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Heat Production and Thermoregulation in the Small-for-Date Infant
Heat Production and Thermoregulation in the Small-for-Date Infant JOHN C. SINCLAIR, M.D. *
Over the last 10 years, there has been a large advance in our knowledge of the qualitative and quantitative aspects of the thermoregulatory capacity of the newborn baby. The newborn's homeothermic responses have been studied by the application of methods for the determination of cutaneous blood flow, rate of evaporative water loss, and rate of heat production. The latter has usually been measured as oxygen consumption, which can be converted to calories expended without appreciable error using a figure of 4.83 Calories per liter of oxygen consumed.27 As a result of these studies, there is now general agreement that the full size, intact newborn baby is a homeotherm, and that deficiencies in thermoregulatory responses cannot be blamed for a thermoregulatory range that is limited by adult standards. Full size babies born at term show minimal rates of oxygen consumption of about 4.6 ml. per kg. per min. in the first hours of life. The rate of oxygen consumption rises substantially during the first day, and continues to rise, but more slowly, during the next few days. Typical values for minimal metabolic rate (expressed as Cal. per kg. per 24 hours, or Cal. per square meter per 24 hours) are given in Table 1. When challenged by heat or by cold, the normal baby shows prompt, typical homeothermic responses designed to maintain deep body temperature near its set-point. In response to heat, the baby shows vasodilation (particularly in the hands and feet), which favors increased rate of heat loss by radiation and convection. In addition, sweating occurs in association with rectal temperatures above 37.2° C., thus favoring increased rate of heat loss by evaporation. When challenged by cold, on the other hand, the normal baby attempts to conserve body heat by cutaneous vasoconstriction, and to maintain body temperature by in'Assistant Professor, Department of Pediatrics, College of PhysiCians and Surgeons of Columbia University; Assistant Attending Pediatrician, Babies Hospital, ColumbiaPresbyterian Medical Center, New York, New York Supported by a Career Development Award (No. 1-K3-4D-34992-03) from the U.S. Public Health Service.
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Table 1. Typical Minimal Metabolic Rates During the Neonatal Period POSTNATAL AGE
Full-term 3500 gm.
Preterm 1500 gm.
MINIMAL METABOLIC RATE
Cal./kg./24 h.
Cal'/m'/24 h.'
Birth to 6 hours Latter half of first day Second or third day
32 37 43
470 550 630
First day Sixth day 2 to 4 weeks 4 to 6 weeks
34 42 50 59
380 470 590 760
'Surface area calculated as A = kW213 , using Lissauer's constant, k = 10.3.
creasing his rate of heat production. Although this latter response may involve muscular thermogenesis (including shivering if the cold stress is severe), the baby usually relies on nonshivering thermogenesis. Babies born prematurely may also show the typical homeothermic responses indicated above, but there is evidence that many of them suffer by comparison with term infants as regards both qualitative and quantitative aspects of thermoregulatory response. The small-for-date infant is worthy of separate consideration, however. While he suffers a limitation to his thermoregulatory range that is imposed by his small body size, he nevertheless may show comparatively well-developed homeothermic responses insofar as these depend on gestational age.
HEAT PRODUCTION (MINIMAL RATE) Among low birth-weight babies, minimal rate of oxygen consumption averages 4.3 to 5.4 mI. per kg. per min. on the first day of life. It rises gradually over the first days of postnatal life, but tends to be slightly lower, per unit weight, than in full-size infants of the same postnatal age. 3. 20. 24. 25. 33. 40 In the late neonatal period (beyond 2 weeks postnatal age), oxygen consumption per unit weight continues to rise,3. 29 reaching values as high as 8 or 9 mI. per kg. per min.20. 25. 41 Thus, with increasing postnatal age, the metabolic rate per unit weight of infants born prematurely not only reaches but ultimately exceeds that of the full-term baby of the same weight. Typical minimal metabolic rates for a preterm baby are indicated in Table 1. Babies who are small for their gestational age systematically tend to have higher rates of oxygen consumption than their normally grown fellows of similar birth weight and postnatal age. The relative hypermetabolism of the small-for-date infant is suggestive during the first day25. 33 but is more readily apparent beyond 2 or 3 days postnatal age. 20 . 25. 28.33.39.40 Beyond 10 days, metabolic rate in this group continues to be high for weight. 25 . 33 Sinclair and Silverman40 proposed that the metabolic
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rate of a brain which is characteristically large in relation to body weight may account for the hypermetabolism, expressed per unit body weight, of the small-for-date infant. In support of this, they noted that oxygen consumption of such infants, although high for body weight, was not high in relation to head circumference. This point may be illustrated by comparing babies of similar body weight but markedly different gestational ages. Table 2 shows such a comparison. The small-for-date infant included in this comparison showed the relative preservation of brain growth that is typical of fetal malnutrition (Fig. 1). When compared to a gestationally less mature infant of similar body size, he showed a substantially increased rate of oxygen consumption that probably is due mainly to his much larger brain. Table 2.
Metabolic Rate and Brain Weight'" in Two Babies of Very Low Birth Weight
Gestational age (weeks) Postnatal age (days) Birth weight (gm.) Head circumference (cm.) Brain weight* (gm.) Body minus brain weight (gm.) Metabolic rate (Cal./24 h.) (Cal./kg./24 h.)
IMMATURE
SMALL-FOR- DA TE
26 9
35
750
860 27.5 230 630
23.2
120 630 28 37
5
47 54
*Estimated from head circumference according to the relationship derived from an au topsied series.
Scopes and Ahmed 33 noted a substantial rise in minimal rate of oxygen consumption on the fourth postnatal day in small-for-date babies. Brain, which appears to contribute substantially to total body oxygen consumption of such infants, uses glucose as an energy source. But in the small-for-date baby, hepatic glycogen content is very low. 34 Symptomatic hypoglycemia has been identified as a characteristic risk/ and is associated with an impaired long-term prognosis for central nervous system function,9 suggesting that the neonatal hypoglycemia injures the brain. These several associations suggest that cerebral metabolism may be limited by glucose availability in some small-for-date babies in the first days of life. It is essential to note that "minimal" metabolic rates underestimate the true maintenance requirements, because the contributions of muscular activity, thermal stress, and fecal loss must be considered as well. Specific dynamic action also increases the caloric need, although this factor is included in estimates of minimal metabolic rates in babies when the measurement is made in the first hour or two after a feeding. The caloric requirement for growth comprises an additional need. The summation of these several factors results in the clinical observation that normal growth in babies and infants is associated with a caloric intake that is usually two to two and one-half times the caloric value derived from "minimal" rates of oxygen consumption.
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Figure 1. Small-for-date infant (smallest of quadruplets, gestational age 35 weeks, birth weight 860 gm.), showing severe growth retardation except for brain. Well-developed flexor tone can be seen in both lower and upper extremities, in accordance with stated gestational age.' Additional data are given in Table 2.
