Comparison of propofol alone vs propofol-phenylephrine combination for intraoperative hemodynamic stability in glioma surgery

Abstract

BACKGROUND

Propofol is widely used for induction in glioma surgery for its neuroprotective effects and favorable recovery profile. However, its dose-dependent hypotension is a major limitation in procedures requiring stable cerebral perfusion.

AIM

To compare the efficacy of propofol vs propofol-phenylephrine (PPE) combination in maintaining hemodynamic stability in patients undergoing glioma surgery.

METHODS

Ninety American Society of Anesthesiologists I-II patients scheduled for elective glioma surgery were randomized to receive either propofol (group P) or a PPE admixture (group PPE). Induction was performed with slow titration of the study drug until loss of verbal response and Bispectral index < 60, followed by a continuous infusion (50 μg/kg/minute) until skin closure. Hemodynamic parameters [mean arterial pressure (MAP), systolic blood pressure, diastolic blood pressure, and heart rate] were recorded at baseline, during induction, immediately after intubation, and at predefined intraoperative time points. The incidence of hypotension, vasopressor and esmolol use, and brain relaxation scores were compared.

RESULTS

Group PPE demonstrated significantly better preservation of MAP, systolic blood pressure, diastolic blood pressure, and heart rate throughout the peri-induction and intraoperative periods (P < 0.05). The mean maximum MAP reduction during induction was greater in group P compared with group PPE (19.7 mmHg vs 12.5 mmHg; P < 0.01). Hypotensive episodes were significantly more frequent in group P than in group PPE (84.4% vs 6.7%; P < 0.001). Rescue phenylephrine requirements were markedly lower in group PPE (P < 0.001). Esmolol use and brain relaxation scores were comparable between groups.

CONCLUSION

Adding phenylephrine to propofol for induction and maintenance provides superior hemodynamic stability without compromising brain relaxation in glioma surgery.

Key Words: Propofol; Phenylephrine; Hemodynamic stability; Glioma surgery; Induction of anesthesia; Neuroanesthesia; Brain relaxation

Core Tip: Propofol is widely preferred for the induction and maintenance in neuroanesthesia due to its neuroprotective properties. However, propofol frequently causes hypotension during the induction of anesthesia in neurosurgical patients, which may compromise cerebral perfusion. Therefore, combining phenylephrine with propofol significantly reduces induction-related hypotension, minimizes vasopressor requirement, and maintains stable intraoperative hemodynamics without affecting brain relaxation, offering a practical approach for neuroanesthesia in glioma surgery.

INTRODUCTION

In neurosurgical patients, the goals of anesthesia include maintaining adequate cerebral oxygenation, cerebral perfusion pressure, stable hemodynamics, and optimal brain relaxation while avoiding techniques or agents that adversely affect these factors[1-3]. Even small hemodynamic fluctuations can alter intracranial dynamics, increase blood loss, or precipitate cerebral ischemia[4-6]. The hemodynamic fluctuations occur maximally during induction, laryngoscopy, surgical manipulations, emergence, and extubation during neurosurgery[7-9]. Therefore, anesthetic techniques that preserve blood pressure and minimize sympathetic surges are essential for safe neurosurgical care.

Propofol is widely preferred for induction and maintenance in neuroanesthesia because of its neuroprotective properties, rapid onset, predictable recovery profile, facilitation of early neurological examination, and ability to decrease cerebral metabolic rate and intracranial pressure[10-13]. However, its major drawback is a dose-dependent fall in arterial blood pressure. This hypotension is attributed to reduced systemic vascular resistance, venous and arterial vasodilation, myocardial depression, and blunting of the baroreceptor reflex[14-16].

Phenylephrine, a selective α1-adrenergic agonist, is commonly used to counteract propofol-induced hypotension. By increasing vascular tone and venous return, it can mitigate the blood pressure drop associated with propofol administration[17-19]. Although phenylephrine boluses or infusions are routinely used during induction, there is limited evidence on the efficacy of premixed propofol-phenylephrine (PPE) admixtures, particularly in neurosurgical patients where maintaining stable hemodynamics is crucial.

Existing studies have largely evaluated this combination in general surgical populations, with hemodynamic observations limited to the immediate post-induction period. Data specific to intracranial surgeries remains sparse, and the impact of this admixture on intraoperative hemodynamics and brain relaxation has not been adequately explored.

This study was designed to address this gap by comparing hemodynamic stability between patients receiving propofol alone and those receiving a PPE admixture during glioma surgery. The primary outcomes were mean arterial pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) during induction. Secondary outcomes included intraoperative hemodynamic trends at key neurosurgical time points, vasopressor and esmolol requirements, hypotensive episodes, and brain relaxation scores.

