Continuous positive airway pressure to reduce the risk of early peripheral oxygen desaturation after onset of apnoea in children: A double-blind randomised controlled trial

Jayme Marques dos Santos Neto; Clístenes Cristian de Carvalho; Lívia Barboza de Andrade; Thiago Gadelha Batista Dos Santos; Rebeca Gonelli Albanez da Cunha Andrade; Raphaella Amanda Maria Leite Fernandes; Flavia Augusta de Orange

doi:10.1371/journal.pone.0256950

. 2021 Oct 1;16(10):e0256950. doi: 10.1371/journal.pone.0256950

Continuous positive airway pressure to reduce the risk of early peripheral oxygen desaturation after onset of apnoea in children: A double-blind randomised controlled trial

Jayme Marques dos Santos Neto ^1,^*,^#, Clístenes Cristian de Carvalho ^2,^3,^‡, Lívia Barboza de Andrade ^2,^‡, Thiago Gadelha Batista Dos Santos ^1,^‡, Rebeca Gonelli Albanez da Cunha Andrade ^2,^‡, Raphaella Amanda Maria Leite Fernandes ^2,^‡, Flavia Augusta de Orange ^1,^2,^#

Editor: Thomas Penzel⁴

PMCID: PMC8486132 PMID: 34597324

Abstract

Continuous positive airway pressure (CPAP) during anaesthesia induction improves oxygen saturation (SpO₂) outcomes in adults subjected to airway manipulation, and could similarly support oxygenation in children. We evaluated whether CPAP ventilation and passive CPAP oxygenation in children would defer a SpO₂ decrease to 95% after apnoea onset compared to the regular technique in which no positive airway pressure is applied. In this double-blind, parallel, randomised controlled clinical trial, 68 children aged 2–6 years with ASA I–II who underwent surgery under general anaesthesia were divided into CPAP and control groups (n = 34 in each group). The intervention was CPAP ventilation and passive CPAP oxygenation using an anaesthesia workstation. The primary outcome was the elapsed time until SpO₂ decreased to 95% during a follow-up period of 300 s from apnoea onset (T1). We also recorded the time required to regain baseline levels from an SpO₂ of 95% aided by positive pressure ventilation (T2). The median T1 was 278 s (95% confidence interval [CI]: 188–368) in the CPAP group and 124 s (95% CI: 92–157) in the control group (median difference: 154 s; 95% CI: 58–249; p = 0.002). There were 17 (50%) and 32 (94.1%) primary events in the CPAP and control groups, respectively. The hazard ratio was 0.26 (95% CI: 0.14–0.48; p<0.001). The median for T2 was 21 s (95% CI: 13–29) and 29 s (95% CI: 22–36) in the CPAP and control groups, respectively (median difference: 8 s; 95% CI: -3 to 19; p = 0.142). SpO₂ was significantly higher in the CPAP group than in the control group throughout the consecutive measures between 60 and 210 s (with p ranging from 0.047 to <0.001). Thus, in the age groups examined, CPAP ventilation and passive CPAP oxygenation deferred SpO₂ decrease after apnoea onset compared to the regular technique with no positive airway pressure.

Introduction

General anaesthesia largely alters the physiology of the respiratory system. Effects such as impairment of functional residual capacity (FRC) and pulmonary compliance, emergence of atelectasis, and disturbances in the ventilation–perfusion ratio (V/Q) increase the chances of hypoxaemia [1–5].

Paediatric patients have the highest risk of desaturation during anaesthesia induction [5–8], particularly because of their physiological characteristics (lower FRC and greater oxygen consumption). Additionally, their anatomy (proportionally large head and tongue, tonsil and adenoid hypertrophy, small and narrow hypopharynx, upper larynx, slanted vocal cords, U-shaped inverted epiglottis, and short airway radius) may complicate airway management. Altogether, these factors contribute to triggering and maintaining hypoxaemia [7,9–11], rendering children more vulnerable to severe complications, such as cardiorespiratory arrest and death [7].

Pre-oxygenation lengthens safe apnoea time and is often used to prevent hypoxaemia [7,9,12]. Despite its benefits, pre-oxygenation, particularly with pure oxygen, can contribute to the occurrence of micro-atelectasis and changes in the V/Q during anaesthesia induction. Alveolar recruitment manoeuvres and the use of positive end-expiratory pressure can reverse and prevent these events [4,5]. Other preventive strategies have also been evaluated; however, an ideal technique has not been determined thus far [13,14].

Continuous positive airway pressure (CPAP) allows patients to breathe spontaneously through a pressurised circuit, thus improving alveolar gas exchange, reducing atelectasis incidence, increasing FRC and tidal volume, and reversing the anaesthetic-induced upper airway cross-sectional area reduction [15,16]. Its use to facilitate the treatment of patients with diseases like obstructive sleep apnoea is well documented and recommended in the perioperative period [17]. In paediatrics, the application of CPAP has been widely studied in patients with bronchiolitis as an alternative to controlled mechanical ventilation [18,19]. Although the evidence for its use during anaesthesia induction in children is limited, the results obtained in the adult population are encouraging [20–24].

Therefore, we aimed to evaluate whether CPAP ventilation and passive CPAP oxygenation would defer oxygen saturation (SpO₂) decrease to 95% after apnoea onset in children compared to the regular technique in which no positive airway pressure is delivered. Additionally, we measured the SpO₂ values and recorded the time until recovery of SpO₂ to pre-apnoea levels.

Materials and methods

We conducted a double-blind, parallel, randomised controlled clinical trial in children who underwent surgery at the Federal University, Pernambuco’s Teaching Hospital between March 2018 and May 2019. This study was approved by the Ethical Committee of Instituto de Medicina Integral Prof. Fernando Figueira, Recife, Brazil (Approval No. CAAE: 79591417.0.0000.5201) on 27 December 2017 and was registered at ClinicalTrials.gov in February 2018 (NCT03432390). Written informed consent was obtained from the parents or legal guardians of all participants (Study protocol https://dx.doi.org/10.17504/protocols.io.bqv5mw86).

Children aged 2–6 years, with an ASA status of I or II, who underwent elective surgery under general anaesthesia were included in the study. The exclusion criteria were pre-existing parenchymal lung disease, cyanosis or SpO₂ <95% prior to anaesthesia induction, and a current upper respiratory tract infection or a history of it in the preceding 4 weeks.

The intervention consisted of CPAP ventilation and passive CPAP oxygenation using the anaesthesia workstation, whereas the main outcome was the elapsed time until SpO₂ decreased to 95% in each patient during the 5-min follow-up after apnoea onset (T1).

Meanwhile, we recorded SpO₂ values. We also noted the time required for recovery of SpO₂ from 95% to pre-apnoea levels (T2).

Likewise, patients in the control group ventilated in the same manner in the anaesthesia workstation without adding positive pressure to the circuit.

Participants were recruited from the surgical ward by a research assistant who was blinded to the group allocation of the patient.

The patients were randomised to either the CPAP or control groups. The random allocation sequence was generated by JMSN using the Random Allocation Software program (Version 1.0) with numbers generated in blocks of eight.

Sequentially numbered, otherwise identical, sealed envelopes, each containing a 2-inch by 2-inch piece of paper with a written code indicating the intervention group or the control group were used for each child to ensure allocation concealment. The envelopes were opaque and sequentially assigned to each new patient. Just before a patient’s admission to the operating room, the attending anaesthesiologist, who was not part of the study team, took note of the allocation group, keeping those involved in the study unaware of the assigned intervention. The attending anaesthesiologist was then required to arrange the setting in order to keep the allocation concealed and ensure protocol compliance.

