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Editors in Chief
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Roland Hetzer
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Formerly
“HSR Proceedings
in Intensive Care
and Cardiovascular
Anesthesia”
Vol. 7 · N° 1
· 2015
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PUEXE
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NO IN
ASSOCIATE EDITORS
Massimo Antonelli
Università Cattolica Sacro Cuore, Policlinico Gemelli, Roma, Italia
Antonio Pesenti
Università degli Studi di Milano Bicocca, Ospedale San Gerardo, Italia
Giovanni Landoni
Università Vita-Salute San Raffaele, Milano, Italia
Marco Ranieri
Università di Torino S. Giovanni Battista Molinette, Torino, Italia
Vol. 7 • N° 1 • 2015
March
Milan, Italy
SECTION EDITORS
Q INTENSIVE CARE
Ludhmila Abrahao Hajjar
University of Sao Paulo, Sao Paulo, Brazil
EDITORS IN CHIEF
Alberto Zangrillo
Università Vita-Salute San Raffaele
Milan, Italy
Roland Hetzer
Deutsches Herzzentrum Berlin, Germany
Q ANESTHESIA
Fabio Guarracino
Azienda Ospedaliera Universitaria Pisana, Pisa, Italia
Q VASCULAR SURGERY
Roberto Chiesa
Università Vita-Salute San Raffaele, Milano, Italia
Q CARDIAC SURGERY
Ottavio Alfieri
Università Vita-Salute San Raffaele, Milano, Italia
Official Journal of
Roland Hetzer International Cardiothoracic
and Vascular Surgery Society
Berlin, Germany
Endorsed by
ITACTA
(Italian Association
of Cardiothoracic Anaesthesiologists)
www.itacta.org
Deutsches Herzzentrum Berlin, Germany
Q PEDIATRIC CARDIAC SURGERY
AND CONGENITAL HEART DISEASES
Eva Maria Javier Delmo Walter
Children‘s Hospital and Harvard Medical School, Boston, MS, USA;
Deutsches Herzzentrum Berlin, Germany
Q TRANSPLANTATION AND IMMUNOLOGY
Paolo Fiorina
Harvard Medical School, Boston, MA, USA
Q CARDIOLOGY
Giuseppe Biondi-Zoccai
Università degli Studi “La Sapienza”, Roma, Italia
Q PEDIATRIC CARDIOLOGY
Brigitte Stiller
Universitaetsklinikum Freiburg, Germany
Publisher
Q ECHOCARDIOGRAPHY
Michele Oppizzi
Università Vita-Salute San Raffaele, Milano, Italia
Q NEW TECHNOLOGIES
Federico Pappalardo
Università Vita-Salute San Raffaele, Milano, Italia
Q IN HOSPITAL EMERGENCIES
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Università Vita-Salute San Raffaele, Milano, Italia
Q PEER-TO-PEER COMMUNICATION
Michael John
Università Vita-Salute San Raffaele, Milano, Italia
Q IMAGING
Antonio Grimaldi
Università Vita-Salute San Raffaele, Milano, Italia
Q FUTURE EVENTS
George Silvay
The Mount Sinai School of Medicine, New York, NY
Q SOCIAL MEDIA
Laura Pasin
Università Vita-Salute San Raffaele, Milano, Italia
EDITORS
Rinaldo Bellomo
Austin Hospital, Melbourne, Australia
Friedhelm Beyersdorf
Universitätsklinikum Freiburg, Freiburg,
Germany
Elena Bignami
Università Vita-Salute San Raffaele,
Milano, Italia
Giovanni Borghi
Università Vita-Salute San Raffaele,
Milano, Italia
Tiziana Bove
Editorial Secretariat
Lara Sussani
Anesthesia and Intensive Care
Università Vita-Salute San Raffaele
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Fax +39 02 26436152
sussani.lara@hsr.it
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on November 26th 2009 (number 532)
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Università Vita-Salute San Raffaele,
Milano, Italia
Maria Grazia Calabrò
Università Vita-Salute San Raffaele,
Milano, Italia
Enrico Camporesi
University of South Florida, Tampa,
Florida
Murali Chakravarthy
Yannick Le Manach
McMaster University, Population Health
Research Institute, Hamilton, Ontario,
Canada
Kevin Lobdell
Sanger Heart and Vascular Institute,
Charlotte, NC, US
Vladimir V. Lomivorotov
State Research Institute of Circulation
Pathology, Novosibirsk, Russia
Patrizio Mazzone
Università Vita-Salute San Raffaele,
Milano, Italia
Carlos Mestres
Hospital Clínico, University of Barcelona,
Barcelona, Spain
Julije Mestrovic
University Hospital of Split, Split, Croatia
Andrea Morelli
Università degli Studi “La Sapienza”,
Roma, Italia
Daniela Pasero
Fortis Hospitals, Bangalore, India
Ospedale San Giovanni Battista, Torino,
Italia
Massimo Clementi
Gianluca Paternoster
Dean, Università Vita-Salute San Raffaele,
Milano, Italia
Massimiliano Conte
Maria Cecilia Hospital
GVM Care & Research,
Cotignola (RA), Italia
Antonio Corcione
AORN Dei Colli, V. Monaldi, Napoli
Laura Corno
Università Vita-Salute San Raffaele,
Milano, Italia
Remo Daniel Covello
Università Vita-Salute San Raffaele,
Milano, Italia
Michele De Bonis
Università Vita-Salute San Raffaele,
Milano, Italia
Francesco De Simone
Università Vita-Salute San Raffaele,
Milano, Italia
Paolo Del Sarto
A.O.R. Ospedale San Carlo,
Potenza, Italia
Emanuele Piraccini
Ospedale “G.B. Morgagni-Pierantoni”,
Forlì, Italia
Jose Luis Pomar
Hospital Clínico, University of Barcelona,
Barcelona, Spain
Martin Ponschab
Trauma Hospital Linz, Linz, Austria
J. Scott Rankin
Vanderbilt University, Nashville, Tennessee,
USA
Marco Ranucci
IRCCS Policlinico San Donato, Milano,
Italia
Zaccaria Ricci
Ospedale Pediatrico Bambino Gesù, Roma,
Italia
Reitze N. Rodseth
Juergen Ennker
Nelson R. Mandela School of Medicine,
University of KwaZulu-Natal, Durban,
South Africa
Mediclin Heart Institute, Lahr, Germany
Stefano Romagnoli
Gabriele Finco
Ospedale Careggi, Firenze, Italia
Università di Cagliari, Cagliari, Italia
Laura Ruggeri
Gian Franco Gensini
Università degli Studi di Firenze, Italia
Università Vita-Salute San Raffaele,
Milano, Italia
Ravi Gill
Anna Mara Scandroglio
Ospedale del Cuore, FTGM, Massa, Italia
University Hospital Southampton NHS
Foundation Trust, Southampton, UK
Università Vita-Salute San Raffaele,
Milano, Italia
Massimiliano Greco
Luca Severi
Università Vita-Salute San Raffaele,
Milano, Italia
Azienda Ospedaliera San Camillo
Forlanini, Roma, Italia
Yoshiro Hayashi
Andrea Szekely
Kameda Medical Center, Kamogawa,
Chiba, Japan
The University of Queensland, Brisbane,
Australia
Semmelweis University, Budapest, Hungary
James L. Januzzi
Emiliano Vitalini
Harvard University, Massachusetts
General Hospital, US
Ospedale San Camillo Forlanini, Roma,
Italia
Chiara Lazzeri
Vasileios Zochios
Azienda Ospedaliero-Universitaria
Careggi, Firenze, Italia
Papworth Hospital NHS Foundation Trust
Cambridge, UK
Luigi Tritapepe
Università degli Studi “La Sapienza”,
Roma, Italia
CONTENTS
Q INVITED EDITORIAL
Lung protective ventilation in Cardiac Surgery ............................................................................ 5
Stefano Romagnoli, Zaccaria Ricci
Q ORIGINAL ARTICLE
Pulmonary capillary wedge pressure and natriuretic peptide levels in patients
with sinus rhythm and severe left atrial enlargement following mitral valve surgery:
early and late changes ........................................................................................................................ 7
S. Hyllén, S. Nozohoor, C. Meurling, P. Wierup, J. Sjögren
Peripheral diagnostic and interventional procedures using an automated injection
system for carbon dioxide (CO2): case series and learning curve ......................................... 18
A. Giordano, S. Messina, M. Polimeno, N. Corcione, P. Ferraro, G. Biondi-Zoccai, G. Giordano
Microvolt T-wave alternans in patients undergoing elective coronary artery
bypass grafting: a pilot study ......................................................................................................... 27
G. Khoueiry, M. Abdallah, M. Shariff, M. Kowalski, J. Lafferty
Beneficial impact of levosimendan in critically ill patients with or at risk
for acute renal failure: a meta-analysis of randomized clinical trials ................................. 35
Tiziana Bove, Andrea Matteazzi, Alessandro Belletti, Gianluca Paternoster, Omar Saleh, Daiana Taddeo,
Roberto Dossi, Teresa Greco, Nikola Bradic, Ino Husedzinovic, Caetano Nigro Neto, Vladimir V. Lomivorotov,
Maria Grazia Calabrò
Use of lyophilized fibrinogen concentrate in cardiac surgery: a systematic review .......... 47
Thiago Augusto Azevedo Maranhão Cardoso, Caetano Nigro Neto, Carlos Gustavo dos Santos Silva,
Pedro Lobo da Rocha, Haward Hideo Uoieno Iosto
Haemodynamic response at double lumen bronchial tube placement - Airtraq vs.
MacIntosh laryngoscope, a randomised controlled trial............................................................ 54
Thomas Hamp, Thomas Stumpner, Georg Grubhofer, Kurt Ruetzler, Rainer Thell, Helmut Hager
Q REVIEW ARTICLE
Biomarkers, diagnosis and management of sepsis-induced acute kidney injury:
a narrative review ............................................................................................................................. 64
Zhongheng Zhang
Q CASE REPORT
Ventilator strategies for VV ECMO management with concomitant tracheal
injury and H1N1 influenza ............................................................................................................. 74
Adam P. Johnson, Nicholas C. Cavarocchi, Hitoshi Hirose
Q IMAGES IN MEDICINE
Idiopathic ascending aortitis as a rare cause of supravalvular aortic stenosis .................. 81
Amedeo Pergolini, Giordano Zampi, Maria Denitza Tinti, Andrea Vallone, Paolo Giuseppe Pino,
Francesco Musumeci, Giampaolo Luzi
Hybrid endovascular repair of Kommerell diverticulum and aberrant
right subclavian artery in a patient with repaired coarctation of the aorta ....................... 83
Marc Najjar, Monir Mohar, Allan Stewart, Isaac George
McConnell’s echocardiographic sign in acute pulmonary embolism:
still a useful pearl ............................................................................................................................... 86
Jorge A. Brenes-Salazar
Q LETTER TO THE EDITOR ................................................................................................................ 89
Q ACKNOWLEDGEMENTS .................................................................................................................. 92
Q FUTURE EVENTS .............................................................................................................................. 93
3
Editorial
Heart, Lung and Vessels. 2015; 7(1): 5-6
Lung protective ventilation
in Cardiac Surgery
Stefano Romagnoli1, Zaccaria Ricci2
1
Department of Anesthesia and Intensive Care, Azienda Ospedaliero-Universitaria Careggi,
Florence, Italy; 2Department of Cardiology and Cardiac Surgery, Pediatric Cardiac Intensive
Care Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
Multicenter, randomized, controlled trials and meta-analyses have
demonstrated that, during abdominal surgery, protective ventilation, based on low tidal volumes, positive end-expiratory pressure,
and recruitment maneuvers improves postoperative outcomes (1).
Protective ventilation strategies are aimed at preventing alveolar
over-distension, cyclic opening and closure of peripheral airways,
trans-pulmonary pressure related lung stress, recruitment and derecruitment of lung units, and local and systemic release of inflammatory mediators. Barotrauma, volutrama, and atelectrauma
are all involved in ventilator induced lung injury, and it is generally accepted that protective ventilation, delivered in patients
with injured lungs (acute respiratory distress syndrome), increases patients’ survival (2, 3). It is also of note that non-injured lungs
(e.g. those undergoing elective surgery) may suffer from ventilator
induced lung injury independently of an underlying pulmonary
or extra-pulmonary disease. General anesthesia reduces muscular tone and alters diaphragmatic position promoting reduction
in lung volume, alteration in ventilation/perfusion ratio, and the
onset of lung atelectasis, all of which are strong predictors of pulmonary complications. Hence, mechanical ventilation is an injurious procedure. Its effects depend on intensity, duration and
underlying predisposing factors. In light of this, patients undergoing cardiac surgery are particularly sensitive to lung damage
for several reasons: mechanical ventilation may be long lasting,
co-morbidities are frequently present, and pro-inflammatory cofactors (cardiopulmonary bypass, transfusions, ischemia/reperfuCorresponding author:
Stefano Romagnoli
Department of Anesthesia and Intensive Care
Azienda Ospedaliero-Universitaria Careggi Florence, Italy
e-mail: stefano.romagnoli@unifi.it
Heart, Lung and Vessels. 2015, Vol. 7
5
S. Romagnoli, et al.
6
sion) negatively affect the lungs. In fact,
respiratory dysfunction is a very common
complication after cardiac surgery, with
an incidence of about 25% (4). Approximately 2-5% of these patients are at risk of
developing severe postoperative lung dysfunction, which contributes to perioperative mortality. Cardiopulmonary bypass
related systemic inflammatory response
syndrome represents an important first
hit for lung injury, and injurious (or nonprotective) ventilation may act as a second
hit that worsens the lung damage. In addition, during cardiopulmonary bypass, the
lungs are under-perfused, non-ventilated
(lung function is carried out by an extracorporeal gas-exchanger, and the absence
of lung movement clearly facilitates surgery) or under low-continuous positive
airway pressure, depending on center
protocols. Recently, beneficial effects of
protective ventilation in cardiac surgery
patients have been published. However,
there is still insufficient evidence supporting specific ventilation strategies in
cardiac surgery patients. In addition, the
role of inspired oxygen fraction has been
poorly evaluated. Oxygenation targets in
intensive care units are established in order to limit oxygen toxicity (5). In spite of
this, recent trials on protective ventilation in patients undergoing surgery have
not included oxygenation targets, and
clear indications about the optimal oxygen inspiratory fraction during mechanical ventilation are missing. Depending on
the concentration and duration of oxygen
exposure, excessive production of reactive oxygen species may lead to the development of oxidative stress, damaging
the lungs and distal organs. Increase in
vascular resistance, reduction in cardiac
output, carotid and downstream cerebral
arteries vasoconstriction and decrease in
coronary blood flow have all been demonstrated in healthy people, during cardiac
surgery and medical emergencies involving the routine use of supplemental oxygen. In conclusion, although the protective ventilation strategy may be beneficial
in a broader population with and without
lung injury, the use of high tidal volume
without positive end-expiratory pressure
is still common during general anesthesia.
The pathogenesis of postoperative pulmonary dysfunction after cardiac surgery is
clearly multifactorial, and multiple strategies should be applied for its prevention.
Among them, the implementation of protective ventilation strategies in these patients may play a crucial role but further
trials (NCT02090205, NCT02081274) are
clearly necessary since evidence is still
too weak.
REFERENCES
1. Futier E, Constantin JM, Paugam-Burtz C, Pascal J, Eurin
M, Neuschwander A, et al. IMPROVE Study Group. A
trial of intraoperative low-tidal-volume ventilation in abdominal surgery. N Engl J Med. 2013; 369: 428-37.
2. Lionetti V, Recchia FA, Ranieri VM. Overview of ventilator-induced lung injury mechanisms. Curr Opin Crit Care
2005; 11: 82-6.
3. Ventilation with lower tidal volumes as compared with
traditional tidal volumes for acute lung injury and the
acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Clinical Network. N Engl J Med
2000; 342: 1301-8.
4. Schreiber JU, Lancé MD, de Korte M, Artmann T, Aleksic I, Kranke P. The effect of different lung-protective
strategies in patients during cardiopulmonary bypass: a
meta-analysis and semiquantitative review of randomized trials. J Cardiothorac Vasc Anesth. 2012; 26: 448-54.
5. Martin DS, Grocott MP. Oxygen therapy in critical illness: Precise control of arterial oxygenation and permissive hypoxemia. Crit Care Med 2013; 41: 423-32.
Cite this article as: Romagnoli S, Ricci Z. Lung protective ventilation in Cardiac Surgery. Heart, Lung and Vessels. 2015; 7(1): 5-6.
Source of Support: Nil. Disclosures: None declared.
