One recent study found that patients with MG had significantly lower FEV1/FVC ratio than controls. This was more marked in patients on acetylcholine esterase inhibitors (Elsais et al., 2010). In myasthenic crisis, bronchodilators may be useful in maintaining airway patency and overcoming bronchospasm. For myasthenics with concomitant chronic obstructive pulmonary disease (COPD), inhaled ipratropium bromide may be the bronchodilator drug of choice because it is safe and can decreased bronchial secretions which may limit the use of cholinesterase inhibitors (Szathmáry et al., 1981; Liggett et al., 1988). A recent pilot study also suggests that terbutaline, a β2 adrenergic agonist, may be an effective adjunct therapy in these patients, although confirmation with larger trials will be required (Soliven et al., 2011).

#### **6.3 Indications and predictors for endotracheal intubation**

Two-thirds to 90% of patients with myasthenic crisis require intubation and mechanical ventilation (Thomas et al., 1997; O'Riordan et al., 1998). Over 20% of patients require intubation during evaluation in the emergency department, and almost 60% are intubated after admission to an ICU (Thomas et al., 1997). The absolute indications for intubation may include cardiac or respiratory arrest, impaired consciousness shock, life-threatening arrhythmias, severe blood–gas alterations, and bulbar dysfunction with confirmed aspiration. Much more difficult is the decision to intubate when such strict criteria are not met.

Patients with crisis should be referred for intensive care. The initial step is stabilization of the airway. The airway should be opened by suctioning secretions after positioning the jaw and tongue. High-flow oxygen should be administered and oxygen saturation be monitored by pulse oximetry continuously. If respirations remain inadequate, patients can be ventilated by a bag-valve mask while preparing to intubate. In the patient without an intact gag reflex, an oral airway may be placed to prevent aspiration. Patients should always be asked about recent difficulty with swallowing, choking, coughing after eating, and nasal regurgitation. If the patient's history or the "slurp" test is suggestive of dysphagia, oral

Once the airway is secured, investigation into the cause of the exacerbation of MG may proceed. Any medication suspected of precipitating crisis should be discontinued (Keesey, 2004). Chest radiography is important in detecting pneumonia. Appropriate broad-spectrum antibiotics are indicated for sepsis and pneumonia. It is important to consider that fluoroquinolones and aminoglycosides may adversely affect muscle function in these

Prompt recognition of impending respiratory paralysis is the key to successful management. The classical signs of respiratory distress, however, often occur too late in these patients to serve as guidelines for management. Respiratory assistance should be provided if VC is < 15-20 mL/kg, the tidal volume < 5–6 mL/kg, or if PaO2 drops to < 85 mm Hg and PaCO2 increases to > 45 mm Hg. Oxygen saturation and ABG abnormalities, however, are generally not considered ideal for use in making intubation decisions because these values change late in the decompensation cycle (Juel, 2004; Rabinstein and Wijdicks, 2003; Bird and Teener,

One recent study found that patients with MG had significantly lower FEV1/FVC ratio than controls. This was more marked in patients on acetylcholine esterase inhibitors (Elsais et al., 2010). In myasthenic crisis, bronchodilators may be useful in maintaining airway patency and overcoming bronchospasm. For myasthenics with concomitant chronic obstructive pulmonary disease (COPD), inhaled ipratropium bromide may be the bronchodilator drug of choice because it is safe and can decreased bronchial secretions which may limit the use of cholinesterase inhibitors (Szathmáry et al., 1981; Liggett et al., 1988). A recent pilot study also suggests that terbutaline, a β2 adrenergic agonist, may be an effective adjunct therapy in these patients, although confirmation with larger trials will be required (Soliven et al., 2011).

Two-thirds to 90% of patients with myasthenic crisis require intubation and mechanical ventilation (Thomas et al., 1997; O'Riordan et al., 1998). Over 20% of patients require intubation during evaluation in the emergency department, and almost 60% are intubated after admission to an ICU (Thomas et al., 1997). The absolute indications for intubation may include cardiac or respiratory arrest, impaired consciousness shock, life-threatening arrhythmias, severe blood–gas alterations, and bulbar dysfunction with confirmed aspiration.

Much more difficult is the decision to intubate when such strict criteria are not met.

**6.1 Initial evaluation and airway management**

patients, and these antibiotics should be avoided if possible.

**6.3 Indications and predictors for endotracheal intubation**

intake is eliminated.

2001).

**6.2 Bronchodilator therapy**

In most patients, repeated measurements of VC and PImax help determine the need for and timing of elective intubation (Ahmed et al., 2005; Rabinstein and Wijdicks, 2003). These indices can be measured as often as every two hours, but typically every four hours. The standard 20/30/40 rule (VC < 20 mL/kg; PImax <\_30 cm H2O and PEmax < 40 cm H2O) is probably the most helpful guide to decide when intubation (Chaudhuri and Behan, 2009). However, these threshold values have not been established through prospective studies, nor do they allow for individual differences in size, sex, and age. In addition, muscle weakness in myasthenic crisis often fluctuates, and patients can develop apnea very suddenly, or may precipitously fatigue with the rapid development of respiratory failure before a downward trend in these parameters is noted. Facial weakness can also lead to inaccurate measurements of these indices due to inability to make a good seal with the mask (Lacomis, 2005). In a retrospective review, repeated measurement of VC did not predict the need for intubation and mechanical ventilation in these patients (Rieder et al., 1995). Thus, these respiratory parameters should always be interpreted in the context of the clinical symptoms and signs, as well as the trend in these measures. Regardless of respiratory function indices, the need for mechanical ventilation is a sufficient criterion to define myasthenic crisis (Ahmed et al., 2005). With close monitoring of the patient's condition, endotracheal intubation can often be performed electively rather than as an emergent response to precipitous respiratory collapse (Juel, 2004; Rabinstein and Wijdicks, 2003; Bird and Teener, 2001).

#### **6.4 Procedures for endotracheal intubation**

Should the need for emergent intubation develop, rapid sequence intubation should be modified because neuromuscular blocking agents (paralytics) should be used with caution when intubating these patients. Depolarizing agents (for example, succinylcholine) are less potent in myasthenics because fewer functional post-synaptic anti-AChR are available. This decrease in receptors also results in a decrease in the safety margin or remaining AChR available for neuromuscular transmission. Nondepolarizing agents (fornexample, vecuronium) have increased potency, and reduced doses are required for paralysis. (Baraka, 1992). A rapid-onset nondepolarizing agent (ie, rocuronium, vecuronium) is the preferred paralytic agent for these patients. Although nondepolarizing agents delay the onset of paralysis, compared with succinylcholine, these medications do not result in unwanted prolonged paralysis. Following paralysis, intubation is accomplished as usual. A soft, lowpressure cuff is recommended. After intubation, chest radiography should be taken to confirm the position of the artificial airway.

#### **6.5 Modification of pharmacotherapy after intubation**

After intubation, cholinesterase inhibitor therapy is usually temporarily withdrawn to avoid the excess secretions that may complicate pulmonary management. In addition, continued use of these medications confounds the assessment of other treatment modalities and can increase muscle weakness if used in excess (Ahmed et al., 2005). These medications do not alter the course of the crisis and offer solely symptomatic relief of MG (Juel, 2004). After patients have shown definitive improvement in muscle strength, usually several days after the initiation of intravenous immunoglobulin (IVIg) or plasma exchange, acetylcholinesterase inhibitors, typically oral pyridostigmine, can be reintroduced after or

Respiratory Care for Myasthenic Crisis 63

hypercarbia and difficulty weaning from the ventilator, low carbohydrate feeds are the

In addition to the aforementioned measures, abnormal laboratory values that could affect muscle strength should also be corrected. Potassium, magnesium, and phosphate depletion can all exacerbate myasthenic crisis and should be repleted. Anemia can also increase weakness, and several experts recommend transfusions when hematocrit values are under 30% (Kirmani et al., 2004; Ahmed et al., 2005). Prophylaxis for deep vein thromboses, such as administration of subcutaneous heparin sodium or use of pneumatic compression boots,

**8. Weaning from mechanical ventilation and risks for extubation failure**

Prolonged intubation in myasthenic patients may lead to several complications such as atelectasis, anemia, urinary tract infection, congestive heart failure (Ahmed et al., 2005), and ventilator-associated pneumonia (VAP) (Wu et al., 2008). Patients with a prolonged intubation were hospitalized 3 times longer and were less likely to be functionally independent upon discharge (Thomas et al., 1997). In one series, 3 independent risk factors for prolonged intubation (>14 days) were identified: age > 50 years, peak VC < 25 mL/kg on post-intubation days 1 to 6, and a serum bicarbonate ≥ 30 mmol/L (Thomas et al., 1997). All of the patients with no risk factors were intubated for less than 2 weeks, whereas 88% of the

Deciding on when to stop mechanical ventilation in myasthenic crisis is a challenge for the intensivists, because the usual criteria don't necessarily apply. Evaluation for weaning should begin when patients are objectively getting stronger on examination. In addition, improvement in the strength of neck flexors and other adjunct muscles is usually associated with improvement in bulbar and respiratory muscle strength and can be a useful tool for assessing clinical improvement (Meriggioli, 2009). Patients should be transitioned to a spontaneous mode of ventilation (eg, pressure support ventilation) in which all breaths are patient initiated. Pressure support can then gradually be decreased to minimal settings, usually 5 to 8 cm H2O. If results of assessments indicate muscle fatigue, the previous level of ventilator support should be reinstituted (Kirmani et al., 2004). In patients with chronic CO2 retention, PaCO2 should be kept above 45 mm Hg to avoid alkalosis and bicarbonate

Current recommendations about managing the weaning process emphasize the daily determination of simple criteria (Fly et al., 1996; Fly et al., 1999). Some criteria are generally used: 1) Satisfactory oxygenation, for instance PaO2/FIO2 ≥ 200 mm Hg with PEEP ≤\_5 cm H2O; 2) A criterion for hemodynamic stability, e.g., no continuous vasopressor infusion; 3) Patient awake or easily aroused and sedation stopped; and 4) Patient able to cough effectively.

Readiness for extubation from a respiratory standpoint is largely judged on the basis of patient performance during an SBT. Two main methods are used: T-piece and a low level of

preferred solution (Varelas et al., 2002).

**8.1 Disadvantages of prolonged intubation**

patients with all 3 risk factors had prolonged intubation.

**8.2 Evaluation for weaning in myasthenia crisis**

wasting, which may make weaning more difficult.

**8.3 Spontaneous breathing trial (SBT)**

is recommended.

just prior to extubation (Juel, 2004; Ahmed et al., 2005). Oral pyridostigmine is preferred, but it may be given intravenously. One milligram of intravenous pyridstigmine is equal to 30 mg of oral pyridostigmine. Patients should be started on a low dose of the medication that is titrated to symptomatic relief (Ahmed et al., 2005). Continuous intravenous infusion of pyridostigmine as treatment for myasthenic crisis may have efficacy similar to that of plasma exchange, but it is associated with an increased risk of life-threatening cardiac arrhythmia (Wendell and Levine, 2011). Unless contraindicated, all patients should be treated with low molecular weight heparin to prevent deep vein thrombosis and pulmonary embolism (Chaudhuri and Behan, 2009).

#### **7. Ventilatory management strategies**

#### **7.1 Ventilator settings**

Once intubated, patients should be placed in a semi-recumbent position with the head of the bed at approximately 30 degrees. Large tidal volumes of 10 mL/kg, along with pressure support of 5 to 15 cm H2O and positive end-expiratory pressure (PEEP) of 5 to 15 cm H2O, are encouraged to limit atelectasis, provided peak airway pressures can be maintained below 40 cm H2O (Kirmani et al., 2004; Varelas et al., 2002). The degree of support required is patientdependent and should be adjusted based on ABG analysis. In patients with chronic carbon dioxide retention (suggested by elevated serum bicarbonate levels), PaCO2 should be kept above 45 mm Hg to avoid alkalosis and bicarbonate wasting, which make weaning more difficult. Frequent checks of cuff pressure, tube placement, and blood gases are recommended.

