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J Pediatr (Rio J). 2019;xxx(xx):xxx---xxx
1

www.jped.com.br

REVIEW ARTICLE

2 Analgesic management of uncomplicated acute

3 sickle-cell pain crisis in pediatrics: a systematic review
4 and meta-analysis夽
∗
5 Q2 Manou Irmina Saramba , Sandeep Shakya , Dongchi Zhao

6 Zhongnan Hospital of Wuhan University, Children’s Digital and Health Data Research Center, Department of Pediatrics, Wuhan,
7 Q3 China

8 Received 26 January 2019; accepted 10 May 2019

9
KEYWORDS Abstract
10
Anemia, sickle cell; Objectives: To capture evidence of the efficacy and safety of pharmacological analgesia for
11
Sickle cell disease; uncomplicated acute sickle-cell pain in pediatric patients compared to placebo.
12
Acute pain; Sources of data: Searches for key evidence were performed from March 1 to 31, 2018, for
13
Analgesic drugs; randomized controlled trials of pharmacological analgesia compared to placebo for uncompli-
14
Pediatrics cated acute sickle-cell pain in a pediatric sample. The authors searched ten scientific databases
15 including, among others, PubMed, MEDLINE, Embase, and Clinicaltrials.gov for this systematic
16 review and meta-analysis.
17 Summary of the findings: Four trials (n = 227) were selected by the inclusion criteria (intranasal
18 fentanyl, intravenous magnesium, arginine, and inhaled nitric oxide). The quality of evidence
19 ranged from low to moderate for each outcome. Meta-analysis of changes in the ladder of pain
20 score (p = 0.72), length-of-stay in hospital (p = 0.65), and amount of narcotics used during the
21 study (p = 0.10) showed non-statistically significant differences and a lack of amelioration pro-
22 vided by pharmaceutical analgesics in treatment group. The adverse events reported that more
23 participants in the intervention arm underwent pain, with statistically significant differences at
24 the drug delivery site in studies using intranasal fentanyl and intravenous magnesium (p = 0.03).
25 Conclusions: Pharmacological analgesia appears to be uncertain in improving the intensity and
26 providing relief of acute pain crisis in pediatric patients with sickle-cell anemia. With respect
27 to clinical advantage, no decisive deduction about the clinical efficacy may be made regarding
28 these medications in acute sickle-cell pain management in the pediatric age group.
29 © 2019 Published by Elsevier Editora Ltda. on behalf of Sociedade Brasileira de Pediatria. This is
30 an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
31 by-nc-nd/4.0/).

夽 Please cite this article as: Saramba MI, Shakya S, Zhao D. Analgesic management of uncomplicated acute sickle-cell pain crisis in

pediatrics: a systematic review and meta-analysis. J Pediatr (Rio J). 2019. https://doi.org/10.1016/j.jped.2019.05.004
∗ Corresponding author.

E-mail: zhao wh2004@hotmail.com (D. Zhao).

https://doi.org/10.1016/j.jped.2019.05.004
0021-7557/© 2019 Published by Elsevier Editora Ltda. on behalf of Sociedade Brasileira de Pediatria. This is an open access article under
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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32
PALAVRAS-CHAVE Manejo analgésico da crise dolorosa falciforme não-complicada em pediatria: uma
33
Anemia falciforme; revisão sistemática e meta-análise
Doença falciforme;
34 Resumo
Dor aguda;
35 Objetivos: Obter evidências da eficácia e segurança da analgesia farmacológica para dor falci-
Drogas analgésicas;
36 forme aguda não-complicada em pacientes pediátricos em comparação com placebo.
Pediatria o
37 Fontes de dados: Uma busca de evidências-chave foi realizada de 1 a 31 de março de 2018
38 por ensaios clínicos randomizados controlados de analgesia farmacológica em comparação com
39 placebo para dor aguda falciforme não-complicada em uma amostra de pacientes pediátri-
40 cos. Os autores pesquisaram dez bases de dados científicos envolvendo, entre outras, PubMed,
41 MEDLINE, Embase e Clinicaltrials.gov para esta revisão sistemática e meta-análise.
42 Resumo dos dados: Quatro ensaios (n = 227) foram considerados para critérios de inclusão (fen-
43 tanil intranasal, magnésio intravenoso, arginina e óxido nítrico inalado). As evidências de
44 qualidade variaram de baixas a moderadas para cada desfecho. A meta-análise de alterações na
45 escala de dor (p = 0,72), tempo de internação hospitalar (p = 0,65) e quantidade de analgésicos
46 utilizados durante o estudo (p = 0,10) mostrou diferença não estatisticamente significativa e a
47 ausência de melhora resultante da utilização do fármaco analgésico no grupo de tratamento. Os
48 eventos adversos relatados mostraram que no braço de intervenção mais participantes sofreram
49 dor com diferença estatisticamente significativa no local de aplicação do fármaco utilizando
50 fentanil intranasal e magnésio intravenoso (p = 0,03).
51 Conclusões: A analgesia farmacológica parece ter um efeito incerto na melhora da intensidade
52 e alívio da crise de dor aguda em pacientes pediátricos com doença falciforme. Em relação à
53 vantagem clínica, ainda é incerta a eficácia clínica desses medicamentos no tratamento da dor
54 aguda falciforme no grupo etário pediátrico.
55 © 2019 Publicado por Elsevier Editora Ltda. em nome de Sociedade Brasileira de Pediatria. Este
56 é um artigo Open Access sob uma licença CC BY-NC-ND (http://creativecommons.org/licenses/
57 by-nc-nd/4.0/).

58 Introduction relies on the usage of non-steroidal anti-inflammatory drugs 86

(NSAIDs), opioids, hydration, common analgesics, adjuvant 87

59 Sickle-cell disease (SCD) is an inherited red cell disorder medications, and with the recent tendency towards dissocia- 88

60 that encompasses a unit of disease that is the world- tive anesthetics. Generally speaking, the opiate derivatives 89

61 wide common molecular origin hemoglobinopathy.1---3 The have been believed to be the ‘‘gold standard’’ analgesic 90

62 most prevalent SCD genotypes quintessentially include the for managing sickle pain secondary to VOC.13,20,21 In case 91

63 homozygous state (HbSS) and compound heterozygous con- of uncontrolled pain after high-dose intravenous opiates, 92

64 ditions such as sickle trait, hemoglobin-C (HbSC) or beta a dissociative anesthetic such as ketamine may be one of 93

65 (␤) thalassemia (HbS␤+ and Hb␤0 thalassemia).4---7 Change the alternatives.21 Dunlop’s intervention review, founded 94

66 to the polymer under a deoxygenated state of hemoglobin on nine randomized controlled trials (RCTs), concluded that 95

67 defines the hallmark of the condition that induces sickling the majority of studies have been unmet and that it was 96

68 formation; hence vaso-occlusive crisis (VOC), which is the impossible to achieve relevant meta-analysis owing to insuf- 97

69 label of SCD causing jammed microvascular beds, and lead- ficiency of data, small sample size, and inconsistencies in 98

70 ing to tissue ischemia.8---10 Acute pain crisis is a key feature methods and reports. Hence, those authors judged that evi- 99

71 of the external expression of VOC, varying from mild to dence for analgesic interventions in sickle-cell pain crises 100

72 burdensome and debilitating pain which may continue from was lacking.22 In 2015, Archer et al. outlined the limits of 101

73 hours to weeks. Most often this is the reason to seek medi- opioids that they are rather in nociceptive frame regarding 102

74 cal care in the emergency department (ED), representing to the pathophysiology highlighting VOC and its inflamma- 103

75 approximately 70% of children with SCD, and is the result tory effects.23 Several approaches were referenced for the 104

76 of increased readmission rates in hospitals.11---17 The inci- advancement of in-depth understanding of the physiopatho- 105

77 dence of painful acute crisis tends to increment throughout genesis underlying of the sickle-cell pain crisis.11,24,25 A 106

78 childhood and reaches its highest in adolescence. The first potential novel therapy pathway is therefore believed nec- 107

79 years of life are, however, the critical phase of the onset of essary to manage the pain crisis. 108

80 acute pain crisis.4,18 Despite the in-depth understanding of Intranasal fentanyl is a suitable opioid choice compared 109

81 acute sickle-cell pain, relieving it remains a big challenge in to the parenteral opiate pathway in order to mitigate the 110