When CPAP was used, the adjustable pressure-limiting (APL) valve was set to provide a pressure of 10 cmH₂O. In the control group, the APL valve was left open, thus maintaining a pressure of 0 cmH₂0. Thereafter, the valve was covered by a surgical sheet so that the allocation remained concealed and no one, other than the attending anaesthesiologist, knew the intervention assigned. Whether or not the patient was premedicated depended on the discretion of the attending anaesthesiologist.

The patient and researchers were thereafter allowed to access the operating room. Routine monitoring was performed with continuous eletrocardiogram, pulse oximeter placed on the patient’s finger, non-invasive blood pressure assessment, and capnography. Inhalation induction of anaesthesia was then performed by JMSN, TGBS, or FAO, who were blinded to the intervention, using a facemask connected to the circle system of the anaesthesia workstation (Carestation 620, Datex-Ohmeda, Inc. Madison, WI) and attached to the patient using an elastic strap. Sevoflurane (8%) along with a 60% fraction of oxygen under a fresh gas flow of 4 L.min^-1 (2 L.min^-1 of oxygen/2 L.min^-1 of air) was initially provided to patients in both groups until the loss of the eyelid reflex. Thereafter, the concentration of sevoflurane was reduced to 4%. The patients remained on spontaneous ventilation. To assess their competence, we evaluated the capnography waveform, ETCO₂, abdominal movement, and chest expansion. At this point, a peripheral vein was cannulated for hydration and a standardised regimen of 3.5 mg.kg^-1 propofol bolus was injected to induce apnoea. All patients were ventilated for an equal period before the start of apnoea.

T1 was timed using an iPhone 7 Plus 12.3.1 (Apple Inc., Cupertino, CA) beginning from the onset of apnoea, identified as an absence of both respiratory movements and a capnography trace. When a period of 300 s was completed without reaching 95% SpO₂, the measurement was halted and manually assisted lung ventilation was initiated. During the T1 recording, SpO₂ was noted. Once 95% SpO₂ was reached or 300 s passed, the attending anaesthesiologist covertly manipulated the APL valve, either truly or falsely, to maintain allocation concealment. When the valve was open, a pressure of 10 cmH₂O was set. This way, regardless of the initial group to which the patient was allocated, from this moment onwards, the patient received assisted lung ventilation supported by a pressure of 10 cmH₂O. At that time, T2 was measured for those who reached 95% SpO₂.

Any adverse event that occurred during the study period was recorded.

A research assistant, the outcome assessor, blinded to patient allocation, performed all data collection.

Statistical analysis

Under the proportional hazards assumption, which we validated using a test based on Schoenfeld residuals, we estimated that with a sample of at least 33 patients in each randomised group, the study would have an 80% power to detect a 50% reduction in the hazard of the CPAP group, allowing only a 5% chance of a type I error in a two-sided significance test. However, to compensate for any losses following randomisation (predicted at approximately 10%), this number was increased to 72 patients, with 36 in each group. The sample size was calculated using Schoenfeld’s procedure. It was based on the a priori calculation, but a posteriori a second analysis was performed based on feedback that the initial assumptions required adjustment, and this analysis revealed that the sample size should be 76. Data analysis was performed using STATA version 12.1 SE (StataCorp, College Station, TX, USA). Descriptive statistical analysis was performed using measures of central tendency and dispersion for the quantitative variables and frequency distribution for the qualitative variables. For continuous measures, results are reported as means and SDs for normally distributed variables and medians and IQRs for non-normal quantities. A standard risk of 1.0 was attributed to the reference category. Survival analysis was conducted on the survival times to an SpO₂ of 95%. Survival probabilities were calculated using the Kaplan–Meier method, and the survival curves were compared using the log-rank test. The association measure for the primary outcome was the hazard risk ratio and, for the secondary endpoints, the median time difference. The medians of survival time in each group were estimated and compared using Laplace regression. Furthermore, a curve was constructed with the mean SpO₂ measurements at 30-s intervals by adjusting a linear regression model for correlated data that also evaluated the significance of time, group, and the interaction between them. The means were compared between the groups at each measured time using the Wald test, and the Benjamini–Hochberg procedure was applied to adjust the p-value to avoid type I error rate inflation. Statistical significance was defined as p<0.05. To test the robustness of the study, we calculated its fragility index using Fisher’s exact test.

Results

Of the 98 patients screened, 72 were included in the study. Four patients were lost to follow-up (n = 2 in each group) due to changes in anaesthetic induction protocol (2), absence of apnoea (1), and surgery suspension (1). Therefore, the final analysis included data from 68 patients for the primary outcome (n = 34 in each group) according to the CONSORT flow diagram (Fig 1). Both groups were similar in terms of physical and clinical characteristics and types of surgery performed (Table 1).

Table 1. Characteristics of children with CPAP-ventilation and passive CPAP-oxygenation (10 cmH₂O) or no positive pressure (0 cmH₂O) during anaesthesia induction for elective surgery.

	Group
	CPAP (n = 34)	Control (n = 34)
Sex
Female	6 (17.7)	10 (29.4)
Male	28 (82.3)	24 (70.6)
Age, years	4.3 (1.4)	4.2 (1.51)
Weight, kg	18.3 (4.9)	17.8 (4.58)
ASA
I	31 (91.2)	33 (97)
II	3 (8.8)	1 (3)
Type of surgery
Urological surgery	15 (44.1)	11 (32.3)
Herniorrhaphy	12 (35.3)	15 (44.1)
Combined surgery	3 (8.8)	3 (8.8)
Intraperitoneal surgery	2 (5.9)	1 (2.9)
Soft tissue tumour	2 (5.9)	4 (11.9)

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ASA, American Society of Anesthesiologists; CPAP, continuous positive airway pressure. Values are mean (SD) or number (proportion).

The median for T1 was 278 s (95% CI: 188–368) in the CPAP group and 124 s (95% CI: 92–157) in the control group (median difference: 154 s; 95% CI: 58–249; p = 0.002). The least time to reach an SpO₂ of 95% was 75 and 30 s in the CPAP and control groups, respectively (Table 2).

Table 2. T1 and T2 in children treated with CPAP ventilation and passive CPAP oxygenation (10 cmH₂O) or no positive airway pressure (0 cmH₂O) during anaesthesia induction for elective surgery.

	Group		Median difference	p-value
	CPAP	Control	Median difference	p-value
T1, s	278 (188–368)	124 (92–157)	154 (58–249)	0.002
T2, s	21 (13–29)	29 (22–36)	8 (-3 to 19)	0.142

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T1, time between apnoea onset and an SpO₂ of 95% during a maximum observation time of 300 s; T2, time from an SpO₂ of 95% until recovery to pre-apnoea levels; SpO₂, pulse oximetry oxygen saturation; CPAP, continuous positive airway pressure. Values are presented as median (95% CI).

Fig 2 shows the Kaplan-Meier curves for the CPAP and control groups. The log-rank test showed a p-value of <0.001. The estimated 300-s cumulative primary event rates were 50% in the CPAP group and 94.1% in the control group (proportional-hazards risk ratio: 0.26; 95% CI: 0.14 to 0.48; p<0.001).

The median for T2 was 21 s (95% CI: 13–29; minimum–maximum values: 10–170) in the CPAP group and 29 s (95% CI: 22–36; minimum–maximum values: 10–360) in the control group, with a non-significant between-group difference (median difference: 8 s; 95% CI: -3 to 19; p = 0.142) (Table 2).

