Noradrenaline Versus Standard Blood Pressure Management for Perioperative Hypotension in Non-cardiac Surgery (HYP-NOR)

The Effect of Noradrenaline Infusion Versus Standard Blood Pressure Management on Perioperative HYPotension in NOn-caRdiac Surgery HYP-NOR Trial

The effect of noradrenaline infusion versus standard blood pressure management on perioperative HYPotension in NOn-caRdiac surgery.

The study aims to determine whether perioperative noradrenaline infusion is superior to standard blood pressure management for the occurrence of perioperative hypotension.

Study Overview

• Status: Recruiting
• Conditions: Intraoperative Hypotension; Non-cardiac Surgery; Blood Pressure Management
• Intervention / Treatment: Drug: noradrenaline infusion for management blood pressure; Combination product: standard blood pressure management

Detailed Description

Patients will receive either noradrenaline infusion or standard blood pressure management during and up to 4 hours after surgery. Patients and health care providers will not be blinded to patients' allocation to either arm of the trial. Continuous blood pressure measurements will be secured in all patients who do not have an arterial line already in place for other indications using a non-invasive volume-clamp method. The medical team will not be aware of the continuous blood pressure monitoring and will use solely non-invasive blood pressure measurements at time intervals at least every 5 minutes in the operating room, and at least every 15 minutes in the post-anaesthesia care unit . In each group, patients will receive balanced crystalloids at 4 ml/kg per hour as maintenance fluid during surgery. In mechanical ventilation, a tidal volume of 8 mL/kg predicted body weight will be recommended. Other ventilatory settings, optimisation of volume status, depth of anaesthesia, patient positioning, as well as prompt diagnosis and treatment of reversible causes of hypotension will be prioritised in all patients in adherence with institutional protocols and current standards of practice.

The study aims to determine whether perioperative noradrenaline infusion can reduce exposure to hypotension compared to reactive treatment of hypotension, whether it is more effective in controlling hypotension during the intraoperatively and postoperatively, whether it reduces the risk of postoperative organ dysfunction, and whether it is safe and does not increase the risk of potential complications.

• Study Type: Interventional
• Enrollment (Estimated): 750
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Bożena Seczyńska, PhD; Phone Number: (+48) 124332847; Email: bozena.seczynska@uj.edu.pl
• Study Contact Backup: Name: Zbigniew Putowski, MD, PhD; Phone Number: (+48) 126308267; Email: zbigniew.putowski@uj.edu.pl

Study Locations

• Poland
  • Katowice, Poland, 40-752
    • Recruiting
    • Uniwersyteckie Centrum Kliniczne im. Prof. Kornela Gibińskiego Śląski Uniwersytet Medyczny
    • Principal Investigator: Anna Szczepańska, MD, PhD
    • Contact: Anna Szczepańska, MD, PhD; Phone Number: (+48) 7894111; Email: badaniakliniczne@uck.katowice.pl
  • Krakow, Poland, 30-901
    • Recruiting
    • 5 Wojskowy Szpital Kliniczny z Polikliniką Samodzielny Publiczny Zakład Opieki Zdrowotnej w Krakowie
    • Principal Investigator: Wojciech Szczeklik, MD, PhD
    • Contact: Wojciech Szczeklik, MD, PhD; Phone Number: (+48) 12 63 08 267; Email: sekretariat@5wszk.com.pl
    • Contact: Zbigniew Putowski, MD, PhD; Phone Number: (+48) 12 63 08 267; Email: sekretariat@5wszk.com.pl
    • Sub-Investigator: Zbigniew Putowski, MD, PhD
  • Olsztyn, Poland, 10-561
    • Active, not recruiting
    • Wojewodzki Szpital Specjalistyczny w Olsztynie
  • Opole, Poland, 45-401
    • Recruiting
    • Uniwersytecki Szpital Kliniczny w Opolu
    • Contact: Ryszard Gawda, MD, PhD; Phone Number: (+48) 774520745; Email: centrum@usk.opole.pl
    • Principal Investigator: Ryszard Gawda, MD, PhD
  • Zabrze, Poland, 41-800
    • Recruiting
    • Samodzielny Publiczny Szpital Kliniczny Nr 1 im. Prof. Stanisława Szyszko Śląskiego Uniwersytetu Medycznego w Katowicach
    • Principal Investigator: Szymon Białka, MD, PhD
    • Contact: Szymon Białka, MD, PhD; Phone Number: (+48) 323704307; Email: sekretariat@szpital.zabrze.pl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. ≥45 years old
2. Elective or accelerated* non-cardiac surgery expected to last ≥1 hour and requiring general, neuraxial, or combined general with neuraxial anesthesia
3. Expected to stay overnight in the hospital after surgery
4. Written informed consent to participate in the HYP-NOR Trial provided
5. American Society of Anesthesiologists (ASA) physical status class II or higher.

