Iris Morag1, Arne Ohlsson2
Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs
1Neonatal Unit, Mayanei HaYeshua Medical Centre, Bnei Brak, Israel
2Departments of Paediatrics, Obstetrics and Gynaecology and Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada
Citation example: Morag I, Ohlsson A. Cycled light in the intensive care unit for preterm and low birth weight infants. Cochrane Database of Systematic Reviews 2011, Issue 1. Art. No.: CD006982. DOI: 10.1002/14651858.CD006982.pub2.
Neonatal Unit
Mayanei HaYeshua Medical Centre
Bnei Brak
Israel
E-mail: irismorag@gmail.com
| Assessed as Up-to-date: | 01 June 2010 |
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| Date of Search: | 28 May 2010 |
| Next Stage Expected: | 09 July 2012 |
| Protocol First Published: | Issue 1, 2008 |
| Review First Published: | Issue 1, 2011 |
| Last Citation Issue: | Issue 1, 2011 |
| Date / Event | Description |
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| Date / Event | Description |
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| 29 October 2008 Amended | Converted to new review format. |
The potential benefits and harms of different lighting in neonatal units have not been quantified.
To compare the effectiveness of cycled lighting (CL) (approximately 12 hours of light on and 12 hours of light off) with irregularly dimmed light or near darkness (ND) and with continuous bright light (CBL) on growth in preterm infants at three and six months of age.
Electronic searches of the literature were conducted (in May 2010) of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, CINAHL and abstracts from Pediatric Academic Societies' annual meetings.
Randomised or quasi-randomised trials of CL versus ND or CBL in preterm and low birth weight infants.
Data collection and analyses were performed according to the methods of the Cochrane Neonatal Review Group.
Five studies enrolling 387 infants compared CL to ND. No study reported on weight at three or six months. In one study (n = 40) there was no statistically significant difference in weight at four months between the CL and the ND groups. In another study (n = 62) the ratio of day-night activity prior to discharge favoured the CL group (mean difference 0.18, 95% CI 0.17 to 0.19) indicating 18% more activity during day than night in the CL group compared to the ND group. Two studies (n = 189) reported on retinopathy of prematurity (stage ≥ 3). There was no statistically significant difference between the CL and ND groups (typical RR 0.53, 95% CI 0.25 to 1.11, I2 = 0%; typical RD -0.09, 95% CI -0.19 to 0.01, I2 = 0%).
Two studies enrolling 82 infants compared CL to CBL. One study (n = 41) reported higher mean weight at three months corrected age in infants cared for in the CL nursery (P < 0.02) and lower mean number of hours spent awake in 24 hours at three months (P < 0.005). In one study (n = 41) days on a ventilator were reduced in the CL group (mean difference -18, 95% CI -31 to -5 days).
For many outcomes the trends favoured CL versus ND as well as CL versus CBL.
Trials assessing the effect of CL have enrolled 469 infants. Trends for many outcomes favoured cycled light (CL) compared to near darkness (ND) and CL compared to continuous bright light (CBL) The studies may have lacked significance due to a lack of statistical power. Future research should focus on comparing CL to ND.
The pregnant woman is exposed to variable intensities of lighting and sound and, in general, lower levels at night. Some of the lighting and sound reaches the fetus in the womb and induces circadian rhythms. Circadian is a term used to describe biological processes that recur naturally on a 24-hour basis. After birth, preterm infants are cared for in an environment that has no planned light-dark cycles or any other circadian entraining signals. Infants are exposed to either continuous bright light, continuous near darkness or an unstructured combination of the two. Our primary objective was to determine the effectiveness of cycled light (approximately 12 hours of light on and 12 hours of light off) on growth in preterm infants at three and six months corrected gestational age. To date fewer than 500 infants have been enrolled in trials assessing the effect of cycled light. One study reported improved growth at three months of age. One study found no difference in weight at four months of age. Only few outcomes reached statistical significance, likely due to the small number of infants enrolled in the studies, but trends for most outcomes (weight gain, length of stay, incidence of retinopathy of prematurity) favoured cycled light compared to near darkness and cycled light compared to continuous bright light.
The term circadian was introduced in the 1950s by Professor Franz Halberg (Halberg 2003; Refinetti 2003). The term is formed irregularly from the Latin words circa (about), dies (day) and anus (ring) (Hallberg 1969). Circadian clocks are believed to have evolved in parallel with the geological history of the earth and have since been fine-tuned under selection pressures imposed by cyclic factors in the environment (Paranjpe 2005). As the earth rotates, all species on the planet are exposed to 24-hour patterns of light and darkness. In response to these regular, daily oscillations to the natural light-dark cycle, these species have evolved endogenous circadian rhythms that repeat approximately every 24 hours. Circadian rhythms are observed in virtually all aspects of mammalian function, from expression of genes to complex physiological processes (Sukumaran 2010).
The circadian rhythm influences the rhythmic production of several hormones (melatonin, cortisol, growth hormone), respiratory and cardiac function, sleep-wake state, the level of alertness and body temperature (Seron-Ferre 1993). The circadian clock in mammals is located in the suprachiasmatic nuclei in the anterior hypothalamus and is present by 18 weeks of gestation. This master circadian clock organizes and orchestrates the timing of all biological functions, from complicated physiological systems to single cells (Rea 2010). Maternal rest-activity patterns may function as entraining signals for the fetus, as documented in animals, and include changes in heart rate, serum cortisol, melatonin levels and body temperature (Seron-Ferre 1993). Rhythms of fetal movements, heart rate and breathing have been described in human fetuses and in preterm infants born at 28 to 34 weeks gestation (Patrick 1982; Arduini 1987; Mirmiran 1990). More recently Kintraia and co-workers (Kintraia 2005) documented pronounced rhythms of activity and locomotion in healthy fetuses at a post-menstrual age (PMA) of 16 to 20 weeks.The circadian clock in baboons is responsive to light very early in gestation and, when the data are extrapolated to humans, equals about 25 weeks of gestation (Stetson 1986; Hao 1999). These findings suggest maternal triggering of fetal rhythms long before the birth at term. The potential advantages of acquiring circadian rhythms during gestation are currently unknown. It may help in timing the physiological functions of the fetus to those of the mother, as well as preparing the fetus for day and night changes and ambient temperature (Seron-Ferre 1993). The circadian system matures progressively and circadian rhythms of temperature has been documented in a human infant exposed only to natural light and darkness by the end of the first week. In the same infant salivary melatonin circadian periodicity was noted by 45 days and circadian rhythms of wake state by 45 days and sleep state by 56 days (McGraw 1999). In adults asynchrony between the internal (clock) circadian rhythms and the actual time is demonstrated in jet lag, which disrupts sleep and affects digestion and alertness (Rea 2008). Disruption of the natural 24-hour pattern of light and dark from rapid flight across time zones or from rotating shift work can lead to a variety of conditions from poor performance to sleep loss, weight gain, metabolic syndrome, inflammatory diseases and cancer (Rea 2010) (Sukumaran 2010). In rats it has been documented that nociception exhibits robust daily rhythmicity. Sensivity to pain is highest late in the dark phase of the light-dark cycle and lowest at the light-dark transition (Christina 2004). This finding may have importance for the timing of painful procedures in neonates. Circadian rhythms in gene expression regulate both the action and disposition of various drugs and affect therapeutic efficacy and toxicity based on dosing time (Sukumaran 2010).
For the purpose of this review we named the condition under study 'Delays or disturbances in the development of circadian rhythms in preterm and low birth weight infants'. In an observational study including 187 preterm and term infants cared for in a neonatal intensive care unit ( NICU) with cycled lighting (CL) conditions (< 30 lux during the night and 300 to 580 lux during the daytime) circadian rhythms were documented as early as zero to three days of postnatal age (ara Begum 2006). The authors concluded that co-existence of circadian cycles with low amplitude in preterm neonates may complimentarily support immature homeostasis and function against unstable physiological conditions (ara Begum 2006). The entrainment and internal synchronization are aspects of the circadian system that appear to be important for adaptation and optimal functioning of the organism (Mirmiran 1996). Circadian rhythms are normally entrained through the natural exposure to light during the day and darkness during the night over a 24-hour period. In the preterm or low birth weight infant it is plausible that interrupting maternal triggering of fetal rhythms because of preterm birth or exposing the infant born preterm to either near darkness (ND) or continuous bright light (CBL) in the NICU could disturb or delay the development of circadian rhythms (Rivkees 2003; Rivkees 2004). Such disturbances in the circadian rhythms could result in adverse clinical outcomes such as poor growth, sleep disturbances, retinopathy of prematurity (ROP) and other adverse outcomes commonly seen in critically sick neonates. These outcomes, if present, are likely to affect the length of stay in hospital and long-term neuro-developmental outcomes.
The potential benefits and harms of different types of lighting in neonatal intensive care and step down units have not been quantified. Continuous bright light (CBL) has been related to infant stress as manifested by increased levels of activity, decreased sleep and bradycardia (Gottfried 1985; Lotas 1992; Blackburn 1998; Rivkees 2000). Reducing exposure to light by covering the isolette, recommended by the Neonatal Individualized Developmental Care and Assessment Program (NIDCAP), has not been shown to improve important short or long-term outcomes (Jacobs 2002; Symington 2006; Ohlsson 2007; Ohlsson 2009). Providing basic developmental care in the form of incubator covers and nesting in the NICU had no effect on short-term physical and neurologic outcomes in infants who were born at < 32 weeks' gestation (Maguire 2008). Follow up of the same study population at one and two years of age showed no positive effect on neurological and mental development or growth (Maguire 2009). Caring for preterm infants in the dark deprives them of the time-of-day information that they would have received if they had been carried to term (40 weeks gestation) (Rivkees 2004). Phelps and Watts (Phelps 2001) in a Cochrane review concluded that decreasing retinal ambient light exposure in preterm infants is very unlikely to reduce the incidence of retinopathy of prematurity (ROP) compared to no light reduction.
