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Table 2 The effect of VAS/OPV at birth on infant mortality overall and by season of enrolment Censored at 18 November 2008 With full follow up time VAS OPV VAS vs. OPV VAS OPV VAS vs. OPV MR MR HR (95% CI) MR MR HR (95% CI) (Deaths/pyrs) (Deaths/pyrs) (Deaths/pyrs) (Deaths/pyrs) All 35.1 21.2 1.66 (0.68 – 4.02) 13.6 9.3 1.46 (0.65 - 3.29) 13/37 8/37 (14/103) (10/108) By season Dry 15.8 28.9 0.54 (0.16 - 1.84) 11.9 23.3 0.53 (0.18 - 1.55) 4/25 7/24 (5/42) (9/39) Rainy 77.1 7.4 10.0 (1.24 – 80.5) 14.9 1.4 9.91 (1.23 - 79.8) 9/12 1/14 (9/61) (1/69) P for interaction 0.02 0.02 MR per 100 years of follow up. Abbreviations: Pyrs person years of follow up. An average of 74% of the children was found at home at each visit. Of the 173 children enrolled in the anthropometry been vaccinated study, and nine supplemented. VAS and two All OPV mothers boys were died who had encouraged beforeto the take last their anthropometry child to a health visit centre at 6at months 6 weeks of after age to enrolment, get BCG, OPV, corresponding and DTP. At every to a relative home visit risk the (RR) assistants of loss checked to follow the children’s up due vaccination to deathcards for VAS and pointed vs. OPV out of missing 4.44 vaccines (0.99 for – the 20.08). mothers to ensure that all children got OPV. Enrolment In the staff subgroup did not take followed part in for the growth, follow-up more of the children children. in the VAS group were stunted at baseline. We therefore interventions adjusted length measures at the following visits for being Vitamin A was given as a 0.5 ml oral supplement which was stunted at baseline in analyses where adjustment changed the slowly released into the mouth of the child with a sterile syringe by a nurse. The estimate supplement by more came than in dark 10%. glass Two bottles weeks that after were enrolment at Skanderborg VAS children Pharmacy, were significantly Denmark, and lighter contained and had prepared 20 doses a lower of 25000 weight-for-age IU vitamin A as z-score retinyl and palmitate MUACand than 10 OPV IU vitamin children. E per These 0.5 ml differences oil. The bottles were were alsokept found at 2-8°C. at the 4, 6, Trivalent 10, and OPV 12 was week supplied visits through (data only the national shown for immunisation the 4 weeks programme visit, Table and administered 5). There were orally. noThere differences was no blinding. length and head circumference between the two groups at any visit Outcomes when length analyses were controlled for being stunted Primary at baseline. outcome: At infant 6 months mortality VAS children were more often The LBW children were visited within the first 3 days after underweight than OPV children (Table 5). Because of enrolment, and children living inside the study area were visited the imbalance of stunted children between the two on day 1–3 after enrolment to check for adverse events. All children groups, who had we not studied died, moved growth or between were travelling baseline were and visited the at 2, 6, 4 and weeks 12 months visit. It of turned age (Figure out 1). that The even children though living stunted inside the BHP children, study area regardless were furthermore of randomisation followed group, by the experienced HDSS. If the significantly child moved outside better linear Bissau growth or was than absent non-stunted at the visit, childrenor between neighbours baseline were asked and 4 if weeks, the child probably was still reflecting alive and a relatives how soon catchthey up growth, would be VAS told children if the child hadied. a significantly Children travelling poorer at 12 months linear growth were visited (Difference again at adjusted 15–18 months for being of age. stunted When at a death baseline was registered, = −1.02 the (−1.66; assistant −0.38)) asked between for the child’s baseline health and card. 4 A weeks). verbal autopsy There was conducted no interaction around between three months growth after and the death by a trained assistant. A local doctor read the autopsy season (data not shown). and proposed a diagnosis. The cause of death in broad categories was determined later after reading the verbal autopsy and taking into account Discussion the local doctor’s diagnosis and possible hospital records. Principal findings A cluster of deaths occurred during the rainy season We collected among information the boys enrolled on temperature, in the trial respiratory of VAS versus frequency, OPV weight gain and a few other variables in the first three days after enrolment to be able to detect possible adverse effects of the intervention (which we did not find); however, we did not collect information on possible specific diagnoses