82 children. pain promptly and efficiently, avoiding the use of intra- 111

83 So far, objectifying therapy on the underlying mecha- venous or intramuscular opiate methods.18,20 Also, the nasal 112

84 nisms of VOC has shown no efficacy.19 Usually, symptomatic mucosa is an attractive and a broad area, with a rich 113

85 alleviation of uncomplicated sickle-cell acute pain crisis vascular plexus, representing a rapid route for medica- 114

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115 tion administration without going through gastrointestinal Inclusion criteria 166

116 degradation or the hepatic metabolism.20 Based on break-

117 throughs in the pathophysiological comprehension of VOC, To be considered, clinical trials needed to have at least ten 167
118 these three components, intravenous magnesium, arginine, participants in each study arm, in any clinical setting, and 168
119 and inhaled nitric oxide, have sparked the curiosity of sci- were required to be randomized, double-blinded, placebo- 169
120 entific literature due to their critical role in endothelium controlled studies, with parallel or single group and/or pilot 170
121 and inflammatory syndrome regulation during the sickle-cell study designs, and whose interventions had an analgesic pur- 171
122 crisis.26---36 pose. The study population was pediatric patients that were 172
123 Thereby, the present authors chose to conduct a sys- aged between 3 and 21 years old, with three SCD genotypes 173
124 tematic review and meta-analysis of RCTs to examine the --- limited to HbSS, HbSC, and HbS-␤ thalassemia --- expe- 174
125 efficiency and safety of these pharmaceuticals with anal- riencing an uncomplicated acute pain episode from VOCs. 175
126 gesic aims. This meta-analysis review was performed to Non-RCTs and RCTs that reported the eligibility combination 176
127 gather an extensive available body of experimental trials of both pediatric and adult participants, studies in animals, 177
128 evaluating the change in the ladder of pain score, length-of- and studies that outlined outcomes in participants with 178
129 stay in hospital, and amount of narcotics used in a pediatric complicated severe sickle-cell pain crisis (e.g., acute chest 179
130 sample with uncomplicated acute VOCs in SCD. syndrome, acute splenic sequestration, and cerebrovascu- 180

lar accident) and chronic sickle-cell pain, studies published 181

with only abstract, and studies with double-blinded active 182

comparator trials of drugs were excluded. Therefore, seven 183

studies were excluded: three non-RCTs,39---41 one study with 184

131 Methods a paucity of available participants,42 one including merely 185

two genotypes,43 one with chronic pain,44 and one with an 186
132 Study research strategy active comparator.45 The included studies had fully out- 187

lined two of these following outcome measures: assessing 188

133 This systematic review and meta-analysis was initiated by pain score, length-of-stay, cumulative amount of narcotic 189
134 manual search of the studies and references from two use, and adverse events (the definitions of outcome mea- 190
135 articles.23,37 Searches were performed irrespective of where sures are reported in Table 2). Effectively, the studies 191
136 the studies were conducted, without language restric- that reported on disease-modifying therapy (e.g., hydrox- 192
137 tions, and were limited to humans. The study plan obeyed yurea) for SCD were excluded, which is beneficial for VOCs. 193
138 the Preferred Reporting Items for Systematic Reviews and The studies addressed interventions particularly in regu- 194
139 Meta-Analyses (PRISMA) guidelines for meta-analyses of lar blood transfusion, erythro-exchange regimens, colloids, 195
140 interventional studies.38 fluid replacement, medications that drive to dwarf the less- 196
141 The authors completed searches for the key evidence in deformable red blood cells, and anticoagulants which are 197
142 ten scientific databases from March 1 to 31, 2018; trials were thought to preclude the SCD-crisis and to minimize the fre- 198
143 published between January 1, 2001, and December 31, 2017: quency of pain by impeding the sickling process were also 199
144 MEDLINE (OvidSP), Embase, PubMed, CENTRAL, LILACS, excluded. Others studies designed interventions featuring 200
145 ISRCTN Registry, CINAHL (EBSCOHost), Web of Science (CPCI- aggressive analgesic therapy with systemic treatment (oral, 201
146 S) for RCTs, and for ongoing trials the authors searched subcutaneous, epidural, and intramuscular administration) 202
147 Clinicaltrials.gov and WHO-ICTRP. For each database, a com- involving strong opioids, weak opioids (codeine and dextro- 203
148 prehensive search strategy was developed by using Boolean propoxyphene), and non-opioids agents (paracetamol and 204
149 operators, and controlled through MeSH terms. Some of the NSAIDs) were not included in the review. 205
150 search terms, as detailed in Table 1, included: "anemia,
151 sickle cell," "pain," "acute pain," "randomized controlled
Data extraction 206
152 trial," p̈lacebo," "clinical trial," and d̈ouble blinded." Addi-
153 tionally, for further searches Google Scholar was used, and
One reviewer (MIS) performed the data extraction from the 207
154 the authors manually searched the other bibliographies from
included trials, which was reviewed by all investigators (SS 208
155 included studies, which were considered for references
and DZ), and all discrepancies were also resolved with all 209
156 supplied to other studies or were missed in the primary elec-
authors by agreement. One investigator (MIS) extracted the 210
157 tronic search. Only the studies published under peer-review
general details from each study according to the Cochrane 211
158 were considered in the search.
Handbook for Systematic Reviews of Interventions,46 which 212

was subsequently crosschecked by all reviewers. The form 213

included the first author and year of publication, study 214

location, setting, design, characteristics of participants, 215

159 Study selection description of interventions, and study results (pre-specified 216

outcomes). 217

160 Two review authors (MIS and SS) independently searched the
161 databases. Also, they independently identified the perti- Quality assessment and risk of bias 218

162 nence of the retrieved studies and examined the full-text

163 papers to decide upon eligibility according the criteria. Any Risk of bias for methodological quality of the eligible tri- 219
164 discrepancies about the inclusion of full-text studies were als was ascertained and assessed by one review author (MIS) 220
165 elucidated and resolved by consensus of all investigators. and followed with a review by all investigators using each 221

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Q1 Table 1 Electronic search strategy.

Database/resource Strategy
PubMed (2001 to 2017) search limited in #1 (änemia, sickle cellÖR s̈ickleÖR s̈ickle cellÖR s̈ickle cell disease¨)
Clinical Trial and "humans"[MeSH Terms] #2 (p̈ainÖR äcute painÖR p̈ainful¨)
n = 102 #3 (r̈andomized controlled trialÖR c̈ontrolled clinical trialÖR r̈andomizedÖR
p̈laceboÖR d̈ouble blinded¨)
#4 #1 AND #2 AND #3
Clinicaltrials.gov (2001 to 2017) n = 171 Search terms: pain
Study type: interventional studies
Conditions: anemia, sickle cell
CENTRAL (Cochrane Central Register of #1 MeSH descriptor: [Anemia, Sickle Cell] explode all threes
Controlled Trials of the Cochrane Library) #2 (s̈ickleör s̈ickle cellör s̈ickle cell disease¨)
search limited in trials (2001 to 2017) n = 110 #3 #1 or #2
#4 MeSH descriptor: [Pain] explode all trees
#5 MeSH descriptor: [Acute Pain] this term only
#6 "painful"
#7 #4 or #5 or #6
#8 #3 and #7
LILACS n = 12 tw: (sickle) AND (instance:r̈egional¨) AND ( db:(L̈ILACS¨) AND
type of study:(c̈linical trials¨))
WHO ICTRP (2001-2017) [Title: pain
n = 78 Condition: sickle
Recruitment Status: ALL]
MEDLINE (OvidSP) 1. exp Anemia, Sickle Cell/
Specific year range (2001-2017) n = 66 2. (sickle or sickle cell or sickle cell disease).tw,kf.
3. or/1-2
4. exp Pain/
5. Acute Pain/
6. painful.tw.
7. or/4-6
8. 3 and 7
9. randomized controlled trial.pt.
10. controlled clinical trial.pt.
11. randomi*.tw.
12. placebo.ab.
13. clinical trial.sh.
14. randomly.ab.
15. groups.ab.
16. trial.tw.
17. or/9-16
18. exp animals/ not humans/
19. 17 not 18
20. 8 and 19
ISRCTN Registry Search 1: pain
n = 11
n=6
Condition: sickle cell
Search 2: pain
Condition: sickle cell disease
CINAHL (Cumulative Index to Nursing and S1 (MH änemia, sickle cell+¨)
Allied Health Literature) Complete S2 TX (s̈ickleÖR s̈ickle cellÖR s̈ickle cell disease¨)
(EBSCOHost): (2001-2017) n = 88 S3 S1 OR S2
S4 (MH p̈ain+¨)
S5 TX (äcute pain¨)
S6 TX (p̈ainful¨)
S7 S4 OR S5 OR S6
S8 S3 AND S7
S9 (MH c̈linical trials+¨)
S10 PT clinical trial
S11 TI (clinic* N1 trial* OR controlled N1 trial*)

