Abstract
Objectives
Current evidence supporting the use of continuous intravenous labetalol for blood pressure (BP) control in neurosurgical patients is limited. This study aims to assess the efficacy and safety of labetalol in neurosurgical patients and identify potential contributing factors to these outcomes.
Methods
We retrospectively reviewed the medical records of neurosurgical patients who received continuous labetalol infusion for BP control. Efficacy was assessed based on the time needed to achieve the target BP (systolic BP ≤ 140 mmHg or diastolic BP ≤ 90 mmHg). Safety was assessed according to adverse events that occurred during labetalol administration. Factors associated with efficacy and safety were analyzed using a logistic regression model.
Results
Among 79 patients enrolled in this study, 47 (59.49%) achieved the target BP within 1 hour (early response). No factors were significantly associated with an early response. Hypotension was observed in 11 patients (13.9%), and bradycardia was observed in 8 patients (10.1%). Hypotension was significantly associated with patient age and motor impairment, while bradycardia was significantly associated with diabetes mellitus.
Conclusion
The efficacy and safety profiles of labetalol infusion suggest this treatment as a promising option for BP control in neurosurgical patients.
Introduction
Hypertension (HT) commonly occurs in patients undergoing neurosurgical procedures, and its prevalence in post-craniotomy cases has been reported to be 21%. 1 Perioperative HT can arise from various factors, including a history of HT, underlying clinical conditions, surgical stress, and anesthetic procedures.2,3 It is imperative to effectively control blood pressure (BP) during the perioperative period, as uncontrolled BP can lead to severe postoperative complications, including intracranial hemorrhage, myocardial ischemia, myocardial infarction, and renal failure.4–6 However, the management of perioperative HT poses a challenge because of the delicate balance required between the risk of organ ischemia and the risk of bleeding. In addition, specific guidelines for HT management tailored to neurosurgical patients are lacking. In our routine clinical practice, a BP goal of ≤ 140/90 mmHg is pursued to prevent intracranial complications, especially rebleeding.7–10 The selection of antihypertensive agents is based on clinical conditions, comorbidities, and expert opinions.
Several intravenous antihypertensive agents, including beta-blockers (labetalol, esmolol), calcium channel blockers (nicardipine), hydralazine, sodium nitroprusside, and nitroglycerin, are recommended for HT management during the perioperative period.2,4 Among these agents, labetalol is considered the drug of choice for BP control in patients with brain pathologies because of its ability to reduce BP while maintaining cerebral blood flow.11–13
Labetalol has shown efficacy in treating HT during craniotomy for tumor resection and in stroke patients, including those with intracerebral hemorrhage.14–16 However, concerns regarding adverse effects, particularly bradycardia and hypotension, have been associated with labetalol use during intensive BP control. Despite a recommended intravenous dose of labetalol of less than 300 mg, previous studies reported that cumulative doses exceeding 300 mg did not significantly increase adverse effects and appeared to be safe for treating hypertensive crises.17,18 Additionally, the incidence rates of bradycardia and hypotension during labetalol use were similar to those during nicardipine use, and both drugs were equally effective in controlling BP.14–16
In our neurocritical care settings, there has been a trend toward the use of continuous infusion of labetalol (Avexa, Great Eastern Drug, Thailand), particularly high cumulative doses, to control BP in neurosurgical patients. However, current evidence supporting its use in this specific patient population is limited. Therefore, we conducted this retrospective observational study to determine the efficacy and safety outcomes associated with the use of intravenous labetalol infusion in neurosurgical patients and to identify factors that may contribute to these outcomes.
