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.

Friday, May 18, 2018

We read with great interest the study from Werner J. and Coll on hydroxyethyl  starch (HES) 6% or 10% or balanced crystalloid use for goal-directed hemodynamic algorithm in pancreatic surgery.[1] As reported in the text, this is a sponsored-initiated study funded by B. Braun Melsungen AG (that is one of the producers of HES containing solutions). The Authors report that the study was "interrupted for futility" when a total of 63 patients have been enrolled (20 in HES 10%, 22 in HES 6% and 21 in balanced crystalloid treatment), while the initial sample size calculation lead to an estimate of 76 patients per group, according the suggestion from a Independent Data Monitoring Committee (IDMC).

We wonder how large was the role that the sponsor had in the IDMC. This is especially relevant since the reported results demonstrate that HES 10% use is associated with an increased acute kidney injury (AKI) and are "a step away" (in terms of statistical significance) from providing evidence on HES 6%-associated AKI. 

As additional point, the listed safety and efficacy tested end points (i.e. total amount of infused fluids and the time until fully on oral solid diet) were not associated with any beneficial HES effect and are disproportionally far from the ongoing concerns related with HES use in the perioperative setting that include AKI and excess of bleeding.[2,3] Since the HES use seems to be challenged by a growing number of possible associated drawbacks, isn't it time to produce clinical trials where "heavy end points" (mortality, functional follow up status at long term, etc) are tested in order to detect if there is a clear clinical benefit in HES use?

Author Correspondence:

Giordano Giovanni, MD, Bilotta Federico, PhD,​



[1]        Werner J, Hunsicker O, Schneider A, et al. Balanced 10% hydroxyethyl starch compared with balanced 6% hydroxyethyl starch and balanced crystalloid using a goal-directed hemodynamic algorithm in pancreatic surgery: a randomized clinical trial. Medicine (Baltimore) 2018 Apr; 97(17): e0579.

[2]        Hartog CS, Natanson C, Sun J, Klein HG, Reinhart K. Concerns over use of hydroxyethyl starch solutions. Brit Med J 2014; 349: g5981.

[3]        Wilson J. Erroneous conclusions about the safety of hydroxyethyl starch 130/0.4 in paediatric cardiac patients? Anaesthesia 2018 May; 73(5): 649-650.

Friday, May 18, 2018

We have recently read the original article entitled "Point-of-care ultrasound versus auscultation in determining the position of double-lumen tube" by Huet al. with great interest.[1]In their study, Hu et al. compared  auscultation and ultrasound (US) methods to confirm the position of double-lumen tubes (DLTs), and reported that US is superior to auscultation method. However, we noticed that Hu et al. defined the motion mode (M-mode) US image of a non-ventilated healthy lung as "barcode (stratosphere) sign" after the endobronchial intubation and showed as a figure.[1] Even so, we consider that the image presented by Hu et al. should have been defined as "lung pulse (LP)", but not as "barcode sign".[2-5]

In recent studies, US has been demonstrated to be used in the confirmation of endotracheal and endobranchial intubation.[3-6] Having separated the right and left lungs after the endobranchial intubation, a few ultrasonographic signs can be used in the determination of the ventilated and non-ventilated lungs.[3,4,7] The most important key sign is the "lung sliding (LS)" in the brightness mode (B-mode) US image. LS is a sign of healthy interpleural cavity determining the movement of visceral pleura to parietal pleura during respiration. If this investigation is carried out on M-mode in a normal ventilated lung, an image called "seashore sign" is formed.[2]

While LS disappears in the non-ventilated healthy lung, the heart beats are transmitted to the immobile lung and the image in the M-mode is called as LP. The vibrations reflected vertically to the pleura form an image in the view of block synchronized with the heart beats. LP sign has the rates of 93% sensitivity and 100% specifity in the selective left side intubation.[2] Although the same image is observed in the consolidated motionless lung or as a result of breath holding, LP is seen more frequently in the selective left side intubation depending on its proximity to the heart. However, if the lung is well-ventilated, LS invalidates LP.

Pneumothorax is characterized by the absence of LS and LP marks.[8] The dynamic motion, a sign of ventilation, disappears with the separation of two pleural layers. The heart beats cannot be transmitted to the pleura due to air layer.The air layer between visceral and parietal pleuras prevents the reflection of both horizontal and vertical movements. Parallel-line image composed of the sonographic view of the skin and muscle layers of thoracic wall on parietal pleura. The sand-like appearance under the pleural line is replaced by this parallel lines with pneumothorax. This image obtained characteristically to the pneumothorax on M-mode is termed as "barcode (stratosphere) sign" [9,10]  .