of the surviving children enrolled in the trial. and affected primarily those who had received VAS. The effect of VAS versus OPV differed significantly between Secondary the dry andoutcome: the rainygrowth season with a 10-fold higher mortalitysubgroup in the rainy of children season. was VASvisited recipients biweekly hadfor a significantly the first 3 A months poorer and growth at 4, measured 5, and 6 months by weight of age and by an MUAC anthropometry up to team 3 months measuring after enrolment. weight, length, and arm and head circumference. This sub study was initiated 10 April 2008 and continued Strengths enrolling and weaknesses children until the main trial was stopped at 18 The November close follow 2008. up Measurements of LBW children were has made been by conducted two trained field assistants who visited the home of the child. The length of since 2002 by the same staff. The trial had to be stopped the child was measured supine using a measuring board (Seca prematurely due to the cluster of deaths and the study Model 416). The weight of the undressed child was measured to therefore the nearest did not 20 g reach using the an electronic anticipated scale sample (Seca size. Model 835/336). Middle upper arm circumference (MUAC) and head circumference Mortality were measured using a TALC insertion tape. Children A suddenwho increase were in temporarily deaths among absent boys were who visited had received later the same VAS in or the following rainy season day, provoked whereas children our attention travelling andwere the only decision visited to at halt the inclusion. following We round. subsequently Children who detected moved that were localised these boys as had described all been above. at the neonatal nursery within the same week. The deaths were mainly due to respiratory sample problems. size Overall considerations the study sample size was clearly too We expected to enrol 900 boys in three years. With a mortality of small to make firm conclusions on the effect of receiving 15% between enrolment and 12 months of age, we had 80% power VAS versus placebo, but it is noteworthy that there were a to detect a 40% reduction in mortality for boys with a confidence level quite of strong 95%. With interaction a sample between size of 300 VAS boys and in season, the growth with study, a we tendency should for be aable beneficial to detect effect a weight in thedifference dry season, of but 150 ag in significant the proposed negativeversus effect the in the current rainypolicy season. with a power of 80% favor of and a one-sided alpha of 0.05. Growth special We found investigations worse growthinitiated for the VAS after recipients the identification than the of the OPVcluster recipients in the first months of life irrespective of Due season. to the Wecluster have studied of deaths the described effect ofin neonatal this paper, VAS one given of the authors with BCG (NL) at supervised birth and found the verbal a beneficial autopsies effect of the on children. growth In November and December 2008, after the cluster was identified, for boys [19]. Also, a trial from Indonesia showed a beneficial overall effect of neonatal VAS on growth up to 3 years we took 20 throat swabs from children currently treated at the neonatal nursery to search for viruses. The sample was collected with of age a cotton [20]. swab Another from trial the back from of Java, the child’s Indonesia, throat found and placed in complex an Eppendorff interactions tube between containing VAS 1 mL and of season alcohol. inThe children tubes were aged stored 6–48 at months room temperature supplementation until analysis with at Statens the least Serum Institut, beneficial Denmark. effect ofThe VAS samples in seasons were with examined a highfor burden Influenza of A and B, Respiratory Syncytial Virus, Human Metapneumovirus, Parainfluenza, Adeno, Corona, Rhino, Entero, and Parecho viruses using PCR on a MagNaPure system. However, when the samples were collected there was no longer a mortality problem at the nursery and nothing was found in the throat swabs. 46 neonatal INTENSIVE CARE Vol. XX No. X Xxxx XXXX neonatal INTENSIVE CARE Vol. 29 No. 4 Fall 2016 3 • •
