Delayed healing as reason for delaying definitive surgery

[Matthew Reeds]

Ivan,

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It depends upon the scenario. Genetics probably play a part as well =A8C =
if
one patient has fairly minor injuries, they may have an overwhelming =
immune
response; whereas someone with major injuries might have a relatively =
minor
immune response. One cannot always predict the response. Undeniably the
trauma of further surgery will activate the inflammatory cascade all the
more =A8C the question is how much. It is this that needs to be =
addressed
rapidly to enable the next stage of DCS or definitive surgery to be
performed early as, until this is limited, further operative trauma may =
well
activate the inflammatory cascade response beyond the level that the
patient=A1=AFs innate immune system can cope with.

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Whether we can actually exclude acidosis at a cellular level as well I =
am
not so convinced. To use one example, trauma etc. causes release of
potassium from cells and, due to the mechanisms of cellular metabolism, =
this
creates a metabolic acidosis. This is only one of many examples =A8C =
although
some mechanisms do push the pH in the opposite direction as well =A8C =
hence
the reason why the underlying pathophysiology is more complex than many
appreciate.

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Regarding the debate of OR-v-ITU, it entirely depends upon what =
facilities
you have in each. In some countries (as in the UK), the ITU is much =
better
equipped for more advanced methods, whereas in other countries the OR in
certain institutions may be as equally-well equipped. Some centres, for
example, have their ITU which is designed to act as a concomitant OR =
=A8C so
it is more a case of substance over form (i.e. it doesn=A1=AFt matter =
what it is
called =A8C but rather what it can do.) For some patients it is the OR =
=A8C if
their physiology is not in extremis and it can be =A1=B0normalised=A1=B1 =
fairly
rapidly to enable further DCS/definitive surgery to be undertaken during
that operative procedure/visit to theatre. For others whose physiology =
is in
extremis, they are not going to be able to withstand the insult of more
invasive procedures and therefore they will be transferred to the ITU =
(or
similar setup) for a period of =A1=B0restoration=A1=B1 of their =
physiology.

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I believe that it would also be useful to define the terminology
=A1=B0perfusion=A1=B1. Cellular perfusion is, I feel, a more appropriate =
terminology
(e.g. as cerebral and renal perfusion is generally auto-regulated for a =
wide
range etc.) It is the cellular hypo-perfusion which acts so vigorously =
to
the patient=A1=AFs detriment. This is what Rick Dutton and his team are =
working
towards improving and forms the basis for their work in testing the
hypothesis that using volume is not bad but it is the high pressure =
approach
that is. I await with interests the results of his research.

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A key component of what I think we can all agree on is the change in =
mindset
over the years and that we all practice a low-pressure approach. Volume =
is
not the same as pressure (although they are inextricably linked.) High
pressure, and not necessarily high volume, will =A1=B0pop the =
clot=A1=B1. Many of us
do not infuse volume because that leads to higher pressures, but if you =
can
counteract that by using anaesthesia etc. (like Rick Dutton is studying)
then this may well negate the problems of low volume (e.g. cellular
hypoperfusion) whilst at the same time limit the adverse problems that
higher volumes currently cause (e.g. =A1=B0popping the clot.=A1=B1) =
Vasodilatation
is much better for the patient, rather than vasoconstriction, in order =
to
increase cellular perfusion (this is part of the reason why the human =
immune
system releases vascular permeability factors and prostaglandins as part =
of
its response to injury.) The old teaching was that this vasoconstriction =
was
counteracted by giving fluid =A8C which is true - but it ignored these
associated problems and the disastrous side-effects. An induced state of
=A1=B0relative=A1=B1 hypotensive vasodilatation may be what is required =
to act more
in accordance with how the innate immune system normally restores
physiologically naturally.

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Matthew

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-----Original Message-----
From: Ivan Hronek [mailto:ivanhronek at yahoo.com]=20
Sent: 25 May 2008 23:16
To: trauma-list at trauma.org
Subject: Delayed healing as reason for delaying definitive surgery

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Matthew,

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I am glad that with your and Karim's help we were able to spell out the
reasoning behind the delayed operation/damage control surgery concept.=20

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I think we're agreeing (hope it is not just my bias again) that the =
reason
for delaying definitive surgery is the delayed normalization of cellular
metabolism, temperature gradients and inflammatory/coagulation cascade
mediator levels.

