Deep Neuromuscular Block With Pipecuronium in Patients Undergoing Robotic Thoracic Surgery

The increasing adoption of robotic technology has substantially changed the surgical management of patients across a growing range of specialties. Thoracic surgery has also increasingly incorporated robot-assisted techniques, which offer several technical advantages over conventional approaches. The surgeon operates from a console using a three-dimensional image and highly articulated robotic instruments capable of extensive movement, including a 360-degree range of motion. Although these characteristics facilitate precise surgical manipulation, they also create specific requirements for intraoperative anesthesia management.

One of the most important anesthetic considerations during robot-assisted thoracic procedures is the prevention of unintended patient movement. Because the robotic instruments are controlled remotely from the surgical console, even relatively small patient movements may interfere with the operative field and, under certain circumstances, may result in tissue or organ injury. Consequently, profound and stable neuromuscular relaxation is particularly important during these procedures. Adequate neuromuscular blockade also produces relaxation of the respiratory musculature, including the diaphragm and chest wall muscles, which may contribute to favorable surgical exposure and visualization.

The use of neuromuscular blocking agents is an established component of anesthesia for procedures involving major body cavities. However, the requirements of robotic surgery make precise control of the depth of neuromuscular blockade particularly relevant. The anesthesiologist must provide sufficient relaxation throughout the critical phases of the operation while avoiding unnecessarily prolonged residual neuromuscular blockade after completion of surgery. This balance is especially important when long-acting neuromuscular blocking agents are used.

Pipecuronium bromide (Arduan®) is an aminosteroid neuromuscular blocking agent developed in Hungary. It is characterized by a relatively long duration of action, reported to be approximately 45-100 minutes. According to the study background, pipecuronium has no relevant cardiovascular adverse effects and does not cause histamine release. Its elimination occurs predominantly through the liver and, to a lesser extent, through the kidneys. The available literature has not reported anaphylactic reactions to pipecuronium to date. These characteristics have traditionally made the drug suitable for prolonged surgical procedures and for use in intensive care. Pipecuronium is also currently the only long-acting neuromuscular blocking agent available in Hungary.

The prolonged action of pipecuronium does not necessarily conflict with contemporary enhanced recovery after surgery (ERAS) principles. Rather, its use requires an approach in which the depth of neuromuscular blockade is objectively measured throughout the procedure and adjusted according to the requirements of the surgical intervention. At the conclusion of surgery, complete pharmacological reversal must be demonstrated before extubation. Thus, the principal issue is not simply the duration of action of the neuromuscular blocking agent, but whether its effect can be adequately controlled, monitored, and reversed in a predictable manner.

Quantitative neuromuscular monitoring is therefore a central component of the proposed anesthetic strategy. At the Department of Anesthesiology and Intensive Care, TetraGraph Sensyme has been routinely implemented in all operating rooms since 2023. The device provides electromyographic assessment of neuromuscular function and enables objective monitoring of both the development and recovery of neuromuscular blockade. Such monitoring is particularly relevant when potent, long-acting neuromuscular blocking agents are administered, because clinical assessment alone cannot reliably exclude residual paralysis.

A further component of the proposed strategy is the use of sugammadex for reversal. Sugammadex (Bridion®) is a cyclodextrin-based antagonist of steroidal neuromuscular blocking agents. It binds these compounds in the plasma and thereby facilitates the rapid reduction of their pharmacologically active concentration. Pipecuronium, as an aminosteroid neuromuscular blocking agent, can therefore be antagonized with sugammadex at effective doses.

The combination of a long-acting neuromuscular blocking agent, quantitative monitoring, and pharmacological reversal creates the basis for investigating whether deep pipecuronium-induced neuromuscular blockade can be incorporated into an ERAS-oriented anesthetic pathway for robot-assisted thoracic surgery. The present protocol focuses specifically on the feasibility of establishing and maintaining deep neuromuscular blockade and on objectively assessing the subsequent recovery following sugammadex administration.

