Medicine, University of Cambridge (Received 29 September 1952) convulsively with each inspiration and to lie without shivering in the intervals.

Transcription

1 115 J. Physiol. (I953) I20, II5-I2I THE NEURAL CONTROL OF SHIVERING IN THE PIG BY J. H. CORT* AND R. A. McCANCE From the Medical Research Council Department of Experimental Medicine, University of Cambridge (Received 29 September 1952) For the first few weeks of their lives piglets huddle together in one corner of the sty for warmth, and if observed closely, can sometimes be seen to shiver convulsively with each inspiration and to lie without shivering in the intervals. The same phenomenon has been noticed in young puppies. Barcroft (1934) made a similar observation when he was studying men who were lying in a cold environment with falling body temperatures, and O'Connor (personal communication) has observed inspiratory shivering in anaesthetized rabbits on artificial respiration. The association of shivering with respiration was brought more forcibly to our attention by some experiments in which tracheal catheterization was being performed on piglets. It was noticed that animals, 3-6 weeks old, anaesthetized with mg pentobarbitone sodium (nembutal) per kg body weight, began to shiver as soon as the trachea was opened and room air, not previously warmed in the upper respiratory passages, was directly inspired. A shiver usually followed the first inspiration after tracheotomy, and this suggested to us the possibility of a neural, rather than a humeral, mechanism. The following experiments were designed to exaamine this possibility. MATERIALS AND METHODS Three male and three female piglets, aged 3-6 weeks, weighing 3-6 kg, were lightly anaesthetized with 25 mg of pentobarbitone per kg body weight, administered half intraperitoneally, half intramuscularly. Young animals were used because the absence of much superficial fat made it possible to alter their body temperature rapidly when required. The trachea was exposed anteriorly and entered just below the thyroid cartilage. Air entered the trachea through a coil of copper tubing and a simple one-way valve system, illustrated in Fig. 1. The valve system, constructed with flat abdominal drainage tubing, reduced partial temperature equilibration in the * A Fellow of the National Foundation for Infantile Paralysis, Inc., New York. 8-2

2 116 J. H. CORT AND R. A. McCANCE dead space and thus maintained the applied temperature gradient in the inspired air. The inflow to this valve system was from wide bore (i in. internal diameter) coils of copper tubing immersed either in an ice-bath or in a Dewar flask water-bath kept at 400 C. The wide bore coil offered very little air-flow resistance. Thus, turning the stopcock at D changed the temperature of the air applied to the trachea from 40 to about 4 C. 400C is about normal body temperature for the pig. D A~~~~~~~~~~~~ F Fig. 1. Temperature apparatus. A and C -are one-way valves, E and F are temperature baths, D is a large bore stopcock and B is the tracheal insert. Both respiration and shivering were recorded pneumographically from an air tube about the piglet's thorax leading to an air tambour in a closed system. The elastic membrane in the tambour was affixed slackly to decrease the frequency response and eliminate mechanical reverberation. Body temperature was raised by means of lamps and a heating pad wrapped about the animal, lowered by removing the source of heat, and recorded by a rectal thermometer which did not have a permanent-reading constriction. Respiration and body shivering were recorded and observed after the application of cold and warm air to the trachea, at different stages of anaesthesia, and before and after bilateral vagotomy. RESULTS The influence of anaesthesia on shivering Anaesthesia to stage III, plane III (Goodman & Gilman, 1941), in which the corneal reflex is lost, completely obliterated all shivering responses, regardless of stimulus or body temperature. On the other hand, in stages I and II there was usually violent shivering even at normal body temperatures, combined with other involuntary movements of somatic muscles. Only raising body temperature well above normal obliterated the shivering complex at this stage. The best level for an experiment on the afferent initiation of shivering was stage III, plane I, just below the stage of involuntary movement when the corneal reflex was still quite vigorous. It is difficult to maintain this stage with an injection anaesthetic, but it was felt to be easier to use one than to try to combine temperature control and an anaesthetic gas mixture in the same sample of inspired gas. After administration of the anaesthetic the animals

