Table of Contents

Prophylactic Acetaminophen for Prevention of Intraventricular Hemorrhage in Premature Infants 2

Introduction: 2

Motivation: 3

Literature review: 4

Hypothesis: 8

Methods: 8

Data and Data Collection Instruments 9

Statistical analysis: 9

Outcomes: 9

References: 11

Appendix 1: Research Budget 17

Appendix 2: Research Time Schedule (2015) 18

ProphylacticAcetaminophen for Prevention of Intraventricular Hemorrhage inPremature InfantsIntroduction:

Intraventricularhemorrhage (IVH) is one of the most common devastated complicationsof prematurity and doubles up as the most common type of naonataintracranial hemorrhage. In particular, has been found to majorlyplague infants below 1.5kg. Moreover, the IVH rates usually exhibitan inverse relationship with an increase in the gestation period.Ordinarily, the incidence of severity resulting from IVH in infantsbelow 28weeks of gestation is double that of those between 28 and 31weeks(1).Intraventricular hemorrhage (IVH) is usually a major determinant ofthe disorder posthermorrhagic hydrocephalus and periventricularleukamolacia when it attacks infants. In order to tackle thiscondition, it is important that randomized clinical prevention isused to structure a neurodevelopment process to evaluate the impactof pharmacologic measures and premature birth on the developmentprocess of the brain. The IVH typically originates from theperiventricular germinal matrix. This section (germinal matrix) isusually situated in the underneath the ventricular ependyma and ischaracterized by glial and neuronal precursor tissues. Thevulnerability of infants to intraventricular hemorrhage in the first2 days of gestation lies in the periventricular region. In as much asthere have been major interventions towards eliminating thepathogenesis of intraventricular hemorrhage in the past few years,prevention of IVH is still a major problem. Two major factors thathave been identified as primarily contributing to IVH in childreninclude the fragility of germinal matrix vasculature and disturbanceof the cerebrospinal fluid(4).In this respect therefore, there is need to develop sophisticatedmedical techniques which enables stabilization of the cerebrospinalfluid without upsetting other mechanisms. This is a situation thatcalls for a delicate balance between restoring the CBF while at thesame time ensuring that paralytic agents and sedatives are not used(2-5).According to National Institute of Child Health and HumanDevelopment (NICHD) Neonatal Research Network, IVH is considered as amajor reason of morbidity and mortality of premature babies. Theetiology of IVH is multifaceted and itfundamentally contributes to IVH in neonate is the disruption ofblood flowing to the cerebrum,(6-12),inherentfragility of germinal matrix vasculature (2,13-18)platelet and coagulation disorder (2-5).The increase in rates of survival for the LBW infants in the past twodecades is attributable to the technological and therapeuticadvancements. However, questions have arose concerning the degree ofimpairment that characterizes the respective survivals courtesy ofthese techniques. Additionally, normalbirth, low Apgar score, severeRDS, pneumothorax, hypoxia,hypercapnia, seizures, patent ductus arteriosus, thrombocytopenia,and infection are situational variables that influence IVH(1-5).

Morethan 90% of IVH happen within three days of life of neonates over3600 new cases of mental retardation each year are children who wereborn premature and suffered IVH. In the treatment of intraventricularhemorrhage, the administration of steroids (antenatal) has been foundto increase chances of survival while decreasing the infection ratesof intraventricular hemorrhage, necrotinizing enterocolitis, reducingthe respiratory distress syndrome and petriventricular leukomalacia(19,20).&nbspOver50% of preterm survivors with IVH develop cerebral palsy, mentalretardation, and/or hydrocephalus (21,22).Approximately, a quarter of non-disabled survivors developpsychiatric disorders and complications in executive function(23-25).&nbsp

Therisk of severe IVH reduces as the gestational age increases and birthweight. Therefore, it occurs primarily in preterm infants belowthirty-two weeks of gestation (26-29).The decrease in incidence of IVH in the late 1980s to reach 20%(27).Theincidence of infantsweighing between 500 and 750g incidence is up to 45% (28).Therefore, IVH remains one of the biggest atrocities of neonatesworldwide, asincreased survival of extremely premature infants has led to moresurvivors with the disorder(30,31).

Astudy covering 2896 premature infants (&lt32 weeks gestation)exemplifies the relationship between gestational age and IVH, showingthat IVH rates decreased 3.5 percent with each added week ofgestation (32).However, IVH has been occasionally seen in near term and term infants(15,33-35).