Study objective

The primary objective of the study is to investigate the establishment and maintenance of deep neuromuscular blockade using pipecuronium bromide during robot-assisted thoracic surgery and to characterize the subsequent reversal of this blockade with sugammadex.

A further objective is to demonstrate the practical applicability of continuous quantitative neuromuscular monitoring during the entire perioperative course. Particular attention is given to the use of post-tetanic count (PTC) during deep blockade and to serial train-of-four (TOF) measurements during recovery. This approach is intended to provide objective information about the depth of neuromuscular blockade and the time course of its reversal.

The study also evaluates whether the proposed strategy can provide conditions compatible with the requirements of robotic thoracic surgery while allowing reliable restoration of neuromuscular function before tracheal extubation. An additional exploratory assessment concerns the surgeon's subjective evaluation of the operative visual field.

Anesthetic management

The anesthetic protocol is based on total intravenous anesthesia. In the institutional practice described in the study protocol, induction is performed using propofol administered through a target-controlled infusion system according to the Schneider effect-site model. Remifentanil is administered by TCI using the Minto effect-site model. Premedication consists of intramuscular midazolam and atropine.

After preoxygenation, propofol is administered at a concentration of 2 mg/mL using TCI, followed by remifentanil at a concentration of 20 μg/mL. Pipecuronium bromide is then administered intravenously at a dose of 0.08-0.1 mg/kg, corresponding to approximately twice the ED95. Following tracheal intubation, an air/oxygen mixture is used for ventilation, with SIMV pressure-controlled ventilation specified in the protocol.

During maintenance of anesthesia, propofol and remifentanil are continued using infusion pumps. Neuromuscular blockade is managed according to quantitative neuromuscular monitoring rather than according to a fixed redosing interval. Once a PTC value of 5 is observed, an additional dose of 0.01-0.02 mg/kg pipecuronium is administered. This strategy allows the depth of neuromuscular blockade to be maintained according to an objectively measured pharmacodynamic endpoint.

Quantitative neuromuscular monitoring

Neuromuscular monitoring is initiated after induction and is continued throughout the surgical procedure. The protocol follows international recommendations for quantitative assessment of neuromuscular function. The TetraGraph Sensyme system is used for electromyographic monitoring.

TetraGraph measures the compound muscle action potential generated following peripheral nerve stimulation. In the study protocol, the ulnar nerve is stimulated and the response of the adductor pollicis muscle is recorded. Following preparation and degreasing of the skin, the stimulation electrodes are positioned on the volar aspect of the wrist along the course of the ulnar nerve, while the recording electrode is positioned in the region of the adductor pollicis muscle.

Before administration of the neuromuscular blocking agent, the system performs an autocalibration procedure. During this process, the device establishes the supramaximal stimulation current required to produce a reproducible muscle response. This calibration is important because quantitative assessment of neuromuscular function depends on reliable stimulation and recording conditions.

The principal stimulation pattern used for routine assessment is the train-of-four (TOF). Four electrical stimuli are delivered sequentially, and the number of detectable muscular responses is expressed as the TOF count (TOFC), ranging from 0 to 4. When all four responses are present, the TOF ratio (TOFR) is calculated as the amplitude of the fourth response (T4) divided by that of the first response (T1). The TOF ratio may be reported either as a decimal value or as a percentage.

The progression of pipecuronium-induced neuromuscular blockade can be followed using these parameters. As neuromuscular transmission becomes progressively inhibited, the fourth response is affected first, resulting in a reduction of the TOF ratio. With increasing blockade, individual responses disappear sequentially, ultimately resulting in a TOF count of zero. During recovery, the process occurs in the opposite direction, with successive responses reappearing and the TOF ratio progressively increasing.

For the purposes of the study, recovery of neuromuscular transmission is considered to have occurred when the TOF ratio reaches at least 0.9. Objective documentation of this endpoint is particularly important before extubation because the absence of obvious clinical signs of weakness does not reliably exclude residual neuromuscular blockade.

Assessment of deep neuromuscular blockade

A conventional TOF stimulus is insufficient to quantify the depth of a profound neuromuscular block when no response can be elicited. For this reason, the protocol incorporates post-tetanic count measurements during deep blockade.

