Literature DB >> 35653380

Nasogastric tube in mechanical ventilated patients: ETCO2 and pH measuring to confirm correct placement. A pilot study.

Samuele Ceruti1, Simone Dell'Era2, Francesco Ruggiero3, Giovanni Bona4, Andrea Glotta1, Maira Biggiogero4, Edoardo Tasciotti2, Christoph Kronenberg2, Gianluca Lollo5, Andrea Saporito2.   

Abstract

INTRODUCTION: Nasogastric tube (NGT) placement is a procedure commonly performed in mechanically ventilated (MV) patients. Chest X-Ray is the diagnostic gold-standard to confirm its correct placement, with the downsides of requiring MV patients' mobilization and of intrinsic actinic risk. Other potential methods to confirm NGT placement have shown lower accuracy compared to chest X-ray; end-tidal CO2 (ETCO2) and pH analysis have already been singularly investigated as an alternative to the gold standard. Aim of this study was to determine threshold values in ETCO2 and pH measurement at which correct NGT positioning can be confirmed with the highest accuracy. MATERIALS &
METHODS: This was a prospective, multicenter, observational trial; a continuous cohort of eligible patients was allocated with site into two arms. Patients underwent general anesthesia, orotracheal intubation and MV; in the first and second group we respectively assessed the difference between tracheal and esophageal ETCO2 and between esophageal and gastric pH values.
RESULTS: From November 2020 to March 2021, 85 consecutive patients were enrolled: 40 in the ETCO2 group and 45 in the pH group. The ETCO2 ROC analysis for predicting NGT tracheal misplacement demonstrated an optimal ETCO2 cutoff value of 25.5 mmHg, with both sensitivity and specificity reaching 1.0 (AUC 1.0, p < 0.001). The pH ROC analysis for predicting NGT correct gastric placement resulted in an optimal pH cutoff value of 4.25, with mild diagnostic accuracy (AUC 0.79, p < 0.001). DISCUSSION: In patients receiving MV, ETCO2 and pH measurements respectively identified incorrect and correct NGT placement, allowing the identification of threshold values potentially able to improve correct NGT positioning. TRIAL REGISTRATION: NCT03934515 (www.clinicaltrials.gov).

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Mesh：

Year:  2022        PMID： 35653380      PMCID： PMC9162373          DOI： 10.1371/journal.pone.0269024

Source DB:  PubMed          Journal:  PLoS One        ISSN： 1932-6203            Impact factor:   3.752


Introduction

Nasogastric tube (NGT) placement is commonly performed in the critical setting [1]. The procedure is not however free of complications, which tend to occur especially in patients undergoing mechanical ventilation (MV), when the cough reflex has been abolished [2]. The incidence of complications during NGT positioning is around 4% and is characterized by a high morbidity [3], possibly leading to prolonged hospital stay and higher hospital costs, and increased mortality [4]. Currently, the gold standard to confirm NGT correct positioning is the standard chest X-ray [5], which implies the use of ionizing radiation (4 μSv for radiography) and patients’ mobilization, which may lead to accidental extubation and hemodynamic instability. Considering that critical patients may require multiple NGT placements or repositioning, the actinic and mobilization-induced risks are not to be neglected. Several alternatives to chest X-ray have been investigated, none of them resulting in a high diagnostic accuracy; these include the so-called bubble technique [6], frozen NGT [7], gastric auscultation [8, 9], aspiration from the NGT [10, 11], gastric ultrasound [12-14], biochemical markers [15, 16] and the use of magnets [17]. Some pilot studies have shown that measuring end tidal CO2 (ETCO2) with a graphic capnometer could be used to determine whether the NGT tip has been erroneously placed at tracheal level [18-22], others that relative pH levels can distinguish between gastric and esophageal NGT positioning [23, 24]. In those studies, however, threshold values of ETCO2 and pH able to discriminate correct NGT positioning have not been determined, the two measurements (pH and ETCO2) have never been combined in the same study, the global accuracy of each methodology was rather low and/or the sample size was insufficient to obtain a statistical significance. The feasibility to implement the two parameters in a hypothetical device, exploiting a double feedback mechanism to detect correct NGT placement with a high accuracy, is an attractive possibility which justifies further investigations. Aim of the study is to analyze distributions between tracheal and esophageal ETCO2 values and between gastric and esophageal pH values in two separate arms in patients on MV, in order to identify thresholds values at which the correct positioning of NGT can be confirmed with high accuracy.

Material & methods

This was a prospective, multicenter, observational trial, conducted over a six-months period in two acute tertiary hospitals. The study has been registered (clinicaltrials.gov, NCT03934515) and approved by the regional Ethical Committee (Comitato Etico Cantonale, Bellinzona, Switzerland, Chairman Prof. Zanini–N. CE3548). The cohort consisted of patients undergoing general anesthesia and receiving MV; inclusion criteria included patients of both sexes, older than 18 years, fasting for at least six hours, undergoing general anesthesia and MV, for whom the need for an oro- or naso-tracheal tube was decided according to clinical criteria. Exclusion criteria were patient’s refusal or inability to give informed consent, pregnancy, known ongoing gastric or esophageal bleeding, coagulation impairment (defined as thrombocytes < 50 G/L, fibrinogen < 1.0 g/L, International Normalized Ratio (INR) > 2.5, activated Prothrombin Time (aPTT) > 70 sec tested at the preoperative assessment), history of traumatic brain injury or polytrauma, esophago-tracheal fistulas, esophageal varices, Ear, Nose and Throat (ENT) malformations and/or tumors, history of radiotherapy for ENT tumors. Patients in whom pH and/or ETCO2 values were not measurable for technical reasons were excluded and considered as drop-outs.

Allocation

Eligible patients were treated according to allocation within site to one of the two groups: group A patients underwent ETCO2 measurement, group B patients underwent pH measurement. In contrast to protocol’s expectations, due to COVID-19 pandemic restriction, Clinica Luganese Moncucco was able to enroll a total of five patients for ETCO2 measurements, while the remaining were enrolled at the Anesthesia Service of Bellinzona and Valli Regional Hospital. As expected by the protocol instead, all patients from group B were enrolled in the Anesthesia Service of “Bellinzona and Valli” Regional Hospital.

Group A

After anesthesia induction and at the beginning of MV, a suction probe was inserted in the endotracheal tube and tracheal ETCO2 was measured through a capnometer connected to it; both the probe and the NGT presented the same diameter (12 Fr). After the measurement, tracheal secretions were aspirated as usual. Afterwards, the NGT was positioned using the standard approach, and esophageal ETCO2 was measured through a capnometer attached to it. After the measurement, the capnometer was disconnected, while the NGT was left in place as usual; at this time, no chest-X-ray was routinely performed. ETCO2 values were registered in the data sheet and subsequently transferred into a codified electronic database; for each patient, two sets of values were therefore obtained: tracheal and esophageal ETCO2.

