Effects of nitroglycerin versus labetalol on peripheral perfusion during deliberate hypotension for sinus endoscopic surgery: a randomized, controlled, double-blinded trial

Controlled hypotension is commonly used during functional endoscopic sinus surgery (FESS) to ensure a bloodless operative field. The main risk in controlled hypotension is impaired peripheral perfusion and subsequent ischemia of vital organs [1, 2]. A target mean arterial pressure (MAP) of 50–65 mmHg has been considered sufficient to achieve acceptable surgical conditions [1]. However, the use of blood pressure as the only hemodynamic target is not sufficient to ensure proper oxygen delivery to different organs, which is the main goal of cardiac output. Because monitoring of vital organ perfusion requires either sophisticated or invasive equipment, the use of deliberate hypotension has been limited by the fear of unmonitored ischemia of vital organs. Monitoring of blood flow in non-vital organs (such as the skin) has been considered to be a good alternative for assessment of the impact of deliberate hypotension on tissue perfusion. Peripheral perfusion of non-vital organs is usually impaired earlier than vital organs [3]; therefore, evaluation of perfusion of non-vital organs is considered to be an adequate measure of patient safety during anesthesia [4]. Furthermore, the development of simple non-invasive measures, such as pulse oximetry-derived peripheral perfusion index (PPI), has provided effective and easy measures for tissue perfusion [3]. Recently, PPI has been reported to be a useful hemodynamic measure during anesthesia [4]. Thus, we hypothesized that monitoring PPI would be a useful tool for evaluating the safety of deliberate hypotension. Serum lactate is another frequently used marker of global tissue perfusion in the operating room as well as the intensive care unit [3].

Nitroglycerin and labetalol are commonly used drugs for controlled hypotension during anesthesia. Both drugs are also used for acute management of emergent hypertension in emergency departments. Nitroglycerin is a direct vasodilator and its main action is through venodilation. Labetalol combines an α1 blocking effect and beta-adrenergic blocking activity to reduce systemic vascular resistance, with little effect on cardiac output [5, 6]. Both drugs were previously compared during controlled hypotension with regard to surgical field quality and blood loss [6‐9]. To date, however, no study has compared the effects of both drugs on peripheral perfusion.

The aim of this study, therefore, was to compare the impact of nitroglycerin and labetalol on peripheral perfusion when used for induction of deliberate hypotension during FESS. We evaluated peripheral perfusion using PPI and serum lactate levels as markers of peripheral and global tissue perfusion.

This randomized, double-blinded, parallel study was conducted at Cairo University Hospital (Cairo, Egypt) after receiving approval (N-53-2016) from the Research Ethics Committee, Faculty of Medicine, Cairo University. Written informed consent was obtained from all participants before enrollment.

Forty adult patients 18–45 years of age, with American Society of Anesthesiologists physical status I-II and scheduled for FESS, were included. Individuals with uncontrolled hypertension, cerebrovascular disorders, coagulation disorders, cardiovascular diseases, renal impairment, liver impairment, and history of allergic reaction to any of the study medications were excluded from the study.

An online randomization program (http://​www.​randomizer.​org) was used by a research assistant to generate random sequences. Each code was enclosed in a sealed opaque envelope. Another research assistant, who was not involved in outcome assessment, was responsible for opening the envelope and preparing the study drug. Patients were allocated before induction of anesthesia into either the nitroglycerin (n = 20) or labetalol (n = 20) group. The patient, attending anesthesiologist, and surgeon were blinded to the study group allocation.

Forty-five patients, recruited from January to May 2019, were screened for eligibility in this study. Two patients did not meet the inclusion criteria, three declined to participate, and 40 were randomly assigned to receive one of the two interventions. All patients completed the intervention and data were available for final analysis (Fig. 1). Patient characteristics and operative data were comparable between the study groups; with the exception of time to reach target SFS, which was lower in the labetalol group (Table 1). The mean nitroglycerin infusion rate and total infused dose were 1.7 ± 0.3 μg/kg/min and 13.9 ± 3.5 mg, respectively. Furthermore, the mean labetalol infusion rate and total infused dose were 0.8 ± 0.2 mg/kg/h and 98.7 ± 19.7 mg, respectively. No patient in either group required doses of rescue atropine or ephedrine.

Mean arterial pressure was comparable between the study groups at most of the time points (Fig. 2). Heart rate was lower in the labetalol group compared to the nitroglycerin group starting from 90 min until 135 min after induction of anesthesia (Fig. 3). The PPI was higher in the nitroglycerin group than in the labetalol group at nearly all records (Fig. 4). Postoperative serum lactate levels were modestly lower in the nitroglycerin group than in the labetalol group (Table 1).

