Apnea of Prematurity:

Diagnosis, Implications for Care,

and Pharmacologic Management
Karen TZleobaId RNC, MS, ARNP
Cad Botwinski, RNC, MS, ARNP
Stephanie Ahanna, RNC, MS, ARNP
Paula MC WiIIiam, MS, ARNP

PNEA OF PREMATURITY (AOP), ONE OF THE MOST

DIAGNOSIS
frequently diagnosed problems in the neonatal intenApnea of prematurity is a diagnosis of exclusion. The etiolsive care unit, contributes substantially to the length of hospiogy of apnea is multifactorial and can be the result of a numtalization for many premature infants.1,2 Apnea, the cessation
ber of pathophysiologic events. Whenever a preterm infant
of respiratory inflow, is a disorder of respiratory control comdevelops apnea, the underlying causes must be evaluated. The
mon in premature infants.
differential diagnosis could
Pathologic apnea is defined as a
include infection, metabolic disABSTRA~
turbances, respiratory comprorespiratory pause of greater than
Apnea is a disorder of respiratory control commonly
mise, cardiovascular (CV) distur20 seconds or any pause in respiseen in premature infants. Several mechanisms have been
bances, central nervous system
ration associated with cyanosis,
proposed to explain apnea, and many clinical conditions
(CNS) abnormalities, hematomarked pallor, hypotonia, or
have been associated with its development. Apnea of prelogic imbalance, gastrointestinal
bradycardia.3-5 Apnea of premamaturity is seen in infants less than 37 weeks gestation,
(GI) abnormalities, disturbances
turity is a pathologic apnea with
with the incidence increasing as gestational age decreases.
in thermoregulation, side effects
no definable cause in infants less
Expert and consistent nursing care is essential for manageof medication, or AOP.1,o~12 If
than 37 weeks gestational age,
ment of premature infants with apnea. This article reviews
an underlying cause is deterusually presenting between days
the differential diagnosis, pathogenesis, and implications for
care of apnea of prematurity.
mined, specific therapy should
2 aud 7 of life.
be directed at correcting the priThe incidence of apnea has
mary disease process. The diagbeen found to increase with
nosis of apnea of prematurity should be made only after the
decreasing gestatioual age. It has been estimated that 25 perexclusion of other causes.3,10,12
cent of all infants less than 34 weeks gestation have at least
Apnea is often one of the first signs of sepsis, pneumonia,
one apncic episode, and 50 to 80 percent of infants less than
necrotizing enterocolitis (NEC), or n~eningitis.1~8~1~12 The
30 weeks gestation experieuce aptlea.6-y Because recurrent
workup could include obtaining a complete blood cell count
apnea episodes can severely compromise the infants wellwith differential, C-reactive protein, and cultures including
being, the neonatal nurse needs to have a clear understanding

of its diagnosis, pathogenesis, and implications for care.

blood, urine, cerebrospinal fluid (CSF), and, if the infant is

1 .i lipd
,101 pLll>ll.lIion Srptrmhcr 1))) Rc\1\ci No\vmhcr IYYY
N I: o s A I-A I.
\()I, I). N

O (>. 51.1l~I~~113IrI< 2000

N E I \x o R K
I-

intubated, endotracheal. A chest x-ray (CXR) to evaluate for

pneumonia and an abdominal x-ray to rule out NEC should
be done. A complete physical examination is warranted, as is
an evaluation of the infants thermal and glucose stability. If
an infectious etiology is suspected, the infant should be
empirically started on antibiotics.8J0-13
Common metabolic disturbances associated with apnea
include hyponatremia, hypernatremia, hypoglycemia,
hypocalcemia, hypermagnesemia, hyperammonemia, and
acid/base disturbances. Evaluation of the infant would
include obtaining a blood gas, serum electrolytes (Na, K, CL,
and COz), magnesium, calcium, glucose, and possibly ammonia level. Any abnormalities found should be corrected.lJ-I2
Airway obstruction and lung disease (pulmonary edema,
atelectasis, and pneumonia) can impair oxygenation, increasing the frequency and severity of apneic episodes.1y8J-14
Respiratory compromise can be evaluated with a CXR, blood
gas, and oxygen saturation monitoring. The nursing assessment should include attention to the infants work of breathing, quality of breath sounds, and air exchange. The neonate
may need oxygen therapy, continuous positive airway pressure
(CPAI), or ventilation for support. Adjunctive therapies may
include chest physiotherapy, bronchodilators (inhaled or systemic), and diuretics.8J-13
Cardiovascular disturbances-including hypotension, patent
duct-us arteriosus, and congenital heart defects-can impair oxygen delivery to the tissues, leading to apnea and bradycardia.1J1~12~15 Neonates with prolongation of the QT interval have
an increased susceptibility to life-threatening ventricular arrhythmias that can be induced by conditions causing a sudden
increase in sympathetic activity. Apnea leading to a chemoreceptive reflex has been identified as a condition that could trigger an
arrhythmia. l5 The CV physical examination should focus on
color, heart sounds, murmurs, pulses, perfusion, blood pressure,
and pulse pressure. A CXR, oxygen saturation monitoring,
blood gas, echocardiogram, and electrocardiogram may be indicated. As the findings dictate, indomethacin, volume expansion,
vasopressor support, prostaglandin, or antiarrhythmia medications should be considered.1J1~12J5
Seizures, intraventricular hemorrhage, ventricular dilatation, CNS anomalies, and meningitis have been associated
with apnea. A neurologic physical examination, CSF evaluation, electroencephalogram, cranial ultrasound, and computed tomography scan of the brain may be indicated for further
evaluation. Based on the findings, treatment may include
antiseizure medications, antimicrobial therapy, or ventricular
decon~pression.8J0-13
The effect of anemia on apnea remains controversial in the
literature.10-12J6-19 The benefits of transfusion with packed
red blood cells may not justify the potential exposure of the
infant to blood-borne pathogens. The use of erythropoietin
and iron supplementation to help optimize the infants
hemoglobin may be of benetit.13~20

