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Proc. Natl.Acad. Sci. USA

Vol. 93, pp. 2608-2613, March 1996 Medical Sciences

Nonlinear control ofheart rate variabilityin human infants

(chaos/infant electrocardiogram/atropine/brain death)

GEORGE SUGIHARA*, WALTER ALLANt, DANIEL SOBELt, AND KENNETH D. ALLANt

*Scripps Institution ofOceanography, University ofCalifornia,San Diego, La Jolla, CA 92093-0202; and tDivisionofNeonatology, Maine Medical Center,

22 Bramhall Street, Portland, ME 04102

Communicated byRobertM. May, UniversityofOxford, Oxford, U.K, October 6, 1995 (receivedforreviewJanuary 7, 1995)

ABSTRACT Nonlinear analyses ofinfant heart rhythms reveal a marked rise in the complexity ofthe electrocardio- gram with maturation. We find that normal mature infants (gestation 2 35weeks) havecomplexanddistinctlynonlinear heart rhythms (consistent with recent reports for healthy adults) but that such nonlinearity is lacking in preterm infants (gestation ' 27 weeks) where parasympathetic- sympathetic interaction and functionare presumed tobe less well developed. Our study further shows that infants with clinicalbraindeath and thosetreatedwith atropineexhibita similar lackofnonlinear feedback control. These three lines ofevidencesupportthehypothesischampionedbyGoldberger etal.[Goldberger,A.L.,Rigney,D.R.& West,B.J.(1990)Sci. Am. 262, 43-49] that autonomic nervous system control underliesthenonlinearityand possiblechaosofnormalheart rhythms. This reportdemonstrates theacquisitionofnonlin- ear heart rate dynamics and possible chaos in developing human infants and its loss in brain death and with the administration of atropine. It parallels earlier work docu- mentingchanges inthevariabilityofheartrhythms ineachof

these cases and suggests that nonlinearity may provideaddi- tional power in characterizing physiological states.

Contrary to conventional wisdom, recent evidence suggests

that sinus heart rhythms in normal human adults are not

strictlyregularbuthaveacomplexvariabilitythatisconsistent

with nonlinear feedback and possible chaost (1-10). More-

over,suchvariabilityappearstobegreatlyreducedorvirtually

absentinadultswithheartdiseaseandinolderadults(>70yr),

where simplerand sometimes cyclicrhythms tend topredom-

inate(7-10,13-15).Itishypothesizedthatinthehealthyadult,

chaotic-like dynamics arise from nonlinear feedback created

by the interaction ofsympatheticand parasympathetic inputs

tothesinoatrialnode (2-4,7,8).Accordingtothishypothesis,

heart disease and agingmay be associatedwith a lossofsuch adaptability and feedback control (8-10). Recent studies of the power spectrum ofsinus rhythm heart rate variabilityby

Akselrodandothers(16-18)havesuggestedthatthisfeedback

controlisnotfullydevelopedininfantsduetoarelativelagin maturation of the parasympathetic influence (19, 20). In a

similarvein,Van Ravenswaaij-Artsetal.(20)haveshown that

heart-ratevariabilityincreases inthe firstthree days oflifein

free-breathingprematureinfants(27-32weeksgestation),and

Szeto etal. (21) have shown an increase in 1/fcomplexity of intrauterine"breathing" (diaphragmmovements) duringmat- urationofthelambfetus.Becausefeedbackcontrolshouldnot be present in earlygestational infants (22),we reasoned that sequential studies of heart rate variability in the neonatal period might reveal the development of nonlinear feedback and chaotic-like dynamics. Similarly, insofar as balanced au- tonomic control is needed to produce normal heart-rate variability,we would expectthatnonlinearitywouldbe absent

The publication costs ofthisarticlewere defrayed in part by page charge

payment. This articlemust thereforebe herebymarked "advertisement" in

accordance with 18 U.S.C. §1734 solelyto indicate this fact.

inbraindeathandwould alsobemuted bytheadministration

of atropine. Well-balanced autonomic functioning should be lackinginbraindeath,wherecentralnervousinputtoboththe sympatheticandparasympatheticnervoussystemisdisrupted.

