Effect of prethymectomy plasma exchange on postoperative respiratory function in myasthenia gravis

J

THoRAc CARDIOVASC SURG

89:592-596, 1985

Effect of prethymectomy plasma exchange on postoperative respiratory function in myasthenia . gravis The effect of prethymectomy plasma exchange on postoperative mechanical ventilation requirement and lengthof stay in the intensive care unit werestudied retrospectively in 37 patients with myasthenia gravis. We founda significantly decreased time on mechanical ventilation (mean 1.02 ± 0.40 versus 3.43 ± 0.60 days) and a shorter stay in the intensive care unit (mean 3.09 ± 0.99 versus 5.15 ± 0.66 days) for 11 patients with respiratory weakness who were treated with preoperative plasma exchange compared with 26 patients who did not receive plasma exchange. Patients with respiratory weakness who received prethymectomy plasma exchange required less time on mechanical ventilation (mean 1.02 ± 0.40 versus 2.73 ± 0.88 days) and a shorter stay in the intensive care unit (mean 3.09 ± 0.99 versus 4.46 ± 1.08 days) than those patients without respiratory weakness who did not receive plasma exchange. Eleven patients met the criteria for plasmaexchangebut did not receive it. They required significantly more time on mechanical ventilation (mean 4.43 ± 0.94 versus 1.02 ± 0.40 days) and in the intensive care unit (mean 6.09 ± 0.86 versus 3.09 ± 0.99 days) than patients who received plasma exchange. Our results indicate that patients with severe forms of myasthenia gravis treated with prethymectomy plasma exchange require less mechanical ventilation and less time in the intensive care unit postoperatively.

Gabriel d'Empaire, M.D.,* David C. Hoaglin, Ph.D.,** Vincent P. Perlo, M.D.,*** and Henning Pontoppidan, M.D.,**** Boston, Mass.

Rsma exchange has been shown to be an effective adjunctive therapy in the management of patients with severe myasthenia gravis (MG)."s It produces transient From the Respiratory-Surgical Intensive Care Unit and Anesthesia Services and the Department of Neurology, the Massachusetts General Hospital, and the Department of Anesthesia, Harvard Medical School, Boston, Mass. Supported in part by Specialized Center of Research Grant No. HL23591-05. Received for publication Feb. IS, 1984. Accepted for publication May 16, 1984. Address for reprints: Henning Pontoppidan, M.D., Department of Anesthesia, Massachusetts General Hospital. Fruit Street, Boston. Mass. 02114. *Research Fellow, Department of Anesthesia, Massachusetts General Hospital. **Department of Statistics, Harvard University; Department of Anesthesia, Massachusetts General Hospital. ***Neurologist. Massachusetts General Hospital; Associate Clinical Professor in Neurology, Harvard Medical School. ****Anesthetist, Massachusetts General Hospital; Professor of Anesthesia. Harvard Medical School.

592

clinical improvement in patients with myasthenic crisis" who have actual or impending respiratory failure, helps to prevent a crisis situation in patients with severe MG, and provides an elective preoperative treatment in preparing myasthenic patients for thymectomy. 7, 8 Approximately 30% of patients undergoing thymectomy for the treatment of MG customarily require more than 48 hours of immediate postoperative mechanical ventilation prior to resumption of adequate spontaneous respiration." This study attempts to assess the effectiveness of preoperative plasma exchange in terms of the duration of postoperative mechanical ventilation in myasthenic patients undergoing thymectomy.

Patients and methods Age, sex, prethymectomy treatment, and immediate postthymectomy status were studied retrospectively in 37 patients with MG who underwent thymectomy at the Massachusetts General Hospital between July, 1975, and February, 1983. The type and severity of MG in each case was determined according to Osserman's'? classification but with the modification of dividing

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Table I. Characteristics of study groups No plasma exchange group Plasma exchange group

All

II 32.9 ± 18.0 2/9 4.44 ± 4.44:j: 426 ± 156

26 32.5 ± 13.7 11/15 3.96 ± 5.13 512 ± 200§

No. or patients Age (yr)* Sex (M/F) Duration or symptoms (yr)* Pyridostigmine dosage (rng /day) "

I

Pre-I 979 comparison group]

I

II 25.5 ± 11.5 5/6 3.62 ± 6.34 521 ± 221

1979-1983 13

37.0 ± 11.8 5/8 4.40 ± 4.55 515 ± 195

* Mean ± standard deviation. t Thesc patients met the criteria for plasma exchange but did not receive it. Two patients who did not meet the criteria are not included.

:j:Exciuding I patient whose record did not give the duration of symptoms. §Excluded arc patients who received pyridostigmine on a totally different dosage schedule, together with prostigmine and prednisone.