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Table 1 (Continued)

Database/resource Strategy
S12 TI (doubl* N1 blind*)
S13 TI (randomi* OR placebo*)
S14 S9 OR S10 OR S11 OR S12 OR S13
S15 S8 AND S14
Embase (2001-2017) n = 89 #1 ’sickle cell anemia’/exp
#2 ’sickle cell anemia’:ab,ti
#3 ’sickle cell’:ab,ti
#4 #1 OR #2 OR #3
#5 ’pain’/exp
#6 ’pain’:ab,ti
#7 #5 OR #6
#8 #4 AND #7
#9 ’randomized controlled trial’:ab,ti
#10 ’controlled clinical trial’:ab,ti
#11 ’placebo’:ab,ti
#12 ’double blind procedure’:ab,ti
#13 #9 OR #10 OR #11 OR #12
#14 #8 AND #13
#15 ’randomized controlled trial’/de
#16 #14 AND #15
#17 [embase]/lim
#18 #16 AND # 17
Web of Science CPCI-S TOPIC: (anemia, sickle cell OR sickle OR sickle cell OR sickle cell disease) AND
(2001-2017) n = 27 TOPIC: (pain OR acute pain OR painful) AND TOPIC: (random OR randomly OR
randomised OR randomized OR blind OR blinded OR control group OR placebo
OR controlled study OR groups OR trial OR trials OR literature search OR
medline OR pubmed OR cochrane OR embase)

Table 2 Definitions of outcome measures.

Outcome measures Definitions

Change in the ladder of pain score
Length-of-stay primarily in the
hospital (hours)
Amount of narcotics used during the
study
Proportion experiencing minor
adverse events
Proportion experiencing serious
adverse events
In all studies only two types of pain scale were used, each addressed 0 ‘‘no pain’’
and 10 ‘‘very great pain’’; decreased pain is from a score of pain < 6 cm on the
visual analog pain scales (VAS) or < 6 on the Faces Pain Scale
Recorded as the number of hours from the time of the start of the first study
medication until the time of discharge from hospital
Cumulative amount of parenteral intravenous opioid used
Includes transient hypotension, pruritus, hives, pain at the drug delivery site,
drowsiness, nausea or vomiting, hypoxia, headache, or tachycardia
Incidence that occurred during the study with acute clinical deterioration, including
serious complications of a vaso-occlusive crisis (VOC) with red blood cell transfusion,
acute chest syndrome, liver function enzymes increased, hospitalization for pain
management, return to emergency department within 1 week, 24 hr, and 72 hr, and
readmission for pain management within 1 month

222 domain of relevant bias in accordance with the Cochrane agreement of all investigators. As advocated in the Cochrane 231

223 risk assessment tools for randomized study designs.47 Each Collaboration, the Grading of Recommendations, Assess- 232

224 trial was judged as low, high, or unclear risk of selection bias ment, Development, and Evaluation (GRADE) Profile48 was 233

225 (random sequence generation and allocation concealment), used to rate the quality of the evidence for individual 234

226 performance bias (blinding of participants and personnel), outcome by using the five leading domains, including the 235

227 detection bias (blinding of outcome assessment), attrition following: limitation of the study design or execution (risk 236

228 bias (incomplete outcome data), reporting bias (selective of bias); inconsistency, indirectness, and imprecision of 237

229 reporting), and other bias (Table 3, more details in Sup- results; and, publication of bias. Hence, the quality of evi- 238

230 plementary material). Any discrepancies were resolved by

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Table 3 Quality judgment of the individual studies.

Study, year Randomized Analyzed Withdrawn Sequence Allocation Blinding of Blinding of Incomplete Selective Quality
(reference) generation conceal- participants outcome outcome reporting
ment and assessment data (reporting
personnel (detection (attrition bias)
(perfor- bias) bias)
mance
bias)
Fein et al.54 130 49 70 11 (lost) Low risk Low risk Low risk Low risk Low risk Low risk High
Goldman et 106 104 2 Low risk Low risk Low risk Unclear risk Low risk Low risk High
al.55
Morris et al.56 56 54 2 Low risk Low risk Low risk Unclear risk Low risk Low risk High
Weiner et al.57 25 20 5 Unclear risk Unclear risk Low risk Unclear risk Low risk Low risk High

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239 dence was judged as very low, low, moderate, or high for Study characteristics 296

240 each outcome.

The summary of the study characteristics are described in 297

241 Data synthesis and analysis Table 4 and in Supplementary Material. Moreover, these 298

studies were published between the year 2003 and 2016. 299

242 From each outcome measure, the authors retrieved and A total of four trials involved 227 participants.54---57 Among 300

243 directly extracted the mean (standard deviation [SD]) or cal- these, 111 patients were incorporated into intervention 301

244 culated it from the median and interquartile ranges (IQRs) arms and 116 into placebo arms. 302

245 by using the method of Hozo et al.49 Continuous outcomes In the studies selected for inclusion in meta-analysis, 303

246 were recorded as mean difference (MD) along with 95% confi- three RCTs were found with interventional drugs that have 304

247 dence intervals (CIs) in outcomes measured using the same crucial interventional role in the pathological mechanism 305

248 scale among studies (length-of-stay, primarily in-hospital), of VOCs, including intravenous magnesium, arginine, and 306

249 and as standardized mean difference (SMD) among studies nitric oxide, and one RCT of intranasal fentanyl, which is 307

250 that had used scales or units in different ways for measur- an opioid derivative. All of the RCTs were compared with a 308

251 ing identical outcomes (change in ladder of pain score and non-treatment arm as placebo control, and those drugs were 309

252 amount of narcotics used during the study). Also, the num- subsequently investigated. There were two studies with par- 310

253 ber of events from each study in the two arms (split by the allel design54,55 ; one single group design56 and one pilot 311

254 same investigator into minor and serious) and the summary design.57 All trials included were of patients admitted to 312

255 statistic, presented by dichotomous outcomes as risk ratios the emergency department (ED) for an acute episode of pain 313

256 (RR) and 95% CIs, were extracted. Contact was established crisis caused by VOC that used scale measurement of pain; 314

257 with the principal authors of the identified reviews and tri- and that were of shorter duration of treatment, and were 315

258 als to ask for any unpublished or missing data. The present achieved in a normal period. Three of the included studies 316

259 authors derived pooled estimates of SMD, MD, and 95% CIs were done in United States54,56,57 and one was conducted in 317

260 from the mean (SD) with inverse variance (IV)-weighted Canada.55 318

261 random-effects models where heterogeneity was moder- The total number of participants in the included tri- 319

262 ated. In contrast, fixed-effects models were used where als was not different regarding the intervention (111) and 320

263 heterogeneity was considered as unimportant or nil. Overall placebo (116) arms, and total number of participants within 321

264 summary estimates of RR and 95% CIs were computed with each trial was between 20 and 104. All studies focused on 322

265 Mantel---Haenszel weighted fixed-effects models for events unpredictable and uncomplicated acute episodes of sickle- 323

266 during the study. To determine the heterogeneity assess- cell pain crisis with phenotypes identified as HbSS, HbSC, 324

267 ment between the effects of intervention, the authors used and HbS␤-thalassemia. Of the 227 participants involved, 149 325

268 Cochran’s chi-squared (chi2 ) test along with p-value less than (65.6%) had HbSS, 61 (26.9%) had HbSC, and only 17 (7.5%) 326

269 0.10 to assess for subgroup analyses. The authors also used had HbS␤-thalassemia; 115 (50.66%) were male and 112 327

270 an alternative measurement of the statistical heterogene- (49.34%) were female. Forty-nine participants were eligi- 328

