Surgical safety analysis and clinical experience sharing of myasthenia gravis patients aged 65 and over

Abstract

Background

To evaluate the surgical safety in myasthenia gravis (MG) patients aged 65 and over.

Methods

A total of 564 patients with MG who underwent surgery in the Department of Thoracic Surgery of Beijing Hospital from November 2011 to March 2022 were included in the study and divided into two groups taking the age of 65 as the boundary. Perioperative data of patients were recorded and statistically analyzed.

Results

Compared with young patients, FEV1, FEV1% and MVV in lung function of elderly MG patients were worse (p < 0.001, p < 0.001, p = 0.002). Postoperative drainage time was longer (p < 0.001), combined with more drainage volume (p = 0.002). The American Society of Anesthesiologists (ASA) score of elderly MG patients was higher (p < 0.001). Complications were more likely to occur (p = 0.008) after surgery and Clavien‐Dindo classification (CDC) of postoperative complications was also higher (p = 0.003). Meanwhile, postoperative myasthenic crisis (POMC) was more likely to occur (p = 0.038). Logistic regression showed that lower DLCO% (p = 0.049) was an independent risk factor for postoperative complications.

Conclusions

Surgical indications should be considered in each elderly MG patient on an individual basis. Moreover, most elderly MG patients safely survive the perioperative period and benefit from surgery through individualized consideration.

To evaluate the surgical safety in myasthenia gravis patients aged 65 and over. Most elderly MG patients can safely survive the perioperative period and benefit from surgery through individualized consideration. Lower DLCO% was also an independent risk factor for postoperative complications.

INTRODUCTION

Aging leads to a decline in the function of various organs, lack of compensatory ability, and the elderly often suffer from a variety of cardio‐cerebrovascular diseases and other complications, resulting in seriously decreased tolerance to anesthesia and surgery. In addition, myasthenia gravis (MG) patients are prone to postoperative MG crisis (POMC); various studies have reported that MG surgery has a certain mortality rate. MG is a rare disease, with a global prevalence of about 150 to 250 per million, and an incidence of 4 to 10 per million. ¹ , ² Consequently, most centers lack experience, and many surgeons are reluctant to perform surgical treatment for elderly MG patients. Many surgeons ³ , ⁴ believe that surgery should be carefully considered in MG patients over the age of 60 and the indications should be more strict. Thymectomy is only used as a treatment option in elderly MG patients with imaging findings of definite thymic abnormalities, rapid progression of MG symptoms, and ineffective medical treatment. For elderly MG patients with ocular or acetylcholine receptor antibody (AChR) negative, medical treatment is the standard method, ⁵ but serum‐negative MG is rare in elderly patients, and therefore many elderly patients can benefit from thymectomy. ⁴ , ⁶ , ⁷ , ⁸ , ⁹

METHODS

From November 2011 to March 2022, thymectomy was performed in 564 MG patients with thymus or thymic hyperplasia or other thymic abnormalities at the Department of Thoracic Surgery, Beijing Hospital. The patients were divided into two groups: ≥65 years old group (84 cases) and <65 years old group (481 cases). The Institutional Review Board‐approved number was 2020BJYYEC‐010‐01.

Perioperative information including gender, age, whether combined with thymoma, Osserman classification, preoperative American Society of Anesthesiologists (ASA) score, lung function, postoperative complications (including any complications and Clavien‐Dindo classification) etc., was collected and recorded.

The indications for surgery in elderly MG patients were as follows: (1) A clear diagnosis of MG; (2) thymus abnormalities in imaging, including thymoma, thymic hyperplasia, etc. The contraindications were as follows: (1) No obvious lesion in the thymus area, (2) negative AChR, (3) ASA score of 4, (4) widespread pleural metastases or unresectable of malignant thymomas and (5) unsatisfactory control of MG symptoms (many patients underwent surgery but their symptoms were not satisfactorily controlled).

