The dose-response relationship between norepinephrine dose and mean arterial pressure with and without general anaesthesia

Q: What are the key findings of this study?

General anaesthesia significantly steepened the dose-response relationship between norepinephrine dose and mean arterial pressure, increasing the slope by 119 mmHg μg-1 kg min compared to the awake state.

Q: What is the clinical evidence from this study?

Study design: Observational. Population: Healthy volunteers (n=36). Intervention: Norepinephrine under general anaesthesia vs. Norepinephrine in awake state. Primary outcome: Slope of the dose-response relationship between norepinephrine dose and mean arterial pressure (MAP) (mmHg μg-1 kg min) (MD 119, 95% CI 119-120, p=<0.001).

Q: What does this research mean for the field?

General anaesthesia significantly steepens the linear dose-response relationship between norepinephrine and mean arterial pressure compared to the awake state. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Ilonka N. de Keijzer; Johannes P. van den Berg; Dario Massari; Anthony Absalom; Dirk J. Bosch; Martijn van Faassen; Thomas Scheeren; Michel MRF Struys; Pieter Colin; Jaap Jan Vos

doi:10.1097/eja.0000000000002312

November 20, 2025European Journal of AnaesthesiologyOpen Access

The dose-response relationship between norepinephrine dose and mean arterial pressure with and without general anaesthesia

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Key result

General anesthesia steepens the norepinephrine-MAP dose-response slope by ~119 units vs. awake state.

MD +119
95% CI 119-120
P<0.001
n=36

Figures

Why the study?

Data on the dose-response relationship between norepinephrine dose and mean arterial pressure and the influence of general anaesthesia on this relationship are limited.

Does general anesthesia alter the dose-response relationship between norepinephrine and mean arterial pressure in healthy volunteers?

Study Design

Type

Observational (n=36)

Multicenter

No

Structured PICO

Does general anesthesia alter the dose-response relationship between norepinephrine and mean arterial pressure in healthy volunteers?

P

Population

36 healthy adult volunteers aged 18 to 70 years undergoing a step-up norepinephrine infusion protocol while awake and subsequently under general anaesthesia.

I

Intervention

Norepinephrine infusion initiated at 0.04 μg/kg/min and increased in four equal increments up to 0.20 μg/kg/min (each lasting 15 minutes) administered under general anesthesia (propofol/remifentanil) with simulated surgical stimuli (intermittent 30-s tetanic electrical stimulus).

C

Comparator

The same norepinephrine dose-escalation infusion protocol administered to the same healthy volunteers while awake, prior to the induction of general anesthesia (self-controlled before-after design).

O

Outcome

The slope of the dose-response relationship between norepinephrine dose or plasma concentration and mean arterial pressure (MAP).surrogate

Main Result

Mean Difference: 119 (95% CI 119–120)

Absolute Event Rate: 222% vs 103%

p-value: p=<0.001

General anesthesia steeply increases the dose-response relationship between norepinephrine and mean arterial pressure, allowing for a linear equation to proactively estimate intra-operative dose requirements.

Limitations

Extrapolation of the data outside the studied blood pressure range is likely biased as linearity may not be assumed on physiological grounds.
Results in healthy volunteers may have limited generalisability to patients undergoing surgery with different comorbidities, surgical blood loss, or anaesthetic regimens.
Positive pressure ventilation used during general anaesthesia could have influenced haemodynamic variables.
Pulse contour analysis was used for cardiac index and stroke volume index, which has acknowledged limitations compared to thermodilution.
Study included healthy volunteers rather than surgical patients with co-morbidities or blood loss.
Cardiac index and stroke volume index were estimated using non-invasive pulse wave analysis rather than the clinical gold standard thermodilution.
Potential systemic bias due to reliance on manual calibration of arterial pressures against oscillometric references.
Dosing scheme might have been insufficient to illustrate the arterial constriction and venous return reduction typically seen at higher doses.

Ask about this paper

Answers are grounded in this paper and cite their sources.

Implication

May inform norepinephrine dosing under anaesthesia in volunteers; leaves open applicability to patients with comorbidities.

Abstract

BACKGROUND: Norepinephrine is commonly used to optimise arterial blood pressure during anaesthesia, yet data on its dose-response relationship are limited. Furthermore, the influence of general anaesthesia on this relationship is not well understood. OBJECTIVES: To examine the dose-response relationship between norepinephrine dose and mean arterial pressure (MAP) in healthy volunteers with and without general anaesthesia. DESIGN: Observational healthy volunteer study. SETTING: Tertiary university medical centre. PARTICIPANTS: Thirty-six healthy volunteers aged 18 to 70 years. INTERVENTIONS: Norepinephrine infusion was initiated at 0.04 μg kg -1 min -1 and increased in four equal increments to 0.20 μg kg -1 min -1 , each lasting 15 min. After a washout period, anaesthesia was induced and maintained with propofol/remifentanil, and the norepinephrine infusion protocol was repeated. Surgical stimuli were simulated using intermittent 30-s tetanic electrical stimulus. MAIN OUTCOME MEASURES: The primary endpoint was the dose-response relationship between norepinephrine dose or plasma concentration and MAP. Secondary outcomes included other haemodynamic variables such as heart rate and cardiac index. RESULTS: Norepinephrine dose-response models outperformed concentration-response models. The slope of the dose-MAP relationship was 103 (95% confidence interval (CI): 81 to 124) mmHg μg -1 kg min during the awake phase. After induction, MAP decreased by 34 mmHg (95% CI: -37 to -31) from 88 mmHg (95% CI: 85 to 91) and slope increased by 119 (95% CI: 119 to 120) mmHg μg -1 kg min during anaesthesia ( P < 0.001 difference in slopes and intercepts; cumulative slope equals approximately 222 mmHg μg -1 kg min). Norepinephrine requirement under anaesthesia can be calculated as ((target MAP - 54)/222) μg kg -1 min -1 . CONCLUSIONS: Linear models accurately described norepinephrine dose-response relationships in healthy volunteers in a simulated surgical environment, with a steeper slope observed during general anaesthesia. This relationship allows for a simple equation to estimate the required norepinephrine dose for a target blood pressure, although clinical observation and titration remain essential.

Discussion

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Cite This Study

Keijzer et al. (2025) conducted an observational in Healthy volunteers (n=36). Norepinephrine under general anaesthesia vs. Norepinephrine in awake state was evaluated on Slope of the dose-response relationship between norepinephrine dose and mean arterial pressure (MAP) (mmHg μg-1 kg min) (MD 119, 95% CI 119-120, p=<0.001). General anaesthesia significantly steepened the dose-response relationship between norepinephrine dose and mean arterial pressure, increasing the slope by 119 mmHg μg-1 kg min compared to the awake state.

synapsesocial.com/papers/6ab09c39865d1a9b3ae78b36 https://doi.org/10.1097/eja.0000000000002312

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The dose-response relationship between norepinephrine dose and mean arterial pressure with and without general anaesthesia

Figures

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

The dose-response relationship between norepinephrine dose and mean arterial pressure with and without general anaesthesia

Figures

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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