Intraoperative hypotension strongly correlates with the subsequent occurrence of postoperative myocardial injury, acute kidney injury and 30-day mortality [1-3]. Hypotension during general anesthesia most commonly occurs during the period following anesthesia induction but preceding surgical stimulation [4,5]. Elderly patients are at high risk for intraoperative hypotension [6], and advanced age is significantly correlated with hypotension after anesthesia induction [5].

The medications commonly used for the induction of general anesthesia generally include opioids, neuromuscular blocking agents and propofol. While the former two demonstrate minimal hemodynamic effects, propofol considerably affects hemodynamics and may lead to significant hypotension [7]. Numerous studies have indicated that clinically relevant doses of propofol often lead to hypotension [8-10]. Several studies [10,11] have shown that hypotension following anesthesia induction with propofol among elderly patients primarily results from a reduction in cardiac output (CO) caused by venodilation without significant alteration in systemic vascular resistance (SVR). Elderly patients are uniquely susceptible to propofol-induced hemodynamic instability, largely due to age-related physiological changes: (1) diminished cardiovascular reserve, with reduced myocardial compliance, limiting compensatory mechanisms to maintain CO [12]; (2) impaired autonomic nervous system regulation, blunting reflex responses to hypotension [13,14]; (3) structural vascular changes (e.g., endothelial dysfunction and arterial stiffening) [15], which exacerbate propofol’s venodilatory effects, reducing venous return; and (4) higher prevalence of comorbidities (e.g., hypertension, heart failure) that further compromise hemodynamic resilience [16]. Collectively, these factors increase their risk of cardiac index (CIx) reduction and hypotension during anesthesia induction.

Norepinephrine (NE) is a potent α-1 and β-1 agonist as well as a mild β-2 agonist. As a vasoconstrictor and inotrope, it increases arterial pressure, mean systemic filling pressure, cardiac contractility, and CO. Current evidence increasingly supports the preferential use of NE in the operating room to manage hypotension following anesthesia induction or during prolonged surgical procedures [17,18]. NE is an effective vasopressor for preserving blood pressure (BP) during spinal anesthesia, exhibiting less tendency to lower CO compared with phenylephrine, a synthetic pure α-adrenergic receptor agonist [19]. However, data on the efficacy of NE in mitigating the reduction in CO during propofol-induced anesthesia in elderly patients remain limited [20,21].

This study aimed to evaluate the effectiveness of NE infusion in mitigating the decrease in CIx during propofol-induced anesthesia in elderly patients (age ≥ 65 years), while maintaining BP.

This is a single-center randomized controlled trial. The protocol was approved by the Institutional Review Board (IRB) of the Beijing Hospital (IRB No. 2022BJYYEC-194-02). We registered at the Chinese Clinical Trial Registry before enrollment (ChiCTR2200062864; August 22, 2022). This study followed clinical practice quality standards and ethical guidelines described by the Declaration of Helsinki. Written informed consents were provided by all patients or their legal representatives before randomization. This article was in line with Consolidated Standards of Reporting Trials (CONSORT) guidelines [22].

Between August 24, 2022, and October 13, 2023, a total of 68 patients were screened for eligibility. Of these, 60 patients were successfully enrolled and randomly assigned to two groups, with 30 patients in each group. Data from all patients were analyzed on the basis of their designated groups (Fig. 1). The demographic characteristics of the groups were well matched, with an average age of 70 years (Table 2).

In the NE group, the CIx decreased from 3.9 to 2.9 L/min/m² at T₁₀, whereas in the CT group, it declined from 3.7 to 2.6 L/min/m². The decrease in △CIx at T₁₀, the primary outcome, was less significant in the NE group (β = 0.63 [95% CI, 0.18 to 1.07], P = 0.006) compared to the CT group, after adjusting for propofol dosage per weight. Similarly, the reduction in △MAP at T₁₀ was less pronounced in the NE group (β = 11.99, [95% CI, 2.05 to 21.94], P = 0.018), but there was no difference in △SVRI between groups (P = 0.101) (Table 3).

Changes in △CIx, △SVRI, △MAP, △SV, △PR and changes in SVV over time were depicted in Fig. 2. When adjusted for propofol dosage per weight, the decreases in △CIx, △MAP, and △SV (P = 0.006, P = 0.039, and P = 0.037, respectively) were less pronounced in the NE group, with a lower SVV (P = 0.004). No significant difference in △SVRI was observed between groups (Table 4). The △PR in the NE group exhibited a more pronounced downward trend, but this trend did not reach statistical significance (P = 0.052) (Fig. 2, Table 4).

