The Improvement of Central Apnea Index after Adenotonsillectomy in Children: A Systematic Review and Meta-analysis

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The Improvement of Central Apnea Index after Adenotonsillectomy in Children: A Systematic Review and Meta-analysis

https://doi.org/10.21203/rs.3.rs-3635444/v1

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Background

Central sleep apnea has been reported in pediatric patients with obstructive sleep apnea (OSA). However, the effect of adenotonsillectomy (TA) on the presentation of the central apnea index (CAI) remains unclear. We investigated the effect of TA on CAI in children with OSA through a systematic review and meta-analysis.

Methods

A systematic search was performed to identify original studies that compare the CAI obtained before and after TA from polysomnography in children under 18 years of age. Non-original studies and full papers that were not available were excluded. Only relevant data were pooled for meta-analysis.

Results

Eleven studies with 689 participants were included. The mean age was 5.6 ± 3.0 years and the mean BMI was 21.0 ± 10.6 kg/m². Post-TA CAI decreased significantly from pre-TA CAI with a mean difference (MD) of 0.70 events/h (95%CI, 0.25–1.15), especially in the non-Down syndrome subgroup [MD of 0.75 events/h (95%CI, 0.24 to 1.26)]. Other parameters, including the apnea-hypopnea index and oxygen saturation, were also significantly improved after TA. However, there was no significant difference in CAI reduction between the subgroups of patients with and without TA, and those with and without obesity.

Conclusion

This meta-analysis revealed that pediatric patients with OSA who underwent TA had a significant reduction in CAI, particularly in patients without Down syndrome. The study suggests that CAI should be considered an important PSG parameter in post-TA patients. A further well-controlled and long-term study considering the impact of pediatric OSA surgery on CAI is needed.

Health sciences/Medical research/Paediatric research

Health sciences/Medical research/Outcomes research

Central sleep apnea

Obstructive sleep apnea

Adenoidectomy

Tonsillectomy

Adenotonsillectomy

Obstructive sleep apnea (OSA), one of the most unfavorable conditions on the spectrum of sleep problems, can potentially affect 2–4 percent of children^1–3. Its common clinical manifestations in pediatric patients include repetitive snoring, restless sleep, excessive daytime drowsiness, neurobehavioral abnormalities during the day, and mood disorders⁴. If OSA is undiagnosed or mistreated, there is a higher risk of development problems, neurocognitive effects, and cardiovascular complications^5–7.

According to the American Academy of Sleep Medicine (AASM) scoring guidelines, a central apnea in children is defined as the absence of chest and/or abdominal movement coupled with a decrease in airflow of at least 90% from the pre-event baseline, lasting more than 20 seconds or at least the duration of two breaths during baseline breathing, associated with an arousal, or at least 3% oxygen desaturation⁸. In children, central apnea is frequently a physiological event that occurs at the onset of sleep, during a body movement during sleep, or right after arousal. An average number of central apnea per hour of sleep is reported as a central apnea index (CAI). According to normative polysomnography (PSG) values using AASM standards, a CAI of a healthy child should be less than 0.4 events/h^9–11. When the CAI is greater than or equal to 5 events/h, central sleep apnea (CSA) can be diagnosed¹². Numerous underlying medical disorders, including brain defects such as Chiari malformation, Prader-Willi syndrome, Down syndrome, gastroesophageal reflux disease (GERD), obesity, and hypothyroidism, can be linked to this condition. However, CAI is frequently found to be higher in pediatric patients with OSA compared to healthy children^{13, 14} as shown by its prevalence of 14.9–16.9% using criteria of CAI ≥ 1 event/h^{15, 16}, and prevalence of 3.3–5.4% using criteria of CAI ≥ 5 events/h^{12, 15}. This factor may be contributing to the higher incidence of respiratory complications after airway surgery in patients with OSA compared to healthy children¹³.

Adenotonsillectomy (TA) is considered the first-line treatment of OSA in children with evidence of postoperative cognitive behavior, school performance, quality of life, and improvement in PSG parameters improvement^17–19. However, children whose PSG findings showed concurrent CSA and OSA are at risk of receiving this operation. Although previous studies reported that obstructive indices and CAI improved following TA^{16, 20–22}, the results remained inconsistent and uncertain. Therefore, the objective of the present study is to determine the effect of TA on CAI in children with OSA.