Gastrointestinal abnormalities-including abdominal distention associated with NEC, obstruction or dysmotility,

swallowing abnormalities, and gastroesophageal reflux
(GER)-have been known to contribute to the incidence of
apnea in preterm infants.1Js12
It is important to consider the thermal environment when
evaluating the infant with apnea because thermoregulation is
necessary for controlling neonatal respiration. Hypo- or
hyperthermia can precipitate an apneic episode. The trigeminal area of the face is particularly thermal sensitive. Blowing
cold oxygen in the face should be avoided. A core temperature between 36.5C and 37C (97.7F and 98.6F) may
reduce the incidence of apnea. Infants with bronchopulmonary dysplasia may have their own specific set point and
usually prefer to be cooler.8J-14J21
Medications administered to the infant-especially narcotics and sedatives-should also be considered as possible
causes for respiratory depression and apnea. Maternal smoking and use of cocaine have been coupled with apnea as
well.l,10~12~13
Although apnea of prematurity is often not associated with
a definable precipitating factor, many of the pathophysiologic
states just described may precipitate an episode. The bulbopontine respiratory centers responsible for generation of
breathing patterns are sensitive to many different stimuli that
may trigger apnea. Apneic episodes are a final response to a
multitude of adverse stimuli from incompletely organized and
only partially interconnected respiratory regulatory mechanisms. This differential must be considered and the appropriate clinical and laboratory evaluation carried out before the
infant can be considered to have idiopathic apnea of prematurity. 8,14,22
PATHOGENESIS
Three types of apnea occur in premature infants: central,
obstructive, and mixed. Central apnea is a pause in alveolar
ventilation caused by a lack of diaphragmatic activity. The
central nervous system fails to transmit a signal to the respiratory muscles, leading to the absence of airflow and respiratory
effort. Obstructive apnea is a pause in alveolar ventilation
caused by obstruction of the upper airway. There is an
absence of airflow with continued respiratory effort. During a
mixed apnea episode, a central apnea pause precedes and/or
follows an obstructive event. Mixed apnea is the most common form in premature infants, representing 40 to 80 percent of all episodes. 12,22m25 These divisions may be somewhat
artificial but provide a basis for understanding the pathogenesis, as reviewed in Tables 1 and 2, and the management of
apnea of prematurity.
CARE CONSIDERATIONS
Expert and consistent nursing care is essential to the management of premature infants with apnea. These infants often

StYi t..,\lREK 2 0 0 0 . VOl. I). N O . 6

exhibit subtle cues as to their apnea triggers.12,26

It is important that cardiac/apnea monitors be
on, with alarms set appropriately: the low heart
rate alarm at SO-100 bpm with a 20.second
apnea delay. When alarms are triggered, the
neonate should be assessed for color, perfusion,
position, respiratory rate and effort, heart rate,
oxygen saturation, and state. The type and
amount of stimulation required and any precipitating event should be recorded.12,25,27,28 If the
infant has frequent episodes, airway patency,
thermal stability, blood pressure, and glucose
regulation should be assessed and reported to
the nurse practitioner or physician.
Other nursing measures include maintaining
the infant in a neutral thermal environment
because any rapid fluctuation in temperature can
precipitate apneic episodes. Cold stress can
occur during transport or a procedure and may
produce apnea. l3 Attention to proper position
technique is essential in these infants. Prone
positioning with the head of the bed elevated
has been shown to improve oxygenation and
minute ventilation, decrease gastric emptying
time, and decrease the risk of GER and aspiration. It is important to avoid neck flexion as well
as hyperextension when positioning the infant to
d e c r e a s e t h e r i s k o f a i r w a y obstruction.8J2,13,21,24,29-32 Care331 attention to gastric
tube placement and position is indicated during
gavage feeding. The feeding should be given
slowly to avoid sudden gastric distension.
Nursing care can be structured so that the infant
has periods of undisturbed sleep. Providing the
infant with undisturbed nap periods of two
hours four times a day was shown to decrease
the incidence of apnea.33
Stimulation can be preventative or curative
for these infants. Sensory stimulation oscillating
beds have been used with mixed success to
decrease the frequency of apneic episodes. The
combined cutaneous and vestibuloproprioceptive sensory inputs these beds provide are
believed to stimulate breathing. Unfortunately,
some infants seem to habituate to the stimuli,
and the effect wears off.,, During an
episode, prompt tactile stimulation, such as rubbing the feet, is often sufficient to stop the
episode. When apneic episodes increase in frequency or fail to respond to gentle tactile stimulation and require vigorous stimulation, oxygen,
or bag and mask ventilation to resolve, other
therapies should be initiated.4,5

