J. Physiol. (1969), 203,pp. 13-29 13 With 2plate and 6text-ftgurem Printedin GreatBritain THE RESPONSE OF THE SWEAT GLANDS OF THE NEW-BORN BABY TO THERMAL STIMULI AND TO INTRADERMAL ACETYLCHOLINE BY K. G. FOSTER, E. N. HEY AND G. KATZ From the M.R.C. Environmental Physiology Research Unit, London School ofHygieneandTropicalMedicine, London, W.C. 1,andtheM.R.C. Research Group on Respiration and Energy Metabolism in the Newborn, The London Hospital Medical College, London, E.1 (Received 28 October 1968) SUMMARY 1. Measurements of evaporative sweat loss were made on fifty-six premature and full-term babies 1-67 days after birth with an infra-red analyzer and a ventilated capsule placed onthe thigh. Measurements were also made of total evaporative water loss while in a closed metabolic chamber and of the regional distribution of sweating with starch-iodine paper. 2. No sweating to thermal stimuli could be detected in infants of less than 210 days post-conceptual age, even when rectal temperature rose as high as 37.8° C. In older infants sweat was detected first on the forehead andtemple, lateronthechest,andusuallyby240-260dayspost-conceptual age on the legs (term 268 days). Generalized sweating on the limbs appeared at an earlier post-conceptual age in the more prematurely born infants. 3. The response ofsweatglands onthethigh to anintradermal injection of2,tg acetylcholine (ACh) was tested. No sweat response was detected in infants under 225 days post-conceptual age, while all infants born within 2 weeks of term responded. The response was often augmented after 2-5 tests at 5-10 min intervals; all the eight infants born within 2 weeks of term who were examined twice in the first 2 weeks of life showed a greater response on the second occasion. 4. An average of 414 active sweat glands/cm2 were detected on the thigh in eight babies 7-10 days old born within 2 weeks ofterm. This was 61 timesthenumberfoundinadults. Themeanpeaksweatratetochemical stimulation was however only 2 4nl./gland.min, which was 3 times lower than the maximum rate recorded in adults. 14 K. G. FOSTER, E. N. HEY AND G. KATZ 5. In five infants with congenital defects of the brain and complete absence oftemperature control there was no sweat response to thermal or direct chemical stimulation ofthe glands. 6. Functional maturation appears to depend on intact central innerva- tion and is marginallyhastened by post-natal factors. Immaturity ofthe sweat glands can account for the lack ofany response to thermal stimuli in premature babies, but not for themodest thermal responseobtainedin babiesatterm. INTRODUCTION Recent studies have shown that in the new-born human infant total evaporative waterlossincreases to onlyalimited extent at ahighenviron- mentaltemperature, evenwhenrectaltemperaturerises ashighas 37.80 C. This limitation is even more marked in infants born more than 3 weeks before term (Hey & Katz, 1969). These findingsreinforcethegeneralbelief that thermal sweating is limited inthe human baby at birth, and that the severelypremature infant isunableto sweatat all. Wehavenowextended this workbymeasuringwaterloss from the skin directlywith aventilated capsule, and determined the effect of post-conceptual age on the ability ofthe sweat glands to respond to both thermal and chemical stimulation. A preliminary report ofsome ofthis work has been given (Foster, Hey & Katz, 1968). METHODS A total offifty-six unrestrained and unsedated healthy babies ofknown gestation were studied with the consent of their parents after delivery in the maternity wards of The LondonHospital.Theparentsofnearlyone-thirdoftheinfantsstudiedwereinthemedical or nursingprofession. Each infant's post-natal age was calculated from the time anddate ofdelivery, while post-conceptual age was takenas originating 14 days afterthe first day ofthe mother's last menstrual period. This date was confirmed by sequential neurological examination ofthe infants after delivery usingthe methods employedin aprevious study of total evaporative water loss (Hey & Katz, 1969), and by detailed assessment of the physicalappearance(Farr,Mitchell,Neligan&Parkin, 1966).Alltheinfantswereofnormal weight forgestation. The