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Pediatr Drugs 2003; 5 (6): 385-405 REVIEW ARTICLE 1174-5878/03/0006-0385/$30.00/0 © Adis Data Information BV 2003. All rights reserved. Nonsteroidal Anti-Inflammatory Agents in Neonates John L. Morris, David A. Rosen and Kathleen R. Rosen Departments of Anesthesia and Pediatrics, West Virginia University, Morgantown, West Virginia, USA Contents Abstract ............................................................................................................... 386 1. Mechanisms of Action of Prostaglandins ............................................................................... 387 1.1 Prostaglandins and Sleep ........................................................................................ 388 1.2 Prostaglandins and Pain ......................................................................................... 388 1.3 Prostaglandins and Cerebral Blood Flow .......................................................................... 389 1.4 Prostaglandins and Neuroprotection .............................................................................. 389 1.5 Prostaglandins and Renal Function ............................................................................... 389 1.6 Prostaglandins and Cardiovascular Function ...................................................................... 389 1.7 Prostaglandins and Gastrointestinal Function ...................................................................... 390 1.8 Prostaglandins and Bone ........................................................................................ 390 1.9 Nonprostanoid Mechanisms of Action of NSAIDs ................................................................... 390 2. NSAID Pharmacokinetics and Dosing .................................................................................. 390 2.1 Indomethacin .................................................................................................. 390 2.1.1 Dosing Information ........................................................................................ 391 2.2 Acetaminophen ................................................................................................ 391 2.2.1 Dosing Information ........................................................................................ 392 2.3 Ibuprofen ...................................................................................................... 393 2.3.1 Dosing Information ........................................................................................ 393 2.4 Mefenamic Acid ................................................................................................ 393 2.4.1 Dosing information ........................................................................................ 393 2.5 Ketorolac ...................................................................................................... 393 2.5.1 Dosing Information ........................................................................................ 393 2.6 Diclofenac ..................................................................................................... 393 2.6.1 Dosing Information ........................................................................................ 393 2.7 Ketoprofen ..................................................................................................... 393 2.7.1 Dosing Information ........................................................................................ 394 3. NSAID Indications and Usage ........................................................................................ 394 3.1 Patent Ductus Arteriosus ......................................................................................... 394 3.1.1 Indomethacin ............................................................................................ 394 3.1.2 Other NSAIDs ............................................................................................. 394 3.2 Fever .......................................................................................................... 395 3.3 Pain ........................................................................................................... 395 3.3.1 Acetaminophen .......................................................................................... 395 3.3.2 Ketorolac ................................................................................................ 396 3.3.3 Indomethacin ............................................................................................ 396 3.3.4 Diclofenac ............................................................................................... 396 3.4 Other Uses of NSAIDs ............................................................................................ 396

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Page 1: Nonsteroidal Anti-Inflammatory Agents in Neonates

Pediatr Drugs 2003; 5 (6): 385-405REVIEW ARTICLE 1174-5878/03/0006-0385/$30.00/0

© Adis Data Information BV 2003. All rights reserved.

Nonsteroidal Anti-Inflammatory Agentsin NeonatesJohn L. Morris, David A. Rosen and Kathleen R. Rosen

Departments of Anesthesia and Pediatrics, West Virginia University, Morgantown, West Virginia, USA

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386

1. Mechanisms of Action of Prostaglandins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387

1.1 Prostaglandins and Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388

1.2 Prostaglandins and Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388

1.3 Prostaglandins and Cerebral Blood Flow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389

1.4 Prostaglandins and Neuroprotection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389

1.5 Prostaglandins and Renal Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389

1.6 Prostaglandins and Cardiovascular Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389

1.7 Prostaglandins and Gastrointestinal Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390

1.8 Prostaglandins and Bone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390

1.9 Nonprostanoid Mechanisms of Action of NSAIDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390

2. NSAID Pharmacokinetics and Dosing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390

2.1 Indomethacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390

2.1.1 Dosing Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391

2.2 Acetaminophen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391

2.2.1 Dosing Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 392

2.3 Ibuprofen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393

2.3.1 Dosing Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393

2.4 Mefenamic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393

2.4.1 Dosing information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393

2.5 Ketorolac . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393

2.5.1 Dosing Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393

2.6 Diclofenac . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393

2.6.1 Dosing Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393

2.7 Ketoprofen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393

2.7.1 Dosing Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394

3. NSAID Indications and Usage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394

3.1 Patent Ductus Arteriosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394

3.1.1 Indomethacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394

3.1.2 Other NSAIDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394

3.2 Fever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395

3.3 Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395

3.3.1 Acetaminophen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395

3.3.2 Ketorolac . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396

3.3.3 Indomethacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396

3.3.4 Diclofenac . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396

3.4 Other Uses of NSAIDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396

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386 Morris et al.

4. NSAID-Associated Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397

4.1 Persistent Pulmonary Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397

4.2 Acetaminophen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397

4.3 Indomethacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397

4.4 Selective Cyclo-Oxygenase-2 Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398

4.5 Ibuprofen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399

4.6 Aspirin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400

4.7 Ketoprofen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400

4.8 Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400

5. Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400

The use of NSAIDs has become routine for adults and children in the management of pain. NSAIDs (otherAbstractthan aspirin [acetylsalicylic acid]) are also enjoying greater popularity as antipyretics since the recognition of

Reye’s syndrome’s putative association with aspirin. In neonates, NSAIDs have been used for many years in an

attempt to pharmacologically close the ductus arteriosus. This review examines the various NSAIDs and their

potential and real applications in the neonatal population. For completeness, acetaminophen (paracetamol),

which has weak NSAID activity and is a widely used analgesic and antipyretic in this patient group, was also

included.

The prostaglandin system is important for healthy development, and conversely there are unique risks posed

by pharmacologic interference with this system in the neonatal period. The prostanoid system in neonates has the

capacity to modulate nociception, but comes at the expense of interfering with nearly every organ system.

Physiologic effects of inhibition of prostaglandin synthesis applicable to neonates include disruption of the sleep

cycle, increased risk of pulmonary hypertension, alterations in cerebral blood flow, decreased renal function,

disrupted thermoregulation, and alterations in hemostasis balance, among others. Prostaglandins are also

important for the normal development of the central nervous, cardiovascular, and renal systems, and there is

evidence that the proper genesis of these systems may be adversely effected by NSAID exposure in utero and in

the neonatal period.

Gastrointestinal adverse effects have provided the impetus for the development and marketing of selective

cyclo-oxygenase type 2 (COX-2) inhibitors. These agents’ reputation for safety in adults may not be applicable

to neonates. COX-2 is involved in the development of several organ systems, and its inhibition may induce a

prothrombotic state. The advent of parenteral formulations of cyclo-oxygenase inhibitors, including

COX-2–selective agents, increases the therapeutic flexibility of NSAIDs. However, objective data on the safety

of these agents have not kept pace with their clinical availability.

NSAIDs are some of the most commonly used medicines. for opioid-sparing analgesics, the interest in NSAIDs is sharpen-

However, their ubiquitous use in adult and pediatric patients has ing. However, NSAIDs may not be a panacea for neonates. While

not translated into an abundance of literature regarding their use in use of NSAIDs in adults is ubiquitous, significant safety issues

the newborn period. While there is a considerable body of evi- still exist. Developmental and metabolic considerations unique to

dence concerning the use of indomethacin for closure of the ductus the neonatal and pediatric populations may further alter the safety

arteriosus in neonates, literature examining the use of NSAIDs for margin of NSAIDs in children.

analgesia, antipyresis, and as anti-inflammatories in this age group This review attempts to summarize available clinical studies ofis lacking. NSAIDs in neonates, assess the biochemical milieu in which

With the advent of a new family of NSAIDs, the selective NSAIDs are given in this age group, and extrapolate on the future

cyclo-oxygenase (COX)-2 inhibitors, and an increasing demand risks and benefits of NSAIDs in newborns. Although not conven-

© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (6)

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NSAIDs in Neonates 387

tionally considered a NSAID, acetaminophen (paracetamol) has In differentiating the physiologic functions of COX-1 and

been included in this review for completeness. Acetaminophen COX-2, it is useful to consider their molecular biology. The gene

exhibits weak NSAID activity. Furthermore, as it is the major for COX-1, located on chromosome 9, lacks a tyrosine-adenosine-other analgesic and antipyretic used in this patient group, aceta- tyrosine-adenosine (TATA) promoter sequence and is much long-minophen provides a useful comparator. While aspirin is a er than the COX-2 gene. Located on chromosome 1, the COX-2NSAID, there is a paucity of information regarding its use in gene’s promoter region contains a TATA box as well as otherneonates. Given the lack of informatin, it is included in this article transcriptional elements common to highly regulated, inducibleonly as a comparator to other more common agents. genes. These genetic codes include nuclear factor kappa b, the

