INTRODUCTION

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A normal cough is considered to be a value as protection against infection of the respiratory tract. Failure of the cough mechanism may occur for a variety of reasons (1). In patients in whom the peripheral nerve and muscle are spared, then it should theoretically be possible to create an "artificial cough" by peripheral nerve stimulation. One such group are patients with tetraplegia caused by transection of the lower segments of the cervical cord; these patients are known to have severely compromised expiratory muscle function (2). Other patients could also be envisaged who are unable to produce an effective cough voluntarily, but who have intact peripheral neuromuscular apparatus; for example, those sedated in the intensive care unit or patients with movement disorders such as Parkinson's disease.

Electrical activation of the expiratory muscles to restore cough has been previously demonstrated in dogs by using electrical stimulation of the thoracic spinal cord (3). Subsequent studies showed that the optimal level, at least in the dog, for thoracic cord stimulation was T9-10 (4). This method, though innovative, requires surgical implantation of the stimulating electrodes, which, to some extent, limits potential applications in humans. It has recently been reported that these nerve roots may be noninvasively stimulated by percutaneous magnetic stimulation (5). We have shown that such stimulation produces a measurable contraction of the abdominal muscles (6). Although this procedure is well tolerated both in normal subjects and patients (7), the absolute pressures produced are insufficient to simulate cough. However, recent data from our laboratory showed both that the transdiaphragmatic pressure elicited by a pair of magnetic phrenic nerve stimuli was substantially greater than that achieved by a single twitch and that such stimuli were acceptable to naive subjects (8). Therefore, the aim of the present study was to investigate whether paired magnetic stimuli administered to the lower thoracic spinal nerve roots of normal subjects could generate expiratory pressures and flows of a comparable order of magnitude to those observed during a natural cough. If this proved to be the case, then construction of a stimulator specifically for the thoracic nerve roots would be justified.

	METHODS

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Six male members of laboratory staff (mean age, 37 yr; mean height, 1.83 m) familiar with respiratory maneuvers and the purpose of the study were recruited. All were in good health and without respiratory disease. The study was approved by our Ethics Committee and all subjects gave their informed consent.

Data Acquisition

Gastric pressure (Pga) was measured using a commercially available balloon-tipped catheter 110 cm in length (P.K. Morgan, Rainham, Kent, UK), positioned in the standard manner. The catheter was connected to a Validyne MP45-1 differential pressure transducer (range ± 300 cm H₂O; Validyne Corporation, Northridge, CA). All pressure traces were displayed continuously during the study.

For protocol 2 we also measured mouth pressure via a fine bore tube 70 cm in length and 1 mm in internal diameter. Expiratory flow was measured with a Fleisch No. 2 pneumotachograph head (Fleisch, Lausanne, Switzerland) linked via a 15-cm tube arranged distally in series to a custom-built occluding valve (see below) and connected to a Mercury CS6 electrospirometer (Mercury Electronics, Glasgow, UK).

All signals were digitized via a 12-bit NB-M10-16 analog-digital converter (National Instruments, Austin, TX) and acquired onto a Macintosh Quadra 700 computer (Apple Computer, Inc., Cupertino, CA) running LabVIEW software (National Instruments).

Protocol 1: Lower Thoracic Spinal Nerve Stimulation

The tension (or pressure) elicited by a pair of nerve stimuli is a function of the interstimulus interval, or frequency (9); in part 1 of the study we therefore determined the interstimulus interval that generated the largest gastric pressure. Paired bilateral stimulation of the thoracic nerve roots was performed with the subjects wearing a nose clip and seated erect "cowboy style" astride a chair such that their anterior chest wall rested against the back. Stimuli were given from a 90-mm circular coil (P/N 8443) powered by two linked Magstim 200 stimulators (Magstim Co., Whitland, Dyfed, UK). The linking circuitry (BiStim Module, Magstim Co.) was capable of precisely controlling the interstimulus interval between 1 and 999 ms to an accuracy of within 0.05 ms. The coil was positioned over the T10 spinal level (6). The subjects were instructed to breathe quietly and to avoid body movements for 20 min prior to stimulation to minimize twitch potentiation, since this is known to influence both the height of a single (6, 10) and paired twitches (11). Three pairs of stimuli were given at FRC with interstimulus intervals of 10, 33, 50, 100, and 999 ms; the corresponding stimulating frequencies were therefore 100, 30, 20, 10, and 1 Hz. All stimuli were given at 100% of maximum stimulator output and in random order.

