Intraoperative hypotension is a common and clinically significant complication of general anaesthesia, particularly during major trauma surgery, where fluctuations in haemodynamic may adversely affect organ perfusion and long-term outcomes [1]. Maintaining optimal blood pressure is essential to minimize the risk of acute kidney injury (AKI), myocardial injury after noncardiac surgery (MINS), and cerebral hypoperfusion [2,3].

Phenylephrine (PE), a selective α₁-adrenergic agonist, has long been the first-line vasopressor for managing anaesthesia-induced hypotension due to its rapid onset and direct vasoconstrictive action [4]. However, PE's use has been associated with reflex bradycardia, decreased cardiac output, and potential compromise of organ perfusion, particularly in patients with limited cardiac reserve [5]. In contrast, norepinephrine (NE), a mixed α- and β-adrenergic agonist, may better maintain cardiac output and end-organ perfusion while still effectively correcting hypotension [6].

A growing body of evidence supports reevaluating the historical reliance on phenylephrine. Mets et al. strongly advocate for norepinephrine as a more physiologically favourable agent in modern anaesthesia practice, emphasizing its ability to preserve stroke volume and renal perfusion [7]. In a multicentre trial involving over 3,600 patients, Legrand et al. found no significant difference in 30-day mortality or AKI incidence between NE and PE groups, but did affirm the safety and feasibility of NE as a frontline option [8].

Furthermore, a study by Hasanin et al. demonstrated that intraoperative NE infusion provided better systolic blood pressure stability without drug-related complications, making it both safe and effective [9]. Similarly, Khanna et al. observed a higher risk of postoperative AKI in patients receiving phenylephrine alone, emphasizing the need for balanced vasopressor selection [10].

Current evidence also highlights a growing shift in clinical practice, as observed in a recent nationwide survey in Malaysia, where anaesthesiologists reported increasing use of NE in high-risk surgical patients [11]. Additionally, new trials are underway to directly compare cerebral and systemic perfusion effects between NE and PE in neurosurgical and trauma settings [12]. These studies underscore a broader trend toward personalized hemodynamic management.

Despite accumulating evidence, the optimal vasopressor strategy for intraoperative hypotension in adult trauma patients remained unclear. This randomized trial was therefore conducted to compare norepinephrine and phenylephrine infusions in their ability to maintain intraoperative mean arterial pressure (MAP) during major trauma surgery under general anaesthesia. The study also evaluated secondary outcomes including incidence of bradycardia, vasopressor bolus requirement, renal function, and ICU admission in the early postoperative period.

This was a single-centre, randomized controlled trial conducted over a six-month period in 2024 at the Department of Trauma and Emergency, Indira Gandhi Institute of Medical Sciences, Sheikhpura, Patna. The study included 100 adult patients undergoing major trauma surgery under general anaesthesia, each receiving intraoperative vasopressor support. Ethical clearance was obtained from the institutional review board prior to patient enrollment, and written informed consent was secured from all participants.

Eligible patients were between 18 and 60 years of age, scheduled for trauma surgeries lasting more than two hours, and anticipated to stay in the hospital for at least one postoperative night. All patients received general anaesthesia with standard intraoperative monitoring and required continuous vasopressor infusion to manage hypotension. Exclusion criteria included patients undergoing cardiac or transplant surgeries, those on extracorporeal membrane oxygenation (ECMO), obstetric procedures, same-day outpatient surgeries, and patients who were already receiving norepinephrine or phenylephrine prior to induction. Patients transferred to another hospital within 24 hours of surgery were also excluded from the analysis.

Patients were randomized into two groups using a computer-generated block randomization list: one group received norepinephrine (NE), and the other received phenylephrine (PE) as the first-line vasopressor to treat intraoperative hypotension. Drug administration was performed by anaesthesia providers who were blinded to the group allocation, and vasopressor infusions were prepared according to local institutional protocols. Phenylephrine was administered at a concentration of 100 mcg/ml, while norepinephrine was titrated between 8–32 mcg/ml based on the clinical condition. Intraoperative hypotension was defined as a sustained drop in mean arterial pressure (MAP) below 65 mmHg or a decrease of more than 20% from baseline. Vasopressor doses were adjusted to maintain MAP between 65–85 mmHg. A total of 126 patients were screened for eligibility, of which 100 were randomized equally into two treatment groups. The flow of participants through the study is depicted in Figure 1.