nakedinfants were studied in an incubator at various environmental temperatures while rectal temperature was monitored continuously with a thermistor. The pattern of regionalsweatingwasstudiedwithstarchpaperpreviouslyimpregnatedwithiodinevapour; thepaperwasnormallyapplied totheskinfor 30sec. Rectaltemperature wasnotallowed above 37-80 C (1000 F). A small Perspex capsule 1 cmin diameterwas secured to the skin onthelateralaspectofthethighinordertostudythesweatresponseofthisareatothermal stimuli in more detail. (This site is often employed when obtainingsweatbypilocarpine iontophoresisfordiagnosticpurposesintheneonate.Itwaschosenforthepresentinvestiga- tion because it offered an adequate flat area, even in premature babies, from which the capsulewasunlikelytobedislodgedbyspontaneousmovement.)Thecapsulewasventilated with dry nitrogen, and this gas together with any evaporated sweat then passed through SWEAT RESPONSES OF THE NEW-BORN BABY 15 acalibrated infra-redgas analyserand flowmeter at 0-1-0-3 1./mintomeasure therateand volume ofsecretion (Foster, 1966). The response ofthe sweat glands under the capsule to chemical stimulation was studied by administering 2Bag acetylcholine in 0-2ml. saline at room temperature intradermally through aneedle into the skin under the capsule (Foster & Weiner, 1967) with full aseptic precautions. Therewasnoresponsetocontrolinjectionsofsaline(Text-fig. 1b).Thepresence ofthe capsule and needle didnot appearto upset the child, though the actual injection of ACh occasionally caused the child towake and cry for afew seconds. The insertion ofthe needle caused momentary discomfort, but the procedure adopted seemed to cause less disturbance than iontophoresis ofdrugs into the skin. Care was taken to keep the site of injection as superficial aspossible inorder to elicit themaximumresponse; whencorrectly placed, each injection caused a transient circular white mark on the surface ofthe skin. Themaximumresponsewasassessedwhilethebabylayinawarmenvironmentof33-35°C witharectaltemperatureofbetween37-3and37.60C.Countsofthenumberofsweatglands activated by maximal stimulation with 2/sg AChwere made oneight ofthe infants using the method ofThomson & Sutarman (1953). A group ofeight healthy men and women were also studied for comparative purposes. Thesubjectssat, dressedintheirnormalclothes,inaroomat24-25'C. Theresponsetoan intradermal injection ofAChwasmeasured atnormal bodytemperatureusinganidentical technique. Estimates of the infants' total evaporative water loss and heat production at various environmental temperatures werealso obtained atleast once onallbutnine ofthe babies, usingthemethoddescribedbyHey&Katz(1969).Directmeasurementsofheatflowthrough theskinweremadeintwenty-seveninfantswithaheat-flowdisk(Hatfield& Wilkins, 1950) on the back ofthe hand, while the whole arm was surrounded by a thermostated water- jacket maintainedat aconstanttemperature. Five other infants with gross congenital abnormalitieswere seenafter admission to the hospital for observation. The parents of these babies also gave their consent to all the experimental proceduresundertaken. Theabilityoftheseinfantstocontrolbodytempera- turewasstudiedcomprehensively, buttheywereonlyexposedtoarangeofenvironmental temperature similarto thatwhichtheycouldexpectto experienceinahospitalnurseryor athome. Infour ofthefiveinfants Quinizarinpowder (Guttman, 1937, 1940) was used to detectathermalsweatresponse.Theresponsetopilocarpineiontophoresis(Gibson& Cooke, 1959) wastestedinall fiveinfants. Twoinfantswithlumbarmeningomyelocoelewerealso studied. RESULTS The thermal response No sweating could be detected in healthy infants ofless than 210 days post-conceptual age (term 268 days) in an environment of 36-37' C, even when rectal temperature rose as high as 37.8° C. Tests with starch- iodine paper and Quinizarin powder were all negative, andnorise in total evaporative water loss occurred. Direct measurement ofheatflow showed, however, thattheinfantswereableto controlheatlossfromthehandeven at this early age (presumably by changing skin blood flow). The infants were also capable ofincreasing their heatproduction in cool surroundings. A significant