Review Article Clinical Pharmacology of Midazolam in ......Clinical Pharmacology of Midazolam in Neonates and Children: Effect of Disease A Review GianMariaPacifici Section of Pharmacology,

Review ArticleClinical Pharmacology of Midazolam in Neonates andChildren Effect of DiseasemdashA Review

Gian Maria Pacifici

Section of Pharmacology Department of Translational Research and New Technologies in Medicine and SurgeryMedical School University of Pisa 56126 Pisa Italy

Correspondence should be addressed to Gian Maria Pacifici pacificibiomedunipiit

Received 9 November 2013 Accepted 26 December 2013 Published 18 February 2014

Academic Editor Steven M Donn

Copyright copy 2014 Gian Maria Pacifici This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Midazolam is a benzodiazepine with rapid onset of action and short duration of effect In healthy neonates the half-life (t12) and the

clearance (Cl) are 33-fold longer and 37-fold smaller respectively than in adults The volume of distribution (Vd) is 11 Lkg bothin neonates and adults Midazolam is hydroxylated by CYP3A4 and CYP3A5 the activities of these enzymes surge in the liver in thefirst weeks of life and thus the metabolic rate of midazolam is lower in neonates than in adults Midazolam acts as a sedative as anantiepileptic for those infants who are refractory to standard antiepileptic therapy and as an anaesthetic Information ofmidazolamas an anaesthetic in infants are very little Midazolam is usually administered intravenously when minimal sedation is requiredintranasal administration of midazolam is employed Disease affects the pharmacokinetics of midazolam in neonates multipleorgan failure reduces theCl ofmidazolamandmechanical ventilation prolongs the t

12of this drug ECMOtherapy increases t

12 Cl

andVd ofmidazolam several timesThe adverse effects ofmidazolam in neonates are scarce pain tenderness and thrombophlebitismay occur Respiratory depression and hypotension appear in a limited percentage of infants following intravenous infusion ofmidazolam In conclusion midazolam is a safe and effective drug which is employed as a sedative as antiepileptic agent for infantswho are refractory to standard antiepileptic therapy and as an anaesthetic

1 Introduction

Midazolam is a short-acting benzodiazepine with rapid onsetof action It has anxiolytic muscle relaxant and anticonvul-sant activity now most widely used to generate anterogradeamnesia and to stop prolonged seizures in children [1]Midazolam is one of the most widely used sedatives inthe ldquoneonatal intensive care unitrdquo [2] The sedative andanticonvulsant properties of midazolam are related to GABAaccumulation and occupation of benzodiazepine receptors[3] Antianxiety properties are related to increasing theglycine inhibitory neurotransmitter [3]

Midazolam exerts most of its effects by interacting withinhibitory neurotransmitter receptors directly activated byGABA GABAA receptors are responsible for most inhibitoryneurotransmission in the central nervous system Benzodi-azepines act at GABAA receptors by binding directly to aspecific site that is distinct from that of GABA binding [4]Midazolam which was approved for clinical use in 1976 acts

as a sedative-hypnotic is used in the treatment of refractoryseizures and induces anaesthesia [3]

In adults the half-life (11990512

) of midazolam is 19 hourswhich is 22-fold shorter than that of diazepam [5] Bioavail-ability of midazolam is about 50 when absorbed directlythrough either oral or nasal mucosa [6]Midazolam ismainlyeliminated by hydroxylation to form 1-hydroxymidazolam byCYP3A4 and CYP3A5 enzymes 1-Hydroxymidazolam hassedative effect [4] Finally this metabolite is glucuronidatedbefore excretion into urine [7] Hepatic CYP3A4 activityappears in the liver during the first weeks of life [8 9] it isthus lower in neonate than adult liver resulting in reducedmidazolam clearance (Cl) in neonates [6 10] CYP3A5expression has been detected in only 10 to 30 of neonateliver samples tested [11] Elimination 119905

12of midazolam is

shorter in neonates it is about from 4 to 6 hours It is quitevariable and may be up to 22 hours in premature infants [3]CYP3A4 and CYP3A5 activities reach adult levels between3 and 12 months of postnatal age [9] Midazolam is highly

Hindawi Publishing CorporationInternational Journal of PediatricsVolume 2014 Article ID 309342 20 pageshttpdxdoiorg1011552014309342

2 International Journal of Pediatrics

bound to plasma protein in adults the bound percentage is98 [5]

The literature on the effects and fate of midazolam inneonates is scarce Most of the published information dealswith the sedative effect with the treatment of refractoryseizures to standard therapies with the metabolism withthe pharmacokinetics and with the adverse effects of mida-zolam The information on the use of midazolam as ananesthetic agent in newborn infants is lacking Mellon et al[12] reviewed the anaesthetic agents in newborn animalsInformation on the anaesthetic activity of midazolam hasbeen reported in Sprague-Dawley rats [13] and in miceC57BL6 [14] both animals were 7 days old No data on theanaesthesia by midazolam in infants are available

Infants may experience moderate to severe pain in theldquoneonatal intensive care unitrdquo and the use of a sedativeto make their life comfortable when undergoing painfulprocedures is useful [15] Midazolam was found to be moreeffective than placebo as a sedative in neonates [16] and itsconcentrations ranging from 100 to 400 ngmL are sufficientfor sedation [17] Jacqz-Aigrain et al [16] Anand et al [18]and Arya and Ramji [19] used midazolam for sedation ofneonates undergoing mechanical ventilation and midazolamhas resulted to be a safe and effective sedation

Benzodiazepines provide effective control of patient agi-tation and these drugs are useful to comfort neonates duringstressing procedures Midazolam represents a convenientchoice among the sedatives because of its fast onset of actionand rapid termination of effect and is thus frequently used inthe ldquoneonatal intensive care unitsrdquo

Up to now little has been done to make comfortablethe life of neonates who undergo stress and pain Lowrieet al [20] created a ldquopediatric sedation unitrdquo to uniformand monitor the therapy for sedation andor analgesia forchildren undergoing invasive and noninvasive proceduresInfants admitted to the ldquopediatric sedation unitrdquo wereassessed medically for risk factors during sedation Many ofthe pediatric patients admitted to this unit were neonatesPharmacological treatment helps neonates to tolerate painprocedures or diagnostic studies requiring prolonged periodsof immobility The majority of children needing sedationreceived midazolam or propofol [20]

Ng et al [21] reviewed the literature on the intravenousmidazolam infusion for sedation of infants in the ldquoneonatalintensive care unitrdquo Three trials were included in the studyand using different sedation scales each study showed ahigher sedation level in the midazolam group compared tothe placebo However Ng et al [21] conclude that thereare insufficient data to promote the use of intravenousmidazolam infusion as a sedative for neonates undergoingintensive care [22]

Sedation may be performed with opioids (fentanylmorphine and diamorphine) or with the sedative-hypnoticmidazolam in ventilated neonates Endotracheal intubationand mechanical ventilation are major components of routineintensive care for very low birthweight newborn infants andsick fullterm newborn infants [22] Sedation is widely usedin neonates although there is limited clinical evidence for

the efficacy and safety of the drugs used or the methods ofadministering them [22]

A useful action of midazolam is the management ofneonatal seizures refractory to conventional treatments Huet al [23] reported that a continuous intravenous infusionof midazolam ranging from 1 to 15120583gkg per min with anaverage of 4 120583gkg per min terminated the seizures in 32infants whose seizures could not be controlled by diazepamphenytoin or phenobarbital Castro Conte et al [24] foundthat midazolam (015mgkg intravenous bolus followed bya continuous infusion of 1 120583gkg per min increasing by 05to 1 120583gkg every 2min until a maximum of 18120583gkg permin) controlled the seizures in 13 neonates refractory to thetreatment with phenobarbital and phenytoin

Troponin T is a prognostic indicator of postoperativerecovery Midazolam propofol or sevoflurane had similarefficacy in the production of troponin T in infants whounderwent cardiac surgery [25]

The information on the effects of midazolam and on thefate of this drug in neonates has been published in differentjournals during the last thirty years and it is scattered Theaims of this article are (1) to gather together and (2) toreview the published data on (a) the metabolism and (b)the pharmacokinetics of midazolam in neonates (c) thetherapeutic effects and finally (d) the adverse effects ofmidazolam in neonates The main objective of this workis (e) to provide neonatologists with a tool that embracesall aspects of the clinical pharmacology of midazolam inneonates Little is known about the effects and the fate of thedrugs administered to neonates This review was written tohelp the neonatologists hoping that theywill find someusefulinformation and thus some advantages for their work fromreading the present paper

2 Bibliographic Search

The bibliographic search was performed electronically usingPubMed and EMBASE databases as search engines Septem-ber 2013 was the cutoff point The following key wordsldquomidazolam neonaterdquo ldquomidazolam mechanism of actionrdquoldquomidazolam therapy neonaterdquo ldquomidazolam pharmacokinet-ics neonaterdquo ldquomidazolam metabolism neonaterdquo ldquoCYP3A4midazolam neonaterdquo ldquoCYP3A5 midazolam neonaterdquo ldquooraladministration midazolam neonaterdquo ldquointranasal administra-tion of midazolam neonatesrdquo ldquomidazolam seizuresrdquo ldquomida-zolam anaesthesia neonaterdquo and ldquomidazolam adverse effectsneonaterdquo were usedThe bibliography of each article was readcarefully and the selected articleswere examined In additionthe books NEOFAX a Manual Used in the Neonatal Care byYoung andMangum [3] and theNeonatal Formulary [1] wereconsulted The findings of the bibliographic search gave riseto 101 original articles 13 review articles and 6 book chaptersThe publication years of this matter ranged from 1979 to 2013

3 Results

31 Doses of Midazolam in Neonates For sedation Youngand Neofax [3] suggest giving intravenously a 50 to 150120583gkg

International Journal of Pediatrics 3

of midazolam over at least 5min Midazolam may also beadministered intramuscularly Repeat as required usually Q2to 4 hours Dosage requirements are decreased by concurrentuse of narcotics For continuous intravenous infusion give a10 to 60 120583gkg midazolam per hour Dosage of this drug mayneed to be increased after several days of therapy becauseof development of tolerance andor increase of Cl ForIntranasal administration give a 200 to 300120583gkgmidazolamper dose using 5mgmL injectable form For sublingualadministration give a 02mgkg per dose of midazolamusing 5mgmL injectable form mixed with small amountsof flavoured syrup For Oral administration give 250120583gper dose For Anticonvulsant therapy give intravenously aloading dose of 150 120583gkg over at least 5min followed by amaintenance infusion dose of 60 to 400120583gkg per hour (1 to7 120583gkg per min)

32 Metabolism ofMidazolam in Neonates Development hasa profound effect on the expression of phase I enzymessuch as the cytochromes P450 (CYPs) Distinct patternsof isoform specific development CYP expression have beenobserved postnatally Although the CYP content in the fetalliver equals about 30 to 60 of adult values [35] isoformshave a specific ontogeny and preclude the generalisationof a simple single developmental pattern for overall CYPactivities necessitating isoenzymes specific assessment [3637]

In adults midazolam is metabolized rapidly [7] therecovery of unchanged midazolam in urine of adult subjectsis 1 [5] suggesting that metabolism is the main route ofmidazolam elimination in man Midazolam is hydroxylatedto form 1-hydroxymidazolam by hepatic CYP3A4 [3 38ndash41] and by CYP3A5 [38 40ndash43] The oxidative metabolismof midazolam is an aliphatic hydroxylation [38] A signif-icant correlation was observed between the fraction of 1-hydroxymidazolam excreted into urine and the postconcep-tional age [10]

Plasma Cl of midazolam is widely used as an in vivosurrogate measurement of CYP3A4 and CYP3A5 activities[44 45] Cl of midazolam is lower in preterm infants thanin older children and adults [2] The percent recovery ofmidazolam into the urine is higher in infants (044) thanin adults (014) confirming that the metabolic rate ofmidazolam is reduced in infants CYP3A4 activity surges inthe liver during the first week of life [8 9] Therefore theexpression of CYP3A4 in the neonatal liver is lower than thatin the adult CYP3A5 expression shows large interindividualvariability and has been detected in only 10 to 30 ofneonate liver samples tested [11]

Ince et al [46] developed a novel maturation functionfor midazolam Cl based on studies in premature neonatesinfants toddlers children adolescents and adults Thismodel provides a quantitative insight in the developmentpattern of in vivo CYP3A activities across the pediatricrange including premature neonates The largest change inCl of midazolam which is metabolised by CYP3A45 in vivoand in vitro appears in the first week of life [40] Ince etal [46] studied the interactions of hepatic CYP3A activity

using midazolam as an in vivo probe The effect of ontogenyon intestinal CYP3A activity is still unknown intestinalCYP3A is of considerable importance The knowledge ofthe maturation of CYP3A mediated first pass eliminationof midazolam is important to understand the contributionof the intestine to the liver to the first-pass elimination ofmidazolam

The ontogeny of midazolam glucuronidation was stud-ied in 22 preterm infants [10] Midazolam (100 120583gkg) wasadministered intravenously (119899 = 15) or orally (119899 = 7) Afterintravenous administration the median percentage of thedose excreted into the urine over 6-hour intervals was 044(midazolam) 004 (1-hydroxymidazolam) and 157 (1-hydroxymidazolam glucuronide) After oral administrationthemedian percentage of the dose excreted into the urine was011 (midazolam) 002 (1-hydroxymidazolam) and 169(1-hydroxymidazolam glucuronide) The glucuronidation of1-hydroxymidazolam is immature in preterm infants less than2 weeks of postnatal age

33 Pharmacokinetics of Midazolam in Neonates and Chil-dren The Cl of midazolam was measured in 24 preterminfants and the mean was 18 (mLkg per min) [26] Inchildren with age gt 2 years the Cl of midazolam was 96 plusmn35mLkg permin (range 58 to 136mLkgmin) [17 47] and66mLkg per min in adults [5] The lower Cl of midazolamobserved in neonates is due to the lower expression ofCYP3A4 and CYP3A5 in neonatal liver [9 11 48 49]

The published literature on the pharmacokinetics ofmidazolam in neonates is scarce and the available informa-tion is heterogeneous because the work was done in healthyneonates [26] in critically ill infants [2 6 27ndash29] or in infantsundergoing extracorporeal membrane oxygenation (ECMO)[30 31]

The information on the pharmacokinetics of midazolamsummarised in this review is organised on the neonate healthstatus and it is reported in (a) healthy neonates (b) incritically ill neonates (c) and in infants undergoing extracor-poreal membrane oxygenation (ECMO) and finally (d) thepopulation pharmacokinetics of midazolam are reviewed inneonatesThe pharmacokinetic parameters of midazolam aresummarised in Table 1

34 Pharmacokinetics of Midazolam in Healthy NeonatesThe pharmacokinetics of intravenous midazolam (100120583gkg)were studied in 24 healthy preterm infants with a gestationalage between 26 and 34 weeks [26] The maximal concentra-tion of midazolam in plasma (Cmax) and the time to reachCmax (Tmax) were 108 ngmL (range 488 to 217 ngmL)and 05 hours (range 05 to 40 hours) respectively Formidazolam 119905

12was 63 hours (range 26 to 177 hours) Cl

was 18mLkg per min (range 07 to 67mLkg per min)Vd was 11 Lkg (range 04 to 42 Lkg) and AUC

0minusminusinfinwas

971 ngsdothmL (range 248 to 2353 ngsdothmL) In the text thesevalues are referred to as the ldquonormal valuesrdquo or the ldquonormalestimatesrdquo

4 International Journal of PediatricsTa

ble1Dem

ograph

icdataof

patie

ntsa

ndph

armacokineticparameterso

fmidazolam

inneon

ates

andchild

ren

Com

ments

GA(w

eeks)

PNA(days)

BW(g)

Doseo

fmidazolam

Num

bero

finfants

11990512(hou

rs)

Cl(m

Lkgm

in)

Vd(Lkg)

Reference

Health

yneon

ates

Intravenou

sadm

inistratio

n26

to34

3to

11na

100120583

gkg

BolusIV

2463a

18a

11a

[26]

Critically

illneon

ates

andchild

ren

Oraladm

inistratio

nthe

values

arec

orrected

for

119865=49

26to

313to

1310

76plusmn240

100120583

gkg

BolusP

O15

76b

27b

14b

[6]

NoteA

2days

17years

mdash38to

245(kg)

90120583gkgh

Infusio

n21

na

014

aLkgh

(dise

ased)

028

aLkgh

(health

y)119875=00350

na[27]

Infantsrequiredmechanical

ventilatio

nSomed

rugs

were

administered

33plusmn33

1to5

1900plusmn700

Infusio

n60120583gkgh

1512plusmn06

17plusmn18

12plusmn06

[28]

Respira

tory

distresssynd

rome

(119899=5)a

ndneon

atalinfection

(119899=5)

37plusmn23

2to

53150plusmn520

200120583

gkg

Bolus

IV10

65plusmn23

20plusmn12

09plusmn03

[29]

Neonatesu

ndergoingldquoextracorporealm

embraneo

xygenatio

nrdquo(ECM

O)

NoteB

395plusmn19

38a

340

0plusmn60

050

to250120583

gkgh

Infusio

n10

68a

Initial

14aInitial

31a (L)

Initial

[30]

