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. 2017 Jun 27;2017(6):CD012706. doi: 10.1002/14651858.CD012706

Pharmacological pain and sedation interventions for the prevention of intraventricular hemorrhage in preterm infants on assisted ventilation ‐ an overview of systematic reviews

Olga Romantsik 1, Matteo Bruschettini 1,2,✉, Maria Grazia Calevo 3, Rita Banzi 4, David Ley 1
PMCID: PMC6481855

Abstract

This is a protocol for a Cochrane Review (Overview). The objectives are as follows:

To summarize the evidence from systematic reviews regarding the effects and safety of pharmacological interventions related to pain and sedation management in order to prevent GMH‐IVH in ventilated preterm infants.

Background

Description of the condition

Prematurity remains the major risk factor for developing germinal matrix‐intraventricular hemorrhage (GMH‐IVH), which occurs in 25% of very low birth weight (VLBW) infants (Vermont Oxford Network 2013). Complications of germinal matrix‐intraventricular hemorrhage, including periventricular hemorrhagic infarction (PVHI), posthemorrhagic ventricular dilatation (PHVD), cerebellar hemorrhagic injury (CHI) and periventricular leukomalacia (PVL) are critical determinants of neonatal morbidity, mortality, and long‐term neurodevelopmental sequelae (Sherlock 2005). Although modern perinatal medicine has led to a significant decrease in the overall incidence of GMH‐IVH in preterm infants (from 50% in the late 1970s to the current 15% to 25% (Hamrick 2004; Horbar 2002; Philip 1989)), GMH‐IVH continues to be a significant problem in the modern neonatal intensive care unit. Advances in neonatal‐perinatal medicine have led to a higher incidence of preterm births and a major increase in the survival of preterm infants, reaching as high as 85% to 90% (EXPRESS 2009; Ishii 2013). In addition, the incidence of birth and survival of the smallest preterm infants who are at the highest risk for developing GMH‐IVH and its complications has increased during the last decade. Specifically, the incidence of GMH‐IVH reaches 45% in infants with birth weights less than 750 grams, and 35% of these lesions are severe (Wilson‐Costello 2005). It has been suggested that the encouraging decrease in the overall incidence of GMH‐IVH may have reached a plateau during the last decade (Horbar 2002; Horbar 2012).

These trends may lead to the survival of more critically ill infants and as a consequence increase the rate of neurodevelopmental problems caused both by extreme prematurity and GMH‐IVH. Approximately 50% to 75% of preterm survivors with IVH (any grade) develop cerebral palsy, mental retardation, PHVD, or a combination of these conditions, with serious sequelae on neurodevelopmental outcome (Luu 2009). Moreover, around a quarter of non‐disabled survivors develop psychiatric disorders and problems with executive function (Indredavik 2010; Nosarti 2007; Whitaker 2011). Hence, GMH‐IVH and its resultant neurologic and psychiatric sequelae continues to be an important public health concern worldwide. GMH‐IVH in preterm infants is typically diagnosed during the first days of life, 50% on the first day and 90% within the first four days. Between 20% and 40% of these infants undergo progression of hemorrhage during these first days of life (Volpe 2008). The incidence of antenatal IVH is unclear, although an estimate for intracranial bleeding of 1 in 10,000 pregnancies has been suggested (Vergani 1996). Antenatal fetal intracranial hemorrhages may occur spontaneously or in association with various maternal or fetal conditions. Predisposing maternal conditions include platelet and coagulation disorders, medications (warfarin), illicit drugs (cocaine), seizure, smoking, trauma, amniocentesis, and febrile disease; fetal conditions include twin–twin transfusion, demise of a co‐twin, hydrops fetalis, congenital tumors, and feto‐maternal hemorrhage (Kutuk 2014). IVH may undergo spontaneous resolution or, especially for grade 3 and 4, may cause the development of PHVD.

Furthermore, both low‐ and high‐grade GMH‐IVH may affect cerebellar growth, resulting in reduced cerebellum volumes and impaired white matter and motor tract microstructure (Morita 2015; Sancak 2016;Sancak 2017;Srinivasan 2006;Tam 2009;Tam 2011). The cerebellum is the fastest growing portion of the brain, its volume increasing fivefold from 24 to 40 weeks of postmenstrual age (Volpe 2009). During this period, extravasation of hemoglobin due to GMH‐IVH into cerebrospinal fluid (CSF) and further hemolysis of free hemoglobin may result in deposition of hemosiderin on the cerebellar surface, disturbing the normal development of the cerebellar cortex (Fukumizu 1995; Koeppen 2008;Messerschmidt 2005). It is well recognized that the cerebellum plays a crucial role not only in motor function but also in many higher‐order cognitive and affective functions, such as executive functions, working memory and emotional processing (van Overwalle 2014; Volpe 2009). Thus, preventing GMH‐IVH would also help to preserve cerebellum integrity.

The etiology of GMH‐IVH is multifactorial, complex, and heterogeneous. An inherent fragility of the germinal matrix vasculature predisposes for hemorrhage, and fluctuation in the cerebral blood flow induces the rupture of vasculature. The association between cerebral blood flow (CBF) fluctuations and IVH appearance in ventilated neonates with RDS in the first day of life was suggested by Perlman and colleagues (Perlman 1983). In a subsequent study of the same group it has been shown that the elimination of CBF fluctuation by neuromuscular paralysis (pancuronium) resulted in reduction of IVH (Perlman 1985). The question remained as to whether the fluctuations in CBF were due to breathing against the respirator, which could be explained by increased pleural pressure fluctuations. Two studies confirmed that CBF fluctuations were related to RDS extent and pleural pressure fluctuations and that those could be damped by mechanical ventilation (Mullaart 1994; Perlman 1988). To date, it has been suggested that loss of cerebral autoregulation, which is important to maintain constant CBF, may predispose preterm infants to hemorrhagic and ischemic cerebral injury (Boylan 2000; Tsuji 1998). However, the subsequent studies on impaired autoregulation were not predictive of the subsequent development of IVH; nevertheless it was correlated to higher mortality (Soul 2007; Wong 2008). Vaginal delivery, low Apgar score, severe respiratory distress syndrome, pneumothorax, hypoxia, hypercapnia, seizures, patent ductus arteriosus, infection, and other conditions seem to increase primarily the fluctuations in the cerebral blood flow and thus represent important risk factors to the development of IVH (Ballabh 2014). If there are associated platelet or coagulation disorders, the homeostasis mechanisms are impaired, which might accentuate the hemorrhage. Furthermore, the germinal matrix lies within an arterial end zone, and it is directly connected to the deep galenic venous system (Nakamura 1990; Pape 1979), thereby exposing it to insults of arterial ischemia‐reperfusion and to venous congestion (Pape 1979; Takashima 1978). The immature deep galenic system is prone to venous congestion and stasis, making it of potentially major importance for the development of GMH‐IVH and its complications (Pape 1979; Volpe 2008).