Similarly,with the use ofatropine, apostganglionicparasym-

patholytic drug, pharmacologic interruption of parasympa- thetic input is produced (involving blockage of vagal nerve

inputatthesinoatrialnodeoftheheart).Boththeseconditions

have been well studied with spectral methods and show reduced variabilityin the overall heart rate (23-25). We present evidence by using nonlinear forecasting to supportthehypothesisthatautonomicnervoussystemcontrol underliesthenonlinearityand possiblechaosofnormal heart rhythms.§ In so doing, we provide the first report from

developinghuman infantsoftheinitialabsence,and eventual acquisition,ofnonlinearityinheartrhythms;atransitionwhich

occurs during a time of rapid autonomic nervous system

maturation. These resultscomplement earlierworkbyAksel-

rod and others (16-18, 23-25), documenting changes in the linearvariability ofheart rhythms in each ofthese settings.

CLINICAL METHODS

Data from three clinical studies are presented here: a matu- ration study, abrain-death study, and an atropine study (Fig.

1). All subjects in these studies were monitored in supine

position at their bedside. Heart rate (RR) intervals were measured using standard EKG electrodes attached to an Aquitron infantmonitor. Output from the monitor (detected R waves from the QRS and chest impedance) was relayed to

aportablebedsidecomputerequippedwithspeciallydesigned

hardware and software. Beat-to-beat (RR) intervals (mea- suredinmilliseconds)were obtained.Eachtimeseriesof1024 heart-rate intervalswas visuallyscreened forartifact,and the

cleanest edited time series were then edited and analyzed.

Editing consisted of removing individual RR intervals that deviated from the time series mean by >50% or cutting segments from the beginning or end of a tracing where

nonstationaritywasobvious.Respiratoryratetimeserieswere

used as a check of quiet sleep and to screen for movement artifact.AllstudiesmetthecriteriaofourInstitutionalReview Board forHuman Experimentation and informedparentalor guardian consent was obtained. In the maturation study,

continuous electrocardiograms (EKGs) were taken from six

very premature infants at birth (25-27 weeks gestation) and

Abbreviations: EKG, electrocardiogram; RR interval, beat-to-beat interval. tWeusethequalifiers"possiblechaos"and"chaotic-like"forreasons

given

in ref. 10. In clinical time series which are noisy, we do not

believeitispossibletouse therigorous definitionofchaos (positive Lyapunov exponent) to make practical determinations of chaotic

dynamics.

In this regard, we think that operational definitions of

chaos may be useful (10-12).

§Nonlinearityisused

here inthe sense ofTong (26) todescribe time

and,assuch,cannotbewell

Inthissense,astable

seriesthatlacka symmetricalwaveform

describedassums ofsineandcosinefunctions.

limitcycle from a nonlinear oscillatorwould be classified as linear.

2608

Medical Sciences: Sugihara et al.

  • 0.40 -

0.38-

A

0.36

-

0.34-

.

.; ~t

  • 0.32 -

  • 0.30 -

U.AU 1

B

^

AA

'

*

t

'X6

f%d

8^;v

o0

.il .

  • 0.34 -

032-

  • C -

0.32-~

Co

cn

fl"

  • 0.28 -

  • 0.26 -

0.24

0.40

0.38-

0,36 -

i

0.34--w'>

0.30

  • 0.40 -

  • 0.38 -

  • 0.36 -

0.34-

  • 0.32 -

0.30

RR interval no.

