EFFECT OF THE THERMAL ENVIRONMENT ON COLD RESISTANCE AND GROWTH OF SMALL INFANTS AFTER THE FIRST WEEK OF LIFE

(1)

(Received October 16; revision accepted for publication December 28, 1967.)

Aided by a grant from the U.S. Public Health Service HD 00540.

WAS. is career investigator of the Health Research Council of the City of New York (Contract 1-181); J.C.S. is supported by the Research Career Development Award of Public Health Service (No. 1 K3 IID-34, 992-01).

ADDRESS: (W.A.S.) 630 West 168th Street, New York, New York 10032.

PEDIATRICS, Vol. 41, No. 6, June 1968

1033

ARTICLES

EFFECT OF THE

THERMAL

ENVIRONMENT

ON

COLD

RESISTANCE

AND

GROWTH

OF

SMALL

INFANTS

AFTER

THE

FIRST WEEK

OF

LIFE

Leonard Glass, M.D., William A. Silverman, M.D., and John C. Sinclair, M.D.

Department of Pediatrics, College of Physicians and Surgeons, Columbia Unicersity;

Harlens Hospital Center, New York

ABSTRACT. Twelve matched pairs of small (1,001-2,000 gm birth weight) asvmptomatic neonates, age

1 week, were placed in either of two frequently recommended thermal environments (“standard”: abdominal skin controlled at 35.0#{176}C to

approxi-mate the thermal state comrrionlv realized in

nurs-eries for l)remattlre infants; “warm”: abdominal skin controlled at 36.5#{176}Cto approximate thermo-neutral condition). Both groups were fed 120 calories/kg/day.

Before and after 2 weeks in the test environ-ment, the infants were placed in a simulated

room environment-28 #{176}C incubator wall-for 1

hour and the change in body temperatures was measured.

Cold resistance-the ability to prevent a fall of deep body temperature in the 28#{176}Cenvironment-was significantly greater among infants who had spent 2 weeks in the slightly cooler environment. The rate of increase in body weight and length was significantly faster in the warmer condition.

Pediatrics, 41:1033, 1968, PHYSIOLOGICAL

ADAPTA-TION, BODY TEMPERATURE, ENvIRONMENT, GROWTH,

PREMATURE INFANT.

T

HERE is convincing evidence’3 that the

rate of survival among small infants iii

the first few days of life may be favorably

influenced by raising them in environments

which make relatively small demands on

their thermoregulatory capabilities.

How-ever, there is considerable uncertainty

about the effects on babies when ambient

conditions are maintained close to

thermo-neutral for extended periods beyond the

first week of life. Asymptomatic small

in-fants are very often reared in incubators

maintained at an arbitrary level of air

temperature’ which is somewhat below the

thermoregulatory limit of most small young

patients (i.e., rectal temperatures below

30-37#{176}C). Since systematic studies have not

been carried out, there is also uncertainty

about the physiologic effects of this common

practice.

Studies in experimental animals suggest

that temperature acclimations,6 and

growth’8 in the postnatal period can be

modified by the external environment. The

present studies were undertaken to

deter-mine whether similar effects could be

de-tected beyond the first week of life in small

human infants maintained in two

fre-quently recommended thermal

environ-ments. The results indicate that cold

resis-tance was greater after 2 weeks in the

slightly cooler environment; growth was

slightly faster in the warmer of the two

conditions.

SUBJECTS AND METHODS

Eighty-three small infants (1,001-2,000

gm birth weight) born in Harlem Hospital

between November 1966 and April 1967

were taken to the premature nursery and

housed in Isolette incubators; air

tempera-tures were mainained at 33-34#{176}C (mercury

thermometer in Model C-86 Isolette

incuba-tor), water reservoirs were filled, and

humid-ity controls were turned to “full.” Appropiate

(2)

“Standard” Infant “Varin” Infant

Ages

Birth Weight (gui)

PairCategory Birth

Number* (Table 1) JJ’eight

(gin)

I Cl 1,990

C II 1780

3 C III 1,790

4 BIll 1,330

3 Clii 1,760

6 All 1,050

7 AIll 1,160

8 Al 1,50

9 C lii 1,560

10 B Ill 1,450

11 III! 1,40

12 CI 1,910

G.A.t Ages

G.A.t

36

2

40

158

158

157

173 189

190

168

177

168

151

199

192

1,660

1,700 1,690 1,370 1,730

1,160

1,110

1,080 1,710 1,380

1,490

I,530

39

80

2

30

31

40

169 185

166

169

160

171 164 207

154

197

196 03

*Order of admission of first member of pair. t Gestational age in completed weeks.

Age (in hours) on enrollment.

TABLE I

BIRTH %V:mc IIT-( ESTATIONAL AGE* CATEGORI ES

Weight-for-(x’estational Age

Birth Weight (gin) Total

Number of Pairs

-1 ,(X)-1--1 ,250 1,251-1,500 1,501-2,000

Pat A! HI CI

(number of pairs) (1) (0) () 3

>P All Bil CII

(number of pairs) (1) (1) (1) 3

Unknown

G.A4 A Ill B III CIII

(nulnber of pairs) (1) () (3) 6

Total Number of pairs 3 3 6

* (iA. = Number of completed weeks from first day of last menstrual period.

t At or below 5th percentile (P23) according to Baltimore nitra-uterine growth standard;9 twins classified using the same standard.

age colisidered unknown when mother did not recall exact day of onset of last menstrual period.

(Similac with iron, 0.67 Cal/ml were

of-fered; the volume was increased as tolerated.

