European Journal of Cardio-Thoracic Surgery 45 (2014) e76–e88 doi:10.1093/ejcts/ezt641 Advance Access publication 12 February 2014
ORIGINAL ARTICLE
Thymectomy in myasthenia gravis: proposal for a predictive score of postoperative myasthenic crisis† Giovanni Leuzzia,*, Elisa Meaccib, Giacomo Cusumanoc, Alfredo Cesariob,c,d, Marco Chiappettab, Valentina Dall’Armie, Amelia Evolif, Roberta Costag, Filippo Lococoh, Paolo Primierig, Stefano Margaritorab and Pierluigi Granoneb a b c d e f g h
Department of Surgical Oncology, Thoracic Surgery Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy Department of Thoracic Surgery, Catholic University of Sacred Heart, Rome, Italy Department of Thoracic Surgery, Azienda Ospedaliero Universitaria Vittorio Emanuele, Catania, Italy IRCCS San Raffaele Pisana, Rome, Italy Unit of Clinical and Molecular Epidemiology, IRCCS San Raffaele Pisana, Rome, Italy Department of Neurology, Catholic University of Sacred Heart, Rome, Italy Department of Anesthesiology and Intensive Care, Catholic University of Sacred Heart, Rome, Italy Thoracic Surgery Unit, IRCCS - Arcispedale Santa Maria Nuova, Reggio Emilia, Italy
* Corresponding author. Department of Surgical Oncology, Thoracic Surgery Unit, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy. Tel: +39-0652665530 or +39-3488893788; e-mail: [email protected] (G. Leuzzi). Received 10 September 2013; received in revised form 28 November 2013; accepted 4 December 2013
Abstract OBJECTIVES: Thymectomy plays an important role in patients with myasthenia gravis (MG). This study aimed to explore predictors of postoperative myasthenic crisis (POMC) after thymectomy and to define a predictive score of respiratory failure. METHODS: The clinical data of 177 patients with MG undergoing thymectomy from January 1995 to December 2011 were retrospectively reviewed. The following factors were analysed in relation to the occurrence of myasthenic crisis: gender, age, body mass index (BMI), antiacetylcholine receptor-antibody level, bulbar symptoms, comorbidities, duration of symptoms, Osserman-stage, Myasthenia Gravis Foundation of America (MGFA) stage, history of myasthenic crisis, use of immoglobulins or plasmapheresis, kind of therapy, spirometric and blood gas parameters, histology, kind of surgery, non-myasthenic complications and duration of intubation. RESULTS: Twenty-two patients experienced postoperative respiratory failure after thymectomy. Univariate analysis revealed a correlation with age >60 years (odds ratio (OR) = 1.79, 95% confidence interval (CI) = 1.04–6.78; P = 0.040); Osserman-stage (IIB- OR = 5.16, 95% CI = 1.10–24.18; P = 0.037, III–IV- OR = 8.75, 95% CI = 1.53–50.05; P = 0.015); bulbar symptoms (OR = 7.42, 95% CI = 1.67–32.84; P = 0.008); BMI >28 (OR = 3.99, 95% CI = 1.58–10.03; P = 0.003); preoperative plasmapheresis (OR = 2.97, 95% CI = 1.18–14.04; P = 0.021); duration of symptoms >2 years (OR = 4.00, 95% CI = 1.09–14.762; P = 0.036); extended surgery (OR = 2.52, 95% CI = 1.02–6.22; P = 0.045); lung (OR = 4.05, 95% CI = 1.44–11.42; P = 0.008), pericardial (OR = 3.78, 95% CI = 1.45–9.82; P = 0.006) or pleural resection (OR = 3.23, 95% CI = 1.30–8.03; P = 0.012); Vital Capacity % 40 mmHg (OR = 3.76, 95% CI = 1.12–12.68; P = 0.032). Multivariate logistic regression analysis showed that Osserman-stage (IIB- OR = 5.69, 95% CI = 1.09–29.69; P = 0.039 (III–IV- OR = 11.33, 95% CI = 1.67–76.72; P = 0.013), BMI >28 (OR = 3.65, 95% CI = 1.10–12.15; P = 0.035), history of myasthenic crisis (OR = 24.10, 95% CI = 2.34–248.04; P = 0.007), duration of symptoms >2 years (OR = 5.94, 95% CI = 1.12–31.48; P = 0.036) and lung resection (OR = 8.48, 95% CI = 2.18–32.97; P = 0.002) independently