Besides the interventions aimed at possibly halting GMH‐IVH progression and reducing its complications, several preventive approaches to GMH‐IVH were proposed which include antenatal and postnatal measures. Several antenatal pharmacologic interventions have been proposed. Antenatal corticosteroids are currently the only modality repeatedly shown in several studies to be associated with a reduction in the incidence of GMH‐IVH and overall reduction in mortality rates (Roberts 2006). Another appealing antenatal treatment is magnesium sulfate, commonly used for tocolysis but also with vascular stabilizing, anti‐inflammatory, and neuroprotective properties. Some authors have suggested a reduction in the incidence of GMH‐IVH following maternal administration of magnesium sulfate (Di Renzo 2005); however, most data do not show any benefit on the incidence of GMH‐IVH per se. Other antenatal therapeutics, such as phenobarbital and vitamin K, seemed not to be beneficial for the prevention of GMH‐IVH (Whitelaw 2001).

Because GMH‐IVH is strongly associated with both intrinsic and extrinsic hemodynamic effectors, optimal ventilation and strict hemodynamic control of the preterm infant are among the cornerstones of preventing GMH‐IVH and its progression. The postnatal GMH‐IVH preventive measures will be analyzed in this overview.

Description of the interventions

Neonatal pain has been poorly understood and often unrecognized until the 1980s, when research describing the developmental physiology of nociception and adverse responses of neonates to noxious stimuli emerged (Anand 1987a; Anand 1987b). Despite early maturation of the ascending neural pathways responsible for nociception, the descending inhibitory pathways, which localize and mitigate pain, do not form until later in maturation (Fitzgerald 1986). Moreover, normal brain development is abruptly interrupted by preterm birth, which results in a unique susceptibility to neurologic remodeling after repetitive noxious stimuli (Taddio 2009). Despite the growing knowledge about long‐term consequences of neonatal pain and discomfort, the consensus regarding a safe and effective strategy for controlling these complications in many routine clinical situations is still missing. Non‐pharmacological therapies, including non‐nutritive sucking and swaddling, form the foundation of neonatal pain and agitation relief, but they are unlikely to be adequate alone to provide comfort for moderate to intense pain (Brummelte 2012; Golianu 2007).

The most common indication for sedation is distress during mechanical ventilation. In this setting sedation may be needed to alleviate stress and facilitate mechanical ventilation (Quinn 1993), thus preventing some of its complications, such as pneumothorax and IVH (Greenough 1983; Perlman 1985).

How the intervention might work

Multiple pharmacological interventions might help to prevent the occurrence of IVH, the onset of which is typically in the first days of life. A reduction in IVH could be achieved through both direct and indirect mechanisms, such as by avoiding the pain, stress and discomfort caused by multiple manual procedures and mechanical ventilation.

Benzodiazepines

Benzodiazepines are used to provide sedation in several clinical settings. Midazolam is the benzodiazepine of choice in the neonatal intensive care unit (NICU). Midazolam is a short‐acting benzodiazepine that is very lipophilic in physiological pH, which contributes to its rapid onset of action. It is two to three times more potent than diazepam due to its increased affinity for benzodiazepine receptors and is preferred to other benzodiazepines because of its water solubility and rapid clearance (Jacqz‐Aigrain 1994). The effect of midazolam on appearance of IVH was studied in preterm infants undergoing mechanical ventilation (Anand 1999; Jacqz‐Aigrain 1994).

Opioids

Opioids act through opioid receptors which are found in the central and peripheral nervous system and the gastrointestinal tract. Morphine and fentanyl are the most commonly used opioids in the NICU. Recommendations have been issued to promote a more aggressive approach to treatment and prevention of pain in the neonate (AAP 2000). However, uncertainty on long‐term effects of opioid treatment remains. Several studies reported occurrence of IVH during opioid sedation. Small studies conducted before 2000 observed no change on IVH occurrence between opioid group infants compared to control group infants (Anand 1999; Dyke 1995; Orsini 1996; Quinn 1993); while a larger randomized control trial (RCT) published in 2003 demonstrated a reduction of IVH rate in the morphine group (Simons 2003).

Anesthetic drugs

Propofol is a short‐acting anaesthetic agent and its clinical effect lasts for only a few minutes. It acts both through potentiation of gamma‐aminobutyric acid‐A (GABA‐A) receptor activity, thereby slowing the channel‐closing time (Krasowski 2001); and also by acting as a sodium channel blocker (Haeseler 2008). The distribution of propofol in neonates is notably different from its distribution in children and adults (Allegaert 2007); and its clearance is slower in cardiopathic and preterm neonates, thus the accumulation risk is increased (Rigby‐Jones 2002). Based on the experience in the pediatric population, propofol has been used in neonates and proved to be especially effective in neonates with oropharyngeal complications (Golden 2001). However, serious side effects associated with propofol use have been reported (Welzing 2010). Data on propofol influence on IVH rate are not available.