At the age of 1 week, infants with birth

weights from 1,001-2,000 gm, whose course

had been uneventful (i.e., no

manifesta-tions of illness, no adverse findings on

phys-ical examinations, and satisfactory

respira-tory and gastrointestinal performance),

were considered eligible for enrollment in

the trial if a specially equipped study

incu-bator was unoccupied. Twenty-six infants

satisfied these criteria; the conditions of the

trial were explained to one or both parents,

written permission was obtained, and the

TABLE II

(3)

Apgar Score 0-4

5-10 Sex

10

male female

7

3

Route of delivery vaginal cesarean ARTICLES

9

3

candidates were admitted to the study at

ages ranging from 154 to 207 hours.

Enrollees were classified according to

birth weight and gestational age into nine

possible categories

(

Table I), and within

each class the infants were paired at

ran-dom. One member of each pair was

as-signed to the “standard” condition, and his

match to the “warm” incubator according to

a prearranged order in sealed envelopes

which were opened ad seriatim as each

in-fant satisfied the enrollment criteria. Two

infants, both in the “standard” group, were

removed from the study prior to completion

of the trial conditions; one infant developed

gastroenteritis (salmonella) and the other

developed (suspected) septic pyarthrosis.

The study was arbitrarily terminated when

24 infants (12 matched pairs) completed the

trial; the characteristics of these babies, who constitute the study population of the

present report, are given in Tables II and

III.

Before being placed under the assigned

study conditions, all infants underwent a

1-hour cold-resistance test which consisted

of transferring each enrollee to an Isolette

incubator (pairs numbered 1 to 7, 11 and 12)

or closed-circuit respirometer’#{176} (pairs

num-bered 8, 9, and 10) which had been

stabi-lized at an inner side-wall temperature of

28#{176}C(range 27.7 to 28.4#{176}C), a condition

which was considered to simulate the

ther-mal state in the “average room.” The

in-fants were placed in the supine position on

a nylon mesh cradle, and a pacifier was

used to placate babies in the incubator if

they became restless (this could not be

done for the three pairs in the

respirome-ter, but muscular activity in these infants

was watched for and noted when present).

By means of an Elab Electric Universal

Thermometer (type TE3) and

thermocou-ple sensors suspended in the air, taped to

surfaces, and inserted in the colon,

temper-atures at various sites were measured at 0,

30, and 60 minutes in the test environment.

The sites measured were: incubator air (6

in. above the infant), inner side wall of the

incubator (at the same level as the air

sen-sor), anterior abdominal wall (midway

be-tween the umbilicus and xiphoid), colon

(5 cm beyond the anal sphincter), left

axilla (with upper arm bound to the side),

dorsum of the left foot, and interscapular

area (midline at the most cephalad level of

the scapula). Cold resistance was judged

by the relationship between the total

gradientl 1-temperature gradient from the

colon to the incubator wall (T

-

T,,. )-at

the beginning and at the end of the

60-min-ute test period, expressed as an index:

Te, - T

X 100 = cold resistance

T0 - T index (CIII).

An index of 100% indicated “maximum”

re-sistance (i.e., no reduction in colon-to-wall

gradient after 60 minutes of exposure to

sim-ulated room conditions). The relative

warmth of the interscapular area at the end

of the cold resistance test was evaluated by

examining the relationship between the

temperature gradient from the colon to the

interscapular (nape) area (C - N) and the

total gradient (colon-to-incubator vall, C

-W) expressed as a ratio:12

C-N

= H

C

-A low ratio indicated a relatively warm

interscapular area (i.e., at the end of cold

TABLE III

1)ISTHIBUTION OF CIIARACTERISTICS

(4)

LEVELS OF AxILI.AI4Y (‘F8) AND INCUBATOR AIR (T,) TEMI’ERATUIIES DURING TIlE ‘2WEEK STUDY

PERIOD BETWEEN AGES IAND 3 WEEKS

“Standard” Infant

Patient

Number

‘V1

“.9 T

36. St

36.6 36.5 36.9 36.6

36.6

36.6

36.’2

36.6

36.5

36.3 36.3 36.3

T8ir

‘29.9 31.9 30.7

.4 33.4 33.0

#{149}‘2

31.9 3’2.7

34.‘2

.7

33.7 .8 33.8

1 ,‘251-1 ,500

1,001-I ,‘250

36.3 33.7

* Pairs numbered in order of admission of first member and arranged in this table ill order of decreasing mean birth weight of tile pairs.

t Gd means of means of daily ranges, in #{176}C.

1036

TABLE IV

Birth IJ’eight

(;rp (Gui) Patient

Number*

1,501-2,000 $

$5 53

$12

SI

59

Group Median

511

510

54

Group Median SO

57

56

Group

Mediaii

“JJ’ar,n” Infant

T,1,

37.0 35.1

37.0 33.9

37.0 34.7

37.’2 33.6

37.0 35.’2

37.1 33.5

Group

Median 37.0 34.3

WI1 37.1 35.0

W,o ‘37.1 35.’2

36.8 33.4

Group

Mediami 37.1 ‘35.0

W’0 37.1 34.7

37.1 35.5

“6 37.0 ‘35.3

Group

Median 37.1 35.3

resistance test the colon-nape difference is

small as compared with the total drop of

temperature between colon and wall).

Infants assigned to the “standard”

con-dition were placed in Isolette incubators

equipped with conventional air heaters and

proportional-type servo-controllers.

An-terior abdominal wall temperature (TsA)

was controlled at 35#{176}C,a level which

ap-proximated the TSA most frequently

ob-served in a preliminary survey of

asympto-matic infants (age > 1 week) receiving

standard care in the premature nursery of

Harlem Hospital. Infants assigned to the

“warm” category were placed in similar

study incubators set to control TSA at

36.5#{176}C, which was considered to

approx-imate a thermoneutral condition.13 All

babies remained unclothed during the trial

except for a diaper.