rise in total evaporative water loss always occurred in infants of more than 220 days post-conceptual age tested at comparable temperatures, and sweating could always be detected onthe forehead, the 16 K. G. FOSTER, E. N. HEY AND G. KATZ anterior part ofthe scalp and the temples. Aprogressive increase occurred in the number of areas where sweat could be detected in infants of over 230 days post-conceptual age, and there appeared to be an increase in the magnitude of the response in the areas tested. A response was usually detected on the shoulders and chest before it was found on the limbs. In the majority of infants born within 2 weeks of term sweating could be detected over most ofthe exposed areas ofthe body 4-14 days afterbirth. 0-3 Sweatsecretion(al./min) (a) 02( 2Pg ACh s Restless Sleeping Crying Coolair Sweatsecretion (al./min) 0 4 8 (b) 0-06 = = s Ui 0-03 U UU U U Xo DoboU0 b Text-fig. 1. Records oftherateandvolumeofsweatsecretionbeneathaventilated capsule 1 cmindiameterplacedonthelateralaspectofthethighoftwonew-born babies. (a) The response on the ninth dayafter birth ofa 3-7kg infant born 2weeks beyondterm.Thereisalargeresponseto2jugintradermalAChin02ml.saline.An abnormally large thermal response appeared when rectal temperature exceeded 37.-3 C;thisirregularresponsewasaugmentedwhenthebabywokeandcriedbriefly butceased promptlywhencool airwas blown overthe whole body. (b) Theresponseontheeighthdayafterbirthofa2-7kgSinghaleseinfantborn 1weekbeyondterm.Therewasnothermalresponseevenwhenrectaltemperature exceeded37.8 C(aresponsewaspresent1weeklater).Therewasnoresponsetothe firsttwointradermalinjectionsofAChandanincreasingresponsetothreefurther injections. Therewasnoresponsetoanequalvolumeofsaline (thesmallresponse seen after the first ofthe two saline injections is assumed to be due to the small amount ofAChleftinthelumen oftheindwelling needle). Sweat always appeared most profuse on the forehead; it was often de- tectedtherewhentherectaltemperaturewas only a little above 370 C and before sweat was evident anywhere else on the body. A particular analysis was made of the sweat response on the lateral aspect ofthe thigh: there was good general agreement between the results obtained with starch-iodine paper and the results obtained with the ventilatedcapsule. Mostinfants bornwithin 2 weeks ofterm sweatedhere. Occasionally therewas a latent periodduringwhich temperature was high but apparently constant before the thermal response appeared. The response obtained on the thigh was characteristically irregular; it was often initiated or augmented when the child became restless or cried SWEAT RESPONSES OF THE NEW-BORN BABY 17 (Text-fig. 1a), but sweating appeared to cease abruptly when cool air was blown over the body. Most, but not all, infants of more than 260 days post-conceptualagesweatedslightlyonthethighbeforerectaltemperature rose to 37.80 C. In infants born several weeks before term, the response appeared on the thigh at an earlier post-conceptual age; these infants when tested more than 2 weeks after birth began to sweat about 240 days after conception (Text-fig. 2). It seems clear that the onset of a thermal responseonthethighisrelatedtobothpost-conceptualandpost-natalage; tests with starch-iodine paper suggested that other areas ofskin behaved in a similar way. The highest rate of secretion at a rectal temperature of 37.6-37.8° C varied with post-conceptual age in the manner outlined in Text-fig. 3a; 0 Lessthan 2weeks 00 o 0000@o°@o0-- after birth 0 000 00000000 More than 2weeks o 00 Oreo** ... after birth 00000 0 Term I Post-conceptual I I I I I I I age (days) 180 220 260 300 Text-fig. 2. The thermal response on the thigh under the ventilated capsule in infants of differing post-conceptual and post-natal age. Rectal temperature was 37 80 Cexceptinafewinfantswhosweatedprofuselyatalowerrectaltemperature. *,Secretionofsweattothermalstimulidefinitelyrecorded; 0,not observedatthe highesttemperatureemployed.AX2testonthetwenty-threeresults obtainedfrom babies between 239 and 259 days after conception indicated that the onset ofa thermal response was related to post-natal age as well as post-conceptual age (P = 