Opioid and benzodiazepine requirements in critically ill post-surgical children with down syndrome: a systematic review and meta-analysis

Shaimaa Alsulami; Ashjan Alghanem; Renad AlShuraim; Khalid Al Sulaiman; Omer Ahmed Abdelwahab; Sarah Aljohani; Hadeel Alkofide; Mashael AlFaifi; Tarek Hazwani; Ohoud Aljuhani

doi:10.1186/s12887-024-04971-0

. 2024 Aug 7;24:504. doi: 10.1186/s12887-024-04971-0

Opioid and benzodiazepine requirements in critically ill post-surgical children with down syndrome: a systematic review and meta-analysis

Shaimaa Alsulami ¹, Ashjan Alghanem ², Renad AlShuraim ³, Khalid Al Sulaiman ^4,^5,^6,^7,^8,^17,^✉, Omer Ahmed Abdelwahab ^10,¹¹, Sarah Aljohani ¹², Hadeel Alkofide ^13,¹⁴, Mashael AlFaifi ^3,⁷, Tarek Hazwani ^6,^15,¹⁶, Ohoud Aljuhani ⁹

PMCID: PMC11304697 PMID: 39112949

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 and sedation after surgery. The aim of this systematic review and meta-analysis is to evaluate the variations of the requirement needed for pain management and sedation in patients with DS who have undergone surgery compared to 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, Cochrane Library, 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 a limited 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 with DS showed a slight increase in OME needs on the first day, but this increase was not statistically significant (mean difference [MD] = 0.09; 95% Confidence Interval [CI]: [-0.02, 0.20]; P = 0.11). There was also no significant difference in the 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).

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.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12887-024-04971-0.

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, and recovery in the intensive care unit (ICU) is necessary [4]. Additionally, individuals with DS are susceptible to other comorbidities, 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 the challenges faced in achieving appropriate pain management and sedation in patients with DS. One of these theories suggests that this condition’s unique physiological and 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, patients with DS may react to pain stimuli more slowly and have decreased 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 with DS, the results were conflicting. A retrospective cohort study reported that patients with DS after cardiac surgery required significantly higher doses of morphine and utilized 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 in the 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 and sedative needs remain inconsistent.

To optimize post-surgery care in patients with DS, it is necessary to understand the differences in sedation and analgesia requirements in those patients. Hence, our systematic review and meta-analysis aimed to evaluate the literature results on the variation in the requirements for pain 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 registered in 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 back to their inception through November 18, 2023, using the terms related to ‘Down syndrome,’ ‘intensive care unit,’ ' post-surgery’ and combined with terms related to analgesia and sedation management. A comprehensive search strategy can be found in Appendix 1.

Following the identification of studies using predetermined search terms in various databases, we utilized the Rayyan software for abstract screening and reference organization after removing duplicate entries [14]. Two investigators (SA and AA) independently screened all the identified studies for inclusion based on predetermined eligibility criteria, using the titles and abstracts of the articles. In cases of discrepancy between the two reviewers, a third investigator (OA) was consulted to reach a consensus. Studies that were deemed eligible after the initial screening phase were then retrieved, and their full 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 pediatric patients with DS aged 18 years or younger were considered eligible for inclusion. The studies included patients 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 for procedures 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 primary and secondary outcomes were determined based on the most frequently reported outcome after screening the included studies. In this systematic review and meta-analysis, 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 equivalent Midazolam 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 utilized a standardized data extraction form to extract relevant data, while a third investigator (RA) assisted in case of discrepancies. Information about study design, patient numbers, 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 the risk 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, 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 5 or fewer stars were deemed to have high ROB [18].

Furthermore, the GRADE approach was applied to assess 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 and reported on the same scale (days), mean differences (MD) were employed to summarize effect estimates, and their uncertainty was expressed through 95% confidence intervals (CIs). For studies reporting only medians and interquartile 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]. When SD was not reported, we adhered to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions, either by calculating the SD from other available 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 was assessed using the Chi-square test (Cochrane Q test) and the 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 the significance 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 these records using Rayyan software. Only 19 studies met the eligibility criteria after this screening phase and were selected for full-text screening. Finally, ten studies were included in the systematic review, seven of which were sufficiently homogeneous in design and outcome to be compared in the meta-analysis. All details regarding the screening and selection process of the included studies are illustrated in the PRISMA flow diagram Fig. 1.