Methods
Study design and patient population
This study was a retrospective review that investigated the efficacy and safety of continuous intravenous infusion of labetalol for BP control in neurosurgical patients who were admitted to our institution between 1 November 2021 and 31 October 2022. This study was conducted in accordance with the Declaration of Helsinki and was approved by the Human Research Ethics Committee of Thammasat University (Medicine) (Approval No. 245/2022); for this type of retrospective study, formal consent is not required. The study was registered with the Thai Clinical Trials Registry (TCTR20221227005). All patients’ details were de-identified. The reporting of this study conforms to the STROBE guidelines. 19
The inclusion criteria consisted of patients aged 18 years or older who underwent surgery and received continuous intravenous infusion of labetalol for BP control. This study did not include patients who had suffered brain death, had bone marrow disease or other neurosurgical diseases that do not involve the brain (such as spine or peripheral nerve diseases), or received any other concomitant antihypertensive agents or other agents that affected the cardiovascular system during the hospitalization period. Pregnant patients and patients who required high BP retention (such as those receiving triple-H therapy for cerebral vasospasm) were also excluded. The sample size calculation was based on a previous study that indicated an adverse event rate of 44.3% in patients receiving high-dose intravenous labetalol. 17 Assuming an error rate of 20% and study power of 90% at the 5% significance level, the estimated sample size was calculated as at least 70 patients.
Data collection
All data were obtained from the electronic medical records of patients. Demographic data, including age, sex, height, weight, body mass index, medical history, and concomitant use of antiplatelets or anticoagulants, were collected. Neurologic examination data were also collected, including the Glasgow Coma Scale (GCS) score, motor power score, and sensory function. In addition, the types of neurosurgical procedures were classified as supratentorial surgery, infratentorial surgery, and other procedures (such as external ventricular drainage).
Radiographic images of all patients were thoroughly reviewed and classified as either having mass lesions (tumor or hemorrhage) or lacking mass lesions. The mass volume was calculated using the ABC/2 method. We did not calculate blood volume in patients with diffused subarachnoid hemorrhage. In addition, the presence of a pressure effect of the mass, defined as evidence of brain compression, brain edema, or midline shift, on the scan was evaluated.
Management of HT
Systolic BP (SBP), diastolic BP (DBP), and heart rate (HR) were monitored and measured using noninvasive BP measurement. Vital sign readings were collected at two timepoints, including at baseline before labetalol was administered and at the time the target BP was achieved. We also collected the cumulative time and dose of labetalol when the target BP was achieved and when an adverse event occurred. We observed adverse events that occurred during labetalol infusion, such as hypotension (SBP < 90 mmHg and DBP < 60 mmHg), bradycardia (< 60 bpm), and hypoglycemia (plasma glucose concentration < 60 mg/dL).
In our routine neurocritical care, labetalol is administered at a concentration of 2 mg/mL at an initial rate of 30 mg/hour and then increased by 30 mg/hour every 15 minutes as required, up to a maximum dose of 480 mg/hour. Once the target BP is reached, the dose is gradually reduced and maintained between 5 and 20 mg/hour before tapering off.
Measurement of efficacy and safety
To assess the efficacy of labetalol in the study population, we defined the target BP as SBP ≤ 140 mmHg or DBP ≤ 90 mmHg based on our clinical practice along with previous clinical trials.8,10 The guideline for the management of HT (the Eighth Joint National Committee guideline) was also taken into consideration when setting the BP target. 7 Additionally, we classified patients who achieved the target BP within 1 hour into the early response group, and patients who achieved the target BP after 1 hour were classified into the late response group.8,10
The primary efficacy outcome was assessed according to the number of early-response patients. The secondary efficacy outcomes included the time required to achieve the target BP after labetalol administration and the BP change from baseline. The secondary safety outcomes were the number of adverse events that occurred during labetalol administration and the association between the cumulative dose of labetalol and the adverse event rate. In addition, we categorized the cumulative dose when adverse events occurred as ≤ 300 mg or > 300 mg, based on the recommended maximum dose of labetalol. 17
Statistical analysis
Descriptive statistics were calculated to summarize all variables. Continuous variables are reported as the mean (standard deviation) or median (interquartile range, IQR) as appropriate. Categorical variables are reported as frequencies and percentages. All efficacy and safety outcomes were analyzed using a Chi-square test or Fisher’s exact test for categorical variables and Student’s t-test or the Wilcoxon rank-sum test for continuous variables as appropriate.
Univariable logistic regression was performed to identify potential factors that were associated with efficacy or safety outcomes. Factors with a p-value less than 0.2 were subsequently included in the multivariable logistic model. The receiver operating characteristic curve and Youden’s J statistic were used to determine the optimal cut-off values of continuous variables from the logistic regression analysis.