HEAT DISSIPATION Heat generated by metabolism is dissipated along a temperature gradient from the interior of the body to the body surface to the surrounding air. Burton6 distinguished two portions of the total drop in temperature-the "internal gradient" (rectal-skin) and the "external gradient" (skin-air). Although the baby may exert physiologic control over the internal gradient by regulation of vasomotor activity, the external gradient is of a purely physical nature. Thermal interchanges with the environment occur through radiation, convection, conduction, and evaporation. In a thermal steady state, heat produced by metabolism is lost by these routes at precisely the same rate as it is produced. Babies have a relatively large surface area in relation to body mass. This surface-to-mass handicap is exaggerated in the infant of low birth weight. However, the surface available for heat loss by radiation and convection is not the total surface, but rather a portion of the total surface that varies with posture. Postures characteristic of various gestational ages have been described by Amiel-Tison. 2 These postures tend toward increasing flexion of the extremities with increasing gestational age (see Fig. 1). Thus, the small-for-date infant achieves an effective surface area that is somewhat less than that of the preterm baby of similar size, and to this extent he can limit heat loss better. No
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HEAT PRODUCTION AND THERMOREGULATION
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quantitative description is as yet available of the thermoregulatory benefit derived.
Thermal Insulation A major handicap of small body size is limited thermal insulation. Two components of total thermal insulation may be described: (1) surface-air insulation; and (2) tissue insulation. Small-for-date babies share with small babies of short gestation the thermoregulatory consequence of small body size. The smaller the body, the more easily does it exchange heat with the environment for a given gradient of temperature between skin and environment (low surface-air insulation). More important, the absolute amount of tissue through which heat must be transferred, either by conduction from core to surface or by the flow of blood from hotter to cooler parts, is small (low tissue insulation). At body weights below 2 kg., tissue insulation decreases substantially. Thus, the ambient and tissue components of total thermal insulation act synergistically to produce particularly low values for total insulation in the smallest infants. This important handicap of small body size is not modified by differences in gestational age, since small-for-date infants lack subcutaneous fat, as do pre term infants of similar size, and are geometrically similar as well. PHYSIOLOGIC RESPONSES TO HEAT VasodiIation Day12 and others observed peripheral vasodilation in low-birthweight infants exposed to heat stress. The effect of this response is to decrease tissue insulation and to favor the loss of heat to the environment. The response depends on an intact central nervous system, and is seen only after rectal temperature exceeds 36.6 to 37.3 0 C.23 Sweating Evaporative water loss, in babies as in adults, normally accounts for about one-fourth of the heat loss under resting thermoneutral conditions.2i The ability of the homeotherm to increase evaporative water loss in response to environmental overheating constitutes his principal defense against serious hyperthermia. There was, at first, some doubt about the ability of newborn infants, particularly low-birth-weight infants, to sweat. Day12 detected no consistent sweating in low-birthweight babies exposed to rising environmental temperatures. More recently, however, Hey and Katz 21 observed that for sweating to be elicited regularly in newborn infants, environmental temperatures higher than those used by Day must be employed. Hey and Katz noted a threshold of about 37.20 C. rectal temperature for sweating, with a tendency for the threshold to be higher on the first day than later. Figure 2 shows their findings: babies born at term could triple their evaporative water loss, but those born more than 3 weeks before term showed a smaller and sometimes absent response. Visible sweating appeared first on the forehead and temples, later on the chest, and by 240 to 260 days
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o~--~--~----~~~--~
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Post· conceptual age (days) Figure 2. (a) Maturation of the sweat response with post·conceptional age, as shown by minimal (environmental temperature 33 to 34.5° C., rectal temperature 36.5 to 37.0° C.) and maximal (environmental temperature> 36° C., .rectal temperature 37.5 to 37.8° C.) rates of evaporative water loss in 49 babies. Dotted lines link results obtained in small·for-date babies. (b) The development of a sweat response in eight of these babies who were born more than 6 weeks before term. From Hey, E. N., and Katz, G.," reproduced by permission.
post conception, on the legs. A similar response was seen in normally grown and small-for-date babies of the same gestational age. Thus, the sweat response appears to mature as a function of gestational age rather than of body size.
PHYSIOLOGIC RESPONSES TO COLD Vasoconstriction Briick3 showed that constriction of skin blood vessels occurred in response to cold in both term and preterm infants. The effect of peripheral vasoconstriction is to increase the internal (core-skin) temperature gradient, and to increase tissue insulation to its maximum value. Even when maximally constricted, however, the tissue insulation of the lowbirth-weight infant is low by comparison with larger individuals. This defect is essentially a function of small body size, and is not modified to any important extent by gestational differences. Increase in Heat Production Briick3 demonstrated definitively that newborn babies, when challenged by cold, increase their rate of heat production. Both term and preterm babies show this response, although the metabolic rise is less in the smaller and younger infants. The maximal rate of heat production in healthy term babies is about two and one-half times the resting rate. Briick noted that infants in a cool environment were restless and often cried, but did not appear to shiver unless there was a rapid fall in rectal temperature. There was not a clear relationship between the level of heat production and the amount of muscular activity in the cold; thus, nonmuscular thermogenesis may have contributed. The increase in metabolic rate with fall in environmental temperature is approximately linear. Figure 3 shows the acute responses observed by Hey20 in a group of low-birth-weight babies (2.0 to 2.5 kg.).
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•
16
o o
•
Age: 9-' 1 days
Age: 4-12 hr 32
Environmental temp. (0 0) Figure 3. The relation between environmental temperature and oxygen consumption in 15 babies 4 to 12 hours old and 9 to 11 days old weighing between 2.0 and 2.5 kg. at birth. The results obtained in small-for-date infants are indicated by closed symbols. From Hey, E. N.,'o reproduced by permission.