In all patients, surgical resection included all thymus and surrounding fat tissues, bilateral mediastinal fat, and diaphragmatic angle fat. Surgical approaches included median sternotomy, bilateral thoracoscopy, right or left thoracoscopy, and subxiphoid thoracoscopy.

Postoperative myasthenic crisis (POMC) was classified as grade IV of Clavien‐Dindo because it is potentially life‐threatening.

Statistical analysis

All analyses were performed in SPSS version 26.0 (IBM Corporation). Descriptive statistics are shown as counts and percentages for categorical variables, while means ± standard deviations are reported for continuous variables. Pearson χ ² test or Fisher's exact test were used for categorical variables and independent‐samples t test or Mann–Whitney test were used for continuous variables. Variables with a p‐value lower than 0.10 in univariate logistic regression analysis were entered into a multivariate logistic regression analysis. p‐values lower than 0.05 were considered statistically significant.

RESULTS

Of the 564 MG patients, 292 were male and 273 were female, with an average age of 47.1 years (range:15 to 86 years).

The comparison of gender, age, whether combined with thymoma, Osserman classification, preoperative lung function (FEV1, FEV1/FVC, FEV1%, MVV%, DLCO%), ASA score, operation duration, whether to switch to thoracotomy, intraoperative blood loss, whether to transfuse blood, drainage volume in the first 3 days, days with drainage tube after operation, hospital stays after operation, whether there are postoperative complications after operation and Clavien‐Dindo classification of postoperative complications and so on between both groups are shown in Table 1.

TABLE 1.

Basic data

Variables	Patients aged below 65 years old	Patients aged 65 years old or above	t or z or χ 2	p‐value
N	481 (85.1%)	84 (14.9%)	‐	‐
Gender (male/female)	239/242	53/31	5.147	0.023
Whether combined with thymoma (no/yes)	331/150	56/28	0.153	0.696
Osserman classification			4.424	0.352
I	108 (22.5%)	17 (20.2%)
IIA	153 (31.8%)	21 (25.0%)
IIB	176 (36.6%)	33 (39.3%)
III	21 (4.4%)	7 (8.3%)
IV	23 (4.8%)	6 (7.1%)
Whether combined with other autoimmune diseases (no/yes)	436/45	72/12	1.916	0.166
Preoperative course (≤12/>12 months)	309/172	59/25	1.132	0.287
Preoperative history of myasthenic crisis (no/yes)	464/17	82/2	0.293	0.588
Bromobistigmine (no/yes)	57/424	5/79	2.546	0.111
Preoperative daily dose of pyridostigmine bromide (≤240/>240 mg)	390/91	65/19	0.624	0.429
Steroid (no/yes)	433/48	80/4	2.329	0.127
Immunosuppressants (no/yes)	421/60	73/10	0.012	0.913
FEV1	2.59 ± 0.72	1.98 ± 0.60	−6.490	0.000
FEV1/FVC	81.49 ± 8.93	76.67 ± 9.89	−4.160	0.000
FEV1%	83.72 ± 17.95	82.52 ± 21.34	−1.726	0.084
MVV%	77.82 ± 21.48	75.69 ± 25.42	−3.168	0.002
DLCO%	88.67 ± 18.37	85.40 ± 19.17	−1.052	0.293
ASA score (1/2/3)	267/177/37	18/47/19	39.160	0.000
Surgical procedure (OT/VAST)	74/407	17/67	1.247	0.264
Operation duration	127.55 ± 45.73	127.38 ± 48.89	−0.229	0.819
Whether to switch to thoracotomy (no/yes)	478/3	84/0	0.527	0.468
Intraoperative blood loss (<400/400–1000/>1000)	471/4/6	82/2/0	2.665	0.264
Whether to transfuse blood (no/yes)	476/5	83/1	0.016	0.901
Drainage volume in the first 3 days (≤800/>800)	350/131	47/37	9.675	0.002
Days with drainage tube after operation (≤3/>3)	338/143	42/42	13.342	0.000
Hospital stays after operation			−0.783	0.434
Postoperative complications (no/yes)	396/85	57/27	9.674	0.008
Clavien Dindo classification of postoperative complications (1/2/3/4)	4/13/3/65	0/8/0/19	16.030	0.003

Note: The significance of bold value in this Table is that the p‐value is less than 0.05.