This systematic review and meta-analysis were registered in PROSPERO on November 17, 2021 with registration number CRD42021285541. According to registration number 068/2565, the Siriraj Institutional Review Board authorized the exemption. The following protocol has been written according to the Preferred Reporting Item for Systematic Review and Meta-Analyses (PRISMA) and Meta-analyses Of Observational Studies in Epidemiology (MOOSE) guidelines^{23, 24}.

Eligibility Criteria

The inclusion criteria for this study were randomized controlled trials, cohort studies, retrospective studies, and case series that evaluated the effectiveness of adenoidectomy, tonsillectomy, or adenotonsillectomy in children under the age of 18 years of age and reported relevant data on pre / postoperative CAI from PSG. Included studies were restricted to the English language. Exclusion criteria were non-original studies (e.g., review, letter to editors) and studies that full paper were not available.

Search Strategy

A systematic search was done using OVID Medline, EMBASE database, and manual bibliographic search. The following PICO elements were used in the search strategy for this study: children with OSA (patient), adenotonsillectomy (intervention), preoperative and postoperative (comparator), and central apnea index (outcome). The search term was “Sleep apnea”, “Central sleep apnea”, “Obstructive sleep apnea”, “Adenoidectomy”, “Tonsillectomy” and “Adenotonsillectomy” as keywords. (Supplemental material) The last search was performed on June 11, 2023. Duplication records were removed.

Study Selection and Data Extraction

The title and abstract screening were performed by two independent reviewers (SW, NK) who then decided which studies to include. The full text articles of relevant reports were reviewed according to the eligibility criteria by two independent reviewers (SW, NK). The final decision on study inclusion was made and disagreements were resolved by the third reviewer (AT). The data collection was then performed. The following characteristics of the included studies were extracted: year, nation, number of participants, mean age, sex, body mass index (BMI), comorbidities, tonsil/adenoid size, and complications. The preoperative and postoperative PSG parameters, including the apnea-hypopnea index (AHI), CAI, minimum oxygen saturation (minSpO₂), mean oxygen saturation (meanSpO₂), oxygen desaturation index (ODI), arousal index (AI) and duration of each sleep stage, were also retrieved. If there was insufficient information from the publications, the corresponding authors of each article were contacted for more data.

Assessment of Risk of Bias

The quality of the included studies was assessed by two independent reviewers (SW, NK). The risk of bias in retrospective study, cohort study, and case series was assessed according to the Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS) in six domains (selection of participants, confounding variable, intervention (exposure) measurement, blinding of outcome assessment, incomplete outcome data, and selective outcome reporting)²⁵. Each domain was categorized as low, high or unclear risk. Randomized control trials (RCT) were evaluated using the Cochrane risk-of-bias tool for randomized trials (RoB tool) in six domains (random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective reporting)²⁶. Disagreements were resolved by the third reviewer (AT).

Data Synthesis

For the meta-analysis, data were combined. The effect size of the continuous outcome data was reported as the mean difference (MD) or standard mean difference (SMD) with standard deviation (SD) and a 95% confidence interval. In the absence of SD, the Cochrane Handbook for Systematic Reviews of Interventions recommended calculating standard errors, confidence intervals, t values and P values²⁷. Review Manager version 5.4 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark, 2020) was used for the statistical analysis. A random-effects model was applied. The Cochrane Q test and the I² statistic were used as measures of heterogeneity. An I² was interpreted as follows: 0–40%: may not be important; 30–60%: may represent moderate heterogeneity; 50–90%: may represent substantial heterogeneity; and 90–100%: considerable heterogeneity. Subgroup analysis was performed to assess the potential effect of related factors (syndrome and obesity). Publication bias was reported by funnel plot. Sensitivity analysis was performed to ensure that the effects were still significant.

Study Selection

The search results revealed 7,484 studies (Ovid Medline, 2,825; EMBASE, 4,659; and Manual search, 0). After 1,617 duplicates were eliminated, 5,867 studies' titles and abstracts were checked, and 56 studies had their full texts retrieved. For the following reasons, the remaining 45 articles were eliminated from the final analysis: lingual tonsillectomy procedure; lack of central apnea data; complete text not available; lack of postoperative PSG; and non-original studies. Thus, the final analysis included 11 studies for both qualitative and quantitative analysis. The overall agreement rate of the reviewers was 96% (Cohen's kappa correlation: 0.88). The study retrieval and selection process was illustrated in Fig. 1.

