Every year more than 20 million patients are affected by post-operative complications related to anesthesia and inadequate perioperative monitoring.
Paralytic drugs are used as an essential adjunct to anesthesia in over 70 million patients per year. Extensive research has shown that inadequate monitoring of these patients can lead to postoperative respiratory complications, the second most common complication following surgery. In a recent clinical study of 100 patients, implementation of quantitative (objective) neuromuscular monitoring was shown to reduce the incidence of postoperative complications by 52%, while completely eliminating the need for emergent tracheal re-intubation. (Todd MM, Anesth Analg 2014).
The most severe complications related to anesthsia are post-operative Critical Respiratory Events (CREs). These life-threatening and costly adverse events are related to anesthesia and inadequate monitoring of neuromuscular paralysis (Thomsen JL, 2015). CREs can lead to major morbidity and mortality, decrease patient satisfaction during recovery from anesthesia and cause excess cost and needless delays in post surgical care. These events are most efficiently avoided by objectively and reliably defining when patients are able to breathe again after surgery without assistance (Todd MM, 2014).
“The incidence of residual neuromuscular block varies widely among studies, with reported frequencies ranging from 2% to 64%” (Murphy GS, 2010a). Unfortunately, millions of patients are affected by post-operative complications due to anesthesia and inadequate perioperative monitoring every year (Murphy GS, 2010a; Brull SJ, 2010b).
CREs can lead to major postoperative morbidity and mortality, decrease patient satisfaction during recovery from anesthesia, and cause increased costs and prolonged hospital length of stay (Murphy GS, 2006). These preventable complications are most efficiently avoided by objectively, reliably and easily defining the appropriate time when patients are able to breathe spontaneously without the aid of artificial ventilation (Brull SJ, 2010b).
Senzime designs and develops perioperative monitoring solutions that help reduce the incidence of post-operative complications and CREs, while at the same time decreasing the actual cost of post-operative care. Senzime’s solutions are developed out of clinical needs by leading, internationally recognized leaders in the field of perioperative medicine, and are based on clinically recognized markers, industry-set standards, and validated and established technology (EMG).
Worldwide, 70 million patients are at risk every year
Senzime’s solutions target the worldwide market in excess of 234.2 million major surgical cases per year (Weiser TG, 2008); of these surgeries, most (172.3 million, or 73.6% of all major surgeries) are performed in middle- and high-expenditure countries such as those of the European Union and the U.S.
In the U.S, a total 51.4 million inpatient (in-hospital) surgeries are performed yearly (www.cdc.gov). Approximately 50% of these surgical procedures in the U.S. require general anesthesia and the use of neuromuscular blocking agents (NMBAs) (Ishizawa Y, 2011). Conservative estimations, based on U.S. data, are that there are an additional 45 million surgical cases requiring the use of NMBAs in the rest of the world, for a total of 70 million surgical cases per year. These estimates are in concordance with the 50 million endotracheal tubes (needed during general anesthesia) sold yearly worldwide (Frost & Sullivan, 2008)(www.EnoxBiopharma.com).
More than 20 million patients are affected by post-operative complications
In 1979, Viby-Mogensen et al. reported that 42% of patients receiving NMBAs and standard doses of reversal agents in the operating room had a TOF ratio <0.7 on arrival to the PACU. Since then, many other clinical studies have reported similar (20-45%) incidence of postoperative neuromuscular weakness (paralysis), impaired oxygenation and breathing difficulties due to residual effects of NMBAs (Baillard C, 2000) (Debaene B, 2003) (Cammu G, 2006). Between 0.8%-6.9% of the patients who suffer from postoperative residual paralysis will experience severe post-operative complications (critical respiratory events, CREs), defined as upper airway obstruction; hypoxemia; signs of respiratory distress or impending ventilatory failure; inability to breathe deeply; need for tracheal reintubation; and clinical evidence of pulmonary aspiration (Eikermann M, 2003)(Murphy GS, 2011)(Hines R, 1992)(Rose DK, 1994).