395plusmn19

38a

340

0plusmn60

050

to250120583

gkgh

Infusio

n10

333

aTerm

inal

41Term

inal

142

a

(L)

Term

inal

MedianEC

MOdu

ratio

nwas

70to

275ho

urs

404

a079

a300

0a200120583

gkg

Bolus

IV20

18aInitial

26a

Initial

14a

Initial

[31]

11990512fro

mtheo

nsetto

steady-sta

tewas

prolon

ged

5-fold

404

a079

a300

0a200120583

gkg

Bolus

IV20

na76

aTerm

inal

49a

Term

inal

Popu

lationph

armacokineticso

fmidazolam

inneon

ates

andchild

ren

NoteD

26to

420to

9700to

5200

NoteC

187

99a

12plusmn02

10plusmn02

[32]

NoteE

24to

312to

15523to

1400

100120583

gkg

Bolus

IV60

141a

0938a

115a

[33]

Age

ranged

from

2days

to17

years

mdashmdash

35to

6050

to40

0120583gkgh

Infusio

n18

55plusmn35

50plusmn39

17plusmn11

[34]

Adultsub

jects

Adults

mdashmdash

mdashmdash

mdash19plusmn06

66plusmn18

11plusmn06

[5]

Figuresa

rethem

eanplusmnSD

unlessotherw

isesta

tedIn

somec

asesresultsareg

iven

asar

angeF

oralbioavailabilityw

hich

is49[6]

a meansta

ndarddeviationisno

tavailable

b medianGAgestatio

nalagePNA

postn

atalageBW

bod

yweight11990512120573

-phase

elim

ination

ClclearanceV

dapparent

volumeof

distr

ibution

nan

otavailableIVintraveno

uslyP

Obymou

thN

oteAn

eonatesw

eresufferin

gfro

mcongenita

lheartd

isease(119899=4)up

pera

irway

infection(119899=4)pn

eumon

ia(119899=2)po

stcardiac

surgery(119899=2)pu

lmon

aryhypertensio

n(119899=2)andother(119899=7)NoteB

midazolam

was

administered

viaacentralo

rperip

heralvenou

scatheterNoteC

midazolam

was

administered

intravenou

slyas

acon

tinuo

usinfusio

nto

109infantsas

abolus

dose

to22

infantsandas

acom

binatio

nof

both

to56

infantsTh

ebolus

dose

was

210plusmn239120583

gkgTh

econtinuo

usinfusio

nwas

69plusmn63120583gkg

perh

NoteDallneon

ates

received

midazolam

durin

gartifi

cialventilatio

nNoteE

neon

ates

undergoing

mechanicalventilationhadabo

dyweight

lt15

00g


No significant relationships were detected between age(gestational postnatal or postconceptional) and midazo-lam Cl Vd and 119905

12 For 1-hydroxymidazolam Cmax was

82 ngmL (range lt05 to 682 ngmL) and Tmax was 6 hours(range 1 to 12 hours) The median 1-hydroxymidazolamAUC0ndasht to midazolam AUC

0ndasht ratio was low (009) andshowed a large interindividual variation (range lt0001 to 1)There were no relationships between 1-hydroxymidazolampharmacokinetic parameters and midazolam Cmax AUCand 11990512

No 4-hydroxymidazolam could be detectedAnderson and Larsson [50] described a maturation

model for midazolam Cl in neonates and children Clmaturation standardized to a 70 kg person was describedusing the Hill equationMature Cl was 523 (CV32)mLminper 70 kg The maturation 119905

12was 736 weeks Predicted

Cl changes with age based on this model were in closeagreement with physiologically based pharmacokineticmod-els Previously published pharmacokinetic parameters canbe used to develop maturation models that address gaps incurrent knowledge regarding the influence of age on a drugrsquosdisposition If midazolam sedation target concentration of100 ngmL similar to that given to adults is assumed wemight anticipate steady-state infusion rates of 14 120583gkg perhour in neonates 50 120583gkg per hour in a 1-year-old infant60 120583gkg per hour in a 5-year-old infant and 50 120583gkg perhour in a 12-year-old child Age-related pharmacodynamicdifferences that will affect dose and the impact of activemetabolites on response have not yet been quantified

35 Pharmacokinetics of Midazolam in Critically Ill Neonatesand Children Disease reduces the midazolam eliminationrate in neonates In critically ill neonates undergoingmechanical ventilation 119905

12was 98 hours after a 200120583gkg

bolus of midazolam and 12 hours after a constant infusion of60 120583gkg per hour of midazolam [28] In normal values 119905

12is

63 hoursThese estimates are 155 and 190 respectively ofthe normal values [26]

A 151-year-old girl suffering from renal failure withmalignant hypertension and with a creatinine concentrationof 691 120583molL received an intravenous bolus of 100 120583gkgmidazolam 119905

12 Cl andVdofmidazolamof this girl were 63-

fold longer 26-fold greater and 145-fold larger respectively[34] than the normal values [26] The patientrsquos mean of 1-hydroxymidazolam plus 1-hydroxymidazolam glucuronidewas more than 3 times above the population value [34]

A 11-year-old boy suffering from pneumonia receivedthe CYP3A4 inhibitor erythromycin and the CYP3A4 sub-strate fentanyl He had a 119905

12and aCl ofmidazolamof 38-fold

longer and 18-fold greater respectively [34] than the normalvalues [26]

Vet et al [27] determined the effects of inflammationand disease severity on midazolam pharmacokinetics andpharmacodynamics in 21 critically ill children aged between2 days and 17 years Midazolam continuous infusion was90 120583gkg per hour (range 50 to 270 120583gkg per hour) Thepharmacokinetic parameters of midazolam are summarisedin Table 1 Eleven severely critically ill 25-year-old patients(range 01 to 90 years) needed midazolam for sedation

They were suffering from congenital heart disease upperairway infection pneumonia postcardiac surgery and pul-monary hypertension and other diseases Midazolam Cl wassignificantly lower in these children (median = 014 Lkgper hour) than in 10 patients with less severe disease theirmedian Cl was 028 Lkg per (119875 = 0035) A significantnegative correlation was found between disease severity andmidazolam Cl corrected for body weight (119903 = minus049 119875 =002) These results suggest that increased disease severity isassociated with reduced midazolam Cl Likely these resultsreflect a reduction of CYP3A activity

Alternative explanations could be the altered proteinbinding midazolam being highly bound to plasma proteins(98 in adults [5]) or less likely reduced blood flow becausemidazolam has an intermediate extraction rate [51]

The pharmacokinetics of midazolam was studied in 15preterm infants undergoing mechanical ventilation for respi-ratory distress syndrome [28] Midazolam was administeredas an intravenous continuous infusion of 60 120583gkg per hourthe infusion lasted for 600 plusmn 233 hours In these patients11990512

estimate was double the normal value [26] Hypotensionassociated with a slight reduction of heart rate was observedin 4 cases aftermidazolam administration [28] Mean systolicand diastolic blood pressure fell from 5940 to 3525mmHgIn 3 infants the hypotension occurred immediately afterthe administration of midazolam bolus dose In these threeinfants themidazolam plasma concentrations were 017 058and 124 120583gmL in two cases the patients received fentanylbefore midazolam The metabolic ratio of midazolam to 1-hydroxymidazolam was 161 plusmn 212 (119899 = 11) at 48 hours afterthe administration Various drugs were coadministered withmidazolam during the study they were fentanyl (119899 = 7)antibiotics in most cases betalactams and aminoglycosides(119899 = 13) albumin (119899 = 5) and vasopressin drugs (119899 =3) Jacqz-Aigrain et al [28] conclude that the eliminationof midazolam was markedly delayed in premature infantswith respiratory distress syndrome undergoing mechanicalventilation However these authors did not take into consid-eration the possible effects of the drugs coadministered withmidazolam In particular fentanyl a substrate for CYP3A4[52] can inhibit the metabolism of midazolam increasing its11990512

Ten critically ill preterm infants with a postnatal age

of 2 to 5 days received a single intravenous bolus dose of200120583gkg of midazolam [29] Midazolam was well toleratedduring and after the intravenous administration There wasno clinical evidence of any adverse effects after midazolamadministration and the heart rate and the arterial bloodpressure remained unchanged during the study 119905

12 Cl and

Vd were 65 plusmn 23 hours 20 plusmn 12mLkg per min and 09 plusmn03 Lkg respectively The kinetic parameters in these infantswere similar to those of normal values [26]

Ince et al [43] performed a population pharmacokineticmodelling using a joint dataset of 3 studies Fifty-fourchildren aged between 1 month and 17 years who receivedintravenous midazolam (bolus andor continuous infusion)for sedation were enrolled in the study The parameter


estimates from the final model were used for simulationand to predict the concentrations from the following mida-zolam schedules (intravenous bolus of 100 120583gkg followedby an intravenous infusion of either 50120583gkg per hourfor postoperative monitoring or 100120583gkg per hour forconscious sedation) In children a large variability in thepharmacokinetic parameters of midazolam was observedMidazolam is a substrate for CYP3A4 and CYP3A5 and theexpression of these enzymes considerably varies in neonates[6 10 11]

The wide variability of midazolam pharmacokineticparameters cannot be explained by age-related changes aloneInce et al [43] studied these age-related changes in rela-tion to other covariates to explain the variability in thepharmacokinetics of midazolam The following covariateswere tested for all parameters bodyweight postnatal agespecific subpopulation and mechanical ventilation (yesno)Midazolam 1-hydroxymidazolam and 1-hydroxymidazolamglucuronide concentrations were considered to determinethe pharmacokinetics of midazolam and metabolites usingNONMEN 62 A SimCYP pediatric simulator was used forsimulation A reduction of 93 for CYP3A45 (midazo-lam to 1-hydroxymidazolam) and 86 for uridine diphos-phate glucuronosyltransferase (1-hydroxymidazolam to 1-hydroxymidazolam glucuronide) mediated Cl was found inpediatric intensive care patients compared with the other2 patient groups Ince et al [43] did not find a significantinfluence of age or body weight on CYP3A45 mediatedtotal Cl For uridine diphosphate glucuronosyltransferasemediated Cl body weight explained 415 of the variabilityFrom infancy to adolescence critical illness seems to be themajor determinant of midazolam Cl which may result fromreduced CYP3A45 activity due to inflammation This mayhave important implications for dosing of midazolam andother CYP3A drug substrates in critically ill children

A new dosing schedule was designed aiming for midazo-lam concentrations between 45 and 64 ngmL for postoper-ative monitoring after procedural sedation [53] and between205 and 307 ngmL for conscious sedation in ldquoneonatal inten-sive care unitrdquo patients [54]These concentrations correspondwith previously reported adequate sedation levels of therespective population groups and are used for indicativepurposes only

36 Pharmacokinetics of Midazolam in Neonates UndergoingExtracorporeal Membrane Oxygenation (ECMO) Extracor-poreal membrane oxygenation (ECMO) is a form of pro-longed cardiopulmonary bypass used to support patientswith life-threatening respiratory or cardiac failure [55] Inneonates ECMO is used for a variety of indications includingsepsis and pulmonary disease such as meconium aspirationsyndrome persistent pulmonary hypertension or congenitalhernia [55]

ECMO yields variability and lack of predictability in drugbehaviour The most common mechanisms by which ECMOaffects pharmacokinetics are sequestration of the drug in thecircuit and the increase of drug Cl and Vd [55 56] Thepharmacokinetic parameters of drugs undergoing ECMO

vary during this therapy Thus Table 1 gives two values foreach pharmacokinetic parameter an estimate was obtained atthe start and another one was obtained at the end of ECMOtherapy

Adequate sedation of neonates receiving ECMO is essen-tial to allay the physical emotional and psychologic distressexperienced during intensive careMidazolam a short-actingbenzodiazepine derivative with rapid onset of action is thesedative of choice and is preferred over other benzodi-azepines because of its water solubility and the perceivedrapid elimination [30]

Twenty neonates with gestational age of 395 plusmn 19 weekspostnatal age of 38 days and body weight of 3400 plusmn600 g were enrolled in the study [30] The infants wererandomized into two groups group 1 (119899 = 10) receivedmidazolam extracorporeally (into the circuit) via a pigtailcatheter whereas group 2 (119899 = 10) received the drugvia a central or peripheral venous catheter Midazolam wasadministered as a continuous infusion at a rate between 50and 250 120583gkg per hour initiated as soon as cannulation wasachieved and extracorporeal blood flow was established Thepharmacokinetic parameters obtained byMulla et al [30] aresummarised in Table 1

The mean metabolic ratio was of 1-hydroxymidazolamto midazolam 017 (range 003 to 09) and appeared to besignificantly higher than that previously reported in non-ECMO infants (009) and it was similar to those observedin older children and adults (range 013 to 025 [57 58])

DeBerry et al [59] determined the general practiceguideline used for pain and anxiolytic pharmacotherapy ofpediatric patients at ECMO centers Fentanyl was the mostcommonly used drug for pain medication and continuousinfusion However midazolamwas considered to be themosteffective agent used

Ahsman et al [31] studied 20 neonates undergoingECMOThemedian gestational age postnatal age and body-weight were 404 weeks 079 days and 3000 g respectivelyMidazolam (200120583gkg) was administered by a venoarterialcatheter as a bolus infusion before cannulation The medianECMO duration was 124 hours (range 70 to 275 hours)When discomfort occurred midazolam was started as acontinuous infusion of 100 120583gkg per hour The midazolamdose was incrementally adjusted (with steps of 100120583gkg perhour) on the basis of the required level of sedation whichwas objectified with the validated COMFORT behaviourscale Once the patient was fully sedated the midazolaminfusion was interrupted until COMFORT scores indicatedthat additional sedation was necessary

Midazolam Cl and Vd rapidly increased in 5 days ofECMO therapy The kinetic parameters of midazolam aresummarised in Table 1 In contrast the Vd estimates for1-hydroxymidazolam and 1-hydroxymidazolam glucuronideremained constant at 102 L and 12 L respectively

To quickly reach stable serum concentrations of400 ngmL the optimal dose regimen would be a continuousinfusion of 300 120583gkg per hour for the first 6 hours afterwhich the infusion rate should be reduced to 150120583gkg perhour After 5 days the infusion rate should be increasedto 200120583gkg per hour to compensate for the continual


increasing of midazolam Cl and 1-hydroxymidazolam Cl1-Hydroxymidazolam glucuronide accumulated duringECMO providing an increased proportion of the overalleffect up to 34 after 7 days of ECMO therapy Largeunexplained interindividual variability warrants carefultitration of sedation effects Ahsman et al [31] did not findany effect of serum creatinine on pharmacokinetic param-eters The use of creatinine as a marker of renal function innewborn infants is in dispute [60 61]

37 Population Pharmacokinetics of Midazolam in Neonatesand Children In literature there are three studies of mida-zolam population pharmacokinetics [32ndash34] One hundredand eighty-seven neonates requiring intravenous sedationfor mechanical ventilation were enrolled in the study [32]Their gestational and postnatal ages ranged from 26 to 42weeks of amenorrhea and from 0 to 9 days respectivelyThe birthweight ranged from 700 to 5200 g Midazolam wasadministered intravenously as a continuous infusion of 69 plusmn93 120583gkg per hour (range 11 to 603 120583gkg per hour) to 109infants the infusion lasted for 6 to 171 hours (62 plusmn 31 hours)A bolus dose of 210 plusmn 239 120583gkg (range 32 to 1600 120583gkg)was administered to 22 infants and a combination of bothwas administered to 56 neonates The mean midazolamdoses required for critically ill neonates are lower than thoserequired for wealthy neonates Mean 119905

12was 99 hours Cl

was 12plusmn 02mLminkg andVdwas 10plusmn 02 Lkg [32]Therewas a large interindividual variability in the Cl (CV 17) andVd (CV 20) Compared with the population estimate Clwas 16 times higher in neonateswith a gestational age ofmorethan 39 weeks and was 07-fold lower in neonates receivinginotropic support The postnatal age had no apparent effecton midazolam pharmacokinetics The estimates of the popu-lation pharmacokinetic parameters and their interindividualcoefficients of variation (CV) without covariates were Cl =0107 Lkg (CV 83) Vc (central volume) = 0788 L (CV92) and Vp (peripheral volume) = 0969 L (CV 163)Birthweight was clearly correlated with Cl and Vc and toa lesser extent with Vp The authors did not give the levelof significance of these correlations The gestational agecorrelated with the birthweight (119903 = 089 119875 = 00001) The531 measured plasma concentrations of midazolam rangedfrom 0 to 7100 ngmL 105 samples were above 1000 ngmLMidazolam was not detected in 19 samples Aminoglyco-sides aminopenicillins and third generation cephalosporinsincreased the plasma midazolam concentrations for 738722 and 487 respectively Aminoglycoside treatmentwas associated with a 50 decrease in midazolam Cl

Lee et al [33] studied the population pharmacokineticsin 60 premature infants undergoing mechanical ventilationTheir mean gestational age was 27 weeks (range 24 to 31weeks) their postnatal age was 45 days (range 2 to 15 days)and their body weight was 965 g (range 523 to 1470 g)A rapid intravenous bolus of 100120583gkg was administeredevery 4 to 6 hours Average parameter values for infantswith birthweight of 1000 g were as follows Systemic Cl was0783mLmin (CV = 83) and Vd of central comportmentwas 473mL (CV = 70) 119905