271 ity with the inconsistency (I2 ) method, which expresses a ble and were included for analysis in the intranasal fentanyl 329

272 range from 0% to 100%, and it was calculated as unimportant trial, 104 in the intravenous magnesium trial, 54 in the argi- 330

273 (I2 < 50%), moderate (I2 ≥ 50%), or substantial (I2 < 80%).50,51 nine trial, and only 20 in the nitric oxide trial. Across two 331

274 Analyses were performed to explore the impact of the groups (treatment and control) in all studies, the lowest 332

275 pharmaceutical analgesic interventions versus control on mean (SD) age of participants ranged from 10.6 (5.3) to the 333

276 the SMD of the change in the ladder of pain score for uncom- highest mean (SD) of 17.6 (2.4) years. The splits of parti- 334

277 plicated acute sickle-cell pain crisis, on the MD of hospital cipants in each arm (intervention and placebo) through all 335

278 length-of-stay, and on the SMD of the amount of narcotics trials were almost equal (24---25) in the intranasal fentanyl 336

279 used during the study. Subgroup analyses were performed trial, 51---53 in the intravenous magnesium trial, 26---28 in 337

280 to consider the diverse adverse events that occurred in the the arginine trial; and ten-ten in the nitric oxide trial.54---57 338

281 two arms throughout each study.

282 Assessment of publication bias in order to generate
Risk of bias 339
283 funnel plots and sensitivity analyses could not be per-
284 formed, since only a few studies were retrieved (less than
285 10).50,52 Furthermore, it would not be possible to achieve The Cochrane risk of bias assessment tool for individual 340

286 a meta-analysis review if the heterogeneity identified was trials is shown in Table 3 and in Supplementary Material. 341

287 80% or more. All analyses were performed with Review Additionally, the quality of the evidence is shown for each 342

288 Manager (Review Manager (RevMan) [Computer program]. outcome, which in accordance with the GRADE approach 343

289 version 5.3. Copenhagen: The Nordic Cochrane Centre, The was classified from ‘‘low’’ to ‘‘moderate’’ (Table 5). The 344

290 Cochrane Collaboration, 2014).53 three randomized controlled trials were judged to be at low 345

risk of selection bias given that randomization method was 346

reported by using the tables in block, and the sequence was 347
291 Results engendered through the pharmacy research.54---56 One trial 348

was judged to have an unclear risk of selection bias, as the 349

292 The search for key evidence retrieved 692 studies, of which study did not suitably describe the method of randomiza- 350
293 14 potentially relevant studies were selected for full-text tion and had insufficient information regarding allocation 351
294 review. From these, four randomized controlled trials were concealment (Supplementary material).57 All four studies 352
295 considered that met the inclusion criteria (Fig. 1). were graded to be at low risk of performance, attrition, and 353

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Table 4 Main characteristics and summary of the studies outcomes included in the meta-analysis.

+Model
Study Population Trial design Treatment groups Total size Mean (SD) age Mean (SD) Mean (SD) Mean (SD)
change in pain length of stay amount of
score (hours) narcotics used

I P I P I P I P I P
Fein et al.54 Participants Randomized Intranasal fentanyl 24 25 10.6 12.5 2.12 1 NR NR NA NA
with any parallel citrate vs. Placebo (5.3) (5.1) (4.984)a (2.399)a
SCD study (normal saline)
genotype Dosage: single dose
aged 3-20 of 2 ␮g/kg,
years maximum of 100 ␮g
Goldman Participants Randomized Intravenous 51 53 12.4 12.4 5.4 5.3 132.6 117.9 14.47 14.96
et al.55 with any parallel magnesium sulfate (4.0) (3.7) (2.5) (2.3) (106.6) (72.8) (7.67) (6.46)

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SCD study vs. placebo (normal
genotype saline)
aged 4---18 Dosage: every
years 8 hours doses of
100 mg/kg,
maximum of 2 g per
dose
Morris Participants Randomized 26 28 13.3 13.8 1.9 3.9 98.4 115.2 1.9 4.1
et al.56 with any single group Intravenous or oral (3) (4) (2.4) (2.9) (43.2) (60) (2.0) (4.1)b
SCD study L-arginine
genotype hydrochloride vs.
aged 3.6-19 placebo (saline or
years sugar pill)
Dosage: In thrice
daily doses of
100 mg/kg,
maximum of 10 g for
15 doses or until
discharge
Weiner Participants Randomized Inhaled nitric oxide 10 10 17.6 15.2 2 1.2 78 100 0.63 0.91
et al.57 with any pilot study vs. placebo (2.4) (2.6) (6.702)c (4.021)c (134.556) (223.08) (1.26) (1.82)
SCD (inspired oxygen)
genotype Dosage: 80 ppm
aged 10-21 with 21% final
years concentration of

Saramba MI et al.
inspired oxygen
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NR, not reported; NA, not applicable; I, intervention; P, placebo; vs., versus.
a Mean and SD calculated from median and IQR by using Hozo et al. method.
b Represents the decrement of the participant number in placebo arm due to non-completion of narcotic reports.
c SD provided from sample size, mean, and p-value.
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Figure 1 Flow chart of study selection.

a
Google Scholar citation.

354 selective reporting bias because all reported that their trials reason was that the target sample size was not attained 368

355 were double-blinded and that the placebo treatments were (Supplementary material). 369

356 not discernible from the study intervention. All analyzed Owing to the poor number of included trials into the 370

357 participants had been included in the final data. Reports meta-analysis review (less than ten), implementation of a 371

358 of all intended pre-specified outcome measures were cited funnel plot to explore the risk of publication bias and sensi- 372

359 in the online trial registry.54---57 Three trials had an unclear tivity analyses were not feasible. 373

360 risk of detection bias because in the trial registry there

361 were insufficient clear details to judge, and no supplemen- Change in the ladder of pain score 374
362 tary statements of information were given for the outcome
363 assessors that were incorporated into the blinding.55---57 One In the analysis of the change in the ladder of pain score, 375
364 trial was considered as having a low risk of detection bias pooling the four studies (pain intensity rating was assessed 376
365 because the blinding incorporated outcome assessors that either by visual-analogue scale (VAS) or other tools with 377
366 were stated in the trial registry.54 Furthermore, all stud- age-appropriateness, i.e., the Faces Pain Scale) in an IV- 378
367 ies had a high risk of other potential sources of bias; the weighted random-effects meta-analysis (Fig. 2) indicated 379

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Figure 2 Change in the ladder of pain.

Figure 3 Length-of-stay primarily in hospital.

Figure 4 Narcotics used during the study.

380 that the SMD estimate did not show a significant differ- Amount of narcotics used during the study 397

381 ence between analgesic drug and control arms (SMD: −0.08,
382 95% CI: −0.53, 0.37); p = 0.72. There was moderate hetero- The same three trials55---57 reported the estimated pooled 398
383 geneity (I2 > 50%) among studies that estimated the outcome standardized mean difference, calculated with IV-weighted 399
384 of change in pain rating (chi2 = 7.66, p = 0.05, I2 = 61%). The fixed-effects meta-analysis (SMD: −0.25, 95% CI: −0.55, 400
385 quality of evidence was low (Table 5). 0.05); p = 0.10 (Fig. 4). A non-statistically significant dif- 401

ference between the analgesic drug and control arms for 402

the amount of narcotics used throughout the study was 403

found, along with no important heterogeneity (2 = 3.06, 404

386 Length-of-stay in hospital p = 0.22, I2 = 35%). The quality of evidence was moderate 405

(Table 5). This outcome analysis was reported by one study 406

387 For the three trials that reported hospital length-of-stay for (intranasal fentanyl) as an event.54 Five (20%) participants 407

388 uncomplicated acute episodes of sickle-cell pain crisis,55---57 in placebo group received parenteral morphine compared to 408

389 the pooled mean difference estimate calculated with IV- one (4%) participant in intervention group. In another study 409

390 weighted fixed-effects meta-analysis (Fig. 3) indicated no (arginine),56 two participants in placebo arms were ruled out 410

391 statistically significant difference between the analgesic from the analysis of the amount of opioid consumption on 411

392 drug and control groups (MD: −5.05 h, 95% CI: −26.64, account of the narcotic records being incomplete. Thus, the 412

393 16.55); p = 0.65. The quality of evidence was low (Table 5), number of participants in placebo arm for the total opioid 413

394 with no evidence of heterogeneity for the hospital length-of- use outcome in this study was decreased from 28 to 26. How- 414

395 stay outcome among those three trials (2 = 1.94, p = 0.38, ever, these participants were involved in all other outcomes 415

396 I2 = 0%). analyses. 416

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Figure 5 Proportion experiencing minor events.