Motivation:

IVHcan be divided into four grades based on extent of bleeding(36).Grades1 and 2manifest a lesser extent in bleeding, while (3 &amp 4)exhibit more severe bleeding. Clotting of blood can lead to ablockage that may inhibit the flow of cerebrospinal fluid. This canlead to increased fluid in the brain (hydrocephalus). Preterm birthswith sever IVH have exhibited a higher rate of mortality as comparedto the infants without IVH.(37).Hemorrhagichydrocephalus, mental retardation and cerebral palsy are most commonin infants with medium to severe IVH. On the other hand, immatureneonates with mild IVH are at risk of developmental IVH-relateddisorders. The developmental abilities, the correlation between theperinatal brain injury and other mild malfunctions in the motorperformance and the general cognitive ability of the low birth weightchildren has not been studied exhaustively. This is however necessarysince neonatal cranial ultrasound abnormalities in LBW children andtheir relationship with the functionality of the motor and influenceon cognitive ability (38,39).Thereis a likelihood of developing major cognitive malfunctions by over45% of premature infants graded as moderate through to those who areat the severity level most of whom need special education.(40).Contrary to a majority of study outcomes on IVH impact on cognitiveability, it has been espoused that neonates with perventricularhemorrhagic infarction exhibit better functional outcomes. However,the study espoused that a majority of survivors with periventricularhemorrhagic infarction experienced cerebral palsy accompanied byfewer functional impairments at a more advanced age (41).

Literaturereview:

Anumber of postnatal pharmacologic prevention techniques have beeninvestigated owing to the prevalence of intraventricular hemorrhageand the significant medical and societal impact of this disease, suchas indomethacin, ibuprofen, phenobarbitone, vitamin E, pavulon,ethamsylate and recombinant activated factor VIIa(42).

Ofthose, indomethacin and vitamin E have been used and effective asprophylaxis for IVH. Indomethacin is a non-selective COX inhibitorsacts through a general impairment of the constitutive and inducibleisoforms of cyclooxygenase (COX-1, and COX-2) respectively thatultimately reduce central and peripheral prostaglandin synthesis.Indomethacin prevents intraventricular hemorrhage both throughcentrally impacts on blood flow and on maturation of basementmembranewithout cause any serious lasting adverse effects.Indomethacin crosses the barrier of the blood brain in quantitiessufficient to inhibit the release of prostanoid into thecerebrospinal fluid in the brain. The intravenous administration ofindomethacine therefore is used to reduce blood flow to thecerebrospinal fluid and to attenuate the cerebral hyperemia ininfants. The mechanisms through which indomethacine decreases bloodflow and ultimately attenuate the cerebral hyperemia are found to befree of prostanoids. However, indomethacine does not affect theresponsiveness of the pial arteriolar to prostanoid-associatedstimuli. The phenomenon is attributed to the fact that theprostacyclin plays a vital role in the responses that involvevasogenic stimuli like histamisne and hypercapnia(43-45).Althoughit&nbspappearsto have some short-term benefits, it apparently fails to provide anylong-term benefits and results in significant severe effects. Theshort-term benefits associated with prophylactic indomethacinincluded a decrease in the rate of severe IVH andneed for surgical ligation of patent ductus arteriosus (PDA)comparedwith placebo (46).Therewas&nbspno&nbspdifferencein long-term outcome of death or severe neurosensory impairmentbetween the indomethacin and placebo groups proposing itsuse should be limited to achieving short-term benefits only.Additionally,it appears that there is no substantial distinction in the risk ofany or severe IVH between early (before six hours of life) and lateprophylactic administration (47).VitaminE&nbspisa strong antioxidant and reduces the risk of IVH, especially severeIVH, but it increases the risk of sepsis, particularly when givenintravenously to preterm infants. Therefore, it is&nbspnot&nbsprecommendedfor routine use in prevention of IVH (48).

Phenobarbitalis considered as ineffective IVH prophylaxis. Postnataladministration of phenobarbital is crucial in the stabilization ofblood pressure and additionally provides protection from freeradicals. However, in the practice, administrationof phenobarbital does not appear to prevent IVH in premature infants.Results of randomized controlled studies have also found thatphenobarbitone may reduce the incidence of intraventricularhemorrhage (IVH) infants. Following this realization, it is proposedthat a reduction in the cerebral metabolic rate, a reduced release ofcatecholamine, free radical inactivation, reduced intracellular andextracellular oedema have been espoused as possible mechanisms tocheck the incidence of intraventricular hemorrhage especially wheneach mechanism is mediated by barbiturates(49).