predict POMC. Excluding history of preoperative myasthenic crisis (statistically associated with Osserman-stage), we built a scoring system according to the OR of Osserman-stage (I–IIA, IIB, III–IV), BMI ( 85–90%; pO2 > 50–60 mmHg; pH > 7.32; increase in PaCO2 < 10 mmHg); (3) haemodynamic stability ( pulse < 120–140 bpm; systolic blood pressure < 180–200 mmHg) and (4) stable ventilation pattern (respiratory rate < 30–35 breaths/min). The spontaneous breathing trial was performed with a pressure support ventilation, using a gradual decrease in the pressure support to a minimum level of 5–8 cm H2O. Postoperative analgesia was maintained with an intravenous administration of ketorolac (every 12 h) or paracetamol (every 8 h). In our study, POMC was defined as an event of respiratory failure due to neuromuscular weakness occurring in patients with a prolonged postoperative intubation (more than 24 h) or who were successfully weaned from a mechanical ventilator after thymectomy and required a re-intubation or a resuscitation support. Cholinergic crises or respiratory failures due to phrenic paralysis, lung infection or COPD exacerbation were excluded from the definition of POMC. Patients’ clinical records were reviewed and the following parameters were recorded: gender, age, body mass index (BMI), antiacetylcholine receptor (AChR)-antibody level, comorbidities, duration of symptoms, bulbar symptoms, Osserman-stage, Myasthenia Gravis Foundation of America (MGFA) stage, history of preoperative crisis, use of immoglobulins or plasmapheresis, kind of drug therapy, spirometric and blood gas parameters, histology, extension of surgery, myasthenic complication, non-myasthenic complications (NMCs), duration of mechanical ventilation, the need of re-intubation, hospital stay and ICU stay. Thymic lesions were classified according to the WHO classification; Masaoka staging annotations were added in all cases of thymoma.
Statistical analysis The primary endpoint of the study was the incidence of POMC and this was defined before the start of the study. Secondary endpoints were: occurrence of complications, ICU stay longer than 24 h, intubation longer than 6 h and re-intubation. The sample characteristics were summarized by absolute and relative frequencies for categorical variables and by means ± standard deviations for continuous variables. For each outcome, simple logistic regression analysis was carried out to estimate the pure effect of all factors (unadjusted odds ratios (ORs)); subsequently, multiple logistic regression analysis was implemented to identify independent predictors of all outcomes and to obtain adjusted estimates of effect (adjusted ORs). The final multiple logistic regression models for all outcomes were achieved by applying a forward variable selection procedure, iteratively; the selection procedure was stopped when no statistically significant contribution could be obtained by the inclusion of an additional variable into the model; variables associated with previously selected factors were excluded from the model selection.
THORACIC
G. Leuzzi et al. / European Journal of Cardio-Thoracic Surgery
e78
G. Leuzzi et al. / European Journal of Cardio-Thoracic Surgery
A new scoring system for POMCs was built based on the estimation results obtained by the multivariable logistic regression analysis on POMCs. Description of the criteria applied is provided in the results section. The predictive role of this new score was also evaluated by means of logistic regression analysis and findings are presented in the results section. The threshold for statistical significance was set at P < 0.05. All analyses were performed in the STATA/SE V12.0 software package.
