Apnea of Prematurity:Diagnosis, Implications for Care,

and Pharmacologic Management

Karen TZleobaId RNC, MS, ARNPCad Botwinski, RNC, MS, ARNP

Stephanie Ahanna, RNC, MS, ARNPPaula MC WiIIiam, MS, ARNP

A PNEA OF PREMATURITY (AOP), ONE OF THE MOST D I A G N O S I Sfrequently diagnosed problems in the neonatal inten- Apnea of prematurity is a diagnosis of exclusion. The etiol-sive care unit, contributes substantially to the length of hospi- ogy of apnea is multifactorial and can be the result of a num-talization for many premature infants.1,2 Apnea, the cessation ber of pathophysiologic events. Whenever a preterm infantof respiratory inflow, is a disorder of respiratory control com- develops apnea, the underlying causes must be evaluated. Themon in p remature in fan ts . differential diagnosis couldPathologic apnea is defined as a

ABSTRA~include infection, metabolic dis-

respiratory pause of greater than20 seconds or any pause in respi- Apnea is a disorder of respiratory control commonly

turbances, respiratory compro-mise, cardiovascular (CV) distur-

ration associated with cyanosis, seen in premature infants. Several mechanisms have beenproposed to explain apnea, and many clinical conditions

bances, central nervous systemmarked pa l lo r , hypo ton ia , o r (CNS) abnormalities, hemato-bradycardia.3-5 Apnea of prema-

have been associated with its development. Apnea of pre-maturity is seen in infants less than 37 weeks gestation,

logic imbalance, gastrointestinal

turity is a pathologic apnea with with the incidence increasing as gestational age decreases. (GI) abnormalities, disturbancesno definable cause in infants less Expert and consistent nursing care is essential for manage- in thermoregulation, side effectsthan 37 weeks gestational age, ment of premature infants with apnea. This article reviews of medication, or AOP.1,o~12 Ifusually presenting between days the differential diagnosis, pathogenesis, and implications for an underlying cause is deter-2 aud 7 of life. care of apnea of prematurity. mined, specific therapy should

The incidence of apnea has be directed at correcting the pri-been found to increase with mary disease process. The diag-decreasing gestatioual age. It has been estimated that 25 per- nosis of apnea of prematurity should be made only after thecent of all infants less than 34 weeks gestation have at least exclusion of other causes.3,10,12one apncic episode, and 50 to 80 percent of infants less than Apnea is often one of the first signs of sepsis, pneumonia,30 weeks gestation experieuce aptlea.6-y Because recurrent necrotizing enterocolitis (NEC), or n~eningitis.1~8~1~12 Theapnea episodes can severely compromise the infants well- workup could include obtaining a complete blood cell countbeing, the neonatal nurse needs to have a clear understanding with differential, C-reactive protein, and cultures includingof its diagnosis, pathogenesis, and implications for care. blood, urine, cerebrospinal fluid (CSF), and, if the infant is

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intubated, endotracheal. A chest x-ray (CXR) to evaluate forpneumonia and an abdominal x-ray to rule out NEC shouldbe done. A complete physical examination is warranted, as isan evaluation of the infants thermal and glucose stability. Ifan infectious etiology is suspected, the infant should beempirically started on antibiotics.8J0-13

Common metabolic disturbances associated with apneainclude hyponatremia, hypernatremia, hypoglycemia,hypocalcemia, hypermagnesemia, hyperammonemia, andacid/base disturbances. Evaluation of the infant wouldinclude obtaining a blood gas, serum electrolytes (Na, K, CL,and COz), magnesium, calcium, glucose, and possibly ammo-nia level. Any abnormalities found should be corrected.lJ-I2