Complications with costs in excess of $10 billion
Postoperative respiratory complications are the second most common postoperative surgical complications, after wound infection (Dimick JB, 2004), and contribute to a significant financial burden on hospitals and patients. The average surgical cost is $5,015 for patients without respiratory complications, increasing 12-fold to $62,704 for patients who experience respiratory complications. (Kuhri SF, 2005)(Ramachandran sK, 2011)(Smetana GW, 2006)
Critical respiratory events secondary to residual neuromuscular weakness increase PACU and hospital length-of-stay by 33% (Butterly A, 2010), patient dissatisfaction (Murphy G, 2011), and healthcare costs (operating room average charge is $62/min and PACU average charge is $6/min)(Macario A, 2010). Recent studies have also shown that residual weakness is a cause of postoperative aspiration-induced pneumonia in healthy elderly patients (Asai T, 2014).
The average hospital costs related to complications from NMBAs amount to $650,000 per year, excluding direct costs of tracheal re-intubation, additional drugs, increased personnel requirement, etc. For a hospital, this increase in the level of care translates into more than 1800 hours of additional and unnecessary PACU utilization time (or a potential increase of 10% in postoperative patient load).
There is a universally established solution
The only method to reliably and precisely evaluate the level of intraoperative neuromuscular paralysis or ensure adequate neuromuscular function to facilitate spontaneous and unassisted breathing is to assess neuromuscular function by monitoring the train-of-four (TOF) ratio (Baillard C, 2005)(Murphy GS, 2010a)(Brull SJ, 2010b) through peripheral nerve stimulation and recording of muscle responses. TOF pattern of nerve stimulation was introduced in the early 1970s and is a universally established technique.
Data published during the past two decades have demonstrated that residual neuromuscular block is defined whenever the TOF ratio is <0.9 (Murphy GS, 2010a). Most clinicians, however, do not use objective monitoring, partly due to the limitations of the available technology (Naguib M, 2007). There is ample evidence in the literature indicating that failure to use a simple peripheral nerve stimulator to monitor, even subjectively, the degree of paralysis or adequacy of recovery is frequently associated with clinically significant muscle weakness, critical respiratory events, and delays in PACU discharge (Murphy, 2013).
In light of the overwhelming existing evidence that NMBA use is associated with postoperative complications, and that intraoperative objective monitoring markedly reduces these complications, some experts have opined, “It is thus perhaps not surprising that we continue to disregard obvious findings that for decades have shown us repeatedly that residual postoperative weakness from the use of NMBAs is a real patient safety issue. Because we can in most instances “get away” with our clinical assessment and intuition about the state of reversal of our patients, we have little incentive to spend extra resources on purchasing monitors or expend additional time applying the somewhat unwieldy electrodes and wires of the nerve stimulators” (Brull SJ, 2011). However, clinicians must ask whether we are really doing the best for our patients when we cut corners.
Proven clinical benefits, but inadequate technology prevents universal adoption
Meta-analyses have shown that neuromuscular function was monitored in only 24.4% of eligible surgical patients (Naguib M, 2007). The low adoption rate is a function of several factors: most current monitors are cumbersome to use and require >10 min to set up and calibrate correctly; they are very sensitive to external disturbances; the results are often not easy to interpret, since the measured responses are not sufficiently sensitive to residual paralysis; and training and routine use of this monitor are necessary to maintain competency (Viby-Mogensen 2010). In view of the increasing number of national societies (France, Czech Republic, Germany, Australia, United Kingdom, among others) that have developed clinical guidelines for the perioperative monitoring of neuromuscular function Senzime expects that objective neuromuscular monitoring will become a mandated standard of clinical care, similar to the mandates for the perioperative use of oximetry and capnography.