12was not given For infants

with body weight more than 1000 g Cl was 124mLmin(CV = 78) and Vd was 823mL (CV = 43) The averagepopulation Cl in boys (0642mLmin) was less than in girls(0808mLmin) The level of significance of this differencewas not givenThe populationmeanCl of overall patients was0938mLkg per min The average Vd of overall infants was115 Lkg which agreed closely with the Vd of 10 Lkg in termand preterm infants [32]

The population kinetics of midazolam was studied ineighteen pediatric patients aged from 2 days to 17 years[34] Midazolamwas administered as an intravenous bolus of100 120583gmL followed by a continuous infusion ranging from50to 400120583gkg per hour for 38 hours to 25 days for conscioussedation 119905

12 Cl and Vd of midazolam were 55 plusmn 35 hours

50 plusmn 39mLkg per min and 17 plusmn 11 Lkg respectively Halfof the patients had an age less than 6 months [34] Mean Clrate is lower than that reported in patients with age greaterthan 2 years (mean plusmn SD = 96 plusmn 35mLkg per min [61 62])

The Cl reported by de Wildt et al [34] is comparableto that obtained in another study performed with pediatricintensive care patients aged between 26 days and 5 years(mean plusmn SD = 58 plusmn 38mLkg per min [17]) when studiedduring the first 24 to 48 hours of midazolam infusionThese data support an age-related increase of midazolam Clconsequent to an age-related surge in CYP3A4 and CYP3A5activities [49]

1-Hydroxymidazolam to midazolam ratio (mean plusmn SD =021 plusmn 020 [34]) is in agreement with the ratio obtainedin pediatric patients who received midazolam after cardiacsurgery (mean plusmn SEM = 025 plusmn 003 [59]) In contrast theratio obtained by Wildt et al [34] was higher than that innewborn infants lt2 weeks of age during continuous infusionof midazolam (006 plusmn 005 [28])

38 Pharmacodynamics ofMidazolam inNeonates Very littleis known about the pharmacodynamics of midazolam ininfants and only two articles are available in literature [54 63]Swart et al [63] stated that from the clinical studies it isclear that there is a large variability in response to a givenconcentration of midazolam Vet et al [27] did not find acorrelation between inflammation severity and COMFORTscore Trouiller et al [64] and Arbor et al [65] said that theoptimal measure to monitor the pharmacodynamic endpointstill needs to be determined Dosing regimens in childrenare based upon rather empirical extrapolations from thedosing regimens in adults Several authors have developedscaling methods to predict midazolam Cl as a function ofage taking ontogeny into account [66ndash68] From these datait can be concluded that body weight increases with age fromapproximately 006 Lkg per hour in preterm neonates to06 Lkg per hour in children 5 years of age before decreasingto 04 Lkg per hour in adult patients

Twenty-one infants aged from 2 days to 17 yearsreceived a continuous infusion of midazolam from 50 to400 120583gkg per hour for a period of 38 hours to 25 days [54]A possible pharmacokinetic-pharmacodynamic relationshipfor midazolam in pediatric intensive care patients and thedetermination of how adequate sedation could be reached


using the COMFORT scale was studied Sedation levelswere determined using the COMFORT scale as well asthe plasma concentrations of midazolam and metabolitesAn evident pharmacokinetic-pharmacodynamic relationshipwas not found In 20 of the 21 patients studied midazolamdosing could be effectively titrated to the desired level ofsedation assessed by the COMFORT scale Based on thesefindings there is no relationship between pharmacodynamicparameters and pharmacodynamic outcome De Wildt et al[54] recommend that midazolam dosing should be titratedaccording to the desired clinical effect combination witha validated assessment instrument such as the COMFORTscale The COMFORT scale rates 6 behavioural and 2 physi-ologic dimensions of distress each scored on a subscale from1 to 5 Thus a maximum score is considered reflective ofoversedation between 17 and 26 as effectiveoptimal seda-tion as proposed byMarx et al [69] As reflected by the Pedi-atric Risk ofMortality (PRISM) score disease severity amongour patients varied considerably Seven patients requiredanalgesia (morphine codeine fentanyl and acetaminophen)during the midazolam infusion No significant relationshipbetween sedation level category and drug or metaboliteconcentrations was detected The ranges of midazolam study(50 to 400 120583gkg per hour) were in agreement with other datafrom studies in pediatric intensive care patients [70 71]

39 Sedation of Neonates and Children by Midazolam Neo-nates can perceive pain when mechanically ventilated thisfact has been demonstrated by the physiological biochemicaland behavioural changes indicative of pain and stress innewborn infants during mechanical ventilation [72] Paininduces agitation in the newborn and the newbornrsquos agitationmay contribute to asynchrony between the newborn and theventilator To sedate neonates with midazolam this drug isusually given intravenously or by intranasal administrationThe oral administration of midazolam in neonates is littleused and in literature only two articles on oral midazolamin neonates are available [2 6] No data of sublingual admin-istration of midazolam in neonates was found in literature

D A Rosen and K R Rosen [73] wrote a review onthe sedation with midazolam in conscious pediatric patientsThese authors stated that the advantages of midazolaminclude quick onset and short duration of action and hemo-dynamic stability which may be associated with improvedpatient acceptance The comparison with diazepam showedthat midazolam has a more controlled sedation with aquicker recovery time Midazolam yields a shorter recoveryand less vomiting than diazepam in children who underwentsurgery The safety and tolerability profile of midazolam inpediatric patients is comparable or superior to that observedin adults Patients who are haemodynamically unstable aswell as preterm and term infants are at greater risk ofhypotension while receiving sedation Midazolam providesan important additional option for providing intravenousconscious sedation in the pediatric population

The American Academy of Pediatrics Committee onDrugs has issued guidelines categorizing pharmacologicalintervention into three levels conscious sedation deep

sedation and general anaesthesia [74] Conscious sedationrefers to a state of depressed consciousness that ldquoallowsprotective reflexes to be maintainedrdquo and ldquopermits appro-priate responses by the patient to physical stimuli or verbalcommandsrdquo Deep sedation is defined in part as ldquopartial orcomplete loss of protective reflexesrdquo and lack of purposefulresponse to physical stimulation Deep sedation requires thepresence of personnel skilled in airway management andcardiopulmonary resuscitation [20]

Intravenous infusion of benzodiazepines is importantto assist ventilation and other potentially distressing proce-dures Combined with intermittent or continuous infusionwith opioids the benzodiazepines provide smooth controlof anxiety pain and agitation [75] The major adverseeffects of long-term benzodiazepine infusion are withdrawalsymptoms and delayed awakening Intravenous midazolamrepresents an important choice among drugs used for seda-tion in the ldquoneonatal intensive care unitrdquo for short-termuse in infants undergoing assisted ventilation and gener-ally rapid awakening when the drug is discontinued [76]Midazolam and lorazepam are the most frequently employedbenzodiazepines in the ldquoneonatal intensive care unitrdquo Thesetwo drugs are distinguished from the other benzodiazepinesby their relatively higher water solubility rapid onset andshort duration of action [47]These pharmacologic propertiesof midazolam facilitate regulation of the level of sedationMidazolam is usually given by continuous infusion followinga loading dose

Treluyer et al [77] determined the minimal effective doseof intravenous midazolam required for appropriate sedationin 95 of patients 1 hour after drug administration Twenty-three newborn infants hospitalized in intensive care unitwere enrolled in the study Their gestational age was gt33weeks and midazolam was administered as an intravenousbolus at a dose from 75 to 200120583gkg followed by a mainte-nance dose ranging from 375 to 100 120583gkg per hour over 47hours The sedation procedure was classified as a success ifall the following clinical criteria were met no agitation nogrimacing and no crying facial expression before as well asduring tracheal suctioningThe estimated success probabilityupdated after each patient was lt95 for all dose levels andled to allocation of the maximum loading dose (200 120583gkg)Based on the 23 patients studied the final estimated prob-ability of success was 769 (95 credibility interval was566 to 914) for the 200120583gkg loading dose The posteriorsuccess probability for the six doses 75 100 125 150 175and 200120583gkg corresponded to 277 327 381 473525 and 769 respectively Failures were recorded in 5(25) of 20 patients receiving a 200120583gkgmidazolam loadingdose No significant effect of sedation on pulse oximetryoxygenation index or triggering of ventilator breathing wasevident after the onset of midazolam administration Nosignificant adverse effects were observed Pneumothorax wasreported in two children who had received a 200120583gkg initialloading dose and were classified as ldquosuccessrdquo for sedation Adecrease of more than 30 for systolic diastolic and meanblood pressure was observed during the study inclusion innone two (87) and one (43) children respectively (allreceived the 200 120583gkg loading dose of midazolam)


Forty-six infants undergoing mechanical ventilation forrespiratory distress syndrome were randomly assigned toreceive midazolam (119899 = 24) or placebo (119899 = 22) as a con-tinuous infusion [16] Jacqz-Aigrain et al [16] performed aprospective placebo controlled study of the effects of mida-zolam on hemodynamic variables and sedation as judgedby a five-item behaviour score Doses of midazolam werecalculated to obtain plasma concentrations between 200 and1000 ngmL within 24 hours of starting treatment and tomaintain these values throughout the study In the treatmentgroup infants of 33-week gestation or more received a con-tinuous infusion of 60120583gkg per hour of midazolam Infantsbelow 33-week gestation received the same continuous infu-sion of 60 120583gkg per hour during the first 24 hours of treat-ment followed by a continuous infusion of 30 120583gkg per hourof midazolam The assigned treatment lasted for 5 days butsedation with midazolam could be continued if prescribedby the attending neurologist Midazolam gave a significantlybetter sedative effect than placebo (119875 lt 005) Heart rateand blood pressure were reduced by treatment but remainedwithin the normal range for gestational age and there wasno effect on ventilatory indices Hemodynamic instabilityrequiring albumin andor vasoactive drugs occurred in 14infants 8 of whomwere in themidazolamgroup and 6 infantswere in the placebo group Intraventricular haemorrhageoccurred in 8 infants in the midazolam group and 6 infantsin the placebo group Blood samples were obtained from 23of 24 infants Mean midazolam concentrations were 634 plusmn234 ngmL 628 plusmn 327 ngmL and 543 plusmn 327 ngmL at 24 and48 hours and at the end of treatment respectively Substantialvariability in plasma concentrations of midazolam was seenbut none of the infants had values below 200 ngmL andonly 2 infants (with a gestational age below 32 weeks) had aplasma concentration ofmidazolamabove 1000 ngmLTherewas no correlation between sedation score and correspondingmidazolam concentration No midazolam-related adverseeffects were noted Continuous infusion of midazolam atdoses adapted to gestational age induces effective sedationin newborn infants on mechanical ventilation with positiveeffects on hemodynamic variablesMidazolamwas given overonly a few days and the limited effects on heart rate and bloodpressure that were reported should not encourage long-termadministration

Midazolam was administered as a continuous infusion ata dosage of 50 to 400 120583gkg per hour to 24 infants partlyin combination with fentanyl (05 to 25120583gkg per hour) foranalgesia and sedation [17]Themean duration ofmidazolaminfusion was 116 days (range 38 hours to 40 days) Theefficiency of sedation in correlation with the midazolamconcentration was evaluated by a clinical sedation scoreSerum midazolam concentrations from 100 to 400 ngmLwere sufficient for sedation Dosage had to be increasedduring therapy according to an increased midazolam Cl Theevaluation of sedation score showed that sedation of artifi-cially ventilated infants and young children can be establishedby continuous intravenous infusion of midazolam

Arya and Ramji [19] performed a double blind random-ized placebo controlled trial to determine the efficacy ofmidazolam as a sedative in mechanically ventilated newborn

infants for 7 days Seventeen neonates with a body weightlt2000 g received a bolus of midazolam of 200120583gkg followedby continuous infusion of 60 120583gkg per hour Sixteen infantsreceived placeboThemidazolam group had significantly bet-ter sedation than the placebo group from 18 to 24 hours afterenrollment At 48 hours there were no significant differencesin sedation betweenmidazolam and placebo groups None ofthe infants had hypotension on loading midazolam Sedationprovided by continuous infusion of midazolam appearedto be comparable to morphine alone in newborn infantson mechanical ventilation These authors observed that thebehavioural assessment was used to demonstrate the sedativeeffect of midazolam in ventilated newborn infants Opioidand benzodiazepines combination is most commonly usedto sedate newborns but their use is limited by prolongedvariable elimination of these drugs leading to prolongedsedation Midazolam produces a rapid and consistent effectbecause of its short 119905

12 Hypotension has been reported as an

adverse effect of midazolam in few infants after intravenousadministration of midazolam [28 78] Arya and Ramji [19]did not find hypotension in any neonates

When minimal sedation is required intranasal midazo-lam is an excellent sedative [79] Intranasal strategies havebeen introduced to maximize the potential for successfulsedation and to minimize risk These authors reviewed theliterature to evaluate the effectiveness of a second dose ofintranasal midazolam The strategy incorporates a seconddose of intranasal midazolam 10 to 15min after the firstdose to obtain the desired level of anxiolysis One hundredinfants with an age ranging from 1 to 59months were enrolledin the study Eighty patients (80) obtained satisfactorysedation effects There were no reported complications min-imal untoward side reactions and no delays in discharge Asecond-dose of intranasal midazolam strategy was effectivein achieving satisfactory minimal sedation in childrenTheseauthors stated that only a small proportion of patients wouldbenefit from one dose of intranasal midazolam

Intranasal midazolam use has been reported since 1988[80] The intranasal route is desirable because it obviates theneed for intravenous access avoids the pain of the intra-muscular injection and is easily accessible Due to the reachvascular plexus of the nasal cavity and the communication tothe subarachnoid space via the olfactory nerve and sheathadequate cerebrospinal fluid levels can be achieved rapidly[81 82] The bioavailability of intranasal midazolam rangedfrom 50 to 83 [83ndash85] The most common adverse effectsreported following intranasal midazolam are burning orirritation in the nose and a bitter taste in the mouth [86ndash88]

Intranasal midazolam was studied by Lane and Schunk[89] using a unique atomization delivery system Two hun-dred and five children admitted to the study aged from15 to 60 months had mean plusmn SD age of 313 plusmn 132monthsThemedian initial dose of intranasalmidazolamwas400 120583gkg (range 300 to 800120583gkg) Laceration repair wasthe most common procedure necessitating sedation (89)Eleven patients (54) required an additional sedative dose tocomplete the procedure Ten of 11 patients received ketamineas the adjunctive sedative and 1 patient required additionalintranasal midazolam There was 1 adverse event (05)


This was a minor desaturation episode following ketamineadministration requiring a brief blow by oxygen Therewere no adverse events in patients who received intranasalmidazolamThese authors conclude that atomized intranasalmidazolam is effective in providing anxiolysis to childrenundergoing minor procedures in the pediatric Department

Harcke et al [90] reviewed 162 consecutive sedations inwhich midazolam was employedThe patientsrsquo mean age was41 years (range 19 days to 19 years) Midazolam is effective inproviding anxiolysis to children based upon a calculated doseof 200 to 400120583gkg Intranasal midazolam has a rapid onsetand is more convenient than intravenous agents because ofits short duration A dose of 200120583gkg is safe and effective In142 of 162 cases (88) midazolam demonstrated a positiveeffect in 20 cases (12) it was ineffectiveThe adverse effectswere brief coughing sneezing or crying often occurringimmediately after midazolam administration but these werenot considered adverse reactions unless they persisted In91 of 162 cases (56) midazolam was used in conjunctionwith another agent Fifteen adverse reactions (9) occurredincluding delay in awakening in 4 patients reactive airwayin 2 cases desaturation and apnea in 4 cases seizure in 1case agitation in 2 cases and vomiting in 2 cases Midazolamwas the sole sedative in 71 of 162 (44) cases The use ofmidazolam to minimize the difficulty of starting an intra-venous infusion constitutes the most common applicationIn 89 of the patients it accomplished the desired effect Ofparticular interest was the use of midazolam as a primarymeans of sedation since its intranasal route obviates the needfor intravenous medication An intranasally administeredsedative with quick onset and short duration seems veryinnocuous

310 Oral Administration of Midazolam in Neonates Datadescribing midazolam disposition following oral adminis-tration to preterm infants are few In literature there areonly two articles on the fate of midazolam following oraladministration to neonates [2 6] A single oral bolus doseof 100 120583gkg was administered to 15 preterm infants withgestational and postnatal ages ranging from 26 to 31 weeksand from 3 to 13 days respectively Mean plusmn SD of bodyweight was 1076 plusmn 240 g In 8 out of these 15 patientsthe pharmacokinetics of intravenous midazolam was alsostudied Apparent oral Cl apparent Vd and plasma 119905

12are

given as median and range Cl was 27mLkgmin (range064 to 155mLkgmin) Vd was 14 Lkg (range 03 to121 Lkg) and 119905

12was 76 hours (range 12 to 151) hoursThe

absolute bioavailability was 049 (range 012 to 10)In another study De Wildt et al [2] evaluated the phar-

macodynamics and safety of midazolam after intravenouscontinuous infusion or oral administration Patients wererandomly assigned to initially receive an oral bolus doseof 100 120583gkg midazolam Pharmacodynamic measurementsconsisted of a COMFORT score at baseline and at 05 12 4 and 6 hours after dose A total of 24 infants wereenrolled of whom seven received both intravenous and oralmidazolam 13 infants received only intravenous midazolamand 4 received only oral midazolam