#### **7.2 Chest physiotherapy and airway clearance**

Meticulous attention to pulmonary toilet is required because of an ineffective cough mechanism. Aggressive chest physiotherapy and airway clearance should be implemented (Varelas et al., 2002). Inspired gas humidity should be around 80% at 37°C. Various modalities, include percussion, vibration, and postural drainage. should be carried out to loosen and remove bronchial secretions and to achieve better aeration of collapsed areas of the lung (Brooks-Brunn, 1995; Lewis, 1980; Selsby and Jones, 1990). Regular suctioning serves to not only remove excess oropharyngeal and tracheal secretions but also to stimulate coughing (Varelas et al., 2002). Patients with a cough PEF < 180 L/min can augment cough response with manual physiotherapy and using insufflation-exsufflation devices (Chatwin et al., 2003) and this augmented cough level is associated with improved prognosis independent of VC or breathing pattern (Bach, 1995).

If atelectasis is severe and does not respond to routine measures, therapeutic fiberoptic bronchoscopy can be performed to promote airway toilet. Frequent body repositioning is effective in enhancing oxygen transport by changing the ventilation and perfusion of the lungs through gravitational effects and by enhancing mobilization of secretions. Early mobilization and ambulation as tolerated is also encouraged.

#### **7.3 Nutrition and other issues during mechanical ventilation**

Adequate nutrition is important to avoid a negative energy balance and worsening of muscle strength (Kirmani et al., 2004). All patients received adequate nutritional support (25–35 calories per kilogram) via enteral route whenever possible. In patients with

just prior to extubation (Juel, 2004; Ahmed et al., 2005). Oral pyridostigmine is preferred, but it may be given intravenously. One milligram of intravenous pyridstigmine is equal to 30 mg of oral pyridostigmine. Patients should be started on a low dose of the medication that is titrated to symptomatic relief (Ahmed et al., 2005). Continuous intravenous infusion of pyridostigmine as treatment for myasthenic crisis may have efficacy similar to that of plasma exchange, but it is associated with an increased risk of life-threatening cardiac arrhythmia (Wendell and Levine, 2011). Unless contraindicated, all patients should be treated with low molecular weight heparin to prevent deep vein thrombosis and pulmonary

Once intubated, patients should be placed in a semi-recumbent position with the head of the bed at approximately 30 degrees. Large tidal volumes of 10 mL/kg, along with pressure support of 5 to 15 cm H2O and positive end-expiratory pressure (PEEP) of 5 to 15 cm H2O, are encouraged to limit atelectasis, provided peak airway pressures can be maintained below 40 cm H2O (Kirmani et al., 2004; Varelas et al., 2002). The degree of support required is patientdependent and should be adjusted based on ABG analysis. In patients with chronic carbon dioxide retention (suggested by elevated serum bicarbonate levels), PaCO2 should be kept above 45 mm Hg to avoid alkalosis and bicarbonate wasting, which make weaning more difficult. Frequent checks of cuff pressure, tube placement, and blood gases are recommended.

Meticulous attention to pulmonary toilet is required because of an ineffective cough mechanism. Aggressive chest physiotherapy and airway clearance should be implemented (Varelas et al., 2002). Inspired gas humidity should be around 80% at 37°C. Various modalities, include percussion, vibration, and postural drainage. should be carried out to loosen and remove bronchial secretions and to achieve better aeration of collapsed areas of the lung (Brooks-Brunn, 1995; Lewis, 1980; Selsby and Jones, 1990). Regular suctioning serves to not only remove excess oropharyngeal and tracheal secretions but also to stimulate coughing (Varelas et al., 2002). Patients with a cough PEF < 180 L/min can augment cough response with manual physiotherapy and using insufflation-exsufflation devices (Chatwin et al., 2003) and this augmented cough level is associated with improved prognosis

If atelectasis is severe and does not respond to routine measures, therapeutic fiberoptic bronchoscopy can be performed to promote airway toilet. Frequent body repositioning is effective in enhancing oxygen transport by changing the ventilation and perfusion of the lungs through gravitational effects and by enhancing mobilization of secretions. Early

Adequate nutrition is important to avoid a negative energy balance and worsening of muscle strength (Kirmani et al., 2004). All patients received adequate nutritional support (25–35 calories per kilogram) via enteral route whenever possible. In patients with

embolism (Chaudhuri and Behan, 2009).

**7.1 Ventilator settings**

**7. Ventilatory management strategies**

**7.2 Chest physiotherapy and airway clearance**

independent of VC or breathing pattern (Bach, 1995).

mobilization and ambulation as tolerated is also encouraged.

**7.3 Nutrition and other issues during mechanical ventilation**

hypercarbia and difficulty weaning from the ventilator, low carbohydrate feeds are the preferred solution (Varelas et al., 2002).

In addition to the aforementioned measures, abnormal laboratory values that could affect muscle strength should also be corrected. Potassium, magnesium, and phosphate depletion can all exacerbate myasthenic crisis and should be repleted. Anemia can also increase weakness, and several experts recommend transfusions when hematocrit values are under 30% (Kirmani et al., 2004; Ahmed et al., 2005). Prophylaxis for deep vein thromboses, such as administration of subcutaneous heparin sodium or use of pneumatic compression boots, is recommended.

#### **8. Weaning from mechanical ventilation and risks for extubation failure**

#### **8.1 Disadvantages of prolonged intubation**

Prolonged intubation in myasthenic patients may lead to several complications such as atelectasis, anemia, urinary tract infection, congestive heart failure (Ahmed et al., 2005), and ventilator-associated pneumonia (VAP) (Wu et al., 2008). Patients with a prolonged intubation were hospitalized 3 times longer and were less likely to be functionally independent upon discharge (Thomas et al., 1997). In one series, 3 independent risk factors for prolonged intubation (>14 days) were identified: age > 50 years, peak VC < 25 mL/kg on post-intubation days 1 to 6, and a serum bicarbonate ≥ 30 mmol/L (Thomas et al., 1997). All of the patients with no risk factors were intubated for less than 2 weeks, whereas 88% of the patients with all 3 risk factors had prolonged intubation.

#### **8.2 Evaluation for weaning in myasthenia crisis**

Deciding on when to stop mechanical ventilation in myasthenic crisis is a challenge for the intensivists, because the usual criteria don't necessarily apply. Evaluation for weaning should begin when patients are objectively getting stronger on examination. In addition, improvement in the strength of neck flexors and other adjunct muscles is usually associated with improvement in bulbar and respiratory muscle strength and can be a useful tool for assessing clinical improvement (Meriggioli, 2009). Patients should be transitioned to a spontaneous mode of ventilation (eg, pressure support ventilation) in which all breaths are patient initiated. Pressure support can then gradually be decreased to minimal settings, usually 5 to 8 cm H2O. If results of assessments indicate muscle fatigue, the previous level of ventilator support should be reinstituted (Kirmani et al., 2004). In patients with chronic CO2 retention, PaCO2 should be kept above 45 mm Hg to avoid alkalosis and bicarbonate wasting, which may make weaning more difficult.

Current recommendations about managing the weaning process emphasize the daily determination of simple criteria (Fly et al., 1996; Fly et al., 1999). Some criteria are generally used: 1) Satisfactory oxygenation, for instance PaO2/FIO2 ≥ 200 mm Hg with PEEP ≤\_5 cm H2O; 2) A criterion for hemodynamic stability, e.g., no continuous vasopressor infusion; 3) Patient awake or easily aroused and sedation stopped; and 4) Patient able to cough effectively.

#### **8.3 Spontaneous breathing trial (SBT)**

Readiness for extubation from a respiratory standpoint is largely judged on the basis of patient performance during an SBT. Two main methods are used: T-piece and a low level of

Respiratory Care for Myasthenic Crisis 65

atelectasis and re-intubation (American Association for Respiratory Care, 1991), but its

The risk of spontaneous relapse of myasthenic crisis is low in early-onset disease. A third of late onset severe disease, especially in MuSK-MG, may experience recurrent crisis (Chaudhuri and Behan, 2009). Therefore, close observation for 72 hours in the ICU is recommended for each patients after extubation. The duration of observation may have to

The rate of extubation failure in medical patients undergoing invasive mechanical ventilation ranges from 3% to 19% (Epstein et al., 1997; Mador, 1998). This percentage seems to be much higher in neuromuscular diseases. One study published in 1997 reported that only half of patients were extubated within two weeks after intubation (Thomas et al., 1997). More recent studies indicate that extubation failure still occurs in more than 25% of these patients (Rabinstein and Mueller-Kronast, 2005; Seneviratne et al., 2008). Reintubaton is a significant event because these patients have significantly longer ICU and hospital stays (Rabinstein and Mueller-Kronast, 2005).  Atelectasis is the most important risk factor for extubation failure in myasthenic crisis. Two retrospective studies found atelectasis in all patients requiring reintubation (Rabinstein and Mueller-Kronast, 2005; Seneviratne et al., 2008). Other factors identified include older age, pneumonia, acidosis, decreased VC, and need for noninvasive ventilatory support are predictors of reintubation (Rabinstein and Mueller-Kronast, 2005; Seneviratne et al., 2008; Wu et al., 2008). Cough power is a strong predictor for extubation success in neuromusclar diseases. Bach and Saporito have reported that all patients with a cough PEF < 160 L/min had to be reintubated within 48 hours, the most likely reason being airway congestion because of the lack of adequate cough assistance (Bach and Saporito, 1996). In addition, patients who had passed SBT but presented cough PEF of 60 L/min or less were nearly 5 times more likely to fail extubation compared with those with cough PEF higher than 60 L/min (Salam et al., 2004). In myasthenics, our data indicate that extubation failure is most commonly associated with a weak cough and inadequate airway clearance, and Pemax is useful in predicting

Tracheostomy is generally not needed in myasthenic crisis because the duration of intubation is often less than 2 weeks. Tracheostomy placement ranges from 14 to 40% (Thomas et al., 1997; Rabinstein and Mueller-Kronast, 2005). In our retrospective analysis of 41 episodes, tracheostomy was performed in four (9.8 %) patients after being ventilated for a median duration of 26 days (range: 20 to 30 days) (Wu et al., 2009). All these four patients were finally liberated from mechanical ventilation (Wu et al., 2009). One rare condition in myasthenic crisis that often requires tracheostomy is severe upper airway obstruction due to bilateral vocal cord paralysis. Approximately 11 such cases have been been reported in the literature and tracheotomy was required in the majority of these patients (Hanson et al.,

usefulness in myasthenic crisis patients is not clear.

cough strength after extubation (Wu et al., 2009).

**8.7 Tracheostomy**

1996).

**8.6 Extubation outcome and the risk of extubation failure**

be longer for less stable patients.

PSV, with a duration ranging from 30 min to 2 hours (Esteban et al., 1997). It should always begin early in the day. During this period, patient anxiety, pulse and respiratory rates, and tidal volume again are frequently documented. There are no good clinical criteria for when and how to try extubation safely, thus avoiding the need for reintubation. Fluctuating weakness and pulmonary complications often confound the decision to extubate (Seneviratne et al., 2008). Patients are typically extubated if VC and PImax are ≥ 15 mL/kg and ≤\_- 20 cm H2O, respectively, and tidal volume ≥ 5 mL/kg (Kirmani et al., 2004; Meriggioli, 2009). In our study, a PEmax of > 40 cm H2O was a good predictor of extubation success in these patients (Wu et al., 2009). If the patient complains of fatigue or shortness of breath, extubation should not be performed even if the criteria of these indices are met and blood gases are normal (Berrouschot et al., 1997; Gracey et al., 1983; Kelly, 1991). Our experience also indicates that the rapid shallow breathing index (breathing frequency divided by tidal volume) is a poor predictor for extubation outcome in patients with neuromuscular diseases (Kuo et al., 1996; Wu et al, 2009).