SFS was modestly lower in the first 20 min after drug infusion in the labetalol group compared with the nitroglycerin group. Subsequent SFS values in both groups were acceptable (< 3) until the conclusion of surgery (Table 2). Intraoperative blood loss was comparable in both groups (Table 1).

Results of our study revealed that nitroglycerin-induced deliberate hypotension was associated with more preserved PPI compared with labetalol-induced deliberate hypotension. Both study drugs provided acceptable surgical conditions; however, nitroglycerin infusion appeared to be safer in terms of peripheral tissue perfusion. We also found that using nitroglycerin for induction of controlled hypotension did not impair peripheral tissue perfusion.

There are two possible mechanisms that may account for the superiority of peripheral perfusion in nitroglycerin compared to labetalol. 1. Administration of vasodilator drugs improves microcirculatory blood flow by increasing precapillary inflow pressure [12, 13]. 2. Nitroglycerin is a vasodilator with specific effects on peripheral perfusion dynamics. It acts on the venous capacitance vessels, resulting in a decrease in venular outflow pressure, with further increase in pressure gradient in the microvascular bed. This may favor an increase in microvascular blood flow and microcirculatory recruitment [14]. On the other hand, Labetalol acts as an antagonist of α1 and β-adrenergic receptors at a ratio of 1:7 on intravenous administration; thus, it is considered to be a beta-blocker with some alpha-blocking activity [5, 8]. This explanation is supported by the positive effects of nitroglycerin infusion on microvascular flow in patients with septic shock [12, 13] and those with circulatory shock [14]. Furthermore, nitroglycerin-induced controlled hypotension was not associated with reduction in cerebral oxygen saturation or postoperative cognitive function [15].

We evaluated tissue perfusion using the oximetry-derived PPI. PPI is characterized as a non-invasive, real-time measure that increases during vasodilatation [16], and decreases during sympathetic stimulation and impaired peripheral perfusion [17, 18]. Moreover, parameters for evaluation of peripheral perfusion in the skin, including PPI, are increasingly being recommended as useful measures for body perfusion [19, 20]. PPI is used as an indicator of peripheral perfusion in intensive care units [20, 21] and operating theaters [4, 22]. A recent study reported that monitoring PPI reflects changes in systemic hemodynamics during general anesthesia in a setting of changing preload conditions [4]. We used the PPI for real-time monitoring of the peripheral perfusion while we measured the serum lactate at only two points because it is a slowly changing perfusion marker which is usually measured at 6-h intervals [3].

Nitroglycerin and labetalol were previously compared in achieving deliberate hypotension [6‐9]. However, the results of previous studies did not totally favor one drug over the other. Our study revealed that SFS values were modestly lower in the labetalol group in the first 10 min; however, the median SFS in the nitroglycerin group at 20 min was 2 (IQR 2–2.5), which is sufficient for good field quality. The subsequent SFS values were comparable in both groups until the end of the operation. In our patients, we found that the nitroglycerin group exhibited a higher heart rate in some intraoperative periods, while heart rate was comparable between the groups in most of the other readings. El-Shamma et al. and Hadavi et al. reported that nitroglycerin infusion was associated with more prominent reflex tachycardia compared with labetalol [6, 8]. The difference between our results and those reported by El-Shamma et al. and Hadavi et al. may be due to the higher dose of nitroglycerin or the larger sample sizes of their studies [6, 8].

The “art” of hypotensive anesthesia is to achieve proper surgical conditions without suppressing perfusion of vital organs [1]. The risk for impairment of tissue perfusion has been the primary concern that limits the use of deliberate hypotension [23]. However, in our patients, we found that PPI did not decrease in the nitroglycerin group throughout the operation, despite the low blood pressure. Furthermore, serum lactate concentration was not significantly elevated in both groups. Therefore, we believe that deliberate hypotension should not be considered a state of circulatory shock. We assume that, under well-monitored peripheral perfusion, nitroglycerin could be a good choice to induce controlled hypotension if it is surgically indicated.

There were several limitations to our investigation, the first of which was that it was a single-center study. Second, we induced hypotension in only one type of surgery; thus, our findings with regard to surgical field may differ in other procedures. Third, our patients received the available drugs (i.e., isoflurane and fentanyl) in our hospital; the impact of study drugs in peripheral perfusion with other agents, such as sevoflurane and remifentanil, may require further research. Fourth, our findings are restricted to patients with no serious comorbidities. Finally, although we demonstrated that deliberate hypotension did not impair peripheral perfusion under the conditions of our study, more studies aimed at evaluating the effect of deliberate hypotension on the perfusion of vital organs are warranted.

Nitroglycerin-induced deliberate hypotension was accompanied by higher PPI and lower serum lactate levels compared with labetalol-induced deliberate hypotension during sinus endoscopic surgery.