RESULTS Essential features of the patient population The clinical, pneumological and surgical characteristics of the total sample are summarized in Table 1. We performed trans-sternal thymectomy by a standard or cosmetic incision in 111 (63%) and 66 (37%) patients, respectively. The average length of the surgical procedure was 118.2 ± 23.4 min (range 71–212). Pathological examination identified a benign thymic disease in 53 (30%) cases (thymic atrophy in 24, hyperplasia in 24, lymphoid hyperplasia in 4 and cyst in 1 patient). Thymomas were diagnosed in 124 (70%) patients and classified according to the Masaoka (39% in Stage I, 38% in Stage II, 18% in Stage III and 5% in Stage IV) and the WHO (6% type A; 12% type AB; 6% type B1, 55% type B2; 11% type B2– B3; 8% type B3 and 2% type C) staging systems. MGFA classification was also evaluated in a subset of 92 patients (Stage I: 4%, Stage II: 30%, Stage III: 47%, Stage IV: 7%, Stage V: 12%): since this subset constitutes 52% of the total sample, MGFA was not taken into account in inferential statistics. Postoperative complications occurred in 56 (32%) patients: in particular, POMC was diagnosed in 22 (12%) cases. Forty-three patients experienced at least a NMC (blood loss in 26 patients, myocardial infarction and arrhythmia, respectively, in 2 and 9 cases, pneumonia in 7 patients). Thirty-day mortality occurred in 1 patient, who died of myocardial infarction.
Overall complications, postoperative myasthenic crisis, non-myasthenic complications The occurrence of postoperative complications was investigated to identify factors predictive of any complication, POMC and NMC. Regarding the occurrence of any complication, simple logistic regression identified eight variables with a statistically significant pure effect: age >60 years (P = 0.023), Osserman-stage higher than IIB (IIB P = 0.007; III–IV P = 0.003), bulbar symptoms (P < 0.001), BMI ≥28 (P = 0.008), cardio-vascular comorbidities (P = 0.008), plasmapheresis (P = 0.001), lung resection (P = 0.027) and thymoma with WHO classification higher than B2 (P = 0.046). From multivariable logistic regression analysis, it emerged that Osserman classification, duration of MG and immunosuppressive therapy were independent predictive factors for a complication. More specifically, it was estimated that Osserman-stage IIB, vs Stages I–IIA, had and OR of 5.75 [2.05–16.12] with P = 0.001 and Osserman-stages III–IV, vs Stages I–IIA, had and OR of 10.05 [2.69– 37.62] with P = 0.001; immunosuppressive therapy had a protective effect with an OR of 0.28 [0.10–0.80] with P = 0.017 and duration of MG >2 years, vs 60 years (P = 0.040), Osserman-stage higher than IIB (IIB P = 0.037; III–IV P = 0.015), bulbar symptoms (P = 0.008), BMI ≥ 28 (P = 0.003), preoperative use of plasmapheresis (P = 0.021), duration of symptoms >2 years (P = 0.036), extended surgery (P = 0.045) with lung (P = 0.008) or pericardial (P = 0.006) or pleural resection (P = 0.012), vital capacity (VC)% ≤ 80% (P = 0.025) and PaCO2 ≥ 40 mmHg (P = 0.032) were associated with the occurrence of POMC. Multivariate analysis confirmed that Osserman-stage higher than IIB (IIB vs I–IIA: OR = 5.69 [1.09–29.69], P = 0.039; III–IV vs I–IIA: OR = 11.33 [1.67–76.72], P = 0.013), BMI ≥ 28 (OR = 3.65 [1.10–12.15], P = 0.035), duration of MG >2 years (OR = 5.94 [1.12– 31.48], P = 0.036) and pulmonary resection (OR = 8.48 [2.18–32.97], P = 0.002) were independent predictive factors for POMCs. These data were subsequently combined to create a scoring system. A statistically significant effect for preoperative myasthenic crises (OR = 24.10 [2.34–248.04], P = 0.007) also emerged; however, this should not be considered concomitantly to the Osserman classification due to a strong statistical association. Concerning the analysis of NMCs, the following variables were found to be significantly associated with the outcome: Osserman-stages III–IV (P = 0.024), bulbar symptoms (P < 0.001), cardio-vascular comorbidities (P = 0.006) and preoperative plasmapheresis (P = 0.012). Multiple logistic regression analysis confirmed that bulbar symptoms (OR = 8.89 [2.97–26.58], P < 0.001) and cardio-vascular comorbidities (OR = 2.73 [1.25–5.96], P = 0.012) were independent predictive factors for NMCs.