Group B

After anesthesia induction and at the beginning of MV, NGT insertion was performed according to local protocols. As the NGT was progressively inserted, pH was measured at two different points located at 25 and 40 cm from the teeth, respectively intended as esophageal and gastric levels; a chest-X-ray was then performed as standard of care to confirm the sites. The assessment from each of the two levels was performed as following: 10 ml of NaCl 0.9% were first injected and then aspired back in the NGT, and the liquid was then placed on litmus paper for pH assessment. All reported values were then registered and archived as described above. Two sets of values were therefore obtained for each patient: esophageal and gastric pH.

Outcomes

Primary outcome was to analyze values distributions between tracheal and esophageal ETCO2 measurements (group A) and between gastric and esophageal pH measurements (group B). Secondary outcome was to identify, for each distribution, the threshold value at which correct NGT positioning can be confirmed with the best accuracy.

Statistical analysis

The power analysis was based on the primary outcomes within each of the two groups. For the ETCO2 group, a tracheal value around 40 mmHg was assumed as normal [25-27], while a normal esophageal value was considered around 20 mmHg [28]. In order to obtain a significant difference between tracheal and esophageal values, with a power of 90% and a significance level of 0.01 (one-tailed paired t-test), we calculated the need for 35 patients; anticipating a 10% drop-out rate, 40 patients were included in the ETCO2 group. With regard to the pH group, an esophageal value of around 7 was assumed as normal [29], while gastric pH was considered normal when ranging from 1.0 to 2.5 [30]. In order to obtain a significant difference between esophageal and gastric pH values, with a power of 90% and a significance level of 0.01 (one-tailed paired t-test), we calculated the need for 30 patients; similarly, anticipating a 10% of drop-out rate, we included 35 patients for each measurement in the pH group. We tabulated the distribution of baseline variables across the study’s sections, summarizing categorical variables by frequencies and percentage and numerical variables either by mean and standard deviations (±SDs) or by medians and interquartile ranges (IQR). Data distribution was verified using a Kolmogorov- Smirnov test. We executed a paired t-test to compare the two proportions, refusing the null hypothesis of no difference between the two if p-value was ≤ 0.01. In order to identify the threshold value of ETCO2 and pH signaling, respectively, endotracheal and gastric NGT positioning with high accuracy, the area under the receiver operating characteristic (ROC) curve was calculated for both ETCO2 and pH values, calculating the sensitivity, specificity and the likelihood ratios for the optimal cut-off point (CP) of the scale (Youden index and Number Necessary to Diagnose, J and NND respectively) [31]. Beginning from the ROC curve, a “cumulative distribution analysis” (CDA) was performed [32], to better identify a grey zone defined by the values associated with both sensitivity and specificity of 90% [33]. All hypothesis tests were one-tailed and considered significant if p-value was ≤0.01. Statistical analysis was performed using SPSS.26 (IBM, Chicago, IL, USA) for MacOS.

Results

From November 2020 to March 2021, 85 consecutive patients were enrolled: 40 in the ETCO2 group and 45 in the pH group; 17 dropouts occurred, due to incomplete information sampling during the procedure (such as the impossibility to measure pH). Sixty-eight patients were therefore included in the analysis, 33 in the ETCO2 group and 35 in the pH group (Fig 1); the mean age was 54 years old (min/max 46–62) and 36 (55%) were men. All demographic data are reported in Table 1.
Fig 1

Patients distribution.

Study patients’ allocation and distribution.

Table 1

Demographics characteristic population.

ETCO2 grouppH groupp value
n = 33n = 35
Age 54 (13.7)60 (9.8)0.09
Sex male 22 (66%)14 (43%)0.05
BMI [Kg/m 2 ] 25.4 (6)30.6 (7.4)0.36
Systolic arterial pressure [mmHg] 145 (29)152 (28)0.36
Heart rate [bpm] 80 (21)77 (17)0.43
Respiratory rate [min] 14 (3)14 (2)0.7

Demographic characteristics. Data distribution were expressed as mean ± SD according to Kolmogorov-Smirnov test.

Patients distribution.

Study patients’ allocation and distribution. Demographic characteristics. Data distribution were expressed as mean ± SD according to Kolmogorov-Smirnov test. With regard to the ETCO2 distribution analysis, 22 (66%) patients were men, 7 (21%) presented a diagnosis of Chronic Obstructive Pulmonary Disease—COPD (4 patients of second degree, 1 patient of third degree); one (3%) patient presented a previous diagnosis of pulmonary embolism. Five (15%) patients had a history of heart disease (two patients with severity New York Heart Association–NYHA—1, three patients with NYHA 2) (Table 1), all with a cardiac ejection fraction (EF) greater than 50%. Mean tracheal ETCO2 was 40 mmHg (SD 7.14), while mean esophageal ETCO2 resulted 11 mmHg (SD 9.3); a t-test score (Fig 2) confirmed a significant difference (CI 99%, 24–33, p < 0.001).
Fig 2

Tracheal and esophageal ETCO2 distribution.

Boxplots: The black bar indicates median ETCO2 (38 mmHg and 14 mmHg respectively), while the blue areas include the interquartile ranges for each group.

Tracheal and esophageal ETCO2 distribution.

Boxplots: The black bar indicates median ETCO2 (38 mmHg and 14 mmHg respectively), while the blue areas include the interquartile ranges for each group. Regarding pH distribution analysis, 14 (40%) patients were male, 6 (18%) presented a history of hiatal hernia, and 13 (39%) presented a diagnosis of gastroesophageal reflux disease, with 12 (36%) patients receiving Proton Pump Inhibitors (PPI) therapy at the time of data sampling (Table 1); no patient was on enteral feeding during the analysis. Median gastric pH was 3.1 (1.6–4.95), while median esophageal pH resulted 5.15 (4.52–6.0); a t-test score confirmed a significant difference (CI 99%, 0.9–2.9, p = 0.004, Fig 3).
Fig 3

Measured of esophageal and gastric pH.

Boxplot distribution in all patients and in patients without PPI use. Regarding the whole group analysis, a t-test score confirmed a significant difference between esophageal and gastric values (CI 99%, 0.9–2.9, p = 0.004). The subgroup analysis involving patients without PPI showed a greater difference (p < 0.001) compared to the whole group. The black bar indicates median pH, while the blue areas include the interquartile ranges for each group.

Measured of esophageal and gastric pH.

Boxplot distribution in all patients and in patients without PPI use. Regarding the whole group analysis, a t-test score confirmed a significant difference between esophageal and gastric values (CI 99%, 0.9–2.9, p = 0.004). The subgroup analysis involving patients without PPI showed a greater difference (p < 0.001) compared to the whole group. The black bar indicates median pH, while the blue areas include the interquartile ranges for each group. A subgroup analysis involving 20 (62.5%) patients without PPI, showed a median gastric pH of 2.45 (1.05–4.05) and a median esophageal pH of 5.05 (4.52–6.0), with a greater difference of t-test score (CI 99%, 1.2–3.1, p < 0.001) compared to all patients (Fig 3). A comparison between the mean esophageal pH value in all patients and in patients without PPI did not present a significant difference (5.1 vs 4.9, p = 0.265).

