The Veterinary Journal 273 (2021) 105677

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The Veterinary Journal

journal homepage: www.elsevier.com/locate/tvjl

Critical illness-related corticosteroid insufficiency in dogs with

systemic inflammatory response syndrome: A pilot study in 21 dogs
M. Marchetti, A. Pierini* , G. Favilla, V. Marchetti
Department of Veterinary Science, University of Pisa, via livornese lato monte, San Piero a Grado, 56122, Pisa, Italy

A R T I C L E I N F O A B S T R A C T

Article history: Critical illness-related corticosteroid insufficiency (CIRCI) refers to a lack of adequate corticosteroid
Accepted 12 April 2021 activity, which occurs in up to 48% of dogs with sepsis. However, data regarding the occurrence of CIRCI in
critically-ill dogs are still scarce. This study aimed to assess: (1) the relationship between CIRCI and
Keywords: clinicopathological inflammatory markers, hypotension and mortality; and (2) the impact of low-dose
Canine hydrocortisone treatment on survival. Twenty-one dogs diagnosed with systemic inflammatory response
Emergency syndrome (SIRS) were enrolled in a prospective case-control study. All dogs were initially evaluated for
Hypoadrenocorticism
adrenal function with an ACTH stimulation test and dogs with Dcortisol  3 mg/dL were diagnosed with
Hypotension
Sepsis
CIRCI. Mean arterial pressure (MAP), white blood cell (WBC), band neutrophils (bNs), c-reactive protein
(CRP), and 28-day mortality rate were assessed. Fourteen dogs were treated with low-dose
hydrocortisone. The relationships between CIRCI and MAP, WBC, bN, CRP, basal cortisol and mortality
were investigated, as was the association between mortality and hydrocortisone treatment.
Ten of 21 (48%) dogs were diagnosed with CIRCI. Increased bNs were associated with the presence of
CIRCI (P = 0.0075). CRP was higher in dogs with CIRCI (P = 0.02). Fourteen of 21 (66%) dogs died during the
study (6/14 had CIRCI). Basal hypercortisolemia (>5 mg/dL) was associated with increased risk of
mortality (P = 0.025). Based on our diagnostic criteria, CIRCI occurs frequently in dogs with SIRS and was
associated with increased bNs and increased CRP. In this study, CIRCI and low-dose hydrocortisone
treatment were not significantly associated with mortality, but basal hypercortisolemia was associated
with increased mortality.
© 2021 Elsevier Ltd. All rights reserved.

Introduction
Systemic inflammatory response syndrome (SIRS) is the clinical
manifestation of the systemic response to an infectious or non-
infectious injury with a massive release of inflammatory mediators
(Bone et al., 1992). SIRS can lead to shock, multiple organ
dysfunction syndrome (MODS), and potentially death (Brady
and Otto, 2001; De Laforcade, 2014).
In critically-ill dogs, activation of the hypothalamic-pituitary–
adrenal axis (HPAA) is presumed to be a fundamental part of the
physiological stress response, which is essential for maintaining of
homeostasis and adaptation during severe illness (Martin, 2011).
However, abnormalities of the HPAA have been identified in
critically-ill human patients, especially in those with sepsis and
septic shock, with high or normal basal cortisol levels and a
blunted response to ACTH stimulation test (Sibbald et al., 1977;
Rothwell et al., 1991; Span et al., 1992; Soni et al., 1995; Briegel
* Corresponding author.
E-mail address: pierini.alessio2004@gmail.com (A. Pierini).
et al., 1996; Annane et al., 2000; Schroeder et al., 2001; Beishuizen
and Thijs, 2001; Marik and Zaloga, 2002; Annane et al., 2002;
Marik and Zaloga, 2003). This syndrome is called critical illness-
related corticosteroid insufficiency (CIRCI), which is described as
inadequate corticosteroid activity in relation to the patient’s
current degree of stress or illness (Marik et al., 2008). CIRCI occurs
in 30–45% of critically-ill human patients and in up to 60% in
patients with sepsis (Annane et al., 2006; Marik, 2009).
In human medicine, although there is currently no consensus
regarding the diagnosis of CIRCI, 9 mg/dL of Dcortisol, which was
defined as the difference of cortisol concentrations between pre
and post ACTH-stimulation test, has been proposed as a diagnostic
criterion (Marik et al., 2008; Annane et al., 2017). CIRCI has been
associated with refractory hypotension and increased mortality
(Rothwell et al., 1991; Soni et al., 1995; Annane et al., 2000;
Schroeder et al., 2001; Annane et al., 2002). Despite the
controversies on the treatment of this syndrome, some studies
have suggested that the use of low doses of hydrocortisone
significantly improves survival (Schneider, 1991; Bollaert et al.,
1998; Briegel et al., 1999; Chawla et al., 1999; Annane et al., 2002;
Oppert et al., 2005).

