What is the ultimate sepsis treatment paradigm and what measures need to be taken to achieve this goal?
I am concerned about two things in many institutions. The first is that physicians may only focus on controlling blood pressure, especially if the patient is hypotensive, which is a cardinal sign of septic shock. Fluids may be given initially, followed by some vasopressors before targeting the arterial pressure. That’s it, they don’t do anything more, but that is not sufficient: hypotension is an important sign of septic shock, but it is not sufficient to only correct hypotension. Physicians must recognise that septic shock is a state of altered tissue perfusion with inadequate oxygen availability to tissues, so cardiac output and haemoglobin concentration also need to be monitored and treated accordingly.
Secondly, although physicians may measure cardiac output, haemoglobin concentration and central venous pressure, they may just collect numbers and not do anything with the data. On the other hand, some physicians may simplify matters and focus only on one measurement that they would like to maintain at a supra-normal level, such as cardiac output, but this is also not sufficient. The repeated monitoring of patients is essential. A single measurement of cardiac output, lactate levels or ScvO2, using a central venous catheter, is not sufficient, but needs to be repeated over time, so that measurements can be optimised. We need to repeat fluid challenges, to try to make sure that we optimise the volume status of the patient. In some cases, if there is significant myocardial dysfunction, we need to add dobutamine as an inotropic agent, in order to maintain a sufficient cardiac output. Other options exist, not only the control of blood pressure and administration of fluids. The treatment of septic shock is actually a very complex issue.
In the future we will, hopefully, have other therapies for sepsis, to help the body react against invading organisms. Activated protein C (Xigris), is no longer available, following a negative clinical trial. We would like to develop some other agents to give to sepsis patients, to try to better regulate their inflammatory response.
Do you think the focus should be on prevention rather than treatment? Are there things that can be done in the operating room which could help to reduce the incidence of sepsis?
Patients need to be optimally monitored in the operating room to be in the best condition in the postoperative period. We have made a great deal of progress with the forms of haemodynamic monitoring that could be used in the operating room, by measuring cardiac output and monitoring signs of fluid responsiveness; better monitoring systems may somewhat decrease the incidence of postoperative sepsis. Hygienic measures are, of course, of paramount importance. I am less sure, however, that the use of antibiotic-coated material and, in particular, antibiotic-coated catheters, will affect the incidence of sepsis very much. The important point is to identify early those patients who are at risk and, as I mentioned previously, to try and act as early as possible.
Are there any particular ongoing, randomised, controlled trials which you think hold potential to improve the management of perioperative sepsis?
The research industry lost confidence in intensive care medicine following the failure of the activated protein C trial, to which I previously referred. The industry doesn’t want to hear the word ‘sepsis’ any more, because so much money has been spent on sepsis trials, with only a very small return. This is, in part, the fault of the intensive care community, who have been too sceptical vis à vis the development of new compounds. The other difficulty for the industry, and for intensivists, is to develop better phenotypes to identify the right patient for the right intervention. We tend to put all patients in the same group as soon as they have a fever, infection and some hypotension; we put them into the same trial for a given drug, which may perhaps improve some patients but not others. In this way potential drug benefits may be missed, which results in a negative trial. I am concerned that, due to the negative connotations surrounding intensive care medicine, we do not have any major trials researching new sepsis therapies.
That being said, there are ongoing trials for the shocked state. There is an interesting trial involving a vasopressin derivative, called selepressin. This may somewhat increase blood pressure, as although it has some vasoconstricting properties, it may perhaps limit oedema formation by better maintaining endothelial cell function and preventing the capillary leaks that result in oedema throughout the body. This is now expanding into a larger clinical trial following some interesting initial observations.
There are currently two ongoing large, multicentre trials, assessing the value of targeting a given ScvO2 level in patients with septic shock. A third trial has been completed and the data will be presented at the 34th International Symposium on Intensive Care and Emergency Medicine in Brussels, next March. We are looking forward to hearing these results, as this will help to guide therapy by ScvO2 measurements.
What do you foresee changing over the course of the next 10 years?
I think that new sepsis therapies will be available, guided by appropriate biomarkers. We may better identify, and appropriately treat, patients with an excessive inflammatory response that could lead to organ failure. There are also many patients that are immunosuppressed following the initial inflammatory response who may develop nosocomia infections that could lead to septic shock. These patients may need some immuno- stimulating interventions to boost their immune response and thereby limit the risk of postoperative infections. Such interventions need appropriate biomarkers, whose discovery will enable a better characterisation of patients, which will undoubtedly lead to new therapeutic approaches to treat sepsis.
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The opinions and factual claims contained above are solely those of the interviewee and do not necessarily reflect those of the publisher, Editor-in-Chief, Editorial Board or supporting company.
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