Table Il, Length of stay in RICU and duration of mechanical ventilation by study group No plasma exchange group Plasma exchange group

All

3.09 ± 0.99 1.02 ± 0.40

5.15 ± 0.66 3.43 ± 0.60

Length or RICU stay (days)* Mechanical ventilation (days)*

I

Pre-I 979 comparison gro.lpt 6.09 ± 0.86 4.43 ± 0.94

I

1979-/983

4.46 ± 1.08 2.73 ± 0.88

Legend: R ICU, Respiratory/surgical intensive care unit.

* Mean ± standard error of the mean. tThese patients met the criteria for plasma exchange but did not receive it. Two patients who did not meet the criteria are not included.

Group 2 into Subgroups A and B and the elimination of Group 5. The patients were divided into two main groups: Group I comprised 26 patients with MG, Class 2B, who underwent thymectomy without preoperative plasmapheresis. In 13 of these 26 patients, plasma exchange was not indicated because they did not have respiratory weakness. The remaining 13 patients were operated on before plasma exchange became clinically available at the Massachusetts General Hospital in 1979. Group II comprised 11 patients with MG, Class 2B, who underwent thymectomy after treatment with plasma exchange. Most patients given preoperative plasma exchange had a previous history of respiratory weakness. Plasma exchange was performed one to four times between 2 and 13 days (mean 7.4 days) before thymectomy,with the use of an 1MB 2997 blood cell separator. The vascular access was a large antecubital vein or, less often, a femoral vein. A small vein, usually in the hand, was used to receive the blood flow. Blood was anticoagulated with acid citrate dextrose (ACD-A) in a ratio of one part of ACD-A to 13 parts of whole blood. Plasma 50 mljkg of body weight was removed and replaced with 5% albumin and normal saline solution having potassium 4 mEqjL and magnesium 1.6 mEqjL. The

net removal was approximately 60% to 70% of the patient's plasma. Anesthesia and postoperative respiratory care. The basic principles of anesthesia and postoperative respiratory care for patients undergoing thymectomy for MG have remained unchanged over the period of this retrospective survey. The anesthesiologist inserts a softcuff, large-volume, plastic endotracheal tube via either the mouth or the nose after the induction of anesthesia. Muscle relaxants are used only in a few patients to facilitate laryngoscopy and tracheal intubation. In such cases, a single dose of succinylcholine, 60 to 80 mg, is administered intravenously. After completion of the operation, the patient's respiratory status is assessed. The endotracheal tube is most often left in place (in 29 of 37 patients in the present study). The patient is then transferred to the respiratory jsurgical intensive care unit (RICU), and mechanical assistance to ventilation in the intubated patient is initiated with standard techniques of either controlled mechanical ventilation or intermittent mandatory ventilation. As soon as the patient is awake and cooperative, respiratory muscle strength is assessed by the measurement of maximum negative inspiratory pressure against an occluded airway (inspiratory force) and vital capacity. Patients are weaned from ventilator

594

The Journal of Thoracic and Cardiovascular Surgery

d'Empaire et a/.

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Fig. 1. Comparison of time on mechanical ventilation between plasma exchange patients and all non-plasma exchange patients.

Fig. 2. Comparison of length of stay in the respiratory/ surgical intensive care unit (RICU) between plasma exchange patients and all non-plasma exchange patients.

support by intermittent mandatory ventilation with continuous positive airway pressure of 5 to 10 em H 20 ." Weaning ability is repeatedly assessed by measurement of respiratory mechanics and arterial blood gases and by clinical assessment of the patient's strength. The patient is extubated when the following three criteria are met. First, adequate spontaneous ventilation with continuous positive airway pressure can be sustained without fatigue for at least 12 hours. This usually is feasible when the inspiratory force exceeds 30 em H 20 and the vital capacity exceeds 15 mljkg of body weight at the initiation of the weaning process and remains so for at least 12 hours. Second, the patient has adequate strength to cough to raise secretions. Third, one can expect protective airway reflexes to be adequate to prevent aspiration after extubation. The decision to extubate is based on the patient's overall strength, taking into consideration whether the patient has primarily bulbar or nonbulbar manifestations of MG. After tracheal extubation, oxygen is given by face mask until arterial blood gas determinations document that breathing of room air is appropriate. Three patients, none of whom was in the plasma exchange group, required reintubation for failure to clear secretions. None of the

eight patients extubated in the operating room required reintubation after transfer to the RICU. Postoperative anticholinesterase drug management also has remained unchanged since 1975. No anticholinesterase drugs are given for the first 2 to 3 days after the operation. Then, if the patient's strength and respiratory performance so indicate, a small dose of neostigmine is administered and the patient's response is carefully observed. Additional therapy then is administered in the usual fashion.12 The patient is discharged from the RICU after having remained in a stable, extubated state for 24 hours. Statistical analysis. Comparisons of a continuous measure between groups used the two-sample t test and the Wilcoxon-Mann- Whitney test. The tests were onesided to compare therapies and two-sided for other characteristics. Comparisons of proportions in a twoby-two table employed Fisher's exact test. Possible adjustments for covariates were examined in multiple regression analyses with indicator variables. Results Thirty-seven patients with MG, Class 2B, were studied. Twenty-four were women (65%) and 13 were