Exclusion Criteria:

1. Newly diagnosed, untreated, or uncontrolled hypertension -in two measurements on the day before surgery Systolic Blood Pressure (SBP) ≥180 mm Hg or Diastolic Blood Pressure (DBP) ≥110 mm Hg
2. Persistent difference in recorded SBP between right and left upper limb >10 mm Hg
3. Persistent atrial fibrillation
4. Have a documented history of dementia
5. Have language, vision, or hearing impairments that may compromise cognitive assessments
6. Have a condition that precludes routine blood pressure management such as surgeon request for relative hypotension
7. Receiving irreversible nonselective monoamine oxidase inhibitors (e.g. tranylcypromine, phenelzine) within 2 weeks preceding study enrolment
8. The use of tricyclic antidepressants
9. Have Prinzmetal angina
10. Have contraindications to noradrenaline per clinician judgement
11. Noradrenaline infusion started before surgery or plan to use continuous noradrenaline infusion throughout the procedure
12. Treating physician (surgeon/anaesthetist) decides on the necessity of extended continuous hemodynamic monitoring during or after surgery
13. Severe kidney disease (MDRD creatinine clearance <15 mL/min/1.73m2) or renal replacement therapy
14. End-stage heart failure: defined as NYHA Class IV - severe limitations in daily activity. Patients experience symptoms even while at rest. Mostly bedbound patients.
15. Known severe liver disease: defined as the presence of liver cirrhosis or any of the symptoms of severe liver dysfunction: portal hypertension (esophageal varices, ascites), hepatocellular insufficiency (e.g., jaundice, hepatic encephalopathy) and coagulopathy (prolonged INR/APTT associated with known liver dysfunction).
16. Emergency and urgent surgery defined as performed within 24 hours of sudden illness/unplanned admission to hospital
17. Have previously participated in the trial: patient already took a part in the HYP-NOR trial in the past
18. Pregnant or breastfeeding women.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Intervention group; In the intervention group, a standardized noradrenaline infusion at a concentration of 10 µg/mL will be initiated 15 to 60 seconds before induction of anaesthesia. The infusion will be titrated and maintained during surgery and postoperatively for up to 4 hours, with a minimum duration of 2 hours, until haemodynamic stability is achieved. Haemodynamic stability is defined as stable blood pressure requiring minimal noradrenaline support of 0.01 µg/kg/min or less for at least 1 hour. We will mandate avoidance of mean arterial pressure decreasing below 60 to 70 mm Hg. Once haemodynamic stability is achieved during the postoperative observation period, noradrenaline infusion may be discontinued. Safety criteria for discontinuation include systolic blood pressure above 180 mm Hg, in which case the infusion will be stopped. If systolic blood pressure is between 140 and 170 mm Hg, dose reduction or continuation at a very low noradrenaline infusion of 0.005 µg/kg/min, approximately 1 mL per h	Drug: noradrenaline infusion for management blood pressure; A single concentration of noradrenaline (10 μg/ml) will be initiated 15-60 seconds prior to the induction of anaesthesia, then titrated and maintained until 4 hours after surgery to meet pre-specified mean arterial pressure (MAP) targets. The drug infusion will be started at a dose of 0.01 μg/kg/min and will be titrated to a maximum of 0.1 μg/kg/min. Anaesthesiologists will be advised to use the lowest possible dose of noradrenaline. Avoidance of MAP decreases of >20% from baseline values or <60-70 mm Hg will be required in both groups. Individual baseline MAP value will be defined as resting blood pressure obtained in at least two measurements at the surgery ward on the day before surgery. Noradrenaline will be administered peripherally in all patients who do not have a central venous catheter in place.
Active Comparator: Control group; Standard blood pressure management reactive to blood pressure values. According to the 2022 ESA/ESC guidelines, patients in the control group will be treated to avoid a mean arterial pressure below 60 to 70 mm Hg. Ephedrine boluses (5 mg per bolus, up to a total intravenous dose of 25 mg) are recommended as first line treatment for hypotension. If hypotension persists, peripheral noradrenaline may be administered. Due to variability in clinical practice regarding the choice and timing of vasopressors and fluid therapy during and after surgery, further protocolization of hypotension management will not be mandated in order to enhance feasibility and generalizability of the trial.	