Airway obstruction and lung disease (pulmonary edema,atelectasis, and pneumonia) can impair oxygenation, increas-ing the frequency and severity of apneic episodes.1y8J-14Respiratory compromise can be evaluated with a CXR, bloodgas, and oxygen saturation monitoring. The nursing assess-ment should include attention to the infants work of breath-ing, quality of breath sounds, and air exchange. The neonatemay need oxygen therapy, continuous positive airway pressure(CPAI), or ventilation for support. Adjunctive therapies mayinclude chest physiotherapy, bronchodilators (inhaled or sys-temic), and diuretics.8J-13

Cardiovascular disturbances-including hypotension, patentduct-us arteriosus, and congenital heart defects-can impair oxy-gen delivery to the tissues, leading to apnea and bradycar-dia.1J1~12~15 Neonates with prolongation of the QT interval havean increased susceptibility to life-threatening ventricular arrhyth-mias that can be induced by conditions causing a suddenincrease in sympathetic activity. Apnea leading to a chemorecep-tive reflex has been identified as a condition that could trigger anarrhythmia. l5 The CV physical examination should focus oncolor, heart sounds, murmurs, pulses, perfusion, blood pressure,and pulse pressure. A CXR, oxygen saturation monitoring,blood gas, echocardiogram, and electrocardiogram may be indi-cated. As the findings dictate, indomethacin, volume expansion,vasopressor support, prostaglandin, or antiarrhythmia medica-tions should be considered.1J1~12J5

Seizures, intraventricular hemorrhage, ventricular dilata-tion, CNS anomalies, and meningitis have been associatedwith apnea. A neurologic physical examination, CSF evalua-tion, electroencephalogram, cranial ultrasound, and comput-ed tomography scan of the brain may be indicated for furtherevaluation. Based on the findings, treatment may includeantiseizure medications, antimicrobial therapy, or ventriculardecon~pression.8J0-13

The effect of anemia on apnea remains controversial in theliterature.10-12J6-19 The benefits of transfusion with packedred blood cells may not justify the potential exposure of theinfant to blood-borne pathogens. The use of erythropoietinand iron supplementation to help optimize the infantshemoglobin may be of benetit.13~20

Gastrointestinal abnormalities-including abdominal dis-tention associated with NEC, obstruction or dysmotility,swallowing abnormalities, and gastroesophageal reflux(GER)-have been known to contribute to the incidence ofapnea in preterm infants.1Js12

It is important to consider the thermal environment whenevaluating the infant with apnea because thermoregulation isnecessary for controlling neonatal respiration. Hypo- orhyperthermia can precipitate an apneic episode. The trigemi-nal area of the face is particularly thermal sensitive. Blowingcold oxygen in the face should be avoided. A core tempera-ture between 36.5C and 37C (97.7F and 98.6F) mayreduce the incidence of apnea. Infants with bronchopul-monary dysplasia may have their own specific set point andusually prefer to be cooler.8J-14J21

Medications administered to the infant-especially nar-cotics and sedatives-should also be considered as possiblecauses for respiratory depression and apnea. Maternal smok-ing and use of cocaine have been coupled with apnea aswell.l,10~12~13

Although apnea of prematurity is often not associated witha definable precipitating factor, many of the pathophysiologicstates just described may precipitate an episode. The bulbo-pontine respiratory centers responsible for generation ofbreathing patterns are sensitive to many different stimuli thatmay trigger apnea. Apneic episodes are a final response to amultitude of adverse stimuli from incompletely organized andonly partially interconnected respiratory regulatory mecha-nisms. This differential must be considered and the appropri-ate clinical and laboratory evaluation carried out before theinfant can be considered to have idiopathic apnea of prematu-rity. 8,14,22

P A T H O G E N E S I SThree types of apnea occur in premature infants: central,

obstructive, and mixed. Central apnea is a pause in alveolarventilation caused by a lack of diaphragmatic activity. Thecentral nervous system fails to transmit a signal to the respira-tory muscles, leading to the absence of airflow and respiratoryeffort. Obstructive apnea is a pause in alveolar ventilationcaused by obstruction of the upper airway. There is anabsence of airflow with continued respiratory effort. During amixed apnea episode, a central apnea pause precedes and/orfollows an obstructive event. Mixed apnea is the most com-mon form in premature infants, representing 40 to 80 per-cent of all episodes. 12,22m25 These divisions may be somewhatartificial but provide a basis for understanding the pathogene-sis, as reviewed in Tables 1 and 2, and the management ofapnea of prematurity.

