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Diaphragm pacing
Diaphragm pacing Application to a patient with chronic obstructive pulmonary disease In a 66-year-old patient with chronic obstructive pulmonary disease (COPD) complicated by arterial hypoxemia and repeated episodes of respiratory and right ventricular failure, a satisfactory level of oxygenation could not be maintained despite controlled oxygen therapy. To enable oxygen to be administered without depressing ventilation, artificial respiration by means of phrenic nerve stimulation (diaphragm pacing) has been employed. Evidence of clinical improvement since pacing was begun 32 months ago include fewer episodes of respiratory failure and better control of congestive heart failure despite a gradual worsening of pulmonary function.
William W. L. Glenn, M.D., J. Bernard L. Gee, M.D., and Edwin N. Schachter, M.D., New Haven. Conn.
Stimulation of the phrenic nerve by radiofrequency transmission of a programmed train of electrical impulses (diaphragm pacing) has been employed successfully in the management of chronic ventilatory insufficiency in two types of patients, those with defective central respiratory control': 2 and those with an upper motor neuron paralysis of the diaphragrn.v 4 This communication reports another type of patient with ventilatory insufficiency for whom diaphragm pacing has been effective treatment. A patient with chronic obstructive pulmonary disease (COPD) whose course was characterized by repeated episodes of carbon dioxide retention, hypoxemia, and congestive heart failure reacted to the administration of low-flow oxygen by a further depression of ventilation. This was effectively managed by artificial respiration by means of diaphragm pacing.
Case report A 66-year-old man was admitted to Yale-New Haven Hospital in June, 1972, with exertional dyspnea of I week's From the Departments of Surgery and Internal Medicine, Yale University School of Medicine, New Haven, Conn. Supported by Grant HL-04651 and the Culpeper Foundation. Received for publication June 30, 1977. Accepted for publication Aug. 22, 1977. Address for reprints: Dr. William W. L. Glenn, Department of Surgery, YaleUniversity School of Medicine, 333 CedarStreet, New Haven, Conn. 06510.
duration as his chief complaint. Insomnia and daytime somnolence had been prominent for some time. In 1949, at the age of 44 years, the patient was hospitalized for elective herniorrhaphy. Postoperatively pneumonia in the lower lobe of the right lung cleared slowly over a 2 week period. He was next seen in 1964 for acute urinary retention secondary to prostatic hypertrophy, and at that time he gave a history of chronic cough and purulent sputum production. The chest roentgenogram was said to be indicative of emphysema. He had been smoking one to two packs of cigarettes daily for many years. At the present admission he was cyanotic and in mild respiratory distress. The respiratory rate was 30 breaths per minute and breath sounds were distant. Examination of the heart showed an 53 gallop and multiple premature contractions. The liver was enlarged and ankles were edematous. Laboratory findings included a hematocrit value of 60 percent; otherwise the complete blood count was normal. Electrolytes and blood urea nitrogen were within normal limits with the exception of a serum carbon dioxide content of 36 mEq. per liter. The arterial blood gas (ABG) studies on admission showed the pH to be 7.28, the Pa~ 36 mm. Hg, and the Pac~ 68 mm. Hg. A sputum culture grew Pneumococcus. There was no pulmonary infiltrate. The electrocardiographic pattern was sinus tachycardia, with frequent premature atrial contractions, many aberrantly conducted, and occasional premature ventricular contractions. On treatment with low-flow oxygen, erythromycin, and digoxin, as well as a phlebotomy, the patient's condition gradually improved over the subsequent week. Just prior to discharge, and during the breathing of room air, the arterial pH was 7.34, Pa~ 52 mm. Hg, and PaC02 53 mm. Hg. The discharge regimen included digoxin, chlorothiazide, and elixophyllin. The patient was followed at intervals of I to
0022-5223/78/0275-0273$00.90/0 © 1978 The C. V. Mosby Co.
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274 Glenn, Gee, Schachter
Table I. Serial pulmonary function data TLC (L.)
Date
Predicted 7/10/72 6/28/73 2/13/75 9/28/76 2/15/77
3.05 1.87 1.69 0.93 0.70 1.00
2.27 0.32 0.46
2.38 0.88 0.88 0.39 0.43 0.47
2.36 5.9
5.42 5.6
5.2
1.9
0.23 0.21
Legend: FVC, Forced vital capacity. FEV" Forced expiratory volume in I
second. Vrnaxg, Maximal expiratory flow rate at 50 percent of vital capacity. RV, Residual volume. TLC, Total lung capacity.
Table II. Sensitivity to low-flow oxygen PaC02
Pa02
Ventimask, Date of study
24% O2 (hr.)
6/23/73 9/3/73 12/23/73 7/30/74
10
2 3 1
(mm. Hg)
(mm. Hg)
Before 0 2 1 After O2 Before 0 2 1 After O2
49 43 36 23
46 41 40 32
55 53 65 58
82 63 72 70
2 months in the chest clinic, and on several occasions he received antibiotic therapy for increased sputum production. Pulmonary function testing in July, 1972, demonstrated severe airway obstruction (Table I). At the end of June, 1973, the patient presented with anorexia and increased coughing, sputum production, and dyspnea. Antibiotic treatment failed to ameliorate his condition. Outpatient ABG studies showed a pH of 7.39, a Pa 0 2 of 36 mm. Hg, and a PaCIJ2 of 64 mrn, Hg. He was rehospitalized and was treated with intravenous aminophylline and low-flow oxygen administered with a 24 percent Ventimask, Sequentially checked blood gas values demonstrated progressive carbon dioxide retention (Table II) accompanied by mental confusion and increased daytime somnolence. Oxygen therapy was discontinued. Treatment was continued with bronchodilators, postural drainage, and antibiotics. Dyspnea and confusion gradually lessened and he was discharged. A pulmonary function test just prior to discharge (Table I) demonstrated little change from previous tests. Despite close observation in the clinic, rehospitalization was necessary in September, 1973, because of increasing dyspnea and sputum production. On admission the Pa
a 24 percent Ventimask were repeatedly unsuccessful because of alveolar hypoventilation. The patient's condition on conventional treatment slowly improved, and he was discharged. By now it was obvious that the patient's ventilatory status was deteriorating and was not amenable to treatment with supplemental oxygen. In view of his extreme sensitivity to small increments of oxygen in inspired air, evident particularly during states of decompensation, the question was raised whether artificial respiration by diaphragm pacing might not be a way to prevent respiratory depression during oxygen administration. With this in mind we readmitted the patient for further evaluation. The following studies were carried out: Roentgenography. On fluoroscopy with the patient supine, the diaphragm was domed and descended 4 ern. on maximum inspiration. Laminagraphy confirmed the presence of apical bullae (Fig. I). Xenon ventilation-perfusion scanning revealed decreased ventilation to both upper lung fields, with air trapping and delayed washout. There was also a decrease in perfusion of the same areas. Respiratory control. Study of the patient's respiratory control by the methods outlined by Alexander and associates" demonstrated reduced responsiveness to the inhalation of 5 percent carbon dioxide, depression of minute ventilation following inhalation of 100 percent oxygen, and improvement of the ABG values by voluntary hyperventilation (see Table III, study of Sept. 24, 1973). Pulmonary mechanics. Pulmonary mechanics were studied by volume-displacement plethysmography" and by use of an esophageal balloon." Lung compliance, derived from the deflation static pressure-volume curve (Fig. 2, A), was increased at 0.6 L. per centimeter of water). Specific compliance, however, was 0.076 ern. of water, which is within normal limits. M Maximum expiratory flow rates were related to lung elastic recoil (Fig. 2, B). Maximal expiratory flows were expressed as a fraction of the predicted total lung capacity." The lung elastic recoil pressure in Fig. 2, B is derived from the static pressure-volume curve (Fig. 2, A). This pressure was plotted against maximum flow at the same lung volume derived from a maximum expiratory flow-volume curve. The normal range for this relation of flow to recoil pressure, as established by Leaver and associates," is indicated by the shaded area. This approach, which essentially described the airway resistance of the upstream segment, \0 indicated that our patient had increased resistance of this segment. We concluded that the causes of the airway obstruction in this patient were intrinsic airway disease in addition to loss of elastic recoil. Since there was no previous experience with pacing in patients with COPD, further information on the natural history of this patient's disease seemed desirable, and he was followed closely as an outpatient. Despite careful conservative management he presented in December, 1973, in respiratory failure. He was again treated in the conventional manner but showed progressive hypercapnia, somnolence, and confusion when given 24 percent oxygen by Ventimask (Table II). This was discontinued and he recovered after a week of therapy. He was followed once again in the outpatient clinic at monthly intervals but was rehospitalized with respiratory failure in March, June, and July, 1974. On the latter two admissions, he required endotracheal intubation and subsequent temporary tracheostomy. These episodes
Volume 75 Number 2 February, 1978
Diaphragm pacing
275
Fig. I. A, Preoperative roentgenogram of chest (December, 1973). The lung markings are decreased in the apices bilaterally owing to the presence of bullae. B, Chest roentgenogram 30 months after implantation of buried components of the diaphragm pacemaker (February, 1977). The radio receiver of the pacemaker implanted in the subcutaneous tissue can be seen on the left side. Electrode wires extend upward to connect to wires that extend downward from the neural electrode secured around the left phrenic nerve in the neck. During pacing, radiofrequency pulses, generated in a pocket-sized transmitter located outside the body, are coupled to the receiver through an antenna placed on the skin overlying the receiver.
