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discussions, stats, and author profiles for this publication at: http://www.researchgate.net/publication/5826069

Serum cortisol and thyroxine concentrations

as predictors of death in critically ill puppies
with parvoviral diarrhea
ARTICLE in JOURNAL OF THE AMERICAN VETERINARY MEDICAL ASSOCIATION DECEMBER 2007
Impact Factor: 1.56 DOI: 10.2460/javma.231.10.1534 Source: PubMed

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Amelia Goddard

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SMALL ANIMALS

Serum cortisol and thyroxine concentrations

as predictors of death in critically ill puppies
with parvoviral diarrhea
Johan P. Schoeman, bvsc, mmedvet; Amelia Goddard, bvsc, mmedvet; Michael E. Herrtage, ma, dvsc

ObjectiveTo evaluate the role of adrenal and thyroid hormones in the prediction of death
in a population of critically ill puppies with parvoviral diarrhea by measuring serial daily serum concentrations of cortisol and thyroxine.
DesignProspective case-control study
Animals57 critically ill puppies with parvoviral diarrhea admitted to the hospital and 17
clinically normal control puppies.
ProceduresBasal serum cortisol and thyroxine concentrations were measured for each
dog with parvoviral diarrhea at admission (prior to treatment) and daily until death, euthanasia, or discharge.
ResultsMedian time between admission and death was 48 hours (ie, on day 3). Median
serum cortisol concentration on day 1 (admission) in all dogs with parvoviral diarrhea (248
nmol/L) was significantly higher than in control dogs (77 nmol/L). No significant difference
was found in the day 1 median serum cortisol concentration of 11 dogs that died (302
nmol/L) and 46 dogs that survived (238 nmol/L). A significantly higher median serum cortisol concentration was, however, found in nonsurvivor group dogs, compared with survivor
group dogs, on days 2 and 3. Median serum thyroxine concentration on day 1 in dogs with
parvoviral diarrhea was significantly lower than in control dogs (8.12 nmol/L vs 35 nmol/L,
respectively). Median serum thyroxine concentration of nonsurvivor group dogs (4.4 nmol/
L) was significantly lower than that of survivor group dogs (9.2 nmol/L) at admission and
became even lower on days 2 and 3.
Conclusions and Clinical RelevanceHigh serum cortisol and low serum thyroxine concentrations at 24 and 48 hours after admission were associated with death in dogs with
parvoviral diarrhea. (J Am Vet Med Assoc 2007;231:15341539)

he adrenal response to critical illness is essential for

survival. Physical trauma varying in severity from
general anesthesia and surgery to major trauma and
septicemia has been shown to increase cortisol secretion and serum cortisol concentrations.1
Several studies110 on critically ill humans have
shown a positive correlation between high serum cortisol
concentration and mortality. In others, a positive association between serum cortisol concentration and degree of
illness was convincingly shown.11,12 However, many other studies failed to show an association between serum
cortisol concentration and mortality.1316 One previous
study17 conducted in dogs failed to show any significant
difference in serum cortisol concentrations between survivor and nonsurvivor groups. The dearth of information
on serum cortisol concentrations in critically ill dogs has
been highlighted in a recent review.18
Critical illness in humans is characterized by multiple and complex alterations in the thyroid axis.1921
From the Department of Companion Animal Clinical Studies, Faculty
of Veterinary Science, University of Pretoria, Onderstepoort 0110,
South Africa (Schoeman, Goddard); and the Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES,
England (Herrtage).
Presented in part at the 49th British Small Animal Veterinary Association Congress, Birmingham, England, April 2006.
Address correspondence to Dr. Schoeman.
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Scientific Reports: Original Study