CARE CONSIDERATIONSExpert and consistent nursing care is essential to the man-

agement of premature infants with apnea. These infants often

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exhibit subtle cues as to their apnea triggers.12,26It is important that cardiac/apnea monitors beon, with alarms set appropriately: the low heartrate alarm at SO-100 bpm with a 20.secondapnea delay. When alarms are triggered, theneonate should be assessed for color, perfusion,position, respiratory rate and effort, heart rate,oxygen saturation, and state. The type andamount of stimulation required and any precipi-tating event should be recorded.12,25,27,28 If theinfant has frequent episodes, airway patency,thermal stability, blood pressure, and glucoseregulation should be assessed and reported tothe nurse practitioner or physician.

Other nursing measures include maintainingthe infant in a neutral thermal environmentbecause any rapid fluctuation in temperature canprecipitate apneic episodes. Cold stress canoccur during transport or a procedure and mayproduce apnea. l3 Attention to proper positiontechnique is essential in these infants. Pronepositioning with the head of the bed elevatedhas been shown to improve oxygenation andminute ventilation, decrease gastric emptyingtime, and decrease the risk of GER and aspira-tion. It is important to avoid neck flexion as wellas hyperextension when positioning the infant tod e c r e a s e t h e r i s k o f a i r w a y obstruc-tion.8J2,13,21,24,29-32 Care331 attention to gastrictube placement and position is indicated duringgavage feeding. The feeding should be givenslowly to avoid sudden gastric distension.Nursing care can be structured so that the infanthas periods of undisturbed sleep. Providing theinfant with undisturbed nap periods of twohours four times a day was shown to decreasethe incidence of apnea.33

Stimulation can be preventative or curativefor these infants. Sensory stimulation oscillatingbeds have been used with mixed success todecrease the frequency of apneic episodes. Thecombined cutaneous and vestibulopropriocep-tive sensory inputs these beds provide arebelieved to stimulate breathing. Unfortunately,some infants seem to habituate to the stimuli,and the effect wears off.,, During anepisode, prompt tactile stimulation, such as rub-bing the feet, is often sufficient to stop theepisode. When apneic episodes increase in fre-quency or fail to respond to gentle tactile stimu-lation and require vigorous stimulation, oxygen,or bag and mask ventilation to resolve, othertherapies should be initiated.4,5

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

EtiologyCentral immaturity

Alterations in CO, response

Hypoxia

Immature sleep patterns

Mechanism

Decreased synaptic connectionsIncreased brain stem conduction timesImbalance of positive and depressive respiratory

neurotransmitters (adenosine)

Immature central chemoreceptor activitySmaller tidal volume changes in response to

triggered respiratory control mechanismsDiaphragmatic fatigue

Biphasic response: initial increase in respiratoryrate and then a decrease in respiratory rate

Immaturity of cerebral autoregulation causingcentral chemoreceptors to sense falseelevation in oxygenation with resultant dropin ventilation

More time spent in active sleep, a moreprimitive state (for premature infants)

Increased respiratory irregularity and tidalvolume in active sleep

Maturation of sleep patterns coinciding withresolution of apnea of prematurity

PharmacologyPharmacologic management of AOP includes

the use of methylxanthines. In this drug class,aminophylline, theophylline, and caffeine are themost common medications used in the manage-ment of apnea. Although they reduce the num-ber and severity of events, they do not shortenthe overall course. AOP resolves only throughthe maturation process. 3~36 Methylxanthines actprimarily on the respiratory center and brain

