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792106 JFM Journal of Feline Medicine and SurgeryTroìa et al

Original Article

Journal of Feline Medicine and Surgery

Multiorgan dysfunction syndrome 2019, Vol. 21(6) 559­–565


© The Author(s) 2018
Article reuse guidelines:
in feline sepsis: prevalence and sagepub.com/journals-permissions
DOI: 10.1177/1098612X18792106
https://doi.org/10.1177/1098612X18792106

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This paper was handled and processed
by the European Editorial Office (ISFM)
for publication in JFMS

Roberta Troìa, Giulia Mascalzoni, Stefano Calipa,


Ilaria Magagnoli, Francesco Dondi and
Massimo Giunti

Abstract
Objectives The current study was designed to evaluate the prevalence and prognostic significance of multiorgan
dysfunction syndrome (MODS) in cats with sepsis.
Methods Cats hospitalised in the intensive care unit of a veterinary university hospital with a diagnosis of sepsis were
prospectively enrolled and divided according to disease severity and outcome (survivors; non-survivors). The feline
acute patient physiological and laboratory evaluation (APPLE) scores were calculated upon admission, as previously
described. Specific criteria to identify selected organ dysfunction (hepatic, renal, respiratory, cardiocirculatory,
haemostatic) were adapted from the available human and veterinary literature, and evaluated at baseline and at
the end of hospital stay. MODS was defined as the presence of at least two dysfunctional organs simultaneously.
Non-parametric statistics were used for comparisons. Univariate and multivariate regression analyses to evaluate
significant risk factors for death were carried out. Correlations between variables were assessed by the Spearman's
rank correlation coefficient. Significance was set at P <0.05.
Results A total of 43 cats with heterogeneous sources of sepsis were included. MODS was identified in 25/43 cats
upon admission and in 32/43 cats at the end of hospital stay. Regression analyses showed a significantly elevated
odds ratio for mortality for the presence of MODS, renal and cardiovascular dysfunction upon admission, as well as
for the number of dysfunctional organs. The latter was the only variable retained by the model from the multivariate
binary logistic regression analysis. Significant correlations were documented between the number of dysfunctional
organs and the APPLE scores.
Conclusions and relevance MODS is a frequent complication of feline sepsis, and is associated with worse
outcomes. In particular, renal and cardiovascular dysfunction significantly increase the odds for death. Hence,
systematic screening for organ dysfunction is advocated in cats with sepsis.

Keywords: Septic shock; acute kidney injury; organ dysfunction; prognosis; APPLE score

Accepted: 6 July 2018

Introduction to infection’.2 Progression from sepsis to MODS has been


Multiorgan dysfunction syndrome (MODS), the progres- investigated in dogs; similar to human findings, the
sive dysfunction of organ systems following an acute
threat to systemic homeostasis, is a common complica-
Department of Veterinary Medical Science, Alma Mater
tion of critical illness and a leading cause of mortality Studiorum–University of Bologna, Ozzano dell’Emilia, Bologna,
in human intensive care units (ICUs).1,2 Among the Italy
spectrum of critical care conditions, sepsis represents
the major inciting cause for MODS. The inter-relationship Corresponding author:
Massimo Giunti DVM, PhD, Department of Veterinary Medical
between sepsis and MODS is supported by the recent re- Sciences, Alma Mater Studiorum–University of Bologna, Via
definition of the sepsis syndrome as ‘the life-threatening Tolara di Sopra 50, Ozzano dell'Emilia, Bologna 40064, Italy
organ dysfunction caused by a dysregulated host response Email: massimo.giunti@unibo.it
560 Journal of Feline Medicine and Surgery 21(6)