Combination product: standard blood pressure management; Patients in the control group will receive standard blood pressure management reactive to blood pressure values. In the light of the current ESA/ESC 2022 guidelines, all patients in the control group will be treated to avoid MAP <60-70 mm Hg. Ephedrine boluses (5 mg each, up to 25 mg total intravenous dose) will be recommended as a first-line hypotension treatment. Subsequent treatment will involve administering peripheral noradrenaline. Notwithstanding, there is a variation in clinical practice regarding the choice and timing of vasopressors and fluids to be administered during and after surgery, therefore, hypotension treatment will not be further protocolized to increase the feasibility and generalizability of the trial.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Perioperative hypotension	Number of episodes of perioperative hypotension defined as any mean arterial pressure (MAP) reading ≤55 mm Hg in the setting of a continuous blood pressure measurement.	During and up to 4 hours after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Myocardial Injury after Non-cardiac Surgery (MINS)	Number of patients who experience MINS defined as any myocardial infarction and any acutely elevated postoperative cardiac troponin judged as resulting from myocardial ischemia using Roche's fifth generation Elecsys hsTnT, with an established cut-off of 20 ng/L combined with an absolute change of 5 ng/L or more (judged as due to ischemia)	During hospitalization and up to 30 days after surgery
Acute kidney injury fulfilling Kidney Disease Improving Global Outcomes (KDIGO) criteria	Number of patients who experience an acute kidney injury (fulfilling KDIGO criteria)	During hospitalization and up to 30 days after surgery
Stroke	Number of patients who experience a stroke is defined as a new focal neurological deficit thought to be vascular in origin with signs or symptoms lasting more than 24 hours or leading to death. Stroke will be sub-classified into hemorrhagic and non-hemorrhagic stroke.	During hospitalization and up to 30 days after surgery
Non-fatal cardiac arrest	Number of patients who experience non-fatal cardiac arrest defined as successful resuscitation from either documented or presumed ventricular fibrillation, sustained ventricular tachycardia, asystole, or pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation, pharmacological therapy, or cardiac defibrillation	During hospitalization and up to 30 days after surgery
Sepsis	Number of patients who experience sepsis is defined as an increase in SOFA score of 2 or more, with evidence of infection. This outcome includes septic shock defined as sepsis with shock (vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mM [above18 mg/dL] in the absence of hypovolemia). Infection is defined as a pathologic process caused by the invasion of normally sterile tissue or fluid or body cavity by pathogenic or potentially pathogenic organisms.	During hospitalization and up to 30 days after surgery
Death	Number of patients who die of any cause	During hospitalization and up to 30 days after surgery
Infusion-related reactions	The number of patients who experience infusion-related reactions, defined as disorders such as flushing, rash, fever, rigors, chills, dyspnoea, bronchospasms, cardiac dysfunction, and anaphylaxis. Grades of infusion site extravasation are defined according to the Common Terminology Criteria for Adverse Events.	During the infusion of noradrenaline and up to 30 days after drug administration, with assessment occurring postoperatively.
Days alive and out of hospital	Number of days when a patient is alive and out of hospital	30 days after surgery
Clinically important atrial fibrillation	Number of patients who experience clinically important atrial fibrillation, defined as new-onset atrial fibrillation or atrial flutter of any duration on an ECG or rhythm strip, which results in angina, congestive heart failure, symptomatic hypotension, or requires treatment with a rate-controlling drug, antiarrhythmic drug, or electrical cardioversion	During hospitalization and up to 30 days after surgery
Major bleeding	Number of patients who experience an International Society on Thrombosis and Haemostasis (ISTH) major bleeding	During hospitalization and up to 30 days after surgery
Peripheral ischemia	Number of patients who experience peripheral ischemia defined as the fingertip necrosis of upper and lower limbs	During hospitalization and up to 30 days after surgery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median mean arterial pressure		During and up to 4 hours after surgery
Median heart rate		During and up to 4 hours after surgery
Acute Myocardial Infarction	Number of patients who experience acute myocardial injury according to the Fourth Universal Definition of Myocardial Infarction as a detection of an elevated cTn value above the 99th percentile URL with a rise and/or fall of cTn values.	During hospitalization and up to 30 days after surgery
Peak troponin concentration	Peak troponin concentration	The first three days after surgery
Area under the curve troponin	Area under the curve troponin is defined as total cTn release measured as area under the Troponin-Time curve	The first three days after surgery