TABLE 2 m Pathogenesis of Obstructive Apnea*,14,636s

Etiology

Pharyngeal obstruction

MechanismDecreased ability to maintain pharyngeal

patencyDecreased ability to counteract collapsing

tendency of pharynxAggravation by neck flexion and improper

positioning

Laryngeal obstruction

Uncoordinated movement between diaphragmand upper airway muscles

Smaller airway diameter of larynx in comparisonto trachea

Prolonged stimulation of laryngealchemoreceptors

Reflux induced

Functional immaturity of irritant receptors

Vagal mediated response secondary to acidreflux exposure

Stimulation of mechano- and chemoreceptors inlarynx and nasopharynx

Esophageal pain leading to airway narrowingdue to hyperventilation

Beta-endorphin triggered release in response topain

Impaired oxygenation secondary to aspirationpneumonitis

stem neurons to stimulate the CNS by increasing the sensitiv-ity to catecholamines and blocking adenosine receptors, neu-rotransmitters that cause respiratory depression.10>34,35137Additional actions of methylxanthines include enhancingrhythmic respiratory drive, increasing respiratory rate,decreasing the carbon dioxide (COI) threshold, improvingCO2 responsiveness, increasing resting pharyngeal muscletone , and reduc ing rap id eye movement sleep.34-36Methylxanthines have also been shown to strengthen theforce of diaphragmatic contractions, increasing mean respira-tory airflow and decreasing diaphragmatic fatigue.34l37 Theyalso increase metabolic rate, leading to relative hyperventila-tion and improved alveolar ventilation. The number of cen-tral, mixed, and obstructive events is reduced by methylxan-thine therapy. These events are not completely abolished,however, because mixed and obstructive events may requirecp~p.23,35,3840

The most common adverse effects of methylxanthinesinclude tachycardia, tachypnea, glucose instability, jitteriness,restlessness, tremors, irritability, vomiting, and feeding intoler-ance. The medication increases metabolic rate and can lead todecreased weight gain. A diuretic effect can occur withmethylxanthines and can potentiate electrolyte imbalance in theinfant. Aminophylline and theophylline have been shown toaffect sleep/wake state patterns. No long-term effect ongrowth and development or sleep/wake cycles has been report-ed in the preterm infants treated for apnea, however.12y34,37,41,42

Because of the stimulant effect on the CNS, methylxan-thines can decrease the seizure threshold level and predisposeinfants to increased seizure activity. Methylxanthines and anti-convulsants interact at a kinetic and pharmacodynamic level.Infants receiving methylxanthines and phenobarbital requirehigher doses of methylxanthines to achieve a therapeutic leveland to control the apnea. Higher doses of phenobarbital maybe needed to achieve a therapeutic level for seizure con-tr01.~~~~~ Methylxanthines should be avoided in neonates withdysrhythmias such as Wolff-Parkinson-White and supraven-tricular tachycardia because of the potential for developmentof hypertension, premature ventricular contractions, or othertachyarrhythmias. 41,44 Infants receiving methylxanthines arealso at increased risk of developing nephrocalcinosis andosteopenia because renal excretion of calcium increases. Thiseffect is potentiated if the infant is concurrently receivingmrosemide or dexamethasone.45

Aminophylline is the ethylenediamine salt of theophyllineand contains 70 to 85 percent anhydrous theophylline. Thepharmacokinetics of aminophylline and theophylline is thesame and can be considered jointly.34,41,46 Caffeine, theo-phylline, and aminophylline are equally effective in preventingapnea and bradycardia episodes in premature infants. Theyexert similar pharmacodynamic effects but vary in theirpotency at specific receptor sites.34,37 Theophylline convertsN7-methylates to caffeine in the immature neonatal liver.

Approximately 60 percent of aminophylline or theophylline isexcreted unchanged by the kidney. The remainder is excretedas caffeine. It has been inferred that the therapeutic respirato-ry stimulant effect of theophylline is provided by this conver-sion to caffeine.37

Theophylline and aminophylline have been shown to havea greater effect on pulmonary compliance than caffeine. Theyexhibit greater bronchodilatation, improve pulmonary bloodflow, and have an increased diuretic effect, all of which maybe beneficial to infants with chronic lung disease.13,37>47Theophylline and aminophylline are both available as com-mercial preparations, with Food and Drug Administration(FDA) approval for use in neonates with AOI?

