Centre, Stoke Mandeville Hospital, Aylesbury, Bucks

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1 547 J. Physiol. (I957) I36, VASOMOTOR RSPONSS IN TH FOOT TO RAISING BODY TMPRATUR IN TH PARAPLGIC PATINT BY K.. COOPR, HLN M. FRRS AND L. GUTTMANN From the M.R.C. Group for Research on Body Temperature Regulation, The Radcliffe Infirmary, Oxford, and the National Spinal Injuries Centre, Stoke Mandeville Hospital, Aylesbury, Bucks (Received 11 January 1957) Studies have been made by a number of workers on the level of the outflow from the spinal cord, of vasomotor nerves to the hind limbs in the dog (Bayliss & Bradford, 1894), and in the monkey (Geogehan, Wolf, Adair, Hare & Hinsey, 1941). Reports on the spinal level of the sympathetic nerve supply to the foot are scanty and equivocal. Randall, Cox, Alexander, Coldwater & Hertzman (1955) have obtained some evidence by direct stimulation of preganglionic fibres during the operation of lumbar sympathectomy in man under spinal anaesthesia. It was considered that a study of the foot blood flow responses to raising body temperature in a series of patients with complete lesions of the spinal cord at various levels would provide evidence of the level of vasomotor outflow to the foot in the conscious subject. The vasomotor impulses concerned would be those derived from neurones whose activity is modified by thermal change. The level of outflow thus determined would not necessarily be identical with that demonstrated by direct stimulation of the pre- or post-ganglionic trunks, or with that deduced from histological surveys of the sympathetic efferent pathways. At the same time it was possible to determine whether the impulses arising from the isolated cord could be modified by changes in temperature which were larger than the increments in temperature known to affect the central temperature regulating mechanism. MTHODS Subject&. The subjects were twenty-one paraplegic patients of both sexes at the National Spinal Injuries Centre, who were free from active infections of the urinary tract or other disorders, such as bedsores. Nineteen had complete lesions of the spinal cord at levels ranging from C5 to L2, and two cauda equina lesions below L3-5 and L4 respectively. The lesions were the result of 35-2

2 548 K.. COOPR, HLN M. FRRS AND L. GUTTMANN trauma in all but three cases. Of the three, one was a case of complete transverse spinal cord syndrome below T 1 due to transverse myelitis. The second was a complete spinal cord syndrome below T 6, 7, following lobectomy and paravertebral abscess. The third was a transverse spinal cord syndrome, incomplete below T9 on the right hand and T8 on the left, but complete below L 1 on the right and T 12 on the left, as a result of laminectomy for removal of a disk. The controls were two subjects with no demonstrable neurological disorder. Technique. Foot blood flows were measured by means of a water-filled venous occlusion plethysmograph. The water in the plethysmograph was maintained at the desired temperature by circulating it through a copper coil immersed in a thermostatically controlled water-bath. The greatest range of plethysmograph temperatures during an experiment was.8 C and the mean temperature achieved was approximately 32 C. Volume recording was carried out electrically (Cooper & Kerslake, 1951). The venous occlusion cuff was alternately inflated and deflated for 1 sec while recordings were taken. The patient sat in a wheel chair with the leg concerned horizontal. The ankle was supported on a 'Sorbo' rubber cushion in the plethysmograph, and some support was afforded to the back of the knee with pillows when required. The room temperature varied between 19 and 24 C. Oral temperatures were taken at intervals with a clinical thermometer, which was left in the mouth for a minimum of 3 min. In two experiments the skin temperature on the great toe was measured by means of a thermocouple, which was strapped to the toe with adhesive tape. In these experiments a sock was worn on the foot which was in the plethysmograph. This retarded the heat loss from the toes to the water in the plethysmograph and consequently the toe skin temperature provided an index of the temperature of blood entering the toe. Readings of toe temperature were taken every 2 min. Foot blood flow recordings were taken over an initial period of 3-4 min. Both forearms were then placed in stirred water-baths in which the water was maintained between 4 and 44 C for a further 3 min. The foot blood flow recordings were continued during this period. RSULTS vidence that the foot blood flow responses to arm warming were not invalidated by the sitting posture xperiments were performed in which the foot blood flow was measured in the sitting and the supine positions in the same subject. The response of the foot blood flow to immersion of the forearms in water and the subsequent rise of oral temperature was measured in both positions. An example of such an experiment is shown in Fig. 1. The subject was a young adult male with no demonstrable neurological disorder. The right-hand graph shows the response to arm warming in the sitting position and the left-hand graph shows the response in the supine position. The rate of increase in foot blood flow is the same in both cases. Foot blood flow responses in paraplegic patients when the forearms are immersed in water at 4-44 C Results from two of the twenty-one paraplegic patients are shown in Figs. 2 and 3, being cases of lesions complete below T 1 and T 8 respectively. In Fig. 2 it may be seen that there was an increase in oral temperature of 1.1 C with heating of the forearm, but no change in foot blood flow was apparent. The results shown in Fig. 3 again demonstrate the absence of an increase in foot