In most nurseries preterm infants are cared for in an environment that has no planned light-dark cycles. Infants are exposed to either CBL, continuous ND or an unstructured combination of the two. The 'Recommended Standards for Newborn ICU Design' state in 'NICU Standard 14 Ambient lighting in infant care area': "In very preterm infants, there has been no demonstrable benefit to exposure to light. After 28 weeks gestation, there is some evidence that diurnally-cycled lighting has potential benefit to the infant. Caregivers benefit from moderate levels of ambient light in order to perform tasks and maintain wakefulness (White 2007).
ND is being practiced in some nurseries because of its similarity to the relative darkness of the womb. Infants receiving ND are exposed to minimal light throughout day and night except for the time of shift change or handling. Some nurseries define ND as 5 to 10 lux. Light protective devices or dimming the lights are used in order to achieve those settings. This approach overlooks the fact that the fetus develops in an environment that is relatively dark but rich with auditory, tactile and kinaesthetic sensory stimuli. These maternal stimuli expose the fetus to circadian rhythms and help in synchronizing the fetal clock with the external light-dark cycle. Keeping preterm infants in the dark during their stay in the neonatal nursery deprives them of the time-of-day information that they would have received throughout gestation (Rivkees 2003; Rivkees 2004).
There is no protocol or single definition for the time cycles or the maximal and minimal lux lighting used for CL. CL is usually provided in a 12 hours on (11 to 13 hours), 12 hours off (11 to 13 hours) pattern similar to the changes in natural light outside. There is a minimal time of transition between light and darkness at the change of nursing shifts. A day versus night lighting difference is achieved either by artificial lighting or by using the regular nursery lighting and uncovering windows during the day. At that time the incubator cover is folded on top of the incubator or taken off, achieving 200 to 500 lux lighting or more (Brandon 2002; Mirmiran 2003; ara Begum 2006). At night time windows are covered by dark, lined curtains, lights are dimmed or turned out and the only illumination is low intensity night light (< 30 lux) (ara Begum 2006). Eye pads are used to protect the infant when greater intensity light is needed for medical procedures. It is still not clear how early preterm infants in the nursery should be introduced to artificial circadian cycles in order to reach the same level of 'clock' maturity as infants born at term. It has been shown that a higher percentage of circadian rhythms with regard to body temperature and heart rate were found to be appropriate for gestational age infants compared to small for gestational age, preterm infants (Glotzbach 1995). It is important to evaluate the influence of CL as an entraining signal in these groups of infants (preterm and small for gestational age infants).
The presence or absence of circadian rhythms in the newborn infant probably results from the combined influence of prenatal and postnatal environmental conditions (Mirmiran 2000). The postnatal development of human circadian rhythms may be hampered by maternal, fetal or perinatal disturbances. This is observed when the intimate mother-fetus relationship is dramatically altered by preterm birth. Preterm infants are deprived of several important postnatal maternal entrainment factors and they are exposed to CBL or irregular light for several weeks or months in the neonatal intensive care unit (NICU). This lack of maternal entrainment, the exposure to irregular extrauterine lighting and care in the nursery may contribute to the disturbances in body temperature, sleep and feeding patterns that are commonly experienced by preterm infants (Keener 1988; Thoman 1989a; Thoman 1989b). Using artificial entraining signals in the nursery, that is CL, may prevent those disturbances and help in promoting growth as well as preventing other morbidities. CL has the potential to promote circadian rhythms that have health benefits, including hormonal regulation, activity-rest cyclicities and vital sign regulation, with the potential of promoting infant growth (Kennaway 1992; Rivkees 2003). CL could increase the satisfaction of care experienced by parents and healthcare providers and thus have an indirect beneficial effect on the infant. On the other hand, CL might decrease staff satisfaction and have adverse effects on the ability to observe infants.
To determine the effectiveness and safety of CL (approximately 12 hours of light on and 12 hours of light off) on growth in preterm infants at three and six months corrected age.
In separate analyses, to compare CL with irregularly dimmed light or near darkness (ND) and to compare CL with continuous bright light (CBL) on growth in preterm infants at three and six months corrected age.
To assess, in subgroup analyses, the effectiveness and safety of CL (versus the control interventions listed above) introduced at different post-menstrual ages (PMA); CL initiated before 32 weeks, at 32 weeks, and from 36 weeks PMA; and to compare the effectiveness and safety of CL for small for gestational age infants versus appropriately grown infants.
Randomised or quasi-randomised controlled trials. Trials were included if the randomisation was either by cluster (whole or part of a neonatal intensive care unit) or at the individual patient level.
Preterm infants (< 37 weeks post-menstrual age (PMA) or low birth weight < 2500 g) admitted and cared for in a neonatal intensive care unit (NICU) or a stepdown unit.
Cycled light versus irregularly dimmed light or ND or CBL initiated during hospitalisation in the NICU.
Time to full oral or nasogastric feeds (days)
Chronic lung disease or bronchopulmonary dysplasia (CLD/BPD) (oxygen requirement above 0.21 at 28 days and 36 weeks PMA)
Days on assisted ventilation
Days in oxygen above 0.21
Retinopathy of prematurity (ROP); any stage and stages > 3
Days of initial hospitalisation
Long-term outcomes: growth and neuro-developmental including visual and auditory outcome at any age reported by the authors using standardized and validated tests
Any clinically important outcome not listed above but reported by the authors (not pre-specified)
Caregivers' satisfaction or dissatisfaction with the intervention
Parents' satisfaction or dissatisfaction with the intervention
Potential adverse effects: any clinically important adverse outcome or side effect not listed above but reported by the authors (not pre-specified).
The search strategy used to identify studies was according to the guidelines of the Cochrane Neonatal Review Group.
All electronic searches were conducted in May, 2010. The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 5), MEDLINE (1966 to May 2010) using MeSH terms: "premature infant OR preterm infant OR low birth weight" AND "cycling light" OR "cycled light" OR "periodicity", OR "circadian rhythm", OR darkness" OR "light OR "lightening"; EMBASE (1980 to May 2010) and CINAHL (1982 to May 2010). Abstracts from the PAS annual meetings (Pediatric Academic Societies) were searched electronically (2000 to May 2010).
The search was initiated by review of personal files and published reviews. The reference list of identified studies and subsequently retrieved articles were scanned for additional references. Unpublished data were not sought, but authors of published trials were contacted to clarify or provide additional information. No language restrictions were applied.
Data collection and analyses were performed in accordance with the methods of the Cochrane Neonatal Review Group. The statistical analyses were performed using the RevMan 5.024 software. The estimates of the treatment effects included typical relative risk (RR), typical risk difference (RD), and if the RD was statistically significant the number needed to treat to benefit (NNT) or number needed to treat to harm (NNH) for dichotomous outcomes, and weighted mean difference (WMD) for continuous outcomes. All estimates of treatment effects are reported with 95% confidence intervals (CI). A fixed-effect model was used for meta-analyses. The results of one cluster trial were reported separately.
All abstracts and published full reports identified as potentially relevant by the literature search were assessed for inclusion in the review by the two review authors.
Each review author extracted data separately using a predesigned data abstraction form and then compared the results. One review author (AO) entered the data into RevMan 5.024 and the other review author (IM) cross checked the printout against her own data abstraction forms and errors were corrected by consensus. For some studies identified as abstracts, primary authors were contacted to ascertain whether a full publication is available. Information from the primary author was obtained if the published article provided inadequate information for the review.
An assessment of the quality of the included studies (excluding abstracts) was performed independently by IM and AO using the criteria developed by the Cochrane Neonatal Review Group. These criteria included: i) blinding of randomisation, ii) blinding of intervention, iii) complete follow up, and iv) blinding of outcome measurement. For each criterion there were three possibilities: yes, can't tell, or no. The assignment was not done with the assessors blinded to author, institution, journal of publication or results as both assessors were familiar with most of the studies and the typographical layout of the journals and would have had knowledge of these even when blinded. In addition the results sections of articles often include methodological information. After the independent evaluation, the two assessors discussed the results for each study and any discrepancies were resolved.
The following issues were evaluated and entered into the 'Risk of bias' table.
1. Sequence generation: was the allocation sequence adequately generated?
2. Allocation concealment: was allocation adequately concealed?
3. Blinding of participants, personnel and outcome assessors: Was knowledge of the allocated intervention adequately prevented during the study? At study entry? At the time of outcome assessment?
4. Incomplete outcome data: were incomplete outcome data adequately addressed?
5. Selective outcome reporting: are reports of the study free of suggestion of selective outcome reporting?
6. Other sources of bias: was the study apparently free of other problems that could put it at a high risk of bias?
Heterogeneity tests including the I2 statistic were performed to assess the appropriateness of pooling the data.
We did not perform funnel plots as the maximum number of trials included in a meta-analysis was two.
In planned subgroup analyses the effectiveness of CL (versus the control interventions listed in secondary objectives) introduced at different PMAs were studied: CL initiated before 32 weeks, at 32 weeks, and from 36 weeks PMA and comparison of small for gestational age infants versus appropriately grown infants.