were associated with profound hypoxemia, right ventricular failure, and progressive hypercapnia when he was exposed to low concentrations of oxygen (see Table II, study of July, 1974). The decision was made to pace the patient's diaphragm. It was based, principally, on four factors: (I) rapid and progressive deterioration of ventilation, as evidenced by an increasing number of episodes of respiratory failure requiring hospital admission for treatment; (2) intolerance to the administration of low-flow oxygen (24 percent) at times of ventilatory decompensation (Table II); (3) the presence of a domed diaphragm that descended 4 ern. during voluntary inspiration from functional residual capacity; (4) improvement in ABG levels during hyperventilation (see Table III, study of Sept. 24, 1973). On Aug. 6, 1974, the patient underwent a dissection in the left side of the neck. The left phrenic nerve was isolated and electrodes were attached by previously described techniques." 4 Pacing of the diaphragm was begun 2 weeks postoperatively. Oxygen, 2 L. per minute, was administered by nasal prongs during sleep. Base-line studies soon after nocturnal pacing was established included pacing during the night both with and without oxygen. The results of these studies, illustrated in Fig. 4, demonstrated adequate oxygenation during pacing. Cardiac catheterization revealed mild pulmonary hypertension in the presence of hypoxemia during breathing of room air (Table IV). After the administration of 100 percent oxygen, there was no change in pulmonary artery pressure despite a moderate increase in oxygenation. With the addition of pacing, there was a further increase in oxygenation but little change in pulmonary artery pressure. II The patient was observed twice monthly in the chest clinic.
His drug regimen remained unchanged from that used before pacemaker implantation. At night, with the diaphragm being paced, he received oxygen through nasal prongs for 12 hours at a rate of 4 L. per minute. He reported no difficulty in sleeping, and moreover the daytime somnolence and nighttime insomnia present prior to pacing were corrected. Studies of the hematocrit value were made at intervals and showed a progressive decrease (Table V). From the time pacing began in September, 1974, until November, 1976, the patient required only three hospitalizations for respiratory failure; all were due to his failure to adhere to the medical regimen. In May, 1977, his family noted the onset of daytime somnolence, and several mornings later he was found profoundly cyanotic and comatose. The pacemaker, when tested, was nonfunctional. On admission to the emergency room, positive-pressure ventilation was instituted after endotracheal intubation. The radiofrequency pacemaker receiver which had failed was replaced. and pacing at night was resumed. At present he is at home receiving low-flow oxygen intermittently when awake and continually when paced during sleep. He has no symptoms of ventilatory or congestive failure. Phrenic nerve function on the stimulated side has been periodically evaluated since pacing was instituted. The conduction time in the stimulated (left) nerve before application of the neural cuff was 9.6 msec.. which is within normal limits. 12. 13 After the neural cuff was applied, the threshold to stimulation was 837 p.,A, (that is, the current measured at the first visible contraction of the diaphragm at fluoroscopy. or the first diaphragm muscle action potential recorded when the stimulus to the nerve was applied); and the conduction time from neck to diaphragm (eighth intercostal space) was 9.6
The Journal of Thoracic and Cardiovascular Surgery
276 Glenn, Gee, Schachter
<>:":
TLCzS.12L
9
-e
.f ---.J:.--
8
f.
~
~ T"
-•• u
06
...... ~
0.5
" :!
0.4
~
FRC=7.82L
.!!
"e Q.
--;. 0 .j
_______ RYz'.72L
0.3 0.2
LUN8 COMPLIANCE (CLI 'O.8L/cmH~
6
CD
0.1
SPECIFIC LUN8 COMPLIANCE (SCLI z o.076Cm H2O I
0
I
I
5
10
PSTI Ll cmH20
(!)
0
/ 5
10
PSTlLlcmH20
Fig. 2. A, Static pressure-volume curve demonstrating marked hyperinflation with normal specific compliance. B, Lung elastic recoil-maximum expiratory flow curve. Maximum expiratory flow is measured as a fraction of the predicted total lung capacity (TLC). These data demonstrate a reported increase in upstream airway resistance.!" FRC, Functional residual capacity.
Table III. Respiratory control studies Conditions a/studies Room air
Date
Study
9/24/73
Pa02 (mm. Hg) Pacoz (mm. Hg) pH Minute volume (L./min.) Resp. rate (breaths/min.) Tidal volume (L.)
42 52 7.42 15.7 24 0.652 tlVE/tl PaC0 2*
9/18/74
Paoz (mm. Hg) PacozCmm. Hg) pH Minute volume (L./min.) Resp. rate (breaths/min.) Tidal volume (L.)
44 47 7.44 10.4 16.5 0.630 tlVE/tl Pacoz*
3/10/75
Paoz (mm. Hg) Pacoz (mm. Hg) pH Minute volume (L./min.) Resp. rate (breaths/min.) Tidal volume (L.)
43 54 7.36 9.79 17 0.576 tl "it E/tl Pacoz*
3/21/77
Paoz (mm. Hg) Pacoz (mm. Hg) pH Minute volume (L./min.) Resp. rate (breaths/rnin.) Tidal volume (L.)
43 49 7.42 11.51 19.5 0.590 tl VE/tl Pacoz*
'Observed during breathing of 5 percent carbon dioxide.
Hypervent .
I
72 43 7.44 25
= 2 L./min./mm. Hg
= 0.6
= 0.5
I
100% O.
66 56 7.38 23.6 30 0.786
440 55 7.39 10.3 17 0.603
71 48 7.39 16.9 20 0.846
390 38 7.45 8.92 15 0.595
57 63 7.31 11.39 21.5 0.530
335 75 7.21 6.327 20 0.316
48 57 7.34 16.03 26 0.616
355 52 7.34 10.26 21.5 0.477
L./min./mm. Hg
L./min./mm. Hg 43 44 7.42 18.4
= 0.6
5% CO.
L./min./mm. Hg
Volume 75 Number 2
Diaphragm pacing
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February, 1978
A.B. W d 68 YRS C.O. P.O. Date of Study 9/30/74 70
0--0
PaC02
e-e Pa02 ARTERIAL 60 BLOOD GAS TENSION 50
•
/
e
(mm Hg)
40
30
I am
2
3
4
5
6
7
8
I-------ASLEEP lhours)------iI I
PACER O N - - - - !I
Fig. 3. Nocturnal blood gas study made Sept. 30, 1974. After the patient fell asleep, the Pa(J:llevel decreased and the PaCt':! level increased owing to hypoventilation. Pacing of the left hemidiaphragm increased ventilation and resulted in a modest rise in Pall:! and a fall in PaC(J:l' The addition of oxygen (2 L. per minute) in the inspired air caused a further rise in oxygen without an appreciable change in the carbon dioxide level. It should be noted that on this admission the patient was not in respiratory failure, as evidenced by the lack of carbon dioxide retention during the administration of oxygen without pacing demonstrated several nights later. msec. These are normal values in our experience. 13 There was an initial rise in threshold, as commonly accompanies longterm phrenic nerve stimulation," followed by a decrease (Table V). In the most recent study on this patient, 30 months after neural stimulation was begun, the threshold was J ,060 f.LA and the conduction time 9.4 msec. For another test of phrenic nerve function, the descent of the diaphragm was measured during maximum voluntary inspiration with the body supine. At the start of pacing in 1974, the left hemidiaphragm descended 4 em. on maximum voluntary inspiration and during pacing, 4 em. This is less than the normal 6 to 7 em. descent expected with maximum voluntary effort, 14 but it is close to the "just under 5 em." observed by McKenzie and associates;" in cases of COPD caused predominantly by bronchitis. After 30 months of pacing the maximum diaphragm descent on the left during stimulation had increased to 6.5 em. (Table V).
