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Cardiovascular and endocrine responses during the cold pressor test in subjects with cervical spinal cord injuries
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Cardiovascular and Endocrine Responses During the Cold Pressor Test in Subjects With Cervical Spinal Cord Injuries Takashi Mizushima, MD, PhD, Fumihiro Tajima, MD, PhD, Hiroyuki Okawa, RPT, MS, Yuichi Umezu, MD, PhD, Kazunari Furusawa, MD, PhD, Hajime Ogata, MD, PhD ABSTRACT. Mizushima T, Tajima F, Okawa H, Umezu Y, Furusawa K, Ogata H. Cardiovascular and endocrine responses during the cold pressor test in subjects with spinal cord injuries. Arch Phys Med Rehabil 2003;84:112-8. Objective: To investigate cardiovascular regulation and endocrine responses during the cold pressor test in patients with chronic spinal cord injury (SCI). Design: Experimental and control study. Setting: University laboratory, department of rehabilitation medicine, in Japan. Participants: Eight quadriplegic subjects with complete spinal cord transection at the C6 to C8 level and 6 age-matched healthy subjects. Interventions: Cardiovascular and endocrine responses were examined during 2 minutes of control, 3 minutes of ice-water immersion of the foot, followed by a 3-minute recovery. Main Outcome Measures: Blood pressure, heart rate, the Borg 15-point Rating of Perceived Pain Scale, and blood samples for measurement of plasma norepinephrine, epinephrine, plasma renin activity, plasma aldosterone, and arginine vasopressin. Results: The rise in the mean arterial blood pressure during the cold pressor test in patients with SCI (baseline, 81.6⫾3.7mmHg; increased by 30%⫾6.1%) was significantly (P⬍.05) higher than that in healthy subjects (baseline, 101.2⫾4.5mmHg; increased by 20%⫾4.5%). The SCI subjects had no change in heart rate throughout the test, in contrast to the tachycardia noted in normal subjects. Baseline plasma norepinephrine in SCI subjects (63.0⫾18.3pg/mL) was significantly lower than in normal subjects (162.3⫾19.6pg/mL) and plasma norepinephrine increased significantly during the cold pressor test in both groups. Conclusions: In the SCI subjects, a reflex sympathetic discharge through the isolated spinal cord results in a more profound rise in mean blood pressure during ice-water immersion. This response was free of inhibitory impulses from supraspinal center and baroreceptor reflexes, either of which might restrain the increase in blood pressure.
From the Department of Rehabilitation Medicine, Hamamatsu University School of Medicine, University Hospital, Hamamatsu (Mizushima, Tajima); Department of Rehabilitation Medicine, University of Occupational and Environmental Health, Kitakyushu (Okawa, Ogata); Department of Rehabilitation Medicine, Kurume University School of Medicine, Kurume (Umezu); and Department of Rehabilitation Medicine, Kibikougenn Medical Rehabilitation Center, Okayama (Furusawa), Japan. Supported by Japanese National Foundation for Scientific Research and Yutaka Nakamura Memorial Foundation. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the authors or upon any organization with which the authors are associated. Reprint requests to Fumihiro Tajima, MD, PhD, Dept of Rehabilitation Medicine, Hamamatsu University School of Medicine, University Hospital, 1-20-1 Handayama, Hamamatsu-shi 431-3192, Japan, e-mail: [email protected]. 0003-9993/03/8401-7156$35.00/0 doi:10.1053/apmr.2003.50072
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Key Words: Blood pressure; Heart rate; Immersion; Norepinephrine; Quadriplegia; Rehabilitation; Water. © 2003 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation HE COLD PRESSOR TEST is an established challenge T test of autonomic vascular regulation. The normal response to a brief cold stimulus consists of a transient peripheral 1-5
vasoconstriction, tachycardia, and a rise in blood pressure. Some studies6,7 have shown that cardiovascular responses to the cold pressor test predict future resting blood pressure and the development of hypertension. Somatosensory stimulation induced by the cold stimulus increases blood pressure; impulses from receptors in the skin relay via afferent pathways to C1 cells in the rostral ventrolateral (RVL) reticular nucleus and are transmitted via efferent sympathetic neurons to peripheral blood vessels from thoracic spinal cord.8 The pressor response to stimulation of somatic afferent nerves is called the somatosympathetic reflex.9 Thus, somatosensory stimulation produces the pressor response during the cold pressor test. Severance of the pathways that transmit sensory afferent impulses is usually present in persons who have a complete cervical spinal cord transection. In these patients, the cardiovascular response to somatosensory stimuli may become abnormal because of the lack of supraspinal vasomotor control. Watson and Nance10 measured heart rate and blood pressure in 10 subjects with thoracic spinal lesion during 2 time intervals: 5 minutes before and 15 minutes after a 20-second ice-water immersion of the feet. However, these investigators did not measure heart rate and blood pressure during the cold pressor test itself and the physiologic mechanisms of the pressor response during immersion were not completely established. To our knowledge, no studies have previously examined the cardiovascular responses during a 3-minute cold pressor test in humans who had a stable complete transection of the cervical spinal cord. Previous studies11-16 have described the presence of abnormal and unstable cardiovascular control in subjects with spinal cord injury (SCI); the results have indicated that the lack of supraspinal vasomotor control in these patients may lead to considerable clinical problems. Low tonic discharge can cause hypotension and intense sympathetic discharge in response to reflex stimulation can result in hypertension, bradycardia, headache, and sometimes severe cerebrovascular complications.11,16,17 These reactions, known as autonomic hyperreflexia, can also be elicited by cutaneous, visceral, and muscle stimulation.11,16,18-20 The purpose of the present study was to investigate cardiovascular regulation and endocrine responses during a cold pressor test in chronic spinal patients, as evidenced by a complete loss of supraspinal control of the sympathetic outflow,21 and to explore the mechanisms of hyperreflexia in these patients.