Abbreviation: ASA, American Society of Anesthesiologists. FEV1: forced expiratory volume in 1 second FEV1%: predicted forced expiratory volume in 1 second FVC: forced vital capacity MVV: maximal voluntary ventilation DLCO: predicted diffusion lung capacity for carbon monoxide OT: open thoracotomy VAST: video‐assisted thoracic surgery.

The logistic regression of postoperative complications is shown in Table 2. Univariate analysis showed age (p = 0.002), whether combined with thymoma (p = 0.004), ASA score (p < 0.001), FEV1 (p < 0.001), FEV1% (p < 0.001), MVV% (p < 0.001), DLCO% (p < 0.001), surgical procedure (p = 0.011), whether to switch to thoracotomy (p = 0.087), whether to transfuse blood (p = 0.015) and blood loss (p = 0.014) were risk factors for postoperative complications. Variables with a p‐value lower than 0.10 in univariate logistic regression analysis were entered into a multivariate logistic regression analysis. The results showed that lower DLCO% was an independent risk factor for postoperative complications.

TABLE 2.

Logistic regression analysis

Variables	Univariate analysis			Multivariate analysis
	OR	95% CI	p‐value	OR	95% CI	p‐value
Gender
Female	Reference
Male	1.202	0.793–1.822	0.385
Age	1.022	1.008–1.036	0.002	1.003	0.982–1.023	0.810
Thymoma	1.863	1.217–2.853	0.004	1.079	0.605–1.924	0.796
Other autoimmune disorders	1.088	0.55–2.133	0.806
ASA score
I	Reference			Reference
II + III	2.224	1.446–3.421	0.000	1.593	0.898–2.827	0.111
FEV1	0.368	0.257–0.529	0.000	0.586	0.315–1.091	0.092
FEV1/FVC	0.986	0.965–1.007	0.196
FEV1%	0.970	0.958–0.982	0.000	0.989	0.970–1.009	0.281
MVV%	0.979	0.968–0.989	0.000	0.998	0.984–1.012	0.737
DLCO%	0.977	0.965–0.989	0.000	0.986	0.973–1.000	0.049
Operation duration	1.004	0.999–1.008	0.131
Surgical procedure
OT	Reference			Reference
VAST	0.518	0.312–0.860	0.011	0.978	0.481–1.986	0.950
Whether to switch to thoracotomy	8.218	0.738–91.454	0.087	5.361	0.316–90.879	0.245
Whether to transfuse blood	8.352	1.510–46.192	0.015	6.634	0.289–152.340	0.237
Blood loss
0–400	Reference
>400	4.217	1.334–13.334	0.014	1.509	0.128–17.800	0.744

Note: The significance of bold value in this Table is that the p‐value is less than 0.05.

Abbreviation: ASA, American Society of Anesthesiologists.FEV1: forced expiratory volume in 1 second FEV1%: predicted forced expiratory volume in 1 second FVC: forced vital capacity MVV: maximal voluntary ventilation DLCO: predicted diffusion lung capacity for carbon monoxide OT: open thoracotomy VAST: video‐assisted thoracic surgery.

DISCUSSION

MG is a rare disease with two peak incidences in women, 20 to 40 years and 50 to 70 years, respectively, while the peak incidence in men is 60 to 80 years old. ¹ , ¹⁰ The incidence of MG in the elderly has increased significantly, while early‐onset MG has shown a downward trend. A study in Japan showed that the incidence of MG in the elderly (age > 60 years) increased 20 times from 2001 to 2006 compared with 1981 to 1990, ¹¹ and its proportion increased rapidly, in 2006, the proportion of patients aged 65 years or older increased to 16.8%. ¹² Many studies have suggested that the incidence of women in the young group was slightly higher, and the incidence of men in the elderly group was higher. ¹³ Our study also arrived at a similar conclusion. The proportion of men/women in the elderly group was greater than that in the young group (p = 0.023). We will face more and more elderly MG patients in the foreseeable future.