Heart, Lung and Vessels. 2015, Vol. 7
ORIGINAL ARTICLE
Heart, Lung and Vessels. 2015; 7(1): 7-17
Pulmonary capillary wedge pressure
and natriuretic peptide levels in
patients with sinus rhythm and severe
left atrial enlargement following mitral
valve surgery: early and late changes
S. Hyllén1,2, S. Nozohoor1,2, C. Meurling3,4, P. Wierup1,2, J. Sjögren1,2
1
Department of Cardiothoracic Surgery, Anesthesia and Intensive Care, Skane University Hospital, Lund, Sweden; 2Lund University,
Department of Clinical Sciences, Cardiothoracic Surgery, Lund, Sweden; 3Department of Heart Failure and Valvular Disease, Skane
University Hospital, Lund, Sweden; 4Lund University, Department of Clinical Sciences, Cardiology, Lund, Sweden
Heart, Lung and Vessels. 2015; 7(1): 7-17
ABSTRACT
Introduction: Chronic mitral regurgitation is often accompanied by left atrial and ventricular remodeling and
elevated natriuretic peptide levels. Our aim was to examine the relation between severe preoperative left atrial
enlargement and changes in hemodynamics and natriuretic peptide levels after mitral valve surgery.
Methods: A prospective study was conducted including 40 consecutive patients in sinus rhythm, with severe
degenerative mitral regurgitation. N-terminal protype-B natriuretic peptide levels and hemodynamics were measured at predefined time points. An echocardiographic evaluation was performed the day before valve surgery
and six months postoperatively.
Results: Patients with left atrial volume index ≥60 mL/m2, n=26, had higher baseline mean pulmonary capillary wedge pressure (17±9 mmHg vs 9±4 mmHg, p=0.010) and N-terminal protype-B natriuretic peptide
(1326±2573 ng/L vs 233±221 ng/L, p=0.002) than patients with left atrial volume index <60 mL/m2. The
mean pulmonary capillary wedge pressure decreased to normal in patients with severe left atrial enlargement
early after surgery, while it remained normal in patients without severe left atrial enlargement. The natriuretic
peptide levels increased during the early postoperative period and decreased in both groups at 6-month follow-up.
Conclusions: A severe left atrial enlargement in patients with chronic degenerative mitral regurgitation and
sinus rhythm indicates higher pulmonary capillary wedge pressure and natriuretic peptide levels than in those
without. These findings may support early referral to surgery and may facilitate perioperative management. The
potential reversibility of left atrial enlargement after surgery may be associated with postoperative reductions in
pulmonary capillary wedge pressure and natriuretic peptide levels.
Keywords: mitral regurgitation, cardiac surgery, pulmonary capillary wedge pressure, natriuretic peptide.
INTRODUCTION
Severe chronic mitral regurgitation (MR) is
often accompanied by left atrial (LA) and
ventricular remodeling, which may reflect
Corresponding author:
Snejana Hyllén, MD
Department of Cardiothoracic Surgery
Anesthesia and Intensive Care
Lund University and Skane University Hospital
Lund, Sweden
Getingev. 4 - SE-221 85 Lund
e-mail: snejana.hyllen@med.lu.se
the severity of the regurgitation volume and
thus the severity of disease (1). LA remodeling is characterized by chamber enlargement and contractile dysfunction due to
volume and pressure overload. In addition,
the increase in atrial and ventricular wall
tension induces hormonal activation, leading to elevated levels of natriuretic peptides
(2, 3). The current evidence suggests that
preoperative LA enlargement or elevated
levels of natriuretic peptides, in combina-
Heart, Lung and Vessels. 2015, Vol. 7
7
S. Hyllén, et al.
8
tion with severe degenerative MR, may be
indicators for referral to surgery (4).
Mitral valve surgery (MVS), especially
repair, relieves the volume and pressure
overload on the left sided chambers inducing left ventricular and left atrial reverse
remodeling (LARR) (5, 6), leading to an
early reduction in natriuretic peptide levels
(7, 8). In previous studies on conservatively treated MR, severe LA enlargement has
been suggested as a predictor of impaired
cardiovascular outcome (9). However, the
outcome in conservatively managed MR
may not be the same in surgically managed
patients (9). In a previous study by our
group, we were not able to verify any negative effects of persistent postoperative LA
enlargement (10).
The early changes in postoperative hemodynamics and the release of natriuretic peptides in relation to preoperative LA enlargement in chronic degenerative MR following
surgery have not been fully elucidated. The
aim of the present study was, therefore, to
examine the relation between severe preoperative LA enlargement and early and late
changes in hemodynamics and natriuretic
peptide levels following MVS.
METHODS
Patient population. This single-center study
was a prospective study, in which 40 consecutive adult patients in sinus rhythm
scheduled for elective MVS at Skane University Hospital, Lund, Sweden, were recruited between April 2010 and March
2013. The primary aim was to study
changes in hemodynamic variables and
N-terminal protype-B natriuretic peptide
(NT-proBNP) levels in patients with severe
preoperative LA enlargement (≥60 mL/m2)
in sinus rhythm and compare them to those
without (<60 mL/m2). Patients with an
echocardiographic diagnosis of chronic se-
vere degenerative MR with leaflet prolapse
in which the intention of surgery was repair were included.
Exclusion criteria were: MR of etiologies
other than degenerative mitral valve disease; permanent atrial fibrillation, concomitant aortic, tricuspid or pulmonary valve
stenosis or more than mild regurgitation;
concomitant Cox-Maze procedure; previous cardiac surgery; infective valve endocarditis and emergency surgery. Written
consent was obtained from all the participants, and the study was approved by The
Ethics Committee for Clinical Research at
Lund University, Sweden.
Perioperative data and invasive measurements. Mitral valve surgery was performed
under general anesthesia and followed the
study protocol using midazolam, fentanyl,
propofol, celocurine and rocuronium, and
isoflurane or sevoflurane in oxygen/air.
MVS was performed using a standard cardiopulmonary bypass technique with aorto-bicaval cannulation.
Transesophageal echocardiography was
used to assess valve repair or prosthesis
function perioperatively. All patients were
admitted postoperatively to the intensive
care unit (ICU) intubated, ventilated and
sedated with propofol.
The following hemodynamic variables were
studied: arterial blood pressure, pulmonary
artery pressure, pulmonary capillary wedge
pressure (PCWP), central venous pressure,
and cardiac output. Data were collected at
predefined time points using a 7.5F singlelumen, balloon-tipped, flow-directed thermodilution fiberoptic pulmonary artery
catheter (ICU Medical, Inc., San Clemente,
CA USA). The wedge position of the catheter was confirmed by demonstrating a definite difference between the waveforms in
the pulmonary artery and PCWP tracings.
Cardiac output was determined using the
bolus thermodilution method taking the average of the three middle measurements in
Heart, Lung and Vessels. 2015, Vol. 7
Wedge pressure and natriuretic peptides following mitral valve surgery
a sequence of five, and indexing the result
to the body surface area.
Systemic and pulmonary vascular resistances were calculated as the ratio between the
pressure drop along the vascular bed and
the cardiac output, and were indexed to the
body surface area (dynes·sec·m2/cm5). All
pressure monitors were zeroed at the midaxillary line before each measurement. Invasive hemodynamic measurements were
performed by a single investigator after the
induction of anesthesia (T0), after extracorporeal circulation weaning (T1), after
admission to the ICU (T2), and on postoperative day 1 (T3). Complete hemodynamic
data were obtained for all 40 patients.
Blood sampling. In order to indirectly evaluate the left-sided filling pressures we measured NT-proBNP levels for each patient
by collecting blood samples at the following time points: preoperatively (Dpre), after admission to the ICU (D0), on postoperative day 1 (D1), on postoperative day 4
(D4), and six months after surgery.
The timing and number of blood samples
were similar to previous studies presenting
data on mitral valve and cardiac surgery
(7, 8, 11, 12). Plasma levels of NT-proBNP
were determined using the Elecsys proBNP® electrochemiluminescence immunoassay (Roche Diagnostics, Mannheim, Germany).
Echocardiography. An echocardiographic
evaluation was performed the day before
MVS and six months postoperatively. An
additional echocardiographic study was
performed within 4-7 days postoperatively
as routine practice outside the study protocol. All echocardiographic measurements
within the study protocol were performed
by two investigators who were blinded to
the clinical data.
The severity of MR, and the chamber size
and function were quantified using color
Doppler and 2D echocardiography, and
evaluated according to previously validated
criteria (13, 14). The atrial volumes were
determined using the bi-plane modified
Simpson method, and indexed to the body
surface area. The ejection fraction was
measured using the bi-plane Simpson disk
method. LARR was defined as a postoperative reduction in left atrial volume index
(LAVi) ≥15% (5, 6). Patients were categorized as having severe preoperative LA enlargement when LAVi exceeded 60 mL/m2
(9).
Statistical analysis. Categorical variables
were expressed as proportions and percentages and continuous variables as the mean
± 1 standard deviation. The paired-samples T-test was used for continuous variables, and categorical data were compared
using the chi-squared test, or Fisher’s exact
test when the expected frequency was less
than five. For skewed distributed variables,
the Mann-Whitney U test was used. Statistical significance was defined as p<0.05.
Statistical analysis was performed using
the SPSS software package (SPSS 20.0 Chicago, IL, USA)
Follow-up. Follow-up was 100% complete
for survival at 6.3±1.5 months (median
6.1 months, interquartile range 6.0-7.2),
and totaled 18.7 patient-years. One 84-yearold patient succumbed from pneumonia 3.5
months after surgery.
One patient declined to participate in the
study 5 months postoperatively, and two
patients had incomplete echocardiographic
data. Data obtained six months after surgery included NT-proBNP levels and an
echocardiographic assessment including
severity of residual MR, determination of
LAVi with assessment of LARR.
RESULTS
Patient characteristics. The clinical characteristics of the study population are given in
Table 1. The etiology of MR was degenerative in all cases, including prolapse of the
Heart, Lung and Vessels. 2015, Vol. 7
9
S. Hyllén, et al.
10
posterior leaflet (77.5%, n=31), anterior
leaflet (5%, n=2), or both leaflets (17.5%,
n=7). Five patients with no history of angina or myocardial infarction underwent
concomitant coronary artery by-pass grafting in addition to mitral valve repair. All patients were scheduled for repair, although
three patients underwent valve replacement: two due to repair failure (replacement with a bioprosthesis and a mechanical prosthesis) and one due to extensive
valvulo-annular calcification (replacement
with a bioprosthesis). Perioperative trans-
esophageal echocardiography did not reveal any systolic anterior motion, stenosis,
paravalvular leakage, or more than residual
mitral valve regurgitation in any of the patients after weaning from extracorporeal
circulation. The early postoperative clinical
outcome is presented in Table 2. The 30-day
mortality was 0%. At six months followup 100% of the patients (n=36) were in
NYHA functional class I to II.
Hemodynamic changes. The mean PCWP
was significantly higher at T0 in patients
with severe preoperative LA enlargement
Table 1 - Pre- and perioperative characteristics.
Preoperative
LAVi <60 mL/m2
(n=14)
Preoperative
LAVi ≥60 mL/m2
(n=26)
p-value
Preoperative data
Age (y)
68±9
66±10
0.551
Male
11 (79)
17 (65)
0.484
26±4
26±4
0.819
92±19
80±20
0.063
0
1 (4)
1.000
6 (43)
16 (62)
0.257
Sinus rhythm
14 (100)
26(100)
Hypertension
7 (50)
17 (65)
0.343
Beta-blockers or/and ACEinhibitors
8 (57)
18 (69)
0.501
Diuretics
7 (50)
16 (62)
0.481
2
BMI (kg/m )
2
e-GFR (mL/min/1.73 m )
COPD (patients)
NYHA class III-IV
Diabetes mellitus
0
2 (8)
0.533
Logistic EuroSCORE I
4.0±3.2
4.2±2.4
0.830
Biochemical data
NT-proBNP (ng/L)
233±221
1326±2573
0.002
0
3 (12)
0.539
ECC time (min)
118±40
121±45
0.819
Cross clamp time (min)
92±38
91±39
0.969
Concomitant surgery
CABG (patients)
2 (14)
3 (12)
1.000
Perioperative data
Repair failure
The values given are the mean ± standard deviation or numerical values (%).
LAVi=left atrial volume index; BMI=body mass index; e-GFR=estimated glomerular filtration rate; COPD=chronic obstructive pulmonary disease; NYHA=New York Heart Association; ACE=angiotensin converting enzyme; EuroSCORE=European
System for Cardiac Operative Risk Evaluation; NT-proBNP=N-terminal protype-B natriuretic peptide; ECC=extracorporeal
circulation; CABG=coronary artery by-pass grafting.
Heart, Lung and Vessels. 2015, Vol. 7
Wedge pressure and natriuretic peptides following mitral valve surgery
(LAVi≥60 mL/m2) than in those without
(p=0.010). The mean PCWP decreased
from 17±9 mmHg (T0) to 9±4 mmHg
(T3) over the first 24 hours, in patients with
severe preoperative LA enlargement, which
is equivalent to a 32% reduction from
baseline (p<0.001), Figure 1. In patients
without severe preoperative LA enlargement, the mean PCWP was 11±3 mmHg
(T0) and 11±3 mmHg (T3), p=0.644. No
significant differences were seen in mean
pulmonary artery pressure, central venous
Table 2 - Postoperative clinical outcome.
Preoperative
LAVi <60 mL/m2
(n=14)
Preoperative
LAVi ≥60 mL/m2
(n=26)
30 days mortality
0
0
CVI
0
0
6 (43)
16 (62)
0.257
Atrial fibrillation
Reoperation for bleeding
Time on ventilator (hours)
Inotropic-vasoactive drugs requirement >12 hours
- norepinephrine
- dobutamine or levosimendan
- nitroglycerine or sodium nitroprusside
ICU LOS (hours)
p-value
0
1 (4)
1.000
5.0±2.8
6.7±4.4
0.204
1 (7)
1 (7)
2 (14)
3 (12)
5 (19)
1 (4)
1.000
0.399
0.276
21.6±2.9
31.2±16.5
0.067
The values given are the mean ± standard deviation or numerical values (%).
LAVi=left atrial volume index; CVI=cerebrovascular insult; ICU=intensive care unit; LOS=length of stay.
Figure 1 - Per- and early postoperative changes in pulmonary capillary wedge pressure (PCWP).
LAVi=left atrial volume index.
Error bars indicate the 95% confidence interval. *p<0.05.
Heart, Lung and Vessels. 2015, Vol. 7
11
S. Hyllén, et al.
12
pressure, cardiac index, systemic and pulmonary vascular resistances between patients with and without severe preoperative
LA enlargement at any of the time points.
Changes in hemodynamic variables at the
different time points are presented in Figure 2 and Table 3.
Natriuretic peptide levels. The mean NTproBNP level in patients with severe preoperative LA enlargement was higher preopFigure 2 - Mean percentage
change in hemodynamic variables after induction of anesthesia
(T0) and on postoperative day 1
(T3). Error bars indicate the 95%
confidence interval.
MVS=mitral
valve
surgery;
LAVi=left atrial volume index;
ABPm=mean arterial blood pressure; PAPm=mean pulmonary artery pressure; PCWP=pulmonary
capillary wedge pressure; CI=cardiac
index; SVRI=systemic vascular resistance index; PVRI=pulmonary
vascular resistance index.
*p<0.05.
Figure 3 - Changes in NTproBNP measured preoperatively (Dpre), on postoperative
day 1 (D1), on postoperative day
4 (D4), and 6 months after surgery (D6m).
LAVi=left atrial volume index.
Error bars indicate the 95% confidence interval. *p<0.05.
Heart, Lung and Vessels. 2015, Vol. 7
Wedge pressure and natriuretic peptides following mitral valve surgery
Table 3 - Hemodynamic variables.
Variables
13
After induction
of anesthesia
(T0)
After
ECC-weaning
(T1)
On admission
to ICU
(T2)
Post-operative
day 1
(T3)
Patients with preoperative LAVi <60 mL/m2 (n=14)
HF (bpm)
64±16
82±6
82±5
79±10
ABPm (mmHg)
71±17
70±12
84±12
77±6
PAPs (mmHg)
34±14
32±13
35±12
41±12
PAPd (mmHg)
15±7
14±5
17±4
17±5
PAPm (mmHg)
23±10
21±6
24±6
25±7
PCWP (mmHg)
11±3
12±3
12±4
11±3
CVP (mmHg)
7±3
8±2
9±2
10±4
2
CI (L/min/m )
2.1±0.4
2.7±0.6
2.2±0.4
3.1±0.5
SVRI (dynes · sec · m2/cm5)
2463±717
1957±564
2844±668
1771±290
PVRI (dynes · sec · m2/cm5)
433±232
283±161
422±168
395±180
2
Patients with preoperative LAVi ≥60 mL/m (n=26)
HF (bpm)
64±14
85±10
85±6
84±7
ABPm (mmHg)
70±14
70±12
83±15
78±11
PAPs (mmHg)
37±15
35±12
39±12
40±11
PAPd (mmHg)
19±8
17±7
18±5
17±6
PAPm (mmHg)
27±10
24±8
26±7
25±7
PCWP (mmHg)
17±9
13±5
11±5
9±4
CVP (mmHg)
9±4
10±4
9±3
11±4
2
CI (L/min/m )
2.0±0.5
2.6±0.5
2.4±0.4
3.1±0.7
SVRI (dynes · sec · m2/cm5)
2501±748
1779±736
2568±778
1820±433
PVRI (dynes · sec · m2/cm5)
374±164
345±226
500±186
418±168
The values given are the mean ± standard deviation or numerical values (%).