Discussion Clinical application of diaphragm pacing to COPD. The management of COPD includes therapeutic measures directly aimed at improving the intrinsic functions of the cardiopulmonary system and measures aimed at the relief of hypoxemia. Oxygen administration is important both in the acute exacerbations characterized by increasing carbon dioxide retention and hypoxemia and also in the long-term management of patients in more stable condition. The development by Campbell 16 of controlled oxygen therapy in which oxygen is administered so as to provide satisfactory oxygenation (Sa02 80 to 90 percent) was an important advance, since it minimized carbon dioxide retention and
respiratory acidemia arising from depression of ventilation by higher concentrations of oxygen. 17. 18 However, like our patient, there are some patients in whom even controlled oxygen therapy causes carbon dioxide retention, particularly when the latter is present prior to oxygen administration. Furthermore, there is an additional difficulty in cases in which domiciliary oxygenation is required, since oxygen administration at home is necessarily less well controlled than that in the hospital. Thus, in both of these clinical situations, a device which maintains alveolar ventilation during oxygenation may prove helpful. We have shown in this patient that diaphragm pacing provides significant protection from the adverse effects of oxygen administration both in the acute situation and in the more stable respiratory status at home. It should be stressed that the fundamental purpose of pacing in COPD is not the amelioration of carbon dioxide retention or the augmentation of ventilation but rather the prevention or reduction of ventilatory depression during oxygen administration. Thus the proposed objective can be termed pacingprotected oxygenation. Evidence for the benefits of pacing in COPD. The major benefit to be expected from pacing is effective and safe oxygenation, particularly during sleep, both in the hospital and at home. In patients with chronic bronchitis and emphysema, oxygenation improves cardiac and cerebral function and partially reduces pulmonary arterial hypertension. 19 Pacing alone is effective in re-
The Journal of Thoracic and Cardiovascular
278 Glenn, Gee, Schachter
Surgery
A.B.d 70yrs C.O.P.D. Date of Study 2/ 15/77 80 0--0 PaCOz
70
°2
e -e Pa
60
ARTERIAL BLOOD GAS
50
TENSION (mm Hg) 40
30 4 Llmin 02 (Nasal P,anQs) 20
II PM
12
1<
lAM
2
3
4
5
6
PACER O N - - - - - + >1 >I I_ASLEEP----+
Fig. 4. Nocturnal arterial blood gas study made on Feb. 15, 1977. The first arterial blood gas determination was made with the patient awake and breathing room air spontaneously. Subsequent determinations were made after the pacemaker was turned on and oxygen was administered by nasal prongs at the rate of 4 L. per minute. Competition between paced respirations and spontaneous respirations was frequently evident. In contrast to the study made 30 months before (Fig. 3), which was carried out when there was no carbon dioxide retention, pacing did not prevent carbon dioxide retention during oxygen administration. This could be due to a deterioration of pulmonary function (see Table I) and a diminished effectiveness of pacing owing to competition from spontaneous respirations.
ducing pulmonary hypertension in patients with primary central alveolar hypoventilation.P Additionally, as in this patient, pacing probably prevented fatal apneic episodes when, later in the course of his disease, carbon dioxide retention and pulmonary function worsened. The evidence that pacing aided in the management of this patient is as follows: First, prior to pacing, there were eight admissions over a 13 month period for respiratory failure with carbon dioxide retention and profound hypoxemia. These admissions culminated in two intubations and a tracheostomy. By contrast, after the institution of pacing, there were three admissions for cardiorespiratory decompensation over a 32 month period. All of these admissions were caused by the patient's failure to adhere to medical advice. Second, for 32 months, the patient received approximately 10 hours of both nightly oxygen (4 L. per minute) and diaphragm pacing. This nocturnal oxygenation was
accomplished without complications. Third, there was a consistent decline in the hematocrit value (Table V), indicating adequate oxygenation. Fourth, the patient reported that pacing ameliorated his insomnia and daytime somnolence. Parenthetically, this patient showed no clinical or physiological evidence of an obstructive cause of the sleep apnea syndrome. 20.21 Fifth, when the pacemaker failed, profound ventilatory insufficiency and coma developed. In summary, pacing-protected oxygenation was practical on a domiciliary basis, minimized hospitalization, and resulted in symptomatic improvement. Physiological factors and diaphragm pacing. In some cases of COPD there are particularly striking derangement of ABG values. This phenomenon is not entirely explained by the mechanical features of the lung, even though there are distinctive patterns in chronic bronchitis and in emphysema. In this respect, several features have been emphasized by Altose and colleagues;" They studied two groups of patients with COPD, namely, a eucapnic and a hypercapnic group. These groups were similar as judged by conventional spirometry, and both groups predictably showed subnormal ventilatory responses to carbon dioxide. However, they differed when respiratory control responsiveness was assessed with the occlusion pressure method;" which measures the inspiratory pressure developed at functional residual capacity when inspiration is attempted against a closed external airway. The hypercapnic patients showed subnormal increases in inspiratory occlusion pressure in response to carbon dioxide breathing, whereas eucapnic patients with COPD exhibited responses similar to those observed in normal subjects. The finding in hypercapnic patients is compatible with a most important observation, namely, the diminution in electromyographic responsiveness of the diaphragm to carbon dioxide in hypercapnic patients with COPD as reported by Lourenco and Miranda.>' One explanation for these observations may be an associated defect in respiratory control in some hypercapnic patients. In these circumstances, respiratory drive and control of ventilation may be dependent largely on Pa02' Thus, in this situation, pacing-protected oxygenation would seem a rational therapeutic approach. In addition, whereas some degree of hypoventilation is a feature of sleep in normal subjects, considerable hypoventilation and potentially dangerous hypoxia can occur during sleep in many patients with COPD.25 The diminution of the hypoxic drive by oxygen administration during sleep presumably implies a greater dependence of respiratory drive on carbon dioxide under these circumstances.
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Diaphragm pacing
Number 2 February. 1978
Table IV • Cardiac catheterization data Blood gas tension (mm. Hg)
Arterial pressure (mm. Hg)
I
Pulmonary (mean)
Ventilatory state Breathing room air Breathing 100% oxygen Pacing + 100% oxygen
(22) (24) (20)
34/14 34/16 32/12
Aortic (mean)
Paco,
160/80 (110) 150/80 (lID) 140/80 (100)
35 45 43
I
Pao, 45 54 71
Table V. Studies before and after diaphragm pacing was instituted Diaphragm motion (em.) Voluntary
Hematocrit * Date of study
(%)
Right
Preoperative (8/74) Prepacing (9/74) Pacing (3/75) (5/76) (2/77)
57 62 50t 49 50
6 5.5 5 4
I
Electrical parameters
Left
Paced: Left
5 4.5 4 4.5
4 4 5.5 6.5
Threshold
Conduction time (msec.)
(uA)
Right
837 1380 1560* 1025 1060
10.4 10 10 10.4
I
Left 9.6 9.6 8 9 9.4
* Percent packed red blood cells.
t Studies performed in April. 1975.
Since carbon dioxide ventilation responses diminish in the sleeping normal subject, 26, 27 the rationale for pacing-protected oxygenation during sleep seems evident. Elastic recoil provides the force generating expiratory flows during much of expiration, Patients with severe loss of recoil associated with carbon dioxide retention and hypoxia would be less susceptible to improvement with pacing, because the marked degrees of hyperinflation associated with this state make diaphragmatic respiration ineffective. In contrast, those patients with minimal loss of elastic recoil and predominantly intrinsic airway disease might derive more benefit. This latter group of patients, in whom chronic bronchitis as opposed to panacinar emphysema predominates, are also those in whom both hypercapnia and hypoxia develop earlier in the course of the disease. Thus this group not only might benefit from pacing but also might well need it most. The function of the diaphragm in relation to the degree of lung inflation and also in COPD clearly requires consideration, since we are suggesting a role for diaphragm pacing in COPD. The downward pressure exerted by the contracting diaphragm depends on the tension in the muscle fibers and the radius of curvature of the diaphragm. The latter depends on the degree of lung inflation. Thus, at constant electric stimulation of the diaphragm, transdiaphragmatic pressure falls with lung inflation. 28 Furthermore, at lung volumes exceeding total lung capacity, the diaphragm can be everted
and become an expiratory muscle. For these reasons it is essential to pay careful attention to diaphragm mobility. This necessitates radiologic screening to establish that the diaphragm motion is adequate. Limitations to and indications for pacingprotected oxygenation. The majority of patients with COPD obviously do not require pacing, since they are either in stable condition or can be safely oxygenated. Furthermore, there are definite limits to the efficacy of pacing. These may be imposed by diaphragm flattening, diminished elastic recoil, very high airway resistance, and a degree of lung hyperinflation that approaches the limits of the inspiratory movement of the thoracic cage. The efficiency of pacing in our patient diminished as the disease progressed, as judged by deterioration of pulmonary function (Table I) and by worsening of carbon dioxide retention (Fig. 4). At the time of the study shown in Fig. 4, the forced vital capacity and FEV 1 * approached 50 percent of the values obtained in 1972. Under these circumstances, pacing could not maintain carbon dioxide levels during both sleep and oxygen administration comparable to those observed while the patient was awake and breathing room air. However, in spite of the incomplete control of Pa C02, pacing still offered several important advantages. First, it permitted oxygenation to be maintained (Pao2 55 mm. Hg). Second, the rise in PaC02 was no more than that ob*Forced expiratory volume in I second.