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COLD PRESSOR TEST IN CERVICAL SCI, Mizushima Table 1: Profile and Lesion Level in SCI Subjects ASIA Score Patient
Age (y)
Lesion Level
Years Since Injury (y)
Motor
Sensory
Pain Touch
1 2 3 4 5 6 7 8 Mean SEM
33 46 33 46 58 33 33 50 41.5 3.3
C7 C8 C7 C6 C6 C7 C7 C7
10 17 16 10 18 12 16 2 12.6 1.8
28 38 28 21 21 30 31 27
22 24 25 19 22 25 26 23
24 28 24 21 22 25 26 24
METHODS Participants We studied 8 men with traumatic chronic cervical SCI who were between the ages of 33 and 58 years (mean ⫾ standard error of the mean [SEM], 41.5⫾3.3y). Each had a physiologically complete cervical spinal cord transection between C6 and C8, with complete sensory and motor loss at and below the level of the injuries. All subjects were classified as American Spinal Injury Association (ASIA) Impairment Scale class A. All SCI subjects’ spinal cords were assessed by using magnetic resonance imaging and the lesion of SCI was confirmed. SCI had occurred at least 2 years before the present study (range, 2–18y; avg, 12.6y; table 1). Of the SCI subjects, 3 were recruited from the outpatient clinic of the university hospital, 2 were inpatients of the university hospital, and 3 were in a nursing home. All voluntarily participated in this study. None had any systemic disease or complication except for their SCI. None was on medications except for a purgative given at the time of the study to prevent possible constipation that might affect autonomic nervous system function. None was bedridden in the daytime, and all were mobile in their wheelchairs. Six healthy male volunteers, between the ages of 31 and 62 years (mean, 40.7⫾3.1y), were also included as control subjects. None of these subjects was on any medication or had any systemic disease (table 1). Informed consent was obtained from all subjects, and the experimental protocol was approved by the institutional review board for human research at the University of Occupational and Environmental Health, Japan. Experimental Procedures All subjects reported to the laboratory of University of Occupational and Environmental Health at 3:00 PM and rested on a bed in supine position throughout the test. A catheter was introduced percutaneously into the dorsalis pedis artery for measurement of arterial blood pressure. The catheter was connected via saline-filled manometer tubing to an electromanometer (SPB-106a), which was placed on the same level with the fourth intercostal space, just anterior to the midaxillary line. The arterial catheter contained heparinized saline to prevent clotting during measurement of arterial blood pressure. The electrocardiograph (Bioview 1000a) and blood pressure were recorded on a chart recorder (Omniace RT2108Aa) and a tape recorder,b and were digitized into a personal computer (PC9821-BRa) using an analog-to-digital converterc at 2-kHz sampling rate.
All tests were performed after the subjects rested quietly in the supine position for 15 minutes in a quiet room (ambient temperature, 28°C), and their right knee joint was positioned at 90° of flexion hanging off end of table for the ice-water immersion procedure. Each test consisted of 8 minutes of recording. After a basal recording for 2 minutes (control period), the right foot was immersed to the ankle into 0°C water bath without any foot movement (immersion period) for a period of 3 minutes, followed by removal of the foot from the bath and continuation of recording for another 3 minutes (recovery period). Each subject was then asked to rate the severity of the perceived pain. We also recorded the skin temperature of the right foot and the oral temperature every 30 seconds by using a copper-constantan thermocouple thermometer.d In addition, blood samples for measurement of plasma norepinephrine (NE), epinephrine, plasma renin activity (PRA), plasma aldosterone (Paldo), and arginine vasopressin (AVP) were withdrawn at the first minute of the control period and at the second minute of the immersion and recovery periods. Measurements of Physiologic Variables and Determination of Hormonal Levels Heart rate computed from the R-R interval (distance from peak to peak of consecutive R waves on an electrocardiogram) and blood pressure were averaged over each 10-second period of foot immersion and compared with average values obtained during the 2-minute prestress control period and 3-minute poststress recovery period. The mean arterial blood pressure (MABP) is stated in the present report. The Borg 15-point Rating of Perceived Pain Scale22 was used to determine the severity of perceived pain during icewater immersion. The Borg scale was used to measure subjective rating of perceived pain before, during, and after the stress period. Blood samples were withdrawn (6mL) from a catheter inserted into the left antecubital vein. The samples used for measurement of plasma NE, epinephrine, PRA, Paldo, and AVP were immediately transferred into ice-cooled plastic tubes containing ethylenediaminetetraacetic acid and ascorbic acid, placed in ice, and centrifuged at 3000rpm at 4°C for 10 minutes. The plasma was pipetted into ice-cooled plastic storage tubes until analysis. NE and epinephrine were extracted from plasma by using alumina and measured by high-performance liquid chromatography using a modification of the procedure described by Hunter et al.23 PRA was determined with an angiotensin I radioimmunoassay (RIA) kit,e with a detection limit of 0.1ng䡠mL⫺1䡠h⫺1, and intra- and interassay coefficients Arch Phys Med Rehabil Vol 84, January 2003
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of variation (CVs) of 5.7% and 10.5%, respectively. AVP was measured in duplicates by using RIA kitsf after extraction using Sep-Pak C18.g The sensitivity of this RIA was .06pg/tube, and the recovery of AVP ranged from 71.1% to 85.5%. The interassay CVs were 7.6% and 7.2% for concentration between 1.4 and 2.4pg/mL, respectively, and 12.5% and 4.5% for concentrations between 0.2 and 2.7pg/mL, respectively. Paldo was measured by RIA,h with intra- and interassay CVs of 6.4% and 7.8%, respectively. Statistical Analysis Data were reported as mean ⫾ SEM. Differences between SCI and control subjects at each period, and between control and each time period in each group were evaluated by nonparametric Mann-Whitney U and the Wilcoxon matched-pairs signed-rank test,24 respectively. Two-sided significance was defined as P less than .05. RESULTS Cardiovascular Responses The average resting mean arterial blood pressure in SCI subjects (81.6⫾3.7mmHg) was significantly lower than that of healthy control subjects (101.2⫾4.4mmHg, P⫽.012), but the resting heart rate was similar in both groups (67.7⫾2.4 beats/ min, 67.6⫾3.5 beats/min, respectively). Immersion of the foot in cold water resulted in a significant rise in MABP in SCI subjects (to 101.5⫾4.5mmHg, P⫽.028) and in control subjects (to 110.8⫾4.1mmHg, P⫽.012). In addition, relative to the baseline level, the percentage increase in MABP in SCI (to 121.3%⫾5.5%, P⫽.012) and normal subjects (to 112.6%⫾1.1%, P⫽.028) significantly increased during icewater immersion and returned to baseline within 2 minutes (fig 1). The SCI subjects experienced a slight decrease in heart rate during ice-water immersion, from 67.7⫾2.4 beats/min to 66.1⫾2.3 beats/min, and a further decrease during recovery,
Fig 2. Percentage of change in heart rate in 6 control and 8 SCI subjects during 3 minutes of the cold pressor test (foot immersion in 0°C water) and 3 minutes of recovery. Data are mean ⴞ SEM. *P<.05 compared with control period. #P<.05 control vs SCI subjects.
from 67.8⫾2.4 beats/min to 65.0⫾2.3 beats/min. This difference was, however, not statistically significant. In control subjects, the average increase in heart rate from 67.3⫾4.0 beats/ min to 72.8⫾3.9 beats/min during ice-water immersion was significant (P⫽.028). The percentage change in heart rate relative to baseline was significantly higher in normal subjects than in SCI subjects during the period extending from the first 60 seconds of the immersion period to 60 seconds after the immersion period (P⬍.04; fig 2). Endocrine Responses The plasma concentrations of NE, epinephrine, and AVP in SCI subjects (63.0⫾18.3pg/mL, 9.7⫾2.1pg/mL, 1.01⫾19pg/ mL, respectively) were significantly lower than in control subjects (162.3⫾19.6pg/mL, 46.6⫾10.3pg/mL, 2.78⫾0.51pg/mL, respectively, P⬍.05). However, the basal concentrations of PRA and Paldo were similar in both groups (P⬍.05). There was a significant (P⬍.05) increase in plasma NE during the immersion period in normal subjects, and the concentration decreased at recovery although it was still significantly higher than the baseline concentration (fig 3). In SCI subjects, foot immersion in cold water resulted in a significant increase in plasma NE, but the concentration returned almost to the baseline level at recovery (fig 3). Although there was a trend for a rise in plasma epinephrine level during foot immersion in normal subjects, the change was not statistically significant (fig 3). Similar to control subjects, there were no significant changes in the plasma concentration of epinephrine (fig 3), PRA, Paldo, and AVP (fig 4) during the cold pressor test in either SCI or control subjects.