In various studies with similar findings where US was used in the confirmation of the place of DLTs, the image formed when there was no LS was called as LP, but not as barcode (stratosphere).[2-5] As a consequence, while LP image is obtained when LS disappears in a non-ventilated normal lung due to any reason, the barcode (stratosphere) sign takes place when pneumothorax develops (Figure 1).


Figure 1: A: Seashore sign, B: The lung pulse, C: Barcode (stratosphere) sign.

 lte determination.jpg



Corresponding Author:

Funda Gok MD     


Alper Kilicaslan MD, DESA    ​



  1. Hu WC, Xu L, Zhang Q, et al. Point-of-care ultrasound versus auscultation in determining the position of double-lumen tube. Medicine.  2018 ; 97 (13).
  2. Lichtenstein DA, Lascols N, Prin S, et al. The lung pulse an early ultrasound sign of complete atelectasis. Intensive Care Med. 2003; 29: 2187-92.
  3. Álvarez-Díaz N, Amador-García I, Fuentes-Hernández M, et al. Comparison between transthoracic lung ultrasound and a clinical method in confirming the position of double-lumen tube in thoracic anesthesia. A pilot study. Rev Esp Anestesiol Reanim. 2015; 62(6):305-312.
  4. Sustić A1Protić ACicvarić Tet al. The addition of a brief ultrasound examination to clinical assessment increases the ability to confirm placement of double-lumen endotracheal tubes. J Clin Anesth 2010; 22(4): 246-9.
  5. Nam JS, Park I, Seo H, et al. The use of lung ultrasonography to confirm lung isolation in an infant who underwent emergent video-assisted thoracoscopic surgery -a case report. Korean J Anesthesiol. 2015; 68(4):411-4.
  6. Sim SS, Lien WC, Chou HC, et al. Ultrasonographic lung sliding sign in confirming proper endotracheal intubation during emergency intubation. Resusciation 2012; 83: 307-12.
  7. Blaivas M, Tsung JW. Point-of-care sonographic detection of left endobronchial main stem intubation and obstruction versus endotracheal intubation. J Ultrasound Med 2008; 27: 785-9.
  8. Volpicelli G. Sonographic diagnosis of pneumothorax. Intensive Care Med. 2011; 37: 224-232.
  9. Chuang TJ, Lai CC. Sonographic barcode sign of pneumothorax. QJM. 2017; 110 (8): 525-526.
  10. Lichtenstein DA. Lung ultrasound in acute respiratory failure an introduction to the BLUE-Protocol. Minerva Anestesiol. 2009; 75: 313-7. 

Thursday, April 5, 2018

Peng and Zhang[1] showed that after <24 hours of prophylactic common iliac artery (CIA) balloon occlusion at cesarean section for placenta accreta, CIA pseudoaneurysm with extravasation manifested. An endovascular stent was placed, which stopped bleeding. They claimed that the novel point was pseudoaneurysm occurring at CIA: however, uniqueness exists in the following three points (Figure 1).

Firstly, cause-result relationships between endovascular procedures and pseudoaneurysm formation are different. Their Table 1 and statement are incorrect. They state, "PubMed search found a total of 25 cases with 'pseudoaneurysm associated with pelvic artery balloon occlusion or other obstetric vascular interventional methods'". They made Table 1 to show patients with "the occurrence of pseudoaneurysm 'after' obstetric vascular intervention". This was not the case. The pseudoaneurysm "required" endovascular procedures "as a result" and was not "caused by" it in these 25 patients, whereas pseudoaneurysm was "caused" by the endovascular procedures in Peng and Zhang's patient. We retrieved 112 patients with delivery-related pseudoaneurysm, with almost all receiving/requiring transarterial embolization[2], thus, the former type. The cause-result relationship is vice versa.