No sensitivity analyses were planned a priori but could have been conducted if warranted by the results. The only quasi-randomised trial reported on the effects of CL versus CBL (Miller 1995) and the outcomes reported on differed from those in the only other randomised trial that looked at this comparison (Mann 1986). Therefore, a secondary analysis based on quality was not required.
See table 'Characteristics of included studies' and table 'Characteristics of excluded studies'.
The searches resulted in seven trials for inclusion. Five included studies (total n = 387) (Seiberth 1994; Boo N-Y 2002; Brandon 2002; Mirmiran 2003; Rivkees 2004) compared CL to ND and two included studies (total n = 82) compared CL to CBL (Mann 1986; Miller 1995). The included studies were conducted in England (n = 1), Germany (1), the USA (n = 4) and Malaysia (n = 1). Four studies (Blackburn 1991; Kennedy 2001; Hoogeveen 2004; Braz 2006) were excluded. One study (Jung 2005) (n = 20) is awaiting classification as it is written in Korean and we have only been able to access the abstract written in English in spite of attempts to contact the author.
Seven studies were included. For details see table 'Characteristics of included studies'.
Five studies compared CL to near darkness.
Table 1 describes the lighting conditions for CL versus dim lighting or near darkness (ND). The light intensity applied to the infants was similar for studies using the term 'dim lighting' and those using the term 'near darkness'. In the only two studies for which results could be combined in meta-analyses (Seiberth 1994; Brandon 2002) the contrast between day and night time light intensity was similar enough to justify combination of the data from the two studies.
The study by Seiberth and co-workers (Seiberth 1994) was a single centre study conducted in the NICU at the Women's Hospital of the University of Heidelberg, Germany.
65 infants mean (SD) BW 1091 g (233 g) and mean (SD) PMA 29 weeks (1.7 weeks) were assigned to cycled light. Reduced daylight was present during the day (mean (SD) illuminance, 342 lux (55 lux)). At night, light intensity was reduced during most of the night hours (mean (SD) intensity of light, 62 lux (53 lux)). When stable infants were transferred to the preterm unit (step down unit) where the amount of daylight allowed was dampened during day as well (mean (SD) intensity of light 415 lux (42 lux)), whereas at night light was reduced to nearly complete darkness (mean (SD) intensity of light 26 (18) lux). Thus cycled lighting conditions were present in both units.
62 infants mean (SD) BW 1125 g (232 g) and mean (SD) PMA 29.3 weeks (2.1 weeks) were assigned to near darkness (patched eyes). Patches of black opaque plastic covered by cotton were placed over both eyes and secured with tiny pieces of adhesive tape to the temple on both sides. The light reduction achieved was more than 99.9%. Eye patching was applied continuously from the first day after birth to 35 weeks PMA.
The study by Boo and co-workers ( Boo N-Y 2002) was a single centre study conducted in the Hospital Universiti Kebangsaan, Malaysia.
50 infants with a mean (SD) birth weight of 1482 g (236 g) and mean (SD) PMA of 31.6 weeks (2.2 weeks) were assigned to the 'day-and-night' cyclical lightning group. Intensity of light mean (SD): 78.4 lux (24.7 lux). The lights in the cubicles were switched on between 07.00 and 19.00 h, and switched off between 19.00 and 07.00 h.
46 infants with a mean (SD) birth weight of 1465 g (280 g) were assigned to the 'continuously dim environment' group. Intensity of light mean (SD): 5.9 lux (1.9 lux). The lights in the cubicles were switched off throughout both day and night. Lights were switched on temporarily only during physical examination, treatment procedures or nursing care.
The study by Brandon and co-workers (Brandon 2002) was a single centre study conducted at an intensive care and a transitional care nursery of Duke University Medical Center and a level II special care nursery of Durham Regional Hospital, Durham, NC, US.
neonates (mean (SD) PMA 27.1 weeks (2.0 weeks); mean (SD) birth weight 1000 g (223 g) across the 3 intervention groups) were assigned randomly to one of three light intervention groups: (1) CL from birth, (2) CL at 32 weeks PMA, and (3) CL at 36 weeks PMA in transition for discharge home.
22 infants were assigned to cycled light from birth and 19 infants were cared for in near darkness until 32 weeks PMA when they were cared for in cycled light. Cycled light was provided in an 11 hours on, 11 hours off pattern with one transition hour at the change of shifts. The incubator cover was folded on top of the incubator or the bassinet cover was off to achieve daylight at 200 to 225 lux between 7:30 AM and 6:30 PM.
21 infants were assigned to the near darkness group. Near darkness (5 to 10 lux) was provided by using protective devices during the daytime and either dimming the room light or using protective devices at nighttime. Infants receiving ND were exposed to 5 to 10 lux light throughout the day except during 6:30 to 7:30 am and 6:30 to 7:30 PM, when lighting levels varied based on change of shift nursing care needs. These transition hours were applied to all groups.
The study by Mirmiran an co-workers (Mirmiran 2003) was a single centre study conducted at Lucile Packard Children's Hospital at Stanford, Palo Alto, CA US.
19 infants; mean (SD) PMA 30.7 weeks (1.3 weeks) were allocated to the 'cycled' group and were cared for in a day-night lighted room. Their incubator or bassinet was covered from 1900 hr to 0700 hr with a nearly opaque blanket except during feeding or other interventions. The blanket was removed from 0700 hr to 1900 hr at which time the room lighting was turned up to standard lighting levels (approximately 300 lux) to produce a regular light-dark cycled condition.
21 infants; mean (SD) PMA 29.8 weeks (1.7 weeks) were allocated to the 'dim' group and were cared for in dimly lighted room (below 20 lux) around the clock. Their incubator/bassinet covered with a nearly opaque blanket except during feeding or other interventions by parents and caregivers.
The study by Rivkees and co-workers (Rivkees 2004) was a single centre study conducted in the Department of Pediatrics, Yale School of Medicine, New Haven, CT, US.
29 infants mean (SD) PMA 28.5 weeks (0.5 weeks) and mean (SD) birth weight 1072 g (62 g) were assigned to CL mean (SD) 239 (29) lux, from 7 AM to 7 PM; < 25 lux, 7 PM to 7 AM for 25 days.
33 infants mean (SD) PMA 28.5 weeks (0.4 weeks) and mean (SD) birth weight 1110 g (64 g) were assigned to dim lighting mean (SD) 28.5 lux (3 lux) from 7 AM to 7 PM; from 7 PM to 7 AM mean (SD) 15 lux (5) for 24 days.
Table 2 describes the lighting conditions for CL and CBL in the two studies. In the study by Mann and co-workers (Mann 1986) the light intensity was not described in lux but the conditions were likely to have been similar.
The study by Mann and coworkers (Mann 1986) was a single centre study conducted in Nottingham, England.
20 infants with mean PMA (SD) 32.0 weeks (2.0 weeks) (range 28 to 35 weeks), mean birth weight (SD) 1620 g (350 g) (range 1130 to 2370 g) were cared for in a day and night nursery. During the daytime the environment was identical in the two nurseries, but at 7 PM the windows in the night and day nursery were covered by dark, lined curtains, the lights were turned out, and the only illumination was provided by a low intensity night light. The radio was turned off, and staff and visitors were urged to make as little noise as possible. Low light and noise intensity was then maintained until 7 AM.
21 infants mean PMA (SD) 31.6 weeks (1.9) weeks, mean birth weight (SD) 1640 g (390 g), (range 1020 to 2430 g) were cared for in a control nursery. The control nursery contained six cots, measured 23 x 13 feet, had a large exterior window and smaller internal windows without curtains, and was lit by bright fluorescent strip lights that remained permanently on. No attempt was made to reduce noise from the radio, staff, parents, or other visitors at any time.
The study by Miller and co-workers (Miller 1995) was a single centre study conducted at Notre Dame, IN, US.
20 infants mean (SD) birth weight 1151 g (360 g) and mean (SD) PMA 28.0 weeks (2.2 weeks) were assigned to CL.
The infants received a day/night lighting pattern both in the intensive care room and the continuing care room. During day-time (7 AM to 6 PM) this group received 156-201 lux and during night time (6 PM to 7 AM) 20 to 32 lux.
21 infants mean (SD) birth weight 1049 g (330 g) and mean (SD) PMA 28.0 weeks (2.1 weeks) were assigned to CBL. Infants received 176 to 232 lux during day time and 206 to 274 lux during night time
Four studies were excluded (Blackburn 1991; Kennedy 2001; Hoogeveen 2004; Braz 2006). For details see table 'Characteristics of excluded studies'. None of these studies had CL as an intervention.
For details see the 'Risk of bias' table for each included study. Two of the studies had adequate sequence generation (Rivkees 2004: table of random numbers; Brandon 2002: computer-generated random list). One study had adequate allocation concealment (Boo N-Y 2002: sequentially numbered sealed envelopes which were opened in order). Information on sequence generation was lacking in four studies and allocation concealment was unclear in five studies. No single study had documented both adequate sequence generation and concealed allocation.
One study was a quasi-randomised trial; Infants were assigned to either CL or continuous lighting subject to the availability of space and staff (Miller 1995).
The studies could not be blinded. Outcomes were reported for all infants who entered the studies. To our knowledge no trial had been entered into a trials registry at the protocol stage. Study protocols were not available to us.
