The Ether Way

Awareness in the Persistent Vegetative State

Every now and then you hear talks that astonish and fundamentally change the way you view some issue or disease state. I heard one of these at this year’s Society for Neurosurgical Anesthesia and Critical Care (http://www.snacc.org/) meeting in San Francisco in October 2007. This one was about the persistent vegetative state (PVS)  and how not all may be as it seems.

Dr Adrian M Owen of the University of Cambridge in the United Kingdom presented his studies of functional Magnetic Resonanace Imaging (fMRI) in patients in the persistent vegetative state (PVS) showing clear evidence of awareness and cognitive ability in some of these patients.( fMRI uses the MRI to indicate areas of the brain that are active) His work has been formally published in Science 313:1402, 2006.

 PVS is a syndrome wherein a patient by every bedside test shows no interaction with his/her environment. The patient does not attend to any external stimuli, does not track with his/her eyes and seems totally unconscious. Families (like the Schiavo clan) however may be struck by the patient’s apparent wakefulness, lack of need for a ventilator, and persistence of ordinary vegetative bodily functions. The patient can look seductively awake but is not. Of this I was certain till I heard this talk.

 Dr Owen presented the fMRI method whereby various inputs to a subject in an MRI scanner can create reproducible patterns. For example tell a patient to think about something and you get a stereotypical fMRI pattern. Tell a patient to think about riding a bike or think about a specific place and different reproducible patterns of activation arise in the brain. OK… neat.

 
Well Dr Owen presented a patient with all the stigmata of PVS from traumatic brain injury with diffuse axonal injury. This vegetative patient, however, when asked to think about a place or to think about riding a bike showed fMRI activation absolutely the same as that produced when an ordinary awake patient responded to the same command. In fact this patient was fully able to interact with the investigators in this manner. “If you can hear me think about riding a bike” leading to the bike riding pattern. I took a picture of this slide showing this and reproduce it here:

The fMRI of the PVS patient is at the top and the control volunteers at the bottom. The left images are those of tennis playing imagery and on the right of spatial recollection imagery. I believe this is going to have implications for decisions about extent of life support in such patients. Certainly many(probably most) PVS patients really are in PVS.  Unlike this case, I don’t expect patients with neocortical death will be responsive like this. Nonetheless it does suggest that before we make such PVS declarations that we should make sure on tests like those presented by Dr Owen that the PVS patient really is in PVS.

For starts, in those patients in whom we find that PVS is really “pseudoPVS,” I expect this will be an objective measure to use for rehab. Just keep thinking about that bike riding and after awhile the physiatrists, wonder workers that they are, may be able to have the patient really bike riding or doing other cognitive things. It will tell them to not give up.

So it seems that what we thought we knew for sure we’re not so sure of anymore. Déjà vu.

 

Deep Hypothermic Circulatory Arrest for Aortic Arch Surgery: A Global Brain Ischemia Situation

 Mitch Keamy reviews some pretty interesting material on aortic arch dissection. Surgery for this is a full time affair at Penn.

I am especially interested in the deep hypothermic circulatory arrest used for this because it’s a great example of survivable human brain ischemia. My colleagues in cardiac anesthesia are particularly interested in brain protection during cardiac surgery and I am interested in brain protection in all situations. So I have taken a bit of an interest in this. (Click on all figures to expand)

Some observations:

Here is the number of DHCA cases that my colleagues do annually:

 

 

 
Some pretty good program growth here.

 

 

 

 

 

Here is the distribution of time of DHCA for aortic arch repair. John Augoustides gave me this figure:

       

 

 

 

 

 

 I forgot to mention that one way to help the brain tolerate this is to provide a bit of backwards blood flow from the vena cava up thru the brain and out the carotids. This means we can sample the blood coming out of the ischemic brain.

 

Doc in a Box

Yes that’s me! The doc in the box!! At Penn we have developed the use of a telemedicine system, marketed and sold by Visicu, to do remote monitoring and intervention of ICU patients throughout our health system in different Philadelphia  hospitals. We call it Penn eLert.  I am sitting at a console that looks like this:

 

 

 

 

From this vantage point I can control a video camera to “go into” a room with two way audio communications, see a page summarizing all the patient’s main points, follow the bedside monitor continuously, read progress notes, view chest x rays, and review labs, among other things….everything except physically examine a patient or do a procedure on a patient. Also there is a sentry system that alarms when there is a trend or overt problem indicating that something is amiss…..wow.

