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Which factors influence decisions to transfer and treat patients with acute intracerebral haemorrhage and which are associated with prognosis? A retrospective cohort study

Objectives To identify factors associated with the decision to transfer and/or operate on patients with intracerebral haemorrhage (ICH) at a UK regional neurosurgical centre and test whether these decisions were associated with patient survival. Design Retrospective cohort study. Setting 14 acute and specialist hospitals served by the neurosurgical unit at Salford Royal NHS Foundation Trust, Salford, UK. Participants All patients referred acutely to neurosurgery from January 2008 to October 2010. Outcome measures Primary outcome was survival and secondary outcomes were transfer to the neurosurgical centre and acute neurosurgery. Results We obtained clinical data from 1364 consecutive spontaneous patients with ICH and 1175 cases were included in the final analysis. 140 (12%) patients were transferred and 75 (6%) had surgery. In a multifactorial analysis, the decision to transfer was more likely with younger age, women, brainstem and cerebellar location and larger haematomas. Risk of death in the following year was higher with advancing age, lower Glasgow Coma Scale, larger haematomas, brainstem ICH and intraventricular haemorrhage. The transferred patients had a lower risk of death relative to those remaining at the referring centre whether they had surgery (HR 0.46, 95% CI 0.32 to 0.67) or not (HR 0.41, 95% CI 0.22 to 0.73). Acute management decisions were included in the regression model for the 227 patients under either stroke medicine or neurosurgery at the neurosurgical centre and early do-not-resuscitate orders accounted for much of the observed difference, independently associated with an increased risk of death (HR 4.8, 95% CI 2.7 to 8.6). Conclusions The clear association between transfer to a specialist centre and survival, independent of established prognostic factors, suggests aggressive supportive care at a specialist centre may improve survival in ICH and warrants further investigation in prospective studies.


THE STUDY
I believe the important information in the tables are adequately describe in the body of the manuscript.

GENERAL COMMENTS
Good job with this paper. This is a fairly large data set of people that supports the notion that specialized/focused care even in disease conditions where there is not too many specific treatment (like ICH) can improve outcomes.

GENERAL COMMENTS
Further clarification of statistical methods is required and particularly about how the decision was made to include certain variables in the analysis. Only multivariable analysis is conducted but this is not clarified and is not made clear in the results, tables or discussion. It is also important to clarify coding decisions. For instance, the authors have coded cerebellar haematomas as lobar haematomasthis is a very unusual classification. This may have led to problems in the analysis of transferred patients who had surgery versus those who did not (complete separation is suggested by a very wide confidence interval). The authors should check for the number of cases who had cerebellar haematoma and whether they all had surgery or all did not have surgery. Why did the authors omit presence of hydrocephalus and location of haematoma: deep versus lobar from the analysis of predictors of surgical care? Especially since the published evidence for treatment take into account these factors. Under Table 2 the note states that referring hospital was included in the regression model but it is not shown in the table. It would have required 13 dummy variables and led to considerable overfitting. This would therefore be an inappropriate analysis. Table 1 contains more than just the baseline characteristics stated in the results section. It shows the characteristics of patients not transferred, transferred with no surgery and transferred with surgery. The second paragraph goes on to say that the decision to transfer was based, among other factors, on female sex. It is very important to emphasize that this is after controlling for the other variables. Table 1 shows no difference in the proportion of female patients in each group and therefore the statement that Table 2 shows there is a difference will be confusing. The discussion of the factors that affect transfer fails to mention GCS which is more significant than gender. However the text does mention differences in referring centre without providing any evidence for the statement. They state that there is no evidence of differences in decision making between the 19 consultant neurosurgeons but there is no information on how this was assessed. They have excluded location and hydrocephalus as there was "no evidence of an association" but they have included other variables with no evidence of an association. They do not appear to have been consistent in their decision making about which variables to include in the analysis. Paragraph 3 of the results discusses transferred patientsit refers to 56 who had vascular imaging (this is irrelevant to this paragraph) and to table 5 (this is incorrecttable 5 reports on other data). They state that there is no evidence that the presence of IVH or hydrocephalus were associated with the decision to operate but table 1 shows that patients were much more likely to have surgery if they had an IVH or if they had hydrocephalus. The correct statement would be that after taking into account GCS, location of the haematoma and volume of the haematoma there is no evidence that the other variable affected the decision to operate in this small dataset. Of course patients with an IVH tend to have lower GCS and the haematoma is likely to be deep and supratentorial so the variables are confounded. Again for the Cox regression analysis there is no justification for the variables included in the analysis or for the exclusion of other variables.
In the comparison of the surgical and medical patients from SRFT although they suggest differences in baseline measures between the patients most are not statistically significant as the sample sizes are too small. "I believe the important information in the tables are adequately describe in the body of the manuscript. Good job with this paper. This is a fairly large data set of people that supports the notion that specialized/focused care even in disease conditions where there is not too many specific treatment (like ICH) can improve outcomes."