PTC is performed at five-minute intervals. The technique consists of a 5-second tetanic stimulation at a frequency of 50 Hz, followed by 20 single stimuli delivered at 1 Hz. Tetanic stimulation increases acetylcholine release at the neuromuscular junction and produces post-tetanic facilitation. This transient increase in neuromuscular transmission may make it possible to detect responses that are absent during conventional TOF stimulation.

The number of post-tetanic responses provides information about the depth of the block. In an extremely profound block, no response may be detectable even after tetanic stimulation. As the effect of the neuromuscular blocking agent begins to diminish, post-tetanic responses become detectable, with PTC values potentially ranging from 1 to 20. Thus, PTC provides a quantitative framework for distinguishing different levels of deep neuromuscular blockade when TOF count remains zero.

Within the proposed anesthetic protocol, a PTC value of 5 serves as the trigger for administration of an additional pipecuronium dose. This permits the depth of blockade to be maintained within a predefined range without relying exclusively on elapsed time or clinical observation.

Reversal of neuromuscular blockade

At the end of the surgical procedure, the residual neuromuscular block is objectively assessed before reversal. In patients with a deep block characterized by TOFC 0 and PTC ≥1, the protocol specifies administration of sugammadex at a dose of 2 mg/kg.

The effect of sugammadex is then assessed quantitatively using repeated TOF measurements at 20-second intervals. The purpose of this high-frequency monitoring during reversal is to accurately determine the time required for restoration of neuromuscular transmission.

The primary pharmacodynamic endpoint is defined as the interval between the beginning of sugammadex administration and achievement of a TOF ratio of 0.9. This threshold represents the predefined criterion for resolution of clinically relevant neuromuscular blockade.

A secondary endpoint is the time from the beginning of sugammadex administration to attainment of a TOF ratio of 1.0. Recording both endpoints provides information not only about the time required to reach the accepted threshold for adequate recovery but also about the subsequent return to complete quantitative normalization of the measured neuromuscular response.

The anesthetic is discontinued once neuromuscular function has recovered. Tracheal extubation is performed only when adequate neuromuscular recovery is accompanied by other standard clinical requirements, including sufficient spontaneous ventilation, an appropriate response to verbal commands, and stable cardiovascular function. This combined approach is intended to prevent extubation in the presence of clinically significant residual neuromuscular blockade.

Surgical conditions and visual field assessment

In addition to the objective neuromuscular endpoints, the protocol includes an ad hoc assessment of the quality of the surgical visual field. This reflects the practical purpose of deep neuromuscular blockade during robotic thoracic surgery: the intervention is not intended solely to produce a measurable pharmacological effect but also to provide stable and favorable operating conditions.

The operating surgeon evaluates the quality of the visual field using a five-point scale based on the methodology described by Baete et al. The scale ranges from 1 to 5, where 1 corresponds to a very poor visual field, 2 to a poor field, 3 to an acceptable field, 4 to a good field, and 5 to an optimal field.

This subjective assessment is incorporated as an exploratory endpoint. It may provide complementary information regarding whether the degree of neuromuscular relaxation achieved with pipecuronium is perceived as sufficient for the technical requirements of robotic surgery.

Data analysis

The statistical analysis is designed to account for the distributional characteristics of the collected variables. Continuous variables are initially subjected to a normality assessment. Depending on the resulting distribution, continuous data are reported either as mean ± standard deviation or as median with interquartile range.

Categorical variables are analyzed using the chi-square test for comparison. The study's principal pharmacodynamic analysis is centered on the time intervals associated with reversal of neuromuscular blockade, specifically the time required to achieve TOF ratios of 0.9 and 1.0 following administration of sugammadex.

The protocol therefore combines descriptive analysis of perioperative and neuromuscular monitoring data with endpoint-based assessment of reversal kinetics. Quantitative TOF and PTC measurements provide the objective physiological variables on which the evaluation of the anesthetic strategy is based.