This review utilized the Medline search terms NSAID, neonate, cytosine-adenosine-adenosine-tyrosine (CAAT) enhancer-bindingprostaglandin, and acetaminophen to locate all available literature protein, and the cyclic adenosine monophosphate (cAMP) res-applicable to the neonatal population. This review was not restrict- ponse element-binding protein.[6] These sequences are common toed to the English language. genes involved in inflammation. COX-2 also contains signals that

allow rapid degradation of the messenger RNA (mRNA) tran-1. Mechanisms of Action of Prostaglandins script. Differences in the expression of COX-1 and COX-2 are

present in utero. COX expression patterns change throughout theProstaglandin physiology has recently been reviewed.[1-3] All

development of the fetus. Known tissue changes are summarizedknown NSAIDs possess, to varying degrees, the ability to inhibit

in table I.one or both COX enzymes (COX-1 and -2), the rate-limiting step

COX-1 is ubiquitous in human tissues and is constitutivelyin prostaglandin production, and this is their putative mechanismexpressed in most tissues (lacking TATA and CAAT sequences inof action for analgesia and anti-inflammation. Several NSAIDsits promoter region).[6] The physiologic functions of COX-1 in-have also been shown to have nonprostaglandin-synthesis–mediat-clude maintenance of the protective mucus barrier of the gastriced mechanisms of action.mucosa, platelet aggregation, maintenance of glomerular filtrationThe two known isoforms of COX (COX-1 and COX-2) convertrate (GFR), vascular homeostasis, and macrophage differentiation.arachidonic acid to the unstable intermediate prostaglandin H. TheIn contrast, COX-2 is primarily constitutively expressed, or con-synthesis of prostaglandin H is the point of differentiation intinuously induced, in the kidney and brain, but is induced in areasprostanoid production, with individual cell types possessing pre-of injury. COX-2 mRNA expression also changes during organo-dominantly different terminal synthases. The terminal synthasesgenesis and in the newborn period, particularly in the intestine,generate the effector prostaglandins. Although COX-1 and COX-2lung, and kidney.[7] COX-2 induction is inhibited by glucocorti-govern the maximum production of prostaglandins, acute changescoids.[6] COX-2 expression in the brain increases after seizurein production are regulated proximally by activation of phospho-

activity and N-methyl-D-aspartate (NMDA) stimulus. In the kid-lipase A2.

ney, COX-2 expression is increased by salt restriction. COX-2 isThe ability of different NSAIDs to differentially inhibit COX-1

also important developmentally in the kidney; gene knockout miceand COX-2 has been well studied.[4] Structural differences in the

for COX-2 have had severe renal abnormalities.[8,9] COX-2 is alsotwo COX isozymes permit selective inhibition.[5]

Table I. Cyclo-oxygenase (COX)-1 and COX-2 messenger RNA (mRNA) changes during human fetal development (reproduced from Olson et al.,[7] withpermission from Elsevier Science)

Organ COX isoform First trimester Second trimester Third trimester Neonate

Lung COX-1 ++++ +++ ++ +

COX-2 + ++ +++ ++++

Intestine COX-1 ++ +++ ++ +++

COX-2 + ++ ++++ +++

Kidney COX-1 +++ +++ +++ +++

COX-2 0 + ++ ++++

+, ++, +++, ++++ = relative abundance of mRNA within each organ.

© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (6)

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388 Morris et al.

induced in the endothelium by hypoxia,[10] and is induced by After injury, prostaglandin synthesis is increased. In a study of

mice transgenic for overexpression of human PGD synthase, sleepinterleukin (IL)-1α.[11] COX-2 is also induced by bacterial lipo-

was only significantly increased in transgenic mice after an injury.polysaccharides, growth factors, cytokines, and phorbol esters, a

In scenarios in which prostaglandin H production, the precursor toproperty similar to other inflammatory mediators.[12]

PGD2, is increased, patients may have more non-REM sleep. ThisProstaglandins generally work in an autocrine, paracrine fash-biology explains the phenomenon previously observed by behavi-ion. The prostaglandins (PG) are divided into thromboxane A2,oralists of increased sleep in neonates subjected to painful proce-prostacyclin (PGI2), PGF2α, PGD2, PGE1, and PGE2. Thrombo-dures without analgesia.[19] Pinzar and colleagues[18] confirmedxane A2 is synthesized primarily in platelets where it is athis by measuring increased levels of PGD2 production in theprocoagulant, increasing intraplatelet ion calcium (Ca2+) concen-brains of mice following painful stimulus. Following a painfultration. Prostacyclin is manufactured by endothelial and smoothstimulus in neonates, the brain responds with increasing PGD2,muscle cells, and acts to increase intracellular cAMP, resulting inproducing increased sleep as an adaptive mechanism. This has

vasodilation. The prostacyclin receptor also binds PGE1. PGE2been shown in a study where non-REM sleep increased in neo-

mediates inflammatory responses with the inflammatory responsenates after stressful procedures, such as circumcision and heel

abolished by anti-PGE2 antibodies. Anti-PGE2 monoclonal anti-lancing, were performed without analgesia.[19] The application of

body reduces inflammation, hyperalgesia, and IL-6 production inan NSAID would enhance comfort, but would alter sleep architec-

the rat.[13] PGE1 and prostacyclin appear to be the most importantture. Thus, it may be important to assess the impact of sleep

dilators of the ductus arteriosus. In the CNS, PGD2 is integral toalteration on the use of agents that inhibit prostaglandin synthesis

the regulation of sleep, temperature maintenance, pain modula-in humans, particularly regarding the complicated sleep-wake

tion, and odor sense. The biology of prostaglandins in the CNS hascycles of patients in the intensive care unit.

recently been reviewed.[14] In the periphery, PGD2 production isPGD synthase may not be the rate-limiting step in PGD2more diverse, causing pulmonary vascular constriction, bronchos-

synthesis; in most tissues the rate-limiting step is COX. Therefore,pasm, and systemic vasodilation.

agents that decrease global prostaglandin production, such as

NSAIDs, may interfere with non-REM sleep, and sleep induction.1.1 Prostaglandins and Sleep Another mechanism by which NSAIDs may affect sleep is a result

of decreased melatonin production that would disrupt sleep andSleep is critical to the developing neonate. The impact of sleep thermoregulation. Aspirin (acetylsalicylic acid) and ibuprofen, but

deprivation in neonates is just beginning to be elucidated. Sleep not acetaminophen, have been shown to disrupt sleep in a random-deprivation results in impaired immunity, impaired protein synthe- ized controlled trial of healthy adult volunteers.[20] NSAIDs havesis, respiratory abnormalities, and altered thermoregulation. Stress also been shown to suppress nocturnal melatonin production asand sleep deprivation have been reported as potential etiologies for well as suppress the normal nocturnal fall in body temperature.[21]

sudden infant death syndrome.[15]

The role of PGD2 in sleep has recently been reviewed.[16] 1.2 Prostaglandins and Pain

Prostaglandins have been shown to be integral to sleep regulation

in several animal models, including mice and monkeys. The site of Pain is a complex process, with early and late responses causedaction of PGD2, a potent somnogogue, has been localized to the by the injury and the body’s response to the injury. Prostaglandins

arachnoid trabecular cells of the basal forebrain in mice where are important peripheral and central mediators of pain signaling.

PGD2 receptors are co-localized with the PGD synthase.[17] PGD2 Prostaglandins are released both peripherally at the site of injury

is most important for inducing non-rapid eye movement (REM) and proximally in the CNS in response to afferent activation.[22]

sleep, and is believed to act via the adenosine A2A receptor system. Prostaglandin receptor agonists given intrathecally stimulateThe sleep induced by PGD2 infusion is indistinguishable from pain pathways, while COX inhibitors or prostaglandin antagonistsphysiologic sleep by electroencephalogram, electromyogram, inhibit late pain responses.[22] However, these antagonists do not

brain temperature, locomotor activity, heart rate, or behavior of affect early pain processes. COX-2 is constitutive in the spinal

animals.[18] cord. COX-2 inhibitors have also been shown to have a predomi-

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NSAIDs in Neonates 389

nant central analgesic action. This was confirmed in an adult rat evidenced by brain morphologic changes in rat models of ischemic

model study where an intrathecal application of a water-soluble brain injury.[31] COX-2 is upregulated in humans and mammals in

COX-2 inhibitor had an opioid-sparing effect, whereas this same neurons, blood vessels, and inflammatory cells in the injured

water-soluble COX-2 inhibitor given systemically at approximate- brain.[30] While animal studies using COX-2 inhibitors have shown

ly a 10-fold higher dose did not.[23] promise in ischemic brain injury, human trials are lacking.[32,33]

Acetaminophen is a much more potent central than peripheral Putative mechanisms for the neuroprotective effects of COX-2

prostaglandin synthesis inhibitor.[24,25] It must achieve adequate inhibitors include decrease in PGE2 production or other chemical

concentrations in the CNS. This explains the 1–2 hour delay to products of COX-2 acting via NMDA-mediated cytotoxicity.[30]

achieve analgesic efficacy. Piletta et al.,[26] using a technique that For instance, COX-2 is known to contribute to superoxide free

selectively provides a painful stimulus to nerves without local radical synthesis.

