Variability of Respiratory Rate Measurements in Neonates- Every Minute Counts

doi:10.21203/rs.3.rs-929172/v1

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Variability of Respiratory Rate Measurements in Neonates- Every Minute Counts

https://doi.org/10.21203/rs.3.rs-929172/v1

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published 03 Jan, 2022

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Background: Respiratory rate is difficult to measure, especially in neonates who have an irregular breathing pattern. The World Health Organisation recommends a one-minute count, but there is limited data to support this length of observation. We sought to evaluate agreement between the respiratory rate (RR) derived from capnography in neonates, over 15 seconds, 30 seconds, 120 seconds and 300 seconds, against the recommended 60 seconds.

Methods: Neonates at two hospitals in Nairobi were recruited and had capnograph waveforms recorded using the Masimo Rad 97. A single high quality 5 minute epoch was randomly chosen from each subject. For each selected epoch, the mean RR was calculated using a breath-detection algorithm applied to the waveform. The RR in the first 60 seconds was compared to the mean RR measured over the first 15 seconds, 30 seconds, 120 seconds, full 300 seconds, and last 60 seconds. We calculated bias and limits of agreement for each comparison and used Bland-Altman plots for visual comparisons.

Results: A total of 306 capnographs were analysed from individual subjects. The subjects had a median gestation age of 39 weeks with slightly more females (52.3%) than males (47.7%). The majority of the population were term neonates (70.1%) with 39 (12.8%) having a primary respiratory pathology. There was poor agreement between all the comparisons based on the limits of agreement [confidence interval], ranging between 11.9 [-6.79 to 6.23] breaths per minute in the one versus two minutes comparison, and 34.7 [-17.59 to 20.53] breaths per minute in the first versus last minute comparison. Worsening agreement was observed in plots with higher RRs.

Conclusions: Neonates have high variability of RR, even over a short period of time. A slight degradation in the agreement is noted over periods shorter than one minute. However, this is smaller than observations done three minutes apart in the same subject. Longer periods of observation also reduce agreement. For device developers, precise synchronization is needed when comparing devices to reduce the impact of RR variation. For clinicians, where possible, continuous or repeated monitoring of neonates would be preferable to one time RR measurements.

Pediatrics

neonates

respiratory rate measurement

variability

Respiratory rate (RR), though regarded as critically important for the diagnosis and management of respiratory and non–respiratory disease, remains a difficult parameter to monitor reliably (1). It is affected by various factors including fever, feeding, agitation as well as sleep versus awake state (2). This challenge is amplified in neonates, who have an irregular breathing pattern during the first few months of life as the respiratory control mechanisms mature (3). The current recommendation from the World Health Organisation (WHO) is to count breaths over 60 seconds (4). This one-time measurement is then used to decide if an infant has respiratory disease and to direct clinical management decisions. The Integrated Management of Newborn and Childhood Illnesses booklet, for example, gives the criteria of more than 60 breaths/minute in an infant less than two months old, to classify the child as having a possible severe bacterial infection or very serious disease (5).

Counting the rate for shorter periods and then multiplying by a factor to estimate a one-minute rate is commonly utilized but has been suggested to amplify observer error. On the other hand, counting for a longer period of time may be impractical in a busy clinical environment. Given the high variability of the breathing pattern in neonates, there is uncertainty on whether a 60 second measurement accurately captures a rate that is reflective of the respiratory status. Indeed, there is no proven method or period that is considered a gold standard for monitoring the respiratory rate (6). A better understanding of the impact of the duration of monitoring will guide clinicians on the utility of RR while making clinical decisions.

We therefore sought to evaluate agreement between the recommended 60 seconds compared to 15 seconds, 30 seconds, 120 seconds and 300 seconds of respiratory rate derived from capnography in neonates.

Following ethics approval and informed consent, neonates (age < 28 days) were enrolled in the Evaluation of Technologies for Neonates in Africa (ETNA) study. The study was conducted at the neonatal unit of Aga Khan University Hospital and at Pumwani Maternity Hospital, both in Nairobi, Kenya. Information on gestational age, gender, current weight, anthropometric measurements, clinical signs, and diagnosis were collected for all neonates.

The Masimo Rad-97 pulse CO-oximeter with capnography (Masimo Corporation, USA) was used to collect continuous capnograph waveforms from neonates. Following data collection, the capnograph (carbon dioxide, CO₂) waveform data at approximately 20Hz was inputted into a custom breath detection algorithm developed in MATLAB (Math Works, USA) based on adaptive pulse segmentation (7). The algorithm analysed the waveform’s shape and identified the start and end of each breath (waveform trough to trough), and this breath duration was used to calculate an instantaneous respiratory rate (breaths per minute) for each breath. A mean respiratory rate was calculated by taking the mean of the instantaneous rates for all breaths within the epoch. A breath was considered to be within the epoch if its peak, as identified by the algorithm, was within the epoch. Additionally, the algorithm calculated a capnography quality score at 2Hz. The statistical program R was used to process this information and randomly select high quality 5-minutes epochs for each subject. The high-quality criteria threshold was 90% of RR quality scores in the epoch meeting the minimum quality score of two, indicating a regular capnography waveform with an appropriate shape (that is, minimal variation of amplitude, time interval, up-slope and down-slope of waveform peaks when compared).