FIG. 1. Illustrative examples of time series of RR

intervals for a

premature infant at 25 weeks gestation (patient 3a) (A), the same

infantas inA,mature at36weeks (patient3b) (B),a brain-dead infant

(patient 18)(C),an infantbefore atropinetreatment (patient22b) (D), and thesame infantas inD afteradministering atropine (patient22b')

(E). Very premature infants, brain-dead infants, and infants treated with atropine all exhibit a similar lack ofnonlinearity, although their variances are very different.

again at 35-37 weeks gestation (age of a normal full-term

birth). These six sequential pairs were augmented by seven

additional subjects falling into either the early or the late age

class, giving a total of 19 time series. The only selection

criterionusedwas thateach subjecthas no evidence ofcentral

nervous system dysfunction, consistently normal cranialultra-

sound scans over the studyperiod, and lackscardiacpathology

or arrhythmia. The initial EKG in the maturation study was

taken within the first 10 days of life while

infants received

mechanical ventilation. Arterial blood gases were monitored

frequently. Ventilatory and/or oxygen settingswere adjusted

tomaintainpH, 02 and CO2valuesinnormal ranges toprevent

interpretive difficulties due to hypoxemia, hypercarbia, or acidosis.Thisprecautionshould eliminatepathologicalbreath-

ingepisodes and the drivingeffect that such abnormal breath-

ing may have on heart rhythms (27-29). All but two of the

subjectsinthe 35-to 37-week group were monitoredwhile free

Proc. Natl. Acad. Sci. USA 93 (1996)

2609

breathing. Two of the 35-37 week-old infants received me- chanical ventilation and are included to demonstrate that, in this particular protocol, regular respiratory rhythms do not

mask nonlinear cardiac rhythms (27-29). All selected studies

were performed during artifact-free quiet sleep, asjudged by bedside observational criteriaand inspectionofheartrateand respiratoryratetime series.These criteriawere chosen sothat therespiratoryrateofthefreebreathingmature infantswould

be as regular as possible, to mimic the regularity of the mechanically ventilated premature infants. This also elimi- nates respiratory driving of cardiac rhythms that can occur

during pathological breathing episodes (27-29). The population forthe brain death studyconsisted ofeight children. Methods similar to those used to study the preterm infants were used to record heart-rate intervals in adults and children evaluated forbrain death. All ofthese subjectswere

studied at bedside while receiving mechanical ventilation.

Standard determinations of brain death were conducted by physiciansunrelated tothestudy.The atropine studyincluded three infants, and EKGs were taken before and after admin-

istering atropine. Atropine (0.01 mg/kg) was given intrave-

nously to reduce bradycardia and hypoxemia associated with endotracheal tube suctioning. Patientswere studied insimilar fashion over several hours to include at least two periods of suctioning priorto and following atropine administration. No additional selection criteria were used for either the brain death or the atropine studies.

ANALYTICAL METHODS

Empirical evidence for nonlinear behavior in normal heart rhythms has been based largely on observations ofthe 1/for fractalcharacteristicsinthepower spectrum and on measure- ments ofthecorrelationdimensionofreconstructed attractors (2, 3, 6, 8, 30-32). Such evidence is consistent with the hypothesis that human heart rhythms are driven by nonlinear and possibly chaotic processes. However, it is possible to

reproducesimilarpatternsnonchaoticallywithvariousrandom

processes (6, 11, 33, 34). More substantial evidence for the

operation of nonlinear dynamics may be obtainable with nonlinear forecasting or with the construction ofcareful null models (10-12, 33-37). The basic idea behind applying non- linearforecastinginthiscontext isto examine whether or not

there is significant improvement in out-of-sample forecast

performance with a nonlinearversus a linear forecast model.

