Abstract
Objective
To compare systemic inflammatory response syndrome–based (Sepsis-2) and Sequential Organ Failure Assessment–based (Sepsis-3) definitions of sepsis in a population of dogs admitted to a small-animal hospital ICU. A secondary objective was to determine whether fulfilment of either definition was predictive of in-hospital mortality.
Methods
This was a prospective study. Clinical and clinicopathological data of 151 dogs entering an ICU at a university veterinary teaching referral hospital were prospectively collected over a total of 40 weeks, from March 1, 2020, through October 18, 2021, and used to retrospectively diagnose sepsis as per Sepsis-2 and Sepsis-3 definitions. We then evaluated the ability of Sepsis-2 and Sepsis-3 criteria to predict in-hospital mortality in this population.
Results
Of the 151 dogs admitted to the ICU during the study period, 20 dogs (13.2%) fulfilled the definition of sepsis according to Sepsis-2 criteria, whereas only 8 dogs (5.3%) met the Sepsis-3 criteria; only 2 dogs fulfilled both definitions of sepsis. All-cause in-hospital mortality of dogs fulfilling Sepsis-2, Sepsis-3, or both definitions was 40%, 62.5%, and 100%, respectively. Fulfilment of Sepsis-3 criteria was associated with a 4.6 times greater risk of in-hospital mortality compared to dogs who did not fulfill the Sepsis-3 criteria.
Conclusions
Sepsis-2 and Sepsis-3 criteria identified different populations of dogs. Fulfilment of Sepsis-3 criteria was associated with an increased risk of in-hospital mortality.
Clinical Relevance
Further studies on the application of Sepsis-2 and Sepsis-3 definitions are required to further explore differences in phenotypic expression of sepsis in dogs and their impact on outcome.
Sepsis is a life-threatening syndrome of dysregulated systemic host response to an infection and a leading cause of mortality and critical illness in human medicine.1 In veterinary medicine, sepsis is also a well-recognized cause of mortality, with reported rates ranging from 20% to 80%.2,3 While the creation of consensus definitions and guidelines for sepsis in human medicine has resulted in an improvement in detection and a reduction in mortality in people,4 veterinary-specific definitions or guidelines have not yet been established.5
Due to a better understanding of the pathobiology of sepsis in recent years, human guidelines have moved from defining sepsis based on the presence of a systemic inflammatory response to infection (Sepsis-1 and Sepsis-2 guidelines)6,7 to defining sepsis as the development of organ dysfunction associated with infection (Sepsis-3).1 Sepsis-3 guidelines employ a sepsis/Sequential Organ Failure Assessment (SOFA) score in place of systemic inflammatory response syndrome (SIRS) criteria to define sepsis. The newer definition recognizes the fact that SIRS criteria do not necessarily indicate a dysregulated, life-threatening response to infection and that some critically ill patients with infection-related organ failure may not fulfill the Sepsis-2–based definition of sepsis.1 Several studies8–10 in human medicine have shown that fulfilment of Sepsis-3 criteria appears to be more predictive of mortality than previous definitions.
Despite the introduction of the Sepsis-3 definitions in human medicine in 2016,1 most veterinary clinicians continue to use SIRS criteria to define sepsis, and there is scant research evaluating the application of Sepsis-3 guidelines to companion animals.5 One study11 applied a SOFA-based scoring system to critically ill dogs and found that it was a useful prognostic indicator and significantly associated with mortality. A second study,12 which compared Sepsis-2 and a modified Sepsis-3 definitions in a population of dogs with parvovirus infection, found that fewer dogs were diagnosed with sepsis when Sepsis-3 definitions were used and that fulfilment of Sepsis-3 criteria was associated with a higher risk of mortality compared to Sepsis-2. To the authors’ knowledge, there have been no studies evaluating Sepsis-3 definitions in dogs with bacterial infection.
The aim of this study was to compare Sepsis-2 and Sepsis-3 definitions in a population of dogs admitted to an ICU at a referral small-animal hospital. A secondary objective was to investigate the prognostic utility of each definition. Based on the current literature, we hypothesized that the Sepsis-3 definition of sepsis would characterize fewer dogs with sepsis than the Sepsis-2 definition and that fulfilling Sepsis-3 criteria would be associated with a higher in-hospital mortality.
