抜管後の呼吸補助を選択する方法

Article

Author: Jean-Michel Arnal、上級集中治療専門医、サント・ミュス病院（フランス、トゥーロン）

Date of first publication: 04.12.2023

最近のいくつかの研究において、抜管後呼吸補助は患者のウィーニング失敗のリスクに基づいて選択できることが示唆されています。

WEAN SAFE試験では、組み入れられた患者の14%で抜管失敗（「抜管後7日以内に再挿管が必要」と定義される）が見られました（Pham T, Heunks L, Bellani G, et al. Weaning from mechanical ventilation in intensive care units across 50 countries (WEAN SAFE): a multicentre, prospective, observational cohort study [published correction appears in Lancet Respir Med. 2023 Mar;11(3):e25]. Lancet Respir Med. 2023;11(5):465-476. doi:10.1016/S2213-2600(22)00449-01）。さらに、再挿管された患者の30%が最終的に死亡に至りました。抜管失敗の病態生理は複雑であり、同じ患者で複数のメカニズムが関連していることも少なくありません（Roca O, Blanch L, Hernández G. Postextubation Respiratory Support: One More Piece to the Puzzle. Am J Respir Crit Care Med. 2022;206(12):1437-1438. doi:10.1164/rccm.202208-1485ED2）。再挿管を防ぐために、いくつかのタイプの抜管後呼吸補助が使用できます。最善策は個々の患者に応じて抜管後呼吸補助を行うことですが、最近実施されたいくつかの大規模な無作為化対照試験により、抜管後呼吸補助の方法は抜管失敗のリスクに基づいて選択できることが実証されています（Hernández G, Vaquero C, González P, et al. Effect of Postextubation High-Flow Nasal Cannula vs Conventional Oxygen Therapy on Reintubation in Low-Risk Patients: A Randomized Clinical Trial. JAMA. 2016;315(13):1354-1361. doi:10.1001/jama.2016.27113、Hernández G, Vaquero C, Colinas L, et al. Effect of Postextubation High-Flow Nasal Cannula vs Noninvasive Ventilation on Reintubation and Postextubation Respiratory Failure in High-Risk Patients: A Randomized Clinical Trial [published correction appears in JAMA. 2016 Nov 15;316(19):2047-2048] [published correction appears in JAMA. 2017 Feb 28;317(8):858]. JAMA. 2016;316(15):1565-1574. doi:10.1001/jama.2016.141944、Maggiore SM, Jaber S, Grieco DL, et al. High-Flow Versus VenturiMask Oxygen Therapy to Prevent Reintubation in Hypoxemic Patients after Extubation: A Multicenter Randomized Clinical Trial. Am J Respir Crit Care Med. 2022;206(12):1452-1462. doi:10.1164/rccm.202201-0065OC5、Hernández G, Vaquero C, Ortiz R, et al. Benefit with preventive noninvasive ventilation in subgroups of patients at high-risk for reintubation: a post hoc analysis. J Intensive Care. 2022;10(1):43. Published 2022 Sep 11. doi:10.1186/s40560-022-00635-26、Hernández G, Paredes I, Moran F, et al. Effect of postextubation noninvasive ventilation with active humidification vs high-flow nasal cannula on reintubation in patients at very high risk for extubation failure: a randomized trial [published correction appears in Intensive Care Med. 2023 Mar;49(3):385]. Intensive Care Med. 2022;48(12):1751-1759. doi:10.1007/s00134-022-06919-37）。

非常に低い失敗リスク

再挿管のリスクが非常に低い患者：低流量酸素療法

超低リスクの基準

人工呼吸器装着時間が48時間未満
65歳未満
人工呼吸の主な適応症として心不全がない
COPDがない
抜管当日のAPACHE IIスコアが12ポイント未満
ボディマス指数が30未満
気道開存性の問題がない
呼吸分泌物に対処できる
短いウィーニング（1日以下）
併存疾患が2つ未満

低いまたは中程度の失敗リスク

再挿管のリスクが低いまたは中程度の患者：高流量鼻カニューレ療法

低リスクの基準

人工呼吸器装着時間が7日未満
65歳未満
人工呼吸の主な適応症として心不全がない
COPDがない
抜管当日のAPACHE IIスコアが12ポイント未満
ボディマス指数が30未満
気道開存性の問題がない
呼吸分泌物に対処できる
短いウィーニング（1日以下）
併存疾患が2つ未満