The Journal of Thoracic and Cardiovascular
280 Glenn, Gee. Schachter
tained prior to pacing (Table II). Third, somnolence, confusion, and respiratory arrests did not occur. Thus pacing still provides protection during nocturnal oxygenation even in the presence of deteriorating respiratory function. Finally, it is important to exclude the association of COPO with an upper airway obstructive cause for the sleep apnea syndrome.P? since pacing either does not ameliorate the latter condition or else worsens it. 21 These considerations and the physiological factors discussed previously suggest that several conditions must be met for diaphragm pacing to be of help to patients with COPO. First, significant hemodynamically compromising hypoxia is a prerequisite, since it is safe oxygenation rather than the elimination of carbon dioxide retention that represents the major therapeutic objective. Second, either the failure or the presence of a high risk from even well-controlled oxygen therapy should be evident prior to more complex approaches such as pacing. Third, an adequate expiratory flow is required, since in COPO the latter is always more rate limiting than inspiratory flow. Fourth, since pacing affects only one inspiratory muscle, the diaphragm, adequate function of this muscle must be demonstrated. Fifth, experience in this case suggests that pacing will prove to be particularly useful at night, when the most severe respiratory failure occurs. Therefore, it can be used primarily as a device for the safe maintenance of adequate respiration and blood gases while full oxygenation is provided. It will be appreciated that, while theoretically desirable, the use of prolonged domiciliary oxygen therapy in COPO is still sub judice and the subject of trials sponsored by the National Heart, Lung and Blood Institute. We suggest, however, that pacing-protected nocturnal oxygenation may be a useful approach to oxygenation both during respiratory failure and for safe domiciliary oxygenation. Rationale and safety of diaphragm pacing. Evidence for the effectiveness of diaphragm pacing as a method of long-term artificial respiration has been demonstrated conclusively by the achievement of total ventilatory support in patients with respiratory paralysis owing to spinal cord injury. 4 In the first such patient to undergo this treatment, a quadriplegic subject, bilateral stimulators were implanted in late 1970 and full support by pacing was established in early 1971. 3 Since that time the patient has been living at home and has been gainfully employed. Of primary consideration in long-term employment of this treatment is injury of the phrenic nerve either by factors related to the placement of the neural stimulator
Surgery
or by the applied electrical current. In an earlier report, we 29 presented evidence that implicated the technique of securing the electrodes to the nerve, rather than the electrical current, as the cause of nerve injury. In all instances a bipolar electrode had been employed. During the past year a simplified technique using a monopolar electrode''" has been applied successfully for pacing in eight patients with ventilatory insufficiency. Application of this electrode should minimize the problem of iatrogenic nerve injury. REFERENCES
2
3
4
5
6
7
8 9
10
II
12 13
14
ludson lP, Glenn WWL: Radiofrequency electrophrenic respiration. lAMA 203: 1033-1037, 1968 Glenn WWL, Holcomb WG, Hogan 1, et al: Diaphragm pacing by radiofrequency transmission in the treatment of chronic ventilatory insufficiency. 1 THoRAc CARDIOVASC SURG 66:505-520, 1973 Glenn WWL, Holcomb WG, McLaughlin Al, et al: Total ventilatory support in a quadriplegic patient with radiofrequency electrophrenic respiration. N Engl 1 Med 286:513-516, 1972 Glenn WWL, Holcomb WG, Shaw RK, et al: Long-term ventilatory support by diaphragm pacing in quadriplegia. Ann Surg 183:566-577, 1976 Alexander lK, West lR, Wood lA, et al: Analysis of respiratory response to carbon dioxide inhalation in varying clinical states of hypercapnia, anoxia and acid-base derangement. 1 Clin Invest 34:511-532, 1955 Mead 1: Volume displacement body plethysmograph for respiratory measurements in human subjects. 1 Appl Physiol 15:736-746, 1960 Mead 1, Gaensler EA: Esophageal and pleural pressures in man, upright and supine. 1 Appl Physiol 14:81-83, 1959 Comroe lH: Physiology of Respiration. ed. 2, New York, 1974, Year Book Medical Publishers, Inc., pp. 104-105 Leaver DG, Tattersfield AE, Pride NB: Contributions of loss of lung recoil and of enhanced airways collapsibility to the airflow obstruction of chronic bronchitis and emphysema. 1 Clin Invest 52:2117-2128, 1973 Mead 1, Turner 1M, Nocklem PT, et al: Significance of the relationship between lung recoil and maximal expiratory flow. 1 Appl Physiol 22:95-108, 1967 Langou RA, Cohen LS, Sheps D, et al: Ondine's Curse: Hemodynamic response to diaphragm pacing (electrophrenic respiration). Am Heart 1. In press Davis IN: Phrenic nerve conduction in man. 1 Neurol Neurosurg Psychiat 30:420-426, 1967 Shaw RK, Glenn WWL, Holcomb WG: Phrenic nerve conduction studies in patients with diaphragm pacing. Surg Forum 26:195-197,1975 Wade OL, Gilson lC: The effect of posture on diaphragmatic movement and vital capacity in normal subjects with a note on spirometry as an aid in determining radiological chest volumes. Thorax 6:103-126, 1951
Volume 75 Number 2 February, 1978
15 McKenzie HI, Outhred KG, Glick M: Postmortem evaluation of the use of diaphragmatic excurcus in assessment of pulmonary emphysema in coal mines. Thorax 27:359-364, 1972 16 Campbell ElM: Respiratory failure: the relation between oxygen concentrations of inspired air and arterial blood. Lancet 2: 10-I I, 1960 17 Eldridge F, Gherman C: Studies of oxygen administration in respiratory failure. Ann Intern Med 68:569-578, 1968 18 Sykes MK, McNicol MW, Campbell ElM: Respiratory failure. ed. 2, Oxford, 1976, Blackwell Scientific Publications, pp. 288-290 19 Leggett Rl, Cooke Nl, Clancy L, et al: Long-term domiciliary oxygen therapy in cor pulmonale complicating chronic bronchitis and emphysema. Thorax 31:414418, 1976 20 Guilleminault C, Tilkian A, Dement We: The sleep apnea syndromes. Ann Rev Med 27:465-484, 1976 21 Glenn WWL, Gee JBL, Cole D, et al: Combined central alveolar hypoventilation and upper airway obstruction. Treatment by tracheostomy and diaphragm pacing. Am 1 Med. In press 22 Altose MD, McCauley WC, Kelsen, SG, et a1: Effects of hypercapnia and inspiratory flow-resistance loading on respiratory activity in chronic airways obstruction. 1 Clin Invest 59:500, 1977 23 Whitelaw WA, Derenne lP, Milic-Emili 1: Occlusion
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25
26
27
28
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pressure as a measure of respiratory center output in conscious man. Resp PhysioI23:181-199, 1975 Lourenco RV, Miranda 1M: Drive and performance of the ventilatory apparatus in chronic obstructive lung disease. N Engl 1 Med 279:53-59, 1968 Koo KW, Sax DS, Snider GL: Arterial blood gases and pH during sleep in chronic obstructive pulmonary disease. Am 1 Med 58:663, 1975 Robin ED, Whaley RD, Crump CH, et a1: Alveolar gas tensions, pulmonary ventilation and blood pH during physiologic sleep in normal subjects. 1 Clin Invest 37:981-989, 1958 Kellogg RH: Central clinical regulation of respiration, Handbook of Physiology, Section 3, Respiration, Vol. I. WO Feen, H Rahn, eds., Washington D. c., 1964, American Physiologic Society, pp. 507-534 Minh V, Dolan GF, Konopka RF, et al: Effect of hyperinflation on inspiratory function of the diaphragm. 1 Appl Physiol 40:67-73, 1976 Kim JH, Manuelidis EE, Glenn WWL, et al: Diaphragm pacing: histopathological changes in the phrenic nerve following long-term electrical stimulation. 1 THoRAc CARDIOVASC SURG 72:602-608, 1976 Glenn WWL, Holcomb WG, Hogan IF, et al: Long-term stimulation of the phrenic nerve for diaphragm pacing. Proc NIH Workshop on Functional Electrical Stimulation. In press
William W. L. Glenn, M.D., J. Bernard L. Gee, M.D., and Edwin N. Schachter, M.D., New Haven. Conn.
