CORTISOL AS AN INDICATOR OF STRESS IN PREMATURE INFANTS: THE EFFECT
OF ELECTRIC STIMULATION OF ACUPUNCTURE MERIDIANS IN BLUNTING THIS RESPONSE
Lynnae Schwartz, M.D.,* Washington, DC,
Howard Bauchner, M.D., Richard Blocleer, M.D., Katherine Jorgensen,
BSN, Colleen Pearson, Regina O'Donnella, Merle Mirochniclc, M.D.
Ophthalmologic examination for retinopathy
of prematurity (ROP) is a stressful procedure required as standard
care for premature neonates. Pharmacologic options to reduce stress
and pain during ROP exam are limited. The use of transcutaneous
electrical stimulation of acupuncture meridians to reduce stress
during ROP examination has not been previously investigated.
To confirm preliminary data showing salivary
cortisol to be an immediate stress marker in premature infants;
to determine if electrical stimulation of acupuncture meridians
blunts the rise in salivary cortisol associated with ROP examination.
Randomized, single-blind, controlled
pilot study, ongoing between January, 1995 and August, 1996.
Prematurely born infants requiring ophthalmologic
examination for ROP.
Main Outcome Measure
Salivary cortisol levels measured by
radioimmunoassay (RIA) at baseline; compared to post-ROP examination
Thirteen infants were studied (three
crossed over), resulting in 16 paired saliva samples. Treatment
and control infants were comparable; no adverse effects were observed.
Salivary cortisol concentration increased in both groups; the
change was statistically significant only in control infants (P=0.0272).
Comparison of change in salivary cortisol between control and
treatment infants suggests trend towards blunted stress response
in treatment infants (P=0.0592). A minimum N of 192 paired samples
will be needed to show statistical significance, assuming continuation
of the observed trends.
Salivary cortisol rises, with ROP examination.
Electrical stimulation appears to blunt this stress response.
A larger study is needed to determine significance and delineate
the optimal characteristics of the electrical stimulation applied.
Acupuncture, Electroacupuncture, Premature
Infants, Cortisol, Salivary, Electrical Stimulation, Retinopathy
of Prematurity (ROP)
Routine care for prematurely born infants
in the Neonatal Intensive Care Unit NICU (Children's National
Medical Center, Washington, DC) typically requires many intrusive,
stressful procedures, including venipuncture, diagnostic procedures,
and multiple therapeutic interventions. Even routine care may
be stressful (1,2). In addition, the NICU environment itself can
be harsh, despite efforts to reduce noise, bright lights, unnecessary
handling, and random interruptions of rest.
Ophthalmologic examination for retinopathy
of prematurity (ROP) may be a particularly noxious event; it requires
immobilization, handling by at least one additional care provider,
administration of dilating eye medications, insertion of retractors,
extremely bright light directed to all areas of the retina, and
prolonged time, especially in the teaching environment. Potentially
significant physiologic instability may follow (3), consistent
with cardiovascular, respiratory, autonomic, and metabolic responses
known to occur in neonates subject to pain and stress (4).
Although assessment of pain and stress
in premature infants in the NICU is primarily observational (5),
the hypothalamic-pituitary-adrenocortical (HPA) system is reactive
in even the most premature of viable infants (6,7), releasing
cortisol from the adrenal cortex in response to multiple endogenous
and exogenous stimuli. Plasma and salivary cortisol levels provide
a physiological marker of HPA activity, especially stress, with
plasma concentrations peaking within 20-30 minutes after the onset
of noxious stimulation (8), followed by a parallel rise in salivary
cortisol reflecting unbound (active) cortisol levels in the Serum
(9). Salivary cortisol assays, therefore, allow noninvasive determination
of HP.A activity and stress response in adults (10,11), and infants
Environmental efforts to decrease stress
are routine in NICU care, but not always sufficient. Pharmacologic
stress reduction and/or analgesic interventions may be added,
but options are limited in situations such as ROP examination,
where the risk of respiratory and cardiovascular depression requiring
invasive support far outweighs potential benefit.
Electroacupuncture has been shown to
be analgesic in multiple small animal models (13,14), and in humans
undergoing surgical procedures (15), raising the possibility that
electrical stimulation of acupuncture points might also be analgesic
and/or have a stress reducing effect in infants.