For each selected 5-minute epoch, the mean RR of the first 60 seconds was compared to the derived mean RR measured over the first 15 seconds, 30 seconds, 120 seconds, full 300 seconds, and last 60 seconds (beginning three minutes later). The agreement was calculated using Bland Altman analysis (8) that compares two quantitative measurements by plotting the differences against the average and calculating the bias and 95% limits of agreement (LOA). The bias denotes the average of the mean differences between the two sets of values, while the LOA represents the interval that contains 95% of the differences between them. The bias and LOA from each comparison were then displayed on plots. We noted that variability seemed significantly increased at higher RRs. To account for this, we took the data through normalization by dividing the bias and the limits of agreement by the overall mean and expressing this as a percentage. Intra-patient agreement was assessed by comparing the first and last one minute of the five-minute period.

A total of 327 capnograph waveforms from 327 subjects were available from the ETNA data set, collected between June 2019 and December 2020. For 21 cases, we were not able to select a full 5-minute epoch of high-quality data, and so these cases were excluded. The diagnoses of the remaining 306 neonates included a wide range of conditions typical of the new-born unit (Table 1). The population included both pre-term and full-term neonates with 39 (12.8%) having a primary respiratory pathology.

Table 1

Neonate Characteristics
Characteristic (units)	Median (range)
Gestational Age in weeks ((weeks)	39 (25–44)
25–34 weeks gestation	17%
35–36 weeks gestation	12.9%
37 weeks and above	70.1%
Weight in grams(grams)	2970 (885–5075)
Apgar Score at 5 minutes	9 (2–10)
Oxygen Saturation (%)	98 (91–100)
Characteristic	n (%)
Sex - Males	146 (47.7)
Primary Diagnosis
Asphyxia	35 (11.4)
Hypoglycemia	8 (2.6)
Jaundice	31 (10.1)
Low birth weight	11 (3.6)
Meconium aspiration syndrome	11 (3.6)
Healthy neonate	69 (22.5)
Other primary diagnosis	15 (4.8)
Sepsis/suspected sepsis	32 (10.5)
Prematurity	66 (21.6)
Respiratory distress syndrome	28 (9.2)

There was poor agreement between all the comparisons, with a large spread of the 95% LOA [CI], ranging from 11.9 [-6.79 to 6.23] breaths per minute in the one versus two minutes comparison, to 34.7 [-17.59 to 20.53] breaths per minute in the first versus last minute comparison (Fig. 1). The LOA were increased with both shorter and longer periods of observation, but the largest LOA range was with the repeated observations in the same subject, showing significant intra-patient variability (Fig. 2). Initial analysis showed worse agreement at higher RR but this effect was attenuated by normalization.

The findings of this study demonstrate that respiratory rate in neonates varies considerably over a 5-minute period of time. Furthermore, measuring respiratory rate over periods of more than one minute had poor agreement with the standard one-minute rate. Measuring the respiratory rate over 15 and 30 seconds also reduced agreement with the one-minute rate but this was a relatively small effect compared to within individual variability.

This study provides important information for device developers looking to validate new methods and techniques for measuring respiratory rate and also for clinicians measuring respiratory rate in neonates.

When comparing two independent measurements, lack of agreement may be due to the lack of precision of timings of the measurements but is also significantly degraded by the within subject variability in respiratory rate. To accurately compare two methods of respiratory rate measurement, the synchronization in time must be very precise – the same exact time period (and breaths) should be used.

For clinicians, this study demonstrates that the respiratory rate in neonates is highly variable, even over a short period of time, and so a single one-minute measurement may not accurately depict the true physiological status of the patient. We observed that the limits of agreement (LOA) was widest when comparing a one-minute period to a second one-minute period only three minutes later. From the start to the end of a 5-minute period the RR of a neonate can increase or decrease by 15 breaths per minute. This is within the 95% LOA of our results. This observation is important because it means that one single RR measurement in critically ill neonates may not give an adequate assessment of a neonate. Continuous or repeated RR monitoring of neonates is likely to be more beneficial than a single spot check measurement.

The optimum time period for counting the respiratory rate is yet to be determined. We found in this study that measuring RR over periods of more than one minute did not improve agreement. As the measurement length increased, the agreement to one-minute decreased. There was a difference of 6 breaths/minute within the spread of 95% LOA when comparing two-minutes with the standard one-minute rate, and a difference of 10 breaths/minute with the 5-minute comparison. Increasing the duration of respiratory rate counting for longer than one minute will likely not improve accuracy.