During the study, the cumulative propofol administration was significantly greater in the NE group (3.02 ± 0.71 mg/kg) than in the CT group (2.47 ± 0.63 mg/kg; P = 0.003). A total of 4.2 ± 1.4 ml NE was delivered in the NE group, whereas 5.1 ± 2.0 ml normal saline was administered in the CT group, with no statistically significant difference between groups (P = 0.053). Cumulative fluid administration volume was comparable between the NE group (375 ml [320-400 ml]) and the CT group (400 ml [350-455 ml]; P = 0.062). During the 15-min peri-intubation period (from T_-5 to T₁₀), 8 of 30 patients (26.7%) in the CT group experienced at least one episode of hypotension (SBP < 100 mmHg), compared with only 2 of 30 patients (6.7%) in the NE group (P = 0.038). Additionally, 2 patients in the CT group received 6 mg of ephedrine to manage hypotension. Notably, no patient in the NE group required rescue administration of vasoactive agents.

Our findings indicated that in elderly patients receiving anesthesia induction with propofol, prophylactic NE infusion effectively mitigated the decrease in △CIx while maintaining BP compared with the CT group, with no significant difference observed in △SVRI.

Elderly patients are vulnerable to hypotension because of diminished physiological reserves in the cardiovascular and autonomic nervous systems. Both advancing age (≥ 50 years) and the use of propofol for induction of anesthesia are significant predictors of hypotension following induction [4]. Treatment can be delayed because of the simultaneous management of hemodynamics and the airway after induction of general anesthesia. Thus, it is imperative to investigate optimal strategies for preventing hypotension after anesthesia induction in elderly patients. More importantly, treatment of hypotension should be directed to the cause(s), because cause-specific treatments are more likely to be effective than generic treatments for organ perfusion [23]. Early isolated experiment revealed that hypotension induced by propofol resulted from its direct vasodilatory impact on both veins and arterioles, and the concentrations required to induce vasodilation in veins were significantly lower than those necessary to elicit similar effects in arteries [26]. Age-related structural changes in arteries include endothelial dysfunction, vascular wall thickening, increased stiffening, and impaired endothelium-dependent vasorelaxation [27]. Thus, in elderly patients, propofol predominantly causes venous vasodilation, leading to reduce venous return, while arteriolar dilation is minimal due to vessel stiffening associated with aging. This finding aligns with clinical observation, as the typical hemodynamic response to anesthesia induction with propofol in elderly patients involves a reduction in CO resulting from diminished venous return, subsequently causing hypotension [10]. Therefore, the administration of a vasopressor that enhances venous return and sustains CO is considered appropriate.

One notable limitation of pure α-adrenergic agents, such as phenylephrine, is their tendency to decrease CIx and SV in patients with preload independence [28]. Although pure α-adrenergic agonists can increase venous return by constricting capacitance vessels, this effect may be countered by an elevation in venous resistance, potentially resulting in reducing venous return [29,30]. NE is a potent agonist of α-adrenergic receptor and comparatively weak agonist at β-adrenergic receptors. Veins also possess β-adrenergic receptors, and studies have demonstrated that NE is capable of constricting capacitance vessels without inducing a concurrent increase in venous resistance [29,31]. To ensure that patients were not in a hypovolemic state, additional fluids were administered as needed following intubation and initiation of mechanical ventilation to maintain SVV below 13%. This threshold was selected because under mechanical ventilation with tidal volumes ≥ 8 ml/kg, SVV values < 13% indicate normovolemia [32]. In our study, the attenuated decline in △CIx observed in the NE group was primarily associated with a smaller reduction in △SV. This smaller change in SV is likely attributable to enhanced venous return, which is supported by the lower SVV observed in the NE group. Furthermore, a mild positive inotropic effect of NE may have contributed to the smaller change in SV. Given its favorable effects on venous return and CIx, NE may be a more suitable option for managing or preventing hypotension induced by propofol anesthesia in elderly patients.

The use of NE for prophylaxis against postspinal hypotension has shown promising results [19,25,33], and several studies have explored the optimal dose for NE infusion during cesarean delivery [34,35]. In contrast, few studies have assessed the effectiveness of NE in managing hypotension during general anesthesia in noncardiac surgeries [36,37]. Legrand et al. [37] investigated the association of NE use with acute kidney injury (AKI), 30-day mortality, myocardial injury after noncardiac surgery (MINS), length of hospital stay, and rehospitalization within 30 days among adult patients who underwent major non-cardiac surgery. In our study, prophylactic NE infusion was administered exclusively during the induction period, which yielded short-term improvements in CIx; however, the potential long-term benefits of this approach were not explored. To our knowledge, this study is the first to evaluate the effectiveness of prophylactic NE infusion in mitigating the decrease in CIx during propofol-induced anesthesia in elderly patients. We acknowledge that prophylactic NE might carry potential risks, such as hypertension and increased cardiac workload. However, these risks were preemptively controlled in our study through a strict titration protocol and continuous radial artery BP monitoring, which effectively prevented significant or sustained elevations in BP and myocardial strain. In contrast, the benefit of reliably avoiding hypotension—a frequent and detrimental event in propofol-anesthetized elderly patients—confers a favorable risk-benefit profile in this carefully selected population.