Fig 1. Percentage of change in MABP in 6 control and 8 SCI subjects during 3 minutes of the cold pressor test (foot immersion in 0°C water) and 3 minutes of recovery. Data are mean ⴞ SEM. *P<.05 compared with the control period. #P<.05 control vs SCI subjects.
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Skin Temperature and Pain Sensation The oral temperature remained constant throughout the experiment in both groups (data not shown). Foot skin temperature abruptly fell to 17.5°⫾0.5°C at 30 seconds of immersion, and progressively decreased to 14.6°⫾0.5°C at 3 minutes of
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ice-cold water in SCI subjects and greater percentage of change in MABP in SCI subjects during the first minute of the test relative to the control; (2) a lack of change in heart rate response to the cold pressor test; (3) a significant rise in NE during the cold pressor test in SCI subjects; and (4) a lack of changes in the epinephrine, PRA, AVP, and Paldo before, during, and after immersion of the foot in ice-water (cold pressor test) in SCI subjects and controls. These results indicate that cold stimulation of the foot activates sympathetic nerve input to peripheral vessels but not to either the heart or kidney and results in increased blood pressure and sustained heart rate during the cold pressor test in SCI subjects. It is well known that the cardiovascular responses to cold stimuli represent part of the somatosympathetic reflexes in which impulses from the skin receptors relay via afferent pathways to the C1 cells in RVL reticular nucleus8 and are then
Fig 3. Changes in plasma (A)epinephrine and (B) NE concentrations in 6 control and 8 SCI subjects during 3 minutes of the cold pressor test (foot immersion in 0°C water) and recovery. Data are mean ⴞ SEM. *P<.05 compared with control period. #P<.05 control versus SCI subjects.
immersion in normal subjects (fig 5). In SCI subjects, skin temperature was 19.7°⫾1.6°C at 30 seconds of immersion and 15.1°⫾1.0°C at 3 minutes of immersion. Then the foot was removed from the water, skin temperature immediately rose toward the baseline level in both groups (fig 5). This finding suggests that there was no difference between the 2 groups in the magnitude of cold stimulation during immersion. As expected, the Borg scale did not change in SCI subjects throughout the test, because of their cervical spinal cord transection and the associated damage to the afferent spinothalamic tract and other sensory pathways. In contrast, the Borg scale increased significantly in normal subjects during ice-water immersion, but recovered during the recovery period (fig 6). DISCUSSION The major findings of the present study were (1) the presence of augmented pressor response to immersion of the foot in
Fig 4. Changes in (A) PRA, (B) Paldo, and (C) AVP in 6 control and 8 SCI subjects during 3 minutes of the cold pressor test (foot immersion in 0°C water) and recovery. Data are mean ⴞ SEM. #P<.05 control vs SCI subjects.
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Fig 5. Changes in skin temperature of the immersed foot in 6 control and 8 SCI subjects during 2 minutes of control, 3 minutes of the cold pressor test (foot immersion in 0°C water), and 3 minutes of recovery. Data are mean ⴞ SEM. *P<.05 compared with control period. #P<.05 control vs SCI subjects.
transmitted via efferent pathways to blood vessels. SCI subjects in the present study had complete cervical spinal cord transections with a total loss of the sensory pathways. Wallin and Stjernberg25 noted that to evoke sympathetic reflex discharges in SCI subjects, much stronger stimuli were required than normal. Therefore, we expected an attenuated pressor response during ice-water immersion in our subjects. However, our results showed that cold stimulation elicited a brisk and greater increase of MABP, but heart rate did not increase during the cold pressor test in these subjects. What are the mechanisms of the pressor response in our chronic spinal patients? In the present study, skin temperature in SCI subjects was similar to control subjects during ice-water immersion. This finding suggests that the level of afferent stimulation from skin thermoreceptors in the immersed foot in SCI subjects was no more intense than in normal subjects. Hence, the brisk blood pressure response was not because of increased stimulus input at the skin level. SCI subjects have intact neural pathways between the cortex and the medullary vasomotor center and they did not sense any skin thermal stimuli during the cold pressor test. In comparison, the pain sensation was activated in normal subjects during the test. Therefore, we concluded that the afferent stimuli from skin thermoreceptors did not reach the vasomotor center in the medulla in SCI subjects. Several investigators26 have previously described the cold pressor response in normal subjects, in which the blood pressure rises during immersion in cold water but returns to baseline within 2 minutes. This was also true in the present study: MABP in SCI and control subjects significantly increased during ice-water immersion and returned to baseline within 2 minutes. The rise in MABP because of the cold stimulus must be mediated to a large extent through the spinal cord or sympathetic chain. Moreover, the percentage of change in MABP in the SCI subjects was higher than that in normal subjects during the first 60 seconds of the immersion period and during the first 20 seconds of the recovery period (see fig 1). This finding suggests that reflex sympathetic discharge to the peripheral vessels is likely activated through the isolated spinal Arch Phys Med Rehabil Vol 84, January 2003
cord, which is not influenced by inhibitory pathways. In addition, we suggest that the absence of a buffering baroreflex arc, which attenuates peripheral sympathetic nerve activity, contributed to the higher blood pressure response in SCI subjects. In contrast to normal subjects, heart rate remained stable in SCI subjects during ice-water immersion. This result might indicate that the increase in heart rate during the cold pressor test was totally controlled by supraspinal centers located above the cervical lesion. In other words, the tachycardia normally seen during the cold pressor test may be induced mainly through a reflex arc between the ascending supraspinal sensory pathways from skin thermoreceptors and descending supraspinal sympathetic pathways to the heart. It is known that the cortical area triggers acceleration of heart rate during muscle contraction (exercise), whereas stimulation of peripheral chemoreceptors in the contracting muscles gradually increases the activity of postganglionic sympathetic nerves to peripheral vessels.27 Another possible explanation for the stable heart rate exhibited by SCI subjects during the cold pressor test is that the intensity of reflex excitation of cardiac sympathetic neurons induced by activation of skin thermoreceptors matches the intensity of parasympathetic excitatory input to the heart, induced by activation of arterial baroreceptors, which were stimulated by the rise in blood pressure during foot cooling. In view of the lack of increased heart rate during foot cooling in SCI subjects, the finding of hyperreflexia in SCI could be accounted for by a higher increase in sympathetic discharge to resistance vessels. Moreover, the reflex arc from foot skin thermoreceptors to cardiac sympathetic neurons through spinal cord was attenuated in SCI subjects. Resting levels of plasma NE and epinephrine were significantly lower in our SCI subjects than in the controls. This finding is consistent with the results reported previously by Mathias et al28 and suggests that the low levels of NE and epinephrine contributed to the low resting MABP in SCI sub-
Fig 6. Changes in the rating of perceived pain using the Borg scale in 6 control and 8 SCI subjects during 2 minutes of control, 3 minutes of the cold pressor test (foot immersion in 0°C water), and 3 minutes of recovery. Data are mean ⴞ SEM. *P<.05 compared with control period. #P<.05 control vs SCI subjects.