The repeated-measures saturation values were higher in the CPAP group with a significant between groups difference in the 60–210 s interval (Fig 3).

Fig 3 — Mean SpO₂ values in children with either CPAP ventilation and passive CPAP oxygenation (10 cmH₂O) or no positive airway pressure (0 cmH₂O) during anaesthesia induction for elective surgery and their respective confidence intervals in the two-group interaction (p ranging from 0.047 to <0.001 for the interaction between the curves in the 60–210 s interval).

No adverse events of a specific type and severity, such as laryngospasm, bronchospasm, bradycardia, cardiac arrest, or death, occurred in either group.

The study’s Fragility Index was 9, meaning that it would take nine patients in the CPAP group to have their status change from non-events to events for the between-group difference to shift to being not statistically significant.

Discussion

In this study, CPAP ventilation and passive CPAP oxygenation deferred SpO₂ decrease to 95% after apnoea onset compared to the regular technique in which no positive airway pressure was applied. Patients took more time to reach an SpO₂ of 95% in the CPAP group than in the control group. In the CPAP group, patients presented a 50% probability of reaching an SpO₂ of 95% within 5 min; in the control group, this probability increased to 94.1%. In addition, the risk of desaturation to SpO₂ in the CPAP group was approximately a quarter of that in the control group. Therefore, as swift tracheal intubation is not always possible, mainly for difficult airways, the assurance of optimal SpO₂ for longer periods would be of great value to enhance patient safety. As children have an increased basal metabolic rate, once an imbalance between oxygen supply and consumption arises, the final result is an overall progressive decrease in oxygen levels (hypoxic hypoxia). Accordingly, CPAP could possibly play a critical role in preventing the occurrence of secondary severe complications due to oxygen desaturation, consistent with findings of the Paediatric Difficult Intubation Registry, which showed that such complications were more frequent in patients with unanticipated difficult airways [7]. Thus, in clinical practice, CPAP would be useful in situations where apnoea is either expected to occur (such as during anaesthesia induction) or required (e.g., during magnetic resonance imaging).

The shortest interval spent to reach an SpO2 of 95% in the CPAP group was 75 s, whereas in the control group it was 30 s. In other words, for desaturation to be avoided in our cohort, the airway should be defined within 30 s for patients with no pressure support, and within 75 s for those given the support.

To better assess the reliability of our results, we calculated the fragility index (FI = 9) for the association found, which provided further support for our findings and ensured a low chance of random error. In other words, it would take nine non-event patients in the CPAP group for their status to change to having events for statistical significance to be lost. This number exceeds the number of patients lost to follow-up. Moreover, FI has been used in clinical trials with dichotomous outcomes to appraise its robustness and to complement the interpretation of the P-value. Although there is no cut-off, the greater the FI value, the greater the robustness of the study’s results [25].

This may be the first study evaluating the role of CPAP in paediatric patients during anaesthesia induction. However, despite the shortage of investigations in children, there have been many studies that have evaluated the application of positive airway pressure in adult populations during preoxygenation and anaesthesia induction [20–24]. Their results point mostly in the same direction as ours, showing improvements in outcomes, such as longer duration of apnoea before clinically significant arterial desaturation, better oxygenation and prevention of desaturation episodes, upon the use of positive airway pressure. These authors attributed the improved outcomes to the increase in FRC (associated with reduction of shunt areas and improvement in the V/Q). Presumably, the most suitable means for the anaesthesiologist to manage situations where apnoea is expected to occur is to apply techniques that increase lung oxygen reserves. This is also our main hypothesis, although a CT scan-based study carried out in children was unable to confirm the association between CPAP-assisted oxygenation and the smallest areas of atelectasis [26]. Thus, further studies are necessary to better understand the basal mechanisms involved in CPAP benefits.

Two randomised clinical trials in adults have demonstrated results similar to ours. The first study in obese patients demonstrated extended nonhypoxic apnoea time when applying pressure support, using a combination of CPAP and PEEP, compared to the regular technique in which no positive airway pressure support was applied [23,24]. The second study, also in adults, with methods similar to ours, applied CPAP during both preoxygenation and a given period of apnoea. It also demonstrated a slowed desaturation [22]. Consistent with these findings, the use of CPAP—5 cmH₂O through a Mapleson A circuit, only during preoxygenation, was likewise shown to defer desaturation in adults [20]. Thus, the use of positive airway pressure during anaesthesia induction to improve respiratory outcomes has been demonstrated to succeed in many different scenarios.

As previously stated, we expected CPAP to prevent atelectasis, preserving the FRC, and achieving the improved outcomes we observed. This technique is assumed to provide more oxygen during apnoea by increasing the transpulmonary pressure secondary to a continuous flow of gases, which delays the occurrence of hypoxaemia [27]. Likewise, CPAP also manages to preserve the upper airway’s cross-sectional area. Altogether, these effects improve both spontaneous ventilation and patient lung volumes, and are in accordance with our findings.

To reduce the use of pure oxygen and minimise the likelihood of absorption atelectasis due to denitrogenation, we applied an inspired oxygen fraction of 60% [4,28]. Thus, a combination of lower fractions of oxygen and improved FRC, achieved by the use of positive airway pressure, may constitute a more effective and less harmful way of obtaining satisfactory pre-oxygenation.

Regarding the limit of 95% set as our endpoint for SpO₂, although lower levels are usually reported in studies about safe apnoea time [13,20,29], we chose this threshold to ensure patient safety. Since a decrease in SpO₂ below that level unsettles heart function and haemodynamic parameters such as the systolic index [30], and because we did not aim to document such changes, we avoided submitting the participants to these threats. Hence, we were also convinced to limit the observation time to 5 min due to ethical issues discussed with members of our hospital’s anaesthesiology clinical staff.

Here, CPAP failed to shorten the time to restore the previous levels of SpO₂. Similarly, another clinical trial also did not demonstrate statistically significant differences when analysing the same outcome in apnoeic adults after pre-oxygenation with and without CPAP 5 cmH₂O. For this study, the authors started timing from an SpO₂ of 93% [20]. However, for this outcome, our results may be considered underpowered as the sample-size estimation did not take this parameter into account, which may have led us to a type 2 error.

Further grounding the benefit of early CPAP application during anaesthesia is the progress of the measured SpO₂. Oxygen saturation was consistently higher in the CPAP group during the period between 60 and 210 s (p ranging from 0.047 to <0.001). Different clinical trials in diverse scenarios have likewise presented CPAP to be firmly associated with the highest arterial oxygen pressure [20–24]. However, we were not able to find significant between-group differences for up to 1 min or > 210 s. Studies powered for these specific periods of time might better investigate such associations.

Despite the relevant statistical results obtained, this was a small, single-centre study with a narrow population age range; thus, further studies are necessary to establish the benefits demonstrated in this study. The results may be underpowered as highlighted during the a posteriori adjustment made in the sample size calculation. The actual study sample was 68 patients. With this sample size we achieved 72,4% power to detect a 50% reduction in the hazard of the experimental group, with a 5% significance level. We did not record expired oxygen and nitrogen, the amount of CO₂ expired in the return of pulmonary ventilation, or the stomach size during induction. In particular, the pressure used was 10 cmH₂O, which was below the values related to stomach enlargement in anaesthetized children [31,32]. Although the APL valve was covered with a surgical sheet, the researchers had access to each patient’s saturation and apnoea time, which may have potentially compromised the blinding process. We did not address the prevalence of obstructive sleep apnoea or calculate body mass index; therefore, it was not possible to perform subgroup analyses. Furthermore, the CPAP group received positive airway pressure during both spontaneous ventilation and apnoea, whereas the control group did not. As patients who received CPAP would have received a degree of apnoeic oxygenation, halting positive airway pressure from apnoea onset might be more informative for clinical practice.