中程度のリスク：以下の基準のいずれかに該当：

65歳以上
人工呼吸の主な適応症として心不全がある
中等度から重度のCOPD
抜管当日のAPACHE IIスコアが12ポイント以上
ボディマス指数が30以上
気道開存性の問題がある（喉頭水腫の発現リスクが高いなど）
呼吸分泌物に対処できない（咳反射が不十分、抜管前8時間以内の吸引回数が3回以上）
中程度または長いウィーニング
2つ以上の併存疾患
人工呼吸器装着時間が7日以上

高い失敗リスク

再挿管のリスクが高い患者：NIV + 48時間のNIVセッションの合間に高流量鼻カニューレ療法（20～50 L/min）

高リスク：以下の基準の4つ以上に該当：

65歳以上
人工呼吸の主な適応症として心不全がある
中等度から重度のCOPD
抜管当日のAPACHE IIスコアが12ポイント以上
ボディマス指数が30以上
気道開存性の問題がある（喉頭水腫の発現リスクが高いなど）
呼吸分泌物に対処できない（咳反射が不十分、抜管前8時間以内の吸引回数が3回以上）
中程度または長いウィーニング
2つ以上の併存疾患
人工呼吸器装着時間が7日以上
ウィーニングトライアル終了時の高炭酸ガス血症（PaCO2 > 45 mmHg）

Footnotes

References

1. Pham T, Heunks L, Bellani G, et al. Weaning from mechanical ventilation in intensive care units across 50 countries (WEAN SAFE): a multicentre, prospective, observational cohort study [published correction appears in Lancet Respir Med. 2023 Mar;11(3):e25]. Lancet Respir Med. 2023;11(5):465-476. doi:10.1016/S2213-2600(22)00449-0
2. Roca O, Blanch L, Hernández G. Postextubation Respiratory Support: One More Piece to the Puzzle. Am J Respir Crit Care Med. 2022;206(12):1437-1438. doi:10.1164/rccm.202208-1485ED
3. Hernández G, Vaquero C, González P, et al. Effect of Postextubation High-Flow Nasal Cannula vs Conventional Oxygen Therapy on Reintubation in Low-Risk Patients: A Randomized Clinical Trial. JAMA. 2016;315(13):1354-1361. doi:10.1001/jama.2016.2711
4. Hernández G, Vaquero C, Colinas L, et al. Effect of Postextubation High-Flow Nasal Cannula vs Noninvasive Ventilation on Reintubation and Postextubation Respiratory Failure in High-Risk Patients: A Randomized Clinical Trial [published correction appears in JAMA. 2016 Nov 15;316(19):2047-2048] [published correction appears in JAMA. 2017 Feb 28;317(8):858]. JAMA. 2016;316(15):1565-1574. doi:10.1001/jama.2016.14194
5. Maggiore SM, Jaber S, Grieco DL, et al. High-Flow Versus VenturiMask Oxygen Therapy to Prevent Reintubation in Hypoxemic Patients after Extubation: A Multicenter Randomized Clinical Trial. Am J Respir Crit Care Med. 2022;206(12):1452-1462. doi:10.1164/rccm.202201-0065OC
6. Hernández G, Vaquero C, Ortiz R, et al. Benefit with preventive noninvasive ventilation in subgroups of patients at high-risk for reintubation: a post hoc analysis. J Intensive Care. 2022;10(1):43. Published 2022 Sep 11. doi:10.1186/s40560-022-00635-2
7. Hernández G, Paredes I, Moran F, et al. Effect of postextubation noninvasive ventilation with active humidification vs high-flow nasal cannula on reintubation in patients at very high risk for extubation failure: a randomized trial [published correction appears in Intensive Care Med. 2023 Mar;49(3):385]. Intensive Care Med. 2022;48(12):1751-1759. doi:10.1007/s00134-022-06919-3

Weaning from mechanical ventilation in intensive care units across 50 countries (WEAN SAFE): a multicentre, prospective, observational cohort study.