417 Adverse events enzymes increased; hospitalization for pain management; 426

requiring blood transfusion; return to ED within 24 h, 72 h, or 427

418 The subgroup analyses results are shown in Figs. 5 and 6. one week; and readmission for pain management within one 428

419 Each trial had their own manner to describe and tabulate month) during the study. For the proportion experiencing 429

420 the different numbers of adverse events. Therefore, the minor adverse events presented by pain at the drug delivery 430

421 present authors planned to exhibit adverse events data in site, there was a statistically significant difference (p = 0.03) 431

422 proportion to the minor (transient hypotension, pruritus, in the combination of data from two studies (intranasal fen- 432

423 hives, pain at the drug delivery site, drowsiness, nausea tanyl citrate and intravenous magnesium)54,55 along with 433

424 or vomiting, hypoxia, headache, and tachycardia) and seri- no important heterogeneity (2 = 0.17, p = 0.68, I2 = 0%). The 434

425 ous adverse events (acute chest syndrome; liver function quality of evidence was low (Table 5). 435

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Figure 6 Proportion experiencing serious events.

436 Discussion Since opioid derivatives have been assigned as the ‘‘gold 451

standard’’ to manage sickle-cell pain crisis, their actions are 452

437 The results of this systematic review and meta-analysis limited only to a nociceptive, but they do not show relevant 453

438 show that most of the studies that reported on pain score action upon the tremendous cascade that gives rise to VOC 454

439 ratings demonstrate a non-significant improvement to the associated with inflammatory syndrome. Thus, there has 455

440 changes in the ladder of pain scores for acute sickle-cell been an increase in the ongoing search for new treatment 456

441 pain crisis. Only three studies reported on hospital length-of- options.20,23 Given these breakthroughs, the pathophysio- 457

442 stay and amount of narcotics used, finding a non-significant logical comprehension of VOC has sparked curiosity in the 458

443 reduction in these outcome measures. In the adverse event scientific literature. These three components (intravenous 459

444 outcome of those experiencing minor side-effects, signifi- magnesium, arginine, and inhaled nitric oxide) have there- 460

445 cant evidence of association of pain at the drug delivery site fore revolutionized this in-depth understanding, as well as 461

446 was demonstrated only in the studies that used intravenous promoting new therapeutic approaches,9,10,25,43,58 but they 462

447 magnesium and intranasal fentanyl citrate. These pharma- require more evidence. 463

448 cological analgesics have inadequate treatment impacts on To the authors’ knowledge, the present study is the 464

449 managing uncomplicated and isolated acute sickle-cell pain most recent investigation exhibiting the gaps of pharmaco- 465

450 crisis in pediatric departments. logical drug effects in the pediatric age group with acute 466

sickle cell pain crisis. Moreover, three of the included trials 467

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Table 5 Summary of findings.

Pharmacological analgesic drugs compared to placebo for pediatric patients with acute painful crisis in sickle-cell disease (SCD)

Patient or population: pediatric patients with SCD Settings: large urban quaternary children’s hospital (pediatric emergency
department [ED], Montefiore, New York, United States); ED (Toronto, Canada), children’s hospital research center (Oakland,
California, United States); urban, tertiary care academic children’s hospital (United States). Intervention: pharmacological
analgesic drugs Comparison: placebo
Outcomes Illustrative comparative risksa Relative effect No. of Quality of the Comments
(95% CI) (95% CI) Participants evidence
Assumed risk Corresponding (studies) (GRADE)
risk
Placebo Pharmacological
analgesia drugs
Change in ladder NAg The standardized NAg 227 (4 studies) ⊕⊕ −− lowb,c No significant
of pain score (as mean change in difference was
measured by rate of pain evident in the
scale of pain vaso-occlusive standardized mean
with important crises (as pain score between
pain) Visual measured by the intervention
analog scale and scale of pain compared to
the modified with important placebo arms
Wong-Baker pain) in the
FACES Pain intervention
Rating Scale. groups was 0.08
Scale from: 0 to lower (0.53
10. Follow up: lower to 0.37
not reported higher)
Length-of-stay NAg The mean NAg 178 (3 studies) ⊕⊕ −− lowd,e No significant
primarily in length-of-stay difference was
hospital (hours) primarily in evident in the mean
Follow up: not hospital (hours) length-of-stay
reported in the primarily in hospital
intervention between the
groups was 5.05 intervention and
lower (26.64 the placebo arms
lower to 16.55
higher)
Amount of NAg The standardized NAg 176 (3 studies) ⊕⊕⊕ − No significant
narcotics used mean amount of moderated difference was
during the study narcotics used evident in the
Follow up: not during the study standardized mean
reported in the amount of narcotics
intervention used between the
groups was 0.25 intervention and
lower (0.55 the placebo arms
lower to 0.05
higher)
Adverse effects 3 out of 116 3 out of 111 RR 1.40 (0.22 to 227 (4 studies) ⊕⊕ −− lowb,e No significant
(minor) : participants participants 4.91) association was
transient evident in transient
hypotension hypotension
Follow up: not between the
reported intervention and
the placebo arms
Adverse effect 2 out of 78 2 out of 75 RR 1.04 (0.19 to 153 (2 studies) ⊕⊕ −− lowb,e No significant
(minor): pruritus participants participants 5.80) association was
Follow up: not evident in pruritus
reported between the
intervention and
the placebo arms

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Table 5 (Continued)

Pharmacological analgesic drugs compared to placebo for pediatric patients with acute painful crisis in sickle-cell disease (SCD)

Adverse effect 0 out of 28 1 out of 28 RR 3.22 (0.14 to 54 (1 study) ⊕⊕

−− lowd,e No significant
(minor): hives participants participants 75.75) association was
Follow up: not evident in hives
reported between the
intervention and
the placebo arms
Adverse effect 2 out of 78 10 out of 75 RR 4.37 (1.14 to 153 (2 studies) ⊕⊕
−− lowb,e There was
(minor): pain at participants participants 16.72) evident
the drug delivery significant
site Follow up: association in
not reported pain at the drug
delivery site
between the
intervention and
the placebo arms
Serious adverse 3 out of 53 2 out of 50 RR 0.75 (0.16 to 103 (2 studies) ⊕⊕
−− lowb,e No significant
events: acute participants participants 3.62) association was
chest syndrome evident in acute
Follow up: not chest syndrome
reported between the
intervention and
the placebo arms
Serious adverse 16 out of 25 13 out of 24 RR 0.85 (0.53 to 49 (1 study) ⊕⊕⊕− No significant
events: participants participants 1.36) moderatef association was
hospitalization evident in
for pain hospitalization
management for pain
Follow up: not management
reported between the
intervention and
the placebo arms
Serious adverse 1 out of 53 2 out of 50 RR 1.58 (0.27 to 103 (2 studies) ⊕⊕
−− lowb,e No significant
events: requiring participants participants 9.30) association in
blood transfusion requiring blood
Follow up: not transfusion
reported between the
intervention and
the placebo arms
a The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk

(and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its
95% CI).CI, confidence interval; NA, not applicable; RR, risk ratio.GRADE Working Group grades of evidenceHigh quality: Further research
is very unlikely to change confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact
on confidence in the estimate of effect and may change the estimate.Low quality: Further research is very likely to have an important
impact on confidence in the estimate of effect and is likely to change the estimate.Very low quality: The authors are very uncertain
about the estimate.
b Evidence downgraded by one due to serious limitation of risk of bias: blinding of outcome assessment was not clearly described in

some study and the aimed sample size intended for studies was not attained.
c Evidence downgrade due to moderate inconsistency: studies analysis represent a moderate heterogeneity. Heterogeneity was

explained by differences in outcomes (diminishing treatment effect with time). The quality of evidence was downgraded by one level
from high to moderate.
d The authors downgraded the quality of evidence by one due to serious risk of bias. Method of blinding of outcome assessment was

not clearly reported; thus, it was downgraded by one level from high.
e Evidence downgraded by one due to imprecision: wide 95% confidence intervals of the effect of outcomes of the intervention.
f Evidence downgraded by one due to serious limitation of risk of bias: the aimed sample size intended from protocol not reached its

goal.
g The results from the trial were displayed as median or mean difference, thus an appraisal of risk within the control arm is not feasible.