Conclusions

CPAP ventilation and passive CPAP oxygenation deferred SpO₂ decrease after apnoea onset in the age groups examined in this study compared to the regular technique in which no positive airway pressure was used. The CPAP technique was easy to apply and appeared to enhance patient safety.

Supporting information

S1 Fig. CONSORT diagram of patient recruitment.

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Click here for additional data file.^{(1.6MB, tif)}

S2 Fig. Kaplan–Meier curves for the CPAP and control groups.

Occurrence of an SpO₂ of 95% during a 5-min follow-up in children with CPAP ventilation and passive CPAP oxygenation (10 cmH₂O) or no positive airway pressure (0 cmH₂O) during anaesthesia induction for elective surgery showing a significant difference between the survival curves (log-rank test; p<0.001).

(TIF)

Click here for additional data file.^{(981.7KB, tif)}

S3 Fig. Repeated-measures saturation values curves.

Mean SpO₂ values in children with either CPAP ventilation and passive CPAP oxygenation (10 cmH₂O) or no positive airway pressure (0 cmH₂O) during anaesthesia induction for elective surgery and their respective confidence intervals in the two-group interaction (p ranging from 0.047 to <0.001 for the interaction between the curves in the 60–210 s interval).

(TIF)

Click here for additional data file.^{(119.8KB, tif)}

S1 File. CONSORT 2010 Checklist.

(PDF)

Click here for additional data file.^{(237.2KB, pdf)}

S2 File. Study Protocol in Portuguese.

(PDF)

Click here for additional data file.^{(343.2KB, pdf)}

S3 File. Study Protocol.

(DOCX)

Click here for additional data file.^{(14.8KB, docx)}

S4 File. CPAP group data Time to desaturation.

Database containing each CPAP group patients time to a SpO₂ of 95% or 300 seconds.

(PDF)

Click here for additional data file.^{(22.3KB, pdf)}

S5 File. Control group data Time to desaturation.

Database containing each Control group patients time to a SpO₂ of 95% or 300 seconds.

(PDF)

Click here for additional data file.^{(22.3KB, pdf)}

S6 File. Repeated-measures saturation values.

Database containing each patient SpO₂ during apnoea time until SpO₂ of 95% or 300 seconds.

(PDF)

Click here for additional data file.^{(104KB, pdf)}

S7 File. CPAP group data Time for recovery.

Database containing each CPAP group patients time required for recovery of SpO₂ from 95% to pre-apnoea levels (T2).

(PDF)

Click here for additional data file.^{(19.4KB, pdf)}

S8 File. Control group data Time for recovery.

Database containing each Control group patients time required for recovery of SpO₂ from 95% to pre-apnoea levels (T2).

(PDF)

Click here for additional data file.^{(19.3KB, pdf)}

S9 File. Data used to build repeated-measures saturation values curves.

(PDF)

Click here for additional data file.^{(113.2KB, pdf)}

S10 File. Database with raw data of all patients.

(XLSX)

Click here for additional data file.^{(18.9KB, xlsx)}

S11 File

(PDF)

Click here for additional data file.^{(333.8KB, pdf)}

Acknowledgments

The authors acknowledge the support received from the Teaching Hospital of the Federal University of Pernambuco, where patient data were collected, and Instituto de Medicina Integral Prof. Fernando Figueira, where the study was conceived. The authors are grateful to Professor José Natal Figueroa for his essential contribution to data analysis and interpretation, and to the medical residents in anaesthesiology, Raniere Nobre Fonseca, and Victor Lemos Macedo for their valuable collaboration in performing the data collection. We would like to thank Editage (www.editage.com) for English language editing.

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

JMSN received a scholarship provided by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) (https://www.gov.br/capes/pt-br). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS One. doi: 10.1371/journal.pone.0256950.r001

Decision Letter 0

Thomas Penzel

16 Dec 2020

PONE-D-20-33942

Continuous positive airway pressure to reduce the risk of early peripheral oxygen desaturation following apnoea onset in children: randomised double-blind controlled trial

PLOS ONE

Dear Dr. dos Santos Neto,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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PLOS ONE

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Reviewer #1: The authors aimed, with a randomized double-blind parallel controlled clinical trial, to evaluate whether CPAP-ventilation and passive CPAP oxygenation would reduce the risk of a SpO2 decrease to 95% following apnea onset in children as compared to no positive airway pressure. This trial was successfully accomplished in 68 children aging 2-6 years during anesthesia, and is commendable. The timeframe evaluated was 5 minutes after the start of an apnea, and recording was every 30 seconds. They found that while in the CPAP group, patients presented a 50% probability of having reached a SpO2 of 95% within 5 minutes, in the Control group this chance increased to 94.1%. In other words, a prosperous result.

Two minor comments are:

1. Could the authors elaborate on the stability and the severity of SpO2 in the 30-second intervals within the CPAP group? Namely, this analysis (and hence result) could be related back to the limitation of the spontaneous ventilation and apnea situation during their anesthesia.

2. Could the authors discuss the applicability of this approach to children with developmental disabilities undergoing surgery.

Reviewer #2: - the primary outcome is not clearly described. At first reading, it seems to be the risk of SpO2 of 95% within a 5 minute period (indeed the sample size calculation is that for estimating a risk/proportion). However, reading the manuscript it is repeatedly referred to as hazard of the outcome, implying that the outcome is a time-to-event. The authors need to clarify this.

- the units and resolution of measurement of the outcome T1 is not clear: was it measured down to the second or was it also measured in 30 second increments?

- if the primary outcome is a risk/proportion, then the sample size calculation is not sufficiently described as it does not include the 'baseline' risk of the outcome; this should be included along with a citation to support it. It is also not clear whether the 50% risk reduction proposed is an absolute or relative reduction. However, if the outcome is time-to-event, then the sample size calculation is incorrect, because other than including the hazard of the outcome in the 'baseline' group, it must also include some determination of the expected number of events.

- for the descriptive analysis the authors should follow standard reporting for randomised trials, where the mean and SD for continuous baseline variables or counts and proportions for categorical baseline variables be presented by treatment arm without statistical tests comparing the arms.

- if the primary outcome is a risk within a defined time period (5 minutes) therefore describing it as a hazard and estimating hazard ratios comparing the treatment arms for this outcome is not appropriate. It is however appropriate for the secondary outcome T1 (and perhaps T2).

- the results for the three outcomes should be tabulated in the standard reporting format for a clinical trial i.e. including the event numbers and denominators per group, risks/hazards/rates as appropriate and their ratios, confidence intervals and p-values.

- please indicate whether the trial protocol submitted with this manuscript was published before the analysis was undertaken, as I am not able to determine that.

**********

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PLoS One. 2021 Oct 1;16(10):e0256950. doi: 10.1371/journal.pone.0256950.r002

Author response to Decision Letter 0

28 Jan 2021

Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. Adjusted in the manuscript.

We suggest you thoroughly copyedit your manuscript for language usage, spelling, and grammar. If you do not know anyone who can help you do this, you may wish to consider employing a professional scientific editing service. The original manuscript with tracked changes has been sent to Editage website (www.editage.com). Some changes in the text has been made before and after the edition. Due to this, the Revised Manuscript with Track Changes is different from the Manuscript.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Please include your amended statements within your cover letter. Funding-related text removed from the manuscript. JMSN received a scholarship provided by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) (https://www.gov.br/capes/pt-br). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Please include a separate caption for each figure in your manuscript. Adjusted in the manuscript.