Secondly, Peng and Zhang's case showed a very short "lag time" between the preceding procedures and pseudoaneurysm-manifestation. Delivery-associated pseudoaneurysms occurred with a median lag time of 31 days (range: 6-140) after "preceding procedures (delivery/abortion)"[3]. This is why pseudoaneurysm developed "abruptly/unexpectedly". Preceding procedures injure the arterial wall, from which pseudoaneurysm is gradually formed and finally its wall ruptures. Thus, clinicians usually encounter pseudoaneurysm "unexpectedly". This "unexpectedness" characterizes pseudoaneurysm, and, thus, we referred to it as a "chameleon in obstetric emergency": a chameleon, hidden there, abruptly and unexpectedly appears[3]. Contrarily, in Peng and Zhang's case, the lag time was very short, <24 hours. Its occurrence may have also been "unexpected"; however, the meaning of "unexpected" is different.

Thirdly, in almost all reported patients with pseudoaneurysm, the preceding arterial injury was from "outside" the artery, whereas in Peng and Zhan's patient, it was from "inside". Transfemoral arterial catheterization actually "causes" pseudoaneurysm[4, 5], but it is at the puncture site: the arterial wall is punctured and thus injured from "outside" the artery, similarly to delivery-related pseudoaneurysm.

The pseudoaneurysm of Peng and Zhang's patient was simply due to "vascular damage caused by traumatic endovascular procedures". There are some analogies between this case and cases with pulmonary artery stenosis undergoing balloon dilation angioplasty. A balloon dilates the stenotic lesion, causing "intimal tear", which usually spontaneously resolves. However, if the balloon is too large and "tear" is severe, the tear spreads and causes pseudoaneurysm[6]. In this scenario, the balloon is intentionally/therapeutically used to "dilate" the stenotic site, and so the situation is different from "prophylactic hemostatic balloon" use that we discuss here.

Peng and Zhang outlined many methods/considerations to prevent pseudoaneurysm on performing arterial balloon occlusion, with which we agree. However, these preventative methods have already been widely/routinely employed by practitioners. Peng and Zhang showed that pseudoaneurysm can occur due to "direct arterial damage from inside", which, however, is avoidable with the present standard level of interventional radiology.  

 Medicine figure 1.jpg

Figure legend

Figure 1. Schema illustrating the mechanism of pseudoaneurysm occurrence: A previously reported delivery-related pseudoaneurysm case (upper panels) and Peng and Zhang's case (lower). The upper panels indicate the typical case: uterine artery pseudoaneurysm, with the parent artery being the ascending branch of the left uterine artery. Its rupture causes vaginal bleeding, postpartum hemorrhage.

  1. The arterial wall is injured from "inside" during delivery (typically at cesarean) in a typical case of delivery-related pseudoaneurysm (upper) whereas it is injured from "inside" due to endovascular balloon use (possibly too tight) (lower).
  2. Pseudoaneurysm is formed gradually (upper) and acutely (lower), respectively.
  3. Pseudoaneurysm ruptures, causing postpartum hemorrhage (upper) and intra-abdominal/retroperitoneal hemorrhage (lower), respectively. The lag time (from a to c) is long (upper) and short (lower), respectively.
  4. Transarterial embolization usually arrests bleeding in cases of delivery-related pseudoaneurysm (upper). In Peng and Zhang's case, an endovascular stent was placed.


Looking from a to d, a "cause-result" relationship is evident. The endovascular procedure was the "result" in a typical delivery-related pseudoaneurysm (upper) whereas it was the "cause" in Peng and Zhang's case (lower).



Shigeki Matsubara,1 Hironori Takahashi,1 Daisuke Matsubara,2 Hiroyasu Nakamura3

Department of 1Obstetrics and Gynecology, 2Pediatrics, and 3Radiology,

Jichi Medical University, Tochigi, Japan


Shigeki Matsubara, MD, PhD

Director and Professor, Department of Obstetrics and Gynecology,

Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan



E-mail addresses of coauthors:

Hironori Takahashi:

Daisuke Matsubara:

Hiroyasu Nakamura:


[1] Peng QZhang W. Rupture of multiple pseudoaneurysms as a rare complication of common iliac artery balloon occlusion in a patient with placenta accreta: A case report and review of literature. Medicine (Baltimore). 2018 Mar;97(12):e9896. doi: 10.1097/MD.0000000000009896.


[2] Baba YMatsubara SKuwata T, et al. Uterine artery pseudoaneurysm: not a rare condition occurring after non-traumatic delivery or non-traumatic abortion. Arch Gynecol Obstet. 2014;290:435-40.