Table 3 The fraction of dead/enrolled children by place o Lund et al. BMC Pediatrics 2014, 14:214 Table 3 The fraction of dead/enrolled children by Page place 7 of of 11 enrolment, month of enrolment, and randomisation group http://www.biomedcentral.com/1471-2431/14/214 enrolment, month of enrolment, and randomisation group No. of deaths/enrolled (% dead) No. of deaths/enrolled (% dead) Enrolled Enrolled at neonatal neonatal Enrolled at maternity Enrolled at maternity nursery nursery ward or health ward centres or health centre Table 3 The fraction of dead/enrolled children by place of Month of enrolment VAS OPV VAS OPV enrolment, Month of month enrolment of enrolment, VAS and randomisation OPV VAS group OPV February 0/0 (0) 1/2 (50) 0/4 (0) 1/4 (25) February No. 0/0 of deaths/enrolled (0) 1/2 (50) (% dead) 0/4 (0) 1/4 (25) March 2/3 (67) 0/4 (0) 0/11 (0) 1/10 (10) March Enrolled 2/3 at neonatal (67) 0/4 Enrolled (0) at maternity 0/11 (0) 1/10 (10) April 2/6 (33) nursery 1/4 (25) ward 0/8 (0) or health 1/10 centres (10) April 2/6 (33) 1/4 (25) 0/8 (0) 1/10 (10) Month May of enrolment 0/5 VAS (0) 3/4 OPV (75) 1/9 VAS (11) 1/7 OPV (14) February Total, May dry season 4/14 0/0 (29) (0) 0/55/14 1/2 (0)(50) (36) 3/4 1/32 0/4 (75) (0) (3) 1/9 4/31 1/4 (11) (25) (13) 1/7 (14) June March Total, dry season 2/3 0/2 (67) (0) 4/140/4 (29) (0) 5/14 0/11 0/5 (36) (0) 1/32 1/10 0/6 (10) (0) (3) 4/31 (13) July April June 1/3 2/6 (33) 1/4 0/1 (25) 0/2 (0) (0) 1/6 0/8 (17) (0) 0/4 (0) 1/10 0/8 (10) 0/5 (0) 0/6 (0) August May 1/2 0/5 (50) (0) 3/4 0/2 (75) (0) 1/9 0/8 (11) (0) 1/7 0/5 (14) (0) July 1/3 (33) 0/1 (0) 1/6 (17) 0/8 (0) September Total, dry season 4/14 5/6 (83) (29) 5/14 1/6 (17) (36) 1/32 1/9 (11) (3) 4/31 0/9 (13) (0) August 1/2 (50) 0/2 (0) 0/8 (0) 0/5 (0) October June 0/4 0/2 (0) 0/0 0/4 (0) 0/17 0/5 (0) 0/20 0/6 (0) November JulySeptember 1/3 0/0 (33) (0) 5/6 0/1 0/3 (83)(0) 1/6 1/6 0/8 (17) (0) 1/9 0/8 0/7 (11) (0) 0/9 (0) Total, August October rainy season 7/17 1/2 (50) (41) 0/41/16 0/2 (0) (0) (6) 0/0 2/53 0/8 (0) (4) 0/17 0/55 (0) 0/20 (0) Figure 2 Cumulative mortality curves as a function of receiving VAS or OPV. (a) Overall, (b) Dry season, (c) Rainy season. respiratory diseases [21]. However, VAS was not harmful. The effect of OPV0 on growth has not been studied before. Figure 2 Cumulative mortality curves as a function of receiving VAS or OPV. (a) Overall, (b) Dry season, (c) Rainy season. Figure Chance 2. 2 Cumulative or cluster mortality mortality curves curves as a function as a function of receiving of VAS receiving or OPV. (a) Overall, The(b) sudden Dry season, increase (c) Rainy in season. VAS or the number of deaths among respiratory OPV. (a) Overall, diseases (b) [21]. Dry season, However, (c) Rainy VAS was season. not harmful. boys who had received VAS and who had been in contact The effect of OPV0 on growth has not been studied before. with the neonatal nursery made us speculate that they had been infected with a pathogen that either interacted negativelyamong with VAS children or was recruited dealt better in October with byand OPV November. vaccinated Likewise Chance we conducted or cluster immunological examinations of cytokine responses The sudden increase in the number of deaths among Few children boys. Awere pathogen included could and the easily cluster haveof spread deaths had among the boys who had received VAS and who had been in contact passed. children Hence, through the results thewere suboptimal unrevealing. hygienic conditions. We Chancewith or cluster the neonatal nursery made us speculate that they had could not identify any likely pathogen or immunological been infected with a pathogen that either interacted negatively statistical methods Statistical analysis with VAS was or performed was dealt better using Stata with 11.2 by OPV software vaccinated (Stata boys. Corporation, A pathogen College could Station, easily TX). have Baseline spread characteristics among the of children children in the through VAS group the suboptimal vs. children hygienic in the OPV conditions. group were We compared couldusing not logistic identifyor any linear likely regression. pathogen or immunological respiratory diseases [21]. However, VAS was not harmful. The effect of OPV0 on growth has not been studied before. The sudden increase in the number of deaths among boys who had received VAS and who had been in contact with the neonatal nursery made us speculate that they had been infected with a pathogen that either interacted negatively with VAS or was dealt better with by OPV vaccinated boys. A pathogen could easily have spread among the children through the suboptimal hygienic conditions. We Total September November 11/31 5/6 (83) (35) 0/06/30 1/6 (0)(17) (20) 0/3 3/85 1/9 (0) (11) (4) 0/8 4/86 0/9 (0) (5) 0/7 (0) October 0/4 (0) 0/0 (0) Total, rainy season 7/17 (41) 0/17 (0) 1/16 (6) 0/20 (0) 2/53 (4) 0/55 (0) November 0/0 (0) 0/3 (0) 0/8 (0) 0/7 (0) We differences used Total Cox between regression theto two 11/31 calculate groups (35) Hazard which 6/30 (20) Ratios could(HR) 3/85 explain (4) for 4/86 (5) mortality Total, rainy with season 95% Confidence 7/17 (41) Intervals 1/16 (6) (CI). 