Medicine Correspondence Blog

The Medicine Correspondence Blog allows authors to post Letters to the Editors, Reviews, and other editorial writings that are not considered original research.

Monday, August 28, 2017

A key challenge in the mechanical ventilation of patients with acute respiratory distress syndrome (ARDS) is improving oxygenation without compounding pre-existing alveolar damage. In addition to a lung-protective ventilation (low tidal volumes and positive end-expiratory pressure), alveolar recruitment-maneuvers (RMs) may be applied to increase oxygenation. Although RMs may transiently increase aerated lung volume, improve gas exchange, and minimize lung stress during tidal-ventilation, the precise mechanisms involved in the therapeutic roles of RMs remain underexplored [1].

In a previous issue of Medicine, Chung and coworkers [2] provide interesting results in 24 ARDS patients who were divided into two groups depending on whether RMs were applied or not on Day 1 in addition to  lung-protective ventilation. RMs improved both oxygenation and the extravascular lung water (EVLW) index, as measured by transpulmonary thermodilution using a PICCO-system (Pulsion). The use of RMs was associated with a decreased use of mechanical ventilation and a decreased length of stay in the intensive care unit (ICU).

The authors hypothesized that a decrease in EVLW after RMs indicates increased pulmonary permeability and oxygenation and that RMs may improve lung water clearance to better distribute aeration in the lung. They also hypothesized that RMs may reduce alveolar epithelial cell injury. We agree with this hypothesis, which outlines mechanistically and biologically plausible relationships between RMs, the extent of lung injury, and the degree of impairment of alveolar fluid-clearance (AFC) in ARDS; but this is much more than a simple hypothesis.

ARDS is characterized by a protein-rich alveolar edema, the amount of which is influenced, at least in part, by active transepithelial fluid transport through epithelial channels. Impaired AFC is frequent during ARDS and is associated with clinical outcomes [3]. By providing alveolar recruitment, RMs reduce lung stretch and the inflammatory reaction caused by mechanical ventilation and, therefore may increase AFC [4]. Furthermore, when RMs induce alveolar recruitment, net AFC is observed, likely resulting in resorption of alveolar edema [5]. Recently, the levels of soluble receptor for advanced glycation end-products (sRAGE) have been reported as reliable predictors of impaired-AFC and increased lung epithelial injury in both mice and patients with ARDS [6,7]. Also, the kinetics of RM-induced changes in plasma sRAGE have recently been explored [8] showing a transient but significant decrease in sRAGE after RM in patients with non-focal ARDS. In this study, baseline sRAGE was associated with a response to RM in terms of improved oxygenation, which supports the hypothesis that RM-induced changes in sRAGE may provide indirect information on AFC, even when RMs do not improve oxygenation [9]. RM-induced increases in regional AFC rates may reduce alveolar edema in some lung regions, as fluid is ''pushed-out'' from the alveoli during RM.

Because AFC is possibly the endotype that explains focal and non-focal ARDS phenotypes [1], RMs seems indicated only in patients with non-focal-ARDS [10]. Such phenotypes, which were initially described using lung CT-scan, have a distinct prognosis, distinct functional pathobiological mechanisms [11, 12], and a differential response to therapy that may impact prognosis [13].


Blondonnet R., Jabaudon M., Constantin J-M.

Department of Perioperative Medicine, CHU Clermont-Ferrand, and Université Clermont Auvergne, CNRS UMR 6293, INSERM U1103, GReD, Clermont-Ferrand, France.


1.           Constantin J-M, Godet T, Jabaudon M, Bazin J-E, Futier E. Recruitment maneuvers in acute respiratory distress syndrome. Ann Transl Med. 2017;5: 290.

2.        Chung F-T, Lee C-S, Lin S-M, Kuo C-H, Wang T-Y, Fang Y-F, et al. Alveolar recruitment maneuver attenuates extravascular lung water in acute respiratory distress syndrome. Medicine . 2017;96: e7627.

