HIgh Versus STAndard Blood Pressure Target in Hypertensive High-risk Patients Undergoing Major Abdominal Surgery

Study Overview
=================
Brief Summary
-----------------
This study is a multicenter randomized controlled trial comparing two strategies of mean arterial blood pressure management (MAP ≥ 80mmHg vs MAP ≥ 65 mmHg) in high-risk surgical patients undergoing elective laparotomic/laparoscopic surgery.

Detailed Description
-----------------
Intraoperative hypotension has been associated with major postoperative complications after non-cardiac surgery. However, is is still unclear the optimal intraoperative mean arterial pressure (MAP) target in the subgroup of those patient with an history of hypertension at home, and at risk of developing postoperative complications. The objective of this study is to assess the effects of an intraoperative blood pressure management strategy aiming at keeping the MAP ≥ 80mmHg), as compared to the conventional practice (to maintain intraoperative MAP ≥ 65mmHg), on a composite outcome considering the death rate and the incidence of major events in patient scheduled for elective laparotomic/laparoscopic surgery. The primary outcome is a composite of 30-days from operation mortality rate and at least one major organ dysfunction including the renal, respiratory, cardiovascular and neurologic systems or new onset of sepsis and septic shock occurring by day 7 after surgery.

Official Title
-----------------
HIgh Versus STAndard Blood Pressure Target in Hypertensive High-risk Patients: The HISTAP Randomized Clinical Trial.

Conditions
-----------------
Blood Pressure, Complication,Postoperative, Intraoperative Hypotension