Large-scale Scandinavian studies assessed the impact of residual neuromuscular block on the incidence of postoperative pulmonary complications (Berg H, 1997), and found that even when intraoperative monitoring was used, the incidence of pneumonia and atelectasis in the first 6 postoperative days was three times higher in those patients who had residual weakness in the PACU. More recently, databased studies have demonstrated (again) the association between residual neuromuscular blockade and adverse outcomes.
In an 11-year study of 518,294 anesthetics at Mayo Clinic, 37.5% of cardiac arrests attributable to anesthesia were related to the use of NMBAs (Sprung J, 2003). In a Dutch case-controlled study of over 869,000 patients, the most significant risk factor associated with death or coma was related to neuromuscular management. Monitoring and reversal of the effects of NMBAs were associated with a marked reduction in mortality and coma (Arbous MS, 2005). Other studies have shown that repeated clinical, qualitative, and quantitative evaluation of the depth of neuromuscular blockade may result in a reduction of NMBA dose and a subsequent decrease in the risk of complications from residual neuromuscular blockade (Brull SJ, 2010b)(Murphy GS, 2010a).
Despite these results, a majority of patients are still assessed by subjective, qualitative monitoring techniques, such as tactile or visual “assessment.” During surgery, when muscle paralysis is needed to facilitate the procedure, many anesthesiologists use larger doses of NMBAs than usual, in order to ensure full muscle relaxation and optimize surgical exposure – but in a significant number of these patients, the doses of NMBAs are excessive, because administration of NMBAs is not guided by objective measurement of muscle function (Brull SJ, 2010a)(Murphy GS, 2010b). This unnecessary overdosing of NMBAs results in increased OR time, prolonged residual paralysis, patient discomfort, prolonged PACU stay, critical respiratory events, increased hospital costs, and rarely, increased mortality.
Use of reversal agents and the need for objective monitoring
In a published survey (Baillard C, 2005) the researchers compared the incidence of residual neuromuscular blockade (RNMB) during four different time periods (1995, 2000, 2002 and 2009) and found a reduction from 60% in 1995 to 3% in 2004. They found that absence of neuromuscular monitoring more than doubled the risk of RNMB and related the reduction in RNMB to the increased use of quantitative neuromuscular monitors and reversal of neuromuscular blockade.
In a recent study published in Anesthesiology (Sasaki N, 2014) the researchers came to a similar conclusion that neostigmine, especially when given in high doses and not guided by neuromuscular monitoring, was associated with an increased incidence of respiratory complications.
The recommended sugammadex dose varies depending on the depth of neuromuscular blockade, ranging from 2 mg kg−1 for a moderate block (at least two TOF responses) to 4 mg kg−1 for a deep block (one to two posttetanic count responses) and 16 mg kg−1 for immediate reversal after rocuronium administration. It is essential to carefully monitor the patient with an objective neuromuscular monitor to ensure the correct dose of reversal agents.
In an observational study (Kotake Y, 2013), researchers questioned the ability of sugammadex to eliminate residual neuromuscular blockade (RNMB) without the use of neuromuscular monitoring. It was concluded that sugammadex decreased the incidence of RNMB when compared with neostigmine (4.3 versus 23.9% for TOF<0.9), but the risk of RNMB with sugammadex remained between 1.7 and 9.4% when no neuromuscular monitor was used.
Need for more effective solutions – clear consensus
The need of better objective neuromuscular monitors is actively discussed in the anesthesiology community (Brull SJ, Prielipp RC, 2015). The Anesthesia Patient Safety Foundation (APSF, at www.APSF.org) has already announced that “Postoperative Residual Neuromuscular Block” is a patient safety issue that will need to be addressed by development of Perioperative Guidelines (APSF Newsletter, 2013)(APSF Newsletter, 2014). Such Guidelines, supported and promoted by the American Society of Anesthesiologists (ASA, www.ASAhq.org) should become a reality within the next 18-24 months.