The nonlinearityofadataseriesisevaluatedaccordingtohow

much out-of-sample forecasting improvement can be realized as the underlying model is tuned to have progressively more

nonlinear structure. To do thiswe shallapplythe method ofS maps, as outlined

below (37). Suppose we have an embedding of an observed

heartrate time series(EKG) X,,s Rm+1, where X, (0)-1 (for theconstant term inthesolutionofEq.2below).Letthe time seriesvalue TP time steps forward be X1+TP(l) = Y,.Then the forecast at Tp is

m

ft=

j =O

ctumu)Xti-

Foreachpredictee,Xt,onefindsthesingularvaluedecomposition

solution for C by using historical points from the

fittingset or

libraryset (referredto below bythe subscript"i")as follows:

where

B = A-C,

Bi = w(1| Xi -X, II)Yi,

[2]

  • 2610 Medical Sciences: Sugihara et al.

and

Aij = w( ||Xi - Xt 11)Xi(j)7

and

w(d) = e(-O)d/d

[3]

  • 0 0,disthedistancebetween thepredicteeand theneighbor

vector, and thescalefactor,d, isthe average distancebetween neighbors. Note thatA has dimensions ni X (m + 1),where n, = size of the library. To maintain independence in the

out-of-sample solution for each fitted map, we eliminate all vectors from the librarywhose coordinates include any ofthe

coordinates ofthe predictee X, in the time series. Notice that

a different map is constructed for each prediction, with the degreeofnonlinearitycontrolledby0:0= 0correspondstothe maximum likelihood global linear solution, as 0 is tuned to higher positive values, the solution becomes more local and hence nonlinear.Thus,S maps provide a continuousspectrum

ofmodels, from global linear 0 = 0,to nonlinear models, 0 > 0,with the models becoming more local and nonlinear as 0is tuned to higher values. The specificprocedure usedhereconsistsoftwo parts. First,

with 0 = 0,the embedding dimension, m, isvaried between 1 and 14 to find the dimension that minimizes out-of-sample

linear forecast error. An

search limit of 14 is the

conventionusedinadultstudies.lByusingthebestembedding dimension forthe linear model, 0isthen tuned upwards from 0 to 1 to examine the extent to which the added nonlinearity

upper

might reduce forecast error or improve the correlation be-

tween predictions and observations. Following convention (9-12, 34), all data are converted to first-differences before analysis to enhance stationarity. All analyses reported here were done out-of-sample as follows: when constructing the model for each prediction, we omit allvalues nearby in time

(within a radius of 10 points) to the predictee. Similar results are obtained bydividing the time seriesinhalf,where the first half is used to construct the model which is then used to forecast the second half.

RESULTS AND DISCUSSION

The results from the S maps are summarized in Fig. 2 and Tables 1-3. These tables characterize model performance by

using two different metrics of model fit: forecast error (err) and the correlation coefficient (p). Whereas forecast error should scale with the linear variability, the correlation coef- ficient need not do so. They show the difference in the fit obtained with the optimal linear model (err11, plin)versus the

nonlinearmodel where 0 = 1 (err,,,Pnl).Here, thedecrease in average forecast error (Aerr = errli, - err,,) and the increase inthe correlation coefficientobtainedwith a nonlinearmodel

(Ap

= Plin -

err,,)

are measures of

nonlinearity.

first.

We will consider the maturation study

In pooled age

comparisons (Table 1, summaries 1i and 2i), healthy mature

infants (.35 weeks gestation) show a marked reduction in forecast error of 129.76 ,usecon average, and an increase inp of 0.046 as the models are tuned to have more nonlinear

structure. Younger infants (.27 weeks gestation) show a relatively small degree ofimprovement of 29.02 ,usec and Ap

= 0.016 with a nonlinear forecast model. Thus, the heart

rhythms of healthy mature infants are significantly more

nonlinear and irregular than those of younger infants (P

0.007 (Aerr) and P

0.003 (Ap) by t test). Moreover, in the six

subjectswhereyoung andoldpairedage comparisonscouldbe

made (Table 1,summaries liiand 2ii),allsixhad lessapparent

Proc. Natl.Acad. Sci. USA 93 (1996)

20

16

E

4)