3.        Ware LB, Matthay MA. Alveolar Fluid Clearance Is Impaired in the Majority of Patients with Acute Lung Injury and the Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2001;163: 1376–1383.

4.        Koh W-J, Suh GY, Han J, Lee S-H, Kang EH, Chung MP, et al. Recruitment maneuvers attenuate repeated derecruitment-associated lung injury. Crit Care Med. 2005;33: 1070–1076.

5.        Constantin J-M, Cayot-Constantin S, Roszyk L, Futier E, Sapin V, Dastugue B, et al. Response to recruitment maneuver influences net alveolar fluid clearance in acute respiratory distress syndrome. Anesthesiology. 2007;106: 944–951.

6.        Jabaudon M, Blondonnet R, Roszyk L, Bouvier D, Audard J, Clairefond G, et al. Soluble Receptor for Advanced Glycation End-Products Predicts Impaired Alveolar Fluid Clearance in Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2015;192: 191–199.

7.        Blondonnet R, Constantin J-M, Sapin V, Jabaudon M. A Pathophysiologic Approach to Biomarkers in Acute Respiratory Distress Syndrome. Dis Markers. 2016;2016: 3501373.

8.        Jabaudon M, Hamroun N, Roszyk L, Guérin R, Bazin J-E, Sapin V, et al. Effects of a recruitment maneuver on plasma levels of soluble RAGE in patients with diffuse acute respiratory distress syndrome: a prospective randomized crossover study. Intensive Care Med. 2015;41: 846–855.

9.        Constantin J-M, Jaber S, Futier E, Cayot-Constantin S, Verny-Pic M, Jung B, et al. Respiratory effects of different recruitment maneuvers in acute respiratory distress syndrome. Crit Care. 2008;12: R50.

10.      Constantin J-M, Grasso S, Chanques G, Aufort S, Futier E, Sebbane M, et al. Lung morphology predicts response to recruitment maneuver in patients with acute respiratory distress syndrome. Crit Care Med. 2010;38: 1108–1117.

11.      Mrozek S, Jabaudon M, Jaber S, Paugam-Burtz C, Lefrant J-Y, Rouby J-J, et al. Elevated Plasma Levels of sRAGE are Associated with Non-Focal CT-Based Lung Imaging in ARDS patients.: A Prospective Multicenter Study. Chest. 2016; doi:10.1016/j.chest.2016.03.016

12.      Jabaudon M, Blondonnet R, Lutz J, Roszyk L, Bouvier D, Guérin R, et al. Net alveolar fluid clearance is associated with lung morphology phenotypes in acute respiratory distress syndrome. Anaesth Crit Care Pain Med. 2016; doi:10.1016/j.accpm.2015.11.006

13.      Jabaudon M, Godet T, Futier E, Bazin J-É, Sapin V, Roszyk L, et al. Rationale, study design and analysis plan of the lung imaging morphology for ventilator settings in acute respiratory distress syndrome study (LIVE study): Study protocol for a randomised controlled trial. Anaesth Crit Care Pain Med. 2017; doi:10.1016/j.accpm.2017.02.006

Thursday, August 17, 2017

We read with great interest the systematic review and meta-analysis of Lv et al (1) about the impact of remnant lymph node metastases after neoadjuvant therapy and surgery in patients with pathologic T0 esophageal carcinoma. The authors conclude that pT0 patients with remnant lymph node metastases have a poor survival.

We congratulate the author with this important work, but a couple of points in their manuscript merit discussion:

First, the definition of ypT0N1 in the manuscript is "complete response in the primary tumor with residual tumor in lymph nodes". Complete response in the primary tumor means that not a single viable tumor cell is present anymore or tumor regression grade 1 according to Mandard (TRG1) (2).  From the manuscript of Reynolds et al (3) the authors included survival of TRG1 and TRG2 which is information of 61 patients in the ypT0N0 group instead of the correct number of 36 and 14 patients in the ypT0N+ group instead of the correct number of only 1 patient.  On the other hand, TRG1N1 and TRG2N1 might follow a similar survival curve, as both are categorized as "major responders" (4). 