Postoperative myasthenic crisis scoring system As shown in the analysis of POMCs, we could identify four independent prognostic factors for the occurrence of such complications: Osserman-stage, BMI, duration of symptoms and lung resection. As explained before, history of preoperative myasthenic crisis was not taken into account since statistically strongly associated with Osserman-stage. Thus, we considered Osserman-stage (categorized into three groups: I–IIA, IIB, III–IV), BMI (divided into two groups:
ORIGINAL ARTICLE
Thymectomy in myasthenia gravis: proposal for a predictive score of postoperative myasthenic crisis† Giovanni Leuzzia,*, Elisa Meaccib, Giacomo Cusumanoc, Alfredo Cesariob,c,d, Marco Chiappettab, Valentina Dall’Armie, Amelia Evolif, Roberta Costag, Filippo Lococoh, Paolo Primierig, Stefano Margaritorab and Pierluigi Granoneb a b c d e f g h
Department of Surgical Oncology, Thoracic Surgery Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy Department of Thoracic Surgery, Catholic University of Sacred Heart, Rome, Italy Department of Thoracic Surgery, Azienda Ospedaliero Universitaria Vittorio Emanuele, Catania, Italy IRCCS San Raffaele Pisana, Rome, Italy Unit of Clinical and Molecular Epidemiology, IRCCS San Raffaele Pisana, Rome, Italy Department of Neurology, Catholic University of Sacred Heart, Rome, Italy Department of Anesthesiology and Intensive Care, Catholic University of Sacred Heart, Rome, Italy Thoracic Surgery Unit, IRCCS - Arcispedale Santa Maria Nuova, Reggio Emilia, Italy
* Corresponding author. Department of Surgical Oncology, Thoracic Surgery Unit, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy. Tel: +39-0652665530 or +39-3488893788; e-mail: [email protected] (G. Leuzzi). Received 10 September 2013; received in revised form 28 November 2013; accepted 4 December 2013
Abstract OBJECTIVES: Thymectomy plays an important role in patients with myasthenia gravis (MG). This study aimed to explore predictors of postoperative myasthenic crisis (POMC) after thymectomy and to define a predictive score of respiratory failure. METHODS: The clinical data of 177 patients with MG undergoing thymectomy from January 1995 to December 2011 were retrospectively reviewed. The following factors were analysed in relation to the occurrence of myasthenic crisis: gender, age, body mass index (BMI), antiacetylcholine receptor-antibody level, bulbar symptoms, comorbidities, duration of symptoms, Osserman-stage, Myasthenia Gravis Foundation of America (MGFA) stage, history of myasthenic crisis, use of immoglobulins or plasmapheresis, kind of therapy, spirometric and blood gas parameters, histology, kind of surgery, non-myasthenic complications and duration of intubation. RESULTS: Twenty-two patients experienced postoperative respiratory failure after thymectomy. Univariate analysis revealed a correlation with age >60 years (odds ratio (OR) = 1.79, 95% confidence interval (CI) = 1.04–6.78; P = 0.040); Osserman-stage (IIB- OR = 5.16, 95% CI = 1.10–24.18; P = 0.037, III–IV- OR = 8.75, 95% CI = 1.53–50.05; P = 0.015); bulbar symptoms (OR = 7.42, 95% CI = 1.67–32.84; P = 0.008); BMI >28 (OR = 3.99, 95% CI = 1.58–10.03; P = 0.003); preoperative plasmapheresis (OR = 2.97, 95% CI = 1.18–14.04; P = 0.021); duration of symptoms >2 years (OR = 4.00, 95% CI = 1.09–14.762; P = 0.036); extended surgery (OR = 2.52, 95% CI = 1.02–6.22; P = 0.045); lung (OR = 4.05, 95% CI = 1.44–11.42; P = 0.008), pericardial (OR = 3.78, 95% CI = 1.45–9.82; P = 0.006) or pleural resection (OR = 3.23, 95% CI = 1.30–8.03; P = 0.012); Vital Capacity % 40 mmHg (OR = 3.76, 95% CI = 1.12–12.68; P = 0.032). Multivariate logistic regression analysis showed that Osserman-stage (IIB- OR = 5.69, 95% CI = 1.09–29.69; P = 0.039 (III–IV- OR = 11.33, 95% CI = 1.67–76.72; P = 0.013), BMI >28 (OR = 3.65, 95% CI = 1.10–12.15; P = 0.035), history of myasthenic crisis (OR = 24.10, 95% CI = 2.34–248.04; P = 0.007), duration of symptoms >2 years (OR = 5.94, 95% CI = 1.12–31.48; P = 0.036) and lung resection (OR = 8.48, 95% CI = 2.18–32.97; P = 0.002) independently predict POMC. Excluding history of preoperative myasthenic crisis (statistically associated with Osserman-stage), we built a scoring system according to the OR of Osserman-stage (I–IIA, IIB, III–IV), BMI ( 85–90%; pO2 > 50–60 mmHg; pH > 7.32; increase in PaCO2 < 10 mmHg); (3) haemodynamic stability ( pulse < 120–140 bpm; systolic blood pressure < 180–200 mmHg) and (4) stable ventilation pattern (respiratory rate < 30–35 breaths/min). The spontaneous breathing trial was performed with a pressure support ventilation, using