Alsulami et al. BMC Pediatrics(2024) 24:504
https://doi.org/10.1186/s12887-024-04971-0

BMC Pediatrics

RESEARCH

Open AccessOpioid and benzodiazepine requirements
in critically ill post-surgical children with down
syndrome: a systematic review and metaanalysis
Shaimaa Alsulami1, Ashjan Alghanem2, Renad AlShuraim3, Khalid Al Sulaiman4,5,6,7,8,17*,
Omer Ahmed Abdelwahab10,11, Sarah Aljohani12, Hadeel Alkofide13,14, Mashael AlFaifi3,7, Tarek Hazwani6,15,16 andOhoud Aljuhani9
Abstract
Background Down syndrome (DS), or Trisomy 21, is defined by the existence of an additional chromosome 21.
Various physiological considerations in DS patients might lead to challenges in adequate pain management andsedation after surgery. The aim of this systematic review and meta-analysis is to evaluate the variations of therequirement needed for pain management and sedation in patients with DS who have undergone surgery comparedto patients without DS.
Methods A systematic review and meta-analysis of studies were conducted, focusing on critically ill patients with
DS who were admitted to Intensive care units (ICUs) post-surgery and received opioids and/or benzodiazepines.
Searches were conducted in four databases from their inception to November 18, 2023 (Pubmed, Scopus, CochraneLibrary, and Web of Science). The primary outcome measured was the dosage of Oral Morphine Equivalent (OME)
administered in the days following surgery. Fixed-effect models were used, an approach advisable when only alimited number of studies are available.
Results Out of the 992 studies initially screened, the systematic review included ten studies, encompassing 730
patients, while the meta-analysis consisted of seven studies, encompassing 533 patients. Of the seven studies
included in the analysis, 298 patients were identified to have DS, and 235 patients served as controls. Patients withDS showed a slight increase in OME needs on the first day, but this increase was not statistically significant (meandifference [MD] = 0.09; 95% Confidence Interval [CI]: [-0.02, 0.20]; P = 0.11). There was also no significant difference inthe requirement for Midazolam on the first day among DS patients (MD = 0.01; CI [-0.16, 0.19]; P = 0.88). In addition,
the duration of mechanical ventilation was not statistically significant in patients with DS compared with the control
group (MD = -1.46 hours; 95% CI [-9.74, 6.82]; P = 0.73).

*Correspondence:
Khalid Al Sulaiman
alsulaimankh@hotmail.com
Full list of author information is available at the end of the article© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0
International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you
give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified thelicensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it.The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to thematerial. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation
or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit http://
creativecommons.org/licenses/by-nc-nd/4.0/.

Alsulami et al. BMC Pediatrics(2024) 24:504

Page 2 of 10

Conclusion Patients with Down syndrome did not require more sedation or analgesia in the first three days after
surgery than patients without Down syndrome. Additionally, the two groups showed no significant difference in the
duration of mechanical ventilation.
Keywords Down syndrome, Trisomy 21, Analgesia, Sedation, Critical care, Post surgery

Introduction
Down syndrome (DS) is a genetic disorder characterized
by an additional chromosomal copy 21, resulting in the
DS-associated phenotypic manifestation [1]. According
to one study, up to 6,000 children are diagnosed annually with DS in the United States [2]. Children with DS
carry a higher risk of having various congenital abnormalities, especially congenital heart disease, in up to 60%
of DS patients [3]. Consequently, cardiac repair surgeries
are typically required in infancy for these patients, andrecovery in the intensive care unit (ICU) is necessary [4].
Additionally, individuals with DS are susceptible to othercomorbidities, including blood disorders and frequent
infections that necessitate painful and invasive interventions [5].
Achieving optimal sedation and analgesia is required
during their ICU stay to reduce stress and promote
recovery [6]. However, it can be challenging, with several
studies reporting the need for higher doses of sedation
and analgesia in this population [7].
Several theories have been proposed to explain thechallenges faced in achieving appropriate pain management and sedation in patients with DS. One of these theories suggests that this condition’s unique physiologicaland anatomical features may play a role. These features
include changes in the GABAergic transmission system,
which could affect their response to sedation and analgesia management, possibly leading to increased requirements compared to children without DS [7]. According
to the results of sensory neurography studies, patientswith DS may react to pain stimuli more slowly and havedecreased peripheral sensory nerve conduction. However, the findings regarding the degree of pain sensitivity
in children with DS are inconclusive [8].
A clinical perspective remains that achieving optimal pain management and sedation in children with DS
is challenging. As multiple studies were done to investigate the analgesia dose requirement in patients withDS, the results were conflicting. A retrospective cohort
study reported that patients with DS after cardiac surgery required significantly higher doses of morphine andutilized more sedatives and muscle relaxants when compared to a matched control group [9]. Nevertheless, a retrospective study found no significant correlation between
patients with DS and high opioid doses in the first 24–96
hours after surgery [10].
Moreover, pharmacokinetic and pharmacodynamic
studies revealed that there is no significant difference inthe need for morphine between patients with and without DS after surgery [11, 12]. When comparing children
with DS to their peers, the results of their analgesic andsedative needs remain inconsistent.
To optimize post-surgery care in patients with DS, it isnecessary to understand the differences in sedation andanalgesia requirements in those patients. Hence, our systematic review and meta-analysis aimed to evaluate theliterature results on the variation in the requirements forpain management and sedation in critically ill post-surgical children with DS.

