The effect of proactive versus reactive treatment of hypotension on postoperative disability and outcome in surgical patients under anesthesia (PRETREAT): an adaptive, multicenter randomized controlled trial

Over 1.4 million surgical procedures are performed every year in the
Netherlands, of which one million under general or regional anesthesia.
Unfortunately, surgery is not without complications. A risk factor for
complications that commonly occurs during surgery under anesthesia is low blood
pressure (hypotension). When a patient undergoes anesthesia, the body loses
control over the compensatory mechanisms to regulate blood pressure and
counteract hypotension. Hypotension, even for one minute, increases the risks
of complications, such as myocardial infarction, renal failure, and
postoperative death. Finding a solution for hypotension has therefore been
prioritized in the 2018 TOP-10 research agenda of the Dutch Society of
Anesthesiology.
Anesthesiologists have been using cardiovascular drugs since the emergence of
large-scale anesthesia to fight hypotension, but despite those efforts, in more
than 75% of surgical procedures (approximately 750.000 procedures per year)
patients have one or more episodes of hypotension (a Mean Arterial Pressure
(MAP) below 65 mmHg).
Anesthetic drugs, surgical manipulation and blood loss typically cause many
fluctuations in a patient*s blood pressure. Not all patients are affected
equally: the frequency and magnitude of blood pressure fluctuations depend on
the type of surgery and on the patient*s comorbidity. Patients with more and
greater blood pressure fluctuations have a greater chance of their blood
pressure dropping below the currently advocated minimal acceptable threshold of
a MAP of 65 mmHg, and are thus at greater risk of perioperative morbidity and
mortality.
The current paradigm of blood pressure management is predominantly reactive:
blood pressure is treated when it approaches the minimally acceptable threshold
or when it is rapidly dropping. From a risk perspective it makes more sense to
shift the paradigm to a proactive approach: keeping the blood pressure at a
safe margin above the minimal acceptable blood pressure threshold. Patients at
greater risk of severe blood pressure fluctuations need to be kept at a higher
target blood pressure to keep them safe. This requires an intervention
guideline for the anesthesia team with advise how to keep their patients* blood
pressures at the appropriate level.

The aim of this adaptive multicentre randomized controlled trial is to maintain
patients at a target blood pressure level with a sufficient margin from the
minimal acceptable blood pressure threshold of a MAP of 65 mmHg to reduce the
incidence of hypotension. This study will investigate whether a proactive blood
pressure management approach improves functional disability at six months
compared to the reactive blood pressure management approach, i.e. care as
usual, in adult patients after elective noncardiac surgery.

This study is a multicenter adaptive randomized controlled trial. The
risk-based intervention strategy will be implemented, further refined and
studied for its impact in an adaptive randomized controlled trial, randomizing
patients to either the intervention (proactive risk-based intervention
strategy) or care-as-usual (predominantly reactive). Patients are either
treated at the University Medical Center Utrecht (UMCU) or Amsterdam University
Medical Center, location Academic Medical Center (AMC).

The hypothesis of this study is that a proactive strategy keeps the blood
pressure at a safe margin and avoids dropping below the minimal acceptable
threshold of a MAP of 65 mmHg. The proactive strategy consists of two
components: 1) a target blood pressure that provides a sufficient safety margin
above the minimal acceptable threshold of a MAP of 65 mmHg; 2) a guideline with
suggestions how to keep patients at their target blood pressure.
Patients with a high likelihood of IOH require larger safety margins and thus
higher target blood pressures compared to those with a low IOH likelihood. In
the current literature, no comprehensive list of risk factors is available for
this purpose. Hence, using combined historic data from the UMC Utrecht and the
Amsterdam AMC, risk factors for the development of intraoperatieve hypotension
were identified. Based on their hypotension risk - i.e. their individual
predicted risk - patients will be divided into low-, intermediate- and
high-risk strata, with resulting blood pressure targets of MAP 70, 80, and 90
mmHg respectively.
The guideline with suggestions how to keep patients at their target blood
pressure will have the same core components for all centers, i.e. each center
will use the class of drugs that are indicated for the cause of hypotension.
The actual drug used may differ between centers and hence the guideline will be
adapted to local practices. This way our risk based intervention strategy will
have the highest chance of success of widespread implementation in the
Netherlands.
The attending anesthesiologist can make patient-specific adjustments to the
intervention strategy. The aim of the guidelines is only to reach the target
blood pressure, not to make specific treatment decisions. Adjustments that the
anesthesiologist can make include adjusting the target blood pressure or use a
different vasopressor dosing regimen. Interventions are already documented in
the electronic patient record, and the anesthesia team will further be
encouraged to document reasons for making patient-specific adjustments.

Benefits:
With the proactive risk-based intervention strategy, a possible dangerous low
blood pressure may be avoided. Avoiding intraoperative low blood pressure can
possible lead to less functional disability after surgery. Besides the positive
effect of this intervention strategy for the patient, it is likely that
avoiding hypotension and possibly reducing complications after surgery will
reduce the healthcare costs by millions of euros.

Burden:
The burden for participating patients is considered low. All interventions will
take place whilst the patient is undergoing surgery. All patients undergoing
intermediate/high risk procedures will receive the WHODAS 2.0 and EQ5D-5L
questionnaires as part of usual care.

Risks:
It is important to explain that the physiology of patients undergoing elective
surgery under general anesthesia is different from patients undergoing an
emergency procedure, coming from the intensive care unit or residing at the
nursing ward after surgery. Patients undergoing elective surgery are at high
risk of developing hypotension as a result of loss of sympathetic tone,
vasodilatation and myocardial depression of due to the administration of
anesthetics and analgesics. Under elective circumstances, all measures taken by
the anesthesia team to maintain adequate blood pressure levels, for example by
administrating fluids or vasopressors, serve to counteract the side effects
induced by the anesthesia and surgery itself. During urgent procedures or
emergency situations, there are either major *mechanical* alterations in a
patient*s circulatory system (e.g. hemorrhage or heart failure), or an
increased stress response that cause the low blood pressure or even circulatory
shock. Specific events during an elective procedure can cause similar
mechanical alterations, resulting in an emergency situation that are beyond the
scope of the intervention of this study.
The main aim of anesthesia is to attenuate the stress response induced by
tissue damage, especially during the surgical procedure. That is why under
elective conditions, an elevated stress response that results in atrial
fibrillation or circulatory shock do not occur unless a specific event has
triggered it (e.g. anaphylaxis). When such a specific event occurs this thus
becomes an emergency situation that is beyond the scope of the intervention of
this study, and for which other specific clinical guidelines exist are present
as emergency checklists in the operating room.

Adverse events can occur both in the intervention group, but also in the
care-as-usual group. The intervention is based on treatments options that are
widely accepted in standard care, only more uniformilized. Fluid administration
and vasopression is not likely to cause atrial fibrillation or decompensation
in patient undergoing elective surgery because patients that can not receive a
fluid challenge of at least 250-500 ml will not be planned for elective surgery.
To improve the safety of the intervention strategy the decision was made to
provide guidelines in the form of a medical protocol instead of a fixed
protocol that should be followed at all times. The anaesthesia team
continuously monitors the patient during the procedure - including the blood
pressure - and are at complete liberty to intervene if they believe a different
blood pressure strategy is in the best interest of the patient. In addition, we
will closely monitor how the strategy works out on intraoperative blood
pressure management during the adaptive phase of the trial and adjust the
proactive strategy or the clinical guideline if necessary. In summary, the risk
of participating in this study is moderate.