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jects. These changes probably resulted from a reduction in sympathetic nerve activity due to a loss of impulses from supraspinal centers.29 This change may produce vasomotor atonia and account for the lower resting blood pressure in SCI subjects. There is probably some residual reflex sympathetic activity through the isolated spinal cord, because of minimal superficial and deep stimulation, and this activity may account for the low level of plasma NE present at rest. The rise in MABP induced by the cold pressor test was associated with a significant rise in plasma NE in both SCI and normal subjects. MABP and plasma NE increased in parallel during ice-water immersion in both groups. Because the chemical transmitter present at most sympathetic postganglionic endings is NE, the rise in MABP during the cold pressor test may be mediated by sympathetic discharge to peripheral vessels through the isolated spinal cord. On the other hand, the renin-angiotensin-aldosterone system and AVP also play an important role in the regulation of blood pressure.30 However, the cold pressor test is not associated with increased secretion of renin, aldosterone, or AVP.31-33 The present results of stable concentrations of PRA, Paldo, and AVP in both groups are consistent with these previous reports. Increased concentrations of NE suggest that the rise in blood pressure was mainly due to activation of peripheral sympathetic nerves. The level of plasma NE during the cold pressor test in SCI subjects did not exceed the resting level in normal subjects. Nevertheless, the delta change in MABP in SCI subjects was significantly higher than control subjects during the first 60 seconds of the immersion period and the first 20 seconds of the recovery period (see fig 1). Such rise in MABP might be caused by a combination of physiologic mechanisms, such as spinal sympathetic reflexes, increased noradrenergic receptor sensitivity,14,34 postjunctional changes in the effector organs resulting from prolonged inactivity,35,36 and a lack of baroreceptor reflexes restraining a rise in blood pressure.37 Stjernberg et al38 reported that an attenuated postganglionic muscle sympathetic nerve activity occurred in subjects with traumatic spinal cord lesions, and that increases in intravesical pressure induced only weak increases in muscle sympathetic activity but, nevertheless, marked hypertensive reactions occurred. The weak increase in NE in SCI subjects during ice-water immersion suggests a slight increase of postganglionic sympathetic outflow. Therefore, we believe that mechanisms other than exaggerated sympathetic outflow must be important in elevating blood pressure in SCI subjects and that such mechanisms were activated by cold stimuli on the skin.14,34-37 CONCLUSION A brisk increase of blood pressure during ice-water immersion, accompanied by a stable heart rate, was noted in subjects with transected cervical spinal cord. The profound rise in blood pressure, which results from skin stimulation, was probably caused by a reflex sympathetic discharge through the isolated spinal cord and, once the reflex responses occurred, they were greater and sustained longer than normal. Activation of heart rate in persons without SCI during the cold pressor test might be controlled by the supraspinal area. Acknowledgment: We thank Dr. Mitsuru Yamamoto, Kouichi Monji, Satoko Aoki, and Aya Katayama for technical assistance in data acquisition, and Dr. Keizou Shiraki, University of Occupational and Environmental Health, Japan, for his helpful advice. We also thank Dr. Faiq G. Issa for the careful reading and editing of our manuscript.
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24. Snedeccor GW, Cochran WG. Statistical methods. 7th ed. Ames (IA): Iowa State Univ Pr; 1980. 25. Wallin BG, Stjernberg L. Sympathetic activity in man after spinal cord injury. Outflow to skin below the lesion. Brain 1984;107: 183-98. 26. Godden JO, Roth GM, Hines ED. The changes in the intra-arterial pressure during immersion of the hand in ice-cold water. Circulation 1955;12:963-73. 27. Mark AL, Victor RG, Nerhed C, Wallin BG. Microneurographic studies of the mechanisms of sympathetic nerve responses to static exercise in humans. Circ Res 1985;57:461-9. 28. Mathias CJ, Christensen NJ, Corbett JL, Frankel HL, Goodwin TJ, Peart WS. Plasma catecholamines, plasma renin activity and plasma aldosterone in tetraplegic man, horizontal and tilted. Clin Sci Mol Med 1975;49:291-9. 29. Mathias CJ, Christensen NJ, Corbett JL, Frankel HL, Spalding JM. Plasma catecholamines during paroxysmal neurogenic hypertension in quadriplegic man. Circ Res 1976;39:204-8. 30. Davis JO, Freeman RH. Mechanisms regulating renin release. Physiol Rev 1976;56:1-56. 31. Edelson JT, Robertson GL. The effect of the cold pressor test on vasopressin secretion in man. Psychoneuroendocrinology 1986; 11:307-16. 32. Laurian L, Oberman Z, Kisch E, Fitermann A. Changes in serum dopamine-beta-hydroxylase activity during cold pressor test in subjects with high and low basal activity of this enzyme. J Neural Transm 1982;53:127-32. 33. Levy SB, Holle R, Hsu L, Lilley JJ, Stone RA. Physiologic and pharmacologic influences on adrenergic regulation of renin release. Clin Pharmacol Ther 1977;22:511-8.