[3] Matsubara S. Pseudoaneurysm: a chameleon in obstetrical emergency practice. Arch Gynecol Obstet. 2011;283:669-70.


[4] Petrou E, Malakos I, Kampanarou S, Doulas N, Voudris V. Life-threatening Rupture of a Femoral Pseudoaneurysm after Cardiac Catheterization. Open Cardiovasc Med J. 2016 Sep 30;10:201-204. eCollection 2016.


[5] Katzenschlager R, Ugurluoglu A, Ahmadi A, et al. Incidence of pseudoaneurysm after diagnostic and therapeutic angiography. Radiology. 1995;195:463-6.


[6] Lock JE, Castaneda-Zuniga WR, Fuhrman BP, Bass JL. Balloon dilation angioplasty of hypoplastic and stenotic pulmonary arteries. Circulation. 1983;67:962-7.

Friday, March 23, 2018

Dear Editor,

We read with interest the paper "Association of rs2279744 and rs117039649 promoter polymorphism with the risk of gynaecological cancer" by Zhang et al. in Medicine [1].

 In this paper, the authors assess the impact of the MDM2 promoter SNPs rs2279744 (SNP309) and rs117039649 (SNP285) on risk of gynaecological cancers by performing a meta-analysis of original case-control studies. Based on their findings, the authors conclude that both SNP309 and SNP285 are associated with risk of gynaecological cancers. While this conclusion may well be correct, we would like to raise some issues of concern.

Regarding endometrial cancer, the authors, included 6 original articles, with a total of 759 cases and 1,041 controls, omitting our study from 2012, which, as far as we know, is the largest study on SNP309 and SNP285 in endometrial cancer to date [2]. In our study, we included 910 Caucasians diagnosed with endometrial cancer and 2,465 controls. If this data-set had been included in the meta-analysis, it would weigh more than 50% and would therefore have a major impact on the output, both in the overall assessments, and even more so in the subgroup of Caucasians. Notably, our data-set, in addition to being published in our original article [2], was also included in a previous meta-analysis assessing the impact of SNP309 on endometrial cancer risk [3].

Regarding breast cancer, the authors included 11 original articles, with a total of 3,513 cases and 3,950 controls. Here, they omitted our studies from 2011 and 2015 including 1,973 cases and 3,646 controls [4] and 1,717 cases and 3,749 controls [5], respectively.

Further, regarding ovarian cancer, the authors included 3 original articles, with a total of 599 cases and 622 controls (although these numbers must be read with caution since there are apparent errors in Table 1; reference 7 and 31 are listed with identical clinical data). Here, the authors omitted our study from 2011, including 1,993 cases and 3,646 controls [4]. Since they cite our paper in their discussion (reference 48), we assume they are aware of its contents.

Given the number of patients enrolled in our studies mentioned above, neglecting these data-sets could seriously bias the results presented by Zhang et al. This is particularly the case for SNP285, where the data presented are from 3 studies only.

The referencing regarding identification of SNP285 is potentially misleading since the authors here refer to a previous editorial letter [6]. This SNP was first published by the teams of Drs Lane and Thompson in Dundee, UK [7] along with functional and demographic characterization performed by us [4, 8, 9]. Also SNP285's role, counteracting SNP309 was described in 2011 [4], not in the meta-analysis given as reference 25 by Zhang et al

Taken together, the data presented by Zhang et al might give some insight into the effects of MDM2 polymorphisms. However, due to the lack of a substantial amount of the available data published in peer-reviewed journals, their data-set may not be read as a comprehensive meta-analysis on the subject. ​

Stian Knappskog1,2, Liv B. Gansmo1,2 and Per E. Lønning1,2

1Section of Oncology, Department of Clinical Science, University of Bergen, Norway
2Department of Oncology, Haukeland University Hospital, Bergen, Norway



[1].         Zhang J, Zhang Y, Zhang Z. Association of rs2279744 and rs117039649 promoter polymorphism with the risk of gynecological cancer: A meta-analysis of case-control studies. Medicine (Baltimore). 2018;97:e9554.

[2].         Knappskog S, Trovik J, Marcickiewicz J, et al. SNP285C modulates oestrogen receptor/Sp1 binding to the MDM2 promoter and reduces the risk of endometrial but not prostatic cancer. Eur J Cancer. 2012;48:1988-96.