#### **8.4 Potential utility of new modes of mechanical ventilation**

Some new modes of mechanical ventilation, which are aimed at unloading the inspiratory muscles and preventing patient-ventilator dyssynchrony, may be useful in neuromuscular patients with difficult weaning. These modes include proportional assist ventilation (PAV), adaptive support ventilation (ASV), and neurally-adjusted ventilatory assist (NAVA). However, there is still no evidence from randomized controlled trials to support or refute the use of these modes in myasthenic crisis. Automatic tube compensation (ATC) is a special mode of ventilatory support which delivers the amount of pressure necessary to overcome the resistive load imposed by the endotracheal tube for the flow measured at the time (Fabry et al., 1994). This mode therefore unloads the flow-resistive properties of the artificial airway and can increase the probability of successful extubation. One recent report indicates that the addition of ATC to a standard PSV-based **weaning** protocol significantly shortened time needed to wean patients with severe neuromuscular paralysis (Agarwal et al., 2009). It is possible that ATC will be a useful weaning mode in myasthenic crisis, especially for patients who are intubated with a small-size endotrachel tube.

#### **8.5 Respiratory care after extubation**

To enhance mucous clearance and prevent sputum impaction after extubation, it is reasonable to consider airway clearance techniques, such as positive expiratory pressure, autogenic drainage, and active cycle of breathing techniques in these patients (Hardy and Anderson, 1996). The addition of mechanical insufflation/exsufflation may shorten airwayclearance sessions in neuromuscular patients with chest infection (Chatwin and Simonds, 2009). The intrapulmonary percussive ventilator and high-frequency chest wall oscillator with vests may show growing promise in this area (Toussaint et al., 2003). However, these modalities have not been specifically in myasthenics. Externally applied pressure, such as with the In-Exsufflator or the cyclically inflated pneumatic belt, can augment the patient's own efforts and is sometimes helpful. Normalizing the VC and FRC typically helps to improve the ability to cough and clear secretions. Sputum mobilization can be facilitated with the Flutter valve therapy without the assistance of another caregiver, as long as the patient has the motivation. Incentive spirometry can also be used to reduce the risk of

PSV, with a duration ranging from 30 min to 2 hours (Esteban et al., 1997). It should always begin early in the day. During this period, patient anxiety, pulse and respiratory rates, and tidal volume again are frequently documented. There are no good clinical criteria for when and how to try extubation safely, thus avoiding the need for reintubation. Fluctuating weakness and pulmonary complications often confound the decision to extubate (Seneviratne et al., 2008). Patients are typically extubated if VC and PImax are ≥ 15 mL/kg and ≤\_- 20 cm H2O, respectively, and tidal volume ≥ 5 mL/kg (Kirmani et al., 2004; Meriggioli, 2009). In our study, a PEmax of > 40 cm H2O was a good predictor of extubation success in these patients (Wu et al., 2009). If the patient complains of fatigue or shortness of breath, extubation should not be performed even if the criteria of these indices are met and blood gases are normal (Berrouschot et al., 1997; Gracey et al., 1983; Kelly, 1991). Our experience also indicates that the rapid shallow breathing index (breathing frequency divided by tidal volume) is a poor predictor for extubation outcome in patients with

Some new modes of mechanical ventilation, which are aimed at unloading the inspiratory muscles and preventing patient-ventilator dyssynchrony, may be useful in neuromuscular patients with difficult weaning. These modes include proportional assist ventilation (PAV), adaptive support ventilation (ASV), and neurally-adjusted ventilatory assist (NAVA). However, there is still no evidence from randomized controlled trials to support or refute the use of these modes in myasthenic crisis. Automatic tube compensation (ATC) is a special mode of ventilatory support which delivers the amount of pressure necessary to overcome the resistive load imposed by the endotracheal tube for the flow measured at the time (Fabry et al., 1994). This mode therefore unloads the flow-resistive properties of the artificial airway and can increase the probability of successful extubation. One recent report indicates that the addition of ATC to a standard PSV-based **weaning** protocol significantly shortened time needed to wean patients with severe neuromuscular paralysis (Agarwal et al., 2009). It is possible that ATC will be a useful weaning mode in myasthenic crisis, especially for patients

To enhance mucous clearance and prevent sputum impaction after extubation, it is reasonable to consider airway clearance techniques, such as positive expiratory pressure, autogenic drainage, and active cycle of breathing techniques in these patients (Hardy and Anderson, 1996). The addition of mechanical insufflation/exsufflation may shorten airwayclearance sessions in neuromuscular patients with chest infection (Chatwin and Simonds, 2009). The intrapulmonary percussive ventilator and high-frequency chest wall oscillator with vests may show growing promise in this area (Toussaint et al., 2003). However, these modalities have not been specifically in myasthenics. Externally applied pressure, such as with the In-Exsufflator or the cyclically inflated pneumatic belt, can augment the patient's own efforts and is sometimes helpful. Normalizing the VC and FRC typically helps to improve the ability to cough and clear secretions. Sputum mobilization can be facilitated with the Flutter valve therapy without the assistance of another caregiver, as long as the patient has the motivation. Incentive spirometry can also be used to reduce the risk of

neuromuscular diseases (Kuo et al., 1996; Wu et al, 2009).

who are intubated with a small-size endotrachel tube.

**8.5 Respiratory care after extubation**

**8.4 Potential utility of new modes of mechanical ventilation**

atelectasis and re-intubation (American Association for Respiratory Care, 1991), but its usefulness in myasthenic crisis patients is not clear.

The risk of spontaneous relapse of myasthenic crisis is low in early-onset disease. A third of late onset severe disease, especially in MuSK-MG, may experience recurrent crisis (Chaudhuri and Behan, 2009). Therefore, close observation for 72 hours in the ICU is recommended for each patients after extubation. The duration of observation may have to be longer for less stable patients.

#### **8.6 Extubation outcome and the risk of extubation failure**

The rate of extubation failure in medical patients undergoing invasive mechanical ventilation ranges from 3% to 19% (Epstein et al., 1997; Mador, 1998). This percentage seems to be much higher in neuromuscular diseases. One study published in 1997 reported that only half of patients were extubated within two weeks after intubation (Thomas et al., 1997). More recent studies indicate that extubation failure still occurs in more than 25% of these patients (Rabinstein and Mueller-Kronast, 2005; Seneviratne et al., 2008). Reintubaton is a significant event because these patients have significantly longer ICU and hospital stays (Rabinstein and Mueller-Kronast, 2005).  Atelectasis is the most important risk factor for extubation failure in myasthenic crisis. Two retrospective studies found atelectasis in all patients requiring reintubation (Rabinstein and Mueller-Kronast, 2005; Seneviratne et al., 2008). Other factors identified include older age, pneumonia, acidosis, decreased VC, and need for noninvasive ventilatory support are predictors of reintubation (Rabinstein and Mueller-Kronast, 2005; Seneviratne et al., 2008; Wu et al., 2008).

Cough power is a strong predictor for extubation success in neuromusclar diseases. Bach and Saporito have reported that all patients with a cough PEF < 160 L/min had to be reintubated within 48 hours, the most likely reason being airway congestion because of the lack of adequate cough assistance (Bach and Saporito, 1996). In addition, patients who had passed SBT but presented cough PEF of 60 L/min or less were nearly 5 times more likely to fail extubation compared with those with cough PEF higher than 60 L/min (Salam et al., 2004). In myasthenics, our data indicate that extubation failure is most commonly associated with a weak cough and inadequate airway clearance, and Pemax is useful in predicting cough strength after extubation (Wu et al., 2009).

#### **8.7 Tracheostomy**

Tracheostomy is generally not needed in myasthenic crisis because the duration of intubation is often less than 2 weeks. Tracheostomy placement ranges from 14 to 40% (Thomas et al., 1997; Rabinstein and Mueller-Kronast, 2005). In our retrospective analysis of 41 episodes, tracheostomy was performed in four (9.8 %) patients after being ventilated for a median duration of 26 days (range: 20 to 30 days) (Wu et al., 2009). All these four patients were finally liberated from mechanical ventilation (Wu et al., 2009). One rare condition in myasthenic crisis that often requires tracheostomy is severe upper airway obstruction due to bilateral vocal cord paralysis. Approximately 11 such cases have been been reported in the literature and tracheotomy was required in the majority of these patients (Hanson et al., 1996).

Respiratory Care for Myasthenic Crisis 67

found that NIPPV was never aborted because of excessive respiratory secretions in myasthenics, and there was no difference in pulmonary complications between those supported with NIPPV and those supported with endotracheal intubation mechanical ventilation (Seneviratne et al., 2008). In our study, independent predictors of NIPPV success were a serum bicarbonate < 30 mmol/L and an APACHE (Acute Physiological And Chronic Health Evaluation) II score < 6 (Wu et al., 2009). Our experience also suggests that intubation should be performed if the patient on NIPPV has continued or worsening

Early application of NIPPV after extubation can reduce the risk of respiratory failure and lowered mortality in hypercapnic patients with chronic respiratory disorders (Ferrer et al., 2009). Use of NIPPV to avoid reintubation in myasthenic crisis is well established but relatively uncommon practice (Saeed and Patel, 2011). Some studies reported that NIPPV prevented reintubation in 70% of patients (Wu et al., 2009; Rabinstein and Wijdicks, 2002). Randomized controlled trials on the technique should be conducted before concluding the

In recent years, the development of more portable and flexible devices has resulted in the renewed interest in the use of negative pressure ventilation to minimise the complications associated with positive pressure ventilation. Many of these devices can make the patients more comfortable with the ability to talk, eat and breathe freely around the mandatory negative pressure breaths. For example, the latest generation of biphasic cuirass ventilators are versatile and the duration and pressure can be altered in both the inspiratory and expiratory phases, which can promote the removal of secretions by external high-frequency oscillation as well as expiratory (cough) assistance (Linton, 2005; Koto et al., 2009). For myasthenic patients with relatively normal pulmonary compliance and airway resistance, it makes good sense to try cuirass ventilation to achieve earlier extubation. It should also reduce the incidence of VAP and laryngeal injury. Patients can then be moved to a step

down or intermediate care facility, or even home, until muscle strength recovers.

Patients in myasthenic crisis have an excellent outcome if respiratory support can be provided adequately and in time. The prognosis of myasthenic crisis has substantially improved. During the early 1960s, respiratory care of these patients was transitioned from negative external pressure ventilation to positive pressure ventilation in an ICU. The mortality rate during hospitalization has decreased from 42% in the early 1960s to 6% by the late 1970s, between 3% and 10% in the early 1980s, and less than 3% in the 1990s. The median age at death also increased (Cohen and Younger, 1981). The rate of mortality has continued to decline after 1990, presumably because of improvements in respiratory care and availability of treatment options including IVIG and plasma exchange (Alshekhlee et al., 2009). Based on the data in the US from 2000 through 2005, the overall in-hospital mortality

shortness of breath, tachypnea, or hypercapniea.

**10. Role of negative pressure ventilation**

**9.4 NIPPV to prevent reintubation**

overall beneficial outcome.

**11. Outcome and prognosis**

**11.1 Mortality**

### **9. Role of non-invasive positive pressure ventilation (NIPPV)**

#### **9.1 Advantages of NIPPV in neuromuscular diseases**

The application of NIPPV can augment airflow and prevents airway collapse and maintaining gas exchange by offering positive airway pressure both in the inhalation and exhalation phases of respiration. It has been applied successfully in slowly progressive neuromuscular diseases, such as Duchenne muscular dystrophy or amyotrophic lateral sclerosis (Seneviratne et al., 2008). NIPPV should be started at low pressures initially and then inspiratory pressure is gradually increased while monitoring tolerance, symptoms, and gas exchange. NIPPV is also increasingly being used to prevent extubation failure in these patients. A recent prospective study suggests that application of NIPPV, combined with assisted coughing after extubation, averts the need for reintubation or tracheostomy in patients with neuromuscular diseases and shortening their stay in the ICU (Vianello et al., 2011). It should be included in the routine approach to these patients at high risk for postextubation respiratory failure.