 

Being Best At Who We Are

A recent editorial in the Philadelphia Inquirer by Chris Satullo (Aug 19, 2007) caught my eye. He discusses the myriad manners in which one’s pluck and one’s luck interact to result in one’s life story. I was struck how much of my own bio is luck in the context of some pluck. But thinking about it more, perhaps whatever pluck I have applied to my life is really luck….the happenstance of genes, role models, training, NIH study section assignments of my grants, and parenting.

So here I am a professor of anesthesiology at a major medical center, the culmination of a series of unlikely events, starting from the improbability of conception and survival of birth-related asphyxia. Then one summer day Mike Ruscher, in 1967 on his skateboard on the street in front of 115 Windsor Drive, suggests we volunteer as junior ambulance attendants at the local ambulance service. What a cool idea, sure lets do it! This leads by a circuitous path to medical school and then an interest in cardiac arrest associated brain ischemia and acute care medicine. This then leads to a variety of interactions with many other basically randomly encountered life influencing people and experiences and here I am!! If I had not met my health teacher Ted Kondrad in junior high, my buddy Mike Ruscher, Harold Heine in college chemistry, Peter Safar in med school, and numerous others, undoubtedly everything would have worked out differently. Probably much differently. Sometimes I look at my tattooed drug addled Viet   Nam vet biker patients and think how easily that could have been me….just one or two more C’s in college and my lottery number of 92 would have been enough.

Patient Safety in Anesthesia...A success story

December 7, 1941  Pearl Harbor.... Lots of casualties. Patient safety routine efforts primarily consist of finger on the pulse, eyes on the chest, observation of skin color. The recently released drug, thiopental, is employed. Some of the soldiers die…of anesthesia (1-3). Anesthesia-related death rate reported at 1 in 450 (2).

September 1979 – September 1981 (WAK residency time). The operating surgeon calmly notes blood’s dark.  WAK’s reaction: BLOOD'S DARK!!! Dr. Todres says the first 3 things to check for with any problem in the OR is, first airway, then the airway, and finally the airway. So he checks it and finds a disconnect which somehow was not able to be heard with the esophageal stethoscope over the orthopedists’ hammers and drills. No oxygen analyzer, no disconnect alarm, no pulse oximeter, no automated blood pressure monitor; by today’s standards, no nothing, although we did have manual blood pressure cuffs, EKG machines,  and the beginnings of advanced hemodynamic monitoring. WAK’s attendings were fond of saying “when I was a resident…” followed by some parable of how he managed with no monitors other than his five senses.  It seemed like at least once a year at M&M there was discussion about an intraoperative death by undetected disconnect. Anesthesia death rate said to be about 1 in 10,000.

 

Brain Damage From Anesthetics

Say it aint so.....

So far no one has shown a direct effect of anesthetics to produce brain damage in people.  However, there are some disturbing reports about post operative cognitive dysfunction after surgery, especially in the elderly.  The Mayo group published data suggesting a link between age of onset of alzheimers and cumulative lifetime anesthetic exposure.  Moreover, Monk's group has shown an association between depth of anesthesia by BIS and one year mortality.  So what's up?

Pretty much every category of anesthetic has been impugned:

Opioids.

I am pretty sure I (and my colleagues) published the first papers showing histologic injury from a clinically used anesthetic drug (Anesth Analg 75:953‑964, 1992.   see fig).  We showed that high doses of alfentanil in paralyzed ventilated rats produced seizures and limbic system  brain damage in paralyzed ventilated physiogically controlled rats.  The doses were about ten times higher than analgesic, a dose range commonly used in cardiac surgery.  Similar results were produced with sufentanil, fentanyl, and remifentanil.  Given to monkeys in a PET scanner we saw FDG temporal lobe activation with fentanyl.  We gave brief high dose remifentanil to five humans fully paralyzed and ventilated also showing limbic system activation.  I just published another paper reporting limbic system activation at low doses of remifentanil in 29 volunteers with a variation in the activation pattern according to apolipoprotein E genotype.  Kearse and Tempelhoff have shown limbic epileptiform activity from fentanyl in humans.  Sullivan et al and Augoustides et al have shown that the proconvulsant properties of  remifentanil make for easier ECTs.  I had one patient seize from a remi injection before ect (do we shock or not?) and another developed post remi-ect status epilepticus.