tissue action, found an analgesic effect from intravenous acetamin- COX-2 inhibition may also be of benefit in late cerebral injuryophen, but not from intravenous aspirin (acetylsalicylic acid), both from neurovascular insult, by reducing inflammation. This isgiven prophylactically. There is some evidence that this central supported by evidence that administration of COX-2 inhibitors upaction of acetaminophen is mediated by prostaglandin synthesis to several hours after neurovascular insult reduces injury size ininhibition. Further evidence of the central analgesic action of animal models,[30] a time window in excess of that afforded byacetaminophen is demonstrated by the fact that systemic adminis- thrombolytics. In preterm neonates, COX inhibition has beentration of acetaminophen in rats inhibits the hyperalgesic response shown to decrease the incidence of severe intraventricular hemor-to intrathecal NMDA.[27] rhage (IVH), but without long-term mortality benefit.[34]

1.3 Prostaglandins and Cerebral Blood Flow 1.5 Prostaglandins and Renal Function

Another physiologic area of involvement for prostaglandins COX-1 and COX-2 have been shown to be important for both

appears to be regulation of cerebral blood flow in neonates. the function and development of the kidney. Gene knockout mice

Infusion of PGE1, PGE2, PGF2α, and prostacyclin all increased models lacking COX-2 have demonstrated severe renal abnormali-

cerebral blood flow by varying degrees in piglets.[28] During ties.[35-37] The day-to-day function of the kidneys also appears to be

systemic hypotension, cerebral production of PGE, PGF2α, and regulated, at least in part, by prostaglandins. COX-2 has been

thromboxane B2 (a metabolite of thromboxane A2) are in- shown to be an important stimulant of the renin system in

creased.[28] Animal studies have indicated wide differences in the humans,[38] with the increased renin response to furosemide

effects of various NSAIDs on cerebral blood flow. In a study of (frusemide) and low sodium blunted by administration of the

newborn piglets, indomethacin, aspirin, naproxen, and ibuprofen, COX-2 inhibitor rofecoxib. These findings have been supported

each at doses that decreased prostaglandins to undetectable levels, by gene knockout mice models[35,36] which have shown a lack of

and which exceeded the dosages used in humans, differed in their appropriate renin response to low-salt diets and ACE inhibitor

effects on cerebral blood flow. Neither ibuprofen nor naproxen administration. Adverse renal effects are similar in patients given

affected cerebral blood flow; aspirin increased cerebral blood selective COX-2 inhibitors versus other NSAIDs.[39]

flow, and indomethacin decreased cerebral blood flow.[28] These Neonates treated with indomethacin for patent ductus arteriosusfindings indicate that changes in prostaglandin concentrations may (PDA) closure had a 40% incidence of renal impairment comparednot be the only mediators of the effects of NSAIDs on cerebral with only 16% of infants with PDA who underwent surgery.[40]

blood flow. This is supported by human studies using indometha- Indomethacin causes a decrease in renal perfusion in humancin and ibuprofen.[29] neonates.[41] This decrease has been shown to be reversed by low-

dose dopamine infusion.1.4 Prostaglandins and Neuroprotection

1.6 Prostaglandins and Cardiovascular FunctionLack of COX-2 expression, as achieved in gene knockout mice,

has been shown to be neuroprotective in ischemic brain injury.[30] Surprisingly, COX-2 inhibition has been shown to inhibit pros-

COX-2 inhibitors have also been shown to be neuroprotective, as tacyclin formation in humans.[12] As prostacyclin is predominantly

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390 Morris et al.

synthesized by the systemic and renal endothelium, which in turn of most NSAIDs for inhibiting COX-1 versus COX-2 have also

was believed to express predominantly COX-1 constitutively, this been determined and are reviewed elsewhere.[50]

represents an unexpected finding. This offers another possible Neonates differ from adults and older children in drug absorp-etiology for the increase in macrovascular complications seen in tion, distribution, and metabolism. Oral administration in neonateslarge multicenter adult trials of COX-2 inhibitors. This also repre- results in unpredictable or reduced absorption secondary to irregu-sents at least a theoretical additional risk for neonates with, or at lar gastric emptying, alkaline gastric pH, and decreased intestinalrisk of, pulmonary hypertension, as prostacyclin is a potent pul- and biliary function. Gastric pH does not begin to fall until themonary vasodilator. PGE2 was also inhibited by celecoxib (a eighth or tenth day of life. Rectal absorption is relatively rapid inCOX-2 inhibitor) in this study.[12] Decreases of prostacyclin urin- neonates, with limited presystemic clearance secondary to imma-ary metabolites were also reported in elderly humans taking ture hepatic metabolism. Decreases in muscular blood flow makerofecoxib (a COX-2 inhibitor) long-term.[12]

intramuscular administration unpredictable, and increased skin

permeability accelerates drug absorption by the transdermal route.1.7 Prostaglandins and Gastrointestinal Function

In general, the decreased serum albumin and total protein, the

presence of fetal hemoglobin, the increased bilirubin, and reducedThere are developmental differences in the expression of COXsadipose tissue in neonates relative to adults results in increasedin the gastrointestinal tract. In neonatal rats, the levels of stomach,free fraction of drug, a decreased volume of distribution of hydro-small and large bowel COX-1 are significantly lower than inphobic drugs, and an increased volume of distribution of hydro-adults, while COX-2 mRNA concentrations do not demonstratephilic drugs. All currently clinically available NSAIDs are hydro-significant differences.[42] The lower levels may be related to thephobic.higher gastric pH in neonates.

1.8 Prostaglandins and Bone 2.1 Indomethacin

PGE, as well as other prostaglandins, stimulates osteogenesis.Postnatal age, rather than gestational age, is the most important

NSAIDs inhibit bone repair and formation, decrease osteoblastfactor in indomethacin distribution and clearance.[64] Sulindac and

proliferation and differentiation, and upset the balance betweenindomethacin undergo enterohepatic recirculation.

osteoblasts and osteoclasts. These effects may be independent ofWiest et al.[64] found the mean plasma drug concentration forprostaglandin inhibition, and may impact healthy bone

neonates achieving ductal closure after the administration of intra-growth.[43,44]

venous indomethacin to be 1.45 mg/L, but hesitated to recommend

this as a target concentration. Brash et al.[65] found a 20-fold range1.9 Nonprostanoid Mechanisms of Action of NSAIDs

of plasma indomethacin concentrations that resulted in ductalNSAIDs have been shown to act via nonprostaglandin-medi- closure and, therefore, were unable to recommend a target plasma

ated mechanisms. For instance, aspirin has been found to inhibit concentration for this use after studying 35 patients.lysophosphatidic acid G protein-mediated signaling in vitro at

In a recent review of renal development and its effects onclinically relevant concentrations. This signaling pathway is im-

pharmacokinetics in preterm infants, van den Anker[66] found thatportant for hemostasis and immune function.[45] Indomethacin

GFR increased with gestational age, but when there was antenatalpossesses calcium channel antagonist abilities[46] and inhibits his-

exposure to indomethacin the GFR decreased. This reduction intamine release.[47] Aspirin uncouples oxidative phosphoryl-

GFR after indomethacin exposure results in a clinically significantation.[48]

decrease in clearance of some drugs.[67,68] However, the effect of

indomethacin on decreasing drug clearance is complicated by the2. NSAID Pharmacokinetics and Dosingfact that closing the ductus decreases the volume of distribution of

many drugs. The change in volume of distribution of indomethacinThe pharmacology of the various NSAIDs has been extensively

before and after ductal closure has been offered as a reliable, if notreviewed elsewhere.[49] Available pharmacokinetic parameters for

cumbersome, means of validating successful treatment.[69] Thisneonates and children are listed in table II. The relative potencies

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NSAIDs in Neonates 391

Table II. Pharmacokinetics of common NSAIDs and acetaminophen in neonates and children

Agent No. of Patients Regimen t1/2 (h) Vd (L/kg) Referencepatients (single dose unless stated [mean] [mean]

otherwise)

Acetaminophen 5 Term neonates, DOL <10 days IV 3.5 0.7 51

Acetaminophen 10 Term neonates Suppository (four doses q6h) 2.7 ND 52

Acetaminophen 30 DOL 1 PO, suppository (over 3 days) ND 1.7 53

Acetaminophen 30 DOL 14 PO, suppository (over 3 days) ND 0.99 53

Acetaminophen 21 28–32wks gestational GA Suppository 11 ND 54

Acetaminophen 7 32–36wks GA Suppository 4.8 ND 54

Acetaminophen 9 Neonates Suppository 3.8 ND 55

Acetaminophen 3 Neonates Via nasogastric tube 2.8 ND 55

Acetaminophen 17 Perioperative neonate Suppository 4.1 ND 56

Acetaminophen 120 2–15 years PO, suppository ND 59.9 57

Ibuprofen 21 Preterm neonates IV 30.5 0.0621 58

Indomethacin 10 1–4y IV 366 0.74 59

Indomethacin 17 31wks GA IV 20.7 ND 60

Indomethacin 37 DOL <2 IV 17.7 0.27 61

Indomethacin 37 DOL 2–7 IV 21.4 0.25 61

Ketorolac 10 4–8y IV 6.1 0.26 62

Mefenamic acid 17 Preterm neonates PO (daily results after first dose) 18.7 ND 63