3 SHIVERING AND RESPIRATION 117 passed rapidly from stage III plane I to plane III and most of the records were made during recovery which takes a much longer time-usually about 45 min. Effect of cold air inspired directly into the trachea Fig. 2 shows records taken on an ink-writing kymograph. The top row shows a record of maximal shivering, which can only be obtained just before the animal regains consciousness, in stage I or stage II. When the animal was in a stable anaesthetized state, a change from warmed air to either room air or cold air through the inspiring valve precipitated rhythmic shivering, usually with the next consecutive inspiration. The shivering started either with inspiration or at the height of the inspiratory pause, and continued during the expiration and about the first quarter of the expiratory rest. The remainder of the expiratory rest was quiescent. If the stimulus of cold air was maintained, the respiratory rhythm of shivering lasted for 6-15 respirations, and then the This shivering crescendoed to increased amplitude and became continuous. sequence is shown in Fig. 2 B. The relationship of body temperature to respiratory shivering If the stimulus of cold air was removed after the shivering had been established, the animal went on shivering. Only by raising its body temperature could the shivering be stopped (Fig. 2 C). With the first inspiration after application of the cold air, the rhythmic response was initiated. Within several inspirations the shivering became more generalized. After about a minute, the air input to the trachea was put back to 400 C, and external heating was applied. Only after the body temperature had risen from 39-0 to C several minutes later did the shivering stop. The mere cessation of the cold air stimulus did not end the reflex movement. Shivering, whether produced by this or one of the other possible mechanisms (to be discussed later), could be elicited easily only when the body temperature was either normal or below normal. It became progressively more difficult to initiate the response as body temperature rose above the normal level. The participation of the vagus in respiratory shivering Fig. 2D shows the response of the same animal as in C to the same stimulus after bilateral section of the vagi. The two records were taken 10 min apart, and no change in anaesthetic status had occurred. It can be seen that the immediate response of the intact animal was obliterated, and respiration went on unchanged without shivering. As the inspiration of cold air gradually cooled the blood, the animal began to shiver, but without any respiratory rhythm. This shivering was also obliterated only by warming the animal with external heat.

4 .C) **c 4 X c e u - Ln 4f u 0 rn) 04 C)4~ as.ow ^ea 0 Ca "e c Ca ) * C ~0C P Ca a SCa o~c 4 Ca= C) 4._ Ca8 C).;..* 4 t * C-Q em c k C)1 C) U

5 SHIVERING AND RESPIRATION 119 DISCUSSION Two separate mechanisms have been implicated in the initiation of shivering. Jung, Doupe & Carmichael (1937) showed that cooling large areas of skin could elicit shivering by nervous reflexes from peripheral receptors, while the fall of temperature in the venous return from a cooled surface has been itself supposed to work on some central receptor to elicit the motor response (Uprus, Gaylor & Carmichael, 1935; Glaser & Holmes Jones, 1951). Fulton (1949) gives a detailed account of the central organization of the motor pathways of shivering, but the observations reported there tell nothing about the afferent pathways. The well-known association of the hypothalamus with temperature control tempts one to look there for part of the integration of the shivering response, but recent evidence is rather contradictory on this point. Str6m (1950) has reported failure to produce shivering by cooling the hypothalamus of unanaesthetized dogs, while Forster & Ferguson (1951) irregularly produced shivering by cooling the hypothalamus of unanaesthetized cats. Until the central loci of integration of shivering are more accurately known so that local effects may be directly tested, it must be accepted that both falling blood temperature and peripheral nervous afferent sensation of cold can elicit the response. The experiments reported here seem to indicate the existence of a temperature receptor in the walls of the trachea, bronchi or bronchioles, with afferent fibres in the vagus, capable of initiating shivering. The trachea and bronchi are more probable sites for the receptor than the bronchioles since partial temperature equilibration is inevitable at the lower level. Since the inspired air gets warmer as it descends into the respiratory passages, opening the trachea would have the effect of exposing the mucosa there and lower down to an unusually sharp stimulus. This initiated the shivering, but the complex did not continue as a simple stimulus-response phenomenon. When shivering became continuous, removing the stimulus did not end the response until the body temperature had been raised. It did not seem to matter whether this had been done by external means or by the increased production of heat in the muscles. This work suggests that there were two phases in the shivering response. The initial rhythmic response, which was abolished by cutting the vagi, was due to the activity of temperature receptors. If the stimulus continued, the response increased and lost its rhythmicity, probably due to a fall in the temperature of the blood reaching central loci. The inhalation of cold air might be expected to bring this about more efficiently than the exposure of the skin to cold, because blood cooled by inhalation would pass more directly and rapidly to the central nervous system. Since respiratory shivering is so obvious in the normal, unanaesthetized young animal, and usually absent in the adult, it may be that the young animal