The cold-induced metabolic rise was similar in small-for-date and normally grown infants, both when 4 to 12 hours old and when 9 to 11 days old. Silverman and Agate,35 on the other hand, found that smaller babies « 1500 gm.); who were exposed to mild cold stress for somewhat longer periods, increased heat production more successfully if they were gestationally more mature. Again, no shivering was observed. Gestationally immature babies of comparable size often showed no response. Silverman, Sinclair, and Agate 37 also found, among small « 1500 gm.) infants exposed to minor cold stress, that those who were gestationally more mature generally maintained a somewhat higher rate of metabolism and a larger temperature gradient between deep and superficial tissues. Lees, Younger and Babson28 noted not only increased muscular activity, but also increased excretion of norepinephrine and its metabolites in small-for-date infants who showed successful homeothermic responses to environmental cold stress. A similar catecholamine response occurs in full-size infants exposed to cold stress. 31 . 43 These observations, and prior studies in the newborn kitten,30 suggest that at least part of the thermoregulatory heat production is under the control of the sympathetic nervous system, and that norepinephrine is the chemical mediator in the newborn. The site of nonshivering thermogenesis in response to cold and to norepinephrine is of obvious interest. Major attention has been directed recently to the role of cold and catecholamines in stimulating metabolism in brown adipose tissue, where catecholamine-induced enhancement of triglyceride breakdown appears responsible for thermogenesis. Smith and Roberts 42 noted that heat produced in brown fat is applied directly to the flowing blood as it passes
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to and from the cooler periphery, to the thoracocervical spinal cord, and to the vital organs of the thorax. Aherne and Hull l described the extent and distribution of brown fat in newborn human infants (Fig. 4). In the human, primitive brown fat cells begin to differentiate from reticular cells at about 26 to 30 weeks' gestational age. Development is not complete at term, for by the third to fifth postnatal week the amount of cytoplasm per cell has increased to over 150 per cent of that seen at birth. The brown fat cell possesses numerous small lipid inclusions in the cytoplasm, rather than the single large lipid vacuole characteristic of white fat. In the newborn rabbit, the metabolic response to cold and to norepinephrine is correlated with the lipid content of his brown fat. 26 The newborn rabbit whose brown fat is depleted of lipid cannot produce extra heat in response to cold, but the ability to do so can be restored by milk feeding. 18 There is indirect evidence that brown fat plays a role in the response of human babies to cold. II, 38 Heim et al. 19 compared brown fat from babies who died after having been nursed either in incubators (34 to 35° C.) or who were conventionally swaddled and nursed at room temperature (23 to 27° C.). The tissues studied from the infants nursed in the warm condition were replete with fat, whereas 83 per cent of the brown fat derived from infants conventionally swaddled showed fat depletion. It is unusual to find brown fat wholly depleted of lipid at necropsy, but Aherne and Hull l collected a small series of such cases. Prominently represented among this group were babies who were smallfor-date and who suffered total depletion of their brown fat within 3 or 4 days of birth; and, secondly, infants who were admitted to hospital with neonatal cold injury and died with massive pulmonary hemorrhage and with brown fat wholly depleted of lipid at a mean age of 8 days. Hey and
Figure 4. Distribution of brown adipose tissue in the newborn human infant, who possesses an interscapular mass lying in a thin diamondshaped sheath, smaller masses around the muscles and blood vessels of the neck, large deposits in the axillae, moderately large masses in the mediastinum, and a large mass around the kidneys and adrenals. (From Aherne, W., and Hull, D.: The site of heat production in the newborn infant. Proc. Roy. Soc. Med., 57:1172, 1964, reproduced with permission.)
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Katz22 documented a temporary loss of the metabolic response to cold in three infants of low birth weight who experienced both subthermoneutral environments and negative caloric balance throughout the first week of life. They suggested that exhaustion of fat stores available to brown adipose tissue could have been responsible for the temporary loss of metabolic response to cold stress. Failure of the metabolic response to cold is also seen in the smallfor-date baby with symptomatic hypoglycemia. 32 Here the defect may well be a central one, since it is known that intact central nervous system function is essential to a normal response. Babies born with severe defects of the central nervous system (e.g., anencephaly) do not increase heat production when environmental temperature is lowered. In one anencephalic studied by Cross et al.,l0 brown fat replete with lipid was demonstrated at autopsy, indicating that the failure to respond could not be attributed to lack of development of this tissue.
CLINICAL CONSEQUENCES OF COLD STRESS Chilling After Birth Routine delivery room care often results in excessive chilling of the low-birth-weight infant. With special measures to reduce heat loss (e.g., infrared heater 4 ), certain biochemical improvements may be expected: a lesser metabolic acidosis after birth,15 and a higher blood glucose concentration at 4 and 6 hours of age. s These rewards may be particularly important in the small-for-date infant. Survival Silverman et al.,36 Buetow and Klein,s and Day et al,13 all observed an increased mortality in the first days of life in low-birth-weight infants raised in incubators providing a thermal environment below the neutral range. The mechanism of the increased mortality was not determined, and no distinctive or unique cause of death was revealed at necropsy. These clinical trials were performed before much of the information about the newborn's capacity for nonshivering thermogenesis had been acquired. Consequently, some critical clinical and pathological observations were not made (e.g., lipid content of brown fat at autopsy). It is attractive to speculate that the energy cost of defending deep body temperature against cold contributes to the lethal effect (particularly in the first days of life, when the balance between caloric supply and caloric expenditure is marginal). Our expectation may be that the small-for-date infant, with deficient fat and glycogen stores, high rate of energy metabolism, and mature mechanism for increasing oxygen consumption in response to cold by nonshivering thermogenesis, is at great risk in the first days of life as regards the possibly lethal caloric penalty of cold exposure. Cold Resistance Bruck and Wunnenberg4 found that nonshivering thermogenesis is almost completely replaced by shivering within 4 weeks in guinea pigs
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reared at the neutral temperature (30 to 32° C.). Conversely, the replacement of nonshivering by shivering thermogenesis could be retarded but not completely inhibited by rearing the guinea pigs at 8° C. These observations suggest that, in guinea pigs, reduction in nonshivering thermogenetic capacity following birth is a develQpmental process that can be modified by environmental temperature. In the human baby, however, brown fat continues to develop for some weeks after birth, as does capacity for nonshivering thermogenesis, particularly in low-birth-weight babies. Glass and co-workers l6 tested the effect of varying temperature on this developmental process. They found that low-birth-weight infants, raised between 1 and 3 weeks postnatal age in slightly subthermoneutral conditions, had improved cold resistance at the end of that interval, whereas matched controls raised under thermoneutral conditions and fed isocalorically, did not. The improved cold resistance was associated with an improved capacity to increase oxygen consumption in response to a cold stress.
Growth Glass et al. 16 also explored rates of growth in low-birth-weight babies continuously exposed to contrasting thermal environments between 1 and 3 weeks after birth. Although each group received identical feeding (120 Cal. per kg. per day), the babies raised in the thermoneutral condition grew faster in both weight and length than the cooler controls. The latter were able to make up the difference when given a caloric supplement sufficient to match the calculated cost of the cold-induced metabolic rise. 17
SUMMARY Small-for-date babies have limited ability to conserve body heat because of their small size and scant subcutaneous fat. Their thermoregulatory range is considerably narrower than that of full-size babies; however, in comparison to gestationally less mature infants of similar small size, they are somewhat favorably placed because of their better developed flexor tonus, which reduces slightly the effective surface for heat loss, and their higher rates of resting heat production. The thermal sweat response matures as a function of gestational age. Infants born within 3 weeks of term show a well-developed capacity for sweating, evert though small-for-date. Similarly, capacity to increase heat production acutely in response to cold is well developed in most small-for-date infants. The cold-induced increment is accomplished partly by increased muscular activity (usually without shivering) and partly by heat production in brown adipose tissue, evidently mediated by norepinephrine. Limitation of lipid stores may terminate this response if cold stimulation is continued, and a profound fall in body temperature may result. Failure of metabolic response to cold may also be seen in small-for-date babies with symptomatic hypoglycemia. Excessive chilling in the delivery room, and cold stress in the newborn nursery, are to be avoided in the small-for-date infant, as these
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stresses may lead to slower recovery from birth asphyxia, exhaustion of limited fat and glycogen stores, and increased risk of hypoglycemia. Strict thermoneutrality (exposed abdominal skin temperature maintained at about 36.5° C.) should be sought during the first week of life. Later in the neonatal period, optimal thermal conditions are less certain, for both growth in weight and length, and development of cold resistance, are sensitive to minor variations in environmental temperature.