ECC=extracorporeal circulation; ICU=intensive care unit; LAVi=left atrial volume index; HF=heart frequency; bpm=beat
per minute; ABPm=mean arterial blood pressure; PAPs=pulmonary artery pressure systolic; PAPd=pulmonary artery pressure
diastolic; PAPm=mean pulmonary artery pressure; PCWP=pulmonary capillary wedge pressure; CVP=central venous pressure;
CI=cardiac index; SVRI=systemic vascular resistance index; PVRI=pulmonary vascular resistance index.
eratively (1326±2573 ng/L) than in those
without severe preoperative LA enlargement (233±221 ng/L), p=0.002. Following MVS, the mean NT-proBNP in patients
with severe preoperative LA enlargement
was highest on D4 (3515±4316 ng/L) and
decreased to 708±680 ng/L six months
postoperatively (Figure 3). In patients
without severe preoperative LA enlargement, an increase in mean NT-proBNP to
1936±1099 ng/L was seen on D4, which
fell to 355±341 ng/L six month postop-
eratively. The mean NT-proBNP levels differed significantly between the two groups
at the 6-month follow-up, p=0.028.
Late outcome. The pre- and postoperative
echocardiographic data are presented in
Table 4. Patients with severe preoperative
LA enlargement demonstrated a 32±18%
reduction in LAVi, compared to 20±15%
in those without severe preoperative LA
enlargement (p=0.059) six months postoperatively. LARR was observed in 75%
(27/36) of the study population six months
Heart, Lung and Vessels. 2015, Vol. 7
S. Hyllén, et al.
14
Table 4 - Echocardiographic data.
Preoperative data
Postoperative data
(6 months)
p-value
Patients with preoperative LAVi<60 mL/m2 (n=12)
LAVi (mL/m2)
47±4
37±7
0.001
LAd (mm)
50±8
46±6
0.103
LVEF (%)
66±10
57±9
0.004
LVEF<50%
1 (8)
1 (8)
LVEF<30%
0
0
IVSD (mm)
12±2
12±2
0.851
LVEDD (mm)
62±6
52±4
<0.001
LVPWD (mm)
10±2
10±2
0.586
LVESD (mm)
37±7
31±9
0.101
RAVi (mL/ m )
27±5
27±8
0.935
RVIT (mm)
39±5
38±5
0.833
RVMCD (mm)
30±5
31±5
0.652
TAPSE (mm)
25±4
15±2
<0.001
45±12
31±11
0.001
LAVi (mL/m2)
79±17
53±18
<0.001
LAd (mm)
54±7
49±8
0.015
LVEF (%)
65±10
56±10
<0.001
LVEF<50%
2 (8)
6 (25)
LVEF<30%
0
0
IVSD (mm)
11±2
11±2
0.502
LVEDD (mm)
63±9
54±8
<0.001
LVPWD (mm)¤
9±1
10±2
0.088
LVESD (mm)
38±8
37±9
0.398
RAVi (mL/ m )
36±13
34±11
0.537
RVIT (mm)
41±6
40±7
0.697
RVMCD (mm)¤
32±7
33±7
0.825
TAPSE (mm)
23±6
15±3
<0.001
PASP (mmHg)
50±15
34±9
<0.001
2
PASP (mmHg)*
2
Patients with preoperative LAVi ≥60 mL/m (n=24)
2
The values given are the mean ± standard deviation or numerical values (%).
*Data arrived from 10 patients
¤Data arrived from 23 patients
LAVi=left atrial volume index; LAd=left atrial dimension; LVEF=left ventricular ejection fraction; IVSD=interventricular
septal dimension; LVEDD=left ventricular end-diastolic dimension; LVPWD=left ventricular posterior wall dimension;
LVESD=left ventricular end-systolic dimension; RAVi=right atrial volume index; RVIT=right ventricular inflow tract;
RVMCD=right ventricular mid cavity dimension; TAPSE=tricuspid annular plane systolic excursion; PASP=pulmonary artery systolic pressure.
Heart, Lung and Vessels. 2015, Vol. 7
Wedge pressure and natriuretic peptides following mitral valve surgery
postoperatively, of which 83% (n=20) were
patients with severe preoperative LA enlargement and 58% (n=7) without severe
preoperative LA enlargement (p=0.126).
Another 17% (6/36) of the patients demonstrated a reduction in LAVi not reaching the cut-off of <15% and 8% (3/36)
showed an increase in LAVi. The estimated
preoperative mean left ventricular ejection
fraction (LVEF) was 65±10% (median 67,
interquartile range 60-72%) and did not
differ significantly between patients with
and without severe preoperative LA enlargement (p=0.882). LVEF decreased to
56±10% in those with severe preoperative
LA enlargement (p<0.001) and to 57±9 %
in those without (p=0.004). No significant
difference was seen between the two groups
six months after surgery (p=0.790). The
left ventricular end-diastolic dimension decreased to 52±4 mm (p<0.001) in those
with severe preoperative LA enlargement
and to 54±8 mm (p<0.001) in those without severe preoperative LA enlargement.
No significant difference was seen between
the two groups six months after surgery
(p=0.254). The preoperative left ventricular end-systolic dimension was 38±8 mm
in those with severe preoperative LA enlargement and 37±7 mm in those without,
p=0.444. The left ventricular end-systolic
dimension was significantly higher in those
with severe preoperative LA enlargement
than in those without 6 months postoperatively (37±9 mm and 31±9 mm, respectively, p=0.045). Three patients with severe preoperative LA enlargement and one
patient without had moderate MR at the
6-month echocardiographic follow-up.
DISCUSSION
In the current study, patients
preoperative LA enlargement
cantly higher baseline mean
NT-proBNP levels than those
with severe
had signifiPCWP and
without se-
vere preoperative LA enlargement. The
mean PCWP was reduced to normal levels
in patients with severe preoperative LA enlargement early after MVS, while the mean
PCWP remained normal in patients without severe preoperative LA enlargement.
The overall incidence of postoperative
LARR was 75% six months after surgery,
with no significant difference between the
groups. The left ventricular end-diastolic
dimension and LVEF decreased postoperatively, and no significant difference was
seen between patients with and without
severe preoperative LA enlargement. The
NT-proBNP levels increased initially during the early postoperative period, but had
decreased significantly six months after
surgery in both groups.
LA enlargement in patients with conservatively managed MR has previously been described as a predictor of stroke, atrial fibrillation, systo-diastolic ventricular failure,
and impaired survival (9, 15). However,
those undergoing MVS demonstrate a high
potential for left sided reverse remodeling
(6) with the same risk of postoperative complications of patients without LARR (10).
The predisposing mechanism for this process is not fully understood. Measurement
of PCWP has been established as a surrogate for estimation of the left ventricular
end-diastolic pressure (16), but also as an
accurate method of assessing LA pressure
in patients with MR (17). However, the LA
pressure in patients with LA enlargement
and MR may also be normal (18), indicating preserved compliance of the left atrium
during the progression of mitral valve disease (19). Thus, elevated PCWP in patients
with a severely enlarged left atrium may
reflect impaired compliance as a late stage
of MR with long-standing volume overload.
We could demonstrate a significant difference in mean baseline PCWP levels in patients with severe preoperative LA enlargement, compared to those without. This is
Heart, Lung and Vessels. 2015, Vol. 7
15
S. Hyllén, et al.
16
in contrast to previous studies from the 80s
(19, 20), who could not show a relationship
between LA size and PCWP. This is probably due to heterogeneous study populations
and different methods to estimate LA size
in their studies. Normalization of mean
PCWP following MVS in patients with severe preoperative LA enlargement occurred
rapidly in response to relief of volume overload on the left atrium. These changes may
facilitate postoperative left sided reverse
remodeling. However, the process of postoperative LARR was not initiated in all patients and the reason for this is not fully
understood, but may be related to myocardial fibrosis.
In chronic MR, preload might be increased
by the volume overload of the left ventricle,
while afterload is decreased in the later part
of systole. These adaptive changes tend to
normalize the LVEF, even in the presence of
left ventricular dysfunction which may be
reflected in a high PCWP (21). In the present study, the majority of the patients had
normal or hyperdynamic left ventricular
function, as assessed by preoperative echocardiography. Simultaneously, invasive hemodynamic measurements demonstrated
impaired cardiac output at baseline in the
same population. Following MVS, the volume and pressure overload was relieved to
the left sided chambers and the PCWP decreased together with an increase in cardiac
output (Table 3). At six months follow-up
the echocardiographic data demonstrated a
postoperative left sided reverse remodeling
with a significant reduction in LA volume
as previously described (5). Furthermore,
the left ventricular end-diastolic dimension
decreased and the hyperdynamic LVEF was
normalized in analogy with previously published data (22, 23).
The variability in natriuretic peptide release (NT-proBNP or protype-B natriuretic
peptide) following cardiac surgery has been
extensively investigated previously (24).
Hormonal activation, with the release of
natriuretic peptides, has been used to identify asymptomatic patients with MR at high
risk of left ventricular dysfunction or death
(2) suggesting that hormonal activation in
MR is a predictor of poor outcome (3, 4).
However, to date, there have been no reports
of changes of NT-proBNP in relation to LA
enlargement and reverse remodeling. The
present study confirms preoperative NTproBNP activation, especially in patients
with severe preoperative LA enlargement.
Levels of NT-proBNP continued to increase
during the early postoperative period in
both groups, and decreased significantly
six months postoperatively. Based on these
findings, we conclude that a late postoperative reduction in NT-proBNP may reflect
the process of reverse remodeling initiated
by the early relief of volume and pressure
overload mirrored by the decrease in PCPW
as well as the reduction in left-sided chamber dimensions following MVS.
Limitations
Invasive hemodynamic evaluations may
be influenced by: different hemodynamic
states (e.g. hypovolemia, tachycardia), general anesthesia, effects of sternotomy and
sternal closure, and pharmacological treatment. However, in this prospective study
all patients were evaluated under similar
conditions, with the patient being his or
her own control. Furthermore, the diastolic
heart function, which could influence baseline PCWP and NT-proBNP, was not specifically evaluated preoperatively.
CONCLUSION
A severe LA enlargement in patients with
chronic degenerative MR and sinus rhythm
indicates higher mean baseline PCWP and
NT-proBNP than in those without. In our
opinion, these findings may support early
referral to surgery and may also facilitate
Heart, Lung and Vessels. 2015, Vol. 7
Wedge pressure and natriuretic peptides following mitral valve surgery
perioperative management. The potential
reversibility of left atrial enlargement after
mitral valve repair may be associated with
postoperative reductions in PCWP and NTproBNP.
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11. Feringa HH, Poldermans D, Klein P, Braun J, Klautz RJ,
van Domburg RT, et al. Plasma natriuretic peptide levels
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Cite this article as: Hyllen S, Nozohoor S, Meurling C, Wierup P, Sjogren J. Pulmonary capillary wedge pressure and natriuretic peptide levels in patients with sinus rhythm and severe left atrial enlargement following mitral valve surgery: early and late
changes. Heart, Lung and Vessels. 2015; 7(1): 7-17.
Source of Support: Nil. Disclosures: None declared.
Heart, Lung and Vessels. 2015, Vol. 7
17
ORIGINAL ARTICLE
Heart, Lung and Vessels. 2015; 7(1): 18-26
18
Peripheral diagnostic and
interventional procedures using
an automated injection system
for carbon dioxide (CO2):
case series and learning curve
A. Giordano1, S. Messina1, M. Polimeno1, N. Corcione1, P. Ferraro1,
G. Biondi-Zoccai2, G. Giordano1
1
Operative Unit of Cardiovascular Interventions, Pineta Grande Clinic, Castelvolturno, and Operative Unit of Hemodynamics,
S. Giuseppe Vesuviano, Italy; 2Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
Heart, Lung and Vessels. 2015; 7(1): 18-26
ABSTRACT
Introduction: The administration of iodinated contrast media in doses sufficient for diagnosis and procedural
guidance, when coincident with renal insufficiency, presents a considerable risk of exacerbating and hastening
renal failure. Carbon dioxide has been proposed in the past as an alternative, but only recently dedicated injection systems have become available. We aimed to review our ongoing experience with an automated carbon
dioxide injector for peripheral diagnostic and interventional procedures.
Methods: Details on 21 patients undergoing peripheral procedures with carbon dioxide angiography were systematically collected. An automated injector enabling customized and repeated carbon dioxide injections was
used in all cases, with iodinated contrast media used only as bailout.
Results: No major or minor complications occurred in these patients, either during the procedure or up to
discharge. Comparison according to phase of the learning curve showed that with accruing experience operators relied progressively more on carbon dioxide only, as there was a significantly reduced need for additional
iodinated contrast media injections per procedure (from 2.5±2.1 to 0.6±2.1 injections per patient, p=0.005).
Accordingly, in the second phase of our learning curve, iodinated contrast media were avoided in 91% of cases
in comparison to 20% of procedures performed in the beginning of our experience (p=0.002). Concomitantly,
no significant change in the duration of the procedure occurred.
Conclusions: Carbon dioxide-based angiography using an automated injection system is feasible and safe in
patients undergoing diagnostic or interventional procedures for infra-diaphragmatic conditions, especially for
transcatheter renal sympathetic denervation.
Keywords: angiography, angioplasty, carbon dioxide, peripheral artery disease.
INTRODUCTION
Corresponding author:
Dr. Arturo Giordano
Operative Unit of Cardiovascular Interventions
Pineta Grande Clinic
Strada Statale Domiziana Km 30
81030 Castel Volturno CE, Italy
e-mail: arturogiordano@tin.it
The burden of peripheral artery disease
continues to increase worldwide. Given
the favorable results of endovascular therapy in patients with PAD, also its role is increasingly important (1). Even patients undergoing surgical therapy or maintained on
Heart, Lung and Vessels. 2015, Vol. 7
Peripheral procedures with CO2
maximal medical therapy only usually undergo invasive assessment with angiography relying on administration of iodinated
contrast media (2). However, the safety of
such iodinated media is less than satisfactory. Their adverse effects, especially contrast nephropathy, potentially undermine
their diagnostic benefits (3). Accordingly,
endovascular procedures may be limited in
scope or aggressiveness in patients at high
risk of contrast nephropathy, or avoided
altogether in patients with severe allergic
diathesis.
Alternatives to iodinated contrast media
have been proposed over the decades, including ultrasound, gadolinium, and carbon dioxide (CO2). The latter has been
proposed for digital subtraction angiography several years ago, given its high dissolubility and lack of hypersensitivity or
nephrotoxic adverse effects (4). Indeed,
for most diagnostic or interventional procedures, almost unlimited cumulative volumes of CO2 can be injected. Despite these
theoretical and practical advantages, its use
is until now very limited. Some of the main
hurdles faced by physicians using CO2 as
contrast medium are: suboptimal imaging
yield, discomfort, and lack of dedicated automated and digital injection systems. Recently several non-digital (5) or homemade
devices have been proposed (6). However,
recent works suggest that dedicated injection systems with modifiable parameters
are required to improve the diagnostic yield
(7). In addition, the increasingly common
performance of transcatheter renal sympathetic denervation, which requires invasive
imaging of the renal arteries in patients
who can be at high risk of iodinated contrast media because of refractory hypertension and chronic renal failure, calls for alternative invasive imaging approaches.
A dedicated automated and fully digital
injector for CO2 angiography has been recently developed. It builds upon prior less
sophisticated ones,(8) and our cardiovascular catheterization laboratory has begun
to use it. We hereby report our experience
and learning curve, in order to provide
guidance on adoption and improvement.
METHODS
Design. This study was a retrospective observational registry. All patients provided
written informed consent for the procedure and data collection. Ethical approval
was waived given the retrospective observational design.
Patients. Patients undergoing invasive angiography for peripheral artery disease or
transcatheter renal sympathetic denervation with CO2 as contrast of choice were
retrospectively identified in our institutional database, irrespective of whether
other imaging modalities had been used as
well. Carbon dioxide angiography was attempted in patients with decreased renal
function (glomerular filtration rate <60
mL/min), when selective renal injection
was envisioned, or whenever the diagnostic or interventional procedure was deemed
to require >100 mL of iodinated contrast
media. No patient was excluded, with the
notable exception of those requiring only
supradiaphragmatic angiography.
Device. Carbon dioxide was administered
using a dedicated injection system (Angiodroid, Angiodroid Srl, Bologna, Italy).
Angiodroid is a digital automatic injector,
which ensures stable CO2 pressure and
high accuracy of volumes, as well as a builtin control system to avoid air contamination. The Angiodroid workstation is movable on steerable wheels and it is similar in
size to a iodinated contrast media injector.
The main advantages over other approaches to CO2 injection, including hand injection or other CO2 injectors, are: digital
volume dose settings, digital pressure in-
Heart, Lung and Vessels. 2015, Vol. 7
19
A. Giordano, et al.
20
jection settings, fast automated reload (20
seconds) for repeatable injections, high accuracy of the set pressure injection, high
accuracy of the set volume doses, dual microcontroller to ensure high safety and performance, safety limits to avoid errors and
patient injury, remote controller to start
injections, possibility to save injection settings for different vascular districts, and a
touch screen control. Angiodroid is to date
the first totally computerized CO2 injection
system. Injections can vary between 1 and
100 mL in volume and between 45 and 700
mm Hg in pressure (respectively 6 and 93
KPa), with an accuracy for volume delivery of ± 1 mL and for pressure delivery of
±1.5%. Notably, no specific injection parameters are recommended, as physicians
choose the better dose, the but they must
remain within the above safety limits.