All tests of statistical significance were two-tailed, and a p-value < 0.05 was considered statistically significant. Statistical analyses were performed using STATA software version 17.0 (StataCorp, College Station, TX, USA) and GraphPad Prism 9.5.0 (GraphPad Software, San Diego, CA, USA).
Results
The patient selection process is shown in Figure 1. Eighty-three patients were screened, from which four patients were excluded because of age < 18 years (n = 1), SBP ≤ 140 mmHg and DBP ≤ 90 mmHg (n = 1), and not receiving labetalol as a single agent (n = 2). The remaining 79 patients were enrolled and included in the final analysis.
Flowchart of patient selection.
Table 1 presents a summary of the baseline characteristics and neurologic conditions of the patient population. The average age was 55.2 ± 15.8 years, and 50.6% of patients were female. HT was the most prevalent medical history (54.4%). Most patients presented with a GCS score of 13 to 15 (78.5%). Cerebrovascular diseases (50.6%) and brain tumors (36.7%) were common diagnoses. Mass lesions were found in 92.4% of patients, with 53.2% having brain hemorrhage and 39.2% having brain tumors.
Baseline characteristics of the study population, compared by the time of target blood pressure achievement.
SD, standard deviation, IQR: interquartile range, GCS: Glasgow Coma Scale.
Patients who achieved the target blood pressure within 1 hour.
Patients who achieved the target blood pressure after 1 hour.
Patients who had at least one (motor or sensory) impaired limb.
Cerebrovascular disease includes both ischemic and hemorrhagic diseases.
Other diagnoses include skull defect and shunt malfunction.
The presence of subarachnoid hemorrhage (SAH) or non-SAH.
The mass volume was measured only in patients with non-SAH (n = 17).
Significance level of 0.05.
In this study, the median time to achieve the target BP in all patients was 1.0 hour (IQR: 0.5–2.0 hours), and the median cumulative dose of labetalol at target BP achievement was 40 mg (IQR: 16–100 mg). Upon classifying patients into two groups, early response (achieving the target BP within 1 hour) and late response (achieving the target BP after 1 hour), we found that 47 patients (59.49%) were in the early response group, which was slightly more than the number of patients in the late response group (n = 32, 40.51%). The median times required to achieve the target BP were 0.5 hours (IQR: 0.3–0.8 hours) and 2.3 hours (IQR: 1.9–3.8 hours) in the early and late response groups, respectively (p < 0.01). Additionally, the median cumulative labetalol doses administered were 20 mg (IQR: 10–40 mg) and 125 mg (IQR: 65–298 mg) in the early and late response groups, respectively (p < 0.01).
There was no significant difference in the median BP between the two groups (early response vs. late response) at baseline or at the time of target BP achievement, as shown in Figure 2. The analysis also revealed similar reductions in BP from baseline when comparing the early response group vs. the late response group; the median SBP changes were −23 mmHg (IQR: −42 to −15 mmHg) vs. −30 mmHg (IQR: −37 to −20 mmHg), and the median DBP changes were −9 mmHg (IQR: −21 to −2 mmHg) vs. −9 mmHg (IQR: −20 to −4 mmHg). However, the early response group exhibited a significantly higher baseline HR than the late response group (p = 0.01, Figure 2). Following labetalol administration, a slight reduction in the HR from baseline occurred in both groups, with an overall median decrease of 6 bpm (IQR: −14 to −2 bpm).
Box plots of systolic blood pressure (a), diastolic blood pressure (b), and heart rate (c) at each timepoint compared between the early response group (N = 47) and the late response group (N = 32). The medians are indicated by the horizontal lines inside the boxes with the interquartile range indicated by the bottom and top of the boxes. The minimum and maximum values are shown as the small horizontal lines below and above the boxes. Statistical analysis was performed using Student’s t-test or the Wilcoxon rank-sum test: *p-value < 0.05.