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34. Mathias CJ. Role of sympathetic efferent nerves in blood pressure regulation and in hypertension. Hypertension 1991;18(5 Suppl): III22-30. 35. Emmelin N. Supersensitivity following pharmacological denervation. Pharmacol Rev 1961;13:17-38. 36. Trendelenburg U. Supersensitivity and subsensitivity to sympathomimetic amines. Pharmacol Rev 1963;15:225-76. 37. Krum H, Louis WJ, Brown DJ, Howes LG. Pressor dose responses and baroreflex sensitivity in quadriplegic spinal cord injury patients. J Hypertens 1992;10:245-50. 38. Stjernberg L, Blumberg H, Wallin BG. Sympathetic activity in man after spinal cord injury. Outflow to muscle below the lesion. Brain 1986;109:695-715. Suppliers a. NEC Corp, 7-1, Shiba 5-chome, Minato-ku, Tokyo 108-8001, Japan. b. XR50; Teac Corp, 3-7-3 Naka-cho, Musashino-shi, Tokyo 1808550, Japan. c. BIMUTAS; Kissei Comtec Co Ltd, 3F 3-4-2 Otsuka, Bunkyo-ku, Tokyo, Japan. d. AM-7001; Anritsu Meter Co, 5-10-27, Minami-Azabu, Minato-ku, Tokyo 106, Japan. e. SRL Corp, 2-41-19, Akebono-cho, Tachikawa, Tokyo, Japan. f. Mitsubishi Chemical Co, 5-2, Marunouchi 2-chome, Chiyoda-ku, Tokyo, Japan. g. Waters Chromatography Div, Millipore Corp, 34 Maple St, Milford, MA 01757. h. SPAC-S Aldosterone RIA kit; Daiichi Pharmaceutical Corp, 11 Philips Pkwy, Montvale, NJ 07645-1810.
Cardiovascular and Endocrine Responses During the Cold Pressor Test in Subjects With Cervical Spinal Cord Injuries Takashi Mizushima, MD, PhD, Fumihiro Tajima, MD, PhD, Hiroyuki Okawa, RPT, MS, Yuichi Umezu, MD, PhD, Kazunari Furusawa, MD, PhD, Hajime Ogata, MD, PhD ABSTRACT. Mizushima T, Tajima F, Okawa H, Umezu Y, Furusawa K, Ogata H. Cardiovascular and endocrine responses during the cold pressor test in subjects with spinal cord injuries. Arch Phys Med Rehabil 2003;84:112-8. Objective: To investigate cardiovascular regulation and endocrine responses during the cold pressor test in patients with chronic spinal cord injury (SCI). Design: Experimental and control study. Setting: University laboratory, department of rehabilitation medicine, in Japan. Participants: Eight quadriplegic subjects with complete spinal cord transection at the C6 to C8 level and 6 age-matched healthy subjects. Interventions: Cardiovascular and endocrine responses were examined during 2 minutes of control, 3 minutes of ice-water immersion of the foot, followed by a 3-minute recovery. Main Outcome Measures: Blood pressure, heart rate, the Borg 15-point Rating of Perceived Pain Scale, and blood samples for measurement of plasma norepinephrine, epinephrine, plasma renin activity, plasma aldosterone, and arginine vasopressin. Results: The rise in the mean arterial blood pressure during the cold pressor test in patients with SCI (baseline, 81.6⫾3.7mmHg; increased by 30%⫾6.1%) was significantly (P⬍.05) higher than that in healthy subjects (baseline, 101.2⫾4.5mmHg; increased by 20%⫾4.5%). The SCI subjects had no change in heart rate throughout the test, in contrast to the tachycardia noted in normal subjects. Baseline plasma norepinephrine in SCI subjects (63.0⫾18.3pg/mL) was significantly lower than in normal subjects (162.3⫾19.6pg/mL) and plasma norepinephrine increased significantly during the cold pressor test in both groups. Conclusions: In the SCI subjects, a reflex sympathetic discharge through the isolated spinal cord results in a more profound rise in mean blood pressure during ice-water immersion. This response was free of inhibitory impulses from supraspinal center and baroreceptor reflexes, either of which might restrain the increase in blood pressure.
From the Department of Rehabilitation Medicine, Hamamatsu University School of Medicine, University Hospital, Hamamatsu (Mizushima, Tajima); Department of Rehabilitation Medicine, University of Occupational and Environmental Health, Kitakyushu (Okawa, Ogata); Department of Rehabilitation Medicine, Kurume University School of Medicine, Kurume (Umezu); and Department of Rehabilitation Medicine, Kibikougenn Medical Rehabilitation Center, Okayama (Furusawa), Japan. Supported by Japanese National Foundation for Scientific Research and Yutaka Nakamura Memorial Foundation. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the authors or upon any organization with which the authors are associated. Reprint requests to Fumihiro Tajima, MD, PhD, Dept of Rehabilitation Medicine, Hamamatsu University School of Medicine, University Hospital, 1-20-1 Handayama, Hamamatsu-shi 431-3192, Japan, e-mail: [email protected]. 0003-9993/03/8401-7156$35.00/0 doi:10.1053/apmr.2003.50072
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Key Words: Blood pressure; Heart rate; Immersion; Norepinephrine; Quadriplegia; Rehabilitation; Water. © 2003 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation HE COLD PRESSOR TEST is an established challenge T test of autonomic vascular regulation. The normal response to a brief cold stimulus consists of a transient peripheral 1-5
vasoconstriction, tachycardia, and a rise in blood pressure. Some studies6,7 have shown that cardiovascular responses to the cold pressor test predict future resting blood pressure and the development of hypertension. Somatosensory stimulation induced by the cold stimulus increases blood pressure; impulses from receptors in the skin relay via afferent pathways to C1 cells in the rostral ventrolateral (RVL) reticular nucleus and are transmitted via efferent sympathetic neurons to peripheral blood vessels from thoracic spinal cord.8 The pressor response to stimulation of somatic afferent nerves is called the somatosympathetic reflex.9 Thus, somatosensory stimulation produces the pressor response during the cold pressor test. Severance of the pathways that transmit sensory afferent impulses is usually present in persons who have a complete cervical spinal cord transection. In these patients, the cardiovascular response to somatosensory stimuli may become abnormal because of the lack of supraspinal vasomotor control. Watson and Nance10 measured heart rate and blood pressure in 10 subjects with thoracic spinal lesion during 2 time intervals: 5 minutes before and 15 minutes after a 20-second ice-water immersion of the feet. However, these investigators did not measure heart rate and blood pressure during the cold pressor test itself and the physiologic mechanisms of the pressor response during immersion were not completely established. To our knowledge, no studies have previously examined the cardiovascular responses during a 3-minute cold pressor test in humans who had a stable complete transection of the cervical spinal cord. Previous studies11-16 have described the presence of abnormal and unstable cardiovascular control in subjects with spinal cord injury (SCI); the results have indicated that the lack of supraspinal vasomotor control in these patients may lead to considerable clinical problems. Low tonic discharge can cause hypotension and intense sympathetic discharge in response to reflex stimulation can result in hypertension, bradycardia, headache, and sometimes severe cerebrovascular complications.11,16,17 These reactions, known as autonomic hyperreflexia, can also be elicited by cutaneous, visceral, and muscle stimulation.11,16,18-20 The purpose of the present study was to investigate cardiovascular regulation and endocrine responses during a cold pressor test in chronic spinal patients, as evidenced by a complete loss of supraspinal control of the sympathetic outflow,21 and to explore the mechanisms of hyperreflexia in these patients.