MG patients with thymoma should undergo extended thymectomy, which has become the standard surgical method for the treatment of thymoma and MG with thymic hyperplasia. ¹⁴ , ¹⁵ For patients with nonthymoma ocular MG (OMG), thymectomy can be performed if they are refractory to other treatments. Juvenile myasthenia gravis (JMG) is mainly ocular muscle type and rarely transforms to systemic type, ¹⁶ , ¹⁷ and surgical treatment is generally not recommended; however, elderly OMG often transforms to systemic type, and thymectomy can prevent secondary systematization. ¹⁸ For nonthymoma AChR‐generalized myasthenia gravis (AChR‐GMG), thymectomy is recommended in the early stage of the disease, which can reduce the use of other immunosuppressants. A global multicenter randomized controlled trial (MGTX) found that thymectomy can improve the clinical symptoms of AChR‐GMG in the long‐term, and it is helpful for glucocorticoid reduction and concurrent use of immunosuppressants such as azathioprine. ¹⁹ , ²⁰ Thymectomy has also been reported to be beneficial for older patients. ⁴ , ⁶ , ⁷ , ⁸ , ⁹

Elderly patients often have various comorbidities determined before surgery, and the risk of surgery and anesthesia will inevitably increase, as will the risk of postoperative complications accordingly. To assess the association, we applied the ASA grading system to assess preoperative comorbidities. This system was originally designed for the prediction and assessment of anesthesia risk during surgery, but many studies have confirmed that ASA score can also predict the occurrence of postoperative complications quite well. ²¹ , ²² , ²³ In order to minimize various interference and ensure accuracy, the same investigator performed preoperative ASA scores for all patients, and these scores were made after excluding MG‐related symptoms and grades. Not surprisingly, we found that older patients had higher ASA scores, higher rates of postoperative complications and higher complication scores, but no increased risk of surgery or anesthesia, such as duration of surgery or intraoperative bleeding. In another of our studies, ²⁴ univariate and multivariate analyses of MG patients showed that ASA score was an independent predictor of POMC. This suggests that the ASA score is important in the preoperative evaluation of patients with MG, which has not been mentioned in any previous study.

Compared with the young group, the elderly patients with MG had longer postoperative drainage time and more drainage volume, which might be caused by the fact that anticoagulants are far more likely to to be used before and after surgery in the elderly than the young group. ²⁴ However, these did not result in longer hospital stays or other adverse outcomes.

A few previous studies have suggested that elderly MG patients are more likely to suffer from POMC, ²⁵ and we found that the incidence of POMC in the elderly group was significantly higher than that in the young group. In our study, the preoperative ventilation function of elderly patients was significantly worse than that of the young patients. Many studies ²⁶ , ²⁷ , ²⁸ have also found that the occurrence of POMC is significantly correlated with lung function. As the body ages, breathing muscles strength decreases as does chest wall compliance and the lungs elastic retraction force is reduced. Elderly patients are more likely to suffer from other chronic respiratory system diseases, especially lung structural lesions, such as chronic bronchitis, chronic obstructive pulmonary emphysema, bronchial asthma, bronchiectasis, atelectasis, which destroy smooth muscle and cartilage of the tracheal tube wall, resulting in collapse of the airway wall and damage to lung structure, and the natural barrier of respiratory tract disappear accordingly. The above problems also lead to a decline in ventilatory function in the elderly. In addition, long‐term chronic inflammatory stimulation caused by the above complications in the elderly breaks the elastic fibers of the alveolar wall, and the weakening alveolar elasticity leads to alveolar expansion. At the same time, due to the infiltration of a large number of inflammatory cells and macrophages around the tracheal wall, increased glands, and fibrotic hyperplasia, the sputum is thick and difficult to discharge from the respiratory tract. Long‐term chronic inflammatory stimulation leads to metaplasia of respiratory epithelial cells from columnar to squamous, which reduces, or even deprives, the activity of cilia, resulting in the decline of airway secretion clearance function. Intraoperative endotracheal intubation stimulation, pyridostigmine bromide and other reasons lead to more airway secretions. Also, saliva in the oral cavity and gastric fluid regurgitation prevent patients being able to swallow. They also they often disgorge feebly, which can easily cause aspiration. A study by Kikuchi et al. pointed out that the acute onset of pneumonia in elderly patients is closely related to latent aspiration. ²⁹ In another prospective multicenter study, ³⁰ the incidence of aspiration pneumonia in hospitalized elderly patients aged ≥70 years was 80.1%, and the high incidence of aspiration in elderly patients was related to various underlying diseases, cough and weakened pharyngeal reflex. ²⁸ These will obviously lead to a greater increase in the incidence of POMC and postoperative pneumonia.