TABLE 1 n Pathogenesis of Central Apnea8,14,26,30~31,62

Etiology
Central immaturity

Mechanism
Decreased synaptic connections
Increased brain stem conduction times
Imbalance of positive and depressive respiratory
neurotransmitters (adenosine)

Alterations in CO, response

Immature central chemoreceptor activity

Smaller tidal volume changes in response to
triggered respiratory control mechanisms
Diaphragmatic fatigue

Hypoxia

Biphasic response: initial increase in respiratory

rate and then a decrease in respiratory rate
Immaturity of cerebral autoregulation causing
central chemoreceptors to sense false
elevation in oxygenation with resultant drop
in ventilation

Immature sleep patterns

More time spent in active sleep, a more

primitive state (for premature infants)
Increased respiratory irregularity and tidal
volume in active sleep
Maturation of sleep patterns coinciding with
resolution of apnea of prematurity

Pharmacology
Pharmacologic management of AOP includes
the use of methylxanthines. In this drug class,
aminophylline, theophylline, and caffeine are the
most common medications used in the management of apnea. Although they reduce the number and severity of events, they do not shorten
the overall course. AOP resolves only through
the maturation process. 3~36 Methylxanthines act
primarily on the respiratory center and brain
TABLE 2 m Pathogenesis of Obstructive Apnea*,14,636s

Etiology
Pharyngeal obstruction

Mechanism
Decreased ability to maintain pharyngeal
patency
Decreased ability to counteract collapsing
tendency of pharynx
Aggravation by neck flexion and improper
positioning
Uncoordinated movement between diaphragm
and upper airway muscles

Laryngeal obstruction

Smaller airway diameter of larynx in comparison

to trachea
Prolonged stimulation of laryngeal
chemoreceptors
Functional immaturity of irritant receptors

Reflux induced

Vagal mediated response secondary to acid

reflux exposure
Stimulation of mechano- and chemoreceptors in
larynx and nasopharynx
Esophageal pain leading to airway narrowing
due to hyperventilation
Beta-endorphin triggered release in response to
pain
Impaired oxygenation secondary to aspiration
pneumonitis

stem neurons to stimulate the CNS by increasing the sensitivity to catecholamines and blocking adenosine receptors, neurotransmitters that cause respiratory depression.10>34,35137
Additional actions of methylxanthines include enhancing
rhythmic respiratory drive, increasing respiratory rate,
decreasing the carbon dioxide (COI) threshold, improving
CO2 responsiveness, increasing resting pharyngeal muscle
t o n e , a n d r e d u c i n g r a p i d e y e m o v e m e n t sleep.34-36
Methylxanthines have also been shown to strengthen the
force of diaphragmatic contractions, increasing mean respiratory airflow and decreasing diaphragmatic fatigue.34l37 They
also increase metabolic rate, leading to relative hyperventilation and improved alveolar ventilation. The number of central, mixed, and obstructive events is reduced by methylxanthine therapy. These events are not completely abolished,
however, because mixed and obstructive events may require
cp~p.23,35,3840

The most common adverse effects of methylxanthines

include tachycardia, tachypnea, glucose instability, jitteriness,
restlessness, tremors, irritability, vomiting, and feeding intolerance. The medication increases metabolic rate and can lead to
decreased weight gain. A diuretic effect can occur with
methylxanthines and can potentiate electrolyte imbalance in the
infant. Aminophylline and theophylline have been shown to
affect sleep/wake state patterns. No long-term effect on
growth and development or sleep/wake cycles has been reported in the preterm infants treated for apnea, however.12y34,37,41,42
Because of the stimulant effect on the CNS, methylxanthines can decrease the seizure threshold level and predispose
infants to increased seizure activity. Methylxanthines and anticonvulsants interact at a kinetic and pharmacodynamic level.
Infants receiving methylxanthines and phenobarbital require
higher doses of methylxanthines to achieve a therapeutic level
and to control the apnea. Higher doses of phenobarbital may
be needed to achieve a therapeutic level for seizure contr01.~~~~~ Methylxanthines should be avoided in neonates with
dysrhythmias such as Wolff-Parkinson-White and supraventricular tachycardia because of the potential for development
of hypertension, premature ventricular contractions, or other
tachyarrhythmias. 41,44 Infants receiving methylxanthines are
also at increased risk of developing nephrocalcinosis and
osteopenia because renal excretion of calcium increases. This
effect is potentiated if the infant is concurrently receiving
mrosemide or dexamethasone.45
Aminophylline is the ethylenediamine salt of theophylline
and contains 70 to 85 percent anhydrous theophylline. The
pharmacokinetics of aminophylline and theophylline is the
same and can be considered jointly.34,41,46 Caffeine, theophylline, and aminophylline are equally effective in preventing
apnea and bradycardia episodes in premature infants. They
exert similar pharmacodynamic effects but vary in their
potency at specific receptor sites.34,37 Theophylline converts
N7-methylates to caffeine in the immature neonatal liver.

