“The Yentl Syndrome” coined in 1991 by Bernadine Healy is the different course of action that the treating physicians usually follow for women than for men (1,2). The name is taken from the 1983 film Yentl starring Barbra Streisand in which her character plays the role of a male in order to attend school and study the Talmud. Being "just like a man" has historically been a price women have had to pay for equality. Throughout the centuries women, considered different and second-class from men, have too often been treated less than equally in various aspects of life, including education and health care (2). Bernadine Healy (1) pointed out in an editorial for the two studies (3,4) published in the same journal demonstrating that women who are hospitalized for coronary heart disease undergo fewer major diagnostic and therapeutic procedures than men as physicians pursue a less aggressive management approach in women than in men, despite greater cardiac disability in women.
Later, two studies (5,6) demonstrate under-treatment of women with medication, including lower rates of aspirin and ACE inhibitor use in stable women compared with men, as well lower rates of ACE inhibitor, beta-blocker and statin medication in acute coronary syndrome women compared with men. Both studies also show gender differences in use of procedures, where stable women undergo more repeat angiography, whereas acute coronary syndrome women undergo fewer angiograms, percutaneous coronary interventions and coronary artery bypass graft procedures compared with their male counterparts.
Prevalence data for childhood asthma in Switzerland suggest a substantial underdiagnosis which seems to be more pronounced in girls (7). Furthermore, women aged 46 to 60 years had less than half the chance of receiving a transplant when compared with men of the same age and race (8).
Recently, it has been reported (9) that patient gender influences diagnosis of idiopathic pulmonary fibrosis (IPF). Sixty clinical cases collected from a single centre, were scored by 404 physicians from 76 countries for a total of 24240 physician-case evaluations. Using clinical information, physicians were asked to provide up to five diagnoses, together with their diagnostic confidence.
A diagnosis of IPF was made significantly more frequently in male patients compared with female (37.8% vs 10.6%; p<0.0001), and with greater mean diagnostic confidence (p<0.001). The odds of a male patient receiving an IPF diagnosis was greater than that of female patients, after adjusting for confounders (OR=3.05, 95% CI: 2.81 to 3.31), especially if the scan was not definite for the usual interstitial pneumonia (UIP) pattern. This was true whether IPF was listed as a first choice or second-choice diagnosis. The first-choice diagnosis of IPF was made in 37.8% of male patients and 10.6% of female patients. In contrast, female patients more frequently received a first-choice diagnosis of connective tissue disease related interstitial lung disease (CTD-ILD) (p<0.001) or of hypersensitivity pneumonitis (p<0.001).
Mortality was higher in women (HR=2.21, 95% CI: 2.02 to 2.41) than in men (HR=1.26, 95% CI: 1.20 to 1.33), suggesting that men were more often misclassified as having IPF. This difference in mortality was especially pronounced when the diagnosis of IPF in females was made by the subgroup of physicians who were considered experts in the field (HR=4.16, 95%CI: 3.10 to 5.90).
Actually, this is the first study to actually assess how an international sampling of pneumonologists considers patient gender in their diagnostic impression for IPF, suggesting clinicians place a remarkable emphasis on male gender in their pre-test diagnostic probability of this disease (10, 11). These data suggest that the Yentl syndrome seems to be alive today and may be present in other clinical entities that should be investigated meticulously in further studies.