[3].         Peng Q, Mo C, Qin A, et al. MDM2 SNP309 polymorphism contributes to endometrial cancer susceptibility: evidence from a meta-analysis. J Exp Clin Cancer Res. 2013;32:85.

[4].         Knappskog S, Bjornslett M, Myklebust LM, et al. The MDM2 Promoter SNP285C/309G Haplotype Diminishes Sp1 Transcription Factor Binding and Reduces Risk for Breast and Ovarian Cancer in Caucasians. Cancer Cell. 2011;19:273-82.

[5].         Gansmo LB, Knappskog S, Romundstad P, et al. Influence of MDM2 SNP309 and SNP285 status on the risk of cancer in the breast, prostate, lung and colon. Int J Cancer. 2015;137:96-103.

[6].         Knappskog S, Lonning PE. MDM2 SNP309 and risk of endometrial cancer. Pol J Pathol. 2013;64:69.

[7].         Paulin FE, O'Neill M, McGregor G, et al. MDM2 SNP309 is associated with high grade node positive breast tumours and is in linkage disequilibrium with a novel MDM2 intron 1 polymorphism. BMC Cancer. 2008;8:281.

[8].         Knappskog S, Gansmo LB, Dibirova K, et al. Population distribution and ancestry of the cancer protective MDM2 SNP285 (rs117039649). Oncotarget. 2014;5:8223-34.

[9].         Knappskog S, Lonning PE. MDM2 promoter SNP285 and SNP309; phylogeny and impact on cancer risk. Oncotarget. 2011;2:251-8.

Wednesday, March 21, 2018

Letter to the Editor: Medicine Dear editors: In our article entitled "Association of croup with asthma in children: A cohort study'', we use large database to evaluate the relationship between croup and asthma development (1). In previous study, one revealed that croup with wheezing significantly increased with lower airway obstruction (2). Another study revealed that neither croup nor bronchiolitis was related to asthma development (3). However, no study has reported the effects of urbanization, sex, age, and bronchiolitis on the association of croup and its duration with asthma development. We assumed that croup is associated with asthma development and investigated several variables to establish whether they are risk factors for asthma in children with croup. Hospitalization may cause a cluster effect influencing the relationship between croup and asthma. To minimize this effect, we used a robust sandwich covariance matrix

estimation method for hospitalization cluster dependence. Bronchiolitis was associated with asthma in young children in the previous study (3). Adjustments were also made for age, gender, bronchiolitis and urbanization. In this article we found younger children with croup should be closely monitored for asthma development for at least 3 years according to our cumulative hazard rate curves (1). Our analyses also indicated that sex, age, bronchiolitis, and urbanization level are significantly associated with croup and asthma development (1). To be more informative, our study population was divided into subgroups as recurrent and first episode croup. (Table 1) The total number of croup was 1204. The number of first episode croup was 566 (47%) and recurrent croup was 638 (53%). First episode croup had significantly higher adjusted HRs for presence asthma (HR 2.18, 95% CI 1.52-3.14). Recurrent croup also had significantly higher adjusted HRs for presence asthma (HR 1.53, 95% CI 1.07-2.20). In conclusion, croup was association with developing asthma in children no matter it is first episode or recurrent.

Table 1 Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for Asthma among the Croup patients during the up to 5-year follow-up period.

Variable  Presence of Asthma  
P-value Adjusted HR 95% CI
Croup first episode croup <0.001 0.020 2.18 1.52-3.14
Recurrent croup  1.531.07-2.20
Adjustment for age, sex, urbanization, and interaction of age and croup  



Correspondence: Hui-Wen Lin, PhD Department of Mathematics, Soochow University, Taiwan.

Email: ​



  1. Lin SC, Lin HW, Chiang BL. Association of croup with asthma in children: A cohort study. Medicine (Baltimore). 2017; 96(35):e7667.
  2. Castro-Rodríguez JA, Holberg CJ, Morgan WJ, et al. Relation of two different subtypes of croup before age three to wheezing, atopy, and pulmonary function during childhood: a prospective study. Pediatrics 2001;107:512–8.
  3. Sherman CB, Tosteson TD, Tager IB, et al. Early childhood predictors of asthma. Am J Epidemiol 1990;132:83–95.
  4. Lin HW, Lin SC. Environmental factors association between asthma and acute bronchiolitis in young children—a perspective cohort study. Eur J Pediatr 2012;171:1645–50.​