Pham T, Heunks L, Bellani G, et al. Weaning from mechanical ventilation in intensive care units across 50 countries (WEAN SAFE): a multicentre, prospective, observational cohort study [published correction appears in Lancet Respir Med. 2023 Mar;11(3):e25]. Lancet Respir Med. 2023;11(5):465-476. doi:10.1016/S2213-2600(22)00449-0

https://pubmed.ncbi.nlm.nih.gov/36693401/

BACKGROUND Current management practices and outcomes in weaning from invasive mechanical ventilation are poorly understood. We aimed to describe the epidemiology, management, timings, risk for failure, and outcomes of weaning in patients requiring at least 2 days of invasive mechanical ventilation. METHODS WEAN SAFE was an international, multicentre, prospective, observational cohort study done in 481 intensive care units in 50 countries. Eligible participants were older than 16 years, admitted to a participating intensive care unit, and receiving mechanical ventilation for 2 calendar days or longer. We defined weaning initiation as the first attempt to separate a patient from the ventilator, successful weaning as no reintubation or death within 7 days of extubation, and weaning eligibility criteria based on positive end-expiratory pressure, fractional concentration of oxygen in inspired air, and vasopressors. The primary outcome was the proportion of patients successfully weaned at 90 days. Key secondary outcomes included weaning duration, timing of weaning events, factors associated with weaning delay and weaning failure, and hospital outcomes. This study is registered with ClinicalTrials.gov, NCT03255109. FINDINGS Between Oct 4, 2017, and June 25, 2018, 10 232 patients were screened for eligibility, of whom 5869 were enrolled. 4523 (77·1%) patients underwent at least one separation attempt and 3817 (65·0%) patients were successfully weaned from ventilation at day 90. 237 (4·0%) patients were transferred before any separation attempt, 153 (2·6%) were transferred after at least one separation attempt and not successfully weaned, and 1662 (28·3%) died while invasively ventilated. The median time from fulfilling weaning eligibility criteria to first separation attempt was 1 day (IQR 0-4), and 1013 (22·4%) patients had a delay in initiating first separation of 5 or more days. Of the 4523 (77·1%) patients with separation attempts, 2927 (64·7%) had a short wean (≤1 day), 457 (10·1%) had intermediate weaning (2-6 days), 433 (9·6%) required prolonged weaning (≥7 days), and 706 (15·6%) had weaning failure. Higher sedation scores were independently associated with delayed initiation of weaning. Delayed initiation of weaning and higher sedation scores were independently associated with weaning failure. 1742 (31·8%) of 5479 patients died in the intensive care unit and 2095 (38·3%) of 5465 patients died in hospital. INTERPRETATION In critically ill patients receiving at least 2 days of invasive mechanical ventilation, only 65% were weaned at 90 days. A better understanding of factors that delay the weaning process, such as delays in weaning initiation or excessive sedation levels, might improve weaning success rates. FUNDING European Society of Intensive Care Medicine, European Respiratory Society.

Postextubation Respiratory Support: One More Piece to the Puzzle.

Roca O, Blanch L, Hernández G. Postextubation Respiratory Support: One More Piece to the Puzzle. Am J Respir Crit Care Med. 2022;206(12):1437-1438. doi:10.1164/rccm.202208-1485ED

https://pubmed.ncbi.nlm.nih.gov/36018568/

Effect of Postextubation High-Flow Nasal Cannula vs Conventional Oxygen Therapy on Reintubation in Low-Risk Patients: A Randomized Clinical Trial.

Hernández G, Vaquero C, González P, et al. Effect of Postextubation High-Flow Nasal Cannula vs Conventional Oxygen Therapy on Reintubation in Low-Risk Patients: A Randomized Clinical Trial. JAMA. 2016;315(13):1354-1361. doi:10.1001/jama.2016.2711