One study (Mann 1986) randomised 20 infants to be cared for in a nursery with CL and reduced noise and 21 to be cared for in a nursery with no reduction in the intensity of light or noise. Thus this study had a co-intervention of reduced noise in addition to CL. All data for this study were reported in graphic form only and could not be entered in RevMan.
Weight at three or six months of age were not reported in any study.
Weight at four months (Outcome 1.1):
One study (n = 40) (Mirmiran 2003) reported on weight at four months. There was no statistically significant difference between the CL and the ND groups, mean difference 181 g (95% CI -484 to 846 g).
Weight at 35 weeks PMA (Outcome 1.2):
One study (n = 40) (Mirmiran 2003) reported on weight at 35 weeks PMA. There was no statistically significant difference between the CL and the ND groups, mean difference 106 g (95% CI -42 to 254 g).
Weight on day 14 (Outcome 1.3):
One study (n = 96) (Boo N-Y 2002) reported on weight on day 14. There was no statistically significant difference between the CL and the ND groups, mean difference 0 g (95% CI -104 to 104 g).
Weight gain by day 14 (Outcome 1.4):
One study (n = 96) (Boo N-Y 2002) reported on weight gain by day 14. There was no statistically significant difference between the CL and the ND groups, mean difference -9 g (95% CI -51 to 34 g).
Mean age when birth weight was regained (Outcome 1.5):
One study (n = 96) (Boo N-Y 2002) reported on mean age when birth weight was regained. There was no statistically significant difference between the CL and the ND groups, mean difference 0.1 days (95% CI -2.6 to 2.8 days).
Cumulative average weekly weight gain (g) (CL from birth) (Outcome 1.6):
One study (n = 43) (Brandon 2002) reported on cumulative average weekly weight gain (g). There was no statistically significant difference between the CL and the ND groups, mean difference 24 g (95% CI -51 to 99 g).
Cumulative average weekly weight gain (g) (CL from 32 weeks PMA) (Outcome 1.7):
One study (n = 40) (Brandon 2002) reported on cumulative average weekly weight gain (g). There was no statistically significant difference between the CL and the ND groups, mean difference 29 g (95% CI -53 to 111 g).
Calories/kg/day (CL from birth) (Outcome 1.8):
One study (n = 43) (Brandon 2002) reported on kcal/kg/day (CL from birth). There was no statistically significant difference between the CL and the ND groups, mean difference 8 kcal/kg/day (95% CI -19 to 34 kcal/kg/day).
Calories/kg/day (CL from 32 weeks PMA) (Outcome 1.9):
One study (n = 40) (Brandon 2002) reported on kcal/kg/day (CL from 32 weeks PMA). There was no statistically significant difference between the CL and the ND groups, mean difference 0.2 cal/kg/day (95% CI -18 to 18 kcal/kg/day).
Day of life to start feeds (CL from birth) (Outcome 1.10):
One study (n = 43) (Brandon 2002) reported day of life to start feeds (CL from birth). There was no statistically significant difference between the CL and the ND groups, mean difference 2 days (95% CI -7 to 11 days).
Day of life to start feeds (CL from 32 weeks) (Outcome 1.11):
One study (n = 40) (Brandon 2002) reported day of life to start feeds (CL from 32 weeks PMA). There was no statistically significant difference between the CL and the ND groups, mean difference -2 days (95% CI -5 to 2 days).
Day of life to full feeds (CL from birth) (Outcome 1.12):
One study (n = 43) (Brandon 2002) reported day of life to full feeds (CL from birth). There was no statistically significant difference between the CL and the ND groups, mean difference 1 day (95% CI -21 to 22 days).
Day of life to full feeds (CL from 32 weeks PMA) (Outcome 1.13):
One study (n = 40) (Brandon 2002) reported day of life to full feeds (CL from birth). There was no statistically significant difference between the CL and the ND groups, mean difference -7 days (95% CI -25 to 12 days).
One study published in abstract form (n = 39) (Mirmiran 2003) reported statistically significantly shorter time to reach full oral feeds in the CL group 26 days versus 38 days in the ND group (P = 0.04).
Ventilator days (cycled light from birth) (Outcome 1.14):
Two studies (n = 170) reported on ventilator days (CL from birth) (Brandon 2002; Seiberth 1994). There was no statistically significant difference between the CL and the ND groups, weighted mean difference 1 day (95% CI -2 to 3 days). There was no statistically significant heterogeneity for this outcome (I2 = 39%).
Ventilator days (cycled light from 32 weeks PMA) (Outcome 1.15):
One study (n = 40) reported on ventilator days (CL from 32 weeks PMA) (Brandon 2002). There was no statistically significant difference between the CL and the ND groups, mean difference -3 days (95% CI -19 to 13 days).
Days in supplemental oxygen (CL from birth) (Outcome 1.16):
One study (n = 43) (Brandon 2002) reported on supplemental oxygen (CL from birth). There was no statistically significant difference between the CL and the ND groups, mean difference -16 days (95% CI -47 to 14 days).
Days in supplemental oxygen (CL from 32 weeks PMA) (Outcome 1.17):
One study (n = 40) (Brandon 2002) reported on supplemental oxygen (CL from 32 weeks PMA). There was no statistically significant difference between the CL and the ND groups, mean difference -18 days (95% CI -47 to 12 days).
One study published in abstract form (n = 39) (Mirmiran 2003) reported no statistically significant difference on 'days in supplemental oxygen' between the CL (11 days) and ND (25 days) groups (P = 0.09).
Length of stay (cycled light from birth) (Outcome 1.18):
Two studies (n = 170) reported on length of stay (days) (CL from birth) (Seiberth 1994; Brandon 2002). There was no statistically significant difference between the CL and the ND groups, weighted mean difference - 5 days (95% CI -15 to 5 days). There was no statistically significant heterogeneity for this outcome (I2 = 0%).
Mirmiran 2003 (n = 39) reported in abstract form on shorter length of stay in the CL compared to the ND group (6 weeks versus 8 weeks; P = 0.05).
Length of stay (cycled light from 32 weeks PMA) (Outcome 1.19):
One study (n = 40) reported on length of stay (days) (Cycled light from 32 weeks PMA) (Brandon 2002). There was no statistically significant difference between the CL and the ND groups, mean difference -12 days (95% CI -37 to 13 days).
Retinopathy of prematurity (any stage) (Outcome 1.20):
Two studies (n = 189) (Seiberth 1994; Brandon 2002) reported on ROP (any stage). There was no statistically significant difference between the CL and ND groups (typical RR 0.83, 95% CI 0.60 to 1.13, I2 = 0%; typical RD -0.09, 95% CI -0.23 to 0.06, I2 = 15%). There was no statistically significant heterogeneity for this outcome.
Retinopathy of prematurity (stage >/= 3) (Outcome 1.21):
Two studies (n = 189) (Seiberth 1994; Brandon 2002) reported on ROP (stage ≥ 3). There was no statistically significant difference between the CL and ND groups (typical RR 0.53, 95% CI 0.25 to 1.11, I2 = 0%; typical RD -0.09, 95% CI -0.19 to 0.01, I2 = 0%). There was no statistically significant heterogeneity for this outcome.
Infants requiring laser surgery (Outcome 1.22):
One study (n = 62) (Brandon 2002) reported on infants requiring laser surgery. There were no statistically significant difference between the CL and the ND groups (RR 0.51, 95% CI 0.11 to 2.32; RD -0.07, 95% CI -0.24 to 0.10).
Post hoc analyses
Ratio of day-night activity over the 10 days preceding discharge from the hospital (Outcome 1.23):
One study (n = 62) reported on the ratio of day-night activity over the 10 days preceding discharge from hospital (Rivkees 2004). There was a statistically significant difference between the CL and the ND groups, mean difference 0.18 (95% CI 0.17 to 0.19).
Period of entrained circadian rhythms over the first 10 days at home (Outcome 1.24):
One study (n = 51) reported on the period of entrained circadian rhythms over the first 10 days at home (Rivkees 2004). There was a statistically significant difference between the CL and the ND groups, mean difference -0.78 (95% CI -0.89 to -0.67).
Total number of movements per day (10 to 0 days before discharge) (Outcome 1.25):
One study (n = 62) reported on total number of movements per day (Rivkees 2004). There was a statistically significant difference in the total number of movements per day between the CL and the ND groups, mean difference 73 movements/day (95% CI 44 to 102 movements per day).
Total number of movements per day (1 to 10 days after discharge) (Outcome 1.26):
One study (n = 51) reported on total number of movements per day (Rivkees 2004). There was a statistically significant difference in the total number of movements per day between the CL and the ND groups, mean difference 82 movements/day (95% CI 23 to 141 movements/day).
Total number of movements per day (11 to 20 days after discharge) (Outcome 1.27):
One study (n = 51) reported on total number of movements per day (Rivkees 2004). There was a statistically significant difference in the total number of movements per day between the CL and the ND groups, mean difference 429 movements/day (95% CI 342 to 516 movements/day).
Total number of movements per day (21 to 30 days after discharge) (Outcome 1.28):
One study (n = 29) reported on total number of movements per day (Rivkees 2004). There was a statistically significant difference in the total number of movements per day between the CL and the ND groups, mean difference 536 movements/day (95% CI 397 to 675 movements/day).
Neurobehavioral assessment of the preterm infant (NAPI) (Outcome 1.29):
One study (56 of 62 randomised infants) (Brandon 2002) reported on NAPI at 32 and 36 weeks PMA. There was no significant effect of lighting on short-term developmental outcomes in preterm infants, except for popliteal angle. Since this was the only significant effect of the lighting environment of the 18 variables examined, it was probably a chance finding.