005). the peak rate recorded in fifteen infants 1-14 days old born within 2 weeks of term was 0-109+0-031 ,il./cm2.min (mean +S.E.). Such rates of secretion were, however, usually only detected while the child was crying and active, and were seldom maintained for more than a few minutes; little sweating was observed on the thigh at this temperature when the infants were quiet, in contrast to the fairly copious sweat response detected on the head, and, on occasion, the trunk. The sweat rates in Text-fig. 3a maybe comparedwitha calculatedestimate forbasal transepidermal water loss of a little over 0-01 /td./cm2.min under most conditions oflow airmovement andnormalhumidity (Hey & Katz, 1969). Response to acetylcholine The response ofthe skin on the thigh ofeach baby was also tested to an intradermal injection of 2 ,ag ACh in 0-2 ml. saline. This strength ofdrug was selected because studies had shown that although secretion was pro- 18 K. C. FOSTER, E. N. HEY AND G. KATZ longed by a larger dose in adults, the rate of secretion recorded under a capsule 1 cm in diameter only increased by an average of 7-5 % after injection of 20jtgACh (Table 1). Tests on seven babies failed to demon- strate a significantly greater maximum rate of secretion after the intra- dermal injection of 20 instead of 2/tg ACh in the same volume ofsaline (Table 1). Noresponse to ACh was detected on the thigh ofinfants under 225 days post-conceptualage,whiletheresponseofinfantsbetween225and250days old was variable (Table 2). However, all infants born within two weeks of term (between 254 and 282 days after conception) and tested within TABLE 1. Themaximumsweatrateinadultsandbabiesrecordedwithaventilatedcapsule 1 cm in diameter after an intradermal injection of 2 or 20Itg ACh in 0-2ml. saline. Mean results (+±S.E. ofmean) Full-term Healthy babies 3-10 adults 18-36 days old years old Number ofsubjects ... 7 7 Response to 2/tg ACh (,ul./min) 0-214+0-078 0-377+0-058 Response to 20jug ACh (/zl./min) 0-238+0-083 0-405+0-061 Mean paired difference in 0-024+0-011 0028+0-011 maximum sweatrate Significance ofthis difference P 007 P < 0-05 14 days ofbirth responded to this stimulus, though the maximum rate of secretion variedgreatly (Text-fig. 3b). In many ofthe infants theresponse to the first injection was small but an augmented response was obtained after 2-5 tests were performed at 5-10 min intervals (Text-fig. lb). No sex differences were detected. Ineight mature infantsthe response to ACh was tested twice in the first 14 days after birth when rectal temperature was 37 437 6° C. In each case the response was greater on the second occasion (Text-fig. 4) andin five ofthe infants the increase was significant at the 5% level. Sweat-gland counts were made in four ofthe infants: the increase in response with post-natal age could not be accounted for by changes in the number ofactivated glands. Infourteeninfantsbornwithin 2weeks oftermthetestwasundertaken inthe first 2 weeks afterbirth both atnormalbodytemperature, whenthe child was vasoconstricted, and at high temperature on the same occasion while vasodilated. The order ofthe tests was random; in the majority of the experiments heat flow through the hand was measured continuously during the study. The secretary response was slightly greater at high rectal temperature in ten of the fourteen studies (paired variate test: P < 0-01); the mean difference was 0-04/Ll./min. There was a clear correlation between the highest rate of secretion recordedunderthecapsuleinresponsetothermalstimuliandthemaximum rate achieved in response to 2 fig ACh. However, the response to ACh SWEAT RESPONSES OF THE NEW-BORN BABY 19 always exceeded the response to thermal stimuli with rectal temperature between 37X6 and 37.80 C. Sixteen infants who responded slightly to 2,ag AChdidnotrespondtothehighestthermalstimulus applied; the converse never occurred. 0* 04 0.3r * W 4D0_ a- a _ '- 0-3 * m2 00*00 - 2 * 0 0 00W 02 00 0 (a) 00 0-1I. (b) 0 .0..0 -I1C1Rs. WW0k.0*-10 oL0...l..i-2 m2o0 a 0*000~0~~~~~~~g1~~.