#### **9.2 Contraindications and disadvantages of NIPPV**

Contraindications remain to the application of NIPPV in the acute setting, including respiratory arrest, severe inability to protect the airway, uncontrollable airway secretions despite use of noninvasive aids, life-threatening hypoxemia, severely impaired mental status or agitation, hemodynamic or electrocardiographic instability, and bowel obstruction (Hill et al., 2011). In patients with bulbar involvement, air blowing through a mask can lead to aspirated secretions and great care must be taken when using this modality (Wu et al., 2009). Current evidence suggests that NIPPV should be used judiciously, if at all, in patients with postextubation respiratory failure (Aqarwal et al., 2007).

#### **9.3 Application of NIPPV in myasthenic crisis**

The definition of myasthenic crisis was introduced before NIPPV was widely applied to patients with hypercapnic respiratory failure. One common dilemma is whether to do immediate intubation in a patient presenting with warning signs of imminent respiratory failure or to start with NIPPV support. There are studies that lend some credence to its use in selected patients with myasthenic crisis. In 2002, Rabinstein et al. first reported their experience of using NIPPV in these patients. In their case series, NIPPV was well tolerated and the length of hospital stay was significantly reduced compared to those who were intubated (mean 7 ± 5 days vs. 23 ± 16 days; *p =* 0.03). Most failures (75%) occurred within the first 24 hours of NIPPV use (Rabinstein et al., 2002). Several subsequent reports suggest that NIPPV may be useful in preventing intubation as well as reintubation in these patients (Rabinstein and Wijdicks, 2002; Rabinstein and Wijdicks, 2003; Seneviratne et al., 2008; Wu et al., 2009). In 60 episodes of crisis in 52 patients, Seneviratne et al. reported that NIPPV was the initial method of ventilatory support in 24 episodes, and intubation was avoided in 14 of these episodes (Seneviratne et al., 2008). Patients treated initially with NIPPV require ventilatory support for a median of 4 days versus 9 days in those patients initially intubated. A recent report also indicate that patients undergoing NIPPV spend one-third less time in the ICU and in the hospital, and the predictor of NIPPV failure was a PaCO2 level exceeding 45 mm Hg on NIPPV initiation (Seneviratne et al., 2008). One retrospective cohort study

The application of NIPPV can augment airflow and prevents airway collapse and maintaining gas exchange by offering positive airway pressure both in the inhalation and exhalation phases of respiration. It has been applied successfully in slowly progressive neuromuscular diseases, such as Duchenne muscular dystrophy or amyotrophic lateral sclerosis (Seneviratne et al., 2008). NIPPV should be started at low pressures initially and then inspiratory pressure is gradually increased while monitoring tolerance, symptoms, and gas exchange. NIPPV is also increasingly being used to prevent extubation failure in these patients. A recent prospective study suggests that application of NIPPV, combined with assisted coughing after extubation, averts the need for reintubation or tracheostomy in patients with neuromuscular diseases and shortening their stay in the ICU (Vianello et al., 2011). It should be included in the routine approach to these patients at high risk for

Contraindications remain to the application of NIPPV in the acute setting, including respiratory arrest, severe inability to protect the airway, uncontrollable airway secretions despite use of noninvasive aids, life-threatening hypoxemia, severely impaired mental status or agitation, hemodynamic or electrocardiographic instability, and bowel obstruction (Hill et al., 2011). In patients with bulbar involvement, air blowing through a mask can lead to aspirated secretions and great care must be taken when using this modality (Wu et al., 2009). Current evidence suggests that NIPPV should be used judiciously, if at all, in patients

The definition of myasthenic crisis was introduced before NIPPV was widely applied to patients with hypercapnic respiratory failure. One common dilemma is whether to do immediate intubation in a patient presenting with warning signs of imminent respiratory failure or to start with NIPPV support. There are studies that lend some credence to its use in selected patients with myasthenic crisis. In 2002, Rabinstein et al. first reported their experience of using NIPPV in these patients. In their case series, NIPPV was well tolerated and the length of hospital stay was significantly reduced compared to those who were intubated (mean 7 ± 5 days vs. 23 ± 16 days; *p =* 0.03). Most failures (75%) occurred within the first 24 hours of NIPPV use (Rabinstein et al., 2002). Several subsequent reports suggest that NIPPV may be useful in preventing intubation as well as reintubation in these patients (Rabinstein and Wijdicks, 2002; Rabinstein and Wijdicks, 2003; Seneviratne et al., 2008; Wu et al., 2009). In 60 episodes of crisis in 52 patients, Seneviratne et al. reported that NIPPV was the initial method of ventilatory support in 24 episodes, and intubation was avoided in 14 of these episodes (Seneviratne et al., 2008). Patients treated initially with NIPPV require ventilatory support for a median of 4 days versus 9 days in those patients initially intubated. A recent report also indicate that patients undergoing NIPPV spend one-third less time in the ICU and in the hospital, and the predictor of NIPPV failure was a PaCO2 level exceeding 45 mm Hg on NIPPV initiation (Seneviratne et al., 2008). One retrospective cohort study

**9. Role of non-invasive positive pressure ventilation (NIPPV)**

**9.1 Advantages of NIPPV in neuromuscular diseases**

**9.2 Contraindications and disadvantages of NIPPV**

with postextubation respiratory failure (Aqarwal et al., 2007).

**9.3 Application of NIPPV in myasthenic crisis**

postextubation respiratory failure.

found that NIPPV was never aborted because of excessive respiratory secretions in myasthenics, and there was no difference in pulmonary complications between those supported with NIPPV and those supported with endotracheal intubation mechanical ventilation (Seneviratne et al., 2008). In our study, independent predictors of NIPPV success were a serum bicarbonate < 30 mmol/L and an APACHE (Acute Physiological And Chronic Health Evaluation) II score < 6 (Wu et al., 2009). Our experience also suggests that intubation should be performed if the patient on NIPPV has continued or worsening shortness of breath, tachypnea, or hypercapniea.

#### **9.4 NIPPV to prevent reintubation**

Early application of NIPPV after extubation can reduce the risk of respiratory failure and lowered mortality in hypercapnic patients with chronic respiratory disorders (Ferrer et al., 2009). Use of NIPPV to avoid reintubation in myasthenic crisis is well established but relatively uncommon practice (Saeed and Patel, 2011). Some studies reported that NIPPV prevented reintubation in 70% of patients (Wu et al., 2009; Rabinstein and Wijdicks, 2002). Randomized controlled trials on the technique should be conducted before concluding the overall beneficial outcome.

#### **10. Role of negative pressure ventilation**

In recent years, the development of more portable and flexible devices has resulted in the renewed interest in the use of negative pressure ventilation to minimise the complications associated with positive pressure ventilation. Many of these devices can make the patients more comfortable with the ability to talk, eat and breathe freely around the mandatory negative pressure breaths. For example, the latest generation of biphasic cuirass ventilators are versatile and the duration and pressure can be altered in both the inspiratory and expiratory phases, which can promote the removal of secretions by external high-frequency oscillation as well as expiratory (cough) assistance (Linton, 2005; Koto et al., 2009). For myasthenic patients with relatively normal pulmonary compliance and airway resistance, it makes good sense to try cuirass ventilation to achieve earlier extubation. It should also reduce the incidence of VAP and laryngeal injury. Patients can then be moved to a step down or intermediate care facility, or even home, until muscle strength recovers.

#### **11. Outcome and prognosis**

#### **11.1 Mortality**

Patients in myasthenic crisis have an excellent outcome if respiratory support can be provided adequately and in time. The prognosis of myasthenic crisis has substantially improved. During the early 1960s, respiratory care of these patients was transitioned from negative external pressure ventilation to positive pressure ventilation in an ICU. The mortality rate during hospitalization has decreased from 42% in the early 1960s to 6% by the late 1970s, between 3% and 10% in the early 1980s, and less than 3% in the 1990s. The median age at death also increased (Cohen and Younger, 1981). The rate of mortality has continued to decline after 1990, presumably because of improvements in respiratory care and availability of treatment options including IVIG and plasma exchange (Alshekhlee et al., 2009). Based on the data in the US from 2000 through 2005, the overall in-hospital mortality

Respiratory Care for Myasthenic Crisis 69

Myasthenic crisis is a rare but potentially life-threatening medical emergency and the diagnosis should be clinically suspected. The muscles involved and the degree of weakness vary from patient to patient, and respiratory care of these patients presents a challenge for the critical care practioners. Although no single factor determines the need for respiratory support, all patients with questionable respiratory status should be admitted to the ICU. Certain tests of respiratory muscle strength may help to identify impending respiratory failure and allow elective rather than emergent intubation. When treated aggressively adequately, patients generally have good outcomes in current practice. Successful management of patients not only involves the pharmacological aspect but a major part is mechanical ventilation. There is a clear need for formal randomized controlled trial of NIPPV in these patients as it seems to be a promising approach. Patient selection and close monitoring, however, remain important for successful application of NIPPV in myasthenic crisis. Because management of crisis includes treatment of the underlying MG, it is apparent that there is an urgent need for cooperation between specialist chest physicians, neurologists and respiratory therapists to optimize the care of this particular population of patients.

Aggarwal, AN.; Agarwal, R. & Gupta, D. (2009). Automatic tube compensation as an

Ahmed, S.; Kirmani, JF., Janjua, N., Alkawi, A., Khatri, I., Yahia, AM., Souyah, N. & Qureshi,

Alshekhlee, A.; Miles, JD., Katirji, B., Preston, DC., & Kaminski, HJ. (2009). Incidence and

Argov, Z. (2009). Management of myasthenic conditions: nonimmune issues. *Current*

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Alshekhlee, A.; Miles, JD., Katirji, B., Preston, DC. & Kaminski, HJ. (2009). Incidence and

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**12. Conclusion**

**13. References**

rate in patients with MG was 2.2%, being higher in patients with crisis (4.47%) (Alshekhlee et al., 2009). Older age and respiratory failure were the predictors of death, with adjusted odds ratios of 9.28 and 3.58, respectively (Alshekhlee et al., 2009). In that cohort, significantly higher occurrence of cardiac complications, sepsis, and deep vein thrombosis was observed among patients with crisis; however, none of these complications were independent predictors of death (Alshekhlee et al., 2009).

#### **11.2 Duration of mechanical ventilation and prognosis**

Prior reports indicated a median duration of intubation of 13 days or ICU stay of 14 days (Murthy et al., 2005; Tether, 1955). A recent study noted a shorter median length of hospital stay of 6 days. However, this duration was 17 days for myasthenic patients who underwent endotracheal intubation (Alshekhlee et al., 2009). Duration of intubation is an important predictor of functional outcome after crisis. About 25% of patients are extubated on hospital day 7, 50% by hospital day 13, and 75% by hospital day 31. Eighteen percent of patients will require discharge to a rehabilitation center (Alshekhlee et al., 2009). In a retrospective study of 73 episodes of crisis, risk factors for prolonged intubation include patient age over 50 years, preintubation serum bicarbonate levels above 30 mg/dL, and highest VC of less than 25 mL/kg during the first week of intubation (Thomas et al., 1997). The risk of prolonged intubation (i.e., >2 weeks) was 0% in patients with none of these risk factors, 20% in those with one risk factor, 50% in those with two risk factors, and 90% in those with three risk factors (Thomas et al., 1997). In another study, 77% of patients intubated for more than 2 weeks had functional dependence at discharge compared with 36% of patients intubated for less than 2 weeks.