6 120 J. H. CORT AND R. A. McCANCE is unable to warm inspired air up to body temperature in the upper respiratory passages as efficiently as the adult. It may be mentioned that in doing these experiments personal observation has been far more informative than the recordings, for shivering is a response of the whole body that can best be evaluated only by observing the whole animal. SUMMARY 1. Shivering has been initiated in lightly anaesthetized piglets with normal or subnormal temperatures by the introduction of cold air directly into the trachea. 2. The first inspiration of cold air produced a short burst of shivering followed by a pause during the expiratory rest. If the stimulus continued for some time the shivering increased in amplitude and lost its respiratory rhythm. 3. The admission of warmed air into the trachea did not abolish the generalized shivering which lasted until the body temperature had been raised. 4. Cutting the vagus bilaterally obliterated the rhythmic response. 1 3 ',J0UK c 10 sec 4 Fig. 3. Abnormal respiratory rhythms under deep anaesthesia. ADDENDUM The following respiratory abnormalities were sometimes observed at very deep levels of anaesthesia (stage III, plane IV): (1) Phase reversal-the long pause occurring in inspiration, with a short expiratory spike. (2) Cheyne-Stokes respiration. (3) Alternating respiration-one cycle of low amplitude and long duration followed by a cycle of short duration and high amplitude. (4) Amplitude coupling and tripling with or without pause- each cycle was of equal duration, with series of two or three inspirations ofdecreasing amplitude. All of these rhythms disappeared as the animal recovered from deep barbiturate anaesthesia. Abnormalities 1, 3 and 4 are illustrated in Fig. 3.

7 SHIVERING AND RESPIRATION 121 Since the susceptibility of nervous tissue to anaesthesia decreases from cortex to cord (Goodman & Gilman, 1941) these abnormalities are presumably due to the failure of integrating centres above those in the medulla about which at present we know nothing. The authors would like to express their gratitude to Drs B. Strangeways and E. M. Glaser for assistance in the design and performance of these experiments. REFERENCES BAWcorr, J. (1934). Features in the Architecture of Physiological Function, p. 67. Cambridge University Press. FORSTBR, R. E. & FEGusoN, J. B. (1951). Relationship between hypothalamic temperature and thermoregulatory effectors in unanesthetized cat. Fed. Proc. 10, 44. FuLTON, J. F. (1949). Physiology of the Nervous System, 3rd ed. Oxford Medical Publications. GLAsxm, E. M. & HoLMis JoNEs, R. V. (1951). Initiation of shivering by cooled blood returning from the limbs. J. Physidl. 144, GOODMAN, L. & Gurma, A. (1941). The Pharmacoloia Basis of Therapeutics, section II. New York: MacMillan. JU-NG, R., DouPE, J. & CA 1cIHA1Am, E. A. (1937). Shivering: A clinical study of the influence of sensation. Brain, 60, STR6M, G. (1950). Effect of hypothalamic cooling on cutaneous blood flow in the unanesthetized dog. Acta physiol. scand. 21, UrRus, V., GAYLOR, G. B. & CANmcHALm, E. A. (1935). Shivering: a clinical study with especial references to the afferent and efferent pathways. Brain, 58,