Methods
We carried out this systematic review and meta-analysis
in accordance with the 2020 Preferred Reporting Items
for Systematic Reviews and Meta-analyses (PRISMA)
guidelines [13]. Additionally, the study was registeredin the Prospective International Register of Systematic Reviews (PROSPERO) under reference number(CRD42024484678).
Search strategy and study selection

We conducted searches in four databases (PubMed, Scopus, Cochrane Library, and Web of Science) dating backto their inception through November 18, 2023, using theterms related to ‘Down syndrome,’ ‘intensive care unit,’ 'post-surgery’ and combined with terms related to analgesia and sedation management. A comprehensive searchstrategy can be found in Appendix 1.
Following the identification of studies using predetermined search terms in various databases, we utilized theRayyan software for abstract screening and reference
organization after removing duplicate entries [14]. Two
investigators (SA and AA) independently screened all theidentified studies for inclusion based on predetermined
eligibility criteria, using the titles and abstracts of thearticles. In cases of discrepancy between the two reviewers, a third investigator (OA) was consulted to reach aconsensus. Studies that were deemed eligible after the
initial screening phase were then retrieved, and theirfull texts were independently reviewed by SA and AA. In
cases of inter-reviewer disagreement, a fourth investigator, RA, was consulted to ensure a consistent and unbiased selection process.
Randomized control trials, nonrandomized comparative trials, or observational clinical studies of pediatricpatients with DS aged 18 years or younger were considered eligible for inclusion. The studies included patientsAlsulami et al. BMC Pediatrics(2024) 24:504

requiring any surgical or non-surgical sedative or analgesia in the intensive care setting. Eligible studies were
included irrespective of the type, dose, or route of administration of the analgosedative agents (opioids, benzodiazepines, or non-benzodiazepines). Opioid analgesics
such as (Morphine, Hydromorphone, and Fentanyl), sedatives such as Benzodiazepine (Midazolam, Lorazepam,
and Diazepam), and non-benzodiazepine such as (Dexmedetomidine, Ketamine, Propofol and Chloral hydrate)
were all considered for inclusion. Studies were excluded
if they evaluated the sedative or analgesic required forprocedures or general anesthesia, or did not compare DS
and non-DS patients for the primary or secondary outcome. Also, lower quality studies including case reports
or case series studies were excluded from the review.
Study outcomes

Initially, multiple outcomes were selected based on the
preliminary search, including sedation and analgesia
dose requirements, mechanical ventilation duration,
inotropic scores, and vital signs. However, the primaryand secondary outcomes were determined based on themost frequently reported outcome after screening theincluded studies. In this systematic review and metaanalysis, the primary outcome was the Oral Morphine
Equivalent (OME) during the first three days of sedative agent administration. To standardize opioids to an
equivalent OME, formula [15, 16] was applied, and to
standardize various benzodiazepines to an equivalentMidazolam dose, formula [17] was used. Secondary outcomes included the duration of MV. Pooled analysis was
performed when two or more studies provided adequate
data on the same outcome.
Data extraction and quality assessment

Two investigators (SA and AA) independently utilizeda standardized data extraction form to extract relevant
data, while a third investigator (RA) assisted in case of
discrepancies. Information about study design, patientnumbers, inclusion criteria, interventions, and relevant
outcomes were obtained from all included studies.
The methodological quality of the studies was evaluated independently by two investigators (MA and HA)using the Newcastle Ottawa Scale (NOS) for cohort studies. We planned to use the Cochrane Risk of Bias tool
for randomized trials, however no such studies were
included in this review. The NOS’s star allocation system,as outlined in its coding manuals, was used to assess therisk of bias (ROB) in the included studies. The assessment focused on key criteria such as selection bias, comparability of groups, and outcome reporting to evaluate
the risk of bias in each study. It involved evaluating eight
criteria, with a maximum of nine stars. Each criterion
can get a maximum of one star, except for comparability,