References
1. Healy B. The Yentl syndrome. N Engl J Med. 1991; 325:274-276.
2. Yentl Syndrome. WIKIPEDIA, retrieved 25 Feb., 2020
3. Ayanian JZ, Epstein AM. Differences in the use of procedures between women and men hospitalized for coronary heart disease. N Engl J Med 1991;325:221–5.
4. Steingart RM et al. Sex Differences in the Management of Coronary Artery Disease. Survival and Ventricular Enlargement Investigators. N Engl J Med 1991;325:226-30.
5. Johnston N, Schenck-Gustafsson K, Lagerkvist B. Are we using cardiovascular medications and coronary angiography appropriately in men and women with chest pain? Eur Heart J, 2011: 32: 1331-1336
6. Bugiardini R, Yan AT, Yan RT, Fitchett D, Langer A, Manfrini O, Goodman SG. Factors influencing underutilization of evidence-based therapies in women on behalf of the Canadian Acute Coronary Syndrome Registry I and II Investigators, Eur Heart J, 2011; 32:1337-1344
7. Kühni CE, Sennhauser FH. The Yentl syndrome in childhood asthma: Risk factors for undertreatment in Swiss children Pediatric Pulmonology 1995;19956-160
8. Kjellstrand CM. Age, sex, and race inequality in renal transplantation. Arch Intern Med. 1988; 148:1305-1309.
9. Assayag D, Morisset J, Johannson K, Wells AU, Walsh SLF. Patient gender bias on the diagnosis of idiopathic pulmonary fibrosis. Thorax, 2020–213968.
10. Tzilas V, Valeyre D, Tzouvelekis A, Bouros D. Taking a giant step in the diagnosis of idiopathic pulmonary fibrosis. Lancet Respir Med. 2018;6:82-84.
11. Respiratory Diseases in Women. Edited by S. Buist and C.E. Mapp. European Respiratory Society Monographs. 2003, vol. 25.

In a position statement published in March, the British Thoracic Society (BTS) recommended that ‘where a new class of inhaler is commenced, this is a Dry Powder Inhaler (DPI)’. The statement went on to state that ‘ Where patients are using several classes of inhalers and poor inhaler technique is identified with one device, that the DPI class is prioritised if the patient is able to use these safely. Similarly, future and
additional inhalers would ideally also be DPIs; and that during all respiratory reviews, prescribers
recommend low carbon alternatives to patients currently using Pressured Metered Dose Inhalers
(pMDIs), where patients are able to use these safely’.

We are extremely worried by the potential impact that these recommendations could have, since they come from a trusted body which has the reputation to place the health, needs and safety of patients above all. This statement encourages prescribers to change their prescribing habits, not to patient care and safety, but to the systematic exclusion of metered-dose inhalers in favour of dry powder devices for highly debatable environmental concerns. Since the vast majority of prescribers are not experts of inhalation therapy, such guidance may put some patients in danger and lead to a loss of opportunity to optimize care.

Metered-dose inhalers are used much more reliably with spacers by young children and those with impaired respiratory function. It is well established (1) that patient preference and satisfaction, as well as their ability to use a device impacts critically on adherence and disease control, and, speaking on behalf of the patients, we feel that these considerations should overshadow assessment of the effectiveness of the drugs themselves, their cost-effectiveness and environmental considerations.

We have already detailed our concerns about the beliefs concerning the environmental carbon footprint of inhaler device production, because the production of DPIs contributes far more to this footprint than pMDIs (2) in two letters (3, 4) to the Editor, in response to the papers by Wilkinson et al (5) and Jansen et al. (6)

We believe that the very important and emotive green agenda should not lead to overriding patient personalisation and choice of device, and it does require considerable thought and evidence of efficacy.

As an official position statement, this document can have two major deleterious consequences: first, its impact on prescribing decisions can very conceivably lead to destabilisation of disease control; second, it can induce unjustified patient concern leading to additional workload for the healthcare system.

Finally, we are highly concerned by the timing of this position statement, a time when the entire world is in crisis. The papers by Wilkinson and colleagues already resulted in worldwide patient anxiety, augmented workload for GPs and nurses, and anecdotal reports of patients discontinuing their treatment presumably to “Save the Planet”. If such reactions occur again at a time where patients with chronic respiratory diseases, especially asthma and COPD, and their caregivers are extremely concerned about COVID-19, it will almost inevitably place them at risk and generate considerable additional workload for already overwhelmed doctors and nurses having to deal with additional patient confusion.

The authors have no conflicts relevant to this letter.