The infants were weighed by the same

nurse on enrollment, twice each week

(Mondays and Thursdays), and before each

cold resistance test. Weights were taken in

a routine manner (% hour before the first

feeding which was scheduled on the nurses’

day shift, nude, on a Continental Scale

#322KG) and recorded to the nearest 10

gm. The volumes of milk feedings (Similac

with iron, 0.67 Cal/mi) were adjusted

semi-weekly on the basis of the observed weights

to provide all infants with approximately 120

Cal/kg/day. The amounts of milk retained

at each feed and regurgitation or vomiting

were recorded; there were no systematic

(5)

L

COLD RESISTANCE INDEX

Effect of two thermal

Age week to age

environments.

3 weeks.

INTRA- PAIR

STANDARD VS

WARM

S W

#{149} 0

S #{149}

#{149} 0

5 0

S

0 0

0

where

0/

I0

+

11.0-+ 10.0-+

9.0-

+8.0-w

+7.0-+6.OH

+4.0

+30 +2.0 10

+1.0

N,

W 0

-1.0

-2.0

-3.0

-4.0

-5.0

-6.0

CRI(%) - Tc-Ti

- Tc0-Ti X 100

CRI = CRI3-CRI1

Fic. 1. Change in cold resistance index after 2 weeks under the trial conditions. Individual changes (Table V) and intra-pair differences in

change (Table V) are shown here arranged in

serial order by sign and magnitude; medians are

indicated by cross-bars (-) and zero change or

difference is indicated by the horizontal dashed lines. Median change (and range) of CR1 (in %) for groups: “standard” = +3.8% (-0.1 to +10.8)

“warm” = -0.7% (-5.0 to +9.6). Two sample

ranks test (\Vilcoxon-White) :15 sum of ranks,

“standard” 181, “warm” 119; P < 0.10. Median intra-pair differences (and range) of “standard”

minus “warm” change in CR!: +4.1% (-2.0 to

+7.0). Signed ranks test (Wilcoxon):15 sum of signed ranks, +76; P < 0.01.

by infants in the two study groups.

Semi-weekly measurements of length

(

crown-to-heel

)

and head circumference were

ob-tamed by the same physician and recorded

to the nearest 0.5 cm. The rate of weight

gain of each infant during a 2-week study

period was expressed as the daily rate of

in-crease (i.e., the “compound-interest”

growth rate), calculated from the linear

re-lationship between log body weight and

age:

x

ioo

= growth rate (as

%

of current

log e weight per (lay)

where

b = regression coefficient of log1 weight

(kg) on age (days)

e = base of the natural logarithm; log10

e = 0.43429.

Increase in length (crown-to-heel) of

each infant during a biweekly study period

‘as also expressed as a

“compound-inter-est” growth rate (instantaneous relative

growth rate’4):

log L, - log L1 = growth rate (as

%

of

(log e) (t) current length per day)

L, = crown-to-heel length (cm) at age 3

weeks

L1 = crown-to-heel length (cm) at age 1

week

t = elapsed time between measurements

(days)

During the course of the trial, axillary

temperatures and incubator-air

tempera-tures were recorded four times each day.

Infants under “standard” conditions

exhib-ited mean axillary temperatures between

36.2 and 36.9#{176}C (Table IV); there was a

minor, but systematic, variation with birth

size from a median of 36.3#{176}Cfor the group

of smallest infants to 36.6#{176}Cfor the group

with highest birth weights. Under “warm”

conditions mean axiflary temperatures

ranged from 36.8 to 37.2#{176}C,with no

(6)

in-One JVeek

Matched

_______

Pairs* (1) (2)

T 7’,

Si ‘28.1 37.5

‘28.1 36.6

S1 ‘28.1 36.8

W1 27.7 36.9

S, 28.1 36.9

28.0 36.8

S2 ‘27.8 37.4

W, 27.8 37.5

Change in Cold

Resi.otance (3) T60 36.4 35.8 36.4 36.1 36.2 35.9 36.3 36.6 (4) CR!1 wk 88.3 90.6 95.4 91.3 92.1 89.8 88.5 90.7 (5) 27.9 27.9 28.1 ‘28.1 28.1 ‘27.9 28.1 28.1 Three JJ’eek8

(6) (7) (8)

T,0 T,60 CR!, wk

37.6 36.8 91.8

37.4 36.6 91.6

36.7 36.3 95.3

37.5 36.4 88.3

37.6 37.0 93.7

37.2 36.2 89.2

37.6 36.9 92.6

37.5 36.5 89.4

(6) (10) CR! S-JVcj +3.5 25 +1.0 +2.9 +2.2 +5.4 SI “2 S9 S11 SI0 ‘Vie $4 “4 S8 ‘Vs Si Wi 27.9 28.4 ‘28.2 27.8 27.8 27.9 28.0 28.1 ‘28.0 ‘28.0 28.0 28.1 28.0 28.0 37.7 36.5 37.3 36.6 37.0 37.1 37.2 36.6 37.0 37.1 38.0 37.4 37.8 35.3 36.5 35.5 36.5 36.3 36.1 36.2 36.5 35.7 35.5 36.5 36.0 35.8 35.6 34.1 87.8 87.7 91.2 96.6 90.2 90.2 92.4 89.4 83.3 93.4 80.0 82.8 77.6 83.6 28.2 28.0 28.1 ‘28.0 27.8 28.1 ‘28.0 28.1 27.7 28.0 28.0 28.1 28.2 28.0 37.6 37.6 37.3 37.7 37.5 37.6 37.6 37.6 37.3 37.0 37.4 37.8 37.6 37.6 37.0 93.6 36.3 86.3 36.6 9’2.4 36.9 91.6 36.7 91.8 36.6 89.5 37.1 94.8 36.5 88.4 36.6 92.7 36.8 97.8 36.2 87.2 36.3 84.5 36.5 88.3 36.6 89.6 36.1 83.5 36.1 86.2 +5.8 -1.2 +7.0 +1.2 -5.0 +6.2 +1.6

-___

-0.7 +2.3 +‘2.4 -1.0 +3.4 +9.4 -+4.4 +5.0 +7.2 +1.7 +5.5 +I0.S +6.0 +4.8 +7.6 +9.6 -2.0 $6 V6

28.2 36.5 34.5 75.9 28.0

27.9 37.3 35.1 76.6 28.0

37.7

37.4

(I) T = Mean temperature wall (#{176}C)at onset of test. (2) T,0 = Colonic temperature (#{176}C)at onset of test. (3) T,60= Colonic temperature (#{176}C)at end of test.