DOL = day of life; GA = gestational age; IV = intravenously; ND = no data; PO = orally; q6h = every 6 hours; t1/2 = terminal elimination half-life; Vd = volumeof distribution.

finding is probably based upon the physiologically expected result rate by age, with a mean half-life until appearance of metabolites

of closing a left to right shunt. in urine of 4.4–5.5 hours. They found that sulfate conjugation was

the primary pathway of acetaminophen metabolism well intoFindings indicate an early maturation of indomethacin metabol-

childhood. Neonates had a glucuronide to sulfate ratio of 0.34 ±ism.[59]

0.08, compared with an adult ratio of 1.8 ± 0.32. The crossover2.1.1 Dosing Information

from sulfate to glucuronide metabolism occurred in the 9–12 yearWhile a wide range of indomethacin dosages for the treatment

age range. There were no changes in the percentage of drugof PDA and the prevention of IVH have been used, it appears a

excreted in the urine for all ages.dose of 0.1 mg/kg/day for 3–4 days is as effective as higher dosage

Bilirubin concentration in the range of 1.0–11.6 mg/dL hasregimens for both indications.[70,71]

been shown to have no effect on acetaminophen metabolism in2.2 Acetaminophen term neonates.[77]

In neonates and children with fever after cardiac surgery,The pharmacology of acetaminophen has recently been re-nasogastric administration of an equal dose of acetaminophen wasviewed.[72] A lag of 1–2 hours between onset of analgesia andfound to produce higher plasma concentrations than rectal admin-antipyresis has been demonstrated for acetaminophen in adults.[73]

istration.[55] The patients receiving the nasogastric dose alsoThe rate of change of plasma concentration of acetaminophen mayseemed to have a quicker and greater reduction in temperature.also be important to analgesic efficacy.[74]

Furthermore, the researchers found that triglyceride-base supposi-Acetaminophen has been reported to have a slower eliminationtories of acetaminophen at a dose of 15 mg/kg were inadequate,in neonates (half-life 2.2–5 hours compared with 1.5–3 hours inand recommended a 20–25 mg/kg suppository dose.adults).[75] However, in a comparison of neonates, children, and

In a study of 10 term neonates who received four 20 mg/kgadults with a standardized 10 mg/kg oral dose of acetaminophen,

Miller et al.[76] reported no significant differences in elimination doses rectally every 6 hours, van Lingen and colleagues[52] found a

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392 Morris et al.

mean peak serum concentration of 10.79 (SD 6.39) mg/L, with remained until at least day 30 of life. Clearance increased expo-

significantly higher concentrations in boys than girls. No patients nentially (half-life 3.25 months) from birth (4.9 L/h/70kg) to reach

had peak concentrations >120 mg/L, and time to peak concentra- 12.4 L/h/70kg by 12 months. The absorption half-lives in children

tion was 1.5 hours after the first dose. They found no relationship <3 months of age were greater (elixir 368%, suppository 151%)

between plasma concentration and pain score after treatment. than those of children >3 months of age. These changes are similar

to those of morphine, which is also metabolized by sulphate andAcetaminophen suppositories in a dose of 40 mg/kg resulted inglucuronide conjugation. The authors recommend the followinga mean maximum concentration (Cmax) of 0.115 (SD 0.049)acetaminophen dosage parameters for newborns: 30 mg/kg oralmmol/L, time to Cmax (tmax) 2.3 (SD 1.2) hours, and a meanload followed by 15 mg/kg every 8 hours for a total daily dose ofconcentration of 0.07 (SD 0.03) mmol/L at 6 hours in children45 mg/kg; rectally 37.5 mg/kg followed by 20 mg/kg every 8 hoursaged between 12 months and 17 years. This dose achieves the lowfor a daily maximum of 60 mg/kg. The authors recommend forend of the therapeutic range (0.066–0.130 mmol/L).[78]

infants 1 month of age: an oral 25 mg/kg load followed by 15 mg/In a study comparing preterm neonates of 28–32 weeks’ gesta-kg every 6 hours for a total daily dose of 60 mg/kg; rectally a 30tional age with those of 32–36 weeks’ gestational age, the lessmg/kg load followed by 20 mg/kg every 8 hours for a dailymature neonates were found to have higher plasma concentrationsmaximum of 60 mg/kg.of acetaminophen after administration of a 20 mg/kg rectal dose.

Autret et al.[51] recommended an intravenous dosage of aceta-The less mature neonates also had a longer elimination half-lifeminophen 30 mg/kg/day for neonates <10 days of age and 60 mg/and excreted a greater fraction of sulfated metabolites.[54]

kg/day for neonates >10 days of age, based upon the longer half-A rectal acetaminophen dose of 12.5 mg/kg four times daily haslife (3.5 hours versus 2.1 hours) and lower plasma clearancebeen shown to provide unreliable plasma concentrations in chil-(0.149 L/h/kg versus 0.365 L/h/kg) in the <10 days age group.dren.[79] Furthermore, in a study of children aged between 2 and 12These findings were based on administration of the intravenousyears, the pharmacokinetics of 10, 20, and 30 mg/kg rectal dosespropacetamol prodrug.of acetaminophen were compared after orthopedic surgery.[80]

Hansen et al.[56] found that hepatotoxicity occurs at plasmaOnly the 30 mg/kg dose reached therapeutic range. The highestacetaminophen concentrations approximately 10 times the levelconcentration in any patient was 24.6 μg/mL (the recognizedrequired for antipyresis.maximum safe level is 120 μg/mL 4 hours after ingestion). Based

on these findings, the authors recommend a dose of 40 mg/kg. In a study of 120 2- to 15-year-old children presenting for

tonsillectomy using a 40 mg/kg oral or rectal perioperative dose,In a follow-up study, the authors examined a 40 mg/kg rectal

Anderson et al.[57] found that a plasma concentration of 10 mg/Lloading dose, followed by 20 mg/kg rectal doses of acetaminophen

achieved pain scores <4/10 in 50% of patients. The authors deter-at 6 hourly intervals in children aged between 3 and 12 years.[81]

mined a 0.54 relative bioavailability of rectal versus oral, and anThis administration schedule provided therapeutic plasma concen-

EC50 (concentration providing 50% of maximum pain reduction)trations (10–20 μg/mL) over 50% of the time. The highest observ-

of 3.4 mg/L.ed concentration of acetaminophen was 38.6 μg/mL, which oc-

curred after the initial loading dose. Patients who received only the By measuring both plasma and cerebrospinal fluid (CSF) con-loading dose achieved therapeutic levels only 38% of the time. centrations of acetaminophen, after intravenous administration of

the prodrug propacetamol, Bannwarth et al.[82] determined that theAnderson et al.[53] compared elixir, glycogelatin capsule sup-

CSF concentrations of acetaminophen paralleled the time coursepository and triglyceride-base suppository formulations of aceta-

of its analgesic action, with CSF concentrations peaking between 2minophen. The ratio of bioavailability of the suppositories to the

and 4 hours. However, there is a lag peak antipyretic action andelixir was 0.64. They found that the total body clearance of

peak plasma concentration which is not explained by a delay ofacetaminophen at birth was 62% and the volume of distribution

diffusion into the CNS.[83]174% that of older children. They concluded that a median effec-

tive concentration (EC50) of 10 mg/L can be achieved with a 452.2.1 Dosing Informationmg/kg/day dose at birth. The volume of distribution decreased

exponentially (half-life 1.9 days) from 120 L/70kg at birth (1.74 For acetaminophen, Anderson et al.[84] recommended the fol-

times the eventual value) to 69.9 L/70kg by 14 days, where it lowing dosage regimen:

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NSAIDs in Neonates 393

• 30 weeks gestation: 25 mg/kg/day orally or by capsule supposi- variety of plasma half-lives, ranging from 8.4–43.6 hours was

tory, 30 mg/kg/day triglyceride suppository. found. In one patient (gestational age 27 weeks) who received two

courses of mefenamic acid separated by two weeks, the plasma• 34 weeks gestation: 45 mg/kg/day orally.half-life was found to decrease from 26.4 hours to 8.4 hours.[89]• Term: 60 mg/kg/day orally.