Methods
Study design and inclusion criteria
Data were prospectively collected over a total of 40 weeks in blocks of at least 2 weeks from March 2020 through October 2021; discontinuous data collection reflected working restrictions and shift patterns during the COVID-19 pandemic. All dogs admitted to the ICU of a university referral hospital for at least a 24-hour period were eligible for inclusion. Dogs were excluded if they were admitted to the ICU for monitoring for less than 24 hours or for postanesthetic recovery.
Clinical data collection
On admission to the ICU, to allow calculation of SIRS and SOFA scores, all dogs had a complete clinical evaluation comprising a full physical examination (including heart rate, respiratory rate, and rectal temperature); systolic and mean arterial pressure, measured using a noninvasive oscillometric device and a blood pressure cuff of appropriate size (Vet25 Veterinary Blood Pressure Monitor; SunTech Medical Inc); oxygen saturation by pulse oximetry, using a hand-held device (PalmSat 2500A; Nonin); modified Glasgow Coma Scale13; and bloodwork, including hematology and serum biochemistry (Supplementary Table S1). Preadmission administration of antibiotics, including class, was recorded.
Case records were retrospectively reviewed and the final diagnosis recorded. Dogs were classified as having a bacterial infection when the presence of bacteria was evidenced by visualization of intracellular bacteria on cytology, positive growth in a biofluid, effusion or blood culture, or when there was a high index of suspicion based on clinical and clinicopathological data (eg, neutropenia with left shift) coupled with a positive response to antimicrobial therapy. For patients with respiratory disease (pneumonia, bronchopneumonia, or aspiration pneumonia) that were not stable enough to undergo a full diagnostic evaluation (eg, bronchoalveolar lavage), infection was diagnosed based on clinicopathological abnormalities and radiological changes compatible with infection and response to antibiotics as described in the literature.14,15
Definition of sepsis
Sepsis-2 was defined as infection plus 2 or more SIRS criteria as per Sepsis-2 definitions.6,7 Systemic inflammatory response syndrome criteria were based on previously published human SIRS criteria adapted to reflect normal physiological parameters of dogs: a body temperature of ≤ 37.8 °C or ≥ 39.7 °C, a heart rate ≥ 160 beats/min, a respiratory rate of ≥ 40 breaths/min, and a white blood cell count of ≥ 12.0 X 109/L or ≤ 4.0 X 109/L or the presence of ≥ 10% bands.16 Severe sepsis was defined as sepsis complicated by organ dysfunction, and septic shock was defined as the state of acute circulatory failure characterized by persistent arterial hypotension unexplained by other causes.6
Sepsis-3 was defined as the presence of infection plus concurrent organ dysfunction, which was defined as a SOFA score ≥ 2 as defined by The Third International Consensus Definitions for Sepsis.1 For the purpose of our study, for ethical and practical reasons, and to make the scoring system applicable to a canine population, the respiratory component of the SOFA score was calculated by using the ratio of the oxygen saturation by pulse oxymetry to the fraction of inspired oxygen (SpO2:FiO2) as a surrogate of the ratio of the partial pressure of oxygen in arterial blood to the fraction of inspired oxygen (PaO2:FiO2) as previously described in the literature,17 and the human Glasgow Coma Scale assessing the CNS component of the SOFA score was replaced by the modified Glasgow Coma Scale proposed for dogs.13
Patient classification
Data were retrospectively reviewed, and dogs with documented or suspected infection were classified as having Sepsis-2, Sepsis-3, or both Sepsis-2 and Sepsis-3. The results were compared for dogs grouped by infection status (present vs absent), sepsis category (Sepsis-2, Sepsis-3, or Sepsis-2 and Sepsis-3 combined), and whether dogs survived to hospital discharge (survivors) or were euthanized or died while hospitalized (nonsurvivors).