number of dysfunctional organs has been associated reported,12 were registered. Blood was collected by
with an increase in the mortality risk.3–5 venepuncture with vacuum system according to standard
Frequency and clinical manifestation of sepsis and operating procedures, and analysed within 1 h of ICU
MODS are less documented in cats; however, the admission. The following analyses were performed:
reported mortality rate is elevated.6 Biomarkers of feline venous blood gas, including electrolytes and lactate (ABL
sepsis, including meta-rubrocytosis, high circulating 800 FLEX blood gas analyser; Radiometer Medical), com-
muscle enzyme activities (aspartate transaminase; cre- plete blood cell count (ADVIA 2120; Siemens Healthcare
atine kinase), high band neutrophil percentage and ele- Diagnostics) and microscopic evaluation of the blood
vated serum amyloid A (SAA) concentrations, have been smear, chemistry profile – including measurement of
investigated in this species.7–10 However, selected organ serum creatinine, bilirubin and SAA (Beckman Coulter-
dysfunctions have been rarely characterised in septic Olympus AU 480, LZ Test Eiken SAA [Eiken Chemical])
cats,9–11 and studies systematically evaluating MODS in – prothrombin time (PT) and partial thromboplastin
the course of feline sepsis are lacking. time (PTT) (BFT II; Siemens). The feline acute patient
The aim of the present study was to investigate and physiological and laboratory evaluation (APPLE) scores,
characterise organ dysfunctions and MODS in feline APPLEfast and APPLEfull, respectively, were calculated, as
sepsis. We hypothesised that MODS is a complication of previously described.13
feline sepsis, and that its occurrence is associated with Cats were classified according to their outcome as
increased mortality. survivors (alive to discharge) and non-survivors (died
despite medical treatment or humanely euthanased
Materials and methods because of moribund conditions). Cats euthanased for
Animals other reasons were excluded.
Critically ill cats with sepsis presented to the Veterinary
University Hospital of Bologna and hospitalised in the Organ dysfunction criteria
ICU between October 2015 and September 2017 were Criteria to define organ dysfunction were adapted from
prospectively included. The study was approved by the the available human and canine literature.2,3,14,15 Respiratory
local Institutional Animal Care and Use Committee. dysfunction was defined in presence of SpO2 <95% in
Cats were diagnosed with sepsis if they fulfilled at the room air, or if oxygen therapy or mechanical ventilation
time of presentation at least 3/4 feline systemic inflam- were needed. Hepatic dysfunction was defined as serum
matory response syndrome criteria (rectal temperature bilirubin >0.7 mg/dl in absence of haemolysis or biliary
>39.7ºC or <37.8ºC, heart rate >225 beats/min [bpm] or obstruction. Acute kidney injury (AKI) was defined as
<140 bpm, respiratory rate >40 breaths/min, and white serum creatinine (sCr) >1.8 mg/dl and/or increase in
blood cell count >19,500/µl or <5000/µl or band neu- sCr of ⩾0.3 mg/dl from baseline and/or oliguria (urine
trophil fraction >5%), as previously reported,7 and had a output <1 ml/kg/h over 6 h), and graded (I–V) accord-
documented underlying infection. Presence of infection ing to the International Renal Interest Society (IRIS) stag-
was confirmed by means of cytology, microbiology or ing system, proposed by Cowgill and accepted by the
molecular diagnostic methods. Cats discharged against IRIS group.15 Cardiovascular dysfunction was defined as
medical advice or euthanased for financial reasons were hypotension (systolic blood pressure <90 mmHg) in
excluded. volume-replete patients requiring vasopressors therapy.
Haemostatic dysfunction was defined as PT >15 s, and/
Data collection or activated PTT (aPTT) >20 s and/or platelet count
Attending ICU clinicians were responsible for the clini- <100,000/mm3 in the absence of platelets clumps at
cal management of the patients included in the study. blood smear evaluation. Cut-off values for specific vari-
For each enrolled cat, the following data were recorded: ables (serum creatinine, PT and aPTT) were based on the
signalment and body weight, lifestyle, vaccination his- upper bound of the reference intervals of our clinical
tory, presence of comorbidities, prior medical treat- pathology laboratory. MODS was defined as presence of
ments, therapies administered during ICU stay, need of at least two dysfunctional organs simultaneously. The
fluid resuscitation (types and volumes of intravenous number of dysfunctional organs upon admission and at
fluids), blood products, vasopressors and positive ino- the end of hospital stay was recorded.
tropes, and duration of hospitalisation.
Upon admission, clinical findings, non-invasive blood Statistical analysis
pressure measurement (Minidop ES-100VX; Hadeco), Statistical analysis was performed using a medical
pulse oximetry (Dash 3000 Patient Monitor; GE Medical statistic software (MedCalc 16.8.4). Data were assessed
Systems Information Technologies) and ultrasonography for normality with the D'Agostino-Pearson test and
(Z5 Vet; Shenzhen Mindray Bio-Medical Electronics) for evaluated by descriptive statistics. Most data were non-
the evaluation of body cavity fluid scores, as previously parametric; therefore, data are presented as median and
Troìa et al 561