12 -

8-

4

-

0-

0

global

linear

0.25

0.5

Theta

0.75

local

nonlinear

FIG. 2. Theta testforthefivetimeseriesfromFig. 1,showinghow forecast error varies as the S-map model is tuned to exploit more

nonlinear structure in the data. The y axis (Aerr) is the amount of

forecast improvement seen in a nonlinear model over an equivalent

linearmodel (Aerr =

erri, - errni).Thisfigureshowsthatthemodels

forthepremature infant (25weeks gestation),brain-deadinfant,and the infants treated with atropine allshow very little improvement as theta is tuned upwards; therefore, the heart rhythms are essentially linear. In contrast, the models for the mature infants indicate heart

rhythms that are stronglynonlinear.

nonlinearity pre-27 weeks than post-35 weeks (true for both

AerrandAp)(P= 0.014forbothperformancemetricsbyusing the Wilcoxon matched-pairstest).Could thisapparent differ- ence in nonlinearitywith age be due to the factthat thevery premature infantswere mechanicallyventilatedwhilemost of

the mature infantswere freebreathing (27-29)?Although, as

explained in the clinical methods section, precautions were

takenintheprotocoltodiminishthispossibility,we canresolve

thisquestionfurtherbyexaminingthetwo mature caseswhere

mechanical ventilation was used

(Table 1, patients 12b* and

13b*).I1With both metrics, there was a significant difference between the two mechanicallyventilated mature infants and thepremature group [P= 0.029(zverr)andP = 0.017 (Ap)by

Mann-Whitney U test]. On the other hand, there was no

significantdifferencebetweenthetwo mechanicallyventilated matureinfantsandthefree-breathingmaturegroup[P= 0.148

(Aerr)andP = 0.448 (Ap)byMann-Whitney U test].The fact

that respiration here had no observable effect on the cardiac rhythms of infants is consistent with the results of Van

Ravenswaaij-Artsetal.(20),whoshowedalackofinfluenceon

heartratevariabilityinpreterminfantsgoingfromventillation

to spontaneous breathing, and the reverse.

Thus,theacquisitionofnonlinearityinthedevelopingfetus

is consistent with the hypothesis of Allan and Sobel (22) concerningheart-ratevariabilityand the maturation ofthe ner- vous system. That is,in parallelwith other autonomic nervous

systemfunctions,suchasthepupillarylightreflex,whichdevelops at about 30 weeks gestation, sympathetic and parasympathetic functionevolvesandshouldcontributetoheart-ratevariabilityat some time between 27 and 35 weeks gestation.

Itisnoteworthy thatneitherthemean nor thevariance of the RR intervalsthemselves (linearstatistics)couldbe used to discriminate age comparisons significantly and certainly not to the degree that the nonlinear analysis did (see

summary statistics in Table 1, summaries 3 and 4). This isin

 

'Suchcases occur only rarely, hence, the low sample size. These two

1A vector of this length will roughly span two respiratory cycles in

adults, and three respiratory cycles in infants.

subjects

pneumonia.

were put on respirators as a precaution against possible

Medical Sciences: Sugihara et aL

Table 1. Maturation study: Infant agecomparisons

Proc. Natl.Acad. Sci. USA 93 (1996)

