Morning Report

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Morning Report
(My Second)

• Steve Anisman
• July 18, 2002

2
The Case
74 yo F with large L sided CVA 2 years PTA which
had left her unable to meaningfully communicate,
and with R sided paralysis. Hx includes a-fib,
G-tube for inability to swallow, MRSA 1 year ago.
3 days PTA, she fell out of her wheelchair and
hasnt been right since. On day of admission,
family called EMT because Pt was oliguric, and
unresponsive in bed with blankets on. Family was
concerned that Pt may have had another stroke.
EMTs arrive to find Pt as described, with temp
107.6OF.
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The Case
She was transferred to ED, intubated, placed
under cooling mist, fans, and given IF fluids.
Hospital course remarkable for acute renal
failure with eventual resolution, predicted CK
curve, and ultimate return to baseline.
Remaining issues are focused on disposition, as
there is some reluctance to place her back with
family secondary to concerns of neglect, and her
Hx of MRSA make placement difficult.
4
blah blah blah
5
Hyperthermia
Whoops
Instead, lets talk about
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Fever
Definition
Above normal temperature, with set point
modification.
Normal Temperature
600 (99.9oF)
Were assuming oral readings here, which are
expected to be ______________ rectal or tympanic
(both core) readings.
0.6o (1.0o) below
The reason for the discrepancy is

evaporative heat loss from mouth breathing,
particularly in patients with respiratory disease
(and tachypnea).
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Temperature variation
Typically, temperature varies about 0.5oC
throughout the day. In fever, this range can
double diurnal variation remains, but at a
higher level. Womens basal temperature drops by
0.6oC during the two weeks prior to ovulation
increased temp at ovulation persists until the
end of menses. Seasons, pregnancy, digestion all
can change set point but not in a reliable way.
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Fever vs. other hotnesses
Set point is maintained by the thermoregulatory
center in the anterior hypothalamus, and is fixed
in early childhood. Control is maintained by
increasing heat production in muscle and liver or
increasing heat loss through skin and lungs.
In fever, the set point becomes elevated.
Hyperthermia has nothing to do with metabolic
control the body is simply loaded with heat
above its ability to dissipate it. Diurnal
variation is not seen with hyperthermia, and
antipyretics are ineffectual.
Hyperpyrexia is fever 41.5oC, typically as a
result of CNS hemorrhage, but occasionally with
severe infections.
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Why do I feel so
feverish?
The set point is raised (more details soon), and
in order to raise the body temperature to the new
level, vasomotor neurons cause vasoconstriction.
Vasoconstriction shunts blood to the internal
organs, decreasing heat loss from the skin,
making extremities feel cold. Shivering is
initiated to increase heat production from
muscles, and the liver kicks in a few extra
joules. Still, we feel cold.
Silly humans then crawl under a heavy blanket on
the couch and turn up the heat in the warmest
room in the house. The body temperature
eventually fluctuates around the new set point
just as it did around the old one.
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But how?
Pyrogens.
Anything that causes fever is a
pyrogen. Exogenous pyrogens are typically
microbes or their toxins, such as gram negative
lipopolysaccaride endotoxin and the gram
positive toxic shock syndrome toxin (Staph
species).
Toxins from Staph Strep also act as
superantigens they act not only as exogenous
pyrogens, but they also bind with MHC II (major
histocompatibility complex 2) and T cells to
cause the release of endogenous pyrogens.
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Ahh, endogenous pyrogens.
IL-1, IL-6, TNF (tumor necrosis factor), CNTF
(ciliary neurotropic factor), and
interferon-alpha all will cause the hypothalamus
to upregulate the set point. The final common
pathway seems to be IL-6, as absence of the IL-6
gene prevents animals from developing fever from
bacterial infection. Any of these factors,
injected into healthy subjects in miniscule
doses, will cause fever in the absence of actual
infection.
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The hypothalamus, again
These factors are released into the bloodstream
by monocytes, macrophages, endothelial cells, and
other cells in response to infection, and they
collect in areas surrounding the thermoregulatory
centers of the hypothalamus called OVLT (organ
vasculosum lamina terminalis), where
prostaglandin E2 (PGE2) is synthesized. There are
4 receptors for PGE2 in the brain one of them
is the thermoregulator and raises the set point
in response to PGE2, using elevated cAMP as the
cellular messenger.
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Pretty pictures
14
Pretty pictures
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For the linguistically impaired
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and even the brain
The brain responds to many direct viral insults
by releasing IL-1, IL-6, INF, and CNTF these
seem to bypass the PGE2 pathway and are able to
raise the hypothalamic set point all by
themselves. The brain also seems to respond to
various other insults in the same way, which
explains why intracranial hemorrhage also is
often associated with fever. PGE2 is also
synthesized and circulated in the periphery in
response to pyrogenic cytokines this causes
arthrlagia and myalgia.
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Stop the madness!
If you can block PGE2, you can prevent fever.
The rate limiting step in PGE2 production is the
release of arachidonic acid from cell membranes
the arachidonic acid is then used as a substrate
for cyclooxygenase, which itself is a substrate
for PGE2. ASA inhibits cyclooxygenase directly.
Acetominophen is oxidized in the brain by
cytochrome p450 and its metabolite inhibits
cyclooxygenase (but it is less effective in the
periphery because the metabolite does not appear
there). Corticosteroids inhibit cyclooxygenase
and also block mRNA transciption of the pyrogenic
cytokines.
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More dyswordia assistance
?
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The call from Gail
Dr. Anisman sorry to call so late Mrs.
Rodriguez is a 4A patient youre covering shes
here for DKA but her sugars have been fine she
has a fever of 102 I woke her up to check it and
shes sleeping again Ill give her a few Tylenol,
OK? MY RESPONSE
Umm Who is this?
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Your response
It depends.
Fever can be our friend...
or