REFERENCES 1. Aherne, W., and Hull, D.: Brown adipose tissue and heat production in the newborn infant. J. Path. Bact., 91 :223, 1966. 2. Amiel-Tison, C.: Neurological evaluation of the maturity of newborn infants. Arch. Dis. Child., 43:89, 1968. 3. Bruck, K: Temperature regulation in the newborn infant. BioI. Neonat., 3:65, 1961. 4. Bruck, K, and Wunnenberg, B.: Influence of ambient temperature in the process of replacement of nonshivering by shivering thermogenesis during post-natal development. Fed. Proc., 25:1332, 1966. 5. Buetow, K C., and Klein, S. W.: Effect of maintenance of "normal" skin temperature on survival of infants of low birth weight. Pediatrics, 34: 163, 1964. 6. Burton, A. C.: The application of the theory of heat flow to the study of energy metabolism. J. Nutr., 7:497, 1934. 7. Cornblath, M., Odell, G. B., and Levin, E. Y.: Symptomatic neonatal hypoglycemia associated with toxemia of pregnancy. J. Pediat., 55:545,1959. 8. Cornblath, M., and Schwartz, R: Disorders of Carbohydrate Metabolism in Infancy. Philadelphia, W. B. Saunders Co., 1966, p. 35. 9. Cornblath, M., Segal, S., and Smith, C. A.: Carbohydrate and energy metabolism in the newborn-an international exploration. Pediatrics, 39:582, 1967. 10. Cross, K W., Gustavson, J., Hill, J. R, and Robinson, D. C.: Thermoregulation in anencephalic infant as inferred from its metabolic rate under hypothermic and normal conditions. Clin. Sci., 31 :449, 1966. 11. Dawkins, M. J. R, and Scopes, J. W.: Non-shivering thermogenesis and brown adipose tissue in the human new-born infant. Nature, 206:201, 1965. 12. Day, R: Respiratory metabolism in infancy and childhood. XXVII. Regulation of body temperature of premature infants. Amer. J. Dis. Child., 65:376,1943. 13. Day, R L., Caliguiri, L., Kamenski, C., and Ehrlich, F.: Body temperature and survival of premature infants. Pediatrics, 34: 1 71, 1964. 14. Du, J. N. H., and Oliver, T. K: The baby in the delivery room: A suitable microenvironment. J.A.M.A., 207:1502,1969. 15. Gandy, G. M., Adamsons, K, Jr., Cunningham, N., Silverman, W. A., and James, L. S.: Thermal environment and acid-base homeostasis in human infants during the first few hours of life. J. Clin. Invest., 43:751, 1964. 16. Glass, L., Silverman, W. A., and Sinclair, J. C.: Effect of the thermal environment on cold resistance and growth of small infants after the first week of life. Pediatrics, 41 :1033, 1968. 17. Glass, L., Silverman, W. A., and Sinclair, J. C.: Relationship of thermal environment and caloric intake to growth and resting metabolism in the late neonatal period. BioI. Neonat., 14:324, 1969. 18. Hardman, M. J., Hey, E. N., and Hull, D.: Energy sources of thermogenesis in the newborn rabbit. J. PhysioI., 201 :84P, 1969. 19. Heim, T., Kellermayer, M., and Dani, M.: Thermal conditions and the mobilization of lipids from brown and white adipose tissue in the human neonate. Acta Paediat. Acad. Sci. Hung., 9:109,1968. 20. Hey, E. N.: The relation between environmental temperature and oxygen consumption in the new-born baby. J. PhysioI., 200:589, 1969. 21. Hey, E. N., and Katz, G.: Evaporative water loss in the new-born baby. J. PhysioI., 200: 605,1969. 22. Hey, E. N., and Katz, G.: Temporary loss of a metabolic response to cold stress in infants of low birth-weight. Arch. Dis. Child., 44:323, 1969. 23. Hey, E. N., and Katz, G.: The range of thermal insulation in the tissues of the new-born baby. J. PhysioI., (in press). 24. Hill, J. R, and Rahimtulla, K A.: Heat balance and the metabolic rate of new-born babies in relation to environmental temperature; and the effect of age and of weight on basal metabolic rate. J. PhysioI., 180:239, 1965.
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25. Hill. J. R, and Robinson, D. C.: Oxygen consumption in normally grown, small-for-dates and large-for-dates new-born infants. J. Physio!., 199:685, 1968. 26. Hull, D., and Segall, M. M.: Heat production in the new-born rabbit and the fat content of the brown adipose tissue. J. Physio!., 181:468,1965. 27. Karlberg, P.: Determination of standard energy metabolism (basal metabolism) in normal infants. Acta Paediat. (Stockholm), Vol. 41, Supp!. 89, 1952, p. 67. 28. Lees, M. H., Younger, E. W., and Babson, S. G.: Thermal requirements of undergrown human neonates. BioI. Neonat., 10:288, 1966. 29. Mestyan, J., Fekete, M., Bata, G., and Jarai, I.: The basal metabolic rate of premature infants. BioI. Neonat., 7:11, 1964. 30. Moore, R E., and Underwood, M. C.: Hexamethonium, hypoxia and heat production in new-born and infant kittens and puppies. J. Physio!., 161 :30,1962. 3l. Schiff, D., Stern, L., and Leduc, J.: Chemical thermogenesis in new-born infants: Catecholamine excretion and the plasma non-esterified fatty acid responses to cold exposure. Pediatrics, 37:577, 1966. 32. Scopes, J. W., and Ahmed, I.: Indirect assessment of oxygen requirements in newborn bflbies by monitoring deep rectal temperature. Arch. Dis. Child., 41 :25, 1966. 33. Scopes, J. W., and Ahmed, I.: Minimal rates of oxygen consumption in sick and premature newborn infants. Arch. Dis. Child., 41 :407, 1966. 34. Shelley, H., and Neligan, G. A.: Neonatal hypoglycemia. Brit. Med. Bull., 22:34, 1966. 35. Silverman, W. A, and Agate, F. J., Jr.: Variation in cold resistance among small newborn infants. BioI. Neonat., 6:113, 1964. 36. Silverman, W. A., Fertig, J. W., and Berger, A. P.: The influence of the thermal environment on the survival of newly born infants. Pediatrics, 22:876, 1958. 37. Silverman, W. A., Sinclair, J. C., and Agate, F. J., Jr.: Oxygen cost of minor variations in heat balance of small newborn infants. Acta Paediat. Scandinav., 55:294, 1966. 38. Silverman, W. A, Zamelis, A, Sinclair, J. C., and Agate, F. J., Jr.: Warm nape of the newborn. Pediatrics, 33:984, 1964. 39. Sinclair, J. C., and Silverman, W. A.: Relative hypermetabolism in undergrown human neonates. Lancet, 2:49,1964. 40. Sinclair, J. C., and Silverman, W. A.: Intrauterine growth in active tissue mass of the human fetus, with particular reference to the undergrown baby. Pediatrics, 38 :48, 1966. 4l. Sinclair, J. C., and Silverman, W. A., unpublished data. 42. Smith, R E., and Roberts, J. C.: Thermogenesis of brown adipose tissue in cold-acclimated rats. Amer. J. Physiol., 206:143, 1964. 43. Stern, L., Lees, M. H., and Leduc, J.: Environmental temperature, oxygen consumption, and catecholamine excretion in newborn infants. Pediatrics, 36:367, 1965. College of Physicians and Surgeons Columbia University New York, New York 10032
Over the last 10 years, there has been a large advance in our knowledge of the qualitative and quantitative aspects of the thermoregulatory capacity of the newborn baby. The newborn's homeothermic responses have been studied by the application of methods for the determination of cutaneous blood flow, rate of evaporative water loss, and rate of heat production. The latter has usually been measured as oxygen consumption, which can be converted to calories expended without appreciable error using a figure of 4.83 Calories per liter of oxygen consumed.27 As a result of these studies, there is now general agreement that the full size, intact newborn baby is a homeotherm, and that deficiencies in thermoregulatory responses cannot be blamed for a thermoregulatory range that is limited by adult standards. Full size babies born at term show minimal rates of oxygen consumption of about 4.6 ml. per kg. per min. in the first hours of life. The rate of oxygen consumption rises substantially during the first day, and continues to rise, but more slowly, during the next few days. Typical values for minimal metabolic rate (expressed as Cal. per kg. per 24 hours, or Cal. per square meter per 24 hours) are given in Table 1. When challenged by heat or by cold, the normal baby shows prompt, typical homeothermic responses designed to maintain deep body temperature near its set-point. In response to heat, the baby shows vasodilation (particularly in the hands and feet), which favors increased rate of heat loss by radiation and convection. In addition, sweating occurs in association with rectal temperatures above 37.2° C., thus favoring increased rate of heat loss by evaporation. When challenged by cold, on the other hand, the normal baby attempts to conserve body heat by cutaneous vasoconstriction, and to maintain body temperature by in'Assistant Professor, Department of Pediatrics, College of PhysiCians and Surgeons of Columbia University; Assistant Attending Pediatrician, Babies Hospital, ColumbiaPresbyterian Medical Center, New York, New York Supported by a Career Development Award (No. 1-K3-4D-34992-03) from the U.S. Public Health Service.