Mefenamic acid pharmacokinetics were studied in 17 preterm• Six months: 90 mg/kg/day orally. Half the dose is recommen-neonates who received a 2 mg/kg/day oral dose for PDA.[63]ded if the baby is jaundiced. The risk of hepatotoxicity in-Pharmacokinetic parameters were highly variable: Cmax wascreases after 2–3 days.1.2–6.1 μg/mL, mean 3.8 μg/L; tmax was 2–18 hours, mean 7.7

hours; elimination half life was 3.8–43.6 hours, mean 18.7 hours.2.3 Ibuprofen

Infants whose ducts were successfully closed had lower mefena-In the first pharmacokinetic study of ibuprofen in premature mic acid clearance, longer half-life, and higher plasma concentra-

neonates, Aranda et al.[58] examined 21 neonates with a mean tions. The authors recommend a target plasma concentration >2.0birthweight of 945g, and a mean gestational age of 26.8 weeks, μg/mL.who received a single intravenous bolus of ibuprofen 10 mg/kg

2.4.1 Dosing informationwithin the first 3 hours of life. A maintenance dose of 5 mg/kg/dayFor the treatment of PDA, mefenamic acid can be given orallyresulted in a mean plasma concentration of 113.6 mg/L in a subset

as three doses of 2 mg/kg at 12-hour intervals. The suspension hasof 10 patients. The plasma half-life was more than 10 times that ofa concentration of 50mg in 5mL.[90]a 3-month-old. Similarly, the volume of distribution was larger

and the clearance was reduced in neonates as opposed to older

patients. The authors also found that ibuprofen was less extensive- 2.5 Ketorolacly protein bound in neonates than in older patients, resulting in

Ketorolac pharmacokinetics were studied in 10 children agedgreater bioavailability of the active drug.4–8 years after minor surgery who received a 0.5 mg/kg intrave-A lag of 1–3 hours between peak plasma level of ibuprofen andnous dose.[62] Children demonstrated a clearance and volume ofpeak decrement in temperature has been demonstrated.[85] How-distribution twice that of adults. We are not aware of any pharma-ever, younger children received greater and quicker antipyresiscokinetic data in neonates.from ibuprofen than older children. No effective concentration

was determined.2.5.1 Dosing Information

Ibuprofen is a racemate with R less active than S. R is convertedFor the treatment of pain in infants, a dose of 0.5 mg/kgto S in vivo.[86]

intravenously every 8 hours for up to 2 days is recommended.[91]

2.3.1 Dosing Information

Ibuprofen is not recommended for antipyresis or pain in neo- 2.6 Diclofenacnates. The manufacturer’s recommended dosage for infants is

50mg orally every 6–8 hours, not exceeding four doses per day. The pharmacokinetics of diclofenac (0.5 mg/kg intravenously)

have been studied in children aged between 4 and 6 years,[92] butFor the treatment of PDA, either an oral dosage regimen of 10

we are not aware of any pharmacokinetic data in neonates.mg/kg/dose given every 24 hours for 3 days, or an intravenous

regimen of 10 mg/kg, followed by two more doses of 5 mg/kg2.6.1 Dosing Informationevery 24 hours, is acceptable. There is no definitive evidence toDiclofenac is used as a postoperative analgesic for infants andsupport either oral or intravenous administration for all neo-

children at a dose of 1 mg/kg rectally every 12 hours.[93]nates.[87,88]

2.7 Ketoprofen2.4 Mefenamic Acid

Mefenamic acid metabolism was studied in five preterm neo- We are not aware of any pharmacokinetic data for ketoprofen in

nates, ranging in gestational age from 25–35 weeks. A wide neonates.

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394 Morris et al.

2.7.1 Dosing Information controlled trial involving 1202 patients.[100] The Cochrane data-An oral ketoprofen dosage of 0.5–1 mg/kg every 8 hours is base of 2002 reported that preterm infants benefited from a pro-

recommended for fever in children aged 3 months to 14 years, but phylactic course of indomethacin.[34] Indomethacin producedis not currently recommended for use in neonates. Ketoprofen may ductal closure in symptomatic patients and decreased the inci-also be administered via a transdermal patch in adults, with a dence of grade 3 and 4 IVH, but no positive or negative effects onlimited incidence of site erythema and no additional adverse long-term neurologic development could be documented.events.[94]

The timing of when to give indomethacin, whether prophylacti-

cally, when PDA is clinically suspected, or when PDA is3. NSAID Indications and Usage hemodynamically significant, has also been examined in the litera-

ture. In a randomized comparison of prophylactic indomethacinNSAIDs approved for use in children <14 years of age in the

within the first 15 hours of birth and symptomatic treatment,US include aspirin, choline magnesium trisalicylate (Trilisate®1),

earlier treatment correlated with better ductal closure, both initial-ibuprofen, naproxen, and tolmetin sodium. Indomethacin is also

ly and permanently.[101] However, in both groups, patency ratesindicated for closure of a symptomatic ductus. Although not

remained relatively high. No differences in incidence of necro-possessing significant anti-inflammatory properties, acetamino-

tizing enterocolitis, intracerebral hemorrhage, or lung disease werephen is also generally considered along with the NSAIDs, and is

noted between groups. Indomethacin appeared protective for cys-approved for use in children. The use of acetaminophen was

tic periventricular leukomalacia.recently reviewed in infants.[95]

A subsequent study of early prophylactic infusion of indometh-Indications for which NSAIDs are regularly used in neonates

acin (3 doses of 0.2 mg/kg at 12-hourly intervals) compared withinclude closure of the patent ductus arteriosus, prevention of IVH,

lower dose therapy, showed an increase in closure rates, but alsoreduction of fever, and pain management. Possible or less com-

an increase in adverse effects, with no apparent long-term benefitmon uses of NSAIDs include Bartter’s syndrome, sepsis, preven-

in preterm infants already on ventilator support.[102] Longer-termtion of bronchopulmonary dysplasia, and oxygen-induced reti-

follow-up of extremely low birthweight (ELBW, <1000g) infantsnopathy. In general, high doses of salicylates relieve inflamma-

who received prophylactic indomethacin demonstrated that pro-tion, and low doses are analgesic.

phylactic indomethacin did not improve the rates of overall survi-

val without neurologic deficit.[103] However, a study of very low3.1 Patent Ductus Arteriosusbirthweight (VLBW) infants followed for up to 54 months showed

One of the best researched uses of NSAIDs in this age group is higher IQs among infants who received prophylactic indomethacin

closure of the patent ductus arteriosus. This topic has recently been compared with those who received placebo, with no difference in

reviewed in this journal and elsewhere.[96,97] In a recent compre- incidence of cerebral palsy.[104] A smaller randomized placebo-

hensive review of this topic, Knight[98] found no advantage of controlled trial of 30 ELBW and VLBW infants found no long-

prophylactic or asymptomatic treatment of PDA with NSAIDs or term adverse effects of indomethacin for PDA closure, and also

surgery, and concluded that an individualized approach based on demonstrated a marked decrease in the incidence of severe

hemodynamic status was preferred in determining treatment. IVH.[105]

3.1.2 Other NSAIDs3.1.1 Indomethacin

Ibuprofen and mefenamic acid have also received significantA review and meta-analysis of prophylactic indomethacin forattention for use in treating PDA.PDA found a number of immediate benefits, but lacked long-term

outcome information.[99] The question of whether or not prophy- Varvarigou et al.[106] found prophylactic intravenous ibuprofen

lactic indomethacin given to reduce the incidence of PDA and IVH in neonates with a gestational age of 26.9 (range 22.4–31 weeks),

correlates with improved long-term neurodevelopment should be at a dose of 10 mg/kg at birth, followed by 5 mg/kg/day for 2 days,

answered by the recently completed Trial of Indomethacin Pro- resulted in a dramatic decrease in the incidence of PDA. These

phylaxis in Preterm Infants (TIPP), a multicenter randomized authors found a single 10 mg/kg intravenous dose much less

1 The use of tradenames is for product identification purposes only and does not imply endorsement.

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NSAIDs in Neonates 395

effective. The incidence of adverse events was not increased over 3.3 Pain

placebo. A separate group utilizing the same multidose ibuprofenThe physiologic and ethical benefits of treating pain in neonates

regimen compared prophylactic with symptomatic treatment andhave been well reviewed by Anand and Hickey.[119] However, the

found both were effective and relatively free of adverse effects inuse of NSAIDs for this purpose in this population has not been

closing PDA.[107] A recent report in the literature found three caseswell studied. In a standard pediatric pain management textbook,

of ibuprofen inducing severe pulmonary hypertension in a study of the chapter on pain management in the neonatal intensive care unitibuprofen prophylaxis for ductal closure in preterm neonates.[108]