Bradycardia	Number of patients who experience bradycardia, defined as a heart rate less than 40 beats per minute	During surgery, up to 4 hours after surgery, and up to 30 days after surgery.
Acute congestive heart failure	Number of patients who experience acute congestive heart failure defined as an episode characterized by at least one of the following clinical signs (i.e. any of the following signs: elevated jugular venous pressure, respiratory rales/crackles, crepitations, or presence of S3) and at least one of the following: (I) Radiographic findings (i.e. vascular redistribution, interstitial pulmonary edema, or frank alveolar pulmonary edema) OR (II) Heart failure treatment implemented with diuretics with documented clinical improvement	During hospitalization and up to 30 days after surgery
Acute Kidney Injury stage 2-3	Number of patients who experience acute kidney injury stage 2-3 according to KDIGO criteria	30 days after surgery
Pneumonia	Number of patients who experience pneumonia, defined according to the US Centers for Disease Control criteria	During hospitalization and up to 30 days after surgery
Postoperative pulmonary complications	Number of patients who experience postoperative pulmonary complications which are a composite outcome comprised of the following outcomes: 1. Atelectasis detected on computed tomography or chest radiograph 2. Pneumonia using US Centers for Disease Control criteria 3. Acute respiratory distress syndrome (according to Berlin definition) 4. Pulmonary aspiration (clear clinical history AND radiological evidence)	During hospitalization and up to 30 days after surgery
Surgical site infection	Number of patients who experience surgical site infection defined according to the Centers for Disease Control and Prevention (CDC) criteria	During hospitalization and up to 30 days after surgery
Discharge destination	Number of patients discharged from the hospital to home/long-term care facility/other	30 days after surgery
Cognitive decline	Number of patients who experience cognitive decline (defined as a decline of at least 2 points on the Montreal Cognitive Assessment, MoCA, performed via telephone) compared to the assessment conducted after consent and before randomization	30 days after surgery
Days alive and outside the intensive care unit	Number of days when a patient is alive and outside the intensive care unit	30 days after surgery
Health-related quality of life	Health-related quality of life will be evaluated (based on the EuroQol 5 Dimension, five-level version [EQ-5D]), compared to the assessment made after consent and before randomization.	30 days after surgery
Lowest MAP throughout the procedure	Number of patients who experience the lowest MAP throughout the procedure, defined as the lowest punctual measurement of mean arterial pressure	During surgery
Lowest MAP during the 4 hours postoperative period	The lowest recorded mean arterial pressure during postoperative monitoring lasting at least 2 hours and up to 4 hours after surgery.	up to 4 hours after surgery
Postoperative delirium	Number of patients who experience delirium (based on The Nursing Delirium Screening Scale - NuDESC). A total score of 2 or higher on the scale indicates a positive result for the diagnosis of delirium.	Assessment on postoperative days 1, 2, 3
Perioperative myocardial infarction/injury	Number of Participants with Perioperative myocardial infarction/injury as defined by the 2022 European Society of Cardiology (ESC) Guidelines on cardiovascular assessment and management of patients undergoing non-cardiac surgery: an absolute increase in hs-cTn concentration of more than the 99th percentile URL after surgery compared to the pre-operative level. In the absence of a preoperative hs-cTn T/I concentration, a hs-cTn more than five-times the 99th percentile URL or an absolute increase or decrease more than the 99th percentile URL	up to 72 hours (3 days) postoperatively

Collaborators and Investigators

• Sponsor: Jagiellonian University
• Collaborators: Medical Research Agency, Poland
• Investigators: Study Director: Wojciech Szczeklik, MD, PhD, Centre for Intensive Care and Perioperative Medicine, Jagiellonian University Medical College

Study record dates

Study Major Dates

• Study Start (Actual): June 25, 2025
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: March 11, 2025
• First Submitted That Met QC Criteria: March 17, 2025
• First Posted (Actual): March 20, 2025

Study Record Updates

• Last Update Posted (Estimated): January 14, 2026
• Last Update Submitted That Met QC Criteria: January 12, 2026
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: perioperative care; hypotension; noradrenaline infusion
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Hypotension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Neurotransmitter Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Adrenergic Agents; Sympathomimetics; Vasoconstrictor Agents; Norepinephrine
• Other Study ID Numbers: HYP-NOR; 2023-508255-39-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No