fever can be our enemy.
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Diagnostic benefit to fever?
Obviously, fever is an indicator that there is
something wrong, usually infectious in nature.
Our usual response to fevers 101.5o is to
examine for something focal and send appropriate
cultures (or simply send pan cultures and CXR if
between 0100 and 0630). Some diseases have
characteristic fever curves. For example, typhoid
fever and disseminated TB

have reversal of diurnal
highs and lows (daily high 0600, daily low
1600).
P. vivax and P. ovale have

fever spikes q 48 h (P. falciparums cycle
48 hrs temp doesnt always correlate).
P. malariae has
fever
spikes q 72 h.
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Diagnostic benefit to fever?
An entity called cyclic neutropenia is
characterized by
pharyngitis, aphthous stomatitis, and rare
bacterial systemic infections. If it isnt
treated, it can result in chronic gingivitis with
tooth loss /or perforation of abdominal viscus.
Fevers last 3 days, and recur every 18-24 days.
Every degree farenheit should correlate with 10
beats per minute. With 99o and 80 as normal,
104o should have pulse of 140.
Relative bradycardia (temperature-pulse
dissociation) can be seen in
M. pneumoniae pneumonia,
typhoid fever, blackwater fever (P. falciparum
with hemolysis) brucellosis, leptospirosis, some
drug-induced fevers, and factitious fever.
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Diagnostic benefit to fever?
Sustained fever (one that ignores the diurnal
rhythm of which weve become so fond) can be seen
in

central nervous system
injury, pneumococcal pneumonia, or psittacosis.
Remittant fever (one with a baseline fever,
interspersed with daily spikes above that
baseline) can be seen in