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468 (intravenous magnesium, arginine, and inhaled nitric oxide) focusing only on participants aged 3---22. One of them defines 530

469 used interventions with non-analgesic properties but hav- the ideal level of intranasal ketamine that has shown a salu- 531

470 ing an analgesic purpose, which is to limit the sickle-cell tary effect for analgesia in subsequent trials of pediatric 532

471 pathophysiological mechanisms from VOC. The findings of patients in prehospital medicine, emergency medicine, and 533

472 this meta-analysis are consistent with the previous meta- oncology.62,63 Prior studies confirm that ketamine also pro- 534

473 analysis conducted by Dunlop and Bennett22 there were vides clinically substantial analgesia for sickle-cell pain, as 535

474 gaps of cross advantage of treatment trials in dwarfed of well as reducing opiate consumption.21,64,65 In one study that 536

475 the acute episode sickle-cell pain crisis as well as in opi- compared the analgesic benefits of intranasal fentanyl to 537

476 oid consumption, and hospital length-of-stay. However, their intranasal ketamine, it was found that both provide equiv- 538

477 meta-analysis involved nine RCTs (six with placebo control alent analgesia.66 All confidence intervals in the present 539

478 and three inter-treatment trials), and included children and study were revealed to be wide, thus highlighting the sig- 540

479 adults without combining them. Their findings did show the nificance and magnitude of continued research in this realm 541

480 complete alleviation of acute sickle-cell pain crisis in all to fully manage the crisis and to recognize the additional 542

481 participants, but distinctly proved that none of the inter- reason for these important differences. The meta-analysis 543

482 vention trials were able to entirely manage this crisis state, of other outcomes apart from the change in the ladder of 544

483 and additionally the evidence bases were inadequate. pain score showed the non-importance of statistical hetero- 545

484 The heterogeneity test of the included studies across all geneity, although these outcomes had insufficient statistical 546

485 outcomes in the efficacy of these treatments in pediatric power. Notwithstanding, the GRADE analysis of the qual- 547

486 patients with acute sickle-cell pain crisis was not substantial ity for outcomes almost evinces a low level of strength of 548

487 (I2 > 80%). There was moderate risk of statistical heterogene- evidence owing to the presence of bias, inconsistency, and 549

488 ity across the meta-analysis of the change in the ladder of imprecision; except for the amount of narcotics used, for 550

489 pain score. This heterogeneity could be explained by the which the evidence had a moderate level of quality. 551

490 different tools used and the methods of pain assessment, This meta-analysis review has some limitations that can 552

491 such as the VAS or the Faces Pain Scale, and the small sam- be reduced in prospective research. The majority of the tri- 553

492 ple sizes of the included studies. The non-risk of statistical als involved in this review originated in areas with a low 554

493 heterogeneity in meta-analysis of hospital length-of-stay is burden of SCD, despite the authors’ extensive scientific 555

494 accounted for by the use across studies of the same or similar research strategy, which identified numerous pertinent tri- 556

495 methods to estimate the length-of-stay in hospital; beside als. Thereby, the greater part of the eligible studies had 557

496 to it minimizes the inconstantly of this outcome. Also, the inadequate sample size, which may have promoted the 558

497 non-important risk of statistical heterogeneity in the amount confounders of reduction of the precision in the effect 559

498 of narcotics used is partially consistent with the moderate size estimate, the lessening of the significance of find- 560

499 level of the quality of evidence. ings, and the under-powered design of the studies. Some 561

500 The meta-analysis excluded studies that recruited and included studies were conducted in a single center, which 562

501 combined different age groups, and those that compared may lead to confounding factors in the insufficient sam- 563

502 between-treatments, which was done in order decrease the ple size. Most of the RCTs exploring sickle-cell pain crisis 564

503 risk of inclusion bias. In four small-scale studies of uncom- recruited and combined three different age groups (chil- 565

504 plicated acute sickle-cell pain crisis treatment, contributing dren, young adults, adults and seniors), and did not provide 566

505 data from 227 registered patients, the present study did not unique data for each participants’ age group, the use of 567

506 have enough evidence emphasizing the adequate manage- which would have involved many trials in the review. The 568

507 ment of the pediatric age group with sickle-cell pain crisis. pain scale assessments and methods --- whether regarding its 569

508 Furthermore, a multicenter sickle-cell randomized placebo- intensity or relief --- used in the studies included in the meta- 570

509 controlled trial with intravenous magnesium reported only analysis review were not standardized; for instance, two 571

510 sickle-cell cases including the HbSS and HbS␤0 phenotypes, trials used two types of pain scales.55,56 Thus, the compari- 572

511 with inadequate and trivial results regarding length-of- son between trials and the pooling of data were challenging. 573

512 stay and opioid derivatives used.43 Besides, there were the Nevertheless, these circumstances might affect the analysis 574

513 immense barriers during the literature search, as studies outcomes. Owing to the poor number of eligible trials into 575

514 appraising acute sickle-cell painful episode management the meta-analysis review, implementation of a funnel plot to 576

515 have ended in an untimely manner because of the lack of explore the risk of publication bias and sensitivity analyses 577

516 available participants in trials.42,58,59 The adverse events was not feasible. 578

517 were split as the proportion experiencing minor and seri-

518 ous events for this meta-analysis, data were overly diverse
519 and were difficult to investigate, hindering distinct pooled Conclusion 579

520 examination. In contrast, it was possible to pool two studies

521 showing that intravenous magnesium and intranasal fentanyl In this study, pharmacological analgesic treatments 580

522 citrate caused pain at the drug delivery site. The intravenous appeared dubious in the improvement of pain intensity and 581

523 magnesium event was consistent with another study that relief for acute pain crisis in pediatric patients with SCD. 582

524 showed warmth at the delivery site in the treatment arm.43 Therefore, no decisive deduction about the clinical efficacy 583

525 The pertinent strengths of this systematic review and of these pharmacological analgesics was made. More RCTs 584

526 meta-analysis include that the study provided the latest are required and may attest the strengths evidence of each 585

527 evaluation of the efficiency and safety of uncomplicated study. This may provide further information regarding these 586

528 acute sickle-cell pain crisis treatment in the pediatric age analgesic drugs in order to improve reduction in the length 587

529 group. The authors also found three ongoing studies,60---62 of stay, primarily in-hospital, and in reducing the amount 588

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589 of narcotics used. Well-designed studies along with plenty disorders. 2nd ed. New York: Cambridge University Press; 2009. 640
590 of participants are needed for demonstrating significant p. 101---18. 641

591 differences. Studies should ensure the inclusion of a large 9. Hebbel RP. Pathobiology of sickle cell disease. In: Hoffman R, 642

592 sample size and a balance of each SCD phenotype in trials, Benz JE, Silberstein LE, Heslop HE, Weitz JI, Anastasi J, editors. 643

593 to avert overestimation of results in the upcoming research. Hematology: basic principles and practice. Red blood cells. 6th 644

Single-center trials should be joined to multi-center trials ed Philadelphia: Elsevier Saunders; 2013. p. 536---47. 645
594
10. Morrone KA, Davila J, Mitchell WB, Manwani D. Pathobiology 646
595 in order to have enough participants and to have sufficient
of sickle cell disease vaso-occlusion and targeted therapies. 647
596 study power. Researchers should consider expanding their In: Meier ER, Abraham A, Fasano RM, editors. Sickle cell dis- 648
597 studies in settings with a high burden of SCD. ease and hematopoietic stem cell transplantation. Sickle cell 649
disease. Cham: Springer International Publishing AG; 2018. p. 650
41---64.
598 Funding 651
11. Saunthararajah Y, Vichinsky EP. Sickle cell disease: clinical fea- 652
tures and management. In: Hoffman R, Benz JE, Silberstein 653
599Q4 This work was supported by grants from the Chinese National LE, Heslop HE, Weitz JI, Anastasi J, editors. Hematology: basic 654
600 Natural Science Fund, No. 81170005 and No. 81670007. principles and practice. Red blood cells. 6th ed. Philadelphia: 655
Elsiever Saunders; 2013. p. 548---72, e5. 656
12. Ballas SK, Eckman JR. Sickle cell pain: biology, etiology, and 657
601 Conflicts of interest treatment. In: Steinberg MH, Forget BG, Higgs DR, Weatherall 658
DJ, editors. Disorders of hemoglobin genetics, pathophysiology, 659
602 The authors declare no conflicts of interest. and clinical management. Sickle cell disease. 2nd ed. New York: 660
Cambridge University Press; 2009. p. 497---524. 661
13. Expert Panel Report, 2014. Evidence-based management 662
603 Acknowledgments of sickle cell disease. Bethesda, MD: National Heart, Lung, 663
and Blood Institute, US Department of Health and Human 664