range (minimum–maximun). The Mann–Whitney U-test Major causes of sepsis were the following: pyothorax
was used to compare continuous variables between (n = 13), feline panleukopenia (n = 11) and septic perito-
groups. Univariate and multivariate logistic regressions nitis (n = 9). Other sources of sepsis were urinary tract
were used to identify variables able to predict outcome; infection (n = 3), bacterial cholangiohepatitis (n = 2),
results are presented as odds ratio (OR) and 95% confi- endocarditis (n = 1), myocarditis (n = 1), septic arthritis
dence interval (CI). Correlations between variables were (n = 1), pyelonephritis (n = 1) and ocular abscess (n = 1).
assessed by the Spearman's rank correlation coefficient. Main clinical and clinicopathological findings in the
Significance was set at P <0.05. overall study population at presentation are shown in
Table 1.
Results Seventeen of 43 cats required fluid resuscitation upon
Forty-three cats met the criteria for inclusion in this admission. Isotonic crystalloid solutions were used by
study. Median age was 5.2 years (range 0.2–15.7) and the primary clinician for fluid resuscitation in the whole
median body weight was 4.0 kg (range 0.4–6.6). There population with a median value of 20 ml/kg (range 10–
were 19/43 female cats (eight sexually intact and 11 85). Tetrastarch (6% hydroxyethyl starch 130/0.4; Voluven)
spayed) and 24/43 males (eight sexually intact and 16 or 7.5% hypertonic saline were administered in a minor-
castrated). Comorbidities were recognised in the ity of the patients at the following doses: 2 ml/kg (1–8; n
majority of the patients (n = 28): polytrauma (n = 7), = 4) and 4 ml/kg (n = 1), respectively. Ten of 17 cats
chronic enteropathy (n = 6), diabetes mellitus (n = 4), were not responsive to fluid resuscitation and required
feline lower airway disease (n = 4), chronic kidney vasopressors. Non-responders received a significantly
disease (n = 2), hypertrophic cardiomyopathy (n = 2), higher volume of crystalloid solution compared with
neoplasia (n = 2) and feline lower urinary tract responders (20.5 ml/kg [range 10–85] vs 15.0 ml/kg
disease (n = 1). Upon presentation, 8/43 patients [range 10–20]; P = 0.02). Vasopressor and inotropic sup-
were receiving immunosuppressive drugs (steroids, n port in cats with cardiovascular dysfunction in the
= 6; steroids plus melphalan, n = 2) and 17/43 were whole study period (n = 18/43) included noradrena-
treated with antimicrobial agents by the referring line alone (n = 18/18) or in combination with dobu-
veterinarian. tamine (n = 14/18). During the ICU stay blood products

Table 1 Descriptive statistics for selected variables measured at the time of admission in cats with sepsis (n = 43)

Variable Cats with sepsis RI

Body temperature (°C) 37.2 (32–40.9) NA


Respiratory rate (rpm) 48 (20–160) NA
Heart rate (bpm) 180 (120–240) NA
SBP (mmHg) 113 (50–220) NA
APPLEfast score 31 (12–46) NA
APPLEfull score 53 (33–66) NA
Haematology
WBCs (cells × 103/mm3) 9.07 (0.05–81.48) 5–19
Platelets (cells × 103/mm3) 190 (20–1189) 50–500
Chemistry
Creatinine (μmol/l) 103.4 (29.2–433.2) 70.72–159.1
Creatinine (mg/dl) 1.17 (0.33–4.90) 0.8–1.8
Total bilirubin (μmol/l) 4.96 (0.34–140.05) 0–5.98
Total bilirubin (mg/dl) 0.29 (0.02–8.19) 0–0.35
SAA (μg/dl) 157 (1–584) 0–10
Lactate (mmol/l) 2.6 (0.8–11.6) 0.5–2
Coagulation profile
PT (s) 9.8 (6.6–18.2) 9–15
PTT (s) 16.5 (9.1–90.4) 9–20
Additional data
Number of dysfunctional organs at presentation 3 (0–4)

Values for each analyte are presented as median (range). RI = reference interval; NA = not applicable; rpm = respirations per min; bpm =
beats per min; SBP = systolic blood pressure; APPLE = acute patient physiological and laboratory evaluation; WBCs = white blood cells;
SAA = serum amyloid A; PT = prothrombin time; PTT = partial thromboplastin time
562 Journal of Feline Medicine and Surgery 21(6)

Table 2 Univariate and multivariate binary logistic regression of variables that were associated with outcome (survivors/
non-survivors) in 43 cats with sepsis