Barbiturates

Phenobarbital is a long‐acting barbiturate and one of the most commonly used to treat neonatal seizures (Booth 2004). It acts through GABA‐A receptors in the central nervous system. It is thought that phenobarbital could act by stabilizing blood pressure, thereby reducing cerebral flow fluctuation (Wimberley 1982). The evidence from animal experimental data showed that barbiturates could be protective against hypoxic/ischemic damage (Steen 1979); and it could act as a free radical scavenger after cerebral hypoxic/ischemic injury (Ment 1985). However, phenobarbital might be detrimental to preterm infants by causing respiratory depression, cardiac depression and hypotension.

Alpha‐2 agonists

Alpha‐2 agonists (e.g. clonidine and dexmedetomidine) are used as adjunctive (or alternative) sedative agents alongside opioids and benzodiazepines. They have a wide range of effects, including sedation, analgesia and relief of anxiety (Mantz 2011; Pichot 2012). These effects are mediated through alpha‐2 adrenergic receptor subtypes, located in the locus ceruleus. Both clonidine and dexmedetomidine reduce the activity of neurons in the locus ceruleus without affecting the respiratory drive (Hoy 2011). Moreover, it has been suggested that alpha‐2 agonists might have neuroprotective function (Laudenbach 2002; Paris 2006) and anti‐inflammatory action (Mantz 2011). The adverse events of alpha‐2 agonists, such as bradycardia and hypotension, are mediated via the alpha‐2 adrenoreceptors in the medullary dorsal motor nucleus and motor complex and thus they are independent of sedative effect (Gregoretti 2009; Pichot 2012). A randomized placebo‐controlled trial in ventilated term newborns showed that continuous infusion of clonidine decreased fentanyl and midazolam demand, with deeper levels of analgesia and sedation without substantial side effects (Hünseler 2014).

Why it is important to do this overview

There are now numerous intervention reviews available for the prevention of GMH‐IVH in preterm infants. The totality of evidence from RCTs of postnatal pharmacological interventions for pain and sedation management has never been assembled before in a systematic and comprehensive way. An 'overview of reviews' will provide a clinically meaningful summary of one of the most important topics in neonatology. The overview provides a coherent and up‐to‐date summary of the totality of evidence, without the need to access many individual systematic reviews. This may help clinicians, policy makers, childbirth educators and consumers.

Objectives

To summarize the evidence from systematic reviews regarding the effects and safety of pharmacological interventions related to pain and sedation management in order to prevent GMH‐IVH in ventilated preterm infants.

Methods

Criteria for considering reviews for inclusion

Types of studies

We will include any published Cochrane Review on postnatal pharmacological interventions for pain and sedation management in ventilated preterm infants. Cochrane Review protocols and titles will be identified for future inclusion.

Types of participants

This overview will include reviews on preterm infants less than 37 weeks of gestational age on assisted ventilation. As incidence of IVH dramatically decreases with advancing gestational age, we plan to perform a subgroup analysis for both extreme and very preterm infants.

Types of interventions and comparison

This overview will assess the following categories of interventions: benzodiazepines, opioids, anaesthetics, barbiturates, antiadrenergics (Description of the interventions). We will exclude other comfort measures and non‐pharmacological interventions, e.g. sucrose.

Interventions must be started within the first week of life as IVH commonly occurs in this period. Although causes of IVH might originate before birth (Kutuk 2014), we will exclude reviews on antenatal interventions.

This is an overview of systematic reviews and not a review of primary studies: due to the large number of possible comparisons among these interventions, we do not plan to specify in advance the comparisons to be included. We expect to retrieve reviews comparing the above mentioned interventions to:

  • placebo;

  • no treatment;

  • other interventions.

Types of outcome measures

As the objective of this overview is the prevention of GMH‐IVH, we will consider only reviews that include GMH‐IVH among their outcomes.

Primary outcomes

  1. Any intraventricular hemorrhage: Any IVH, ultrasound diagnosis grade 1 to 4 (according to Papile classification (Papile 1978)).

  2. Severe intraventricular hemorrhage (IVH), ultrasound diagnosis grade 3 and 4 (according to Papile classification (Papile 1978)).

  3. All‐cause neonatal death (death within 28 days of birth).

Secondary outcomes

  1. All‐cause death during initial hospitalization.

  2. Any retinopathy of prematurity: any stage (ICROP 1984).

  3. Severe retinopathy of prematurity: stage 3 or greater (ICROP 1984).

  4. Cerebellar hemorrhage at brain ultrasound in the first month of life (yes/no, Graça 2013).

  5. Cystic periventricular leukomalacia at brain ultrasound in the first month of life (yes/no); or at term equivalent age (yes/no).

  6. Brain magnetic resonance imaging (MRI) abnormalities at term equivalent age (yes/no), defined as white matter lesions (i.e. cavitations; Rutherford 2010) and punctate lesions (Cornette 2002); GM‐IVH (Parodi 2015); or cerebellar hemorrhage (Limperopoulos 2007).

  7. Major neurodevelopmental disability: cerebral palsy, developmental delay (Bayley Mental Developmental Index (Bayley 1993; Bayley 2006) or Griffiths Mental Development Scale assessment (Griffiths 1954) more than two SD below the mean), intellectual impairment (IQ more than two standard deviations below mean), blindness (vision < 6/60 in both eyes), or sensorineural deafness requiring amplification (Jacobs 2013). We plan to evaluate each of these components as a separate outcome and to extract data on this long‐term outcome from studies that evaluated children after 18 months of chronological age. Data on children aged 18 to 24 months and those aged three to five years are to be assessed separately.

Search methods for identification of reviews

The Information Specialist of Cochrane Neonatal will identify Cochrane Reviews on pain and sedation management in the Cochrane Library.

Data collection and analysis

The methodology for data collection and analysis is based on Chapter 22 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Selection of reviews

Reviews on postnatal pharmacological interventions for pain and sedation management in ventilated preterm infants will be checked for inclusion by two independent review authors. We will resolve any disagreement through discussion or, if required, we will consult a third author. As the objective of this overview is the prevention of GMH‐IVH, we will consider only reviews that include GMH‐IVH among their outcomes.

Data extraction and management

Two review authors will independently extract data from the reviews using a predefined data extraction form. We will resolve discrepancies through discussion or, if required, we will consult a third author.