Abbreviation
IQR

Interquartile range

Low concentrations of thyroxine have been shown to

indicate prolonged illness and a poor prognosis in human critical care.2225 Nonthyroidal illness in dogs is a
well-known cause of the euthyroid sick syndrome, and
the effects of such illness on lowering various thyroid
hormone concentrations have been well described.2629
The use of thyroxine in outcome prediction for dogs
has not received much attention in veterinary medicine, and to our knowledge, no reports are found in the
veterinary literature demonstrating a significant difference in thyroxine concentrations between nonsurvivor
and survivor groups in the care of critically ill dogs.
In a large human study30 on several endocrine predictors, basal cortisol and thyroxine concentrations correlated best with outcome. The aim of the study reported
here was to assess the usefulness of serial basal serum
cortisol and thyroxine concentrations in the prediction
of outcome in puppies with parvoviral diarrhea.
Materials and Methods
AnimalsThis prospective study was performed
on 57 puppies with severe parvoviral diarrhea, admitJAVMA, Vol 231, No. 10, November 15, 2007

Study designBlood samples in the patient population were collected prior to treatment on admission
(day 1) and daily thereafter between 8:00 am and 11:00
am, until death, euthanasia, or hospital discharge. Day
2 blood sample collection took place at approximately
20 to 24 hours after that of day 1 and at 24 hour intervals thereafter. Blood samples from control dogs were
collected once in the consulting room after they had
waited a similar period as the study dogs in the reception area of the same hospital. Blood was collected from
the jugular vein by needle venipuncture in all dogs and
placed into plastic tubes for serum collection. Blood
samples were allowed to clot and tubes were centrifuged within 1 hour of collection. The serum was harvested and stored at 80C until analyzed.
AssaysAll samples from the patient population
were assayed in a single batch; samples from control
dogs were assayed in a second batch. Serum cortisol
and thyroxine concentrations were determined in duplicate on a gamma counter with a previously validated
radioimmunoassay kit.a Sensitivities of the cortisol and
JAVMA, Vol 231, No. 10, November 15, 2007

thyroxine assays were 5.5 nmol/L and 2.8 nmol/L, respectively. For statistical analysis, values < 5.4 nmol/L
and 2.7 nmol/L, respectively, were considered below the
limit of detection.
Data analysisThe usefulness of high serum cortisol concentration (ie, > 224 mmol/L) as a predictor
of death in puppies with parvovirus diarrhea was determined. Sensitivity, specificity, positive predictive
values, and negative predictive values for high serum
cortisol concentrations on day 3 (approx 48 hours after admission) were calculated by use of the following
equations:
Sensitivity = TP/(TP + FN)
Specificity = TN/(FP+TN)
Positive predictive value = TP/(TP+FP)
Negative predictive value = TN/(FN+TN)

where TP, FN, TN, and FP are the number of true-positive results, false-negative results, true-negative results,
and false-positive results, respectively.
Data were tested for normality by the Kolmogorov-Smirnov test. Within-group serial daily differences
were measured by use of the Friedman test for related
samples. Differences in median serum cortisol and thyroxine concentrations between nonsurvivor and survivor groups were analyzed by use of the Mann-Whitney
U test for nonparametric data. Comparisons between
nonsurvivor and survivor groups were only made up to
day 3, after which only 2 dogs in the nonsurvivor group
remained, precluding any further reliable comparisons
between the outcome groups. Correlation between variables was assessed by the Spearman rank correlation
coefficient (rs). For all comparisons and correlations,
values of P < 0.05 were considered significant. Values
are reported as median and range or IQR, as indicated.
Statistical analysis was performed on a personal computer by use of a commercial software package.b
Results
Patient populationFifty-seven dogs with parvoviral diarrhea were included in the study. Eleven dogs
were in the nonsurvivor group and 46 in the survivor
group. Of nonsurvivor group dogs, 2 died on admission
(day 1), and another dog died on day 2. Six dogs died
during day 3, and of the remaining 2 dogs, 1 was euthanatized on day 4 and the other on day 6. Euthanasias
were performed because of a poor prognosis; these dogs
were included for analysis in the nonsurvivor group. Of
the 11 dogs that died, 10 were male and 1 was female.
Overall, 38 of 57 (67%) dogs with parvoviral diarrhea
were male and 19 (33%) were female. Median patient
age was 3.5 months (range, 2 to 12 months). Median
body weight was 5.7 kg (12.6 lb) with a range of 3 to
19 kg (6.6 to 41.9 lb). Median time between hospital
admission and death was 48 hours (range, 2 to 120
hours). Median length of hospital stay for all dogs was 4
days (range, 1 to 13 days). No patient received adrenal
suppressive agents such as etomidate or corticosteroids
at any time during the study period. Severe dehydration resulted in scant serum harvest, and as such serum
cortisol and thyroxine concentrations were not determined for 3 dogs (2 dogs in the survivor group and 1
Scientific Reports: Original Study