2611

Age,

Mean

Patient

mo

E

N

erriin

errIn

Aerr

Plin

Pni

Ap

R-R

SD

la

26

14

548

953

949

4

0.639

0.639

0

353.2

6.098

lb

36

5

852

1113

1064

  • 49 0.348

0.241

0.107

268.1

14.65

2a

25

11

967

2028

1981

  • 47 0.515

0.490

0.025

379.1

9.381

2b

36

7

1016

1379

1331

  • 47 0.631

0.598

0.033

340.7

7.81

3a

25

13

1009

1449

1426

  • 23 0.499

0.483

0.016

349.9

5.651

3b

36

5

977

4690

4516

173

0.491

0.529

0.038

338.8

11.31

4a

24

12

999

965

952

13 0.414

0.403

0.011

396.0

7.996

4b

35

6

717

1062

1019

42 0.528

0.472

0.056

306.5

4.19

Sa

27

10

879

546

524

22 0.807

0.795

0.012

330.9

7.502

Sb

37

7

1015

2080

1932

148

0.567

0.641

0.074

382.7

8.032

6a

27

  • 14 764

594

581

13

0.744

0.751

0.007

326.4

7.535

6b

36

  • 13 631

5948

5729

219

0.764

0.780

0.016

474.9

15.06

7a

25

  • 12 690

613

597

16 0.518

0.487

0.031

346.9

6.659

8a

26

  • 12 1009

    • 1396 1315

      • 80 0.838

0.823

0.015

365.6

7.49

9a

27

7

1014

  • 1161 1116

    • 44 0.583

0.554

0.029

370.1

6.12

10b

37

  • 12 890

    • 3393 0.542

3276

117

0.506

0.036

372.3

6.705

llb

37

  • 14 979

    • 1263 1208

      • 56 0.750

0.730

0.020

427.1

7.382

12b*

37

9

852

959

883

76 0.756

0.709

0.047

354.7

6.012

13b*

37

12

969

10037

9668

369

0.513

0.546

0.033

465.3

31.10

1) Nonlinear Aerr i) Pooled age comparison:

Summary statistics

<27 weeks:

N

=

9, mean = 29.02, mean rank = 5.78

>35 weeks:

N = 10, mean = 129.76, mean rank = 13.80

Unpaired t value = -2.979

P= 0.007

P= 0.001

Mann-Whitney: U = 7, U' = 83, Z = -3.103

ii)Paired age comparison:

N= 6, meanX-Y= -93.01

P =

P =

0.018

0.014

Paired t value = -2.843

Wilcoxon matched pairs test

2) Nonlinear: Ap i)Pooled age comparison:

<27 weeks:

N

= 9, mean =

0.016, mean rank = 5.72

>35 weeks:

N = 10, mean = 0.046, mean rank = 13.85 Unpaired t value = -3.209

P= 0.003

Mann-Whitney: U = 6.5, U' = 83.5, Z = -3.144

P = 0.001

ii) Paired age comparison:

N = 6, mean X-Y = -0.042

Paired tvalue = -2.707

P =

P =

0.021

0.014

Wilcoxon matched pairs test

3) Linear: mean R-R

i) Pooled age comparison:

<27 weeks:

>35 weeks:

N = 9, mean = 358, mean rank = 9.33

N = 10, mean = 373, mean rank = 10.60

Unpaired tvalue = -0.696

51,Z = -0.490

P =

P =

0.251

0.312

NS

NS

Mann-Whitney: U = 39, U' =

ii)Paired age comparison:

N = 6, mean X-Y = 4

P =

0.460

P = 0.377

NS

NS

Paired t value = 0.107

Wilcoxon matched pairs test

4) Linear: SD R-R

i)Pooled age comparison:

<27 weeks:

N

=

9, mean =

7.16, mean rank = 8.33

>35 weeks:

N = 10, mean = 11.25, mean rank = 11.50

Unpaired t value = - 1.616

P =

0.070

NS

Mann-Whitney: U = 30, U' = 60,Z = - 1.225

P = 0.110

NS

ii)Paired age comparison:

N = 6, mean X-Y = -2.81

Paired t value = -

1.345

P =

0.118

NS

Wilcoxon matched pairs test

P = 0.124

NS

Patientsareidentifiedbyuniquenumericalcodes,witha

indicatingthatthepatientislessthan28weeks

gestation

andb

indicating

thatthe

patient

isatleast35weeksgestation.E,embeddingdimension;N,numberofpredictions;errli",averageforecasterror

model (0 = 0);err,,I,average forecasterror

in

nonlinearity of the original

psecwhen

usinga

nonlinearlinearforecastmodel

(0

nonlinearforecastmodel;Ap

in msec; SD, the standard deviation ofthe

inpsecwhen

using

err,,,

a linearforecast

a measure ofthe

= 1);Aerr = errs,, -

timeseries; pl,,, correlation coefficient of the above linear forecast model; p,,I, correlation coefficient of the above