Our investigation had two objectives:
the first, to confirm preliminary data showing salivary cortisol
response to be an immediate marker of stress in premature infants;
secondly, to determine if electrical stimulation of acupuncture
meridians could blunt the stress response provoked by ROP examination,
without apparent adverse effects. We hypothesized that salivary
cortisol levels would rise significantly with ROP examination,
and that noninvasive electrical stimulation of acupuncture points
would safely blunt this physiologic index of pain and stress in
With Institutional Review Board approval,
and written, informed parental consent, premature NICU infants
were recruited between January, 1995 through August, 1996, into
this randomized, singleblind, controlled study to receive true
(current on) or sham (current off) transcutaneously applied electrical
stimulation of acupuncture meridians during ROP examination. Approximately
85% of parents asked consented to their infant's participation.
Oral feeds were stopped two hours prior
to study. All investigators, laboratory personnel, and observers
were blinded, except for the one technician applying electrodes
and treatment. No infant was studied more than two times, regardless
of the total number of sequential ROP examinations performed.
Treatment versus sham electrical stimulation crossed over for
infants studied twice.
Demographic data was collected for all
subjects including birth weight, post-conception age at time of
delivery and at time of study, gender, twin status, level of supportive
care, significant medical problems, prenatal exposure to illicit
drugs, current medications, and level of physiologic stability
prior to and during study. Duration of ROP examination was noted,
as were all potential adverse events during the following 24 hours.
An ITO-F3 electroacupuncture unit, with
lead wires to four electromagnetic electrodes (3000 gauss/electrode)
applied to paired points on the hands (Hegu) and feet (Taichong),
delivered 1.3 Hz constant current at the lowest possible intensity
to treatment infants. Saliva was obtained by gentle aspiration
of the oral cavity prior to electrode placement, and again at
15 minutes after completion of ROP examination. Electrical stimulation
of treatment infants was discontinued upon completion of ROP examination.
All electrodes were removed after collection of the second saliva
Saliva samples were coded and stored
at -80 degree C pending analysis. Pre- and post-examination salivary
cortisol levels were determined by radioimmunoassay (Diagnostic
Products Corporation, Los Angeles, California), reported as ugms/dl.
Results reported as below detectable limits of the assay were
recorded as 0.05 ugms/dl.
Data was analyzed using BMDP statistical
software (Los Angeles, California). Differences were evaluated
pre-to-post ROP exam within each study group by using paired t-tests.
Between groups, comparison was performed using the Student's t-test
and Mann-Whitney rank-sums non-parametric analysis. Data for the
three crossover patients was included only once for between-group
comparisons; treatment (current on) pre and post-cortisol values
were used in this analysis. Statistical significance was determined
with critical alpha at 0.05. Preliminary data was then used to
estimate future sample size sufficient to show statistically significant
difference (within the realm of clinical relevance), assuming
maintenance of current trends and normalized distributions.
Twenty-two infants were enrolled; all
were not ultimately examined prior to discharge. One patient died
prior to ROP examination. Efforts to obtain sufficient quantities
of saliva were unsuccessful in five instances. Paired saliva samples
were available for 13 patients; three infants were studied twice
in a crossover manner, resulting in 16 total study events. Treatment
and control infants were comparable (Table 1).
No statistically significant differences were found between treatment
and control infants with respect to all demographic factors assessed,
including race, gender, twin status, birth weight, post-conception
age at birth and time of study, general level of NICU support,
prenatal drug exposure, including cocaine, important medical problems,
medications, and physiologic stability. No adverse effects were
observed in either group.
As shown in Table 2,
salivary cortisol concentration increased following ROI> exam
in both groups, although the change was statistically significant
only in control infants (P=0.0272). Comparison of the change in
salivary cortisol between control and treatment infants suggests
a trend towards blunting the salivary cortisol stress response
in infants receiving electrical stimulation (P=0.0592). A minimum
N of 192 paired samples would be needed to show statistical significance,
assuming continuation of the observed trends.
The potential negative effects of pain
and stress in premature infants have been widely appreciated,
prompting significant changes in the NICU environment, as well
as in sedation, analgesic, and anesthetic management for this
vulnerable population. There are, however, situations such as
ROP examination, where the risks of systemic sedation and/or
1 - Comparison of Control Versus Treatment Groups*
|BW in grams
[741 - 1515]
of exam in Minutes
* All comparisons
were statistically insignificant for difference. Birth weight
(BW), gestational age (GA) at birth, post-conception age at exam,
and duration of exam all expressed as means. GA and post-conception
age at exam expressed in weeks.
analgesia appear to outweigh the risk of procedure. Unfortunately,
topical anesthesia appears not to blunt the physiologic instability
associated with ROP examination (3).