3 \ \ \ \ \ \. FOOT BLOOD FLOW IN PARAPLGIA 549 c._ Lying 14. ix. 55 Siitting 11. ix '- /v-j36 6 f~~~~~~ r 1-4 o 2 72o..' I,, n Time (min) Fig. 1. Foot blood flows, -, and oral temperature, -, in a normal subject. During the period marked by cross-hatching, the arms were immersed in hot water. Left trace, subject lying supine; right trace, subject sitting upright. Blood flows shown are the average of three readings. -C 37._ v X A,v-A I ' 35 " DL Q I Time (min) Fig. 2. ffect on foot blood flow of raising body temperature in a patient with a spinal cord lesion complete below T 1. Conventions as Fig _: I 35 ~ ~ ~ ~ ~ ~ ~ ~ ~~ 4 V 2. o ax\\\m \\\\ Time (min) Fig. 3. ffect of raising body temperature on foot blood flow in a patient with a spinal cord lesion complete below T8. Conventions as Fig. 1. ach blood flow point shown is the mean flow for a 4-5 min period.

4 55 K.. COOPR, HLN M. FRRS AND L. GUTTMANN blood flow, while the oral temperature rose 1.95 C after immersion of the forearms for 44 min. This failure to provoke vasodilatation in the foot by arm warming occurred in the experiments on nine patients with lesions at levels between C5 and T 1. In Fig. 4 are plotted the blood flow readings and oral temperatures during the same type of experiment on a patient whose lesion was complete below L 3 on the right side and L 5 on the left. In this case the oral temperature rose 1.2 C during the heating period. The foot blood flow increased from a mean value of 2-6 ml./1 ml. foot/min, for the 1 min immediately before immersion of the forearms, to 12-5 ml. in the last 4 min. This increase is very highly significant, although the individual readings show considerable variability. A marked vasodilatation was found to occur in the experiments on six patients with complete lesions at spinal segments from LI downwards. ] 38Yu o I o 14)/ LL Time_ (min) Fig. 4. ffect of raising body temperature on foot blood flow in a patient with a spinal cord lesion complete below L3 on the right side and L5 on the left. Conventions as Fig. 1. ach blood flow point is the mean flow for a 4-5 min period. The results of investigations on five patients with lesions complete below T 1 and T 12 were not so clearly defined. One patient with a lesion complete below T 1/TI 1 gave the results depicted in Fig. 5. The mean value rose from 1-5 ml./1 ml. foot/min, for the 1 min immediately before immersion of the forearms, to 2- ml. for the 1th to 2th min after immersion. Although this increase is highly significant (significant difference is -14 at P=1), it is very small. Such a small change in blood flow might result from a marginal area of leg skin being included in the foot plethysmograph. Of the remaining four patients in this group, one (T 12 lesion) gave a possible dilatation and in three cases (one below T I/T I1 and two below T 11) the change in foot blood flow was definitely not significant.