Link to article

IMPORTANCE Studies of mechanically ventilated critically ill patients that combine populations that are at high and low risk for reintubation suggest that conditioned high-flow nasal cannula oxygen therapy after extubation improves oxygenation compared with conventional oxygen therapy. However, conclusive data about reintubation are lacking. OBJECTIVE To determine whether high-flow nasal cannula oxygen therapy is superior to conventional oxygen therapy for preventing reintubation in mechanically ventilated patients at low risk for reintubation. DESIGN, SETTING, AND PARTICIPANTS Multicenter randomized clinical trial conducted between September 2012 and October 2014 in 7 intensive care units (ICUs) in Spain. Participants were 527 adult critical patients at low risk for reintubation who fulfilled criteria for planned extubation. Low risk for reintubation was defined as younger than 65 years; Acute Physiology and Chronic Health Evaluation II score less than 12 on day of extubation; body mass index less than 30; adequate secretions management; simple weaning; 0 or 1 comorbidity; and absence of heart failure, moderate-to-severe chronic obstructive pulmonary disease, airway patency problems, and prolonged mechanical ventilation. INTERVENTIONS Patients were randomized to undergo either high-flow or conventional oxygen therapy for 24 hours after extubation. MAIN OUTCOMES AND MEASURES The primary outcome was reintubation within 72 hours, compared with the Cochran-Mantel-Haenszel χ2 test. Secondary outcomes included postextubation respiratory failure, respiratory infection, sepsis and multiorgan failure, ICU and hospital length of stay and mortality, adverse events, and time to reintubation. RESULTS Of 527 patients (mean age, 51 years [range, 18-64]; 62% men), 264 received high-flow therapy and 263 conventional oxygen therapy. Reintubation within 72 hours was less common in the high-flow group (13 patients [4.9%] vs 32 [12.2%] in the conventional group; absolute difference, 7.2% [95% CI, 2.5% to 12.2%]; P = .004). Postextubation respiratory failure was less common in the high-flow group (22/264 patients [8.3%] vs 38/263 [14.4%] in the conventional group; absolute difference, 6.1% [95% CI, 0.7% to 11.6%]; P = .03). Time to reintubation was not significantly different between groups (19 hours [interquartile range, 12-28] in the high-flow group vs 15 hours [interquartile range, 9-31] in the conventional group; absolute difference, -4 [95% CI, -54 to 46]; P = .66]. No adverse effects were reported. CONCLUSIONS AND RELEVANCE Among extubated patients at low risk for reintubation, the use of high-flow nasal cannula oxygen compared with conventional oxygen therapy reduced the risk of reintubation within 72 hours. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01191489.

Effect of Postextubation High-Flow Nasal Cannula vs Noninvasive Ventilation on Reintubation and Postextubation Respiratory Failure in High-Risk Patients: A Randomized Clinical Trial.

Hernández G, Vaquero C, Colinas L, et al. Effect of Postextubation High-Flow Nasal Cannula vs Noninvasive Ventilation on Reintubation and Postextubation Respiratory Failure in High-Risk Patients: A Randomized Clinical Trial [published correction appears in JAMA. 2016 Nov 15;316(19):2047-2048] [published correction appears in JAMA. 2017 Feb 28;317(8):858]. JAMA. 2016;316(15):1565-1574. doi:10.1001/jama.2016.14194

Link to article

Importance High-flow conditioned oxygen therapy delivered through nasal cannulae and noninvasive mechanical ventilation (NIV) may reduce the need for reintubation. Among the advantages of high-flow oxygen therapy are comfort, availability, lower costs, and additional physiopathological mechanisms. Objective To test if high-flow conditioned oxygen therapy is noninferior to NIV for preventing postextubation respiratory failure and reintubation in patients at high risk of reintubation. Design, Setting, and Participants Multicenter randomized clinical trial in 3 intensive care units in Spain (September 2012-October 2014) including critically ill patients ready for planned extubation with at least 1 of the following high-risk factors for reintubation: older than 65 years; Acute Physiology and Chronic Health Evaluation II score higher than 12 points on extubation day; body mass index higher than 30; inadequate secretions management; difficult or prolonged weaning; more than 1 comorbidity; heart failure as primary indication for mechanical ventilation; moderate to severe chronic obstructive pulmonary disease; airway patency problems; or prolonged mechanical ventilation. Interventions Patients were randomized to undergo either high-flow conditioned oxygen therapy or NIV for 24 hours after extubation. Main Outcomes and Measures Primary outcomes were reintubation and postextubation respiratory failure within 72 hours. Noninferiority margin was 10 percentage points. Secondary outcomes included respiratory infection, sepsis, and multiple organ failure, length of stay and mortality; adverse events; and time to reintubation. Results Of 604 patients (mean age, 65 [SD, 16] years; 388 [64%] men), 314 received NIV and 290 high-flow oxygen. Sixty-six patients (22.8%) in the high-flow group vs 60 (19.1%) in the NIV group were reintubation (absolute difference, -3.7%; 95% CI, -9.1% to ∞); 78 patients (26.9%) in the high-flow group vs 125 (39.8%) in the NIV group experienced postextubation respiratory failure (risk difference, 12.9%; 95% CI, 6.6% to ∞) [corrected]. Median time to reintubation did not significantly differ: 26.5 hours (IQR, 14-39 hours) in the high-flow group vs 21.5 hours (IQR, 10-47 hours) in the NIV group (absolute difference, -5 hours; 95% CI, -34 to 24 hours). Median postrandomization ICU length of stay was lower in the high-flow group, 3 days (IQR, 2-7) vs 4 days (IQR, 2-9; P=.048). Other secondary outcomes were similar in the 2 groups. Adverse effects requiring withdrawal of the therapy were observed in none of patients in the high-flow group vs 42.9% patients in the NIV group (P < .001). Conclusions and Relevance Among high-risk adults who have undergone extubation, high-flow conditioned oxygen therapy was not inferior to NIV for preventing reintubation and postextubation respiratory failure. High-flow conditioned oxygen therapy may offer advantages for these patients. Trial Registration clinicaltrials.gov Identifier: NCT01191489.