Primary data included demographic details, duration of surgery, total vasopressor requirement (mcg/kg/min), hemodynamic variables (MAP, heart rate), and need for vasopressor boluses. Secondary data included postoperative outcomes such as urine output, serum creatinine, incidence of acute kidney injury (as per KDIGO criteria), ICU admission, and 30-day complications. All data were collected prospectively by trained research assistants and recorded in a standardized electronic case report form.

Statistical analysis was performed using SPSS version 26.0 (IBM Corp., Armonk, NY). Continuous variables were expressed as mean ± standard deviation (SD) or median with interquartile range (IQR) where appropriate. Categorical variables were presented as frequencies and percentages. Between-group comparisons were analyzed using independent t-tests or Mann-Whitney U tests for continuous variables, and chi-square or Fisher's exact test for categorical variables. A p-value < 0.05 was considered statistically significant. No imputation was made for missing data.

Baseline and Clinical Characteristics

A total of 100 patients were enrolled and randomized equally into the phenylephrine (PE) and norepinephrine (NE) groups. The mean age in the NE group was 44.2 ± 7.9 years, compared to 39.7 ± 9.3 years in the PE group. The proportion of male patients was higher in the PE group (66.0%) than in the NE group (50.0%).

ASA class distribution showed a greater proportion of ASA III patients in the PE group (44.0%) compared to 22.0% in the NE group. Comorbidity profiles varied slightly, with the PE group having more patients with no comorbidities (58.0%) and a higher proportion of diabetic patients (22.0%) compared to the NE group (14.0%). Conversely, hypertension was more common in the NE group (30.0% vs. 12.0%).

The average body mass index (BMI) was slightly higher in the NE group (25.5 ± 4.4) than the PE group (24.1 ± 2.7). The duration of surgery was comparable between groups, with a mean of 142.9 ± 32.0 minutes in the NE group and 138.2 ± 31.0 minutes in the PE group.

Baseline and Clinical Characteristics

A total of 100 patients were enrolled and randomized equally into the phenylephrine (PE) and norepinephrine (NE) groups. The mean age in the NE group was 44.2 ± 7.9 years, compared to 39.7 ± 9.3 years in the PE group. The proportion of male patients was higher in the PE group (66.0%) than in the NE group (50.0%).

American Society of Anaesthesiologists Physical Status Classification System (ASA) class distribution showed a greater proportion of ASA III patients in the PE group (44.0%) compared to 22.0% in the NE group. Comorbidity profiles varied slightly, with the PE group having more patients with no comorbidities (58.0%) and a higher proportion of diabetic patients (22.0%) compared to the NE group (14.0%). Conversely, hypertension was more common in the NE group (30.0% vs. 12.0%).

The average body mass index (BMI) was slightly higher in the NE group (25.5 ± 4.4) than the PE group (24.1 ± 2.7). The duration of surgery was comparable between groups, with a mean of 142.9 ± 32.0 minutes in the NE group and 138.2 ± 31.0 minutes in the PE group. Complete demographic and clinical characteristics for both groups are summarized in Table 1.

Table 1. Baseline and Clinical Characteristics

Values are presented as mean ± standard deviation or n (%), as appropriate.

Intraoperative Hemodynamic Outcomes

The intraoperative mean arterial pressure (MAP) was significantly higher in the norepinephrine group (72.5 ± 3.7 mmHg) compared to the phenylephrine group (65.6 ± 4.8 mmHg), with a statistically significant difference (t = -7.84, p < 0.0001). Similarly, the mean heart rate (HR) was higher in the norepinephrine group (63.0 ± 9.2 bpm) than in the phenylephrine group (58.1 ± 9.0 bpm), and this difference was also statistically significant (t = -2.64, p = 0.0098).

Vasopressor dose requirements were notably lower in the norepinephrine group (0.78 ± 0.17 mcg/kg/min) than in the phenylephrine group (1.21 ± 0.33 mcg/kg/min), with a highly significant p-value (< 0.0001). The frequency of rescue vasopressor boluses was also reduced in the norepinephrine group (0.9 ± 0.8) compared to the phenylephrine group (2.1 ± 1.5), supported by a statistically significant difference (p = 0.0002).