We will extract the following key information from each review.

  • Objective or clinical research question.

  • Date that the review was assessed as up to date.

  • Number of included trials.

  • Number and characteristics of participants (sex, gestational age).

  • Interventions and comparisons.

  • Outcome measures.

  • Effect measurements for variables such as IVH occurrence and severity, death, and other secondary outcomes (risk ratio (RR) with the 95% confidence interval (CI); number of studies; number of participants reporting on each outcome).

  • Overall judgment on the certainty of evidence included (GRADE table).

  • Strength and limitations of the review.

We plan to retrieve this information from the reports of the included reviews. However, it is likely that some details needed for this overview are only available from the original primary studies (e.g. gestational age, IVH in different sub‐populations). In these cases, we will analyze the reports of the studies included in each review and present the adapted forest plot in the overview.

We will enter data into Review Manager 5 software and check for accuracy (Review Manager 2014). If the information is unobtainable from the published reports, then we will contact the review authors or authors of the original reports to provide clarification and further details.

Assessment of methodological quality of included reviews

Quality of included reviews

Two review authors will independently assess the methodological quality of the included reviews using the AMSTAR measurement tool (Shea 2007). This instrument has good inter‐rater agreement, test‐retest reliability, and face and construct validity (Shea 2009). Specifically, we will address the following questions.

  1. Was an 'a priori' design provided?

  2. Was there duplicate study selection and data extraction?

  3. Was a comprehensive literature search performed?

  4. Was the status of publication (i.e. grey literature) used as an inclusion criterion?

  5. Was a list of studies (included and excluded) provided?

  6. Were the characteristics of the included studies provided?

  7. Was the scientific quality of the included studies assessed and documented?

  8. Was the scientific quality of the included studies used appropriately in formulating conclusions?

  9. Were the methods used to combine the findings of studies appropriate?

  10. Was the likelihood of publication bias assessed?

  11. Was conflict of interest stated?

Possible responses to each question are 'yes' (item/question fully addressed), 'no' (item/question not addressed), 'cannot answer' (not enough information to answer the question), and 'not applicable'. We will provide rationale for judgments for each AMSTAR item and will report a summary score.

Because some of the authors of this overview (OR, MB, MGC) are also the authors of one of the reviews that might be included, quality assessments will be conducted by RB and DL.

Quality of the body of evidence in included reviews

'Summary of findings' tables will be created for the three primary outcomes. The quality of the evidence of the effects of intervention for pain and sedation on IVH and mortality will be assessed using the GRADE approach (Guyatt 2011). When 'Summary of findings' tables are not available in the included reviews or do not completely match the PICO of this overview (e.g. different gestational age or definition of the outcomes), we will prepare them from scratch. When such tables are reported in the included reviews, we will 're‐grade' the quality of evidence of the three primary outcomes to ensure a homogeneous assessment. Potential discrepancies with the original reviews will be discussed in this overview. We will grade the quality of evidence considering the following criteria: study limitations (that is risk of bias), consistency of effect, imprecision, indirectness and publication bias.

Data synthesis

We will provide a narrative summary of the method and results of each of the included reviews and summarize this information using tables and figures (e.g. characteristics of included reviews, summary of quality of evidence within individual systematic reviews, AMSTAR evaluation for each systematic review).

For primary and secondary outcomes, we will report the effect estimates and 95% CIs as reported in the meta‐analyses conducted by the authors of the systematic reviews if available.

We will re‐format data in text, table and figures. A table on outcomes will show: comparison; number of subjects and studies; measure of effect with 95% CI; I²; certainty of evidence (GRADE).

We will not pool data deriving from different reviews in meta‐analyses, as we expect substantial heterogeneity. We will not draw inferences about the comparative effectiveness of multiple interventions, i.e. avoid any ranking (which would require network meta‐analysis). However, we plan to classify the interventions that are effective for the prevention of IVH and the ones that are not, according to effect estimates and 95% CIs as reported in the meta‐analyses conducted by the authors of the systematic reviews. However, if some details needed for this overview are only available from the original primary studies (e.g. gestational age, IVH in different sub‐populations), we will analyze the reports of the studies included in each review to re‐calculate effect estimates and 95% CIs (fixed‐effect model). Whenever feasible, data on primary outcomes will be summarized in 'Summary of findings' tables as described in the Cochrane Handbook for Systematic Reviews of Interventions, Chapter 11 (Higgins 2011). Tables based on each comparison will be constructed using the GRADE profiler (GRADEpro; http://tech.cochrane.org/revman/gradepro). For future updates of this overview, if the data allow we may perform some indirect comparisons of interventions across reviews for the primary outcomes.

We plan, if possible, to present data from the following subgroups (if these data are available within the included systematic reviews).

  1. Gestational age, with three subgroups: extreme preterm (< 28 weeks) vs very preterm (≥ 28 but < 32 weeks) vs preterm infants ≥ 32 but < 37 weeks.

  2. Birth weight, with three subgroups: very low birth weight (less than 1500 grams) versus low birth weight (≥ 1500 grams but < 2500 grams) versus ≥ to 2500 grams.

  3. Timing of initiation of intervention, with three subgroups: < 12 hours vs < 72 hours versus ≥ 72 hours of life but within 7 days of life.

Acknowledgements

We thank Yolanda Brosseau and Colleen Ovelman for editorial support, Roger Soll for substantial assistance in scoping and designing the protocol.

Contributions of authors

OR, MB, RS conceptualized this overview. OR, MB, MGC, RB, and DL drafted the protocol.

All the authors reviewed the protocol and approved its final version.

Sources of support

Internal sources

  • Institute for Clinical Sciences, Lund University, Lund, Sweden.

    OR, MB and DL are employed by this organization

  • Istituto Giannina Gaslini, Genoa, Italy.

    MGC is employed by this organization

External sources

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, USA.

    Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201600005C

Declarations of interest

OR, MB, MGC, RB, and DL declare to have no known conflicts of interest.

