There's a number of issues to address, starting with upgrading your database -- SQL Server 2008/2008R2 support is deprecated at 10.3 (not supported by 10.4 & higher [top of p3])
Are your 40 databases really completely independent? Are they all active, or do you need to look at archiving at least some of them to a neutral format (e.g. file geodatabase)?
FYI: "Very large" has a specific meaning in the context of databases, usually referring to tables with more than tens or hundreds of millions of rows. While it's possible for a 50K+ row table to be unwieldy, it's rare that one can achieve "very large".
Even medium to large tables (more than 200k features) which have evolved over time often benefit from spatial defragmentation (export and reimport, or export and rename, as can be achieved using the Sort utility). Actually, the draw performance of all tables improves with spatial sorting, but the difference is often only noticeable over 100-200k+ rows.
In general, performance optimization cannot begin until you accurately capture metrics of existing performance. From there the rule of thumb is to optimize the capabilities with the longest runtime ("longest pole" first).
Good luck.
- V