Moreover,since the pathogenesis of intraventricular hemorrhage has been foundto be sophisticated, the proceeds realized through phenobarbitoneapparently involves various mechanisms. Examining for the incidencesof different species of hemorrhage in recipients of phenobarbital,studies have shown that among severe hemorrhage, germinal matrixhemorrhage and other types of hemorrhage, the levels of incidence arethe same. However, in as much as the incidence rates have beenobserved to be same across board, the risk probabilities of any formof hemorrhage increased in the recipients of phenobarbital than ininfants. Studies have even sought to investigate the underlyingjustification for the administration of postnatal phenobarbital topreventintraventricular hemorrhage in LBW infants and the resultsespouse that phenobarbital is particularly preferred for the reasonthat it works to smoothen the volatility of systemic blood pressurein preterm infants. The use of phenobarbital serves to reduce theincidence level of intracranial hemorrhage complete withphenylephrine. There are findings to the effect that the free radicalscavenging capacity that is typical of phenobarbital may provideadditional protection in the post hypoxia-ischemia(50-53).In a systematic review, postnatal administration of phenobarbitalnever reduced the rate ofintraventricular hemorrhage, severe IVH,neurologic impairment, ventricularenlargement, or death, and was leads to increased need for mechanicalventilation (54,55).Likephenobarbitalpostnatal intravenous ibuprofen is also ineffective as preventionstrategy of IVH in preterm babies. Intravenous ibuprofen is anon-selective COX inhibitor was tested in infant due to evidence innewborn animals that Intravenous ibuprofen augmented the cerebralblood flow autoregulation (56).A randomized trial of infants &lt28 weeks gestation was assigned toprophylactic administration of intravenous ibuprofenversus control. The results reported a decrease in the rate of severeintraventricular hemorrhage (23 to 11 percent), but did not showimproved survival in children treated with prophylactic ibuprofencompared with control patients. In addition, ibuprofen led to ahigher frequency of serious adverse events (including severehypoxemia, necrotizing enterocolitis, intestinal perforation,oliguria, pulmonary hypertension, and elevated serum creatinine level(57). The trial was prematurely terminated because of three incidences ofsevere pulmonary hypertension in the ibuprofen group. Anotherrandomized trial included 155 premature infants gestational age lessthan 28 weeks with documented IVH (grades II to IV) in 16 percent ofibuprofen-treated infants versus 13 percent of placebo-treatedinfants(58).The third trial is a controlled trial included 415 premature infants(gestational age &lt31 weeks) and were randomly assigned toprophylactic administration of ibuprofen or placebo (within six hoursof birth), administration of ibuprofen had no effect on the severityof IVH (8 to 9 percent in both groups(59).Inreviewing the efficacy of using ibuprofen in neonates, Aranda andThomas ascertained that in as much as ibuprofen has a similar effectto indomethacin as far as the closing of the patent ductus arteriosusis concerned, it was ineffective in the prevention of IVH (60).