When the patient baseline characteristics were compared between the two groups (Table 1), the early response group had a significantly higher proportion of patients with cerebrovascular diseases and brain trauma, while patients with brain tumors were more prevalent in the late response group (p = 0.04). In addition, the radiographic findings showed a significantly higher proportion of patients with tumor lesions in the late response group (53.1%) than in the early response group (29.8%) (p = 0.04). However, the multivariable analysis did not indicate statistically significant predictive factors associated with early BP control (Supplementary Table 1).
During labetalol administration with a mean cumulative dose of 492 mg (ranging from 5 mg to 3960 mg), adverse events occurred in 18 patients (22.8%); hypotension was observed in 11 patients (13.9%), followed by bradycardia in 8 patients (10.1%). One patient experienced hypotension and bradycardia at cumulative doses of 230 mg and 570 mg, respectively. Other patients experienced only one adverse event. The median cumulative dose in the non-adverse event group (n = 61) was not significantly different from that in the adverse event group (n = 19) (180 vs. 230 mg). In addition, when the cumulative dose was categorized as ≤ 300 mg or > 300 mg, there was no statistically significant difference in the rate of adverse events between the two groups (57.9% vs. 42.1%).
There were no significant factors related to the risk of overall adverse events (Supplementary Table 2). However, when individual adverse events were examined using multivariable logistic regression, the results showed that the occurrence of hypotension during labetalol infusion was significantly related to patient age (p = 0.04) and motor impairment (p = 0.02), while bradycardia was significantly associated with diabetes mellitus (DM) (p = 0.03) (Table 2). Only patient age exhibited a significant association with the risk of hypotension in both the univariable and multivariable analyses (p = 0.04 for both). Based on the receiver operating characteristic curve analysis, the optimal cut-off point for age of patients who were likely to experience hypotension was 60 years, which yielded 72.7% sensitivity (95% confidence interval (CI): 39.0–94.0) and 63.8% specificity (95% CI: 51.3–75.0).
Factors associated with hypotension and bradycardia observed during continuous infusion of labetalol in neurosurgical patients.
CI: confidence interval, OR: odds ratio, aOR: adjusted odds ratio.
The radiographic findings showed one of the following: brain compression, brain edema, or midline shift.
Surgical procedure refers to supratentorial surgery and infratentorial surgery.
Significance level of 0.05.
Discussion
BP control is crucial in neurosurgical patients to prevent postoperative complications, which can lead to unfavorable outcomes. Our results demonstrated that continuous infusion of labetalol effectively controlled BP in a relatively short period, with a median time of 1 hour for all patients.20,21 In addition, a previous retrospective study revealed an average time of 24 minutes to achieve the target BP after continuous infusion of labetalol in acute stroke settings. 14
Interestingly, we observed considerable variation in the time required to achieve the target BP in this patient population, with some patients achieving the target BP within 30 minutes, while others required up to 12 hours after introduction of continuous labetalol infusion. This observation highlights the heterogeneity in response to labetalol, which may be attributed to several factors, such as the characteristics of patients or neurologic conditions.
In our study, we found that the type of brain pathology may be associated with the efficacy of continuous infusion of labetalol. Specifically, we observed a significantly higher proportion of patients diagnosed with cerebrovascular diseases and brain trauma in the early response group. This finding highlights that continuous labetalol infusion may have some advantages in achieving a rapid response when administered to patients with these conditions. However, the presence of brain tumors was significantly associated with a late response to the treatment. Nevertheless, it is important to note that the influence of other confounding variables was not adjusted in this finding.
To adjust for confounding variables, we conducted a multivariable logistic regression analysis to identify significant predictive factors associated with early BP control. The results did not reveal any significant factors that were associated with early BP control in our patient population. Nonetheless, other interesting factors were revealed that should be further investigated. For instance, having a past history of stroke was identified as a significant factor associated with failure to achieve the target SBP within 30 minutes in a previous study. 22 It should be noted that this finding was derived from two antihypertensives (labetalol and nicardipine) and has not been investigated in the context of continuous infusion of labetalol as a monotherapy.