Bibliography

1. Plaza V, Giner J, Calle M, Rytila P, Campo C, Ribo P, et al. Impact of patient satisfaction with his or her inhaler on adherence and asthma control. Allergy Asthma Proc. 2018;39(6):437-44.
2. Carbon Trust. GlaxoSmithKline PLC. Product Carbon Footprint Certification Summary Report 2014 [Available from: https://networks.sustainablehealthcare.org.uk/sites/default/files/media/....
3. Levy ML, Murnane D, Barnes PJ, Sanders M, Fleming L, Scullion J, et al. Inhaler devices and global warming: Flawed arguments: BMJ Open; 2019 [Available from: https://bmjopen.bmj.com/content/9/10/e028763.responses#inhaler-devices-a....
4. Murnane D, Scullion J, Levy ML, Barnes PJ, Sanders M, Capstick TGD, et al. Carbon footprint, environmental impact, and patient outcomes in inhalation therapy: No simple solution to the complex challenges 2019 [
5. Wilkinson AJK, Braggins R, Steinbach I, Smith J. Costs of switching to low global warming potential inhalers. An economic and carbon footprint analysis of NHS prescription data in England. BMJ Open. 2019;9.
6. Janson C, Henderson R, Löfdahl M, Hedberg M, Sharma R, Wilkinson AJK. Carbon footprint impact of the choice of inhalers for asthma and COPD. Thorax. 2020;75(1):82-4.

The SUPERNOVA trial was a prospective observational phase II study supported by an unrestricted grant from three companies (Alung, Maquet, and Novalung) and by the European Society of Intensive Care Medicine (ESICM). The three companies provided equipment and covered costs for data monitoring, site visits, and insurance fees. The grant (€171,000) was made available to ESICM that supported data collection and analysis, and all administrative costs. As owner of the data, ESICM appointed the two principal investigators (AC and VMR) and the independent Data and Safety Monitoring Board (Jukka Takala, Chair). The study included 95 patients. The proportion of patients who achieved ultra-protective settings by 24 hours was 82%. Number of patients that experienced severe and ECCO2R-related adverse events was 2 (2%) and 37 (39%)1. Retrospective analysis of these data showed that (a) efficacy of ECCO2R to facilitate further reduction of tidal volume was lower with smaller artificial lungs and running at lower blood flow than with larger artificial lungs and running at a higher blood flow2; (b) haemolysis and bleeding was higher with the former than with the latter2; (c) applying these data to a previously described theoretical model3 we predicted that incorporating higher CO2 removal rates as factors to design randomized clinical trial might substantially reduce screening and sample size requirements4.
In her letter, Dr Lund, expressed several concerns about these findings related to (a) the improper categorization of ECCO2R device; (b) the non-controlled collection and biased analysis of safety data.
First, the scientific basis of distinction between lower and higher CO2 extraction relies on blood flow rate (350-550 ml/min vs 800-1000 L/min) and membrane lung surface (0.6 vs 1.3m2) that are the main determinant of CO2 extraction. A recent experimental study tested several lung membranes with varying surface areas (0.4, 0.8, 1.0 and 1.3 m2) at different stepwise increases of blood flow (from 250 to 1000 ml/min) at a constant sweep gas of 8 L/min. The combination of blood flow of 750-1000 ml/min with a membrane lung surface of at least 0.8 m2 was optimal in correcting respiratory acidosis highlighting the concept that a complex interplay exists between blood flow rate and membrane lung surface that may affect the efficiency of CO2 extraction5. Moreover, despite the engineering aspects of CO2 removal elegantly discussed by Drs Lund and Kimmel, the retrospective analysis of the SUPERNOVA database revealed that, with the due recognition of the limits related to the retrospective analysis and the lack of measurement of amount of CO2 extracted, the clinical performance of the different technological settings was substantially different2. Second, because of the retrospective nature of our data2,3, all analyses were purely descriptive and we only performed bivariate comparisons. The initial sample size decided in the protocol was pragmatic and not intended to reach a specific power or any Type 1 error calculation. If we take as an example the rate of patients reaching a tidal volume of 4mL/kg at 24h, the power was strong enough to detect a difference between groups (64% vs 92%) and p value was lower than 0.01 meaning that it is unlikely to have such a difference only by chance. It should also be noted that respiratory rate and minute ventilation needed to keep PaCO2 within 20% of its baseline value (by protocol) were significantly higher for the device running at the lower blood flow2. Analysis of 70 patients treated with ECCO2R within the great Paris area, showed that biological hemolysis and bleeding were significantly higher with the device we classified as low CO2 extraction than with the device we classified high CO2 extraction6.