=

p,,l

  • - pa,,,ameasure

ofthenonlinearity;

periodbetween successive

mean R-R,the

averageperiod

in

msec;

betweentheR

peaks

R peaks, measured

NS, not significant

at

ofthe EKG,measured

the 5% level.

  • 2612 Medical Sciences: Sugihara et al.

Table 2. RR analysis forbrain-dead subjects

Proc. Natl.Acad. Sci. USA 93 (1996)

Mean

Patient

E

N

errij,

errni

Aerr

Plin

PnI

Ap

R-R

  • 14 1011

10

426

408

18

0.969

0.971

0.002

380.6

  • 15 1011

11

718

674

44

0.894

0.905

0.011

339.9

  • 16 1009

13

428

415

12

0.900

0.906

0.006

237.0

  • 17 1007

14

253

239

14

0.944

0.949

0.005

385.6

  • 18 909

12

103

92

10

0.997

0.998

0.001

389.0

  • 19 1008

14

211

206

5

0.957

0.959

0.002

289.0

  • 20 11

971

676

656

20

0.803

0.812

0.009

375.1

  • 21 238

14

968

 

214

25

0.995

0.996

0.001

407.7

 

Summary statistics

1) Nonlinear: Aerr Brain dead (infants only):

N

= 8, mean = 18.66, mean rank = 4.63

 

Normal >35 weeks (Table 1):

N = 10, mean = 129.76, mean rank = 13.40

 

Unpaired tvalue = 3.352

 

P = 0.004

 

Mann-Whitney: U = 1, U' = 79,Z =

-3.465

P =

0.0003

2) Nonlinear: Ap Brain dead (infantsonly):

N

=

8, mean =

 

Normal >35 weeks (Table 1):

N = 10, mean

0.0046, mean rank = 4.50 = 0.046, mean rank = 13.50

 

Unpaired tvalue = 4.743 Mann-Whitney: U = 0, U' = 80, Z = -3.554

P = 0.0005 = 0.0002

P

 

3) Linear: mean R-R

 

Brain dead (infants only):

 

N = 8, mean = 350, mean rank = 9.13

 

Normal >35 weeks (Table 1):

N = 10, mean

= 373, mean rank = 9.80

 

Unpaired tvalue = 0.764

 

P = 0.228

 

NS

Mann-Whitney: U = 37, U' =

43,Z = -0.267

P = 0.395

NS

4) Linear: SD R-R

 

Brain dead (infantsonly):

N

=

8, mean = 2.02, mean rank = 4.50

 

Normal

>35 weeks (Table 1):

N = 10, mean

= 11.23, mean rank = 13.50

Unpaired tvalue = 3.691

P =

0.0025

Mann-Whitney: U = 0, U' = 80,Z = -3.554 Abbreviations are as described in the legend to Table 1.

P = 0.0002

 

SD

2.058

2.347

1.865

2.678

0.948

1.50

2.683

2.119

accordwith previous findingsthatover and abovevariance in subjects. The relatively small degree of forecast improvement beat-to-beatrhythms(13),nonlinearitymayprovideadditional (Aerr = 18.66,usecandAp = 0.0046)asthemodelistunedtobe

  • powerforcharacterizingdifferentphysiologicalstates,includ- more nonlinear, is similar to that seen in young infants and

ing aging and heart disease (10). Tables 2 and 3 provide further evidence to buttress the

argument that both parasympathetic and sympathetic func-

significantlylower

infants [P =

than the nonlinearityseen inhealthymature

0.0003 (Aerr),andP = 0.0002 (Ap)].These results

show that heart rhythms with brain death appear to be very

tion are needed to produce nonlinear heart rhythms. Table regular, lackingthe complexities thatwould otherwise be asso-

2showstheresultsoftheS-map analysisforninebrain-dead

Table 3. RR analysis for atropine-treatedinfants

ciatedwith normal nonlinearfeedback.