Second, building on the same ypT0N1 definition, this means that the number of invaded lymph nodes is not defined, although the authors refer to American Joint Committee on Cancer (AJCC) esophageal staging 7th edition, were N1 is defined as 1 or 2 invaded lymph nodes. However, most included papers in the analysis - but not all (5) - made use of the AJCC esophageal staging 6th edition, were N1 was defined as one or more invaded locoregional lymph nodes. Further analysis of the included studies showed that at least 8 patients are N2 or N3 according to the 7th edition. Furthermore there is a significant difference in overall survival between ypT0N1 and ypT0N2/3 according to AJCC 7th edition (6).

Third, the authors did not include the largest study performed on this topic by Chao et al (6) in 1102 patients of which 319 ypT0N0, 50 ypT0N1 according to the 6th edition or 41 ypT0N1 according to the 7th edition, but they might have had a good reason for that.

Altogether this means that in the very small group of 131 ypT0N1 patients in the analysis, at least 13 patients should be removed and potentially 50 patients should be added depending on the definitions used. This is worth a recalculation of overall survival curves for ypT0N1 according to the 6th edition, for ypT0N according to the 7th edition and even for TRG1+TRG2N1.

Therefore we suggest correct definitions for ypT0N1 in esophageal carcinoma to be able to compare all results in future trials. Nevertheless, the main message that complete response in the primary tumor with residual tumor in lymph nodes portens poor survival, will probably stand even after recalculation.  Indeed the final remark that ypT0N1 should be included in a modified staging was heard and ypT0N1 was suggested to become Stage IIIA while ypT0N2 became stage IIIB in current AJCC esophageal staging 8th edition (7).


The authors have no potential conflicts of interest to declare.


Lieven Depypere

Department of thoracic surgery, University hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium


1 Lv HW, Li Y, Zhou MH, Cheng JW, Xing WQ. Remnant lymph node metastases after neoadjuvant therapy and surgery in patients with pathologic T0 esophageal carcinoma impact on prognosis: A systematic review and meta-analysis. Medicine. 2017 Jun;96(26):e7342.

2 Mandard AM, Dalibard F, Mandard JC, et al.. Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations. Cancer. 1994;73:2680–2686.

3 Reynolds JV, Muldoon C, Hollywood D, Ravi N, Rowley S, O'Byrne K, Kennedy J, Murphy TJ. Long-term outcomes following neoadjuvant chemoradiotherapy for esophageal cancer.  Ann Surg 2007;245:707-716.

4 Depypere L, Moons J, Lerut T, et al. Neoadjuvant chemoradiation treatment followed by surgery for esophageal cancer: there is much more than the mandard tumor regression score. Acta Chir Belg. 2016 Jul 29:1-7.

5 Blackham AU, Yue B, Almhanna K, Saeed N, Fontaine JP, Hoffe S, Shridhar R, Frakes J, Coppola D, Pimiento JM. The prognostic value of residual nodal disease following neoadjuvant chemoradiation for esophageal cancer patients with complete primary tumor response. J Surg Oncol. 2015 Nov;112(6):597-602.

6 Chao YK, Chen HS, Wang BY, Hsu PK, Liu CC, Wu SC. Prognosis of patients with pathologic T0 N+ esophageal squamous cell carcinoma after chemoradiotherapy and surgical resection: results from a nationwide study. Ann Thorac Surg. 2016 May;101(5):1897–902.

7 Rice TW, Ishwaran H, Kelsen DP, Hofstetter WL, Apperson-Hansen C, Blackstone EH, et al. Recommandations for neoadjuvant pathologic staging (ypTNM) of cancer of the esophagus and esophagogastric junction for the 8th edition AJCC/UICC staging manuals. Dis Esophagus. 2016 Nov;29(8):906-912.  