(NICU) contained only one paragraph on acetaminophen as anThe use of mefenamic acid is more common in Asian centers analgesic adjunct to opioids.[120] In a recent publication of the

than it is in North America and Europe. In a nonrandomized Canadian Paediatric Society’s policy statement on neonatal pain

and stress prevention, only two efficacy studies, both using aceta-comparison of mefenamic acid and indomethacin involving 46minophen, are cited.[121] Pain management in the NICU was re-preterm infants, a higher PDA closure rate was found with mefen-cently reviewed.[122] The authors found limited evidence regardingamic acid (93.3%) than with indomethacin (70%, p > 0.05).[90]

NSAIDs in the neonatal age group. In a review of pain relief inIn a randomized controlled trial involving 75 premature infants

infants, the section devoted to NSAIDs was remarkably short,(mean gestational age 29.6 weeks) of aspirin versus indomethacin

based on the lack of published evidence regarding these agents.[123]

for PDA, aspirin was significantly less effective than indometha-However, the author recommended NSAIDs be used with ‘particu-

cin (43% vs 92% closure rate, p < 0.001).[109]

lar caution’ in infants.In a multicenter comparison of ibuprofen with indomethacin A cross-sectional survey of Canadian NICUs found that proce-

for the treatment of symptomatic PDAs involving 148 neonates, dural pain in neonates was woefully undertreated.[124] This isibuprofen was found to be as efficacious as indomethacin, with a despite ample evidence that neonates are capable of experiencinglesser degree of oliguria.[110,111] A small study comparing sulindac pain, and possibly experiencing long-term consequences fromand indomethacin found both were effective in ductal closure in it.[124] Over a 1-week period, 239 neonates underwent a total of

preterm neonates, with sulindac having a lower incidence of renal 2134 invasive procedures. Analgesia was given specifically for 17

of these procedures (0.8%), while for another 129 procedures theadverse effects, but a higher incidence of gastrointestinal prob-patient was already on analgesics. Opioids were the predominantlems.[112]

analgesics used, with acetaminophen the only non-opioid analge-Animal studies have indicated a possible role for selectivesic reported.[124] This lack of treatment of pain in neonates is

COX-2 inhibitors for ductal closure.[113]

certainly multifactorial; however, one reason for this may be a

feeling on the part of practitioners of a lack of safe and effective3.2 Fever analgesics for this age group.

3.3.1 AcetaminophenThe decision of whether or not to treat fever in neonates is aThere have been a few analgesic comparison trials of NSAIDsclinical one. Determining if a neonate presenting with fever repre-

and acetaminophen.[125] The efficacy of acetaminophen in alleviat-sents a serious infectious process or a more benign etiology has

ing moderate to severe pain appears mixed at best.been the subject of significant research.[114,115]

In a trial of 2-year-old children presenting for tonsillectomy,In neonates, one study found the target plasma concentration of patients receiving 12.5mg (average 1 mg/kg) diclofenac rectally

acetaminophen for an antipyretic effect to be 10–20 mg/L, or prior to surgery required significantly less supplemental post-66–132 μmol/L.[56] While acetaminophen enjoys popularity in the operative analgesia than children receiving 125mg (average 10US for antipyresis, two studies have demonstrated greater efficacy mg/kg) of acetaminophen rectally.[126] While there was increasedfor ibuprofen and other NSAIDs over acetaminophen in chil- bleeding in the diclofenac group, it was not significant and theredren.[116,117] However, NSAIDs may have an increased risk in was no difference in the complication rate between groups.

febrile patients experiencing infectious diseases as they may im- Acetaminophen 20 mg/kg rectally, given within 1 hour of birth,

pair the immune response.[118] did not alleviate the pain or significantly improve the clinical

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396 Morris et al.

condition of neonates delivered by vacuum extraction.[127] No In a study of neonatal rats, ketorolac was found to be ineffective

differences were noted between the placebo and acetaminophen for analgesia in 3-day-old rat pups (equivalent to gestational age in

groups, but significant differences in pain and clinical condition humans of approximately 30 weeks), but was effective in 21-day-

(grunting, pain on handling, irritability, poor feeding) were noted old rats (equivalent age of young children).[137] Whether this

between all infants delivered by vacuum extraction and those by finding indicates an age dependency for the efficacy of NSAIDs in

spontaneous vaginal delivery. humans is unclear. Morphine was efficacious at both ages. In our

clinical practice, opioids are used as the standard analgesic forAcetaminophen 40 mg/kg rectally at anesthesia induction didpainful procedures in neonates and children, with ketorolac (0.5not have opioid-sparing properties in small children (11.4 ± 9.9mg/kg) used for breakthrough pain.months of age) undergoing cleft palate repair.[128] However, this

dose (as well as the lower 10 and 20 mg/kg doses) did not achieve 3.3.3 Indomethacintherapeutic plasma concentrations in most patients. Both rectal[138] and intravenous[139] indomethacin have been

In neonates, limited evidence seems to indicate that acetamino- shown to have opioid-sparing properties in children.phen lacks efficacy as analgesia for painful procedures. In a Prophylactic indomethacin infusion has been shown to reduceplacebo-controlled trial of acetaminophen for neonatal circumci- postoperative pain in children aged between 1 and 16 years. Givension, no appreciable differences in pain score or behavior between as an intravenous bolus dose of 0.35 mg/kg, followed by antreatment groups were found.[129] The neonates received acetamin- infusion at 0.07 mg/kg/h for 24 hours and compared with placebo,ophen 15 mg/kg orally 2 hours before circumcision. After circum- indomethacin reduced the need for postoperative morphine andcision, neonates were also found to have a decrement in feeding improved the children’s evaluation of their own pain.[139] In abehavior, which may have sequelae. In another trial of 75 term separate safety analysis, indomethacin was found to significantlyneonates, acetaminophen 20 mg/kg given orally 1–11/2 hours increase bleeding, but in no cases was treatment required.[140]

before heel stick did not reduce pain scores over placebo.[130]Indomethacin also seemed to reduce the incidence of post-

Acetaminophen 20 mg/kg intrarectal solution has also been shown operative fever in these patients.to lack efficacy for postoperative pain in children aged between 1

3.3.4 Diclofenacand 8 years.[131] A comparison of oral ibuprofen and acetamino-Opioid-sparing properties in children have been demonstratedphen found ibuprofen more effective for analgesia in children

with intravenous diclofenac.[126]undergoing dental procedures.[132]

In disagreement with these findings is a study of 50 patients3.4 Other Uses of NSAIDs

aged between 2 and 15 years comparing ketorolac 1 mg/kg or

rectal acetaminophen 35 mg/kg, which found acetaminophen to be Hyperprostaglandin E syndrome, or Bartter’s syndrome, con-as efficacious as ketorolac in reducing tonsillectomy pain.[133] sists of salt wasting, hypercalciuria with nephrocalcinosis, hyper-

prostaglandinuria, and secondary hyperaldosteronism. In utero3.3.2 Ketorolac these patients have polyhydramnios secondary to polyuria. Indo-

Ketorolac has been shown to have opioid-sparing properties in methacin has long been used to treat this disorder, with good

pediatric patients.[134] At a dose of 1–1.5 mg/kg/day intravenously, results.[141] In a recent study, Nusing et al.[142] found nimesulide, a

morphine requirements were reduced in infants <6 months of age COX-2 inhibitor, as equally effective as indomethacin in a cross-

after abdominal surgery.[91] over study of six well managed patients with Bartter’s syndrome,

ranging in age from 8–18 years. While increasing the treatmentIn a study comparing intravenous ketorolac versus morphine inoptions for this disease, this work also implicates COX-2 in thechildren aged between 3 and 12 years, ketorolac was less potentpathogenesis of Bartter’s syndrome.but longer lasting than morphine for postoperative pain.[135] How-

ever, in a different study comparing intravenous ketorolac 0.9 mg/ Ibuprofen has been found to antagonize the effects of group B

kg with morphine 0.1 mg/kg intraoperatively in children aged streptococci infection on the inflammatory mediators nuclear fac-

between 5 and 15 years undergoing elective surgery, ketorolac was tor kappa B and inducible nitric oxide synthase in vitro,[143] and

found to be as efficacious as morphine in postoperative pain therefore it may prove useful in limiting the systemic effects of

management.[136] neonatal sepsis.