New

References

Additional references

  1. American Academy of Pediatrics. Prevention and management of pain and stress in the neonate. American Academy of Pediatrics. Committee on Fetus and Newborn. Committee on Drugs. Section on Anesthesiology. Section on Surgery. Canadian Paediatric Society. Fetus and Newborn Committee. Pediatrics 2000;105(2):454‐61. [PubMed] [Google Scholar]
  2. Allegaert K, Peeters MY, Verbesselt R, Tibboel D, Naulaers G, Hoon JN, et al. Inter‐individual variability in propofol pharmacokinetics in preterm and term neonates. British Journal of Anaesthesia 2007;99(6):864‐70. [DOI] [PubMed] [Google Scholar]
  3. Anand KJ, Hickey PR. Pain and its effects in the human neonate and fetus. New England Journal of Medicine 1987;371(21):1321‐9. [DOI: 10.1056/NEJM198711193172105; PUBMED: 3317037 ] [DOI] [PubMed] [Google Scholar]
  4. Anand KJ, Sippell WG, Aynsley‐Green A. Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response. Lancet 1987;329(8527):243‐8. [PUBMED: 2879174 ] [DOI] [PubMed] [Google Scholar]
  5. Anand KJ, Barton BA, McIntosh N, Lagercrantz H, Pelausa E, Young TE, et al. Analgesia and sedation in preterm neonates who require ventilatory support: results from the NOPAIN trial. Neonatal Outcome and Prolonged Analgesia in Neonates. Archives of Pediatrics & Adolescent Medicine 1999;153(4):331‐8. [DOI] [PubMed] [Google Scholar]
  6. Ballabh P. Pathogenesis and prevention of intraventricular hemorrhage. Clinics in Perinatology 2014;41(1):47‐67. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bayley N. Bayley Scales of Infant Development. 2nd Edition. San Antonio, TX: The Psychological Corporation, 1993. [Google Scholar]
  8. Bayley N. Bayley Scales of Infant and Toddler Development. San Antonio, Texas: Harcourt Assessment, 2006. [Google Scholar]
  9. Booth D, Evans DJ. Anticonvulsants for neonates with seizures. Cochrane Database of Systematic Reviews 2004, Issue 4. [DOI: 10.1002/14651858.CD004218.pub2] [DOI] [PubMed] [Google Scholar]
  10. Boylan GB, Young K, Panerai RB, Rennie JM, Evans DH. Dynamic cerebral autoregulation in sick newborn infants. Pediatric Research 2000;48(1):12‐7. [PUBMED: 10879794] [DOI] [PubMed] [Google Scholar]
  11. Brummelte S, Grunau RE, Chau V, Poskitt KJ, Brant R, Vinall J, et al. Procedural pain and brain development in premature newborns. Annals of Neurology 2012;71(3):385‐96. [PUBMED: 22374882] [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cornette LG, Tanner SF, Ramenghi LA, Miall LS, Childs AM, Arthur RJ, et al. Magnetic resonance imaging of the infant brain: anatomical characteristics and clinical significance of punctate lesions. Archives of Disease in Childhood. Fetal and Neonatal Edition 2002;86(3):F171‐7. [PUBMED: 11978747] [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Renzo GC, Mignosa M, Gerli S, Burnelli L, Luzi G, Clerici G, et al. The combined maternal administration of magnesium sulfate and aminophylline reduces intraventricular hemorrhage in very preterm neonates. American Journal of Obstetrics and Gynecology 2005;192(2):433‐8. [DOI] [PubMed] [Google Scholar]
  14. Dyke MP, Kohan R, Evans S. Morphine increases synchronous ventilation in preterm infants. Journal of Paediatrics and Child Health 1995;31(3):176‐9. [DOI] [PubMed] [Google Scholar]
  15. Fellman V, Hellström‐Westas L, Norman M, Westgren M, Källén K, Lagercrantz H, et al. EXPRESS Group. One‐year survival of extremely preterm infants after active perinatal care in Sweden. JAMA 2009;301(21):2225‐33. [DOI] [PubMed] [Google Scholar]
  16. Fitzgerald M, Koltzenburg M. The functional development of descending inhibitory pathways in the dorsolateral funiculus of the newborn rat spinal cord. Brain Research 1986;389(1‐2):261‐70. [PUBMED: 3948011 ] [DOI] [PubMed] [Google Scholar]
  17. Fukumizu M, Takashima S, Becker LE. Neonatal posthemorrhagic hydrocephalus: neuropathologic and immunohistochemical studies. Pediatric Neurology 1995;13(3):230–4. [DOI] [PubMed] [Google Scholar]
  18. Golden S. Combination propofol‐ketamine anaesthesia in sick neonates. Pediatric Anesthesia 2001;11(1):119‐22. [DOI] [PubMed] [Google Scholar]
  19. Golianu B, Krane E, Seybold J, Almgren C, Anand KJ. Non‐pharmacological techniques for pain management in neonates. Seminars in Perinatology 2007;31(5):318‐22. [DOI: 10.1053/j.semperi.2007.07.007; PUBMED: 17905187 ] [DOI] [PubMed] [Google Scholar]
  20. Graça AM, Geraldo AF, Cardoso K, Cowan FM. Preterm cerebellum at term age: ultrasound measurements are not different from infants born at term. Pediatric Research 2013;74(6):698‐704. [DOI] [PubMed] [Google Scholar]
  21. Greenough A, Morley C, Davis J. Interaction of spontaneous respiration with artificial ventilation in preterm babies. Journal of Pediatrics 1983;103(5):769‐73. [DOI] [PubMed] [Google Scholar]
  22. Gregoretti C, Moglia B, Pelosi P, Navalesi P. Clonidine in perioperative medicine and intensive care unit: more than an anti‐hypertensive drug.. Current Drug Targets 2009;10(8):799–814. [DOI] [PubMed] [Google Scholar]
  23. Griffiths R. The abilities of babies: a study in mental measurement. New York, NY: McGraw‐Hill Book Co. Inc, 1954. [Google Scholar]