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Table 1. Typical Minimal Metabolic Rates During the Neonatal Period POSTNATAL AGE
Full-term 3500 gm.
Preterm 1500 gm.
MINIMAL METABOLIC RATE
Cal./kg./24 h.
Cal'/m'/24 h.'
Birth to 6 hours Latter half of first day Second or third day
32 37 43
470 550 630
First day Sixth day 2 to 4 weeks 4 to 6 weeks
34 42 50 59
380 470 590 760
'Surface area calculated as A = kW213 , using Lissauer's constant, k = 10.3.
creasing his rate of heat production. Although this latter response may involve muscular thermogenesis (including shivering if the cold stress is severe), the baby usually relies on nonshivering thermogenesis. Babies born prematurely may also show the typical homeothermic responses indicated above, but there is evidence that many of them suffer by comparison with term infants as regards both qualitative and quantitative aspects of thermoregulatory response. The small-for-date infant is worthy of separate consideration, however. While he suffers a limitation to his thermoregulatory range that is imposed by his small body size, he nevertheless may show comparatively well-developed homeothermic responses insofar as these depend on gestational age.
HEAT PRODUCTION (MINIMAL RATE) Among low birth-weight babies, minimal rate of oxygen consumption averages 4.3 to 5.4 mI. per kg. per min. on the first day of life. It rises gradually over the first days of postnatal life, but tends to be slightly lower, per unit weight, than in full-size infants of the same postnatal age. 3. 20. 24. 25. 33. 40 In the late neonatal period (beyond 2 weeks postnatal age), oxygen consumption per unit weight continues to rise,3. 29 reaching values as high as 8 or 9 mI. per kg. per min.20. 25. 41 Thus, with increasing postnatal age, the metabolic rate per unit weight of infants born prematurely not only reaches but ultimately exceeds that of the full-term baby of the same weight. Typical minimal metabolic rates for a preterm baby are indicated in Table 1. Babies who are small for their gestational age systematically tend to have higher rates of oxygen consumption than their normally grown fellows of similar birth weight and postnatal age. The relative hypermetabolism of the small-for-date infant is suggestive during the first day25. 33 but is more readily apparent beyond 2 or 3 days postnatal age. 20 . 25. 28.33.39.40 Beyond 10 days, metabolic rate in this group continues to be high for weight. 25 . 33 Sinclair and Silverman40 proposed that the metabolic
149
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rate of a brain which is characteristically large in relation to body weight may account for the hypermetabolism, expressed per unit body weight, of the small-for-date infant. In support of this, they noted that oxygen consumption of such infants, although high for body weight, was not high in relation to head circumference. This point may be illustrated by comparing babies of similar body weight but markedly different gestational ages. Table 2 shows such a comparison. The small-for-date infant included in this comparison showed the relative preservation of brain growth that is typical of fetal malnutrition (Fig. 1). When compared to a gestationally less mature infant of similar body size, he showed a substantially increased rate of oxygen consumption that probably is due mainly to his much larger brain. Table 2.
Metabolic Rate and Brain Weight'" in Two Babies of Very Low Birth Weight
Gestational age (weeks) Postnatal age (days) Birth weight (gm.) Head circumference (cm.) Brain weight* (gm.) Body minus brain weight (gm.) Metabolic rate (Cal./24 h.) (Cal./kg./24 h.)
IMMATURE
SMALL-FOR- DA TE
26 9
35
750
860 27.5 230 630
23.2
120 630 28 37
5
47 54
*Estimated from head circumference according to the relationship derived from an au topsied series.
Scopes and Ahmed 33 noted a substantial rise in minimal rate of oxygen consumption on the fourth postnatal day in small-for-date babies. Brain, which appears to contribute substantially to total body oxygen consumption of such infants, uses glucose as an energy source. But in the small-for-date baby, hepatic glycogen content is very low. 34 Symptomatic hypoglycemia has been identified as a characteristic risk/ and is associated with an impaired long-term prognosis for central nervous system function,9 suggesting that the neonatal hypoglycemia injures the brain. These several associations suggest that cerebral metabolism may be limited by glucose availability in some small-for-date babies in the first days of life. It is essential to note that "minimal" metabolic rates underestimate the true maintenance requirements, because the contributions of muscular activity, thermal stress, and fecal loss must be considered as well. Specific dynamic action also increases the caloric need, although this factor is included in estimates of minimal metabolic rates in babies when the measurement is made in the first hour or two after a feeding. The caloric requirement for growth comprises an additional need. The summation of these several factors results in the clinical observation that normal growth in babies and infants is associated with a caloric intake that is usually two to two and one-half times the caloric value derived from "minimal" rates of oxygen consumption.
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Figure 1. Small-for-date infant (smallest of quadruplets, gestational age 35 weeks, birth weight 860 gm.), showing severe growth retardation except for brain. Well-developed flexor tone can be seen in both lower and upper extremities, in accordance with stated gestational age.' Additional data are given in Table 2.