The BIS monitor is a widely recognized tool for assessing the depth of hypnosis during anesthesia [38,39]. In this study, the BIS monitor was used to titrate the propofol dosage to maintain a BIS value between 50 and 60 in both groups, ensuring an appropriate depth of anesthesia. Indeed, there is an association between the BIS and metrics of cerebral perfusion, such as MAP. Studies have shown that increasing MAP and cerebral blood flow velocity are correlated with increasing BIS values [40]. This correlation may explain the greater amount of propofol administered in the NE group than in the CT group in our study. In order to assess the impact of NE on propofol-induced negative hemodynamics, we adjusted for the dosage of propofol administration. The higher propofol consumption in the NE group (3.02 ± 0.71 vs. 2.47 ± 0.63 mg/kg) likely reflects BIS-guided titration: NE-induced vasoconstriction may increase cerebral perfusion pressure, which in turn elevates the BIS [40] and thus requires a higher propofol dosage to maintain the target hypnotic depth (BIS 50-60). Importantly, statistical adjustment for the dose of propofol in our analytical models—GLM and GEE—demonstrated that the beneficial effects of NE on CIx and MAP were independent of the amount of propofol. These findings suggest that even with higher propofol exposure, NE preserved hemodynamic stability, thereby reinforcing its efficacy in counteracting propofol-induced decrease in CIx and hypotension.

The transient elevations in MAP and CIx observed at T₁-T₃ in the NE group (shown in Fig. 2) reflect a synergistic response to intubation-induced sympathetic activation [41,42] and the α₁/β₁-adrenergic agonist properties of NE. Critically, this early hemodynamic peak does not confound the calculation of △CIx at T₁₀ (T₁₀ value−baseline value), as the preinduction baseline was strictly defined prior to any anesthetic or study intervention. Furthermore, to mitigate potential bias, the intergroup variability in intubation-induced hemodynamic responses was rigorously controlled by standardized protocols. Notably, CIx returned to a stable plateau by T₄-T₅, with no residual elevation persisting at T₁₀— which is consistent with the well-documented transient nature of intubation-related hemodynamic perturbations [42].

Our study had several limitations. First, we employed the FloTrac/Vigileo system to estimate the hemodynamic values. Compared with pulmonary artery catheters, which are recognized as the clinical gold standard for CO measurement, the FloTrac/Vigileo system may introduce systematic errors in absolute CO values [43], although it reliably tracks hemodynamic trends [44]. In our analysis, this limitation was addressed by normalizing all hemodynamic measurements relative to baseline values. Second, patients received sufentanil and cisatracurium in addition to propofol for anesthetic induction to attenuate the intubation response, which is routine practice in our institution. The potential interactions of these drugs with propofol and their minor hemodynamic effects were not accounted for in our analysis. Third, despite the use of appropriate opioid and drug combinations, laryngoscopy and intubation may still have influenced hemodynamic measurements. To minimize variability between groups, laryngoscopy and intubation were performed by the same experienced anesthesiologist in this study. And another potential limitation of our study is the use of HES (200/0.5/6%) for preload optimization, which is consistent with our institutional protocol for elderly patients undergoing major abdominal surgery (HES is preferred for rapid volume expansion to prevent the induction of hypotension). While HES is associated with AKI risk in high-risk groups [45], the dose administered in our study (5 ml/kg) is low and within the range considered safe for short-term use in patients with essentially normal renal function [46]—yet this limits generalizability to crystalloid-based settings (e.g., lactated Ringer’s solution). Future crystalloid studies should validate the benefits of NE to enhance external validity of our findings. Lastly, a key limitation of this study is the lack of systematic assessment of long-term clinical outcomes (e.g., MINS, AKI, 30-day mortality). Our focus on peri-induction hemodynamics (≤ 10 min post-intubation) allowed us to isolate the effects of NE on propofol-induced hypotension and CIx decline, but we cannot confirm whether these short-term benefits reduce adverse clinical events. Future studies should explore the association between peri-induction NE use, sustained hemodynamic stability, and long-term postoperative outcomes in elderly patients.

In conclusion, our findings indicated that prophylactic NE infusion effectively counteract the decrease in CIx during propofol-induced anesthesia in elderly patients while maintaining MAP. Further research is warranted to assess the efficacy of NE on CIx during prolonged surgical procedures and investigate whether its benefits on CIx and MAP may be associated with a reduction in postoperative complications.