  24. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, BrozekJ, et al. GRADE guidelines: 1. Introduction ‐ GRADE evidence profiles and summary of findings tables. Journal of Clinical Epidemiology 2011;64(4):383–94. [DOI] [PubMed] [Google Scholar]
  25. Haeseler G, Karst M, Foadi N, Gudehus S, Roeder A, Hecker H, et al. High‐affinity blockade of voltage‐operated skeletal muscle and neuronal sodium channels by halogenated propofol analogues. British Journal of Pharmacology 2008;155(2):265‐75. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Hamrick SE, Miller SP, Leonard C, Glidden DV, Goldstein R, Ramaswamy V, et al. Trends in severe brain injury and neurodevelopmental outcome in premature newborn infants: the role of cystic periventricular leukomalacia. Journal of Pediatrics 2004;145(5):593‐9. [DOI] [PubMed] [Google Scholar]
  27. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
  28. Horbar JD, Badger GJ, Carpenter JH, Fanaroff AA, Kilpatrick S, LaCorte M, et al. Members of the Vermont Oxford Network. Trends in mortality and morbidity for very low birth weight infants, 1991‐1999. Pediatrics 2002;110(1 Pt 1):143‐51. [DOI] [PubMed] [Google Scholar]
  29. Horbar JD, Carpenter JH, Badger GJ, Kenny MJ, Soll RF, Morrow KA, et al. Mortality and neonatal morbidity among infants 501 to 1500 grams from 2000 to 2009. Pediatrics 2012;129(6):1019‐26. [DOI] [PubMed] [Google Scholar]
  30. Hoy SM, Keating GM. Dexmedetomidine:
 a review of its use for sedation in mechanically ventilated patients in an intensive care 114. setting and for procedural sedation. Drugs 2011;71(11):1481–501. [DOI] [PubMed] [Google Scholar]
  31. Hünseler C, Balling G, Röhlig C, Blickheuser R, Trieschmann U, Lieser U, et al. Continuous infusion of clonidine in ventilated newborns and infants: a randomized controlled trial. Pediatric Critical Care Medicine 2014;15(6):511‐22. [DOI] [PubMed] [Google Scholar]
  32. International Committee for the Classification of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. Pediatrics 1984;74(1):127‐33. [PubMed] [Google Scholar]
  33. Indredavik MS, Vik T, Evensen KA, Skranes J, Taraldsen G, Brubakk AM. Perinatal risk and psychiatric outcome in adolescents born preterm with very low birth weight or term small for gestational age. Journal of Developmental and Behavioral Pediatrics 2010;31(4):286‐94. [DOI] [PubMed] [Google Scholar]
  34. Ishii N, Kono Y, Yonemoto N, Kusuda S, Fujimura M, Neonatal Research Network, Japan. Outcomes of infants born at 22 and 23 weeks' gestation. Pediatrics 2013;132(1):62‐71. [DOI] [PubMed] [Google Scholar]
  35. Jacobs SE, Berg M, Hunt R, Tarnow‐Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database of Systematic Reviews 2013, Issue 1. [DOI: 10.1002/14651858.CD003311.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Jacqz‐Aigrain E, Daoud P, Burtin P, Desplanques L, Beaufils F. Placebo‐controlled trial of midazolam sedation in mechanically ventilated newborn babies. Lancet 1994;344(8923):646‐50. [DOI] [PubMed] [Google Scholar]
  37. Koeppen AH, Michael SC, Li D, Chen Z, Cusack MJ, Gibson WM, et al. The pathology of superficial siderosis of the central nervous system. Acta Neuropathologica 2008;116(4):371–82. [DOI] [PubMed] [Google Scholar]
  38. Krasowski MD, Jenkins A, Flood P, Kung AY, Hopfinger AJ, Harrison NL. General anesthetic potencies of a series of propofol analogs correlate with potency for potentiation of gamma‐aminobutyric acid (GABA) current at the GABA(A) receptor but not with lipid solubility. Journal of Pharmacology and Experimental Therapeutics 2001;297(1):338‐51. [PubMed] [Google Scholar]
  39. Kutuk MS, Yikilmaz A, Ozgun MT, Dolanbay M, Canpolat M, Uludag S, et al. Prenatal diagnosis and postnatal outcome of fetal intracranial hemorrhage. Child's Nervous System : ChNS : Official Journal of the International Society for Pediatric Neurosurgery 2014;30(3):411‐8. [PUBMED: 23907139] [DOI] [PubMed] [Google Scholar]
  40. Laudenbach V, Mantz J, Lagercrantz H, Desmonts JM, Evrard P, Gressens P. Effects of alpha(2)‐adrenoceptor agonists on perinatal excitotoxic brain injury: comparison of clonidine and dexmedetomidine. Anesthesiology 2002;96(1):134‐41. [DOI] [PubMed] [Google Scholar]
  41. Limperopoulos C, Bassan H, Gauvreau K, Robertson RL Jr, Sullivan NR, Benson CB, et al. Does cerebellar injury in premature infants contribute to the high prevalence of long‐term cognitive, learning, and behavioral disability in survivors?. Pediatrics 2007;120(3):584‐93. [PUBMED: 17766532] [DOI] [PubMed] [Google Scholar]
  42. Luu TM, Ment LR, Schneider KC, Katz KH, Allan WC, Vohr BR. Lasting effects of preterm birth and neonatal brain hemorrhage at 12 years of age. Pediatrics 2009;123(3):1037‐44. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Mantz J, Josserand J, Hamada S. Dexmedetomidine: new insights. European Journal of Anaesthesiology 2011;28(1):3‐6. [DOI] [PubMed] [Google Scholar]
  44. Ment LR, Stewart WB, Duncan CC. Beagle puppy model of intraventricular hemorrhage. Effect of superoxide dismutase on cerebral blood flow and prostaglandins. Journal of Neurosurgery 1985;62(4):563‐9. [DOI] [PubMed] [Google Scholar]