In February 2000, the FDA approved the drug Cafcit (caf-feine citrate) injection, produced by Roxanne Laboratories foruse in the treatment of AOP.48 With its fewer reported sideeffects, caffeine use has many advantages over theophyllineand aminophylline in the NICU population. Theophyllineand aminophylline cause a greater increase in heart rate with amore sustained and selective action on the cardiac muscle at alower serum level than does caffeine. Theophylline andaminophylline also have more CNS effects, causing a greaterdecrease in the seizure threshold and more alterations insleep/wake cycles. 34,37,47 Caffeine has a more rapid diflitsionin the CSF, resulting in earlier effects, whereas theophyllineand aminophylline must first be metabolized. Caffeine is alsoabsorbed more rapidly than theophylline and aminophyllinewhen given enterally. Tachycardia, GI distress, and feedingintolerance are reported less frequently with caffeine.34b7147

Because of their shorter half-life, dosing intervals are morefrequent for theophylline and aminophylline (two to fourtimes per day, versus one to two times for caffeine).Theophylline and aminophylline exhibit more variations indaily plasma levels at steady state than caffeine. Caffeine levelsare more stable, with a wider range between therapeutic andtoxic serum concentrations.34~37~47~49

Caffeine may also have a greater effect on the enhance-ment of diaphragmatic contraction, offering a greaterdecrease in diaphragmatic fatigue.50 Unless bronchodilation isdesired, caffeine is recommended for the treatment of AOPbecause of its potent respiratory stimulant effects, once-a-daydosing, fewer reported side effects, stable predictable plasmaconcentrations, and wide therapeutic range.13,34,35137147 Withits once-a-day dosing, it is often more cost-effective to usecaffeine.

Until the introduction of Cafcit, it was necessary for thehospital pharmacy to prepare a caffeine solution, a time-con-suming process, requiring precise compounding skills. Cafcitis available in ready-to-use, 3 ml single-dose vials. Each vial ofCafcit contains a concentration of 20 mg/ml caffeine citrate,which is equivalent ot 10 mg/ml of caffeine base.48 It isimportant to clearly distinguish between caffeine citrate andcaffeine base when ordering or dosing caffeine because caf-

feine base is twice as potent as caffeine.34>41>42 To reach a ther-apeutic 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 caffeinebase (equivalent to 5 to 10 mg/kg of caffeine citrate). It isgiven once daily and should begin 24 hours after the loadingdose is given.41)42>49 Currently, Cafcit is available in parenteralform and an oral preparation has recently become available.Because caffeine is usually given orally, until then, a solutioncan be made with 2.5 gm of caffeine anhydrous powder in250 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 theinfants clinical response (efficacy and adverse reactions) andserum caffeine levels. Steady-state levels can be obtained afterthree to six days of treatment. Serum concentrations should bemonitored as clinically indicated. Some units routinely mea-sure them once a week or every two weeks. Others feel thatcaffeine levels are no longer considered absolutely necessary inthe management of infants with apnea.4,41,42 A therapeutictrough serum level is 5 to 20 ug/ml. Side effects (especiallytachycardia, restlessness, and feeding intolerance) are reportedat levels greater than 20 pg/ml, with serum concentrationsgreater than 40 to 50 ug/ml considered toxic.34,41p42

Doxapram hydrochloride is an analeptic agent with potentrespiratory and CNS stimulant properties sometimes used forAOP refractory to methylxanthines. Some centers havereported improvement in apnea density when theophyllineand doxapram were combined. j1,52 Doxapram increases affer-ent input from peripheral chemoreceptors to the respiratorycontrol center in the brain. The increased peripheralchemoreceptor response may shorten the duration of respira-tory pauses and prevent cyclic changes in ventilation that caninitiate apnea events. With changes in intracellular calciumconcentrations and adenosine diphosphate/adenosinetriphosphate ratios, doxapram increases phrenic nerve activityand decreases diaphragmatic fatigue.53 Doxapram has beenshown to decrease the mean frequency of central apnea by 75percent after two days of therapy. It can also improve inspira-tory drive, minute ventilation, tidal volume, and mean respi-ratory flow and decrease PC02.s2,54

