BJA/RCoA Project Grants

Background
Around 1.5 million patients in the UK require a breathing machine as part of their surgery each year. The mode of breathing (ventilation) delivered can vary according to the anaesthetist's preference and type of surgery. We believe that the mode of ventilation could alter how often complications after surgery occur by altering the body's own internal timekeeping mechanism termed "the body clock".

Humans have our own "clock" which ensures each tissue knows what time it is. For example, this clock helps us to sleep at night but also ensures that we know when to get up for the day. It takes time for the clock to shift when our environment changes, resulting in "jet-lag" however light and other stimuli ensures that this shift occurs. We now have discovered that one of these resetting stimuli is ventilation resulting in big shifts of the body clock after an operation. Since shifts in the body clock increase the likelihood of infection we believe this is an important cause of chest infections after surgery which can affect 1 in 5 patients.

Aim1: How breathing machines affect the body clock
We will identify how best to program the breathing machine so that it does not affect the "body clock" but still keeps people alive during surgery. We can do this by visualising the body clock after ventilation. In addition we will use tests to identify the effects e.g. infection of circadian disruption on the lung.

Aim 2: We will identify the important cell type and the changes in the cell as a result of disruption to the body clock
We will use the ventilation method identified in aim1 to ventilate lung slices and cells in the lab. By examining how the lung slices behave we will be identify which cell type(s) are important. We will then look at these cells in more detail to identify the changes inside the cell caused by shifts in the body clock which occur as a result of ventilation. Finally, we will then use drugs which target these changes to see if we can prevent them from happening or reduce their effects.

Expected outcomes
1: Discover how we can give ventilation so that it does not affect the body clock.
2. Identify how we can prevent the damage if we do have to give ventilation which alters the body clock.

Implications
We hope to identify how to give ventilation in a way that does not affect the body clock. This will allow a clinical trial to be performed so that this discovery can be incorporated into clinical practice hopefully reducing bad outcomes after surgery.

Advances in clinical care have reduced mortality rate and improved short-term recovery post-surgery, however the long-term functional recovery from surgery still needs to be improved. Reduced activity following surgery contributes to muscle wasting and weakness. This results in functional limitation which remains even after a year, especially in frail and elderly patients. Therefore new treatment that promotes recovery and prevent reduction in quality of life post-surgery are desirable. Nutrition, physical therapy and pharmaceuticals treatment have been tried before to reduce muscle loss and promote recovery. However these treatments have not been effective. Therefore to design an effective therapy, we need to know the extent and time course of muscle loss and weakness after surgery.

We have already carried out study to show patients undergo 10 % muscle mass loss during the first week after major abdominal surgery, and there is associated weakness. In this study we will carry out closer monitoring of muscle mass and strength to gather information on the rate and lowest point of muscle mass loss and weakness after major abdominal surgery. We will use ultrasound images to assess muscle mass and carry out hand grip strength test and assess breathing muscle strength using a sniff test. These assessments will be carried out before surgery, a day after surgery; thereafter on alternate days until hospital discharge (normally ~7 days) and 6 weeks after discharge.

In addition, to assess the impact of surgery on physical function and we will carry out physical function test such as 'sit to stand' and timed walks before surgery, at hospital discharge and 6 weeks after discharge. Blood samples will be collected at pre, day 1 post-surgery; at hospital discharge (or day 7 postsurgery if still in hospital) and 6 weeks after discharge and optional diaphragm biopsy during surgery taken by the surgeons. These biological samples will be used for laboratory analysis to assess the mechanism behind the loss of muscle mass and strength.

The outcome of our study will help design future interventional studies. Treatment to reduce muscle loss and weakness post-surgery would reduce functional decline, promoting good quality of life after surgery. In addition it would also reduce financial burden through shorter stay in hospital; likely to discharged home; fewer complications and readmission.

In Uganda, and numerous other low-income countries, many patients cannot access timely and affordable surgery whilst those who do may frequently develop complications or die. Recent studies from across the continent show that African surgical patients are younger, with less chronic illness, but twice as likely to die after surgery when compared to the global average. These studies also show that most patients die after surgery whilst recovering on a hospital ward. Life-threatening complications are often not identified in time. Many lives could be saved through timely, often simple and cheap treatments, such as additional oxygen, intravenous fluids or antibiotics. At Mbale Regional Referral Hospital in Uganda, a single nurse may often be responsible for more than 35 patients at one time, a common situation in low-income countries. In many hospital wards, basic 'vital signs' such as heart rate, breathing rate and temperature are never monitored. This lack of patient monitoring is a key reason for the high rates of preventable death after surgery in Africa. The opportunity to identify life threatening complications is missed because there aren't enough trained healthcare staff.

We propose a novel solution to the need for routine vital signs monitoring after surgery. In many African hospitals, family members provide much of the basic personal care for patients. We propose to train family carers to measure four key vital signs using basic equipment, and document them for nursing and medical staff to review. We will teach a simple method to spot patterns which suggest a patient is at risk, so family carers know when to ask nursing staff for help. The four vital signs are heart rate (number of heartbeats in one minute), respiratory rate (number of breaths in one minute), oxygen saturation (how much oxygen is delivered to the tissues, measured by a simple handheld electronic device) and conscious level using the 'AVPU' scale (alert; responds voice, responds to pain; unconscious). We will hold 30-minute training sessions twice a day for family carers to attend as often as they wish. These will include safety and quality checks to ensure family carers understand the task correctly.

To test how well our new intervention works, we will introduce this into four surgical wards, one at a time, in a carefully structured clinical trial over a 6-month period. We will include 2000 patients having surgery, and their family carers, provided they consent to take part. The trial will be reviewed by local and national research ethics committees and conducted according to international standards. The trial findings will show whether we can maintain the training programme for a sustained period, confirm whether the training does indeed lead to a higher rate of vital signs monitoring, and provide an initial estimate of how many lives this approach may save. If the results are promising, we will use this information to design a very large trial to run across many African countries, to prove whether this is an effective way to prevent deaths after surgery.