  45. Messerschmidt A, Brugger PC, Boltshauser E, Zoder G, Sterniste W, Birnbacher R, et al. Disruption of cerebellar development: potential complication of extreme prematurity.. AJNR. American Journal of Neuroradiology 2005;26(7):1659–67. [PMC free article] [PubMed] [Google Scholar]
  46. Morita T, Morimoto M, Yamada K, Hasegawa T, Morioka S, Kidowaki S, et al. Low‐grade intraventricular hemorrhage disrupts cerebellar white matter in preterm infants: evidence from diffusion tensor imaging. Neuroradiology 2015;57(5):507‐14. [DOI] [PubMed] [Google Scholar]
  47. Mullaart RA, Hopman JC, Rotteveel JJ, Daniels O, Stoelinga GB, Haan AF. Cerebral blood flow fluctuation in neonatal respiratory distress and periventricular haemorrhage. Early Human Development 1994;37(3):179‐85. [PUBMED: 7925076] [DOI] [PubMed] [Google Scholar]
  48. Nakamura Y, Okudera T, Fukuda S, Hashimoto T. Germinal matrix hemorrhage of venous origin in preterm neonates. Human Pathology 1990;21(10):1059‐62. [DOI] [PubMed] [Google Scholar]
  49. Nosarti C, Giouroukou E, Micali N, Rifkin L, Morris RG, Murray RM. Impaired executive functioning in young adults born very preterm. Journal of the International Neuropsychological Society : JINS 2007;13(4):571‐81. [DOI] [PubMed] [Google Scholar]
  50. Orsini AJ, Leef KH, Costarino A, Dettorre MD, Stefano JL. Routine use of fentanyl infusions for pain and stress reduction in infants with respiratory distress syndrome. Journal of Pediatrics 1996;129(1):140‐5. [DOI] [PubMed] [Google Scholar]
  51. Pape KE, Wigglesworth JS. Haemorrhage, ischaemia and the perinatal brain. Philadelphia: J.B. Lippincott, 1979. [Google Scholar]
  52. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. Journal of Pediatrics 1978;92(4):529‐34. [PUBMED: 305471] [DOI] [PubMed] [Google Scholar]
  53. Paris A, Mantz J, Tonner PH, Hein L, Brede M, Gressens P. The effects of dexmedetomidine on perinatal excitotoxic brain injury are mediated by the alpha2A‐adrenoceptor subtype. Anesthesia and Analgesia 2006;102(2):456‐61. [DOI] [PubMed] [Google Scholar]
  54. Parodi A, Morana G, Severino MS, Malova M, Natalizia AR, Sannia A, et al. Low‐grade intraventricular hemorrhage: is ultrasound good enough?. Journal of Maternal‐fetal & Neonatal Medicine 2015;28(1):2261‐4. [PUBMED: 23968243] [DOI] [PubMed] [Google Scholar]
  55. Perlman JM, McMenamin JB, Volpe JJ. Fluctuating cerebral blood‐flow velocity in respiratory‐distress syndrome. Relation to the development of intraventricular hemorrhage. New England Journal of Medicine 1983;309(4):204‐9. [PUBMED: 6866033] [DOI] [PubMed] [Google Scholar]
  56. Perlman JM, Goodman S, Kreusser KL, Volpe JJ. Reduction in intraventricular hemorrhage by elimination of fluctuating cerebral blood‐flow velocity in preterminfants with respiratory distress syndrome. New England Journal of Medicine 1985;312(21):1353‐7. [DOI] [PubMed] [Google Scholar]
  57. Perlman J, Thach B. Respiratory origin of fluctuations in arterial blood pressure in premature infants with respiratory distress syndrome. Pediatrics 1988;81(3):399‐403. [PUBMED: 3344182] [PubMed] [Google Scholar]
  58. Philip AG, Allan WC, Tito AM, Wheeler LR. Intraventricular hemorrhage in preterm infants: declining incidence in the 1980s. Pediatrics 1989;84(5):797‐801. [PubMed] [Google Scholar]
  59. Pichot C, Ghignone M, Quintin L. Dexmedetomidine and clonidine: from second‐to‐first‐line sedative agents in the critical care setting?. Journal of Intensive Care Medicine 2012;27(4):219‐37. [DOI] [PubMed] [Google Scholar]
  60. Quinn MW, Wild J, Dean HG, Hartley R, Rushforth JA, Puntis JW, et al. Randomised double‐blind controlled trial of effect of morphine on catecholamine concentrations in ventilated pre‐term babies. Lancet 1993;342(8867):324‐7. [DOI] [PubMed] [Google Scholar]
  61. The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager 5 (RevMan 5). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
  62. Rigby‐Jones AE, Nolan JA, Priston MJ, Wright PM, Sneyd JR, Wolf AR. Pharmacokinetics of propofol infusions in critically ill neonates, infants, and children in an intensive care unit. Anesthesiology 2002;97(6):1393‐400. [DOI] [PubMed] [Google Scholar]
  63. Roberts D, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database of Systematic Reviews 2006, Issue 3. [DOI: 10.1002/14651858.CD004454.pub2] [DOI] [PubMed] [Google Scholar]
  64. Rutherford MA, Supramaniam V, Ederies A, Chew A, Bassi L, Groppo M, et al. Magnetic resonance imaging of white matter diseases of prematurity. Neuroradiology 2010;52(6):505‐21. [PUBMED: 20422407] [DOI] [PubMed] [Google Scholar]
  65. Sancak S, Gursoy T, Imamoglu EY, Karatekin G, Ovali F. Effect of prematurity on cerebellar growth. Journal of Child Neurology 2016;31(2):138‐44. [DOI] [PubMed] [Google Scholar]
  66. Sancak S, Gursoy T, Karatekin G, Ovali F. Effect of intraventricular hemorrhage on cerebellar growth in preterm infants. Cerebellum (London, England) 2017;16(1):89‐94. [DOI] [PubMed] [Google Scholar]
  67. Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Medical Research Methodology 2007;7:10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Shea BJ, Hamel C, Wells GA, Bouter LM, Kristjansson E, Grimshaw J, et al. AMSTAR is a reliable and valid measurement tool to assess the methodological quality of systematic reviews. Journal of Clinical Epidemiology 2009;62(10):1013‐20. [PUBMED: 19230606] [DOI] [PubMed] [Google Scholar]