Statistical methods
R, version 4.4.0 (R Foundation for Statistical Computing) was used for data processing and analysis. Confidence intervals around observed incidences were calculated using the Wilson interval method.18 The association between Sepsis-2 status and in-hospital mortality was assessed using the χ2 test; the Fisher exact test was used to assess the association between Sepsis-3 status and in-hospital mortality due to the low count of dogs with Sepsis-3. The threshold for statistical significance was set at P < .05.
Ethical statement
Ethical approval for this study was granted by the institutional veterinary ethical review committee (approval No. EA35/19). Owner consent for treatment and data collection was obtained for all animals at the time of admission.
Results
Study population
There were 227 cases admitted to the ICU that met the inclusion criteria for the study. After exclusion, due to incomplete records or missing clinical data, 151 dogs were finally included in the final dataset, of which 32 dogs (21.2%) were considered to have a bacterial infection (Figure 1); of these, 19 dogs had a confirmed bacterial infection based on a positive culture (n = 17) and the visualization of intracellular bacteria on cytology of peritoneal effusion (n = 2); there was a high index of suspicion for bacterial infection in a further 13 dogs based on compatible clinical/clinicopathological data combined with a positive response to antibiotics. Of these, 8 had pneumonia and were considered unstable for obtaining a sample, and the remainder were diagnosed with emphysematous cholecystitis (n = 1), intestinal necrosis (n = 1), osteomyelitis (n = 1), and an antibiotic-responsive febrile illness or pyrexia of unknown origin (n = 2); all had negative blood cultures (n = 5) and/or a negative culture of a peritoneal effusion (n = 1), and with the exception of the dog with osteomyelitis, all dogs had received prior antibiotic therapy (Supplementary Table S2).
Consort flow diagram summarizing the case selection of all dogs admitted to the ICU from March 2020 through October 2021 and sample selection and inclusion for analysis of dogs fulfilling Sepsis-2, Sepsis-3, or Sepsis-2 and Sepsis-3 of dogs with infection.
Citation: American Journal of Veterinary Research 86, 5; 10.2460/ajvr.24.12.0413
Dogs fulfilling Sepsis-2 criteria
Of the dogs with infection, 20 were diagnosed with sepsis based on Sepsis-2 definitions, giving an incidence of 13.2% (95% CI, 8.7 to 19.6). Of these, 11 had a SIRS score of 2 (55%), 5 had a score of 3 (25%), and 4 had a score of 4 (20%). Two dogs with SIRS scores of 3 and 4 also had organ dysfunction and were classified as having severe sepsis. No dogs in this study were classified as having septic shock. In dogs fulfilling Sepsis-2 criteria, sepsis was associated with pneumonia (n = 5); septic peritonitis (n = 4); intestinal disease (n = 4), including acute hemorrhagic diarrhea syndrome (n = 2), salmonellosis (n = 1), and intestinal necrosis (n = 1); immunological disease (n = 3), including myelodysplastic leukemia and pyrexia of unknown origin (n = 2); surgical site infection (n = 1); septic arthritis (n = 1); osteomyelitis (n = 1); and urinary tract infection (n = 1).
Dogs fulfilling Sepsis-3 criteria
Eight dogs fulfilled the Sepsis-3 definition, giving an incidence of 5.3% (95% CI, 2.7 to 10.1). Of these, 2 dogs had a SOFA score of 2 out of 24, 2 dogs had a score of 3, and 1 of each dog had a score of 4, 5, 7, and 9 (Supplementary Table S3). In dogs diagnosed with sepsis based on Sepsis-3 criteria, sepsis was associated with septic peritonitis (n = 2) and 1 each of liver abscess, emphysematous cholecystitis, pyothorax, acute hemorrhagic diarrhea syndrome, intestinal necrosis, and neutrophilic vasculitis. No dogs with pneumonia fulfilled Sepsis-3 criteria.
Dogs fulfilling both Sepsis-2 and Sepsis-3 criteria
Only 2 dogs fulfilled both definitions of sepsis; both of these dogs were classified as having severe sepsis according to Sepsis-2 definitions. One dog had a SIRS score of 4 and SOFA score of 4, and sepsis was associated with intestinal necrosis; the other dog with septic peritonitis secondary to pyometra had a SIRS score of 3 and a SOFA score of 9 out of 24.