Once the injector has been prepared for use
and activated, it automatically charges the
required amount of CO2 from a 2 L CO2
cylinder. Afterwards, the injector must
simply be connected through a disposable
connecting tube to the diagnostic or guiding catheter or sheath of choice and injection is already possible without further
delay. Thanks to the low viscosity of CO2,
even 3 French catheters and 22G tubings
or syringes can be used to obtain satisfactory angiographic images with digital subtraction angiography.
Despite its recent introduction into clinical
practice, there are already favorable scholarly reports on the use of Angiodroid (9).
Procedures. All procedures were performed
by a single operator (A G) with extensive
(>20 years) experience in peripheral diagnostic and interventional procedures
with iodinated contrast media, performed
according to the standard of care and using standard diagnostic and interventional
materials. Carbon dioxide was administered using standard sheaths and catheters.
After the first two cases, the CO2 delivery
approach was modified, introducing a oneway check valve to prevent air aspiration
and blood backflow. Since CO2 is very soluble in air and lighter than blood, air or
blood could fill the delivery system for CO2
and make repeated CO2 injections cumbersome, or increase the risk of air embolism.
In addition, in arteries with a reference vessel diameter of 10 mm or less, a 7 French
Swan-Ganz catheter was used in order to
reduce antegrade blood flow and increase
CO2 opacification of the arterial lumen by
maximizing blood displacement by CO2.
For instance, when performing left lower
limb arteriography, the Swan-Ganz was
deployed uninflated through contralateral
access up to the distal segment of the external iliac artery. Then, it was slowly and
gently inflated before CO2 injection in order to minimize competitive blood flow and
ensure almost complete filling of the vessels
of interest with CO2.
Complete injections were administered at
volumes ranging from 20 mL (for smaller vessels such as the renal artery) to 50
mL (for larger vessels such as the abdominal aorta), at a 350-400 mm Hg pressure.
Scouts were instead based on 10 mL of CO2
delivered at 350 mm Hg. No pain medication or sedation was administered.
Definitions. Adequate image quality was defined as that enabling complete diagnostic
appraisal of the anatomic structure of choice
and, if pertinent, satisfactory guidance of
the interventional procedure and eventual
control of the angiographic results. Severe
pain or discomfort was defined as the one
requiring discontinuation of CO2 administration. Glomerular filtration rate was estimated according to the Modification of Diet
in Renal Disease (MDRD) formula.
Analysis. Continuous variables are reported as mean±standard deviation or n (%).
Categorical variables are reported as n (%).
In order to appraise the potential learning
curve required to master CO2 angiography,
Heart, Lung and Vessels. 2015, Vol. 7
Peripheral procedures with CO2
the 21-patient case series was divided in
two groups, the first 10 and the subsequent
11 patients. Statistical testing was performed with the Mann-Whitney U test for
continuous variables, with the Fisher exact
test for categorical variables when organized in two by two tables and chi-squared
test when organized in larger tables. Statistical significance was set at the two-tailed
0.05 level. Computations were performed
with SPSS 20 (IBM, Armonk, NY, USA).
RESULTS
Between March 2013 and February 2014,
out of a total of 273 endovascular diagnostic
or interventional procedures involving in-
fradiaphragmatic vessels, 21 patients (8%)
underwent CO2 angiography as part or
whole of their diagnostic or interventional
procedure (Table 1). Age was 67.9±10.0
years and 12 (57%) were men. Procedures
were performed in the aorto-iliac or femoro-popliteal district for diagnostic-only purposes in 3 (14%) cases and for angiography
or interventions in 8 (38%) cases (Figure 1;
Figure 2). Ten (48%) cases were transcatheter renal sympathetic denervations (Figure 3). In 2 (10%) procedures, which were
performed at the beginning of our clinical
experience, CO2-based angiography did not
provide adequate quality images in the aorto-iliac and ilio-femoral district, due to lack
of complete vessel filling with CO2. Thus,
these procedures were mainly performed
Table 1 - Patient features.
Overall
(N=21)
Feature
First cases
(N=10)
Following cases
(N=11)
P value*
Age (years)
67.9±10.0
67.1±6.1
68.6±12.9
0.888
Female gender
9 (42.9%)
3 (30.0%)
6 (54.5%)
0.387
Hypertension
18 (85.7%)
7 (70.0%)
11 (100%)
0.090
Dyslipidemia
6 (28.6%)
3 (30.0%)
3 (27.3%)
1.0
Never
17 (81.0%)
8 (80.0%)
8 (81.8%)
Former
3 (14.3%)
1 (10.0%)
2 (18.2%)
Current
1 (4.8%)
1 (10.0%)
0
Diabetes mellitus
9 (42.9%)
4 (40.0%)
5 (45.5%)
1.0
Prior PTA
4 (19.0%)
2 (20.0%)
2 (18.2%)
1.0
Left ventricular ejection fraction <50%
4 (19.1%)
3 (30.0%)
1 (9.1%)
0.221
Glomerular filtration rate <60 mL/min
5 (23.8%)
3 (30.0%)
2 (18.2%)
0.635
Fontaine class
2A
2B
3
4
NA
2 (9.5%)
7 (33.3%)
0
2 (9.5%)
10 (47.6%)
1 (10.0%)
6 (60.0%)
0
1 (10.0%)
2 (20.0%)
1 (9.1%)
1 (9.1%)
0
1 (9.1%)
8 (72.7%)
Procedure
Angiography only
PTA ad hoc or after angiography
RSD
3 (14.3%)
8 (38.1%)
10 (47.6%)
3 (30.0%)
4 (40.0%)
3 (30.0%)
0
4 (36.4%)
7 (63.6%)
Smoking status
0.510
*at Fisher exact, chi-squared, or Mann-Whitney U tests.
PTA = percutaneous transluminal angioplasty; RSD = renal sympathetic denervation.
Heart, Lung and Vessels. 2015, Vol. 7
0.155
0.102
21
A. Giordano, et al.
Figure 1 - Comparison between iodinated contrast media and carbon
dioxide angiography for superficial
femoral artery angiography and
intervention: A) baseline iodinated
contrast media angiography; B)
baseline carbon dioxide angiography; C) iodinated contrast media
angiography after stenting; D) carbon dioxide angiography after stenting.
22
Table 2 - Procedural features.
Overall
(N=21)
First cases
(N=10)
Following cases
(N=11)
16 (76.2%)
0
6 (60.0%)
0
10 (90.9%)
0
0.149
Abdominal aortic injections performed with
CO2
ICM
1.1±1.3
0.1±0.5
1.1±1.4
0.3±0.7
1.1±1.3
0
0.970
0.129
Right renal injections performed with
CO2
ICM
2.5±3.2
0.4±1.0
1.3±2.3
0.4±0.7
3.6±3.5
0.4±1.2
0.084
0.304
Left renal injections performed with
CO2
ICM
3.6±4.6
0.3±0.8
1.8±2.4
0.4±0.7
5.3±5.5
0.3±0.9
0.084
0.304
Right lower limb injections performed with
CO2
ICM
3.0±5.5
0.3±1.2
4.4±6.6
0.7±1.6
1.6±4.1
0
0.166
0.129
1.8±3.7
0.3±0.8
12.0±5.7
1.5±2.3
12 (57.1%)
19 (90.5%)
6 (28.6%)
98.6±28.9
3.2±4.8
0.7±1.1
11.8±6.5
2.5±2.1
2 (20.0%)
8 (80.0%)
5 (50.0%)
102.1±30.4
0.6±1.8
0
12.2±5.2
0.6±2.1
10 (90.9%)
11 (100%)
1 (9.1%)
95.1±28.4
0.090
0.024
0.972
0.005
0.002
0.214
0.063
0.650
Feature
Arterial access
Right femoral
Left femoral
Left lower limb injections performed with
CO2
ICM
Total injections performed with CO2
Total injections performed with ICM
No injection of ICM
Use of unidirectional valve
Use of Swan-Ganz catheter
Procedural duration
*at Fisher exact or Mann-Whitney U tests. C02 = carbon dioxide; ICM = iodinated contrast media.
Heart, Lung and Vessels. 2015, Vol. 7
P value*
Peripheral procedures with CO2
23
Figure 2 - Angiography with solely carbon dioxide to diagnose and treat a significant stenosis of the left
common iliac artery: A) baseline angiography with a standard JR 4 diagnostic catheter to also image the
carrefour; B) baseline angiography with an inflated 7 French Swan-Ganz catheter (arrow) to increase
image quality in the distal vessel; C) final angiographic result after stenting.
Figure 3 - Angiography with solely carbon dioxide to perform transcatheter renal sympathetic denervation: A) baseline angiography in the right renal artery; B) ablation with the Simplicity catheter
(Medtronic, Minneapolis, MN, USA); C) control angiography after 6 ablation runs.
with iodinated contrast administration.
In order to minimize CO2 washout due to
blood flow during digital subtraction angiography when standard injection proved
unsatisfactory, the Swan-Ganz catheter
(Table 2; Figure 2) was added. This lead to
improved imaging yield in these small-caliber vessels. Indeed, among the subsequent
cases, many procedures could be completed
without using any iodinated contrast. The
remaining ones could be performed exploiting CO2 as main contrast agent, and reserving iodinated contrast administration only
to exclude minor angiographic features
such as post-procedural intimal dissection.
No major or minor complications occurred
in these patients, either during the proce-
dure or up to discharge. Accordingly, no
patient referred discomfort or pain, other
than mild and transient symptoms.
Comparison according to phase of the
learning curve (i.e. distinguishing the
first 10 cases from the 11 following ones)
showed that baseline patient features were
similar in the two groups (Table 1). Conversely, analysis of procedural features
showed that the overall number of ICM injections per procedure decreased over time
(from 2.5±2.1 to 0.6±2.1, p=0.005). A
similar trend was found also for the number of injections of ICM required for lower
limb procedures (from 0.7 to 0, p=0.024).
Accordingly, in the second phase of our
learning curve, iodinated contrast media
Heart, Lung and Vessels. 2015, Vol. 7
A. Giordano, et al.
24
were avoided altogether in 10 (91%) cases, in comparison to 2 (20%) procedures
performed in the beginning of our experience (p=0.002). Notably, no significant
increase in the duration of the procedure
occurred (p=0.650).
DISCUSSION
This case series, reporting on the clinical
use of the Angiodroid automated injection
system for CO2 in patients with peripheral
artery disease or undergoing transcatheter
sympathetic renal denervation, has the following implications: a) CO2 injection for
infradiaphragmatic diagnostic and interventional procedures appears feasible; b)
despite an obvious learning curve, imaging
accuracy could be improved with the use of
simple ancillary devices, such as the SwanGanz balloon-tipped dual lumen catheter;
c) CO2 may be particularly appealing as a
contrast medium in patients undergoing
transcatheter sympathetic renal denervation, given its adequate imaging yield
and lack of renal toxicity; d) based on our
learning curve analysis, we may tentatively speculate that experienced endovascular specialists after only 10 cases could be
confident to rely only or mostly on CO2 for
their diagnostic or interventional procedures in infra-diaphragmatic vessels.
Despite ongoing improvements in the safety of iodinated contrast media in the last
decades, even current generation agents
are associated with adverse events, in particular with the risk of contrast nephropathy and anaphylactic reactions (10). Alternatives to iodinated media include CO2,
which is already produced throughout the
body and can be easily expelled by the
lungs. Indeed, CO2 was proposed instead
of iodinated media several decades ago, but
being a gas it is more difficult to manage
in the catheterization laboratory (4). More-
over, while iodinated contrast media may
opacify a vessel even if it is not completely
filled, CO2 needs to displace all or most of
the blood to achieve adequate images (7).
In addition, digital subtraction angiography with summation is usually required.
Accordingly, CO2 angiography is hitherto
available only in few centers, and even in
those institutions with a specific expertise
in CO2-guided procedures, it is used very
selectively.
Most probably, the main hurdle for a more
widespread use of CO2 in peripheral invasive procedures is the difficulty in handling
this gas, due to the lack of user-friendly
digital automated injection systems, until recently (5). Indeed, the present work
is built upon prior experiences with other
dedicated injection systems, showing that
such means to deliver CO2 is particularly
effective.
We found that, on top of sophisticated imaging algorithms, the use of the Swan-Ganz
catheter improves the ease and imaging
yield. In addition, we found that adding a
simple one-way valve to the injection tubing remarkably improved the ease of use of
the system, by reducing blood backflow inside the tubes themselves. Accordingly, this
contrast media appears attractive for infra-diaphragmatic invasive procedures, especially in those with or at risk for contrast
nephropathy or other contraindications to
iodinated contrast media. Moreover, our
preliminary experience suggests that CO2
may be useful in patients with resistant hypertension undergoing transcatheter renal
sympathetic denervation.
Similarly favorable results have been recently reported by other authors. For instance, Criado et al. have reported favorable
data on CO2-guided endovascular abdominal aneurysm repair in 114 patients in the
US (11), and other positive data come from
Asian colleagues (12). Even homemade delivery systems have been proposed, but fur-
Heart, Lung and Vessels. 2015, Vol. 7
Peripheral procedures with CO2
ther details concerning their safety and efficacy are required (13). Finally, alternative
imaging approaches relying only on ultrasound have also been proposed (14), with
Kusuyama and colleagues and Kawasaki et
al. both recommending the combination of
intravascular ultrasound and CO2 to maximize imaging yield and avoid nephrotoxic
contrast (15-16).
Notwithstanding the above mentioned evidence, CO2 is not devoid of safety issues.
Supra-diaphragmatic injections are absolutely contraindicated in proximal vessels,
given the risk of cerebral or coronary ischemia, even if shunt or distal upper limb
procedures appear safe.
In addition, CO2 may cause discomfort
when excessive or repeated injections are
administered, and other complications,
such as gas trapping and ischemia, must be
borne in mind.
Indeed, at least 2-3 minutes should pass between two repeated series of CO2 boluses
each building up to 100 mL. Nonetheless,
these limits are difficult to overcome, as
the operator typically takes time to review
the images and plan the best management
strategy between injections.
This work has all the limitations typical
of retrospective single center registries, including the small sample size, lack of control group, and reliance on surrogate clinical outcomes (17).
In addition, all procedures were performed
by a very experienced operator, thus these
findings may not apply as well to less skilled
colleagues (e.g. trainees).
Notably, given the few patients included
and the varying patterns in the types of procedures over time, the play of chance cannot be disregarded as explanation for our
results. Learning curves for CO2 angiography could obviously differ substantially between trainees and experienced operators,
and accordingly our findings can be extrapolated mainly to operators who are already
proficient in diagnostic and interventional
procedures with iodinated contrast media.
Finally, as other automated injectors for
CO2 already exist, further studies from
other centers with different expertise and
patient populations will be required to verify the present findings.
CONCLUSION
Carbon dioxide-based angiography using
an automated injection system appears
feasible in patients undergoing infra-diaphragmatic diagnostic or interventional
procedures. This technology may appear
particularly promising for transcatheter
renal sympathetic denervation and lower
limb procedures.
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KA, Fowkes FG, et al. Inter-society consensus for the management of peripheral arterial disease. Int Angiol 2007; 26:
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et al. Carbon dioxide angiography in lower limbs: a prospective comparative study with selective iodinated contrast angiography. Kaohsiung J Med Sci 2003; 19: 599-607.
6. Madhusudhan KS, Sharma S, Srivastava DN, Thulkar S,
Mehta SN, Prasad G, et al. Comparison of intra-arterial digital subtraction angiography using carbon dioxide by ‘home
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7. Penzkofer T, Slebocki K, Grommes J, Bruners P, Isfort PP,
Heussen N, et al. Carbon dioxide-contrasted computed tomography angiography: high pitch protocols and adapted
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repair with carbon dioxide-guided angiography in patients
with renal insufficiency. J Vasc Surg 2012; 55: 1570-5.
Chao A, Major K, Kumar SR, Patel K, Trujillo I, Hood DB,
et al. Carbon dioxide digital subtraction angiography-assisted endovascular aortic aneurysm repair in the azotemic
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Kawasaki D, Fujii K, Fukunaga M, Masutani M, Nakata
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Cite this article as: Giordano A, Messina S, Polimeno M, Corcione N, Ferraro P, Biondi-Zoccai G, Giordano G. Peripheral diagnostic and interventional procedures using an automated injection system for carbon dioxide (CO2): case series and learning
curve. Heart, Lung and Vessels. 2015; 7(1): 18-26.
Source of Support: Nil. Disclosures: None declared.