Acetaminophen(also known as Paracetamol) acts by directly inhibiting the activityof prostaglandin synthase. There is a consensus amongst the vast bodyof literature in this discipline to the effect that Paracetamol doesindeed act at the segment of the enzyme and what is not immediatelyascertainable is the specific mechanism through which paracetamolfunctions. Further, studies have found that paracetamol does promoteductal constriction but this has been found to be particularly truein pregnant animals through there have been special cases reportedfor human beings(61).Incontrast to non-selective COX inhibitors (ibuprofenand indomethacin), thebasic preoccupation of acetaminophen is the inhibition ofcyclooxygenase (COX), with a domineering effect on COX-2 in centralnervous system (CNS). In addition, acetaminophenis thought to act on prostaglandin synthase at the peroxidase regionof the enzyme and lead to inhibit peroxidase (POX) (PGG2 to PGH2conversion, POX) as one of its mechanisms of action. Paracetamolinhibition is facilitated by a decreased local concentration ofhydroperoxides. Controlling for the intervening factors, theeffective management of pain ought to be based on a logicalinvestigation of pain followed by a cautious administration of themost appropriate treatment complete with subsequent re-evaluations.The administration of analgesics to patients need to take intoconsideration the stress, pain and agitation on one hand as well asthe bowel perisis, and withdrawal on the other hand(62,63).Themetabolism of arachidonic acid to prostaglandinH2isenabled by the inhibition of COX enzymes. Contrary to expectations,the use of the i.v. paracetamol does not result in the increase inliver enzymes during and after in neonates. However, it graduallyleads to a decrease in AST levels. In patients for whom i.v.paracetamol was administered for 3 days, AST levels were also foundto have fallen especially for preterm neonates. The essence of theseresults is that i.v paracetamol is properly tolerated in pretermneonate, concordant with reports in infants. The progressive decreasein AST levels when i.v. paracetamol is administered to pretermneonates probably manifests the functioning of i.v. paracetamol in a‘negative feedback mechanism’ to restore AST levels toequilibrium after the fluctuations occasioned by a traumatic birthprocess or non-hepatic cytolysis(62-65).Unlikeindomethacine, acetaminophen haslittle impact on peripheral sites and onlyvery weak peripheral PG related effects and exerts its main effectsthrough the central nervous system. Fetalpatency of the ductus together with it closure which automaticallyresults after birth is due to the balanced interaction betweenprostaglandins and the remotely produced mediators which booth seekto condition a stable internal balance. An enduring patency of theductus has been found to occur in about 60% of the low birth weight(LBW) preterm neonates. The cyclooxygenase inhibitors play a vitalsupplementing role by inducing the closure of the ductus, as theprostaglandins are significant in the patency of the ductus. Thereare a few studies that have however endeavored to investigate themechanisms of through which paracetamol work when administered topreterm neonates. To this end, it has been established thatparacetamol produces an analgestic impact when administered which ismediated through the activation of descending serotonergic pathways.The exact site of action of paracetamol is the prostaglandininhibition or through active metabolism affecting the cannabinoidreceptors. Concentrations of paracetamol in the cerebrospinal fluid(CBF) reflects pain and fever to a greater degree than concentrationsof paracetamol in plasma.Co-administration of paracetamol withtropisetron or granisetron (5-HT3 receptor antagonists)(62, 66, 67).

Recentstudies have shown acetaminophen is as efficient as indomethacine andibuprofen in treatment the significant PDA and manifested low risk ofhyperbilirubinemia and gastrointestinal bleeding. These comparisonsassessing the functionality of paracetamol and ibuprofen havedemonstrated that paracetamol is indeed not inferior to ibuprofen asfar as the duct closure is concerned. Moreover, the incidence ofhyperbiliribinemia or gastrointestinal bleeding as observed inpatients to whom paracetamol was administered was much lower relativeto the incidences in the patients treated for ibuprofen. The essenceof these outcomes is that paracetamol is as much acceptable as afirst-line drug in the treatment of PDA in preterm infants. Comparedto other analgesics and sedatives, the hemodynamic changes typical ofi.v. paracetamol are only reduced but not completely eliminated. Therefore, hemodynamic of i.v. paracetamol is markedly distinct inneonates(68, 69).Therefore, acetaminophen can be used as a reliable medication forsignificant PDA treatment in neonates.

Hypothesis:

Ourhypothesis is thatacetaminophen can be alternative to indomethacin as prophylacticagainst IVH in neonate. Adrug like IV acetaminophen, if successful, would not only eliminatethe adverse effects of indomethacin but can also offer a cheaper andbetter alternative. Thishypothesis came from the effect of acetaminophen in inhibition theprostaglandin synthesis by inhibition of COX enzymes in CNS andconsequently regulate the cerebral blood flow and at the same timeacetaminophen’s positive effect on PDA closure and avoid thepotential side effects that is associated with non-selectivecyclooxygenase inhibitors.

Methods:

Studydesign:National randomized control double blind trial, single center study.

The studywill be conducted in King Saud Medical City, Pediatric Hospital, andNeonatal Intensive Care Unit

The studywill include neonates with a gestational age less than 30 weeks and abirth weight of less than 1250 g will randomly assigned to

GroupA: will received Paracetamol (Perfalgan© Bristol-Meyers Squibb)Intravenous 15mg/kg every 6 h for 3 days.