http://dx.doi.org/10.1016/j.tvjl.2021.105677
1090-0233/© 2021 Elsevier Ltd. All rights reserved.
M. Marchetti, A. Pierini, G. Favilla et al. The Veterinary Journal 273 (2021) 105677

In veterinary medicine, there are few studies on CIRCI. Based on
a diagnostic criterion of Dcortisol 3 mg/dL, CIRCI has been
reported to occur in 48% of septic dogs and was associated with
hypotension and increased mortality (Burkitt et al., 2007). Previous
studies on one dog and two cats with CIRCI reported resolution of
septic shock and refractory hypotension and complete recovery
with low-dose hydrocortisone or dexamethasone (Durkan et al.,
2007; Peyton and Burkitt, 2009; Pisano et al., 2017).
Based on these backgrounds, the aims of our study were set to
assess (1) the frequency of CIRCI in dogs with SIRS; (2) the
relationship between CIRCI and clinicopathological inflammatory
markers, hypotension and mortality; (3) the impact on survival of
low-dose hydrocortisone therapy in dogs with CIRCI. Our hypothesis
was that CIRCI frequently occurs in dogs with SIRS, that it is
associated with inflammatory markers, hypotension and mortality,
and that low-dose hydrocortisone could improve outcome.
Materials and methods
Cases
This prospective study was performed between December 2016 and May 2017,
with approval from the Animal Welfare Organization of the University of Pisa
(Protocol number 63711, Approval date, 20 December 2016), at the Veterinary
Teaching Hospital of the University of Pisa. Owners completed an informed consent
for enrollment in the study.
Dogs were included in the study if referred to the intensive care unit with at
least two of the following SIRS criteria: (1) rectal temperature >39.0  C or <38.0  C;
(2) heart rate >120 bpm; (3) respiratory rate >20 bpm; and (4) white blood cell
(WBC) <6000/mL or >16,000/mL or band neutrophils (bNs) >3%. Dogs were
excluded if they had a history or suspicion of hypoadrenocorticism or hyper-
adrenocorticism. Dogs were also excluded if they had received glucocorticoids or
other drugs known to affect the HPAA (benzodiazepines, opioids, etomidate,
dexmedetomidine, progestin, and azole antifungals) within the previous 72 h and if
they had received corticosteroids for more than 1 week or long-acting formulations
within the previous month, in accordance with the exclusion criteria of previous
studies (Burkitt et al., 2007; Martin et al., 2008).
Blood examinations
Blood samples were collected via venipuncture for a complete blood count
(Procyte DX, IDEXX Laboratories) and a biochemical profile (Biochemical analyzer
Liasys, ASSEL srl) at admission. Results regarding WBC, bNs and c reactive protein
(CRP) were collected. Band neutrophils count was collected from cytological blood
smear evaluation and were considered high if >3%. Leukopenia was defined as WBC
< 6000/mL, and leukocytosis as WBC > 16,000/mL. Reference range of normality for
CRP was <0.30 mg/dL. Non-invasive blood pressure was measured with an
oscillometric device (PetMAP graphic II, Ramsey Medical). Hypotension was defined
as a mean arterial pressure (MAP) <60 mmHg.
An ACTH stimulation test was performed in all dogs immediately after inclusion in
the study. Two mL of blood were collected for measurement of baseline serum cortisol
concentration (BC). Each dog then received 0.5 mg/kg IV synthetic ACTH (Synacthen
0.25 mg/mL, Novartis S.p.A.). One hour later, 2 mL of venous blood was collected for
measurement of post-stimulation serum cortisol concentration (PC). All serum
samples were stored in plastic tubes at – 80  C until analysis which was performed in
May 2017. Serum cortisol was determined by a fluorometric enzyme immunoassay
(AIA-360, Tosoh Bioscience). Reference ranges of normality for BC and PC were 1 5 mg/
dL and 6 18 mg/dL, respectively. Delta (D) cortisol was calculated as the difference
between PC and BC. As previously reported, dogs with Dcortisol 3 mg/dL were
diagnosed with CIRCI (Burkitt et al., 2007; Martin et al., 2008).
Treatment
Regardless of the results of ACTH stimulation test, dogs were assigned to one of
two treatment groups: the treated group (TG) and the non-treated group (nTG). The
dogs were randomly assignment to the two groups based on the order of visit to the
hospital (the first 14 dogs were assigned to TG and the following seven dogs to nTG).
The investigator (V.M.) assigned dogs to each group and was not masked to the
diagnosis or clinical status of each dog.
The dogs in TG received 0.5 mg/kg of hydrocortisone (Flebocortid 100 mg/2 mL,
Richter, Sanofi S.p.A.) IV every 6 h after ACTH stimulation test on the day of
admission (Day 0). Hydrocortisone was tapered as follows: every 8 h on Day 1, every
12 h on Day 2, and every 24 h until discharge from the hospital. The dogs in nTG did
not receive hydrocortisone or other corticosteroids during hospitalization.
Survival analysis
Twenty-eight-day survival rate was calculated. Dogs still alive on Day 28 were
considered surviving dogs, and those died or were euthanased by Day 28 were
considered non-surviving dogs. Dogs euthanased from financial reasons were
excluded for this analysis. Information on survival on Day 28 was collected by
telephone or during follow up.
Statistical analysis
With expected mortality rate of 90% in nTG and 30% in TG, enrollment ratio (TG/
nTG) of 2:1, alpha of 0.05 and beta of 0.20, a priori total sample size was calculated to
be 21 dogs. Data was expressed as median and range because it was not normally
distributed. A correlation between MAP and Dcortisol was investigated with
Spearman’s correlation test. MAP, WBC, bNs and CRP were compared between the
CIRCI group (CG) and non-CIRCI group (nCG) using unpaired Mann-Whitney U test.
Associations between CIRCI and hypotension, leukocytosis, leukopenia, increased
bNs and increased CRP were evaluated with Fisher’s exact test. Comparisons of
Dcortisol and BC between surviving and non-surviving dogs were evaluated with