Although we strongly agree that any comparisons between devices must be considered with caution due to the retrospective nature of our analysis, and understand the concerns expressed by ALung Technologies, we claim our commitment as independent scientists to make available to the clinical and scientific community all data for carrying out future studies and optimizing the clinical management of our patients
 

1. Combes A, Fanelli V, Pham T, et al. Feasibility and safety of extracorporeal CO2 removal to enhance protective ventilation in acute respiratory distress syndrome: the SUPERNOVA study. Intensive Care Med 2019;45(5):592-600. doi: 10.1007/s00134-019-05567-4 [published Online First: 2019/02/23]
2. Combes A, Tonetti T, Fanelli V, et al. Efficacy and safety of lower versus higher CO2 extraction devices to allow ultraprotective ventilation: secondary analysis of the SUPERNOVA study. Thorax 2019;74(12):1179-81. doi: 10.1136/thoraxjnl-2019-213591 [published Online First: 2019/08/15]
3. Goligher EC, Amato MBP, Slutsky AS. Applying Precision Medicine to Trial Design Using Physiology. Extracorporeal CO2 Removal for Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med 2017;196(5):558-68. doi: 10.1164/rccm.201701-0248CP [published Online First: 2017/06/22]
4. Goligher EC, Combes A, Brodie D, et al. Determinants of the effect of extracorporeal carbon dioxide removal in the SUPERNOVA trial: implications for trial design. Intensive Care Med 2019;45(9):1219-30. doi: 10.1007/s00134-019-05708-9 [published Online First: 2019/08/23]
5. Karagiannidis C, Strassmann S, Brodie D, et al. Impact of membrane lung surface area and blood flow on extracorporeal CO2 removal during severe respiratory acidosis. Intensive Care Med Exp 2017;5(1):34. doi: 10.1186/s40635-017-0147-0 [published Online First: 2017/08/03]
6. Augy JL, Aissaoui N, Richard C, et al. A 2-year multicenter, observational, prospective, cohort study on extracorporeal CO2 removal in a large metropolis area. J Intensive Care 2019;7:45. doi: 10.1186/s40560-019-0399-8 [published Online First: 2019/08/28]

Dear Editor,

We read with great interest the recently published article in Thorax by Combes and colleagues titled “Efficacy and safety of lower versus higher CO2 extraction devices to allow ultraprotective ventilation: secondary analysis of the SUPERNOVA study” [1]. In this article, the authors present brief, post-hoc analyses of safety and efficacy data derived from the SUPERNOVA trial, a single-arm, multi-center, pilot study assessing the feasibility and safety of extracorporeal carbon dioxide removal (ECCO2R) to facilitate ultra-protective ventilation in patients with moderate acute respiratory distress syndrome (ARDS) [2]. The study was conducted at 23 centers, each of which used one of three different ECCO2R devices.

We wish to communicate significant concerns regarding improper categorization of ECCO2R device performance as well as important study limitations impacting interpretation and value of the presented data. The differentiation between devices based on the terms “higher CO2 extraction” and “lower CO2 extraction” is incorrect based on supporting evidence and engineering principles summarized in this letter. In addition, safety data was presented and statistically compared without including available associated data that would bring in to question the implications of the analyses. As the manufacturer of one of the ECCO2R devices used in the SUPERNOVA pilot study, we are strong believers in the life-saving potential of ECCO2R technology and its role as a critical care lung support option. However, we also recognize the risks of ECCO2R therapy and the importance of providing users with all available safety data to enable accurate characterization of the risk profile. While we support the authors in publishing available safety data from this study, the data presented lacked critical information and represented key limitations that preclude the basis of the analysis as well as the stated conclusions.

