X-Message-Number: 4143
Date: 03 Apr 95 22:28:37 EDT
From: Mike Darwin <>
Subject: SCI.Cryonics My last post

In my last post on cerebral ischemia I stated:

>Excitoxicity does occur however, and we are currently looking hard at kainate
>and quisqualate receptor blockers as well as others which, for priprietary

>reasons, I cannot talk about publically.  I can tell you that we have recovered
>one dog named Jake after 10 minutes of cardiac arrest at 37.5xC followed by 5
>minutes of reperfusion (using bypass) at a mean arterial pressure (MAP) of 155
>mmHg or less and ANOTHER 5 minutes of reperfusion at a MAP of 30 mmHg or less,
>followed by hypertensive , (MAP =140 mmHg) hypothermic reperfusion.

There is both a serious error and an omission in this paragraph.  Where I say
"we have recovered a dog named Jake after 10 minutes of cardiac
arrest...followed by five minutes of reperfusion at MAP of 155 mmHg" the text
should read" "followed by five minutes of reperfusion at a MAP of *15* mmHg or
lower." An extra 5 got tacked onto the end of the 15.

The omission was explaining the significance of this period of low pressure
perfusion following cardiac arrest:  we want to simulate trickle flow with poor
CPR, followed by better flow (MAP of 30 mmHg) when drugs such as high dose
epinephrine are given during CPR, and then good flow with full-tilt
extracorporeal support.  Thus, the model is made more clinically relevant by
simulating what is likely to actually happen in real circumstances.  What makes
Jake's recovery especially impressive is that trickle flow in many studies has
been shown to cause more injury than *no* flow.  Also, I might add that unlike
Safar and some others, every dog we've ever subjected to 10 minutes of global
ischemia (cardiac arrest) has died no matter what we did.  Others get some

animals back, albeit compromised after this interval.  We have not.  I am, still
smiling ear-to-ear that we had success with Jake, but of course we need to do
more animals.

Finally, I meant to comment that Lutz's book is somewhat dated and that the
cause of failed post-ischemic cerebral perfusion (the so-called no-reflow
phenomenon) is usually *not* increased intracranial pressure.  Indeed in both
humans and animals the intracranial pressure does not start to rise after a
global ischemic insult until around 24 hours post insult if it occurs at all..

Failed cerebral perfusion may occur even in the absence of elevated intracranial
pressure and typically begins (in untreated animals subjected to 10 or more
minutes of ischemia) within about an hour of reperfusion.  Immediately upon
reperfusion overall cerebral blood flows are greatly elevated and the brain (if
exposed to view) is frankly hypereimic.  Flow then starts to decrase with
no-reflow being complete in some animals at the 1-4 marks.

The etiology of this no reflow phenomenon continues to be a source of
controversy within the cerebral resuscitation community.  Certainly the influx
of calcium which Nimov mentions may be a material factor since not only is
calcium involved in neurotransmission and membrane functions (including
activation of phospholipases which tear brain cell membranes apart) but it is
also critically involved in vasmotion and vasospasm and in initiating the
inflammatory/immunse response cascade (leukotrienes, prostaglandins, etc.).
Added evidence for this is that calcium channel blockers which are

cerebrospecific such a lidoflazine and nomidipine protect to some extent against
the no reflow phenomenon and help maintain better post-insult cerebral blood
flow.

But these drugs are *not* in my opinion the answer in and of themselves.  For,
even if you maintain good cerebral blood flow you will experience delayed
neuronal loss (death) in certain areas of the brain.  Especially hard hit are
the structures which seem to underlie consciousness (the RAS) and memory (the
CA1 area of the hippocampus).  Understanding why these cells die many hours or

days after the insult, even when cerebral blood flow is preserved, is one of the
hottest areas in clinical research and neuroscience.  And I don't mind saying
that I think we (21st Century Medicine) are in there with the big boysand maybe
towards the front of pack in solving this problem.

We are now developing models which will be very useful in evaluating our brain
resuscitation interventions and in better understanding injury.  Just this last
Friday we did our first chronic electrode implantation in a cat and we seem to

have mastered the technique (we have been being tutored in this technique by one
of the best people in the country who has done nearly 400 cats).  While the
animals look like poster children for the animal rights people, they do very

well and live normal lifespans with no pain: our guy from last Friday is sitting
on my lap purring as I write this.

We hope to use this technique not only in cerebral resuscitation but in brain
cryopreservation experiments as well.  And I think we are well on our way to
achieving this: not only did the animal do well, but we've got lovely EEGs from
our Nihon-Kohden EEG machine -- the first we've gotten from a chronic animal.

(I mention the manufactueer's name here because we were using an old Grass 6, 16
channel machine which used tube technology; it was real bear and we scrapped it
for a new solid state model.  This was one of the best decisions we ever made!
We looked at more current Grass machines but nothing beat the ease of use of NK

machine we setlled on -- and by the way, anybody out there want to buy a Grass 6
REAL cheap?))

Finally, my thanks to Joe Strout for pointing us towards a good lab capable of
3-D EM imaging.


Mike Darwin

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