Table 1
Comparisons of clinical and clinicopathological variables between dogs with critical illness-related corticosteroid insufficiency (CIRCI) and those without CIRCI. Data for white
blood cells (WBC), band neutrophils, C reactive protein (CRP), mean arterial pressure (MAP) and basal cortisol is expressed as median (range).

Variables All dogs CIRCI P

Yes No
WBC (K/mL) 7.5 (0.2 44.1) 2.9 (0.2 37.7) 21.8 (0.4 44.1) 0.085a
Band neutrophils (%) 4 (0 30) 4.5 (0 16) 0.0 (0 30) 0.0145a
CRP (mg/dL) 2.7 (0.1 6.3) 3.2 (1.7 6.3) 1.5 (0.1 4.3) 0.02a
MAP (mmHg) 92 (43 148) 88 (45 139) 102 (43 148) 0.47a
Basal cortisol (mg/dL) 10.1 (1.4 50.0) 11.8 (1.4 34.9) 10.1 (1.8 50.0) 0.70a
WBC (K/mL)
<6 9 6 3 0.198b
6 12 4 8
WBC (K/mL)
16 13 9 4 0.024b
>16 8 1 7
Band neutrophils (%)
3 9 1 8 0.008b
>3 12 9 3
CRP (mg/dL)
<0.3 1 0 1 1b
0.3 20 10 10
MAP (mmHg)
<60 7 3 4 1b
60 14 7 7
a
Unpaired Mann–Whitney U test.
b
Fisher’s exact test.