#### Table 2. Summary of respiratory care for myasthenic crisis

#### **12. Conclusion**

68 A Look into Myasthenia Gravis

rate in patients with MG was 2.2%, being higher in patients with crisis (4.47%) (Alshekhlee et al., 2009). Older age and respiratory failure were the predictors of death, with adjusted odds ratios of 9.28 and 3.58, respectively (Alshekhlee et al., 2009). In that cohort, significantly higher occurrence of cardiac complications, sepsis, and deep vein thrombosis was observed among patients with crisis; however, none of these complications were

Prior reports indicated a median duration of intubation of 13 days or ICU stay of 14 days (Murthy et al., 2005; Tether, 1955). A recent study noted a shorter median length of hospital stay of 6 days. However, this duration was 17 days for myasthenic patients who underwent endotracheal intubation (Alshekhlee et al., 2009). Duration of intubation is an important predictor of functional outcome after crisis. About 25% of patients are extubated on hospital day 7, 50% by hospital day 13, and 75% by hospital day 31. Eighteen percent of patients will require discharge to a rehabilitation center (Alshekhlee et al., 2009). In a retrospective study of 73 episodes of crisis, risk factors for prolonged intubation include patient age over 50 years, preintubation serum bicarbonate levels above 30 mg/dL, and highest VC of less than 25 mL/kg during the first week of intubation (Thomas et al., 1997). The risk of prolonged intubation (i.e., >2 weeks) was 0% in patients with none of these risk factors, 20% in those with one risk factor, 50% in those with two risk factors, and 90% in those with three risk factors (Thomas et al., 1997). In another study, 77% of patients intubated for more than 2 weeks had functional dependence at discharge compared with 36% of patients intubated for

independent predictors of death (Alshekhlee et al., 2009).

**11.2 Duration of mechanical ventilation and prognosis**

less than 2 weeks.

1. Referred for intensive care.

5. NIPPV if no contraindications.

generally not needed.

2. Initial step is stabilization of the airway 3. Adequate oxygenation and ventilation.

4. Airway protection if bulbar dysfunction to prevent aspiration.

(VC, PImax, SNIP, PEmax, peak cough flow…).

10. Aggressive chest physiotherapy and airway clearance.

(T-piece, PS, automatic tube compensation...).

Table 2. Summary of respiratory care for myasthenic crisis

8. Elective rather than emergency intubation.

6. Monitor vital signs and repeated measurements of muscle strength

7. 20/30/40 rule to guide intubation ( symptoms and signs more important).

9. Recommended initial ventilator settings: tidal volume 10 mL/kg, PS 5-15 cm H2O and PEEP 5-15 cm H2O, peak airway pressure < 40 cm H2O

11. Evaluation for weaning when muscular strength is objectively improved. 12. Identify readiness for extubation by spontaneous breathing trials

13. Close monitoring and airway toilet after extubation. Tracheostomy is

Myasthenic crisis is a rare but potentially life-threatening medical emergency and the diagnosis should be clinically suspected. The muscles involved and the degree of weakness vary from patient to patient, and respiratory care of these patients presents a challenge for the critical care practioners. Although no single factor determines the need for respiratory support, all patients with questionable respiratory status should be admitted to the ICU. Certain tests of respiratory muscle strength may help to identify impending respiratory failure and allow elective rather than emergent intubation. When treated aggressively adequately, patients generally have good outcomes in current practice. Successful management of patients not only involves the pharmacological aspect but a major part is mechanical ventilation. There is a clear need for formal randomized controlled trial of NIPPV in these patients as it seems to be a promising approach. Patient selection and close monitoring, however, remain important for successful application of NIPPV in myasthenic crisis. Because management of crisis includes treatment of the underlying MG, it is apparent that there is an urgent need for cooperation between specialist chest physicians, neurologists and respiratory therapists to optimize the care of this particular population of patients.

#### **13. References**

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ventilation and factors predicting extubation outcome in myasthenic crisis.

**6**

**Unilaterally Extended Thoracoscopic**

Myasthenia gravis (MG) is a heterogeneous disorder with a protean, clinical, pathologic, and immunobiological picture(Beekman, Kuks, and Oosterhuis 1997, 244:112-118) Myasthenia gravis (MG) is the best studied and understood autoimmune disease. The autoimmune origin of the disease was suggested for the first time by Simpson (Simpson 1982, 226:1045-1050), but Almon and colleagues(Almon and Appel 1976, 274:235-243) were the first to demonstrate circulating antibodies to acetylcholine receptor (AchR) sites of the neuromuscular junction. Elevated antibody levels are found in approximately 90% of patients and are roughly correlated with the clinical severity of the disease(Beekman, Kuks, and Oosterhuis 1997, 244:112-118). As Lennon (Lennon, Lindstrom, and Seybold 1976, 274:283-299) showed, the thymus is evidently implicated in the production not only of these end-plate antibodies but also to striated muscle antibodies through some aberration in its

In most cases, the target of the autoimmune attack is the nicotinic acetylcholine receptor (AChR) located in the postsynaptic muscle endplate membrane. AChR antibodies produce

• antibodies activate complement leading to destruction of the postsynaptic

Other neuromuscular junction antigens, distinct from AChR, also play a role in autoimmune attack of patients with MG. Up to 20% of patients with generalized MG are seronegative for AChR antibodies with 30% of these patients having autoantibodies directed against a distinct endplate membrane intrinsic protein, muscle-specific receptor tyrosine kinase (MuSK) (Evoli et al. 2003, 126:2304-2311). Some MuSK antibodies compromise AChR channel function, but specific pathogenic mechanisms have not been defined. One would predict that MuSK antibodies compromise neuromuscular transmission by affecting AChR clustering at the neuromuscular jonction. Patients who have late onset non-tumoral MG may also have tintin

deficient neuromuscular transmission by three different mechanisms:

• they promote endocytosis and accelerate the degradation rate of AchR

surface(Hughes, Moro De Casillas, and Kaminski 2004, 24:21-30).

• they bind to the AChR and alter function;

**1. Introduction**

normal function.

**Thymectomy: The Right Side or**

*Fundeni Clinical Institute, Center of General Surgery*

**the Left Side Approach**

*and Liver Transplant "Dan Setlacec"*

Victor Tomulescu

*Romania*

## **Unilaterally Extended Thoracoscopic Thymectomy: The Right Side or the Left Side Approach**

Victor Tomulescu

*Fundeni Clinical Institute, Center of General Surgery and Liver Transplant "Dan Setlacec" Romania*

#### **1. Introduction**

Myasthenia gravis (MG) is a heterogeneous disorder with a protean, clinical, pathologic, and immunobiological picture(Beekman, Kuks, and Oosterhuis 1997, 244:112-118) Myasthenia gravis (MG) is the best studied and understood autoimmune disease. The autoimmune origin of the disease was suggested for the first time by Simpson (Simpson 1982, 226:1045-1050), but Almon and colleagues(Almon and Appel 1976, 274:235-243) were the first to demonstrate circulating antibodies to acetylcholine receptor (AchR) sites of the neuromuscular junction. Elevated antibody levels are found in approximately 90% of patients and are roughly correlated with the clinical severity of the disease(Beekman, Kuks, and Oosterhuis 1997, 244:112-118). As Lennon (Lennon, Lindstrom, and Seybold 1976, 274:283-299) showed, the thymus is evidently implicated in the production not only of these end-plate antibodies but also to striated muscle antibodies through some aberration in its normal function.

In most cases, the target of the autoimmune attack is the nicotinic acetylcholine receptor (AChR) located in the postsynaptic muscle endplate membrane. AChR antibodies produce deficient neuromuscular transmission by three different mechanisms:

Other neuromuscular junction antigens, distinct from AChR, also play a role in autoimmune attack of patients with MG. Up to 20% of patients with generalized MG are seronegative for AChR antibodies with 30% of these patients having autoantibodies directed against a distinct endplate membrane intrinsic protein, muscle-specific receptor tyrosine kinase (MuSK) (Evoli et al. 2003, 126:2304-2311). Some MuSK antibodies compromise AChR channel function, but specific pathogenic mechanisms have not been defined. One would predict that MuSK antibodies compromise neuromuscular transmission by affecting AChR clustering at the neuromuscular jonction. Patients who have late onset non-tumoral MG may also have tintin

Unilaterally Extended Thoracoscopic Thymectomy: The Right Side or the Left Side Approach 79

cooperation with the neurologist that supervised the treatment. Coordinated and strong multidisciplinary collaboration among neurologists, surgeons and anaesthesiologists is mandatory in making appropriate decisions regarding patient selection, therapeutic options

There is a current consensus that a patient with generalized non-tumoral MG who is between puberty and 60 years of age should undergo surgery, but the optimal approach is still under debate(Toyka KV and Gold R 2007, 158:309-321). Surgery for patients older than 60 years is controversial. In patients with ocular myasthenia the benefit is uncertain (Bulkley

Nowadays surgical procedures for thymectomy in non-tumoral MG comprise transternal, transthoracic, transcervical, subxifoidian or thoracoscopic thymectomy. The primary goal of every technique, of every surgeon doing thymectomy is "to remove as much thymus and ectopic thymus as possible"(Rubin 2006, 82:1007-1008). An optimal approach should

This is related with Jaretski's (Jaretzki, Steinglass, and Sonett 2004, 24:49-62;Jaretzki, III and Wolff 1988, 96:711-716) now classic point of view in relation to thymus anatomy: that the main body of the gland, incapsulated consisting in a right and a left lobe that join at their central portion just caudal to the left innominate vein, is accompanied with small extracapsular foci of thymic tissue distributed widely in mediastinal and cervical adipose tissue. This is the reason why the surgical technique consists in rigorous emptying of the anterior mediastinum from diaphragm to the cervical area, between the phrenic nerves, of all thymus and fatty tisuue. Advantages of thoracoscopic thymectomy besides minimizing the trauma and undoubted cosmetic advantages consist in the exceptional intraoperative overview (the new high definition cameras make these images even more accurate) that make the procedure safer, and diminishing the risk of injury of fine structures not related

The diagnosis of myasthenia gravis is based on the patient's history, physical examination, positive response to anticholinesterase agents and electrophysiology studies. Preoperative diagnostic tests should include spirometry and a CT scan. The immunologic profile with AchR antibodies assay and anti-MuSK antibody should be performed on all patients. Thymectomy should be performed when MG is in a stable condition; there is no indication for "emergency operation". Al the patients should be well prepared for the intervention. In our experience patients were considered suitable for a surgical procedure only when evidence showed good treatment tolerance and a decrease of the quantitative myasthenia gravis score (Myastenia Gravis Foundation of America (MGFA) recommendations for

clinical research standards (Jaretzki, III et al. 2000, 70:327-334)) to at least 10 points.

approach should be performed with the same dexterity, safety and preciseness.

Unilaterally extended thoracoscopic thymectomy is performed with the patient under general anesthesia with double-lumen tube placement and lying in a 15-30° off-centre

Choice of the side is matter of training, mentoring, safe complete removal of the thymus and peri-thymic fatty tissue from diaphragm to cervical area being the main goal. A versatile thoracic surgeon should be able to approach the thymus by a variety of methods and if a left side approach is not possible due to previous thoracotomy for example, a right side

and the timing of surgery.

with the procedure.

position (fig1).

et al. 1997, 226:324-334;Guillermo et al. 2004, 109:217-221)

combine least invasiveness and maximal radicality.

(an intracellular muscle protein) and ryanodine receptor antibodies, the presence of these antibodies being associated with a worse prognosis (Romi, Gilhus, and Aarli 2006, 183:24-25).

The thymus plays a key role in tolerance induction to self-antigens and in responsiveness of lymphocytes to foreign antigens. Several findings indicate that the thymus is involved in MG pathogenesis:

Most myasthenic thymuses contain B cells capable of producing AchR antibodies, particularly those hyperplastic thymuses with germinal centers(Leite et al. 2007, 171:893- 905). Normal and myasthenic human thymuses express gene transcripts and epitopes of all AchR As subunits(Navaneetham et al. 2001, 24:203-210).