Could the authors elaborate on the stability and the severity of SpO2 in the 30-second intervals within the CPAP group? Namely, this analysis (and hence result) could be related back to the limitation of the spontaneous ventilation and apnea situation during their anesthesia. Thank you. The curve of repeated measures shows a less pronounced drop compared to that of the control group. We can theorize that this is due to greater alveolar stability with maintenance of the opening of these and preservation of the functional residual capacity, the main body oxygen supply. During situations of limited ventilation and apnoea, the continuous flow of oxygen to the alveoli could maintain the levels of partial pressure of the gas in the blood at adequate levels for a longer time, increasing the safety margin for the patient and a greater time for the anesthesiologist to define strategies to face the situation.

Could the authors discuss the applicability of this approach to children with developmental disabilities undergoing surgery. Thank you for the opportunity. Oxyhemoglobin desaturation is faster in patients with reduced O2 transport capacity, that is, in those with reduced FRC. General anesthesia appears as a major risk factor for mortality in pediatric surgical patients, as well as problems with airway management in patients with comorbidities seems to add life-threatening to this population. In paediatric patients, lung volume and capacity are directly related to weight, height, and age, i.e. the younger and smaller the child, the lower the FRC, this risk being apparently greater in children under three years of age. We can speculate, therefore, that children with developmental disabilities may be at increased risk of hypoxemia during the period of apnea since they have in theory impaired pulmonary oxygen reserves. This work did not direct its scope to the investigation of these patients, however, it is possible to imagine that in a research that applies CPAP to these children under the conditions described here, documenting the effect of this ventilatory mode on FRC, the outcomes could be favorable in relation to the reduction of risk desaturation and prolonging a safe apnea time.

The primary outcome is not clearly described. At first reading, it seems to be the risk of SpO2 of 95% within a 5 minute period (indeed the sample size calculation is that for estimating a risk/proportion). However, reading the manuscript it is repeatedly referred to as hazard of the outcome, implying that the outcome is a time-to-event. The authors need to clarify this. Thank you. We tried to clarify it in the text with some modifications.

The units and resolution of measurement of the outcome T1 is not clear: was it measured down to the second or was. it also measured in 30 second increments? Thank you. The T1 was measured down to the second. Once its record was 95%, we stopped the clock and registered the exact second in which it occurred. During the time elapsed from the start of the apnoea and the 95% threshold, we chose the reference points 10, 20, 30, 40 seconds and so on to record the pulse oximetry value at that moments. Therefore, we recorded SpO2 values every 10 seconds on the data collection form of each patient. For graphic recording purposes, we group these measurements at a 30-second intervals.

If the primary outcome is a risk/proportion, then the sample size calculation is not sufficiently described as it does not include the 'baseline' risk of the outcome; this should be included along with a citation to support it. It is also not clear whether the 50% risk reduction proposed is an absolute or relative reduction. However, if the outcome is time-to-event, then the sample size calculation is incorrect, because other than including the hazard of the outcome in the 'baseline' group, it must also include some determination of the expected number of events. The sample size was calculated using Schoenfeld’s procedure with a sample of at least 33 patients in each randomized group. The study would have a 80% power to detect a 50% reduction in the hazard of the CPAP group, allowing only a 5% chance of a type I error at a two-sided significance test. However, after your observation, we reviewed this calculation and in fact we did not account for the percentage of censored values in the control group. Thus, using the Schoenfeld method, the expected number of events was 66. But supposing that, in the control group, 5% of patients reach the end of the follow-up time with SPO2> 95%, the sample size of each group would be 38 with a significance level of 5% and a power of 80%. On the other hand, if we change only the hazard ratio to 0.45, the sample size for each group would be 30 and the expected number of events would be 50. Please, would be so kind as to help us to find a way out of this issue?

For the descriptive analysis the authors should follow standard reporting for randomised trials, where the mean and SD for continuous baseline variables or counts and proportions for categorical baseline variables be presented by treatment arm without statistical tests comparing the arms. Thank you. Altered in the manuscript

If the primary outcome is a risk within a defined time period (5 minutes) therefore describing it as a hazard and estimating hazard ratios comparing the treatment arms for this outcome is not appropriate. It is however appropriate for the secondary outcome T1 (and perhaps T2). Thank you. We tried to clarify it in the text with some modifications.

The results for the three outcomes should be tabulated in the standard reporting format for a clinical trial i.e. including the event numbers and denominators per group, risks/hazards/rates as appropriate and their ratios, confidence intervals and p-values. Added Table 2.

Please indicate whether the trial protocol submitted with this manuscript was published before the analysis was undertaken, as I am not able to determine that. The trial protocol was published in February 14, 2018, and the data collection begun in March, 2018. The study protocol was then published before the study analysis was undertake.

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(12.3KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0256950.r003

Decision Letter 1

Thomas Penzel

25 Mar 2021

PONE-D-20-33942R1

Continuous positive airway pressure to reduce the risk of early peripheral oxygen desaturation after onset of apnoea in children: a double-blind randomised controlled trial

PLOS ONE

Dear Dr. dos Santos Neto,

As academic editor, I agree with the assessment of the reviewers and I am happy to transmit their Overall positive evaluation. Now, we ask you for carefully addressing their comments, because they can be important for improving your mansucript.

Please submit your revised manuscript by May 09 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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Thomas Penzel

Academic Editor

PLOS ONE

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Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: (No Response)

Reviewer #3: All comments have been addressed

Reviewer #4: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: No

**********

6. Review Comments to the Author

Reviewer #2: Abstract: in the third-from-bottom line, please report the exact p-value instead of p<0.05 unless it is very small e.g. p<0.001.

Introduction: given your response to the previous round of reviews, it is not correct to say that you measured SpO2 every 30 seconds as indicated in the last paragraph of the introduction; perhaps it is just better to say that you measured time to recovery of pre-apnoea SpO2 levels. (The way this has been described in the paragraph in the methods just above 'statistical analysis' seems fine though.)

Methods:

- similar to the comment above, given your response it is misleading to say in the 'materials and methods' section that you recorded SpO2 values every 30 seconds, if you were continuously checking SpO2 to determine the actual time in seconds to recovery to pre-apnoea levels, unless you were doing this in 30-second increments, which you have indicated in the response that you were not doing.

- indicating the number of children in the first line of materials and methods is actually a non-standard reporting practice, as this is actually a result. It would have been sufficient to say 'we conducted a randomised double blind controlled parallel group trial in children undergoing surgery at...'

- the methods also need to describe the treatment received by the control group. You could add this immediately after describing the intervention, just before where you describe the recruitment in the surgical wards.

- the description of the sample size calculation is still incomplete and not reproducible. Now that it is clearer that this was a time-to-event outcome, for 80% power to detect a 50% relative reduction in hazard you would expect to observe 66 events (this is not the sample size); however your sample size calculation should further indicate what the expected proportions remaining event-free at 300 seconds, given that the sample size would be obtained by dividing the expected number of events by [1 - ((S1+S2)/2)] where S1 and S2 are the proportions in the control and intervention groups respectively that remain event-free at 300 seconds. If under standard care S1 participants remain event free at 300 seconds, then for a relative reduction in hazard of 50%, S2 = S1 x exp(0.5). S1 should have been determined based on information available before this study.

- it is unclear where the chi-squared tests, Fisher's exact test, students t-test etc referred to in the statistical methods were applied. In any case, they don't appear to be necessary at any stage of the analysis.