Heart, Lung and Vessels. 2015, Vol. 7
ORIGINAL ARTICLE
Heart, Lung and Vessels. 2015; 7(1): 27-34
Microvolt T-wave alternans in patients
undergoing elective coronary artery
bypass grafting: a pilot study
G. Khoueiry1, M. Abdallah2, M. Shariff3, M. Kowalski4, J. Lafferty2
1
Department of Cardiology, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA; 2Department of Cardiology, Staten Island
University Hospital, NY, USA; 3Department of Cardiothoracic surgery Staten Island University Hospital, NY, USA;
4
Department of Electrophysiology, Staten Island University Hospital, NY, USA
Heart, Lung and Vessels. 2015; 7(1): 27-34
ABSTRACT
Introduction: We designed a prospective observational study targeting a selective population of patients undergoing elective coronary artery bypass grafting with normal systolic function. In this study we looked at the
prevalence of pre-operative microvolt T-wave alternans and if it predicts atrial fibrillation after surgery.
Methods: The inclusion criteria included all patients referred to the cardiothoracic outpatient clinic for elective bypass, who can perform aerobic exercise, with a recent exercise stress test exercising at least to 85% of the
maximal predicted heart rate (220 - age) and with non-limiting chest pain at maximal exercise. Twenty patients
met the inclusion/exclusion criteria between May 2008 and February 2010. The hospital course of those patients was followed, and in-hospital events were recorded.
Results: Nine out twenty (45%) of patients had a non-negative microvolt T-wave alternans tracing. Six patients
(30%) developed new onset atrial fibrillation post surgery. Patients with non-negative microvolt level T-wave
alternans are more likely to develop atrial fibrillation post coronary artery bypass grafting then patients with
negative microvolt level T-wave alternans (p=0.05).
Conclusions: This pilot study provides the first clinical evidence that patients with ischemic heart disease and
normal systolic function have a high prevalence of abnormal microvolt T-wave alternans and might be at higher
risk of sudden cardiac death. In addition our results show that microvolt level T-wave alternans predicts post
coronary artery bypass grafting new onset atrial fibrillation.
Keywords: microvolt T, wave alternans, atrial fibrillation, sudden cardiac death.
INTRODUCTION
T-wave alternans is characterized by beatto-beat change in the morphology, amplitude and/or polarity of the T wave. Microvolt level T-wave alternans (MTWA) has
been proposed to assess the abnormalities
in ventricular repolarization, which favors
the occurrence of reentrant arrhythmias
(1). In 1994, a first clinical study by RosenCorresponding author:
Georges Khoueiry, M.D.
Staten Island University Hospital
475 Seaview Avenue
Staten Island, NY 10305
baum and coworkers demonstrated that
MTWA is closely related to arrhythmia induction in the electrophysiology laboratory
as well as to the occurrence of spontaneous ventricular tachyarrhythmias during
follow-up (2, 3). Microvolt TWA analysis
has been implicated as one of the strongest predictors of ventricular arrhythmias
and sudden cardiac death (also superior to
other non-invasive markers of ventricular
repolarization, such as QTc interval prolongation) in several trials including patients
with myocardial infarction, heart failure
and implantable defibrillators (3 -5). Two
main hypotheses have been proposed for
Heart, Lung and Vessels. 2015, Vol. 7
27
G. Khoueiry, et al.
28
the mechanism of MTWA, the action potential restitution and the calcium cycling
hypothesis. There is considerable experimental and clinical trials that do not support the restitution hypothesis (6, 7) on the
other hand there is considerable evidence
to support the abnormal calcium cycling
hypothesi (8).
Patients undergoing elective coronary artery bypass grafting (CABG) tend to be
relatively healthy and subsequently their
surgery is significantly delayed when compared to urgent cases. The cumulative presurgical risk of death from cardiovascular
disease was found to be similar in the semiurgent and elective CABG cases due to the
longer wait for surgery in the later group
(9). The in-hospital death was also shown
to be significantly higher when the surgery
is delayed beyond the recommended time
of 12 weeks in non-urgent cases (10). However there is no data that reports on the risk
of sudden cardiac death in elective CABG
patients with no structural heart disease.
Also, none of the studies looked at the prevalence of MTWA as a predictor of sudden
cardiac death (SCD) in this population.
Also, in patients undergoing CABG, new
onset post operative atrial fibrillation (Afib)
is a very common complication (11). Patient
with this complication were found to have
a significant higher mortality at 10 years of
follow up (11). Recently Afib was linked to
abnormal calcium handling, a mechanism
proposed for abnormal MTWA tracing (12,
13). Although MTWA and Afib may share
a similar underlying mechanism, there are
no reports on the risk of new onset Afib in
patients with abnormal T wave alternans
testing.
We designed a prospective observational
study targeting a selective population of
patients undergoing elective CABG with
normal systolic function. In this study
we looked at the prevalence of pre-operative MTWA. We followed these patients
throughout their hospital stay and looked
at the incidence of new onset Afib in patients with normal and abnormal MTWA
tracing.
METHODS
This study was conducted at a 700 bed University Affiliated urban teaching hospital. It
is an observational study. The institutional
review boards approved the study protocol.
All patients signed an informed consent after a detailed explanation of the study aim
and purpose. The inclusion criteria included all patients referred to the cardiothoracic
outpatient clinic for elective CABG, who
can perform aerobic exercise, and agree to
have a MTWA testing prior to the scheduled surgery. Since MTWA testing involves
a submaximal treadmill exercise test, and
our population involves patients with significant coronary artery disease (CAD), we
pre-specified a safety measure in our protocol. We only considered patients with a
recent exercise stress test who reached at
least 85% of the maximal predicted heart
rate (220 - age) and non-limiting chest pain
at maximal exercise. The exclusion criteria included any of the following criteria;
age less than 18, pregnancy, left ventricular ejection fraction (LVEF) less than 50%,
Patients on any antiarrhytmic medications,
baseline electrolyte abnormalities, known
history of atrial fibrillation, stage 5 chronic
kidney disease (CKD), and inability to perform a submaximal treadmill test.
The patients were recruited between May
2008 and February 2010 at an outpatient
cardiothoracic office at Staten Island University Hospital. In this study we used the
Heartwave System (Cambridge Heart Inc.,
Cambridge, MA, USA). HearTwave® II System detects the presence of MTWA By electrocardiogram (EKG) measurements during
rest, exercise, and then rest again. Fourteen
Heart, Lung and Vessels. 2015, Vol. 7
MTWA pre-CABG
sensors - 7 Micro-V Alternans Sensors and
7 standard electrodes - are placed in the
Frank-lead configuration. The electrodes
are connected to the digital EKG amplifier
that leads back to the MTWA enabled system.
After checking the system for correct lead
placement, the patient is directed to begin
walking on a treadmill to raise the heart
rate. The exercise part consists of two levels. The first aims to maintain the heart
rate at 100-110 bpm for a total 90 seconds,
while the second goal is to achieve a heart
rate of 110-120 for the same time interval.
The total time of submaximal exercise can
range between 5-10 minutes to achieve and
adequate recording. The patients were instructed to hold calcium channel blockers
or beta-blockers on the day of testing to
achieve adequate heart rate with minimal
exercise.
Based on the previously defined criteria
by Bloomfield et al., MTWA tracing was
interpreted as either negative or non-negative which included patient with positive
or intermediate tracing (14). Studies have
well shown that intermediate and positive
MTWA tracing, have similar prognostic
value (15, 16). Each test was analyzed by
the same electrophysiologist (cardiologist),
and confirmed by a trained technician from
the company, who was blinded to the study
and patients.
The hospital course of all patients included
in the study was followed, and in-hospital
events were recorded. This included, post
surgery Afib, sustained ventricular tachycardia, ventricular fibrillation, cardiac arrest, arrhythmias requiring anti-arrhythmic
treatment, and hospital death.
In order to assess the prevalence of atrial
fibrillation in patients with a non-negative
MTWA we divided the sample into two
groups. The first involved all patients with
non-negative test MTWA (+), while the
second included all with a negative test
MTWA (-). We also studied variables that
were shown to predict atrial fibrillation post
CABG. Based on a study done by Amar et.
al, 4 variables were shown to predict Afib
post CABG. These included older age, prior
history of Afib, P-wave duration >110 ms
on surface EKG, and low cardiac output defined as cardiac index <2 l/min/m2 for >
8 h after surgery (17). In that study a point
score was developed to predict the probability of post CABG Afib. In our study we used
this validated score to compare the risk of
post-CABG Afib in the MTWA groups (Table 1).
Table 1 - Clinical characteristic and outcome by Microvolt T-wave Alternans (MTWA) groups.
MTWA (+) test
(n=9)
MTWA (-) test
(n=11)
p-value
History of MI
1 (11%)
3 (27%)
0.4
History of DM
3 (33%)
4 (36%)
1.0
GFR (ml/min/m2)
75* (35-105)**
90* (43-115)**
0.1
Ejection fraction (%)
58* (50-70)**
58* (55-65)**
0.8
Post CABG Afib
5 (55%)
1 (9%)
0.05
Point score
68* (50-80)
64* (45-80)**
0.3
1 (11%)
0 (0%)
0.4
for risk of post CABG Afib
Post CABG cardiac arrest
*Mean, **Range
MTWA = Microvolt level T-wave alternans; MI = myocardial infarction; DM = diabetes mellitus; GFR = glomerular filtration rate; CABG = coronary artery bypass graft; Afib = atrial fibrillation.
Heart, Lung and Vessels. 2015, Vol. 7
29
G. Khoueiry, et al.
30
Statistical analysis. Continuous variables
were expressed as a mean ± standard deviation (SD) and were compared using an
unpaired two-tailed Student’s t-test.
Unpaired categorical variables were compared using Fisher’s exact test. A probability cutoff of p<0.05 was considered significant for all statistical determinations.
A multivariate logistic regression model was
used to evaluate the independent contribution of baseline clinical characteristics to the
development of the end point in a forward
stepwise manner.
At each step, a significance of 0.10 was required to enter into the model while those
with probabilities less than 0.05 were considered statistically significant. All analyses were performed using SPSS 19.0 (SPSS
Inc., Chicago, IL).
RESULTS
Sixty three patients were initially considered for enrollment. Only 36 met the inclusion criteria that were specified in our
study protocol. Out of those, twenty four
consented and were further followed. Of
the 24 patients, 4 did not show up on the
day of the MTWA testing and were dropped
out of the study. The characteristics of the
studied sample population are listed in Table 2. The mean age was 62.3±10.97 years.
The majority were male (90%), and white
(75%). Hypertension and hyperlipidemia
were highly prevalent (90%). The average
number of bypassed vessels was 3.5.
The median and mean time elapse from coronary angiography to bypass surgery was
29 and 23 days, respectively. All MTWA
tests were performed within a week prior
to the scheduled surgery. The results are
shown in Table 1. Nine out twenty (45%)
patients had a non-negative MTWA tracing. The mean age of MTWA (+) group
was 64 years slightly older than the MTWA
Table 2 - Demographics and hospital events.
Demographics
Sex
Count
Percent
Male
18
90%
Female
2
10%
White
15
75%
All Other
5
25%
Hypertension
18
90%
History of dysrhythmias
0
0%
Diabetes Mellitus
7
35%
Hyperlipidemia
18
90%
Myocardial Infarction
4
20%
History of atrial fibrillation
0
0%
Beta Blocker
16
80%
Aspirin
18
90%
Clopidogrel
12
60%
ACE/ARB
13
65%
CCB
4
20%
13
65%
Race
Past Medical History
Medications
Social History
Smoking
Post Surgical Complications
Cerebrovascular Accident
0
0%
Atrial Fibrillation
6
30%
Myocardial Infarction
0
0%
Asystole
1
5%
ACE = angiotensin converting enzyme inhibitor; ARB =
angiotensin receptor blocker; CCB = calcium channel blocker.
(-) group which was 61years. Diabetes mellitus (DM) and prior history of myocardial
infarction (MI) was slightly higher in the
MTWA (-) group. The mean glomerular filtration rate was lower in the MTWA (+),
but none of the patients had a stage 5 CKD,
as this was one of the exclusion criteria.
The Point score that predicts the risk of
post CABG Afib was similar in both groups
(Table 1).
All patients were followed throughout the
hospital course. The mean hospital stay
Heart, Lung and Vessels. 2015, Vol. 7
MTWA pre-CABG
Figure 1 - The incidence of postcoronary artery bypass graft
atrial fibrillation by Microvolt
T-wave Alternans (MTWA)
groups.
AF =atrial fibrillation.
was 4 and 7 days among MTWA (-) and
MTWA (+) groups, respectively. The
hospital stay did not differ between the 2
groups. There was no in-hospital death.
One patient in the MTWA (+) group
had a cardiac arrest post surgery and was
successfully resuscitated. There were no
events of sustained ventricular tachycardia
or ventricular fibrillation in both groups.
One (9%) patient with negative MTWA
developed AF in comparision to 5 (55%)
paitens with non-negative MTWA. Patients
with non-negative MTWA are more likely
to develop AF post CABG then patiens with
negative MTWA (p=0.05) (Table 1, Figure
1). In multivarient logistic regresion, a nonnegative MTWA was the only predictor of
AF (p=0.042). Two patients with Afib required electrical cardioversion, while the
others were converted chemically.
Finally we looked at the 30 months mortality using the national death registry. There
was no reported death in any of the groups.
DISCUSSION
In MADIT-2 trial MTWA was shown to
have a better risk stratification for SCD
when compared to QRS duration on EKG
in patients with ischemic heart disease
(18). In several studies, MTWA was shown
to have a prognostic value after acute myocardial infarction (19, 20).
In our study we found that the prevalence
of abnormal MTWA is very high when compared to previous reports on healthy adults.
In this study we aimed to assess the prevalence of abnormal cardiac repolarization in
patients with ischemic heart disease scheduled for elective CABG. All of our patients
had a systolic function of more than 50%,
and none of them had a significant CKD as
we specified in our study protocol (Table
1). The reported prevalence of abnormal
MTWA in healthy adults ranged between 4
and 5% (21, 22). Post MI it was reported to
be abnormal in up to 44% of patients (20).
Abnormal MTWA was also reported to be
high in diabetics, in patients with uremic
cardiomyopathies, and in patients on hemodialysis (23-27). Neither ischemic, nor
uremic cardiomyopathy can explain the
high prevalence of abnormal MTWA in our
studied population (45%). Moreover, looking at other potential clinical predictors for
abnormal MTWA, there was more patients
with history of DM and prior MI in the
Heart, Lung and Vessels. 2015, Vol. 7
31
G. Khoueiry, et al.
32
MTWA (-) group. In the MTWA (+) group,
one patient had history of MI, and 3 had
DM. None of those patients had a concomitant history of MI and DM. On the other
hand in the MTWA (-) group, three had a
prior history of MI, and 4 where diabetic.
Of those, two had DM and MI. There was
no statistically significant difference in any
of the known clinical predictors of abnormal MTWA in both groups (Table 1). For
this reason, although DM and prior history
of MI could have contributed to the MTWA
test results in this population, it does not
exclusively explain the high prevalence noted in our population.
Animal studies have shown that regional
myocardial ischemia in structurally normal
hearts can lead to regional action potential
alternans (28, 29). This can lead electrical
dispersion and arrhythmias (29). Regional
Ischemia induced by exercise might explain
the prevalence of abnormal MTWA in this
population. There are no previous studies
that looked at MTWA as a predictor of SCD
in patients with ischemia but normal systolic function. One patient with abnormal
MTWA tracing had a post surgical asystole,
and was successfully resuscitated. There
was no recorded death in both groups at 30
months of follow up.
Although our observation may suggest that
patients awaiting elective CABG are at high
risk of arrhythmias and SCD, Further studies are needed to assess the potential risk
in this population before drawing further
conclusion.
The incidence on new onset atrial fibrillation post CABG varies between 11% and
40% depending on the study cohort and
method of detection used (11, 30). In this
study we excluded patients with history of
Afib. Post-op, 30% of patients developed
new onset atrial fibrillation. Interestingly,
most of those had an abnormal MTWA
tracing. Patients with non-negative MTWA
are more likely to develop atrial fibrillation
(AF) post CABG then patiens with negative
MTWA with a significant p value (p=0.05)
(Table 1, Figure 1). In multivarient logistic
regresion, a non-negative MTWA was the
only predictor of AF (p=0.042).
There is growing evidence that links atrial
fibrillation to abnormal calcium handling/
calcium alterans (12, 13). Similarly, there
are considerable evidence that abnormal
calcium cycling/calcium alternans is the
mechanism behind action potential and T
wave alternans. Since MTWA tracing in patients with atrial fibrillation is not feasible,
no studies have looked at the prevalence
of abnormal MTWA in patient with Afib.
Also there no previous reports on the risk
of new onset Afib in patients with abnormal T wave alternans testing. Knowing that
both Afib and abnormal MTWA might have
a common electrical mechanism, this study
presents the first direct link between the
two. We think that the risk of post-CABG
atrial fibrillation might be further stratified
by pre-CABG MTWA in groups with comparable other risk scores. Although this
finding is very interesting we only suggest
a potential association between abnormal
MTWA and Afib, and further studies with
more patients are needed to consolidate our
finding.
There are several limitations to this study.
The sample size is small and limits us from
generalizing our results. Although this is
a significant limitation we think that our
results are very interesting to report especially that we targeted a very specific group
of patients.
We had many exclusion criteria to assure
patient safety, which limited our ability to
recruit a larger sample. A multicenter study
will be needed to recruit a larger and more
representative sample. Another limitation
is that the prognosis of abnormal MTWA
testing is not well established in patients
with ischemic heart disease with normal
systolic function. For this reason even with
Heart, Lung and Vessels. 2015, Vol. 7
MTWA pre-CABG
this high prevalence of abnormal MTWA
results, the risk of SCD is still unknown.