Outcome
Four dogs in the group of no infection were lost to follow-up, leaving 115 dogs for statistical comparison. The all-cause in-hospital mortality rate of dogs admitted to the ICU without infection was 27% (31 of 115) in contrast to an in-hospital mortality rate of 37.5% (12 of 32) in the group of dogs diagnosed with an infection. Dogs with a diagnosis of sepsis by Sepsis-2, Sepsis-3, or both had an in-hospital mortality of 40%, 62.5%, and 100%, respectively (Table 1). When considering the study population as a whole, fulfilment of Sepsis-2 criteria was not associated with an increased likelihood of death (χ2 test P = .3), whereas dogs diagnosed with sepsis based on fulfilment of Sepsis-3 criteria were statistically significantly more likely to die (OR, 4.55; 95% CI, 0.84 to 30.71; Fisher exact test P = .04).
Survival to discharge and all-cause in-hospital mortality (nonsurvivors) among all dogs admitted to a referral hospital ICU and grouped based on infection status (no infection vs infection) and adherence to Sepsis-2, Sepsis-3, or both criteria.
| All population (n = 147) | No infection (n = 115) | Infection (n = 32) | Sepsis-2 (n = 20) | Sepsis-3 (n = 8) | Sepsis-2 and -3 (n = 2) | |
|---|---|---|---|---|---|---|
| Survivors | 104 (70.7%) | 84 (73%) | 20 (62.5%) | 12 (60%) | 3 (37.5%) | 0 (0%) |
| Nonsurvivors | 43 (29.3%) | 31 (27%) | 12 (37.5%) | 8 (40%) | 5 (62.5%) | 2 (100%) |
The results for survival and nonsurvival are reported in percentages for each group.
Outcome data were obtained for 147 dogs.
Discussion
In this study, we set out to compare the fulfilment of Sepsis-2 and Sepsis-3 definitions of sepsis in a population of dogs admitted to the ICU of a university teaching hospital and to evaluate the utility of each definition in predicting in-hospital mortality. As hypothesized, we observed differences in the incidence of sepsis depending on which definition was used, with Sepsis-3 defining fewer dogs as having sepsis (5.3%) in comparison to Sepsis-2 (13.2%). Interestingly, there was very little overlap between Sepsis-2 and Sepsis-3, with only 2 dogs fulfilling both definitions, both of which being classified as having severe sepsis according to Sepsis-2 definitions. We also found that fulfilment of Sepsis-3 criteria was associated with an increased risk of in-hospital mortality compared to dogs who did not fulfill the criteria, whereas fulfilment of Sepsis-2 criteria was not associated with an increased risk of in-hospital mortality.
Since the publication of the Sepsis-3 consensus statement in 2016,1 there have been several publications comparing Sepsis-2 and Sepsis-3 definitions in human healthcare settings, and as observed in our study, the incidence of sepsis tends to be lower when the Sepsis-3 definition is applied.9,19,20 This has also been shown in a study comparing Sepsis-2 and Sepsis-3 definitions in dogs with parvovirus, where only 32.2% of dogs fulfilling Sepsis-2 criteria met the Sepsis-3 definition.12
At face value, this observation may merely reflect the fact that Sepsis-3 identifies a subpopulation of individuals with more severe disease9,12,19 as the criteria used to define sepsis in the Sepsis-3 consensus include the presence of organ dysfunction associated with infection, whereas Sepsis-2 criteria focus on the identification of individuals with systemic inflammatory response to infection, the latter potentially representing an appropriate response to infection.1 However, as we observed, not all individuals who fulfill Sepsis-3 criteria also fulfill Sepsis-2 criteria and vice versa.21–23 In our study, 6 of the dogs that fulfilled the Sepsis-3 definition of sepsis (75%) did not meet the requisite 2 SIRS criteria to fulfill the Sepsis-2 definition. The reason for this discordance is not entirely clear but has been attributed to different sepsis phenotypes, reflecting the complex pathobiology of sepsis.24–27
Interestingly, the site of infection has been found to have a relationship with the phenotypic variation, severity of disease, and mortality28 and also appears to have an impact on the discrimination and predictive ability of SOFA-based definitions of sepsis.29 More specifically, pneumonia seems to be associated with lower SOFA scores than other types of infections,30 and while pneumonia is a leading cause of sepsis in people, only around a third of cases of pneumonia develop severe sepsis.31 Along similar lines, while 5 of the 10 dogs with pneumonia in our study population met the Sepsis-2 definition, none of them had severe sepsis, and none of them fulfilled Sepsis-3 criteria. As pneumonia accounted for the source of infection or presumed infection in just under a third of cases, this may, in part, explain the relatively high rate of discordance between Sepsis-2 and Sepsis-3 definitions in our study.