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COLD PRESSOR TEST IN CERVICAL SCI, Mizushima Table 1: Profile and Lesion Level in SCI Subjects ASIA Score Patient
Age (y)
Lesion Level
Years Since Injury (y)
Motor
Sensory
Pain Touch
1 2 3 4 5 6 7 8 Mean SEM
33 46 33 46 58 33 33 50 41.5 3.3
C7 C8 C7 C6 C6 C7 C7 C7
10 17 16 10 18 12 16 2 12.6 1.8
28 38 28 21 21 30 31 27
22 24 25 19 22 25 26 23
24 28 24 21 22 25 26 24
METHODS Participants We studied 8 men with traumatic chronic cervical SCI who were between the ages of 33 and 58 years (mean ⫾ standard error of the mean [SEM], 41.5⫾3.3y). Each had a physiologically complete cervical spinal cord transection between C6 and C8, with complete sensory and motor loss at and below the level of the injuries. All subjects were classified as American Spinal Injury Association (ASIA) Impairment Scale class A. All SCI subjects’ spinal cords were assessed by using magnetic resonance imaging and the lesion of SCI was confirmed. SCI had occurred at least 2 years before the present study (range, 2–18y; avg, 12.6y; table 1). Of the SCI subjects, 3 were recruited from the outpatient clinic of the university hospital, 2 were inpatients of the university hospital, and 3 were in a nursing home. All voluntarily participated in this study. None had any systemic disease or complication except for their SCI. None was on medications except for a purgative given at the time of the study to prevent possible constipation that might affect autonomic nervous system function. None was bedridden in the daytime, and all were mobile in their wheelchairs. Six healthy male volunteers, between the ages of 31 and 62 years (mean, 40.7⫾3.1y), were also included as control subjects. None of these subjects was on any medication or had any systemic disease (table 1). Informed consent was obtained from all subjects, and the experimental protocol was approved by the institutional review board for human research at the University of Occupational and Environmental Health, Japan. Experimental Procedures All subjects reported to the laboratory of University of Occupational and Environmental Health at 3:00 PM and rested on a bed in supine position throughout the test. A catheter was introduced percutaneously into the dorsalis pedis artery for measurement of arterial blood pressure. The catheter was connected via saline-filled manometer tubing to an electromanometer (SPB-106a), which was placed on the same level with the fourth intercostal space, just anterior to the midaxillary line. The arterial catheter contained heparinized saline to prevent clotting during measurement of arterial blood pressure. The electrocardiograph (Bioview 1000a) and blood pressure were recorded on a chart recorder (Omniace RT2108Aa) and a tape recorder,b and were digitized into a personal computer (PC9821-BRa) using an analog-to-digital converterc at 2-kHz sampling rate.
All tests were performed after the subjects rested quietly in the supine position for 15 minutes in a quiet room (ambient temperature, 28°C), and their right knee joint was positioned at 90° of flexion hanging off end of table for the ice-water immersion procedure. Each test consisted of 8 minutes of recording. After a basal recording for 2 minutes (control period), the right foot was immersed to the ankle into 0°C water bath without any foot movement (immersion period) for a period of 3 minutes, followed by removal of the foot from the bath and continuation of recording for another 3 minutes (recovery period). Each subject was then asked to rate the severity of the perceived pain. We also recorded the skin temperature of the right foot and the oral temperature every 30 seconds by using a copper-constantan thermocouple thermometer.d In addition, blood samples for measurement of plasma norepinephrine (NE), epinephrine, plasma renin activity (PRA), plasma aldosterone (Paldo), and arginine vasopressin (AVP) were withdrawn at the first minute of the control period and at the second minute of the immersion and recovery periods. Measurements of Physiologic Variables and Determination of Hormonal Levels Heart rate computed from the R-R interval (distance from peak to peak of consecutive R waves on an electrocardiogram) and blood pressure were averaged over each 10-second period of foot immersion and compared with average values obtained during the 2-minute prestress control period and 3-minute poststress recovery period. The mean arterial blood pressure (MABP) is stated in the present report. The Borg 15-point Rating of Perceived Pain Scale22 was used to determine the severity of perceived pain during icewater immersion. The Borg scale was used to measure subjective rating of perceived pain before, during, and after the stress period. Blood samples were withdrawn (6mL) from a catheter inserted into the left antecubital vein. The samples used for measurement of plasma NE, epinephrine, PRA, Paldo, and AVP were immediately transferred into ice-cooled plastic tubes containing ethylenediaminetetraacetic acid and ascorbic acid, placed in ice, and centrifuged at 3000rpm at 4°C for 10 minutes. The plasma was pipetted into ice-cooled plastic storage tubes until analysis. NE and epinephrine were extracted from plasma by using alumina and measured by high-performance liquid chromatography using a modification of the procedure described by Hunter et al.23 PRA was determined with an angiotensin I radioimmunoassay (RIA) kit,e with a detection limit of 0.1ng䡠mL⫺1䡠h⫺1, and intra- and interassay coefficients Arch Phys Med Rehabil Vol 84, January 2003
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of variation (CVs) of 5.7% and 10.5%, respectively. AVP was measured in duplicates by using RIA kitsf after extraction using Sep-Pak C18.g The sensitivity of this RIA was .06pg/tube, and the recovery of AVP ranged from 71.1% to 85.5%. The interassay CVs were 7.6% and 7.2% for concentration between 1.4 and 2.4pg/mL, respectively, and 12.5% and 4.5% for concentrations between 0.2 and 2.7pg/mL, respectively. Paldo was measured by RIA,h with intra- and interassay CVs of 6.4% and 7.8%, respectively. Statistical Analysis Data were reported as mean ⫾ SEM. Differences between SCI and control subjects at each period, and between control and each time period in each group were evaluated by nonparametric Mann-Whitney U and the Wilcoxon matched-pairs signed-rank test,24 respectively. Two-sided significance was defined as P less than .05. RESULTS Cardiovascular Responses The average resting mean arterial blood pressure in SCI subjects (81.6⫾3.7mmHg) was significantly lower than that of healthy control subjects (101.2⫾4.4mmHg, P⫽.012), but the resting heart rate was similar in both groups (67.7⫾2.4 beats/ min, 67.6⫾3.5 beats/min, respectively). Immersion of the foot in cold water resulted in a significant rise in MABP in SCI subjects (to 101.5⫾4.5mmHg, P⫽.028) and in control subjects (to 110.8⫾4.1mmHg, P⫽.012). In addition, relative to the baseline level, the percentage increase in MABP in SCI (to 121.3%⫾5.5%, P⫽.012) and normal subjects (to 112.6%⫾1.1%, P⫽.028) significantly increased during icewater immersion and returned to baseline within 2 minutes (fig 1). The SCI subjects experienced a slight decrease in heart rate during ice-water immersion, from 67.7⫾2.4 beats/min to 66.1⫾2.3 beats/min, and a further decrease during recovery,
Fig 2. Percentage of change in heart rate in 6 control and 8 SCI subjects during 3 minutes of the cold pressor test (foot immersion in 0°C water) and 3 minutes of recovery. Data are mean ⴞ SEM. *P<.05 compared with control period. #P<.05 control vs SCI subjects.
