Hello ,
Using ISSU we can upgrade without any downtime . But it depends upon from which version to which version you are upgrading
Till 12.1X44 we have some limitation , but upgrading from 12.1X46 and above does not have any limitations and personally have done multiple upgrades without any issues . But make sure the cluster is in good health .
From 11.4 if you need to upgrade , its not much recommended since we have seen multiple issue . But from 12.1X46 it works fine.