Volume 89 Number 4

men (35%). The mean age was 32.5 ± 13.7 years in Group I and 32.9 ± 18.0 years in Group II (Table I). Fifteen of the 37 patients (40.5%) required mechanical ventilation for more than 48 hours. There was a significant difference between the two groups of patients in terms of both mechanical ventilation requirement and length of stay in the RICU (Table II). The patients in Group II required a mean of 1.02 ± 0.40 days on mechanical ventilation, compared with a mean of 3.43 ± 0.60 days for Group I patients (p = 0.0175, two-sided Mann-Whitney test) (Fig. 1). Patients in Group II required a mean of 3.09 ± 0.99 days in the RICU, compared with a mean of 5.15 ± 0.66 days for Group I patients (p = 0.0349, two-sided Mann-Whitney test) (Fig. 2). The three long stays in the RICU-12, 12, and 14 days-were required by patients with complications (pneumothorax, arrhythmia and renal failure, and pneumonia, respectively). Thirteen patients who underwent thymectomy before plasma exchange was clinically available at the Massachusetts General Hospital were further evaluated retrospectively to establish which of them would have met the criteria for plasma exchange. The 11 patients who met these criteria required 4.43 ± 0.94 days on mechanical ventilation. In comparison, the patients who were treated with prethymectomy plasma exchange required on mechanical ventilation 1.02 ± 0.40 days (p = 0.0058, two-sided Mann-Whitney test) (Fig. 3). Similarly, these 11 patients required 6.09 ± 0.86 days in the RICU, compared to 3.09 ± 0.99 days for the patients who received plasma exchange (p = 0.0115, two-sided Mann-Whitney test). No differences were found in operative technique or postoperative care that could explain this difference. In the group of 24 patients operated on after 1979, we found that the 13 patients who did not receive plasma exchange required more time on mechanical ventilation (2.73 ± 0.88 days; p = 0.19, two-sided Mann-Whitney test) and had a longer stay in the RICU (4.46 ± 1.08 days; p = 0.28, two-sided Mann-Whitney test) than the 11 patients who did receive plasma exchange (1.02 ± 0.40 days and 3.09 ± 0.99 days, respectively) (Fig. 3). When considered as covariates, age, sex, duration of symptoms,and preoperative dosage of anticholinesterase made no significant adjustment in the comparison of time on mechanical ventilation or length of stay in the RICU between Group I and Group II. Among the eight patients who were extubated in the operating room prior to the RICU, five had preoperative plasma exchange. None required reintubation postoperatively.

595

Myasthenia gravis

April, 1985

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Fig. 3. Comparisons of time on mechanical ventilation among three groups: Pre-1979 patients who met the criteria for plasma exchange but did not receive it, patients who received plasma exchange, and post-I 979 patients who did no', receive plasma exchange.

Discussion

This study shows a significantly decreased time on mechanical ventilation and a shorter stay in the RICU for myasthenic patients treated with plasma exchange before thymectomy. It is assumed that removal of immunologically active plasma protein accounts for the transient improvement in voluntary muscle strength after plasma exchange.t" Acetylcholine receptor antibody has been found in 87% of myasthenic patients." However, thus far, no positivecorrelation has been noted between acetylcholine receptor antibody titer and clinical course.v" Even when plasma exchange produces a transient drop in the acetylcholine receptor antibody titer," there is no linear correlation between this titer and the clinical improvement after plasma exchange.3.15.17 Both clinical experience and available knowledge of the role of immunologic factors justify measuring early postoperative outcome in terms of mechanical ventilation requirement and duration of stay in the RICO. In a randomized experiment, one would focus primary attention on comparison between the treatment group and the control group. The structure of the present nonrandomized retrospective study requires consideration of two comparison groups. First, to assess the

5 9 6 d'Empaire et al.