Protocol 2: Measurement of Gastric Pressure and Flow

Having established the interstimulus interval generating the greatest twitch Pga for each subject (either 30 or 100 Hz), we investigated the magnitude of "cough" that could be achieved. Normal cough usually begins with an inspiration followed by an increase in abdominal and thoracic pressure as a result of expiratory muscle contraction against a closed glottis. The glottis then opens suddenly while subglottal pressure continues to rise. Expiratory flow at the mouth accelerates rapidly and reaches a high peak followed by a lower, more sustained expiratory flow (1).

To reproduce this pressure build-up during abdominal muscle stimulation, we constructed a special valve similar in principle to that of Knudson and coworkers (12). The valve consisted of a cylinder (internal diameter, 29 mm) onto which a flanged mouthpiece was attached; within the cylinder an occluding balloon (Serial No. 9308, Hans Rudolph Inc.) was mounted. The balloon could be rapidly inflated (by compressed air) and deflated. The controlling circuitry for the valve was arranged so that it could be inflated by the operator once the subject achieved relaxation at the end of the inspiratory phase; the valve was automatically opened and kept open once the mouth pressure reached a predetermined pressure level. Although we chose to use the pressure measured at the mouth, it would have been equally practical to use the pressure recorded from gastric or esophageal balloons.

The subjects were asked to relax against the closed valve of the apparatus at the end of a normal expiration. Then a paired stimuli was given. The pressure level at which the valve would open was determined for each subject by seeking the greatest peak expiratory flow created by stimulations of the nerve roots with the valve set at different pressure levels. A minimum of 5 paired stimuli were then performed under these conditions. These stimuli were repeated with a maximum voluntary contraction of the abdominal muscles lasting 5 s (maximal expiratory pressure maneuver) just before each stimulation in order to investigate the effect of potentiation of the abdominal muscles. Likewise, stimuli were performed with the patient taking a deep breath (as if to perform a natural cough) and relaxing against the valve. The magnitude of the inspiration prior to stimulation was not determined. Gastric pressures and flows elicited by a maximal voluntary cough were also recorded using the same apparatus for the purpose of comparison.

	RESULTS

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Paired stimuli of the lower thoracic nerve roots were well tolerated by all subjects. Mean gastric pressure elicited by paired magnetic stimuli (pTw Pga) for the six subjects at each interstimulus interval are shown in Figure 1. During a maximal voluntary cough, the mean (SD) Pga was 212 (21) cm H₂O, and the mean peak expiratory flow was 649 L/min (101). Representative pTw Pga and flow traces from protocol 2 are shown in Figure 2. The mean opening pressure measured at the mouth was 24.5 cm H₂O (range, 19 cm H₂O to 36 cm H₂O). The sensation could be best described as bizarre but not uncomfortable. The mean of the maximum flow and gastric pressure responses for the six subjects during stimulation of the abdominal muscles with the subject relaxing against the closed valve both at end expiration and after inspiration are presented in Table 1, as is the influence of potentiation. The pTw Pga was less variable (mean coefficient of variation, 7.2%) than the expiratory flow (mean coefficient of variation, 20%).

View larger version (8K): [in this window] [in a new window]   Figure 1.   "Force-frequency" relationship of the abdominal muscles at FRC, unpotentiated.

View larger version (11K): [in this window] [in a new window]   Figure 2.   Representative trace of gastric pressure and expiratory flow taken from a subject stimulated after potentiation and after inspiration.

	DISCUSSION

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Our data show that the gastric pressure and expiratory flow achieved by the combination use of the occlusion valve and paired percutaneous lower thoracic nerve root stimuli are 30% to 50% less than those observed during maximal natural cough. Further discussion will follow a CRITIQUE OF THE METHODS.