HEAT DISSIPATION Heat generated by metabolism is dissipated along a temperature gradient from the interior of the body to the body surface to the surrounding air. Burton6 distinguished two portions of the total drop in temperature-the "internal gradient" (rectal-skin) and the "external gradient" (skin-air). Although the baby may exert physiologic control over the internal gradient by regulation of vasomotor activity, the external gradient is of a purely physical nature. Thermal interchanges with the environment occur through radiation, convection, conduction, and evaporation. In a thermal steady state, heat produced by metabolism is lost by these routes at precisely the same rate as it is produced. Babies have a relatively large surface area in relation to body mass. This surface-to-mass handicap is exaggerated in the infant of low birth weight. However, the surface available for heat loss by radiation and convection is not the total surface, but rather a portion of the total surface that varies with posture. Postures characteristic of various gestational ages have been described by Amiel-Tison. 2 These postures tend toward increasing flexion of the extremities with increasing gestational age (see Fig. 1). Thus, the small-for-date infant achieves an effective surface area that is somewhat less than that of the preterm baby of similar size, and to this extent he can limit heat loss better. No
I
HEAT PRODUCTION AND THERMOREGULATION
151
quantitative description is as yet available of the thermoregulatory benefit derived.
Thermal Insulation A major handicap of small body size is limited thermal insulation. Two components of total thermal insulation may be described: (1) surface-air insulation; and (2) tissue insulation. Small-for-date babies share with small babies of short gestation the thermoregulatory consequence of small body size. The smaller the body, the more easily does it exchange heat with the environment for a given gradient of temperature between skin and environment (low surface-air insulation). More important, the absolute amount of tissue through which heat must be transferred, either by conduction from core to surface or by the flow of blood from hotter to cooler parts, is small (low tissue insulation). At body weights below 2 kg., tissue insulation decreases substantially. Thus, the ambient and tissue components of total thermal insulation act synergistically to produce particularly low values for total insulation in the smallest infants. This important handicap of small body size is not modified by differences in gestational age, since small-for-date infants lack subcutaneous fat, as do pre term infants of similar size, and are geometrically similar as well. PHYSIOLOGIC RESPONSES TO HEAT VasodiIation Day12 and others observed peripheral vasodilation in low-birthweight infants exposed to heat stress. The effect of this response is to decrease tissue insulation and to favor the loss of heat to the environment. The response depends on an intact central nervous system, and is seen only after rectal temperature exceeds 36.6 to 37.3 0 C.23 Sweating Evaporative water loss, in babies as in adults, normally accounts for about one-fourth of the heat loss under resting thermoneutral conditions.2i The ability of the homeotherm to increase evaporative water loss in response to environmental overheating constitutes his principal defense against serious hyperthermia. There was, at first, some doubt about the ability of newborn infants, particularly low-birth-weight infants, to sweat. Day12 detected no consistent sweating in low-birthweight babies exposed to rising environmental temperatures. More recently, however, Hey and Katz 21 observed that for sweating to be elicited regularly in newborn infants, environmental temperatures higher than those used by Day must be employed. Hey and Katz noted a threshold of about 37.20 C. rectal temperature for sweating, with a tendency for the threshold to be higher on the first day than later. Figure 2 shows their findings: babies born at term could triple their evaporative water loss, but those born more than 3 weeks before term showed a smaller and sometimes absent response. Visible sweating appeared first on the forehead and temples, later on the chest, and by 240 to 260 days
152
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(a)
C.
SINCLAIR
(b)
-;:;-
..c:: ". 40
e
.§ ill
..
.Q
i
><
oil
o~--~--~----~~~--~
200
250 Term
300
::Ii!
0
200
250 Term
Post· conceptual age (days) Figure 2. (a) Maturation of the sweat response with post·conceptional age, as shown by minimal (environmental temperature 33 to 34.5° C., rectal temperature 36.5 to 37.0° C.) and maximal (environmental temperature> 36° C., .rectal temperature 37.5 to 37.8° C.) rates of evaporative water loss in 49 babies. Dotted lines link results obtained in small·for-date babies. (b) The development of a sweat response in eight of these babies who were born more than 6 weeks before term. From Hey, E. N., and Katz, G.," reproduced by permission.
post conception, on the legs. A similar response was seen in normally grown and small-for-date babies of the same gestational age. Thus, the sweat response appears to mature as a function of gestational age rather than of body size.
PHYSIOLOGIC RESPONSES TO COLD Vasoconstriction Briick3 showed that constriction of skin blood vessels occurred in response to cold in both term and preterm infants. The effect of peripheral vasoconstriction is to increase the internal (core-skin) temperature gradient, and to increase tissue insulation to its maximum value. Even when maximally constricted, however, the tissue insulation of the lowbirth-weight infant is low by comparison with larger individuals. This defect is essentially a function of small body size, and is not modified to any important extent by gestational differences. Increase in Heat Production Briick3 demonstrated definitively that newborn babies, when challenged by cold, increase their rate of heat production. Both term and preterm babies show this response, although the metabolic rise is less in the smaller and younger infants. The maximal rate of heat production in healthy term babies is about two and one-half times the resting rate. Briick noted that infants in a cool environment were restless and often cried, but did not appear to shiver unless there was a rapid fall in rectal temperature. There was not a clear relationship between the level of heat production and the amount of muscular activity in the cold; thus, nonmuscular thermogenesis may have contributed. The increase in metabolic rate with fall in environmental temperature is approximately linear. Figure 3 shows the acute responses observed by Hey20 in a group of low-birth-weight babies (2.0 to 2.5 kg.).
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HEAT PRODUCTION AND THERMOREGULATION
•
16
o o
•
Age: 9-' 1 days
Age: 4-12 hr 32
Environmental temp. (0 0) Figure 3. The relation between environmental temperature and oxygen consumption in 15 babies 4 to 12 hours old and 9 to 11 days old weighing between 2.0 and 2.5 kg. at birth. The results obtained in small-for-date infants are indicated by closed symbols. From Hey, E. N.,'o reproduced by permission.
The cold-induced metabolic rise was similar in small-for-date and normally grown infants, both when 4 to 12 hours old and when 9 to 11 days old. Silverman and Agate,35 on the other hand, found that smaller babies « 1500 gm.); who were exposed to mild cold stress for somewhat longer periods, increased heat production more successfully if they were gestationally more mature. Again, no shivering was observed. Gestationally immature babies of comparable size often showed no response. Silverman, Sinclair, and Agate 37 also found, among small « 1500 gm.) infants exposed to minor cold stress, that those who were gestationally more mature generally maintained a somewhat higher rate of metabolism and a larger temperature gradient between deep and superficial tissues. Lees, Younger and Babson28 noted not only increased muscular activity, but also increased excretion of norepinephrine and its metabolites in small-for-date infants who showed successful homeothermic responses to environmental cold stress. A similar catecholamine response occurs in full-size infants exposed to cold stress. 31 . 43 These observations, and prior studies in the newborn kitten,30 suggest that at least part of the thermoregulatory heat production is under the control of the sympathetic nervous system, and that norepinephrine is the chemical mediator in the newborn. The site of nonshivering thermogenesis in response to cold and to norepinephrine is of obvious interest. Major attention has been directed recently to the role of cold and catecholamines in stimulating metabolism in brown adipose tissue, where catecholamine-induced enhancement of triglyceride breakdown appears responsible for thermogenesis. Smith and Roberts 42 noted that heat produced in brown fat is applied directly to the flowing blood as it passes
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to and from the cooler periphery, to the thoracocervical spinal cord, and to the vital organs of the thorax. Aherne and Hull l described the extent and distribution of brown fat in newborn human infants (Fig. 4). In the human, primitive brown fat cells begin to differentiate from reticular cells at about 26 to 30 weeks' gestational age. Development is not complete at term, for by the third to fifth postnatal week the amount of cytoplasm per cell has increased to over 150 per cent of that seen at birth. The brown fat cell possesses numerous small lipid inclusions in the cytoplasm, rather than the single large lipid vacuole characteristic of white fat. In the newborn rabbit, the metabolic response to cold and to norepinephrine is correlated with the lipid content of his brown fat. 26 The newborn rabbit whose brown fat is depleted of lipid cannot produce extra heat in response to cold, but the ability to do so can be restored by milk feeding. 18 There is indirect evidence that brown fat plays a role in the response of human babies to cold. II, 38 Heim et al. 19 compared brown fat from babies who died after having been nursed either in incubators (34 to 35° C.) or who were conventionally swaddled and nursed at room temperature (23 to 27° C.). The tissues studied from the infants nursed in the warm condition were replete with fat, whereas 83 per cent of the brown fat derived from infants conventionally swaddled showed fat depletion. It is unusual to find brown fat wholly depleted of lipid at necropsy, but Aherne and Hull l collected a small series of such cases. Prominently represented among this group were babies who were smallfor-date and who suffered total depletion of their brown fat within 3 or 4 days of birth; and, secondly, infants who were admitted to hospital with neonatal cold injury and died with massive pulmonary hemorrhage and with brown fat wholly depleted of lipid at a mean age of 8 days. Hey and
Figure 4. Distribution of brown adipose tissue in the newborn human infant, who possesses an interscapular mass lying in a thin diamondshaped sheath, smaller masses around the muscles and blood vessels of the neck, large deposits in the axillae, moderately large masses in the mediastinum, and a large mass around the kidneys and adrenals. (From Aherne, W., and Hull, D.: The site of heat production in the newborn infant. Proc. Roy. Soc. Med., 57:1172, 1964, reproduced with permission.)