Furthermore, there was no difference in
mortality at any interval follow up in both
groups. For this reason no assumption can
be drawn on the risk of SCD in this population until we have more data.
10.
11.
12.
CONCLUSION
13.
This pilot study provides the first clinical
evidence that patients with ischemic heart
disease and normal systolic function have
a high prevalence of abnormal MTWA and
might be at higher risk of SCD.
In addition our results shows that MTWA
predicts post CABG new onset atrial fibrillation. MTWA might be studied as a potential factor in future Afib risk scores. Despite
our interesting findings, we suggest a multicenter study with a larger representative
sample to confirm our findings.
14.
15.
16.
17.
18.
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Cite this article as: Khoueiry G, Abdallah M, Shariff M, Kowalski M, Lafferty J. Microvolt T-wave alternans in patients undergoing elective coronary artery bypass grafting: a pilot study. Heart, Lung and Vessels. 2015; 7(1): 27-34.
Source of Support: Nil. Disclosures: None declared.
Heart, Lung and Vessels. 2015, Vol. 7
ORIGINAL ARTICLE
Heart, Lung and Vessels. 2015; 7(1): 35-46
Beneficial impact of levosimendan
in critically ill patients with or at risk
for acute renal failure: a meta-analysis
of randomized clinical trials
Tiziana Bove1, Andrea Matteazzi1, Alessandro Belletti1, Gianluca Paternoster2,
Omar Saleh1, Daiana Taddeo1, Roberto Dossi1, Teresa Greco1,3, Nikola Bradic4,
Ino Husedzinovic4, Caetano Nigro Neto5, Vladimir V. Lomivorotov6,
Maria Grazia Calabrò1
1
Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy; 2Anesthesia and Intensive
Care, A.O. Regionale “San Carlo”, Potenza, Italy; 3Section of Medical Statistics and Biometry Giulio A. Maccacaro, Department
of Occupational and Environmental Health, University of Milan, Milan, Italy; 4Department of Cardiovascular Anesthesia and
Cardiac Intensive Care Medicine, Clinic of Anesthesiology, Reanimatology and Intensive Care Medicine, University Hospital
Dubrava, Zagreb, Croatia; 5Dante Pazzanese Institute of Cardiology, São Paulo, Brazil; 6Department of Anesthesiology and
Intensive Care, State Research Institute of Circulation Pathology, Novosibirsk, Russia
Heart, Lung and Vessels. 2015; 7(1): 35-46
ABSTRACT
Introduction: The incidence of Acute Kidney Injury is nowadays high in critically ill patients. Its etiology is
multifactorial and a primary role is played by low cardiac output syndrome. Everything targeted to normalize
cardiac output should increase the renal perfusion and abolish the secondary vasoconstriction. Levosimendan
is a calcium sensitizer drug with inotropic properties that improves cardiac output and seems to increase renal
blood flow. The aim of this meta-analysis was to evaluate the role of levosimendan in critically ill patients with
or at risk of Acute Kidney Injury.
Methods: We performed a meta-analysis of randomized controlled trials searching for trials that compared
levosimendan with any comparator. The endpoints were the number of patients receiving Renal Replacement
Therapy after randomization and the number of patients developing Acute Kidney Injury.
Results: Final analysis included 33 trials and 3,879 patients (2,024 levosimendan and 1,855 control). The
overall analysis showed that the use of levosimendan was associated with a significant reduction in the risk
of Renal Replacement Therapy (17 of 492 [3.5%] in the levosimendan group versus 37 of 427 [8.7%] in the
control group, relative risk =0.52 [0.32 to 0.86], p for effect =0.01) and of Acute Kidney Injury (114 of 1,598
[7.1%] in the levosimendan group versus 143 of 1,529 [9.4%] in the control arm, relative risk =0.79 [0.63 to
0.99], p for effect =0.048).
Conclusions: This meta-analysis suggests that the use of levosimendan is associated with a significant reduction of Renal Replacement Therapy in critically ill patients.
Keywords: levosimendan, acute kidney injury, critical care, renal replacement therapy.
INTRODUCTION
Despite considerable progress in terms of
diagnosis and treatment, the incidence of
Corresponding author:
Tiziana Bove, MD
Department of Anesthesia and Intensive Care,
San Raffaele Scientific Institute
Via Olgettina, 60 - 20132 Milan, Italy
e-mail: bove.tiziana@hsr.it
Acute Kidney Injury (AKI) remains high in
critically ill patients. Interventions or medications that can alter the clinical course of
AKI and change the outcome of critically ill
patients are scarce (1).
The etiology of acute renal failure in critically ill patients is multifactorial and a primary role is played by low cardiac output
Heart, Lung and Vessels. 2015, Vol. 7
35
T. Bove, et al.
36
syndrome and sepsis. The main determinants of renal perfusion are cardiac output,
blood pressure and blood volume. The kidneys normally receive 20-25% of the cardiac output, although their total weight is less
than 1% of total body weight. The decrease
in cardiac output due to hypovolemia or
cardiac dysfunction decreases renal perfusion with direct and indirect mechanisms.
Indeed, in addition to the reduction in renal blood flow, activation of sympathetic
nervous system, renin-angiotensin system
and vasopressin secretion occur. Each intervention targeted to normalize cardiac
output and systemic perfusion should be
able to increase the renal perfusion and
abolish the secondary vasoconstriction.
Levosimendan is a calcium sensitizer drug
with inotropic properties (2). It also has vasodilating properties interacting with ATPsensitive K+channels of vascular smooth
muscles cells. Levosimendan seems to reduce the release of pro-inflammatory cytokines and to prevent the cardiomyocyte
apoptosis. Therefore, it improves cardiac
output and seems to increase renal blood
flow by its vasodilating effects. Levosimendan has already been associated with reduction of mortality in critically ill patients
in a meta-analysis of randomized clinical
trials, but its effects on renal function have
never been systematically assessed (3).
The aim of this meta-analysis of randomized trials was to evaluate the role of levosimendan in critically ill patients with or at
risk of AKI.
METHODS
We performed a systematic review and
meta-analysis of randomized trials in accordance with the PRISMA (Preferred Reporting Items for Systematic reviews and
Meta-Analyses) guidelines.
We searched for all randomized controlled
trials that compared levosimendan with
any pharmacological comparator or placebo in any clinical setting. Potentially eligible trials were identified by searching the
Cochrane central register, Embase, Scopus
and Medline using a combination of subject
headings and text words to identify randomized controlled trials of levosimendan.
The search was updated at January 2013.
The full PubMed search strategy is available
in the supplemental item S1. Searches were
not restricted by language or publication
status. To identify ongoing or unpublished
trials, we searched the Clinical Trial Registry. We also examined the reference lists of
eligible trials and reviews together with the
abstracts of international congresses. The
following inclusion criteria were used for
potentially relevant studies: random allocation to treatment and comparison of levosimendan vs. control. There were no restrictions on age, drug’s dose or time of administration. Exclusion criteria were overlapping
publications, abstracts published before
2010, oral administration of levosimendan,
and lack of data on renal outcome. Two
authors independently screened the search
output to identify records of potentially eligible trials, the full texts of which were retrieved and assessed for inclusion.
The primary endpoint was the number
of patients receiving Renal Replacement
Therapy (RRT) after randomization; the
secondary endpoint was the number of patients developing AKI (as per author definition). We also collected data on serum
peak creatinine and glomerular filtration
rate. We contacted trial authors to obtain
any missing outcome data. We extracted
data on setting, dose of levosimendan, type
of comparator, outcome data and length of
follow up. We assessed the risk of bias associated with the method of sequence generation, allocation concealment, blinding, and
completeness of outcome data. We rated the
risk of bias as being low, unclear, or high
according to established criteria (4).
Heart, Lung and Vessels. 2015, Vol. 7
Levosimendan and acute renal failure
Statistical analysis. For binary outcome
we calculated the natural logarithm (ln)
of risk ratios (RR) and its standard deviation. We pooled these using the inverse
variance method and a fixed effect model
in case of low statistical inconsistency (Isquare≤25%) or with random-effect model
(which better accommodates clinical and
statistical variations) in case of moderate or high statistical inconsistency (Isquare>25%). Weighted Mean Difference
(WMD) and 95% confidence intervals were
computed for continuous variables using
the same methods as just described (4). To
assess heterogeneity in results of individual
studies, we used Cochran’s Q statistic and
the I-square statistic (I-square>25% was
considered as a threshold indicating significant heterogeneity). Publication bias
was assessed by visually inspecting funnel
plots of the primary outcome, by analytical
appraisal based on the Begg adjusted-rank
correlation test and on Egger’s linear regression test (a two-sided p value of 0.10 or
less was regarded as significant).
Subgroup analyses were carried out to examine whether the effect of levosimendan
on RRT varied by setting or type of infusion. Sensitivity analyses were done to
quantify the effect of levosimendan when
restricted to trials with low risk of bias. We
also investigated the influence of a single
study on the overall risk estimate by sequentially removing study in order to test
the robustness of the main results.
Statistical significance was set at the twotailed 0.05 level for hypothesis testing.
Data analysis was performed using STATA
11.0 Software (StataCorp LP, College Station, TX, USA).
RESULTS
Characteristics of the included individual
studies. Our search strategy identified 599
unique publications, the titles and abstracts
of which were screened for inclusion. The
full text of 97 articles was retrieved, of
which 33 (5-37) met the inclusion criteria (Figure 1). Reasons for exclusion of the
Figure 1 - Flow diagram: selection process
of included articles.
Heart, Lung and Vessels. 2015, Vol. 7
37
T. Bove, et al.
38
Table 1 - Description of the 33 studies included in the meta-analysis.
Author
Year Journal
Control
Setting
Setting details
Al-Shawaf E
2006 J Cardiothorac Vasc Anesth
Milrinone
Cardiac surgery
LCOS after CABG
Alvarez J
2005 Rev Esp Anestesiol Reanim
Dobutamine
Cardiac surgery
LCOS after cardiac surgery with CPB
Alvarez J
2006 Rev Esp Cardiol
Dobutamine
Cardiac surgery
LCOS after cardiac surgery with CPB
Barisin S
2004 J Cardiovasc Pharmacol
Placebo
Cardiac surgery
20 min before surgery OPCABG
Baysal A
2013 J Cardiothorac Vasc Anesth
Inotropes
Cardiac surgery
Cardiac surgery
Bonios MJ
2012 Int J Cardiol
Dobutamine
Cardiology
HF (end stage)
Bragadottir G
2013 Crit Care Med
Placebo
Cardiac surgery
Cardiac surgery
De Hert SG
2007 Anesth Analg
Milrinone
Cardiac surgery
Cardiac surgery with CPB
Flevari P
2006 Am J Cardiol
Placebo
Cardiology
HF (decompensated advanced)
Fuhrmann JT
2008 Crit Care Med
Enoximone
Cardiology
Patients with acute myocardial infarction and cardiogenic shock
Hou ZQ
2013 Cardiovasc Ther
Placebo
Cardiology
LVEF<40%
Iyisoy A
2010 Turk J Med Sci
Dobutamine
Cardiology
ADHF
Cardiac surgery
After induction in aortic valve surgery with
severe aortic valve stenosis and LV hypertrophy
Jarvela K
2008 J Cardiothorac Vasc Anesth
Placebo
Kurt IH
2010 Heart Vessels
Standard of treatment
Cardiology
HF (NYHA class III-IV)
Lahtinen P
2011 Crit Care Med
Placebo
Cardiac surgery
Heart valve surgery
Leppikangas H
2008 Acta Anaesthesiol Scand
Placebo
Vascular surgery
Infrarenal abdominal aortic aneurysm
Levin R
2008 Rev Esp Cardiol
Dobutamine
Cardiac surgery
LCOS after CABG
Malfatto G
2012 J Cardiovasc Pharmacol
Furosemide
Cardiology
HF (chronic)
Mebazaa A
2007 JAMA
Dobutamine
Cardiology
ADHF
Moertl D
2005 Eur J Heart Fail
Pge1
Cardiology
HF (decompensated chronic)
Momeni M
2011 J Cardiothorac Vasc Anesth
Milrinone
Neonatal cardiac surgery
Cardiac surgery
Morelli A
2005 Intensive Care Med
Dobutamine
Sepsis
LV dysfunction post septic shock after 48 hours of
conventional treatment
Morelli A
2010 Crit Care
Dobutamine
Septic shock
Nijhawan N
1999 J Cardiovasc Pharmacol
Placebo
Cardiac surgery
ASA III-IV undergoing elective cardiac surgery
Packer M
2013 JACC Heart Fail
Placebo and standard
HF treatment
Cardiology
Cardiology
Parissis JT
2006 Heart
Placebo
Cardiology
HF (NYHA III-IV and LVEF≤30%)
Ricci Z
2012 Intensive Care Med
Standard inotropic
management
Pediatric cardiac surgery
Cardiac surgery
Ristikankare A
2012 J Cardiothorac Vasc Anesth
Placebo
Cardiac surgery
Cardiothoracic surgery
Slawsky MT
2000 Circulation
Placebo
Cardiology
HF (NYHA class III-IV)
Tritapepe L
2009 Br J Anaesth
Placebo
Cardiac surgery
CABG
Yilmaz MB
2007 Cardiovasc Drugs Ther
Dobutamine
Cardiology
Worsening of HF
Yontar OC
2010 Arq Bras Cardiol
Dobutamine
Cardiology
HF (ischemic)
Zemljic G
2007 J Card Fail
Nothing
Cardiology
HF (advanced, waiting for heart transplantation)
LCOS = low cardiac output syndrome; CABG = coronary artery bypass grafting; OPCABG = off-pump coronary artery
bypass grafting; CPB = cardiopulmonary bypass; HF = heart failure; ADHF = acute decompensated heart failure; NYHA
= New York Heart Association; ASA = American Society of Anesthesiology Physical Classification System; LV = left ventricle; LVEF = left ventricular ejection fraction.
Heart, Lung and Vessels. 2015, Vol. 7
Levosimendan and acute renal failure
remaining articles are detailed in Figure 1.
The list of the 97 major exclusions is available in the supplemental Table S1.
The 33 included trials randomized 3,879
patients (2,024 to levosimendan and 1,855
to control). Clinical heterogeneity was
mostly due to setting, dose and control
treatment (Tables 1 and 2). In details, 15
studies used levosimendan in a cardiological setting (decompensated heart failure,
NYHA III-IV), 15 in cardiac surgery (two
of these in pediatric patients), two studies were conducted in septic patients and
one in vascular surgery patients. Twenty-
Table 2 - Description of levosimendan administration in the 33 studies included in the meta-analysis.
Author
Year
Levosimendan
bolus (ug/kg)
Levosimendan continuous
infusion (ug/kg/min)
Lenght of levosimendan
infusion (hours)
Al-Shawaf E
Alvarez J
Alvarez J
Barisin S
Baysal A
Bonios MJ
Bragadottir G
De Hert SG
Flevari P
Fuhrmann JT
Hou ZQ
Iyisoy A
Jarvela K
Kurt IH
Lahtinen P
Leppikangas H
Levin R
Malfatto G
Mebazaa A
Moertl D
Momeni M
Morelli A
Morelli A
Nijhawan N
2006
2005
2006
2004
2013
2012
2013
2007
2006
2008
2013
2010
2008
2010
2011
2008
2008
2012
2007
2005
2011
2005
2010
1999
12
12
12
12 or 24
6
0.1-0.2
0.2
0.2
24
24
24
0.1
0.3
0.1
0.1
0.1
0.1 for 50 min then 0.2
0.05 or 0.1 or 0.2
0.1
0.2
0.1
0.2
0.2
0.1
0.1-0.4
0.2
0.1
0.05
0.2
0.2
0.2 or 0.3
24
6 hours for 6 months
Packer M
2013
12 (6 if under treatment with oth- 0.1 (0.2 if tolerated 0.1-0.05
er inotropic or vasodilating drugs) if not tolerated)
24
Parissis JT
Ricci Z
Ristikankare A
Slawsky MT
Tritapepe L
Yilmaz MB
Yontar OC
Zemljic G
2006
2012
2012
2000
2009
2007
2010
2007
6
0.1-0.4
0.1
0.2
0.1-0.4
24
72
24
4-6
0.1-0.2
0.1-0.2
0.1
24
24
24
12
12
12
12
12
24
24
10
12
12
18 or 26
12
6
24
0.3-0.6
12
Heart, Lung and Vessels. 2015, Vol. 7
19+4
24
50 min- other 23 hours
24
24
24
24
24
24
24
24
24
24
48
24
24
6
39
T. Bove, et al.
40
three authors administered a loading dose
and thirty-one used a continuous infusion
(twenty-one of them following bolus). Dose
varied between 0.3 and 0.6 mcg/kg as intravenous bolus and between 0.05 and
0.4 mcg/kg/min as a continuous infusion.
Thirteen studies (39% of all) used placebo as control while ten (30% of all) used
dobutamine and 31% other comparators.