(4) CR11 wk = (2) - X 100 = cold resistance test at age 1 week;

* Pairs are numbered in order of admission of first member and arranged in this table in order of decreasing mean

birth weight of time pairs.

TABLE\’

COLD RESISTANCE TESTS

colon to wall gradient at end of test divided by C-W gradient at onset expressed as per cent;

CHI3Wk = X 100

(9) CRI = (8) -(4) = change in cold resistance between ages 1 and 3 weeks.

(10) S-W’CR, = (9)- (9)w = intra-pair difference (“standard” minus “warni”) of change in Coi(l resistance

(7)

TABLE VI

RELATIVE WARMTH OF INTERSCAPULAR AREA AT END OF COLD RESISTANCE TESTS

Matched Pair.e*

One Week Three Week8 Changeof Gradientsin Ratio

(1) C-W (2) C-N (3) R1 (4) C-W (P5) C-N (6) R, (7) Ratio (8) S - WRaI,

Si \V1 8.3 7.7 0.8 1.0 .096 .130 8.9 8.7 0.5 1.3 .056 .149 - .040 +019 o 9 SO \\5 8.3 8.4 0.9 1.2 .108 .143 8.2 8.3 0.5 1.0 .061 .120 - .047 - .023 024 ‘ 53 \V3 8.1 7.9 0.7 0.9 .086 .114 8.9 8.3 0.4 1.0 .045 .121 - .041 +007 04 #{149} 512 W12 8.5 8.8 1.0 1.0 .118 .114 8.8 8.4 1.3 0.8 .148 .095 +030

- .019 049

S’2 \V, 8.6 7.1 1.5 0.7 .174 .099 8.8 8.3 1.0 0.9 .114 .108 - .060 +009 069 59 \V9 8.3 8.5 1.3 1.2 .157 .141 8.5 8.9 1.1 1.6 .129 .180 - .028 +039 . .067 S11 W,1 8.3 8.3 0.6 1.2 .072 .145 8.9 8.5 1.2 0.9 .135 .106 +063

- .039 +102

510 V10 8.5 7.6 0.9 0.3 .106 .040 9.1 8.4 1.6 1.2 .176 .143 +070 +103 .033 54 \V4 7.5 8.5 0.8 0.8 .107 .094 8.9 8.8 0.5 1.0 .056 .114 - .051 +020 .071 S8 %Vq Si \V7 8.0 7.7 7.6 6.1 1.2 1.4 0.8 0.6 .150 .182 .105 .098 8.2 8.2 8.3 8.6 1.0 1.2 0.8 0.7 .122 .146 .096 .081 - .028 .036 - .009 - .017 +008 +008 S6 “6 6.3 7.’2 0.7 0.9 .111 .125 8.1 8.1 0.6 1.0 .074 .123 - .037 - .002

(I) C- \V = Total Gradient = T010 minus Taii at end of cold resistance test.

(2) C- N = Gradient between temperature of colon and temperature over interscapular area (nape) at end of

cold resistance test.

(3) R1= (2)/(1) =Ratio of colon-nape gradient to total gradient at age 1 week; and R,=(5)/(4) at age 3 weeks. (7) ‘ Ratio = (6) - (3) =change in ratio of gradients between ages 1 and 3 weeks.

(8) S-W0= (7)s-(7)w intra-pair difference (“standard” minus “warm”) of change in ratio of gradients.

* Pairs numbered in order of admission of first member and arranged in this table in order of decreasing mean

(8)

STANDARD VS WARM

Ts

w

0

S

0

S

8

S

8

0

$8

S

INTRA-PAIR

DIFFERENCE

S -W

G

+

L

RATIO OF GRADIENTS

AT END OF COLD TEST

Effect of two thermal environments

Age week to age 3 weeks.

I-+

.10- +09-10

! +08

+07

+06-U)

+05-

+04-I

* C- N GRADIENT #{176}C

RATIO =

C-WGRADIENT #{176}C

RATIO R-R1

FIG. 2. Change in relative warmth of interscapu-lar area (measured at the end of the cold resis-tance test) after 2 weeks under the trial condi-tions. Individual changes (Table VI) and intra-pair differences are shown here arranged in serial order b sign and magnitude; medians are indi-cated by cross-bars (-) and zero change or

dif-ference is indicated by the horizontal dashed lines.

Median change (and range) of ratio of gradients

for groups: “standard” -0.033 (-0.060 to

+0.070) and “warm” +0.005 (-0.039 to +0.103).

Two sample ranks test (Wilcoxon-White): sum of

ranks, “standard” 120, “warm” 180; 1’ = 0.10.

Median intra-pair difference (and range) of

change in ratio of gradients: -0.034 (-0.071 to +0.102). Signed ranks test (Wilcoxon): sum of

signed ranks -34; P > 0.10.

cubator air temperature required to maintain

each of the two trial conditions varied

con-siderably from infant to infant

(

Table IV).

The babies remained in the thermal

condi-tions to which they were assigned for 2

weeks. At this time, they were removed to a

prepared study incubator

(

or respirometer)

for a repetition of the 1-hour cold resistance

test

(

infants who were assigned to the

“standard” condition were warmed so that

TSA 36.5#{176}Cwas maintained for 2 hours

be-fore the test

)

. The trial conditions were

ter-minated at the end of 2 weeks

(

age 3

weeks

)

in pairs numbered 1, 2, 9, and 12

be-cause one or both partners were ready to

be sent home at this time. The assigned

thermal conditions, measurements, and

ob-servations were continued for another

2-week period in pairs numbered 3 to 8, 10,

and 11; the cold resistance test was repeated

at the end of this time

(

age 5 weeks).