bacterial
endocarditis, brucellosis, or malignancy.
A fever that spikes sharply twice a day is seen
in
gonococcal endocarditis (but not in gonococcemia
alone).
Other than malaria, causes of relapsing
infection include
Spirillum minus (rat bite)
infection, Streptobacillus moniliformis infection
(Haverhill fever), chronic meningococcemia, and
10-15 of Hodgkins disease.
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Is fever our enemy?
Peripheral PGE2 is a potent immunosuppressant.
Patients dont like feeling feverish.
Metabolic demands of fever (particularly during
the shivering phase) are high, and particularly
in patients with cardiac or pulmonary disease and
high metabolic load, reducing O2 demand (by as
much as 20 in critically ill patients if
paralysis is also used!) seems like a good idea.
Fever reduction in experimental patients
(innoculated with sandfly fever) led to
amelioration of fever-induced losses in mental
work performance.
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Is fever our enemy?
If bacterial toxins act as pyrogens (which they
do), it seems like poor teleologic strategy
unless fever offered a survival advantage for
these bacteria.
The fever often seen post-MI has no survival
benefit (Pts with fever do no better than those
without), and this is likely to be a case where
the increased metabolic load is dangerous. Most
important to us, however, is the fact that
Gail doesnt like fever.
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Is fever our friend?
Higher temperatures impair the replication of
many microorganisms. They lead to the release of
acute phase reactants by the liver, some of which
bind divalent cations which are needed for the
replication of many microorganisms. They lead to
anorexia, which reduces available glucose, and
metabolism is shifted towards proteolysis and
lipolysis. Somnolence is induced, leading to
decreased energy demand.
Higher temperatures seem to help leukocytes in
identifying and attacking antigenic tumor cells.
It seems that it would be unwise evolutionary
strategy for every higher animal to develop and
maintain a febrile response if there were no
benefit.
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Is fever our friend?
Animals innoculated with bacteria show a
survival rates directly related to febrile
response. The febrile animals had lower bacterial
load in tissue, had more frequent sterile blood
cultures, and greater accumulation of leukocytes
at the site of innoculation than animals without
fever. The degree of fever had no effect, however.
Low temperatures (sub-physiologic) are
correlated with poor immunologic response.
Studies have demonstrated reduced bacterial
killing directly related to reductions in
temperature, that lymphocytes are more sluggish
at low temperatures, and that patients cooled
intraoperatively are more likely to develop
infection.
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Is fever our friend?
IL-1 not only acts as a pyrogen, but also as a
lymphocyte activator, a trigger for the release
of endorphins, a trigger for the release of ACTH,
and a direct stimulator of the adrenal gland to
release corticosteroid.
PMNs display higher chemotactic and phagocytic
activity at 40oC than at 37oC (but were
ineffectual at 42oC or higher).
PMN motility improves progressively as temp
increases from 37 to 42.
The improved effectiveness of PMNs at higher
temperatures does not seem to be true for Staph
species.
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Is fever our friend?
T-lymphocyte mediated toxicity is enhanced when
sensitization to antigens occurs at higher
temperatures. Subsequent antibody levels are
higher.
LIF (leukocyte migration inhibition factor) is
produced in greater quantities by monocytes at
greater temperatures, keeping cells at the site
of infection.
Lymphocyte-produced IFN (interferon), which can
activate monocytes and NK (natural killer) cells,
and which is an indicator for effective antigen
recognition, works 4-16 times better at higher
temperatures.
Monocytes proliferate at a greater rate and
function more effectively at 38.5-40oC than at 37o

not only that, but they were
more resistant to damage by viruses.
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Is fever just an acquaintance?
The benefits in recognition and activation are
not maintained for B cells and for NK cells at
higher temperatures in fact, these cells work
less well during fever. Fortunately, they are not
essential in the initial phase of most
infections, and the loss seems to be outweighed
by the benefit to T cells and PMNs.
Additionally, the suppression of NK cells during
active infection may help limit collateral damage
to viable tissue in the region of infection.
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Take home points

• Fever is our friend

it helps us diagnose.

• Fever is our friend

it helps us fight infection.

• Fever is our friend

it makes life harder for bugs.

• Be nice to your friends.

• If you have to treat, use acetominophen.