ROC curve analysis

The ETCO2 ROC curve analysis for predicting NGT tracheal misplacement (Fig 4A) demonstrated a perfect diagnostic accuracy with an AUC of 1.0 (CI 95%, 1.0 to 1.0, p < 0.001); the optimal cutoff value resulted in an ETCO2 value greater than 25.5 mmHg (Youden index J = 1), where both sensitivity and specificity reached 1.0. The pH ROC curve analysis for predicting correct gastric placement (Fig 4B) demonstrated a mild diagnostic accuracy, with an AUC of 0.79 (CI 95%, 0.67 to 0.90, p < 0.001); the optimal cutoff value was a pH below 4.25 (Youden index J = 0.593), with a sensitivity of 0.908 and a specificity of 0.687.
Fig 4

ROC curves of ETCO2 and pH.

Receiver operating characteristic (ROC) curves showing the ability of the ETCO2 method (Fig 4A) and pH method (Fig 4B) to respectively identify a tracheal NGT misplacement (ROC AUC 1.0, p < 0.001) or a gastric NGT correct placement (ROC AUC 0.79, CI 95% 0.67–0.90, p < 0.001).

ROC curves of ETCO2 and pH.

Receiver operating characteristic (ROC) curves showing the ability of the ETCO2 method (Fig 4A) and pH method (Fig 4B) to respectively identify a tracheal NGT misplacement (ROC AUC 1.0, p < 0.001) or a gastric NGT correct placement (ROC AUC 0.79, CI 95% 0.67–0.90, p < 0.001). The subgroup analysis involving only patients without PPI confirmed a mild diagnostic accuracy, with an AUC of 0.78 (CI 95%, 0.63–0.93, p = 0.002) and with an optimal cutoff pH value below 3.9 (Youden index J = 0.6). The NND obtained for misplacement of the NGT with the ETCO2 method was 1, while the NND obtained for correct placement of the NGT the pH method was 1.68 (1.66 in patients without PPI). Grey zone plots were drawn throughout CDA curves starting from the Youden index (Fig 5), between the 90th percentages of both sensibility and specificity on the two sigma curves for each ETCO2 and pH; for pH, the gray zone laid between 4.25 and 5.7 (Fig 5), while for ETCO2 no gray zone was identified, as the tracheal and the esophageal distribution did not cross each other (Fig 6).
Fig 5

Cumulative distribution analysis of pH detection.

Performed to determine the correct NGT gastric placement with ‘Fig 5A’ and without ‘Fig 5B’ PPI use. The red line indicates the cutoff limit according to Youden Index (pH below 4.25 and pH below 3.9, with J = 0.593 and J = 0.6 respectively); the grey zone is shown, with sensibility and specificity of 90%.

Fig 6

Cumulative distribution analysis of ETCO2 detection.

Performed to exclude the NGT tracheal misplacement. The red line indicates the cutoff limit according to Youden Index (J = 1).

Cumulative distribution analysis of pH detection.

Performed to determine the correct NGT gastric placement with ‘Fig 5A’ and without ‘Fig 5B’ PPI use. The red line indicates the cutoff limit according to Youden Index (pH below 4.25 and pH below 3.9, with J = 0.593 and J = 0.6 respectively); the grey zone is shown, with sensibility and specificity of 90%.

Cumulative distribution analysis of ETCO2 detection.

Performed to exclude the NGT tracheal misplacement. The red line indicates the cutoff limit according to Youden Index (J = 1).

Discussion

Nasogastric tube placement in sedated and intubated patients is a procedure potentially associated with dangerous complications. The gold standard to assess correct positioning is Chest X-Ray, which exposes patients to mobilization-related complications, such as devices displacement and hemodynamic and respiratory instability, as well as to actinic risk. Alternatives to this gold standard, including pH and ETCO2 measurements taken alone, failed to show a superiority in determining correct NGT tip position [18, 23, 34], especially due to the lack of threshold values. Our study analyzed these two techniques, in order to determine if they can accurately detect a correct positioning of the NGT tip. The use of a double feedback mechanism involving both pH and ETCO2 could in fact prove more accurate than just one of the two measurements by itself. In this study, ETCO2 distribution between the trachea and esophagus was evaluated intended as a potential negative marker to detect NGT misplacement in the upper airways; at the same time, pH distribution between stomach and esophagus was evaluated as a potential positive marker for NGT correct placement. Significant differences between tracheal and esophageal ETCO2 measurements allowed a complete differentiation in the curve plotting distribution. Based on these results, the use of a qualitative capnometer connected to the NGT and set to detect the threshold value of 25.5 mmHg would be a potentially accurate negative-marker mechanism for tracheal NGT placement, with a very high sensitivity, thus avoiding any NGT misplacement. Concerning the differences in results between gastric and esophageal pH, the distributional differences between the two obtained curves is not neat, especially in case of proton pump inhibitors usage, although extremely low pH values were shown to have a high specificity for gastric NGT placement. Fernandez et al published a review of diagnostic studies to test pH of aspirate fluids using a litmus paper; with this method, they evaluated if the NGT had been correctly positioned. It is to be noted that litmus paper color variation could report a value lower than the actual gastric pH, due to the paper’s limited sensitivity [16]. A recent clinical trial by Gilbertson et al identified the cut off pH of < 5.5 to presume correct NGT positioning in the stomach [23]. Comparing these two studies with our trial, we identified the threshold pH value of 4.25 as the value at which false positive rate is minimized, thus increasing the specificity of this positive marker. Noticeably, even if specificity for very low pH appears to be high, the consensually lower sensitivity would affect the global test accuracy, invalidating the positive marker mechanism for the detection of correct gastric NGT placement (NND = 1.68), thus leading to potential misses of a correct placement. Furthermore, analyzing the data based on PPI therapy allows determining an even lower pH threshold for patients not receiving this class of medications (pH of 3.9), nonetheless guaranteeing the same accuracy. In practice, a pH threshold of 4.25 would therefore assure an even better specificity in this subgroup of patients. Based on our study, a future device capable of combining the presence of a negative marker (such as ETCO2) with a positive marker (such as pH) could be accurate enough in identifying the correct positioning of NGTs. Further studies are required to validate the reproducibility of these results with a specific device, whose accuracy also ought to be compared with chest X-ray, the current gold standard. This study presented some limitations. First, in our trial a small sample of Swiss population was enrolled; for a more robust analysis and validation of the current findings, it could be interesting to perform a larger study involving more hospitals or different geographical areas. Second, this was a preliminary study assessing determined physiological variables; it is still unknown whether a device simultaneously sensing ETCO2 and pH could determine correct NGT placement with high accuracy. The presumed esophageal and gastric NGTs placement have been determined based on the distance of the NGT tip from the teeth and 2D chest-X-ray; there is not, therefore, complete certainty about NGT tip location; however, NGT placed at 40 cm from the teeth was conventionally considered into the stomach. Third, in about 20% of patients there was a difficulty concerning the measurements collection, particularly in relation to pH; moreover, due to the small group size it was not possible to perform a sub-analysis concerning the effect of gastric hernia and reflux. In future studies, it will be necessary to implement the usage of the pHmeter, to reduce the rate of dropouts caused by the current limitation of litmus paper. Finally, the accuracy of the pH threshold value for the discrimination between esophageal and gastric NGT positioning resulted suboptimal. The use of a normal saline injection in order to measure pH on the aspirated fluid in case secretions could not be aspirated may have affected pH values in these cases.