GroupB: will receive indomethacin 0.2 mg /kg in the first day and 0.1mg/kg in 24hr and 48hr after the first dose. Echocardiography andhead ultrasound will be done in the first 12 hours of age beforestarting paracetamol or indomethacin. Echocardiography and headultrasound will be repeated at the end of the course and at day7 andday 14 of life

Exclusioncriteria: major congenital anomalies, congenital heart disease,intraventricular hemorrhage II-IV, life-threatening infectionhyperbilirubinemia needs exchange transfusion, urine output less than1 ml/kg/hr during the preceding 8 hr, creatinine higher than 100mmol/l, platelet count less than 50 ×10³, necrotizingenterocolitis, liver dysfunction. We will collect, in a specificreporting form, data regarding GA, sex, mode of delivery, birthweight (BW), Apgar score at 5 minutes, weight at enrollment, age atenrollment, contraindication to COXinhibitor use (ibuprofen andindomethacin)and Maternal data.

Cranialultrasound will be performed at 3rdday of life as routine procedure,

Echocardiographicexamination will be performed by the pediatric cardiologist after 3days for assessment of hsPDA.

Safetyof paracetamol treatment, serum concentration of liver enzymes (theserum level of aspartate transaminase, total and direct bilirubin)creatinine and urea nitrogen will be monitored in daily base.

Dataand Data Collection Instruments

Thisstudy utilized both secondary and primary time series data. For somevariables, panel data was obtained and incorporated together with thepooled time series data. The data, which is 95% primary data wascollected using structured questionnaires in a field survey conductedby experts who were assisted by the hotel administration. As for thesecondary data, content analysis, which was done by qualifiedresearchers, was used to obtain data from secondary sources andsubsequently perform a cross-tabulation of the aggregated results.This method of scrutinizing and analyzing secondary data was usedsince it is a robust method in circumstances that involve analysis offigures and interpretation of tabulated outcomes. Moreover, thissecondary sources review technique has always been found to providean in depth analysis and refinement of already existing data.

Statisticalanalysis:

Patientattributes will be presented as measures of statistical dispersions(IQR: interquartile range) in case of non-normally distributedobservations and as means (standard deviations) in case of normallydistributed observations. Fisher exact tests will be used in case ofdummy variables. Data analyses were performed with SPSS version 21.0(SPSS Inc.). A p value of 0.05 set as a level of ascertainingstatistical significance of variables.

Outcomes:

Primaryoutcome:To test the hypothesis that administration of acetaminophenprophylaxis within 12 hours of life results in a lower incidence ofintraventricular hemorrhage (IVH) comparing with administration ofindomethacin within 12 hours of life.

Secondaryoutcome:To test the effect of acetaminophen on the incidence of significantpatent ductus arteriosus, neonatal sepsis, necrotizing enterocolitis,bronchopulmonary dysplasia, length of stay at the hospital,retinopathy of prematurity.

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Appendix 1:Research Budget

Serial

Item

Amount ($)

Total ($)

1.

Researchers

{Expenses for contracted local research assistants and expert team leaders}

Ksh. 2100 for 100 interviews

210000

Project administrators, technical assistants for data coding, entry and analysis using big data machines.

154000

Tuition waiver and benefits

62500

Total Expenses of Research Assistants

426500

2.

Direct Expenses

{Review of transcriptions}

100 interviews @ Ksh. 60/ interview.

60000

60000

3.

Transport and travel expenses

Ksh 300 for 100 interviews

30000

30000

4.

Miscellaneous Expenses

Ksh 500 for 100 interviews

50000

50000

Total Expenses

512000

Overhead @ 12%

(61440)

Appendix 2:Research Time Schedule (2015)

Period

Research Activity

Week One

  • Deciding on a topic of study and reviewing it for feasibility. Preliminary literature review.

Week 2 &amp 3

  • Selecting literature for review.

  • Conducting Literature review and formulating the hypothesis for the study.

Week 4, 5 &amp 6.

  • Coming up with a sampling design.

  • Conducting a field reconnaissance to familiarize with the area.

  • Identifying target respondents.

  • Conducting a preliminary survey to test data collection tools.

  • Improving on the mistakes identified

Week 7 &amp 8

  • Actual collection of data: Distribution of questionnaires and interviews are conducted to their conclusion.

Week 9 &amp 10

  • Coding of data

  • Data Entry

  • Data Analysis

Week 11, 12 &amp 13.

  • Further analysis

  • Discussion of results and review

  • Presentation of findings

  • Dissemination of research findings.