The SUPERNOVA trial was not designed to investigate potential differences in device performance and safety, nor was such an analysis planned a priori [3]. However, in this post-hoc analysis, the data was reviewed retrospectively to compare differences in safety and efficacy between two groupings of the 3 devices, defined as either “higher CO2 extraction” or “lower CO2 extraction”. The question of “how much CO2 extraction is needed” to achieve certain therapeutic objectives is important, but the rationale used to categorize ECCO2R devices as “higher” versus “lower” extraction to address this question is fundamentally incorrect and, hence, undermines the entire analysis. In the SUPERNOVA study, CO2 extraction was not actually measured. It was assumed that CO2 extraction differences can be inferred based solely on differences in the operational blood flow rates and membrane surface area between devices.

The CO2 extraction rate of a given blood gas exchange device depends strongly on its unique gas transport efficiency [4,5]. In the device characterized as “low CO2 extraction” (the Hemolung RAS), gas transport efficiency is significantly increased by secondary flow patterns achieved through integration of a centrifugal pump within the fiber bundle to achieve higher CO2 extraction at lower flows with less membrane surface area and using smaller catheters. This is the defining design feature of the Hemolung device.
Data supporting similar CO2 extraction rates in ECCO2R devices operating at lower vs higher blood flows can be found in the literature. Hermann et al. published the results of a small study prospectively measuring CO2 extraction rates in 10 patients treated with ECCO2R using one of the devices also used in the SUPERNOVA trial that has been characterized as “higher CO2 extraction” [6]. With a membrane surface area of 1.3 m2, CO2 extraction rates of 70 mL/min (range of 42-85 mL/min), normalized to an inlet PCO2 of 45 mmHg, were measured at a blood flow of 1.0 L/min and a sweep gas flow of 14 L/min [7].

Barrett and colleagues recently published an in-vitro study characterizing CO2 extraction using the Hemolung RAS, which has a membrane surface area of 0.59 m2. CO2 extraction rates of 89 - 98 mL/min were measured at a blood flow of 0.4 L/min, a sweep gas flow of 10 L/min, and an inlet PCO2 of 45 mmHg [8]. The study followed ISO 7199:2016 standards for blood gas exchanger conformance testing and utilized three different CO2 extraction measurement methodologies.

This data from the literature indicates that use of the higher versus lower CO2 extraction nomenclature is not appropriate without validated measures of actual CO2 extraction. When comparing one ECCO2R device to another, higher blood flow and/or higher membrane surface area does not necessarily correlate with CO2 extraction. Thus, the conclusions drawn in the post-hoc analysis regarding differences in device CO2 extraction are incorrect.

So then, if not CO2 extraction, how can the observed differences between the two groups of devices be explained? Unlike the original publication of the SUPERNOVA results, this publication did not clearly reiterate the important limitations in the study design that can’t be ignored when trying to draw meaningful and scientifically sound conclusions from the data. As a pilot study conducted at 23 different sites in Europe and Canada, SUPERNOVA was not designed to generate standard-of-care or inter-device control data, thus post hoc analyses of data subsets are speculative. Many potential site-dependent differences or biases could exist in patient selection, cannulation techniques, anticoagulation management, ECCO2R management, and ventilation management. While many of these factors had constraints imposed by the protocol procedures, these procedures provided for enough variation in practice to open the door to bias impact. Thirty-three of the 95 patients enrolled were treated with the Hemolung device at five different centers with an enrollment variation of 1, 3, 7, 8, and 14 subjects. This variation alone is large enough to enable site-dependent differences just within subjects treated with the Hemolung device. One of the more notable limitations in the study design with respect to conducting between-device comparisons is that each site only used one of the three possible devices.