Tuesday, August 1, 2017

​Thanks for your meticulous review of our study and prudent scientific attitude.

The adverse effect of SNRI did need to be further explored and the deviation of our result might come from the limited quantity of study included. There were only two studies reported the adverse effect of SNRI in our network meta-analysis and both of them showed a comparatively same or even better safety than placebo 1, 2. On the other hand, other treatments were much worse than placebo in adverse effect. Thus, our result suggested SNRI as the safest treatment among all the medication. The adverse effect of duloxetine is severe but it did not involve in our study. The SNRI used in our meta-analysis were venlafaxine and atomoxetine while both of them showed comparatively mild adverse effect.

Secondly, cognitive behavioural therapy was efficacious in curing depression and the adverse effect was milder than antidepressant. However, our meta-analysis was investigated to compare the efficacy and safety of antidepressants and we did not included cognitive behavioural therapy in our study. Moreover, according to the study cited by you 3, the author illustrated cognitive behavioural therapy as an adjunct for individuals whose depression has not responded to pharmacotherapy was clinically effective and antidepressants were included as usual care for depression patients. Thus, we did not evaluate the efficacy and safety of cognitive behavioural therapy in our network meta-analysis.

Corresponding Author

Ronghuan Jiang, Department of Psychological Medicine, Chinese PLA (People's Liberation Army) General Hospital, 28 Fuxing Road, Haidian District, Beijing 100853, China (e-mail:


1.     Richard IH, McDermott MP, Kurlan R, et al. A randomized, double-blind, placebo-controlled trial of antidepressants in Parkinson disease. Neurology. 2012;78:1229-1236.

2.     Weintraub D, Mavandadi S, Mamikonyan E, et al. Atomoxetine for depression and other neuropsychiatric symptoms in Parkinson disease. Neurology. 2010;75:448-455.

3.     Wiles NJ, Thomas L, Turner N, et al. Long-term effectiveness and cost-effectiveness of cognitive behavioural therapy as an adjunct to pharmacotherapy for treatment-resistant depression in primary care: follow-up of the CoBalT randomised controlled trial. Lancet Psychiatry. 2016;3:137-144.

Tuesday, August 1, 2017

Zhuo et al conclusion's  "serotonin and norepinephrine reuptake inhibitors (SNRI) are the safest medication with high efficacy for depression (in Parkinson disease)" deserves comment.(1)

SNRI cannot be the safest as they not only share the adverse effects of serotonin specific reuptake inhibitors but also produce serious specific complications due to their action on norepinephrine, provoking noradrenergic adverse effects, mainly cardiovascular – tachycardia, hypertension, severe cardiac arrhythmia due to QT prolongation. These adverse effects can be fatal (Torsades de pointe) in the case of overdose or risk factor (eg. hypokalaemia, poly-medication), with no compensation in terms of efficacy.(2-4)

Moreover, considering a pharmacological class as homogenous is a dangerous shortcut for safety issues. Eg, duloxetine, a SNRI, is not characterized by advantages but only by specific serious adverse effects: a) life-threatening liver injury;(5) b) severe skin reactions including Stevens-Johnson syndrome.(

Last, trials showed robust evidence that cognitive behavioural therapy is an effective treatment for depression, including for those who have not responded to antidepressants, without serious adverse effects.(6) Moreover, it is patient's preference.(7) Antidepressant should not be the first option, even more in older adults, as those with Parkinson's disease, a population specifically prone to adverse effects.

Corresponding Author

Alain Braillon

Dept. of Medicine, University Hospital, 80000 Amiens, France.

No funding



1 Zhuo C, Xue R, Luo L et al. Efficacy of antidepressive medication for depression in Parkinson disease: a network meta-analysis. Medicine (Baltimore) 2017;96:e6698.

2 Batista M, Dugernier T, Simon M et al. The spectrum of acute heart failure after venlafaxine overdose. Clin Toxicol (Phila). 2013;51:92-5.