Approximately 60 percent of aminophylline or theophylline is

excreted unchanged by the kidney. The remainder is excreted
as caffeine. It has been inferred that the therapeutic respiratory stimulant effect of theophylline is provided by this conversion to caffeine.37
Theophylline and aminophylline have been shown to have
a greater effect on pulmonary compliance than caffeine. They
exhibit greater bronchodilatation, improve pulmonary blood
flow, and have an increased diuretic effect, all of which may
be beneficial to infants with chronic lung disease.13,37>47
Theophylline and aminophylline are both available as commercial preparations, with Food and Drug Administration
(FDA) approval for use in neonates with AOI?
In February 2000, the FDA approved the drug Cafcit (caffeine citrate) injection, produced by Roxanne Laboratories for
use in the treatment of AOP.48 With its fewer reported side
effects, caffeine use has many advantages over theophylline
and aminophylline in the NICU population. Theophylline
and aminophylline cause a greater increase in heart rate with a
more sustained and selective action on the cardiac muscle at a
lower serum level than does caffeine. Theophylline and
aminophylline also have more CNS effects, causing a greater
decrease in the seizure threshold and more alterations in
sleep/wake cycles. 34,37,47 Caffeine has a more rapid diflitsion
in the CSF, resulting in earlier effects, whereas theophylline
and aminophylline must first be metabolized. Caffeine is also
absorbed more rapidly than theophylline and aminophylline
when given enterally. Tachycardia, GI distress, and feeding
intolerance are reported less frequently with caffeine.34b7147
Because of their shorter half-life, dosing intervals are more
frequent for theophylline and aminophylline (two to four
times per day, versus one to two times for caffeine).
Theophylline and aminophylline exhibit more variations in
daily plasma levels at steady state than caffeine. Caffeine levels
are more stable, with a wider range between therapeutic and
toxic serum concentrations.34~37~47~49
Caffeine may also have a greater effect on the enhancement of diaphragmatic contraction, offering a greater
decrease in diaphragmatic fatigue.50 Unless bronchodilation is
desired, caffeine is recommended for the treatment of AOP
because of its potent respiratory stimulant effects, once-a-day
dosing, fewer reported side effects, stable predictable plasma
concentrations, and wide therapeutic range.13,34,35137147 With
its once-a-day dosing, it is often more cost-effective to use
caffeine.
Until the introduction of Cafcit, it was necessary for the
hospital pharmacy to prepare a caffeine solution, a time-consuming process, requiring precise compounding skills. Cafcit
is available in ready-to-use, 3 ml single-dose vials. Each vial of
Cafcit contains a concentration of 20 mg/ml caffeine citrate,
which is equivalent ot 10 mg/ml of caffeine base.48 It is
important to clearly distinguish between caffeine citrate and
caffeine base when ordering or dosing caffeine because caf-

feine base is twice as potent as caffeine.34>41>42 To reach a therapeutic serum level and steady state, a loading dose is given.
Loading doses range from 5 to 20 mg/kg of caffeine base
(equivalent to 10 to 40 mg/kg of caffeine citrate).
Maintenance doses range from 2.5 to 5 mg/kg of caffeine
base (equivalent to 5 to 10 mg/kg of caffeine citrate). It is
given once daily and should begin 24 hours after the loading
dose is given.41)42>49 Currently, Cafcit is available in parenteral
form and an oral preparation has recently become available.
Because caffeine is usually given orally, until then, a solution
can be made with 2.5 gm of caffeine anhydrous powder in
250 ml of water, yielding a final concentration of 10 mg/ml,
which is stable for four weeks refrigerated.42
The maintenance dose should be adjusted based on the
infants clinical response (efficacy and adverse reactions) and
serum caffeine levels. Steady-state levels can be obtained after
three to six days of treatment. Serum concentrations should be
monitored as clinically indicated. Some units routinely measure them once a week or every two weeks. Others feel that
caffeine levels are no longer considered absolutely necessary in
the management of infants with apnea.4,41,42 A therapeutic
trough serum level is 5 to 20 ug/ml. Side effects (especially
tachycardia, restlessness, and feeding intolerance) are reported
at levels greater than 20 pg/ml, with serum concentrations
greater than 40 to 50 ug/ml considered toxic.34,41p42
Doxapram hydrochloride is an analeptic agent with potent
respiratory and CNS stimulant properties sometimes used for
AOP refractory to methylxanthines. Some centers have
reported improvement in apnea density when theophylline
and doxapram were combined. j1,52 Doxapram increases afferent input from peripheral chemoreceptors to the respiratory
control center in the brain. The increased peripheral
chemoreceptor response may shorten the duration of respiratory pauses and prevent cyclic changes in ventilation that can
initiate apnea events. With changes in intracellular calcium
concentrations and adenosine diphosphate/adenosine
triphosphate ratios, doxapram increases phrenic nerve activity
and decreases diaphragmatic fatigue.53 Doxapram has been
shown to decrease the mean frequency of central apnea by 75
percent after two days of therapy. It can also improve inspiratory drive, minute ventilation, tidal volume, and mean respiratory flow and decrease PC02.s2,54
Because it has only a 30.minute half-life, doxapram must
be given by continuous intravenous (IV) infusion. Enteral
administration is not recommended because of poor absorption with variable serum levels and a reported association with
NEC.t315 An initial loading dose of 2.5-3 mg/kg IV, administered over 15-30 minutes, is followed by continuous infu
sion of 1 mg/kg/hour. Doxaprnm should be titrated to the
lowest dose at which apnea is controlled, with a maximum
dose of 2.5 mg/kg/hour.34,41
Doxapram should be used w,ith caution because the U.S.
product preparation does contain benzyl alcohol. At the