In 1992, Clavien et al. ³¹ established an evaluation system for postoperative complications according to whether they required medical intervention and formulated a unified evaluation standard which greatly increased the comparability among postoperative complications. ³² After years of application and development, this system provides a standard with excellent reliability and validity for the definition and severity grading of postoperative complications, which is widely used and verified by hundreds of studies in many surgical fields. ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷ At present, this system has not been used in thymectomy for MG patients. In order to make postoperative complications comparable and statistical, we applied this system and found that the incidence and severity of postoperative complications in elderly patients with MG were higher than those in young patients. Further analysis showed that the incidence of grade II and IV complications was mainly higher in the elderly group, while the incidence of complications of other grades was not high. Among grade II complications, atrial fibrillation and other arrhythmias were more common, while POMC was more common in grade IV complications. The ASA score and Clavien‐Dindo classification were both higher in elderly patients, and after statistical analysis no direct relationship was found. It indicates that the occurrence of postoperative complications in elderly patients with MG is not directly related to preoperative complications, but more influencing factors, such as lung function and MG symptoms. We then performed univariate and multivariate analysis of postoperative complications in MG patients, and found that age, combined with thymoma, ASA score, FEV1, FEV1%, MVV%, DLCO%, surgical procedure, whether to switch to thoracotomy, intraoperative blood transfusion and intraoperative bleeding were associated with postoperative complications in univariate analysis. In multivariate analysis, only DLCO% was an independent risk factor for postoperative complications.