Variable RC SEM OR (95% CI) P value

Univariate logistic regression


Presence of renal dysfunction at presentation 1.552 0.695 4.72 (1.208–18.468) 0.025
Presence of cardiovascular dysfunction at presentation 1.68 0.787 5.37 (1.147–25.105) 0.033
Requirement of fluid resuscitation at presentation 1.81 0.688 6.111 (1.584–23.567) 0.009
Number of dysfunctional organs at presentation 0.874 0.313 2.397 (1.296–4.434) 0.005
Number of dysfunctional organs at the end of ICU stay 0.525 0.255 1.69 (1.025–2.788) 0.040
Multivariate binary logistic regression
Number of dysfunctional organs at presentation 0.962 0.33 2.618 (1.368–5.007) 0.004

P value indicates difference between survivors and non-survivors in the overall population of septic cats; bold indicates significance (P <0.05).
RC = regression coefficient; SEM = standard error of the mean; OR = odds ratio; CI = confidence interval; ICU = intensive care unit

latter variables were retained from the univariate


regression analysis.

Organ dysfunction: prevalence and associations


with outcome
At presentation, 25/43 cats had evidence of MODS and
frequencies of dysfunctional organs were distributed as
follows: haemostatic dysfunction (n = 24), respiratory
dysfunction (n = 23), hepatic dysfunction (n = 15), renal
dysfunction (n = 14) and cardiovascular dysfunction
(n = 10). During ICU stay, 37/43 cats developed MODS
with the following frequencies: 32 had haemostatic dys-
function, 26 had hepatic dysfunction, 26 had respiratory
dysfunction, 18 had cardiovascular dysfunction and 18
had renal dysfunction. Upon admission, the majority of
Figure 1 Scatter diagram showing the relationship between the cats with renal dysfunction (n = 11/14) had an
the number of dysfunctional organs (ODs) and the feline increased sCr and were classified as IRIS stage 2 (n = 6)
acute patient physiological and laboratory evaluation (APPLE) and stage 3 (n = 5), respectively, whereas only 3/14 cats
score, APPLEfast, in cats with sepsis (n = 43). The Spearman’s had an IRIS stage of 1 and a sCr within the normal range.
rank correlation coefficient was 0.66 (P <0.0001) Results of the univariate logistic regression showed a
significantly elevated OR for mortality for the presence of
MODS, renal and cardiovascular dysfunction, as well as
were administered in 12/43 cats, with 10/12 receiving
for requirement of fluid resuscitation and for the number
fresh frozen plasma, 3/12 packed red blood cells and
of dysfunctional organs recorded upon admission and at
2/12 fresh whole blood. Twenty-six of 43 cats were sur-
the end of ICU stay. When the multivariate binary logistic
vivors, whereas 17/43 were non-survivors (9/17 cats
regression analysis was performed, the number of dys-
were humanely euthanased because of moribund con-
functional organs recorded upon admission was the only
ditions and 8/17 died despite medical treatment).
variable retained by the model (Table 2).
The following variables evaluated at presentation
The Spearman’s rank correlation coefficient between
were significantly different between survivors and
the number of dysfunctional organs and the APPLEfast
non-survivors: body temperature (38.4°C [range 33.2–
score at presentation was 0.66 (P <0.0001; Figure 1). The
40.9°C] vs 35.6°C [range 32–40.5°C]; P = 0.04); APPLEfast
Spearman’s rank correlation coefficient between the
score (26 [range 18–40] vs 34 [range 12–46]; P = 0.02),
number of dysfunctional organs and the APPLEfull score
leukocyte count (12.185 cells × 103/mm3 [range 0.25–
at presentation was 0.56 (P = 0.011).
81.48 cells × 103/mm3] vs 4.01 cells × 103/mm3 [range
0.05–60.91 cells × 103/mm3]; P = 0.03); total amount of
intravenous fluids administered during hospitalisation Discussion
(47 ml/kg/day [range 5–93 ml/kg/day] vs 87 ml/kg/ The present study investigated the prevalence and the
day [range 30–148 ml/kg/day]; P = 0.001). None of the prognostic significance of MODS in a population of cats
Troìa et al 563