HEAT PRODUCTION AND 'THERMOREGULATION
155
Katz22 documented a temporary loss of the metabolic response to cold in three infants of low birth weight who experienced both subthermoneutral environments and negative caloric balance throughout the first week of life. They suggested that exhaustion of fat stores available to brown adipose tissue could have been responsible for the temporary loss of metabolic response to cold stress. Failure of the metabolic response to cold is also seen in the smallfor-date baby with symptomatic hypoglycemia. 32 Here the defect may well be a central one, since it is known that intact central nervous system function is essential to a normal response. Babies born with severe defects of the central nervous system (e.g., anencephaly) do not increase heat production when environmental temperature is lowered. In one anencephalic studied by Cross et al.,l0 brown fat replete with lipid was demonstrated at autopsy, indicating that the failure to respond could not be attributed to lack of development of this tissue.
CLINICAL CONSEQUENCES OF COLD STRESS Chilling After Birth Routine delivery room care often results in excessive chilling of the low-birth-weight infant. With special measures to reduce heat loss (e.g., infrared heater 4 ), certain biochemical improvements may be expected: a lesser metabolic acidosis after birth,15 and a higher blood glucose concentration at 4 and 6 hours of age. s These rewards may be particularly important in the small-for-date infant. Survival Silverman et al.,36 Buetow and Klein,s and Day et al,13 all observed an increased mortality in the first days of life in low-birth-weight infants raised in incubators providing a thermal environment below the neutral range. The mechanism of the increased mortality was not determined, and no distinctive or unique cause of death was revealed at necropsy. These clinical trials were performed before much of the information about the newborn's capacity for nonshivering thermogenesis had been acquired. Consequently, some critical clinical and pathological observations were not made (e.g., lipid content of brown fat at autopsy). It is attractive to speculate that the energy cost of defending deep body temperature against cold contributes to the lethal effect (particularly in the first days of life, when the balance between caloric supply and caloric expenditure is marginal). Our expectation may be that the small-for-date infant, with deficient fat and glycogen stores, high rate of energy metabolism, and mature mechanism for increasing oxygen consumption in response to cold by nonshivering thermogenesis, is at great risk in the first days of life as regards the possibly lethal caloric penalty of cold exposure. Cold Resistance Bruck and Wunnenberg4 found that nonshivering thermogenesis is almost completely replaced by shivering within 4 weeks in guinea pigs
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reared at the neutral temperature (30 to 32° C.). Conversely, the replacement of nonshivering by shivering thermogenesis could be retarded but not completely inhibited by rearing the guinea pigs at 8° C. These observations suggest that, in guinea pigs, reduction in nonshivering thermogenetic capacity following birth is a develQpmental process that can be modified by environmental temperature. In the human baby, however, brown fat continues to develop for some weeks after birth, as does capacity for nonshivering thermogenesis, particularly in low-birth-weight babies. Glass and co-workers l6 tested the effect of varying temperature on this developmental process. They found that low-birth-weight infants, raised between 1 and 3 weeks postnatal age in slightly subthermoneutral conditions, had improved cold resistance at the end of that interval, whereas matched controls raised under thermoneutral conditions and fed isocalorically, did not. The improved cold resistance was associated with an improved capacity to increase oxygen consumption in response to a cold stress.
Growth Glass et al. 16 also explored rates of growth in low-birth-weight babies continuously exposed to contrasting thermal environments between 1 and 3 weeks after birth. Although each group received identical feeding (120 Cal. per kg. per day), the babies raised in the thermoneutral condition grew faster in both weight and length than the cooler controls. The latter were able to make up the difference when given a caloric supplement sufficient to match the calculated cost of the cold-induced metabolic rise. 17
SUMMARY Small-for-date babies have limited ability to conserve body heat because of their small size and scant subcutaneous fat. Their thermoregulatory range is considerably narrower than that of full-size babies; however, in comparison to gestationally less mature infants of similar small size, they are somewhat favorably placed because of their better developed flexor tonus, which reduces slightly the effective surface for heat loss, and their higher rates of resting heat production. The thermal sweat response matures as a function of gestational age. Infants born within 3 weeks of term show a well-developed capacity for sweating, evert though small-for-date. Similarly, capacity to increase heat production acutely in response to cold is well developed in most small-for-date infants. The cold-induced increment is accomplished partly by increased muscular activity (usually without shivering) and partly by heat production in brown adipose tissue, evidently mediated by norepinephrine. Limitation of lipid stores may terminate this response if cold stimulation is continued, and a profound fall in body temperature may result. Failure of metabolic response to cold may also be seen in small-for-date babies with symptomatic hypoglycemia. Excessive chilling in the delivery room, and cold stress in the newborn nursery, are to be avoided in the small-for-date infant, as these
HEAT PRODUCTION AND THERMOREGULATION
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stresses may lead to slower recovery from birth asphyxia, exhaustion of limited fat and glycogen stores, and increased risk of hypoglycemia. Strict thermoneutrality (exposed abdominal skin temperature maintained at about 36.5° C.) should be sought during the first week of life. Later in the neonatal period, optimal thermal conditions are less certain, for both growth in weight and length, and development of cold resistance, are sensitive to minor variations in environmental temperature.