5 FOOT BLOOD FLOW IN PARAPLGIA 551 c o - D o_ I C_ -38U 1- _ 37 v Time (min) Fig. 5. ffect of raising body temperature on foot blood flow in a patient with a spinal cord lesion complete below T1/T11. Convention as Fig. 1. ach blood flow point is the mean flow for a 4-5 min period of recording. 36 'o1 Subject G.P. A.W..F. J.V. D.H. R.B. I.H. S.M. P.W. A.H. A.H. D.C. A.H. J.G. A.S. C.N. G.Y. G.T. W.M. G.W. J.C. P.C. F.B. Level C5 C6 C7 C6 C7 TI C6 T3 T4 T5 T6 T7T6 T8 T1OT9 TIOT1l T1 Tll Tll Tll Tll T12 Li L2 L2 L4 L3 L5 S None None TABL 1 Foot blood flow (ml./1 ml. Temperature ( C) foot/min),k A 5 Time from Last Last 1 loth-2th injury before min before min during (years) heating Increase heating heating Increase * * 1-1 4*

6 552 K.. COOPR, HLN M. FRRS AND L. GUTTMANN The details of each experiment are set out in Table 1, showing the level of the lesion, the time elapsed since the onset of paraplegia, the oral temperature changes and the foot blood flow changes. The change in foot blood flow is calculated as the mean flow during the 1 min immediately before immersion of the forearms less the flow during the 1th to 2th min after immersion. A graphical summary of the findings is given in Fig. 6, in which the foot blood flow changes following arm warming are plotted against the segmental level of the lesion of the spinal cord. The graph can be divided into three sections. All cases of lesions at L I and below show definite dilatations; those at T 11 and T 12 are not clearly defined, while in no case of lesions above T I1 is a significant vasodilatation produced by arm warming. Fig. 7 shows the foot blood flows, toe temperatures and oral temperatures occurring during the standard experiment on a patient with the lesion complete below T 1. Not only did the oral temperature rise by 1. C during the 23 min heating, but the toe temperature rose.75 C. Despite the change in foot skin temperature, which must have been associated with a rise of foot blood temperature of at least.75 C, and probably more, no increase in foot blood flow occurred. These results indicate that a small increase in blood temperature has no direct effect on the foot blood vessels, but, being derived from only two experiments, cannot be regarded as conclusive. DISCUSSION Vasodilatation has been elicited in the foot with the subject sitting, both in patients with low lesions and in normal subjects. Although the actual level of the flow recorded may have been modified by the hydrostatic pressure within the foot veins, the change in foot blood flow resulting from arm warming was not affected by the posture. The supine position was impracticable because it was not possible to immerse the forearms properly when the subject was recumbent, and in addition leg muscle spasms are more common in this position in the paraplegic. The vasodilatation which, in normal subjects, accompanies immersion of the forearm in hot water has been demonstrated to depend on the rise in blood temperature which occurs (Gibbon & Landis, 1932; Pickering, 1932). The location of the central mechanism, which is thereby excited, is still open to conjecture. It is, however, sensitive to temperature changes of between 5 and.2 C (Snell, 1954). The rise in oral temperature in the experiments reported leaves no doubt that the threshold for vasodilator activity of the central mechanism had been reached. The absence of a vasodilator response to arm heating in patients with lesions between C 5 and T 1 implies that this mechanism must be located above the 5th cervical segment of the cord. An intact pathway from above C5 to at least T 11 and probably L1, is required to mediate the vasodilatation in the foot. It is possible that some inter-subject

7 FOOT BLOOD FLOW IN PARAPLGIA 553 Qoo c, (5 o o- 4.' l = U lac I.. C' * p ~~~~~~~ sfim -... C 1 _ 1 1 t I I I I t I I I I I CS C7 T2 T4 T6 T8 T1 T12 L2 L4 S No lesion C6 TI T3 T5 T7 T9 Til LI L3 L5 Level of lesion Fig. 6. Foot blood flow changes following body warming plotted against the level of the spinal cord lesion. The flow changes are calculated as described in the text for preparation of Table 1. K 36- I 38 & & *, a 3 -_ o - D3 O o o v- U _ 36* * I I- kn-n\\x\nn" RNN71.' g}! U ww Time of day Fig. 7. ffect of raising body temperature on foot blood flow and toe temperature in a patient with a spinal cord lesion complete below TI. ach blood flow measurement is shown. Cross-hatching denotes period of body heating; continuous line, foot blood flow; oral temperature, -; toe temperature,. '35- I-