Conclusions

In patients under general anesthesia and receiving MV, ETCO2 and pH measurements to identify NGT tracheal misplacement (ETCO2) and correct gastric NGT placement (pH) allow to identify threshold values potentially able to improve adequate NGT placement detection in MV patients.

NGT clinical protocol.

(DOCX) Click here for additional data file.

The preprint version charged on MedRxiv server.

(DOC) Click here for additional data file.

NGT codified dataset.

(XLSX) Click here for additional data file. 7 Dec 2021
PONE-D-21-20567
Nasogastric tube in critical care setting: combining ETCO2 and pH measuring to confirm correct placement
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For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. We will update your Data Availability statement on your behalf to reflect the information you provide. Additional Editor Comments: The study presents the results of the original research; however, the design has some limitations raised by the reviewers. - The authors should elaborate on the details of randomization, justify no measurement of CO2 and pH, and non-checking the proper position of NGT with Chest X-ray as the standard of care in all patients. - The authors have to justify the validity of measuring oesophagal or gastric CO2. The statistics are not described in sufficient detail. - The authors should carefully address the concerns about sample size calculation and statistical tests and significance raised by the reviewer. The Conclusion is not supported by the data. - The conclusion should be derived from the positive findings of the study. The Methods, Results, and manuscript should follow the CONSORT-statement and checklist. The authors should remove the redundant text throughout the manuscript. The authors should send the next version of the manuscript to a professional Medical English editor who is a native English speaker for substantial English editing and rewriting the manuscript. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Partly Reviewer #2: Partly Reviewer #3: Partly ********** 2. 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The study was approved by the respective IRB/Ethics Committee, and has a valid NCT number (registered within clinicaltrials.org). While the study objectives sound interesting, is important, and on target, a number of shortcomings were observed, in regards to abiding by the CONSORT guidelines for conducting and reporting results of high-quality trials. Some other (statistical) comments were also added. 1. Methods: Methods reporting require an orderly manner following CONSORT guidelines, without repeating information, such as Trial Design, Participant Eligibility criteria and settings, Interventions, Outcomes, sample size/power considerations, Interim analysis and stopping rules. Randomization (details on random number generation, allocation concealment, implementation), and Blinding considerations should be mentioned explicitly. The authors are advised to create separate subsections for each of the possible topics (whichever necessary), and that way produce a very clear writeup. I see the Authors already made a sincere attempt; however, they are advised to write it carefully, following nice examples in the manuscript below: https://www.sciencedirect.com/science/article/pii/S0889540619300010 Specific comments below: (a) For instance, the randomization and allocation concealment should be made very clear (they are NOT the same thing); the trial staff recruiting patients should NOT have the randomization list. Randomization should be prepared by the trial statistician, and he/she would not participate in the recruiting. (b) More details on randomization needed, like what methods were used. Was it block randomization? (c) Sample size/Power: The study objectives doesn't compare between the two arms (ETCO2 and pH), but actually compares between the tracheal and esophageal measures for the ETCO2 (and similar groups, gastric and esophageal, for pH). The sample sizes were thus computed "within ETCO2", or "within pH" groups. Also, two sets of values (tracheal & esophageal) were obtained from same patients, for both arms. However, in the sample size/power calculations, authors do not mention the statistical test used, as well as the desired effect size they wanted to power the study upon. I assume, some paired tests used (given that 2 measures were taken for the same subjects)? This needs to be made clear. It is also not clear if study was powered based on the primary outcomes within both groups. (d) Statistical Analysis: I do not understand the justification of using a z-test at 1% significance (over a t-test at 5% significance). Also, exactly what test was used (a paired test, or something else) needs to be specified, given that same subjects were used to generate responses, corresponding to tracheal vs esophageal groups. 3. Results: (a) The authors should check that any statement of significance should be followed by a p-value in the entire Results section. Otherwise, it looks OK. 4. Conclusions and Discussion: (a) Writeup should reflect that study findings from this trial are based on only a sample (Swiss) population, and allude to future studies enrolling more centers/hospitals, or geographical regions for a more robust analysis, and validation of the current findings. Reviewer #2: This manuscript describes the results of a prospective multicenter (in fact bi-center) observational trial aiming to determine the accuracy of "EtCO2" and pH measurements during nasogastric tube (NGT) placement in critical care setting to predict right position. If the research question is appropriate, I have some concerns about the method and the description of results. First of all, the title includes some wrong informations: "critical care setting" = Most of patients are enrolled in an anesthesia setting; "combining" = the 2 technics are studied separately in 2 distinguished groups. Furthermore, ETCO2 is End tidal CO2 usually used for the CO2 measurement in respiratory airway at the end of expiration and I am not sure it is applicable to esophageal or gastric CO2 measurement. The authors stated that chest X-rays, the gold standard to confirm correct placement of the NGT, have serious downsides (mobilization and exposure to ionising radiation). This is not completely false but chest X-rays are also useful for many other reasons in ICU and this exam can be done once for all. The aim to find an alternative technic useful at the bed side and immediately is probably interesting. In several places in the manuscript, the authors talk about the combine measurement of EtCO2 and pH but it is clear that the patients were randomly assigned either to EtCO2 monitoring in the tracheal tube and in the NGT or to the pH determination in esophageal and gastric position. The main major concerns about method are: - How was assessed the correct position in both groups?: no comparison with the gold standard technic is described. - "Patients in whom pH and/or ETCO2 values were not measurable for technical reasons were excluded and considered as drop-outs": It seems like 17 patients were excluded with reference to figure 1 and the number of analyzed patients. Of note, there is probably a mistake in the line 152 stating "19 dropouts occurred". The failure rate is high (17 out of 85, 20%) and should be taken in consideration to balance the conclusion. But I should recommend to include these patients in this analysis as a failure of the technic when compared to the gold standard. Here this is a serious biais but not highlighted in the limitation section. - the correct placement or misplacement of the NGT should be considered by the difference between tracheal and esophageal EtCO2 value or between esophageal and gastric pH values and the respective predictive values should be compared to the chest X-ray as a gold standard. The incidence of tracheal or esophageal misplacement should be given for meaningful interpretation. Minor comments: - several abbreviations are not described before first use - How was the randomization process run out in both centers with allocation of group B patients only in one center? - The number of patients in each group should be reported in the title column of the table. The comparison between the groups was not planed in the method and not applicable in most variables. Is it really useful? - There is some repetitions in results between text and tables or figures. For the same variable, mean or median values are given here and there which is disturbing. Given the small population, it would be preferable to describe the variables in medians with interquartiles - Discussion, line 229: "Our study combines these two techniques": In this study the 2 technics were studied separately in 2 groups and not combined together - There is very few comparisons of the results with the literature in the discussion section, maybe due to the lack of data in this field... - The conclusion is about an hypothesis on the interest of "a device capable of combine the presence of a negative marker to exclude NGT misplacement (like ETCO2) and a positive marker to confirm correct NGT placement (as pH evaluation)". This is not directly issued from the results of the study but more a next step of research. Reviewer #3: - Relevant topic and objective, worth while studying, good ideas, nice graphics - But English language is not OK and is compromising the understanding of the article and study by the reader. English language needs to be reviewed both grammatically as with respect of appropriate use in the context of the study. Evident errors or improper word use are highlighted in yellow in an edited PDF version. From time to time I inserted suggestions in textboxes with red characters. - The study design could have been much better. There are 2 major weaknesses that could easily have been addressed by a more careful study design. 1. why were both measurements (EtCO2 and pH) not performed in all patients and measurements analysed separately; this would have allowed to directly compare both methods. 