as large as in medicine. If you’ve never been in a surgery I can do all I can to explain it in an informed consent process but perhaps hearing about it, seeing it in real time.

That said I though the novelty of using social media during surgery would’ve died down by now. As well as its use. Its not like the social media observer experience has been widely adopted by patients. I’ve never run across a patient in practice whose referenced having used social media to experience surgery as part of their information gathering process. Not that I think the effort is fruitless but the whole ‘live’ experience is overstated. In effect these livetweets of surgery are a publicity stunt.

And yet, here we are in Houston with a proposed first use of Youtube and Pintrest in a livetweeting of a brain surgery.

“What will come out of this is a detailed, real-time sequence of what happens in a brain surgery through all the stages from preparation, to shaving the hair, to making the incision, to draping,” Dr. Kim says. “People are very anxious and want to know what goes on in a brain surgery like this.”

While Dr. Kim (left) works in the operating room, a team outside the room will work the social platforms. A brain tumor specialist will be present to help answer questions from the digital audience via Twitter. But the operation will expand to other social networks too.

Video clips from inside the operating room will be posted to YouTube, and photos shared on Pinterest. Storify compilations will recap each hour of the broadcast.

A big enough story to prompt Mashable’s attention and CNN and Medgadet.

The web and social media are a great source of information for patients and families of all types, including those facing surgery. I applaud providers and hospitals and others for putting such information out there and using social media. The live presentation of that information though and, especially, the hype surrounding such seems overdone. Five years from now we will neither be giving fanfare to livetweets of surgery nor will be doing it on a regular basis. In some respects it seems a waste of resources in using social media and the internet to distribute information.

If you want to tune in though the livetweet begins today at 9am central time and can be found @houstonhospital.

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The New York Times has an interesting history of the potent malarial drugs derived from artemisinin.

In the 1960s, [Mao] got an appeal from North Vietnam: Its fighters were dying because local malaria had become resistant to all known drugs. He ordered his top scientists to help.

But it wasn’t easy. The Cultural Revolution was reeling out of control, and intellectuals, including scientists, were being publicly humiliated, forced to labor on collective farms or even driven to suicide. However, because the order came from Mao himself and he put the army in charge, the project was sheltered. Over the next 14 years, 500 scientists from 60 military and civilian institutes flocked to it.

[...]

China’s effort formally began at a meeting on May 23, 1967, and was code-named Project 523, for the date.

Researchers pursued two paths. One group screened 40,000 known chemicals. The second searched the traditional medicine literature and sent envoys into rural villages to ask herbal healers for their secret fever cures.

One herb, qinghao, was mentioned on tomb carvings as far back as 168 B.C. and praised on medical scrolls through the centuries, up to the 1798 Book of Seasonal Fevers. Rural healers identified qinghao as what the West calls Artemisia annua, or sweet wormwood, a spiky-leafed weed with yellow flowers.

Worth a read without a doubt. Interesting stories like this make the New York Times the best newspaper in the world.

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Senator Mark Kirk is the junior Senator from Illinois. He currently holds President Obama’s old seat which he won in a special election in 2010 to replace Roland Burris.

He has apparently suffered a large right sided, non-dominant hemisphere middle cerebral artery stroke, potentially after a carotid artery dissection on that side. And he’s now undergone a decompressive craniectomy on the right from the late edema suffered with such a large stroke.

Dr. Fessler said the stroke “will affect his ability to move his left arm, possibly his left leg and possibly will involve some facial paralysis. Fortunately, the stroke was not on the left side of his brain, in which case it would affect his ability to speak, understand and think.”

Chances for a full mental recovery were “good” but chances for a full physical recovery were “not great,” Fessler said.

The doctor said he was hopeful that, after rehabilitation at an acute care facility, Kirk would regain the use of his left leg, but said prospects for regaining the full use of his left arm were “very difficult.”

He said recovery is a matter of weeks or months — “it’s not going to be days.” Kirk’s relative youth and good physical shape are positives, Fessler said, and he expects Kirk could return to “a very vibrant life.”