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NSAIDs in Neonates 397

Ibuprofen has also been used as prophylaxis for bronchopul- 4.2 Acetaminophen

monary dysplasia, based on its anti-inflammatory activity, withThe overall prognosis of both acute salicylate and acetamino-

equivocal results.[144]

phen toxicity, when appropriately treated, has long been consid-Indomethacin has been shown to have beneficial effects on ered good.[125]

oxygen-induced retinopathy separate from its hemodynamic In the case of acetaminophen, the same concerns regardingmechanisms in mice.[145]

hepatotoxicity as in adults occur. However, hepatotoxicity has not

been found in the few reports of acetaminophen overdose in

neonates. This has been attributed to the slower oxidative metabol-4. NSAID-Associated Adverse Eventsism and faster glutathione synthesis in neonates and younger

animals.[154] In one reported case of a premature neonate overdoseNonselective NSAIDs have been associated with adverse ef-of acetaminophen 136 mg/kg orally (over twice the recommendedfects in children involving nearly every organ system, albeitmaximum daily dose) no long-term sequelae or hepatotoxicity was

uncommonly.[146] Their risks and benefits in children (excludingnoted.[155] Furthermore, a cross-sectional study that included 416

neonates) have recently been reviewed in this journal.[147] Thesepediatric patients with acetaminophen overdoses found a decreas-

adverse effects are usually described in terms of alterations ining incidence of toxicity and symptom severity with younger

prostaglandin biology or as idiosyncratic reactions. However, notchildren.[156]

all literature regarding antenatal exposure to NSAIDs has shownThe danger of acetaminophen toxicity in neonates is real, both

harmful effects. In one randomized trial of 88 rheumatic mothers from self-medication at home and in the hospital. A survey of Newwho either received or did not receive NSAIDs during pregnancy, Zealand in-hospital pediatric practitioners found a 17% incidenceno increased incidence of adverse events was noted in the NSAID of prescription of an overdose of acetaminophen; however, onlygroup.[148] 3% of the children actually received a dosage >90 mg/kg/day.[157]

Even more practitioners were not comfortable prescribing aceta-

minophen to neonates at all.4.1 Persistent Pulmonary HypertensionChronic acetaminophen toxicity is notoriously difficult to diag-

nose in the pediatric population. One possible aid for this is theOf particular concern in neonates, pulmonary hypertensiondevelopment of an antigenic biomarker for toxicity, which hasresulting from NSAID exposure has been relatively well de-been tested in children.[158]

scribed. A relatively small (n = 103 persistent pulmonary hyper-

tension [PPH] infants, 298 control individuals) retrospective study4.3 Indomethacin

of mothers of infants with PPH found that maternal ingestion of

Although indomethacin has been used for tocolysis since ataspirin and NSAIDs during pregnancy increased the risk of PPHleast 1974, there are limited data regarding its effects on the fetusby a factor of 4.9 (1.6–15.3) and 6.2 (1.8–21.8) respectively.[149]

and neonate. One study of long-term (maximum 120 days) expo-This work was supported by a subsequent study that examined

sure to indomethacin prenatally reported no increased incidence ofthe meconium of newborns with PPH for the presence of NSAIDs.

adverse events. However, 2 of 31 exposed fetuses did have persis-This study found a significantly increased risk of PPH with mater-

tent pulmonary hypertension and two had decreased amniotic fluidnal ingestion of NSAIDs, including aspirin, ibuprofen, naproxen,

volume.[159] Adverse events in nearly every organ system haveand indomethacin, and also found that mothers were poor histori- been attributed to indomethacin.ans regarding NSAID ingestion.[150] Similarly, a larger cross- Vanhaesebrouck and colleagues[160] described a constellation ofsectional study found a nearly 7-fold increase in risk of miscar- defects in three neonates exposed to indomethacin in utero. Theriage within 1 week of maternal ingestion of an NSAID.[151] Case newborns had edema, hydrops, oliguric renal failure, bleedingreports have also described persistent pulmonary hypertension diathesis, and ileal perforation which presented at the end of theafter antenatal exposure to naproxen,[152] diclofenac,[153] and ibu- first week of life. Each of these organ systems is a known site for

profen.[108] adverse effects of NSAIDs. Another case series of five neonates

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398 Morris et al.

exposed to either ibuprofen or indomethacin in utero reported cerebral blood volume.[172] In another trial of indomethacin versus

severe renal abnormalities, with a common specific pathologic ibuprofen for PDA that examined cerebral blood flow, ibuprofen

finding of incomplete tubular differentiation.[161] Interestingly, produced a stable cerebral blood flow, whereas indomethacin

four of these five patients were members of four different sets of caused significant reductions in cerebral blood flow, cerebral

twins. oxygen delivery, and cerebral blood volume.[173] However, this

was a small study involving only 33 patients and the ibuprofenThere have been other case reports of indomethacin-inducedgroup had a lower PDA closure rate (78%) than the indomethacinrenal dysfunction.[162] In a case-control study of nine pretermgroup (93%). As both agents have the same putative effects onneonates exposed in utero to indomethacin, with nine matchedprostaglandins, additional mechanisms apparently mediate the ef-control individuals, the newborns treated with indomethacinfects of indomethacin on cerebral blood flow.[174]showed decreased urine output, increased edema, lower inulin

Indomethacin has been shown to be well tolerated for coronaryclearance, higher serum creatinine levels, higher urine osmolarity,

perfusion in neonates, as evidenced by an absence in elevation ofand lower osmolar and free water clearance.[163] The authors

cardiac troponin T levels after infusion in 23 preterm infants.[175]concluded that these changes were significant enough to require

modification of fluid treatment in these patients. In this study, the Indomethacin has been shown to compromise mesenteric and

range of plasma indomethacin concentrations resulting from pla- renal blood flow to a greater degree than ibuprofen in neonates

cental transfer was comparable to the concentrations achieved in treated for PDA when the agents were given in a randomized

conventional indomethacin treatments for ductal closure (0.1–1.9 controlled trial.[176] These changes occurred in the absence of a

μg/mL). In a double-blind controlled trial of indomethacin versus change in mean arterial pressure. In a different study of preterm

placebo in neonates, indomethacin lowered urine output, fractional infants treated with indomethacin, the addition of low-dose dop-

excretion of sodium and chloride, and urinary kallikrein signifi- amine was able to increase renal and mesenteric blood flow

cantly.[164] without increasing cerebral blood flow.[177]

In contrast, Ojala and colleagues[165] compared 31 children with Indomethacin use may also result in bowel perforation in

perinatal indomethacin exposure to 33 without, and found no neonates, particularly neonates of a younger age.[178] These bowel

increased incidence of long-term renal abnormalities at 2–4 years perforations result in a marked increase in mortality (53% survival

of age. Furthermore, there have been case reports of the successful with perforations versus 96% without).[179]

use of indomethacin to treat PDA in VLBW neonates already A prospective study of indomethacin infusions in VLBW in-experiencing renal impairment.[166] A study of 14 preterm infants fants found a significant decrease in blood glucose values afterwhose mothers received indomethacin tocolysis found no evi- indomethacin infusion.[180]

dence of renal impairment during the first 10 postnatal days.[167] A study of 252 preterm infants found an increased risk of

Various modalities have been attempted to limit the renal necrotizing enterocolitis in patients treated with indomethacin

adverse effects of indomethacin, without success. These include using a dose of 0.2 mg/kg every 12 hours × three doses.[181]

dopamine infusion[168] and furosemide administration.[169] However, the control individuals in this study were neonates

without PDA and/or who did not receive indomethacin, thereforeA treatment course of longer duration with a lower dosage (5 orintroducing a significant confounding error. A retrospective re-6 days of indomethacin 0.1 mg/kg/day) has been shown to offer noview of 240 infants found an increased risk of necrotizing entero-benefit over traditional dosage.[170] In one case series of fourcolitis with longer exposure to indomethacin.[182]neonates who had received a 10-fold overdose of indomethacin,

none had long-term sequelae attributed to the overdose.[171] Indomethacin also increases oxygen and surfactant require-

ment, prolonging ventilatory support.[183]Indomethacin has been shown to reduce cerebral blood flow,

while ibuprofen preserves cerebral blood flow dynamics. In one

head-to-head trial of indomethacin and ibuprofen, indomethacin 4.4 Selective Cyclo-Oxygenase-2 Inhibitorscaused significant reductions in cerebral blood flow and volume,

and a suggested decrease in oxidized cytochrome oxidase (an The assumption that COX-2 inhibition is therapeutic, while

indicator of oxygen consumption) concentration, whereas ibupro- COX-1 inhibition causes adverse effects, is an oversimplification,

fen had no effect on these parameters and actually increased particularly in neonates. The adverse events of NSAIDs occur

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NSAIDs in Neonates 399

through the same inhibition of prostanoid synthesis that leads to abnormalities included being small in size and pale. Renal abnor-

their anti-inflammatory and analgesic actions. These predominant- malities were present in varying degrees in all homozygous ani-

ly affect hemostasis, renal function, and the gastrointestinal sys- mals, but were more severe in males and worsened with age. These

tem. Among the NSAIDs, only the COX-2–specific inhibitors and abnormalities appear to develop postnatally; 3-day-old pups had

the nonacetylated salicylates (salsalate or choline magnesium no visible pathologic kidney changes. It should be noted that renal

trisalicylate) do not prolong the bleeding time. development in mice does not end until several weeks postnatally.