2. Why was Chest Xray not described and used as a gold standard to be compared with the results of EtCO2 and pH? Are chest X rays available? if sufficiently available why not incorporate in these in an additional analysis and revised article?; I leave it to the editor to decide if such would be advised. - Abstract reflects insufficiently the study; conclusions in abstract not coherent with methods and study results - It looks to me as if the use of combined measurement (positive/negative prediction) is a late and awkward interpretation of the results and could have been addressed in a prospective (intentional) way. The advantage of the combined use of both methods is not supported by the way the study is done and described. Furthermore taking the absolute discriminative power of EtCO2 into account the advantage of adding a second method (pH practically inferior) is not clear to me and should be better clarified. - The EtCO2 method has been recently described in a publication and may therefore have escaped the attention of the writers. This should be referenced and discussed in a revised version. Therefore I recommend thorough revision of the paper. See attachments 1- annotated PDF version 2- Word document ********** 6. 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 #1: No Reviewer #2: No Reviewer #3: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. Submitted filename: review NG paper PR.docx Click here for additional data file. Submitted filename: PONE-D-21-20567-FB PR.pdf Click here for additional data file. 25 Jan 2022 Dear Dr. Emily Chenette, On behalf of my co-authors, I have the pleasure to submit the answers to your reviewers’ comments. We appreciated the reviewers’ suggestions that allow us to clarify our key message. Please note that we have uploaded the two versions of the revised manuscript, one in which the new paragraphs were highlighted and an unmarked version, as required. We also uploaded the anonymized data set as Supporting Information file so that the access to our database is provided; all the files meet PLOS ONE’s style requirements. ACADEMIC EDITOR: • The study presents the results of the original research; however, the design has some limitations raised by the reviewers. The authors should elaborate on the details of randomization, justify no measurement of CO2 and pH, and non-checking the proper position of NGT with Chest X-ray as the standard of care in all patients. The authors have to justify the validity of measuring oesophagal or gastric CO2. We thank the editor for this important aspect. As reported by the reviewers, the study was intended as a prospective, multicenter, observational trial, without any randomization. This design was already reported both in the original protocol than on clinicaltrials.gov (NCT03934515). The study was an “allocation within sites” (line 93); the typo regarding randomization that has been entered in the Methods section was removed and modified according to the observational nature of the study (lines 93-98). • The statistics are not described in sufficient detail. The authors should carefully address the concerns about sample size calculation and statistical tests and significance raised by the reviewer. We appreciate the opportunity to clarify this important aspect of the manuscript. The power analysis/sample size was based on the primary outcomes within each group. Due to the design of the study (two sets of values for each patient), a paired t-test was used to make comparisons. According to reviewers’ suggestion, we have deepened and improved the power analysis session, underlining how the study objectives did not compare between the two arms, but actually compared between the tracheal and esophageal measures for the etCO2 and similarly, gastric and esophageal for pH (lines 132-7 and 141-147). Moreover, according to the reviewers’ suggestion, we added the explanation that we utilized one-side paired t-tests, given the nature of the study design, as explained above (lines 127-141). Given the distribution of normal values, and since these are diagnostic tests for which an error of 5% would be too high in relation to a possible position error of the NGT placement, we preferred to run tests and accept them as valid using even more stringent criteria like 1%. • The Conclusion is not supported by the data. The conclusion should be derived from the positive findings of the study. We thank the editor for this important aspect. According to reviewers’ suggestion, the Conclusions section in the abstract and in the main text were both revised and made more consistent with the results and discussion. • The Methods, Results, and manuscript should follow the CONSORT-statement and checklist. We thank the editor for this suggestion. As reported by the reviewers, the study was intended as a prospective, multicenter, observational trial, without any randomization; this pilot study was an “allocation within sites” study (lines 93-98), without randomization process; in this scenario, the CONSORT-statement and checklist was not adequate for this kind of trial. • The authors should remove the redundant text throughout the manuscript. We thank the editor for this suggestion; we’ve removed the redundant text throughout the entire manuscript. • The authors should send the next version of the manuscript to a professional Medical English editor who is a native English speaker for substantial English editing and rewriting the manuscript. We thank the editor for this suggestion; we took note of the grammar suggestions and arranged for a further linguistic revision to be carried out by an English native speaker. Reviewer #1 The objective of this prospective, multicenter, observational trial is to determine thresholds in combine measurements of ETCO2 and pH values. The study was approved by the respective IRB/Ethics Committee, and has a valid NCT number (registered within clinicaltrials.org). While the study objectives sound interesting, is important, and on target, a number of shortcomings were observed, in regards to abiding by the CONSORT guidelines for conducting and reporting results of high-quality trials. Some other (statistical) comments were also added. 1. Methods: Methods reporting require an orderly manner following CONSORT guidelines, without repeating information, such as Trial Design, Participant Eligibility criteria and settings, Interventions, Outcomes, sample size/power considerations, Interim analysis and stopping rules. Randomization (details on random number generation, allocation concealment, implementation), and Blinding considerations should be mentioned explicitly. The authors are advised to create separate subsections for each of the possible topics (whichever necessary), and that way produce a very clear writeup. I see the Authors already made a sincere attempt; however, they are advised to write it carefully, following nice examples in the manuscript below: https://www.sciencedirect.com/science/article/pii/S0889540619300010 Response: We thank the reviewer for this important aspect. As reported by the reviewer, the study was intended as a prospective, multicenter, observational trial, without any randomization. This design was already reported both in the original protocol than on clinicaltrials.gov (NCT03934515). The typo that has been entered in the Methods section was removed and modified according to the observational nature of the study (lines 93-98). Specific comments below: (a) For instance, the randomization and allocation concealment should be made very clear (they are NOT the same thing); the trial staff recruiting patients should NOT have the randomization list. Randomization should be prepared by the trial statistician, and he/she would not participate in the recruiting. Response: We thank the reviewer for this important aspect. As reported before, the study was intended as a prospective, multicenter, observational trial, without randomization, as reported both in the original protocol than on clinicaltrials.gov (NCT03934515). The study was an “allocation within sites”; the typo regarding randomization that has been entered in the Methods section was removed and modified according to the observational nature of the study (lines 93-98). (b) More details on randomization needed, like what methods were used. Was it block randomization? Response: We thank the reviewer for this aspect; as discussed before, this was a study with an “allocation within sites” (lines 93-98), without randomization process. (c) Sample size/Power: The study objectives doesn't compare between the two arms (ETCO2 and pH), but actually compares between the tracheal and esophageal measures for the ETCO2 (and similar groups, gastric and esophageal, for pH). The sample sizes were thus computed "within ETCO2", or "within pH" groups. Also, two sets of values (tracheal & esophageal) were obtained from same patients, for both arms. However, in the sample size/power calculations, authors do not mention the statistical test used, as well as the desired effect size they wanted to power the study upon. I assume, some paired tests used (given that 2 measures were taken for the same subjects)? This needs to be made clear. It is also not clear if study was powered based on the primary outcomes within both groups. Response: We appreciate the opportunity to clarify this important aspect of the manuscript. The power analysis/sample size was based on the primary outcomes within each group. Due to the design of the study (two sets of values for each patient), a paired t-test was used to make comparisons. According to reviewer’s suggestion, we have deepened and improved the power analysis session, underlining how the study objectives did not compare between the two arms, but actually compared between the tracheal and esophageal measures for the etCO2 and similarly, gastric and esophageal for pH (lines 127-137 and 143-149). (d) Statistical Analysis: I do not understand the justification of using a z-test at 1% significance (over a t-test at 5% significance). Also, exactly what test was used (a paired test, or something else) needs to be specified, given that same subjects were used to generate responses, corresponding to tracheal vs esophageal groups. Response: We thank the reviewer for this important aspect. According to the reviewer’s suggestion, we added the explanation that we utilized one-side paired t-tests, given the nature of the study design, as explained above (lines 127-137). Given the distribution of normal values, and since these are diagnostic tests for which an error of 5% would be too high in relation to a possible position error of the NGT placement, we preferred to run tests and accept them as valid using even more stringent criteria like 1%. 