a gradual decrease in the pressure support to a minimum level of 5–8 cm H2O. Postoperative analgesia was maintained with an intravenous administration of ketorolac (every 12 h) or paracetamol (every 8 h). In our study, POMC was defined as an event of respiratory failure due to neuromuscular weakness occurring in patients with a prolonged postoperative intubation (more than 24 h) or who were successfully weaned from a mechanical ventilator after thymectomy and required a re-intubation or a resuscitation support. Cholinergic crises or respiratory failures due to phrenic paralysis, lung infection or COPD exacerbation were excluded from the definition of POMC. Patients’ clinical records were reviewed and the following parameters were recorded: gender, age, body mass index (BMI), antiacetylcholine receptor (AChR)-antibody level, comorbidities, duration of symptoms, bulbar symptoms, Osserman-stage, Myasthenia Gravis Foundation of America (MGFA) stage, history of preoperative crisis, use of immoglobulins or plasmapheresis, kind of drug therapy, spirometric and blood gas parameters, histology, extension of surgery, myasthenic complication, non-myasthenic complications (NMCs), duration of mechanical ventilation, the need of re-intubation, hospital stay and ICU stay. Thymic lesions were classified according to the WHO classification; Masaoka staging annotations were added in all cases of thymoma.
Statistical analysis The primary endpoint of the study was the incidence of POMC and this was defined before the start of the study. Secondary endpoints were: occurrence of complications, ICU stay longer than 24 h, intubation longer than 6 h and re-intubation. The sample characteristics were summarized by absolute and relative frequencies for categorical variables and by means ± standard deviations for continuous variables. For each outcome, simple logistic regression analysis was carried out to estimate the pure effect of all factors (unadjusted odds ratios (ORs)); subsequently, multiple logistic regression analysis was implemented to identify independent predictors of all outcomes and to obtain adjusted estimates of effect (adjusted ORs). The final multiple logistic regression models for all outcomes were achieved by applying a forward variable selection procedure, iteratively; the selection procedure was stopped when no statistically significant contribution could be obtained by the inclusion of an additional variable into the model; variables associated with previously selected factors were excluded from the model selection.
THORACIC
G. Leuzzi et al. / European Journal of Cardio-Thoracic Surgery
e78
G. Leuzzi et al. / European Journal of Cardio-Thoracic Surgery
A new scoring system for POMCs was built based on the estimation results obtained by the multivariable logistic regression analysis on POMCs. Description of the criteria applied is provided in the results section. The predictive role of this new score was also evaluated by means of logistic regression analysis and findings are presented in the results section. The threshold for statistical significance was set at P < 0.05. All analyses were performed in the STATA/SE V12.0 software package.
RESULTS Essential features of the patient population The clinical, pneumological and surgical characteristics of the total sample are summarized in Table 1. We performed trans-sternal thymectomy by a standard or cosmetic incision in 111 (63%) and 66 (37%) patients, respectively. The average length of the surgical procedure was 118.2 ± 23.4 min (range 71–212). Pathological examination identified a benign thymic disease in 53 (30%) cases (thymic atrophy in 24, hyperplasia in 24, lymphoid hyperplasia in 4 and cyst in 1 patient). Thymomas were diagnosed in 124 (70%) patients and classified according to the Masaoka (39% in Stage I, 38% in Stage II, 18% in Stage III and 5% in Stage IV) and the WHO (6% type A; 12% type AB; 6% type B1, 55% type B2; 11% type B2– B3; 8% type B3 and 2% type C) staging systems. MGFA classification was also evaluated in a subset of 92 patients (Stage I: 4%, Stage II: 30%, Stage III: 47%, Stage IV: 7%, Stage V: 12%): since this subset constitutes 52% of the total sample, MGFA was not taken into account in inferential statistics. Postoperative complications occurred in 56 (32%) patients: in particular, POMC was diagnosed in 22 (12%) cases. Forty-three patients experienced at least a NMC (blood loss in 26 patients, myocardial infarction and arrhythmia, respectively, in 2 and 9 cases, pneumonia in 7 patients). Thirty-day mortality occurred in 1 patient, who died of myocardial infarction.