- what you report in the methods regarding the test for normality is actually a result; instead it would have been sufficient to indicate here that for continuous measures, the test for normality was conducted and you reported means and SDs of normally distributed variables or medians and IQRs for non-normal quantities - without alluding to the results of this test.

Results

- the key to figure 3 doesn't enable the reader to distinguish between the intervention and control group.

Reviewer #3: The authors answered all comments correctly.

I've only some minor comments:

A) Method section: The authors should specify whether children with genetic syndromes, acute and chronic cardiovascular and neurological diseases were included or excluded from the study.

B) page 11: please correct the following sentences:

-"Fig 2 shows the plots of Kaplan-Meier curves for groups CPAP and Control" with "Figure 2 shows the Kaplan-Meier curves for the CPAP and control groups"

-"between-group with between groups"

Reviewer #4: The authors present a revised manuscript on the effects of apneic CPAP after general anesthesia induction in children, concluding that the use of CPAP can prolong time to desaturation. While these results are not surprising, they do highlight that post-induction CPAP may be underutilized in pediatrics and provide a nice literature review in the discussion on pre-intubation CPAP use in pediatric and adult anesthesia.

The article is well-written and has been edited for language and grammar since the prior version, although still contains some grammatical and syntax issues and would benefit from English language editing. I have attempted to highlight some of these below but my suggestions are by no means complete.

The study is well-designed and controlled, appearing to be scientifically sound. The concerns of the prior reviewers seem to have been adequately addressed. Regarding point #9 on power analysis, as any change to the power calculation would be a posteriori I would recommend still reporting the calculations that were performed a priori. If the authors wish to include an additional a posteriori calculation based on the reviewer recommendations to demonstrate the true power of the study, I would suggest stating exactly what happened: the study population size was based on the a priori calculation, but a posteriori a second analysis was performed based on feedback that the initial assumptions required adjustment, and this analysis revealed the study was powered at X% to detect Y difference, or something to that effect.

Specific comments:

Abstract: as a result of deletions, T1 is no longer defined in the abstract, but T2 is. The T1 definition can be appended to the sentence about the primary outcome.

P7 third paragraph: by ‘cardioscopy’ do you mean electrocardiogram?

P7 third paragraph: if 60% fraction was oxygen, was the rest nitrogen gas (room air)? This should be stated.

P8 first paragraph: change ‘halt’ to ‘halted’

P11/Figure 3: why does the control group return to a non-significant difference at 240 seconds? Is this due to patients in the control group getting bag mask ventilation due to falling saturations (post T1 measurement)? If so this figure is misleading and the more appropriate analysis would be to look at only patients who had not yet reached the T1 endpoint when comparing the groups.

P13 second paragraph: change ‘define the airway’ to ‘secure the airway’

P13 last word: change overpasses to surpasses

P14 second paragraph: you state that other studies ‘[show] improvements in outcomes by the use of positive pressure’. Is there definitive evidence that outcomes are improved with CPAP? I can see reduced rates of transient hypoxia during apnea, as you have shown here, but I don’t believe there is evidence that meaningful case outcomes such as postop oxygen requirements, reintubation requirements, etc. are reduced. Thus I would recommend defining what outcomes, if any, are improved.

P14 third paragraph: change ‘being one’ to ‘one being’

P14 third paragraph: change ‘showed’ to ‘shown’

P14 fourth paragraph: change ‘hold the small airways opened’ to ‘prevent atelectasis’

P15 first paragraph: I would change the word ‘threatening’ to something else, maybe ‘the impairment of these factors may predispose patients to harm’ or delete the whole sentence

**********

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Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

PLoS One. 2021 Oct 1;16(10):e0256950. doi: 10.1371/journal.pone.0256950.r004

Author response to Decision Letter 1

25 Apr 2021

Initially, we are grateful for all the suggestions. Without a doubt, they praised our paper. All questions were answered directly in the original text and we remain at your disposal for any clarifications that are still needed.

1. Abstract: in the third-from-bottom line, please report the exact p-value instead of p<0.05 unless it is very small e.g. p<0.001. Thank you.

Corrected in the manuscript

2. Introduction: given your response to the previous round of reviews, it is not correct to say that you measured SpO2 every 30 seconds as indicated in the last paragraph of the introduction; perhaps it is just better to say that you measured time to recovery of pre-apnoea SpO2 levels. (The way this has been described in the paragraph in the methods just above 'statistical analysis' seems fine though.).

Thank you. Corrected in the manuscript.

Methods:

3. similar to the comment above, given your response it is misleading to say in the 'materials and methods' section that you recorded SpO2 values every 30 seconds, if you were continuously checking SpO2 to determine the actual time in seconds to recovery to pre-apnoea levels, unless you were doing this in 30-second increments, which you have indicated in the response that you were not doing.

Corrected in the manuscript.

4. indicating the number of children in the first line of materials and methods is actually a non-standard reporting practice, as this is actually a result. It would have been sufficient to say 'we conducted a randomised double blind controlled parallel group trial in children undergoing surgery at…'

Thank you. Corrected in the manuscript.

5. the methods also need to describe the treatment received by the control group. You could add this immediately after describing the intervention, just before where you describe the recruitment in the surgical wards.

Added in the manuscript.

6. the description of the sample size calculation is still incomplete and not reproducible. Now that it is clearer that this was a time-to-event outcome, for 80% power to detect a 50% relative reduction in hazard you would expect to observe 66 events (this is not the sample size); however your sample size calculation should further indicate what the expected proportions remaining event-free at 300 seconds, given that the sample size would be obtained by dividing the expected number of events by [1 - ((S1+S2)/2)] where S1 and S2 are the proportions in the control and intervention groups respectively that remain event-free at 300 seconds. If under standard care S1 participants remain event free at 300 seconds, then for a relative reduction in hazard of 50%, S2 = S1 x exp(0.5). S1 should have been determined based on information available before this study.

Thank you for the support. To recalculate the sample size, a 5% survival rate was admitted in the control group at the end of the study. Thus, S1 = 0.05. Therefore, S2= 0.050.5 = sqrt(0.05) = 0.2236 and the sample size would be approximately equal to 76 patients: ([1 - (S1+S2)/2)] = [1 – (0.05 +0.2236)/2] = [1 - 0.2736/2] = 1 - 0.1368 = 0.8632, n = 66/0.8632 = 76.45968). With a sample of 68 patients, the power of the study is 72,4%. During the discussion with our hospital's anaesthesiology clinical staff to limit the observation time to 5 min due to ethical issues, we decided to use data previously obtained in our own unit (pilot study) before patient collection to determine the 5% threshold.

7. it is unclear where the chi-squared tests, Fisher's exact test, students t-test etc referred to in the statistical methods were applied. In any case, they don't appear to be necessary at any stage of the analysis.

Thank you. Corrected in the manuscript.

8. what you report in the methods regarding the test for normality is actually a result; instead it would have been sufficient to indicate here that for continuous measures, the test for normality was conducted and you reported means and SDs of normally distributed variables or medians and IQRs for non-normal quantities - without alluding to the results of this test.

Thank you. Corrected in the manuscript.

Results

9. the key to figure 3 doesn't enable the reader to distinguish between the intervention and control group.

Figure corrected

10. Method section: The authors should specify whether children with genetic syndromes, acute and chronic cardiovascular and neurological diseases were included or excluded from the study.