with sepsis. A focused organ-by-organ assessment was with it (data not shown). According to the univariate
prospectively performed in the enrolled cats, both at the logistic regression analysis, the presence of cardiovascu-
time of presentation and at the end of the ICU stay. lar dysfunction upon admission was associated with
Organ dysfunction occurred frequently in septic cats and elevated odds for mortality. This result parallels the data
was related to higher APPLE scores and worse outcomes. available from human and small animal studies, as per-
Specifically, presence of MODS, renal and cardiovascular sistent hypotension despite fluid-resuscitation is consid-
dysfunction at presentation significantly increased the ered the most serious manifestation of sepsis, with a
risk of death. The overall number of dysfunctional organs reported mortality rate as high as 80–90% in both spe-
was the strongest predictor of mortality in the current cies.2–5,19,23,24 As such, the presence of cardiovascular dys-
population. These results are novel in feline critical care function might reflect greater disease severity and be
medicine, resemble the data reported in humans and associated with worse outcomes. The negative impact of
dogs with sepsis, and further corroborate the link hypotension on systemic organ perfusion and oxygen
between this syndrome and the development of organ supply has to be considered as a further mechanism
dysfunction.3–5,16–19 leading to worsening clinical pictures and, eventually,
Moreover, the number of dysfunctional organs in this death.25
population was positively correlated with the feline Hepatic, respiratory and haemostatic dysfunction
APPLE scores. The latter are outcome predictors vali- occurred with a variable frequency in the current study
dated in critical feline patients,13 but only the APPLEfast population, but no association with outcome was noted.
score was significantly higher in non-survivors com- Icterus and hyperbilirubinaemia have been described as
pared with survivors, even though it was not prognostic markers of sepsis in cats,7,9 and seem to have a potential
according to the univariate logistic regression. Although prognostic role.10 Prevalence of hepatic dysfunction was
the latter result was not completely expected, the feline elevated in the study reported herein, and raised during
APPLE scores lack an extensive validation in sepsis; hospitalisation. Whether hyperbilirubinaemia reflected
thus, their potential prognostic significance in this clini- true hepatocyte dysfunction or sepsis-induced cholesta-
cal setting needs to be confirmed. sis remains unknown.
Renal dysfunction was defined as the presence of AKI Despite the recent definition of criteria to identify
according to the recent IRIS guidelines established in acute respiratory distress syndrome in small animals,11,26
veterinary patients.15 AKI is a common complication of respiratory dysfunction is commonly identified as the
human sepsis, being related to inflammatory mediators, need for oxygen therapy, mechanical ventilation or
tubular injury and renal microcirculatory alteration.16,17,20 hypoxaemia.3,14 However, such criteria are subjective
There is a paucity of studies concerning sepsis-related (eg, opinions may differ over the need for supplemental
AKI in veterinary medicine,21 and standardised criteria oxygen therapy), and, owing to technical reasons, arte-
for the early identification of this syndrome have been rial PaO2 assessment through blood gas analysis was
only occasionally used in cats.22 The prevalence of AKI only rarely performed herein. The prevalence of respira-
was elevated in this population of septic cats at the time tory dysfunction was elevated in our study, but mainly
of presentation. In this regard, two of the azotaemic cats documented in cats diagnosed with pyothorax (n =
had primary renal involvement due to urosepsis (one cat 10/23) and not necessarily associated with lung disease.
with pyelonephritis, one cat with septic uroabdomen). Additionally, the presence of respiratory dysfunction
Additionally, CKD was suspected in other two cases was not related to outcome in this study population. The
owing to history and imaging findings. These results favourable survival rate documented in the majority of
could have influenced the real frequency of sepsis- the cats with pyothorax might partially explain the latter
related AKI in our population. However, the presence of result. Moreover, it is possible that the degree of respira-
AKI at presentation was a strong predictor of mortality tory dysfunction was only moderate in this population
in our study. This result could support the use of the of septic cats.
application of the IRIS staging system to aid early identi- Abnormalities in the haemostatic profile were com-
fication of renal dysfunction in septic cats. mon in our population, representing the most frequently
Cardiovascular dysfunction was defined as hypoten- reported organ system dysfunction at the time of inclu-
sion in volume-replete patients requiring vasopressor sion and during ICU stay. No association between hae-
support. Despite hypotension and relative bradycardia mostatic dysfunction and outcome was identified.
being described in cats with sepsis, epidemiological data Potential limitations in the criteria used for the assess-
for feline sepsis-induced cardiovascular dysfunction are ment of haemostatic dysfunction in the present study
lacking.6,7 Cardiovascular dysfunction occurred fre- must be considered, not allowing specific characterisa-
quently in this population, with septic peritonitis and tion of either the severity or the nature of the dysfunc-
feline panleukopenia being the main diseases associated tion itself (presence of a hyper- or hypocoagulable state).
564 Journal of Feline Medicine and Surgery 21(6)

Blood product administration was reserved to cats con-


ORCID iD Massimo Giunti https://orcid.org/0000-0002-
sidered at risk of bleeding (n = 10/12) or with signs of 7957-9320
active bleeding (n = 2/12), and could have potentially
affected their outcome.
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