     So the evidence seems overwhelming that opioids can produce limbic activation and in the right setting   produce brain damage, but we still don't know about people.(NB: when i suggested to several NIH study sections and the AHA in the early 90's that what we were seeing in rats might be relevant they returned non scored critiques...real visionaries there...)

Gabergic drugs

Drugs like barbiturates and benzodiazepines have been long considered to be protective.  Thus the chagrin from many quarters when todorovic, olney and colleagues showed that neonatal exposure to midazolam and nitrous oxide produced later histologic damage and cognitive dysfunction. 

using all the evidence

Anesthesiologists and intensivists face a variety of different patient problems. Often the best treatment approach to a given problem is unclear. Evidence-based medicine has been advo­cated as the most logical approach for clinicians to use to apply research to clinical practice (1, 2). Unfortunately, the database of suitable clinical studies upon which the clinician bases important therapeutic decisions is often incomplete. It is in this setting that the anesthesiologist and col­leagues must nonetheless endeavor to make logical decisions while avoiding an uncertainty-induced pa­ralysis of action—a paralysis that may ensure that an adverse situation will result in an adverse outcome. Another source of information that can be logically applied to some clinical situa­tions is animal studies. Unfortunately, conclusions from animal studies may not always translate to hu­mans, and clinical studies may be too specific or too generalized to be relevant to some cases. There are advantages and disadvantages of basing clinical decisions on animal research and of applying the results of clinical studies to specific patient populations. The full text has been previously published (

Kofke WA: Making clinical decisions based on animal research data: Pro. J Neurosurg Anesth 8:68-72, 1996).

postoperative visual loss (POVL)

POVL is vanishingly rare but when it happens its a nightmare on (insert your hospital's street) street.
It occurs typically during prone surgery even when pins are applied and there is clearly no eyeball pressure.
Opth exam shows ischemia of either the retina or the nerve.  predisposing factors include long case, hypotension, bleeding.  notably with longer cases intraocular pressure has been noted to rise.   I have always hunched that it was somehow related to high venous pressure too.  One clue for this was a patient of a colleagues from a few yrs back during thoracic vertebral surgery from an anterior approach they got into bleeding and had to occlude the svc to stop the bleeding. after all the face swelling finally subsided the patient was quite blind with not even light perception.  similarly cavernous carotid fistuas also produce blindness.
So based on the above physiologic considerations for prone cases my approach is to give just enough anesthesthetic to ensure unconsciousness and if that makes the MAP go less than 80 mmHg i run dilute neosynephrine to make it so.  Use bis and keep it at 55.  transfuse to Hb 10.

the path to new knowledge

Experience is good, science is extolled.  are they mutually exclusive?  Is the scientific method the only path to knowledge.  Is a randomized controlled trial really needed for everything?  Can the effect be so robust based on historical "experience" as to obviate the need for a randomized trial.  I think the discovery of penicillin was in this category.  before most people died, and afterwards most lived.  Is EBM over rated or maybe it needs to be used appropriately and selectively:

Download parachute.bmp
from http://www.auahq.org/Summer2005.pdf

(click on pic to see big version)

So now we have the budget meisters, in the name of quality and safety, refusing requests from experienced clinicians for expensive new therapies.  I requested dexmedetomidine from the UPenn P&T committee with use restricted to neuro patients.  It has some qualities that seem perfect for this group, like producing a sedative state with easy arousability to do a neuro check.  sorry....no rct's on dex for that purpose.    Also, too expensive.    doesn't much matter that there's not an RCT for the use of say, desflurane or sevo for cerebral aneurysm surgery, or even for a  TURP......