I’m sure they’ve been aggressive considering his age and functional status, not to mention his stature. But to feel the need to go ahead with a craniectomy following a stroke implies a large area of ischemia. Decompressive craniectomy for large middle cerebral artery strokes is not terribly uncommon and the popularity for it has probably grown over the decades. As one, admittedly international paper, describes it.

Decompressive craniotomy in the setting of acute brain swelling from massive MCA infarct is a life saving procedure. It should be considered in patients with initial good GCS, who are deteriorating in neurological status. With the team effort of neurologist and neurosurgeons these cases have good outcome contrary to the natural history of disease…Thus an ideal candidate for decompressive craniotomy is the victim who is young, with no risk factors, who presents early and has nondominant, middle cerebral artery territory infarct, with a reasonable Glasgow Coma Scale with no (or) early signs of herniation. The key for success of these cases of large MCA infarcts is early detection. Clinicians should concentrate on formulating newer clinical, radiological and technical protocols to detect the suitable patients at an early stage.

Certainly from what we know Senator Kirk appears to be an ideal candidate. From the description of his possible long term deficits he appears to have had a large non-dominant hemisphere middle cerebral artery stroke. He is relatively young and fit. And, as The Chicago Tribune describes it, he presented with a relatively good exam and deteriorated quickly.

My thoughts and prayers are with him and his family. He has a long road ahead of him.

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Background

• Although the specifics of assessment and technique in fusion remain for debate spinal fusion for pain with spinal instability has become a generally accepted treatment
• Surgery for fusion attempts to promote new boney growth between the unstable vertebral segments
• Early last decade saw the rise in the clinical use of a naturally occurring cytokine, bone morphogenic protein-2, which serves to promote osteoblast differentiation and new bone formation in the body
• Initial studies demonstrated great success, as compared to bone grafts alone, in promoting boney fusion between unstable segments when BMP was used during surgery
• The Spine Journal June 2011 issue is dedicated to editorials and studies reviewing the growing evidence that BMP use has a number of risks that were underreported as adverse events in the initial studies which trumpted its use. Amongst these studies is a literature review by Carragee et al which criticizes the lack of reported adverse events in the initial industry sponsored BMP studies

Carragee, Eugene, Eric Hurwitz, and Bradley Weiner. “A Critical Review of Recombinant Human Bone Morphogenetic Protein-2 Trials in Spinal Surgery: Emerging Safety Concerns and Lessons Learned.” The Spine Journal 11 (2011): 471-91.

Design

• Systemic review looking at adverse events reported in original 13 industry sponsored publications looking at rhBMP-2 use in spinal use representing 780 patients versus adverse events reported in subsequent publications and FDA data sets

Results

• 13 original studies of BMP
• All first authors had significant financial ties to Medtronic, the industry manufacturer of BMP
• Meta-analysis of the 13 studies shows 0 complications associated with BMP
• Review of subsequent studies, unpublished data from the original studies submitted to the FDA leads the authors to conclude that BMP has a true adverse event rate of 10-50%. Newer studies may also associate the product with a cancer risk
• Dr. Carragee’s group proposes that the financial ties of the authors of the original 13 studies may help explain the lack of reported complications with BMP

Conclusion
Spine surgery is facing a real scandal with BMP. The association with cancer and the implication that financial considerations influenced the studies which led to its approval as a device by the FDA and to its widespread use is a big enough story that it has crept out of the pages of Spine and into the mainstream media. Reuters, the AP have both reported on it, as have major papers like the San Francisco Chronicle and the New York Times and the Wall Street Journal.

Infuse and other BMP based products are likely rightly dead and recalls are in the future. As for what this plays into the long going debate about the association between researchers and industry remains to be seen. But this is a big deal.

I’m going to be less than reactionary here. I think severing the ties between academic medicine and industry is impossible without hurting the common good. This country is the leader in advancing medical science partly because of funding from industry. I think the oversight is going to have to come from the academic institutions themselves. That’s a tough thing and there are major obstacles to people policing their colleagues. I’m not sure exactly what form that might take. But certainly I don’t think the government is not in a position to police it all. And the alternative is severing all ties to industry funded research.

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Background
The Corticosteroid Randomization After Significant Head injury (CRASH) trail was a huge international double blinded randomized trial which collected a huge cohort of patients suffering traumatic brain injuries with GCS less than 14 on presentation and presenting within 8 hours of injury and randomizing them to receiving a 48 hour course of methylprednisolone versus a placebo. The final results were published in The Lancet in 2005.