Two studies (Miller 1995; Mann 1986) randomised infants to be cared for in a nursery with CL or to a nursery with CBL.
One study (Miller 1995) randomised 20 infants to be cared for in a nursery with CL and 21 to be cared for in a nursery with no reduction in the intensity of light and noise. The following outcomes refer to this study.
Weight at three or six months of age were not reported in this study.
Average daily caloric intake (cal/kg/day) (Outcome 2.1):
There was no statistically significant difference in the average caloric intake comparing the CL the to CBL group; mean difference 9.6 kcal/kg/day (95% CI -0.5 to 19.7 kcal/kg/day)
Days to first oral feeding (Outcome 2.2):
There was a statistically significant difference in the number of days to first oral feeding comparing the CL to the CBL group; mean difference -7 days (95% CI -13 to -0.3 days).
Length of stay (Outcome 2.3):
There was no statistically significant difference in the length of stay comparing the CL to the CBL group; mean difference -16.0 days (95% CI -32 to 0.3 days).
Days requiring supplemental oxygen (Outcome 2.4):
There was no statistically significant difference in the number of days requiring supplemental oxygen comparing the CL to the CBL group; mean difference -21 days (95% CI -44 to 3 days).
Days on ventilator (Outcome 2.5):
There was a statistically significant difference in the number of days on ventilator comparing the CL to the CBL group; mean difference -18 (95% CI -31 to -5.) days.
Infant growth (Outcome 2.6):
A statistically significant difference in weight gain was found with the infants in the CL group gaining on average 9.4% of their weight over the course of one week, whereas the infants in the CBL group gained on average 7.4% (P < 0.05).
Nursing behaviour (Outcome 2.7):
No significant relationships were found between lighting condition and nursing behaviour. There was no evidence that staff behaviours mediated the effects of lighting conditions.
One study (Mann 1986) randomised 20 infants to be cared for in a nursery with CL and reduced noise and 21 to be cared for in a nursery with no reduction in the intensity of light or noise.
All data were reported in graphic form only and could not be entered in RevMan. The following outcomes refer to this study.
Growth at three months and six months
Growth at six months of age was not reported but growth at three months of age was.
Mean weight at 12 weeks corrected age (Outcome 2.8):
The mean weight at 12 weeks corrected age (ca three months) was statistically significantly higher in the infants cared for in the CL nursery (P < 0.02).
Mean weight at six weeks corrected age (Outcome 2.9):
The mean weight at six weeks corrected age was statistically significantly higher in the infants cared for in the CL nursery (P < 0.05).
Mean weight at expected date of birth (Oucome 2.10):
The mean weight at expected date of birth was not statistically significantly different between the two groups (p = NS).
Mean weight at discharge from hospital (Outcome 2.11):
The mean weight at discharge was not statistically significantly different between the two groups (p = NS).
Mean number of hours spent awake in 24 hrs at 12 weeks corrected age (Outcome 2.12):
The mean number of hours spent awake at 12 weeks corrected age (three months) was statistically significantly lower in infants cared for in the CL light nursery (P < 0.005).
Mean number of hours spent awake in 24 hrs at six weeks corrected age (Outcome 2.13):
The mean number of hours spent awake at six weeks corrected age was statistically significantly lower in infants cared for in the CL light nursery (P < 0.01).
Mean number of hours spent awake in 24 hrs at expected date of birth (Outcome 2.14):
The mean number of hours spent awake at expected date of birth was statistically significantly lower in infants cared for in the CL light nursery (P < 0.05).
Mean number of hours spent awake in 24 hrs at discharge from hospital (Outcome 2.15):
The mean hours spent awake at discharge from hospital was not statistically significantly different between the groups (P = NS).
Mean number of hours spent feeding in 24 hrs at 12 weeks corrected age (Outcome 2.16):
The mean number of hours spent feeding in 24 hrs at 12 weeks corrected age was statistically significantly lower in infants cared for in the CL nursery (P < 0.02)
Mean number of hours spent feeding in 24 hrs at six weeks corrected age (Outcome 2.17):
The mean number of hours spent feeding in 24 hrs at six weeks corrected age was not statistically significantly different between the two groups (P = NS).
Mean number of hours spent feeding in 24 hrs at expected date of birth (Outcome 2.18):
The mean number of hours spent feeding in 24 hrs at expected date of birth was not statistically significantly different between the two groups (P = NS).
Mean number of hours spent feeding in 24 hrs at discharge from hospital (Outcome 2.19):
The mean number of hours spent feeding in 24 hrs at discharge from hospital was not statistically significantly different between the two groups (P = NS).
No study reported on any adverse effects of the interventions, nor did they report on caregivers' or parents' satisfaction/dissatisfaction with the interventions.
Five studies including a total of 387 infants were identified. All studies had small sample sizes (range 40 to 127 infants). The quality varied with few studies reporting on sequence generation and concealed allocation. Few studies reported on sample size calculations. A wide variety of outcomes were reported and none included our primary outcomes of growth at three and six months PMA. However, one study (Mirmiran 2003) reported on weight at four months PMA. We report on 29 different outcomes and of these only four outcomes included data from a total of two trials (Seiberth 1994; Brandon 2002) with a maximum of 189 infants; all other outcomes included only data from one study. Some studies used the term 'dim lighting' and others 'near darkness' for the reduced lighting condition (Table 1). We consider the light intensity levels similar enough to use the term 'dim lighting' and 'near darkness' interchangeably.
There was no statistically significant difference in weight at four months of age although the results favoured the CL group (mean difference 181 g; 95% CI -484 to 846 g). In one study (Rivkees 2004) infants showed significantly increased total number of movements from 10 days before discharge to 30 days after discharge (Actogram data) and the ratio of day-night activity over the 10 days preceding discharge from hospital favoured the CL group by 18% (95% CI 17 to 19 %). These data indicate that the infants in the CL group showed more movements but that most of the movements occurred during day time. In this study the mean period length of entrained circadian rhythms over the first 10 days at home (hrs) was 24 hrs versus 24.77 hrs for the ND infants indicating synchronization to the 24-hour solar day (mean difference -0.78, 95% CI -0.89 to -0.67). There were no other statistically significant findings. In the study by Brandon and co-workers (Brandon 2002) there were two groups exposed to CL; one group started CL at birth and one group started CL at 32 weeks PMA. None of the individual outcomes reached statistical significance compared to ND. There did not seem to be any obvious trends favouring starting CL at birth versus starting at 32 weeks PMA, which may have implications for the planning of future studies.
It is of note that the incidence of ROP both any stage and stage ≥ 3 (n = 189) and 'infants requiring laser surgery' (n = 62) showed important trends towards a reduction (RD - 0.9, 95% CI -0.19 to 0.01 for ROP stage ≥ 3; and RD -0.07, 95% CI -0.24 to 0.10 for laser surgery). Several other outcomes showed trends favouring the CL group. Phelps and Watts (Phelps 2001) in a Cochrane review concluded that decreasing ambient light exposure in preterm infants is very unlikely to reduce the incidence of ROP. One study (Seiberth 1994) was included in that review.
The small sample sizes of the included trials preclude any secondary analyses.
Only two studies (Mann 1986; Miller 1995) with a sample size of 41 infants each have studied the effects of CL versus CBL. Mann and co-workers (Mann 1986) provided no information on sequence generation or allocation concealment. The study by Miller 1995 was a quasi-randomised trial. Mann 1986 reported the data in graphic form only and the data from the two studies could not be combined. In the study by Mann 1986 there was a co-intervention in the CL group as noise as well as lighting was reduced at night.
In the study by Mann 1986 the mean weight at 6 and 12 weeks (3 months) PMA was statistically significantly higher in the infants cared for in the CL nursery and at the same time points the mean number of hours spent awake was statistically significantly lower in infants cared for in the CL light nursery. The mean number of hours spent awake at expected date of birth was statistically significantly lower in infants cared for in the CL light nursery and the mean number of hours spent feeding in 24 hrs at 12 weeks (3 months) PMA was statistically significantly lower in infants care for in the CL nursery. The results for these outcomes would indicate a positive effect of CL versus CBL.
In the study by Miller 1995 CL versus CBL reduced the number of days to first oral feeding by 7 days (95% CI -13 to -0.3) and the days on a ventilator by 18 days (95% CI -31 to -5 days) in favour of CL. Miller 1995 reported a statistically significant difference in weight gain with the infants in the CL group gaining on average 9.4% of their weight over the course of one week, whereas the infants in the CL group gained on average 7.4% (P < 0.05). All other reported outcomes (length of stay, days requiring supplemental oxygen, and average caloric intake) favoured the CL group but the results did not reach statistical significance, likely because of a lack of power. The Recommended Standards for Newborn ICU Design standard 14 states: "Caregivers benefit from moderate levels of ambient light in order to perform tasks and maintain wakefulness" (White 2007). In the only study that addressed aspects of lighting on healthcare providers Miller 1995 found no significant relationships between lighting condition and nursing behaviour. There was no evidence that staff behaviours mediated the effects of lighting conditions (Miller 1995).
These two small studies both with limitations suggest that CL has an advantage over CBL mainly resulting in improved growth and sleep. CBL has been related to infant stress as manifested by increased levels of activity, decreased sleep, and bradycardia (Gottfried 1985; Lotas 1992; Blackburn 1998; Rivkees 2000). The statistically significant results and all trends for the comparisons of CL versus CBL in the current review all favoured CL. CBL does not occur in nature and it is difficult to perceive how such a lighting condition could induce circadian rhythms.