Page 3 of 10

which can get up to two stars. Based on this system, studies with 8 to 9 stars were classified as having low ROB,
those with 6 to 7 stars as medium ROB, and those with 5or fewer stars were deemed to have high ROB [18].
Furthermore, the GRADE approach was applied toassess the certainty of evidence regarding the risk of bias,
inconsistency, indirectness, imprecision, and publication bias. Two authors (HA, MA) independently assessed
the certainty of evidence, resolving any discrepancies
through discussion.
Data synthesis & analysis

As all study outcomes were continuous variables andreported on the same scale (days), mean differences(MD) were employed to summarize effect estimates, andtheir uncertainty was expressed through 95% confidence
intervals (CIs). For studies reporting only medians andinterquartile ranges, these data were converted to means
and standard deviations (SD) using the method outlined
by Luo et al., 2018 and Wan et al., 2014 [19, 20]. WhenSD was not reported, we adhered to the recommendations of the Cochrane Handbook for Systematic Reviewsof Interventions, either by calculating the SD from otheravailable data (e.g., p-values or CIs) or by computing the
average SD when there was insufficient information to
impute the missing SDs.
A fixed-effects model was used to pool the studies
with no heterogeneity, and the DerSimonian Liard random meta-analysis model was used when there was significant heterogeneity. Heterogeneity among studies wasassessed using the Chi-square test (Cochrane Q test) andthe I-squared (I²) tests. χ² p-value of < 0.1 indicates significant heterogeneity. The I² values can be interpreted
as follows: 0–40% might not be important, 30–60%may
represent moderate heterogeneity, 50–90%may represent
substantial heterogeneity, and 75–100% considerable heterogeneity. All statistical tests were two-tailed, and thesignificance criterion was < 0.05.

Results
Literature search results

A total of 992 records were retrieved through our literature search process, and after removing 190 duplicate
records, we were left with 802 unique records. Additionally, we manually searched the references of the included
studies but did not find any additional articles that met
our inclusion criteria. Two independent investigators
underwent screening of titles and abstracts of theserecords using Rayyan software. Only 19 studies met theeligibility criteria after this screening phase and wereselected for full-text screening. Finally, ten studies were
included in the systematic review, seven of which were
sufficiently homogeneous in design and outcome to becompared in the meta-analysis. All details regarding theAlsulami et al. BMC Pediatrics(2024) 24:504

screening and selection process of the included studies
are illustrated in the PRISMA flow diagram Fig. 1.
Characteristics of the included studies

The systematic review included ten studies encompassing
730 patients, while the meta-analysis consisted of sevenstudies with 533 patients. Of the seven studies includedin the analysis, 298 patients were identified to have DS
and, 235 patients served as controls. All included studies
were observational since no interventional studies were
found during the literature search. Additionally, the initial search focused on all pediatric admitted to the ICU.
However, all the studies found focused only on postoperative cardiac patients, and no studies were found toassess the desired outcome in non-surgical ICU patients.
The detailed baseline characteristics of the included studies are presented in the supplementary materials Table
S1.
Quality assessment

The ROB in the analyzed studies varied from high to lowrisk of bias. It is important to note that the majority ofFig. 1 PRISMA flow diagram of the study selection process

Page 4 of 10

these studies either neglected to assess confounders oromitted key confounders in their analysis, leading to several studies receiving no more than one star for comparability Table S2.
Oral morphine equivalent (OME)
At day one

Seven studies compared the patients with DS to the controls regarding the OME on day one with a total of 530
patients. The overall MD between the DS and the control groups showed that the OME at day one was higher
in the DS group, but the results did not reach statistical significance (MD = 0.09 mg/kg; 95% CI [-0.02, 0.20];
P = 0.11). The pooled studies were homogeneous (P = 0.22;
I2 = 27%) Fig. 2. We downgraded the evidence due to high
ROB and imprecision Table 1.
At day two

Five studies compared the patients with DS to the controls regarding the OME at day two with a total of 323
patients. The overall MD between the DS and the control groups showed that the OME at day two was higher

Alsulami et al. BMC Pediatrics(2024) 24:504

Page 5 of 10

Fig. 2 Forest plot comparing the DS and the control groups regarding the OME at day 1