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SMALL ANIMALS

ted consecutively to the high care isolation ward at the

Onderstepoort Veterinary Academic Hospital of the
University of Pretoria in South Africa between October 2004 and March 2005. Seventeen healthy puppies
admitted to the Onderstepoort Veterinary Academic
Hospital for routine vaccination were used as control
dogs. They were considered healthy on the basis of a
full physical examination and routine laboratory testing (ie, CBC determination and serum biochemical
analysis). The study was reviewed and approved by the
institutional animal use and care committee. All owners signed a written consent form allowing daily blood
samples to be obtained from their dogs.
Patients with a diagnosis of parvoviral diarrhea
that fulfilled the following criteria were considered
eligible for inclusion in the study: their disease condition necessitated admission to the hospital, their body
weights were > 3 kg (6.6 lb), the diagnosis of parvoviral
diarrhea was confirmed by the detection of parvoviral
particles in feces by use of electron microscopy, no Babesia parasites or Ehrlichia morulae were detected on
capillary and central venous blood smear evaluation,
no clinical signs consistent with canine distemper such
as conjunctival or nasal discharge or neurologic signs
were present, and no distemper viral particles were observed on electron microscopic examination of feces.
A history of previous administration of corticosteroids to dogs or known malignancies that might have
involved the adrenal glands was an exclusion criterion
for the study. Dogs were treated according to a standard
hospital protocol comprising rehydration by IV administration of crystalloid fluid or colloid fluid (when in
severe shock or when severely hypoproteinemic) and
IV administration of amoxicillin with gentamicin added once patients were rehydrated. Buprenorphine was
administered as necessary for abdominal pain. Fluids
for IV administration were spiked with potassium chloride or 50% dextrose when indicated. Metoclopramide
or ondansetron was administered to control vomiting.
Dogs were also started on enteral feeding soon after rehydration.

SMALL ANIMALS

dog in the nonsurvivor group) on day 1 and for 1 dog

(nonsurvivor group) on day 2.
Control populationHealthy dogs consisted of 10
sexually intact males and 7 sexually intact females. Median age was 3 months (range, 2 to 13 months). Median
body weight was 7 kg (15.4 lb) with a range of 2 to 24
kg (4.4 to 52.9 lb).
Serum cortisol concentrations on admissionMedian serum cortisol concentrations on admission (day
1) in all dogs with parvoviral diarrhea was significantly
higher than in control dogs (248 nmol/L [IQR, 115 to
451 nmol/L] vs 77 nmol/L [IQR, 43 to 94 nmol/L], respectively). Although the median serum cortisol concentration was higher in nonsurvivor group dogs (302
nmol/L [IQR, 106 to 392 nmol/L]) than in survivor
group dogs (238 nmol/L [IQR, 119 to 384 nmol/L]),
the difference was not significant (P = 0.361; Figure 1).
Of the 54 serum cortisol concentrations determined for
dogs with parvoviral diarrhea at the time of admission,
34 (63%) were greater than the established reference
range limit for dogs (ie, > 160 nmol/L).31
Subsequent daily serum cortisol concentrations
On days 2 and 3, the proportions of patients with serum
cortisol concentrations of > 160 nmol/L were 28% and
17%, respectively. On day 2, the remaining 9 nonsurvivor group dogs had significantly (P < 0.001) higher median serum cortisol concentrations (266 nmol/L [IQR,
202 to 365 nmol/L]) than survivor group dogs (n = 45;
96 nmol/L [IQR, 43 to 127 nmol/L; Figure 1]). Median
serum cortisol concentrations were significantly (P <
0.001) different on day 3 between 8 nonsurvivor group
dogs and 46 survivor group dogs (279 nmol/L [IQR,
209 to 529 nmol/L] vs 62 nmol/L [IQR, 33 to 118 nmol/
L], respectively). Six of 8 nonsurvivor group dogs died
later on day 3. Median serum cortisol concentrations
remained high in the nonsurvivor group and did not
change significantly (P = 0.867) in this group from days
1 to 3, whereas the survivor group had a significant
(P < 0.001) decrease in median serum cortisol concentrations from days 1 to 3.
None of the surviving dogs had a cortisol concentration of > 224 nmol/L at 48 hours after admission (day 3),
whereas 6 of 8 nonsurvivor group dogs had serum cortisol concentrations above this cutoff point at this juncture. These data indicate that a cortisol concentration of
> 224 nmol/L at 48 hours after admission in a dog with
parvoviral diarrhea has a sensitivity of 75%, specificity of
100%, positive predictive value for nonsurvival of 1 (ie,
100% certainty that dogs with cortisol concentrations >
224 nmol/L will die), and negative predictive value of
0.96 (ie, 96% certainty that dogs with cortisol concentrations of 224 nmol/L will not die).
Serum thyroxine concentrations on admission
Median serum thyroxine concentrations on admission (day 1) in all dogs with parvoviral diarrhea was
significantly lower than in control dogs (8.12 nmol/L
[IQR, 3.07 to 14.7 nmol/L] vs 35 nmol/L [IQR, 30 to
37 nmol/L], respectively; Figure 2). Median serum thyroxine concentrations on admission of dogs with parvoviral diarrhea were significantly (P = 0.037) lower
in nonsurvivor group dogs (4.41 nmol/L [IQR, 2.7 to
1536