High-Flow Versus VenturiMask Oxygen Therapy to Prevent Reintubation in Hypoxemic Patients after Extubation: A Multicenter Randomized Clinical Trial.

Maggiore SM, Jaber S, Grieco DL, et al. High-Flow Versus VenturiMask Oxygen Therapy to Prevent Reintubation in Hypoxemic Patients after Extubation: A Multicenter Randomized Clinical Trial. Am J Respir Crit Care Med. 2022;206(12):1452-1462. doi:10.1164/rccm.202201-0065OC

https://pubmed.ncbi.nlm.nih.gov/35849787/

Rationale: When compared with VenturiMask after extubation, high-flow nasal oxygen provides physiological advantages. Objectives: To establish whether high-flow oxygen prevents endotracheal reintubation in hypoxemic patients after extubation, compared with VenturiMask. Methods: In this multicenter randomized trial, 494 patients exhibiting PaO2:FiO2 ratio ⩽ 300 mm Hg after extubation were randomly assigned to receive high-flow or VenturiMask oxygen, with the possibility to apply rescue noninvasive ventilation before reintubation. High-flow use in the VenturiMask group was not permitted. Measurements and Main Results: The primary outcome was the rate of reintubation within 72 hours according to predefined criteria, which were validated a posteriori by an independent adjudication committee. Main secondary outcomes included reintubation rate at 28 days and the need for rescue noninvasive ventilation according to predefined criteria. After intubation criteria validation (n = 492 patients), 32 patients (13%) in the high-flow group and 27 patients (11%) in the VenturiMask group required reintubation at 72 hours (unadjusted odds ratio, 1.26 [95% confidence interval (CI), 0.70-2.26]; P = 0.49). At 28 days, the rate of reintubation was 21% in the high-flow group and 23% in the VenturiMask group (adjusted hazard ratio, 0.89 [95% CI, 0.60-1.31]; P = 0.55). The need for rescue noninvasive ventilation was significantly lower in the high-flow group than in the VenturiMask group: at 72 hours, 8% versus 17% (adjusted hazard ratio, 0.39 [95% CI, 0.22-0.71]; P = 0.002) and at 28 days, 12% versus 21% (adjusted hazard ratio, 0.52 [95% CI, 0.32-0.83]; P = 0.007). Conclusions: Reintubation rate did not significantly differ between patients treated with VenturiMask or high-flow oxygen after extubation. High-flow oxygen yielded less frequent use of rescue noninvasive ventilation. Clinical trial registered with www.clinicaltrials.gov (NCT02107183).

Benefit with preventive noninvasive ventilation in subgroups of patients at high-risk for reintubation: a post hoc analysis.