The post-hoc analysis also presented comparisons of safety data to support statistical differences in rates of hemolysis and bleeding between the two groupings of devices. These findings were of significant concern because they suggested higher rates than previously observed. Following publication of this article, we requested further information associated with the incidences of hemolysis presented in the analysis. Review of the additional information revealed several relevant observations with important implications for assessment of severity and device-relatedness. For example, of the seven hemolysis events reported with the Hemolung device, six were reported at a single site that treated only eight subjects which suggests possible biased reporting of hemolysis (or perhaps other unknown site-specific anomalies). Five of the seven incidents of hemolysis were reported to have occurred only on Day 0 of treatment, but there were no accompanying baseline measures taken prior to initiation of ECCO2R. The actual levels of plasma-free hemoglobin on which these five incidents of hemolysis were based was between 100 – 330 mg/L, which is an uncommonly low threshold for reporting of device-related hemolysis. The Extracorporeal Life Support Organization defines moderate hemolysis as peak plasma hemoglobin of 500-1000 mg/L occurring at least once during extracorporeal therapy and sustained for at least two consecutive days [8]. Given the severity of illness in the underlying patient population, it cannot be ruled out that the low levels of plasma-free hemoglobin reported to have occurred on Day 0 weren’t present at baseline, making it difficult to determine device-relatedness. Furthermore, the use of simple bivariate comparisons in a post-hoc analysis cannot ignore Type 1 error inflation where the likelihood of observing a statistically significant p-value increases with the number of comparisons made. In short, the safety data presented is not controlled, is without baseline comparisons, reflects a reasonable likelihood of bias, and does not reflect a priori Type 1 error control for analysis.

Additionally, the safety data was presented without any relevant details that would enable readers to effectively weigh the risks of ECCO2R against the risks of ventilator-associated lung injury. What impact did these events have on the patient? What medical interventions were required? How did the events impact ECCO2R therapy or ventilation status? Was ICU length of stay impacted? Without this perspective and without control data, the information presented could be misinterpreted or misused. The communication concludes with the statement, “Future randomised clinical trials assessing the overall benefit and harm of ultraprotective ventilation should be carried out with ECCO2R devices equipped with a larger membrane lung and blood flows between 800 and 1000 mL/min.” Given the many limitations of this post-hoc analysis, the incorrect differentiation in CO2 extraction between devices, and the paucity of information provided with the safety data, this conclusion is not supported.

Respectfully,

Laura W. Lund, Ph.D. Jeremy D. Kimmel, Ph.D.
Vice President of Clinical Science Vice President of New Technology
ALung Technologies, Inc. ALung Technologies, Inc.

Section Bibliography

1. Combes A, Tonetti T, Fanelli V et al. Efficacy and safety of lower versus higher CO2 extraction devices to allow ultraprotective ventilation: secondary analysis of the SUPERNOVA study. Thorax 2019; 74: 1179-1181
2. Combes A, Fanelli V, Pham T, Ranieri VM. Feasibility and safety of extracorporeal CO2 removal to enhance protective ventilation in acute respiratory distress syndrome: the SUPERNOVA study. Intensive Care Medicine 2019; 45: 592-600
3. Fanelli V, Ranieri MV, Mancebo J et al. Feasibility and safety of low-flow extracorporeal carbon dioxide removal to facilitate ultra-protective ventilation in patients with moderate acute respiratory distress sindrome. Critical Care 2016; 20: 1-7
4. AAMI Standards and Recommended Practices. Association for the Advancement of Medical Instrumentation. Cardiovascular implants and artificial organs — Blood-gas exchangers (oxygenators). ANSI/AAMI/ISO 7199:2009/(R)2014 and ANSI/AAMI/ISO 7199:2009/A1:2012(R)2014.
5. Hattler B, and Federspiel W: Chapter 6: Gas exchange in the venous system: Support for the failing lung. In: The artificial lung. Edited by Vaslef S, Anderson R. Georgetown, TX: Landes Bioscience; 2002: 133–174.