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

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

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.

Study Overview

• Status: Recruiting
• 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)

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.

• Study Type: Interventional
• Enrollment (Estimated): 636
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Antonio Messina; Phone Number: +390282241; Email: antonio.messina@humanitas.it

Study Locations

• Italy
  • Abruzzo
    • Chieti, Abruzzo, Italy
      • Not yet recruiting
      • Department of Anesthesia, Critical Care and Pain Medicine, SS. Annunziata Hospital
      • Contact: Salvatore Maurizio Maggiore
  • Emilia Romagna
    • Modena, Emilia Romagna, Italy
      • Not yet recruiting
      • Department of Anesthesia and Intensive Care, University Hospital of Modena
      • Contact: Massimo Girardis
  • Lazio
    • Roma, Lazio, Italy
      • Not yet recruiting
      • Policlinico A. Gemelli
      • Contact: Massimo Antonelli
  • Milano
    • Rozzano, Milano, Italy, 20089
      • Recruiting
      • Humanitas Research Hospital
      • Contact: Antonio Messina, PhD; Phone Number: 0282241; Email: antonio.messina@humanitas.it
  • Puglia
    • Foggia, Puglia, Italy
      • Recruiting
      • Ospedali Riuniti Foggia- Università di Foggia
      • Contact: Lucia Mirabella
      • Contact: Email: lucia.mirabella@unifg.it
  • Sicilia
    • Cefalù, Sicilia, Italy
      • Recruiting
      • Fondazione Istituto San Raffaele G. Giglio
      • Contact: Giovanni Misseri
      • Contact: Email: giovannimisseri1987@gmail.com
    • Messina, Sicilia, Italy
      • Not yet recruiting
      • Division of Anesthesia and Intensive Care, University of Messina, Policlinico "G. Martino"
      • Contact: Alberto Noto
    • Palermo, Sicilia, Italy
      • Not yet recruiting
      • Department of Surgical Oncological and Oral Science, University of Palermo
      • Contact: Andrea Andrea Cortegiani
  • Toscana
    • Firenze, Toscana, Italy, 50134
      • Recruiting
      • Careggi University Hospital
      • Contact: Stefano Romagnoli, MD
  • Veneto
    • Verona, Veneto, Italy
      • Not yet recruiting
      • Unit of Anesthesiology and Intensive Care B, Department of Surgery, Dentistry, Gynecology and Pediatrics, AOUI-University Hospital Integrated Trust of Verona
      • Contact: Katia Donadello

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria (all the following)

1. Adult patients ≥ 60 years
2. History of chronic hypertension requiring home therapy.
3. Scheduled for major elective abdominal surgery (laparoscopic, robotic or laparotomic)
4. Expected surgical duration of at least 3 hours.
5. 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):

1. American Society of Anesthesiologists (ASA) class 3 or 4
2. Known or documented history of coronary artery disease (angina, myocardial infarction or acute coronary syndrome).
3. Known or documented history of peripheral vascular disease.
4. Known or documented history of heart failure requiring treatment.
5. Ejection fraction less than 30% (echocardiography)
6. Signs of diastolic moderate to severe dysfunction or chronic hypertensive cardiomyopathy (echocardiography)
7. Moderate or severe valvular heart disease (echocardiography)
8. Diagnosis of Chronic Obstructive Pulmonary Disease (COPD) Radiographically confirmed or according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria.
9. Diabetes currently treated with an oral hypoglycemic agent and/or insulin
10. Morbid obesity (BMI ≥35 kg/m2)
11. Preoperative serum albumin <30 g/l
12. Anaerobic threshold (if done) <14 ml/kg/min
13. Exercise tolerance equivalent to six metabolic equivalents (METs) or less as defined by American College of Cardiology/American Heart Association guidelines