Hernández G, Vaquero C, Ortiz R, et al. Benefit with preventive noninvasive ventilation in subgroups of patients at high-risk for reintubation: a post hoc analysis. J Intensive Care. 2022;10(1):43. Published 2022 Sep 11. doi:10.1186/s40560-022-00635-2

https://pubmed.ncbi.nlm.nih.gov/36089625/

BACKGROUND High-flow nasal cannula (HFNC) was shown to be non-inferior to noninvasive ventilation (NIV) for preventing reintubation in a general population of high-risk patients. However, some subgroups of high-risk patients might benefit more from NIV. We aimed to determine whether the presence of many risk factors or overweight (body mass index (BMI) ≥ 25 kg/m2) patients could have different response to any preventive therapy, NIV or HFNC in terms of reduced reintubation rate. METHODS Not pre-specified post hoc analysis of a multicentre, randomized, controlled, non-inferiority trial comparing NFNC and NIV to prevent reintubation in patients at risk for reintubation. The original study included patients with at least 1 risk factor for reintubation. RESULTS Among 604 included in the original study, 148 had a BMI ≥ 25 kg/m2. When adjusting for potential covariates, patients with ≥ 4 risk factors (208 patients) presented a higher risk for reintubation (OR 3.4 [95%CI 2.16-5.35]). Patients with ≥ 4 risk factors presented lower reintubation rates when treated with preventive NIV (23.9% vs 45.7%; P = 0.001). The multivariate analysis of overweight patients, adjusted for covariates, did not present a higher risk for reintubation (OR 1.37 [95%CI 0.82-2.29]). However, those overweight patients presented an increased risk for reintubation when treated with preventive HFNC (OR 2.47 [95%CI 1.18-5.15]). CONCLUSIONS Patients with ≥ 4 risk factors for reintubation may benefit more from preventive NIV. Based on this result, HFNC may not be the optimal preventive therapy in overweight patients. Specific trials are needed to confirm these results.

Effect of postextubation noninvasive ventilation with active humidification vs high-flow nasal cannula on reintubation in patients at very high risk for extubation failure: a randomized trial.

Hernández G, Paredes I, Moran F, et al. Effect of postextubation noninvasive ventilation with active humidification vs high-flow nasal cannula on reintubation in patients at very high risk for extubation failure: a randomized trial [published correction appears in Intensive Care Med. 2023 Mar;49(3):385]. Intensive Care Med. 2022;48(12):1751-1759. doi:10.1007/s00134-022-06919-3

https://pubmed.ncbi.nlm.nih.gov/36400984/

PURPOSE High-flow nasal cannula (HFNC) oxygen therapy was noninferior to noninvasive ventilation (NIV) for preventing reintubation in a heterogeneous population at high-risk for extubation failure. However, outcomes might differ in certain subgroups of patients. Thus, we aimed to determine whether NIV with active humidification is superior to HFNC in preventing reintubation in patients with ≥ 4 risk factors (very high risk for extubation failure). METHODS Randomized controlled trial in two intensive care units in Spain (June 2020‒June 2021). Patients ready for planned extubation with ≥ 4 of the following risk factors for reintubation were included: age > 65 years, Acute Physiology and Chronic Health Evaluation II score > 12 on extubation day, body mass index > 30, inadequate secretions management, difficult or prolonged weaning, ≥ 2 comorbidities, acute heart failure indicating mechanical ventilation, moderate-to-severe chronic obstructive pulmonary disease, airway patency problems, prolonged mechanical ventilation, or hypercapnia on finishing the spontaneous breathing trial. Patients were randomized to undergo NIV with active humidification or HFNC for 48 h after extubation. The primary outcome was reintubation rate within 7 days after extubation. Secondary outcomes included postextubation respiratory failure, respiratory infection, sepsis, multiorgan failure, length of stay, mortality, adverse events, and time to reintubation. RESULTS Of 182 patients (mean age, 60 [standard deviation (SD), 15] years; 117 [64%] men), 92 received NIV and 90 HFNC. Reintubation was required in 21 (23.3%) patients receiving NIV vs 35 (38.8%) of those receiving HFNC (difference -15.5%; 95% confidence interval (CI) -28.3 to -1%). Hospital length of stay was lower in those patients treated with NIV (20 [12‒36.7] days vs 26.5 [15‒45] days, difference 6.5 [95%CI 0.5-21.1]). No additional differences in the other secondary outcomes were observed. CONCLUSIONS Among adult critically ill patients at very high-risk for extubation failure, NIV with active humidification was superior to HFNC for preventing reintubation.

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人工呼吸からのウィーニングにおける現在の管理慣行とアウトカム

最近公表されたある文献で、ICU患者でのウィーニングの管理とアウトカムについて調査した過去最大規模の国際研究の結果が報告されました。