In the past 10 years, there have been no perioperative deaths in MG patients at our center. Although elderly patients have a higher risk of surgery, and the incidence and severity of postoperative complications were higher than young patients, all elderly patients were safely discharged, and there was no prolongation of hospital stay. We summarize our experience as follows. (1) Before surgery, the condition of all organs of the body should be carefully checked, especially for cardio‐cerebrovascular diseases. After multidisciplinary consultation, if necessary, the cardiovascular and cerebrovascular problems should be solved first. Postoperative anticoagulant and antiplatelet drugs should be preferentially used. Blood pressure fluctuation, especially hypotension, should be avoided as much as possible during and after surgery. (2) Preoperative MG symptoms should be controlled as far as possible, so that the patients could be operated in a better state. If necessary, preoperative gamma globulin or glucocorticoid shock therapy should be used. (3) On the morning of the operation day, pyridostigmine bromide and anisodamine should be taken as usual. We always try to control the operation and anesthesia time to minimize the amount of muscle relaxant drugs. In recent years, laryngeal mask assisted ventilation has been used instead of traditional tracheal intubation in most thymic surgeries, which further reduces the irritation of the airways and the dosage of muscle relaxants. (4) If it is predicted that the patient may have swallowing problems after surgery or may need endotracheal intubation which prevents eating, an indwelling stomach tube should be placed during the operation to facilitate oral medication and enteral nutrition. (5) After operation, the dosage of cholinesterase should be adjusted timely according to the MG symptoms of patients, and the dosage of anisodamine is often increased according to the patient's secretions. (6) Postoperative symptoms such as gasp, excessive secretion and inability to discharge should not be ignored because of the high blood oxygen saturation on the monitor. Most patients with crisis first appear with elevated partial pressure of carbon dioxide and not low partial pressure of oxygen, so examination of arterial blood gas analysis on time is essential. In general, noninvasive or invasive mechanical ventilation should be given when the PaCO₂ is significantly higher than before surgery (in many patients with severe symptoms, the PaCO₂ is significantly higher before surgery, which may be well tolerated). Our experience is that if the oxygen saturation starts to drop on the monitor, it usually gives us less time and may require emergency endotracheal intubation to keep the patient safe. (7) When faced with a patient's crisis, it is not necessary to determine whether it is a myasthenic or a cholinergic crisis (in fact, the two conditions often exist together). Instead, noninvasive or invasive mechanical ventilation should be given first to ensure the patient's safety. (8) Noninvasive mechanical ventilation was used as far as possible in postoperative myasthenic crisis. We found that most patients could safely survive the postoperative myasthenic crisis with the assistance of a noninvasive ventilator. (9) If the patient requires endotracheal intubation ventilator assisted ventilation, and it is expected that the endotracheal intubation cannot be removed in a short time, it is recommended that anticholinesterase drugs such as pyridostigmine bromide are discontinued and the patient allowed to rest sufficiently, and then such drugs are reapplied to improve MG symptoms when the patient's general condition improves, so as to try to remove the endotracheal intubation. (10) Gamma globulin can help most patients avoid POMC or quickly pass the POMC stage. For patients who are predicted to have myasthenic crisis after surgery, preoperative application of gamma globulin can reduce the probability of postoperative crisis. The application of gamma globulin in patients with postoperative crisis generally begins to be effective on the fourth to fifth day, and most patients can safely and quickly overcome the POMC period. (11) If gamma globulin therapy effect is poor, in the case of secure recovery after the operation, shock therapy with glucocorticoids can be applied. Generally, the treatment effect begins to appear after 1 to 2 weeks, and reaches a peak after 6 to 8 weeks. After achieving the treatment goal, the dose should be maintained for 6 to 8 weeks, and then should gradually be reduced. The efficacy of glucocorticoid shock therapy is higher than that of gamma globulin, but it should be noted that there is often a brief exacerbation period in the early stage. In addition, rapid reduction of the dose may cause relapse or exacerbation of the disease. (12) Because of the shortage of blood supply, we have little experience in plasmapheresis.

Preoperative evaluation is very important for elderly patients. After all, aging will lead to decreased organ function and poor compensatory ability. Also, because MG symptom improvement after thymectomy takes a long time, the surgical risk, MG improvement time and life expectancy should be fully considered when judging the surgical indications for such patients. ³

In conclusion, as aging progresses, surgeons are increasingly faced with surgical decision‐making problems in elderly patients. The surgical risk for elderly MG patients is higher than that of young people. Surgical indications should be considered on an individual basis for each elderly MG patient. After careful evaluation and full preparation before surgery, close observation during and after surgery, and timely response to changes in the condition, the vast majority can safely go through the perioperative period.

AUTHOR CONTRIBUTIONS

Hongfeng Tong: Project administration and supervision. Peng Jiao: Conceptualization, methodology, data curation and writing original draft. Fanjuan Wu: Methodology, data curation, writing original draft and editing. Jiangyu Wu: Data curation, writing original draft and editing. Yaoguang Sun, Wenxin Tian, Hanbo Yu, Chuan Huang, Donghang Li, Qingjun Wu, Chao Ma: Data curation, writing review, and editing. All authors contributed to the article and approved the submitted version.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

Jiao P, Wu F, Wu J, Sun Y, Tian W, Yu H, et al. Surgical safety analysis and clinical experience sharing of myasthenia gravis patients aged 65 and over. Thorac Cancer. 2023;14(8):717–723. 10.1111/1759-7714.14799

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.