Characteristics of the studies and participants

A total of 689 participants from the eleven selected studies were included, each study sample ranging from 20 to 242 participants. The mean BMI was 21.0 ± 10.6 kg/m², and the mean age was 5.6 ± 3.0 years (range: 2.7 to 13.5 years). Detailed characteristics of the studies and participants are presented in Table 1. The included studies were published from 2008 to 2021. The studies were conducted in the United State^{15, 16, 22, 28, 29}, Japan³⁰, Belgium³¹, Brazil³², Spain³³, Germany³⁴, and Sweden³⁵. There were 6 retrospective studies^{14, 15, 20, 29, 30, 32}, 2 prospective cohort studies^{28, 34}, 2 case series^{16, 22}, and 1 randomized control trial³⁵. The postoperative evaluation of PSG ranged from 1 day to 108 months. According to the variations in CAI mean, funnel plots for the standard errors were produced. As a result of the funnel plot's symmetries. Sensitivity analysis was performed considering the follow-up period on CAI, and the result remained unchanged. Additional data were provided in supplemental Fig. 1. Subgroup analysis was performed in 2 subgroups of comorbidities: Down syndrome and obese patients. There was not enough data on other comorbidities, ODI, AI, duration of each sleep stage, tonsil / adenoid size and complication after TA for analysis.

Table 1

Summary of the characteristics of studies and participants.
	Authors	Year	Country	Study design	n	Age, year (Mean ± SD)	Boy, n (%)	BMI, kg/m² (Mean ± SD)	CAI, events/h (Mean ± SD)		AHI, events/h (Mean ± SD)			minSpO₂, % (Mean ± SD)		Follow up time, months
	Authors	Year	Country	Study design	n	Age, year (Mean ± SD)	Boy, n (%)	BMI, kg/m² (Mean ± SD)	Pre-op	Post-op	Pre-op		Post-op	Pre-op	Post-op
1	Arima³⁰	2019	Japan	Retrospective	242	5.35 ± 2.26	168 (69%)	16.31 ± 2.94	1.35 ± 1.73	0.83 ± 1.20	24.06 ± 19.5		3.28 ± 3.69	82.5 ± 9.3	89.62 ± 4.57	7.2 ± 2.4
2	Baldassari¹⁶	2012	US	Case series	15	5.63 ± 5.23	10 (67%)	NA	3.9 ± 2.9	1.9 ± 4.8	22.8 ± 16.63		5.4 ± 5.25	NA	NA	NA
3	Boudewyns²⁰	2016	Belgium	Retrospective	41	2.7 ± 2.38	NA	16.3 ± 1.69	2.2 ± 1.62	1.3 ± 1.39	10.9 ± 12.54		1.2 ± 1.62	86.6 ± 6	91 ± 3.1	Range 3–6
4	da Rocha³²	2017	Brazil	Retrospective	27	6.7 ± 3.6	15 (56%)	NA	1.33 ± 1.81	1.99 ± 3.53	14.6 ± 11.8		13.6 ± 16.7	75 ± 19	83 ± 7	Range 3.03–108.2
5	De A²⁸	2017	US	Prospective cohort	20	13.5 ± 2.25	15 (75%)	39.9 ± 10.1	2.3 ± 5.2	0.7 ± 1.0	29.4 ± 23.4		27.6 ± 34.5	80.1 ± 7.9	82.0 ± 8.7	First night after TA
6	de la Chaux³⁴	2008	Germany	Prospective cohort	20	4.1 ± 2.0	NA	NA	0.3 ± 0.8	0.3 ± 0.6	14.9 ± 8.7		1.1 ± 1.6	71.7 ± 11.1	91.2 ± 3.5	Range 3–12
7	Del-Río Camacho³³	2019	Spain	Retrospective	TA = 66	4.84 ± 0.71	NA	NA	2.63 ± 0.87	1.26 ± 1.35	NA		NA	NA	NA	Range 6–12
7	Del-Río Camacho³³	2019	Spain	Retrospective	No TA = 43	4.84 ± 0.71	NA	NA	2.12 ± 3.40	1.74 ± 1.95	NA		NA	NA	NA	Range 6–12
8	Fehrm³⁵	2020	Sweden	Randomized controlled trial	TA = 29	3.25 ± 0.66	15 (52%)	BMI z score 0.2 ± 1.4	1.7 ± 1.6	NA	4.8 ± 1.9		NA	89.6 ± 3.7	NA	6
8	Fehrm³⁵	2020	Sweden	Randomized controlled trial	No TA = 31	3.08 ± 0.92	19 (61%)	BMI z score 0.2 ± 1.1	2.1 ± 2.2	NA	5.1 ± 2.2		NA	88.0 ± 5.5	NA	6
9	Ingram²⁹	2017	US	Retrospective	75	5.1 ± 3.6	41 (55%)	NA	1.5 ± 1.9	1.4 ± 1.7		21.3 ± 19.8	8.1 ± 8.1	78.6 ± 7.4	81.3 ± 5.1	6
10	Judd¹⁵	2021	US	Retrospective	123	5.53 ± 4.26	78 (63%)	BMI percentile 92	2.1 ± 2.23	0.42 ± 0.82		21.32 ± 17.85	3.81 ± 4.27	88.5 ± 7.69	86.0 ± 10.25	4.14 ± 2.50 (Range 0.59–11.89)
11	Thottam²²	2015	US	Case series	36	5.0 ± 3.53	18 (50%)	17.3 ± 8.1	0.8 ± 2.08	0.3 ± 1.65		10.4 ± 14.6	3.5 ± 14.7	86 ± 10.25	88 ± 8.25	NA
Abbreviations: n, number; BMI, body mass index; CAI, central apnea index; AHI, apnea-hypopnea index; minSpO₂, minimum oxygen saturation; SD, standard deviation; TA, adenotonsillectomy; NA, not available data.