In view of the positive trends for better outcomes with CL and the lack of power in the included studies we recommend further well designed studies of adequate sample sizes to confirm or refute the use of CL in the NICUs and the stepdown units. Future research in preterm infants should focus on comparisons between CL and ND. Comparing CL to ND is justifiable as CL is of importance for the induction of circadian rhythm and ND is close (but not identical) to the lighting conditions the fetus is exposed to in utero until birth at term. In the CL group studies should aim for a day time (12 hours) light intensity of > 200 lux and a night time (12 hours) light intensity of < 20 lux, which would also be the light intensity in the ND group for 24 hours. The sample size could be based on the reduction in ROP stage ≥ 3 or the increase in weight reported in this review.
Important questions have still to be investigated; weight gain, sleep patterns, effect on ROP, and long-term neuro-developmental outcomes.
Five studies (n = 387) compared CL to ND. Most outcomes were reported only in single studies. One study (n = 40) reported on weight at 4 months. There was no statistically significant difference between the CL and the ND groups (mean difference 181 g, 95% CI -484 to 846) . One study (n = 39) reported statistically significantly shorter time to reach full oral feeds in the CL group 26 days versus 38 days in the ND group (P = 0.04). Ratio of day-night activity prior to discharge favoured the CL group [mean difference 0.18 (95% CI 0.17 to 0.19).
Two studies (n = 82) compared CL to CBL. Days on a ventilator were reduced in the CL group (mean difference -18 days, 95% CI -31 to -5 days) as were days to first oral feeding (mean difference 7 days, 95% CI -13 to -0.3 days). One study (n = 41) reported statistically significant higher mean weight at 6 (P < 0.05) and 12 weeks (3 months) (P < 0.02) corrected age in infants cared for in the CL nursery. In the same study mean number of hours spent awake in 24 hrs at 12 weeks (3 months) (P < 0.005); six weeks (P < 0.01) corrected age and at expected date of birth (P < 0.05) were lower in the CL group.
For many outcomes the trends showed a benefit of CL versus ND as well as for CL versus CBL.
Although the results of this review favours the use of CL versus ND and CL versus CBL the studies published to date preclude a clear recommendation because of a lack of power. Cycled light appears preferable to CBL.
Future research should focus on studying the comparison between CL and ND as there are some encouraging trends noted especially with regards to the reduction in ROP and increased wight gain. Sample size calculations could be based on the results of this review. For such studies CL could be defined as < 20 lux during the night (12 hours) and > 200 lux during the daytime (12 hours) and ND as < 20 lux throughout 24 hours.
We acknowledge the help of Ms Elizabeth Uleryk, Chief Librarian, The Hospital for Sick Children, Toronto, for assistance in developing the search strategy.
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. HHSN267200603418C.
Iris Morag and Arne Ohlsson have contributed to all sections of the protocol and the full review.
| Methods | Single centre, randomised, controlled trial |
|---|---|
| Participants | 41 preterm infants with PMA 27-35 weeks, postnatal age on study entry 1-63 days Study period: August - December 1984 |
| Interventions | 20 infants with mean PMA (SD) 32.0 weeks (2.0 weeks) (range 28-35 weeks), mean birth weight (SD) 1620 g (350 g) (range 1130-2370 g) were cared for in a day and night nursery The infants spent at least 10 days in one of the two nurseries The night and day nursery was identical in size and the number The control nursery contained six cots, measured 23 x 13 feet, had a large |
| Outcomes | Number of hours spent awake in 24 hours, number of hours spent feeding in 24 hours, and weight on discharge, at expected date of birth, at 6 weeks corrected age and at 12 weeks (3 months) corrected age. The average time spent asleep, awake, or feeding was calculated from 48 hours of recordings. |
| Notes | All outcome results were presented in graphic form only and could not be entered into RevMan |
| Item | Judgement | Description |
|---|---|---|
| Adequate sequence generation? | Unclear | No information provided |
| Allocation concealment? | Unclear | "...randomly assigned" |
| Blinding? (All outcomes) | No | The study could not be blinded |
| Blinding? (All outcomes) | No | The study could not be blinded |
| Incomplete outcome data addressed? | Yes | Outomes reported for all infants enrolled |
| Free of selective reporting? | Yes | |
| Free of other bias? | Yes | Appears free of other bias |
| Methods | Single centre, randomised, controlled trial |
|---|---|
| Participants | 169 infants (birth weight < 1500 g; PMA < 33 weeks) entered the study. 42 infants were excluded (see Risk of bias table - Incomplete outcome data addressed?). Setting: Single centre, NICU at the Women's Hospital of the University of Heidelberg, Heidelberg, Germany. Study period: January 1, 1987 to July 31, 1991. |
| Interventions | 65 infants mean (SD) birth weight 1091 g (233 g) and mean (SD) PMA 29 weeks (1.7 weeks) were assigned to cycled light. In the NICU in the cycled light group, reduced daylight was present during the day [mean (SD) illuminance, 342 lux (55 lux) ]. At night, light intensity was reduced during most of the night hours [mean (SD) illuminance, 62 lux (53 lux ) ]. When stable infants were transferred to the preterm unit (step-down unit) where the amount of daylight allowed was dampened during day as well (mean (SD) illuminance 415 lux (42 lux ), whereas at night light was reduced to nearly complete darkness (mean (SD) illuminance 26 lux (18 lux ). Thus cycled lighting conditions were present in both units. 62 infants mean (SD) birth weight 1125 g (232) g and mean (SD) PMA 29.3 weeks (2.1 weeks) were assigned to near darkness (patched eyes). Patches of black opaque plastic covered by cotton were placed over both eyes and secured with tiny pieces of adhesive tape to the temple on both sides. The light reduction achieved was more than 99.9%. Eye patching was applied continuously from the first day after birth to 35 weeks PMA. |
| Outcomes | ROP (all stages) and ROP (stages >II); duration of ventilation therapy (days) , duration of hospital stay (days) |
| Notes |
| Item | Judgement | Description |
|---|---|---|
| Adequate sequence generation? | Unclear | No information provided |
| Allocation concealment? | Unclear | "... each infant was randomly assigned to the near darkness or cycled lighting group". Randomizatin was done separately for three birth-weight groups; < 1000 g, 1000 to 1249 g, and 1250 to 1500 g. |
| Blinding? (All outcomes) | Yes | Examination for retinopathy of prematurity was done by one observer who was unaware of the infants' group assignment. |
| Blinding? (All outcomes) | No | The assessors were not blinded for the outcomes of duration of ventilation therapy (days), duration of hospital stay (days). |
| Incomplete outcome data addressed? | Yes | Of the 169 preterm infants who entered the study, 42 were excluded because of death (six infants in the near darkness group, 8 infants in the cycled lighting group); parents' withdrawal of informed consent (3 infants in the near darkness roup, 0 infants in the cycled lighting group), or transfer to another hospital (14 infants in the near darkness group and 11 infants in the cycled lighting group). A total of 127 infants remained in the study. |
| Free of selective reporting? | Yes | |
| Free of other bias? | Yes | Appears free of other bias |
| Methods | Single centre, quasi-randomised, controlled trial |
|---|---|
| Participants | 41 infants < 37 weeks PMA and birth weight < 2500 g Setting: single centre Notre Dame, IN, US Study period not stated |
| Interventions | 20 infants mean (SD) birth weight 1151 g (360 g) and mean (SD) PMA 28.0 weeks (2.2) weeks were assigned to CL and 21 infants mean (SD) birth weight 1049 g (330 g) and mean (SD) PMA 28.0 weeks (2.1 weeks) were assigned to CBL. Infants in the CL group received a day/night lighting pattern both in the intensive care room and the continuing care room. During daytime (7 AM to 6 PM) this group received 156-201 lux and during night time (6 PM to 7 AM) 20-32 lux. Infants in the continuous lighting group received 176-232 lux during day time and 206-274 lux during night time |
| Outcomes | Length of stay, days requiring supplemental oxygen, days on ventilator, days to first oral feeding, average daily caloric intake, percent weight gain per week, nursing behaviour. |
| Notes | We did not include the results of the Brazelton Neonatal Behavioral Assessment Scale, as to our knowledge it has not been validated. |
| Item | Judgement | Description |
|---|---|---|
| Adequate sequence generation? | No | No sequence was created. |
| Allocation concealment? | No | Infants were assigned to either CL or continuous lighting subject to the availability of space and staff (quasi-randomised trial) |
| Blinding? (All outcomes) | No | The study could not be blinded |
| Blinding? (All outcomes) | Yes | The Brazelton Neonatal Behavioral Assessment Scale examiner was masked to group assignment at the exams at discharge from hospital. We did not include this outcome. |