8 554 K.. COOPR, HLN M. FRRS AND L. GUTTMANN variation may occur in the innervation of the foot, accounting for the variable responses from patients with lesions at T 11 and T 12. Reflex vasomotor responses, mediated through the autonomic pathways with cell stations in the isolated cord, have been demonstrated (Guttmann & Whitteridge, 1947; Cunningham, Guttmann, Whitteridge & Wyndham, 1953). These reflexes were initiated by mechanical stimuli such as bladder stretching. It is possible that other stimuli also cause vasomotor impulses to pass down the sympathetic vasomotor fibres to the foot. Whatever the origin of these impulses, they are not modified by changing the temperature of the spinal cord in the manner described. There was no evidence for the presence of temperature-sensitive vasomotor centres in the isolated spinal cord. The upper limit of the vasomotor outflow to the foot at L1, with possibly a contribution from T 11 and T 12, is comparable with the observations reported in the literature for the hind limbs in animals, but gives more precise information about the foot. The lower limit of the outflow could not be defined by this method. The level of outflow for the foot vasomotor fibres which respond to excitation of the central mechanism is higher than the level for foot sudomotor activity found by electrical stimulation of the pre-ganglionic trunks (Randall et al. 1955) and is in fair agreement with histological studies (Sheehan, 1941). SUMMARY 1. The foot blood flow was measured in twenty-one paraplegic patients and two normal subjects. The response to raising body temperature by arm heating was studied. 2. There was no increase in foot blood flow in patients with lesions at or above T 1 up to C 5, although there was a marked rise in oral temperature. 3. Two patients with lesions at T 11 and T 12 had very small vasodilatations in the foot following arm warming, while three other patients with lesions at these levels showed no response. 4. In all cases of patients with lesions from L1 downwards, and the two normal subjects, arm warming produced marked vasodilatation as well as a rise in oral temperature. 5. The evidence presented implies that there is no thermoregulatory centre in the spinal cord below the 5th cervical segment in man. 6. The upper level of vasomotor nerve outflow from the spinal cord to the foot occurs at L 1 with possible inclusion of T 11 and T 12. RFRNCS BAYLISS, W. M. & BRADFORD, R. (1894). Innervation of the vessels of the limbs. J. Phy8iol. 16, COOPR, K.. & KRSLAK, D. McK. (1951). An electrical volume recorder for use with plethysmo. graphs. J. Phy8iol. 114, 1 P. CUNNINGHAM, D. J. C., GUTTMANN, L., WMITTRIDG, D. & WYNDHAM, C. H. (1953). Cardiovascular responses to bladder distension in paraplegic patients. J. Phy8iol. 121,

9 FOOT BLOOD FLOW IN PARAPLGIA 555 GOGAN, W. A., WOLF, G. A., ADAM,. J., HAR, K. & HINSY, J. C. (1941). The origin of the pre-ganglionic fibres to the limbs in the cat and monkey. Amer. J. Phy8iol. 135, GIBBON, J. H. & LANDIS,. M. (1932). Vasodilatation in the lower extremities in response to immersing the forearms in warm water. J. clin. Inve8t. 11, GUTTMANN, L. & WHITTRIDG, D. (1947). ffects of bladder distension on autonomic mechanisms after spinal cord injuries. Brain, 7, PICKRING, G. W. (1932). The vasomotor regulation of heat loss from the human skin in relation to external temperature. Heart, 16, RANDALL, W. C., COX, J. W., ALXANDR, W. F., COLDWATR, K. B. & HRTZMAN, A. B. (1955). Direct examination of the sympathetic outflows in man. J. appl. Phy8iol. 7, SHHAN, D. (1941). Spinal autonomic outflows in man and monkey. J. comp. Neurol. 75, SNLL,. S. (1954). The relationship between the vasomotor response in the hand and heat changes in the body induced by intravenous infusions of hot or cold saline. J. PhyoiOl. 125,