effects of plasma exchange, we identified those patients who would have met the criteria for prethymectomy plasma exchange but who were operated on before 1979. Regarding treatment associated with the thymectomy, this group of patients differs from the plasma exchange group only in not having received plasma exchange. However, because the characteristics of the patient population and other aspects of the treatment of MG (e.g., the criteria for thymectomy itself) may have changed over time, it is informative to include the second comparison group. Patients in this group were operated on during the same period (1979 to 1983) as the patients in the plasma exchange group, but absence of preoperative respiratory difficulty meant that they did not meet the criteria for plasma exchange. Thus, this second group of patients differs from the plasma exchange group primarily in the severity of their disease, so that they would be expected to do better in the early postoperative period. It would have been desirable for a more systematic set of comparisons to include a group of patients who were operated on before 1979 and who would not have met the criteria for plasma exchange, but in the present study this group contains only two patients. Relative to the pre-1979 patients with preoperative respiratory difficulty, the plasma exchange patients spent significantly less time on mechanical ventilation and in the RICU. No changes in surgical technique or postoperative care can explain the difference. In the second comparison, the patients chosen after 1979 for preoperative plasma exchange had a more favorable experience, in terms of postoperative mechanical ventilation requirement and days in the RICU, than patients not receiving plasma exchange, despite a preoperative history of respiratory compromise in the group receiving plasma exchange. However, these differences were not significant. In the present study, duration of symptoms, prethymectomy medication, age, and sex did not show any significant correlation with time required on mechanical ventilation or in the RICU. In summary, our results indicate that patients with severe forms of MG treated with plasma exchange before thymectomy require less mechanical ventilation and a shorter stay in the RICU postoperatively. REFERENCES Pinching AJ, Peters DK, Newsom-Davis J: Remission of myasthenia gravis following plasma-exchange. Lancet 2:1373-1376,1976

The Journal of Thoracic and Cardiovascular Surgery

2 Dau PC, Lindstrom JM, Cassel CK, Denys EH, Shev EE, Spitler LE: Plasmapheresis and immunosuppressive drug therapy in myasthenia gravis. N Engl J Med 297:11341140, 1977 3 Perlo VP, Shahani BT, Huggins CE, Hunt J, Kosinski K, Potts F: Effect 'of plasmapheresis in myasthenia gravis. International Myasthenia Symposium. Ann NY Acad Sci 377:709-724, 1981 4 Olarte MR, Schoenfeldt RS, Penn AS, Lovelace RE, Rowland LP: Effect of plasmapheresis in myasthenia gravis 1978-1980. International Myasthenia Symposium. Ann NY Acad Sci 377:725-728, 1981 5 Dau PC: Response to plasmapheresis and immunosuppressive drug therapy in sixty myasthenia gravis patients. International Myasthenia Symposium. Ann NY Acad Sci 377:700-708, 1981 6 Dau PC: Plasmapheresis therapy in myasthenia gravis. Muscle Nerve 3:468-482, 1980 7 Pouyau G, Teyssier G, Gannat B, Colmant A, Chaurier Y, Freycon F: Myasthenia. The value of plasma exchange before thymectomy. Pediatrie 37:219-223, 1982 8 Roses AD, Olanow CW, McAdams MW, Lane RJM: No direct correlation between serum antiacetylcholine receptor antibody levels and clinical state of individual patients with myasthenia gravis. Neurology 31:220-224, 1981 9 Mintz S, Petersen SR, MacFarland D, Petajan J, Richards RC: The current role of thymectomy for myasthenia gravis. Am J Surg 140:734-737, 1980 10 Osserman KE: Myasthenia gravis, New York, 1958, Grune & Stratton, Inc. 11 Pontoppidan H, Wilson RS, Rie MA, Schneider RC: Respiratory intensive care. Anesthesiology 47:96-116, 1977 12 Perlo VP: Treatment of the critically ill patient with myasthenia, Neurology and Neurosurgical IntensiveCare, ed I, AH Ropper, SK Kennedy, NT Zervas, eds., Baltimore, 1983, University Park Press, pp 157-161 13 Newsom-Davis J, Pinching AJ, Vincent A, Wilson SG: Function of circulating antibody to acetylcholine receptor in myasthenia gravis. Investigation by plasma exchange. Neurology 28:266-272, 1978 14 Lindstrom JM, Seybold ME, Lennon VA, Whittingham S, Duane DD: Antibody to acetylcholine receptor in myasthenia gravis. Neurology 26:1054-1059, 1976 15 Kornfeld P, Ambinder EP, Mittag T, Bender AN, Papatestas AE, Goldberg J, Genkins G: Plasmapheresis in refractory generalized myasthenia gravis. Arch Neurol 38:478-481, 1981 16 Newsom-Davis J, Wilson SG, Vincent A, Ward CD: Long-term effects of repeated plasma exchange in myasthenia gravis. Lancet 1:464-468, 1979 17 Riley TL, Monaghan WP: Antireceptor-antibody decline without improvement after plasmapheresis in myasthenia gravis. Ann Intern Med 92:713, 1980