Overall mean COMFORT score decreased (ie seda-tion increased) significantly within 30min after intravenousadministration and within 1 hour after oral administration(119875 = 0003) No relationship was found between overallCOMFORT scores or change in COMFORT score frombaseline and midazolam Diastolic blood pressure decreasedsignificantly (approximately 11) after intravenous but notafter oral midazolam administration No serious adverseevents were reported Midazolam administered as an intra-venous infusion or oral bolus dose appears to be effectiveand well tolerated in a small majority of preterm infantsHowever a considerable number of neonates did not respondto midazolam The lack of response may be due to the factthat patients truly experienced therapeutic failure andorconsequent to the inability of the COMFORT score toadequately reflect sedation uniformly in sick preterm infants

311 Management of Refractory Seizures in Neonates byMidazolam Slaughter et al [91] reviewed the literatureon the pharmacological treatment of neonatal seizuresTheir research was based on 557 initial articles and 14additional studies after reference reviews with 16 meetinginclusion criteria Seizures suspected in high-risk neonatesrequire confirmation of seizures with electroencephalogramIf seizures are confirmed by electroencephalogram givephenobarbital 20mgkg intravenously and start phenobarbi-tal maintenance 5mgkg per day If seizures continue giveadditional 20mgkg intravenously If seizures continue thereare three possible drugs to take into consideration leve-tiracetam (50mgkg intravenously then 40mgkg per daymaintenance divided twice daily) phenytoinfosphenytoin(20mgkg intravenously and start a second maintenancemedication 5mgkg per day divided every 8 hours) or lido-caine (2mgkg intravenously bolus then 6mgkg per hourthen titrate down by 2mgkg per hour every 12 hours) Ifseizures continue administer midazolam (015mgkg intra-venous bolus then 1 120583gkg per min up to a maximumof 18 120583gkg per min) If seizures continue consider phe-nobarbital drip or lidocaine drip if not yet tried (unlessphenytoinfosphenytoin has been used)

The neonatal period is one of the highest risk periods forseizures [92] which occurs in 1 to 5of neonates [93] and isindicative of underlying neurologic dysfunction Seizures arerefractory to the first-line antiepileptic drugs phenobarbitaland phenytoin in more than 50 of infants and children[94] Midazolam succeeded to manage refractory neonatalseizures In neonates antiepileptic drugs can be even lesseffective in controlling seizures than in adults [95] Littleinformation is available on the use of midazolam in neonatalseizures However rapid control of status epilepticus withmidazolam has been demonstrated with complete clinicaland electrographic response in neonates who did not respondto phenobarbital and phenytoin [23 24 96]

Van Roij et al [97] reviewed the treatment of neonatalseizures Midazolam has also been used for phenobarbitalrefractory seizures with an efficacy between 67 and 80In other studies midazolam was compared to lidocaine as asecond-line anticonvulsive drug [24 92 98 99] In a study


by Shany et al [98] four of the eight neonates treatedwith midazolam showed a partial response Three neonateswith status epilepticus did not respond to phenobarbital andphenytoin [92] but they responded to midazolam infusionMidazolamwas infused at a rate of 010 to 013 120583gkg per hourfor a period of 43 to 54 hours Midazolammay be considereda safe and effective antiepileptic drug in refractory neonatalseizures of diverse aetiologies

Status epilepticus a serious life-threatening emergencycharacterized by prolonged seizure activity occurs mostcommonly in pediatric patients Diazepam phenytoin orphenobarbital terminates seizures within 30 to 60min butthere are patients who are refractory to standard therapyMidazolam has emerged as a new treatment option Thereview by Holmes and Riviello [100] compared the use ofmidazolam with that of phenobarbital in published reportsof pediatric patients refractory status epilepticus Most ofstatus epilepticus can be controlled by benzodiazepinesphenytoin or phenobarbital in refractory cases that persistedbeyond this therapy the potential treatment options areless than ideal The antiepileptic properties of midazolamwere identified during the late 1970s and more recentlythe drug has emerged as an effective treatment for resis-tant status epilepticus Midazolam was well tolerated bypediatric patients with refractory status epilepticus In thestudy by Holmes and Rivielo [100] only one incidence ofmild hypotension was present in a 4-week-old infant Anumber of published case reports showed the successful useof midazolam in terminating refractory status epilepticus in atotal of 29 pediatric patients [100] Although midazolam hasnot been directly comparedwith pentobarbital in a controlledstudy the antiepileptic effectiveness and apparent safety ofmidazolam in children warrant its consideration as the initialtreatment in pediatric cases of refractory status epilepticus[100]

Castro Conde et al [24] stated that the outcome of 45neonates with electroencephalogram-confirmed seizures wasanalyzed with regard to treatment Seizures persisted in 17of 32 neonates receiving phenobarbitalphenytoin Thirteenneonates had a poor outcome and 4 died In contrast seizureswere rapidly controlled in 13 of 13 nonresponders to phe-nobarbitalphenytoin treated with midazolam (015mgkgintravenous bolus followed by continuous infusion of 1120583gkgpermin increasing by 05 to 1120583gkg permin every 2min untila favourable response or a maximum of 18 120583gkg per min) Ifthe status epilepticus persisted after the initial bolus anotherbolus of 100 to 150 120583gkg was administered 15 to 30min laterNonresponders to phenobarbitalphenytoin were controlledby midazolam

The efficacy of a combination of midazolam and pheny-toin in treating generalized convulsive status epilepticus wasstudied in 122 children with the median age of 244 months(range 05 to 197 months) [101] Forty-three percent ofpatients required artificial ventilation Thirty-two percentof patients developed respiratory insufficiency during initialtherapy with midazolam Three patients had an apnea and 8patients were intubated after a bolus of midazolam Twenty-two percent of patients were artificially ventilated to pro-tect the airway No deaths were attributable to generalized

convulsive status epilepticus itself The treatment protocolconsisted of a stepwise use ofmidazolamandphenytoinLevel1 rectal midazolam of 500120583gkg or 100 120583gkg intravenouslywas administered Level 2 after 10min 20mgkg phenytoinwas administered intravenously Level 3 after phenytoin load200120583gkg midazolam was administered intravenously as abolus followed by a continuous infusion of 100120583gkg perhour of midazolam increased by 100 120583gkg per hour every10min after extra loading of 100 120583gkg to a maximum of1mgkg per hour Level 4 phenobarbital 20mgkg intra-venously or pentobarbital 2 to 5mgkg intravenous load 1 to2mgkg per hour of phenobarbital was continuously intra-venously infused Eighty-two of 122 infants (68) receivedinitial rectal diazepam Cessation of epileptic activity wasachieved with midazolam in 58 patients (48) Midazolamis an effective agent for seizure control [102] Several studiesin a small number of children have described the effectiveuse of intravenous intramuscular rectal nasal or sublingualmidazolam [96 102ndash104]

Hu et al [23] determined the efficacy and safety of con-tinuous midazolam infusion in neonates with uncontrollableneonatal seizures Thirty-two neonates whose seizures couldnot be controlled by diazepam phenytoins or phenobarbitalwere enrolled in the study Midazolam was given as an intra-venous bolus dose followed by a continuous infusion Themaximum infusion of midazolam ranged from 1 to 15120583gkgper min with an average of 4 120583gkg per min There were nosignificant changes in serum sodium potassium calcium orglucose in any of the patients Four patients had recurrentseizures which stopped after midazolam was reinstitutedAdverse effects included hypotension in 12 patients (38)that was successfully controlled with dopamine andor dobu-tamine and transient urinary retention in 38 of infants Allthe patients enrolled in the study had a successful manage-ment of seizuresThese results suggest that midazolam is safeand effective for the treatment of uncontrollable seizures

Midazolam is a highly effective antiepileptic agent evenin patients who have not responded to other benzodiazepines[102] Compared with phenobarbital midazolam has fewerhemodynamic consequences minimizing the need for inva-sive monitoring The need for endotracheal intubation andmechanical ventilation also appears to be less frequentlynecessary with midazolam Patients recovery after midazo-lam is shorter than with phenobarbital Althoughmidazolamhas not been directly compared with phenobarbital in acontrolled study the antiepileptic effectiveness and apparentsafety of midazolam in children warrant its consideration asthe initial treatment in pediatric cases of refractory statusepilepticus

Sheth et al [96] studied six neonates with gestationaland postnatal ages ranging from 30 to 41 weeks and 1 to 9days respectively These neonates developed seizures fromvarying causes In each case seizures persisted for gt12 hoursdespite high dose of phenobarbital with or without theaddition of phenytoin All infants received intravenously 20to 40mgkg of phenobarbital Maintenance phenobarbitaldosage was approximately 8mgkg and was administeredin two divided doses Four of the six infants also received20mgkg of phenytoin Three infants were suffering from


focal clonic seizures two infants had tonic seizures and onehad myoclonic seizures Onset of the seizure was between1 and 24 hours except in the patients with meningitis inwhom the onset was at 9 days All infants received a standardintravenous loading dose of 20mgkg and subsequently anadditional 20 to 40mgkg of phenobarbital Maintenancephenobarbital dosage approximated 8mgkg andwas admin-istered in two divided doses Four of the six infants alsoreceived 20mgkg of phenytoin In all six infants midazolaminfusionwas startedwith a loading dose of 150120583gkg and thenmaintained between 100 and 400120583gkg per hour After theloading dose clinical seizureswere no longer observed in fourinfants The remaining became seizure free within one hourafter the administration of midazolam These results showthat midazolam administrated by continuous intravenousinfusion may be a valuable adjunct in the management ofrefractory neonatal seizures

312 The Safety and Efficiency of Midazolam versus Diazepamfor the Treatment of Febrile Seizures in Children McIntyre etal [105] compared rectal diazepam and buccal midazolamfor emergency room treatment in 177 children who hada median age of 3 years with acute febrile seizures Thedose of diazepam and midazolam ranged from 25 to 10mgThe primary endpoint was the cessation of seizures within10min and for at least 1 hour without respiratory depressionrequiring ventilation The therapeutic success was 56 forbuccal midazolam and 27 for rectal diazepam The rateof respiratory depression did not differ between groupsBuccal midazolam was more effective than rectal diazepamfor children presenting to hospital with acute febrile seizuresand was not associated with increased incidence of repertorydepression

Mahmoudian and Zadeh [106] determined whetherintranasal midazolam is as safe and effective as intra-venous diazepam in the treatment of acute childhoodseizures Seventy children aged between 2 months and15 years with acute febrile seizures were admitted to theldquopediatric emergency departmentrdquo of a general hospitalIntranasal midazolam (02mgkg) and intravenous diazepam(02mgkg) were administered after intravenous lines wereestablished Intranasal midazolam and intravenous diazepamwere equally active The main time to control seizures was358 plusmn 168min (midazolam) and 294 plusmn 262 (diazepam)No significant side effects were observed in either groupsAlthough intranasal midazolam was as safe and effectiveas diazepam seizures were controlled more quickly withintravenous diazepam than with intranasal midazolam

313 Comparison of the Sedatives Effects of Midazolam withThose of Other Sedatives in Neonates Many agents candepress the function of the central nervous system producingcalming or drowsiness (sedation) Sedation may be per-formed with opioids (fentanyl morphine and diamorphine)with the sedative-hypnotic midazolam and with the aestheticpropofol in ventilated neonates

Endotracheal intubation of premature infants is per-formed frequently in the ldquoneonatal intensive care unitsrdquo and

delivery roomThe procedure is associatedwith physiologicaland biochemical responses and now there is strong evidencethat premedication (sedation and analgesia) improves thephysiological stability decreases the difficulty of procedureand also reduces the potential for airway injury [107]

Penido et al [108] compared intubation conditionsbetween midazolam and propofol in a blinded randomizedand controlled study in 20 neonates Ten patients with agestational age of 32 plusmn 16 weeks and with a bodyweight of1653 plusmn 357 g were treated with midazolam as an intravenousbolus of 200120583gkg and 1 120583gkg remifentanilThe remaining 10patients with a gestational age of 315 plusmn 15 weeks and a bodyweight of 1523 plusmn 35 g were treated with 2000 120583gkg propofoland 1 120583gkg remifentanil All neonates were in nasal contin-uous airway pressure therapy before intubation with similarventilatory parameters and degree of respiratory system Nostatistical differenceswere observed aswell between the drugsregarding pain and stress level before and after the intubationusing the NIPS scale No differences were observed in heartrate and blood pressure between the two drugs Adverseeffects such as hypotension were observed in two infantsin each drug and bradycardia was seen in one infant inthe propofol group The present findings did not show anydifference in the quality of intubation presence of adverseeffects changes on the hemodynamic variables and qualityof sedation and analgesia achieved when midazolam orpropofol was used as a hypnotic associated with remifentanilas premedication for tracheal intubation in pretermneonatesThe pharmacokinetics of propofol was studied in 25 neonatesafter a bolus injection of 3000 120583gkg [109] and found thatthere is a remarkable variation in the propofol Cl which maybe influenced by postmenstrual and postnatal ages

Malagon et al [25] compared the effect of three anaes-thetics midazolam propofol and sevoflurane on the post-operative production of cardiac troponin T in 90 pediatricpatients undergoing cardiac surgery Patients received pre-medication consisting of oral atropine (20120583gkg) and mida-zolam (500 120583gkg) 30min before induction of anaesthesiaAnaesthesia was induced with sevoflurane (1 120583gkg) fol-lowed by a bolus of sufentanil (1 120583gkg) and pancuronium(200120583gkg) The groups were comparable with respect tosex age weight type of surgery cardiopulmonary bypassaortic cross clamp and circulatory arrest time The valuesfor acyanotic patients were similar with midazolam propo-fol and sevoflurane The corresponding values for cyanoticpatients were similar to the three anaesthetics There was asignificant correlation between ventilator hours and troponinT concentrations at the time of 8 hours in the sevofluranegroup (119903 = 045) and midazolam group (119903 = 050) butnot in the propofol group The present findings show thatthe postoperative production of troponin T in pediatricpatients undergoing cardiac surgery is similar to midazolampropofol or sevoflurane anaesthesia

Hartwig et al [17] studied the continuous intravenoussedation using midazolam and fentanyl in patients recoveredin the pediatric intensive care unit Twenty-four artificiallyventilated children aged from 26 days to 5 years (17 infantsyounger than 1 year) received an intravenous midazolaminfusion of 100 120583gkg per hour Fifteen of the 24 children


received a combination ofmidazolamwith fentanyl the latterwas infused at a rate of 05 to 2 120583gkg per hour The meanduration of fentanyl infusion was 64 hours (range 20 to 188hours) No cardiovascular or respiratory adverse effects wereseen After stopping the fentanyl infusion the children weresedated with midazolam With midazolam as the only seda-tive drug a significantly (119875 lt 005) highermean infusion rateofmidazolamwas necessary to reach a reliable sedation and itwas of 209120583gkg per hour (range 100 to 500120583gkg per hour)Mean serum concentration of midazolam decreased from513 120583gL (range 124 to 1093120583gL) to 330 120583gL (range 58120583gLto 1240 120583gL) after 4 to 5 days Midazolam Cl increased inrelation to the duration of midazolam therapy (119903 = 0544119875 lt 001) In the early phase of midazolam therapy Clof midazolam was 58 + 38mLkg per min and increasedsignificantly by 133 to 136 + 106mLmin permin in the latephase of therapy The reason for the increase of midazolamCl may be either an increase of the Vd or an increase ofthe hepatic Cl due to an enzyme induction of midazolam orby increasing hepatic blood flow during a treatment over alonger period During the first 24 to 72 hours of midazolamtherapy the sedation score was significantly correlated withthe serum midazolam concentration (119903 = 076 119875 lt 0001)The desirable sedation score could be achieved during thistime period at a serum concentration between 100 and500 ngmL with an infusion rate of 100 to 400120583gkg perhour Midazolam seems to guarantee reliable sedation andanxiolytic actionThe evaluation of the sedation score showedthat reliable sedation can be achieved at amidazolam infusionof 100 to 400120583gkg per hour and at a serum midazolamconcentration between 100 and 500 ngmL In combinationwith fentanyl the midazolam infusion rate could be held at alower level Continuous intravenous infusion of fentanyl andmidazolam has been shown to provide satisfactory analgesia

Ketamine and midazolam are commonly used in chil-dren undergoing cardiac catheterization Jobeir et al [110]reviewed pediatric cardiac catetherization procedures in 154patients (age from 03 to 192 months) who underwent a totalof 205 procedures They received ketamine (119899 = 79 105 plusmn088mgkg per hour) midazolam (119899 = 35 157 plusmn 103mgkgper hour) or both (119899 = 91 ketamine 113 plusmn 084mgkgper hour and midazolam 157 plusmn 103mgkg per hour) In185 of patients there were complex cardiac lesions Pre-and postprocedure systolic and diastolic mean blood pres-sure were 72 plusmn 14 and 68 plusmn 12mmHg respectively Meanprocedure time was 79 plusmn 362min The anaesthesiologistrsquosassistance was required by the cardiologist in 21 proceduresPre- and postprocedure O