3. Results: (a) The authors should check that any statement of significance should be followed by a p-value in the entire Results section. Otherwise, it looks OK. Response: We thank the reviewer for this aspect. We have checked and inserted all p-values in the entire Results section. 4. Conclusions and Discussion: (a) Writeup should reflect that study findings from this trial are based on only a sample (Swiss) population, and allude to future studies enrolling more centers/hospitals, or geographical regions for a more robust analysis, and validation of the current findings. Response: We thank the reviewer for this important consideration; we have inserted this indication in the Discussion, in the limit section (lines 268-270). Reviewer #2 This manuscript describes the results of a prospective multicenter (in fact bi-center) observational trial aiming to determine the accuracy of "EtCO2" and pH measurements during nasogastric tube (NGT) placement in critical care setting to predict right position. If the research question is appropriate, I have some concerns about the method and the description of results. First of all, the title includes some wrong informations: "critical care setting" = Most of patients are enrolled in an anesthesia setting; "combining" = the 2 technics are studied separately in 2 distinguished groups. Furthermore, ETCO2 is End tidal CO2 usually used for the CO2 measurement in respiratory airway at the end of expiration and I am not sure it is applicable to esophageal or gastric CO2 measurement. Response: We thank the reviewer for these considerations. According to reviewer suggestions, we changed the title removing "critical care" and focusing on the fact that the patients were on mechanical ventilation (MV). Similarly, for what concerns "combining" in the title, we agree with the reviewer and we have removed it from the title. Concerning the consideration of CO2 measurement, we disagree with the reviewer; although ETCO2 is a ventilator measure, it is known that accidental esophageal intubation events are not infrequent (Benumof JL. Interpretation of capnography. AANA J. 1998 Apr;66(2):169-76. PMID: 9801479). In these cases, it is possible to record ETCO2 values, even if very low, as a diagnostic method to confirm an extra-tracheal intubation. Our study has specifically positioned the CO2 detector to the NGT positioned into the esophagus, in order to measure esophageal CO2 values and to be able to determine the difference with the tracheal CO2 values, in order to analyze the CO2 distribution in the trachea and in the esophagus and then determine a "threshold value" that is able to distinguish with high accuracy the NGT positioning in these different two sites. In several places in the manuscript, the authors talk about the combine measurement of EtCO2 and pH but it is clear that the patients were randomly assigned either to EtCO2 monitoring in the tracheal tube and in the NGT or to the pH determination in esophageal and gastric position. Response: We thank the reviewer for this important consideration; to avoid any misunderstanding, we removed the word “combining” throughout the entire manuscript, to eliminate any confounding factor. The main major concerns about method are: - How was assessed the correct position in both groups?: no comparison with the gold standard technic is described. Response: We appreciate the opportunity to clarify this important aspect of the manuscript. The study method involved open measurements of ETCO2 in the endotracheal tube (trachea site) and in the NGT (esophagus site). Therefore, the different location was chosen by the operator. As for the pH, the use of cm from the dental arch was used for the esophageal (25 cm) and gastric (40 cm) distance, with radiological control as standard. We thank the reviewer for the suggestion and we have implemented this aspect in the text (lines 111-116). - "Patients in whom pH and/or ETCO2 values were not measurable for technical reasons were excluded and considered as drop-outs": It seems like 17 patients were excluded with reference to figure 1 and the number of analyzed patients. Of note, there is probably a mistake in the line 152 stating "19 dropouts occurred". The failure rate is high (17 out of 85, 20%) and should be taken in consideration to balance the conclusion. But I should recommend to include these patients in this analysis as a failure of the technic when compared to the gold standard. Here this is a serious biais but not highlighted in the limitation section. Response: We appreciate the opportunity to clarify another important aspect of the manuscript. According to the reviewer's suggestions, we included this within the boundaries of the study in the conclusions considerations. Again, we modified the typo of the 19 dropouts patients, who actually were 17. We have also further implemented the limit section of on this aspect (lines 276-278). - the correct placement or misplacement of the NGT should be considered by the difference between tracheal and esophageal EtCO2 value or between esophageal and gastric pH values and the respective predictive values should be compared to the chest X-ray as a gold standard. The incidence of tracheal or esophageal misplacement should be given for meaningful interpretation. Response: We thank the reviewer for this important aspect. We agree with the reviewer, but to date there is no "threshold value" for the etCO2, nor for the pH above/below which it is possible to determine with certainty where the NGT was inserted without a chest-X-ray. In this first study we voluntarily measured in two different sites, with the aim to report the different values of etCO2 and pH and then analyze the distribution of the values and determine the thresholds. In a future study we will analyze if, by applying these thresholds we have determined, we are able to obtain results with high accuracy, compared to gold-standard method. Minor comments: - several abbreviations are not described before first use Response: We thank the reviewer for this aspect. We have changed the text by inserting the explanation before the first use of the abbreviation. - How was the randomization process run out in both centers with allocation of group B patients only in one center? Response: We thank the reviewer for this important aspect; the study was not a randomized study, as presented in the clinicaltrials.gov and in the protocol. There was a typo in the method, referred to the allocation and not to the randomization. The study was an “allocation within sites” design. - The number of patients in each group should be reported in the title column of the table. Response: We thank the reviewer for this suggestion, that we have implemented in the table. The comparison between the groups was not planed in the method and not applicable in most variables. Is it really useful? - There is some repetitions in results between text and tables or figures. For the same variable, mean or median values are given here and there which is disturbing. Given the small population, it would be preferable to describe the variables in medians with interquartiles Response: We thank the reviewer for this aspect. We have simplified the text by removing the redundant parts; furthermore, in this specific context, we have simplified table 1 as suggested by the reviewer. - Discussion, line 229: "Our study combines these two techniques": In this study the 2 technics were studied separately in 2 groups and not combined together Response: We thank the reviewer for this important aspect. In the data analysis, we did not compare the two arms, but we compared the data between the tracheal and esophageal measures for the etCO2 and similarly, gastric and esophageal for pH. According to reviewer’s suggestion, we have removed all sentences referred to “combination”. - There is very few comparisons of the results with the literature in the discussion section, maybe due to the lack of data in this field... Response: We thank the reviewer for this suggestion; up today, in the literature there is no similar data; this preliminary study was necessary to implement future studies in which we will build a device capable of combining the two aspects of the two tests we have performed here (etCO2 and pH). In order to carry out these future accuracy studies, through comparison with the gold-standard, it was necessary to have reference values which, not being present in the literature, we measured. We thank the reviewer for his suggestion; we have changed the title, suggesting that this was a pilot study, to furtherly avoid any misunderstanding. - The conclusion is about an hypothesis on the interest of "a device capable of combine the presence of a negative marker to exclude NGT misplacement (like ETCO2) and a positive marker to confirm correct NGT placement (as pH evaluation)". This is not directly issued from the results of the study but more a next step of research. Response: We thank the reviewer for this important aspect. According to reviewer suggestion, we have removed all references to the term "combine" and the conclusions were revised and made more consistent with the results and discussion. Reviewer #3 - Relevant topic and objective, worth while studying, good ideas, nice graphics - But English language is not OK and is compromising the understanding of the article and study by the reader. English language needs to be reviewed both grammatically as with respect of appropriate use in the context of the study. Evident errors or improper word use are highlighted in yellow in an edited PDF version. From time to time I inserted suggestions in textboxes with red characters. Response: We thank the reviewer for this suggestion; we took note of the grammar suggestions and arranged for a further linguistic revision to be carried out by an English native speaker. - The study design could have been much better. There are 2 major weaknesses that could easily have been addressed by a more careful study design. 