recommended dose range, an infant would receive 5-27

mg/kg/day of benzyl alcohol, with toxicity reported at
greater than 100 mg/kg/day. 34,41 Side effects of doxapram
can include signs of excessive CNS stimulation such as agitation, excessive crying, disturbed sleep, jitteriness, irritability,
and seizures. Hypertension, increased gastric residuals,
abdominal distention and vomiting, second-degree heart
block caused by QT interval prolongation (with return to
normal sinus rhythm after discontinuation of doxapram),
tachycardia, and hyperglycemia have also been reported.34,41,j6 The effects of doxapram are usually transient, lasting approximately one week. Doxapram is not considered
standard of care because its use requires continuous IV inmsion and it has the risk of benzyl alcohol toxicity.5
Other Interventions
In addition to the pharmacologic management described,
the nurse needs to consider other interventions in managing
an infant with AOP. A mild degree of hypoxia can induce respiratory inhibitory mechanisms and may predispose infants to
apnea and bradycardia.17,19>30T31 Oxygen administered at an
FiO;, 22-25 percent to help keep the oxygen saturation on
the higher side of normal may be a protective mechanism
decreasing the frequency and severity of AOP.16>17p30>31~57 In
the past, there has been a hesitance to administer oxygen to
premature infants as a treatment for AOP because of the risk
of retinopathy of prematurity (ROP). Although further
research is needed, studies have indicated that the risk of ROP
may actually increase with the fluctuations in oxygenation
associated with AOP and not with higher oxygen
saturations.31
Nasal CPAP enhances rhythmic control of breathing primarily by splinting the upper airway, opposing pharyngeal
collapse, and maintaining adequate resting lung volumes.
Oxygenation and gas exchange are thereby enhanced, with an
improved functional residual capacity.10J2~58 Positive airway
pressure can ease the work of breathing and improve lung
compliance. Nasal CPAP, administered via nasal prongs or a
nasal pharyngeal tube at 3 to 8 cm H20, has been shown to
be effective in treating mixed and obstructive apnea but not
central apnea.23,58,59
If severe apneic spells persist despite intervention, endotracheal intubation and ventilation are indicated. Initial settings
should be adjusted to prevent episodes of desaturation. To
minimize barotrauma, settings should be weaned to a minimum peak inspiratory pressure and positive end expiratory
pressure with a short inspiratory time. The infant may need to
remain on a low rate for a few weeks while the respiratory
control system matures.r0J2J3
Although AOP is common in the nursery, it resolves in
most infants by 40 weeks postconceptional age. Some premature infants, especially those born at less than 28 weeks gestational age, however, will continue to have episodcs.*xs

Eichenwald and colleagues found that approximately 32 percent of infants born between 24 and 26 weeks gestation and
13 percent of infants born at 28 weeks gestation continued to
have apnea beyond 38 weeks postconceptional age.60 There is
no consensus yet on the appropriate management of these
infants, but emphasis is on decreasing the number of episodes
so that the infant can be cared for at home. The use of home
monitors with methylxanthines remains controversial. The
American Academy of Pediatrics recommended guidelines for
hospital discharge of the high-risk neonate include that the
infant has demonstrated physiologic maturity and stable cardiorespiratory function of sufficient duration. Yet no recommendations have been made regarding duration, and the
decision to use home cardiorespiratory monitoring has been
left as a matter of individual clinical judgment.61 Although
much has been written on the incidence, pathogenesis, etiology, and treatment of AOP, the literature is lacking in defining
criteria for discharge of infants who have experienced significant apnea. Home monitoring use has not been proven to
prevent morbidity and mortality associated with apnea; however, most neonatologists feel that it is the best approach
available at this time.4
SUMMARY
With advances in neonatal care, the complexity of hospital
and posthospital care issues for these infants has increased.
Nursing care of the infant with apnea include knowledge of
its pathophysiology, careful evaluation of its potential causes,
and continual assessment of the infants response to therapeutic interventions. This allows for a rational approach to its
management, with nurses in the optimal position to provide
and coordinate the multidisciplinary support needed for these
infants and families. @
REFERENCES
1. Eichenwald EC, and Stark AR. 1992. Apnea of prematurity:
Etiology and management. Neonatal Respiratory Diseases 2( 1):
1-11.
2. Darnall RA, et al. 1997. Margin of safety for discharge after
apnea in preterm infants. Pediatrics lOO(5): 7955801.
3. Halliday H, McClure BG, and Reid M. 1998. Apnoeic attacks.
In Handbook of Neonatal Care, 4th ed., Bell A, and Reid M, eds.
London: WB Saunders, 252-259.
4. Gomella T, et al. 1999. Neonatology: Management, Procedures,
On-Call Problems, Diseases, and Drugs, 4th ed., Stamford,

Connecticut: Appleton & Lange, 494-498.