2saturation were 9319 plusmn 872 and

9363 plusmn 83 respectively The mortality was zero The twogroups were not different in relation to the drug use (119875 =0283) or the complexity of the cardiac lesion (119875 = 0051)However there was significant difference between the tworegarding the need for supporting drugs (321 versus 3184119875 = 002) or oxygen treatment (721 versus 26184 119875 =0014) These authors conclude that low dose of ketamineand midazolam can be administered safely to most pediatricpatients by the cardiologist who can safely predict the needfor an anaesthesiologist

314 Adverse Effects of Midazolam in Neonates Midazolam isincompatible with fat emulsion albumin ampicillin bumet-anide cefepime ceftazidime dexamethasone fospheny-toin furosemide hydrocortisone succinate micafungin naf-cillin dimenhydrinate perfenazine ranitidine hydrochlo-ride thiopental prochlorperazine edisylate and sodiumbicarbonate [3 111] Ketoconazole and erythromycin arepotent inhibitors of CYP3A4 and must not be used inassociation with midazolam

There have been reports of life-threatening adverse respi-ratory and cardiovascular events occurring after administra-tion of midazolam Pain tenderness and thrombophlebitishave occurred following injection of midazolam Hiccupshave been reported Death due to respiratory depressionhypotension or cardiac arrest has been reported in patientsgiven intravenous midazolam for conscious sedation [111]

Midazolam is not free from adverse effects when admin-istered to neonates The first intravenous loading dose ofmidazolam administered to premature infants not infre-quently causes respiratory depression with hypotension afall in cerebral blood flow and paradoxical agitation [1] Theparadoxical effect such as hyperexcitability and myoclonusmay be responsible for the low number of GABAA receptorsin the neonate [72]

Respiratory depression and hypotension are commonwhen midazolam is used in association with narcotics orfollowing rapid bolus administration Hypotension has alsobeen reported after continuous infusion of midazolam Thepercentage of infants who develop hypotension varies withthe studies Seizure-like myoclonus has been reported in8 of premature infants receiving continuous infusion [3]This also may occur following rapid bolus administrationand in patients with underlying disorders of the centralnervous system Nasal administration may be uncomfortablebecause of a burning sensation [3] Drug accumulationmay occur with repeated doses prolonged infusion therapyof midazolam or concurrent administration of cimetidineerythromycin or fluconazole [3]

Van den Anker and Sauer [112] observed several adverseeffects in premature neonates with a gestational age below32 weeks Heart rate and arterial blood pressure decreaseddirectly following an intravenous bolus injection of 200120583gkgmidazolam but the most disturbing observation was theappearance of involuntary epileptiform movements lastingfor 15 to 30 sec The pathogenesis of this phenomenon isspeculative but perhaps in these preterm infants the decreasein arterial pressure and heart rate has also an impact oncerebral blood flow or there is a direct effect of midazolamon the brain

Ng et al [21] recently reviewed the effects of midazolamadministered intravenously to infants aged 28 days or less forsedationThese authors reached the conclusion that there areno sufficient data to administrate midazolam intravenouslyfor sedation to neonates undergoing intensive care Sincebrain maturation is incomplete in infants side effects ofcentrally acting drugs may differ from those in older patients[75]

The major adverse effects associated with continuousinfusion of midazolam are related to tolerance and an


associated abstinence or withdrawal syndrome [71 76 113114] Withdrawal syndromes with central nervous systemmanifestations have been observed These syndromes havebeen characterized by seizures agitation inability to com-municate and hallucinations or by somatic manifestationssuch as vomiting tachycardia and fever Bergman et al [114]suggested that prolonged administration of midazolam toinfants especially to those who had hypoalbuminemia orwho were receiving concomitant fentanyl may produce along-lasting encephalopathy Hepatic biotransformation donot mature until 5 months of age midazolam is metabolizedslowly in young infants Since brain maturation is incompletein this age group side effects of centrally acting drugsincluding manifestations of an abstinence syndrome maydiffer from those in older patients Midazolam is highlybound to plasma protein (98 in adults [5]) low serumalbumin concentrations may result in higher brain levels andmay exacerbate the effects of midazolam by increasing theplasma concentration of unbound drug [115]

Harte et al [116] evaluated the effects of intravenousmidazolam injection on cerebral blood flow in very lowbirthweight ventilated infants Ten infants with birthweightle1500 g were treated with an intravenous bolus of 100 120583gkgmidazolam No change in heart rate occurred during thestudy periodwhilemean arterial blood pressure decreased by3mmHg 5min after midazolam administration comparedto baseline values A nonspecific fall in transcutaneous PCO

2

was seen at 20min after midazolam administration Meancerebral blood flow decreased from baseline by 12 at 5minafter midazolam administration then returned to predosevalues Midazolam concentrations in the therapeutic rangewere proved to be effective in sedation of pediatric intensivecare infants As onlyminor cerebral andhemodynamic effectswere found with the use of midazolam in stable ventilatedpreterm infants it appears that midazolam is a safe short-term sedative agent

The administration of a loading dose of 200120583gkg mida-zolam followed by a constant infusion of 200120583gkg perhour to 11 ventilated premature infants caused changes incerebral oxygenation and hemodynamics [117] Van Leuvenet al [118] reported a brief and moderate suppression ofthe electroencephalogram background pattern lasting lessthan 2 hours in 4 out of 15 infants after a loading doseof 50 120583gkg midazolam followed by a continuous infusionof 150120583gkg per hour Harte et al [116] reported minorcerebral and hemodynamic effect after the intravenous bolusadministration of 100 120583gkg of midazolam to 10 infants witha birthweight le1500 g

4 Discussion

The present paper reviews the clinical pharmacology ofmidazolam most of the work was performed in neonatesand several data have been obtained in children Benzodi-azepines provide effective control of patient agitation withoutimposing a significant load on the cardiovascular systemMidazolam is a short-acting benzodiazepine with rapid onsetof sedation and is preferable to diazepam 119905

12of midazolam

is 22-fold shorter than that of diazepam [5] In adults mida-zolam 119905

12 Cl and Vd are 19 hours 66mLkg per min and

11 Lkg respectively In healthy preterm infants 11990512

is 33-fold longer Cl is 44-fold smaller and Vd is 11 Lkg in adultand neonates The rate of midazolam elimination is slowerin infants than in adults Midazolam is mainly eliminatedby metabolism in adults It is hydroxylated in position 1 toform 1-hydroxymidazolam by CYP3A4 and CYP3A5 Theseenzymes surge in the liver during the first weeks of life [8 911] and thus their activities and consequently the metabolicrate of midazolam are lower in neonates than in older infantsand adults These findings explain the longer 119905

12and the

slower Cl observed in neonates than in older infants andadults

Children with an age greater than 2 years had a Cl ofmidazolam that ranged from 58 to 136mLkg permin (meanplusmn SD = 96 plusmn 35mLkgmin) [17 47] The work based on18 patients aged from 2 days to 17 years with half of thepatients having an age less than 6 months revealed that Cl ofmidazolam was 50 plusmn 39mLkg per min [34] This estimateis lower than that reported in patients with age greater than2 years [17 47] Thus Cl of midazolam increases with the ageup to at least 2 years of life

Disease affects the pharmacokinetics of midazolam Apatient suffering from renal failure with malignant hyper-tension and having a creatinine concentration of 691 120583molLand treated with midazolam had a 119905

12 Vd and Cl of this

drug 63-fold longer 145-fold greater and 26-fold largerrespectively [34] than the normal values [26] Multiple organfailure reduces the Cl of midazolam [27] The severity ofdisease lowers the Cl of midazolam likely by reducing theactivities of CYP3A4 and CYP3A5

Fifteen preterm infants requiringmechanical ventilationwere treatedwithmidazolamcontinuous infusion of 60120583gkgper hour [28] They had a 119905

1219-fold longer than the

normal value [26] Some of these infants were treated withdifferent drugs 7 infants received fentanyl a substrate ofCYP3A4 [52] Fentanyl may compete with the metabolism ofmidazolam reducing the midazolam hydroxylation rate thuslengthening the midazolam 119905

12 The long 119905

12of midazolam

observed by Jacqz-Aigrain et al [28] may reflect the effectof the mechanical ventilation and the interaction with drugscoadministered with midazolam ECMO therapy increasesseveral times 119905

12 Cl and Vd of midazolam [31 119]

In literature there are three studies on the populationpharmacokinetics of midazolam [32ndash34] Burtin et al [32]studied 187 neonates with a gestational age ranging from 26to 42 weeks and Lee et al [33] studied 60 preterm infantswith a gestational age ranging between 24 and 31 weeks Allthese infants underwent mechanical ventilation Mean 119905

12

was 16-fold greater [32] than the normal value [26] and 22-fold greater [33] than normal estimate [26] These findingssuggest that mechanical ventilation may increase midazolam11990512

in neonates The infants studied by Lee et al [33] had asmaller gestational age than the infants studied byBurtin et al[32] The longer 119905

12observed by Lee et al [33] might at least

in part reflect the different gestational ages The populationkinetics of midazolam was studied in 18 pediatric patientsaged from 2 days to 17 years half of the patients had an agelt 6


months [34] Midazolam 11990512

Cl and Vdwere 55 plusmn 35 hours50plusmn 39mLkg permin and 17 plusmn 11 Lkg respectivelyTheseparameters were 087-fold lower 30-fold higher and 15-foldlarger than the normal values These data suggest that the Clof midazolam increases with the neonatal development

The data on midazolam pharmacodynamics in neonatesare few and do not allow any conclusion De Wildt et al[54] did not find any relationship between sedation levelcategory and drug concentrations Vet et al [27] did not finda correlation between inflammation severity and COMFORTscore Trouiller et al [64] and Arbour et al [65] statedthat the optimal measure to monitor the pharmacodynamicendpoint still needs to be determined

Neonates may undergo uncomfortable procedures andmay experience moderate to severe pain in the ldquoneonatalintensive care unitrdquoThe availability of an appropriate sedativethat reduces the stress and pain is desirable Midazolamis an effective sedative and represents a convenient choiceamong the sedatives because of its fast onset of action andthe rapid termination of effect The use of midazolam fornewborn sedation remains empirical and further researchon the effectiveness and safety of midazolam in ventilatedneonates is needed before its employment can be consideredin routine clinical use [22 111]

Sedation of neonates with midazolam may be performedby intravenous administration (bolus or continuous infusion)or by intranasal administration when minimal sedation isrequired [79] The median initial dose of intranasal midazo-lam is 400120583gkg (range 300 to 800120583gkg)The bioavailabilityof intranasal midazolam ranged from 50 to 83 [83ndash85]A second dose of intranasal midazolam 10 to 15min afterthe first dose to obtain the desired level of sedation may beadministered The oral administration of midazolam is notused in neonates and only two reports were found [2 6]No information is available in literature on the sublingualadministration of midazolam to neonates

Treluyer et al [77] determined the minimal effectivedose of intravenous midazolam required for appropriatesedation in 95 of infants 1 hour after sedationThe sedationprocedurewas considered a success if all the following criteriawere met no agitation no grimacing and no crying facialexpression before and during tracheal suctioning Adminis-tering 200120583gkg midazolam the final estimated probabilityof success is 769 Using lower midazolam concentrationsthe probability of success decreased

Mulla et al [30] administered diazepam to 45 infants toobtain a plasma midazolam concentration between 200 and1000 ngmL within 24 hours to start treatment Infants withage greater than 33 weeks of gestation received a continuousinfusion of midazolam of 60120583gkg per hour Infants below33 weeks of gestation received the same continuous infusionrate during the first 24 hours of treatment followed by acontinuous infusion of 30 120583gkg per hour of midazolamMean midazolam concentrations were 634 plusmn 234 ngmL 628plusmn 327 ngmL and 543 plusmn 327 ngmL at 24 and 48 hours andat the end of treatment Remarkable variability in midazolamplasma concentrations was observed but none of the infantshad levels of midazolam below 200 ngmL and only 2 infantshad a plasma concentration ofmidazolam above 1000 ngmL

A dose of midazolam between 50 and 400 120583gkg per hourproduced midazolam concentrations sufficient for sedationof infants [17] Dosage of midazolam must be increasedduring therapy due an increase of midazolam Cl Arya andRamji [19] administered midazolam as a bolus of 200 120583gkgfollowed by a continuous infusion of 60 120583gkg per hour to 17infants with a body weight lt2000 g undergoing mechanicalventilation No significant adverse effects were observedThe course of mechanical ventilation was not influencedby the use of midazolam These authors observed that thebehavioural assessment was used to demonstrate the sedativeeffect of midazolam in ventilated infants

Data describing midazolam pharmacokinetics followingoral administration to neonates are few only two articles areavailable in literature [2 6] A single oral dose of 100 120583gkgwas administered to infants (119899 = 15) with gestational ageranging from 26 to 31 weeksThe apparent oral Cl and Vd andthe plasma 119905

12(given as median) were 27mLkg per min

14 Lkg and 11990512

76 hours respectively These values are notconsiderably different from the normal values The absolutebioavailability ldquoFrdquo of midazolam was 049

The neonatal period is one of the highest risk periods forseizures [92] which occur in 1 to 5 of neonates [93] Littleinformation is available on the treatment of neonatal seizuresby midazolamThis drug emerged as an antiepileptic drug inthe 1970s and more recently it has become an effective agentfor the treatment of status epilepticus refractory to standardantiepileptic treatment Rapid control of the status epilepticushas been demonstrated with midazolamThis drug produceda complete clinical and electrographic response in neonatesrefractory to phenobarbital and phenytoin [23 24 96]

The efficacy of a combination of midazolam and pheny-toin in treating generalized convulsive status epilepticuswas studied in 122 children with the median age of 244months [101] Forty-three percent of infants required artificialventilationThirty-two percent of the patients developed res-piratory insufficiency during initial therapy with midazolamEight-nine percent of infants managed on midazolam andphenytoin

Midazolam successfully managed seizures in 32 neonateswho did not respond to diazepam phenytoin or pheno-barbital [23] Midazolam was given as an intravenous bolusdose of 100 120583gkg followed by a continuous infusion of1 to 15120583gkg per min Twelve patients (38) developedhypotension Midazolam emerged as a treatment optionagainst the status epilepticus in patients who did not respondto diazepam phenytoin or phenobarbital [100] Comparedwith phenobarbital midazolam has fewer hemodynamicconsequences minimizing the need for invasive monitoring[102]

Many drugs depress the function of the central nervoussystem producing sedation in ventilated infants They are theopioids (fentanyl morphine and diamorphine) the sedative-hypnotic midazolam and the anaesthetic propofol Mah-moudian and Zadeh [106] did not find statistical differencesregarding pain stress level and adverse effects betweenmidazolam and propofol

Hartwig et al [17] experienced the treatment of mida-zolam with that of fentanyl in patients recovered in the


ldquoneonatal intensive care unitrdquo Twenty-four children wereartificially ventilated for respiratory support after cardiacsurgery Their age ranged from 26 days to 5 years (17infants were younger than 1 year) and they received anintravenous bolus of 100 or 200120583gkg midazolam followedby an infusion of this drug at a rate of 100120583gkg per hourFifteen of the 24 infants received a combination ofmidazolamwith fentanyl The latter was infused at a rate of 05 to2 120583gkg per hour No cardiovascular or respiratory adverseeffectswere seenMidazolamguarantees reliable sedation andanxiolytic actionWithmidazolam as the only sedative druga significantly higher mean infusion rate of 209120583gkg perhour (range 100 to 500 120583gkg per hour) was necessary toreach a reliable sedation In the early phase of midazolamtherapy Cl was 58 plusmn 38mLkg per min and increased by133 to 136 plusmn 106mLkg permin in the late phase of therapy

Ketamine was infused at a rate of 1050 plusmn 880 120583gkg perhour (119899 = 79) and midazolam infusion was 140 plusmn 90 120583gkgper hour (119899 = 35)There were no differences between the twogroups regarding the need for supporting drugs or oxygentreatment In 185 of patients there were complex cardiaclesions No difference was found in relation to the drug used(119875 = 0283) or the complexity of cardiac lesions (119875 =0051) These authors conclude that low dose of ketamineand midazolam can be administered safely to most pediatricpatients by the cardiologist who can safely predict the needfor an anaesthesiologist

Life-threatening adverse respiratory and cardiovascu-lar events have been reported in adults after midazolamadministration Pain tenderness and thrombophlebitis haveoccurred following intravenous midazolam administration[109] In neonates intravenous midazolam may cause res-piratory depression with hypotension and a fall in cerebralblood flow Myoclonus is sometimes seen and paradoxicalagitation has been reported [1]The paradoxical effect such ashyperexcitability and myoclonus are due to the low numberof GABAA receptors present in the neonate [72]

The major adverse effects associated with continuousinfusion of midazolam are related to tolerance and an associ-ated abstinence or withdrawal syndrome [21 71 76 112] Onehundred 120583gkg midazolam reduces the mean arterial bloodpressure by 12 at 5min after midazolam [114] Hypoten-sion may occur after continuous intravenous infusion ofmidazolam to neonates The percentage of neonates whodeveloped hypotension varies with the studies Hu et al[23] observed hypotension in 38 of infants treated with acontinuous infusion ofmidazolam ranging from 1 to 15120583gkgpermin to treat seizures Twenty-seven percent of the infantsreceiving a continuous midazolam infusion of 60120583gkg perhour developed hypotension [28] These infants were treatedwith several drugs and the contribution of these drugs indeveloping hypotension is unknown Hypotension has beenreported in few infants with respiratory distress syndromewho received amidazolam infusion of 60120583gkg per hour [78]