REFERENCES 1. Aherne, W., and Hull, D.: Brown adipose tissue and heat production in the newborn infant. J. Path. Bact., 91 :223, 1966. 2. Amiel-Tison, C.: Neurological evaluation of the maturity of newborn infants. Arch. Dis. Child., 43:89, 1968. 3. Bruck, K: Temperature regulation in the newborn infant. BioI. Neonat., 3:65, 1961. 4. Bruck, K, and Wunnenberg, B.: Influence of ambient temperature in the process of replacement of nonshivering by shivering thermogenesis during post-natal development. Fed. Proc., 25:1332, 1966. 5. Buetow, K C., and Klein, S. W.: Effect of maintenance of "normal" skin temperature on survival of infants of low birth weight. Pediatrics, 34: 163, 1964. 6. Burton, A. C.: The application of the theory of heat flow to the study of energy metabolism. J. Nutr., 7:497, 1934. 7. Cornblath, M., Odell, G. B., and Levin, E. Y.: Symptomatic neonatal hypoglycemia associated with toxemia of pregnancy. J. Pediat., 55:545,1959. 8. Cornblath, M., and Schwartz, R: Disorders of Carbohydrate Metabolism in Infancy. Philadelphia, W. B. Saunders Co., 1966, p. 35. 9. Cornblath, M., Segal, S., and Smith, C. A.: Carbohydrate and energy metabolism in the newborn-an international exploration. Pediatrics, 39:582, 1967. 10. Cross, K W., Gustavson, J., Hill, J. R, and Robinson, D. C.: Thermoregulation in anencephalic infant as inferred from its metabolic rate under hypothermic and normal conditions. Clin. Sci., 31 :449, 1966. 11. Dawkins, M. J. R, and Scopes, J. W.: Non-shivering thermogenesis and brown adipose tissue in the human new-born infant. Nature, 206:201, 1965. 12. Day, R: Respiratory metabolism in infancy and childhood. XXVII. Regulation of body temperature of premature infants. Amer. J. Dis. Child., 65:376,1943. 13. Day, R L., Caliguiri, L., Kamenski, C., and Ehrlich, F.: Body temperature and survival of premature infants. Pediatrics, 34: 1 71, 1964. 14. Du, J. N. H., and Oliver, T. K: The baby in the delivery room: A suitable microenvironment. J.A.M.A., 207:1502,1969. 15. Gandy, G. M., Adamsons, K, Jr., Cunningham, N., Silverman, W. A., and James, L. S.: Thermal environment and acid-base homeostasis in human infants during the first few hours of life. J. Clin. Invest., 43:751, 1964. 16. Glass, L., Silverman, W. A., and Sinclair, J. C.: Effect of the thermal environment on cold resistance and growth of small infants after the first week of life. Pediatrics, 41 :1033, 1968. 17. Glass, L., Silverman, W. A., and Sinclair, J. C.: Relationship of thermal environment and caloric intake to growth and resting metabolism in the late neonatal period. BioI. Neonat., 14:324, 1969. 18. Hardman, M. J., Hey, E. N., and Hull, D.: Energy sources of thermogenesis in the newborn rabbit. J. PhysioI., 201 :84P, 1969. 19. Heim, T., Kellermayer, M., and Dani, M.: Thermal conditions and the mobilization of lipids from brown and white adipose tissue in the human neonate. Acta Paediat. Acad. Sci. Hung., 9:109,1968. 20. Hey, E. N.: The relation between environmental temperature and oxygen consumption in the new-born baby. J. PhysioI., 200:589, 1969. 21. Hey, E. N., and Katz, G.: Evaporative water loss in the new-born baby. J. PhysioI., 200: 605,1969. 22. Hey, E. N., and Katz, G.: Temporary loss of a metabolic response to cold stress in infants of low birth-weight. Arch. Dis. Child., 44:323, 1969. 23. Hey, E. N., and Katz, G.: The range of thermal insulation in the tissues of the new-born baby. J. PhysioI., (in press). 24. Hill, J. R, and Rahimtulla, K A.: Heat balance and the metabolic rate of new-born babies in relation to environmental temperature; and the effect of age and of weight on basal metabolic rate. J. PhysioI., 180:239, 1965.
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25. Hill. J. R, and Robinson, D. C.: Oxygen consumption in normally grown, small-for-dates and large-for-dates new-born infants. J. Physio!., 199:685, 1968. 26. Hull, D., and Segall, M. M.: Heat production in the new-born rabbit and the fat content of the brown adipose tissue. J. Physio!., 181:468,1965. 27. Karlberg, P.: Determination of standard energy metabolism (basal metabolism) in normal infants. Acta Paediat. (Stockholm), Vol. 41, Supp!. 89, 1952, p. 67. 28. Lees, M. H., Younger, E. W., and Babson, S. G.: Thermal requirements of undergrown human neonates. BioI. Neonat., 10:288, 1966. 29. Mestyan, J., Fekete, M., Bata, G., and Jarai, I.: The basal metabolic rate of premature infants. BioI. Neonat., 7:11, 1964. 30. Moore, R E., and Underwood, M. C.: Hexamethonium, hypoxia and heat production in new-born and infant kittens and puppies. J. Physio!., 161 :30,1962. 3l. Schiff, D., Stern, L., and Leduc, J.: Chemical thermogenesis in new-born infants: Catecholamine excretion and the plasma non-esterified fatty acid responses to cold exposure. Pediatrics, 37:577, 1966. 32. Scopes, J. W., and Ahmed, I.: Indirect assessment of oxygen requirements in newborn bflbies by monitoring deep rectal temperature. Arch. Dis. Child., 41 :25, 1966. 33. Scopes, J. W., and Ahmed, I.: Minimal rates of oxygen consumption in sick and premature newborn infants. Arch. Dis. Child., 41 :407, 1966. 34. Shelley, H., and Neligan, G. A.: Neonatal hypoglycemia. Brit. Med. Bull., 22:34, 1966. 35. Silverman, W. A, and Agate, F. J., Jr.: Variation in cold resistance among small newborn infants. BioI. Neonat., 6:113, 1964. 36. Silverman, W. A., Fertig, J. W., and Berger, A. P.: The influence of the thermal environment on the survival of newly born infants. Pediatrics, 22:876, 1958. 37. Silverman, W. A., Sinclair, J. C., and Agate, F. J., Jr.: Oxygen cost of minor variations in heat balance of small newborn infants. Acta Paediat. Scandinav., 55:294, 1966. 38. Silverman, W. A, Zamelis, A, Sinclair, J. C., and Agate, F. J., Jr.: Warm nape of the newborn. Pediatrics, 33:984, 1964. 39. Sinclair, J. C., and Silverman, W. A.: Relative hypermetabolism in undergrown human neonates. Lancet, 2:49,1964. 40. Sinclair, J. C., and Silverman, W. A.: Intrauterine growth in active tissue mass of the human fetus, with particular reference to the undergrown baby. Pediatrics, 38 :48, 1966. 4l. Sinclair, J. C., and Silverman, W. A., unpublished data. 42. Smith, R E., and Roberts, J. C.: Thermogenesis of brown adipose tissue in cold-acclimated rats. Amer. J. Physiol., 206:143, 1964. 43. Stern, L., Lees, M. H., and Leduc, J.: Environmental temperature, oxygen consumption, and catecholamine excretion in newborn infants. Pediatrics, 36:367, 1965. College of Physicians and Surgeons Columbia University New York, New York 10032