Because it has only a 30.minute half-life, doxapram mustbe given by continuous intravenous (IV) infusion. Enteraladministration is not recommended because of poor absorp-tion with variable serum levels and a reported association withNEC.t315 An initial loading dose of 2.5-3 mg/kg IV, admin-istered over 15-30 minutes, is followed by continuous infusion of 1 mg/kg/hour. Doxaprnm should be titrated to thelowest dose at which apnea is controlled, with a maximumdose 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 5-27mg/kg/day of benzyl alcohol, with toxicity reported atgreater than 100 mg/kg/day. 34,41 Side effects of doxapramcan include signs of excessive CNS stimulation such as agita-tion, excessive crying, disturbed sleep, jitteriness, irritability,and seizures. Hypertension, increased gastric residuals,abdominal distention and vomiting, second-degree heartblock caused by QT interval prolongation (with return tonormal sinus rhythm after discontinuation of doxapram),tachycardia, and hyperglycemia have also been report-ed.34,41,j6 The effects of doxapram are usually transient, last-ing approximately one week. Doxapram is not consideredstandard of care because its use requires continuous IV inm-sion and it has the risk of benzyl alcohol toxicity.5

Other InterventionsIn addition to the pharmacologic management described,

the nurse needs to consider other interventions in managingan infant with AOP. A mild degree of hypoxia can induce res-piratory inhibitory mechanisms and may predispose infants toapnea and bradycardia.17,19>30T31 Oxygen administered at anFiO;, 22-25 percent to help keep the oxygen saturation onthe higher side of normal may be a protective mechanismdecreasing the frequency and severity of AOP.16>17p30>31~57 Inthe past, there has been a hesitance to administer oxygen topremature infants as a treatment for AOP because of the riskof retinopathy of prematurity (ROP). Although furtherresearch is needed, studies have indicated that the risk of ROPmay actually increase with the fluctuations in oxygenationassoc ia ted wi th AOP and no t wi th h igher oxygensaturations.31

Nasal CPAP enhances rhythmic control of breathing pri-marily by splinting the upper airway, opposing pharyngealcollapse, and maintaining adequate resting lung volumes.Oxygenation and gas exchange are thereby enhanced, with animproved functional residual capacity.10J2~58 Positive airwaypressure can ease the work of breathing and improve lungcompliance. Nasal CPAP, administered via nasal prongs or anasal pharyngeal tube at 3 to 8 cm H20, has been shown tobe effective in treating mixed and obstructive apnea but notcentral apnea.23,58,59

If severe apneic spells persist despite intervention, endotra-cheal intubation and ventilation are indicated. Initial settingsshould be adjusted to prevent episodes of desaturation. Tominimize barotrauma, settings should be weaned to a mini-mum peak inspiratory pressure and positive end expiratorypressure with a short inspiratory time. The infant may need toremain on a low rate for a few weeks while the respiratorycontrol system matures.r0J2J3

Although AOP is common in the nursery, it resolves inmost infants by 40 weeks postconceptional age. Some prema-ture infants, especially those born at less than 28 weeks gesta-tional age, however, will continue to have episodcs.*xs