Assessment of risk of bias

Assessments of risk of bias in included studies are presented in Fig. 2. Ten nonrandomized studies were evaluated using RoBANS. A low risk of bias was present in inadequate outcome data and selective outcome reporting. A high risk of bias was present in the participant selection, confounding variable, and intervention measurement domains, whereas the risk of bias in the blinding of the outcome assessment domain was unclear. Using the RoB tool, an RCT was evaluated and found to have a low risk of bias in the six domains. Additional data are provided in Supplemental Fig. 2.

Comparison I: pre-TA versus post-TA

Outcome 1. CAI

Eleven studies evaluated CAI at pre-and post-TA^{14–16, 20, 22, 28–30, 32, 34, 35}. The total number of patients for the outcome was 689. The meta-analysis revealed that the CAI after TA was statistically significantly lower than before TA for 0.70 events/h (95% CI, 0.25 to 1.15; P < 0.002). There was substantial heterogeneity (I² = 81%). The forest plot was demonstrated in Fig. 3.

1.1 CAI subgroup analysis: Down syndrome versus non-Down syndrome

A subgroup analysis was performed to compare Down syndrome versus non-Down syndrome. The meta-analysis revealed that the post-TA CAI was lower than the pre-TA CAI, with no statistically significant differences in the subgroup of patients with Down syndrome. (MD = 0.14 events/h; 95% CI, -0.32 to 0.60; P = 0.55). However, CAI in post-TA was significantly decreased from pre-TA in the subgroup without Down syndrome (MD, 0.75 events/h; 95% CI, 0.24 to 1.26; P = 0.004). However, there was no significant difference between both groups. (P = 0.08). The forest plot was demonstrated in Fig. 4.

1.2 CAI subgroup analysis: obese versus non-obese group

A subgroup analysis was performed to compare obese versus nonobese groups. The meta-analysis showed that CAI after TA decreased from pre-TA in both groups. However, there were no significant differences (P = 0.35) between obese (MD, 1.6; 95% CI, -0.72 to 3.92) and non-obese group (MD, 0.42: 95% CI, -0.46 to 1.30). Additional data were provided in the supplemental Fig. 3.