RESULTS

The results of cold resistance tests

per-formed before and after 2 weeks under the

trial conditions are given in Table V and

Figure 1. Eleven of the 12 infants who were

assigned to “standard” conditions exhibited

an improved ability to defend deep body

temperature at the end of 1 hour in a

simu-lated room environment (i.e., the cold

re-sistance index increased; Table V); less

than half (5 of 12) of those allotted to

“warm” incubators showed an increase in

cold resistance after 2 weeks. In 11 of the 12

matched pairs, the increase in cold

resis-tance was greater in the member of the pair

who had been raised under “standard”

con-ditions (Table V), and the magnitude of

intra-pair differences (expressed as signed

ranks; see Figure 1) was greater than would

be expected to occur by chance.

Table VI gives the results of

measure-ments of relative warmth of the

interscapu-lar area (nape) at the end of cold

resis-tance tests. As indicated in Table VI and

summarized in Figure 2, in 9 of the 12

“stan-dard” infants the nape became relatively

warmer (i.e., colon-to-nape : colon-to-wall

ratio fell) after 2 weeks under prescribed

(9)

RATE OF GRoWTH’

IN TWO THERMAL ENVIRONMENTS

Age I week to age 3 weeks,

STANDARD VS INTRA-PAIR

WARM OF CE

%/DAY S/DAY

2.2 +0.4

0

2.0 +0.2

I- 0 3

I

‘2 8 0

0 S

2 #{149} 2 ‘

- .6 3 ,,-0.2

I

#{176}

I

DAILY RATE OF INCREASE (i.e.as S of current weight)

X #{149}AGE (DAYS)

Y #{149}tog WEIGHT (Kg)

b #{149}REGRESSION COEFFICIENT (V on X)

GROWTH RATE (S/DAY) .L- oo

log S

FIG. 3. Rates of weight gain during 2 week period under the trial conditions. Individual rates (ex-pressed a.s percent of current weight per day) are shown here in serial order by magnitude and intra-pair differences (S - W) are shown by

sign and magnitude; medians are indicated by cross-bars (-) and zero intra-pair difference is

indicated by a horizontal dashed line. Median

rate (and range) of weight gain for groups: “standard” 1.37%/day (0.92 to 1.64), “warm” 1.56%/day (1.24 to 2.15). Two sample ranks test (\Vilcoxon-White): sum of ranks, “standard” 117, “warm” 183; P < 0.10 > 0.05. Median

intra-pair difference (and range) of “standard” minus

“warm” rate: -0.25%/day (-0.93 to +0.31). Signed ranks test (Wilcoxon): sum of signed

ranks -56; P < 0.05.

occurred in 6 of the 12 “warm” infants. The

magnitude of change was greater in the

“standard” category, but the difference

be-tween groups could be considered only

sug-gestive (Fig. 2). In 8 of the 12 pairs, the

“standard” infant developed a relatively

warmer interscapular area than his match,

but the size of the intra-pair differences of

measured change was not large enough to

inspire confidence (Fig. 2).

The rates of increase in body size during

the 2-week trial period are shown in

Fig-ures 3 and 4. In 10 of the 12 matched pairs,

growth of the “standard” infant lagged

be-hind the “warm” partner. The calculated

rates of growth in both weight and length

were significantly faster in the infants who

were assigned to “warm” conditions. There

were no significant intra-pair differences in

RATE OF GROWTH (LENGTH)’

in two thermal environments age I week to age 3 weeks.

STANDARD VS INTRA.PAIR

WARM IFFERE

S/DAY

S W S.W

60 +20

0

8

50 +10

0

-J 3

z 8

.40 F

#{149} 0 3

S 3

W 0 5

.30 -.l0 3

3

20 -20

3 3 .

0 -30

DAILY RATE OF INCREASE (i.i. AS S OF CURRENT LENGTH) GROWTH RATE (S/DAY) #{149}log L9. log L1 s 100

Ilog .)ItI

L1#{149}CROWN TO HEEL LENGTH (cmi AGE I WEEK AND L3 AGE 3 WEEKS

I #{149}ELAPSED TIME IN DAYS

FIG. 4. Rates of increase in length (crown-to-heel)

during 2-week period under the trial conditions.

Individual rates (expressed as percent of current

length per day) are shown here in serial order

by magnitude and intra-pair differences (S - W)

are shown by sign and magnitude. Medians are

indicated by cross-bars (-) and zero intra-pair

difference is indicated by a horizontal dashed

line. Median rate (and range) of increase in

length for groups: “standard” 0.33%/day (0.19

to 0.46), “warm” 0.43%/day (0.26 to 0.59). Two

sample ranks test (Wilcoxon-White): sum of

ranks, “standard” 106, “warm” 194; P < 0.05.

Median intra-pair difference (and range) of

“standard” minus “warm” rate: -0.09%/day

(-0.26 to +0.09). Signed ranks test (Wilcoxon):

(10)

‘FABLE VII

ItEI.ATIVE \AItMTlL OF ExTuEssiTlEs (FOOT) AT

ENo OF’ (‘OLD RESISTANCE TESTS

head circumference measurements during

the course of the trial.

OTHER OBSERVATIONS

.518

.708

- .193 +049 24’ .640 .765 -.191

.139 .O52

ifalc/Ie(1 Pair,s*

--(1) (2) RI 113 .--

-

-.

(.3) ‘ Ratio

s

-(4)

.