The availability of AChR in thymus may play a role in pathogenesis of MG. It is considered that the AChR expressed on thymic myoid cells is the original auto-sensitizing antigen, and the thymic changes in MG are primary events in the autoimmune pathogenesis of the disease(Leite, Jones, Strobel, Marx, Gold, Niks, Verschuuren, Berrih-Aknin, Scaravilli, Canelhas, Morgan, Vincent, and Willcox 2007, 171:893-905). It is possible that the myoid cells to be altered by viral illness involving the thymus and the proximity to antigen presenting cells and helper T-cells to facilitate the abnormal immunologic response(Drachman 1994, 330:1797-1810).

Patients with MG have frequently other immune-mediated diseases like rheumatoid arthritis, lupus, Graves' disease, tyroiditis and a family history of autoimmune disorders. That imposed the study of the genetic factor implication in MG. HLA types like HLA-B8, DRw3, Dqw2 have been associated with AChR antibody positive MG and haplotypes DR14 and DQ5 with MuSK antibody positive MG(Carlsson et al. 1990, 31:285-290;Niks et al. 2006, 66:1772-1774).

Since the first case reported by Schumacher and Roth in 1913 (Keesey 2004, 24:5-16), the role of thymectomy in MG treatment has been well established. The main study demonstrating the benefit of thymectomy in MG was that of Buckingham and associates(Buckingham et al. 1976, 184:453-458), who compared the clinical course of patients after thymectomy with a computer-matched cohort receiving medical therapy. The best assessment of potential benefits of thymectomy in modern era comes from a review of 21 controlled but nonrandomized studies(Gronseth and Barohn 2000, 55:7-15) showing that patients undergoing thymectomy were twice as likely to achieve medication-free remissions.

#### **2. Indication (thymectomy in the multimodal treatment of MG)**

The major issues for a surgeon who has an interest in thymectomy are related to patient selection and surgical technique. Regarding patient selection, decision should be taken in

(an intracellular muscle protein) and ryanodine receptor antibodies, the presence of these antibodies being associated with a worse prognosis (Romi, Gilhus, and Aarli 2006, 183:24-25). The thymus plays a key role in tolerance induction to self-antigens and in responsiveness of lymphocytes to foreign antigens. Several findings indicate that the thymus is involved in

• Pathological changes, like lymphoid follicular hyperplasia or thymomas, are frequent in

• MG thymic tissue contains abnormally elevated amounts of mature T cells, most of them AChR-reactive T cells(Sommer et al. 1990, 28:312-319;Sommer, Tackenberg, and

• myasthenic thymic tissue fragments transplanted to severe combined immunodeficiency mice produce human antibodies, which bind to the

Most myasthenic thymuses contain B cells capable of producing AchR antibodies, particularly those hyperplastic thymuses with germinal centers(Leite et al. 2007, 171:893- 905). Normal and myasthenic human thymuses express gene transcripts and epitopes of all

The availability of AChR in thymus may play a role in pathogenesis of MG. It is considered that the AChR expressed on thymic myoid cells is the original auto-sensitizing antigen, and the thymic changes in MG are primary events in the autoimmune pathogenesis of the disease(Leite, Jones, Strobel, Marx, Gold, Niks, Verschuuren, Berrih-Aknin, Scaravilli, Canelhas, Morgan, Vincent, and Willcox 2007, 171:893-905). It is possible that the myoid cells to be altered by viral illness involving the thymus and the proximity to antigen presenting cells and helper T-cells to facilitate the abnormal immunologic response(Drachman 1994,

Patients with MG have frequently other immune-mediated diseases like rheumatoid arthritis, lupus, Graves' disease, tyroiditis and a family history of autoimmune disorders. That imposed the study of the genetic factor implication in MG. HLA types like HLA-B8, DRw3, Dqw2 have been associated with AChR antibody positive MG and haplotypes DR14 and DQ5 with MuSK

Since the first case reported by Schumacher and Roth in 1913 (Keesey 2004, 24:5-16), the role of thymectomy in MG treatment has been well established. The main study demonstrating the benefit of thymectomy in MG was that of Buckingham and associates(Buckingham et al. 1976, 184:453-458), who compared the clinical course of patients after thymectomy with a computer-matched cohort receiving medical therapy. The best assessment of potential benefits of thymectomy in modern era comes from a review of 21 controlled but nonrandomized studies(Gronseth and Barohn 2000, 55:7-15) showing that patients undergoing

The major issues for a surgeon who has an interest in thymectomy are related to patient selection and surgical technique. Regarding patient selection, decision should be taken in

antibody positive MG(Carlsson et al. 1990, 31:285-290;Niks et al. 2006, 66:1772-1774).

thymectomy were twice as likely to achieve medication-free remissions.

**2. Indication (thymectomy in the multimodal treatment of MG)**

MG pathogenesis:

330:1797-1810).

patients with MG.

Hohlfeld 2008, 91:169-212).

AChR(Schonbeck et al. 1992, 90:245-250).

AchR As subunits(Navaneetham et al. 2001, 24:203-210).

cooperation with the neurologist that supervised the treatment. Coordinated and strong multidisciplinary collaboration among neurologists, surgeons and anaesthesiologists is mandatory in making appropriate decisions regarding patient selection, therapeutic options and the timing of surgery.

There is a current consensus that a patient with generalized non-tumoral MG who is between puberty and 60 years of age should undergo surgery, but the optimal approach is still under debate(Toyka KV and Gold R 2007, 158:309-321). Surgery for patients older than 60 years is controversial. In patients with ocular myasthenia the benefit is uncertain (Bulkley et al. 1997, 226:324-334;Guillermo et al. 2004, 109:217-221)

Nowadays surgical procedures for thymectomy in non-tumoral MG comprise transternal, transthoracic, transcervical, subxifoidian or thoracoscopic thymectomy. The primary goal of every technique, of every surgeon doing thymectomy is "to remove as much thymus and ectopic thymus as possible"(Rubin 2006, 82:1007-1008). An optimal approach should combine least invasiveness and maximal radicality.

This is related with Jaretski's (Jaretzki, Steinglass, and Sonett 2004, 24:49-62;Jaretzki, III and Wolff 1988, 96:711-716) now classic point of view in relation to thymus anatomy: that the main body of the gland, incapsulated consisting in a right and a left lobe that join at their central portion just caudal to the left innominate vein, is accompanied with small extracapsular foci of thymic tissue distributed widely in mediastinal and cervical adipose tissue. This is the reason why the surgical technique consists in rigorous emptying of the anterior mediastinum from diaphragm to the cervical area, between the phrenic nerves, of all thymus and fatty tisuue. Advantages of thoracoscopic thymectomy besides minimizing the trauma and undoubted cosmetic advantages consist in the exceptional intraoperative overview (the new high definition cameras make these images even more accurate) that make the procedure safer, and diminishing the risk of injury of fine structures not related with the procedure.

The diagnosis of myasthenia gravis is based on the patient's history, physical examination, positive response to anticholinesterase agents and electrophysiology studies. Preoperative diagnostic tests should include spirometry and a CT scan. The immunologic profile with AchR antibodies assay and anti-MuSK antibody should be performed on all patients. Thymectomy should be performed when MG is in a stable condition; there is no indication for "emergency operation". Al the patients should be well prepared for the intervention. In our experience patients were considered suitable for a surgical procedure only when evidence showed good treatment tolerance and a decrease of the quantitative myasthenia gravis score (Myastenia Gravis Foundation of America (MGFA) recommendations for clinical research standards (Jaretzki, III et al. 2000, 70:327-334)) to at least 10 points.

Unilaterally extended thoracoscopic thymectomy is performed with the patient under general anesthesia with double-lumen tube placement and lying in a 15-30° off-centre position (fig1).

Choice of the side is matter of training, mentoring, safe complete removal of the thymus and peri-thymic fatty tissue from diaphragm to cervical area being the main goal. A versatile thoracic surgeon should be able to approach the thymus by a variety of methods and if a left side approach is not possible due to previous thoracotomy for example, a right side approach should be performed with the same dexterity, safety and preciseness.

Unilaterally Extended Thoracoscopic Thymectomy: The Right Side or the Left Side Approach 81

Pleural cavity exploration is facilitated by the selective right bronchus intubation and by

Fig. 2. CO2 insufflations at a maximum of 10 mmHg pressure enlarge the anterior

keeping in mind the important cosmetic problem of the peri –mammary scars.

The second and third trocars (10–12 and 5–7 mm or 10-12mm, respectively) are placed through the third inter-costal space on the anterior axilary line and through the fourth or fifth inter-costal spaces on the mid-clavicle line. For females the incision should be done

After a careful pleural cavity exploration we spot the anterior mediastinum. The capnotorax helps us also in the dissection. In order to have this support we need to start all the operations with incision of the mediastinal pleura along the two important landmarks of thymectomy: the phrenic nerve and the internal thoracic artery (fig3), allowing the gas

mediastinum space

dissection to help us.

CO2 insufflations at a maximum of 10 mmHg pressure (fig2).

#### **3. Left side approach or right side approach**

Three or four trocars are inserted into the left hemithorax. The operator stays on the left side of the patient in a caudal position to the cameraman, but these positions are not fixed and any improvement in better ergonomics or superior visualization should be taking into account. The monitor is on the right side of the patient. The first trocar (10–12 mm) is placed through the fifth or sixth intercostal space, between the middle and posterior axillar lines.

Fig. 1. Patient and trocar positioning

Three or four trocars are inserted into the left hemithorax. The operator stays on the left side of the patient in a caudal position to the cameraman, but these positions are not fixed and any improvement in better ergonomics or superior visualization should be taking into account. The monitor is on the right side of the patient. The first trocar (10–12 mm) is placed through the fifth or sixth intercostal space, between the middle and posterior axillar lines.

**3. Left side approach or right side approach**

Fig. 1. Patient and trocar positioning

Pleural cavity exploration is facilitated by the selective right bronchus intubation and by CO2 insufflations at a maximum of 10 mmHg pressure (fig2).

Fig. 2. CO2 insufflations at a maximum of 10 mmHg pressure enlarge the anterior mediastinum space

The second and third trocars (10–12 and 5–7 mm or 10-12mm, respectively) are placed through the third inter-costal space on the anterior axilary line and through the fourth or fifth inter-costal spaces on the mid-clavicle line. For females the incision should be done keeping in mind the important cosmetic problem of the peri –mammary scars.

After a careful pleural cavity exploration we spot the anterior mediastinum. The capnotorax helps us also in the dissection. In order to have this support we need to start all the operations with incision of the mediastinal pleura along the two important landmarks of thymectomy: the phrenic nerve and the internal thoracic artery (fig3), allowing the gas dissection to help us.

Unilaterally Extended Thoracoscopic Thymectomy: The Right Side or the Left Side Approach 83

Fig. 4. Dissection of the left inferior thymus horn – beginning of the intervention

order to visualize an eventual posterior thymus vein.

The dissection of the thymic tissue together with pericardial fat goes cephalad on the pericardial plane (fig5) overtaking the median line, to the right of the thymus gland. The contra-laterally mediastinal pleura is opened and the inferior right thymic horn and pericardial fatty tissue is dissected in the same manner (fig6). We continue to dissect anterior, retrosternal, the mediastinal pleura being open on the right side till the right mammary pedicle. The posterior dissection continues similar, the pericardium, the aortic arch, the left brachiocephalic vein, and the superior vena cava are visualized and cleaned of all fat tissue or thymus. The most difficult area to dissect is in the aortopulmonary window (fig 7) and the aortocaval groove (fig 8). At the superior pole, the dissection is performed in the anterior carotidal plane to the internal thoracic artery level. The left superior horn or some time both upper horns may occasionally pass behind, instead of in front of the brahiocephalic vein (fig 9). This anatomical variety is more difficult to be solved by thoracoscopic approach. We have to be aware of the vagus nerve ant left recurrent laryngeal nerve that goes close and dissect carefully inferior and posterior to the brahiocephalic vein and then superior, to free the cervical parts of the upper horns. Afterwards traction of the upper horns caudally permits the dissection of them behind the brahiocephalic vein, in

The incision of the mediastinal pleura and the dissection of the thymus begin anterior to the left phrenic nerve and continue into the entire thymus compartment. The use of the ultrascision scalpel (Harmonic Scalpel Ultrascision; Ethicon Endo-Surgery) facilitates the dissection, decreases the time of the intervention, and avoids the risks of the electrocoagulation in this area. The cranial limit of the dissection, at the level of the mediastinal pleura, is the internal thoracic artery. The operation continues with dissection of the inferior left thymic horn and pericardial fatty tissue (fig 4).

