Mean skin temperatures at the beginning of the study were not statistically different on both days and for all treatments (Table 1). Mean skin temperatures at vasoconstriction were 33.2°C (95% confidence interval [CI]: 32.0°C, 34.4°C), 33.5°C (95% CI: 32.3°C, 34.7°C), and 33.0°C (95% CI: 31.4°C, 34.6°C) (P = 0.79) at slow, medium, and fast rates of skin cooling, respectively. Mean skin temperatures at the shivering threshold were also not statistically significantly different at each skin-cooling rate: 31.4°C (95% CI: 30.3°C, 32.5°C), 31.5°C (95% CI: 30.2°C, 32.8°C), and 30.7°C (95% CI: 28.9°C, 32.5°C) (P = 0.53) for slow, medium, and fast rates, respectively. Thus, mean skin temperatures were similar at vasoconstriction regardless of cooling rate. Likewise, mean skin temperatures at shivering were within 0.5°C at all cooling rates and lower than temperatures at vasoconstriction (Table 1).
Times to onset of vasoconstriction were 53 minutes (30, 93 minutes), 31 minutes (17, 54 minutes), and 18 minutes (10, 31 minutes) (P = 0.003) at the slow, medium, and fast rates of skin cooling, respectively (Fig. 1). Times to shivering onset were also different: 114 minutes (80, 162 minutes), 60 minutes (42, 85 minutes), and 41 minutes (29, 58 minutes) (P < 0.0001) for slow, medium, and fast rates, respectively. Onset of vasoconstriction and shivering was achieved most rapidly at the fastest skin-cooling rate (Table 1, Fig. 1).
The extent to which dynamic responses to rapid core- and skin-temperature changes potentially complicate thermoregulatory studies and induction of therapeutic hypothermia is of considerable physiological and clinical interest. However, the ability to perform such studies in humans has been limited because it is difficult to independently manipulate core and skin temperatures.
With sufficient attention to detail, it is possible to clamp mean skin temperature using either water immersion or a combination of forced air and circulating water. However, it is then difficult to increase or decrease core temperature. One strategy has been to increase core temperature by having volunteers exercise,14 but this approach is suboptimal because exercise per se reduces the sweating threshold,15 thus confounding the results. As early as 1959, investigators tried to independently cool the core by having volunteers ingest an ice and water slurry.30 However, the method is obviously impractical in many clinical situations (i.e., during anesthesia or in critically ill patients) and, at best, produces only a modest degree of hypothermia.30 More recently, gastric and bladder lavage have been attempted, but proved respectively impractical and ineffective.31
Our study was possible because we were able to clamp core temperature using 1 of 3 recently developed endovascular heat-exchanging catheters. This allowed us to independently cool the skin surface without consequent changes in core temperature. (The core response to surface warming or cooling depends on thermoregulatory status, body heat content, and degree of cooling stress; however, the normal consequence is a compensatory opposite change in core temperature.32) The endovascular system we used was effective at maintaining normothermia; core temperatures were thus virtually identical at vasoconstriction and shivering at each skin-cooling rate. The mean skin temperatures triggering each response could therefore be directly compared.
Our primary result is that the mean skin temperature triggering vasoconstriction was similar at skin-cooling rates ranging from approximately 2°C/h to 6°C/h; the skin temperatures triggering shivering were lower than those at vasoconstriction, but again similar at each cooling rate. At least within this factor-of-3 range of cutaneous cooling rates, thermoregulatory response can be considered a pseudo–steady-state. Our results indicate that skin-cooling rates in thermoregulatory investigations no longer need be restricted to ≈2°C/h, but can instead be increased to 6°C/h, which will facilitate and speed the studies. The extent to which this information will speed studies is indicated by the onset times for vasoconstriction and shivering, which decreased by nearly a factor of 3 in our volunteers.
Perhaps more importantly, our results indicate that skin-cooling rates up to 6°C/h can be used during induction of therapeutic hypothermia without increasing the requirement for drugs that induce partial thermoregulatory tolerance.33–35 Being able to cool quickly from the skin surface without provoking dynamic thermoregulatory compensations is clinically important for 2 reasons. The first is that vasoconstriction and shivering are themselves potentially harmful in fragile patients. The second is that they are each effective, thus substantially slowing the rate of core cooling.
We used a combination of circulating water and forced air to reduce skin temperature, and ≈6°C/h was about the fastest decrease we could obtain. (Animal studies have compared responses to skin cooling at rates between 14°C/h and 140°C/h, but these results are difficult to extrapolate to humans.12) However, immersion in cool water certainly reduces mean skin temperature far >6°C/h and newer hypothermia devices probably will as well. It remains probable that yet faster cooling rates will indeed provoke dynamic thermoregulatory responses. Availability of a new generation of endovascular heat-exchange catheters that can cool the core of adult humans as fast as 10°C/h will also allow investigators to determine the relative contributions of dynamic and steady-state thermoregulatory defenses as a function of the core cooling rate.
In summary, onset of vasoconstriction and shivering occurred at similar mean skin temperatures when the skin was cooled at between 2°C/h and 6°C/h. Surface cooling at a rate of ≤6°C/h can thus be used in thermoregulatory studies and for induction of therapeutic hypothermia without provoking dynamic thermoregulatory defenses.
We thank Gilbert Haugh, MS, for the statistical analysis and Nancy L. Alsip, PhD, for editorial assistance (Center for Clinical Research Services & Support at the University of Louisville).
1. Lopez M, Sessler DI, Walter K, Emerick T, Ozaki M. Rate and gender dependence of the sweating, vasoconstriction, and shivering thresholds in humans. Anesthesiology 1994;80:780–8
2. Kim JS, Ikeda T, Sessler D, Turakhia M, Jeffrey R. Epidural anesthesia reduces the gain and maximum intensity of shivering. Anesthesiology 1998;88:851–7
3. Ikeda T, Sessler DI, Tayefeh F, Negishi C, Turakhia M, Marder D, Bjorksten AR, Larson MD. Meperidine and alfentanil do not reduce the gain or maximum intensity of shivering. Anesthesiology 1998;88:858–65
4. Ikeda T, Kim JS, Sessler DI, Negishi C, Turakhia M, Jeffrey R. Isoflurane alters shivering patterns and reduces maximum shivering intensity. Anesthesiology 1998;88:866–73
5. Wadhwa A, Sengupta P, Durrani J, Akca O, Lenhardt R, Sessler DI, Doufas AG. Magnesium sulphate only slightly reduces the shivering threshold in humans. Br J Anaesth 2005;94:756–62
6. Nadel ER, Bullard RW, Stolwijk JA. Importance of skin temperature in the regulation of sweating. J Appl Physiol 1971;31:80–7
7. Cheng C, Matsukawa T, Sessler DI, Kurz A, Merrifield B, Lin H, Olofsson P. Increasing mean skin temperature linearly reduces the core-temperature thresholds for vasoconstriction and shivering in humans. Anesthesiology 1995;82:1160–8
8. Lenhardt R, Greif R, Sessler DI, Laciny S, Rajek A, Bastanmehr H. Relative contribution of skin and core temperatures to vasoconstriction and shivering thresholds during isoflurane anesthesia. Anesthesiology 1999;91:422–9
9. Hardy JD, Oppel TW. The thermal response of the skin to radiation. Physics 1936;7:466–79
10. Libert JP, Candas V, Vogt JJ. Effect of rate of change in skin temperature on local sweating rate. J Appl Physiol 1979;47:306–11
11. Wurster RD, McCook RD. Influence of rate of change in skin temperature on sweating. J Appl Physiol 1969;27:237–40
12. Kozyreva TV, Tkachenko EY, Kozaruk VP, Latysheva TV, Gilinsky MA. Effects of slow and rapid cooling on catecholamine concentration in arterial plasma and the skin. Am J Physiol 1999;276:R1668–72
13. Leslie K, Sessler DI, Bjorksten A, Ozaki M, Matsukawa T, Schroeder M, Lin S. Propofol causes a dose-dependent decrease in the thermoregulatory threshold for vasoconstriction, but has little effect on sweating. Anesthesiology 1994;81:353–60
14. Mekjavic IB, Sundberg CJ, Linnarsson D. Core temperature “null zone.” J Appl Physiol 1991;71:1289–95
15. Lopez M, Sessler DI, Walter K, Emerick T, Ayyalapu A. Reduced sweating threshold during exercise-induced hyperthermia. Pflugers Arch 1995;430:606–11
16. Sessler DI, Moayeri A, Støen R, Glosten B, Hynson J, McGuire J. Thermoregulatory vasoconstriction decreases cutaneous heat loss. Anesthesiology 1990;73:656–60
17. Matsukawa T, Kurz A, Sessler DI, Bjorksten AR, Merrifield B, Cheng C. Propofol linearly reduces the vasoconstriction and shivering thresholds. Anesthesiology 1995;82:1169–80
18. Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E, Kapellou O, Levene M, Marlow N, Porter E, Thoresen M, Whitelaw A, Brocklehurst P. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med 2009;361:1349–58
19. Edwards AD, Brocklehurst P, Gunn AJ, Halliday H, Juszczak E, Levene M, Strohm B, Thoresen M, Whitelaw A, Azzopardi D. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ 2010;340:c363
20. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557–63
21. Hypothermia After Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549–56
22. Doufas AG, Akça O, Barry A, Petrusca DA, Suleman MI, Morioka N, Guarnaschelli JJ, Sessler DI. Initial experience with a novel heat-exchanging catheter in neurosurgical patients. Anesth Analg 2002;95:1752–6
23. Ly HQ, Denault A, Dupuis J, Vadeboncoeur A, Harel F, Arsenault A, Gibson CM, Bonan R. A pilot study: the Noninvasive Surface Cooling Thermoregulatory System for Mild Hypothermia Induction in Acute Myocardial Infarction (the NICAMI Study). Am Heart J 2005;150:933
24. Sessler DI. Perianesthetic thermoregulation and heat balance in humans. FASEB J 1993;7:638–44
25. Rubinstein EH, Sessler DI. Skin-surface temperature gradients correlate with fingertip blood flow in humans. Anesthesiology 1990;73:541–5
26. Tissot S, Delafosse B, Bertrand O, Bouffard Y, Viale JP, Annat G. Clinical validation of the Deltatrac monitoring system in mechanically ventilated patients. Int Care Med 1995;21:149–53
27. Merilainen PT. Metabolic monitor. Int J Clin Monit Comput 1987;4:167–77
28. Komatsu R, Orhan-Sungur M, In J, Podranski T, Bouillon T, Lauber R, Rohrbach S, Sessler D. Ondansetron does not reduce the shivering threshold in healthy volunteers. Br J Anaesth 2006;96:732–7
29. Kurz A, Go JC, Sessler DI, Kaer K, Larson M, Bjorksten AR. Alfentanil slightly increases the sweating threshold and markedly reduces the vasoconstriction and shivering thresholds. Anesthesiology 1995;83:293–9
30. Benzinger TH. On physical heat regulation and the sense of temperature in man. Proc Natl Acad Sci USA 1959;45:645–59
31. Plattner O, Kurz A, Sessler DI, Ikeda T, Christensen R, Marder D, Clough D. Efficacy of intraoperative cooling methods. Anesthesiology 1997;87:1089–95
32. Sessler DI, Moayeri A. Skin-surface warming: heat flux and central temperature. Anesthesiology 1990;73:218–24
33. Mokhtarani M, Mahgob AN, Morioka N, Doufas AG, Sessler DI. Buspirone and meperidine synergistically reduce the shivering threshold. Anesth Analg 2001;93:1233–9
34. Doufas AG, Lin CM, Suleman MI, Liem EB, Lenhardt R, Morioka N, Akça O, Shah YM, Bjorksten AR, Sessler DI. Dexmedetomidine and meperidine additively reduce the shivering threshold in humans. Stroke 2003;34:1218–23
35. Alfonsi P, Passard A, Gaude-Joindreau V, Guignard B, Sessler DI, Chauvin M. Nefopam and alfentanil additively reduce the shivering threshold in humans whereas nefopam and clonidine do not. Anesthesiology 2009;111:102–9
Name: Daniel I. Sessler, MD.
Contribution: This author helped analyze the data and write the manuscript.
Attestation: Daniel I. Sessler has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Yoshie Taniguchi, MD.
Contribution: This author helped design the study, analyze the data, and write the manuscript.
Attestation: Yoshie Taniguchi has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Rainer Lenhardt, MD.
Contribution: This author helped design the study.
Attestation: Rainer Lenhardt has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Andrea Kurz, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Andrea Kurz has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.