Scientific Reports: Original Study

Figure 1Box plots of the daily serum cortisol concentrations in

57 puppies with parvoviral diarrhea from days 1 to 3 of hospitalization and 17 control puppies on day 1 only. For each box plot, T
bars represent the main body of data, which is equal to the range
in most instances (circles indicate outliers). The box represents
the IQR, and the horizontal bar within the box is the median.
Eleven dogs died or were euthanatized as a result of poor prognosis, and 46 dogs survived. *Significantly (P < 0.05) higher than
survivor group dogs on days 2 and 3.

Figure 2Box plots of the daily serum thyroxine (T4) concentrations in 57 puppies with parvoviral diarrhea from days 1 to 3 of
hospitalization and 17 control puppies on day 1 only. For each
box plot, T bars represent the main body of data, which is equal
to the range in most instances (circles indicate outliers). The box
represents the IQR, and the horizontal bar within the box is the
median. Eleven dogs died or were euthanatized as a result of
poor prognosis, and 46 dogs survived. *Significantly (P < 0.05)
lower than control group dogs on day 1. #Significantly (P < 0.05)
lower than survivor group dogs on days 2 and 3.
JAVMA, Vol 231, No. 10, November 15, 2007

Subsequent daily serum thyroxine concentrationsOn day 2, the remaining 9 nonsurvivor group
dogs had significantly (P < 0.001) lower median serum
thyroxine concentrations (2.7 nmol/L [IQR, 2.7 to 2.7
nmol/L]) than 45 survivor group dogs (10.54 nmol/L
[IQR, 4.96 to 17.05 nmol/L]; Figure 2). A significant
difference in serum thyroxine concentration was also
apparent on day 3 between 8 nonsurvivor group dogs
(2.7 nmol/L [IQR, 2.7 to 2.74 nmol/L]) and 46 survivor
group dogs (10.78 nmol/L [IQR, 5.28 to 17.39 nmol/
L]). Serum thyroxine concentrations in survivor group
dogs had a moderate but significant (P = 0.042) increase
from days 1 to 3. The nonsurvivor group, however, had
a significant (P = 0.009) decrease in serum thyroxine
concentrations from days 1 to 3; these values especially
decreased from days 1 to 2.
Serum cortisol versus serum thyroxine concentrationsDaily serum cortisol concentrations correlated
negatively with daily serum thyroxine concentrations
throughout the study period. Correlation coefficients for
day 1, 2, and 3 were rs = 0.673 (P < 0.001), rs = 0.549
(P < 0.001), and rs = 0.628 (P < 0.001), respectively.
Discussion
In this study, basal serum cortisol concentrations
were increased above the normal reference range during the acute stage of infection (ie, hospital admission)
in 63% of puppies with parvoviral diarrhea. Dogs with
more severe illness leading to death had significantly
higher median serum cortisol concentrations on days
2 and 3 of hospitalization than dogs that survived. Results of this study indicate that a dog with parvoviral
diarrhea has a worse prognosis if its serum cortisol concentrations fail to normalize. An important finding in
this study was the striking decrease in median serum
cortisol concentrations in survivor group dogs from day
2 onwards, when serum cortisol concentration became
indistinguishable from that of control dogs.
Median basal serum thyroxine concentration was
lower in nonsurvivor group dogs than survivor group
dogs on admission (day 1) and decreased further,
whereas the median concentrations in dogs that survived showed a marginal increase. As expected, an inverse correlation was found between basal serum cortisol and thyroxine concentrations during critical illness.
Although the current radioimmunoassay for canine
thyroxine is unable to read thyroxine values with accuracy at values < 2.8 nmol/L, which is the lower end of
the linear portion of the graph, it is worth mentioning
that all nonsurvivor group dogs had serum thyroxine
concentrations below this limit of detection at 24 hours