Complete group-wise outcomes are presented in Table 2, with corresponding p-values and test statistics detailed in Table 3. The distributional spread of MAP and HR values across the two groups is further illustrated in Figure 2.

Table 2. Intraoperative Hemodynamic Outcomes

         Values are presented as mean ± standard deviation

Table 3. Statistical Significance of Intraoperative Outcomes

Results of independent samples t-tests comparing intraoperative outcomes between the two vasopressor groups.

Postoperative Outcomes

The mean postoperative change in serum creatinine was significantly lower in the norepinephrine group (0.10 ± 0.06 mg/dL) compared to the phenylephrine group (0.16 ± 0.08 mg/dL), with a statistically significant difference (t = 3.97, p = 0.0001). This may indicate a relative preservation of renal function in patients receiving norepinephrine during intraoperative management.

The incidence of acute kidney injury (AKI) was numerically lower in the norepinephrine group (4 [8.0%]) compared to the phenylephrine group (10 [20.0%]), though this difference did not reach statistical significance (χ² = 3.65, p = 0.0562). Similarly, ICU admission was less frequent in the norepinephrine group (7 [14.0%]) compared to the phenylephrine group (15 [30.0%]), trending toward significance (χ² = 3.68, p = 0.0552). Thirty-day complication rates were comparable between the two groups (norepinephrine: 6 [12.0%], phenylephrine: 11 [22.0%]; χ² = 0.61, p = 0.4349). Complete descriptive outcomes are summarized in Table 4, and the results of statistical comparisons are presented in Table 5.

Table 4. Postoperative Outcomes

         Values are presented as mean ± standard deviation or n (%), as appropriate.

Table 5. Statistical Significance of Postoperative Outcomes

          Results of statistical testing comparing postoperative outcomes between the two vasopressor groups.

Hemodynamic Recovery Time

The mean time to achieve target mean arterial pressure (MAP) following vasopressor initiation was significantly shorter in the norepinephrine group (13.6 ± 3.7 minutes) compared to the phenylephrine group (18.9 ± 4.7 minutes). This difference was statistically significant (t = 6.06, p < 0.0001), indicating more rapid stabilization in patients receiving norepinephrine. Detailed summary is presented in Table 6.

Table 6. Hemodynamic Recovery Time

Values are presented as mean ± standard deviation. Recovery time is defined as the time (in minutes) to achieve target mean arterial pressure after vasopressor initiation.

Cumulative Vasopressor Dose

The total cumulative vasopressor dose administered intraoperatively differed significantly between the two groups. Patients in the norepinephrine group received an average of 680 ± 210 micrograms (mcg), while those in the phenylephrine group required a significantly higher dose of 1806 ± 437 mcg. Statistical analysis confirmed a highly significant difference (t = 15.28, p < 0.0001), suggesting greater pharmacodynamic efficiency of norepinephrine in maintaining hemodynamic targets. Full dosing details are presented in Table 7, and the intergroup distribution is visually illustrated in Figure 3.

Table 7. Cumulative Vasopressor Dose

Values are presented as mean ± standard deviation. Total dose administered intraoperatively per patient is shown in micrograms.

Adverse Events

Adverse event profiles differed between the groups, particularly in relation to bradycardia. The incidence of bradycardia was significantly higher in the phenylephrine group (13 patients, 26.0%) compared to the norepinephrine group (2 patients, 4.0%), consistent with the known reflex bradycardia effect of phenylephrine. Conversely, arrhythmias were more frequent in the norepinephrine group (9 patients, 18.0%) than in the phenylephrine group (4 patients, 8.0%), though the difference was not statistically evaluated. Episodes of intraoperative hypertension were comparable between groups (10.0% for norepinephrine vs 12.0% for phenylephrine). Detailed adverse event rates are summarized in Table 8.

Table 8. Intraoperative Adverse Events

           Adverse events are reported as n (%).

In this randomized trial comparing norepinephrine and phenylephrine for intraoperative hypotension management in major trauma surgeries, norepinephrine demonstrated superior hemodynamic performance, faster response time, reduced vasopressor burden, and a lower incidence of adverse events.