| Incomplete outcome data addressed? | Yes | Outcomes reported on all infants assigned |
| Free of selective reporting? | Yes | |
| Free of other bias? | Yes | Appears free of other bias |
| Methods | Single centre, randomised, controlled trial |
|---|---|
| Participants | 62 infants born at < 31 weeks PMA Setting: An intensive care and a transitional care nursery of Duke University Medical Center and a level II special care nursery of Durham Regional Hospital, Durham, NC, US Study period: May 1998-July 1999 |
| Interventions | Neonates [mean (SD) PMA 27.1 weeks (2.0 weeks); mean (SD) birth weight 1000 g (223 g) across the 3 intervention groups] were assigned randomly to one of 3 light intervention groups: (1) CL from birth, (2) CL at 32 weeks’ PMA, and (3) CL at 36 weeks’ PMA in transition for discharge home. 22 infants were assigned to CL from birth and 19 infants were cared for in near darkness until 32 weeks PMA when they were cared for in cycled light. Cycled light was provided in an 11-hour-on, 11-hour-off pattern with one transition hour at the change of shifts. The incubator cover was folded on top of the incubator or the bassinet cover was off to achieve daylight at 200 to 225 lux between 7:30 AM and 6:30 PM. Light was provided with Philips Cool White fluorescent lamps (Philips, Somerset, NJ) measured as illuminance. 21 infants were assigned to the near darkness group. Near darkness (5-10 lux) was provided by using protective devices during the daytime and either dimming the room light or using protective devices at nighttime. Infants receiving ND were exposed to 5 to 10 lux light throughout the day except during 6:30 to 7:30 AM and 6:30 to 7:30 PM, when lighting levels varied based on change of shift nursing care needs. These transition hours were applied to all groups. |
| Outcomes | Average weekly weight gain, total number of ventilation days, days in supplemental oxygen, hospital stay (days), calories/kg/day, day of life start feeds, day of life to full feeds, brainstem auditory evoked response close to discharge from hospital (not included by us as an outcome), neurobehavioral organization at 32 and 36 weeks PMA, ROP. |
| Notes | For the analyses the group that received cycled light from birth and the group that received CL from 32 weeks PMA were reported as being exposed to cycled light (we report on the data from these two CL groups separately). The near darkness group was exposed to CL at 36 weeks' PMA. We report the data for this group as being the near darkness group. |
| Item | Judgement | Description |
|---|---|---|
| Adequate sequence generation? | Yes | Computer-generated random list |
| Allocation concealment? | Unclear | "... randomly assigned". Each set of multiple births were assigned to the same group. |
| Blinding? (All outcomes) | No | The study could not be blinded |
| Blinding? (All outcomes) | No | The study could not be blinded |
| Incomplete outcome data addressed? | Yes | Outcomes reported on all randomised infants |
| Free of selective reporting? | Yes | |
| Free of other bias? | Yes | Appears free of other bias. |
| Methods | Single centre, randomised, controlled trial |
|---|---|
| Participants | Preterm infants < 37 weeks weight < 2001 g, who were hospitalised in the NICU for at least 7 days and were still not ready for discharge a the time of recruitment. Setting: Single centre study in the Hospital Universiti Kebangsaan, Malaysia 1 August 1998 to 31 July 1999 |
| Interventions | 50 infants with a mean (SD) birth weight of 1482 g (236 g) and mean (SD) PMA of 31.6 weeks (2.2 weeks) were assigned to the “day-and-night” cyclical lighting group. Intensity of light mean (SD): 78.4 lux (24.7 lux). Duration of the intervention: from day 7 of life to discharge. For infants (n = 50) in the “day-and-night” cyclical lighting group, the lights in the cubicles were switched on between 07.00 and 19.00 h, and switched off between 19.00 and 07.00 h. 46 infants with a mean (SD) birth weight of 1465 g (280 g) were assigned “continuously dim environment” group. Intensity of light mean (SD): 5.9 lux (1.9 lux). For infants (n = 46) assigned to the “continuously dim environment” group, the lights in the cubicles were switched off throughout both day and night. Lights were switched on temporarily only during physical examination, treatment procedures or nursing care. |
| Outcomes | The primary outcome measures were the mean age of the infants when they regained their birthweight and the amount of weight gained by day 14 of life. Secondary outcomes included duration of hospital stay, infant's weight on discharge, age when enteral feeds were introduced. |
| Notes | Several outcomes were reported as median range (inter-quartile range), thus preventing the data to be used in RevMan. |
| Item | Judgement | Description |
|---|---|---|
| Adequate sequence generation? | Unclear | No information provided |
| Allocation concealment? | Yes | Sequentially numbered sealed envelopes which were opened in order |
| Blinding? (All outcomes) | No | The study could not be blinded |
| Blinding? (All outcomes) | No | The study could not be blinded |
| Incomplete outcome data addressed? | Yes | Outcome data reported on all randomised infants. No study infant died after recruitment into the study |
| Free of selective reporting? | Yes | |
| Free of other bias? | Yes | Appears free of other bias |
| Methods | Single centre, randomised, controlled trial |
|---|---|
| Participants | Preterm infants admitted to the NICU. Setting: Single centre, Lucile Packard Children's Hospital at Stanford, Palo Alto, CA US. Study period not stated. |
| Interventions | 19 infants; mean (SD) PMA 30.7 weeks (1.3 weeks) (birth weight range 962 -1817 g) were allocated to the "cycled" group and were cared for in a day-night lighted room. Their incubator/bassinet was covered from 1900 hr to 0700 hr with a nearly opaque blanket except during feeding or other interventions by parents and caregivers. The blanket was removed from 0700 hr to 1900 hr at which time the room lighting was turned up to standard lighting levels (approximately 300 lux) to produce a regular light-dark cycled condition. Number of days of intervention mean (SD) 35 days (25 days). 21 infants; mean (SD) PMA 29.8 weeks (1.7 weeks) (birth weight range 751 - 2280 g) were allocated to the "dim" group and were cared for in dimly lighted room (below 20 lux) around the clock. Their incubator/bassinet covered with a nearly opaque blanket except during feeding or other interventions by parents and caregivers. Number of days of intervention mean (SD) 39 days (17 days). No attempt was made to modify the light dark cycle at home. |
| Outcomes | Weight at 35 weeks and at 4 months PMA. Body temperature was recorded continuously for up to 3 days at 36 weeks PMA as well as at home at 1 and 3 months corrected age using a digital ambulatory recorder. Sleep was recorded at the same times using 24 hour time-lapse video recordings in conjunction with the rectal temperature recordings. This provided noninvasive monitoring of sleep. Infrared and low light level cameras allowed for recording of the infant even in the dark periods. Results for body temperature amplitude, active sleep time during the 12 hours night-time and quite sleep during the 12 hours night-time were presented in graph form only and the data could not be entered in RevMan |
| Notes | In a PAS abstract of the same study from 2001 there were 19 infants assigned to the cycled light group and 20 infants assigned to the dim light group. |
| Item | Judgement | Description |
|---|---|---|
| Adequate sequence generation? | Unclear | No information provided |
| Allocation concealment? | Unclear | "...randomly assigned to one of two groups" |
| Blinding? (All outcomes) | Yes | The study could not be blinded |
| Blinding? (All outcomes) | Yes | Some data were scored by an experienced infant sleep researcher who was masked to experimental condition of the infant. |
| Incomplete outcome data addressed? | Yes | The authors successfully recorded 19 infants in the cycled group and 21 infants in the dim group. The authors do not state how many infants were enrolled. See note above about different number of patients enrolled in the trial reported in an abstract in 2001. |
| Free of selective reporting? | Yes | |
| Free of other bias? | Yes | Appears free of other bias |
| Methods | Single centre (US), randomised, controlled trial |
|---|---|
| Participants | 62 infants < 32 weeks PMA and who were medically stable in NICU rooms were randomly assigned between 32 and 34 weeks PMA to either cycled lighting or continuous dim lighting. Setting: Single centre, Department of Pediatrics, Yale School of Medicine, New Haven, CT, US. Study period: Not stated. |
| Interventions | 29 infants mean (SD) PMA 28.5 weeks (0.5 weeks) and mean (SD) birth weight 1072 g (62 g) were assigned to cycled lighting mean (SD) 239 lux (29 lux) , from 7:00 AM to 7:00 PM; <25 lux, 7:00 PM to 7:00 AM for 25 days 33 infants mean (SD) PMA 28.5 weeks (0.4 weeks) and mean (SD) birth weight 1110 g (64 g) were assigned to dim lighting mean (SD) 28.5 lux (3 lux) from 7:00 AM to 7:00 PM; from 7:00 PM to 7:00 AM 15 lux (5 lux) for 24 days Activity (using acti-watches placed on one ankle) was continuously monitored from enrolment until approximately 1 month after discharge from the hospital. |