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I believe we were able to exclude acidosis as the reason (as it can be
normalized) and the myth that resuscitation in the ITU is "better" =
(although
there occasionally are prettier ladies taking care of the patient there, =
I
admit).

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      * next is the question how to decrease the perfusion (and =
temperature)
gradients in the body - be adding narcotics and vasodilating the
persistently constricted areas (muscles, GI tract, subcutaneous areas) =
as
Rick Dutton once told me ? =20

      * attack the immunoparalysis, prevent calcium influx into impaired
cells etc.=20

________________________________

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________________________________

Immunoparalysis and Adverse Outcomes from Critical Illness

Pediatric Clinics of North America - Volume 55, Issue 3 (June 2008)The
clinical significance of immunoparalysis

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http://www.mdconsult.com/das/article/body/95678832-3/jorg=3Dclinics&sourc=
e=3D&sp
=3D20696840&sid=3D708942888/N/645223/1.html?issn=3D0031-3955

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excerpt:

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Trauma=20

Trauma surgeons were among the first clinicians to study the innate =
immune
response in the setting of critical illness. In 1986, Polk and =
colleagues
[16]undertook a systematic evaluation of 20 adults who had severe =
trauma.
The results of their analyses indicated that persistently impaired =
monocyte
antigen-presenting capacity was associated with development of =
nosocomial
sepsis. All of the traumatized patients had reduced monocyte HLA-DR
expression compared with healthy controls when first evaluated on ICU
admission. It was those who exhibited prolonged HLA-DR down-regulation =
in
whom secondary sepsis developed more often. These findings were =
confirmed by
Livingston and colleagues [18]in a separate series of adult trauma =
patients.
It seems that the initial reduction in monocyte HLA-DR expression is
indicative of the CARS state and not itself pathologic. Rather, it is =
the
failure of HLA-DR expression to recover to normal levels over time that
places

 patients at risk for developing nosocomial sepsis.

The ability of HLA-DR expression profile to predict outcome in =
traumatized
adults was strengthened by the work of Cheadle and colleagues [60]in =
1989 in
a study of serial monocyte HLA-DR measurements in 60 trauma victims
beginning the first 24 hours after injury. In their cohort, the depth =
and
persistence of HLA-DR expression was predictive of development of =
secondary
infection. The study differed from previous work in that monocytes with =
low
HLA-DR expression underwent ex vivo LPS-induced stimulation. Patients =
who
developed secondary sepsis but went on to survive had low initial =
monocyte
HLA-DR expression that was reversible by LPS stimulation. In contrast,
persistently low HLA-DR expression, even after ex vivo LPS stimulation, =
was
characteristic of patients who died.

Ex vivo TNF-=A8=BB production also is correlated with outcome in =
clinical trauma
studies. Majetschak and colleagues [28]in 1999 performed ex vivo =
LPS-induced
stimulation of whole blood samples from 46 adult blunt trauma victims. =
They
documented a profound reduction in patients' TNF-=A8=BB production =
compared with
healthy controls. The degree of reduction in the TNF-=A8=BB response was
associated with the severity of injury and this reduction was detectable =
in
samples obtained within 90 minutes after trauma.Patients requiring =
surgery
to treat their injuries experienced a further impairment in their =
TNF-=A8=BB
response.

________________________________

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________________________________

Increased vagal tone accounts for the observed immune paralysis in =
patients
with traumatic brain injury

http://www.mdconsult.com/das/article/body/95678832-3/jorg=3Djournal&sourc=
e=3DMI&
sp=3D20406500&sid=3D708942891/N/628630/1.html?issn=3D0028-3878

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Neurology - Volume 70, Issue 6 (February 2008)=20

