Reversal of Neuromuscular Blockade in Thoracic Surgical Patients
Condition: Residual Neuromuscular Blockade
MeSH terms: Delayed Emergence from Anesthesia
Study type: Observational

Summary: 
      The majority of patients undergoing surgery receive neuromuscular blocking agents (NMBAs) in
      the operating room. Reversal of neuromuscular blockade at the conclusion of a general
      anesthetic is accomplished with cholinesterase inhibitors (primarily neostigmine). Although
      these drugs are often effective in enhancing recovery of muscle strength, the onset of effect
      is often slow (usually 15-30 minutes). More effective neuromuscular reversal agents are
      needed in clinical practice to enhance surgical and anesthetic management of perioperative
      patients. A new reversal agent (sugammadex) will likely be approved for clinical use in the
      United States next year. Unlike neostigmine, sugammadex is effective in providing rapid
      antagonism of all levels of neuromuscular blockade (typically within 2-4 minutes). The aim of
      this prospective observational study is to study neuromuscular and clinical recovery in 100
      consecutive thoracic surgical patients receiving neostigmine, followed by a 100 consecutive
      thoracic surgical patients administered sugammadex (after the drug is approved by the FDA).
      In addition, after data on 100 patients reversed with neostigmine is collected, the data will
      be analyzed to compare patients with residual block (train-of four < 0.9) and without
      residual block (TOF </= 0.9)
    

Detailed description: 
      Patients undergoing thoracic surgical procedures receive a general anesthetic in the
      operating room. As part of this general anesthetic, patients are administered a neuromuscular
      blocking agent (NMBA or muscle relaxant). NMBAs are used to facilitate placement of
      endotracheal tubes (breathing tubes), provide muscle relaxation during surgery, and prevent
      patient movement. Most thoracic surgeons request deep levels of muscle relaxation during
      operative procedures. In particular, deeper levels of neuromuscular blockade are required to
      prevent movement of the diaphragm (diaphragmatic contractions can interfere with the surgical
      procedure).

      Muscle contraction occurs when the neurotransmitter acetylcholine binds to the postjunctional
      nicotinic acetylcholine receptor (nAChR). Non-depolarizing NMBAs inhibit neuromuscular
      transmission primarily by competitively antagonizing or blocking the effect of acetylcholine
      at the postjunctional nAChR. When high enough concentrations of NMBAs are present, binding to
      the nAChR occurs, thus preventing acetylcholine from activating the receptor. Binding of
      NMBAs to the nAChR occurs in a competitive fashion. If higher concentrations of acetylcholine
      are present at the neuromuscular junction, acetylcholine will attach to the postsynaptic
      receptor and facilitate neuromuscular transmission and muscle contraction. Conversely, if
      higher concentrations of nondepolarizing NMBAs are present at the neuromuscular junction,
      binding to the nAChR will preferentially occur, preventing muscle depolarization from
      occurring.

      The effects of NMBAs must be reversed at the end of surgery. One mechanism of antagonizing
      the effects of NMBAs is to increase the concentration of acetylcholine at the neuromuscular
      junction. This can be accomplished using an anticholinesterase drug which inhibits the enzyme
      which breaks down acetylcholine at the neuromuscular junction (acetylcholinesterase). The
      anticholinesterase drug which is most commonly used to reverse neuromuscular blockade is
      neostigmine. At NorthShore University HealthSystem, all patients receiving a NMBA are
      reversed with neostigmine at the conclusion of the surgical procedure. There are two
      important limitations of anticholinesterase reversal agents, which are related to their
      mechanism of action as described above. First, onset of action is slow. In the presence of
      mild degrees of muscle relaxation (four responses to train-of-four (TOF) nerve stimulation
      with a peripheral nerve stimulator, also known as a TOF count of 4), adequate reversal of
      NMBAs takes approximately 10-15 minutes. However, in the presence of deeper neuromuscular
      block (one response to TOF nerve stimulation, or TOF count of 1), complete reversal takes on
      average 30-60 minutes. Second, profound neuromuscular blockade cannot be antagonized. If no
      evidence of neuromuscular recovery is present at the end of surgery (no response to
      peripheral nerve stimulation or a TOF count of 0), reversal agents are ineffective. In this
      situation, the concentration of the NMBA at the neuromuscular junction is too high (NMBA will
      preferentially bind to the nAChR over acetylcholine, and inhibition of acetylcholinesterase
      cannot raise levels of acetylcholine enough to competitively antagonize the NMBA).

      Despite the routine reversal of muscle relaxants in the operating room, patients often arrive
      in the post anesthesia care unit (PACU) with evidence of residual muscle weakness (termed
      residual neuromuscular blockade). Traditionally, residual neuromuscular blockade has been
      measured and defined using quantitative neuromuscular monitoring devices. These devices use
      electrical energy to stimulate the ulnar nerve; four stimuli are provided, and the response
      to nerve stimulation at the thumb measured. The ratio of the fourth contraction is compared
      to the first contraction to generate a TOF ratio (from 0-1.0 or 0-100%). Recent data suggests
      that TOF ratios must recover to > 0.9 to exclude clinically significant residual
      neuromuscular blockade. A number of clinical studies have demonstrated that approximately 40%
      of patients given NMBAs in the operating room have objective evidence of muscle weakness (a
      TOF ratio < 0.9) on admission to the PACU. It is likely that the incidence of residual
      neuromuscular blockade is higher in thoracic surgical patients, since deeper levels of
      neuromuscular blockade are required. However, no previous studies have specifically
      investigated this patient population.