| Outcomes | Total number of movements per day in 10 days intervals (10 to 0 days before discharge; 1 to 10 days after discharge; 11 to 20 days after discharge; 21 to 30 days after discharge). Ratios of day-night activity (10 to 0 days before discharge; 1 to 10 days after discharge; 11 to 20 days after discharge; 21 to 30 days after discharge). Period analysis for circadian rhythms over the first 10 days at home. In the abstract it is stated that weight and head circumference were assessed up to 6 months after discharge from hospital. Those results are not presented in the main text. |
| Notes | The number of infants enrolled in the two groups differ in the 'Table of Patient Characteristics' and the abstract. The numbers are switched. We used the numbers as presented in the main text. We have written to the first author to clarify this difference, but we have not received an answer as of 2010 09 02. |
| Item | Judgement | Description |
|---|---|---|
| Adequate sequence generation? | Yes | Table of random numbers |
| Allocation concealment? | Unclear | One individual randomly assigned infants to the control or experimental group |
| Blinding? (All outcomes) | Yes | The investigators who analysed and interpreted the data were blinded to the treatment groups |
| Blinding? (All outcomes) | Yes | The investigators who analysed and interpreted the data were blinded to the treatment groups |
| Incomplete outcome data addressed? | Yes | At 20 days post discharge activity data were available for 24 experimental and 27 control infants. Total n = 51 infants At 30 days after discharge activity data were available for 15 experimental and 14 control infants. Total n = 29 infants In 11 infants activity data were not available through 20 days after discharge from the hospital, as a result of either premature removal of the acti-watches or mechanical failure |
| Free of selective reporting? | Yes | |
| Free of other bias? | Unclear | Appears free of other bias |
| Reason for exclusion | Not a randomised controlled trial |
|---|
| Reason for exclusion | A randomised controlled trial that compared ocular protection against the ambient light on both eyes. Infants in the control group did not receive ocular protection and were kept under regular light conditions |
|---|
| Reason for exclusion | This is a cohort study with 68 infants cared for in a cycled light room and 41 infants cared for in a dim room |
|---|
| Reason for exclusion | In this randomised controlled trial goggles that reduced visible light by 97% were placed within 24 hours of birth and remained in use until 31 weeks PMA or for a minimum of 4 weeks. The control group was care for in the standard lighting environment for each participating nursery. No group was exposed to cycled lighting. |
|---|
| Methods | Single centre, randomised, controlled trial |
|---|---|
| Participants | 20 low birth weight infants Setting: 2 NICUs in Seoul, South Korea Study period: Not stated |
| Interventions | 10 infants received cycled light for 10 days 10 infants served as a control group |
| Outcomes | Weight, O2 saturation, heart rate |
| Notes | This study was available in abstract form only. The full paper is written in Korean. We have written to the author asking for additional information and if possible a translation to English of the full paper. As of 2010 09 02 we have not received an answer. |
Reference |
Intervention |
Day time light intensity |
Night time light intensity |
|---|---|---|---|
Cycled lighting | Mean 342 lux (SD 55 lux) in the NICU Mean 415 lux (SD 42 lux) in the Stepdown unit | Mean 62 lux (SD 53 lux) in the NICU Mean 38 lux (SD 18 lux) in the Stepdown unit | |
Near darkness | 99.9 % light reduction | 99.9 % light reduction | |
Cycled lighting | Mean 78.4 lux (SD 24.7 lux) | Mean 5.9 lux (SD 1.9 lux) | |
Dim lighting | Mean 5.9 lux (SD 1.9 lux) | Mean 5.9 lux (SD 1.9 lux) | |
Cycled lighting | Range 200-225 lux | Range 5-10 lux | |
Near darkness | Range 5-10 lux | Range 5-10 lux | |
Cycled lighting | 300 lux | <20 lux | |
Dim lighting | < 20 lux | < 20 lux | |
Cycled lighting | Mean 239 lux (SD 29 lux) | < 25 lux | |
Dim lighting | Mean 28.5 lux (SD 3 lux) | < 25 lux |
Reference | Intervention | Daytime light intensity | Night time light intensity |
Cycled light | Lit by bright fluorescent strip lights | Windows were covered with dark lined curtains, lights were turned out, and the only illumination was provided by a low intensity night light | |
Continuous bright light | Lit by bright fluorescent strip lights that remained permanently on | ||
Cycled light | Range156-201 lux | Range 20-32 lux | |
Continuous bright light | Range 172-232 lux | Range 206 - 274 lux | |
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| Outcome or Subgroup | Studies | Participants | Statistical Method | Effect Estimate |
|---|---|---|---|---|
| 1.1 Weight (g) at 4 months | 1 | 40 | Mean Difference (IV, Fixed, 95% CI) | 181.00 [-484.00, 846.00] |
| 1.2 Weight (g) at 35 weeks PMA | 1 | 40 | Mean Difference (IV, Fixed, 95% CI) | 106.00 [-41.66, 253.66] |
| 1.3 Weight on day 14 | 1 | 96 | Mean Difference (IV, Fixed, 95% CI) | 0.00 [-103.88, 103.88] |
| 1.4 Weight gain by day 14 | 1 | 96 | Mean Difference (IV, Fixed, 95% CI) | -8.60 [-51.37, 34.17] |
| 1.5 Mean age when birth weight was regained | 1 | 96 | Mean Difference (IV, Fixed, 95% CI) | 0.10 [-2.57, 2.77] |
| 1.6 Cumulative average weekly weight gain (g) (CL from birth) | 1 | 43 | Mean Difference (IV, Fixed, 95% CI) | 24.00 [-50.97, 98.97] |
| 1.7 Cumulative average weekly weight gain (g) (CL from 32 weeks PMA) | 1 | 40 | Mean Difference (IV, Fixed, 95% CI) | 29.00 [-53.36, 111.36] |
| 1.8 Calories/kg/day (CL from birth) | 1 | 43 | Mean Difference (IV, Fixed, 95% CI) | 7.70 [-18.96, 34.36] |
| 1.9 Calories/kg/day (CL from 32 weeks PMA) | 1 | 40 | Mean Difference (IV, Fixed, 95% CI) | 0.20 [-17.62, 18.02] |
| 1.10 Day of life to start feeds (CL from birth) | 1 | 43 | Mean Difference (IV, Fixed, 95% CI) | 2.00 [-6.64, 10.64] |
| 1.11 Day of life to start feeds (CL from 32 weeks PMA) | 1 | 40 | Mean Difference (IV, Fixed, 95% CI) | -1.50 [-5.40, 2.40] |
| 1.12 Day of life to full feeds (CL from birth) | 1 | 43 | Mean Difference (IV, Fixed, 95% CI) | 0.80 [-20.83, 22.43] |
| 1.13 Day of life to full feeds (CL from 32 weeks PMA) | 1 | 40 | Mean Difference (IV, Fixed, 95% CI) | -6.70 [-25.15, 11.75] |
| 1.14 Ventilator days (CL from birth) | 2 | 170 | Mean Difference (IV, Fixed, 95% CI) | 0.67 [-2.07, 3.41] |
| 1.15 Ventilator days (CL from 32 weeks PMA) | 1 | 40 | Mean Difference (IV, Fixed, 95% CI) | -3.00 [-19.43, 13.43] |
| 1.16 Days in supplemental oxygen (CL from birth) | 1 | 43 | Mean Difference (IV, Fixed, 95% CI) | -16.40 [-46.98, 14.18] |
| 1.17 Days in supplemental oxygen (CL from 32 weeks PMA) | 1 | 40 | Mean Difference (IV, Fixed, 95% CI) | -17.60 [-47.26, 12.06] |
| 1.18 Length of stay (days) (CL from birth) | 2 | 170 | Mean Difference (IV, Fixed, 95% CI) | -4.67 [-14.81, 5.47] |
| 1.19 Length of stay (days) (CL from 32 weeks PMA) | 1 | 40 | Mean Difference (IV, Fixed, 95% CI) | -12.00 [-37.15, 13.15] |
| 1.20 ROP (any stage) | 2 | 189 | Risk Ratio (M-H, Fixed, 95% CI) | 0.83 [0.60, 1.13] |
| 1.21 ROP (stage >/=3) | 2 | 189 | Risk Ratio (M-H, Fixed, 95% CI) | 0.53 [0.25, 1.11] |
| 1.22 Infants requiring laser surgery | 1 | 62 | Risk Ratio (M-H, Fixed, 95% CI) | 0.51 [0.11, 2.32] |
| 1.23 Ratio of day-night activity over the 10 days preceding discharge from the hospital | 1 | 62 | Mean Difference (IV, Fixed, 95% CI) | 0.18 [0.17, 0.19] |
| 1.24 Period length of entrained circadian rhythms over the first 10 days at home (hrs) | 1 | 51 | Mean Difference (IV, Fixed, 95% CI) | -0.78 [-0.89, -0.67] |
| 1.25 Total number of movements per day (10 to 0 days before discharge) (Actogram data) | 1 | 62 | Mean Difference (IV, Fixed, 95% CI) | 73.00 [43.62, 102.38] |
| 1.26 Total number of movements per day (1 to 10 days after discharge) (Actogram data) | 1 | 51 | Mean Difference (IV, Fixed, 95% CI) | 82.00 [22.92, 141.08] |
| 1.27 Total number of movements per day (11 to 20 days after discharge) (Actogram data) | 1 | 51 | Mean Difference (IV, Fixed, 95% CI) | 429.00 [341.94, 516.06] |
| 1.28 Total number of movements per day (21 to 30 days after discharge) (Actogram data) | 1 | 29 | Mean Difference (IV, Fixed, 95% CI) | 536.00 [396.83, 675.17] |
| Outcome or Subgroup | Studies | Participants | Statistical Method | Effect Estimate |
|---|---|---|---|---|
| 2.1 Average caloric intake (kcal/kg/day) | 1 | 41 | Mean Difference (IV, Fixed, 95% CI) | 9.60 [-0.50, 19.70] |
| 2.2 Days to first oral feeding | 1 | 41 | Mean Difference (IV, Fixed, 95% CI) | -6.80 [-13.29, -0.31] |
| 2.3 Length of stay (days) | 1 | 41 | Mean Difference (IV, Fixed, 95% CI) | -16.00 [-32.26, 0.26] |
| 2.4 Days requiring supplemental oxygen | 1 | 41 | Mean Difference (IV, Fixed, 95% CI) | -20.80 [-44.29, 2.69] |
| 2.5 Days on ventilator | 1 | 41 | Mean Difference (IV, Fixed, 95% CI) | -18.20 [-31.40, -5.00] |
This review is published as a Cochrane review in The Cochrane Library, Issue 1, 2011 (see http://www.thecochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review. |
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