Seeking an additional approach to patient
comfort under these circumstances, we investigated the potential
safety and efficacy of noninvasively delivered electrical stimulation
of acupuncture points and meridians in premature infants undergoing
ROP examination, using salivary cortisol as an immediate marker
of stress response. Our data suggests that premature infants respond
to ophthalmologic examination with a significant increase in salivary
cortisol, reflecting an increase in HPA activity. Although the
sample size was too small to assess efficacy, the data trended
toward blunting the rise in salivary cortisol provoked by ROP
exam stress. Electrical stimulation appeared to have been well
tolerated in this small study population.
2 - Cortisol data (ugm/dl)
comparing A cortisol between control and treatment infants.
This is the first report, to our knowledge,
of electrical stimulation of acupuncture meridians to relieve
pain and stress in infants. There is, however, substantial literature
describing electroacupuncture in small non-primates, showing increased
endorphin, mct-enkephalin and serotonin concentrations in blood
and cerebral spinal fluid (CSF) after electrical stimulation of
acupuncture points (16, 17), raising the possibility of similar
effect in humans.
The analgesic effects of electrical stimulation
of acupuncture points may be a function of the frequency of electrical
stimulation (16). Different receptors appear to be stimulated
by different currents, with low frequencies between 2 and 15 Hz
activating endorphin pathways (18), while higher frequencies lead
to the release of norepinephrine and/or serotonin without analgesia
(19). For this reason and out of concern for our patients' comfort,
we used the lowest possible frequency (1.3 Hz) and intensity delivered
by the ITO F-3 electroacupuncture unit.
Our point selection wa.s based upon Traditional
Chinese Medical (TCM) theory. TCM is derived from Buddhist, Taoist,
and more ancient Chinese philosophy (20), modified over at least
2,000 years by experience and observation, without reliance upon
scientific methodology. To briefly summarize, TCM postulates that
there exists a form of universal energy, Qi, flowing throughout
the body in channels, i.e. meridians (21). Hegu and Taichong are
Source points, said to contain Qi with the infant's first breath
(22). Both are used clinically to treat eye diseases, and provide
acupuncture anesthesia for eye surgery.
Our study was limited by its small sample
size of 13 infants, with only 3 crossed over to both conditions,
resulting in limited power to detect statistical difference in
cortisol response between the two groups. In the interest of safety,
only the lowest possible frequency and intensity of electrical
stimulation was applied. Possibly, more intense stimulation would
result in larger differences between control and treatment infants,
or, conversely, have the opposite effect. In addition, although
no apparent adverse effects were observed, given the small number
of patients studied under limited conditions, our data does not
allow the generalization that electrical stimulation of acupuncture
meridians is safe in all infants under more varied circumstances.
Lastly, our primary outcome indicator was salivary cortisol response.
Additional physiologic and behavioral measures of pain and stress
were not concurrently assessed, limiting our ability to correlate
cortisol response with other established indicators of neonatal
comfort and stability.
In conclusion, this pilot data demonstrates
that salivary cortisol is a useful marker of stress response to
ROP examination in premature infants. Electrical stimulation of
acupuncture points was easily applied without apparent toxicity.
A much larger study is necessary to determine if electrical stimulation
of acupuncture meridians is effective in significantly reducing
this stress response, and if so, to delineate the optimal characteristics
of the electrical stimulation applied. (Presented in part at the
Pediatric Anesthesiology Meeting, Feb. 1215, 1998, Phoenix, Arizona.)
The authors wish to thank Ms. Eileen
McNamara for her excellent technical support in determination
of salivary cortisol levels, and Dr. Jill Josephs for her thoughtful
comments during manuscript preparation.
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Dr. Lynnae Schwartz
is a Pediatrician/Anesthesiologist; her subspecialties include
Pediatric Anesthesia and Critical Care. Affiliations include Department
of Critical Care Medicine and Anesthesia, Children's National
Medical Center, Washington, DC, and George Washington University
School of Medicine, Washington, DC. Dr. Schwartz has a Master's
degree from the New England School of Acupuncture, 1996.
Lynnae Schwartz, M.D.
Department of Critical Care Medicine
Children's National Medical Center
111 Michigan Avenue, NW
Washington, DC 20010-2970
Phone: 202-884-3596 · Fax: 202-884-5724
· Email email@example.com
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