JJR0I

21 of 24The extremities

)

at the end

(

footof cold

)

ofresistancemost infantstests

were relatively warmer (i.e., colon-to-foot:

1

\v1

.75 .47

.8.57 .667

- .308 - .190

- .118

colon-to-wall ratios fell

)

after completing

2 weeks under trial conditions. Infants in the

---Sb \\.5

---

-.843 .93

--

---

---.793 .735

---.050 - .158

---+ .108

-. .--

-“standard” group exhibited a relatively

larger change in this direction, but the

difference between groups and between

S3 w3 .778 .886 .56 .60 - .216

- .84 + .068

pairs could easily have been the result of

chance

(

Table VII).

-812 We --

-.558 .796

- ---.534 .4I)

-

---.-- --- .019

- .867

--

---+ ‘348

-Oxygen consumption was measured in a

closed-circuit respirometer1#{176} at the end of

cold resistance tests in three pairs of infants

S.) -W’T -

-S9 \\‘o -

-.80 .887 .711 .659 --.-.466 .976

- .336 + .089

-.-W5 enrolled in the present trial and in two

pairs managed according to the same

proto-col who were admitted after completion of

the trial. The results of these

determina-lions are given in Table VIII. As compared

SI1 .881 with the findings on enrollment at age 1

\\‘lI 810 “IV -.904

-

-.64 .736

----week, oxygen consumption rate in the cold

rose

#{149}

after 2 weeks in all five infants

as-signed to “standard” conditions; the rate in

the simulated room environment remained

.487

.488

- .137

+ .Ill - .48 - -84 “I .827 .847 .640 .739

- .187 - .108

- .079 unchanged or fell in four of the five babies

who had been reared in “warm” incubators,

-

-s \\‘8 --- .-

--.575 .77 . --.549 .671

---_______

- .0’26 - .056

-

-+ .030

---and in the fifth infant (W,

)

the rise was

less than that of his match.

Eightmatchedpairs (numbered3to8, 10

87 Wi .868 .770 (13)) .814 - .9 + .044

- .‘273 and 11

)

remained in the assigned thermal

conditions for 4 weeks

(

until age 5 weeks).

- - - - --

-.-

-- -.

S6 1.111 .457 -.654

- .475

w.v

.944 .765 - .179

- -

-

---At the end of this period, cold resistance

tests were repeated

(

Table IX

)

; all but three infants exhibited increased resistance (1) IL = Ratio of colon-foot gradient to total gradient

at age 1week; and It3it age 3 weeks. (3) Ritio ()

- (1) = Change in ratio of gradients between ages 1 and

3 weeks. (4) .S - \\ Ratio (3)s - (S)w Intra-pair dif-ference (“standard” minus “warni”) of change in ratio of gradients.

Median change (and range) of ratio of gradients for

groups: “standard” -0.19 (-0.654 to -0.019);

“warm” -0.148 (-0.367 to +0.089). Two sample

ranks test (Wilcoxon-White) : suns of ranks, “standard”

180, “warm” 170, P>0.10. Median intra-pairdifference

(amid range) of change in ratio of gradients: -0.066 (-0.475 to +0.848) Signed ranks test (W’ilcoxon): sum of signed ranks -28, P>0.1O.

* Pairs numbered in order of admission of first.

mem-her and arranged in this table in order of decreasing mean birth weight of pairs.

to cold as compared with age one week

(

Table IX

)

. The three babies who were

less able to prevent a fall in deep body

temperature at age 5 weeks than at age 1

week were in the “warm” group

(

\V, W3,

and ; the first three, in order of

decreas-ing birth weight, among eight infants in

this category) . In six of the eight matched

pairs observed for 4 weeks under prescribed

conditions, the increase in cold resistance

index was greater in the “standard” member

of the pair

(

Table IX).

No systematic changes were observed in

(11)

ARTICLES

TABLE VIII

OXYGEN CoNsusmp’rIoN IN SIMULATED Roou

ENVIRONMENT4 (FIVE MATCIIEI) PAIRS)

Oxygen Consutnption kale

(mi-S TPD-/)er Kg

Pair . Percent

per imnute)

u;nberj ___________________________ Change

One JVeek Three JJ’eeks

S0 8.7 9.7 +11

8.9 8.9 0

Sb 8.1 9.7 +20

7.9 8.9 +13

8.6 9.5 +10

W9 10.4 8.7 -16

S10 9.1 10.1 +11

W10 8.6 8.6 0

S 7.1 9.1 +28

Wv 8.7 7.6 -13

* Inner-wall temperature of closed-circuit

respirom-eter stabilized at 28#{176}C.

t Arranged in order of decreasing mean birth weight of the pairs. Pairs a and b were admitted after coinpie-tion of the trial.

the trial. Seven of 16 infants exhibited an

in-crease in relative warmth

(

4 of 8 in the

“standard” group and 3 of 8 in the “warm”

group

)

; the magnitude of change was

greater in the “standard” partner in only

four of the eight matched pairs.

Rate of weight gain and linear growth

was essentially unchanged during the

see-ond 2-week period of study. The median

rate of weight gain for the “standard”

group was 1.36% of current weight per day

and 1.55% per day for the “warm” group.

The median rates for increase in length

were

0.33%

per day in the “standard” group

and 0.43% per day for the “warm” infants.

All infants in tile trial remained well and

asymptomatic except for two infants

(

noted

earlier

)

who were removed soon after

en-rollment. During cold resistance tests there

was no manifest difference in muscular

ac-tivity in the two groups of babies. Shivering

was looked for but never observed in either

group.

DISCUSSION

The present results, obtained in infants

reared in two slightly different thermal

con-ditions, resemble the findings in newborn

experimental animals cared for in test

envi-ronments in which the temperature contrast

was made considerably greater. Hahn and

co-workers observed that newborn rats

raised in surroundings maintained at 3 and

22#{176}Cwere better able to prevent a fall of

rectal temperature during acute cold

expo-sure, than controls in 33#{176}Ccages. Bruck and

W#{252}nnenberge made similar observations in

newborn guinea pigs kept in 8#{176}Cand in

30-32#{176}C environments. In both of these

studies, the difference in cold resistance

be-tween “cold-reared” and “warm-reared”

ani-mals became less marked as the animals

grew older.