2
M. Marchetti, A. Pierini, G. Favilla et al.
unpaired Mann–Whitney U test. The associations of basal hypercortisolemia,
presence of CIRCI and treatment with hydrocortisone with mortality was
investigated with Fisher’s exact test. Statistical analyses were performed using a
statistical software package (GraphPad Prism 6, GraphPad Software). For all
analyses, a P-value 0.05 was considered significant.
Results
Cases
Twenty-one dogs met the inclusion criteria and were enrolled
in the study. The median age was 7.8 years (range 0.3–14 years).
Fourteen of the dogs were male (3 neutered) and seven were
female (two spayed). The following final diagnoses were made:
canine parvovirus (n = 5); sepsis after surgery (n = 5 in total; n = 2
orthopedic surgery, n = 1 pyometra, n = 1 intestinal foreign body, n
= 1 portosystemic shunt); acute pancreatitis and enteritis (n = 1);
acute pancreatitis and cholangiohepatitis (n = 1); pyelonephritis (n
= 1); acute prostatitis (n = 1); cholangiohepatitis and colitis (n = 1);
bite wounds (n = 1); prostatic and renal abscesses (n = 1); acute
necrotic gastroenterocolitis (n = 1); acute colitis and hepatic
abscess (n = 1); emphysematous cholangitis (n = 1); and mucocele,
cholangitis and colitis (n = 1).
Comparisons between the CG and the nCG
Regarding the glucocorticoid adrenal function, CIRCI was detected in
10/21 dogs (48%), with Dcortisol 3 mg/dL as the diagnostic criteria. Age
did not significantly differ between the CG and the nCG (CG: median 3
years, range 0.3–12 years; nCG: 6 years, range 0.3–14 years).
Mean BC did not significantly differ between the CG and the
nCG, and no dogs had BC below the reference range (Table 1).
Median WBC did not significantly differ between the CG and the
nCG. However, the proportion of dogs with leukocytosis was
significantly higher in the nCG than the CG. In addition, median
bNs and the proportion of dogs with increased bNs (>3%) were
significantly higher in the CG than in the nCG. C-reactive protein
was increased in all but one dog, and its concentration was
significantly higher in the CG than in the nCG. Median arterial
blood pressure and the proportion of dogs with hypotension did
not significantly differ between the CG and the nCG, and no
significant correlation was observed between MAP and Dcortisol
(r = 0.37, P = 0.88).
Treatment
Fourteen dogs were treated with hydrocortisone (TG) and seven
dogs were not treated (nTG). Median age did not differ significantly
Table 2
Comparisons of cortisol concentrations, presence/absence of critical illness-related corticosteroid insufficiency (CIRCI) and treatment with low-dose hydrocortisone (LDH) in
survivors and non-survivors.
Variables All dogs
Basal cortisol (mg/dL) 10.1 (1.4 50.0)
Dcortisol (mg/dL) 5.1 ( 10.5 to 57.8)
Basal cortisol (mg/dL)
5 5 4
>5 16
CIRCI
Yes 10
No 11
LDH treatment
Yes 14
No 7 2
a
Unpaired Mann–Whitney U test.
b
Fisher’s exact test.
The Veterinary Journal 273 (2021) 105677
between the TG and thenTG (6.2 and 7.1 years, respectively; P >
0.05). CIRCI and hypotension were similarly distributed in TG and
nTG groups. In the TG, 7/14 dogs were in the CG and the other seven
dogs were in the nCG. In the nTG, 2/7 dogs were in the CG and the
other five dogs were in the nCG. Hypotension was observed in 4/14
(29%) dogs in the TG and in 3/7 (43%) dogs in the nTG.
Outcome
Fourteen (66%) of 21 dogs died during the study. There were no
significant differences in the proportion of dogs with CIRCI, median
Dcortisol, or median BC when survivors and non-survivors were
compared (P > 0.05; Table 2). There was no significant difference in
mortality between the TG and the nTG. However, the proportion of
dogs with basal hypercortisolemia (BC >5 mg/dL) was significantly
higher in non-survivors than survivors.
Discussion
Little information is available regarding the frequency of CIRCI
in veterinary medicine. Our study confirmed that CIRCI, diagnosed
by a Dcortisol 3 mg/dL, occurs frequently in dogs with SIRS. This is
similar to previous studies reporting CIRCI (Dcortisol  3) in dogs