after admission (day 2). These readings, which were all
adjusted to 2.7 nmol/L for statistical purposes, were indeed low, and this upward adjustment thus belied the
true P value for the difference between the survivor and
nonsurvivor groups.
Our data, although concurring with findings of
many human studies,110,2225 seem to be at variance
with a previous veterinary study17 in which no correlaJAVMA, Vol 231, No. 10, November 15, 2007

tion was found between basal serum cortisol and death.

That study involved only 20 patients. These patients
had disparate illnesses, consisting of acute and chronic
conditions. The different neuroendocrine paradigms of
acute and chronic illnesses have been highlighted for
critically ill humans.32 The serial nature of the sample collections in our study supported this important
concept, vindicating the difference between acute and
chronic illness, as far as both serum cortisol and thyroxine concentrations are concerned. The dramatic decrease in serum cortisol concentrations in the survivor
group, occurring beyond the day of admission, on the
one hand indicates the acute nature of the adrenocortical response and on the other demonstrates its near
normal adjustment in more chronic illness. It is thus
not entirely unexpected that serum cortisol concentrations would have failed to predict death in nonacute illness. Finally, the mean hospital stay in the former study
was only 2 days, and only 37% had basal serum cortisol concentrations above the range regarded as normal
for healthy animals, which, in retrospect, confirms the
more chronic nature of their illnesses.17 The mean hospital stay of dogs with parvoviral diarrhea in our study
was 4.7 days, all patients were admitted with the same
acute illness, and 63% had admission basal serum cortisol concentrations above 160 nmol/L.
The study reported here documented the range
of admission basal serum cortisol concentrations in
critically ill dogs with parvoviral diarrhea as 19 to 825
nmol/L and the median as 248 nmol/L (IQR, 115 to 451
nmol/L) and helps to answer the question of an appropriate serum cortisol concentration range in acute critical illness in dogs, as posed in a recent review.18 Low serum cortisol concentrations in many of these sick dogs
with parvoviral diarrhea could potentially be explained
by their antecedent anorexia, as cortisol concentrations
have been shown to decrease in puppies after 24 to 36
hours of fasting.33 It is noteworthy that serum cortisol
concentrations in control dogs ranged from 15 to 226
nmol/L, with an IQR of 43 to 94 nmol/L. Only 2 control dogs had values > 160 nmol/L, which is surprising
considering the excitement and stress associated with
a dogs visit to a veterinary hospital. It was not the aim
of this study to establish a reference range for this age
group of puppies, but their serum cortisol concentrations are probably not different than the reference range
of 10 to 160 nmol/L established for mature dogs.
It is well known that thyroxine concentrations are
suppressed by critical illness in general and high corticosteroid concentrations in particular.34,35 The fact that
the basal thyroxine concentrations were already lower
in nonsurvivor group dogs than in survivor group dogs
on day 1 (while the respective cortisol concentrations
of the groups were similar) seems to indicate that the
pituitary-thyroid axis is suppressed by factors other
than the corticosteroid stress response. It is known in
humans that cytokines such as interleukin-6 exert a
stimulatory role in the function of the hypothalamicpituitary-adrenal axis, whereas interleukin-6 has an
inhibitory effect on the hypothalamic-pituitary-thyroid
axis.36 Results of our study, when seen in combination
with a recently performed pilot studyc showing a positive correlation of interleukin-6 with death in dogs adScientific Reports: Original Study