Stimulation of the phrenic nerve by radiofrequency transmission of a programmed train of electrical impulses (diaphragm pacing) has been employed successfully in the management of chronic ventilatory insufficiency in two types of patients, those with defective central respiratory control': 2 and those with an upper motor neuron paralysis of the diaphragrn.v 4 This communication reports another type of patient with ventilatory insufficiency for whom diaphragm pacing has been effective treatment. A patient with chronic obstructive pulmonary disease (COPD) whose course was characterized by repeated episodes of carbon dioxide retention, hypoxemia, and congestive heart failure reacted to the administration of low-flow oxygen by a further depression of ventilation. This was effectively managed by artificial respiration by means of diaphragm pacing.
Case report A 66-year-old man was admitted to Yale-New Haven Hospital in June, 1972, with exertional dyspnea of I week's From the Departments of Surgery and Internal Medicine, Yale University School of Medicine, New Haven, Conn. Supported by Grant HL-04651 and the Culpeper Foundation. Received for publication June 30, 1977. Accepted for publication Aug. 22, 1977. Address for reprints: Dr. William W. L. Glenn, Department of Surgery, YaleUniversity School of Medicine, 333 CedarStreet, New Haven, Conn. 06510.
duration as his chief complaint. Insomnia and daytime somnolence had been prominent for some time. In 1949, at the age of 44 years, the patient was hospitalized for elective herniorrhaphy. Postoperatively pneumonia in the lower lobe of the right lung cleared slowly over a 2 week period. He was next seen in 1964 for acute urinary retention secondary to prostatic hypertrophy, and at that time he gave a history of chronic cough and purulent sputum production. The chest roentgenogram was said to be indicative of emphysema. He had been smoking one to two packs of cigarettes daily for many years. At the present admission he was cyanotic and in mild respiratory distress. The respiratory rate was 30 breaths per minute and breath sounds were distant. Examination of the heart showed an 53 gallop and multiple premature contractions. The liver was enlarged and ankles were edematous. Laboratory findings included a hematocrit value of 60 percent; otherwise the complete blood count was normal. Electrolytes and blood urea nitrogen were within normal limits with the exception of a serum carbon dioxide content of 36 mEq. per liter. The arterial blood gas (ABG) studies on admission showed the pH to be 7.28, the Pa~ 36 mm. Hg, and the Pac~ 68 mm. Hg. A sputum culture grew Pneumococcus. There was no pulmonary infiltrate. The electrocardiographic pattern was sinus tachycardia, with frequent premature atrial contractions, many aberrantly conducted, and occasional premature ventricular contractions. On treatment with low-flow oxygen, erythromycin, and digoxin, as well as a phlebotomy, the patient's condition gradually improved over the subsequent week. Just prior to discharge, and during the breathing of room air, the arterial pH was 7.34, Pa~ 52 mm. Hg, and PaC02 53 mm. Hg. The discharge regimen included digoxin, chlorothiazide, and elixophyllin. The patient was followed at intervals of I to
0022-5223/78/0275-0273$00.90/0 © 1978 The C. V. Mosby Co.
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274 Glenn, Gee, Schachter
Table I. Serial pulmonary function data TLC (L.)
Date
Predicted 7/10/72 6/28/73 2/13/75 9/28/76 2/15/77
3.05 1.87 1.69 0.93 0.70 1.00
2.27 0.32 0.46
2.38 0.88 0.88 0.39 0.43 0.47
2.36 5.9
5.42 5.6
5.2
1.9
0.23 0.21
Legend: FVC, Forced vital capacity. FEV" Forced expiratory volume in I
second. Vrnaxg, Maximal expiratory flow rate at 50 percent of vital capacity. RV, Residual volume. TLC, Total lung capacity.
Table II. Sensitivity to low-flow oxygen PaC02
Pa02
Ventimask, Date of study
24% O2 (hr.)
6/23/73 9/3/73 12/23/73 7/30/74
10
2 3 1
(mm. Hg)
(mm. Hg)
Before 0 2 1 After O2 Before 0 2 1 After O2
49 43 36 23
46 41 40 32
55 53 65 58
82 63 72 70
2 months in the chest clinic, and on several occasions he received antibiotic therapy for increased sputum production. Pulmonary function testing in July, 1972, demonstrated severe airway obstruction (Table I). At the end of June, 1973, the patient presented with anorexia and increased coughing, sputum production, and dyspnea. Antibiotic treatment failed to ameliorate his condition. Outpatient ABG studies showed a pH of 7.39, a Pa 0 2 of 36 mm. Hg, and a PaCIJ2 of 64 mrn, Hg. He was rehospitalized and was treated with intravenous aminophylline and low-flow oxygen administered with a 24 percent Ventimask, Sequentially checked blood gas values demonstrated progressive carbon dioxide retention (Table II) accompanied by mental confusion and increased daytime somnolence. Oxygen therapy was discontinued. Treatment was continued with bronchodilators, postural drainage, and antibiotics. Dyspnea and confusion gradually lessened and he was discharged. A pulmonary function test just prior to discharge (Table I) demonstrated little change from previous tests. Despite close observation in the clinic, rehospitalization was necessary in September, 1973, because of increasing dyspnea and sputum production. On admission the Pa
a 24 percent Ventimask were repeatedly unsuccessful because of alveolar hypoventilation. The patient's condition on conventional treatment slowly improved, and he was discharged. By now it was obvious that the patient's ventilatory status was deteriorating and was not amenable to treatment with supplemental oxygen. In view of his extreme sensitivity to small increments of oxygen in inspired air, evident particularly during states of decompensation, the question was raised whether artificial respiration by diaphragm pacing might not be a way to prevent respiratory depression during oxygen administration. With this in mind we readmitted the patient for further evaluation. The following studies were carried out: Roentgenography. On fluoroscopy with the patient supine, the diaphragm was domed and descended 4 ern. on maximum inspiration. Laminagraphy confirmed the presence of apical bullae (Fig. I). Xenon ventilation-perfusion scanning revealed decreased ventilation to both upper lung fields, with air trapping and delayed washout. There was also a decrease in perfusion of the same areas. Respiratory control. Study of the patient's respiratory control by the methods outlined by Alexander and associates" demonstrated reduced responsiveness to the inhalation of 5 percent carbon dioxide, depression of minute ventilation following inhalation of 100 percent oxygen, and improvement of the ABG values by voluntary hyperventilation (see Table III, study of Sept. 24, 1973). Pulmonary mechanics. Pulmonary mechanics were studied by volume-displacement plethysmography" and by use of an esophageal balloon." Lung compliance, derived from the deflation static pressure-volume curve (Fig. 2, A), was increased at 0.6 L. per centimeter of water). Specific compliance, however, was 0.076 ern. of water, which is within normal limits. M Maximum expiratory flow rates were related to lung elastic recoil (Fig. 2, B). Maximal expiratory flows were expressed as a fraction of the predicted total lung capacity." The lung elastic recoil pressure in Fig. 2, B is derived from the static pressure-volume curve (Fig. 2, A). This pressure was plotted against maximum flow at the same lung volume derived from a maximum expiratory flow-volume curve. The normal range for this relation of flow to recoil pressure, as established by Leaver and associates," is indicated by the shaded area. This approach, which essentially described the airway resistance of the upstream segment, \0 indicated that our patient had increased resistance of this segment. We concluded that the causes of the airway obstruction in this patient were intrinsic airway disease in addition to loss of elastic recoil. Since there was no previous experience with pacing in patients with COPD, further information on the natural history of this patient's disease seemed desirable, and he was followed closely as an outpatient. Despite careful conservative management he presented in December, 1973, in respiratory failure. He was again treated in the conventional manner but showed progressive hypercapnia, somnolence, and confusion when given 24 percent oxygen by Ventimask (Table II). This was discontinued and he recovered after a week of therapy. He was followed once again in the outpatient clinic at monthly intervals but was rehospitalized with respiratory failure in March, June, and July, 1974. On the latter two admissions, he required endotracheal intubation and subsequent temporary tracheostomy. These episodes
Volume 75 Number 2 February, 1978
Diaphragm pacing
275
Fig. I. A, Preoperative roentgenogram of chest (December, 1973). The lung markings are decreased in the apices bilaterally owing to the presence of bullae. B, Chest roentgenogram 30 months after implantation of buried components of the diaphragm pacemaker (February, 1977). The radio receiver of the pacemaker implanted in the subcutaneous tissue can be seen on the left side. Electrode wires extend upward to connect to wires that extend downward from the neural electrode secured around the left phrenic nerve in the neck. During pacing, radiofrequency pulses, generated in a pocket-sized transmitter located outside the body, are coupled to the receiver through an antenna placed on the skin overlying the receiver.