Study quality appraisal indicated that studies were of variable quality (supplemental
Table S2) with 13 (39%) of them having
low risk of bias. Quantitative data synthesis. Overall analysis on principal endpoint (Figure 2) showed
that the use of levosimendan was associated with a significant reduction in the risk
of RRT (17 of 492 [3.5%] in the levosimendan group versus 37 of 427 [8.7%] in
the control group, RR=0.52, 95% confidence interval (CI) 0.32 to 0.86, p for effect
=0.01, p for heterogeneity =0.9, I-square
=0%, with 13 studies included). Visual
inspection of funnel plots did not identify
a skewed or asymmetrical shape (Figure
3) and quantitative evaluation did not suggest a presence of publication bias, as measured by the Begg test (p=0.3) and Egger
test (p=0.9). All but one studies reporting RRT data administered levosimendan
as bolus and the reduction in the need for
RRT was confirmed in these 12 studies (17
of 480 [3.5%] in the levosimendan group
versus 37 of 415 [8.9%] in the control arm,
Figure 2 - Forest plot for the risk of Renal Replacement Therapy. The use of levosimendan was associated
with a significant reduction in the risk of RRT (17 of 492 [3.5%] in the levosimendan group versus 37
of 427 [8.7%] in the control group, RR=0.52, 95% CI 0.32 to 0.86, p for effect =0.01, p for heterogeneity=0.9, I-square=0%, with 13 studies included).
RR = risk ratio; CI = confidence interval.
Heart, Lung and Vessels. 2015, Vol. 7
Levosimendan and acute renal failure
41
Figure 3 - Funnel plot for the risk of Renal Replacement Therapy.
RR = risk ratio; se = standard error.
RR=0.52, 95% CI 0.31 to 0.86, p for effect
=0.01, p for heterogeneity =0.9, I-square
=0%). All but two studies reporting RRT
data administered levosimendan in the
perioperative period and the reduction in
the need for RRT was confirmed in these
11 studies (12 of 378 [3.2%] in the levosimendan group versus 29 of 363 [8%] in
the control arm, RR=0.48, 95% CI 0.26 to
0.89, p for effect=0.02, p for heterogeneity=0.9, I-square=0%).
The analysis on secondary endpoints
showed that the use of levosimendan was
associated with a significant reduction in
AKI risk (114 of 1,598 [7.1%] in the levosimendan group versus 143 of 1,529 [9.4%]
in the control arm, RR=0.79, 95% CI 0.63
to 0.99, p for effect =0.048, p for heterogeneity =0.8, I-square =0%, with 19 stud-
ies included). This result was confirmed in
the perioperative setting (39 of 411[9.5%]
in the levosimendan arm versus 69 of 396
[17%] in the control arm, RR=0.60, 95%
CI 0.42 to 0.86, p for effect =0.005, p for
heterogeneity =0.9, I-square =0%, with
13 studies included).
Glomerular filtration rate was better after
randomization in patients receiving levosimendan (WMD =8.08, 95% CI 3.35 to
12.80, p for effect =0.001) in the 8 studies
reporting it while no difference was found
in peak serum creatinine values (WMD
=-0.02, 95% CI -0.11 to 0.07, p for effect
=0.7) in the 15 studies reporting it.
Sensitivity analyses considering only data
from studies with low risk of bias confirmed a trend towards reduction in the
risk of RRT (3 of 238 [1.3%] in the levosi-
Heart, Lung and Vessels. 2015, Vol. 7
T. Bove, et al.
42
Figure 4 - Analysis of the influence of levosimendan versus any control on the overall risk of Renal Replacement Therapy. This figure shows the influence of individual studies on the summary Risk Ratio. The
middle vertical axis indicates the overall RR and the two vertical axes represent the 95% CI.
RR = risk ratio; CI = confidence interval.
mendan group versus 10 of 177 [5.6%] in
the control arm, RR=0.41, 95% CI 0.15 to
1.12, p for effect =0.08, p for heterogeneity =0.9, I-square =0%, with 6 studies included). When removing each single study
from the meta-analysis to determine the influence of individual data sets to the pooled
RRs, the corresponding pooled RRs were
not altered (Figure 4) with the exception of
the study of Baysal (9) (p=0.054 when it
was removed).
DISCUSSION
We performed a comprehensive and updated review of randomized controlled trials to
investigate the role of levosimendan in the
prevention and treatment of AKI in critically ill patients. The most important result
of this study is the reduction in the need
for RRT in levosimendan-treated critically
ill patients.
In critically ill patients sepsis, major surgery (especially cardiac surgery) and acute
decompensated heart failure are the most
common triggers of AKI. The mainstay
of prevention and treatment of AKI is the
treatment of the cause of acute renal failure
and withdrawal of nephrotoxic agents. If
there are pre-renal or post-renal factors to
be corrected, they must be identified. The
optimization of hemodynamic conditions
Heart, Lung and Vessels. 2015, Vol. 7
Levosimendan and acute renal failure
should be the main goal of care and intravascular volume must be monitored and
maintained in the normal range. In addition
to the optimization of hemodynamic status and suspension of nephrotoxic agents
no other pharmacological intervention has
been shown to be effective in the prevention and treatment of AKI and a recent web
based survey suggested that the15 interventions that might improve clinically relevant
endpoints in critically ill patients with or at
risk for AKI are supported by low levels of
evidence.
Levosimendan the (-) enantiomer of
4-(1,4,5,6-tetrahydro-4-methyl-6-oxo3-pyridazinyl) phenylhydrazonopropanedinitrile is a new calcium enhancer with calcium-sensitizing activity. The mechanism
of action that makes the levosimendan effective in preventing and treating kidney
damage may be related to its beneficial action on the normalization of hemodynamic
conditions.
The main mechanism of action of this drug
is an increase in affinity of troponin C for
calcium and therefore the stabilization
of the conformation of troponin C. This
mechanism of action translates into inotropic effect without determining increase
intracellular cAMP or the intracellular calcium concentration at the doses used in
clinical practice. This mechanism leads to
acceleration of actin-myosin cross-bridge
formation rate and deceleration of the dissociation rate. The binding becomes considerably weaker during diastole, when the
intracellular calcium concentration is low,
and this has a beneficial effect on the relaxation of myocardial muscle cells, resulting
in improvement of diastolic function. The
positive inotropic effect is obtained without
impairing ventricular relaxation or increasing myocardial oxygen demand.
Levosimendan also has ancillary actions
that may be responsible for the beneficial
actions on renal function. Levosimen-
dan indeed activates the opening of the
ATP-sensitive sarcolemma K+ channels of
smooth muscle cells and myocytes determining their hyperpolarization with consequent vasodilatation, which may contribute to augmentation of renal perfusion
and depression of central venous pressure.
Central venous pressure is an independent
predictor of glomerular filtration rate in
patients with congestive heart failure (38).
An important mechanism of action of levosimendan on renal function may be linked
to its ownership of venodilation, which reduces the renal congestion and increases
renal perfusion pressure. Administration of
levosimendan also entails a reduction of circulating proinflammatory cytokines. This
effect can be considered secondary to the
inotropic and vasodilator properties of the
drug, but may also result from the extracardiac downregulation of the synthesis of cytokines through transcription factors (39).
In addition, the administration of this drug
induces significant reduction of soluble mediators of apoptosis, such as Fas and Fas ligand (40, 41). Still, levosimendan improves
endothelial function through downregulation of soluble cell adhesion molecules such
as ICAM-1 and VCAM1 and regulates the
mediators implicated in oxidative and nitrosative stress. Recent studies show that it
can preserve organ function in acute and
septic shock-induced myocardial depression via cooling down the oxidative burst of
circulating cells (42, 43). Studies in animal
models have yielded conflicting results regarding the effect of levosimendan on renal
function. In fact, while in models of septic
shock seem to outweigh the beneficial effects on hemodynamics, in animal models
of ischemia reperfusion seems to prevail an
effect of organ protection (44-49).
Bragadottir et al. (11) carried out a randomized, placebo-controlled clinical trial
over the effects of levosimendan on the renal blood flow, the GFR, the renal oxygen
Heart, Lung and Vessels. 2015, Vol. 7
43
T. Bove, et al.
44
consumption and the renal oxygen supply/
demand, in cardiac surgical setting. The
main result of this paper is that levosimendan induces renal vasodilation, preferentially of pre-glomerular resistance vessels,
increasing both renal blood flow and glomerular filtration rate, without impairing
renal oxygen demand/supply relationship
as demonstrated by the lack of effect on renal oxygen extraction. The careful analysis
of the literature has identified 33 studies
that evaluated the effect of levosimendan
on renal function performed on critically ill
patients in four different settings: cardiology (16 studies), cardiac surgery (15 studies), vascular surgery (1 study) and sepsis
(2 studies). Although in most of them the
impact of levosimendan on renal function
was not the pre-planned primary outcome
and most of them are individually statistically underpowered, many of them suggested a trend of benefit on renal function, and
the pooled data analysis of 4,082 patients
included in the meta-analysis suggests a
beneficial effect of levosimendan on renal
function including glomerular filtration
rate, AKI as per author definition and RRT
with sensitivity analyses confirming the validity of our findings.
The findings of our manuscript could be
compared to those of three other papers.
In a previous meta-analysis Landoni et al.
highlighted the beneficial effects of levosimendan in critically ill patients (3). However, the authors did not investigate the renal outcomes and the search was updated at
November 2010. A more recent meta-analysis (50) suggested for the first time a beneficial effect of levosimendan on AKI, but
the study was limited to the cardiac surgery
setting and to 529 patients. A recent consensus report (51) suggested a beneficial effect of levosimendan on renal outcomes but
it was a systematic review of the literature
without a meta-analytic approach.
The main limitation of the present meta-
analysis is that several included RCTs were
of suboptimal quality. Furthermore, traditional limitations of meta-analyses due to
variations in the treatment regimens, in
populations or major subgroups within trials, and in the conduct of the trials apply to
this study. On top of that, great variability
of clinical setting and a relative small number of studies analyzed for primary end
point (RRT) should be acknowledged.
CONCLUSION
This meta-analysis shows that the use of
levosimendan is associated with a significant reduction in incidence of RRT in critically ill patients. Since meta-analyses are
hypothesis generating, large multicenter,
randomized, placebo-control clinical trials
designed to assess the role of levosimendan
in the treatment of acute renal failure in
critically ill patients are warranted.
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OO, et al. Levosimendan improves renal function in patients
with acute decompensated heart failure: comparison with
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37. Zemljic G, Bunc M, Yazdanbakhsh AP, Vrtovec B. Levosimendan Improves Renal Function in Patients With Advanced Chronic Heart Failure Awaiting Cardiac Transplantation. J Card Fail. 2007; 13: 417-21.
38. Damman K, Navis G, Smilde TDJ, Voors AA, van der Bij W,
van Veldhuisen DJ, et al. Decreased cardiac output, venous
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872-8.
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40. Parissis JT, Adamopoulos S, Antoniades C, Kostakis G, Rigas A, Kyrzopoulos S, et al. Effects of levosimendan on circulating pro-inflammatory cytokines and soluble apoptosis
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I, Tsiapras D, Farmakis D, et al. Effects of Levosimendan
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on renal ischemia-reperfusion: an experimental study. Interact Cardiovasc Thorac Surg. 2008; 7: 235-9.
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Cite this article as: Bove T, Matteazzi A, Belletti A, Paternoster G, Saleh O, Taddeo D, Dossi R, Greco T, Bradic N, Husedzinovic I, Nigro Neto C, Lomivorotov VV, Calabrò MG. Beneficial impact of levosimendan in critically ill patients with or at risk
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Source of Support: Nil. Disclosures: Dr. V. Lomivorotov has received modest speaker honoraria from Orion Pharma.
Heart, Lung and Vessels. 2015, Vol. 7
ORIGINAL ARTICLE
Heart, Lung and Vessels. 2015; 7(1): 47-53
Use of lyophilized fibrinogen
concentrate in cardiac surgery:
a systematic review
Thiago Augusto Azevedo Maranhão Cardoso1, Caetano Nigro Neto1, Carlos Gustavo
dos Santos Silva1, Pedro Lobo da Rocha1, Haward Hideo Uoieno Iosto2
1
Dante Pazzanese Institute of Cardiology, São Paulo, SP, Brazil;
Federal Hospital of Ipanema, Rio de Janeiro, RJ, Brazil
2
Heart, Lung and Vessels. 2015; 7(1): 47-53
ABSTRACT
Introduction: Use of fibrinogen concentrate among cardiac anesthetists is growing especially for the benefits
related to the reduction in the administration of bleeding and allogeneic blood components, which are exacerbated by cardiopulmonary bypass. Moreover, these products underwent complete viral inactivation, reducing
the risks of contamination associated with transfusion. The purpose of this research was to review the literature
looking for randomized controlled trials regarding fibrinogen concentrate and its benefits in cardiac surgery.
Method: The papers used in this review were searched in BioMed Central, PubMed, Embase, and the Cochrane
Central Register of Clinical Trial by two investigators. The full search strategy was performed to identify all
randomized controlled trials in the last 10 years, comparing the use of fibrinogen in the adult treatment of perioperative bleeding to standard treatment or placebo.
Results: Only four articles matching the selection criteria for final analysis were identified and only 79 patients
received therapy with fibrinogen concentrate in randomized trials performed in cardiac surgery.
Conclusions: During the last 10 years, few randomized controlled trials were performed to confirm the real
benefit of using lyophilized fibrinogen to reduce bleeding in cardiac surgery. However, when indicated, it may be
a good option in order to reduce the consumption of blood products in the treatment of perioperative bleeding,
following an algorithm based on point-of-care testing.
Keywords: cardiac surgery, fibrinogen, bleeding.
INTRODUCTION
In patients undergoing cardiovascular surgery, causes of perioperative bleeding are
multifactorial, determining a huge difficulty in establishing the better hemostatic
strategy (1).
The standard treatment of perioperative
bleeding involves the transfusion of allogeCorresponding author:
Caetano Nigro Neto
Peixoto Gomide street, 502/173 B
Jardim Pailista
São Paulo, SP, Brazil
e-mail: caenigro@uol.com.br
neic blood components (erythrocytes, fresh
frozen plasma (FFP), platelet concentrate,
or cryoprecipitate). Coagulation management algorithms based on point-of-care
testing and goal-directed first-line therapy
with specific coagulation factor concentrates favor fibrinogen in relation to others concentrate factors, like factors VII and
VIII, due to its relevance in the pathophysiology of bleeding and its cost effectiveness
(2-5).
Recently, the use of fibrinogen concentrate
increased among cardiac anesthetists, especially for the benefits related to the re-
Heart, Lung and Vessels. 2015, Vol. 7
47
Azevedo Maranhão Cardoso TA, et al.
48
duction of bleeding and allogeneic blood
components used, which are exacerbated
by cardiopulmonary bypass (CPB). Moreover, fibrinogen concentrate have undergone complete viral inactivation, reducing
the risks of contamination associated with
transfusion (5, 6). The purpose of this research was to review the literature looking
for randomized controlled trials (RCTs) regarding fibrinogen concentrate and its benefits in cardiac surgery.
cant reduction in the use of blood products
or decrease in bleeding in the perioperative
period when fibrinogen concentrate was
used. Author(s), year of publication, study
design, number of total patients studied,
number of patients treated with fibrinogen
concentrate, fibrinogen dose variability,
type of surgery and viability of the therapy
were extracted independently by 2 investigators.
RESULTS
METHODS
The papers used in this review were
searched in BioMed Central, PubMed,
Embase, and the Cochrane Central Register of Clinical Trial (updated on the 30th
of August, 2014) by two investigators.
The full search strategy (Appendix 1) was
performed to identify all randomized controlled trials in the last 10 years, comparing
the use of fibrinogen in the adult treatment
of perioperative bleeding to standard treatment (fresh frozen plasma, platelets and/or
cryoprecipitate) or placebo.
The authors considered relevant articles
in which fibrinogen concentrate was used
as the first line therapy for perioperative
bleeding in cardiac surgery, guided by laboratory tests or algorithms based on pointof-care testing involving or not thromboelastometry/thromboelastography.
Further searches involved conference proceedings from congresses in the field. The
references of retrieved articles were carefully checked. Articles not translated into
English were excluded. References obtained
from data base and literature searches were
at first independently examined at the title/
abstract level by 2 investigators. Divergences were settled by consensus with the
supervision of a third investigator. Eventually, if potentially pertinent, the references
were retrieved as complete articles.
Viable therapy was considered as a signifi-
The flowchart of selected papers (Figure
1) describes the full search. From a total of
1304 articles, 1056 papers were excluded
Figure 1 - Flow chart of the search process of
scientific articles that evaluated the use of lyophilized fibrinogen in cardiac surgery.
RCTs = randomized controlled trials.
Heart, Lung and Vessels. 2015, Vol. 7
Lyophilized fibrinogen in cardiac surgery
Table 1 - Description of the 4 selected studies about the use of lyophilized fibrinogen in cardiac surgery.