1. why were both measurements (EtCO2 and pH) not performed in all patients and measurements analysed separately; this would have allowed to directly compare both methods. 2. Why was Chest Xray not described and used as a gold standard to be compared with the results of EtCO2 and pH? Are chest X rays available? if sufficiently available why not incorporate in these in an additional analysis and revised article?; I leave it to the editor to decide if such would be advised. Response: We appreciate the opportunity to clarify this important aspect of the manuscript. On an ethical and organizational level during the pandemic wave, it was easier to organize only one measurement per patient (etCO2 or pH); in order to avoid overlapping or excessive measurements, with the risk of data confusion and excessive investment of time for each patient during the anesthetic routine, it was preferred to act on each individual patient with only one pair of measurements - tracheal and esophageal measurements for the ETCO2 and gastric and esophageal measurements for pH. The comparison between methods was not studied because we developed a preliminary study to try to obtain threshold values for each method rather than a comparison between methods. For the chest-x-ray (CXR), it was not performed to all patients: as regards the oro-tracheal intubation in the operating room, it was not performed as this procedure is not standard of care. As far as the positioning of the NGT is concerned, we have implemented this aspect by better emphasizing the lack of CXR only in a certain group of patients. - Abstract reflects insufficiently the study; conclusions in abstract not coherent with methods and study results Response: We thank the reviewer for this important aspect; we proceeded to modify the abstract, making the conclusions more consistent with the results of the text. - It looks to me as if the use of combined measurement (positive/negative prediction) is a late and awkward interpretation of the results and could have been addressed in a prospective (intentional) way. The advantage of the combined use of both methods is not supported by the way the study is done and described. Furthermore taking the absolute discriminative power of EtCO2 into account the advantage of adding a second method (pH practically inferior) is not clear to me and should be better clarified. Response: We appreciate the opportunity to clarify this important aspect of the manuscript. Using etCO2 is a great discriminatory method, but it simply allows you to say "you are not in the trachea". It gives no confirmation that it is in the stomach. In this sense, we intended it as a “negative marker”: it allows to identify a mispositioning, but it does not confirm a correct positioning. In this sense it is necessary to identify a method capable of positively confirming the positioning in the stomach, hence the study with the pH in addition to the etCO2. As for the “awkward results”, the method has been specially designed in this way before starting the study. Since in the literature it is not possible to confirm the positioning of the NGT in the stomach with high accuracy (except with CXR), our hypothesis is that it is necessary to put together several methods. One of these (etCO2) is a "negative" method, ie capable of detecting mispositioning with high accuracy. Another of these (the pH) is intended as a "positive" method, capable of positively confirming the correct positioning of the probe. In this preliminary study we were interested in identifying the values of etCO2 (between trachea / esophagus) and pH (between esophagus / stomach) in order to find diagnostic thresholds. - The EtCO2 method has been recently described in a publication and may therefore have escaped the attention of the writers. This should be referenced and discussed in a revised version. Response We thank the reviewer for these suggestions, even if unfortunately the description of the suggested methodology does not help us in the study we have performed in the determinism of threshold values. Finally, we would like to thank the reviewers and the editor for these suggestions, because we feel that the manuscript has improved substantially. Sincerely, Samuele Ceruti, MD 7 Mar 2022
    PONE-D-21-20567R1
    Nasogastric tube in mechanical ventilated patients: ETCO2 and pH measuring to confirm correct placement. A pilot study.
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Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: (No Response) Reviewer #2: Yes Reviewer #3: Yes ********** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: (No Response) Reviewer #2: Yes Reviewer #3: I Don't Know ********** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). 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You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: (No Response) Reviewer #2: Thanks for the clarification of the study and manuscript Just a comment: in my opinion comparison between the 2 groups seems not useful. Reviewer #3: - minor correction to improve unambiguous wording (formulating) as described/suggested in detail in attachment - minor correction in English language as described in attachment ********** 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 #1: No Reviewer #2: Yes: Philippe Gaudard Reviewer #3: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. 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    Submitted filename: review Nr 2 of Naspgrastric tube positiioning manuscript .docx Click here for additional data file. 25 Apr 2022 Reviewer#2 Thanks for the clarification of the study and manuscript Just a comment: in my opinion comparison between the 2 groups seems not useful. AND Reviewer #3 Introduction: - Lines 67-69. This sentence suggests this will be the objective of the study which – in my opinion – is not the case (as measurements were not combined but used separately in 2 arms Response: We thank the reviewers for this relevant aspect, appreciating the opportunity to clarify this key-point of the manuscript. Effectively, a comparative and associative analysis between the two methods has not been done yet; in this first preliminary paper, it was necessary to determine the threshold values of ETCO2 and pH methods, which has still not reported in peer reviewed paper until today. Once obtained this information, a future paper combining and comparing the two methods will be performed. For this reason, as kindly suggested by the reviewer, we removed indication suggesting any “combination” between two methods, as patients were enrolled in 2 separately arms (lines 65-66, line 73). -Lines Study 71: The latter (measurements were not combined but used separately in 2 arms) should be explicitly mentioned in the aim of the study. Response: We thank the reviewer for this important aspect. According to previous modifications, we have removed all sentences suggesting this “combining aspect” of the paper, implementing in the text that the ETCO2 and pH measurements were 2 complete separate analysis, without any direct comparations (line 73). Methods -Line 104 – 105. As opposed to Group B, NGT positioning was not verified (by Chest X ray). This should be mentioned. Response: We thank the reviewer for this suggestion; we have implemented this aspect in the text. Results -Line 185-186 (T-test pH) redundant with Line 180-181; to be improved Response: We thank the reviewer for this suggestion; we’ve removed the unnecessary text in the figure legend. -Has the effect of gastric hernia and reflux been examined in this subset of patients. If YES report. If NOT consider this adding in the discussion section on limitations of the study. Response: We appreciate the opportunity to clarify this important aspect of the manuscript; unfortunately, the small group size did not allow us to perform further sub-analysis; for this reason, we have not reported these data. We have reported this aspect in the limit section. Discussion -Line 232-233: “…. when applied together”: as this was not the case in this study the authors should be more precise. Furthermore the authors should consider adding an explanation why this was not done (as they explained in their answer to the first review (reviewer #3) Response: We thank the reviewer for this important aspect. Currently, a comparative and associative analysis between the two methods has not been done yet; in this first preliminary paper, it was necessary to determine the threshold values of ETCO2 and pH methods, still not reported in peer reviewed paper until today. Once obtained this information, a future paper combining and comparing the two methods will be performed. Consequently, we have removed any indication or word suggesting any “combination” between two methods. - Grammar corrections into lines 55, 65-66, 115-116, 185, 200, 211, 211-212, 215, 218, 251, 278 Response: We thank the reviewer for all these suggestions. All grammar proposals were evaluated and modified according to reviewer’s hints. Finally, we would like to thank the reviewers and the editor for these suggestions, because we feel that the manuscript has improved substantially. Submitted filename: Response to Reviewers_R2.docx Click here for additional data file. 13 May 2022 Nasogastric tube in mechanical ventilated patients: ETCO2 and pH measuring to confirm correct placement. A pilot study. PONE-D-21-20567R2 Dear Dr. Ceruti, 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. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. 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. Kind regards, Mohamed R. El-Tahan, MD Academic Editor PLOS ONE 24 May 2022 PONE-D-21-20567R2 Nasogastric tube in mechanical ventilated patients: ETCO2 and pH measuring to confirm correct placement. A pilot study. Dear Dr. Ceruti: 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, PLOS ONE Editorial Office Staff on behalf of Professor Mohamed R. El-Tahan Academic Editor PLOS ONE
      32 in total