MATERIALS AND METHODS

This double-blinded randomized controlled study was conducted at a tertiary research hospital over an 18-month period after approval from the Institutional Ethics Committee (28 February 2023; approval No. AIIMS/BPL/IHECSR/July/22/SS/02) and registration with the Clinical Trial Registry of India (CTRI No. CTRI/2023/05/052570). Written informed consent was obtained from all participants.

Study population

All consenting patients aged 18-65 years, American Society of Anesthesiologists (ASA) physical status I-II, scheduled for elective glioma surgery were eligible. Patients with allergy to study drugs, uncontrolled hypertension, coronary artery disease, anticipated difficult airway, or clinical features suggestive of raised intracranial pressure were excluded.

Sample size calculation

Sample size was estimated using proportions reported by Imran et al[17], assuming proportions of 0.50 and 0.20 between groups. With 95% confidence, 80% power, and α = 0.05, the minimum required sample was 36 per group. Allowing for 20% attrition, a total of 45 participants were allocated to each group (90 total).

Randomization and blinding

Patients were randomized into group P (propofol) or group PPE (propofol + phenylephrine) using computer-generated random numbers. Allocation concealment was maintained with sealed, opaque envelopes. Study syringes were prepared by an anesthesiologist not involved in induction or data collection. As phenylephrine was mixed with propofol, both study solutions had the same milky-white appearance, eliminating any visible differences between syringes. The anesthesiologist administering anesthesia and the investigator recording outcomes were both blinded to group allocation. The surgical team and postoperative assessors were also unaware of treatment assignments.

Study drug preparation

Group P: 45 mL of 1% propofol + 5 mL normal saline. Group PPE: 45 mL of 1% propofol + 5 mL phenylephrine (100 μg/mL).

Induction protocol

In the operating room, ASA standard monitoring (non-invasive blood pressure, electrocardiography, pulse oximetry, and temperature) was applied in all patients. A radial arterial line was inserted under local anesthesia, and baseline hemodynamic values were recorded after a 10-minute stabilization period.

All patients were preoxygenated with 100% oxygen at 6 L/minute. Anesthesia was induced with fentanyl (2 μg/kg), the study drug was titrated to loss of verbal response and Bispectral index < 60, and vecuronium (0.1 mg/kg). Endotracheal intubation was performed by the same investigator to minimize inter-observer variability.

Anesthesia was maintained with isoflurane in 40% oxygen and 60% nitrous oxide to achieve a minimum alveolar concentration of 0.5-1, with Bispectral index maintained between 40 and 60. A scalp block with 0.25% bupivacaine was administered 5 minutes after intubation. Continuous infusions of fentanyl (1 μg/kg/hour) and vecuronium (0.05 mg/kg/hour) were used.

Study drug infusion protocol

Five minutes after intubation, the allocated study drug infusion (propofol alone or PPE admixture) was started at 50 μg/kg/minute and continued until skin closure.

Hemodynamic definitions and management

Hypotension was defined as a ≥ 20% decrease in MAP from baseline and was initially managed with a bolus of Ringer lactate (5-7 mL/kg over 5-10 minutes). Persistent hypotension was treated with phenylephrine 50 μg boluses. Hypertension, defined as a ≥ 20% increase in blood pressure from baseline, was managed with intravenous esmolol boluses (0.5-1 mg/kg).

Data collection

Hemodynamic parameters (HR, SBP, DBP, MAP) were recorded at baseline; during induction every 30 seconds for 3 minutes; at intubation; every minute for 5 minutes post-intubation; and at head pinning, burr hole creation, craniotomy, bone flap removal, dural opening, dural closure, and skin suturing. Brain relaxation score was assessed after dural opening as per Bhardwaj et al[18]. All episodes of hypotension, hypertension, and phenylephrine or esmolol use were documented.

Statistical analysis

Statistical analysis was performed using the SPSS (Statistical Package for Social Sciences, Version 30.0.0) program for Windows. The normally distributed continuous variables were presented as mean ± SD, and categorical variables were presented as absolute n (%). Parametric tests (t-tests, analysis of variance) were used to make statistical inferences for normally distributed data. Non-parametric tests (Wilcoxon signed rank tests, Mann-Whitney U test, Kruskal-Wallis’s test) were used to analyze non-normally distributed datasets. The association between the nominal or categorical attributes was studied using the χ²/Fisher’s Exact test. For all statistical tests, P < 0.05 was considered significant.