5. Stark A. 1998. Apnea. In Manual of Neonatal Care, 4th ed.,
Cloherty J, and Stark A, cds. Philadelphia: Lippincott Williams &
Wilkins, 374-378.
6. Barrington K, and Finer NN. 1990. Periodic breathing and
apnea in preterm infants, Pediatric Research27(2): 118121.
7. Barrington K, and Finer NN. 1991. The natural history of the
appearance of apnea of prematurity. Pediatric Research 29(4):
372-375

8. Miller MJ, and Martin RJ. 1992. Apnea of prematurity. Clinics

in Perinatology 19(4): 789-808.
9. Spitzer AR, and Fox WW. 1986. Infant apnea. Pediatric Clinics
of No&America 33(3): 561-581.
10. Austin S. 1995. Evaluation and management of apnea of prematurity In CSMC NICU Training Files [on-line]: www.neonatology.org/syllabus/apnea.html.
11. Cifuentes J, et al. 1998. Assessment and management of respiratory dysfunction. In Comprehensive Neonatal Nursing: A
Physiologic Perspective, 2nd ed., Kenner C, Lott JW, and
Flandermeyer AA, eds. Philadelphia: WB Saunders, 252-268.
12. Grisemer AN. 1990. Apnea of prematurity: Current management and nursing implications. Pediatric Nursing 16(6):
606-611.
13. Martin GI. 1993. Infant apnea. In Neonatologyfor the Clinician,
Pomerance JJ, and Richardson CJ, eds. Norwalk, Connecticut:
Appleton & Lange, 267-277.
14. Miller MJ, and Martin RJ. 1992. Pathophysiology of apnea of
prematurity. In Fetal and Neonatal Physiology, vol. 1, Polin RA,
and Fox WW, eds. Philadelphia: WB Saunders, 872-885.
15. Schwartz PJ, et al. 1998. Prolongation of the QT interval and
the sudden infant death syndrome. New En&and Journal o f
Medicine 338(24): 1708-1714.
16. Poets CF, et al. 1991. Oxygen saturation and breathing patterns
in infancy. Archives of Disease in Childhood 66( 5): 574-578.
17. Poets CF, et al. 1993. The relationship between bradycardia,
apnea, and hypoxemia in preterm infants. Pediatric Research
34( 3): 144-147.
18. Rigatto H, and Brady HP. 1972. Periodic breathing and apnea in
preterm infants: Hypoxia as a primary event. Pediatrics 50(2):
219-228.
19. Upton CJ, Milner AD, and Stokes GM. 1991. Apnoea,
bradycardia, and oxygen saturation in preterm infants.
Archives of Disease in Childhood 66(4): 38 l-385.
20. Sola M, and Christensen RD. 1997. Use of hematopoietic
growth factors in the NICU. Journal of Intensive Care Medicine
12(4): 187-205.
21. Hagedorn MI, Gardner SL, and Abman SH. 1998. Respiratory
disease. In Handbook of Neonatal Intensive Care, 4th ed.,
Merenstein GB, and Gardner SL, eds. St. Louis: Mosby-Year
Book, 437495.
22. Ruggins NR. 1991. Pathophysiology of apnoea in preterm
infants. Archives of Disease in Childhood 66( 1 spec. no.): 70-73.
23. Finer NN, et al. 1992. Obstructive, mixed, and central apnea in
the neonate: Physiologic correlates. Journal of Pediatrics 121(6):
943-950.
24. Kurlak LO, Ruggins NR, and Stephenson TJ. 1994. Effect of
nursing position on incidence, type, and duration of clinically
significant apnoea in preterm infants. Archives of Disease in
Childhood. Fetaland Neonatal Edition 71( 1): F16-F19.
25. Mathew OP, Thoppil CK, and Belan M. 1991. Motor activity
and apnea in preterm infants. Is there a causal relationship?
American Review of Respiratory Disease 144(4): 842-844.

26. Blackburn ST, and Loper DL. 1992. Maternal, Fetal, a n d

Neonatal Physiology: A Clinical Perspective. Philadelphia: WB
Saunders, 292-297,560-565.
27. Garcia AI, and White-Tram R 1993. Preterm infants responses
to taste/smell and tactile stimulation during an apneic episode.
Journal of Pediatric Nursing: Nursing Care of Children and
Families8(4): 245-252.