    Review 1.  pH and concentration of bilirubin in feeding tube aspirates as predictors of tube placement.

    Authors:  D Z Bliss
    Journal:  JPEN J Parenter Enteral Nutr       Date:  2000 May-Jun       Impact factor: 4.016

    Review 2.  Measuring end-tidal carbon dioxide: clinical applications and usefulness.

    Authors:  M A Frakes
    Journal:  Crit Care Nurse       Date:  2001-10       Impact factor: 1.708

    3.  A grey zone for quantitative diagnostic and screening tests.

    Authors:  Joël Coste; Jacques Pouchot
    Journal:  Int J Epidemiol       Date:  2003-04       Impact factor: 7.196

    4.  A novel approach to confirming nasogastric tube placement in the ED.

    Authors:  Linda Nguyen; Resa E Lewiss; Jonathan Drew; Turandot Saul
    Journal:  Am J Emerg Med       Date:  2011-11-17       Impact factor: 2.469

    5.  Effectiveness of the auscultatory and pH methods in predicting feeding tube placement.

    Authors:  Ayşe San Turgay; Leyla Khorshid
    Journal:  J Clin Nurs       Date:  2010-06       Impact factor: 3.036

    6.  Colorimetric carbon dioxide detector to determine accidental tracheal feeding tube placement.

    Authors:  Daniel W Howes; Eric S Shelley; William Pickett
    Journal:  Can J Anaesth       Date:  2005-04       Impact factor: 5.063

    7.  Re: 'Effectiveness of the auscultatory method in predicting feeding tube location'.

    Authors:  N Metheny
    Journal:  Nurs Res       Date:  1992 May-Jun       Impact factor: 2.381

    8.  Index for rating diagnostic tests.

    Authors:  W J YOUDEN
    Journal:  Cancer       Date:  1950-01       Impact factor: 6.860

    9.  Sonography as an alternative to radiography for nasogastric feeding tube location.

    Authors:  Cécile Vigneau; Jean-Luc Baudel; Bertrand Guidet; Georges Offenstadt; Eric Maury
    Journal:  Intensive Care Med       Date:  2005-09-20       Impact factor: 17.440

    Review 10.  Accuracy of biochemical markers for predicting nasogastric tube placement in adults--a systematic review of diagnostic studies.

    Authors:  Ritin S Fernandez; Janita Pak-Chun Chau; David R Thompson; Rhonda Griffiths; Hoi-Shan Lo
    Journal:  Int J Nurs Stud       Date:  2010-08       Impact factor: 5.837
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