+~o~~ 0 0 00%0&*00 0:00o 200 250 !trm 300 200 250 t 300 T Term Post-conceptual age (days) Text-fig. 3. The relation between post-conceptual age and the maximum rate of sweat secretionbeneath aventilated capsule on the lateral aspect ofthe thigh. (a) Maximumresponsetothermalstimuliinpul./cm2.minatarectaltemperature of37.6-37-8° C in full-term and premature infants 1-14 days old. Responses this largewereonlytransientlyrecorded. Theenvironmentaltemperaturewasbetween 360 and 370C. (b) Maximumresponsetoanintradermalinjectionof2jigAChin02ml. saline. Sincethereisevidencethatthisstimulusactivatedtheglandsinonlyasmalland variableareaofskinunderthecapsuletheresponsehasbeenexpressedasgl./min. The conditions were as defined in Table 2. *, Full-term and premature infants 0-14 days old; 0, premature infants 15-67 days old. TABLE2.Themaximumsweatresponserecordedafteranintradermal injectionof2jugACh in 0-2ml. saline into the lateral aspect ofthe thigh in premature and full-term new-born babies. The tests were undertaken in a warm environment of 33-35°C when the rectal temperature was between 37.30 and 37-6°C. Meanresults (±s.E. ofmean) Subjects Total sweat Duration of Maximum volume response sweatrate Group Number (Ud.) (min) (Pl./min) Babiesborn43-70 6 0 0 0 daysbefore termand 1-14 days old Babiesborn 14-42 12 0-076+0-029 36+0-8 0-026+0-012 daysbefore termand 1-14 days old Babies bornwithin 13 0-263+0-087 4-9+0-4 0090+0-025 14 days ofterm when 12-72 hours old Babies bornwithin 20 0-491+0-072 6-6+0-4 0-158+0-021 14days oftermwhen 4-14 days old 20 K. C. FOSTER, E. N. HEY AND a. KATZ The response to intradermal AChininfants bornwithin 2 weeksofterm wasalso comparedwiththeresponseobtainedinyoungadults. Thevolume ofsweat secreted was very much greater in the adults, the sweat response persisted for very much longer, and the maximum rate ofsecretion under the capsule was almost always higher (Text-fig. 5). The mean differences were significant at the 0.1% level (Table 3), but this could have resulted from a difference in the way the injected drug spread or was inactivated, 003 c 02 0 9 0-1 0 0 0 5 10 is Post-natal age (days) Text-fig. 4. The effect ofpost-natal age on the maximum rate ofsweat secretion after an injection of2Iug ACh in 0-2ml. saline. Results obtainedin eightinfants bornwithin 2weeksoftermwhowere studiedtwiceundercomparable conditions in the first 2 weeks after birth. The vertical bars indicate the s.E. ofthe means (0) wheren 3 4. rather than a difference in the responsiveness of the glands. The brief response in the baby was certainly not the result ofglandular exhaustion because the response to a further immediate injection was normal (Text- fig. 1b). The number ofactive sweat glandsunder the capsule was counted afterthe injection of2lagACh ineightbabies andeightadults. Therewere 61 times asmany active glands in the babiesper unit surface area, butthe glands were activated over a wider area ofskin in the adults (Plates 1, 2). Infants with developmental defects ofthe c.N.s. Five mature infants were seen who had severe congenital defects ofthe brain: one infant was anencephalic, one had severe hydranencephaly, and three had large occipital encephalocoeles and microcephaly. The infants neither shivered, became active, norincreasedtheirheatproductionabove basal when exposed to a cool environment; no change in the thermal con- ductivity ofthe skinoccurredinresponseto changes inenvironmental and body temperature. It is likely that these observed defects oftemperature .<. 1 ~~~~~~~~~~~~~Min. SWEAT RESPONSES OF THE NEW-BORN BABY 21 control were caused by some derangement of the brain mechanisms in- volved in temperature regulation. The five infants failed to sweat anywhere on the body in response to thermal stimuli, and the total evaporative water loss neverrose above the normal basal leveleven athighenvironmental andbodytemperature. The E 0-6 -7 . 2#egACh0 4 8 o 0-4 0 0-2 u 02. U, Text-fig.5.Recordsoftherateandvolume ofsweat secretion beneathaventilated capsule on the lateral aspect of the thigh, showing the typical response to the intradermalinjection of2jugAChin0-2ml. salineinanadult (-)andinanormal 8-day-oldinfant (......). Thenumberofglandsactivatedunderthecapsuleinthese two subjects byinjection ofACh isrecordedinPlates 1 and 2. TABLE 3. Comparison of the sweat response to an intradermal injection of 2Iug ACh in adults and in new-born babies. The records were obtained from the lateral aspect ofthe thigh usingaventilated capsule 1cm indiameter. Mean results ( s.E. ofmean) Full-term Healthy babies 7-10 adults 17-34 days old yearsold Number ofsubjects ... 