Thank you. Our population was formed by children with physical status I or II according to the American Society of Anesthesiologists classification. The only four children (3 in the CPAP group and 1 control) with ASA physical status equal to II had controlled asthma. Children with genetic syndromes, acute and chronic cardiovascular and neurological diseases were not included.

page 11: please correct the following sentences:

11. “Fig 2 shows the plots of Kaplan-Meier curves for groups CPAP and Control" with "Figure 2 shows the Kaplan-Meier curves for the CPAP and control groups”

Corrected in the manuscript.

12. ”between-group with between groups”

Corrected in the manuscript.

13. The study is well-designed and controlled, appearing to be scientifically sound. The concerns of the prior reviewers seem to have been adequately addressed. Regarding point #9 on power analysis, as any change to the power calculation would be a posteriori I would recommend still reporting the calculations that were performed a priori. If the authors wish to include an additional a posteriori calculation based on the reviewer recommendations to demonstrate the true power of the study, I would suggest stating exactly what happened: the study population size was based on the a priori calculation, but a posteriori a second analysis was performed based on feedback that the initial assumptions required adjustment, and this analysis revealed the study was powered at X% to detect Y difference, or something to that effect.

Thank you. Corrected in the manuscript.

Specific comments:

14. Abstract: as a result of deletions, T1 is no longer defined in the abstract, but T2 is. The T1 definition can be appended to the sentence about the primary outcome.

Corrected in the manuscript.

15. P7 third paragraph: by ‘cardioscopy’ do you mean electrocardiogram?

Yes, that is correct. Modified in the manuscript.

16. P7 third paragraph: if 60% fraction was oxygen, was the rest nitrogen gas (room air)? This should be stated.

Information added in the manuscript.

17. P8 first paragraph: change ‘halt’ to ‘halted’

Corrected in the manuscript.

18. P11/Figure 3: why does the control group return to a non-significant difference at 240 seconds? Is this due to patients in the control group getting bag mask ventilation due to falling saturations (post T1 measurement)? If so this figure is misleading and the more appropriate analysis would be to look at only patients who had not yet reached the T1 endpoint when comparing the groups.

Thank you. The Figure 3 refers to the measurements made during the T1 fase, after the apnoea onset till the pulse oximetry equals 95%. Once the patient reached a 95% pulse oximetry, the fase T2 fase started and this data is not represented in Figure 3. Our hypothesis is that the lack of significance after 240 seconds is because the groups tend to match up from that moment on, that is, the performance of CPAP would have the greatest impact between 60 and 210 seconds. After 240 seconds, those patients in the control group who did not desaturate would probably not benefit from using CPAP, showing that the benefit of the intervention would be in those patients more likely to desaturate early.

19. P13 second paragraph: change ‘define the airway’ to ‘secure the airway’

Corrected in the manuscript.

20. P13 last word: change overpasses to surpasses

Corrected in the manuscript.

21. P14 second paragraph: you state that other studies ‘[show] improvements in outcomes by the use of positive pressure’. Is there definitive evidence that outcomes are improved with CPAP? I can see reduced rates of transient hypoxia during apnea, as you have shown here, but I don’t believe there is evidence that meaningful case outcomes such as postop oxygen requirements, reintubation requirements, etc. are reduced. Thus I would recommend defining what outcomes, if any, are improved.

Thank you. Information added in the manuscript.

22. P14 third paragraph: change ‘being one’ to ‘one being’

Corrected in the manuscript.

23. P14 third paragraph: change ‘showed’ to ‘shown’

Corrected in the manuscript.

24. P14 fourth paragraph: change ‘hold the small airways opened’ to ‘prevent atelectasis’

Altered in the manuscript.

P15 first paragraph: I would change the word ‘threatening’ to something else, maybe ‘the impairment of these factors may predispose patients to harm’ or delete the whole sentence

Deleted in the manuscript.

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(12KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0256950.r005

Decision Letter 2

Thomas Penzel

9 Jul 2021

PONE-D-20-33942R2

Continuous positive airway pressure to reduce the risk of early peripheral oxygen desaturation after onset of apnoea in children: a double-blind randomised controlled trial

PLOS ONE

Dear Dr. dos Santos Neto,

We are happy with your revision. However some very few, but important comments remain to be answered. We look forward for a good statistical treatment of these concerns.

Please submit your revised manuscript by Aug 23 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Thomas Penzel

Academic Editor

PLOS ONE

Journal Requirements:

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: (No Response)

Reviewer #4: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #2: Yes

Reviewer #4: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #2: Yes

Reviewer #4: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #2: Yes

Reviewer #4: Yes

**********

6. Review Comments to the Author

Reviewer #2: The authors have responded very well to previous comments. There is still one issue that the authors need to revisit. The sample size calculation is still insufficiently described. First, I would recommend that the authors include a reference to the Schoenfeld’s procedure which they used in the original sample size calculation, and also state the parameters/assumptions that went into the calculation. In the 'revised' calculation which is included in the authors' response to previous comments, the formula is incorrectly applied, specifically where the authors divide S2 by 2 (the correct application is to first sum up S1 and S2 and then divide this sum by 2; the result of this calculation is then subtracted from 1; and finally, the result of this second part of the calculation is multiplied by the expected number of events (i.e. 66 expected events for 50% relative reduction at 80% power) to obtain the overall sample size. Also, please refer to the sample size calculation as such, and not 'study population size'.

In response to previous reviews, the authors removed mentions of chi-squared tests, Fisher's exact test, students t-test etc. Mentions of Shapiro–Wilk test should also be moved. A reference to the Benjamini–Hochberg procedure should also be included, along with a brief explanation of how it adjusts the p-value to avoid type 1 error.

Reviewer #4: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #4: No

PLoS One. 2021 Oct 1;16(10):e0256950. doi: 10.1371/journal.pone.0256950.r006

Author response to Decision Letter 2

28 Jul 2021

We are grateful for all the suggestions. Without a doubt, they praised our paper. We’ve made some minor adjustments in the text: an excerpt that was previously in the methods was moved to the discussion as we understand that this would be more appropriate since it refers to the limitations of the study, and the reference number 18 was updated. All questions were answered directly in the original text and we remain at your disposal for any clarifications that are still needed.

The authors have responded very well to previous comments. There is still one issue that the authors need to revisit. The sample size calculation is still insufficiently described. First, I would recommend that the authors include a reference to the Schoenfeld’s procedure which they used in the original sample size calculation, and also state the parameters/assumptions that went into the calculation. In the 'revised' calculation which is included in the authors' response to previous comments, the formula is incorrectly applied, specifically where the authors divide S2 by 2 (the correct application is to first sum up S1 and S2 and then divide this sum by 2; the result of this calculation is then subtracted from 1; and finally, the result of this second part of the calculation is multiplied by the expected number of events (i.e. 66 expected events for 50% relative reduction at 80% power) to obtain the overall sample size.

- Thank you for the opportunity. Unfortunately, S2= 0.050.5 was a printing error made by us in the last Response to Reviewers. It was not our intention to and we did not divide S2 by 2. Below we show in detail how the initial and revised sample calculations were performed.

1. Assumptions for original sample size calculations:

1.1 We want to able to detect a 50% reduction in the hazard of the experimental group with a power of 80% and a significance level of 0.05.

1.2 We assumed no censoring.

The reference for Schoenfeld procedure used in original sample size calculation comes from the following Stata’s SE 12.1 command that we used to calculate the sample size:

stpower logrank, hratio(0.5) power(0.8) schoenfeld

Note: By default, stpower assumes an equal allocation design (input parameter: p1 = 0.5000)

Output (original sample size calculation):

2. Revised calculation of sample size:

2.1 We want to able to detect a 50% reduction in the hazard of the experimental group with a power of 80% and a significance level of 0.05.