Table 1 GRADE rating of studies comparing patients with DS to control group with respect to sedation and analgesia requirement
Anticipated absolute effects* (95% CI)
Risk with control
Risk with down
syndrome
Oral Morphine EquivaThe mean oral Morphine
MD 0.09 Mg/Kg higher
lent (OME) at Day One
Equivalent (OME) at Day One(0.02 lower to 0.2 higher)
was 3.32 Mg/Kg
Oral Morphine EquivaThe mean oral Morphine
MD 0.08 Mg/Kg higher
lent (OME) at Day Two
Equivalent (OME) at Day Two(0.02 lower to 0.18 higher)
was 1.60 Mg/Kg
Oral Morphine EquivaThe mean oral Morphine
MD 0.37 Mg/Kg lower
lent (OME) at Day Three Equivalent (OME) at Day Three (2.07 lower to 1.33
was 1.14 Mg/Kg
higher)Total Cumulative dose
The mean total Cumulative
MD 0.11 Mg/Kg lowerof OME for the first two dose of OME for the first two(0.61 lower to 0.39
days
days was 3.19 Mg/Kg
higher)Total Cumulative dose
The mean total Cumulative
MD 1.87 Mg/Kg lowerof OME for the first three dose of OME for the first three (7.35 lower to 3.62
days
days was 4.56 Mg/Kg
higher)Midazolam RequireThe mean midazolam Require- MD 0.01 Mg/Kg higher
ments at Day One
ment at Day One was 1.00
(0.16 lower to 0.19
Mg/Kg
higher)Midazolam RequireThe mean midazolam Require- MD 0.19 Mg/Kg
ments at Day Twoment at Day Two was 0.31
higher(0.3 lower to 0.68
Mg/Kg
higher)Total cumulative dose of The mean total cumulative
MD 0.09 Mg/Kg higher
Midazolam for the firstdose of Midazolam for the first (0.11 lower to 0.29 higher)
two days
two days was 0.95 Mg/Kg
Mechanical Ventilation
The mean mechanical Ventila- MD 1.46 Days fewer(9.74
Durationtion Duration was 36.87 Days fewer to 6.82 more)
Outcomes

No of participants (studies)

Certainty of theevidence(GRADE)

Reason fordowngrade

530 (7 nonrandomised
studies)323 (5 nonrandomised
studies)187 (2 nonrandomised
studies)368 (5 nonrandomised
studies)187 (2 nonrandomised
studies)270 (3 nonrandomised
studies)211 (2 nonrandomised
studies)261 (3 nonrandomised
studies)400 (5 nonrandomised
studies)⨁⨁◯◯ Low

Downgraded due
to high ROB and
imprecision
Downgraded due
to high ROB and
imprecision
Downgraded due tohigh ROB, indirectness, and imprecision
Downgraded due tohigh ROB, indirectness, and imprecision
Downgraded due tohigh ROB, indirectness, and imprecision
Downgraded due
to high ROB and
imprecision
Downgraded due tohigh ROB, inconsistency, and imprecision
Downgraded due tohigh ROB, inconsistency, and imprecision
Downgraded due
to high ROB and
imprecision⨁⨁◯◯ Low⨁◯◯◯ Verylow⨁◯◯◯ Verylow⨁◯◯◯ Very
Low⨁⨁◯◯ Low⨁◯◯◯ Very
Low⨁◯◯◯ Very
Low⨁⨁◯◯ Low

CI: confidence interval; MD: mean difference
GRADE Working Group grades of evidenceHigh certainty: we are very confident that the true effect lies close to that of the estimate of the effectModerate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that
it is substantially different
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effectVery low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effectin the DS group, but the results did not reach statistical significance (MD = 0.08 mg/kg; 95% CI [-0.02, 0.18];
P = 0.13). The pooled studies were homogeneous (P = 0.16;
I2 = 39%) Fig. 3. We downgraded the evidence due to high
ROB and imprecision Table 1.

At day three

Two studies compared the patients with DS to the controls regarding the OME at day three with a total of 187
patients. The overall MD between the DS and the control groups showed that the OME at day three was almost
similar in the two groups with no difference between

Alsulami et al. BMC Pediatrics(2024) 24:504

Page 6 of 10

Fig. 3 Forest plot comparing the DS and the control groups regarding the OME at day 2

Fig. 4 Forest plot comparing the DS and the control groups regarding the OME at day 3

Fig. 5 Forest plot comparing the DS and the control groups regarding the cumulative OME for the first two days

Fig. 6 Forest plot comparing the DS and the control groups regarding the cumulative OME for the first two days after resolving the heterogeneitythem (MD= -0.37 mg/kg; 95% CI [-2.07, 1.33]; P = 0.67)
and pooled studies showed significant heterogeneity(P = 0.01; I2 = 85%) Fig. 4. We downgraded the evidence
due to high ROB, indirectness, and imprecision Table 1.
Total cumulative dose of OME for the first two days

Five studies compared the patients with DS to the controls regarding the cumulative OME for the first two days
with a total of 368 patients. The overall MD between the
DS and the control groups showed that the cumulative
OME for the first two days was almost similar in the twogroups with no difference between them (MD= -0.11 mg/
kg; 95% CI [-0.61, 0.39]; P = 0.67) and pooled studies

showed significant heterogeneity (P = 0.006; I2 = 73%).
Figure 5 The heterogeneity was resolved by performing
the sensitivity analysis excluding Vogel et al. 2022 study(P = 0.10; I2 = 53%); however, the results still show no difference between the two groups (MD = 0.07 mg/kg; 95%
CI [-0.28, 0.41]; P = 0.70) Fig. 6. We downgraded the evidence due to high ROB, indirectness, and imprecision
Table 1.
Total cumulative dose of OME for the first three days