with sepsis, gastric-dilatation-volvulus, and trauma (Burkitt et al.,
2007; Martin et al., 2008). A total of 48% of dogs enrolled in the
present study were diagnosed with CIRCI, and this is the similar
result to that in a previous study that investigated 33 septic dogs
(Burkitt et al., 2007).
According to the international task force of the American
College of Critical Care Medicine and the international task force of
the Society of Critical Care Medicine (SCCM) and European Society
of Intensive Care Medicine (ESICM)), CIRCI can be defined as a
syndrome in which there is not enough glucocorticoid for the
ongoing situation, rather than an intrinsic insufficiency, and a
normal or high basal cortisol level does not exclude the presence of
CIRCI (Marik et al., 2008; Annane et al., 2017). It also suggests that
an endogenous maximal adrenal stimulation may have already
occurred and the adrenal reserve and capacity to react are
exhausted, as has been demonstrated in humane medicine
(Sibbald et al., 1977; Bollaert et al., 1998; Annane et al., 2000;
Rivers et al., 2001). This may explain the high frequency of low
Dcortisol and basal hypercortisolemia (>5 mg/dL) in the dogs with
CIRCI in our study, suggesting that Dcortisol may be more useful
than either BC or PC to predict CIRCI. Moreover, in our study, BC
was not useful in diagnosing CIRCI, and interestingly, none of the
dogs with CIRCI had BC <1 mg/dL, whereas approximately 76% had
basal hypercortisolemia, as previously reported (Burkitt et al.,
2007; Martin et al., 2008).
Mortality P
Survivors Non-survivors
5.0 (1.4 28.8) 12.8 (2.1 50.0) 0.078a
2.6 ( 0.1 to 57.8) 4.7 ( 10.5 to 48.4) 0.870a
1 0.025b
3 13
4 6 0.66b
3 8
5 9 1.00b
5
3
M. Marchetti, A. Pierini, G. Favilla et al.
In the present study, CIRCI and Dcortisol levels were not
associated with mortality. These results agree with those in a
previous study (Martin et al., 2008) but not with those in another
previous study (Burkitt et al., 2007). It is possible that we could not
detect the significant associations due to the small number of
cases, and, for this reason, we believe that further studies using
larger number of cases are needed. Meanwhile, dogs presenting
with basal hypercortisolemia had increased risk of death by 28
days after diagnosis. Previous studies of dogs and humans similarly
found significant associations between basal hypercortisolemia
and increased risk of mortality (Burry et al., 2013; Csondes et al.,
2017). Based on these results, we can speculate that the more
severe the disease, the more intense the adrenocortical response is
likely to be. However, a more concrete hypothesis cannot be made
since our study lacked evaluations of disease severity in each case.
We also investigated associations between systemic hypoten-
sion and CIRCI. Cortisol increases the vasoconstrictive effects of
catecholamines and decreases the production of nitric oxide,
which is a vasodilator. Thus, a cortisol insufficiency, which is
thought to occur during CIRCI, could lead to peripheral vasodilation
and systemic hypotension (Collins et al., 1988; Sakaue and
Hoffman, 1991; Levy-Shraga and Pinhas-Hamiel, 2013). In human
medicine, CIRCI has frequently been associated with systemic
hypotension illnesses (Rothwell et al., 1991; Soni et al., 1995;
Annane et al., 1998, 2000; Schroeder et al., 2001; Rivers et al., 2001;
Annane et al., 2002; Marik et al., 2005). However, in our study,
there were no differences in MAP or the presence of hypotension
between the CG and the nCG. Several other mechanisms can
contribute to systemic hypotension during SIRS regardless of CIRCI
which could explain this lack of association.
One of our aims was to assess the associations between CIRCI
and various inflammatory clinicopathological parameters. The
concentration of CRP was significantly higher in the CG and bNs
were also increased in these dogs, thus confirming the fundamen-
tal role of inflammation in this syndrome. Meanwhile, a previous