RESULTS

A total of 100 participants were screened for eligibility. Ten were excluded (five due to intraoperative uncontrolled hypertension, two due to withdrawal of consent, and three due to severe bradycardia), leaving 90 participants who were randomized and included in the final analysis. The CONSORT flow diagram is presented in Figure 1. Baseline demographic and intraoperative characteristics were comparable between the two groups (Table 1).

Figure 1 CONSORT flow diagram showing patient screening, exclusions, randomization, allocation, follow-up, and inclusion in the final analysis. P: Propofol; PPE: Propofol-phenylephrine.

Table 1 Baseline demographic and perioperative characteristics, mean ± SD.

Parameters	Group P (n = 45)	Group PPE (n = 45)	P value
Age (years)	39.13 ± 14.90	40.80 ± 13.36	0.5781
Gender (male/female)	27/18	21/24	0.2052
BIS	52.11 ± 5.88	52.07 ± 3.59	0.6811
Duration of surgery (minute)	248.67 ± 90.22	252.89 ± 94.60	0.5821
Anesthesia time (minute)	284.22 ± 92.40	284.56 ± 93.98	0.6631

¹t test.

²χ² test.

Group P: Propofol group; Group PPE: Propofol-phenylephrine group; BIS: Bispectral index.

Baseline MAP values were similar between groups. During induction, both groups experienced a fall in MAP, but the decline was consistently smaller in group PPE. Beginning 90 seconds after induction, MAP differed significantly between groups and remained consistently higher in group PPE throughout the induction and intraoperative periods (overall generalized estimating equation P < 0.001). At 90 seconds, the mean MAP difference was 5.9 mmHg (Cohen’s d = 0.60), increasing to 6.6 mmHg at 180 seconds (d = 0.67). Following intubation, MAP remained significantly better preserved in group PPE (mean difference 7.36 mmHg; d = 0.51; P = 0.012). Similar patterns were observed during major neurosurgical stages, including craniotomy and dural opening. Full-time point MAP values are presented in Supplementary Table 1. These trends are illustrated in Figure 2A.

Figure 2 Line graph. A: Line graph showing peri-induction and intraoperative trends in mean arterial pressure in group propofol and group propofol-phenylephrine; B: Line graph showing peri-induction and intraoperative trends in heart rate in group P (propofol) and group propofol-phenylephrine. P: Propofol; PPE: Propofol-phenylephrine.

HR trends were similar between groups at most time points, with a significant difference observed only during head pinning, where group PPE demonstrated a modest reduction (mean difference 5.67 bpm; d = 0.45; P = 0.036), consistent with α-agonist-related reflex bradycardia. Overall HR trajectories differed slightly by generalized estimating equation analysis (P = 0.011). Detailed HR values are available in Supplementary Table 2. These trends are illustrated in Figure 2B.

Hypotension occurred in 84.4% of patients receiving propofol alone compared with 6.7% in the PPE group (P < 0.001), representing a large effect (risk difference 77.7%; Cohen’s h = 1.90) as depicted in Figure 3. Correspondingly, rescue phenylephrine requirements were markedly lower in group PPE (median 0 vs 4 boluses; P < 0.001). Esmolol use was not significantly different between groups (13.3% vs 24.4%; P = 0.17). Brain relaxation scores assessed after dural opening were comparable (P = 0.30), indicating that the addition of phenylephrine did not adversely affect intracranial relaxation or surgical conditions.

Figure 3 Pie charts showing the incidence of hypotension in group P (propofol) and group propofol-phenylephrine. P: Propofol; PPE: Propofol-phenylephrine.

DISCUSSION

The present randomized controlled study evaluated whether adding phenylephrine to propofol could mitigate propofol-induced hypotension and provide more stable hemodynamics during glioma surgery. The principal findings demonstrate that the PPE admixture resulted in clinically meaningful improvement in peri-induction and intraoperative hemodynamic stability, with fewer hypotensive episodes and reduced vasopressor requirements compared with propofol alone. These findings are particularly relevant in neuroanesthesia, where even transient hypotension may compromise cerebral perfusion and predispose to secondary brain injury.

Maintenance of stable cerebral perfusion pressure is a fundamental goal during glioma surgery, as these patients frequently exhibit altered cerebral autoregulation, peritumoral edema, and increased intracranial elastance. Induction-related hypotension may therefore lead to disproportionate reductions in cerebral perfusion pressure, potentially worsening cerebral ischemia. By attenuating propofol-induced vasodilation, the phenylephrine admixture likely contributes to more consistent perfusion pressures during the most hemodynamically vulnerable phases of anesthesia, including induction, intubation, and surgical stimulation.