Eichenwald and colleagues found that approximately 32 per-cent of infants born between 24 and 26 weeks gestation and13 percent of infants born at 28 weeks gestation continued tohave apnea beyond 38 weeks postconceptional age.60 There isno consensus yet on the appropriate management of theseinfants, but emphasis is on decreasing the number of episodesso that the infant can be cared for at home. The use of homemonitors with methylxanthines remains controversial. TheAmerican Academy of Pediatrics recommended guidelines forhospital discharge of the high-risk neonate include that theinfant has demonstrated physiologic maturity and stable car-diorespiratory function of sufficient duration. Yet no recom-mendations have been made regarding duration, and thedecision to use home cardiorespiratory monitoring has beenleft as a matter of individual clinical judgment.61 Althoughmuch has been written on the incidence, pathogenesis, etiolo-gy, and treatment of AOP, the literature is lacking in definingcriteria for discharge of infants who have experienced signifi-cant apnea. Home monitoring use has not been proven toprevent morbidity and mortality associated with apnea; how-ever, most neonatologists feel that it is the best approachavailable at this time.4

S U M M A R YWith 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 ofits pathophysiology, careful evaluation of its potential causes,and continual assessment of the infants response to therapeu-tic interventions. This allows for a rational approach to itsmanagement, with nurses in the optimal position to provideand coordinate the multidisciplinary support needed for theseinfants and families. @

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39. Muttitt SC, et al. 1988. Neonatal apnea: Diagnosis by nurse ver-SLIS computer. Pediatrics 82( 1): 713-720.

40. Upton CJ, Milner AD, and Stokes GM. 1992. Response toobstruction in preterm infants with apnea. Pediatric Pz~lmonology14(4): 233-238.

41. Taketomo CK, Hodding JH, and Kraus DM. 1997. PediatricDosage 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 theophyllincexerts proconvulsant effects. Brain and Development 19(6):403407 .

44. Mehta A, et al. 1997.

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62. Rigatto H. 1992. Maturation of breathing. Clinics inPerinatology 19(4): 739-756.

63. de1 Rosario JF, and Orenstein SR 1996. Evaluation and man-agement 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 fora laryngeal chemoreflex. American Journal of Medicine 103( 5A):12OS-124s.

About the AuthorsKaren lbeobald is a neonatal nurse practitioner in a 60.bed, Level

III NICU at All Childrens Hospital, St. Petersburg, Florida. Shereceived her BSNfiom Russell SaBe College Troy, New York. She workedas a staff nurse and transport nurse for many years at the Universizy ofNorth Carolina Hospitals. She received her cert&ate as an NNPfiomAll Children-s Hospital in 1989 and completed her MS as a neonatalnurse practitioner at SUm Stony Brook, in 1998. She is a member ofNANN and S&ma Theta Tau International and is on the board ofdirectorsfor the Florida Association of NNPs.

Carol Botwinski is a neonatal nurse practitioner in the NICU at AllChildrens Hospital. She received her nursing diploma from Wesley-Passavant School of Nursing, Chicago, and her certificate as an NNPfrom All Childrens Hospital in 1985. She received her BS from theUniversity of St. Francis, Joliet, Illinois, and completed her MS as anNNPfi-om SUNS Stony Brook, in 1999. She is currentLy enrolled in thedoctoral proflram at Nova Southeastern University. She is a member ofNANN, Florida Association of NNPs, and Sigma Theta TauInternational.

Stepbanie Albanna is a neonatal nurse practitioner in the NICU atALL Childrens Hospital. She received her BSN from the University ofCincinnati in 1996, earned her cert$icate as an NNP in 1992jFom theUniversity of Health Sciences in Jacksonville, and completed her MS asan NNPfrom S w Stony Brook, in 1998. She is a member of NA NN,Florida Association of NNPs, and S&ma Theta Tau International. Sheis the proud mother of a new baby boy.

Paula McWilLiam is a neonatal nurse practitioner in the NICU atAll Children% Hospital. She received her BSN fvom Barry University,Miami, Florida, earned her certificate as an NNPfi-om West VirginiaUniversity, and completed her MS as an NNPfi-om SUNy Stony Brook,in 1998. She is currently enrolled in the doctoral program at NovaSoutheastern University.

For further information, please contact:Karen Theobald, RNC, MS, ARNPAll Childrens HospitalDepartment 6200801 Sixth Street SouthSt. Petersburg, FL 33701