As if that was not enough the database collected for the study was the largest, most complete database of patients following head injury in the world. It included more than 10,000 patients from across the world and had a very high rate of follow up through 6 months. This database was used to create a prognostic model for outcome following head injury. Published in the British Medical Journal in 2008 the CRASH model has become one of more widely cited outcome prediction models in clinical practice when dealing with patients with head injury.

MRC CRASH Trial Contributors. “Predicting Outcome after Traumatic Brain Injury: Practical Prognostic Models Based on Large Cohort of International Patients.” Bmj 336.7641 (2008): 425-29

The original paper is available for free as full text on the BMJ website.

Design
This was a retrospective review of outcome of a large cohort of patients.

The database included 10,008 patients originally collected for the CRASH Trial. The database contained information on a large number of variables but the prognostic model focused on 9 initial variables: age, sex, etiology of the trauma, time on presentation, GCS on presentation, pupil reactivity on presentation, results of CT scan, whether the patient had a major extracranial injury, level of per capita income in the country where the injury occured.

They prognosed to two outcomes death within 14 days of injury or outcome at 6 months as measured by the Glasgow Outcome Score which they dicotomized into favorable outcomes (moderate disability or good recovery) and unfavorable outcomes (dead, vegetative state or severe disability).

They developed two models with the above variables: a basic model which excluded the findings on CT imaging and a CT model which included them.

Internally they validated the two models using bootstrap resampling. And then they externally validated the model using the 8000+ patients suffering head injury included in the independent International Mission for Prognosis And Clinical Trial (IMPACT) database. The original description of the IMPACT Trial is here on PubMed.

Results
All nine of the variables included in the final two models independently had strong associations with both outcomes (death at 14 days and poor outcome at 6 months). The table showing the odds ratios for each variable can be found here.

Regression of outcome of model including CT scan findings

After this internal validation they compared their model to outcomes observed in the IMPACT Trial blinded.

CRASH model predictions of outcomes for patients enrolled in IMPACT versus variable outcome

It showed good discrimination in the external validation with a C-score of 0.77 (essentially the area under the reciever operator curve). And for the basic model and the CT model in high income countries there was very good calibration by the Hosmer-Lemeshow test.

The authors have published a calculator with predictive outcomes based on the regression. The calculator gives odds for death at 14 days and poor outcomes at 6 months based on both models.

Critique
The sample size of this study is legitimate and one of the stronger points of it. The database appears well maintained and exceptionaly complete considering the number of patients and the challenges of coordinating data collection across continents. Looking at the demographics it appears relatively representative. As well the follow up to 6 months is a legitimate end point for the goals of the study and the sample included a great number of patients to that end point.

The outcomes measured to seem clinically relevant and were set prior to the models being designed. The variables included in the regressions as well have previously been validated at predicting outcomes in other smaller studies and are clinically readily available.

The study found no difference in outcomes based on treatment, including the randomization to steroids or placebo in the trial itself, which is an important consideration.

It is true the CT model in particular showed comparatively poor calibration for patients injured in lower income countries. Even there however the Hosmer-Lemeshow measure isn’t particularly off. The smaller sample size of patients with readily available CT imaging findings may in part explain such.

The major critiques otherwise of the study seem to be those available to be leveled at all published prognostic models. Generalization is a difficult thing especially to individual anecdotal scenarios. However for a study with in vivo data from patients seemingly encountered early following representative head injury and undergoing real world salvage attempts the model shows remarkable, if not perfect, calibration and discrimination.

Conclusion
The models developed from the CRASH trial are very likely the “best” available prognostic models for predicting outcome early after traumatic head injury. The calculator published by the authors appears a valid and useful tool for any health care provider encountering significant neurotrauma. A “better” prognostic model for the prediction of outcome early after head injury seems unlikely.

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There are strong psychosocial components to pain syndromes. That isn’t a disparaging statement or a claim that pain is anything but real and each individual patient’s unique experience. But I feel that sometimes recognizing that major psychological component of pain and putting it into the decision algorithm for or against surgery is taboo.