The rate of adverse events that occurred in our study (22.8%) was similar to that in previous studies, ranging from 15% to 36.5%.14,17 In addition, we did not find a significant relationship between the cumulative dose of labetalol and the occurrence of adverse events. These results are consistent with previous studies that have reported that high-dose labetalol infusion was well tolerated by patients, with mean total doses ranging from 829 to 996 mg.14,15,17
Hypotension and bradycardia were common adverse events associated with intravenous labetalol administration, as in previous reports. Hypotension occurred in 3% to 15% of stroke patients, while 14% to 22% of these patients experienced bradycardia when intravenous labetalol was administered.14,15,23,24 We observed a similar rate of hypotension (13.9%) and a lower rate of bradycardia (10.1%) in the neurosurgical patients in this study during labetalol infusion.
Our analysis showed that increasing age resulted in a higher risk of hypotension. Age-related differences in the response to labetalol treatment have been noted in previous studies. Labetalol treatment led to a greater reduction in BP in older hypertensive subjects than in younger subjects. 25 Moreover, drug clearance was reduced in older patients, potentially leading to a greater antihypertensive effect of labetalol in this age group. 26 With respect to the optimal cut-off point of age, labetalol infusion appears to be a safe option for managing BP in neurosurgical patients aged 60 years or younger, with a minimal risk of hypotension.
It is essential to acknowledge that the wide 95% CIs observed in the multivariable analysis introduced limitations for deriving definitive conclusions regarding the relationships between motor impairment and DM with hypotension and bradycardia, respectively. Nevertheless, these findings did provide valuable insights into the potential trends and factors that might influence the occurrence of these adverse events. In the case of motor deficit, the increased risk of hypotension might be related to autonomic dysfunction as previously described. 27 The sympathetic hypoactivity presented in these patients may lead to an increased vulnerability to hypotensive events. During labetalol infusion, patients with DM seem to have a higher risk of bradycardia. This information suggests that diabetic patients with continuous infusion of labetalol should be carefully monitored for bradycardia.
The strength of this study is that we focused on labetalol use in real neurosurgical practice, an area with limited published information. Our findings have implications for clinical practice in similar contexts. However, there are some limitations that should be considered. First, the retrospective study design has the potential for selection bias and limited ability to control potential confounders. However, our study aimed to investigate the efficacy and safety of continuous labetalol infusion within our specific patient population. Second, we did not evaluate the long-term efficacy and safety of continuous infusion of labetalol for HT management. We recommend that future studies conduct a prospective multicenter approach to provide more comprehensive evidence.
Conclusion
Continuous infusion of labetalol is a promising treatment option for managing BP in neurosurgical patients, especially those with cerebrovascular pathologies or brain trauma conditions, because of patients being able to rapidly achieve target BP levels. Our findings demonstrate that labetalol was well tolerated in the study population, with no significant increase in adverse events associated with cumulative dose escalation. Instead, we identified older age, motor impairment, and pre-existing DM as potential risk factors for hypotension and bradycardia that occurred during labetalol infusion. This information provides growing evidence regarding the efficacy and safety profile of labetalol infusion in the context of neurosurgical care.
Supplemental Material
sj-pdf-1-imr-10.1177_03000605231212316 - Supplemental material for Safety and efficacy of continuous intravenous labetalol for blood pressure control in neurosurgical patients
Supplemental material, sj-pdf-1-imr-10.1177_03000605231212316 for Safety and efficacy of continuous intravenous labetalol for blood pressure control in neurosurgical patients by Raywat Noiphithak, Gahn Duangprasert, Sasikan Sukhor, Pichayaphong Durongkaweroj Vich Yindeedej in Journal of International Medical Research
Footnotes
Author contributions
All authors contributed to the study conception and design. Material preparation and data collection were performed by Gahn Duangprasert, Sasikan Sukhor, and Pichayaphong Durongkaweroj. Data analysis was performed by Raywat Noiphithak. The first draft of the manuscript was prepared and edited by Raywat Noiphithak and Vich Yindeedej. All authors reviewed and approved the final manuscript.
Declaration of conflicting interest
The authors declare that there is no conflict of interest.
Funding
This study was funded by the Great Eastern Drug Company, Thailand, which also provided financial support for the journal’s publication fee. The company was not involved in any other aspect of the study, including the study design, data collection, data analysis, or presentation of results.
References
Supplementary Material
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