28. Pierce JR, and Turner BS. 1998. Physiologic monitoring. I n

Handbook of Neonatal Intensive Care, 4th ed., Merenstein GB,
and Gardner SL, eds. St. Louis: Mosby-Year Book, 116-128.
29. Jenni OG, et al. 1997. Effect of nursing in the head elevated tilt
position (15 degrees) on the incidence of bradycardic and
hypoxemic episodes in preterm infants. Pediatrics lOO(4):
622-625.
30. Lagercrantz H. 1992. What does the preterm infant breathe for?
Controversies on apnea of prematurity. Acta Paediatrica 8 l( 10):
733-736.
31. Lagercrantz H. 1995. Improved understanding of respiratory
control: Implications for the treatment of apnoea. European
Journal of Pediatrics 154(8 supplement 3): SlO-S12.
32. Thach BT, and Stark AR 1979. Spontaneous neck flexion and
airway obstruction during apneic spells in preterm infants.
Journal ofPediatrics94(2): 275-281.

33. Torres C, et al. 1997. Effect of standard rest periods on apnea

and weight gain in preterm infants. Neonatal Network 16(8):
3543.
34. Aranda JV, et al. 1992. Drug treatment of neonatal apnea. In
Pediatric Pharmacology: %erapeutic Principles in Practice, 2nd
ed., Yaffe SJ, and Aranda JV, eds. Philadelphia: WB Saunders,
193-204.
35. Calhoun LK. 1996. Pharmacologic management of apnea of
prematurity. Journal of Perinatal and Neonatal Nursing 9(4):
56-62.
36. Frank M. 1987. Theophylline: A closer look. Neonatal Network
6(2): 7-13.
37. Larsen PB, et al. 1995. Aminophylline versus caffeine citrate for
apnea and bradycardia prophylaxis in premature neonates. Acta
Paediatrica 84(4): 360-364.

38. Kattwinkel J, et al. 1975. Apnea of prematurity: Comparative

therapeutic effects of cutaneous stimulation and nasal continuous
positive airway pressure. Journal of Pediatrics 86(4): 588-592.
39. Muttitt SC, et al. 1988. Neonatal apnea: Diagnosis by nurse verSLIS computer. Pediatrics 82( 1): 713-720.
40. Upton CJ, Milner AD, and Stokes GM. 1992. Response to
obstruction in preterm infants with apnea. Pediatric Pz~lmonology
14(4): 233-238.
41. Taketomo CK, Hodding JH, and Kraus DM. 1997. Pediatric
Dosage Handbook, 4th ed. Hudson, Ohio: Lexi-Camp.
42. Young TE, and Mangum OB. 1998. NeoFax, 11 th ed. Raleigh,
North Carolina: Acorn, 147-149, 186189,206-207.
43. Yokoyama H, et al. 1997. Therapeutic doses of theophyllinc
exerts proconvulsant effects. Brain and Development 19(6):
403407.
44. Mehta A, et al. 1997. <:.rffeine and cardiac arrhythmias. Acta
~hrdiol~~qica 52( 3): 273A-283A.

45. Zanardo V, et al. 1995. Methylxanthines increase renal calcium

excretion in preterm infants. Biology of the Neonate 68(3):
169-l 74.
46. al-Omran A, and &Alaiyan S. 1997. Theophylline concentration
following equal doses of intravenous aminophylline and oral
theophylline in preterm infants. American J o u r n a l o f
Perinatology 14(3): 147-149.
47. Scanlon JE, et al. 1992. Caffeine or theophylline for neonatal
apnoca? Archives of Disease in Childhood 67(4 spec. no.):
425428.
48. Medscape. February 17,200O. FDA approves new medication to
treat respiratory disorder in infants. MedscapeWire [online]:
1~ttp://pediatrics.medscape.com/medscapewire/2000/0200/
medwire.0217.FDA.html.
4 9 . Sayles R, and McCarthy J, eds. 1995. A C H N e o n a t a l
Formulary. (Available from the Department of Neonatology,
Box 7565, All Childrens Hospital, 801 Sixth Street, South, St.
Petersburg, FL 33701.)
50. Gorgeli A, Ozesmi C, and Ozesmi M. 1995. The effects of theophylline and caffeine on the diaphragm. Acta Physiologica 45(2):
105A-113A.
51. Brion LP, et al. 1991. Low-dose doxapram for apnea unresponsive to aminophylline in VLBW infants. Journal of Perinatology
ll(4): 359-364.
52. Peliowslci A, and Finer NN. 1990. A blinded, randomized, placebo-controlled trial to compare theophylline and doxapram for
the treatment of apnea of prematurity. Journal of Pediatrics
116(4): 648-653.
53. McGuire M, Carey MF, and OConnor JJ. 1997. Almitrine and
doxapram decrease fatigue and increase subsequent recovery in
isolated rate diaphragm. Journal of Applied Physiology 83( 1):
52-58.
54. Bairam A, et al. 1992. Doxapram for the initial treatment of idiopathic apnea of prematurity. Biology of the Neonate 61(4):
209-213.
55. Bairam A, et al. 1991. Gastrointestinal absorption of doxapram
in neonates. American Journal of Perinatology 8(2): 110-l 13.
56. De Villiers GS, et al. 1998. Second-degree atrioventricular heart
block after doxapram administration. Journal of Pediatrics
133( 1): 149-150.
57. Spear ML, Stefano JL, and Spitzer AR 1992. Prolonged apnea
and oxyhemoglobin desaturation in asymptomatic premature
infants. Pediatric Pulmonology 13(3): 151-154.
58. Hannam S, Ingram DM, and Milner AD. 1998. A possible role
for the Hering-Breuer deflation reflex in apnea of prematurity.
Journal of Pediatrics 132( 1): 35-39.
59. Miller MJ, Carlo WA, and Martin RJ. 1985. Continuous positive
airway pressure selectively reduces obstructive apnea in preterm
infants. Journal of Pediatrics 106(6): 91-94.
60. Eichenwald EC, Aina AJ, and Stark AR. 1997. Apnea frequently
persists beyond term gestation in infants delivered at 24 to 28
weeks. Pediatrics lOO(3): 354359.
61. American Academy of Pediatrics. 1998. Hospital discharge of the
high-risk neonate-Proposed guidelines. Pediatrics 102(2):
411417.