from 67.8⫾2.4 beats/min to 65.0⫾2.3 beats/min. This difference was, however, not statistically significant. In control subjects, the average increase in heart rate from 67.3⫾4.0 beats/ min to 72.8⫾3.9 beats/min during ice-water immersion was significant (P⫽.028). The percentage change in heart rate relative to baseline was significantly higher in normal subjects than in SCI subjects during the period extending from the first 60 seconds of the immersion period to 60 seconds after the immersion period (P⬍.04; fig 2). Endocrine Responses The plasma concentrations of NE, epinephrine, and AVP in SCI subjects (63.0⫾18.3pg/mL, 9.7⫾2.1pg/mL, 1.01⫾19pg/ mL, respectively) were significantly lower than in control subjects (162.3⫾19.6pg/mL, 46.6⫾10.3pg/mL, 2.78⫾0.51pg/mL, respectively, P⬍.05). However, the basal concentrations of PRA and Paldo were similar in both groups (P⬍.05). There was a significant (P⬍.05) increase in plasma NE during the immersion period in normal subjects, and the concentration decreased at recovery although it was still significantly higher than the baseline concentration (fig 3). In SCI subjects, foot immersion in cold water resulted in a significant increase in plasma NE, but the concentration returned almost to the baseline level at recovery (fig 3). Although there was a trend for a rise in plasma epinephrine level during foot immersion in normal subjects, the change was not statistically significant (fig 3). Similar to control subjects, there were no significant changes in the plasma concentration of epinephrine (fig 3), PRA, Paldo, and AVP (fig 4) during the cold pressor test in either SCI or control subjects.
Fig 1. Percentage of change in MABP in 6 control and 8 SCI subjects during 3 minutes of the cold pressor test (foot immersion in 0°C water) and 3 minutes of recovery. Data are mean ⴞ SEM. *P<.05 compared with the control period. #P<.05 control vs SCI subjects.
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Skin Temperature and Pain Sensation The oral temperature remained constant throughout the experiment in both groups (data not shown). Foot skin temperature abruptly fell to 17.5°⫾0.5°C at 30 seconds of immersion, and progressively decreased to 14.6°⫾0.5°C at 3 minutes of
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ice-cold water in SCI subjects and greater percentage of change in MABP in SCI subjects during the first minute of the test relative to the control; (2) a lack of change in heart rate response to the cold pressor test; (3) a significant rise in NE during the cold pressor test in SCI subjects; and (4) a lack of changes in the epinephrine, PRA, AVP, and Paldo before, during, and after immersion of the foot in ice-water (cold pressor test) in SCI subjects and controls. These results indicate that cold stimulation of the foot activates sympathetic nerve input to peripheral vessels but not to either the heart or kidney and results in increased blood pressure and sustained heart rate during the cold pressor test in SCI subjects. It is well known that the cardiovascular responses to cold stimuli represent part of the somatosympathetic reflexes in which impulses from the skin receptors relay via afferent pathways to the C1 cells in RVL reticular nucleus8 and are then
Fig 3. Changes in plasma (A)epinephrine and (B) NE concentrations in 6 control and 8 SCI subjects during 3 minutes of the cold pressor test (foot immersion in 0°C water) and recovery. Data are mean ⴞ SEM. *P<.05 compared with control period. #P<.05 control versus SCI subjects.
immersion in normal subjects (fig 5). In SCI subjects, skin temperature was 19.7°⫾1.6°C at 30 seconds of immersion and 15.1°⫾1.0°C at 3 minutes of immersion. Then the foot was removed from the water, skin temperature immediately rose toward the baseline level in both groups (fig 5). This finding suggests that there was no difference between the 2 groups in the magnitude of cold stimulation during immersion. As expected, the Borg scale did not change in SCI subjects throughout the test, because of their cervical spinal cord transection and the associated damage to the afferent spinothalamic tract and other sensory pathways. In contrast, the Borg scale increased significantly in normal subjects during ice-water immersion, but recovered during the recovery period (fig 6). DISCUSSION The major findings of the present study were (1) the presence of augmented pressor response to immersion of the foot in
Fig 4. Changes in (A) PRA, (B) Paldo, and (C) AVP in 6 control and 8 SCI subjects during 3 minutes of the cold pressor test (foot immersion in 0°C water) and recovery. Data are mean ⴞ SEM. #P<.05 control vs SCI subjects.
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Fig 5. Changes in skin temperature of the immersed foot in 6 control and 8 SCI subjects during 2 minutes of control, 3 minutes of the cold pressor test (foot immersion in 0°C water), and 3 minutes of recovery. Data are mean ⴞ SEM. *P<.05 compared with control period. #P<.05 control vs SCI subjects.
transmitted via efferent pathways to blood vessels. SCI subjects in the present study had complete cervical spinal cord transections with a total loss of the sensory pathways. Wallin and Stjernberg25 noted that to evoke sympathetic reflex discharges in SCI subjects, much stronger stimuli were required than normal. Therefore, we expected an attenuated pressor response during ice-water immersion in our subjects. However, our results showed that cold stimulation elicited a brisk and greater increase of MABP, but heart rate did not increase during the cold pressor test in these subjects. What are the mechanisms of the pressor response in our chronic spinal patients? In the present study, skin temperature in SCI subjects was similar to control subjects during ice-water immersion. This finding suggests that the level of afferent stimulation from skin thermoreceptors in the immersed foot in SCI subjects was no more intense than in normal subjects. Hence, the brisk blood pressure response was not because of increased stimulus input at the skin level. SCI subjects have intact neural pathways between the cortex and the medullary vasomotor center and they did not sense any skin thermal stimuli during the cold pressor test. In comparison, the pain sensation was activated in normal subjects during the test. Therefore, we concluded that the afferent stimuli from skin thermoreceptors did not reach the vasomotor center in the medulla in SCI subjects. Several investigators26 have previously described the cold pressor response in normal subjects, in which the blood pressure rises during immersion in cold water but returns to baseline within 2 minutes. This was also true in the present study: MABP in SCI and control subjects significantly increased during ice-water immersion and returned to baseline within 2 minutes. The rise in MABP because of the cold stimulus must be mediated to a large extent through the spinal cord or sympathetic chain. Moreover, the percentage of change in MABP in the SCI subjects was higher than that in normal subjects during the first 60 seconds of the immersion period and during the first 20 seconds of the recovery period (see fig 1). This finding suggests that reflex sympathetic discharge to the peripheral vessels is likely activated through the isolated spinal Arch Phys Med Rehabil Vol 84, January 2003
cord, which is not influenced by inhibitory pathways. In addition, we suggest that the absence of a buffering baroreflex arc, which attenuates peripheral sympathetic nerve activity, contributed to the higher blood pressure response in SCI subjects. In contrast to normal subjects, heart rate remained stable in SCI subjects during ice-water immersion. This result might indicate that the increase in heart rate during the cold pressor test was totally controlled by supraspinal centers located above the cervical lesion. In other words, the tachycardia normally seen during the cold pressor test may be induced mainly through a reflex arc between the ascending supraspinal sensory pathways from skin thermoreceptors and descending supraspinal sympathetic pathways to the heart. It is known that the cortical area triggers acceleration of heart rate during muscle contraction (exercise), whereas stimulation of peripheral chemoreceptors in the contracting muscles gradually increases the activity of postganglionic sympathetic nerves to peripheral vessels.27 Another possible explanation for the stable heart rate exhibited by SCI subjects during the cold pressor test is that the intensity of reflex excitation of cardiac sympathetic neurons induced by activation of skin thermoreceptors matches the intensity of parasympathetic excitatory input to the heart, induced by activation of arterial baroreceptors, which were stimulated by the rise in blood pressure during foot cooling. In view of the lack of increased heart rate during foot cooling in SCI subjects, the finding of hyperreflexia in SCI could be accounted for by a higher increase in sympathetic discharge to resistance vessels. Moreover, the reflex arc from foot skin thermoreceptors to cardiac sympathetic neurons through spinal cord was attenuated in SCI subjects. Resting levels of plasma NE and epinephrine were significantly lower in our SCI subjects than in the controls. This finding is consistent with the results reported previously by Mathias et al28 and suggests that the low levels of NE and epinephrine contributed to the low resting MABP in SCI sub-
Fig 6. Changes in the rating of perceived pain using the Borg scale in 6 control and 8 SCI subjects during 2 minutes of control, 3 minutes of the cold pressor test (foot immersion in 0°C water), and 3 minutes of recovery. Data are mean ⴞ SEM. *P<.05 compared with control period. #P<.05 control vs SCI subjects.