were associated with profound hypoxemia, right ventricular failure, and progressive hypercapnia when he was exposed to low concentrations of oxygen (see Table II, study of July, 1974). The decision was made to pace the patient's diaphragm. It was based, principally, on four factors: (I) rapid and progressive deterioration of ventilation, as evidenced by an increasing number of episodes of respiratory failure requiring hospital admission for treatment; (2) intolerance to the administration of low-flow oxygen (24 percent) at times of ventilatory decompensation (Table II); (3) the presence of a domed diaphragm that descended 4 ern. during voluntary inspiration from functional residual capacity; (4) improvement in ABG levels during hyperventilation (see Table III, study of Sept. 24, 1973). On Aug. 6, 1974, the patient underwent a dissection in the left side of the neck. The left phrenic nerve was isolated and electrodes were attached by previously described techniques." 4 Pacing of the diaphragm was begun 2 weeks postoperatively. Oxygen, 2 L. per minute, was administered by nasal prongs during sleep. Base-line studies soon after nocturnal pacing was established included pacing during the night both with and without oxygen. The results of these studies, illustrated in Fig. 4, demonstrated adequate oxygenation during pacing. Cardiac catheterization revealed mild pulmonary hypertension in the presence of hypoxemia during breathing of room air (Table IV). After the administration of 100 percent oxygen, there was no change in pulmonary artery pressure despite a moderate increase in oxygenation. With the addition of pacing, there was a further increase in oxygenation but little change in pulmonary artery pressure. II The patient was observed twice monthly in the chest clinic.
His drug regimen remained unchanged from that used before pacemaker implantation. At night, with the diaphragm being paced, he received oxygen through nasal prongs for 12 hours at a rate of 4 L. per minute. He reported no difficulty in sleeping, and moreover the daytime somnolence and nighttime insomnia present prior to pacing were corrected. Studies of the hematocrit value were made at intervals and showed a progressive decrease (Table V). From the time pacing began in September, 1974, until November, 1976, the patient required only three hospitalizations for respiratory failure; all were due to his failure to adhere to the medical regimen. In May, 1977, his family noted the onset of daytime somnolence, and several mornings later he was found profoundly cyanotic and comatose. The pacemaker, when tested, was nonfunctional. On admission to the emergency room, positive-pressure ventilation was instituted after endotracheal intubation. The radiofrequency pacemaker receiver which had failed was replaced. and pacing at night was resumed. At present he is at home receiving low-flow oxygen intermittently when awake and continually when paced during sleep. He has no symptoms of ventilatory or congestive failure. Phrenic nerve function on the stimulated side has been periodically evaluated since pacing was instituted. The conduction time in the stimulated (left) nerve before application of the neural cuff was 9.6 msec.. which is within normal limits. 12. 13 After the neural cuff was applied, the threshold to stimulation was 837 p.,A, (that is, the current measured at the first visible contraction of the diaphragm at fluoroscopy. or the first diaphragm muscle action potential recorded when the stimulus to the nerve was applied); and the conduction time from neck to diaphragm (eighth intercostal space) was 9.6
The Journal of Thoracic and Cardiovascular Surgery
276 Glenn, Gee, Schachter
<>:":
TLCzS.12L
9
-e
.f ---.J:.--
8
f.
~
~ T"
-•• u
06
...... ~
0.5
" :!
0.4
~
FRC=7.82L
.!!
"e Q.
--;. 0 .j
_______ RYz'.72L
0.3 0.2
LUN8 COMPLIANCE (CLI 'O.8L/cmH~
6
CD
0.1
SPECIFIC LUN8 COMPLIANCE (SCLI z o.076Cm H2O I
0
I
I
5
10
PSTI Ll cmH20
(!)
0
/ 5
10
PSTlLlcmH20
Fig. 2. A, Static pressure-volume curve demonstrating marked hyperinflation with normal specific compliance. B, Lung elastic recoil-maximum expiratory flow curve. Maximum expiratory flow is measured as a fraction of the predicted total lung capacity (TLC). These data demonstrate a reported increase in upstream airway resistance.!" FRC, Functional residual capacity.
Table III. Respiratory control studies Conditions a/studies Room air
Date
Study
9/24/73
Pa02 (mm. Hg) Pacoz (mm. Hg) pH Minute volume (L./min.) Resp. rate (breaths/min.) Tidal volume (L.)
42 52 7.42 15.7 24 0.652 tlVE/tl PaC0 2*
9/18/74
Paoz (mm. Hg) PacozCmm. Hg) pH Minute volume (L./min.) Resp. rate (breaths/min.) Tidal volume (L.)
44 47 7.44 10.4 16.5 0.630 tlVE/tl Pacoz*
3/10/75
Paoz (mm. Hg) Pacoz (mm. Hg) pH Minute volume (L./min.) Resp. rate (breaths/min.) Tidal volume (L.)
43 54 7.36 9.79 17 0.576 tl "it E/tl Pacoz*
3/21/77
Paoz (mm. Hg) Pacoz (mm. Hg) pH Minute volume (L./min.) Resp. rate (breaths/rnin.) Tidal volume (L.)
43 49 7.42 11.51 19.5 0.590 tl VE/tl Pacoz*
'Observed during breathing of 5 percent carbon dioxide.
Hypervent .
I
72 43 7.44 25
= 2 L./min./mm. Hg
= 0.6
= 0.5
I
100% O.
66 56 7.38 23.6 30 0.786
440 55 7.39 10.3 17 0.603
71 48 7.39 16.9 20 0.846
390 38 7.45 8.92 15 0.595
57 63 7.31 11.39 21.5 0.530
335 75 7.21 6.327 20 0.316
48 57 7.34 16.03 26 0.616
355 52 7.34 10.26 21.5 0.477
L./min./mm. Hg
L./min./mm. Hg 43 44 7.42 18.4
= 0.6
5% CO.
L./min./mm. Hg
Volume 75 Number 2
Diaphragm pacing
277
February, 1978
A.B. W d 68 YRS C.O. P.O. Date of Study 9/30/74 70
0--0
PaC02
e-e Pa02 ARTERIAL 60 BLOOD GAS TENSION 50
•
/
e
(mm Hg)
40
30
I am
2
3
4
5
6
7
8
I-------ASLEEP lhours)------iI I
PACER O N - - - - !I
Fig. 3. Nocturnal blood gas study made Sept. 30, 1974. After the patient fell asleep, the Pa(J:llevel decreased and the PaCt':! level increased owing to hypoventilation. Pacing of the left hemidiaphragm increased ventilation and resulted in a modest rise in Pall:! and a fall in PaC(J:l' The addition of oxygen (2 L. per minute) in the inspired air caused a further rise in oxygen without an appreciable change in the carbon dioxide level. It should be noted that on this admission the patient was not in respiratory failure, as evidenced by the lack of carbon dioxide retention during the administration of oxygen without pacing demonstrated several nights later. msec. These are normal values in our experience. 13 There was an initial rise in threshold, as commonly accompanies longterm phrenic nerve stimulation," followed by a decrease (Table V). In the most recent study on this patient, 30 months after neural stimulation was begun, the threshold was J ,060 f.LA and the conduction time 9.4 msec. For another test of phrenic nerve function, the descent of the diaphragm was measured during maximum voluntary inspiration with the body supine. At the start of pacing in 1974, the left hemidiaphragm descended 4 em. on maximum voluntary inspiration and during pacing, 4 em. This is less than the normal 6 to 7 em. descent expected with maximum voluntary effort, 14 but it is close to the "just under 5 em." observed by McKenzie and associates;" in cases of COPD caused predominantly by bronchitis. After 30 months of pacing the maximum diaphragm descent on the left during stimulation had increased to 6.5 em. (Table V).