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ABSTRACT=20

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Traumatic brain injury (TBI) is a leading cause of death and disability,
especially in the younger population. In the acute phase after TBI, =
patients
are more vulnerable to infection, associated with a decreased immune
response in vitro. The cause of this immune paralysis is poorly =
understood.
Apart from other neurologic dysfunction, TBI also results in an increase =
in
vagal activity. Recently, the vagus nerve has been demonstrated to exert =
an
anti-inflammatory effect, termed the cholinergic anti-inflammatory =
pathway.
The anti-inflammatory effects of the vagus nerve are mediated by the =
=A8=BB7
nicotinic acetylcholine receptor present on macrophages and other
cytokine-producing cells. From these observations, we hypothesize that =
the
immune paralysis observed in patients with TBI may, at least in part, =
result
from augmented vagal activity and subsequent sustained effects of the
cholinergic anti-inflammatory pathway. This pathway may counteract =
systemic

 proinflammation caused by the release of endogenous compounds termed
alarmins as a result of tissue trauma. However, sustained activity of =
this
pathway may severely impair the body's ability to combat infection. =
Since
the cholinergic anti-inflammatory pathway can be pharmacologically =
modulated
in humans, it could represent a novel approach to prevent infections in
patients with TBI.

Mechanisms and innovations Traumatic brain injury: Can the consequences =
be
stopped?

Canadian Medical Association Journal - Volume 178, Issue 9 (April 2008) =
Key
points

* Severe traumatic brain injury is a leading cause of morbidity and
mortality worldwide.=20

* Abnormal intracellular calcium homeostasis is a central feature of =
both
grey and white matter secondary injury.=20

* White matter injury is important in the prognosis of both severe and =
mild
injury.=20

* Recent studies point to trauma-induced changes in neuronal receptor
composition that render cells vulnerable to delayed injury.=20

Box 1. Glossary of terms

=A6=C1II-spectrin: A structural protein involved in the maintenance of =
axonal
shape. A key target of calpains after trauma.

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AMPA (=A6=C1-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid): =
Chemical
agonist selective for the AMPA class of excitatory glutamate receptors.

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Ionic homeostasis: The naturally occurring gradient of intracellular ion
concentrations within a cell.

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=A6=C2-amyloid precursor protein: A protein transported by axons. It can =
be used
as an immunohistochemical marker of axonal injury. This protein =
accumulates
in injured axons with impaired transport and contributes to axonal =
swelling.

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Calpains:A family of enzymes that degrade numerous intracellular =
proteins.
Calpains are activated by high levels of intracellular calcium.

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Caspase-3:A calcium-activated enzyme referred to as the =
=A1=B0executioner
caspase=A1=B1 because of its role in initiating programmed cell death.

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Cytoskeleton:Proteins that comprise the cell=A1=AFs structural =
=A1=B0skeleton.=A1=B1

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Excitoxicity:Over-activation of glutamate receptors leads to a massive
sodium and calcium influx that results in rapid cell death.

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GluR2: The AMPA-receptor subunit that determines whether the receptor is
permeable to calcium. AMPA receptors that include the GluR2 subunit are =
not
permeable to calcium.

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Immunohistochemistry: A technique used to visually identify specific
proteins in tissues by use of antibodies against specific antigens.

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NMDA (N-methyl-D-aspartic acid): Chemical agonist selective for the NMDA
class of glutamate receptors

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Primary cell culture: A laboratory technique of growing cells on a =
plate.
Primary cell culture is often used for in vitro experiments.

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Reactive astrocytosis: A characteristic response of astrocytes (subtype =
of
glial cells) to injuries of the central nervous system. It includes
proliferation and processes extension, and it can be visualized by
histological examination of increased expression of an astrocyte marker
(glial fibrillary aidic protein).

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Secondary axotomy: The process by which axons become disconnected after =
a
delay following initial trauma. Occurs as the result of subcellular =
events
not the force of the initial injury.

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Superoxide, peroxynitrite, nitric oxide: Reactive oxygen species that =
can
contribute to the destruction of cell membranes and DNA breakdown =
leading to
cell death.

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Traumatic axonal injury: The delayed and progressive deterioration of =
white
matter following trauma.

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Tumour necrosis factor =A6=C1:A cytokine secreted by inflammatory cells =
that is
capable of initiating cell-death pathways as well as modulating
glutamate-receptor composition.

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3D1384607

http://www.galenicom.com/zh/medline/article/18048039/Immunoparalysis+afte=
r+m
ultiple+trauma.

http://content.karger.com/ProdukteDB/produkte.asp?Aktion=3DShowFulltext&A=
rtike
lNr=3D18755&Ausgabe=3D225615&ProduktNr=3D223996

 Ivan Hronek MD


SFMC, Los Angeles, CA                                                Do =
not
fear to be eccentric in opinion, for every opinion now

accepted was once eccentric. - Bertrand Russell-

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