In conclusion midazolam is a safe and effective drugwhich may be used as a sedative or as an antiepilepticfor the treatment of infants who are refractory to standardantiepileptic therapy Midazolam is particularly useful in thetreatment of the status epilepticus in infants Midazolam is

also used as an anaesthetic but information aboutmidazolamas an anaesthetic is lacking in neonates Midazolam isextensively hydroxylated by two cytochrome P-450 formsnamely CYP3A4 and CYP3A5 These enzymes surge in theliver during the first weeks of life Neonates have a lowerexpression of these enzymes than older infants and adultsConsequently the metabolic rate of midazolam is lower inneonates Diseases affect the pharmacokinetics of midazo-lam theymay reduce theCl or prolong 119905

12ofmidazolam It is

likely that these effects are due to the lowering of CYP3A4 andCYP3A5 activities We feel that further research is requiredto ensure that the doses of midazolam recommended for thetreatment of neonates are evidence-based

Conflict of Interests

The author declares that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This work has been supported by the Ministry of the Univer-sity and Scientific and Technologic Research (Rome Italy)The author thanks Dr Rosa Baviello and Dr Ida Bertolini ofthe Medical Library of the University of Pisa for the promptretrieving of the literature Particular thanks are due to DrTessa Piazzini of the Biomedical Library of the Universityof Florence who performed the bibliographic search withEMBASE

References

[1] Neonatal Formulary John Wiley amp Sons West Sussex UK 6thedition 2011

[2] S N De Wildt G L Kearns S D Sie W C J Hop and J NVan Den Anker ldquoPharmacodynamics of intravenous and oralmidazolam in preterm infantsrdquo Clinical Drug Investigation vol23 no 1 pp 27ndash38 2003

[3] T E Young and M B Neofax A Manual of Drugs Used inNeonatal Care Thomson Reuters Montvale NJ USA 23rdedition 2010

[4] S J Mihi and R A Harris ldquoHypnotic and sedativesrdquo in Good-man and Gilmanrsquos The Pharmacological Basis of TherapeuticsL Brunton B Chabner and B Knollman Eds McGraw HillNew York NY USA 12th edition 2011

[5] K E Thummel and D D Shen ldquoIsoherranen N Design andoptimization of dosage regimens pharmacokinetic datardquo inGoodman and GilmanrsquosThe Pharmacological Basis ofTherapeu-tics L Brunton B Chabner and B Knollman Eds McGrawHill New York NY USA 12th edition 2011

[6] S N De Wildt G L Kearns W C J Hop D J Murry S MAbdel-Rahman and J N Van Den Anker ldquoPharmacokineticsand metabolism of oral midazolam in preterm infantsrdquo BritishJournal of Clinical Pharmacology vol 53 no 4 pp 390ndash3922002

[7] H Oldenhof M De Jong A Steenhoek and R JanknegtldquoClinical pharmacokinetics of midazolam in intensive carepatients a wide interpatient variabilityrdquo Clinical PharmacologyandTherapeutics vol 43 no 3 pp 263ndash269 1988


[8] G L Kearns S M Abdel-Rahman S W Alander D LBlowey J S Leeder and R E Kauffman ldquoDevelopmental phar-macologymdashdrug disposition action and therapy in infants andchildrenrdquoTheNew England Journal of Medicine vol 349 no 12pp 1157ndash1167 2003

[9] D Lacroix M Sonnier A Moncion G Cheron and T CresteilldquoExpression of CYP3A in the human livermdashevidence that theshift between CYP3A7 and CYP3A4 occurs immediately afterbirthrdquo European Journal of Biochemistry vol 247 no 2 pp 625ndash634 1997

[10] S N De Wildt G L Kearns D J Murry G Koren and J NVan Den Anker ldquoOntogeny of midazolam glucuronidation inpreterm infantsrdquo European Journal of Clinical Pharmacologyvol 66 no 2 pp 165ndash170 2010

[11] S A Wrighton W R Brian M-A Sari et al ldquoStudieson the expression and metabolic capabilities of human livercytochrome P450IIIA5 (HLp3)rdquo Molecular Pharmacology vol38 no 2 pp 207ndash213 1990

[12] R D Mellon A F Simone and B A Rappaport ldquoUse ofanesthetic agents in neonates and young childrenrdquo Anesthesiaand Analgesia vol 104 no 3 pp 509ndash520 2007

[13] V Jevtovic-Todorovic R E Hartman Y Izumi et al ldquoEarlyexposure to common anesthetic agents causes widespreadneurodegeneration in the developing rat brain and persistentlearning deficitsrdquo Journal of Neuroscience vol 23 no 3 pp 876ndash882 2003

[14] C Young V Jevtovic-Todorovic Y-Q Qin et al ldquoPotential ofketamine and midazolam individually or in combination toinduce apoptotic neurodegeneration in the infantmouse brainrdquoBritish Journal of Pharmacology vol 146 no 2 pp 189ndash1972005

[15] E Ng A Taddio and A Ohlsson ldquoIntravenous midazolaminfusion for sedation of infants in the neonatal intensive careunitrdquo Cochrane Database of Systematic Reviews no 2 articleCD002052 2000

[16] E Jacqz-Aigrain P Daoud P Burtin L Desplanques and FBeaufils ldquoPlacebo-controlled trial of midazolam sedation inmechanically ventilated newborn babiesrdquo The Lancet vol 344no 8923 pp 646ndash650 1994

[17] S Hartwig B Roth and M Theisohn ldquoClinical experiencewith continuous intravenous sedation using midazolam andfentanyl in the paediatric intensive care unitrdquo European Journalof Pediatrics vol 150 no 11 pp 784ndash788 1991

[18] K J S Anand N McIntosh H Lagercrantz E Pelausa TE Young and R Vasa ldquoAnalgesia and sedation in pretermneonates who require ventilatory support results from theNOPAIN trialrdquo Archives of Pediatrics and Adolescent Medicinevol 153 no 4 pp 331ndash338 1999

[19] V Arya and S Ramji ldquoMidazolam sedation in mechanicallyventilated newborns a double blind randomized placebo con-trolled trialrdquo Indian Pediatrics vol 38 no 9 pp 967ndash972 2001

[20] L Lowrie AHWeiss andC Lacombe ldquoThepediatric sedationunit a mechanism for pediatric sedationrdquo Pediatrics vol 102no 3 p E30 1998


[22] J V Aranda W Carlo P Hummel R Thomas V T Lehrand K J S Anand ldquoAnalgesia and sedation during mechanicalventilation in neonatesrdquo Clinical Therapeutics vol 27 no 6 pp877ndash899 2005

[23] K-C Hu N-C Chiu C-S Ho S-T Lee and E-Y Shen ldquoCon-tinuous midazolam infusion in the treatment of uncontrollableneonatal seizuresrdquoActa Paediatrica Taiwanica vol 44 no 5 pp279ndash281 2003

[24] J R Castro Conde A A Hernandez Borges E DomenechMartınez C Gonzalez Campo andR Perera Soler ldquoMidazolamin neonatal seizures with no response to phenobarbitalrdquoNeurol-ogy vol 64 no 5 pp 876ndash879 2005

[25] I Malagon K Hogenbirk J van Pelt M G Hazekamp and JG Bovill ldquoEffect of three different anaesthetic agents on thepostoperative production of cardiac troponin T in paediatriccardiac surgeryrdquo British Journal of Anaesthesia vol 94 no 6pp 805ndash809 2005

[26] S N De Wildt G L Kearns W C J Hop D J Murry S MAbdel-Rahman and J N Van Den Anker ldquoPharmacokineticsand metabolism of intravenous midazolam in preterm infantsrdquoClinical Pharmacology andTherapeutics vol 70 no 6 pp 525ndash531 2001

[27] N J Vet CWMVerlaat S NDeWildt D Tibboel andMDeHoog ldquoDaily interruption of sedation in critically ill childrenrdquoPediatric Critical Care Medicine vol 13 no 1 article 122 2012

[28] E Jacqz-Aigrain P Daoud P Burtin S Maherzi and FBeaufils ldquoPharmacokinetics of midazolam during continuousinfusion in critically ill neonatesrdquo European Journal of ClinicalPharmacology vol 42 no 3 pp 329ndash332 1992

[29] E Jacqz-Aigrain C Wood and I Robieux ldquoPharmacokineticsof midazolam in critically ill neonatesrdquo European Journal ofClinical Pharmacology vol 39 no 2 pp 191ndash192 1990

[30] H Mulla P McCormack G Lawson R K Firmin and D RUpton ldquoPharmacokinetics of midazolam in neonates undergo-ing extracorporealmembrane oxygenationrdquoAnesthesiology vol99 no 2 pp 275ndash282 2003

[31] M J Ahsman M Hanekamp E D Wildschut D Tibboel andR A A Mathot ldquoPopulation pharmacokinetics of midazolamand its metabolites during venoarterial extracorporeal mem-brane oxygenation in neonatesrdquo Clinical Pharmacokinetics vol49 no 6 pp 407ndash419 2010

[32] P Burtin E Jacqz-Aigrain P Girard et al ldquoPopulation phar-macokinetics ofmidazolam in neonatesrdquoClinical PharmacologyandTherapeutics vol 56 no 6 part 1 pp 615ndash625 1994

[33] T C Lee B G Charles G J Harte P H Gray P A Steerand V J Flenady ldquoPopulation pharmacokinetic modeling invery premature infants receivingmidazolamduringmechanicalventilation midazolam neonatal pharmacokineticsrdquo Anesthesi-ology vol 90 no 2 pp 451ndash457 1999

[34] S N De Wildt M De Hoog A A Vinks E Van Der Giesenand J N Van Den Anker ldquoPopulation pharmacokinetics andmetabolism of midazolam in pediatric intensive care patientsrdquoCritical Care Medicine vol 31 no 7 pp 1952ndash1958 2003

[35] K Allegaert J N van den Anker G Naulaers and J deHoon ldquoDeterminants of drugmetabolism in early neonatal liferdquoCurrent Clinical Pharmacology vol 2 no 1 pp 23ndash29 2007

[36] J A Ring H Ghabrial M S Ching R A Smallwood and DJ Morgan ldquoFetal hepatic drug eliminationrdquo Pharmacology andTherapeutics vol 84 no 3 pp 429ndash445 1999

[37] M G Ladona B Lindstrom CThyr P Dun-Ren and A RaneldquoDifferential foetal development of theO- andN-demethylationof codeine and dextromethorphan in manrdquo British Journal ofClinical Pharmacology vol 32 no 3 pp 295ndash302 1991

[38] F J Gonzalez M Coughtrie and R H Tukey ldquoDrug Metab-olismrdquo in Goodman and Gilmanrsquos The Pharmacological Basis of


Therapeutics L Brunton B Chabner and B Knollman EdsMcGraw Hill New York NY USA 12th edition 2011

[39] T C Lee and B Charles ldquoMeasurement byHPLC ofmidazolamand its major metabolite 1-hydroxymidazolam in plasma ofvery premature neonatesrdquo Biomedical Chromatography vol 10no 2 pp 65ndash68 1996

[40] J C Gorski S D Hall D R Jones M Van Den Branden and SA Wrighton ldquoRegioselective biotransformation of midazolamby members of the human cytochrome P450 3A (CYP3A)subfamilyrdquo Biochemical Pharmacology vol 47 no 9 pp 1643ndash1653 1994

[41] R W Wang D J Newton N Y Liu M Shou T Rushmoreand A Y H Lu ldquoInhibitory anti-CYP3A4 peptide antibodymapping of inhibitory epitope and specificity toward otherCYP3A isoformsrdquoDrugMetabolism and Disposition vol 27 no2 pp 167ndash172 1999

[42] A Keubler J Weiss W E Haefeli G Mikus and J BurhenneldquoDrug interaction of efavirenz and midazolam efavirenz acti-vates the CYP3A-mediated midazolam 11015840-hydroxylation invitrordquo Drug Metab Dispos vol 40 no 6 pp 1178ndash1182 2012

[43] I Ince S N de Wildt M Y Peeters et al ldquomCritical illness isa major determinant of midazolam clearance in children aged 1month to 17 yearsrdquoTherapeutic Drug Monitoring vol 34 no 4pp 381ndash389 2012

[44] P B Watkins ldquoNoninvasive tests of CYP3A enzymesrdquo Pharma-cogenetics vol 4 no 4 pp 171ndash184 1994

[45] D S Streetman J F Bleakley J S Kim et al ldquoCombined phe-notypic assessment of CYP1A2 CYP2C19 CYP2D6 CYP3AN-acetyltransferase-2 and xanthine oxidase with the lsquoCooper-stown cocktailrsquordquo Clinical Pharmacology and Therapeutics vol68 no 4 pp 375ndash383 2000

[46] I Ince S N de Wildt C Wang et al ldquoA novel maturationfunction for clearance of the cytochrome P450 3A substratemidazolam from preterm neonates to adultsrdquo Clinical Pharma-cokinetics vol 52 no 7 pp 555ndash565 2013

[47] J G Reves R J Fragen H R Vinik and D J GreenblattldquoMidazolam pharmacology and usesrdquo Anesthesiology vol 62no 3 pp 310ndash324 1985

[48] T N Johnson M S Tanner C J Taylor and G T TuckerldquoEnterocytic CYP3A4 in a paediatric population developmen-tal changes and the effect of coeliac disease and cystic fibrosisrdquoBritish Journal of Clinical Pharmacology vol 51 no 5 pp 451ndash460 2001

[49] S N De Wildt G L Kearns J S Leeder and J N Van DenAnker ldquoCytochrome P450 3A Ontogeny and drug dispositionrdquoClinical Pharmacokinetics vol 37 no 6 pp 485ndash505 1999

[50] B J Anderson and P Larsson ldquoA maturation model formidazolam clearancerdquo Paediatric Anaesthesia vol 21 no 3 pp302ndash308 2011

[51] K S Pang and M Rowland ldquoHepatic clearance of drugs ITheoretical considerations of a ldquowell-stirredrdquo model and a ldquopar-allel tuberdquo model Influence of hepatic blood flow plasma andblood cell binding and the hepatocellular enzymatic activityon hepatic drug clearancerdquo Journal of Pharmacokinetics andBiopharmaceutics vol 5 no 6 pp 625ndash653 1977

[52] R B Labroo M F Paine K E Thummel and E D Kha-rasch ldquoFentanyl metabolism by human hepatic and intestinalcytochrome P450 3A4 implications for interindividual vari-ability in disposition efficacy and drug interactionsrdquo DrugMetabolism and Disposition vol 25 no 9 pp 1072ndash1080 1997

[53] M YM Peeters S A Prins C A J Knibbe et al ldquoPharmacoki-netics and pharmacodynamics ofmidazolamandmetabolites in

nonventilated infants after craniofacial surgeryrdquoAnesthesiologyvol 105 no 6 pp 1135ndash1146 2006

[54] S N De Wildt M De Hoog A A Vinks K F M JoostenM Van Dijk and J N Van Den Anker ldquoPharmacodynamicsof midazolam in pediatric intensive care patientsrdquo TherapeuticDrug Monitoring vol 27 no 1 pp 98ndash102 2005

[55] M L Buck ldquoPharmacokinetic changes during extracorpo-real membrane oxygenation implications for drug therapy ofneonatesrdquo Clinical Pharmacokinetics vol 42 no 5 pp 403ndash4172003

[56] K Shekar J F Fraser M T Smith and J A Roberts ldquoPharm-acokinetic changes in patients receiving extracorporeal mem-brane oxygenationrdquo Journal of Critical Care vol 27 no 6 pp741e9ndash741e18 2012

[57] J W Mandema B Tuk A L Van Steveninck D D Breimer AF Cohen andM Danhof ldquoPharmcokinetic-pharmacodynamicmodeling of the central nervous system effects of midazolamand its main metabolite 120572-hydroxymidazolam in healthy vol-unteersrdquo Clinical Pharmacology and Therapeutics vol 51 no 6pp 715ndash728 1992

[58] A R Lloyd-Thomas and P D Booker ldquoInfusion of midazolamin paediatric patients after cardiac surgeryrdquo British Journal ofAnaesthesia vol 58 no 10 pp 1109ndash1115 1986

[59] B B DeBerry J E Lynch J M Chernin J B Zwischenbergerand D H Chung ldquoA survey for pain and sedation medicationsin pediatric patients during extracorporealmembrane oxygena-tionrdquo Perfusion vol 20 no 3 pp 139ndash143 2005

[60] A M Harrison S Davis S Eggleston R Cunningham R BB Mee and P M Bokesch ldquoSerum creatinine and estimatedcreatinine clearance do not predict perioperatively measuredcreatinine clearance in neonates undergoing congenital heartsurgeryrdquo Pediatric Critical Care Medicine vol 4 no 1 pp 55ndash59 2003

[61] J Hughes A M Gill H Mulhearn E Powell and I ChoonaraldquoSteady-state plasma concentrations of midazolam in criticallyill infants and childrenrdquoAnnals of Pharmacotherapy vol 30 no1 pp 27ndash30 1996