The fact is you probably shouldn’t perform a back fusion surgery on a smoker for pain with instability. And its becoming clear that maybe you shouldn’t perform decompressive surgeries for pain on patients with poorly treated depression.

Strong independent associations were seen between depression burden (the sum of preoperative, 3-month and 6-month BDI scores) and 2-year disability, symptom severity, and poor walking capacity.

[...]

Depressive symptoms interfere strongly with the ability of patients to obtain an optimal surgery outcome. Treatment models including the assessment and treatment of depression are encouraged.

This is a tough decision, you’re playing with the chicken and the egg here seeing as it is often a difficult assessment how much a patient’s pain syndrome is contributing to their mental health issues. But the fact is back surgery is major surgery with many, many serious risks and you should want the risk/benefit from the surgery to strongly favor the latter.

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Trying to define what is appropriate care and what is appropriate cost effective care is the long sought goal. Even the government has gotten into the business. The online Medicare Hospital Compare Quality of Care shows reported ‘quality’ metrics as reported by hospitals that participate in Medicare. One of the new statistics they’ve made available is the number of lumbar MRI scans health systems perform for back pain before conservative therapies are attempted for the back pain. Here is the write up on the NPR Shots Blog,

Back surgery is one of the best documented examples of expensive medical treatments that drive up health care costs while not always helping patients, and sometimes even hurting them.

And the latest Medicare data show that doctors frequently order MRI back scans for patients who haven’t tried recommended treatments such as physical therapy. An MRI often prompts surgery.

In 2009, 32 percent of Medicare patients with lower back pain who received a spine MRI at a hospital outpatient imaging center hadn’t tried a more conservative — and cheaper — treatment than surgery, according to data published on Medicare’s Hospital Compare website this month.

The point made at NPR is a little misplaced. I’m not sure we should blame MRIs for creating unnecessary surgeries. And that’s conceding much of spine surgery is unnecessary. If we want to reduce the use of ineffective spine surgery the idea isn’t to reduce the number of MRIs, its to educate and disincentivize ineffective spine surgery.

That aside it remains that I agree that lumbar MRI is an overused test. Since the vast majority of axial back pain does not respond to surgical or procedural intervention there is probably very little gained from most lumbar MRIs in terms of directing therapy. A course of conservative therapies for back pain is probably in order prior to any MRI. IF that fails, if radicular symptoms develop or if symptoms worsen then a lumbar MRI may be considered.

Despite saying that I contribute to the problem of MRI overuse.

Data From HHS At One of The Teaching Hospitals I’m At

At some of the teaching facilities I’m at I review a number of outpatient consult requests for back pain. I routinely refuse consults until MRI scans are available. This is because I’m looking for surgically amenable disease which is really the only issue, as the spine surgeon consultant, I can comment on. But I personally know the vast majority of the lumbar MRIs I review will not have surgically amenable disease. What I should really probably be saying on consults that come to me without MR imaging is that conservative therapy is in order prior to a reconsult with an MRI.

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As recently as 2008 back pain was the number one reason patients visited emergency rooms in the United States. That is incredible to consider.

Chronic lumbar back pain is an incredibly difficult condition to treat often. In some because identifying pain generators in the back is difficult.

I had an interesting discussion and lecture today on the innervation of the lumbar vertebral column.

In very basic terms the anterior portion of the vertebral column and the posterior part of the intervertebral disc are innervated by the sinuvertebral nerves which are recurrent coming off the ventral rami at each level. These nerves form extensive anastamoses with the sympathetic trunk.

The posterior aspect of the vertebral column, including the facet joints, is innervated by lateral, inermediate and medial brances of the dorsal rami. These branches as well enjoy connections with the sympathetic trunk.

Lots more details exist obviously. The most interesting detail however may be that, at least in some animal studies, for all the sinuvertebral and lateral, intermediate and medial branches at all the levels they all eventually “return” through the L1 and L2 dorsal ventral rami.

That means that nocioceptors through a broad area are all returning the same. Is this signal coming from L4 or L1? It may help explain the visceral nature of much back pain and the difficulty in localizing the pain generator at times.

Or maybe I just don’t stand the implications of such. That’s always a possibility as well.

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