Two studies compared the patients with DS to the controls regarding the cumulative OME for the first threedays with a total of 187 patients. The overall MD between

Alsulami et al. BMC Pediatrics(2024) 24:504

Page 7 of 10

Fig. 7 Forest plot comparing the DS and the control groups regarding the cumulative OME for the first three days

Fig. 8 Forest plot comparing the DS and the control groups regarding the midazolam at day 1

Fig. 9 Forest plot comparing the DS and the control groups regarding the midazolam at day 2

Fig. 10 Forest plot comparing the DS and the control groups regarding the midazolam at day 3

the DS and the control groups showed that the cumulative one for the first three days was almost similar in
the two groups with no difference between them (MD=-1.87 mg/kg; 95% CI [-7.35, 3.62]; P = 0.51) and pooled
studies showed significant heterogeneity (P < 0.001;
I2 = 93%) Fig. 7. We downgraded the evidence due to high
ROB, indirectness, indirectness, and imprecision Table 1.
Midazolam
At day one

Three studies compared the patients with DS to the controls regarding the midazolam at day one, with a total of
270 patients. The overall MD between the DS and thecontrol groups showed that the midazolam at day one
was almost similar in the two groups with no difference
between them (MD = 0.01 mg/kg; 95% CI [-0.16, 0.19];
P = 0.88). The pooled studies were homogeneous (P = 0.76;
I2 = 0%) Fig. 8. We downgraded the evidence due to high
ROB, and imprecision Table 1.

At day two

Two studies compared the patients with DS to the controls regarding midazolam at day two with a total of 211
patients. The overall MD between the DS and the control groups showed that the midazolam at day two wasslightly higher, but not statistically significant, in the DS
group compared to the control group (MD = 0.19 mg/kg;
95% CI [-0.30, 0.68]; P = 0.44). The pooled studies were
not homogeneous (P = 0.03; I2 = 78%) Fig. 9. We downgraded the evidence due to high ROB, indirectness, andimprecision Table 1.
At day three

Midazolam at day three was reported only by one study
with a total of 155 patients. The overall MD between the
DS and the control groups showed that the midazolam
at day three was lower, but not statistically significant,in the DS group compared to the control group (MD=-0.08 mg/kg; 95% CI [-0.16, 0.00]; P = 0.05). Figure 10.

Alsulami et al. BMC Pediatrics(2024) 24:504

Page 8 of 10

Fig. 11 Forest plot comparing the DS and the control groups regarding the total cumulative dose of Midazolam for the first two days

Fig. 12 Forest plot comparing the DS and the control groups regarding the mechanical ventilation duration

Total cumulative dose of midazolam for the first two daysThree studies compared the patients with DS to thecontrols regarding the total cumulative dose of Midazolam for the first two days with a total of 261 patients.
The overall MD between the DS and the control groups
showed that the total cumulative dose of Midazolam forthe first two days was slightly higher, but not statistically significant, in the DS group compared to the control
group (MD = 0.09 mg/kg; 95% CI [-0.11, 0.29]; P = 0.38).
The pooled studies were homogeneous (P = 0.34; I2 = 7%).
Figure 1. We downgraded the evidence due to high ROB,
indirectness, and imprecision Table 1, (see Fig. 11).
Mechanical ventilation (MV) duration

Five studies reported the MV duration comparing the DS
and the control groups with a total of 400 patients. The
overall MD showed that there was no significant difference between patients with DS and the controls regarding the MV duration (MD= -1.46 h; 95% CI [-9.74, 6.82];
P = 0.73). The pooled studies were homogeneous (P = 0.42;
I2 = 0%) Fig. 12. We downgraded the evidence due to high
ROB, and imprecision Table 1.

Discussion
To our knowledge, this is the first meta-analysis to evaluate opioid and benzodiazepine requirements in post-surgical children with DS. The results of this meta-analysis
shed light on the inaccurate assumption about increased
sedation and analgesia requirements in DS. Such findings are essential as they can provide healthcare professionals with an accurate estimation to optimize patientcare. However, future randomized clinical trials withlarger cohorts are needed to ensure appropriate dosing inpatients with DS.