Although our investigation has not

pro-vided all of the evidence that might be

used to identify the principal factor (i.e.,

increased heat production versus decreased

heat loss) to account for the observed

difference in cold resistance, there are some

clues that bear on this issue. Rate of flow of

heat from the deep organs of the body to

the surface by “passive” conduction across

tissues is, of course, dependent on

composi-tion of these tissues, but rate is also related

to actual distances involved and it follows

that a reduced rate of heat flow, for purely

physical reasons, is expected with increase

in body size.1’ Since the “standard” infants

in this study grew more slowly than “warm”

babies, it is suggested that greater cold

re-sistance in the former was achieved despite

a body size predisposing to greater flow of

heat to the body surface, and consequently

poorer heat conservation. Measurements of

the temperature of the foot at the end of

cold resistance tests before and after 2

weeks under the trial conditions (Table

VII) did not indicate that the “standard”

infants reduced heat loss more efficiently

than controls by restriction of peripheral

blood flow; thus, no argument could be

made for improvement of this mechanism

of conservation to account for greater cold

resistance. The observation in five pairs of

(12)

1044

TABLE IX

COLD RESISTANCE AT AGE 5 WEEKS

(EIGHT MATCI(ED PAIRS)

Matched

Pairs*

(1) CR1, ak

(2) CR!

(3) S - JVCRI

5,

W’,

98.9

88.8

+ 3.5

- ‘2.5

+ 6.0

+ 4.5

S3 94.7 + 2.6

W3 87.9 - 1.9

S0 96.9 + 6.7

88.1 - 2.1

95.8 + 3.4

W’1 92.6 + 3.2

91.7 + 8.4

W4 93.6 + 0.2

87.3 + 7.3

91.6 + 8.8

S7 90.4 +12.8

W7 85.7 + 2.1

85.9 +10.0

93.3 +16.7

(1) CIII, k(.Old resistance index at age 5 weeks

(expressed as percent, see Table V).

(2) CRI=CItI5 k-CRIm k=Change in cold

re-sistance index between ages 1 and 5 weeks.

(3) 5.S- W.CR1 = (‘2)s- (2) =Intra-pair difference

(“standard” milluS “warm”) of change in cold resistance index.

Pairs are numbered in order of admission of first

member and arranged in this table in order of decreas-ing mean birth weight of the pairs.

rise in oxygen consumption in the cold after

2 weeks under “standard” conditions

(

Table

VIII) offers preliminary support for the

hy-pothesis that greater cold resistance in

these infants was related primarily to their

increased capability to increase heat

pro-duction in response to cold exposure.

Briick and Wunnenberge demonstrated in

guinea pigs that the postnatal differences in

cold resistance paralleled changes in

cold-induced thermogenic activity in the

inter-scapular fat pad and electrical activity of

_______ thigh and neck muscles. Newborn guinea

pigs exposed to cold exhibited increased

ox-ygen uptake and elevation of the

tempera-ture of the fat pad (higher than colon

tern-perature

)

, while electrical activity of

mus-culature was absent or minimal. After 2

weeks in an 8#{176}Cenvironment, animals

con-tinued to show evidence of non-shivering

thermogenesis on acute exposure to cold;

+ 8.8 by contrast, in warm-reared guinea pigs the

-.-- increase in oxygen consumption was

accom-panied by a fall in interscapular fat pad

+ 0.2 temperature

(

paralleling a greater fall in

colon temperature

)

and by a simultaneous

-.- increase in electrical activity in muscle. The

+ 8 2 higher surface temperatures over the

inter-scapular area of the “standard”-reared

ba-bies in the present study suggest that their

relatively greater cold resistance may have

- 1.: been related to heightened thermogenic

ac--- . ______ tivity of interscapular brown fat. However,

the comparatively small colon-to-nape

gra-+10.7 dient in these infants could be equally well

related to a change in the composition of

--- the intervening tissue, resulting in

in-- 6.7 creased heat flow to the superficial site. In

any case, it should be emphasized that the

observed differences were not great enough

to permit a confident verdict concerning the

relationships, and at best these

measure-ments could provide no estimate of the

quantitative contribution of the

interscapu-lax fat pad to cold-provoked heat

produc-tion in the two groups of infants. Further

studies, particularly in heavy neonates with

relatively large brown adipose masses,16 are

required to clarify the exact role of this

“organ” in the total defense against cold of

the human infant during the postnatal

pe-riod. The proportional contribution of other

components (e.g., muscle, viscera) to

cold-induced thermogenesis must also be

deter-mined if we are to understand fully the

mechanisms used to prevent a fall of deep

(13)

TABLE X

SPECULATED RELATIONSHIPS BETWEEN THERMAL ENVIRONMENT, CALORIC BALANCE, AND

GROWTH IN A HYPOTHETICAL 1.5 KG INFANT

- .

I arzabie Warns Standard

Difference

. (If arm-Standard)

Partition of daily caloric intake (Cal/kg/day)* Resting caloric expenditure

Net caloric storage Increment for activity

Other (fecal loss, specific dynamic action, etc.) Total

45t 25 10 40 120

50 20 10 40

120

-5

+5

Rate of weight gain (#{176}/day)

gm/kg/day

Weight gain (gIn/kg/day) per 100 calories ingested (gui)

(1 .56%)

15.6

13 .0

(1 .37(;

13.7

1 1.4

(0.25)

‘2.5

-2.5

= ‘2.0 Cal/gm

Combustion value of a(Iditional weight gaimi in warm condition

(Difference in caloric storage ±

difference in weight gain)

Estimated increment in caloric 1’20

intake to equalize growth rate I sx

(120-40)

(assuming fixed fecal loss, etc.) =7.5 Cal/kg/day

* Theorized from estimates of metabolic activity, changing chemical comnposition and growth of a 1.5 Kg human

infant.

t 11%13 of 45 Cal/Kg/day=5 Cal/Kg/day increased expenditure in “standard conditions,” diverted from

storage.