Discussion Clinical application of diaphragm pacing to COPD. The management of COPD includes therapeutic measures directly aimed at improving the intrinsic functions of the cardiopulmonary system and measures aimed at the relief of hypoxemia. Oxygen administration is important both in the acute exacerbations characterized by increasing carbon dioxide retention and hypoxemia and also in the long-term management of patients in more stable condition. The development by Campbell 16 of controlled oxygen therapy in which oxygen is administered so as to provide satisfactory oxygenation (Sa02 80 to 90 percent) was an important advance, since it minimized carbon dioxide retention and
respiratory acidemia arising from depression of ventilation by higher concentrations of oxygen. 17. 18 However, like our patient, there are some patients in whom even controlled oxygen therapy causes carbon dioxide retention, particularly when the latter is present prior to oxygen administration. Furthermore, there is an additional difficulty in cases in which domiciliary oxygenation is required, since oxygen administration at home is necessarily less well controlled than that in the hospital. Thus, in both of these clinical situations, a device which maintains alveolar ventilation during oxygenation may prove helpful. We have shown in this patient that diaphragm pacing provides significant protection from the adverse effects of oxygen administration both in the acute situation and in the more stable respiratory status at home. It should be stressed that the fundamental purpose of pacing in COPD is not the amelioration of carbon dioxide retention or the augmentation of ventilation but rather the prevention or reduction of ventilatory depression during oxygen administration. Thus the proposed objective can be termed pacingprotected oxygenation. Evidence for the benefits of pacing in COPD. The major benefit to be expected from pacing is effective and safe oxygenation, particularly during sleep, both in the hospital and at home. In patients with chronic bronchitis and emphysema, oxygenation improves cardiac and cerebral function and partially reduces pulmonary arterial hypertension. 19 Pacing alone is effective in re-
The Journal of Thoracic and Cardiovascular
278 Glenn, Gee, Schachter
Surgery
A.B.d 70yrs C.O.P.D. Date of Study 2/ 15/77 80 0--0 PaCOz
70
°2
e -e Pa
60
ARTERIAL BLOOD GAS
50
TENSION (mm Hg) 40
30 4 Llmin 02 (Nasal P,anQs) 20
II PM
12
1<
lAM
2
3
4
5
6
PACER O N - - - - - + >1 >I I_ASLEEP----+
Fig. 4. Nocturnal arterial blood gas study made on Feb. 15, 1977. The first arterial blood gas determination was made with the patient awake and breathing room air spontaneously. Subsequent determinations were made after the pacemaker was turned on and oxygen was administered by nasal prongs at the rate of 4 L. per minute. Competition between paced respirations and spontaneous respirations was frequently evident. In contrast to the study made 30 months before (Fig. 3), which was carried out when there was no carbon dioxide retention, pacing did not prevent carbon dioxide retention during oxygen administration. This could be due to a deterioration of pulmonary function (see Table I) and a diminished effectiveness of pacing owing to competition from spontaneous respirations.
ducing pulmonary hypertension in patients with primary central alveolar hypoventilation.P Additionally, as in this patient, pacing probably prevented fatal apneic episodes when, later in the course of his disease, carbon dioxide retention and pulmonary function worsened. The evidence that pacing aided in the management of this patient is as follows: First, prior to pacing, there were eight admissions over a 13 month period for respiratory failure with carbon dioxide retention and profound hypoxemia. These admissions culminated in two intubations and a tracheostomy. By contrast, after the institution of pacing, there were three admissions for cardiorespiratory decompensation over a 32 month period. All of these admissions were caused by the patient's failure to adhere to medical advice. Second, for 32 months, the patient received approximately 10 hours of both nightly oxygen (4 L. per minute) and diaphragm pacing. This nocturnal oxygenation was
accomplished without complications. Third, there was a consistent decline in the hematocrit value (Table V), indicating adequate oxygenation. Fourth, the patient reported that pacing ameliorated his insomnia and daytime somnolence. Parenthetically, this patient showed no clinical or physiological evidence of an obstructive cause of the sleep apnea syndrome. 20.21 Fifth, when the pacemaker failed, profound ventilatory insufficiency and coma developed. In summary, pacing-protected oxygenation was practical on a domiciliary basis, minimized hospitalization, and resulted in symptomatic improvement. Physiological factors and diaphragm pacing. In some cases of COPD there are particularly striking derangement of ABG values. This phenomenon is not entirely explained by the mechanical features of the lung, even though there are distinctive patterns in chronic bronchitis and in emphysema. In this respect, several features have been emphasized by Altose and colleagues;" They studied two groups of patients with COPD, namely, a eucapnic and a hypercapnic group. These groups were similar as judged by conventional spirometry, and both groups predictably showed subnormal ventilatory responses to carbon dioxide. However, they differed when respiratory control responsiveness was assessed with the occlusion pressure method;" which measures the inspiratory pressure developed at functional residual capacity when inspiration is attempted against a closed external airway. The hypercapnic patients showed subnormal increases in inspiratory occlusion pressure in response to carbon dioxide breathing, whereas eucapnic patients with COPD exhibited responses similar to those observed in normal subjects. The finding in hypercapnic patients is compatible with a most important observation, namely, the diminution in electromyographic responsiveness of the diaphragm to carbon dioxide in hypercapnic patients with COPD as reported by Lourenco and Miranda.>' One explanation for these observations may be an associated defect in respiratory control in some hypercapnic patients. In these circumstances, respiratory drive and control of ventilation may be dependent largely on Pa02' Thus, in this situation, pacing-protected oxygenation would seem a rational therapeutic approach. In addition, whereas some degree of hypoventilation is a feature of sleep in normal subjects, considerable hypoventilation and potentially dangerous hypoxia can occur during sleep in many patients with COPD.25 The diminution of the hypoxic drive by oxygen administration during sleep presumably implies a greater dependence of respiratory drive on carbon dioxide under these circumstances.
Volume 75
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Diaphragm pacing
Number 2 February. 1978
Table IV • Cardiac catheterization data Blood gas tension (mm. Hg)
Arterial pressure (mm. Hg)
I
Pulmonary (mean)
Ventilatory state Breathing room air Breathing 100% oxygen Pacing + 100% oxygen
(22) (24) (20)
34/14 34/16 32/12
Aortic (mean)
Paco,
160/80 (110) 150/80 (lID) 140/80 (100)
35 45 43
I
Pao, 45 54 71
Table V. Studies before and after diaphragm pacing was instituted Diaphragm motion (em.) Voluntary
Hematocrit * Date of study
(%)
Right
Preoperative (8/74) Prepacing (9/74) Pacing (3/75) (5/76) (2/77)
57 62 50t 49 50
6 5.5 5 4
I
Electrical parameters
Left
Paced: Left
5 4.5 4 4.5
4 4 5.5 6.5
Threshold
Conduction time (msec.)
(uA)
Right
837 1380 1560* 1025 1060
10.4 10 10 10.4
I
Left 9.6 9.6 8 9 9.4
* Percent packed red blood cells.
t Studies performed in April. 1975.
Since carbon dioxide ventilation responses diminish in the sleeping normal subject, 26, 27 the rationale for pacing-protected oxygenation during sleep seems evident. Elastic recoil provides the force generating expiratory flows during much of expiration, Patients with severe loss of recoil associated with carbon dioxide retention and hypoxia would be less susceptible to improvement with pacing, because the marked degrees of hyperinflation associated with this state make diaphragmatic respiration ineffective. In contrast, those patients with minimal loss of elastic recoil and predominantly intrinsic airway disease might derive more benefit. This latter group of patients, in whom chronic bronchitis as opposed to panacinar emphysema predominates, are also those in whom both hypercapnia and hypoxia develop earlier in the course of the disease. Thus this group not only might benefit from pacing but also might well need it most. The function of the diaphragm in relation to the degree of lung inflation and also in COPD clearly requires consideration, since we are suggesting a role for diaphragm pacing in COPD. The downward pressure exerted by the contracting diaphragm depends on the tension in the muscle fibers and the radius of curvature of the diaphragm. The latter depends on the degree of lung inflation. Thus, at constant electric stimulation of the diaphragm, transdiaphragmatic pressure falls with lung inflation. 28 Furthermore, at lung volumes exceeding total lung capacity, the diaphragm can be everted
and become an expiratory muscle. For these reasons it is essential to pay careful attention to diaphragm mobility. This necessitates radiologic screening to establish that the diaphragm motion is adequate. Limitations to and indications for pacingprotected oxygenation. The majority of patients with COPD obviously do not require pacing, since they are either in stable condition or can be safely oxygenated. Furthermore, there are definite limits to the efficacy of pacing. These may be imposed by diaphragm flattening, diminished elastic recoil, very high airway resistance, and a degree of lung hyperinflation that approaches the limits of the inspiratory movement of the thoracic cage. The efficiency of pacing in our patient diminished as the disease progressed, as judged by deterioration of pulmonary function (Table I) and by worsening of carbon dioxide retention (Fig. 4). At the time of the study shown in Fig. 4, the forced vital capacity and FEV 1 * approached 50 percent of the values obtained in 1972. Under these circumstances, pacing could not maintain carbon dioxide levels during both sleep and oxygen administration comparable to those observed while the patient was awake and breathing room air. However, in spite of the incomplete control of Pa C02, pacing still offered several important advantages. First, it permitted oxygenation to be maintained (Pao2 55 mm. Hg). Second, the rise in PaC02 was no more than that ob*Forced expiratory volume in I second.