62. Rigatto H. 1992. Maturation of breathing. Clinics in

Perinatology 19(4): 739-756.
63. de1 Rosario JF, and Orenstein SR 1996. Evaluation and management of gastroesophageal reflux and pulmonary disease.
Current Opinion in Pediatrics 8( 3): 209-2 15.
64. Novak DA. 1996. Gastroesophageal reflux in the preterm infant.
Clinics in Perinatology 23(2): 305-320.

65. Thach BT. 1997. Reflux associated apnea in infants: Evidence for
a laryngeal chemoreflex. American Journal of Medicine 103( 5A):
12OS-124s.

proud To cd lxdzas &me.

Vorth area offer-s everythingfrom urban lofts

Buylorl diversefacthties o/fer somethinglor everyone. Suburban

and rural hospitals that combine cutting edge technology with
highly personalized care. And, the States second largest urban
teaching and research hospttal Fine tune your career through
educational and prolessional development programs too varied
and numerow to list. Creute the benefits pahage that& your
unique situation from a choice 01 benefits that will meet your
needs. Enjoy the prestige and satisjaction of a Baylor career

This individual will provide Care Coordination

jar complex infants in the NJCL! Interdisciplinary
communication, stalfdevefopment and NICQ2000
project involvement WIJJ also be priorttics.
Q.tal$icd indivtduals for thts and other
NNP posltlons must be Master: prepared.
Hours are 7:00am-3:30pm M-F
Tojtnd out all the details on our current job openmgs,
n[lyly on line at: wwnhaylorhealthxo~johs
Forward II resume or appJy in person to:

Baylor Health Care System

3500 Gaston, Dahar, 7X 75246

E-Mail: Careers@Baylordallas.edu

About the Authors

Karen lbeobald is a neonatal nurse practitioner in a 60.bed, Level
III NICU at All Childrens Hospital, St. Petersburg, Florida. She
received her BSNfiom Russell SaBe College Troy, New York. She worked
as a staff nurse and transport nurse for many years at the Universizy of
North Carolina Hospitals. She received her cert&ate as an NNPfiom
All Children-s Hospital in 1989 and completed her MS as a neonatal
nurse practitioner at SUm Stony Brook, in 1998. She is a member of
NANN and S&ma Theta Tau International and is on the board of
directorsfor the Florida Association of NNPs.
Carol Botwinski is a neonatal nurse practitioner in the NICU at All
Childrens Hospital. She received her nursing diploma from WesleyPassavant School of Nursing, Chicago, and her certificate as an NNP
from All Childrens Hospital in 1985. She received her BS from the
University of St. Francis, Joliet, Illinois, and completed her MS as an
NNPfi-om SUNS Stony Brook, in 1999. She is currentLy enrolled in the
doctoral proflram at Nova Southeastern University. She is a member of
NANN, Florida Association of NNPs, and Sigma Theta Tau
International.
Stepbanie Albanna is a neonatal nurse practitioner in the NICU at
ALL Childrens Hospital. She received her BSN from the University of
Cincinnati in 1996, earned her cert$icate as an NNP in 1992jFom the
University of Health Sciences in Jacksonville, and completed her MS as
an NNPfrom S w Stony Brook, in 1998. She is a member of NA NN,
Florida Association of NNPs, and S&ma Theta Tau International. She
is the proud mother of a new baby boy.
Paula McWilLiam is a neonatal nurse practitioner in the NICU at
All Children% Hospital. She received her BSN fvom Barry University,
Miami, Florida, earned her certificate as an NNPfi-om West Virginia
University, and completed her MS as an NNPfi-om SUNy Stony Brook,
in 1998. She is currently enrolled in the doctoral program at Nova
Southeastern University.

For further information, please contact:

Karen Theobald, RNC, MS, ARNP
All Childrens Hospital
Department 6200
801 Sixth Street South
St. Petersburg, FL 33701