Effect of hypocapnia on the sensitivity of hyperthermic hyperventilation and the cerebrovascular response in resting heated humans
Journal of applied physiology
Citation: TSUJI, B. ... et al, 2017. Effect of hypocapnia on the sensitivity of hyperthermic hyperventilation and the cerebrovascular response in resting heated humans. ABSTRACT 34 Elevating core temperature at rest causes increases in minute ventilation ( ), which leads to 35 reductions in both arterial CO 2 partial pressure (hypocapnia) and cerebral blood flow. We tested 36 the hypothesis that in resting heated humans this hypocapnia diminishes the ventilatory 37 sensitivity to rising core
... perature but does not explain a large portion of the decrease in 38 cerebral blood flow. Fourteen healthy men were passively heated using hot-water immersion 39 (41°C) combined with a water-perfused suit, which caused esophageal temperature (T es ) to reach 40 39°C. During heating in two separate trials, end-tidal CO 2 partial pressure decreased from the 41 level before heating (39.42.0 mmHg) to the end of heating (30.56.3 mmHg) (P=0.005) in the 42 Control trial. This decrease was prevented by breathing CO 2 -enriched air throughout the heating 43 such that end-tidal CO 2 partial pressure did not differ between the beginning (39.81.5 mmHg) 44 and end (40.92.7 mmHg) of heating (P=1.00). The sensitivity of to rising T es (i.e., slope 45 of the T es -relation) did not differ between the Control and CO 2 -breathing trials (37.143.1 46 vs. 16.511.1 l·min 1 ·°C 1 , P=0.31). In both trials, middle cerebral artery blood velocity 47 (MCAV) decreased early during heating (all P<0.01), despite the absence of 48 hyperventilation-induced hypocapnia. CO 2 -breathing increased MCAV relative to Control at the 49 end of heating (P=0.005) and explained 36.6% of the heat-induced reduction in MCAV. These 50 results indicate that during passive heating at rest, ventilatory sensitivity to rising core 51 temperature is not suppressed by hypocapnia, and that most of the decrease in cerebral blood 52 flow occurs independently of hypocapnia. 53 (249 words) 54 E V E V E V by 10.220.33.6 on October 5, 2017 http://jap.physiology.org/ Downloaded from NEW & NOTEWORTHY 55 Hyperthermia causes hyperventilation and concomitant hypocapnia and cerebral 56 hypoperfusion. The last may underlie central fatigue. We are the first to demonstrate that 57 hyperthermia-induced hyperventilation is not suppressed by the resultant hypocapnia, and 58 that hypocapnia explains only 36% of cerebral hypoperfusion elicited by hyperthermia. These 59 new findings advance our understanding of the mechanisms controlling ventilation and 60 cerebral blood flow during heat stress, which may be useful for developing interventions 61 aimed at preventing central fatigue during hyperthermia. 62 (75/75) 63 64 Downloaded from period of heating, as we did previously (24). Acute restoration of eucapnia after a period of 101 hypocapnia during heating does not enable the relationships among hypocapnia, ventilation 102 and core temperature to be precisely characterized. 103 As mentioned, hyperventilation-induced hypocapnia contributes to the cerebral 104 hypoperfusion during hyperthermia. It is still debatable, however, whether this hypocapnia 105 entirely explains the cerebral hypoperfusion during hyperthermia at rest. When P ETCO2 is 106 acutely restored to normothermic levels through CO 2 inhalation during hyperthermia, the 107 decrease in middle cerebral artery blood velocity (MCAV; an index of anterior cerebral blood 108 flow) is partially (9, 16) or largely (3, 31) reversed. But it is well recognized that restoration of 109 P ETCO2 to eucapnia after sustained hypocapnia causes an overshoot in MCAV beyond the 110 original baseline value (37). Thus restoration of P ETCO2 after sustained hypocapnia during 111 heating could lead to overestimation of the contribution of hypocapnia to the reduction in 112 MCAV. To avoid that issue, it is necessary to clamp P ETCO2 at a eucapnic level throughout the 113 by 10.220.33.6 on October 5, 2017 http://jap.physiology.org/ Downloaded from The procedure used in this study was approved by the Human Subjects Committee of the 126 University of Tsukuba and conformed to the provisions of the Declaration of Helsinki. 127 128 Experimental Design 129 Participants performed two trials wherein they breathed room air (Control trial) or 130 CO 2 -enriched air (CO 2 trial) that prevented a reduction in P ETCO2 during passive heating. The 131 two experimental trials were conducted in a counterbalanced manner and were separated by at 132 least 7 days. Participants were asked to abstain from strenuous exercise, alcohol and caffeine 133 for 24 h before the experiment. The participants drank 500 ml of water on the night before the 134 experiment and then consumed a light meal and 500 ml of water 2 h prior to the experiment. 135 136 by 10.220.33.6 on October 5, 2017 http://jap.physiology.org/ Downloaded from 157 controlled using a heater and monitored using a thermocouple placed in the bath. 158 In the Control trial, participants breathed room air throughout the experiment. In the 159 CO 2 trial, they breathed CO 2 -enriched air (a mixture of room air and 100% CO 2 ), beginning at 160 by 10.220.33.6 on October 5, 2017 http://jap.physiology.org/ Downloaded from Likewise, increases in T _ sk were equivalent during heating in the two trials. Because we were 245 unable to measure sweat rate and cutaneous blood flow on the forearms of three subjects due to 246 technical difficulties, the data analyzed were from the remaining 11 subjects. Forearm sweat 247 rate and cutaneous vascular conductance did not differ between trials (P = 0.52 and 0.68 for a 248 main effect of trial, respectively), and thermal sensation increased similarly in the two trials (P 249 = 0.29 for a main effect of trial). 