Ethical and clinical considerations

The study protocol incorporates written informed consent for participation and for processing of medical data. Participation is voluntary, and participants may withdraw their consent at any time without adverse consequences. Both pipecuronium bromide and sugammadex are registered medicinal products in Hungary.

The proposed monitoring strategy does not require additional invasive procedures. Quantitative neuromuscular monitoring represents established clinical practice in anesthesiology and is routinely performed at the participating institution. According to the protocol, the measurements do not prolong anesthesia or increase operating-room time; rather, objective monitoring and rapid confirmation of adequate reversal may potentially contribute to more efficient perioperative management.

Clinical significance

The particular challenge posed by robot-assisted thoracic surgery is the requirement for a stable and highly controlled operative environment. Robotic instruments can perform complex movements with substantial precision, but their interaction with the patient depends on the absence of unintended movement. Consequently, a sufficiently deep neuromuscular block may be advantageous during the critical phases of the operation.

Pipecuronium provides a pharmacological means of maintaining profound neuromuscular relaxation, but its long duration of action has traditionally represented a potential concern when rapid postoperative recovery is desired. The study protocol addresses this issue through continuous quantitative monitoring and planned pharmacological reversal rather than through avoidance of long-acting neuromuscular blockade per se.

The concept underlying the protocol is therefore based on controllability rather than duration alone. A long-acting neuromuscular blocking agent can potentially be incorporated into an ERAS-oriented pathway if its pharmacodynamic effect is continuously measured, additional doses are administered according to objective monitoring, and complete recovery is confirmed before emergence from anesthesia.

The combination of PTC-guided maintenance and TOF-guided reversal provides a continuous framework for managing the neuromuscular block. PTC measurements are used when the block is too profound for conventional TOF assessment, whereas TOF monitoring becomes increasingly informative during recovery. This creates a monitoring continuum extending from profound blockade to complete quantitative recovery.

The use of sugammadex adds a pharmacological mechanism for terminating the effect of pipecuronium at the end of surgery. The study consequently addresses two clinically relevant questions: whether a stable deep block can be maintained throughout robotic thoracic surgery with pipecuronium, and whether the resulting block can subsequently be reversed in a predictable manner using sugammadex.

Conclusion

This study protocol describes an ERAS-oriented strategy for the use of pipecuronium bromide during robot-assisted thoracic surgery. The approach combines deep neuromuscular blockade with continuous quantitative electromyographic monitoring and planned pharmacological reversal.

The protocol uses an initial pipecuronium dose of 0.08-0.1 mg/kg, followed by PTC-guided supplementation with 0.01-0.02 mg/kg when PTC reaches 5. Deep blockade is assessed using serial PTC measurements, while recovery is followed using frequent TOF measurements. In the presence of TOFC 0 with PTC ≥1, sugammadex is administered at 2 mg/kg, and the subsequent recovery of neuromuscular transmission is recorded at 20-second intervals. The principal outcome is the time required to reach a TOF ratio of 0.9, with achievement of TOF ratio 1.0 serving as a secondary endpoint.

The study also incorporates assessment of the surgeon's visual field to determine whether the neuromuscular conditions produced by the protocol provide satisfactory operative conditions.

The central premise of the study is that the long duration of pipecuronium does not necessarily prevent its use within a modern recovery-oriented anesthetic strategy when its effect is continuously measured and actively controlled. In robot-assisted thoracic surgery, where inadvertent patient movement may have important consequences, deep and stable neuromuscular relaxation may provide valuable surgical conditions. At the same time, objective quantitative monitoring and reliable pharmacological antagonism are essential to ensure that the profound intraoperative block does not translate into residual postoperative neuromuscular weakness.

By integrating PTC-based control of deep blockade, TOF-based assessment of recovery, and sugammadex-mediated reversal, the proposed protocol establishes an objectively measurable pathway from induction of profound neuromuscular relaxation to documented recovery of neuromuscular function. The resulting data are intended to provide a basis for evaluating the feasibility of pipecuronium in robot-assisted thoracic surgery and for determining whether a long-acting aminosteroid neuromuscular blocker can be used in a controlled, quantitatively monitored, and ERAS-compatible manner.