Overall complications, postoperative myasthenic crisis, non-myasthenic complications The occurrence of postoperative complications was investigated to identify factors predictive of any complication, POMC and NMC. Regarding the occurrence of any complication, simple logistic regression identified eight variables with a statistically significant pure effect: age >60 years (P = 0.023), Osserman-stage higher than IIB (IIB P = 0.007; III–IV P = 0.003), bulbar symptoms (P < 0.001), BMI ≥28 (P = 0.008), cardio-vascular comorbidities (P = 0.008), plasmapheresis (P = 0.001), lung resection (P = 0.027) and thymoma with WHO classification higher than B2 (P = 0.046). From multivariable logistic regression analysis, it emerged that Osserman classification, duration of MG and immunosuppressive therapy were independent predictive factors for a complication. More specifically, it was estimated that Osserman-stage IIB, vs Stages I–IIA, had and OR of 5.75 [2.05–16.12] with P = 0.001 and Osserman-stages III–IV, vs Stages I–IIA, had and OR of 10.05 [2.69– 37.62] with P = 0.001; immunosuppressive therapy had a protective effect with an OR of 0.28 [0.10–0.80] with P = 0.017 and duration of MG >2 years, vs 60 years (P = 0.040), Osserman-stage higher than IIB (IIB P = 0.037; III–IV P = 0.015), bulbar symptoms (P = 0.008), BMI ≥ 28 (P = 0.003), preoperative use of plasmapheresis (P = 0.021), duration of symptoms >2 years (P = 0.036), extended surgery (P = 0.045) with lung (P = 0.008) or pericardial (P = 0.006) or pleural resection (P = 0.012), vital capacity (VC)% ≤ 80% (P = 0.025) and PaCO2 ≥ 40 mmHg (P = 0.032) were associated with the occurrence of POMC. Multivariate analysis confirmed that Osserman-stage higher than IIB (IIB vs I–IIA: OR = 5.69 [1.09–29.69], P = 0.039; III–IV vs I–IIA: OR = 11.33 [1.67–76.72], P = 0.013), BMI ≥ 28 (OR = 3.65 [1.10–12.15], P = 0.035), duration of MG >2 years (OR = 5.94 [1.12– 31.48], P = 0.036) and pulmonary resection (OR = 8.48 [2.18–32.97], P = 0.002) were independent predictive factors for POMCs. These data were subsequently combined to create a scoring system. A statistically significant effect for preoperative myasthenic crises (OR = 24.10 [2.34–248.04], P = 0.007) also emerged; however, this should not be considered concomitantly to the Osserman classification due to a strong statistical association. Concerning the analysis of NMCs, the following variables were found to be significantly associated with the outcome: Osserman-stages III–IV (P = 0.024), bulbar symptoms (P < 0.001), cardio-vascular comorbidities (P = 0.006) and preoperative plasmapheresis (P = 0.012). Multiple logistic regression analysis confirmed that bulbar symptoms (OR = 8.89 [2.97–26.58], P < 0.001) and cardio-vascular comorbidities (OR = 2.73 [1.25–5.96], P = 0.012) were independent predictive factors for NMCs.
Postoperative myasthenic crisis scoring system As shown in the analysis of POMCs, we could identify four independent prognostic factors for the occurrence of such complications: Osserman-stage, BMI, duration of symptoms and lung resection. As explained before, history of preoperative myasthenic crisis was not taken into account since statistically strongly associated with Osserman-stage. Thus, we considered Osserman-stage (categorized into three groups: I–IIA, IIB, III–IV), BMI (divided into two groups:
