THERMAL NEUTRALITY Edmund Hey FIG. I. The relation between heat production and environmental temperature 1001-
THERMAL NEUTRALITY 90
EDMUND HEY D.M. D.Phil. M.R.C.P. 80
Vie Hospital for Sick Children, London
ooU°n°V 1 2 3 4
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Concepts of thermal neutrality Physical and physiological thermal equivalence Clinical management Conclusions References
e 60
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° \ °= o ° 9V.
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30
20 Thermoneutral_ zone
24
28 32 Environmental temperature (°C)
Data were obtained from six babies, who weighed approximately 2.5kg when 7-11 days old, lying naked on a mattress In draught-free surroundings of uniform temperature and moderate humidity. The superimposed lines (A and B) show the amount of heat normally dissipated by radiation, convection and evaporation (In the absence of sweating) when skin blood flow Is at a minimum (line A) and at a maximum (line B). Open circles relate to data obtained during periods of restlessness or activity. The zone of minimum heat production extends from 32.5 °C to about 36.5°C, but thermal balance is maintained by sweat loss above a temperature of 33.5°C; and, by International agreement, the term "thermoneutral" is now restricted to the zone from 32.5°C to 33.5°C
zone of minimum heat production. This interconvertibility of the two terms was made quite explicit in later reviews of the subject (Hill, 1961). More recently it has been argued that it is perverse to insist that a sweating baby and a panting calf are in a neutral environment merely because heat production is at a minimum, and that it is preferable to limit the term "neutral" to those environments in which body temperature is normal and remains normal while heat production and evaporative water loss are both at a minimum (Hey & Katz, 1970a). This more restricted definition appeared to be accepted by experts in animal husbandry (Monteith & Mount, 1974) and is now enshrined in the glossary issued by the International Union of Physiological Sciences (IUPS) (Bligh & Johnson, 1973). Since such changes in usage can cause misunderstanding and confusion it is perhaps appropriate to review the various terms now in current use.
Concepts of Thermal Neutrality
The concept of thermal neutrality implicit in the early work of Giaja (1938) equated the zone of thermal neutrality with the ' See David & Stewart, pp. 85-91 of this Bulletin.—ED.
69 Vol. 31 No. 1
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Comparative animal physiologists on the continent of Europe considered the nature of the physical processes by which homoeothermic species regulate their body temperature many years ago (Lefevre, 1911; Giaja, 1938) and established the concept of thermal neutrality. Homoeothermic animals utilize oxygen, increase their metabolism, and generate extra heat to defend their deep body temperature when faced with an unfavourably cold environment. Similarly, in hot surroundings body temperature eventually begins to rise and, as a result, metabolic rate also rises above the basal level. Between these two extremes lies a relatively narrow environmental zone in which the thermal conditions can be considered "neutral" (see fig. 1). However, an environment that is neutral for one species can be intolerably cold for another, while one that provides neutral conditions for an adult may well be lethal for its unprotected offspring in the first few days of life. These concepts were developed in some detail by Scholander, Hock, Walters, Johnson & Irving (1950) and were reviewed in earlier issues ofBritish Medical Bulletin by Hart (1961) and Hill (1961). More recently, we have come to recognize the relevance of this concept to the management of the newborn human infant. The importance of the observations of Day (1943) went unrecognized for many years, but the work of Brilck (1961) eventually made paediatricians realize that the newborn baby defends himself against thermal stress like any other homoeotherm; and evidence soon began to accumulate that quite minor modifications to the environment could alter the figures for total mortality in babies of low birth-weight1 (Silverman, Fertig & Berger, 1958; Jolly, Molyneux & Newell, 1962; Buetow & Klein, 1964; Day, Caliguiri, Kamenski & Ehrlich, 1964). Much of this work was reviewed by Scopes (1966) in an issue of British Medical Bulletin that also contained a review of the physical factors that affect heatflowbetween an animal and its surroundings (Mount, 1966). It is the purpose of the present paper to review recent developments in the concept of thermal neutrality and their relevance to the management of the sick and pre-term human infant. 1.
o
THERMAL NEUTRALITY Edmund Hey Thermoneutral zone. The International Commission of the IUPS for Thermal Physiology have now defined the thermoneutral zone as "The range of ambient temperature within which metabolic rate is at a minimum and within which temperature regulation is achieved by nonevaporative physical processes alone" (Bligh & Johnson, 1973). In the same paper, the lower critical temperature is defined as "The ambient temperature below which the rate of metabolic heat production of a resting thermoregulating animal increases... to maintain thermal balance." It is important to note that the concept of minimum observed metabolic rate (MOMR) referred to in these definitions is not synonymous with the concept of basal metabolic rate (BMR). Basal metabolism relates to measurements of heat production or oxygen consumption in a resting, fasting animal awake in a thermoneutral environment, and it has been well said that the newborn human infant is always either actively digesting one meal or seeking the next. In these circumstances, measurements of resting metabolic rate (RMR) or MOMR clearly provide a more relevant and practical definition of thermal neutrality. Similar considerations apply to ruminants and to most animals that take food at frequent intervals. Dietary intake has been shown to have a marked influence on RMR in growing farm animals (Graham, Wainman, Blaxter & Armstrong, 1959; Verstegen, Close, Start & Mount, 1973), and this, in turn, naturally influences the lower critical temperature (Mount, Close & Verstegen, 1973). Mestyan, Jarai, Fekete & Soltesz (1969) have shown that ingestion of food causes a similar rise in RMR in the newborn baby, and Brooke & Ashworth (1972) have shown that this probably reflects the high-energy cost of protein synthesis within the body, because malnourished children show a significant postprandial rise in RMR only during periods of active growth. The non-evaporative physical processes referred to in the above definition are those autonomic and behavioural responses (such as peripheral vasoconstriction, pilo-erection and changing posture) that vary the thermal conductance of the animal in response to variations of its environment (changes in external insulation from bedding, clothing and the like are excluded from consideration). These autonomic and behavioural responses are normally recruited and brought into play over a fairly broad range of environmental temperature, and under these conditions the thermoneutral zone may be extremely narrow. Indeed in the lamb, for example, in which peripheral vasodilatation is thought to occur below the lower critical temperature (Alexander, 1961; Alexander & Williams, 1962), the thermoneutral zone may constrict to a point. Human infants in congestive heart failure sometimes continue to sweat even when the environmental temperature is several degrees below the lower critical temperature (Kennaird, 1971); it could be argued that such infants never experience thermoneutrality, but such a legalistic definition is perhaps needlessly strict and unhelpful. Zone of minimum heat production. Unfortunately, the use of the term " thermoneutral" to refer to an environment in which heat production and evaporative water loss are both at a minimum leaves no internationally agreed term available to describe the much wider range of environmental temperature over which an animal may be capable of maintaining heat production at a minimum by a combination of vasodilatation, postural change and increased evaporative heat loss. The resultant confusion is increased by the use of the term " upper critical temperature"
to refer not only to "The ambient temperature above which thermoregulatory evaporative heat loss processes... are recruited" (the preferred usage) but also to "The ambient temperature above which there is an increase in metabolic rate due to a rise in core temperature . . . " (the original meaning) (Bligh & Johnson, 1973). This is most unfortunate and unsatisfactory. Preferred thermal environment. The International Commission use the term "thermopreferendum" for "The thermal conditions which an individual organism or a species selects for its ambient environment in natural or experimental circumstances" (Bligh & Johnson, 1973). Very young animals can display such preferences (Ogilvie & Stinson, 1966), but the preferred thermal environment for the newborn human infant is not yet known. The preferred environment is often very similar to the thermoneutral environment, but Mount (1963) found that newborn pigs prefer an environment slightly below the lower critical temperature, and it is perhaps not irrelevant to note that the pre-term infant, like the newborn pig, is particularly vulnerable to hyperthermia because of its inability to sweat. Thermal comfort zone. The International Commission have also offered useful definitions for the zone of thermal comfort and the closely related zone of thermal indifference. These are subjective indices of environmental warmth that are strictly applicable only to man. Kurt Brflck monitored sleep in the newborn baby in order to obtain an indirect index of subjective comfort, and found that babies slept longest in the environments in which their heat production was minimal (Brflck, Parmelee & Brflck, 1962; Parmelee, BrOck & Bruck, 1962). It is known, however, that infants frequently continue to sleep peacefully in non-neutral environments that provoke thermal sweating (Hey & Katz, 1969b; Sulyok, Jequier & Prod'hom, 1973a), and it is doubtful whether sleep can be used as an accurate index of either thermal comfort or thermal indifference. Adults appear to vary in their subjective judgement of comfort but often profess to find maximum comfort in an environment slightly below the thermoneutral range (Cagge, Hardy & Rapp, 1965a; Gagge, Stolwyk & Hardy, 1965b). Optimal thermal environment. It cannot be assumed that a neutral environment is always an optimal environment. Indeed it cannot be assumed that any of the terms listed above are synonymous. Performance and efficiency are greatly influenced by environmental temperature (Grether, 1973), and Auliciems(1969,1972) appears to have established that schoolchildren perform continuous repetitive mental work optimally in an environment that is marginally but significantly cooler than the preferred thermal environment. Animal breeders have long recognized that newborn animals are extremely vulnerable to cold stress, and swaddling has been used to protect the human infant from hypothermia from time immemorial. Until very recently, the problems peculiar to the first few days of life received little study, however, and many clinicians, came to believe that it was safe to keep the rectal temperature of small pre-term babies at between 33°C and 35 °C throughout the first week of life. Some clinicians even used drugs in order to achieve a state of "hibernation" (Lacomme, Chabrun, Boreau & David, 1954), but others simply nursed their small babies in a room at 25 CC (Wagner, 1960) or in an incubator at 29°C (Laurance, 1961). However, the carefully designed trials published by W. A. Silverman and his colleagues between 1957 and 1963 eventually showed that 70
Br. Med. Bull. 1975
THERMAL NEUTRALITY Edmund Hey even small changes in the thermal environment could have a significant effect on neonatal mortality (Silverman & Blanc, 1957; Silvermanet al. 1958; Silverman, Agate &Fertig, 1963); and it is now generally accepted that the very small babies should be nursed in an environment in which heat production is at a minimum Yet it cannot be assumed that an environment in which heat production is at a minimum will necessarily be associated with optimal survival. Deep body temperature is frequently less than 36 °C in the first week of life in small pre-term babies receiving conventional care, and this hypothermia is not always associated with any sustained increase in heat production (Silverman & Agate, 1964; Kintzel, 1966). Many of these babies defend themselves against any increase in the gradient between skin and air temperature that threatens a further fall in deep body temperature by a brisk, if poorly maintained, increase in heat production (Bruck et al. 1962), so it cannot be argued that these infants have entirely lost their thermoregulatory ability. Bruck and his colleagues argued that these infants were regulating their deep body temperature round a low "set point" and that, since heat production was not stimulated, these babies were, by definition, in a neutral environment. But since four controlled trials have shown that mortality rises when deep body temperature is allowed to remain below 36 °C, such an environment is certainly not optimal even if it is neutral. Conversely, we now know that mortality also rises if deep body temperature is allowed to approach 37.8 °C in babies weighing • After 10 days —»• A f t e r 3 w e e k s —»• After 5 weeks narrow, and the theoretical maximum 1.5 For 10 days -2.5 usually starts to rise before tissue insulation reaches a minimum (Hey & Katz, 1969b, • T o estimate operative temperature in a single-walled incubator subtract I°C from 1970b; Ryser & J6quier, 1972; Sulyok et al. incubator air temperature for every 7°C by which this temperature exceeds room 1973a), no practical purpose is served by temperature #
72
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THERMAL NEUTRALITY Edmund Hey increased frequency when small babies are nursed in an environment adjusted to maintain an abdominal skin temperatureof 36.8 °C rather than 36.0°C (Daily, Klaus & Meyer, 1969), and this must be interpreted as further evidence that an environment in which heat production is at a minimum is not always an optimum environment. Babies on a fixed calorie intake grow faster in a thermoneutral environment (Glass, Silverman & Sinclair, 1968, 1969; Glass, Lala, Jaiswal & Nigam, 1974), but naked babies nursed continuously in a neutral environment fail to develop an increased ability to withstand cold stress with time. An analogous situation has been documented in newborn guineapigs (Zeisberger, Bruck, Wunnenberg & Wietasch, 1967), newborn lambs (Alexander, Bell & Williams, 1970) and newborn rabbits (Hardman & Hull, 1971), where the increased cold resistance appears to be the result of brown adipose tissue3 developing an enhanced thermogenic potential. Here, therefore, is a further situation in which a neutral environment may not be an optimum environment. Interestingly, there is some evidence that a few quite short periods of cold stress suffice to stimulate increased resistance to cold stress in newborn babies (Perlstein, Hersh, Glueck & Sutherland, 1973), so clothed infants may well develop cold resistance naturally, as a result of the exposure they experience when they are fed and changed. Delivery room care. Babies inevitably suffer cold stress at the time of delivery (Dahm & James, 1972), when radiant and convective heat losses are high; and a great deal of heat is also lost as water evaporates from the surface of the skin and the stratum corneum dries out. Deliberate hypothermia has been advocated in order to minimize the need for oxygen where resuscitation proves difficult at birth (Dunn & Miller, 1969), but it is very difficult to achieve a rapid enough fall in deep body temperature for this form of treatment to be of value in man, and strenuous steps are usually taken to prevent hypothermia at birth. Ingenious plastic devices such as the "silver swaddler" of Baum & Scopes (1968) and the transparent "baby bag" of Besch, Perlstein, Edwards, Keenan & Sutherland (1971) have recently come into use to swaddle babies immediately after birth; these devices were designed in the first instance to minimize radiant and convective heat losses, respectively, but they are really no more efficient than clothes and blankets in reducing such losses, and they work largely by minimizing evaporative loss. It should be noted that thefiguresin Table I slightly under-estimate thermal requirements in the first few hours of life.
Severe birth asphyxia causes a variable reduction in the metabolicresponseto cold stress (Bruck, Bruck & Lemtis, 1960) that may last many days, and drugs such as diazepam given to control maternal hypertension can have a similar effect (Cree, Meyer & Hailey, 1973). Babies who become hypothermic at this time have a poor prognosis, but it is difficult to show whether the hypothermia influences the outcome or whether the hypothermia is merely a secondary manifestation of underlying hypoxia, asphyxia and cerebral damage. However, recent reports suggest that the incidence of respiratory distress is twice as high in infants who develop a deep body temperature of < 34.5°C after birth as it is in infants of comparable birthweight and gestation in whom deep body temperature remains > 35.5 °C (Pomerance & Madore, 1974). It is also known that healthy babies subjected to cold stress immediately after birth have a low arterial oxygen tension (Stephenson, Du & Oliver, 1970), and that they develop an increased metabolic acidosis (Gandy, Adamsons, Cunningham, Silvennan & James, 1964; Pinter, Kovacs, Szflllfisi, Sztan6 & Boda, 1971). Hypothermia has been shown to affect brain growth in the young rat (Schain & Watanabe, 1971), and follow-up studies have suggested that there may be some association between hypothermia shortly after birth and the risk of subsequent neurological handicap in small pre-term babies (P. A. Davies and J. P. M. Tizard, personal communication). All the evidence, therefore, points to the importance of avoiding cold stress and maintaining a thermoneutral environment in the first few hours of life. Reservations have often been expressed about the safety of correcting severe hypothermia too quickly once it has occurred, but the dangers have probably been exaggerated (Tafari & Gentz, 1974). 4. Conclusions International agreement has now been reached over the definition of environmental thermoneutrality, but terminological uniformity will take some time to achieve and it seems important for the term to be defined, for the moment, whenever it is used. Some confusion is bound to occur because the new definition involves an important change in usage. The concept is valid only under conditions of thermal equilibrium and difficulties arise in evaluating any environment subject to cyclical variation. It can be particularly difficult to define thermoneutrality in the perinatal period, because certain animals (including, on occasion, the pre-term human baby) are heterothermic rather than truly homoeothermic at birth. An environment that is, by agreed definition, neutral may not necessarily be neutral in its influence, since a neutral environment is not always associated with optimum performance or optimum survival.
3 See Hull. Br. Mid. Bull. 1966, 22, 92-96; »lto Hull, pp. 32-36, mud AleMnder, pp. 62-68, of thti Bulletin.—ED.
REFERENCES
Baum, J. D. & Scopes, J. W. (1968) Lancet, 1, 672-673 Besch, N. J., Perlstein, P. H., Edwards, N. K., Keenan, W. J. & Sutherland, J. M. (1971) New Engl. J. Med. 284, 121-124 Bhakoo, O. N. & Scopes, J. W. (1971) Arch. Dis. Child. 46,483-489 Bhakoo, O. N. & Scopes, J. W. (1974) Arch. Dis. Child. 49,583-585 Blackfan, K. D. & Yaglou, C. P. (1933) Am. J. Dis. Child. 46, 1175-1236 Bligh, J. & Johnson, K. G. (1973) / . Appl. Physiol. 35, 941-961 Brooke, O. G. (1973) Arch. Dis. Child. 48, 901-905 Brooke, O. G. & Ashworth, A. (1972) Br. J. Nutr. 27,407-415
Ablett, J. G. & McCance, R. A. (1971) Lancet, 2, 517-519 Abrarns, R., Caton, D., Clapp, J. & Barron, D. H. (1970) Clin. Obstet. Gynecol. 13, 549-564 Alexander, G. (1961) Aust.J. Agric. Res. 12,1152-1174 Alexander, G., Bell, A. W. & Williams, D. (1970) Biol. Neonate, 15,198-210 Alexander, G. & Williams, D. (1962) Aust. J. Agric. Res. 13,122143 Auliciems, A. (1969) / . Hyg. {Cambridge) 67, 59-65 Auliciems, A. (1972) Int. J. Biometeorol. 16, 233-246 73
Vol. 31 No. 1
THERMAL NEUTRALITY Edmund Hey Brooke, O. G. & Cocks, T. (1973) / . Physiol. (Land.) 231,18P-19P Brooke, O. G., Harris, M. ASalvosa, C. B. (1973)7. Physiol. (Lond.) 233, 75-91 Bruck, K. (1961) Biologia Neonat. 3, 65-119 Bruck, K., Bruck, M. & Lemtis, H. (1960) Geburtshilfe Frauenheilkd. 20,461-472 Bruck, K., Pannelee, A. H., jr & Bruck, M. (1962) Biologia Neonat. 4, 32-51 Buetow, K. C. & Klein, S. W. (1964) Pediatrics {Springfield) 34, 163-170 Cree, J. E., Meyer, J. & Hailey, D. M. (1973) Br. Med. J. 4,251Dahm, L. S. & James, L. S. (1972) Pediatrics (Springfield) 49, 504-513 Daily, W. J. R., Klaus, M. & Meyer, H. B. P. (1969) Pediatrics (Springfield) 43, 510-518 Day, R. (1943) Am. J. Dis. Child. 65, 376-398 Day, R. L., Caliguiri, L., Kamenski, C. & Ehrlich, F. (1964) Pediatrics (Springfield) 34,171-181 Dunn, J. M. & Miller, J. A., jr (1969) Am. J. Obstet. Gynecol. 104, 58-67 Fanaroff, A. A., Wald, M., Gruber, H. S. & Klaus, M. H. (1972) Pediatrics (Springfield) 50, 236-245 Foster, K. G.,Hey, E. N. &Katz, G. (1969) J.Physiol.(Lond.)203, 13-29 Gagge, A. P., Hardy, J. D. & Rapp, G. M. (1965a) Trans. Am. Soc. Heat. Refrig. Air-Cond. Eng. 71, pt II, 19-26 Gagge, A. P., Stolwijk, J. A. J. &Hardy, J. D. (1965b) Aerosp. Med. 36,431^*35 Gandy, G. M., Adamsons, K., jr, Cunningham, N., Silverman, W. A. & James, L. S. (1964)/. Clin. Incest. 43, 751-758 Giaja, J. (1938) Actual. Sci. Ind. nos. 576 and 577 Glass, L., Lala, R. V., Jaiswal, V. & Nigam, S. K. (1974) Pediatr. Res. 8, 446 [Abstract] Glass, L., Silverman, W. A. & Sinclair, J. C. (1968) Pediatrics (Springfield) 41,1033-1046 Glass, L., Silverman, W. A. & Sinclair, J. C. (1969) Biol. Neonate, 14,324-340 Gleiss, J. (1956) Z. Kinderheilkd. 77, 653-661 Graham, N. M., Wainman, F. W., Blaxter, K. L. & Armstrong, D. G. (1959)/. Agrtc. Sci. (Cambridge) 52,13-24 Grausz, J. P. (1968) Ada Paediatr. Scand. 57, 98-104 Green, M. &Behrendt,H.(1970)/4m./. Dis. Child. 120,434-^38 Grether, W. F. (1973) Aerosp. Med. 44, 747-755 Hardman, M. J. & Hull, D. (1971)/. Physiol. (Lond.)2U, 191-199 Hart, J. S. (1961) Br. Med. Bull. 17,19-24 Hey, E. N. (1969) / . Physiol. (Lond.) 200, 589-603 Hey, E. N. & Katz, G. (1969a) Arch. Dis. Child. 44, 323-330 Hey, E. N. & Katz, G. (1969b) /. Physiol. (Lond.) 200, 605-619 Hey, E. N. & Katz, G. (1970a) Arch. Dis. Child. 45, 328-334 Hey, E. N. & Katz, G. (1970b) / . Physiol. (Lond.) 207, 667-681 Hey, E. N., Katz, G. & O'Connell, B. (1970)/. Physiol. (Lond.) 207, 683-698 Hey, E. N. & Maurice, N. P. (1968) Arch. Dis. Child. 43, 166-171 Hey, E. N. & Mount, L. E. (1967) Arch. Dis. Child. 42, 75-84 Hey, E. N. & O'Connell, B. (1970) Arch. Dis. Child. 45, 335-343 Hill, J. R. (1961) Br. Med. Bull. 17,164-167 Hill, J. R. & Rahimtulla, K. A. (1965) / . Physiol. (Lond.) 180, 239265 Hill, J. R. & Robinson, D. C. (1968) / . Physiol. (Lond.) 199, 685703 Jolly, H., Molyneux, P. & Newell, D. J. (1962)/. Pediatr. 60, 889894 Jonxis, J. H. P., Vlugt, J. J. van der, Groot, C. J. de, Boersma, E. R. & Meijere, E. D. K. (1968) In: Jonxis, J. H. P., Visser, H. K. A. & Troelstra, J. A., ed. Aspects ofpraematurity and dysmaturity, pp. 201-209 (Nutricia Symposium, Groningen, 10-12 May 1967). Stenfert Kroese, Leiden Kennaird, D. L. (1971) Oxygen consumption and evaporative water loss in infants with congenital heart disease (Thesis for Ph.D. degree). University of London Kintzel, H. W. (1966) Monatsschr. Kinderheilkd. 114, 544-550 Krauss, A. N. & Auld, P. A. M. (1969) / . Pediatr. 75, 952-956 Lacomme, M., Chabrun, J., Borcau, T. & David, G. (1954) Etud. NA>-Nat. 3, 3-29 Laurence, B. M. (1961) Proc. R. Soc. Med. 54, 739-742
Lefevre, J. (1911) Chaleur animate et bioenergttique. Masson, Paris Levison, H., Linsao, L. & Swyer, P. R. (1966) Lancet, 2,1346-1348 Mclntyre, D. A. & Griffiths, I. D. (1972) Environ. Res. 5,471-482 Mann.T. P. (1968)/. Obstet. Gynaecol. Br. Commonw. 75,316-321 Matsaniotis, N., Pastelis, V., Agathopoulos, A. & Constantsas, N. (1971) Pediatrics (Springfield)*!, 571-576 Mestyan, J., Jarai, I., Bata, G. & Fekete, M. (1964) Biologia Neonat. 7, 243-254 Mestyan, J., Jarai, I., Fekete, M. & Soltesz, G. (1969) Pediatr. Res. 3, 41-50 Monteith, J. L. & Mount, L. E., ed. (1974) Heat loss from animals and man: assessment and control (Proceedings of the Twentieth Easter School in Agricultural Science). Butterworths, London Mount, L. E. (1963) Nature (Lond.) 199,1212-1213 [Letter] Mount, L. E. (1966) Br. Med. Bull. 22, 84-87 Mount, L. E., dose, W. H. & Verstegen, M. W. A. (1973) Proc. Nutr. Soc. 32, 71A [Abstract] OgUvie, D. M. & Stinson, R. H. (1966) Can. J. Zool. 44,511-517 Oh, W. & Karecki, H. (1972) Am. /. Dis. Child. 124, 230-232 Oh, W., Yao, A. C , Hanson, J. S. &Lind, J. (1973) ActaPaediatr. Scand. 62,49-54 Pannelee, A. H., jr, BrQck, K. & Bruck, M. (1962) Biologia Neonat. A, 317-339 Perlstein, P. H., Edwards, N. K., Atherton, H. & Sutherland, J. M. (1973) Pediatr. Res. 7, 405 [Abstract] Perlstein, P. H., Edwards, N. K. & Sutherland, J. M. (1970) New Engl. J. Med. 282,461-466 Perlstein, P. H., Hersh, C. B., Glueck, C. J. & Sutherland, J. M. (1973) Pediatr. Res. 7,406 [Abstract] Pintdr, S., Kovacs, L., SzSllSsi, J., Sztan6, P. & Boda, D (1971) ActaPaediatr. Acad. Sci. Hung. 12, 59-67 Pomerance, J. J. & Madore, C. (197'4) Pediatr. Res. 8,449 [Abstract] Pfibylova, H. (1971) Rev. Czech. Med. 17,133-136 Ryser, G. & Jequier, E. (1972) Eur. / . Clin. Invest. 2,176-187 Schain, R. J. & Watanabe, K. (1971) Pediatr. Res. 5, 173-180 Scholander, P. F., Hock, R., Walters, V., Johnson, F. & Irving, L. (1950) Biol. Bull. (Woods Hole, Mass.) 99, 237-258 Scopes, J. W. (1966) Br. Med. Bull. 22, 88-91 Scopes, J. W. & Ahmed, I. (1966a) Arch. Dis. Child. 41, 407^116 Scopes, J. W. & Ahmed, I. (1966b) Arch. Dis. Child. 41, 417-419 Senterre, J. & Karlberg, P. (1970) Ada Paediatr. Scand. 59, 653658 Silverman, W. A. & Agate, F. J., jr (1964) Biologia Neonat. 6,113— 127 Silverman, W. A., Agate, F. J., jr & Fertig, J. W. (1963) Pediatrics (Springfield) 31, 719-724 Silverman, W. A. & Blanc, W. A. (1957) Pediatrics (Springfield) 20, 477-486 Silverman, W. A., Fertig, J. W. & Berger, A. P. (1958) Pediatrics (Sprtngfield)22, S16-8&5 Silverman, W. A., Sinclair, J. C. & Agate, F. J., jr (1966) Ada Paediatr. Scand. 55, 294-300 Stephenson, J. M., Du, J. N. & Oliver, T. K., jr (1970) / . Pediatr. 76, 848-852 Sulyok, E., Jequier, E. & Prod'hora, L. S. (1973a) Pediatr. Res. 1, 888-900 Sulyok, E., Jequier, E. & Prod'hom, L. S. (1973b) Pediatrics (Springfield) 51, 641-650 Sulyok, E., Jequier, E. & Ryser, G. (1972) Biol. Neonate, 21, 210-218 Tafari, N. & Gentz, J. (1974) ActaPaediatr. Scand. 63, 595-600 Varga, F. (1959) Pediatrics (Springfield) 23, 1085-1090 Verstegen, M. W. A., Close, W. H., Start, I. B. & Mount, L. E. (1913) Br.J. Nutr. 30, 21-35 Wagner, H. (1960) Z. Kinderheilkd. 83, 609-617 Wu, P. Y. K. & Berdahl, M. (1974)/. Pediatr. 84, 754-755 Wu, P. Y. K., Wong, W. H., Hodgman, J. E. & Levan, N. (1974) Pediatr. Res. 8, 257-262 Yao, A. C , Wallgren, C. G., Sinha, S. N. & Lind, J. (1971) Pediatrics (Springfield) 47, 378-383 Yashiro, K., Adams, F. H., Emmanouilides, G. C. & Mickey, M. R (1973) / . Pediatr. 82, 991-994 Zeisberger, E., BrOck, K., WQnnenberg, W. & Wietasch, C. (1967) Pflugers Arch. Ges. Phvsiol. 296, 276-288 Zweymuller, E. & Preining, O. (1970) Ada Paediatr. Scand. suppl. no. 205
74
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THERMAL NEUTRALITY 90
EDMUND HEY D.M. D.Phil. M.R.C.P. 80
Vie Hospital for Sick Children, London
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Concepts of thermal neutrality Physical and physiological thermal equivalence Clinical management Conclusions References
e 60
o
° \ °= o ° 9V.
• "o
o«
30
20 Thermoneutral_ zone
24
28 32 Environmental temperature (°C)
Data were obtained from six babies, who weighed approximately 2.5kg when 7-11 days old, lying naked on a mattress In draught-free surroundings of uniform temperature and moderate humidity. The superimposed lines (A and B) show the amount of heat normally dissipated by radiation, convection and evaporation (In the absence of sweating) when skin blood flow Is at a minimum (line A) and at a maximum (line B). Open circles relate to data obtained during periods of restlessness or activity. The zone of minimum heat production extends from 32.5 °C to about 36.5°C, but thermal balance is maintained by sweat loss above a temperature of 33.5°C; and, by International agreement, the term "thermoneutral" is now restricted to the zone from 32.5°C to 33.5°C
zone of minimum heat production. This interconvertibility of the two terms was made quite explicit in later reviews of the subject (Hill, 1961). More recently it has been argued that it is perverse to insist that a sweating baby and a panting calf are in a neutral environment merely because heat production is at a minimum, and that it is preferable to limit the term "neutral" to those environments in which body temperature is normal and remains normal while heat production and evaporative water loss are both at a minimum (Hey & Katz, 1970a). This more restricted definition appeared to be accepted by experts in animal husbandry (Monteith & Mount, 1974) and is now enshrined in the glossary issued by the International Union of Physiological Sciences (IUPS) (Bligh & Johnson, 1973). Since such changes in usage can cause misunderstanding and confusion it is perhaps appropriate to review the various terms now in current use.
Concepts of Thermal Neutrality
The concept of thermal neutrality implicit in the early work of Giaja (1938) equated the zone of thermal neutrality with the ' See David & Stewart, pp. 85-91 of this Bulletin.—ED.
69 Vol. 31 No. 1
,o ° o
o \
3 50 "8
Comparative animal physiologists on the continent of Europe considered the nature of the physical processes by which homoeothermic species regulate their body temperature many years ago (Lefevre, 1911; Giaja, 1938) and established the concept of thermal neutrality. Homoeothermic animals utilize oxygen, increase their metabolism, and generate extra heat to defend their deep body temperature when faced with an unfavourably cold environment. Similarly, in hot surroundings body temperature eventually begins to rise and, as a result, metabolic rate also rises above the basal level. Between these two extremes lies a relatively narrow environmental zone in which the thermal conditions can be considered "neutral" (see fig. 1). However, an environment that is neutral for one species can be intolerably cold for another, while one that provides neutral conditions for an adult may well be lethal for its unprotected offspring in the first few days of life. These concepts were developed in some detail by Scholander, Hock, Walters, Johnson & Irving (1950) and were reviewed in earlier issues ofBritish Medical Bulletin by Hart (1961) and Hill (1961). More recently, we have come to recognize the relevance of this concept to the management of the newborn human infant. The importance of the observations of Day (1943) went unrecognized for many years, but the work of Brilck (1961) eventually made paediatricians realize that the newborn baby defends himself against thermal stress like any other homoeotherm; and evidence soon began to accumulate that quite minor modifications to the environment could alter the figures for total mortality in babies of low birth-weight1 (Silverman, Fertig & Berger, 1958; Jolly, Molyneux & Newell, 1962; Buetow & Klein, 1964; Day, Caliguiri, Kamenski & Ehrlich, 1964). Much of this work was reviewed by Scopes (1966) in an issue of British Medical Bulletin that also contained a review of the physical factors that affect heatflowbetween an animal and its surroundings (Mount, 1966). It is the purpose of the present paper to review recent developments in the concept of thermal neutrality and their relevance to the management of the sick and pre-term human infant. 1.
o
THERMAL NEUTRALITY Edmund Hey Thermoneutral zone. The International Commission of the IUPS for Thermal Physiology have now defined the thermoneutral zone as "The range of ambient temperature within which metabolic rate is at a minimum and within which temperature regulation is achieved by nonevaporative physical processes alone" (Bligh & Johnson, 1973). In the same paper, the lower critical temperature is defined as "The ambient temperature below which the rate of metabolic heat production of a resting thermoregulating animal increases... to maintain thermal balance." It is important to note that the concept of minimum observed metabolic rate (MOMR) referred to in these definitions is not synonymous with the concept of basal metabolic rate (BMR). Basal metabolism relates to measurements of heat production or oxygen consumption in a resting, fasting animal awake in a thermoneutral environment, and it has been well said that the newborn human infant is always either actively digesting one meal or seeking the next. In these circumstances, measurements of resting metabolic rate (RMR) or MOMR clearly provide a more relevant and practical definition of thermal neutrality. Similar considerations apply to ruminants and to most animals that take food at frequent intervals. Dietary intake has been shown to have a marked influence on RMR in growing farm animals (Graham, Wainman, Blaxter & Armstrong, 1959; Verstegen, Close, Start & Mount, 1973), and this, in turn, naturally influences the lower critical temperature (Mount, Close & Verstegen, 1973). Mestyan, Jarai, Fekete & Soltesz (1969) have shown that ingestion of food causes a similar rise in RMR in the newborn baby, and Brooke & Ashworth (1972) have shown that this probably reflects the high-energy cost of protein synthesis within the body, because malnourished children show a significant postprandial rise in RMR only during periods of active growth. The non-evaporative physical processes referred to in the above definition are those autonomic and behavioural responses (such as peripheral vasoconstriction, pilo-erection and changing posture) that vary the thermal conductance of the animal in response to variations of its environment (changes in external insulation from bedding, clothing and the like are excluded from consideration). These autonomic and behavioural responses are normally recruited and brought into play over a fairly broad range of environmental temperature, and under these conditions the thermoneutral zone may be extremely narrow. Indeed in the lamb, for example, in which peripheral vasodilatation is thought to occur below the lower critical temperature (Alexander, 1961; Alexander & Williams, 1962), the thermoneutral zone may constrict to a point. Human infants in congestive heart failure sometimes continue to sweat even when the environmental temperature is several degrees below the lower critical temperature (Kennaird, 1971); it could be argued that such infants never experience thermoneutrality, but such a legalistic definition is perhaps needlessly strict and unhelpful. Zone of minimum heat production. Unfortunately, the use of the term " thermoneutral" to refer to an environment in which heat production and evaporative water loss are both at a minimum leaves no internationally agreed term available to describe the much wider range of environmental temperature over which an animal may be capable of maintaining heat production at a minimum by a combination of vasodilatation, postural change and increased evaporative heat loss. The resultant confusion is increased by the use of the term " upper critical temperature"
to refer not only to "The ambient temperature above which thermoregulatory evaporative heat loss processes... are recruited" (the preferred usage) but also to "The ambient temperature above which there is an increase in metabolic rate due to a rise in core temperature . . . " (the original meaning) (Bligh & Johnson, 1973). This is most unfortunate and unsatisfactory. Preferred thermal environment. The International Commission use the term "thermopreferendum" for "The thermal conditions which an individual organism or a species selects for its ambient environment in natural or experimental circumstances" (Bligh & Johnson, 1973). Very young animals can display such preferences (Ogilvie & Stinson, 1966), but the preferred thermal environment for the newborn human infant is not yet known. The preferred environment is often very similar to the thermoneutral environment, but Mount (1963) found that newborn pigs prefer an environment slightly below the lower critical temperature, and it is perhaps not irrelevant to note that the pre-term infant, like the newborn pig, is particularly vulnerable to hyperthermia because of its inability to sweat. Thermal comfort zone. The International Commission have also offered useful definitions for the zone of thermal comfort and the closely related zone of thermal indifference. These are subjective indices of environmental warmth that are strictly applicable only to man. Kurt Brflck monitored sleep in the newborn baby in order to obtain an indirect index of subjective comfort, and found that babies slept longest in the environments in which their heat production was minimal (Brflck, Parmelee & Brflck, 1962; Parmelee, BrOck & Bruck, 1962). It is known, however, that infants frequently continue to sleep peacefully in non-neutral environments that provoke thermal sweating (Hey & Katz, 1969b; Sulyok, Jequier & Prod'hom, 1973a), and it is doubtful whether sleep can be used as an accurate index of either thermal comfort or thermal indifference. Adults appear to vary in their subjective judgement of comfort but often profess to find maximum comfort in an environment slightly below the thermoneutral range (Cagge, Hardy & Rapp, 1965a; Gagge, Stolwyk & Hardy, 1965b). Optimal thermal environment. It cannot be assumed that a neutral environment is always an optimal environment. Indeed it cannot be assumed that any of the terms listed above are synonymous. Performance and efficiency are greatly influenced by environmental temperature (Grether, 1973), and Auliciems(1969,1972) appears to have established that schoolchildren perform continuous repetitive mental work optimally in an environment that is marginally but significantly cooler than the preferred thermal environment. Animal breeders have long recognized that newborn animals are extremely vulnerable to cold stress, and swaddling has been used to protect the human infant from hypothermia from time immemorial. Until very recently, the problems peculiar to the first few days of life received little study, however, and many clinicians, came to believe that it was safe to keep the rectal temperature of small pre-term babies at between 33°C and 35 °C throughout the first week of life. Some clinicians even used drugs in order to achieve a state of "hibernation" (Lacomme, Chabrun, Boreau & David, 1954), but others simply nursed their small babies in a room at 25 CC (Wagner, 1960) or in an incubator at 29°C (Laurance, 1961). However, the carefully designed trials published by W. A. Silverman and his colleagues between 1957 and 1963 eventually showed that 70
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THERMAL NEUTRALITY Edmund Hey even small changes in the thermal environment could have a significant effect on neonatal mortality (Silverman & Blanc, 1957; Silvermanet al. 1958; Silverman, Agate &Fertig, 1963); and it is now generally accepted that the very small babies should be nursed in an environment in which heat production is at a minimum Yet it cannot be assumed that an environment in which heat production is at a minimum will necessarily be associated with optimal survival. Deep body temperature is frequently less than 36 °C in the first week of life in small pre-term babies receiving conventional care, and this hypothermia is not always associated with any sustained increase in heat production (Silverman & Agate, 1964; Kintzel, 1966). Many of these babies defend themselves against any increase in the gradient between skin and air temperature that threatens a further fall in deep body temperature by a brisk, if poorly maintained, increase in heat production (Bruck et al. 1962), so it cannot be argued that these infants have entirely lost their thermoregulatory ability. Bruck and his colleagues argued that these infants were regulating their deep body temperature round a low "set point" and that, since heat production was not stimulated, these babies were, by definition, in a neutral environment. But since four controlled trials have shown that mortality rises when deep body temperature is allowed to remain below 36 °C, such an environment is certainly not optimal even if it is neutral. Conversely, we now know that mortality also rises if deep body temperature is allowed to approach 37.8 °C in babies weighing • After 10 days —»• A f t e r 3 w e e k s —»• After 5 weeks narrow, and the theoretical maximum 1.5 For 10 days -2.5 usually starts to rise before tissue insulation reaches a minimum (Hey & Katz, 1969b, • T o estimate operative temperature in a single-walled incubator subtract I°C from 1970b; Ryser & J6quier, 1972; Sulyok et al. incubator air temperature for every 7°C by which this temperature exceeds room 1973a), no practical purpose is served by temperature #
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THERMAL NEUTRALITY Edmund Hey increased frequency when small babies are nursed in an environment adjusted to maintain an abdominal skin temperatureof 36.8 °C rather than 36.0°C (Daily, Klaus & Meyer, 1969), and this must be interpreted as further evidence that an environment in which heat production is at a minimum is not always an optimum environment. Babies on a fixed calorie intake grow faster in a thermoneutral environment (Glass, Silverman & Sinclair, 1968, 1969; Glass, Lala, Jaiswal & Nigam, 1974), but naked babies nursed continuously in a neutral environment fail to develop an increased ability to withstand cold stress with time. An analogous situation has been documented in newborn guineapigs (Zeisberger, Bruck, Wunnenberg & Wietasch, 1967), newborn lambs (Alexander, Bell & Williams, 1970) and newborn rabbits (Hardman & Hull, 1971), where the increased cold resistance appears to be the result of brown adipose tissue3 developing an enhanced thermogenic potential. Here, therefore, is a further situation in which a neutral environment may not be an optimum environment. Interestingly, there is some evidence that a few quite short periods of cold stress suffice to stimulate increased resistance to cold stress in newborn babies (Perlstein, Hersh, Glueck & Sutherland, 1973), so clothed infants may well develop cold resistance naturally, as a result of the exposure they experience when they are fed and changed. Delivery room care. Babies inevitably suffer cold stress at the time of delivery (Dahm & James, 1972), when radiant and convective heat losses are high; and a great deal of heat is also lost as water evaporates from the surface of the skin and the stratum corneum dries out. Deliberate hypothermia has been advocated in order to minimize the need for oxygen where resuscitation proves difficult at birth (Dunn & Miller, 1969), but it is very difficult to achieve a rapid enough fall in deep body temperature for this form of treatment to be of value in man, and strenuous steps are usually taken to prevent hypothermia at birth. Ingenious plastic devices such as the "silver swaddler" of Baum & Scopes (1968) and the transparent "baby bag" of Besch, Perlstein, Edwards, Keenan & Sutherland (1971) have recently come into use to swaddle babies immediately after birth; these devices were designed in the first instance to minimize radiant and convective heat losses, respectively, but they are really no more efficient than clothes and blankets in reducing such losses, and they work largely by minimizing evaporative loss. It should be noted that thefiguresin Table I slightly under-estimate thermal requirements in the first few hours of life.
Severe birth asphyxia causes a variable reduction in the metabolicresponseto cold stress (Bruck, Bruck & Lemtis, 1960) that may last many days, and drugs such as diazepam given to control maternal hypertension can have a similar effect (Cree, Meyer & Hailey, 1973). Babies who become hypothermic at this time have a poor prognosis, but it is difficult to show whether the hypothermia influences the outcome or whether the hypothermia is merely a secondary manifestation of underlying hypoxia, asphyxia and cerebral damage. However, recent reports suggest that the incidence of respiratory distress is twice as high in infants who develop a deep body temperature of < 34.5°C after birth as it is in infants of comparable birthweight and gestation in whom deep body temperature remains > 35.5 °C (Pomerance & Madore, 1974). It is also known that healthy babies subjected to cold stress immediately after birth have a low arterial oxygen tension (Stephenson, Du & Oliver, 1970), and that they develop an increased metabolic acidosis (Gandy, Adamsons, Cunningham, Silvennan & James, 1964; Pinter, Kovacs, Szflllfisi, Sztan6 & Boda, 1971). Hypothermia has been shown to affect brain growth in the young rat (Schain & Watanabe, 1971), and follow-up studies have suggested that there may be some association between hypothermia shortly after birth and the risk of subsequent neurological handicap in small pre-term babies (P. A. Davies and J. P. M. Tizard, personal communication). All the evidence, therefore, points to the importance of avoiding cold stress and maintaining a thermoneutral environment in the first few hours of life. Reservations have often been expressed about the safety of correcting severe hypothermia too quickly once it has occurred, but the dangers have probably been exaggerated (Tafari & Gentz, 1974). 4. Conclusions International agreement has now been reached over the definition of environmental thermoneutrality, but terminological uniformity will take some time to achieve and it seems important for the term to be defined, for the moment, whenever it is used. Some confusion is bound to occur because the new definition involves an important change in usage. The concept is valid only under conditions of thermal equilibrium and difficulties arise in evaluating any environment subject to cyclical variation. It can be particularly difficult to define thermoneutrality in the perinatal period, because certain animals (including, on occasion, the pre-term human baby) are heterothermic rather than truly homoeothermic at birth. An environment that is, by agreed definition, neutral may not necessarily be neutral in its influence, since a neutral environment is not always associated with optimum performance or optimum survival.
3 See Hull. Br. Mid. Bull. 1966, 22, 92-96; »lto Hull, pp. 32-36, mud AleMnder, pp. 62-68, of thti Bulletin.—ED.
REFERENCES
Baum, J. D. & Scopes, J. W. (1968) Lancet, 1, 672-673 Besch, N. J., Perlstein, P. H., Edwards, N. K., Keenan, W. J. & Sutherland, J. M. (1971) New Engl. J. Med. 284, 121-124 Bhakoo, O. N. & Scopes, J. W. (1971) Arch. Dis. Child. 46,483-489 Bhakoo, O. N. & Scopes, J. W. (1974) Arch. Dis. Child. 49,583-585 Blackfan, K. D. & Yaglou, C. P. (1933) Am. J. Dis. Child. 46, 1175-1236 Bligh, J. & Johnson, K. G. (1973) / . Appl. Physiol. 35, 941-961 Brooke, O. G. (1973) Arch. Dis. Child. 48, 901-905 Brooke, O. G. & Ashworth, A. (1972) Br. J. Nutr. 27,407-415
Ablett, J. G. & McCance, R. A. (1971) Lancet, 2, 517-519 Abrarns, R., Caton, D., Clapp, J. & Barron, D. H. (1970) Clin. Obstet. Gynecol. 13, 549-564 Alexander, G. (1961) Aust.J. Agric. Res. 12,1152-1174 Alexander, G., Bell, A. W. & Williams, D. (1970) Biol. Neonate, 15,198-210 Alexander, G. & Williams, D. (1962) Aust. J. Agric. Res. 13,122143 Auliciems, A. (1969) / . Hyg. {Cambridge) 67, 59-65 Auliciems, A. (1972) Int. J. Biometeorol. 16, 233-246 73
Vol. 31 No. 1
THERMAL NEUTRALITY Edmund Hey Brooke, O. G. & Cocks, T. (1973) / . Physiol. (Land.) 231,18P-19P Brooke, O. G., Harris, M. ASalvosa, C. B. (1973)7. Physiol. (Lond.) 233, 75-91 Bruck, K. (1961) Biologia Neonat. 3, 65-119 Bruck, K., Bruck, M. & Lemtis, H. (1960) Geburtshilfe Frauenheilkd. 20,461-472 Bruck, K., Pannelee, A. H., jr & Bruck, M. (1962) Biologia Neonat. 4, 32-51 Buetow, K. C. & Klein, S. W. (1964) Pediatrics {Springfield) 34, 163-170 Cree, J. E., Meyer, J. & Hailey, D. M. (1973) Br. Med. J. 4,251Dahm, L. S. & James, L. S. (1972) Pediatrics (Springfield) 49, 504-513 Daily, W. J. R., Klaus, M. & Meyer, H. B. P. (1969) Pediatrics (Springfield) 43, 510-518 Day, R. (1943) Am. J. Dis. Child. 65, 376-398 Day, R. L., Caliguiri, L., Kamenski, C. & Ehrlich, F. (1964) Pediatrics (Springfield) 34,171-181 Dunn, J. M. & Miller, J. A., jr (1969) Am. J. Obstet. Gynecol. 104, 58-67 Fanaroff, A. A., Wald, M., Gruber, H. S. & Klaus, M. H. (1972) Pediatrics (Springfield) 50, 236-245 Foster, K. G.,Hey, E. N. &Katz, G. (1969) J.Physiol.(Lond.)203, 13-29 Gagge, A. P., Hardy, J. D. & Rapp, G. M. (1965a) Trans. Am. Soc. Heat. Refrig. Air-Cond. Eng. 71, pt II, 19-26 Gagge, A. P., Stolwijk, J. A. J. &Hardy, J. D. (1965b) Aerosp. Med. 36,431^*35 Gandy, G. M., Adamsons, K., jr, Cunningham, N., Silverman, W. A. & James, L. S. (1964)/. Clin. Incest. 43, 751-758 Giaja, J. (1938) Actual. Sci. Ind. nos. 576 and 577 Glass, L., Lala, R. V., Jaiswal, V. & Nigam, S. K. (1974) Pediatr. Res. 8, 446 [Abstract] Glass, L., Silverman, W. A. & Sinclair, J. C. (1968) Pediatrics (Springfield) 41,1033-1046 Glass, L., Silverman, W. A. & Sinclair, J. C. (1969) Biol. Neonate, 14,324-340 Gleiss, J. (1956) Z. Kinderheilkd. 77, 653-661 Graham, N. M., Wainman, F. W., Blaxter, K. L. & Armstrong, D. G. (1959)/. Agrtc. Sci. (Cambridge) 52,13-24 Grausz, J. P. (1968) Ada Paediatr. Scand. 57, 98-104 Green, M. &Behrendt,H.(1970)/4m./. Dis. Child. 120,434-^38 Grether, W. F. (1973) Aerosp. Med. 44, 747-755 Hardman, M. J. & Hull, D. (1971)/. Physiol. (Lond.)2U, 191-199 Hart, J. S. (1961) Br. Med. Bull. 17,19-24 Hey, E. N. (1969) / . Physiol. (Lond.) 200, 589-603 Hey, E. N. & Katz, G. (1969a) Arch. Dis. Child. 44, 323-330 Hey, E. N. & Katz, G. (1969b) /. Physiol. (Lond.) 200, 605-619 Hey, E. N. & Katz, G. (1970a) Arch. Dis. Child. 45, 328-334 Hey, E. N. & Katz, G. (1970b) / . Physiol. (Lond.) 207, 667-681 Hey, E. N., Katz, G. & O'Connell, B. (1970)/. Physiol. (Lond.) 207, 683-698 Hey, E. N. & Maurice, N. P. (1968) Arch. Dis. Child. 43, 166-171 Hey, E. N. & Mount, L. E. (1967) Arch. Dis. Child. 42, 75-84 Hey, E. N. & O'Connell, B. (1970) Arch. Dis. Child. 45, 335-343 Hill, J. R. (1961) Br. Med. Bull. 17,164-167 Hill, J. R. & Rahimtulla, K. A. (1965) / . Physiol. (Lond.) 180, 239265 Hill, J. R. & Robinson, D. C. (1968) / . Physiol. (Lond.) 199, 685703 Jolly, H., Molyneux, P. & Newell, D. J. (1962)/. Pediatr. 60, 889894 Jonxis, J. H. P., Vlugt, J. J. van der, Groot, C. J. de, Boersma, E. R. & Meijere, E. D. K. (1968) In: Jonxis, J. H. P., Visser, H. K. A. & Troelstra, J. A., ed. Aspects ofpraematurity and dysmaturity, pp. 201-209 (Nutricia Symposium, Groningen, 10-12 May 1967). Stenfert Kroese, Leiden Kennaird, D. L. (1971) Oxygen consumption and evaporative water loss in infants with congenital heart disease (Thesis for Ph.D. degree). University of London Kintzel, H. W. (1966) Monatsschr. Kinderheilkd. 114, 544-550 Krauss, A. N. & Auld, P. A. M. (1969) / . Pediatr. 75, 952-956 Lacomme, M., Chabrun, J., Borcau, T. & David, G. (1954) Etud. NA>-Nat. 3, 3-29 Laurence, B. M. (1961) Proc. R. Soc. Med. 54, 739-742
Lefevre, J. (1911) Chaleur animate et bioenergttique. Masson, Paris Levison, H., Linsao, L. & Swyer, P. R. (1966) Lancet, 2,1346-1348 Mclntyre, D. A. & Griffiths, I. D. (1972) Environ. Res. 5,471-482 Mann.T. P. (1968)/. Obstet. Gynaecol. Br. Commonw. 75,316-321 Matsaniotis, N., Pastelis, V., Agathopoulos, A. & Constantsas, N. (1971) Pediatrics (Springfield)*!, 571-576 Mestyan, J., Jarai, I., Bata, G. & Fekete, M. (1964) Biologia Neonat. 7, 243-254 Mestyan, J., Jarai, I., Fekete, M. & Soltesz, G. (1969) Pediatr. Res. 3, 41-50 Monteith, J. L. & Mount, L. E., ed. (1974) Heat loss from animals and man: assessment and control (Proceedings of the Twentieth Easter School in Agricultural Science). Butterworths, London Mount, L. E. (1963) Nature (Lond.) 199,1212-1213 [Letter] Mount, L. E. (1966) Br. Med. Bull. 22, 84-87 Mount, L. E., dose, W. H. & Verstegen, M. W. A. (1973) Proc. Nutr. Soc. 32, 71A [Abstract] OgUvie, D. M. & Stinson, R. H. (1966) Can. J. Zool. 44,511-517 Oh, W. & Karecki, H. (1972) Am. /. Dis. Child. 124, 230-232 Oh, W., Yao, A. C , Hanson, J. S. &Lind, J. (1973) ActaPaediatr. Scand. 62,49-54 Pannelee, A. H., jr, BrQck, K. & Bruck, M. (1962) Biologia Neonat. A, 317-339 Perlstein, P. H., Edwards, N. K., Atherton, H. & Sutherland, J. M. (1973) Pediatr. Res. 7, 405 [Abstract] Perlstein, P. H., Edwards, N. K. & Sutherland, J. M. (1970) New Engl. J. Med. 282,461-466 Perlstein, P. H., Hersh, C. B., Glueck, C. J. & Sutherland, J. M. (1973) Pediatr. Res. 7,406 [Abstract] Pintdr, S., Kovacs, L., SzSllSsi, J., Sztan6, P. & Boda, D (1971) ActaPaediatr. Acad. Sci. Hung. 12, 59-67 Pomerance, J. J. & Madore, C. (197'4) Pediatr. Res. 8,449 [Abstract] Pfibylova, H. (1971) Rev. Czech. Med. 17,133-136 Ryser, G. & Jequier, E. (1972) Eur. / . Clin. Invest. 2,176-187 Schain, R. J. & Watanabe, K. (1971) Pediatr. Res. 5, 173-180 Scholander, P. F., Hock, R., Walters, V., Johnson, F. & Irving, L. (1950) Biol. Bull. (Woods Hole, Mass.) 99, 237-258 Scopes, J. W. (1966) Br. Med. Bull. 22, 88-91 Scopes, J. W. & Ahmed, I. (1966a) Arch. Dis. Child. 41, 407^116 Scopes, J. W. & Ahmed, I. (1966b) Arch. Dis. Child. 41, 417-419 Senterre, J. & Karlberg, P. (1970) Ada Paediatr. Scand. 59, 653658 Silverman, W. A. & Agate, F. J., jr (1964) Biologia Neonat. 6,113— 127 Silverman, W. A., Agate, F. J., jr & Fertig, J. W. (1963) Pediatrics (Springfield) 31, 719-724 Silverman, W. A. & Blanc, W. A. (1957) Pediatrics (Springfield) 20, 477-486 Silverman, W. A., Fertig, J. W. & Berger, A. P. (1958) Pediatrics (Sprtngfield)22, S16-8&5 Silverman, W. A., Sinclair, J. C. & Agate, F. J., jr (1966) Ada Paediatr. Scand. 55, 294-300 Stephenson, J. M., Du, J. N. & Oliver, T. K., jr (1970) / . Pediatr. 76, 848-852 Sulyok, E., Jequier, E. & Prod'hora, L. S. (1973a) Pediatr. Res. 1, 888-900 Sulyok, E., Jequier, E. & Prod'hom, L. S. (1973b) Pediatrics (Springfield) 51, 641-650 Sulyok, E., Jequier, E. & Ryser, G. (1972) Biol. Neonate, 21, 210-218 Tafari, N. & Gentz, J. (1974) ActaPaediatr. Scand. 63, 595-600 Varga, F. (1959) Pediatrics (Springfield) 23, 1085-1090 Verstegen, M. W. A., Close, W. H., Start, I. B. & Mount, L. E. (1913) Br.J. Nutr. 30, 21-35 Wagner, H. (1960) Z. Kinderheilkd. 83, 609-617 Wu, P. Y. K. & Berdahl, M. (1974)/. Pediatr. 84, 754-755 Wu, P. Y. K., Wong, W. H., Hodgman, J. E. & Levan, N. (1974) Pediatr. Res. 8, 257-262 Yao, A. C , Wallgren, C. G., Sinha, S. N. & Lind, J. (1971) Pediatrics (Springfield) 47, 378-383 Yashiro, K., Adams, F. H., Emmanouilides, G. C. & Mickey, M. R (1973) / . Pediatr. 82, 991-994 Zeisberger, E., BrOck, K., WQnnenberg, W. & Wietasch, C. (1967) Pflugers Arch. Ges. Phvsiol. 296, 276-288 Zweymuller, E. & Preining, O. (1970) Ada Paediatr. Scand. suppl. no. 205
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