8 8 Total sweatvolume (1A.) 0-52+0-10 3-66+0-34 Duration ofresponse (min) 6-2 +0-4 19-1 +1-3 Maximum sweatrate (gl./min) 0-17+0-03 0-35+0-03 Estimatednumber ofactive sweat 414+49 64+6 glands per cm2 Estimated number ofglands 98+25 48+4 activated under the capsule by injection of2/esgACHin 0-2ml. saline Maximum sweatrate per activated 2-40+0-57 7-51+0-63 sweatgland (nl./min) infantsalso failed to secreteanysweatWhen testedwith pilocarpine onthe thighonatleasttwooccasions. Boththechildrenwhoweretestedalsofailed to respond to injections of 2, 20 or 200,ug ACh in 0-2 ml. saline into the skin of the thigh under a ventilated capsule. The four youngest children have since died. No abnormalities were found in the sympathetic nervous system, the skin, or the sweat glands at autopsy. Two other full-term infants were seen who had lumbar meningo- myelocoeles and a complete flaccidparalysisofthelegs.Whereasthesweat glands on the arm responded to both thermal and chemical stimulation, those on the leg responded to neither. 22 K. G. FOSTER, E. N. HEY AND G. KATZ DISCUSSION Sweat responses at birth Uchino (1939a, b) failed to detect sweating on the chest to thermal stimuli onthe first day oflife,butsweatingwasrecordedbythe fourteenth day after birth in twenty-seven out offifty-seven full-term infants. None of the five premature infants born 3-6 weeks before term sweated until at least 13 days after birth. Bruck (1961), however, reported that in nine full-term infants studied on the first day of life 'beads of sweat appeared on the forehead at rectal temperatures between 37X5 and 37.90 C; in three cases sweat was also observed on the arms, legs and trunk'. Adamsons, Gandy & James reported similar observations in 1965. Again, all the infants born within 3 weeks ofterm studied by Hey & Katz (1969) on the day ofbirth were able to more than double their total evaporative water loss when rectal temperature rose above 37.50 C. It has been thought that these reports conflict with those of Uchino, butthefindingsare notnecessarilyinconsistent. Theobservationsreported here indicate that sweating nearly always occurs first and most profusely on the head, and only later on the trunk and limbs to any significant extent. In several ofthe infants studied here and born within 2 weeks of term no sweat was detected on the chest or limbs using starch-iodine paper, and none recorded under the capsule on the thigh, until the infant was several days old, although the rectal temperature was taken as high as 37.80 C. In other infants generalized sweating was seen on the day of birth, but only when rectal temperature rose above 37.5° C; in many of Uchino'sstudies rectal temperature neverrose above thisvalue during the first few days. We may conclude that all full-term babies were capable of sweating on the day ofbirth, but that thermalsweatingwasmoregeneral- ized and occurred at a lower body temperature in infants a few days old. The sweat response to thermal stimuli ofbabies bornmore than 3 weeks before term was small, and largely limited to the head. The change in response to thermal and chemical stimulation summarized in Text-fig. 3 closely parallels the increase in total evaporative water loss at high environmental temperature with increasing post-conceptual age (Hey & Katz, 1969, Fig. 10). Seven infants capable ofsweating ontheheadwhen hot did not respond to intradermal ACh on the thigh, but this appears to be related to the fact that babies sweat on the head to thermal stimuli at an earlier post-conceptual age than elsewhere onthe body. Every baby that sweated on the thigh to thermal stimuli also responded at the same site toACh. That the converse didnothold suggests that 2 ,tg intradermal AChwasamoreeffective stimulusthanthehighesttemperatureemployed. Uchino (1939a, b) found a clear and persistent sweat response in full-
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