Fig. 3. Landmarks of the anterior mediastinum in thymectomy (right side approach)

The incision of the mediastinal pleura and the dissection of the thymus begin anterior to the left phrenic nerve and continue into the entire thymus compartment. The use of the ultrascision scalpel (Harmonic Scalpel Ultrascision; Ethicon Endo-Surgery) facilitates the dissection, decreases the time of the intervention, and avoids the risks of the electrocoagulation in this area. The cranial limit of the dissection, at the level of the mediastinal pleura, is the internal thoracic artery. The operation continues with dissection of

Fig. 3. Landmarks of the anterior mediastinum in thymectomy (right side approach)

the inferior left thymic horn and pericardial fatty tissue (fig 4).

Fig. 4. Dissection of the left inferior thymus horn – beginning of the intervention

The dissection of the thymic tissue together with pericardial fat goes cephalad on the pericardial plane (fig5) overtaking the median line, to the right of the thymus gland. The contra-laterally mediastinal pleura is opened and the inferior right thymic horn and pericardial fatty tissue is dissected in the same manner (fig6). We continue to dissect anterior, retrosternal, the mediastinal pleura being open on the right side till the right mammary pedicle. The posterior dissection continues similar, the pericardium, the aortic arch, the left brachiocephalic vein, and the superior vena cava are visualized and cleaned of all fat tissue or thymus. The most difficult area to dissect is in the aortopulmonary window (fig 7) and the aortocaval groove (fig 8). At the superior pole, the dissection is performed in the anterior carotidal plane to the internal thoracic artery level. The left superior horn or some time both upper horns may occasionally pass behind, instead of in front of the brahiocephalic vein (fig 9). This anatomical variety is more difficult to be solved by thoracoscopic approach. We have to be aware of the vagus nerve ant left recurrent laryngeal nerve that goes close and dissect carefully inferior and posterior to the brahiocephalic vein and then superior, to free the cervical parts of the upper horns. Afterwards traction of the upper horns caudally permits the dissection of them behind the brahiocephalic vein, in order to visualize an eventual posterior thymus vein.

Unilaterally Extended Thoracoscopic Thymectomy: The Right Side or the Left Side Approach 85

Fig. 6. Dissection of the contra-laterally inferior horn (left side approach)

Fig. 5. Dissection in the pre-pericardial plane

Fig. 5. Dissection in the pre-pericardial plane

Unilaterally Extended Thoracoscopic Thymectomy: The Right Side or the Left Side Approach 87

Fig. 8. Dissection of the aorto-caval groove

Fig. 9. Posterior upper right thymus horn dissection (right side approach)

The thymectomy ends with the identification of the superior part of the gland, the thyroidthymic ligament section, and freeing of the superior horns from the surrounding tissue. After dissecting the surrounding fascia and cutting the vessels that goes caudally from cervix, upper horns can be mobilized caudally by applying gentle traction (fig 10). Cervical skin transillumination is the indication that the cervical limit of the dissection has been reached. During the operation, we can visualize the superior, lateral, or medial arterial

Fig. 7. Dissection of the aortopulmonary window

Fig. 8. Dissection of the aorto-caval groove

Fig. 7. Dissection of the aortopulmonary window

Fig. 9. Posterior upper right thymus horn dissection (right side approach)

The thymectomy ends with the identification of the superior part of the gland, the thyroidthymic ligament section, and freeing of the superior horns from the surrounding tissue. After dissecting the surrounding fascia and cutting the vessels that goes caudally from cervix, upper horns can be mobilized caudally by applying gentle traction (fig 10). Cervical skin transillumination is the indication that the cervical limit of the dissection has been reached. During the operation, we can visualize the superior, lateral, or medial arterial

Unilaterally Extended Thoracoscopic Thymectomy: The Right Side or the Left Side Approach 89

Fig 12. Visualization of the right phrenic nerve (left side approach)

the contra lateral thorax to control the complete dissection (fig 13).

bagged during dissection.

We sometimes used a needle-scope camera that was inserted through the Veress needle in

Thymus extraction is quite easily done by enlarging the hole of one of the trocar ports and bagging the piece before extracting it (fig 14). We prefer to introduce the bag at the beginning of the intervention, this way any small piece of thymus or fatty tissue could be

thymic pedicles. They are clipped and cut or ultrasonically coagulated (fig 11). Dissection of the thymic veins is very important. The veins are very short and enter directly into the left brachiocephalic vein. Tearing out such a pedicle may cause a hemorrhage, which is very difficult to correct thoracoscopically. Visualization of the right phrenic nerve is necessary to complete the dissection of thymus and fatty tissue (fig 12).

Fig. 10. Dissection of the upper left horn

Fig. 11. Clipping the thymus vein

thymic pedicles. They are clipped and cut or ultrasonically coagulated (fig 11). Dissection of the thymic veins is very important. The veins are very short and enter directly into the left brachiocephalic vein. Tearing out such a pedicle may cause a hemorrhage, which is very difficult to correct thoracoscopically. Visualization of the right phrenic nerve is necessary to

complete the dissection of thymus and fatty tissue (fig 12).

Fig. 10. Dissection of the upper left horn

Fig. 11. Clipping the thymus vein

Fig 12. Visualization of the right phrenic nerve (left side approach)

We sometimes used a needle-scope camera that was inserted through the Veress needle in the contra lateral thorax to control the complete dissection (fig 13).

Thymus extraction is quite easily done by enlarging the hole of one of the trocar ports and bagging the piece before extracting it (fig 14). We prefer to introduce the bag at the beginning of the intervention, this way any small piece of thymus or fatty tissue could be bagged during dissection.

Unilaterally Extended Thoracoscopic Thymectomy: The Right Side or the Left Side Approach 91

Thoracoscopic thymectomy through the right side is performed in the same manner, the most difficult part of this approach being the aortopulmonary window(Ruckert et al. 2000,

Fig 15. Landmarks of the anterior mediastinum at the end of thymectomy (right side

horns to upper horns with a right approach.

Yim and colleagues(Yim 1997, 64:584-585) favor the right thoracoscopic approach because: 1. identification of the vena cava is a landmark for easier dissection of innominate vein, 2. the confluence of the innominate veins is easier to dissect by using a right approach, 3. ergonomically, it is easier for right-hand surgeons to dissect the thymus from inferior

To this we would add that the right approach allows a better view in the cervical area. Irrespective of the patient's anatomic characteristics, every effort is made to perform a full removal of the thymic tissue by clearing the innominate vein and anterior pericardium from all mediastinal fat. We believe a left-side approach facilitates the procedure because most of the mediastinal fat is located on the left side of the anterior mediastinum. The use of a 30° endoscope (Karl Storz-Endoscopy) provides significant help. Although we share the opinion of Mineo and colleagues(Mineo, Pompeo, and Ambrogi 1997, 114:516-517) that thymectomy can be performed by either a left-side or a right-side approach, we believe the left-side approach has some advantages. In our experience, the dissection maneuvers are safer when performed on the left side because the right phrenic nerve is situated outside the surgical field, thus reducing the risk of an incidental lesion. It is also easier to perform a dissection of

18:735-736) and left inferior horn.

approach)

Fig. 13. Control of the complete dissection with a needle-scope camera that was inserted through the Veress needle in the contra lateral thorax

Fig. 14. Extractic the specimen in self-made bag

The operation ends with the thymic cavity inspection, which can detect possible remnant tissue (fig 15). Finally, we wash the cavity with warm saline. At the end of the operation one or two drains can be placed in the pleural cavity through the inferior trocar ports.

Fig. 13. Control of the complete dissection with a needle-scope camera that was inserted

The operation ends with the thymic cavity inspection, which can detect possible remnant tissue (fig 15). Finally, we wash the cavity with warm saline. At the end of the operation one

or two drains can be placed in the pleural cavity through the inferior trocar ports.

through the Veress needle in the contra lateral thorax

Fig. 14. Extractic the specimen in self-made bag

Thoracoscopic thymectomy through the right side is performed in the same manner, the most difficult part of this approach being the aortopulmonary window(Ruckert et al. 2000, 18:735-736) and left inferior horn.

Fig 15. Landmarks of the anterior mediastinum at the end of thymectomy (right side approach)

Yim and colleagues(Yim 1997, 64:584-585) favor the right thoracoscopic approach because:

To this we would add that the right approach allows a better view in the cervical area. Irrespective of the patient's anatomic characteristics, every effort is made to perform a full removal of the thymic tissue by clearing the innominate vein and anterior pericardium from all mediastinal fat. We believe a left-side approach facilitates the procedure because most of the mediastinal fat is located on the left side of the anterior mediastinum. The use of a 30° endoscope (Karl Storz-Endoscopy) provides significant help. Although we share the opinion of Mineo and colleagues(Mineo, Pompeo, and Ambrogi 1997, 114:516-517) that thymectomy can be performed by either a left-side or a right-side approach, we believe the left-side approach has some advantages. In our experience, the dissection maneuvers are safer when performed on the left side because the right phrenic nerve is situated outside the surgical field, thus reducing the risk of an incidental lesion. It is also easier to perform a dissection of

Unilaterally Extended Thoracoscopic Thymectomy: The Right Side or the Left Side Approach 93

but subsequently developed clinical findings greater than permitted by these criteria - in 4%

Unilaterally extended thoracoscopic thymectomy is a technically demanding procedure that requires expertise in extended thymectomy and in advanced minimally invasive techniques. The right side, the left side or even bilateral approach should be chosen in relation with the method the surgeon is more comfortable and from which best results (morbidity, mortality,

The maximal thymectomy should remain the benchmark against which other thymectomy techniques are measured (whether or not it is the surgical technique of choice) (Jaretzki, III, Barohn, Ernstoff, Kaminski, Keesey, Penn, and Sanders 2000, 70:327-334;Jaretzki, III and Wolff 1988, 96:711-716; Sonett and Jaretzki, III 2008, 1132:315-328) but we consider that with no mortality, low morbidity, comparable CSR and PR, better cosmetic and pulmonary function-sparing effect, superior compliance from the patients and neurologists with a higher rate acceptance of surgical treatment, this minimally invasive approach could

Almon RR, and Appel SH. 1976. Serum acetylcholine-receptor antibodies in myasthenia

Beekman R, Kuks JB, and Oosterhuis HJ. 1997. Myasthenia gravis: diagnosis and follow-up

Buckingham JM, Howard FM, Jr., Bernatz PE, Payne WS, Harrison EG, Jr., O'Brien PC, and

Bulkley GB, Bass KN, Stephenson GR, Diener-West M, George S, Reilly PA, Baker RR, and

Carlsson B, Wallin J, Pirskanen R, Matell G, and Smith CI. 1990. Different HLA DR-DQ

Evoli A, Tonali PA, Padua L, Monaco ML, Scuderi F, Batocchi AP, Marino M, and

Gronseth GS, and Barohn RJ. 2000. Practice parameter: thymectomy for autoimmune

Hughes BW, Moro De Casillas ML, and Kaminski HJ. 2004. Pathophysiology of myasthenia

Weiland LH. 1976. The value of thymectomy in myasthenia gravis: a computer-

Drachman DB. 1997. Extended cervicomediastinal thymectomy in the integrated

associations in subgroups of idiopathic myasthenia gravis. *Immunogenetics* 31 (5-6):

Bartoccioni E. 2003. Clinical correlates with anti-MuSK antibodies in generalized

myasthenia gravis (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. *Neurology* 55 (1): 7-15. Guillermo GR, Tellez-Zenteno JF, Weder-Cisneros N, Mimenza A, Estanol B, Remes-Troche

JM, and Cantu-Brito C. 2004. Response of thymectomy: clinical and pathological characteristics among seronegative and seropositive myasthenia gravis patients.

become the best first solution in the multimodal treatment of myasthenia gravis.

management of myasthenia gravis. *Ann. Surg.* 226 (3): 324-334.