Outcome 2. AHI

Nine studies with a total of 599 patients evaluated AHI both before and after TA^{15, 16, 20, 22, 28–30, 32, 34}. The meta-analysis showed that AHI after TA decreased significantly from before TA for 12.57 events/h (95% CI, 8.50 to 16.64; P < 0.001). There was substantial heterogeneity (I² = 84%). The forest plot was demonstrated in Fig. 5(a).

Outcome 3. minSpO₂

Eight studies with a total of 584 participants evaluated minSpO2 before and after TA for the outcome^{15, 20, 22, 26–28, 30, 32}. The meta-analysis showed that minSpO₂ after TA increased significantly from pre-TA for 6.46% (95% CI, -9.16 to -3.76; P < 0.001). There was substantial heterogeneity (I² = 87%). The forest plot was demonstrated in Fig. 5(b).

Outcome 4. meanSpO₂

Five studies with a total of 393 patients evaluated meanSpO₂ at before and after TA for the outcome^{16, 20, 29, 30, 34}. The meta-analysis showed that the mean SpO2 after TA increased significantly from pre-TA by 1.31% (95% CI, -2.16 to -0.46; P = 0.003). There was substantial heterogeneity (I² = 78%). The forest plot is demonstrated in Fig. 5(c).

Comparison II: TA versus no surgery

Outcome 1. CAI change from baseline

Two studies evaluated CAI changes between participants who underwent TA and those who did not undergo surgery^{33, 35}. Although the TA group had higher CAI changes than the non-surgery group, there were no significant differences (MD, -3.9 events/h; 95% CI, -1.15 to 0.37; P = 0.32). Additional data are provided in the Supplemental Fig. 4.

Outcome 2. Postoperative CAI

Two studies compared children with OSA who received TA with those who did not, to assess the postoperative CAI^{33, 35}. There was no significant difference in postoperative CAI between both groups (MD, -4.7 events/h; 95% CI, -1.10 to 0.16; P = 0.15). Additional data are provided in the Supplemental Fig. 5.

To our knowledge, this study is possibly the first systematic review and meta-analysis to evaluate the effect of TA on the change in CAI in children with OSA. Numerous studies have looked at this problem as a secondary outcome, however, their findings are inconclusive. Our results showed that CAI was significantly reduced in pediatric patients with OSA who received TA. However, this was not discovered in Down syndrome. CAI reduction did not show significant differences between the obese versus non-obese subgroup (P = 0.35). This study suggests that those without Down syndrome may experience more benefits of TA for the decrease in CAI. The findings of this study were also consistent with the previous meta-analysis, which found that TA improved several sleep parameters in children with OSA, including AHI, meanSpO2 and minSpO₂²¹.

Physiologic CSA can be found in normal sleep, including central apnea that occurs with onset of sleep, post-arousal, post-sigh, phasic REM sleep, and body movement. Therefore, the majority of central apnea in healthy children will not be scored on PSG³⁶. However, central apnea in children lasting more than 20 seconds may cause changes in oxygenation and heart rate comparable to those seen during obstructive apnea events^{36, 37}. Following obstructive episodes, there would be arousal and relative hypercapnia, which would cause hyperventilation and cause carbon dioxide levels to fall below the apneic threshold, resulting in the appearance of central apnea. Children with OSA who receive TA experience a significant reduction in obstructive events, which is responsible for the reduction in arousal events and central apnea remission, supported by the results of a study showing that 62% of patients with CAI ≥ 5 events/h had their CAI drop to less than 1 event / h after TA^{15, 38}. Therefore, prior to further investigation into the origin of CSA, the treatment of children who have both OSA and CSA should focus on obstructive disorders³⁸. However, there was no discernible difference in CAI change and CAI post-TA between participants who received TA and those who did not in this study, which may be related to the limited data with the small number of included participants.

Children with Down syndrome often experience a variety of neurogenetic problems, increasing the risk of CSA and hypoventilation. Patients with Down syndrome and adenotonsillar hypertrophy can share an OSA and CSA pathophysiological mechanism³⁸. TA is the first-line treatment for children with OSA that could reduce AHI by up to 51% in those with Down syndrome³⁹. Our result did not show a significant reduction in CAI (MD 0.14 event/h) after TA in Down syndrome. This may indicate that TA can only treat obstructive upper airway diseases, but not treat other conditions, including neuromuscular problems.