1537

SMALL ANIMALS

8.73 nmol/L]) than in survivor group dogs (9.2 nmol/L

[IQR, 4 to 15.8 nmol/L]).

SMALL ANIMALS

mitted with systemic inflammatory response syndrome,

may lend credence to this cytokine as being instrumental in the endocrine perturbations seen in our dogs.
The relatively small number of dogs in our patient
population precludes generalizations on the sex ratio
in parvoviral diarrhea or the predisposition of males to
die, as was ostensibly shown in this group of dogs. This
aspect would need larger populations to verify its importance, although it is well known in human critical
care medicine that male babies have a higher mortality
rate than female babies.3739
One might also speculate that the initial stress of
hospitalization could have been responsible for the
high basal serum cortisol concentrations on day 1.
However, control dogs, with blood samples collected at
the same hospital and after waiting similar periods in
the same waiting room, did not bear this assertion out.
Furthermore, even the less severely ill surviving dogs
had markedly higher basal serum cortisol and lower
thyroxine concentrations than control dogs, which
would seem to vindicate their acute illness as a cause
of these perturbations. The clinical nature of this study
meant that the researchers had no control over when, in
the course of its disease process, a dog with parvoviral
diarrhea was admitted for treatment. This, as well as the
differing degree of illness, the relatively small sample
size, and other factors such as patient genotype, would
partly explain the lack of uniformity in basal serum
hormone concentrations seen in this study.
Survival depends on the maintenance of homeostasis. By measuring loss of homeostasis, physiologic and
endocrine scoring systems predict survival with high
sensitivity. Prediction of death, however, is less sensitive
because the causes of death in patients in the intensive
care unit (eg, pulmonary edema, gastrointestinal hemorrhage, shock, and dehydration), although induced by
illness, may not be closely related to illness severity, as
death depends not only on physiologic developments
but also on our management of patients.6 This lack of
sensitivity of basal serum cortisol concentrations in the
prediction of death is illustrated in our study by the 2
dogs that died, although their cortisol concentrations
were < 224 nmol/L 48 hours after admission.
As a model of critical illness, there appears to be
a close association between the degree of cortisol and
thyroxine perturbations and death in dogs with parvovirus diarrhea, confirming the predictive capacity of
basal serum cortisol and thyroxine concentrations. This
would not necessarily be expected to be the same in
studies in which combinations of acute and chronically
ill animals with disparate illnesses are used. We advise
caution in overinterpreting the clinical importance of
findings of our study because the data generated refer
to a particular critical illness (ie, parvovirus diarrhea) at
a particular institution. The study reported here does,
however, provide insight into the endocrine perturbations in critical illness.
a.
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Coat-a-count assay, Diagnostic Products Corp, Los Angeles, Calif.

SPSS, version 14.0, SPSS Inc, Chicago, Ill.
Rau S, Kohn B, Richter C, et al. Plasma IL-6 response is predictive for severity and mortality in canine SIRS and sepsis (abstr),
in Proceedings. 16th Cong Eur Coll Vet Intern Med 2006;199.

1538

Scientific Reports: Original Study

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New Veterinary Biologic Products

Product name

Mycobacterium BovisMycobacterium
Tuberculosis
Antibody Test Kit

Species and
indications for use

For the detection of antibodies

to Mycobacterium tuberculosis
and M bovis in elephant serum,
plasma, and whole blood

JAVMA, Vol 231, No. 10, November 15, 2007

Route
of administration

NA

Remarks

USDA licensed 8/15/07

Scientific Reports: Original Study

1539

SMALL ANIMALS

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