Our meta-analysis didn’t detect a significant difference in morphine requirement in DS. Findings arise fromseven studies, and a total of 533 patients compared OME
on day 1 in patients with DS versus the control group.
The results indicated that on day 1, OME was higher inthe DS group without statistical significance; on day 2,
OME was also higher but not statistically significant; andon day 3, OME requirements were similar between thegroups with a significant heterogeneity [9–12, 21–23].
Regarding the hypothesis that individuals with DS have a
different sensitivity to pain, one study among the studies
included in the meta-analysis that had involved 45 infants
undergoing duodenal surgery found no significant differences in pain scores or analgesia requirements comparedto the control group [22].
Two others among the included studies had reported
limitations, including small sample size and variability in underlying cardiac diagnosis between the DS andmatched control, leading to patients undergoing different
cardiac procedures. This is considered a potential confounder as different cardiac diseases have a significant
impact on patient care as well as on clinical outcomes.
An additional limitation that was reported in some of the
included studies is the use of adjunctive non-opioid medications for pain control, which might lead to a reduced
total requirement of opioids among study participants.
Therefore, our findings contradict the common belief
that DS might require more pain medication than theirpeers. In alignment with our results, two pharmacokinetics studies have shown that neither morphine volume of
distribution nor clearance is different in DS in comparison to patients without DS, meaning that DS shall not be
anticipated to require a higher requirement than theirpeers [12, 22]. While our analysis did report higher OME

Alsulami et al. BMC Pediatrics(2024) 24:504

requirements in the DS on certain days, such a difference
did not reach statistical significance. Ultimately, evidence
regarding pain sensitivity in children with DS remains
inconclusive.
Analysis of sedation requirement on day 1 in trisomy
disorder patients across three studies (totaling 270 participants) indicated nearly equivalent use of midazolam
between the groups (MD = 0.01 mg/kg; P = 0.88). On day
2, midazolam requirement was slightly higher in the DS
group, though not statistically significant in two studies[21, 23]. Conversely, one study found that midazolam
requirement on day 3 was lower in the DS group but also
didn’t reach statistical significance [21]. Velkenburg et al.
developed a population pharmacokinetic model for midazolam, which showed that DS was not considered to bea significant covariate. Their pharmacodynamic analysis concluded that there was no observed difference inmidazolam sedative effect between DS and non-DS [22].
Similarly, Vogel et al. demonstrated an insignificant difference in midazolam exposure either preoperatively or
intraoperatively between DS and matched control. Additionally, no differences in pediatric intensive care unit
or hospital length of stay were observed between thegroups. However, limitations include the retrospective
nature impacting sample size matching, the challenges
in accurately assessing pain in non-verbal children withDS, which might lead to underestimation of their actual
needs, and the author noted considerations about thepotential impact of other sedative agents, such as ketamine and dexmedetomidine, on the midazolam requirement [21]. The results of our meta-analysis contradict
previous studies that reported higher midazolam doses
and hypothesized alterations in the GABA transmission
system in patients with DS as the cause [7, 22].
The duration of MV was assessed in our meta-analysis
through the inclusion of five studies [10–12, 21, 22]. The
overall findings revealed that there was no difference in
MV duration between patients with DS and the controls.
However, a study by Goot et al. reported that the lengthof stay for an individual with DS was longer than that of
their peers, which might be indirectly linked to delayed
respiratory recovery or feeding intolerance. It should be
noted that this study was limited by its sample size [11].
Additionally, prolonged length of stay in patients withDS might be attributed to their underlying disease. A
review involving 488 patients with DS found that anesthetic-related consequences such as severe bradycardia
occurred in 3.66% of the patients and up to 1.83% occurrence rate of obstruction in the airway. This complication
might have an impact on the duration of MV in comparison to patients without DS [24].
We acknowledge that this meta-analysis has considerable limitations. Firstly, it includes only a total of 10 studies in the systemic review and 7 in the meta-analysis, all

Page 9 of 10

of which were retrospectively designed. In addition, sedation and analgesia assessment tools were highly diverse
across the analyzed studies. Selecting an accurate toolis crucial, particularly considering reports that children
with DS had restricted ability in verbal and behavioral
expression to painful stimuli [25]. This is of great significance as it could affect the amounts of analgesia actuallyadministered to those patients. The lack of considerationof non-opioid agents or adjunctive sedative agents further adds to the limitation of our findings. Thus, randomized clinical trials or prospective cohort studies
accounting for the additional use of non-opioid medication and using standardized assessment tools are neededto address the gap in knowledge about sedation and analgesia requirements in patients with DS.

Conclusion
Our meta-analysis confirms the inaccurate clinicalassumption about the use of opioids in children with DS.
Our conclusion indicates that patients with DS didn’t
necessitate a higher requirement of sedation or analgesia
in the first three days postoperatively compared to children without DS. Furthermore, there was no significant
difference in the duration of MV between the two groups.
Supplementary Information

The online version contains supplementary material available at https://doi.
org/10.1186/s12887-024-04971-0.
Supplementary Material 1
Supplementary Material 2
Supplementary Material 3
Acknowledgements
We express our appreciation to all researchers affiliated with the Saudi Critical
Care Pharmacy Research (SCAPE) platform, as well as the supporters from theSaudi Society for Multidisciplinary Research Development and Education, fortheir invaluable assistance in this project.
Author contributions
All authors contributed significantly to the work reported, including in the
study conception, design, and execution; the acquisition, analysis, andinterpretation of data; and to all aspects of study orchestration. Additionally,
all authors participated in drafting, revising, and/or critically reviewing thearticle; provided final approval of the version to be published; agreed on thejournal to which the article has been submitted; and committed to being
accountable for all aspects of the work.
Funding
Not applicable.
Data availability
All data generated or analyzed during this study are included in the publishedarticle.