3 Kelly CA, Dhaun N, Laing WJ, Strachan FE, Good AM, Bateman DN. Comparative toxicity of citalopram and the newer antidepressants after overdose. J Toxicol Clin Toxicol 2004;42:67-71

4 [No authors listed]. Venlafaxine: more dangerous than most "selective" serotonergic antidepressants. Prescrire Int 2016;25:96-9.

5 Wernicke J, Pangallo B, Wang F et al. Hepatic effects of duloxetine-I: non-clinical and clinical trial data. Curr Drug Saf 2008;3:132-42.

6 Wiles NJ, Thomas L, Turner N et al. Long-term eff ectiveness and cost-eff ectiveness of cognitive behavioural therapy as an adjunct to pharmacotherapy for treatment-resistant depression in primary care: follow-up of the CoBalT randomised controlled trial. Lancet Psychiatry 2016;3:137-44.

7 McHugh RK, Whitton SW,Peckham AD, Welge JA, Otto MW. Patient preference for psychological vs pharmacologic treatment of psychiatric disorders: a meta-analytic review. J Clin Psychiatry 2013;7:595-602.

The author's reply can be found on the Author Correspondance Blog. 

Thursday, July 13, 2017

Chaara and colleagues have to be commended for rescuing a patient with severe aortic stenosis suffering from cardiac arrest by means of balloon aortic valvuloplasty and intracardiac adrenaline between others1. During resuscitation, manual or automatic massage would probably lead to minimal arterial pressure and output, assessed by low end tidal carbon dioxide (EtCO2), due to obstruction to flow by the diseased aortic valve. Such resuscitation efforts may be vain without treatment of severe aortic stenosis and prognosis may remain dismal even with balloon aortic valvuloplasty attempts in such severe patients. We would like to temper this dismal prognosis by reporting another favorable outcome.

An 87-year old female patient was planned for Trans catheter Aortic Valve Replacement for severe and symptomatic aortic stenosis. The procedure began without intubation by femoral access but circulatory collapse occurred, immediately followed by cardiac arrest. Urgent balloon aortic valvuloplasty, along with adrenaline (50 mg), intubation, defibrillation (6 shocks) allowed an improvement of hemodynamics (Et CO2 from 14 to 37 mmHg) after 45 minutes. Afterward, Trans catheter Aortic Valve Replacement was performed with success. After temporary trans venous pacing leads retrieval, tamponade occurred that necessitated immediate percutaneous drainage. It was hypothesized that external chest compressions may have induced right ventricular perforation. Patient was extubated the second day, recovered without neurological sequel (cerebral performance category 1) and regained her home on the seventh day.

Moreover, we noted that Chaara's patient had ST segment depression despite no obstructive coronary artery. This may be illustrated by the left ventricular pressure curves that can allow calculation of coronary perfusion pressure (end diastolic arterial pressure minus end diastolic ventricular pressure). In their patient, coronary perfusion pressure was null during arrest and very low (<30 mmHg) at recovery.

To conclude, we emphasize the role of balloon aortic valvuloplasty during cardiac arrest complicating severe aortic stenosis to improve the efficacy of resuscitation efforts that may not be vain.


Acknowledgement : Drs Joseph Anconina, Fouad El Buhali, and Huy Long Doan who took care of the patient. 

Sébastien Champion, MD; Grégoire Dambrin, MD

Réanimation, clinique de Parly 2, Ramsay Générale de Santé, 21 rue Moxouris, 78150 Le Chesnay, France.

Corresponding author : Sébastien Cchampion, 27 rue Lafayette, 78000 Versailles, France;

Financial Disclosures: None

Conflicts of Interest: NONE

List of abbreviations: EtCO2: end tidal carbon dioxide 


1.         Chaara J, Meier P, Ellenberger C, et al. Percutaneous Aortic Balloon Valvuloplasty and Intracardiac Adrenaline in Electromechanical Dissociation as Bridge to Transcatheter Aortic Valve Implantation. Medicine (Baltimore) 2015;94(26):e1061.