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280 Glenn, Gee. Schachter
tained prior to pacing (Table II). Third, somnolence, confusion, and respiratory arrests did not occur. Thus pacing still provides protection during nocturnal oxygenation even in the presence of deteriorating respiratory function. Finally, it is important to exclude the association of COPO with an upper airway obstructive cause for the sleep apnea syndrome.P? since pacing either does not ameliorate the latter condition or else worsens it. 21 These considerations and the physiological factors discussed previously suggest that several conditions must be met for diaphragm pacing to be of help to patients with COPO. First, significant hemodynamically compromising hypoxia is a prerequisite, since it is safe oxygenation rather than the elimination of carbon dioxide retention that represents the major therapeutic objective. Second, either the failure or the presence of a high risk from even well-controlled oxygen therapy should be evident prior to more complex approaches such as pacing. Third, an adequate expiratory flow is required, since in COPO the latter is always more rate limiting than inspiratory flow. Fourth, since pacing affects only one inspiratory muscle, the diaphragm, adequate function of this muscle must be demonstrated. Fifth, experience in this case suggests that pacing will prove to be particularly useful at night, when the most severe respiratory failure occurs. Therefore, it can be used primarily as a device for the safe maintenance of adequate respiration and blood gases while full oxygenation is provided. It will be appreciated that, while theoretically desirable, the use of prolonged domiciliary oxygen therapy in COPO is still sub judice and the subject of trials sponsored by the National Heart, Lung and Blood Institute. We suggest, however, that pacing-protected nocturnal oxygenation may be a useful approach to oxygenation both during respiratory failure and for safe domiciliary oxygenation. Rationale and safety of diaphragm pacing. Evidence for the effectiveness of diaphragm pacing as a method of long-term artificial respiration has been demonstrated conclusively by the achievement of total ventilatory support in patients with respiratory paralysis owing to spinal cord injury. 4 In the first such patient to undergo this treatment, a quadriplegic subject, bilateral stimulators were implanted in late 1970 and full support by pacing was established in early 1971. 3 Since that time the patient has been living at home and has been gainfully employed. Of primary consideration in long-term employment of this treatment is injury of the phrenic nerve either by factors related to the placement of the neural stimulator
Surgery
or by the applied electrical current. In an earlier report, we 29 presented evidence that implicated the technique of securing the electrodes to the nerve, rather than the electrical current, as the cause of nerve injury. In all instances a bipolar electrode had been employed. During the past year a simplified technique using a monopolar electrode''" has been applied successfully for pacing in eight patients with ventilatory insufficiency. Application of this electrode should minimize the problem of iatrogenic nerve injury. REFERENCES
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ludson lP, Glenn WWL: Radiofrequency electrophrenic respiration. lAMA 203: 1033-1037, 1968 Glenn WWL, Holcomb WG, Hogan 1, et al: Diaphragm pacing by radiofrequency transmission in the treatment of chronic ventilatory insufficiency. 1 THoRAc CARDIOVASC SURG 66:505-520, 1973 Glenn WWL, Holcomb WG, McLaughlin Al, et al: Total ventilatory support in a quadriplegic patient with radiofrequency electrophrenic respiration. N Engl 1 Med 286:513-516, 1972 Glenn WWL, Holcomb WG, Shaw RK, et al: Long-term ventilatory support by diaphragm pacing in quadriplegia. Ann Surg 183:566-577, 1976 Alexander lK, West lR, Wood lA, et al: Analysis of respiratory response to carbon dioxide inhalation in varying clinical states of hypercapnia, anoxia and acid-base derangement. 1 Clin Invest 34:511-532, 1955 Mead 1: Volume displacement body plethysmograph for respiratory measurements in human subjects. 1 Appl Physiol 15:736-746, 1960 Mead 1, Gaensler EA: Esophageal and pleural pressures in man, upright and supine. 1 Appl Physiol 14:81-83, 1959 Comroe lH: Physiology of Respiration. ed. 2, New York, 1974, Year Book Medical Publishers, Inc., pp. 104-105 Leaver DG, Tattersfield AE, Pride NB: Contributions of loss of lung recoil and of enhanced airways collapsibility to the airflow obstruction of chronic bronchitis and emphysema. 1 Clin Invest 52:2117-2128, 1973 Mead 1, Turner 1M, Nocklem PT, et al: Significance of the relationship between lung recoil and maximal expiratory flow. 1 Appl Physiol 22:95-108, 1967 Langou RA, Cohen LS, Sheps D, et al: Ondine's Curse: Hemodynamic response to diaphragm pacing (electrophrenic respiration). Am Heart 1. In press Davis IN: Phrenic nerve conduction in man. 1 Neurol Neurosurg Psychiat 30:420-426, 1967 Shaw RK, Glenn WWL, Holcomb WG: Phrenic nerve conduction studies in patients with diaphragm pacing. Surg Forum 26:195-197,1975 Wade OL, Gilson lC: The effect of posture on diaphragmatic movement and vital capacity in normal subjects with a note on spirometry as an aid in determining radiological chest volumes. Thorax 6:103-126, 1951
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15 McKenzie HI, Outhred KG, Glick M: Postmortem evaluation of the use of diaphragmatic excurcus in assessment of pulmonary emphysema in coal mines. Thorax 27:359-364, 1972 16 Campbell ElM: Respiratory failure: the relation between oxygen concentrations of inspired air and arterial blood. Lancet 2: 10-I I, 1960 17 Eldridge F, Gherman C: Studies of oxygen administration in respiratory failure. Ann Intern Med 68:569-578, 1968 18 Sykes MK, McNicol MW, Campbell ElM: Respiratory failure. ed. 2, Oxford, 1976, Blackwell Scientific Publications, pp. 288-290 19 Leggett Rl, Cooke Nl, Clancy L, et al: Long-term domiciliary oxygen therapy in cor pulmonale complicating chronic bronchitis and emphysema. Thorax 31:414418, 1976 20 Guilleminault C, Tilkian A, Dement We: The sleep apnea syndromes. Ann Rev Med 27:465-484, 1976 21 Glenn WWL, Gee JBL, Cole D, et al: Combined central alveolar hypoventilation and upper airway obstruction. Treatment by tracheostomy and diaphragm pacing. Am 1 Med. In press 22 Altose MD, McCauley WC, Kelsen, SG, et a1: Effects of hypercapnia and inspiratory flow-resistance loading on respiratory activity in chronic airways obstruction. 1 Clin Invest 59:500, 1977 23 Whitelaw WA, Derenne lP, Milic-Emili 1: Occlusion
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pressure as a measure of respiratory center output in conscious man. Resp PhysioI23:181-199, 1975 Lourenco RV, Miranda 1M: Drive and performance of the ventilatory apparatus in chronic obstructive lung disease. N Engl 1 Med 279:53-59, 1968 Koo KW, Sax DS, Snider GL: Arterial blood gases and pH during sleep in chronic obstructive pulmonary disease. Am 1 Med 58:663, 1975 Robin ED, Whaley RD, Crump CH, et a1: Alveolar gas tensions, pulmonary ventilation and blood pH during physiologic sleep in normal subjects. 1 Clin Invest 37:981-989, 1958 Kellogg RH: Central clinical regulation of respiration, Handbook of Physiology, Section 3, Respiration, Vol. I. WO Feen, H Rahn, eds., Washington D. c., 1964, American Physiologic Society, pp. 507-534 Minh V, Dolan GF, Konopka RF, et al: Effect of hyperinflation on inspiratory function of the diaphragm. 1 Appl Physiol 40:67-73, 1976 Kim JH, Manuelidis EE, Glenn WWL, et al: Diaphragm pacing: histopathological changes in the phrenic nerve following long-term electrical stimulation. 1 THoRAc CARDIOVASC SURG 72:602-608, 1976 Glenn WWL, Holcomb WG, Hogan IF, et al: Long-term stimulation of the phrenic nerve for diaphragm pacing. Proc NIH Workshop on Functional Electrical Stimulation. In press