Fig. 1 — PRISMA flow diagram of the study selection process

Characteristics of the included studies

The systematic review included ten studies encompassing 730 patients, while the meta-analysis consisted of seven studies with 533 patients. Of the seven studies included in 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 to assess 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 low risk of bias. It is important to note that the majority of these studies either neglected to assess confounders or omitted 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.

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

Outcomes	Anticipated absolute effects^* (95% CI)		No of participants (studies)	Certainty of the evidence(GRADE)	Reason for downgrade
Outcomes	Risk with control	Risk with down syndrome	No of participants (studies)	Certainty of the evidence(GRADE)	Reason for downgrade
Oral Morphine Equivalent (OME) at Day One	The mean oral Morphine Equivalent (OME) at Day One was 3.32 Mg/Kg	MD 0.09 Mg/Kg higher (0.02 lower to 0.2 higher)	530 (7 non-randomised studies)	⨁⨁◯◯ Low	Downgraded due to high ROB and imprecision
Oral Morphine Equivalent (OME) at Day Two	The mean oral Morphine Equivalent (OME) at Day Two was 1.60 Mg/Kg	MD 0.08 Mg/Kg higher (0.02 lower to 0.18 higher)	323 (5 non-randomised studies)	⨁⨁◯◯ Low	Downgraded due to high ROB and imprecision
Oral Morphine Equivalent (OME) at Day Three	The mean oral Morphine Equivalent (OME) at Day Three was 1.14 Mg/Kg	MD 0.37 Mg/Kg lower (2.07 lower to 1.33 higher)	187 (2 non-randomised studies)	⨁◯◯◯ Very low	Downgraded due to high ROB, indirectness, and imprecision
Total Cumulative dose of OME for the first two days	The mean total Cumulative dose of OME for the first two days was 3.19 Mg/Kg	MD 0.11 Mg/Kg lower (0.61 lower to 0.39 higher)	368 (5 non-randomised studies)	⨁◯◯◯ Very low	Downgraded due to high ROB, indirectness, and imprecision
Total Cumulative dose of OME for the first three days	The mean total Cumulative dose of OME for the first three days was 4.56 Mg/Kg	MD 1.87 Mg/Kg lower (7.35 lower to 3.62 higher)	187 (2 non-randomised studies)	⨁◯◯◯ Very Low	Downgraded due to high ROB, indirectness, and imprecision
Midazolam Requirements at Day One	The mean midazolam Requirement at Day One was 1.00 Mg/Kg	MD 0.01 Mg/Kg higher (0.16 lower to 0.19 higher)	270 (3 non-randomised studies)	⨁⨁◯◯ Low	Downgraded due to high ROB and imprecision
Midazolam Requirements at Day Two	The mean midazolam Requirement at Day Two was 0.31 Mg/Kg	MD 0.19 Mg/Kg higher(0.3 lower to 0.68 higher)	211 (2 non-randomised studies)	⨁◯◯◯ Very Low	Downgraded due to high ROB, inconsistency, and imprecision
Total cumulative dose of Midazolam for the first two days	The mean total cumulative dose of Midazolam for the first two days was 0.95 Mg/Kg	MD 0.09 Mg/Kg higher (0.11 lower to 0.29 higher)	261 (3 non-randomised studies)	⨁◯◯◯ Very Low	Downgraded due to high ROB, inconsistency, and imprecision
Mechanical Ventilation Duration	The mean mechanical Ventilation Duration was 36.87 Days	MD 1.46 Days fewer(9.74 fewer to 6.82 more)	400 (5 non-randomised studies)	⨁⨁◯◯ Low	Downgraded due to high ROB and imprecision

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CI: confidence interval; MD: mean difference

GRADE Working Group grades of evidence

High certainty: we are very confident that the true effect lies close to that of the estimate of the effect

Moderate 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 effect

Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect

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 in 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.

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

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 them (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.

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

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 two groups 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.

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 heterogeneity

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 three days with a total of 187 patients. The overall MD between 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.

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