Breed-Specific Anaesthetic Mortality in Cats: Evidence from an Analysis of 14,964 Cases

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Anesthetic mortality in cats is very significant. I therefore find any information about mortality risk interesting and very beneficial.

The manuscript is written very carefully, the data presented are important primarily for clinical practice.

The manuscript focuses primarily on breed-specific data. However, within the limits of the study, I would recommend mentioning other data that may be indirectly related to the breed, such as body condition score.

It would also be appropriate to include anesthetic mortality incidence depending on the age of the cats, anesthetic protocols (e.g. use of alpha-2 agonists), types and duration of the procedure, anesthesiologist (participation of diplomates), etc.

I assume that this will be the subject of another manuscript.

The manuscript is interesting, well-written and useful. It requires only minor additions and corrections. I recommend accepting it for publication after minor revisions.

Author Response

The authors would like to thank the reviewer sincerely for the careful reading of the manuscript, the positive assessment of its clinical relevance, and the constructive comments provided. They greatly appreciate the time and expertise devoted to the review.
The authors agree that anaesthetic mortality in cats is a highly relevant topic and are grateful for the reviewer’s recognition of the importance of the data presented and their applicability to clinical practice.
Regarding the suggestion to include additional variables potentially related to breed, such as body condition score, age, anaesthetic protocols (including the use of alpha-2 agonists), type and duration of procedures, and the level of anaesthetic supervision (including the participation of diplomates), the authors fully concur with the reviewer’s perspective. These factors are indeed clinically important and may act as confounders or modifiers of anaesthetic risk.
As the reviewer correctly anticipates, these variables were comprehensively analysed in the primary report from the same prospective, multicentre cohort (Redondo et al., 2024, Veterinary Record). The present manuscript was intentionally designed as a focused secondary analysis, with the specific objective of exploring breed, brachycephalic phenotype, and genomic lineage in relation to anaesthetic-related mortality, while maintaining conceptual clarity and avoiding redundancy with the main publication.
To address the reviewer’s comment, the authors have clarified in the revised manuscript that these additional variables were evaluated in the main study and are outside the scope of this secondary, hypothesis-driven analysis. This has been explicitly acknowledged in the Discussion as a deliberate methodological choice rather than an omission.
The authors are grateful for the reviewer’s overall positive recommendation and supportive comments, and they believe that the minor clarifications introduced have further strengthened the manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

First, I would like to congratulate the authors on their efforts in assembling a large, prospective, multicentre dataset addressing an important clinical question in feline anaesthesia.

This manuscript presents a large, prospective, multicentre analysis of anaesthetic-related mortality in cats, with a specific focus on breed, genomic lineage and brachycephalic phenotype. However, several conceptual and methodological issues require clarification before the manuscript can be considered for publication.

The study hypotheses are clearly formulated. However, the manuscript would benefit from a more explicit prioritisation of objectives. Currently, three aims are presented with similar weight, whereas the analysis and interpretation appear primarily focused on breed and brachycephalic phenotype rather than on population genetic lineage. Clarifying primary versus secondary objectives would improve conceptual clarity and strengthen the overall narrative.

Anaesthetic-related death was determined based on clinical attribution by participating centres. Given the known inter-observer variability in classifying peri-anaesthetic deaths (including that reported by the authors themselves), the potential impact of outcome misclassification warrants deeper consideration. In particular, the authors should discuss how variability in attribution across centres, countries and clinical settings might differentially affect comparisons between breeds or brachycephalic categories.

The multivariable analyses adjust solely for ASA physical status. While ASA is a key determinant of peri-anaesthetic mortality, it does not encompass several other clinically relevant factors, including procedure urgency, surgical invasiveness, duration of anaesthesia, airway management approaches, or breed-associated comorbid conditions. As a result, the potential for residual confounding, particularly in relation to the observed association between Persian or extreme brachycephalic breeds and mortality should be more clearly acknowledged and discussed.

The discussion is generally well written but somewhat lengthy and, at times, repetitive, particularly in comparisons with canine studies. Condensing these sections may help maintain a clearer focus on feline-specific findings and implications, which is particularly relevant given the focus of the study.

The study hypotheses are clearly formulated; however, the manuscript would benefit from a more explicit prioritisation of objectives. Currently, three aims are presented with similar weight, whereas the analysis and interpretation appear primarily focused on breed and brachycephalic phenotype rather than on population genetic lineage. 

Finally, in lines 115–118, the description of country-level contributions would benefit from being ordered by descending number of cases (n). 

Author Response

The authors would like to thank the reviewer sincerely for the careful and thoughtful evaluation of the manuscript, as well as for the constructive suggestions provided. We greatly appreciate the time devoted to reviewing this work and the positive comments regarding the scale, design and clinical relevance of the study.
In response to the reviewer’s comments, several revisions have been made to improve conceptual clarity and methodological transparency. First, the objectives in the Introduction have been explicitly prioritised. The revised text now clearly identifies breed-specific anaesthetic-related mortality, with adjustment for ASA physical status, as the primary objective, while analyses based on genomic lineage and brachycephalic phenotype are presented as secondary aims, intended to provide additional biological and clinical context rather than equal-weighted endpoints.
Second, we have expanded the description and discussion of outcome classification. In the Materials and Methods section, we now clarify that the attribution and classification of anaesthetic-related deaths (including categorisation by type and presumed primary mechanism) were performed by the principal investigator, based on the contemporaneous clinical information and case narratives provided by the attending teams at participating centres. There was no independent or external adjudication committee. In the Discussion, we further address the potential impact of variability in the underlying clinical reporting and acknowledge how differences across centres, countries and clinical settings could influence comparisons between breeds and brachycephalic categories.
Third, the issue of residual confounding has been more explicitly addressed. We now emphasise in the Discussion that, although ASA physical status is a major determinant of peri-anaesthetic mortality, it does not capture other relevant factors such as procedure urgency, invasiveness, duration of anaesthesia, airway management strategies or breed-associated comorbidities. The observed associations, particularly for Persian and extreme brachycephalic breeds, are therefore discussed as risk markers rather than evidence of causality.
In addition, the Discussion has been condensed to reduce repetition, particularly in sections comparing feline data with canine studies, in order to maintain a clearer focus on feline-specific findings and clinical implications.
Finally, the description of country-level contributions has been reordered by descending number of cases, as suggested.
We are grateful for the reviewer’s insightful comments, which have helped to strengthen the manuscript and improve its clarity and balance.