Norepinephrine was significantly more effective in maintaining intraoperative mean arterial pressure (MAP), with a group mean of 72.5 ± 3.7 mmHg compared to 65.6 ± 4.8 mmHg for phenylephrine (p < 0.0001). Heart rate (HR) remained higher in the norepinephrine group (63.0 ± 9.2 bpm vs. 58.1 ± 9.0 bpm, p = 0.0098), consistent with norepinephrine's mixed α- and β-adrenergic activity. These findings echo Mets B’s pharmacologic rationale supporting norepinephrine for preserving cardiac output and reducing bradycardic reflexes [13], as well as the intraoperative hemodynamic superiority observed by Aykanat et al. in a controlled trial of low-dose norepinephrine [14].

Renal function outcomes also favoured norepinephrine. The mean postoperative change in serum creatinine was lower (0.10 ± 0.06 mg/dL) than in the phenylephrine group (0.16 ± 0.08 mg/dL, p = 0.0001). Although not statistically significant, the norepinephrine group experienced fewer acute kidney injury (AKI) events (8.0% vs. 20.0%) and fewer ICU admissions (14.0% vs. 30.0%). These trends are supported by Chiu et al., who reported that norepinephrine use did not worsen renal outcomes following major surgery [15], and by Legrand and Zarbock, who emphasized its renal-sparing effects when titrated to perfusion endpoints [16].

Hemodynamic recovery time was also markedly shorter in the norepinephrine group (13.6 ± 3.7 minutes) versus phenylephrine (18.9 ± 4.7 minutes), with a highly significant difference (p < 0.0001). This suggests norepinephrine achieves target pressures more rapidly, a critical advantage in trauma scenarios where time to stabilization impacts tissue perfusion and outcomes.

Cumulatively, norepinephrine required significantly lower vasopressor dosing — 680 ± 210 mcg compared to 1806 ± 437 mcg in the phenylephrine group (p < 0.0001). This pharmacodynamic efficiency reduces drug exposure and aligns with the dosing principles advocated by Sessler et al. to limit vasopressor-related complications [17].

The adverse event profile further differentiated the two drugs. Bradycardia occurred in 26.0% of phenylephrine-treated patients versus just 4.0% in the norepinephrine group. This significant disparity supports Puthenveettil et al.’s findings in spinal anaesthesia, where phenylephrine was associated with a greater incidence of reflex bradycardia [18]. Arrhythmias were slightly more frequent in the norepinephrine group (18.0% vs. 8.0%), but without clear clinical impact in this cohort.

In totality, our findings suggest that norepinephrine provides more efficient and stable intraoperative blood pressure control with fewer complications and less drug exposure than phenylephrine. These advantages, particularly in high-risk trauma settings, merit consideration in revising vasopressor protocols. Nevertheless, larger multicentre trials are needed to confirm these trends and assess long-term morbidity and mortality endpoints.

Limitations

This study has several limitations that warrant consideration. First, it was a single-centre trial conducted at a tertiary trauma care facility, which may limit generalizability to broader surgical populations or non-trauma settings. Second, while randomization was employed, blinding of anaesthesiologists to the vasopressor infusion was not feasible due to differences in drug titration practices, potentially introducing performance bias.

Third, although the study included multiple outcome measures, it was not powered specifically to detect differences in rare adverse events such as arrhythmias or acute kidney injury. The trends observed in ICU admissions and AKI incidence, while clinically meaningful, did not reach statistical significance and require confirmation in larger trials. Additionally, long-term postoperative outcomes, including mortality and quality of recovery, were not assessed in this 30-day follow-up period.

Finally, while cumulative vasopressor dosing was measured, detailed pharmacokinetic modelling or per-minute infusion rates were not standardized across all cases, which may introduce variability in dose-response interpretation.

In this randomized study comparing norepinephrine and phenylephrine for intraoperative hypotension in major trauma surgery, norepinephrine demonstrated superior hemodynamic control, faster achievement of target blood pressure, and reduced cumulative vasopressor requirements. It was also associated with a significantly lower incidence of bradycardia and more favourable trends in renal function and ICU utilization. These findings support the preferential use of norepinephrine as a primary vasopressor in trauma surgeries requiring general anaesthesia. However, larger multicentre trials are necessary to confirm these results and evaluate long-term outcomes.

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