604 This work was supported by grants from the Chinese National Services; 2014. Available from: http://www.nhlbi.nih.gov/ 665

605 Natural Science Fund, No. 81170005 and No. 81670007. The health-pro/guidelines/sickle-cell-disease-guidelines/. [Cited 666

606 authors would like to recognize the contributions, encour- 20 March 2018]. 667

607 agements, and endorsements from Professor Yi Guo, and 14. Fosdal MB. Perception of pain among pediatric patients with 668
sickle cell pain crisis. J Pediatr Oncol Nurs. 2014;32:5---20. 669
608 Mrs. Loraine S. Castellano. Finally, they would like to express
15. Brousseau DC, Owens PL, Mosso AL, Panepinto JA, Steiner CA. 670
609 their gratitude to Dr. Salama A. Ali and Dr. Elsam Koshy for Acute care utilization and rehospitalizations for sickle cell dis- 671
610 their immense support in reviewing the article. ease. JAMA. 2010;303:1288---94. 672
16. Yusuf HR, Atrash HK, Grosse SD, Parker CS, Grant AM. Emergency 673

611 Appendix A. Supplementary data department visits made by patients with sickle cell disease: a 674
descriptive study, 1999---2007. Am J Prev Med. 2010;38:S536---41. 675
17. Zempsky WT. Evaluation and treatment of sickle cell pain in the 676
612 Supplementary material related to this article can be emergency department: paths to a better future. Clin Pediatr 677
613 found, in the online version, at doi:https://doi.org/ Emerg Med. 2010;11:265---73. 678
614 10.1016/j.jped.2019.05.004. 18. Kelly GS, Stewart RW, Strouse JJ, Anders JF. Intranasal fentanyl 679
improves time to analgesic delivery in sickle cell pain crises. 680
Am J Emerg Med. 2017;36:1305---7. 681
615 References 19. Lanzkron S, Carroll CP, Haywood CJ. The burden of emer- 682
gency department use for sickle-cell disease: an analysis of the 683

616 1. Pecker LH, Little J. Clinical manifestations of sickle cell dis- national emergency department sample database. Am J Hema- 684

617 ease across the lifespan. In: Meier ER, Abraham A, Fasano RM, tol. 2010;85:797---9. 685

618 editors. Sickle cell disease and hematopoietic stem cell trans- 20. Murphy A, O’Sullivan R, Wakai A, Grant TS, Barrett MJ, 686

619 plantation. Sickle cell disease. Cham: Springer International Cronin J, et al. Intranasal fentanyl for the management of 687

620 Publishing AG; 2018. p. 3---39. acute pain in children. Cochrane Database Syst Rev. 2014;10: 688

621 2. Jones P. Genes and disease. New York: Chelsea House; 2008. CD009942. 689

622 3. Jacob E, Mueller BU. Pain experience of children with sickle cell 21. Zempsky WT, Loiselle KA, Corsi JM, Hagstrom JN. Use of low- 690

623 disease who had prolonged hospitalizations for acute painful dose ketamine infusion for pediatric patients with sickle cell 691

624 episodes. Pain Med. 2008;9:13---21. disease-related pain: a case series. Clin J Pain. 2010;26:163---7. 692

625 4. Howard J, Telfer P. Sickle cell disease in clinical practice. Lon- 22. Dunlop R, Bennett KC. Pain management for sickle cell dis- 693

626 don: Springer-Verlag; 2015. p. 300. ease in children and adults. Cochrane Database Syst Rev. 694

627 5. Aubry P, Gaüzère B-A. Hémoglobinoses. Med Trop. 2006;2:CD003350. 695

628 2015;2015:1---11. 23. Archer N, Galacteros F, Brugnara C. Updates in clinical trials for 696

629 6. Adewoyin AS. Management of sickle cell disease: a review for hematological diseases: 2015 clinical trials update in sickle cell 697

630 physician education in Nigeria (sub-Saharan Africa). Anemia. anemia. Am J Hematol. 2015;90:934---50. 698

631 2015;2015:791498. 24. Anderson CL, Darbari DS. Current non-HSCT treatments for SCD. 699

632 7. Kato GJ, Piel FB, Reid CD, Gaston MH, Ohene-Frempong K, In: Meier ER, Abraham A, Fasano RM, editors. Sickle cell dis- 700

633 Krishnamurti L, et al. Sickle cell disease. Nat Rev Dis Primers. ease and hematopoietic stem cell transplantation. Sickle cell 701

634 2018;4:1---22. disease. Cham: Springer International Publishing AG; 2018. p. 702

635 8. Kim-Shapiro DB. Structure and function of hemoglobin and 65---86. 703

636 its dysfunction in sickle cell disease. In: Steinberg MH, 25. Wandersee NJ, Hillery CA. Red blood cells and the vaso- 704

637 Forget BG, Higgs DR, Weatherall DJ, editors. Disorders of occlusive process. In: Costa FF, Conran N, editors. Sickle cell 705

638 hemoglobin genetics, pathophysiology, and clinical manage- anemia: from basic science to clinical practice. Cham: Springer 706

639 ment. The molecular, cellular, and genetic basis of hemoglobin International Publishing AG; 2016. p. 75---90. 707

JPED 811 1---18

 +Model
ARTICLE IN PRESS
Analgesics in acute sickle-cell pain 17

708 26. Than NN, Soe HH, Palaniappan SK, Abas AB, De Franceschi L. of a randomized double blind pilot study. Br J Haematol. 776

709 Magnesium for treating sickle cell disease. Cochrane Database 2012;159:211---5. 777

710 Syst Rev. 2017;4:CD011358. 45. NCT01380197, Date first submitted: 22 June Choosing opioid 778

711 27. Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, management for pain and analyzing acute chest syndrome 779

712 Minter K, et al. Pulmonary hypertension as a risk factor for (ACS) rates equally (compare). Clinicaltrialsgov/ct2/show/ 780

713 death in patients with sickle cell disease. N Engl J Med. NCT01380197; 2011. 781

714 2004;350:886---95. 46. Higgins JP, Deeks JJ. Selecting studies and collecting data. In: 782

715 28. Nath KA, Katusic ZS, Gladwin MT. The perfusion paradox and Higgins JP, Green S, editors. Cochrane handbook for systematic 783

716 vascular instability in sickle cell disease. Microcirculation. reviews of intervention. Version 5.1.0 (updated March 2011). 784

717 2004;11:179---93. The Cochrane Collaboration; 2011. 785

718 29. Rochelson B, Dowling O, Schwart N, Metz CN. Magnesium sulfate 47. Higgins JP, Altman DG, Sterne JA. Assessing risk of bias in 786

719 suppresses inflammatory responses by human umbilical vein included studies. In: Higgins JP, Green S, editors. Cochrane 787

720 endothelial cells (HuVECs) through the NFkappaB pathway. J handbook for systematic reviews of intervention. Version 5.1.0 788

721 Reprod Immunol. 2007;73:101---7. (updated March 2011):. The Cochrane Collaboration; 2011. 789

722 30. Maier JA, Malpuech-Brugère C, Zimowska W, Rayssiguier Y, 48. GRADEpro. Version 3.6 for Windows; 2014. Available from: 790

723 Mazur A. Low magnesium promotes endothelial cell dysfunction: www.gradepro.org. [Cited 20 March 2018]. 791

724 implications for atherosclerosis, inflammation and thrombosis. 49. Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and vari- 792