Critique of the Methods

Previous investigators have found the mean esophageal pressure created by normal subjects during maximal voluntary cough to be in the range 167-209 cm H₂O (13, 14). We are not aware of data for the maximal cough Pga in normal subjects. However, observations from our laboratory suggest that esophageal pressure may slightly underestimate Pga during cough (15), presumably due to diaphragm activation (16). In a sample of 20 normal subjects, we found a mean maximal cough Pga of 225 cm H₂O for mean and 164 cm H₂O for women (15). These values are also comparable to the values observed during a maximal voluntary cough in this study. Thus, the pTw Pga observed in the present study corresponds to approximately 30-50% of a maximal cough, depending on the lung volume and contractile history at the time of stimulation. Reported peak flows during maximal cough in men may be up to 800 L/min (1, 14, 17, 18). Thus, the peak flow observed after paired stimulation in our study would also correspond to roughly 50% of a maximal spontaneous cough. This disparity is not surprising given that we only used two stimuli. On the basis of the known physiology of paired stimuli (9, 19), we would confidently predict from our data that a significantly greater gastric pressure could be obtained using a machine capable of generating repetitive stimuli. There is no technical obstacle to constructing such a machine (20), but we do not know of any published reports of a machine of suitable power.

Our subjects were studied in the seated position, whereas tetraplegic and ICU patients are commonly supine; this might change the tension generated and also make it difficult to accurately position the coil. However, in our previous study of single twitches the supine posture was associated with a slight increase in Tw Pga compared with the seated position (6). A further finding from that study was that the exact intervertebral level had a comparatively small effect on pressure generation. Thus, we doubt if these concerns would be important in a device constructed for clinical use.

In keeping with the known length tension properties of the expiratory muscles (21), we found the greatest pressures to be generated at lung volumes above FRC. The magnitude of the increase after inspiration was not as great as might have been predicted; the techniques used in our previous study (6) could be used to nonvolitonally evaluate the pressure volume relationship of the abdominal muscles. This would not be a problem in clinical practice since patients could either inspire to a higher lung volume if they had intact inspiratory muscles or, if not (and they required mechanical ventilation), then the increased lung volume could be achieved artificially.

As expected from the physiology of twitch potentiation (10, 11, 22), we found that the magnitude of response elicited was greater after a maximum voluntary contraction. Clearly, patients who might benefit form a simulated cough would not be able to do this. However, potentiation does not influence the tension generated during a tetanus; thus, this consideration does not detract from the potential value of a repetitive stimulator.

A functional glottis is an important determinant of cough peak flow. The valve designed for this study is easy to use for subjects with a functional glottis and would also be suitable for those in whom it had been bypassed (for example, by an endotracheal or tracheotomy tube).

Significance of the Findings

The rationale for the present line of investigation depends crucially on the determinants of an effective cough. It is established that patients (with muscular dystrophy) with extreme expiratory muscle weakness (i.e., a maximal static expiratory pressure less than 45 cm H₂O) do not have an effective cough (23). However, for subjects without severe neuromuscular disease, cough peak flow is not related to sputum clearance (24), and indeed, supramaximal flows may be counterproductive (25). Thus, although our data predict that the intrathoracic pressure and peak flow that could be obtained from a repetitive thoracic nerve root stimulator would be approximately doubled and therefore comparable to a maximal natural cough in normal subjects, it is perfectly possible that this degree of power is not required for clearance of sputum. In particular, longer trains might risk both airway collapse and reflex diaphragm activation (16). We believe construction of a sufficiently powerful machine capable of delivering repetitive stimuli is warranted; however, it would be important to evaluate, in terms of sputum clearance from the lungs, the optimal frequencies and lengths of stimulus trains to be delivered by such a machine.

In conclusion, it is shown that substantial intra-abdominal pressures and peak flows may be obtained by paired thoracic nerve root stimulation in normal subjects. The results are sufficiently encouraging to warrant further studies to investigate the functional efficacy and clinical potential of artificial cough induced by thoracic nerve root stimulation.