Exclusion criteria

1. Refusal of consent
2. Chronic kidney disease with glomerular filtration rate <30 ml/min/1.73 m2 or requiring renal-replacement therapy for end-stage renal disease
3. Acute cardiovascular event, including acute or decompensated heart failure and acute coronary syndrome (within prior 30 days).
4. Urgent or time-critical surgery
5. Aortic or Renal vascular surgery (including nephrectomy)
6. Liver Surgery
7. Neurosurgery
8. Surgery for palliative treatment only or ASA physical status 5
9. Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MAP 80; 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; 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; Other Names: Ephedrine bolus; Drug: Norepinephrine; 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.; Other Names: norepinephrine infusion; Drug: Etilefrine Hydrochloride bolus; 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; Diagnostic test: Use of pulse pressure and stroke volume variation (PPV and SVV); use of Mini Fluid Challenge (mini_FC); 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; Other Names: Hemodynamic optimization
Other: MAP 65; 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; 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; Other Names: Ephedrine bolus; Drug: Norepinephrine; 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.; Other Names: norepinephrine infusion; Drug: Etilefrine Hydrochloride bolus; 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; Diagnostic test: Use of pulse pressure and stroke volume variation (PPV and SVV); use of Mini Fluid Challenge (mini_FC); 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; 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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
CARDIOVASCULAR complications	Acute heart failure; Myocardial injury after non-cardiac surgery; Myocardial infarction; Bradycardia; Symptomatic proximal deep venous thrombosis; Peripheral arterial and venous thrombosis	day 7 after operation
NEUROLOGICAL complications	Stroke; Subarachnoid hemorrhage; Cerebral venous thrombosis; Seizure; Acute delirium	day 7 after operation
RESPIRATORY	Acute respiratory distress; Hypoxemia with or without acute respiratory distress; Need for invasive, non-invasive ventilation or high-flow nasal cannula for acute respiratory distress.; Acute respiratory distress syndrome.; Pulmonary edema; Pulmonary embolism	day 7 after operation
RENAL	• Acute Kidney Injury (AKI) and AKI stages defined according to the AKIN classification/staging system of acute kidney injury	day 7 after operation
SEPSIS and Septic shock	Based on the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) criteria, sepsis required a quick Sequential Organ Failure Assessment (qSOFA) Score ≥ 2 points due to infection, septic shock defined as indicated by the Surviving Sepsis Campaign Guidelines	day 7 after operation

Collaborators and Investigators

• Sponsor: Humanitas Clinical and Research Center
• Collaborators: Società Italiana Anestesia, Analgesia, Rianimazione e Terapia Intensiva - SIAARTI
• Investigators: Principal Investigator: Antonio Messina, Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milano, Italy

Publications and helpful links

General Publications

• Walsh M, Devereaux PJ, Garg AX, Kurz A, Turan A, Rodseth RN, Cywinski J, Thabane L, Sessler DI. Relationship between intraoperative mean arterial pressure and clinical outcomes after noncardiac surgery: toward an empirical definition of hypotension. Anesthesiology. 2013 Sep;119(3):507-15. doi: 10.1097/ALN.0b013e3182a10e26.
• Messina A, Robba C, Calabro L, Zambelli D, Iannuzzi F, Molinari E, Scarano S, Battaglini D, Baggiani M, De Mattei G, Saderi L, Sotgiu G, Pelosi P, Cecconi M. Association between perioperative fluid administration and postoperative outcomes: a 20-year systematic review and a meta-analysis of randomized goal-directed trials in major visceral/noncardiac surgery. Crit Care. 2021 Feb 1;25(1):43. doi: 10.1186/s13054-021-03464-1.

Study record dates

Study Major Dates

• Study Start (Actual): March 6, 2023
• Primary Completion (Estimated): March 1, 2024
• Study Completion (Estimated): September 1, 2024

Study Registration Dates

• First Submitted: November 24, 2022
• First Submitted That Met QC Criteria: November 24, 2022
• First Posted (Actual): December 5, 2022

Study Record Updates

• Last Update Posted (Actual): September 28, 2023
• Last Update Submitted That Met QC Criteria: September 26, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Postoperative complications; Blood pressure; Intraoperative Hypotension; Postoperative mortality
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Hypotension; Postoperative Complications; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Protective Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Cardiotonic Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Central Nervous System Stimulants; Adrenergic beta-Agonists; Sympathomimetics; Adrenergic beta-1 Receptor Agonists; Vasoconstrictor Agents; Nasal Decongestants; Norepinephrine; Ephedrine; Pseudoephedrine; Etilefrine
• Other Study ID Numbers: HISTAP TRIAL

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No