Obesity often increases the prevalence of obstructive apnea and central apnea associated with severe desaturation^{40, 41}. This could be explained by factors such as decreased intrathoracic volume, resulting in fewer oxygen reserves⁴², altered ventilatory response to hypoxia and hypercapnia, hypoventilation caused by leptin resistance⁴³, and central apnea, followed by narrowing or collapse of the upper airway^{44, 45}. The previous meta-analysis showed that TA can improve AHI without complete resolution of OSA in obese children⁴⁶. Neither the obese nor the non-obese groups in our study had a statistically significant increase in CAI from pre-TA to post-TA. However, this comparison only covered a small number of individuals.

There were limitations to this study. First, the majority of the included studies were observational studies with higher or uncertain risks of bias and lower levels of evidence. Second, there was high heterogeneity in all comparisons, including the postoperative PSG follow-up time that varied between studies. Finally, there's a limitation in comparing the data concerning the CAI change after TA due to its small sample size. More long-term and well-controlled studies considering CAI in post-TA pediatric OSA are recommended.

This meta-analysis revealed that pediatric patients with OSA who underwent TA had a significant reduction in CAI, particularly in patients without Down syndrome. The study suggests that CAI should be considered an important PSG parameter in post-TA patients. A further well-controlled and long-term study is recommended considering the impact of pediatric OSA surgery on CAI.

PICO

Patient, intervention, comparator and outcomes

OSA

Obstructive sleep apnea

Adenotonsillectomy

CAI

Central apnea index

AHI

Apnea-hypopnea index

minSpO2

minimum oxygen saturation

meanSpO2

mean oxygen saturation

PSG

Polysomnography

CSA

Central sleep apnea

BMI

Body mass index

Mean difference

Confidence interval

Competing interest: none

Acknowledgments

The authors gratefully acknowledge Jeerapa Kerdnoppakhun, Ngamrat Treerassapanich and Chutima Polsrimueng of the Department of Otorhinolaryngology, Faculty of Medicine Siriraj Hospital, Mahidol University for secretarial support.

Compliance with Ethical Standards

Funding: No funding was received for this research.

Conflict of Interest: No Conflicts of Interest.

Ethical Approval: This article does not contain any studies with human participants or animals performed by any of the authors. According to registration number 068/2565, the Siriraj Institutional Review Board authorized the exemption.

Data Availability: The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Sponsorships: none

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No competing interests reported.

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The Improvement of Central Apnea Index after Adenotonsillectomy in Children: A Systematic Review and Meta-analysis

Status:

Version 1

Abstract

Background

Methods

Results

Conclusion

Figures

BACKGROUND

METHODS

Eligibility Criteria

Search Strategy

Study Selection and Data Extraction

Assessment of Risk of Bias

Data Synthesis

Results

Study Selection

Characteristics of the studies and participants

Assessment of risk of bias

Comparison I: pre-TA versus post-TA

Outcome 1. CAI

1.1 CAI subgroup analysis: Down syndrome versus non-Down syndrome

1.2 CAI subgroup analysis: obese versus non-obese group

Outcome 2. AHI

Outcome 3. minSpO₂

Outcome 4. meanSpO₂

Comparison II: TA versus no surgery

Outcome 1. CAI change from baseline

Outcome 2. Postoperative CAI

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1

The Improvement of Central Apnea Index after Adenotonsillectomy in Children: A Systematic Review and Meta-analysis

Status:

Version 1

Abstract

Background

Methods

Results

Conclusion

Figures

BACKGROUND

METHODS

Eligibility Criteria

Search Strategy

Study Selection and Data Extraction

Assessment of Risk of Bias

Data Synthesis

Results

Study Selection

Characteristics of the studies and participants

Assessment of risk of bias

Comparison I: pre-TA versus post-TA

Outcome 1. CAI

1.1 CAI subgroup analysis: Down syndrome versus non-Down syndrome

1.2 CAI subgroup analysis: obese versus non-obese group

Outcome 2. AHI

Outcome 3. minSpO2

Outcome 4. meanSpO2

Comparison II: TA versus no surgery

Outcome 1. CAI change from baseline

Outcome 2. Postoperative CAI

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1

Outcome 3. minSpO₂

Outcome 4. meanSpO₂