250 Cardiovascular and cerebrovascular responses 251 Similar changes in HR and MAP were observed in the two trials (P = 0.25 and 0.99 for a 252 main effect of trial, respectively, Table 1 ). There was a significant interaction between trial and 253 heating duration affecting MCAV and CVC (both P < 0.05). In both trials, MCAV was 254 decreased at and after 10 min of heating in comparison to the pre-heating value. In addition, 255 MCAV was higher in the CO 2 than Control trial at the end of heating (P = 0.005, Fig. 1D ), and E V E V by 10.220.33.6 on October 5, 2017 http://jap.physiology.org/ Downloaded from 16 hyperventilation, and thus resultant hypocapnia, being minimal ( Fig. 1C and D) . This implies 353 that at rest hyperthermia can decrease cerebral blood flow independently of hypocapnia. When 354 the decrease in P ETCO2 was prevented in the CO 2 trial, MCAV was higher than in the Control 355 trial during the latter part of heating (Fig. 1C) ; however, the restoration accounts for only 356 36.6% of total decrease in MCAV (Fig. 1D) . Hence, although hypocapnia appears to contribute 357 to the decrease in cerebral blood flow during passive heating at rest, a larger portion of the 358 response is explained by one or more hypocapnia-independent factors. Furthermore, MCAV 359 was similarly restored by 40% across the range of T es = 38.0-38.8°C (Fig. 4B ), indicating that 360 the relative contribution of hypocapnia to the change in cerebral blood flow during passive 361 heating is similar within this temperature range. 362 Previous studies reported that restoration of P ETCO2 through acute CO 2 inhalation during 363 passive heating increased MCAV by ~28% and ~38% at core temperatures of 37.6°C and 364 38.0°C, respectively (16) and increased MCAV by ~50% at a core temperature of 38.5°C (9). 365 By contrast, the restoration of P ETCO2 reversed reductions in MCAV and posterior cerebral 366 artery blood flow velocity by ~67% and ~84%, respectively, at core temperature of 38.8°C (31), 367 and it increased MCAV by ~75% at a core temperature of 38.7°C (3). It is however noteworthy 368 that the all the results shown above could be influenced by prolonged exposure of hypocapnia, 369 during which MCAV gradually increased despite the sustained hypocapnic state as a result of 370 reductions in brain extracellular bicarbonate and recovery of extracellular pH (8). 371 Consequently, restoration of P a CO 2 to a eucapnic level after prolonged hypocapnic exposure 372 produces an overshoot in MCAV above baseline values (27, 37). We suggest that the different 373 magnitudes of this adaptation, in addition to the postural difference as speculated by Bain et al. 374 (2), may underlie the discrepancy among the earlier studies. 375 The mechanism underlying hypocapnia-independent decrease in MCAV during heat Limitations 411 Coverdale et al. (12) recently reported that MCA diameter measured using magnetic 412 resonance imaging decreased by 4% when P ETCO2 decreased from 36 to 23 mmHg, which is in 413 contrast to previous reports that MCA diameter is unaffected by decreases in P ETCO2 to ~25 414 mmHg (21, 41). It may thus be possible that the degree to which MCAV was reduced in the 415 Control trial underestimated the true degree to which MCA blood flow was reduced, as blood 416 flow was actually decreased farther than was reflected by the change in velocity. 417 418 Perspectives and significance 419 Reduced cerebral blood flow during hyperthermia reportedly leads to increased brain 420 temperature (34) and central fatigue (39) without modulating cerebral metabolism (32, 43). 421 The present study demonstrated that hypocapnia induced through hyperventilation does not 422 modulate ventilatory responses to rising core temperature, but does contribute to the decrease ACKNOWLEDGMENTS 442 We sincerely thank the volunteer subjects. We also greatly appreciate the help of Dr. 443 William Goldman (English editing and critical comments). 444 445 446 GRANTS 447 This study was supported by the grants from Ministry of Education, Culture, Sports, 448 Science and Technology in Japan and Japan Society for the Promotion of Science. 449 450 by 10.220.33.6 on October 5, 2017 http://jap.physiology.org/ Downloaded from 6. Beaudin AE, Walsh ML, White MD. Central chemoreflex ventilatory responses in 466 humans following passive heat acclimation. Respir Physiol Neurobiol 180: 97-104, 2012. 467 7. Brengelmann GL. Control of sweating rate and skin blood flow during exercise. In: 468 Problems with Temperature Regulation During Exercise, edited by Nadel ER. New York: 469 Academic Press, 1977. 470 8. Brian JE, Jr. Carbon dioxide and the cerebral circulation. Anesthesiology 88: 1365-1386, 471 1998. 472 9. Brothers RM, Wingo JE, Hubing KA, Crandall CG. 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The numbers adjacent to the symbols in the Control trial indicate the number of subjects 599 remaining at the corresponding temperature.