Measuring RR over periods of less than one-minute also showed reduced agreement, with the 15 second to one- minute comparison, for example, seeing the spread of LOA of 10 breaths per minute. Yet, this is a relatively small effect compared to the within individual variability that was demonstrated by comparing two one-minute RR counts, taken three minutes apart.

The 30 second period has previously been found to be imprecise since errors are multiplied when converting to “per minute” rates (4). In this study, our method of respiratory rate measurement (using the mean of the instantaneous (single breath) rates of all included breaths) does not include this typical multiplication – there is no increased imprecision in measurements under one minute, only that they are calculated based on less breaths. Despite this difference, in this study we still found the 30 second to one-minute comparison displayed wide variability with a spread of 7 breaths per minute falling within the 95% LOA.

In a similar study done in children under five years of age, comparing different counting periods to a synchronous capnograph recording, they found the least variability when two − 30 second measurements, done three minutes apart, were used (9). This difference in findings is possibly due to the different time periods used for comparison (30 versus 60 seconds). Moreover, our study was exclusively in neonates who have higher variability in their breathing compared to older children. It important to consider this difference between neonates and older children when determining the frequency of RR measurements.

Respiratory rate variability may be affected by agitation, hypoxia, sleep versus awake state, and fever (10–12). A previous study, for example, suggested a RR correction factor of 7–11 breaths per minute for each one degree °C elevation in temperatures above 38.5 degrees (13). Sleep state has also been shown to have a marked effect on the cardio-respiratory system with irregularities being more common in active sleep compared to quiet sleep (11). These factors were not adjusted for during our analysis. We also did not adjust for other physiological factors such as temperature, time of day, age, or gestational age that may contribute to the variability in respiration.

Considering the high variability of the respiratory rate in neonates, clinicians are advised to avoid using this measurement as a single factor in decision-making. This has been echoed in other studies. For example, one study found that hypoxia and increased work of breathing were more important than tachypnoea and auscultatory findings in diagnosing childhood pneumonia (14). A 2019 commentary suggests using a combination of signs and symptoms and biomarkers (for example, C reactive protein levels) in making a clinical diagnosis of pneumonia (15).

Similarly, manufacturers of medical devices that are used in neonates should take into consideration this variability. To accurately compare two methods of respiratory rate measurement, the synchronization in time must be very precise to ensure that the same exact time period is used. Furthermore, depending on a regular inter-breath duration, as is used by some devices, to derive the respiratory rate, may not account for the highly variable respiratory pattern of neonates.

More studies need to be done to investigate the optimum time period for evaluating respirations in the newborn and the benefit of repeat or continuous assessments in making clinical decisions.

Neonates have high variability of RR, even over a short period of time. Variability is observed to increase with rising RR. In addition, measuring RR for shorter periods may reduce agreement with the standard one-minute rate, though this may be a relatively small effect compared to intra-patient variability. Longer periods of observation also reduce agreement. For device developers, precise synchronization is needed when comparing devices. For clinicians, where possible, continuous or repeated monitoring of neonates would be preferable to one time RR measurements.

Ethical Approval and Consent to participate

The data used was collected as part of a larger study evaluating non- invasive continuous physiological monitoring devices for neonates in Nairobi, Kenya(16). The study was conducted in accordance with the ICHGCP and the Declaration of Helsinki 2008. The protocol and other relevant study documents study were approved by the Western Institutional Review Board 20 191 102 (Puyallup, Washington, USA), and the Aga Khan University Nairobi Research Ethics Committee 2019/REC-02 (v2) (Nairobi, Kenya). Written informed consent was obtained in the local language by trained study staff from all eligible neonate’s caregivers prior to enrolment. Potential participants had adequate time to ask questions and a comprehension checklist was administered to ensure participant understanding.

Consent for publication

All the authors have read the manuscript before submission and give consent for publication. There was no consent for publication sought from the participants since there are no identifying images or other personal or clinical details of presented in this manuscript.

Availability of Data and Materials Section

The dataset supporting the conclusions of this article is available in the Dyrad repository, https://doi.org/10.5061/dryad.jdfn2z3c0

Competing Interests

There are no conflicts of interest to declare.

Funding

This data used was collected during a larger study: Evaluation of non- invasive continuous physiological monitoring devices for neonates in Nairobi, Kenya(16), which was supported by the Bill & Melinda Gates Foundation [OPP1196617]

Author Contributions

All four authors were involved in the conception and design of the study. Analysis of the data was done by Dunsmuir D.T and Njeru C.M. The main manuscript text was written by Njeru C.M. with contributions and review from all the authors.

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Journal Publication

published 03 Jan, 2022

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Editorial decision: Major revision
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You are reading this latest preprint version

Variability of Respiratory Rate Measurements in Neonates- Every Minute Counts

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Availability of Data and Materials Section

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