In line with previous studies, we found that Sepsis-3 definition was associated with a higher risk of in-hospital mortality, and Sepsis-2 was not. Several human studies1,10 have shown that Sepsis-3 has better specificity and prognostic accuracy than Sepsis-2, and similarly in dogs with parvovirus, a modified Sepsis-3 scoring system was more predictive of outcome than Sepsis-2.12 The lack of association of Sepsis-2 with outcome may be due in part to the poor specificity of SIRS criteria1,10,32; in a recent canine study,33 a SIRS score of 2 even failed to differentiate heathy and diseased individuals. In a recent study of septic dogs with parvovirus infection, Alves et al34 reported that the prognostic value of SIRS-based criteria was improved when combined with variables reflecting organ dysfunction, and similarly, in a study of human sepsis, Engoren et al24 observed that the combination of Sepsis-2 and Sepsis-3 criteria appeared to be more predictive of mortality than either on its own. We also observed the highest in-hospital mortality rate in those dogs fulfilling both definitions. Further studies evaluating the combination of SIRS- and SOFA-based criteria are therefore warranted.
This study has several limitations, including the difficulty in definitively diagnosing bacterial infection in dogs that are either too unstable to undergo full diagnostic evaluation or that have received recent antibiotic therapy. While every attempt was made to confirm bacterial infection, for instance by performing blood cultures in a subset of patients, we relied on supportive clinical and pathological data and positive response to antibiotics to diagnose infection in 13 dogs, and it is feasible, although unlikely, that these dogs were misclassified. The study design did not exclude dogs that had had previous treatment, including antibiotics, and this might have influenced the SIRS and SOFA scores at admission to the ICU, potentially reducing the number of dogs with severe disease. There were only 2 cases with severe sepsis and none with septic shock, and larger studies are required to verify our observations. While we compared Sepsis-2 and Sepsis-3 in all dogs with bacterial infection, this was quite a heterogenous group, and given the influence of location of infection on the clinical manifestations of sepsis, it may be more appropriate for future studies to concentrate on specific bacterial conditions. Finally, given the relatively low case numbers, statistical analysis may be subject to type 1 and type 2 statistical errors. The small cohort of dogs meeting the Sepsis-3 criteria is a particular limitation and means that the results relating to these dogs must be interpreted cautiously. Despite the statistically significant (P = .04) result of the Fisher exact test for an association with mortality, it must be remembered that only 8 dogs met the Sepsis-3 criteria. These dogs were found to be 4.55 times more likely to die compared to dogs who did not meet the criteria, but this OR had a very wide 95% CI, which included 1 (0.84 to 30.71).
We found that Sepsis-2 and Sepsis-3 definitions identified different sepsis phenotypes in dogs with all-cause bacterial infection. Sepsis-3 classified fewer patients as being septic compared to Sepsis-2 but appeared to be more predictive of in-hospital mortality. Other studies are required to further explore the differences in phenotypic expression of sepsis in dogs and their impact on outcome.
Supplementary Materials
Supplementary materials are posted online at the journal website: avmajournals.avma.org.
Acknowledgments
The authors would like to thank all the clinicians and the ICU nursing team for supporting this study and for their invaluable contribution and help with data collection.
Disclosures
The authors have nothing to disclose. No AI-assisted technologies were used in the composition of this manuscript.
Funding
Funded by a University of Glasgow Vet Fund Small Project Grant.
ORCID
C. Pizarro del Valle https://orcid.org/0000-0002-9762-5300
E. D. Bennet https://orcid.org/0000-0001-9049-1920
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