2/53 (4) Robust 0/55 standard (0) the cluster, but this is perhaps not surprising as the mortality was no longer elevated at the time when we collected errors Total were used to account 11/31 (35) for 6/30 interdependency (20) 3/85 (4) of outcome 4/86 (5) between twins. Age was used as the underlying time and was throat swaps and immunological samples. The pathological thus differences inherently controlled betweenfor the in the two mortality groups analyses. whichTest could for explain pictures of the dead children were quite different and the proportionality differences of hazard rates were computed using Schoenfeldt residuals deaths the did cluster, between and not by occur but the thistwo visual immediately. perhaps groups which inspection of Hence, not the cumulative itsurprising could explain is unlikely risk that as the mortal the curves. Cumulative theity cluster, children wasbut nothis mortality diedlonger perhaps of the curves same elevated not surprising were infection. at the drawn However, time as the using the itwhen mortality was no longer elevated at the time when we collected Kaplan-Meier may bewe collected method. speculated throat We swaps that tested the whether and pathogen immunological there weakened were differences the samples. children in the The who age pathologica throat swaps and immunological samples. The pathological death died later, in a linear possibly regression by encounter model with on the a new log-transformed pathogen. age. pictures pictures of the ofdead the children dead children were quite were different quiteand different the and the When we halted the trial we did not know whether We deaths deaths there tested did might interactions not didoccur not occur immediately. immediately. be morebetween deaths among baseline Hence, children characteristics, itHence, is unlikely it that is unlikely tha with whom season the the children we hadof children not enrolment died of died yet had(rainy theof same contact. season theinfection. same However, June infection. to However, that November, it However, may was not dry be it may be the season case; speculated there December that the werethat to noMay), pathogen the additional and pathogen admission weakened early weakened deaths to theneonatal children among the nursery who the children who before died children died later, enrolment later, possibly recruited possibly by by in Wald encounter October by test encounter statistics. with a new and November. We with analysed pathogen. aThe neweffect problem apparently had passed. However, restart intervention pathogen. modification When weby halted investigating the trial the we homogeneity did not know of the whether effect of When we might bein more the halted different the deaths among categories trial we children of did the with suspected not know whethe whom the trial. Though this may have been due to a pathogen modifier, wethere had not also might yet by Wald had be contact. test more statistics. deaths However, Effect among that modifiers was children not considered thewith whom were case; we age there had at and were not place yet noof additional had enrolment, contact. early place However, deaths of residence, among that birth the was not the weight, Table 4head Causes circumference, of death by MUAC, intervention and maternal and ageMUAC, at death children recruited in October and November. The problem apparently had passed. However, we did Deaths not after restart 2 age, case; there were no additional early deaths among the parity, schooling, and Deaths socioeconomic within status. children recruited first 2 months in October andmonths November. of age The prob the trial. Though this may have been due to a pathogen lem apparently VAShad passed. OPV However, VAS we OPV did not restar Resp. the diseases trial. Though 5 this may 1 have been 2 due to 1 a pathogen Table 4 Causes of death by intervention and age at death Diarrhoea 2 0 0 0 Deaths within Deaths after 2 Sepsis Table 4 Causes1 first of2death months0 by intervention 0months of and age1 age at death Kernicterus VAS 0 OPV 1 Deaths within VAS 0 OPV 0 Deaths after 2 Chickenpox Resp. diseases 05 first 20 1 months 02 months 1 of age Unknown* Diarrhoea 32 VAS 20 OPV 10 VAS 30 OPV Total Sepsis Resp. diseases 11 1 5 40 1 30 61 2 1 Kernicterus *Three families moved before 0 autopsy, and1 a diagnosis could 0 not be 0 established Diarrhoea in six children. 2 0 0 Chickenpox 0 0 0 1 0 Unknown* Sepsis 3 1 2 0 1 03 1 Total Kernicterus 11 0 4 1 3 06 0 *Three Chickenpox families moved before autopsy, 0 and a diagnosis 0could not be established in six children. 0 1 Unknown* 3 2 1 3 neonatal 4 INTENSIVE CARE Vol. 29 No. 4 Fall 2016 Total neonatal INTENSIVE 11 CARE 4 Vol. XX No. X 3Xxxx XXXX 47 6 • • *Three families moved before autopsy, and a diagnosis could not be
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