If you are going to rent a car from a good company in Karachi, majority of which carry a satellite tracking system, make sure that the car driver informs the tracking company that the car is going outside the city limit. Else you will be standing on the road till a clear signal is given.
And if you are taking your own car, make sure it is in good condition, spare wheel is OK.
There are various fuel stops on the way so issue concerning fuel
When approaching a city (you will pass through several small hamlets/cities), slow down. The local inhabitants have build a hump (speed breakers. The objective is to slow you down as there will be people crossing the main highway.
You are travelling to the interior of Sindh, and one of the route that maybe taken by people who steal cars. So on various stops there are police checkpost. Ordinarily they will just inquire, snoop and let you go. However you never know that on that particular day, this cop is having a bad day, and may make your life a bit miserable (only happens to locals). Foreigners visiting will be sorted a different treatment, and will be welcomed as guests...and sometimes, if there is space in the car...will advise you to take along one of theirs as a safety measure.