2.2 We assumed that 5% of the subjects in the control group were expected to survive to end of the study (300 seconds).

Under these assumptions, the required sample size should be:

E = estimated number of events (E = 66 from the output above) and = 1– (S1 + S2)/2. Now,

S2 = S1HR = 0.050.5 = sqrt(0.05) = 0.2236. So, = 0.8632 and the sample size N ≅ 76.

This result is confirmed by the following Stata’s stpower output:

stpower logrank 0.05, hratio(0.5) power(0.8) Schoenfeld

Output:

The actual study sample was 68 patients. With this sample size we achieved 72,4% power to detect a 50% reduction in the hazard of the experimental group, with a 5% significance level.

The reference for Schoenfeld’s procedure (formula) used in original sample size calculation is found in An Introduction to Survival Analysis Using Stata, by Mario Cleves et al. Third Edition, 2010, Stata Press, page 338. Here, the author refers to a Schoenfeld’s paper (The Asymptotic Properties of Nonparametric Tests for Comparing Survival Distributions Biometrika 68:316-319) as the source of the formula used in the sample calculations.

This procedure is an option in the following Stata’s SE 12.1 command that we used to calculate the sample size.

Also, please refer to the sample size calculation as such, and not 'study population size’.

- Altered in the manuscript

In response to previous reviews, the authors removed mentions of chi-squared tests, Fisher's exact test, students t-test etc. Mentions of Shapiro–Wilk test should also be moved.

- Altered in the manuscript

A reference to the Benjamini–Hochberg procedure should also be included, along with a brief explanation of how it adjusts the p-value to avoid type 1 error.

-A reference to the Benjamini–Hochberg procedure could be their original article: Benjamini, Y., and Hochberg, Y. (1995). Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society Series B, 57, 289–300. Briefly, this method is one of several for dealing with the so-called multiplicity of hypothesis tests problem (http://www.biostathandbook.com/multiplecomparisons.html). When there are several hypotheses to be tested with the data from a particular study, the problem of the occurrence of false positives (type I error) arises. The criticism of many more traditional methods is that they greatly diminish the chance of rejecting a null hypothesis. This also leads to an unwanted increase in false negatives. Benjamini-Hochberg's proposal is not to try to reduce the chance of a false negative so drastically, but to accept a certain proportion of false positives. From there, it defines a procedure to define which null hypotheses among the rejected ones should really be rejected (true positives). An explanation of how it adjusts the p-value to avoid type 1 error can be find at https://www.statisticshowto.datasciencecentral.com/benjamini-hochberg-procedure/.

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(163.5KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0256950.r007

Decision Letter 3

Thomas Penzel

20 Aug 2021

Continuous positive airway pressure to reduce the risk of early peripheral oxygen desaturation after onset of apnoea in children: a double-blind randomised controlled trial

PONE-D-20-33942R3

Dear Dr. dos Santos Neto,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Thomas Penzel

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0256950.r008

Acceptance letter

Thomas Penzel

23 Sep 2021

PONE-D-20-33942R3

Continuous positive airway pressure to reduce the risk of early peripheral oxygen desaturation after onset of apnoea in children: a double-blind randomised controlled trial

Dear Dr. dos Santos Neto:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

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on behalf of

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PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Fig. CONSORT diagram of patient recruitment.

(TIF)

Click here for additional data file.^{(1.6MB, tif)}

S2 Fig. Kaplan–Meier curves for the CPAP and control groups.

(TIF)

Click here for additional data file.^{(981.7KB, tif)}

S3 Fig. Repeated-measures saturation values curves.

(TIF)

Click here for additional data file.^{(119.8KB, tif)}

S1 File. CONSORT 2010 Checklist.

(PDF)

Click here for additional data file.^{(237.2KB, pdf)}

S2 File. Study Protocol in Portuguese.

(PDF)

Click here for additional data file.^{(343.2KB, pdf)}

S3 File. Study Protocol.

(DOCX)

Click here for additional data file.^{(14.8KB, docx)}

S4 File. CPAP group data Time to desaturation.

Database containing each CPAP group patients time to a SpO₂ of 95% or 300 seconds.

(PDF)

Click here for additional data file.^{(22.3KB, pdf)}

S5 File. Control group data Time to desaturation.

Database containing each Control group patients time to a SpO₂ of 95% or 300 seconds.

(PDF)

Click here for additional data file.^{(22.3KB, pdf)}

S6 File. Repeated-measures saturation values.

Database containing each patient SpO₂ during apnoea time until SpO₂ of 95% or 300 seconds.

(PDF)

Click here for additional data file.^{(104KB, pdf)}

S7 File. CPAP group data Time for recovery.

Database containing each CPAP group patients time required for recovery of SpO₂ from 95% to pre-apnoea levels (T2).

(PDF)

Click here for additional data file.^{(19.4KB, pdf)}

S8 File. Control group data Time for recovery.

Database containing each Control group patients time required for recovery of SpO₂ from 95% to pre-apnoea levels (T2).

(PDF)

Click here for additional data file.^{(19.3KB, pdf)}

S9 File. Data used to build repeated-measures saturation values curves.

(PDF)

Click here for additional data file.^{(113.2KB, pdf)}

S10 File. Database with raw data of all patients.

(XLSX)

Click here for additional data file.^{(18.9KB, xlsx)}

S11 File

(PDF)

Click here for additional data file.^{(333.8KB, pdf)}

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(12.3KB, docx)}

Attachment

Submitted filename: Response to Reviewers.docx

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Data Availability Statement

All relevant data are within the manuscript and its Supporting Information files.

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PERMALINK

Continuous positive airway pressure to reduce the risk of early peripheral oxygen desaturation after onset of apnoea in children: A double-blind randomised controlled trial

Jayme Marques dos Santos Neto

Clístenes Cristian de Carvalho

Lívia Barboza de Andrade

Thiago Gadelha Batista Dos Santos

Rebeca Gonelli Albanez da Cunha Andrade

Raphaella Amanda Maria Leite Fernandes

Flavia Augusta de Orange

Roles

Abstract

Introduction

Materials and methods

Statistical analysis

Results

Fig 1. CONSORT diagram of patient recruitment.

Table 1. Characteristics of children with CPAP-ventilation and passive CPAP-oxygenation (10 cmH2O) or no positive pressure (0 cmH2O) during anaesthesia induction for elective surgery.

Table 2. T1 and T2 in children treated with CPAP ventilation and passive CPAP oxygenation (10 cmH2O) or no positive airway pressure (0 cmH2O) during anaesthesia induction for elective surgery.

Fig 2. Kaplan–Meier curves for the CPAP and control groups.

Fig 3. Repeated-measures saturation values curves.

Discussion

Conclusions

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Thomas Penzel

Roles

Author response to Decision Letter 0

Decision Letter 1

Thomas Penzel

Roles

Author response to Decision Letter 1

Decision Letter 2

Thomas Penzel

Roles

Author response to Decision Letter 2

Decision Letter 3

Thomas Penzel

Roles

Acceptance letter

Thomas Penzel

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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Table 1. Characteristics of children with CPAP-ventilation and passive CPAP-oxygenation (10 cmH₂O) or no positive pressure (0 cmH₂O) during anaesthesia induction for elective surgery.

Table 2. T1 and T2 in children treated with CPAP ventilation and passive CPAP oxygenation (10 cmH₂O) or no positive airway pressure (0 cmH₂O) during anaesthesia induction for elective surgery.