[62] H M L Mathews I W Carson S M Lyons et al ldquoA pharm-acokinetic study of midazolam in paediatric patients undergo-ing cardiac surgeryrdquo British Journal of Anaesthesia vol 61 no 3pp 302ndash307 1988

[63] E L Swart P R Slort and F B Plotz ldquoGrowing upwithmidazo-lam in the neonatal and pediatric intensive carerdquo Current DrugMetabolism vol 13 no 6 pp 760ndash766 2012

[64] P Trouiller P Fangio C Paugam-Burtz et al ldquoFrequency andclinical impact of preserved bispectral index activity duringdeep sedation in mechanically ventilated ICU patientsrdquo Inten-sive Care Medicine vol 35 no 12 pp 2096ndash2104 2009

[65] R Arbour J Waterhouse M A Seckel and L Bucher ldquoCorre-lation between the Sedation-Agitation Scale and the BispectralIndex in ventilated patients in the intensive care unitrdquoHeart andLung vol 38 no 4 pp 336ndash345 2009

[66] S Bjorkman ldquoPrediction of drug disposition in infants andchildren by means of physiologically based pharmacokinetic(PBPK) modelling theophylline and midazolam as modeldrugsrdquo British Journal of Clinical Pharmacology vol 59 no 6pp 691ndash704 2005

[67] S Bjorkman ldquoPrediction of cytochromeP450-mediated hepaticdrug clearance in neonates infants and children how accurateare available scaling methodsrdquo Clinical Pharmacokinetics vol45 no 1 pp 1ndash11 2006


[68] T N Johnson A Rostami-Hodjegan andG T Tucker ldquoPredic-tion of the clearance of eleven drugs and associated variability inneonates infants and childrenrdquo Clinical Pharmacokinetics vol45 no 9 pp 931ndash956 2006

[69] CMMarx PG Smith LH Lowrie et al ldquoOptimal sedation ofmechanically ventilated pediatric critical care patientsrdquo CriticalCare Medicine vol 22 no 1 pp 163ndash170 1994

[70] D L Silvasi D A Rosen and K R Rosen ldquoContinuousintravenous midazolam infusion for sedation in the PediatricIntensive Care UnitrdquoAnesthesia and Analgesia vol 67 no 3 pp286ndash288 1988

[71] D A Rosen and K R Rosen ldquoMidazolam for sedation in thepaediatric intensive care unitrdquo Intensive Care Medicine vol 17supplement 1 pp S15ndashS19 1991

[72] G Ancora E Garetti A Pirelli et al ldquoAnalgesic and sedativedrugs in newborns requiring respiratory supportrdquo Journal ofMaternal-Fetal and Neonatal Medicine vol 25 supplement 4pp 88ndash90 2012

[73] D A Rosen and K R Rosen ldquoIntravenous conscious sedationwith midazolam in paediatric patientsrdquo International Journal ofClinical Practice vol 52 no 1 pp 46ndash50 1998

[74] American Academy of Pediatrics Committee on DrugsldquoGuidelines for monitoring and management of pediatricpatients during and after sedation for diagnostic and therapeu-tic proceduresrdquo Pediatrics vol 89 pp 1110ndash1115 1992

[75] D A Notterman ldquoSedation with intravenous midazolam in thepediatric intensive care unitrdquo Clinical Pediatrics vol 36 no 8pp 449ndash454 1997

[76] J Hughes A Gill H J Leach et al ldquoA prospective study ofthe adverse effects of midazolam on withdrawal in critically illchildrenrdquo Acta Paediatrica International Journal of Paediatricsvol 83 no 11 pp 1194ndash1199 1994

[77] J-M Treluyer S Zohar E Rey et al ldquoMinimum effective doseofmidazolam for sedation ofmechanically ventilated neonatesrdquoJournal of Clinical Pharmacy andTherapeutics vol 30 no 5 pp479ndash485 2005

[78] P Burtin PDaoud E Jacqz-Aigrain PMussat andGMorietteldquoHypotension with midazolam and fentanyl in the newbornrdquoThe Lancet vol 337 no 8756 pp 1545ndash1546 1991

[79] J P Lazol and C G DeGroff ldquoMinimal sedation second dosestrategy with intranasal midazolam in an outpatient pediatricechocardiographic settingrdquo Journal of the American Society ofEchocardiography vol 22 no 4 pp 383ndash387 2009

[80] N C T Wilton J Leight D R Rosen and U A PanditldquoPreanesthetic sedation of preschool children using intranasalmidazolamrdquo Anesthesiology vol 69 no 6 pp 972ndash975 1988

[81] P Lowhagen B B Johansson and C Nordborg ldquoThe nasalroute of cerebrospinal fluid drainage inman a light-microscopestudyrdquoNeuropathology and Applied Neurobiology vol 20 no 6pp 543ndash550 1994

[82] J Berlin CM D G May-McCarver D A Notterman et alldquoAlternative routes of drug administrationmdashadvantages anddisadvantagesrdquo Pediatrics vol 100 no 1 pp 143ndash152 1997

[83] P D Knoester D M Jonker R T M Van Der Hoeven etal ldquoPharmacokinetics and pharmacodynamics of midazolamadministered as a concentrated intranasal spray A study inhealthy volunteersrdquo British Journal of Clinical Pharmacologyvol 53 no 5 pp 501ndash507 2002

[84] A H Burstein R Modica M Hatton A Forrest and F MGengo ldquoPharmacokinetics and pharmacodynamics of midazo-lam after intranasal administrationrdquo Journal of Clinical Pharma-cology vol 37 no 8 pp 711ndash718 1997

[85] E Rey L Delaunay G Pons et al ldquoPharmacokinetics ofmidazolam in children comparative study of intranasal andintravenous administrationrdquo European Journal of Clinical Phar-macology vol 41 no 4 pp 355ndash357 1991

[86] G Ljungman A Kreuger S Andreasson T Gordh and SSorensen ldquoMidazolam nasal spray reduces procedural anxietyin childrenrdquo Pediatrics vol 105 no 1 part 1 pp 73ndash78 2000

[87] N Griffith S Howell and D G Mason ldquoIntranasal midazolamfor premedication of children undergoing day-case anaesthesiacomparison of two delivery systems with assessment of intra-observer variabilityrdquo British Journal of Anaesthesia vol 81 no6 pp 865ndash869 1998

[88] A Kogan J Katz R Efrat and L A Eidelman ldquoPremedicationwith midazolam in young children a comparison of four routesof administrationrdquo Paediatric Anaesthesia vol 12 no 8 pp685ndash689 2002

[89] R D Lane and J E Schunk ldquoAtomized intranasal midazolamuse for minor procedures in the pediatric emergency depart-mentrdquo Pediatric Emergency Care vol 24 no 5 pp 300ndash3032008

[90] H T Harcke L E Grissom and M A Meister ldquoSedationin pediatric imaging using intranasal midazolamrdquo PediatricRadiology vol 25 no 5 pp 341ndash343 1995

[91] L A Slaughter AD Patel and J L Slaughter ldquoPharmacologicaltreatment of neonatal seizures a systematic reviewrdquo Journal ofChild Neurology vol 28 no 3 pp 351ndash364 2013

[92] D Sirsi S Nangia J LaMothe B E Kosofsky and GE Solomon ldquoSuccessful management of refractory neonatalseizures with midazolamrdquo Journal of Child Neurology vol 23no 6 pp 706ndash709 2008

[93] M Eriksson and R Zetterstrom ldquoNeonatal convulsions Inci-dence and causes in the Stockholm areardquo Acta PaediatricaScandinavica vol 68 no 6 pp 807ndash811 1979

[94] M J Painter M S Scher A D Stein et al ldquoPhenobarbital com-pared with phenytoin for the treatment of neonatal seizuresrdquoThe New England Journal of Medicine vol 341 no 7 pp 485ndash489 1999

[95] G B Boylan J M Rennie R M Pressler G Wilson MMorton and C D Binnie ldquoPhenobarbitone neonatal seizuresand video-EEGrdquoArchives of Disease in Childhood vol 86 no 3pp F165ndashF170 2002

[96] R D Sheth D J Buckley A R Gutierrez M Gingold J BBodensteiner and S Penney ldquoMidazolam in the treatment ofrefractory neonatal seizuresrdquo Clinical Neuropharmacology vol19 no 2 pp 165ndash170 1996

[97] L G van Rooij L Hellstrom-Westas and L S de VriesldquoTreatment of neonatal seizuresrdquo Seminars in Fetal amp NeonatalMedicine vol 18 no 4 pp 209ndash215 2013

[98] E Shany O Benzaqen and N Watemberg ldquoComparison ofcontinuous drip of midazolam or lidocaine in the treatment ofintractable neonatal seizuresrdquo Journal of Child Neurology vol22 no 3 pp 255ndash259 2007

[99] H Yamamoto M Aihara S Niijima and H YamanouchildquoTreatments with midazolam and lidocaine for status epilepti-cus in neonatesrdquo Brain and Development vol 29 no 9 pp 559ndash564 2007

[100] G L Holmes and J J Riviello Jr ldquoMidazolam and pentobarbitalfor refractory status epilepticusrdquo Pediatric Neurology vol 20no 4 pp 259ndash264 1999

[101] J C D Brevoord K F M Joosten W F M Arts R W vanRooij and M de Hoog ldquoStatus epilepticus clinical analysis


of a treatment protocol based on midazolam and phenytoinrdquoJournal of Child Neurology vol 20 no 6 pp 476ndash481 2005

[102] A Kumar and T P Bleck ldquoIntravenousmidazolam for the treat-ment of refractory status epilepticusrdquo Critical Care Medicinevol 20 no 4 pp 483ndash488 1992

[103] E Lahat M Goldman J Barr T Bistritzer and M BerkovitchldquoComparison of intranasal midazolam with intravenousdiazepam for treating febrile seizures in children prospectiverandomised studyrdquo British Medical Journal vol 321 no 7253pp 83ndash86 2000

[104] GGeldnerMHubmann R Knoll andK Jacobi ldquoComparisonbetween three transmucosal routes of administration of mida-zolam in childrenrdquo Paediatric Anaesthesia vol 7 no 2 pp 103ndash109 1997

[105] J McIntyre S Robertson E Norris et al ldquoSafety and efficacyof buccal midazolam versus rectal diazepam for emergencytreatment of seizures in children a randomised controlled trialrdquoThe Lancet vol 366 no 9481 pp 205ndash210 2005

[106] T Mahmoudian and M M Zadeh ldquoComparison of intranasalmidazolam with intravenous diazepam for treating acuteseizures in childrenrdquo Epilepsy and Behavior vol 5 no 2 pp253ndash255 2004

[107] R Carbajal B Eble and K J S Anand ldquoPremedication fortracheal intubation in neonates confusion or controversyrdquoSeminars in Perinatology vol 31 no 5 pp 309ndash317 2007

[108] M G Penido D F De Oliveira Silva E C Tavares and YP E Silva ldquoPropofol versus midazolam for intubating pretermneonates a randomized controlled trialrdquo Journal of Perinatol-ogy vol 31 no 5 pp 356ndash360 2011

[109] K Allegaert M Y Peeters R Verbesselt et al ldquoInter-individualvariability in propofol pharmacokinetics in preterm and termneonatesrdquo British Journal of Anaesthesia vol 99 no 6 pp 864ndash870 2007

[110] A Jobeir M O Galal Z R Bulbul L Solymar A Darwish andA A Schmaltz ldquoUse of low-dose ketamine andor midazolamfor pediatric cardiac catheterization is an anesthesiologistneededrdquo Pediatric Cardiology vol 24 no 3 pp 236ndash243 2003

[111] S Sweetman Ed Martindale The Complete Drug ReferencePharmaceutical Press London UK 34th edition 2005

[112] J N Van den Anker and P J J Sauer ldquoThe use of midazolamin the preterm neonaterdquo European Journal of Pediatrics vol 151no 2 p 152 1992

[113] R L Sheridan M McEttrick G Bacha F Stoddard and RG Tompkins ldquoMidazolam infusion in pediatric patients withburns who are undergoing mechanical ventilationrdquo Journal ofBurn Care and Rehabilitation vol 15 no 6 pp 515ndash518 1994

[114] I Bergman M Steeves G Burckart and A ThompsonldquoReversible neurologic abnormalities associatedwith prolongedintravenousmidazolam and fentanyl administrationrdquo Journal ofPediatrics vol 119 no 4 pp 644ndash649 1991

[115] T B Vree M Shimoda J J Driessen et al ldquoDecreased plasmaalbumin concentration results in increased volume of distribu-tion and decreased elimination of midazolam in intensive carepatientsrdquoClinical Pharmacology andTherapeutics vol 46 no 5pp 537ndash544 1989

[116] G J Harte P H Gray T C Lee P A Steer and B G CharlesldquoHaemodynamic responses and population pharmacokineticsof midazolam following administration to ventilated pretermneonatesrdquo Journal of Paediatrics and Child Health vol 33 no 4pp 335ndash338 1997

[117] A A E M Van Alfen-Van Der Velden J C W Hopman J HG M Klaessens T Feuth R C A Sengers and K D LiemldquoEffects of midazolam and morphine on cerebral oxygenationand hemodynamics in ventilated premature infantsrdquo Biology ofthe Neonate vol 90 no 3 pp 197ndash202 2006

[118] K Van Leuven F Groenendaal M C Toet et al ldquoMidazo-lam and amplitude-integrated EEG in asphyxiated full-termneonatesrdquoActa Paediatrica International Journal of Paediatricsvol 93 no 9 pp 1221ndash1227 2004

[119] H Mulla G Lawson G J Peek R K Firmin and D R UptonldquoPlasma concentrations of midazolam in neonates receivingextracorporeal membrane oxygenationrdquo ASAIO Journal vol49 no 1 pp 41ndash47 2003

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

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OphthalmologyJournal of


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Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


bound to plasma protein in adults the bound percentage is98 [5]

The literature on the effects and fate of midazolam inneonates is scarce Most of the published information dealswith the sedative effect with the treatment of refractoryseizures to standard therapies with the metabolism withthe pharmacokinetics and with the adverse effects of mida-zolam The information on the use of midazolam as ananesthetic agent in newborn infants is lacking Mellon et al[12] reviewed the anaesthetic agents in newborn animalsInformation on the anaesthetic activity of midazolam hasbeen reported in Sprague-Dawley rats [13] and in miceC57BL6 [14] both animals were 7 days old No data on theanaesthesia by midazolam in infants are available

Infants may experience moderate to severe pain in theldquoneonatal intensive care unitrdquo and the use of a sedativeto make their life comfortable when undergoing painfulprocedures is useful [15] Midazolam was found to be moreeffective than placebo as a sedative in neonates [16] and itsconcentrations ranging from 100 to 400 ngmL are sufficientfor sedation [17] Jacqz-Aigrain et al [16] Anand et al [18]and Arya and Ramji [19] used midazolam for sedation ofneonates undergoing mechanical ventilation and midazolamhas resulted to be a safe and effective sedation

Benzodiazepines provide effective control of patient agi-tation and these drugs are useful to comfort neonates duringstressing procedures Midazolam represents a convenientchoice among the sedatives because of its fast onset of actionand rapid termination of effect and is thus frequently used inthe ldquoneonatal intensive care unitsrdquo

Up to now little has been done to make comfortablethe life of neonates who undergo stress and pain Lowrieet al [20] created a ldquopediatric sedation unitrdquo to uniformand monitor the therapy for sedation andor analgesia forchildren undergoing invasive and noninvasive proceduresInfants admitted to the ldquopediatric sedation unitrdquo wereassessed medically for risk factors during sedation Many ofthe pediatric patients admitted to this unit were neonatesPharmacological treatment helps neonates to tolerate painprocedures or diagnostic studies requiring prolonged periodsof immobility The majority of children needing sedationreceived midazolam or propofol [20]

Ng et al [21] reviewed the literature on the intravenousmidazolam infusion for sedation of infants in the ldquoneonatalintensive care unitrdquo Three trials were included in the studyand using different sedation scales each study showed ahigher sedation level in the midazolam group compared tothe placebo However Ng et al [21] conclude that thereare insufficient data to promote the use of intravenousmidazolam infusion as a sedative for neonates undergoingintensive care [22]

Sedation may be performed with opioids (fentanylmorphine and diamorphine) or with the sedative-hypnoticmidazolam in ventilated neonates Endotracheal intubationand mechanical ventilation are major components of routineintensive care for very low birthweight newborn infants andsick fullterm newborn infants [22] Sedation is widely usedin neonates although there is limited clinical evidence for

the efficacy and safety of the drugs used or the methods ofadministering them [22]

A useful action of midazolam is the management ofneonatal seizures refractory to conventional treatments Huet al [23] reported that a continuous intravenous infusionof midazolam ranging from 1 to 15120583gkg per min with anaverage of 4 120583gkg per min terminated the seizures in 32infants whose seizures could not be controlled by diazepamphenytoin or phenobarbital Castro Conte et al [24] foundthat midazolam (015mgkg intravenous bolus followed bya continuous infusion of 1 120583gkg per min increasing by 05to 1 120583gkg every 2min until a maximum of 18120583gkg permin) controlled the seizures in 13 neonates refractory to thetreatment with phenobarbital and phenytoin

Troponin T is a prognostic indicator of postoperativerecovery Midazolam propofol or sevoflurane had similarefficacy in the production of troponin T in infants whounderwent cardiac surgery [25]

