| dc.description.abstract | Both traditional and modern surgery have emperically given
importance to various anti-phlogistic measures,
following the rationale that the inflammatory process
often overshoots its objective as a defense and repair
process and becomes excessive and detrimental. The
anti-inflammatory drugs used in human surgery have
generally been selected according to their performance
in patients with rheumatoid arthritis, and essentially
the same drugs have been adopted for use in veterinary
surgery. Rheumatoid inflammation, however, differs
markedly from an acute post-traumatic inflammatory
reaction.
There is a lack of reliable models for clinical
assessment of anti-inflammatory effects. Recent
research in human oral surgery with a rather unique
model that allows well controlled studies on how antiinflammatory
drugs may modulate a post-operative course,
has for several drugs challenged the common view
regarding their efficiency and suitability in
controlling post-traumatic sequelae. It has remained an
open
apply
body,
question whether the findings in oral surgery also
to surgery and traumata of other parts of the
e.g. the extremities. Appropriate and well
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controlled clinical models for such studies are lacking
in human medicine.
The aim of the present work was to establish a
properly controlled model for investigations on how
steroidal and non-steroidal anti-inflammatory drugs
(NSAID) might modulate the signs of the inflammatory
reaction and the healing process following orthopaedic
surgery. The experiments were designed on a placebocontrolled
crossover basis, with two "identical"
surgical interventions being performed on the forelimbs
of each dog with an interval of 28 days, to enable a
paired comparison of the post-operative courses.
In a standardized way, under general anaesthesia,
the 3rd metacarpus was transected with an oscillating
saw. The fracture was then stabilized with a mini dynamic
compression plate before the wound was sutured. A
special device was designed to allow measurements of
post-operative swelling, while pain and limb function
were assessed by the use of visual analogue scales.
Abnormalities in the wound healing were recorded as
well as clinical signs that could be indicative of
adverse drug effects. Radiographs taken 2, 4, 6 and 8
weeks after the two operations were interpreted and
compared for bone union, callus formation, signs of
infection and foreign body acceptance. The dogs were
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euthanized 8 weeks after the 2nd operation and the two
3rd metacarpi of the forelimbs excised. They were later
cut in a cryo-microtome and the stained sections
assessed for bone healing.
The three anti-inflammatory drugs selected for the
investigations were a glucocorticoid, betamethasone; and
two NSAID, phenylbutazone and indomethacin.
Glucocorticoids are recognized as the most powerful
anti-inflammatory drugs, but their place in surgery is
disputed. Phenylbutazone was selected since it is
probably still the most widely used NSAID in veterinary
practice, while a main reason for including indomethacin
was that it has been reported to delay or inhibit
fracture healing.
In the first trial, a single pre-operative injection
of 3mg betamethasone was tested against placebo in each of
8 dogs. The drug proved to significantly reduce the
post-operative swelling. On the 3rd day the reduction
was 43~. Less pain and limping were assessed after the
glucocorticoid was injected, but the differences did not
reach a level of significance. No adverse effects of
the glucocorticoid on wound or fracture healing were
detected. This trial included measurements of the
endogenous cortisol levels. A marked decline in the
serum cortisol levels followed the glucocorticoid
injection. The levels remained low for about 3 days and
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then returned to normal. It was concluded that the
results of the study support the view that short-term
glucocorticoid administration can efficiently curb an
excessive post-traumatic inflammatory reaction and is
essentially safe.
In the next trial 8 dogs were given 300 mg phenylbutazone
by oral administration twice daily for 8 days
starting on the day before surgery. Phenylbutazone did
not reduce the swelling significantly as compared to
placebo, although the drug gave a significant pain
relief. The clinical observations indicated somewhat
better wound healing after the operation when placebo
was given, and that also applied to the fracture healing
as evaluated by radiographs and bone sections.
In another group of 8 dogs, 25 mg indomethacin was
to be administered orally twice daily for 8 days starting
on the day before surgery. This medication had to be
discontinued after 2 1/2 days when they had received a
total dose of 125 mg indomethacin, since signs of toxicity
became evident, e.g. vomiting, bloody stool and lethargy.
One indomethacin-treated dog died on the 5th post-operative
day. Swelling measurements showed no consistent
difference, but the pain assessments were significantly
lower after the operation when indomethacin was
administered. No noticeable differences were observed
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in wound healing, but the radiological evaluation
revealed tendencies in disfavour of indomethacin.
A trial was then undertaken in another group of 8
dogs with a lower dosage of indomethacin. They each
received 5 mg indomethacin twice daily for 8 days starting
on the day before surgery. Even at this dosage one of
the dogs developed bloody stool on the 5th post-operative
day. With indomethacin there was a tendency towards less
swelling, and the reduction became significant after
one week. The pain assessments showed no consistent
difference and there appeared to be no difference in
wound and fracture healing.
The difficulties encountered in selecting an
appropriate dosage of indomethacin provide a striking
example of how differences in pharmacokinetics may
explain differences in drug response both within as
well as between species. It was difficult to obtain
consistent and reliable assessments of pain and limping
even if the dogs served as their own controls. These
results should therefore be cautiously interpreted.
The present studies provide evidence that
the drug effects on post-operative swelling observed in
oral surgery, also apply to acute traumatic swellings in
other parts of the body, since the recordings with limb
volumetry showed a remarkably good correlation with
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corresponding results obtained in oral surgery. This
conclusion was recently also reached by another researcher
in tests on paracetamol using this model with limb surgery.
In addition to significantly reducing the swelling,
paracetamol also proved to efficiently reduce pain without
any signs of adverse effects.
Indomethacin does not appear to be recommendable in
dogs, while phenylbutazone presents a relatively wide
safety margin. The anti-phlogistic potential was,
however, not impressive for any of the two NSAID. A
short-term glucocorticoid administration or paracetamol
seem to be better choices for curbing the sequelae of an
acute post-traumatic inflammatory reaction. | en |