Intervention / Treatment
-----------------
* Drug: Ephedrine
* Drug: Norepinephrine
* Drug: Etilefrine Hydrochloride bolus
* Diagnostic Test: Use of pulse pressure and stroke volume variation (PPV and SVV); use of Mini Fluid Challenge (mini_FC)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria (all the following) Adult patients ≥ 60 years History of chronic hypertension requiring home therapy. Scheduled for major elective abdominal surgery (laparoscopic, robotic or laparotomic) Expected surgical duration of at least 3 hours. Needing invasive arterial and hemodynamic monitoring as decided by the attending anesthetist, according to the rules of good clinical practice of each involved center. AND At increased risk of postoperative complications (at least one of the following): American Society of Anesthesiologists (ASA) class 3 or 4 Known or documented history of coronary artery disease (angina, myocardial infarction or acute coronary syndrome). Known or documented history of peripheral vascular disease. Known or documented history of heart failure requiring treatment. Ejection fraction less than 30% (echocardiography) Signs of diastolic moderate to severe dysfunction or chronic hypertensive cardiomyopathy (echocardiography) Moderate or severe valvular heart disease (echocardiography) Diagnosis of Chronic Obstructive Pulmonary Disease (COPD) Radiographically confirmed or according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. Diabetes currently treated with an oral hypoglycemic agent and/or insulin Morbid obesity (BMI ≥35 kg/m2) Preoperative serum albumin <30 g/l Anaerobic threshold (if done) <14 ml/kg/min Exercise tolerance equivalent to six metabolic equivalents (METs) or less as defined by American College of Cardiology/American Heart Association guidelines Exclusion criteria Refusal of consent Chronic kidney disease with glomerular filtration rate <30 ml/min/1.73 m2 or requiring renal-replacement therapy for end-stage renal disease Acute cardiovascular event, including acute or decompensated heart failure and acute coronary syndrome (within prior 30 days). Urgent or time-critical surgery Aortic or Renal vascular surgery (including nephrectomy) Liver Surgery Neurosurgery Surgery for palliative treatment only or ASA physical status 5 Pregnancy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study will be a multicentric, randomized, non-blinded clinical trial. Eligible patients will be assigned in a 1:1 ratio to either a to control or treatment group. Randomization list will be created by a computer with the use of a permuted block design and embedded in the Electronic Case Report Form. Randomization will be performed using a 'block of 6 and stratified according to predefined baseline characteristics: Age ≥ 75 years Preoperative systolic pressure < 140 mmHg ≥ 140 mmHg
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MAP 80<br>Intervention group: intraoperative mean blood pressure target > 80 mmHg. Treatment of hypotension (defined as a mean blood pressure of below 80 mmHg) using intravenous bolus or continuous infusion of vasopressors, or fluids using a dedicated algorithm considering the pulse pressure or stroke volume variation and the mini fluid challenge to optimize mean blood pressure values. | Drug: Ephedrine<br>* In both the group, the target MAP can be maintained by means of bolus of ephedrine (2.5 mg). The maximal dose for the ephedrine allowed is 25 mg (10 boluses of 2.5 mg), after this threshold a continuous infusion of norepinephrine will be started<br>* Other names: Ephedrine bolus;Drug: Norepinephrine<br>* In both the group, the target MAP can be maintained by means of bolus of ephedrine (2.5 mg) or Etilefrine (1 mg). The continuous infusion of norepinephrine, as decided by the attending anesthetist, may be started at any point of the intraoperative period. The starting dose of norepinephrine is the lowest needed to reach the predefined MAP target.<br>* Other names: norepinephrine infusion;Drug: Etilefrine Hydrochloride bolus<br>* The maximal dose for the etilefrine allowed is 10 mg (10 boluses of 1 mg), after this threshold a continuous infusion of norepinephrine will be started<br>Diagnostic Test: Use of pulse pressure and stroke volume variation (PPV and SVV); use of Mini Fluid Challenge (mini_FC)<br>* PPV, SVV and mini_FC will guide fluid bolus administration during an episode of intraoperative hypotension, following two predefined algorithms for laparotomic/non laparotomic surgery<br>* Other names: Hemodynamic optimization;|
| Other: MAP 65<br>Control group: intraoperative mean blood pressure target > 65 mmHg. Treatment of hypotension (defined as a mean blood pressure of below 65 mmHg) using intravenous bolus or continuous infusion of vasopressors, or fluids using a dedicated algorithm considering the pulse pressure or stroke volume variation and the mini fluid challenge to optimize mean blood pressure values. | Drug: Ephedrine<br>* In both the group, the target MAP can be maintained by means of bolus of ephedrine (2.5 mg). The maximal dose for the ephedrine allowed is 25 mg (10 boluses of 2.5 mg), after this threshold a continuous infusion of norepinephrine will be started<br>* Other names: Ephedrine bolus;Drug: Norepinephrine<br>* In both the group, the target MAP can be maintained by means of bolus of ephedrine (2.5 mg) or Etilefrine (1 mg). The continuous infusion of norepinephrine, as decided by the attending anesthetist, may be started at any point of the intraoperative period. The starting dose of norepinephrine is the lowest needed to reach the predefined MAP target.<br>* Other names: norepinephrine infusion;Drug: Etilefrine Hydrochloride bolus<br>* The maximal dose for the etilefrine allowed is 10 mg (10 boluses of 1 mg), after this threshold a continuous infusion of norepinephrine will be started<br>Diagnostic Test: Use of pulse pressure and stroke volume variation (PPV and SVV); use of Mini Fluid Challenge (mini_FC)<br>* PPV, SVV and mini_FC will guide fluid bolus administration during an episode of intraoperative hypotension, following two predefined algorithms for laparotomic/non laparotomic surgery<br>* Other names: Hemodynamic optimization;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite endpoint of postoperative mortality and at least one major organ dysfunction (see description in the secondary outcomes). | Composite postoperative outcome | up to 30 days after operation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hospital stay (days) | Hospital stay (days) | up to 30 days after operation | 
| ICU stay (days) | Intensive Care Unit stay (days) | up to 30 days after operation | 
| ICU readmission | Intensive Care Unit readmissions | up to 30 days after operation | 
| Sequential Organ Failure Assessment (SOFA) scores on postoperative | Postoperative organ failure - SOFA scores ranges from 0 (<2% of mortality) to 24 (>90% of mortality) | up to 7 days after operation | 
| Overall intraoperative fluid balance | Intraoperative infusions (crystalloids, colloids, blood products) / Intraoperative loss balance (urine output) | day 1 after the operation | 
| Mortality | Mortality | up to 30 days after operation | 
| Vasopressors use | Dose and timing of vasoactive drug infusion intraoperatively | day 1 after the operation | 
| Need for reoperation | Need of a new surgical treatment | day 30 after operation | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Blood pressure, Intraoperative Hypotension, Postoperative complications, Postoperative mortality