 

Age,

Mean

Patient

mo

E

N

erruin

errni

Aerr

Plin

PnI

Ap

R-R

SD

8a

27

12

1009

1396

1315

80

0.823

0.838

0.015

365.6

7.49

8a'

27

12

1009

636

597

39

0.960

0.963

0.003

367.5

2.8

9a

26

7

1014

1161

1116

44

0.554

0.583

0.029

370.1

6.12

9a'

26

12

1009

320

293

27

0.970

0.975

0.005

342.1

3.55

22b

28

7

1004

2419

2297

122

0.333

0.403

0.070

332.0

17.58

22b'

28

7

703

1205

1198

7

0.846

0.848

0.002

310.8

2.64

 

Summary statistics

 
 

1) Nonlinear: Aerr

 

N= 3

T= 0.0

Z=

1.604

Wilcoxon matched pairstest 2) Nonlinear: Ap

 

P =

0.109

NS

N= 3

T= 0.0

Z =

1.604

Wilcoxon matched pairs test 3) Linear: mean R-R

 

P =

0.109

NS

N= 3

T= 0.0

Z =

1.069

Wilcoxon matched pairs test 4) Linear: SD R-R

 

P =

0.285

NS

N= 3

T= 0.0

Z = 1.604

 

Wilcoxon matched pairs test

 

P = 0.109

 

NS

Abbreviations are as described in the legend to Table 1. Data from patients 8a, 9a, and 22b are before atropine, while data from 8a', 9a', and 22b' are from the same patients but after atropine treatment.

Medical Sciences: Sugihara et aL

Table 3 shows the results before and after administering atropine,adrugthatinhibitsvagusnerveinputtothesinoatrial node.Althoughthesamplesize(threepairedbefore-and-after trials) istoo low for statistical significance, in all three cases, atropineresultedinamarkedreductioninnonlinearbehavior. Before atropine, the heart rhythms were mildly nonlinear; after atropine, they appeared to be essentially linear. We haveexaminedthreeindependentlinesofevidencethat pointtoaneedforfunctionalinputfrombothparasympathetic andsympatheticbranches oftheautonomicnervous systemin producing robust human heart-ratevariability. This evidence isasfollows: the acquisitionofnonlinearity inthe developing fetus,thelackofnonlinearitywithbraindeath,andthelossof nonlinearity with atropine. These findings suggest that non- linearitymay be themechanism forphenomenological trends in heart-rate variability reported in previous studies (16-18, 23-25) and give support to the corresponding patterns found withspectralanalysis.Thisstudyalsoextendsthesefindingsto infants asyoung as 24 weeks gestation. Of particular significance is our finding that the nonlinear analysis using S maps was more sensitive atclassifying heart- rate variability than the simple linear statistical approach of comparing means and variances. This suggests thatinsofar as nonlinearityisan important mechanism underlying increased heart-rate variability, measurements which specifically char- acterizethenonlinearityofheart-ratetimeseries(andnotjust theirvariance)mayprovidemore directandsensitivemethods

for assessing the physiological state.

We thank the following people for their help and critical input:

Louis Bersier, Paul Dixon,Ary Goldberger, Richard Penner, Robert M. May, Arnold Mandel, Pepe Segundo, Laura McAlpine, David G.

Gordon, and George S. Honig. This work was supported by endow-

ment funds from the John Dove Issacs Chair inNatural Philosophy, Grant ONR:N00014-95-1-0034, and bya grantfrom the Maine Med- ical Center Research Committee.

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