Declarations
Ethical approval and consent to participate
Not applicable.

Alsulami et al. BMC Pediatrics(2024) 24:504

Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Author details
1
Department of Pharmacy Practice, College of Pharmacy, Umm Al-Qura
University, Makkah, Saudi Arabia
2
Pharmaceutical Care Division, King Faisal Specialist Hospital andResearch Center, Riyadh, Saudi Arabia
3
Pharmaceutical Care Department, King Saud Medical City, Riyadh, Saudi
Arabia4
Pharmaceutical Care Department, King Abdulaziz Medical City, Riyadh,
Saudi Arabia
5
College of Pharmacy, King Saud bin Abdulaziz University for Health
Sciences, Riyadh, Saudi Arabia
6
King Abdullah International Medical Research Center, Riyadh, Saudi
Arabia7
Saudi Critical Care Pharmacy Research (SCAPE) Platform, Riyadh, Saudi
Arabia8
Saudi Society for Multidisciplinary Research Development and Education(SCAPE Society), Riyadh, Saudi Arabia
9
Department of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz
University, Jeddah, Saudi Arabia
10
Faculty of Medicine, Al-Azhar University, Cairo, Egypt
11
Medical Research Group of Egypt, Negida Academy, Arlington, MA, USA
12
Pharmaceutical Care Services, King Fahad Armed Forces Hospital,
Jeddah, Saudi Arabia
13
Department of Clinical Pharmacy, College of Pharmacy, King Saud
University, Riyadh, Saudi Arabia
14
Drug Regulation Research Unit, College of Pharmacy, King Saud
University, Riyadh, Saudi Arabia
15
Department of Pediatrics, King Abdulaziz Medical City, Ministry of
National Guard - Health Affairs, Riyadh, Saudi Arabia
16
College of Medicine, King Saud bin Abdulaziz University for Health
Sciences, Riyadh, Saudi Arabia
17
King Abdulaziz Medical City (KAMC) - Ministry of National Guard Health
Affairs (MNGHA), King Abdullah International Medical Research Center,
King Saud bin Abdulaziz University for Health Sciences, PO Box 22490,
Riyadh 11426, Saudi Arabia

Page 10 of 10

9.

10.
11.

12.

13.

14.
15.
16.

17.
18.
19.
20.

Received: 19 February 2024 / Accepted: 24 July 2024
21.
References
1. What is Down Syndrome? - Down Syndrome Resource Foundation. (2023,
November 1). Down Syndrome Resource Foundation. https://www.dsrf.org/
resources/information/what-is-down-syndrome/
2. Mai CT, Isenburg JL, Canfield MA, Meyer RE, Correa A, Alverson CJ, Lupo
PJ, Riehle-Colarusso T, Cho SJ, Aggarwal D, Kirby RS. October 3). National
population‐based estimates for major birth defects, 2010–2014. Birth Defects
Res. 2019;111(18):1420–35. https://doi.org/10.1002/bdr2.1589. Tubman, T. R.,
Shields, M. D., Craig, B. G.
3. Mulholland HC, Nevin NC. (1991, June 15). Congenital heart disease
in Down’s syndrome: two year prospective early screening study. BMJ,
302(6790), 1425–1427.https://doi.org/10.1136/bmj.302.6790.1425
4. Antonarakis SE, Skotko BG, Rafii MS, Strydom A, Pape SE, Bianchi DW, Sherman SL, Reeves RH. February 6). Down syndrome. Nat Reviews Disease
Primers. 2020;6(1). https://doi.org/10.1038/s41572-019-0143-7.
5. Bull MJ. Down syndrome. N Engl J Med. 2020;382(24):2344–52. https://doi.
org/10.1056/nejmra1706537.
6. Barnes S, Yaster M, Kudchadkar SR. (2016, May 1). Pediatric Sedation
Management. Pediatrics in Review, 37(5), 203–212. https://doi.org/10.1542/
pir.2014-0116
7. Haydar TF, Reeves RH. Trisomy 21 and early brain development. Trends Neurosci. 2012, February;35(2):81–91. https://doi.org/10.1016/j.tins.2011.11.001.
8. Shaikh A, Li Y, Lu J. Perspectives on pain in Down Syndrome. Med Res Rev.
2023b;43(5):1411–37. https://doi.org/10.1002/med.21954.