Additional weight gain in warm conditions estimated from the median intra-pair difference in weight gain observed during the study period; median weights of study infants’-’-4.5 Kg.

way in which these responses are modifed

by previous environmental history.

The finding of relatively rapid growth

among infants who were in “warm”

incuba-tors and whose caloric intake

(

approximate-ly 120 Cal/kg/day) was the same as that

of matched controls is similar to the results

obtained in experimental animals raised in

more widely discrepant thermal conditions

and fed ad libiturn,6’T Studies of the

compo-sition of weight gain17 will be necessary for

an accurate calculation of the efficiency of

energy storage and to provide firm

esti-mates of the increase in milk requirement

of “standard” infants to equalize growth.

SPECULATION

The observation of a slower rate of

weight gain in the “standard” environment

suggests a diversion, from storage to

ex-penditure, of a portion of the daily caloric

intake. The metabolic cost of the “standard”

environment was not measured. However,

we previously observed an 11% increase

in oxygen consumption among babies after

equilibration overnight in environmental

conditions approximating those of the

pres-ent “standard” environment. Calculations

relating the observed retardation in rate of

weight gain to the presumed thermal

(14)

1046

are given in Table X. These calculations

in-dicate that additional weight accumulated

by a hypothetical 1.5 kg infant raised in

warm conditions has a combustion value of

2.0 Cal/gm, a figure which suggests that

non-combustible material

(

e.g., water

)

con-tributes in part to the composition of the

in-creased weight gain in the warm condition.

Moreover, appropriate assumptions for

par-tition of caloric intake in premature infants

lead to the supposition that equal rates of

growth in the two environments could be

obtained by increasing the caloric intake in

tile standard condition by only 7.5 Cal/kg

/day (i.e., by 6.25%).

It has often been cautioned, in respect to

feeding the premature infant, that a more

rapid rate of weight gain is not necessarily

more desirable. We have obtained support

for this view in the present demonstration

of a dichotomous effect of thermal

environ-ment On rate of weight gain and on

devel-opment of homeostatic capacity to defend

deep body temperature against cold.

SUMMARY

Asymptomatic, 1-week old, small infants

were reared in two frequently

recom-mended thermal conditions for 2-week

pen-ods. Cold resistance-the ability to prevent

a fall of deep body temperature in a

simu-lated room environment-was greater

among infants who had spent 2 weeks in

the slightly cooler environment. The rate of

increase in body weight and length was

faster in the warmer of the two conditions

tested.

Exact elucidation of the mechanisms

re-sponsible for the observed differences and a

value judgment concerning the relative

ad-vantages of one or the other rearing

condi-tions must await further studies.

REFERENCES

1. Silverman, W. A., Fertig, J. W., and Berger, A. P.: The influence of the thermal

environ-ment upon the survival of newly born

in-fants. PEDIATRICS, 22:876, 1958.

2. Buetow, K. C., and Klein, S. W.: Effect of maintenance of “normal” skin temperatures

on survival of infants of low birth weight.

PEDIATRICS, 34:163, 1964.

3. Day, R. L., Caliguiri, L., Kamenski, C., and

Ehrlich, F. : Body temperature and survival

of premature infants. PEDIATRICS, 34:171, 1964.

4. Standards and Recommendations for Hospital Care of Newborn Infants. Evanston, Illinois: American Academy of Pediatrics, 1964. 5. Hahn, P., Koldovskv, 0., Krecek, J., Martinek,

J., and Vacek, Z. : Temperature adaptation during postnatal development. Fed. Proc., 22:824, 1963.

6. Br#{252}ck, K., and Wunnenberg, B. : Influence of ambient temperature on the process of replacement of nonshivering by shivering thermogenesis during I)ost1atal

develop-ment. Fed. Proc., 25:1332, 1966.

7. Chevillard, L., Portet, R., and Cadot, M.: Growth rate of rats horn and reared at 5 and 30#{176}C.Fed. Proc., 22:699, 1963.

8. Bernard, E., and Hull, D. : The effect of envi-ronrnental temperature OR the growth of newborn rabbits reared in incubators. Biol. Neonat., 7:172, 1964.

9. Grucnwald, P. : Growth of the human fetus. I. Normal growth and its variation. Amer. J. Obst. Gynec., 94:1112, 1966.

10. Scopes, J. W. : Studies in oxygen consumption in newborn babies. Ph.D. thesis, University of London, 1965.

11. Burton, A. C.: The application of the theory of heat flow to the study of energy metabolism.

J. Nutr., 7:497, 1934.

12. Silverman, W. A., Zamelis, A., Sinclair, J. C., and Agate, F. J., Jr. : Warm nape of the newborn. PEDIATRICS, 33 : 984, 1964.

13. Silverman, W. A., Sinclair, J. C., and Agate,

F. J., Jr.: Oxygen cost of minor variations of

heat balance. Acta Paediat. Scand., 55:294, 1966.

14. Brody, S. : Bioenergetics and Crowth. New York: Reinhold, 1945.

15. Mainland, D. : Elementary Medical Statistics, ed. 2. Philadelphia: \V. B. Saunders Co., 1963.

16. Aherne, W., and Hull, D.: Brown adipose tis-sue and heat production in the newborn in-fant., J. Path. Bact., 91:223, 1966.

17. Mickelberry, W. C., Rogler, J. C., and Stadel-man, W. J.: The influence of dietary fat and