Reviewer 3 Report

Comments and Suggestions for Authors

This is a well-designed, multicentre prospective study addressing an important and clinically relevant question in feline anaesthesia. The large sample size, international scope, and use of appropriate statistical methods represent clear strengths.

The primary findings are clearly presented and interpreted with appropriate caution, particularly regarding the influence of ASA physical status and the limited number of events in some breed categories. The distinction between breed-level effects and brachycephalic phenotype is biologically plausible and clinically meaningful.

A point that merits consideration is the relatively high proportion of self-citations within the reference list. While several of these studies are directly relevant and originate from large, well-conducted collaborative cohorts, the authors may wish to consider whether additional independent studies could be cited to further contextualise their findings within the broader field of veterinary anaesthesia.

Minor clarifications could further strengthen the manuscript, such as briefly reinforcing in the Discussion that breeds with zero observed deaths should not be interpreted as having a protective effect, given the wide confidence intervals and limited event counts.

Overall, the manuscript makes a valuable contribution to the literature and provides information that is directly applicable to clinical practice.

Author Response

The authors would like to thank the reviewer sincerely for the careful evaluation of the manuscript and for the positive assessment of the study design, international scope, sample size and overall interpretation. We greatly appreciate the time dedicated to the review and the constructive suggestions provided.
With regard to the reference list, we acknowledge the reviewer’s observation about the relatively high proportion of self-citations. In the revised manuscript, we have removed self-citations that were not essential to the aims, methods, or interpretation of the present study, and we have incorporated additional independent literature to better contextualise the findings within the broader field of veterinary anaesthesia. We have retained only those self-citations that we consider directly relevant and necessary for accurate context.
In addition, we have included a brief clarification in the Discussion to reinforce that breeds with no observed anaesthetic-related deaths should not be interpreted as having a protective effect. We now explicitly state that these estimates are limited by small sample sizes and low event counts, which lead to wide confidence intervals and reduced statistical power; therefore, the absence of recorded deaths most likely reflects statistical imprecision rather than true biological protection.
We are grateful for the reviewer’s supportive comments and believe that these revisions have strengthened the manuscript’s clarity and balance, while maintaining its clinical focus.

Reviewer 4 Report

Comments and Suggestions for Authors

The overall perianaesthetic mortality rate of 0.63% in cats reported in this study is an important finding and should be interpreted in relation to other published studies in order to properly assess the study as a whole and its impact. It is not appropriate to compare this value with bibliographic source 4, as the study under review represents a secondary analysis of the same prospective, multicenter cohort of cats conducted by the same authors. When the overall mortality rate is compared with sources 1 and 2, substantially higher percentages are observed in the present study. This discrepancy warrants careful discussion and prompt analysis

The reviewed study defines the observation period as extending from premedication to 48 hours after extubation. However, given that perianaesthetic mortality in other studies has been assessed over periods of up to 7 days, this difference should be explicitly discussed and taken into consideration.

The manuscript states (line 194): “A total of 14,845 cats met the inclusion criteria, of which 94 died during the perianaesthetic period for anaesthetic-related causes.” The specific causes of these deaths are not described, although this information is highly relevant in the context of the present study and the breeds investigated. Considering that the manuscript discusses the impact of anesthesia on brachycephalic breeds, it is particularly important to clarify the role of respiratory complications in these fatalities in order to determine whether brachycephaly represents a primary causal factor rather than a secondary association.

Author Response

We would like to thank the reviewer for the careful reading of the manuscript and for the thoughtful and constructive comments, which have helped us to improve the clarity and robustness of the discussion.

Regarding the interpretation of the overall anaesthetic-related mortality rate, we fully agree that comparison with a previous publication derived from the same prospective cohort was not appropriate. The manuscript has been revised accordingly, and the discussion of the overall mortality rate has been reframed to focus exclusively on comparisons with independent feline cohorts, explicitly acknowledging differences in case mix, study design and outcome definitions.

In response to the comment on the observation period, we have expanded the Discussion to explicitly address differences in follow-up duration between studies, noting that the 48-hour peri-anaesthetic window used in the present analysis may partly account for discrepancies when compared with reports using longer observation periods of up to seven days.

We also recognise the importance of clarifying the causes of anaesthetic-related deaths, particularly in the context of brachycephalic breeds. To address this point, we incorporated a structured description of the presumed primary mechanisms of death into the main manuscript, based on the detailed case narratives and clinical information available. These mechanisms are now defined in the Materials and Methods, summarised in the Results, and interpreted in the Discussion, with specific attention to the relative contribution of respiratory complications in brachycephalic cats. Throughout, we have been careful to avoid causal overinterpretation given the observational design and the limitations inherent to clinical attribution.

We believe that these revisions directly address the reviewer’s concerns and strengthen the interpretation of our findings. We are grateful for the reviewer’s valuable input and for the opportunity to improve the manuscript.