      The presence of residual muscle weakness at the end of surgery, following tracheal extubation
      (removal of the breathing tube), has been associated with a number of adverse postoperative
      events. Patients with TOF ratios < 0.9 on admission to the PACU are at higher risk for
      potentially life threatening airway events, including hypoxemia (low oxygen saturation),
      airway obstruction, and postoperative pulmonary complications. In addition, patients with TOF
      ratios < 0.9 often experience unpleasant symptoms of muscle weakness, such as blurry vision,
      difficultly speaking and swallowing, and general weakness. Patient-perceived quality of
      recovery from anesthesia and surgery is also significantly lower in patients admitted to the
      PACU with TOF ratios < 0.9. Studies have also demonstrated that patients with TOF ratios <
      0.9 take significantly longer to reach discharge criteria from the PACU, and achieve actual
      PACU discharge.

      Improved management of neuromuscular blockade in the operating can beneficially impact both
      the incidence of residual neuromuscular blockade, as well as complications associated with
      incomplete neuromuscular recovery. For example, the use of quantitative neuromuscular
      monitoring, by allowing a more rational titration of NMBAs intraoperatively, has been
      demonstrated to reduce the risk of admission to the PACU with a TOF ratio < 0.9. Furthermore,
      the risk of hypoxemic events, airway obstruction, and unpleasant symptoms of muscle weakness
      is diminished with quantitative monitoring.

      Another potential method of reducing the risk of residual neuromuscular blockade, and the
      complications associated with residual blockade, is through the use of a new class of NMBA
      reversal agent. Sugammadex is a recently developed antagonist of steroidal NMBAs that acts
      via a different mechanism than the anticholinesterase agents. Sugammadex (Org 25969) is a
      modified γ-cyclodextrin and the first selective relaxant binding agent based on an
      encapsulating principle for inactivation of a neuromuscular blocking agent. Sugammadex is a
      cylindric compound with a lipophilic cavity and a hydrophilic exterior. This structure allows
      the drug to take up lipophilic molecules in its core; sugammadex rapidly encapsulates
      steroidal NMBAs like rocuronium that are present in the circulation. Rapid encapsulation of
      rocuronium in the intravascular compartment results in a gradient which draws rocuronium away
      from the neuromuscular junction (where it is also immediately encapsulated). This principle
      for reversal of rocuronium- and vecuronium-induced neuromuscular block was first introduced
      into clinical practice in 2008 and is now available for pediatric and adult anesthesia in a
      majority of countries world-wide. The complex formation of sugammadex and rocuronium or
      vecuronium occur at all levels of neuromuscular block (profound - shallow) and displays a
      more rapidly-acting pharmacological profile as opposed to anticholinesterases for reversal of
      effect. When appropriate dosing of sugammadex is used, all levels of neuromuscular blockade
      can be reversed (TOF ratio > 0.9) within 2-4 minutes. Consequently, sugammadex may have the
      potential to markedly reduce postoperative residual neuromuscular block in the PACU. In
      addition, sugammadex may also reduce the incidence of adverse events related to incomplete
      neuromuscular recovery. Sugammadex has been extensively investigated in a large number of
      clinical trials and has been demonstrated to be significantly more effective and rapid in
      reversing all levels of neuromuscular block, when compared to neostigmine. At the present
      time, the safety profile of sugammadex appears similar to neostigmine, in both clinical
      trials and in world-wide usage (over 4 million uses, per manufacturers report).

      Sugammadex may offer several potential advantages in patients undergoing thoracic surgery.
      Deep levels of neuromuscular blockade can be maintained until the end of the procedure, which
      may facilitate the performance of the surgery. Sugammadex is effective in reversing deep
      levels of blockade (even at a TOF count of 0 or "no twitches"), whereas neostigmine cannot
      antagonize deep blockade. In addition, the time in the operating room may be shortened. It is
      not uncommon for tracheal extubation to be delayed in this patient population due to the slow
      onset of effect of neostigmine when moderate levels of neuromuscular block are present at the
      time of reversal (TOF count of 1-3). Furthermore, patient recovery may be enhanced in the
      PACU if the incidence of residual block is reduced with sugammadex. The aim of this
      prospective observational investigation is to examine the effect of sugammadex (versus
      neostigmine) on recovery following thoracic surgery. In addition, after data on 100 patients
      reversed with neostigmine is collected, the data will be analyzed to compare patients with
      residual block (train-of four < 0.9) and without residual block (TOF </= 0.9) The primary
      outcome variable will be the incidence of residual block (measured with quantitative
      neuromuscular monitoring) at the time of PACU admission. Secondary outcome measures will
      include the incidence of residual block at tracheal extubation, the time from surgical
      closure until tracheal extubation, the frequency of adverse respiratory events in the PACU,
      the presence or absence of symptoms and signs of postoperative muscle weakness, and length of
      stay in the operating room and PACU.
    

Intervention name(s): Neostigmine; Sugammadex
Intervention type(s): Drug; Drug
Intervention description(s): At the conclusion of the surgical procedure, neuromuscular block will be reversed with neostigmine; At the conclusion of the surgical procedure, neuromuscular block will be reversed with sugammadex
Intervention MeSH terms: Neostigmine
Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        200 patients presenting for elective thoracic surgical procedures with an expected duration
        greater than 45 minutes will be enrolled in this study. The study is designed as a "before
        and after" investigation of sugammadex (data will be collected on 100 consecutive patients
        before sugammadex is approved by the FDA for clinical care in the United States
        (neostigmine used), and on 100 consecutive patients after sugammadex is approved). In
        addition, after data on 100 patients reversed with neostigmine is collected, the data will
        be analyzed to compare patients with residual block (train-of four < 0.9) and without
        residual block (TOF </= 0.9)
      
Keywords: residual neuromuscular blockade, sugammadex, neostigmine, thoracic surgery