Drachman DB. 1994. Myasthenia gravis. *N. Engl. J. Med.* 330 (25): 1797-1810.

seronegative myasthenia gravis. *Brain* 126 (Pt 10): 2304-2311.

(12 patients).

**5. Conclusions**

**6. References**

285-290.

completeness of thymectomy) should be expected.

gravis. *Ann. N. Y. Acad. Sci.* 274: 235-243.

*Acta Neurol. Scand.* 109 (3): 217-221.

gravis. *Semin. Neurol.* 24 (1): 21-30.

of 100 consecutive patients. *J. Neurol.* 244 (2): 112-118.

assisted matched study. *Ann. Surg.* 184 (4): 453-458.

the right side of the thymus by a left approach than a dissection of the left side of the thymus by right approach, especially for the aortopulmonary window.

#### **4. Personal results**

Since April 1999, a thoracoscopic approach has been used in all patients admitted in the Department of General Surgery and Liver Transplantation of Fundeni Clinical Institute with either nonthymomatous myasthenia gravis or stage I and IIa Masaoka thymomas. There have been 300 patients with nontumoral myasthenia gravis (NTMG) that have suffered an extended thoracoscopic thymectomy in our center between April 1998 and April 2011.

We considered that favourable outcomes requires highly coordinated teamwork involving a strong collaboration between neurologists, surgeons, and anesthesiologists in making appropriate decisions on selection of patients, therapeutic options, and timing of surgery. All of the patients received specific treatment for at least 3 months before surgery in the Department of Neurology of our institute. Patients were considered suitable for a surgical procedure only when evidence showed good treatment tolerance and a stable quantitative myasthenia gravis (QMG) score of at least 10 points. We did not operate patients with pure ocular myasthenia gravis because we considered that the indication for thymectomy in ocular myasthenia gravis remained controversial. We did not operate patients with age over 60 years.

Treatment, morbidity, mortality, and postinterventional status at follow-up were also assessed according to the MGFA Recommendations for Clinical Research Standards, QMG scores being the most valuable tool in quantitative evaluation of clinical improvement or remission analysis. CSR was used as the end point for the evaluation of the efficacy and prognostic factors. Patients were considered to be in complete stable remission status if they exhibited no symptoms of MG for at least one year and had received no therapy for MG during that time.

A left thoracoscopic approach was used for 29% of the patients and a right thoracoscopic approach for 71% of the patients. Decision to use the right-side or left-side approach was considered in relation with the CT aspect of each patient's thymus. Extensive dissection in the region of the thyroid and lateral neck, through a separate collar incision, was not routinely performed. The low probability of finding aberrant thymic remnants in these locations did not justify this approach as a standard procedure. Minicervicotomies were performed on 7 patients, due to cervical extensions of the thymus. There were no conversions to open thymectomy. The mean operative time was of 80+/- 45 min. There was zero mortality and morbidity was observed in 14 patients (4.66%): 10 patients previously reported(Tomulescu et al. 2006, 82:1003-1007) (severe postoperative myasthenia crisis in 1 patient who needed mechanical ventilation for 5 days, 2 with contralateral pneumothorax after drain removal, 3 with hemothorax that required emergent reintervention, and 6 with prolonged pleural drainage) and 2 patients with postoperative pneumonia.

The mean length of hospitalization was 2.1 days (range: 2-6 days).

Evaluating the post-interventional status according to the MGFA recommendations for Clinical Research Standards complete stabile remission (CSR) have been obtained in 62% (186 patients), pharmacologic remission (PR) in 8% (24 patients), minimal manifestation (MM) in 15% (45 patients), non changed (N) in 10% (30 patients), worse (W) in 1% (3 patients) and exacerbation (E) - patients who have fulfilled the criteria of CSR, PR, or MM but subsequently developed clinical findings greater than permitted by these criteria - in 4% (12 patients).

#### **5. Conclusions**

92 A Look into Myasthenia Gravis

the right side of the thymus by a left approach than a dissection of the left side of the

Since April 1999, a thoracoscopic approach has been used in all patients admitted in the Department of General Surgery and Liver Transplantation of Fundeni Clinical Institute with either nonthymomatous myasthenia gravis or stage I and IIa Masaoka thymomas. There have been 300 patients with nontumoral myasthenia gravis (NTMG) that have suffered an extended thoracoscopic thymectomy in our center between April 1998 and April 2011.

We considered that favourable outcomes requires highly coordinated teamwork involving a strong collaboration between neurologists, surgeons, and anesthesiologists in making appropriate decisions on selection of patients, therapeutic options, and timing of surgery. All of the patients received specific treatment for at least 3 months before surgery in the Department of Neurology of our institute. Patients were considered suitable for a surgical procedure only when evidence showed good treatment tolerance and a stable quantitative myasthenia gravis (QMG) score of at least 10 points. We did not operate patients with pure ocular myasthenia gravis because we considered that the indication for thymectomy in ocular myasthenia gravis remained controversial. We did not operate patients with age over 60 years. Treatment, morbidity, mortality, and postinterventional status at follow-up were also assessed according to the MGFA Recommendations for Clinical Research Standards, QMG scores being the most valuable tool in quantitative evaluation of clinical improvement or remission analysis. CSR was used as the end point for the evaluation of the efficacy and prognostic factors. Patients were considered to be in complete stable remission status if they exhibited no symptoms of MG for at least one year and had received no therapy for MG during that time. A left thoracoscopic approach was used for 29% of the patients and a right thoracoscopic approach for 71% of the patients. Decision to use the right-side or left-side approach was considered in relation with the CT aspect of each patient's thymus. Extensive dissection in the region of the thyroid and lateral neck, through a separate collar incision, was not routinely performed. The low probability of finding aberrant thymic remnants in these locations did not justify this approach as a standard procedure. Minicervicotomies were performed on 7 patients, due to cervical extensions of the thymus. There were no conversions to open thymectomy. The mean operative time was of 80+/- 45 min. There was zero mortality and morbidity was observed in 14 patients (4.66%): 10 patients previously reported(Tomulescu et al. 2006, 82:1003-1007) (severe postoperative myasthenia crisis in 1 patient who needed mechanical ventilation for 5 days, 2 with contralateral pneumothorax after drain removal, 3 with hemothorax that required emergent reintervention, and 6 with

thymus by right approach, especially for the aortopulmonary window.

prolonged pleural drainage) and 2 patients with postoperative pneumonia.

Evaluating the post-interventional status according to the MGFA recommendations for Clinical Research Standards complete stabile remission (CSR) have been obtained in 62% (186 patients), pharmacologic remission (PR) in 8% (24 patients), minimal manifestation (MM) in 15% (45 patients), non changed (N) in 10% (30 patients), worse (W) in 1% (3 patients) and exacerbation (E) - patients who have fulfilled the criteria of CSR, PR, or MM

The mean length of hospitalization was 2.1 days (range: 2-6 days).

**4. Personal results**

Unilaterally extended thoracoscopic thymectomy is a technically demanding procedure that requires expertise in extended thymectomy and in advanced minimally invasive techniques. The right side, the left side or even bilateral approach should be chosen in relation with the method the surgeon is more comfortable and from which best results (morbidity, mortality, completeness of thymectomy) should be expected.

The maximal thymectomy should remain the benchmark against which other thymectomy techniques are measured (whether or not it is the surgical technique of choice) (Jaretzki, III, Barohn, Ernstoff, Kaminski, Keesey, Penn, and Sanders 2000, 70:327-334;Jaretzki, III and Wolff 1988, 96:711-716; Sonett and Jaretzki, III 2008, 1132:315-328) but we consider that with no mortality, low morbidity, comparable CSR and PR, better cosmetic and pulmonary function-sparing effect, superior compliance from the patients and neurologists with a higher rate acceptance of surgical treatment, this minimally invasive approach could become the best first solution in the multimodal treatment of myasthenia gravis.

#### **6. References**

**7**

**Robotic Thymectomy**

*Liver Transplant "Dan Setlacec"*

*Fundeni Clinical Institute, Center of General Surgery and*

After the great success of minimally invasive approach in abdominal surgery, thoracoscopic surgery has gained a broad acceptance for diagnostic and therapeutic procedures due to the fact that permits good exposure of the pleural cavity, enables extensive dissection and combines the advantages of minimal invasive surgery with little tissue trauma, short

Although thoracoscopic surgery brings clear benefits to the patients, surgeons face distinct disadvantages: working through fixed entry points limits maneuverability of the instruments inside the body cavity, looking at a two-dimensional screen. Surgeons are handicapped by the loss of the visual depth perception, the need for a human assistant to hold and move the camera makes surgeons lose the independent ability of controlling the

Telemanipulator robots have been developed in response to limitations placed on the surgeon by endoscopic surgery: reduced visual quality and control, reduced dexterity

Of the two advanced surgical robotic systems that are used for thoracic and abdominal surgery only "da Vinci" remains since the 2003 acquisition of Computer Motion by Intuitive

The Da Vinci system consists of three primary components: the surgeon's viewing and control console (fig 1),a movable cart with three or four articulated robot arms (fig2) and the

The console is located outside the sterile field. The surgeon is seated in front of the console and manipulates handles that are similar to "joysticks" while viewing a high-resolution, truly three-dimensional image of the surgical field through binoculars (fig 4). Manipulation of the handles transmits electronic signals to the computer, which can control and modify the movement of instrument tips by downscaling the movements, by eliminating physiologic tremor, and by adjusting grip strength applied to the tools. The masters are aligned with instrument tips, making the movement of the instruments natural and intuitive. The surgeon can also monitor the status of the instruments and arms without removing the head from the console through the various messages that are displayed on the display. In fact the sensation is that messages appear in the operation field. An infrared

Surgical and the corporate decision to stop production of the Zeus system.

**1. Introduction**

recovery, less pain and improved cosmetic results.

related to the instrumentation, ergonomics.

camera tower(the vision cart) (fig3).

operation field (Vasilescu C and Popescu I 2008, 103:9-11).

Victor Tomulescu

*Romania*

## **Robotic Thymectomy**

#### Victor Tomulescu

*Fundeni Clinical Institute, Center of General Surgery and Liver Transplant "Dan Setlacec" Romania*

#### **1. Introduction**

94 A Look into Myasthenia Gravis

Jaretzki A, III, Barohn RJ, Ernstoff RM, Kaminski HJ, Keesey JC, Penn AS, and Sanders DB.

Jaretzki A, Steinglass KM, and Sonett JR. 2004. Thymectomy in the management of

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Lennon VA, Lindstrom JM, and Seybold ME. 1976. Experimental autoimmune myasthenia gravis: cellular and humoral immune responses. *Ann. N. Y. Acad. Sci.* 274: 283-299. Mineo TC, Pompeo E, and Ambrogi V. 1997. Video-assisted thoracoscopic thymectomy: from the right or from the left? *J. Thorac. Cardiovasc. Surg.* 114 (3): 516-517. Navaneetham D, Penn AS, Howard JF, Jr., and Conti-Fine BM. 2001. Human thymuses

Niks EH, Kuks JB, Roep BO, Haasnoot GW, Verduijn W, Ballieux BE, De Baets MH, Vincent

Ruckert JC, Czyzewski D, Pest S, and Muller JM. 2000. Radicality of thoracoscopic thymectomy--an anatomical study. *Eur. J. Cardiothorac. Surg.* 18 (6): 735-736. Schonbeck S, Padberg F, Hohlfeld R, and Wekerle H. 1992. Transplantation of thymic

Sommer N, Tackenberg B, and Hohlfeld R. 2008. The immunopathogenesis of myasthenia

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