VERSION 1 -AUTHOR RESPONSE
We thank the reviewer for their consideration.
Reviewer 2: Gregson, Barbara Newcastle University, Neurosurgical Trials Unit 1. "Further clarification of statistical methods is required and particularly about how the decision was made to include certain variables in the analysis. Only multivariable analysis is conducted but this is not clarified and is not made clear in the results, tables or discussion." We welcome the opportunity to give further detail on the modelling strategy and have added a paragraph to the methods section under "statistical analysis".
2. "It is also important to clarify coding decisions. For instance, the authors have coded cerebellar haematomas as lobar haematomasthis is a very unusual classification. This may have led to problems in the analysis of transferred patients who had surgery versus those who did not (complete separation is suggested by a very wide confidence interval). The authors should check for the number of cases who had cerebellar haematoma and whether they all had surgery or all did not have surgery." We thank the referee for highlighting this issue and recognise the potential for confusion. We have therefore re-analysed our data with a more conventional classification of "location". This does not alter our conclusions but will aid "readability". In fact, 7 of the 14 cases transferred with cerebellar haematoma underwent surgery.
3. "Why did the authors omit presence of hydrocephalus and location of haematoma: deep versus lobar from the analysis of predictors of surgical care? Especially since the published evidence for treatment take into account these factors." This is now clarified under statistical method. Rather than make a subjective decision regarding each factor"s evidence base we retained those that contributed to the Hemphill ICH score along with those that were statistically significant within our own dataset. In the interests of clarity and consistency we have now removed all factors that are not-statistically significant for any level. Table 2 the note states that referring hospital was included in the regression model but it is not shown in the table. It would have required 13 dummy variables and led to considerable overfitting. This would therefore be an inappropriate analysis."

"Under
The modelling strategy now described was conscious of the danger of over-fitting. An alternative model, treating centre as a stratifying factor, did not materially alter our conclusions and is available on request. The detailed coefficients for each centre are not of interest to readers and are omitted from Table 2 for reasons of space. With over 1000 cases and 140 experiencing the "event" of transfer the model appears to have fitted without instability.
5. " Table 1 contains more than just the baseline characteristics stated in the results section. It shows the characteristics of patients not transferred, transferred with no surgery and transferred with surgery. The second paragraph goes on to say that the decision to transfer was based, among other factors, on female sex. It is very important to emphasize that this is after controlling for the other variables. Table 1 shows no difference in the proportion of female patients in each group and therefore the statement that Table 2 shows there is a difference will be confusing." We have amended the text of this section to clarify the additional breakdown of baseline characteristics and the multifactorial nature of the analyses.
6. "The discussion of the factors that affect transfer fails to mention GCS which is more significant than gender." We apologise for this oversight. We have added some text regarding the GCS and corrected a typographical error in the first paragraph of Discussion.
7. "However the text does mention differences in referring centre without providing any evidence for the statement. They state that there is no evidence of differences in decision making between the 19 consultant neurosurgeons but there is no information on how this was assessed." These issues have now been clarified by the additional paragraph on statistical method. Both were assessed unifactorially and, if statistically significant, re-entered into final models and retained only if retaining significance after controlling for known potential case-mix confounders.
8. "They have excluded location and hydrocephalus as there was "no evidence of an association" but they have included other variables with no evidence of an association. They do not appear to have been consistent in their decision making about which variables to include in the analysis." Again, we apologise for the lack of detailed description of the modelling strategy, which is now included.
9. "Paragraph 3 of the results discusses transferred patientsit refers to 56 who had vascular imaging (this is irrelevant to this paragraph) and to table 5 (this is incorrecttable 5 reports on other data)." We apologise for this error that was carried over from our earlier drafts prior to submission, and have corrected the text.
10. "They state that there is no evidence that the presence of IVH or hydrocephalus were associated with the decision to operate but table 1 shows that patients were much more likely to have surgery if they had an IVH or if they had hydrocephalus. The correct statement would be that after taking into account GCS, location of the haematoma and volume of the haematoma there is no evidence that the other variable affected the decision to operate in this small dataset. Of course patients with an IVH tend to have lower GCS and the haematoma is likely to be deep and supratentorial so the variables are confounded." We agree and have modified the text accordingly.
11. "Again for the Cox regression analysis there is no justification for the variables included in the analysis or for the exclusion of other variables." We have added the modelling strategy under methods.
12. "In the comparison of the surgical and medical patients from SRFT although they suggest differences in baseline measures between the patients most are not statistically significant as the sample sizes are too small." We agree. We are not interested in the baseline differences between the surgical and medical patients at SRFT. We first checked that the medical patients at SRFT were not starkly unrepresentative of non-transferred patients within the Region. On confirmation of this we felt comfortable using our earlier model to adjust for case-mix differences before examining additional factors.

GENERAL COMMENTS
Minor editing: Table 6 has factor "DNAR" should be "DNR". For the editor -it is exceedingly difficult to read Table 3 -it is only readable in the HTML version.