Some of the deaths appeared to be due to spontaneous suppurativeCOX-2 inhibitors have been implicated in renal, cardio-peritonitis of unknown etiology. In crossing heterozygous rodentsvascular, and thrombotic adverse events.[184-188] Renal and cardio-to create homozygous knockout animals, the production of malevascular adverse events of COX-2 inhibitors have been recentlyhomozygotes was significantly reduced below Mendelian predict-reviewed.[185,189] The Vioxx Gastrointestinal Outcomes Researched numbers. This finding has not yet been explained.(VIGOR) trial, which enrolled over 8000 adult patients comparing

The work in gene knockout models has been extended bynaproxen with rofecoxib, demonstrated a statistically significantpharmacologic studies. Antenatal exposure to NSAIDs, partic-4-fold increase in the incidence of myocardial infarction in theularly before the 32nd week of gestation, has been shown to causerofecoxib group;[190] however, the difference was no longer signif-renal developmental abnormalities.[197] COX-2–selective, but noticant when the confounding factor of underuse of aspirin prophy-COX-1–selective, inhibitors given antenatally resulted in markedlaxis in the rofecoxib group was accounted for.[191] The Celecoxibdisruption of glomerulogenesis and renal cortical development,Long-Term Arthritis Safety Study (CLASS) trial, which enrolled awith a decrease in kidney volume, in mice and rats. These resultssimilar number of adult patients and compared celecoxib withwere similar to those of rodents that were gene knockout fortraditional NSAIDs, did not demonstrate this significant increaseCOX-2. These effects were not present in adults rodents, but theyin myocardial infarction.[192] A number of patients received aspirindid extend postnatally.concomitantly in the CLASS trial, and this trial included a younger

age range of patients. A subsequent meta-analysis of VIGOR, COX-2 inhibitors have been shown to reduce the renin response

CLASS, and other trials confirmed an increase in myocardial to hypovolemia, salt restriction, and ACE inhibitors.[198] However,

infarction rates with both rofecoxib (annual event rate 0.74%) and these effects may not be present in neonates. While COX inhibi-

celecoxib (0.80%) over placebo (0.52%).[193] tors may decrease renal function, they may also be kidney protec-

tive in ischemic injury.COX-2 inhibitors have also been shown to be prothrombotic in

Some authors have found a renoprotective role for COX-2dog coronaries in a model of endothelial injury.[194] The effects of

inhibitors in mice models of renal injury. In mice subjected toCOX-1, COX-2, and nonselective COX inhibition on thrombosis

subtotal renal ablation, COX-2 inhibitors decreased glomerularhas recently been reviewed.[195]

sclerosis and proteinuria to a similar degree as enalapril, an ACEGene knockout models of both COX-1 and COX-2 in miceinhibitor. Unlike the ACE inhibitor, the COX-2 inhibitorhave been developed.[8,196] COX-1 deficient mice appeared nor-SC-58236 did not prevent the development of hypertension.[199]mal, with pathology sections of liver, spleen, kidney, gastrointesti-While the mechanism of this putative renoprotection remains to benal tract, reproductive tract, heart, and lungs showing no majorelucidated, it has been shown that COX-2 mRNA expression isabnormalities. However, these mice did have defects in mountinginduced by renal ablation.[200]an inflammatory response and in platelet aggregation. Mating of

homozygous COX-1 deficient mice resulted in a normal litter size,

but a marked decrease in live births. The reason for this finding is 4.5 Ibuprofenunexplained. Surprisingly, COX-1 deficiency was found to be

protective of the gastric mucosa to treatment with indomethacin, In children, the short-term use of ibuprofen has been shown todespite having low levels of PGE2 production in these mice. have no worse renal adverse event profile than acetaminophen.[201]

In contrast, COX-2 knockout mice did not have a deficit in As a possible agent for use in ductal closure, safety comparisons

inflammatory response to chemical irritants, but did have in- with indomethacin have been favorable. In a newborn piglet

creased overall mortality (with deaths occurring at approximately model, both indomethacin and ibuprofen increased renal resis-

8 weeks of age), and marked renal pathology.[196] The kidney tance, but only indomethacin had deleterious effects on gastroin-

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400 Morris et al.

testinal and cerebral blood flow.[202] However, in one rabbit model, The risk potential is such that it should preclude the indiscrimi-

no benefit of ibuprofen over indomethacin was shown for renal nant use of these agents in neonates. At present there seems little

hemodynamics.[203] evidence for the use of NSAIDs as first-line analgesia. Opioids

have a long history of safety, with easily reversible adverse effects4.6 Aspirin should they occur. However, there may be a place for NSAIDs as

analgesic adjuncts. The understanding that PGE is a nociceptiveThe textbook signs of salicylate toxicity (lethargy, emotional

mediator may translate into an increased need for analgesics whenlability, tinnitus, and hyperpnea) may be difficult to detect in

painful procedures are carried out on children receiving PGE.neonates and may mimic neonatal sepsis.[204] In utero exposure to

Indomethacin has been used for nearly 30 years in the US foraspirin (as well as ibuprofen) has been associated with gastros-closure of the PDA. Recent data comparing ibuprofen with indo-chisis.[205] Intracranial hemorrhage in neonates has been attributedmethacin has demonstrated a better adverse effect profile withto maternal aspirin ingestion.[206] However, a study enrolling 50ibuprofen with similar efficacy. The lack of an intravenous formu-neonates born after maternal ingestion of aspirin found no adverselation in the US limits its widespread use.effects on platelet function in the newborn.[207] Safety literature

Prostaglandins are clearly important in the development ofregarding the use of aspirin in the neonatal period is absent.

multiple organ systems, including the kidney, and the long-termThe association of aspirin with Reye’s syndrome has largelyeffects of prostaglandin synthesis inhibition remain to be elucidat-removed it from the armamentarium for febrile children.[208]

ed. Monitoring of serum creatinine levels, sodium, and other4.7 Ketoprofen markers of renal perfusion, particularly in the first 48 hours of

therapy, will increase the safety margin in neonates receivingRenal damage has been demonstrated after antenatal exposure NSAIDs. Similarly, the presence of prostaglandin-mediated sig-

to ketoprofen.[209] Ketoprofen also accumulates in neonates with naling in CNS processes as diverse as nociception, sleep, andrenal failure after in utero exposure.[210]

thermoregulation, raises theoretical concerns about the use of

NSAIDs during this period of rapid development. The importance4.8 Drug Interactions

of the varying effects on cerebral blood flow caused by different

NSAIDs is still unclear.NSAIDs have been shown to affect the metabolism of numer-

ous pharmacologic agents, including digoxin, aminoglycosides, The gastrointestinal adverse effects of NSAIDs appear to becoumarins, and barbiturates.[146] These drug interactions have been less common, but potentially more severe, in neonates than inreviewed in more detail elsewhere.[211] adults. Given the developmental differences in prostaglandin biol-

NSAIDs have been shown to displace warfarin from plasma ogy at this age, the question of whether selective COX-2 inhibitorsproteins. The ability of the NSAID to reduce renal function can will be less irritating to the gastrointestinal tract than nonselectivelead to significant increases in digoxin levels. Similarly, indo- NSAIDs in neonates, as they are in adults, remains unanswered.methacin has been shown to increase the plasma concentrations of Acetaminophen remains the drug of choice for antipyresis ingentamicin and amikacin in neonates.[211] Midazolam plasma neonates. While other NSAIDs may be more potent, the adverseclearance is increased by indomethacin.[212] Ibuprofen has been effect profile of acetaminophen is more favorable. When usingshown to significantly displace bilirubin from albumin in neo- acetaminophen, appreciating the delay of onset as well as the neednates, and may represent a danger in patients with jaundice.[213] An for larger loading doses will result in improved efficacy.allergy to sulfa is a contraindication to use of celecoxib.

With the advent of more parenteral forms of NSAIDs, their

utility and application will likely increase. The advent of parecox-5. Future Directionsib, the first selective COX-2 inhibitor in a parenteral formulation,

Data regarding the use of NSAIDs in pediatric patients is increases the practitioner’s armamentarium dramatically.[214] Al-

limited, and information on neonates is even more scarce. By though NSAIDs have acquired the impression of being a safe

extracting from the currently available findings it is apparent that medication for our patients’ parents, a cautious application of

there are potential risks and benefits, but few conclusive facts. these agents remains the recommendation for neonates.

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NSAIDs in Neonates 401

20. Murphy PJ, Badia P, Myers BL, et al. Nonsteroidal anti-inflammatory drugs affectAcknowledgementsnormal sleep patterns in humans. Physiol Behav 1994 Jun; 55 (6): 1063-6

21. Murphy PJ, Myers BL, Badia P. Nonsteroidal antiinflammatory drugs alter bodyNo sources of funding were used to assist in the preparation of this

temperature and suppress melatonin in humans. Physiol Behav 1996; 59 (1):manuscript. The authors have no conflicts of interest that are directly relevant 133-9to the content of this manuscript. 22. Yaksh TL, Hua XY, Kalcheva I, et al. The spinal biology in humans and animals of

pain states generated by persistent small afferent input. Proc Natl Acad Sci USA1999 July; 96: 7680-6

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