22.

23.

24.

25.

SCOTT -GAKHALB, C. S., MACNAB AJ. Comparison of morphine requirements for sedation in Down’s syndrome and non-down’s patients following
paediatric cardiac surgery. Pediatr Anesth. 1998, May;8(3):229–33. https://doi.
org/10.1046/j.1460-9592.1998.00764.x.
Van Driest SL, Shah A, Marshall MD, Xu H, Smith AH, McGregor TL, Kannankeril
PJ. November). Opioid use after cardiac surgery in Children with Down
Syndrome*. Pediatr Crit Care Med. 2013;14(9):862–8.
Goot BH, Kaufman J, Pan Z, Bourne DWA, Hickey F, Twite M, Galinkin J,
Christians U, Zuk J, da Cruz EM. Morphine Pharmacokinetics in Children with
Down Syndrome following cardiac surgery. Pediatr Crit Care Med. 2018,
May;19(5):459–67. https://doi.org/10.1097/pcc.0000000000001537.
Valkenburg AJ, Calvier EAM, van Dijk M, Krekels EHJ, O’Hare BP, Casey WF,
Mathôt RAA, Knibbe CAJ, Tibboel D, Breatnach CV. Pharmacodynamics andpharmacokinetics of Morphine after Cardiac surgery in children with andwithout Down Syndrome. Pediatr Crit Care Med. 2016, October;17(10):930–8.
https://doi.org/10.1097/pcc.0000000000000904.
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD,
Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R, Glanville J, Grimshaw JM,
Hróbjartsson A, Lalu MM, Li T, Loder EW, Mayo-Wilson E, McDonald S, Moher
D. March 29). The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;71. https://doi.org/10.1136/bmj.n71.
Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan—a web
and mobile app for systematic reviews. Syst Reviews. 2016, December;5(1).
https://doi.org/10.1186/s13643-016-0384-4.
Equianalgesic Doses of Opioid Analgesics, Manual MSD. Retrieved November 29, 2023, from https://www.msdmanuals.com/en-jp/professional/
multimedia/table/equianalgesic-doses-of-opioid-analgesics
Morphine 10 mg/mL injection, 1 mg/mL oral solution. South Australian
Neonatal Medication Guidelines. Retrieved November 29. 2023, fromhttps://www.sahealth.sa.gov.au/wps/wcm/connect/public+content/
sa+health+internet/clinical+resources/clinical+programs+and+practice+g
uidelines/womens+and+babies+health/neonatal+medication+guidelines/
neonatal+medication+guidelines
Kane SP. Benzodiazepine Equivalents Conversion Calculator - ClinCalc.com.
https://clincalc.com/Benzodiazepine/
Wells, George & Shea, Beverley & O’Connell, D & Peterson, je & Welch, Vivian& Losos,M & Tugwell, Peter. (2000). The Newcastle–Ottawa Scale (NOS) for
Assessing the Quality of Non-Randomized Studies in Meta-Analysis
Luo D, Wan X, Liu J, Tong T. Optimally estimating the sample mean from thesample size, median, mid-range, and/or mid-quartile range. Stat Methods
Med Res. 2016;27(6):1785–805. https://doi.org/10.1177/0962280216669183.
Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014, December;14(1). https://doi.
org/10.1186/1471-2288-14-135.
Vogel ER, Staffa SJ, DiNardo JA, Brown ML. Dosing of opioid medications
during and after Pediatric Cardiac surgery for children with Down Syndrome. J Cardiothorac Vasc Anesth. 2022, January;36(1):195–9. https://doi.
org/10.1053/j.jvca.2021.08.019.
Valkenburg A, van Dijk M, de Leeuw T, Meeussen C, Knibbe C, Tibboel D.
Anaesthesia and postoperative analgesia in surgical neonates with orwithout Down’s syndrome: is it really different? Br J Anaesth. 2012, February;108(2):295–301. https://doi.org/10.1093/bja/aer421.
Ellis AP, Kanter RK, Requirements for post-operative analgesics and sedatives in children with down syndrome. January.
Dosing. Crit Care Med. 1998;26(Supplement):97A. https://doi.
org/10.1097/00003246-199801001-00263.
Borland LM, Colligan J, Brandom BW. (2004, August 26). Frequency ofanesthesia-related complications in children with Down syndrome undergeneral anesthesia for noncardiac procedures. Pediatric Anesthesia, 14(9),733–738. https://doi.org/10.1111/j.1460-9592.2004.01329.x
Hennequin M, Morin C, Feine J. Pain expression and stimulus localisation in individuals with Down’s syndrome. Lancet. 2000, December;356(9245):1882–7. https://doi.org/10.1016/s0140-6736(00)03259-1.

Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.