725 Biochim Biophys Acta. 2004;1689:13---21. ance from the median, range and the size of a sample. BMC Med 793

726 31. Kato GJ, Gladwin MT. Mechanisms and clinical complications of Res Methodol. 2005;5:13. 794

727 hemolysis in sickle cell disease and thalassemia. In: Steinberg 50. Deeks JJ, Higgins JP, Altman DG. Analysing data and undertak- 795

728 MH, Forget BG, Higgs DR, Weatherall DJ, editors. Disor- ing meta-analysis. In: Higgins JP, Green S, editors. Cochrane 796

729 ders of hemoglobin genetics, pathophysiology, and clinical handbook for systematic reviews of interventions. Version 5.1.0 797

730 management. pathophysiology of hemoglobin and its disor- (updated March 2011). The Cochrane Collaboration; 2011. 798

731 ders. 2nd ed. New York: Cambridge University Press; 2009. 51. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring incon- 799

732 p. 201---24. sistency in meta-analyses. BJM. 2003;327:557---60. 800

733 32. El-Rassi F, Morris CR. Arginine and glutamine: the future of 52. Sterne JA, Egger M, Moher D. Addressing reporting biases. In: 801

734 amino acid therapy in sickle cell disease. J Sick Cell Dis Higgins JP, Green S, editors. Cochrane handbook for systematic 802

735 Hemoglobinopathies. 2016;1:26---41. reviews of interventions. Version 5.1.0 (updated March 2011). 803

736 33. Rosenthal MD, Carrott PW, Patel J, Kiraly L, Martindale RG. Par- The Cochrane Collaboration; 2011. 804

737 enteral or enteral arginine supplementation safety and efficacy. 53. RevMan. The Nordic Cochrane Center, The Cochrane Collabora- 805

738 J Nutr. 2016;146, 2594S---600S. tion. Review Manager (RevMan). Version 5.3. Copenhagen: The 806

739 34. Moncada S, Higgs EA. The discovery of nitric oxide and its role Nordic Cochrane Center, The Cochrane Collaboration; 2014. 807

740 in vascular biology. Br J Pharmacol. 2006;147:S193---201. 54. Fein DM, Avner JR, Scharbach K, Manwani D, Khine H. Intranasal 808

741 35. Leopold JA, Loscalzo J. The biology of vascular nitric oxide. fentanyl for initial treatment of vaso-occlusive crisis in sickle 809

742 In: Steinberg MH, Forget BG, Higgs DR, Weatherall DJ, edi- cell disease. Pediatr Blood Cancer. 2016;64:6. 810

743 tors. Disorders of hemoglobin genetics, pathophysiology, and 55. Goldman RD, Mounstephen W, Kirby-Allen M, Friedman JN. 811

744 clinical management. Pathophysiology of hemoglobin and its Intravenous magnesium sulfate for vaso-occlusive episodes in 812

745 disorders. 2nd ed. New York: Cambridge University Press; 2009. sickle cell disease. Pediatrics. 2013;132:e1634---41. 813

746 p. 185---200. 56. Morris CR, Kuypers FA, Lavrisha L, Ansari M, Sweeters N, Stew- 814

747 36. Sharma D, Potoka KP, Kato GJ. Nitric oxide, phosphodiesterase art M, et al. A randomized, placebo-controlled trial of arginine 815

748 inhibitors and soluble guanylate cyclase stimulators as can- therapy for the treatment of children with sickle cell disease 816

749 didate treatments for sickle cell disease. J Sick Cell Dis hospitalized with vaso-occlusive pain episodes. Haematologica. 817

750 Hemoglobinopathies. 2016. JSCDH-D-16-00097. 2013;98:1375---82. 818

751 37. Ataga KI, Stocker J. The trials and hopes for drug development 57. Weiner DL, Hibberd PL, Betit P, Cooper AB, Botelho CA, Brugnara 819

752 in sickle cell disease. Br J Haematol. 2015;170:768---80. C. Preliminary assessment of inhaled nitric oxide for acute vaso- 820

753 38. Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. occlusive crisis in pediatric patients with sickle cell disease. 821

754 Preferred reporting items for systematic reviews and meta- JAMA. 2003;289:1136---42. 822

755 analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097. 58. Dampier CD, Smith WR, Wager CG, Kim HY, Bell MC, Miller ST, 823

756 39. Adegoke SA, Shehu UA, Mohammed LO, Sanusi Y, Oyelami OA. et al. Sickle Cell Disease Clinical Research Network (SCDCRN). 824

757 Influence of lime juice on the severity of sickle cell anemia. J IMPROVE trial: a randomized controlled trial of patient- 825

758 Altern Complement Med. 2013;19:588---92. controlled analgesia for sickle cell painful episodes: rationale, 826

759 40. NCT01314300, Date first submitted: 11 March Lidocaine design challenges, initial experience, and recommendations for 827
®
760 5% plasters (Versatis 5%) in pediatric neuropathic pains future studies. Clin Trials. 2013;10:319---31. 828

761 and vasoocclusive sickle cell crisis pains. clinicaltrials- 59. Peters-Lawrence MH, Bell MC, Hsu LL, Osunkwo I, Seaman P, 829

762 gov/ct2/show/NCT001314300; 2011. Blackwood M, et al. Sickle Cell Disease Clinical Research Net- 830

763 41. NCT02316366, Date first submitted: 10 December The use work (SCDCRN). Clinical trial implementation and recruitment: 831

764 of warmed saline in vaso-occlusive episode. Clinicaltrials- lessons learned from the early closure of a randomized clinical 832

765 gov/ct2/show/ NCT02316366; 2014. trial. Contemp Clin Trials. 2012;33:291---7. 833

766 42. NCT00142051, Date first submitted: 31 August Inhaled 60. NCT02536170, Date first submitted: 27 August Randomized con- 834

767 nitric oxide for pediatric painful sickle crisis. Clinicaltrials- trol trial of arginine therapy for pediatric sickle cell disease pain 835

768 gov/ct2/show/ NCT00142051; 2005. [Phase 2]. clinicaltrialsgov/ct2/show/ NCT02536170; 2015. 836

769 43. Brousseau DC, Scott JP, Badaki-Makun O, Darbari DS, Chumpitazi 61. NCT01954927, Date first submitted: 27 September Pain mana- 837

770 CE, Airewele GE, et al. A multicenter randomized controlled gement of VOC in children and young adults with SCD [Phase 2]. 838

771 trial of intravenous magnesium for sickle cell pain crisis in chil- clinicaltrialsgov/ct2/show/ NCT01954927; 2013. 839

772 dren. Blood. 2015;126:1651---7. 62. NCT02573714, Date first submitted: 8 October Comparison of 840

773 44. Osunkwo I, Ziegler TR, Alvarez J, McCracken C, Cherry K, sub-dissociative intranasal ketamine plus standard pain therapy 841

774 Osunkwo CE, et al. High dose vitamin D therapy for chronic versus standard pain therapy in the treatment of pediatric sickle 842

775 pain in children and adolescents with sickle cell disease: results cell disease vaso-occlusive crises in resource-limited setting: 843

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844 a multi-centered, randomized, controlled trial. clinicaltrials- painful crisis in patients with sickle cell disease. J Pain Symptom 853
845 gov/ct2/show/NCT02573714; 2015. Manage. 2014;47:334---40. 854
846 63. Young JR, Sawe HR, Mfinanga J, Nshom E, Helm E, Moore 65. Uprety D, Baber A, Foy M. Ketamine infusion for sickle cell 855
847 CG, et al. Subdissociative intranasal ketamine plus standard pain crisis refractory to opioids: a case report and review of 856
848 pain therapy versus standard pain therapy in the treatment of literature. Ann Hematol. 2014;93:769---71. 857
849 paediatrics sickle cell disease vaso-occlusive crises in resource- 66. Graudins A, Meek R, Egerton-Warburton D, Oakley E, Seith R. 858
850 limited settings: study protocol for a randomised controlled The PICHFORK (pain in children fentanyl or ketamine) trial: a 859
851 trial. BJM Open. 2017;7:e017190. randomized controlled trial comparing intranasal ketamine and 860
852 64. Tawfic QA, Faris AS, Kausalya R. The role of a low-dose fentanyl for the relief of moderate to severe pain in children 861
ketamine-midazolam regimen in the management of severe with limb injuries. Ann Emerg Med. 2015;65:248---54. 862

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