The studies conducted by Imran et al[17] and Farhan et al[19] on assessing the effect of phenylephrine on propofol-induced hypotension were done in general surgical patients requiring laryngeal mask airway placement and endotracheal insertion, respectively. Their results showed that the group receiving phenylephrine maintained significantly higher SBP, DBP, and MAP following induction compared to the control groups. However, the phenylephrine group exhibited a significantly reduced HR, with hypotension ranging from 20% to 24%, compared to 43%-60% in the propofol groups. The reported incidence of hypotension differed, which may be attributed to the shorter observation period, extending only from baseline to 5 minutes post-induction, while the present study extends these observations across multiple neurosurgical stages, providing evidence that the hemodynamic benefits of the admixture persist beyond induction.

Supporting these findings, a systematic review and meta-analysis by Saunders et al[20] demonstrated that prophylactic vasopressors significantly reduce peri-intubation hypotension, with α-agonists such as phenylephrine showing consistent benefit compared with no prophylactic vasopressor use. These results reinforce the role of phenylephrine in counteracting induction-related hypotension and are concordant with the hemodynamic stability observed in the present study.

Kalmar et al[21] further elucidated the physiological effects of phenylephrine, demonstrating that, in the setting of anesthesia-induced vasodilation, phenylephrine not only increases arterial pressure but may also improve venous return and cardiac preload. This effect was associated with improvements in stroke volume and cardiac output, along with reductions in dynamic preload indices, suggesting that blood pressure augmentation does not necessarily occur at the expense of forward flow when appropriately administered.

In contrast, dose-response data from cardiac surgical patients reported by El-Tahan[22] suggested that higher doses of vasopressors, including phenylephrine, may increase systemic vascular resistance and reduce cardiac output, particularly in patients with limited cardiac reserve. These findings highlight the importance of patient selection and cautious dosing. In the present study, which involved ASA I-II patients undergoing intracranial surgery, the phenylephrine admixture was used in low concentrations and titrated carefully, which may explain the favorable hemodynamic profile without evidence of adverse cardiac effects.

Although reflex bradycardia is a recognized consequence of phenylephrine administration, the reduction in HR observed in this study was modest, transient, and confined to periods of intense surgical stimulation. Importantly, this change was not clinically significant and did not require intervention. The slightly higher, though statistically non-significant, esmolol requirement in the combination group likely reflects more active modulation of sympathetic responses during surgical stimulation rather than a deleterious chronotropic effect of phenylephrine.

The markedly lower incidence of hypotension in the PPE group highlights the practical advantages of this approach. By minimizing the need for repeated rescue vasopressor boluses, the admixture reduces blood pressure fluctuations, which may help maintain stable cerebral perfusion and reduce secondary brain injury risk, particularly important in glioma surgery, where autoregulation may be impaired.

A key concern with use of vasopressor in neuroanesthesia is the potential impact on cerebral blood flow and brain relaxation. In the present study, brain relaxation scores were comparable between groups, indicating that the addition of phenylephrine did not adversely affect surgical conditions. This finding is clinically reassuring and suggests that judicious use of an α-agonist does not compromise intracranial relaxation. To our knowledge, this is the first study to examine brain relaxation in the context of a PPE admixture in neurosurgery, representing a meaningful contribution to existing literature.

The inclusion of neurosurgical patients represents a key strength of this study, as this population has a particularly narrow margin for hemodynamic instability. Unlike prior studies that focused primarily on the induction period, the present investigation assessed hemodynamic stability across multiple intraoperative stages, providing a more comprehensive evaluation of the admixture’s clinical utility. Assessment of vasopressor requirements and brain relaxation further strengthens the relevance of these findings to everyday neuroanesthesia practice.

Several limitations of this study should be acknowledged. First, objective intracranial pressure monitoring was not employed, which limited direct correlation between systemic hemodynamic changes and intracranial dynamics. Second, the single-center design and inclusion of only ASA physical status I-II patients may limit the generalizability of these findings to higher-risk populations or patients with raised intracranial pressure. Third, advanced dynamic cardiovascular parameters, such as stroke volume index and systemic vascular resistance index, were not assessed and could have provided additional mechanistic insight into the observed hemodynamic effects. Finally, assessment of brain relaxation relied on a subjective scoring system and was not supplemented by objective measures of intracranial compliance.

CONCLUSION

The addition of phenylephrine to propofol provides superior hemodynamic stability during glioma surgery without compromising brain relaxation. This admixture offers a simple, effective strategy that can be readily incorporated into routine neuroanesthesia protocols to reduce hypotension and ensure stable cerebral perfusion. Further multicenter randomized controlled trials with larger sample sizes, inclusion of higher-risk patients, and incorporation of objective intracranial monitoring are required to confirm and validate these findings.