study of dogs with CIRCI found no significant correlation between
CRP and BC or PC, although they did not investigate any potential
correlation between CRP and Dcortisol (Csondes et al., 2017).
Further examinantios in a larger cohort of dogs is needed to
determine whether our results are repeatable.
In our study, treatment with hydrocortisone was not associated
with lower mortality rate. To date, the effect of low dose corticoste-
roids on survival improvement in critically-ill human patients is still
not clear (Annane et al., 2002; Dellingeretal., 2004; Sprung et al., 2008;
Annane et al., 2009; Sligl et al., 2009; Patel and Balk, 2012). To the best
of our knowledge, only previous three case reports and congress
proceedings in veterinary medicine are available to consider the
effects of treatment with corticosteroids. One dog and two cats had
complete resolution of septic shock and refractory hypotension after
treatment with low-dose hydrocortisone or dexamethasone (Durkan
et al., 2007; Peyton and Burkitt, 2009; Pisano et al., 2017). In another
study (Burkitt and Hopper, 2011), the authors found no statistical
association between treatment and mortality in dogs with CIRCI. More
studies with larger sample size are needed to better explore the
association between corticosteroid treatment and mortality in canine
CIRCI patients.
Our study has some limitations. Firstly, we used a Dcortisol of
3 mg/dL to diagnose CIRCI, since it is the only diagnostic criteria
that has been evaluated in veterinary medicine (Burkitt et al.,
2007). However, more studies are needed in veterinary medicine
to better define the criteria aimed at establishing a diagnosis of
CIRCI. Secondly, we used 0.5 mg/kg synthetic ACTH to perform
ACTH-stimulation tests because it has been reported to adequately
stimulate adrenal glands in healthy and critically-ill dogs, but the
sensitivity of ACTH dosage to diagnose CIRCI in dogs has not been
sufficiently explored (Martin et al., 2007; Martin and
4
The Veterinary Journal 273 (2021) 105677
Holowaychuk, 2010). Moreover, the ACTH stimulation test was
performed only at the time of inclusion in the study. Repeating the
test after hospital discharge might have enabled us to verify
normalization of adrenal function in addition to clinical recovery.
Another limitation of our study was the lack of a clinical severity
score, such as an Acute Patient Physiological and Laboratory
Evaluation (APPLE) score or Sequential Organ Failure Assessment
(SOFA) score. Although all dogs in our study were critically-ill, the
use of a severity score would have enabled better understanding
and stratification of the severity of illness, and the relationship
between disease severity and the presence of CIRCI or Dcortisol
levels. Finally, our study population was heterogeneous, and
variable factors could have influenced our outcome data.
Conclusions
CIRCI occurs frequently in dogs with SIRS and was associated
with increased concentrations of inflammatory markers such as
bNs and CRP. CIRCI and low-dose hydrocortisone treatment did not
influence the mortality rate of dogs with SIRS in our study.
However, basal hypercortisolemia (>5 mg/dL) was associated with
increased mortality. Further studies are needed to investigate CIRCI
in critically-ill dogs and to examine the relationship between
mortality and CIRCI, inflammatory markers, hypotension, basal
cortisol and potential benefits of hydrocortisone therapy.
Conflict of interest
None of the authors has any financial or personal relationships
that could inappropriately influence or bias the content of the
paper.
Acknowledgements
Preliminary results were presented as a poster entitled ‘Critical
illness-related corticosteroid insufficiency (CIRCI) in dogs with
systemic inflammatory response syndrome (SIRS)’ at the 29th
ECVIM-CA Congress, Milan, Italy 19-21 September 2019. This
research did not receive any specific grant from funding agencies in
the public, commercial, or not-for-profit sectors.
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