  69. Sherlock RL, Anderson PJ, Doyle LW, Victorian Infant Collaborative Study Group. Neurodevelopmental sequelae of intraventricular haemorrhage at 8 years of age in a regional cohort of ELBW/ very preterm infants. Early Human Development 2005;81(11):909‐16. [DOI] [PubMed] [Google Scholar]
  70. Simons SH, Dijk M, Lingen RA, Roofthooft D, Duivenvoorden HJ, Jongeneel N, et al. Routine morphine infusion in preterm newborns who received ventilatory support: a randomized controlled trial. JAMA 2003;290(18):2419‐27. [DOI] [PubMed] [Google Scholar]
  71. Soul JS, Hammer PE, Tsuji M, Saul JP, Bassan H, Limperopoulos C, et al. Fluctuating pressure‐passivity is common in the cerebral circulation of sick premature infants. Pediatric Research 2007;61(4):467‐73. [PUBMED: 17515873] [DOI] [PubMed] [Google Scholar]
  72. Srinivasan L, Allsop J, Counsell SJ, Boardman JP, Edwards AD, Rutherford M. Smaller cerebellar volumes in very preterm infants at term‐equivalent age are associated with the presence of supratentorial lesions. AJNR. American Journal of Neuroradiology 2006;27(3):573–9. [PMC free article] [PubMed] [Google Scholar]
  73. Steen PA, Michenfelder JD. Barbiturate protection in tolerant and nontolerant hypoxic mice: comparison with hypothermic protection. Anesthesiology 1979;50(5):404‐8. [DOI] [PubMed] [Google Scholar]
  74. Taddio A, Shah V, Atenafu E, Katz J. Influence of repeated painful procedures and sucrose analgesia on the development of hyperalgesia in newborn infants. Pain 2009;144(1‐2):43–8. [DOI: 10.1016/j.pain.2009.02.012; PUBMED: 19329255] [DOI] [PubMed] [Google Scholar]
  75. Takashima S, Tanaka K. Microangiography and vascular permeability of the subependymal matrix in the premature infant. Canadian Journal of Neurological Sciences [Journal Canadien des Sciences Neurologiques] 1978;5(1):45‐50. [PubMed] [Google Scholar]
  76. Tam EWY, Ferriero DM, Xu D, Berman JI, Vigneron DB, Barkovich AJ, et al. Cerebellar development in the preterm neonate: effect of supratentorial brain injury. Pediatric Research 2009;66(1):102–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Tam EWY, Miller SP, Studholme C, Chau V, Glidden D, Poskitt KJ, et al. Differential effects of intraventricular hemorrhage and white matter injury on preterm cerebellar growth. Journal of Pediatrics 2011;158:366‐71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Tsuji M, duPlessis A, Taylor G, Crocker R, Volpe JJ. Near infrared spectroscopy detects cerebral ischemia during hypotension in piglets. Pediatric Research 1998;44(4):591‐5. [PUBMED: 9773851] [DOI] [PubMed] [Google Scholar]
  79. Overwalle F, Baetens K, Mariën P, Vandekerckhove M. Social cognition and the cerebellum: a meta‐analysis of over 350 fMRI studies. NeuroImage 2014;86:554‐72. [DOI] [PubMed] [Google Scholar]
  80. Vergani P, Strobelt N, Locatelli A, Paterlini G, Tagliabue P, Parravicini E, et al. Clinical significance of fetal intracranial hemorrhage. American Journal of Obstetrics and Gynecology 1996;175(3 Pt 1):536‐43. [PUBMED: 8928712] [DOI] [PubMed] [Google Scholar]
  81. Database of Very Low Birth Weight Infants Born in 2012. Burlington, VT: Vermont Oxford Network, 2013. Nightingale Internet Reporting System, accessed 4 April 2014.
  82. Volpe JV. Neurology of the Newborn. 5th Edition. Philadelphia, PA: Saunders, 2008. [Google Scholar]
  83. Volpe JJ. Cerebellum and the premature infant: rapidly developing, vulnerable, clinically important. Journal of Child Neurology 2009;24(9):1085–104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Welzing L, Kribs A, Eifinger F, Huenseler C, Oberthuer A, Roth B. Propofol as an induction agent for endotracheal intubation can cause significant arterial hypotension in preterm neonates. Paediatric Anaesthesia 2011;20(7):605‐11. [DOI] [PubMed] [Google Scholar]
  85. Whitaker AH, Feldman JF, Lorenz JM, McNicholas F, Fisher PW, Shen S, et al. Neonatal head ultrasound abnormalities in preterm infants and adolescent psychiatric disorders. Archives of General Psychiatry 2011;68(7):742‐52. [DOI] [PubMed] [Google Scholar]
  86. Whitelaw A. Intraventricular haemorrhage and posthaemorrhagic hydrocephalus: pathogenesis, prevention and future interventions. Seminars in Neonatology 2001;6(2):135‐46. [DOI] [PubMed] [Google Scholar]
  87. Wilson‐Costello D, Friedman H, Minich N, Fanaroff AA, Hack M. Improved survival rates with increased neurodevelopmental disability for extremely low birth weight infants in the 1990s. Pediatrics 2005;115(4):997‐1003. [DOI] [PubMed] [Google Scholar]
  88. Wimberley PD, Lou HC, Pedersen H, Hejl M, Lassen NA, Friis‐Hansen B. Hypertensive peaks in the pathogenesis of intraventricular hemorrhage in the newborn. Abolition by phenobarbitone sedation. Acta Paediatrica Scandinavica 1982;71(4):537‐42. [DOI] [PubMed] [Google Scholar]
  89. Wong FY, Leung TS, Austin T, Wilkinson M, Meek JH, Wyatt JS, et al. Impaired autoregulation in preterm infants identified by using spatially resolved spectroscopy. Pediatrics 2008;121(3):e604‐11. [PUBMED: 18250118] [DOI] [PubMed] [Google Scholar]

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