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jects. These changes probably resulted from a reduction in sympathetic nerve activity due to a loss of impulses from supraspinal centers.29 This change may produce vasomotor atonia and account for the lower resting blood pressure in SCI subjects. There is probably some residual reflex sympathetic activity through the isolated spinal cord, because of minimal superficial and deep stimulation, and this activity may account for the low level of plasma NE present at rest. The rise in MABP induced by the cold pressor test was associated with a significant rise in plasma NE in both SCI and normal subjects. MABP and plasma NE increased in parallel during ice-water immersion in both groups. Because the chemical transmitter present at most sympathetic postganglionic endings is NE, the rise in MABP during the cold pressor test may be mediated by sympathetic discharge to peripheral vessels through the isolated spinal cord. On the other hand, the renin-angiotensin-aldosterone system and AVP also play an important role in the regulation of blood pressure.30 However, the cold pressor test is not associated with increased secretion of renin, aldosterone, or AVP.31-33 The present results of stable concentrations of PRA, Paldo, and AVP in both groups are consistent with these previous reports. Increased concentrations of NE suggest that the rise in blood pressure was mainly due to activation of peripheral sympathetic nerves. The level of plasma NE during the cold pressor test in SCI subjects did not exceed the resting level in normal subjects. Nevertheless, the delta change in MABP in SCI subjects was significantly higher than control subjects during the first 60 seconds of the immersion period and the first 20 seconds of the recovery period (see fig 1). Such rise in MABP might be caused by a combination of physiologic mechanisms, such as spinal sympathetic reflexes, increased noradrenergic receptor sensitivity,14,34 postjunctional changes in the effector organs resulting from prolonged inactivity,35,36 and a lack of baroreceptor reflexes restraining a rise in blood pressure.37 Stjernberg et al38 reported that an attenuated postganglionic muscle sympathetic nerve activity occurred in subjects with traumatic spinal cord lesions, and that increases in intravesical pressure induced only weak increases in muscle sympathetic activity but, nevertheless, marked hypertensive reactions occurred. The weak increase in NE in SCI subjects during ice-water immersion suggests a slight increase of postganglionic sympathetic outflow. Therefore, we believe that mechanisms other than exaggerated sympathetic outflow must be important in elevating blood pressure in SCI subjects and that such mechanisms were activated by cold stimuli on the skin.14,34-37 CONCLUSION A brisk increase of blood pressure during ice-water immersion, accompanied by a stable heart rate, was noted in subjects with transected cervical spinal cord. The profound rise in blood pressure, which results from skin stimulation, was probably caused by a reflex sympathetic discharge through the isolated spinal cord and, once the reflex responses occurred, they were greater and sustained longer than normal. Activation of heart rate in persons without SCI during the cold pressor test might be controlled by the supraspinal area. Acknowledgment: We thank Dr. Mitsuru Yamamoto, Kouichi Monji, Satoko Aoki, and Aya Katayama for technical assistance in data acquisition, and Dr. Keizou Shiraki, University of Occupational and Environmental Health, Japan, for his helpful advice. We also thank Dr. Faiq G. Issa for the careful reading and editing of our manuscript.
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Arch Phys Med Rehabil Vol 84, January 2003
34. Mathias CJ. Role of sympathetic efferent nerves in blood pressure regulation and in hypertension. Hypertension 1991;18(5 Suppl): III22-30. 35. Emmelin N. Supersensitivity following pharmacological denervation. Pharmacol Rev 1961;13:17-38. 36. Trendelenburg U. Supersensitivity and subsensitivity to sympathomimetic amines. Pharmacol Rev 1963;15:225-76. 37. Krum H, Louis WJ, Brown DJ, Howes LG. Pressor dose responses and baroreflex sensitivity in quadriplegic spinal cord injury patients. J Hypertens 1992;10:245-50. 38. Stjernberg L, Blumberg H, Wallin BG. Sympathetic activity in man after spinal cord injury. Outflow to muscle below the lesion. Brain 1986;109:695-715. Suppliers a. NEC Corp, 7-1, Shiba 5-chome, Minato-ku, Tokyo 108-8001, Japan. b. XR50; Teac Corp, 3-7-3 Naka-cho, Musashino-shi, Tokyo 1808550, Japan. c. BIMUTAS; Kissei Comtec Co Ltd, 3F 3-4-2 Otsuka, Bunkyo-ku, Tokyo, Japan. d. AM-7001; Anritsu Meter Co, 5-10-27, Minami-Azabu, Minato-ku, Tokyo 106, Japan. e. SRL Corp, 2-41-19, Akebono-cho, Tachikawa, Tokyo, Japan. f. Mitsubishi Chemical Co, 5-2, Marunouchi 2-chome, Chiyoda-ku, Tokyo, Japan. g. Waters Chromatography Div, Millipore Corp, 34 Maple St, Milford, MA 01757. h. SPAC-S Aldosterone RIA kit; Daiichi Pharmaceutical Corp, 11 Philips Pkwy, Montvale, NJ 07645-1810.