The information on the effects of midazolam and on thefate of this drug in neonates has been published in differentjournals during the last thirty years and it is scattered Theaims of this article are (1) to gather together and (2) toreview the published data on (a) the metabolism and (b)the pharmacokinetics of midazolam in neonates (c) thetherapeutic effects and finally (d) the adverse effects ofmidazolam in neonates The main objective of this workis (e) to provide neonatologists with a tool that embracesall aspects of the clinical pharmacology of midazolam inneonates Little is known about the effects and the fate of thedrugs administered to neonates This review was written tohelp the neonatologists hoping that theywill find someusefulinformation and thus some advantages for their work fromreading the present paper

2 Bibliographic Search

The bibliographic search was performed electronically usingPubMed and EMBASE databases as search engines Septem-ber 2013 was the cutoff point The following key wordsldquomidazolam neonaterdquo ldquomidazolam mechanism of actionrdquoldquomidazolam therapy neonaterdquo ldquomidazolam pharmacokinet-ics neonaterdquo ldquomidazolam metabolism neonaterdquo ldquoCYP3A4midazolam neonaterdquo ldquoCYP3A5 midazolam neonaterdquo ldquooraladministration midazolam neonaterdquo ldquointranasal administra-tion of midazolam neonatesrdquo ldquomidazolam seizuresrdquo ldquomida-zolam anaesthesia neonaterdquo and ldquomidazolam adverse effectsneonaterdquo were usedThe bibliography of each article was readcarefully and the selected articleswere examined In additionthe books NEOFAX a Manual Used in the Neonatal Care byYoung andMangum [3] and theNeonatal Formulary [1] wereconsulted The findings of the bibliographic search gave riseto 101 original articles 13 review articles and 6 book chaptersThe publication years of this matter ranged from 1979 to 2013

3 Results

31 Doses of Midazolam in Neonates For sedation Youngand Neofax [3] suggest giving intravenously a 50 to 150120583gkg















0minusminusinfinwas



ble1Dem

ograph

icdataof

patie

ntsa

ndph


fmidazolam

inneon

ates

andchild

ren

Com

ments

GA(w

eeks)

PNA(days)

BW(g)

Doseo

fmidazolam

Num

bero

finfants

11990512(hou

rs)

Cl(m

Lkgm

in)

Vd(Lkg)

Reference

Health

yneon

ates

Intravenou

sadm

inistratio

n26

to34

3to

11na

100120583

gkg

BolusIV

2463a

18a

11a

[26]

Critically

illneon

ates

andchild

ren

Oraladm

inistratio

nthe

values

arec

orrected

for

119865=49

26to

313to

1310

76plusmn240

100120583

gkg

BolusP

O15

76b

27b

14b

[6]

NoteA

2days

17years

mdash38to

245(kg)

90120583gkgh

Infusio

n21

na

014

aLkgh

(dise

ased)

028

aLkgh

(health

y)119875=00350

na[27]


ventilatio

nSomed

rugs

were

administered

33plusmn33

1to5

1900plusmn700

Infusio

n60120583gkgh

1512plusmn06

17plusmn18

12plusmn06

[28]

Respira

tory

distresssynd

rome

(119899=5)a

ndneon

atalinfection

(119899=5)

37plusmn23

2to

53150plusmn520

200120583

gkg

Bolus

IV10

65plusmn23

20plusmn12

09plusmn03

[29]

Neonatesu


embraneo

xygenatio

nrdquo(ECM

O)

NoteB

395plusmn19

38a

340

0plusmn60

050

to250120583

gkgh

Infusio

n10

68a

Initial

14aInitial

31a (L)

Initial

[30]

395plusmn19

38a

340

0plusmn60

050

to250120583

gkgh

Infusio

n10

333

aTerm

inal

41Term

inal

142

a

(L)

Term

inal

MedianEC

MOdu

ratio

nwas

70to

275ho

urs

404

a079

a300

0a200120583

gkg

Bolus

IV20

18aInitial

26a

Initial

14a

Initial

[31]

11990512fro

mtheo

nsetto

steady-sta

tewas

prolon

ged

5-fold

404

a079

a300

0a200120583

gkg

Bolus

IV20

na76

aTerm

inal

49a

Term

inal

Popu

lationph

armacokineticso

fmidazolam

inneon

ates

andchild

ren

NoteD

26to

420to

9700to

5200

NoteC

187

99a

12plusmn02

10plusmn02

[32]

NoteE

24to

312to

15523to

1400

100120583

gkg

Bolus

IV60

141a

0938a

115a

[33]

Age

ranged

from

2days

to17

years

mdashmdash

35to

6050

to40

0120583gkgh

Infusio

n18

55plusmn35

50plusmn39

17plusmn11

[34]

Adultsub

jects

Adults

mdashmdash

mdashmdash

mdash19plusmn06

66plusmn18

11plusmn06

[5]

Figuresa

rethem

eanplusmnSD

unlessotherw

isesta

tedIn

somec

asesresultsareg

iven

asar

angeF


hich

is49[6]

a meansta

ndarddeviationisno

tavailable

b medianGAgestatio

nalagePNA

postn

atalageBW

bod

yweight11990512120573

-phase

elim

ination

ClclearanceV

dapparent

volumeof

distr

ibution

nan


uslyP

Obymou

thN

oteAn

eonatesw

eresufferin

gfro

mcongenita

lheartd

isease(119899=4)up

pera

irway


eumon

ia(119899=2)po

stcardiac

surgery(119899=2)pu

lmon

aryhypertensio


midazolam

was

administered

viaacentralo

rperip

heralvenou

scatheterNoteC

midazolam

was

administered

intravenou

slyas

acon

tinuo

usinfusio

nto

109infantsas

abolus

dose

to22

infantsandas

acom

binatio

nof

both

to56

infantsTh

ebolus

dose

was

210plusmn239120583

gkgTh

econtinuo

usinfusio

nwas

69plusmn63120583gkg

perh

NoteDallneon

ates

received

midazolam

durin

gartifi

cialventilatio

nNoteE

neon

ates

undergoing


dyweight

lt15

00g













12is















12 Cl and




















12was 99 hours Cl


































12are











































2



4 Discussion


12of midazolam





12and the









12 The long 119905

12of midazolam




12
















14 Lkg and 11990512














12ofmidazolam It is




Acknowledgments


References




































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






























0minusminusinfinwas



ble1Dem

ograph

icdataof

patie

ntsa

ndph


fmidazolam

inneon

ates

andchild

ren

Com

ments

GA(w

eeks)

PNA(days)

BW(g)

Doseo

fmidazolam

Num

bero

finfants

11990512(hou

rs)

Cl(m

Lkgm

in)

Vd(Lkg)

Reference

Health

yneon

ates

Intravenou

sadm

inistratio

n26

to34

3to

11na

100120583

gkg

BolusIV

2463a

18a

11a

[26]

Critically

illneon

ates

andchild

ren

Oraladm

inistratio

nthe

values

arec

orrected

for

119865=49

26to

313to

1310

76plusmn240

100120583

gkg

BolusP

O15

76b

27b

14b

[6]

NoteA

2days

17years

mdash38to

245(kg)

90120583gkgh

Infusio

n21

na

014

aLkgh

(dise

ased)

028

aLkgh

(health

y)119875=00350

na[27]


ventilatio

nSomed

rugs

were

administered

33plusmn33

1to5

1900plusmn700

Infusio

n60120583gkgh

1512plusmn06

17plusmn18

12plusmn06

[28]

Respira

tory

distresssynd

rome

(119899=5)a

ndneon

atalinfection

(119899=5)

37plusmn23

2to

53150plusmn520

200120583

gkg

Bolus

IV10

65plusmn23

20plusmn12

09plusmn03

[29]

Neonatesu


embraneo

xygenatio

nrdquo(ECM

O)

NoteB

395plusmn19

38a

340

0plusmn60

050

to250120583

gkgh

Infusio

n10

68a

Initial

14aInitial

31a (L)

Initial

[30]

395plusmn19

38a

340

0plusmn60

050

to250120583

gkgh

Infusio

n10

333

aTerm

inal

41Term

inal

142

a

(L)

Term

inal

MedianEC

MOdu

ratio

nwas

70to

275ho

urs

404

a079

a300

0a200120583

gkg

Bolus

IV20

18aInitial

26a

Initial

14a

Initial

[31]

11990512fro

mtheo

nsetto

steady-sta

tewas

prolon

ged

5-fold

404

a079

a300

0a200120583

gkg

Bolus

IV20

na76

aTerm

inal

49a

Term

inal

Popu

lationph

armacokineticso

fmidazolam

inneon

ates

andchild

ren

NoteD

26to

420to

9700to

5200

NoteC

187

99a

12plusmn02

10plusmn02

[32]

NoteE

24to

312to

15523to

1400

100120583

gkg

Bolus

IV60

141a

0938a

115a

[33]

Age

ranged

from

2days

to17

years

mdashmdash

35to

6050

to40

0120583gkgh

Infusio

n18

55plusmn35

50plusmn39

17plusmn11

[34]

Adultsub

jects

Adults

mdashmdash

mdashmdash

mdash19plusmn06

66plusmn18

11plusmn06

[5]

Figuresa

rethem

eanplusmnSD

unlessotherw

isesta

tedIn

somec

asesresultsareg

iven

asar

angeF


hich

is49[6]

a meansta

ndarddeviationisno

tavailable

b medianGAgestatio

nalagePNA

postn

atalageBW

bod

yweight11990512120573

-phase

elim

ination

ClclearanceV

dapparent

volumeof

distr

ibution

nan


uslyP

Obymou

thN

oteAn

eonatesw

eresufferin

gfro

mcongenita

lheartd

isease(119899=4)up

pera

irway


eumon

ia(119899=2)po

stcardiac

surgery(119899=2)pu

lmon

aryhypertensio


midazolam

was

administered

viaacentralo

rperip

heralvenou

scatheterNoteC

midazolam

was

administered

intravenou

slyas

acon

tinuo

usinfusio

nto

109infantsas

abolus

dose

to22

infantsandas

acom

binatio

nof

both

to56

infantsTh

ebolus

dose

was

210plusmn239120583

gkgTh

econtinuo

usinfusio

nwas

69plusmn63120583gkg

perh

NoteDallneon

ates

received

midazolam

durin

gartifi

cialventilatio

nNoteE

neon

ates

undergoing


dyweight

lt15

00g













12is















12 Cl and




















12was 99 hours Cl


































12are











































2



4 Discussion


12of midazolam





12and the









12 The long 119905

12of midazolam




12
















14 Lkg and 11990512














12ofmidazolam It is




Acknowledgments


References




































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















ble1Dem

ograph

icdataof

patie

ntsa

ndph


fmidazolam

inneon

ates

andchild

ren

Com

ments

GA(w

eeks)

PNA(days)

BW(g)

Doseo

fmidazolam

Num

bero

finfants

11990512(hou

rs)

Cl(m

Lkgm

in)

Vd(Lkg)

Reference

Health

yneon

ates

Intravenou

sadm

inistratio

n26

to34

3to

11na

100120583

gkg

BolusIV

2463a

18a

11a

[26]

Critically

illneon

ates

andchild

ren

Oraladm

inistratio

nthe

values

arec

orrected

for

119865=49

26to

313to

1310

76plusmn240

100120583

gkg

BolusP

O15

76b

27b

14b

[6]

NoteA

2days

17years

mdash38to

245(kg)

90120583gkgh

Infusio

n21

na

014

aLkgh

(dise

ased)

028

aLkgh

(health

y)119875=00350

na[27]


ventilatio

nSomed

rugs

were

administered

33plusmn33

1to5

1900plusmn700

Infusio

n60120583gkgh

1512plusmn06

17plusmn18

12plusmn06

[28]

Respira

tory

distresssynd

rome

(119899=5)a

ndneon

atalinfection

(119899=5)

37plusmn23

2to

53150plusmn520

200120583

gkg

Bolus

IV10

65plusmn23

20plusmn12

09plusmn03

[29]

Neonatesu


embraneo

xygenatio

nrdquo(ECM

O)

NoteB

395plusmn19

38a

340

0plusmn60

050

to250120583

gkgh

Infusio

n10

68a

Initial

14aInitial

31a (L)

Initial

[30]

395plusmn19

38a

340

0plusmn60

050

to250120583

gkgh

Infusio

n10

333

aTerm

inal

41Term

inal

142

a

(L)

Term

inal

MedianEC

MOdu

ratio

nwas

70to

275ho

urs

404

a079

a300

0a200120583

gkg

Bolus

IV20

18aInitial

26a

Initial

14a

Initial

[31]

11990512fro

mtheo

nsetto

steady-sta

tewas

prolon

ged

5-fold

404

a079

a300

0a200120583

gkg

Bolus

IV20

na76

aTerm

inal

49a

Term

inal

Popu

lationph

armacokineticso

fmidazolam

inneon

ates

andchild

ren

NoteD

26to

420to

9700to

5200

NoteC

187

99a

12plusmn02

10plusmn02

[32]

NoteE

24to

312to

15523to

1400

100120583

gkg

Bolus

IV60

141a

0938a

115a

[33]

Age

ranged

from

2days

to17

years

mdashmdash

35to

6050

to40

0120583gkgh

Infusio

n18

55plusmn35

50plusmn39

17plusmn11

[34]

Adultsub

jects

Adults

mdashmdash

mdashmdash

mdash19plusmn06

66plusmn18

11plusmn06

[5]

Figuresa

rethem

eanplusmnSD

unlessotherw

isesta

tedIn

somec

asesresultsareg

iven

asar

angeF


hich

is49[6]

a meansta

ndarddeviationisno

tavailable

b medianGAgestatio

nalagePNA

postn

atalageBW

bod

yweight11990512120573

-phase

elim

ination

ClclearanceV

dapparent

volumeof

distr

ibution

nan


uslyP

Obymou

thN

oteAn

eonatesw

eresufferin

gfro

mcongenita

lheartd

isease(119899=4)up

pera

irway


eumon

ia(119899=2)po

stcardiac

surgery(119899=2)pu

lmon

aryhypertensio


midazolam

was

administered

viaacentralo

rperip

heralvenou

scatheterNoteC

midazolam

was

administered

intravenou

slyas

acon

tinuo

usinfusio

nto

109infantsas

abolus

dose

to22

infantsandas

acom

binatio

nof

both

to56

infantsTh

ebolus

dose

was

210plusmn239120583

gkgTh

econtinuo

usinfusio

nwas

69plusmn63120583gkg

perh

NoteDallneon

ates

received

midazolam

durin

gartifi

cialventilatio

nNoteE

neon

ates

undergoing


dyweight

lt15

00g













12is















12 Cl and




















12was 99 hours Cl


































12are











































2



4 Discussion


12of midazolam





12and the









12 The long 119905

12of midazolam




12
















14 Lkg and 11990512














12ofmidazolam It is




Acknowledgments


References




































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























12is















12 Cl and




















12was 99 hours Cl


































12are











































2



4 Discussion


12of midazolam





12and the









12 The long 119905

12of midazolam




12
















14 Lkg and 11990512














12ofmidazolam It is




Acknowledgments


References




































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

































12was 99 hours Cl


































12are











































2



4 Discussion


12of midazolam





12and the









12 The long 119905

12of midazolam




12
















14 Lkg and 11990512














12ofmidazolam It is




Acknowledgments


References




































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















12was 99 hours Cl


































12are











































2



4 Discussion


12of midazolam





12and the









12 The long 119905

12of midazolam




12
















14 Lkg and 11990512














12ofmidazolam It is




Acknowledgments


References




































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






































12are











































2



4 Discussion


12of midazolam





12and the









12 The long 119905

12of midazolam




12
















14 Lkg and 11990512














12ofmidazolam It is




Acknowledgments


References




































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






























12are











































2



4 Discussion


12of midazolam





12and the









12 The long 119905

12of midazolam




12
















14 Lkg and 11990512














12ofmidazolam It is




Acknowledgments


References




































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















12are











































2



4 Discussion


12of midazolam





12and the









12 The long 119905

12of midazolam




12
















14 Lkg and 11990512














12ofmidazolam It is




Acknowledgments


References




































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















































2



4 Discussion


12of midazolam





12and the









12 The long 119905

12of midazolam




12
















14 Lkg and 11990512














12ofmidazolam It is




Acknowledgments


References




































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of









































2



4 Discussion


12of midazolam





12and the









12 The long 119905

12of midazolam




12
















14 Lkg and 11990512














12ofmidazolam It is




Acknowledgments


References




































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of































2



4 Discussion


12of midazolam





12and the









12 The long 119905

12of midazolam




12
















14 Lkg and 11990512














12ofmidazolam It is




Acknowledgments


References




































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















2



4 Discussion


12of midazolam





12and the









12 The long 119905

12of midazolam




12
















14 Lkg and 11990512














12ofmidazolam It is




Acknowledgments


References




































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























14 Lkg and 11990512














12ofmidazolam It is




Acknowledgments


References




































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























12ofmidazolam It is




Acknowledgments


References




































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of












































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of












































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of












































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of









































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Documents

Review Article Clinical Pharmacology of Midazolam in ......Clinical Pharmacology of Midazolam in Neonates and Children: Effect of Disease A Review GianMariaPacifici Section of Pharmacology,