49
Study
Year
Model study
Number
of
patients
Number of
patients treated
with fibrinogen
Types of Viable
Surgery therapy
Tanaka et al9
2014
Prospective randomized
case-control
20
10
AV
Yes
Rahe-Meyer et al7
2013
Prospective randomized
case-control
61
29
AV/AAA
Yes
Karlsson et al8
2011
Prospective randomized
case-control
20
10
MR
Yes
Karlsson et al10
2009
Prospective randomized
case-control
20
10
MR
Yes
121
59
Total
Abbreviations: Randomized Controlled Trial (RCT); Myocardial Revascularization (MR); Aortic Valve (AV); Ascending
Aorta Aneurysm (AAA).
because they were not randomized controlled trials (RCTs). Of the remaining 248
articles, only 97 publications of the last 10
years were chosen based on the final selection taking into account the title and the
summary analysis.
Four articles (7-10) who matched the selection criteria for final analysis were found,
and a total of 161 patients was included in
these four studies. Only 79 patients were
treated and received therapy with fibrinogen concentrate. All studies considered the
therapy viable.
Table 1 shows the four manuscripts (7-10)
that matched the selection criteria for final
analysis mention. In one study (7), no serious adverse events were considered related
to fibrinogen concentrate. Another study
(9) reported that the median costs of hemostatic components per case were similar between the groups that used or not fibrinogen concentrate (p=0.51). Others studies
(8, 10) included prophylactically fibrinogen
concentrate administered before surgery.
DISCUSSION
We found only four randomized controlled
trials with mention to treatment with fibrinogen concentrate in cardiac surgery
over the past 10 years (7-10). These trials
considered a small number of patients, so
it was not possible to draw firm conclusions except that the lyophilized fibrinogen
is potentially able to reduce the number of
transfusions in cardiac surgery, with less
exposure to a large number of donors, and
that there is some evidence of blood loss reduction.
Excessive blood loss is a feared complication after cardiac surgery, requiring reintervention in about 5-10% of patients,
among which coagulopathy acquired postoperatively is responsible 50% of the cases
(1). Immediately after prolonged CPB, fibrin formation is impaired because fibrinogen levels are drastically reduced. Being
the clotting factor with the longest elimination half-life, the most abundant in human
plasma (representing more than 90% of the
total) and the one that most decreases during CPB, fibrin plays an important role in
hemostasis (Figure 2), affecting on average
34-42% of clot firmness after this period (7,
11). Momeni et al (12) compared fibrinogen
levels in cardiac surgery with or without
CPB and found that plasma threshold that
was once considered normal (0.8-1 g/L)
is now questionable because it was based
only on expert opinion. Keyvan Karkouti et
Heart, Lung and Vessels. 2015, Vol. 7
Azevedo Maranhão Cardoso TA, et al.
50
Figure 2 - Coagulation cascade highlighting the role of fibrinogen comparing its longer elimination
half-life.
al. (13) through a retrospective data analysis of 4606 cardiac surgery patients found
statistically significant (p<0.0001) greater
need for blood transfusion when fibrinogen levels were below 2 g/L, with the largest propensity for RBC transfusion due to
some post-CPB coagulopathy.
Tanaka et al. (9), compared two groups using lyophilized fibrinogen or platelets in
aortic valve surgery, trying to inhibit a postoperative bleeding rated by a visual scale.
Despite having considered the therapy viable in patients who received lyophilized
fibrinogen, they reported no statistical difference in blood loss between groups. However, the author supposes that low statistical significance may be due to a type II error
for small sample (n=20), a type of surgery
with longer CPB time (valve replacement
or repair), or to the fibrinogen dose used
(4 g). Other authors consider that the re-
placement dose of lyophilized fibrinogen in
certain surgeries that involve the manipulation of the aorta should not be less than 5
or 6 g (6).
In the study conducted by Karlsson et al.
(14), the behavior of lyophilized fibrinogen
infused prophylactically in patients without
previous coagulation defects was evaluated.
The authors included patients with plasma
fibrinogen levels ≤3.8 g/L preoperatively in
order to verify its interference in certain
coagulation markers composition, such as
function and the platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), activated clotting
time (ACT), and maximum clot firmness
(MCF). Although no significant difference
was observed between prophylactic or nonprophylactic use of fibrinogen concentrate
in relation to composition of coagulation
markers, the authors supposed that treated
Heart, Lung and Vessels. 2015, Vol. 7
Lyophilized fibrinogen in cardiac surgery
patients showed a reduction in bleeding.
This can be explained because laboratory
tests of primary (platelet count and plasma
fibrinogen dosage) and secondary hemostasis (PT, aPTT and TT) are not useful in the
context of an urgent decision making due
to their delay in providing results, useful
only for pre- and post-operative investigations. According to the guidelines of ASA
(3), replacement of fibrinogen is useful in
continuous postoperative bleeding when
patients are drug users. In this case drugs
can block platelet aggregation, and even before thrombocytopenia is reached, fibrinogen supplementation by itself can stop
bleeding.
Karlsson et al. (8) also refer that the prophylactic use of fibrinogen does not increase
the risk of postoperative hypercoagulability. Therefore, the lyophilized fibrinogen
would be a safe therapy from the viewpoint
of thromboembolic events such as myocardial infarction, cerebrovascular accident,
deep vein thrombosis and pulmonary embolism. Sadeghi et al. (10) in their study,
concluded that lyophilized fibrinogen infused prophylactically 30 minutes before
myocardial revascularization can reduce
postoperative blood loss compared with
placebo (p<0.0001). Considering that they
used a lower dose (1 g) than Karlsson et
al. (8), the risk of thrombogenic event was
excluded, but the reduction in blood components transfusions was not statistically
significant (p=0.096), probably because
of the small sample size. Compared to recombinant factor VII (rfVII) which has also
been widely used on a massive bleeding of
unknown cause, the risk of thromboembolic events such as stroke was not found.
In fact , considering a survey by FDA (6)
(1999-2004 ) regarding the use of fVII offlabel (indicated hemophiliacs), there are
reports of 431 adverse events attributed to
hypercoagulable rfVII.
Rahe-Meyer et al. (7) evaluated the sum of
blood products such as plasma and platelets, offered to patients undergoing aortic
valve replacement or aortic aneurysm, getting 1 g of lyophilized fibrinogen or placebo
after CPB. In bleeding predefined as abundant (>60 and <250 g in 5 minutes of review), they found a significant difference
(p<0.001) and replacement of blood components, in the order of 2 units in the group
that received the lyophilized fibrinogen versus 13 units in the control group. Interestingly in this study, the replacement of the
lyophilized fibrinogen or blood products
followed an algorithm based on point-ofcare testing that included monitoring with
rotational thromboelastometry. Currently
thromboelastometry/thromboelastography
is an important tool to guide the administration of fibrinogen. With its use, the indiscriminate use of blood products tends to decrease, reducing the risk of complications.
According to some authors (15), using the
standard method of Clauss (traditional dosing plasma fibrinogen) delays the diagnosis
of hypofibrinogenemia and so, the treatment of bleeding. Different algorithms are
suggested as a guide to fibrinogen concentrate and blood products transfusion. Many
authors considered algorithms based in rotational tests as the best one on POC, due
to more precise and quick individuation of
causes of perioperative bleeding. Weber et
al. (2) performed a prospective, randomized
clinical trial comparing therapy guided by
conventional analysis of coagulation and
rotational tests (ROTEM® - called Pointof-Care or POC). The results showed that
patients in the POC group received fewer
packed red blood cells (p<0.001), FFP, PC,
rfVII, lost less blood, spending less time
in the intensive care unit (ICU), needed a
shorter period of mechanical ventilation,
and experienced fewer adverse events (renal failure, sepsis, thromboembolic complications and allergic reactions) when compared with the conventional group whose
Heart, Lung and Vessels. 2015, Vol. 7
51
Azevedo Maranhão Cardoso TA, et al.
52
transfusion was based on conventional
methods of assessment of coagulation such
as platelet count, hemoglobin concentration, fibrinogen concentration, INR and activated partial thromboplastin time.
Another important paper, Bilecen et al.
(16), investigated the use of fibrinogen in a
prospective cohort study on a population of
1075 patients undergoing complex cardiac
surgery (coronary artery bypass with valve
replacement or aortic surgery) of which
264 (25%) received fibrinogen concentrate,
with no statistically significant relative
intra-operative blood loss and decreased
transfusion-derived allogeneic blood components (p<0.001). Note that patients
who received fibrinogen were more severe,
were not randomized and the doses used
may have been lower than those suggested
by other authors as Rahe-Meyer (6).
Limitations of the study: Clinical end
points useful to analyze collected data were
not well defined. This was due to a great
variability between different studies, depending on timing of administration, dosage and number of units transfused, treatment in control group and different clotting
monitoring. It became difficult to value a
real benefit of fibrinogen: in particular it
is impossible to distinguish between a real
therapeutic effect of fibrinogen concentrate
and a better outcome related to a strictly
clotting monitoring with point of care. Recent major changes in fibrinogen concentrate indications and formula date back to
2011.
They mainly mentioned that fibrinogen
concentrates should be indicated only for
treatment of acute bleeding episodes in
patients with congenital fibrinogen deficiency, including afibrinogenemia and hypofibrinogenemia, and its effectiveness is
based on maximum clot firmness, which
measures the structural integrity of a clot,
reflecting the underlying effectiveness of
the fibrinogen forming a fibrin clot (17).
CONCLUSION
In conclusion, we can say that during the
last 10 years few randomized controlled
trials were performed to confirm the real
benefit of using lyophilized fibrinogen to reduce bleeding in cardiac surgery. However,
it may be a good option reducing the consumption of blood products when indicated
to treat perioperative bleeding following an
algorithm based on point-of-care testing.
REFERENCES
1. Gielen C, Dekkers O, Stijnen T, Schoones J, Brand A,
Klautz R, et al. The effects of pre- and post-operative fibrinogen levels on blood loss after cardiac surgery: a systematic
review and meta-analysis. Interact Cardiovasc Thorac Surg
2014; 17: 292-298.
2. Weber CF, Gorlinger K, Meininger D, Herrmann E, Bingold
T, Moritz A, et al. Point-of-care testing: a prospective, randomized clinical trial of efficacy in coagulopathic cardiac
surgery patients. Anesthesiology 2012; 117: 531-47.
3. Solomon C, Cadamuro J, Ziegler B, Schöchl H, Varvenne M,
Sørensen B, et al. A comparison of fibrinogen measurement
methods with fibrin clot elasticity assessed by thromboelastometry, before and after administration of fibrinogen concentrate in cardiac surgery patients. Transfusion 2011; 51:
1695-706.
4. Maia PV, Araújo GZ, Faria MD. Tromboelastógrafo em
cirurgia cardíaca: estado atual. Rev Bras Anestesiol 2006;
56: 78-88.
5. Lin DM, Murphy LS, Tran MH. Use of prothrombin complex concentrates and fibrinogen concentrates in the perioperative setting: a systematic review. Transfus Med Rev
2013; 27: 91-104.
6. Rahe-Meyer N, Pichlmaier M, Haverich A, Solomon C,
Winterhalter M, Piepenbrock S, et al. Bleeding management with fibrinogen concentrate targeting a high-normal
plasma fibrinogen level: a pilot study. Br J Anaesth 2009;
102: 785-92.
7. Rahe-Meyer N, Solomon C, Hanke A, Schmidt DS, Knoerzer D, Hochleitner G, et al. Effects of Fibrinogen Concentrate as First-line Therapy during Major Aortic Replacement Surgery. Anesthesiology 2013; 118: 40-50.
8. Karlsson M, Ternström L, Hyllner M, Baghaei F, Flinck
A, Skrtic S, et al. Prophylactic fibrinogen infusion reduces
bleeding after coronary artery bypass surgery. A prospective randomised pilot study. Thromb Haemost 2009; 102:
137-44.
9. Tanaka KA, Egan K, Szlam F, Ogawa S, Roback JD, Sreeram
G, et al. Transfusion and hematologic variables after fibrinogen or platelet transfusion in valve replacement surgery:
preliminary data of purified lyophilized human fibrinogen
concentrate versus conventional transfusion. Transfusion
2014; 54: 109-118.
10. Sadeghi M, Atefyekta R, Azimaraghi O, Marashi S M,
Aghajani Y, Ghadimi F, et al. A randomized, double blind
trial of prophylactic fibrinogen to reduce bleeding in cardiac surgery. Rev Bras Anestesiol 2014; 64: 253-257.
11. Stinger HK, Spinella PC, Perkins JG, Grathwohl KW, Salinas J, Martini WZ, et al. The ratio of fibrinogen to red cells
Heart, Lung and Vessels. 2015, Vol. 7
Lyophilized fibrinogen in cardiac surgery
transfused affects survival in casualties receiving massive
transfusions at an army combat support hospital. J Trauma
2008; 64: 79-85.
12. Momeni M, Carlier C, Baele P, Watremez C, Dyck MV, Matta A, et al. Fibrinogen concentration significantly decreases
after on-pump versus off-pump coronary artery bypass surgery: a systematic point-of-care ROTEM analysis. J Cardiothorac Vasc Anesth 2013; 27: 5-11.
13. Karkouti K, Callum J, Crowther M, McCluskey SA, Pendergrast J, Tait G, et al. The relationship between fibrinogen
levels after cardiopulmonary bypass and large volume red
cell transfusion in cardiac surgery: an observational study.
Anesth Analg 2013; 117: 14-22.
14. Karlsson M, Ternström L, Hyllner M, Baghaei F, Skrtic S,
Jeppsson A. Prophylactic fibrinogen infusion in cardiac
surgery patients: effects on biomarkers of coagulation, fibrinolysis, and platelet function. Clin Appl Thromb Hemost
2011; 17: 396-404.
15. Ranucci M. Fibrinogen supplementation in cardiac surgery: where are we now and where are we going? J Cardiothorac Vasc Anesth 2013; 27: 1-4.
16. Bilecen S, Peelen LM, Kalkman CJ, Spanjersberg AJ, Moons
KG, Nierich AP. Fibrinogen concentrate therapy in complex
cardiac surgery. J Cardiothorac Vasc Anesth 2013; 27: 12-17.
17. RiaSTAP®, Fibrinogen Concentrate (Human) For Intravenous
Use, Lyophilized Powder for Reconstitution. Available at: http://
labeling.cslbehring.com/PI/US/RiaSTAP/EN/RiaSTAP-Prescribing-Information.pdf. Accessed September 2014.
APPENDIX 1
procedures”[MeSH Terms] OR (“cardiac”
[All Fields] AND “surgical” [All Fields]
AND “procedures” [All Fields]) OR “cardiac surgical procedures” [All Fields] OR
(“cardiac”[All Fields] AND “surgery” [All
Fields])) AND (“fibrinogen” [MeSH Terms]
OR “fibrinogen” [All Fields])) AND Randomized Controlled Trial [ptyp]
((“thoracic
surgery”[MeSH
Terms]
OR (“thoracic” [All Fields] AND “surgery” [All Fields]) OR “thoracic surgery”
[All Fields] OR (“cardiac” [All Fields]
AND “surgery”[All Fields]) OR “cardiac
surgery”[All Fields] OR “cardiac surgical
Cite this article as: Azevedo Maranhão Cardoso TA, Nigro Neto C, Santos Silva CG, Lobo da Rocha P, Iosto HHU. Use of
lyophilized fibrinogen concentrate in cardiac surgery: a systematic review. Heart, Lung and Vessels. 2015; 7(1): 47-53.
Source of Support: Nil. Disclosures: None declared.
Heart, Lung and Vessels. 2015, Vol. 7
53
ORIGINAL ARTICLE
Heart, Lung and Vessels. 2015; 7(1): 54-63
54
Haemodynamic response at double
lumen bronchial tube placement Airtraq vs. MacIntosh laryngoscope,
a randomised controlled trial
Thomas Hamp, Thomas Stumpner, Georg Grubhofer, Kurt Ruetzler, Rainer Thell,
Helmut Hager
Department of Cardiothoracic and Vascular Anaesthesia and Intensive Care Medicine, Medical University of Vienna, Austria
Heart, Lung and Vessels. 2015; 7(1): 54-63
ABSTRACT
Introduction: Tracheal intubation causes a haemodynamic response that might be harmful for patients. The
Airtraq® laryngoscope has been shown to decrease the haemodynamic response to single-lumen tube intubation. We hypothesised that double-lumen bronchial tube placement with the Double-lumen Airtraq® laryngoscope would cause a reduced haemodynamic response and decreased catecholamine release compared with the
MacIntosh laryngoscope.
Methods: Forty adult patients were randomly assigned to the Airtraq® group or to the MacIntosh group. Intubation with either the Airtraq® or the MacIntosh laryngoscope was performed two minutes after standardised
induction of anaesthesia. Arterial blood pressure, heart rate, catecholamine levels, bispectral index and duration of the intubation procedure were measured.
Results: Mean (standard deviation [95% confidence interval]) systolic arterial blood pressure at laryngoscopy
with the Airtraq® laryngoscope was 124 (34 [106 to 141]) mmHg and, with the MacIntosh laryngoscope, it
was 110 (25 [99 to 122]) mmHg (p=1.0). Heart rate at laryngoscopy with the Airtraq® laryngoscope was
75 beats·min-1 (16 [67 to 83]) and, with the MacIntosh laryngoscope, it was 64 beats·min-1 (14 [58 to 71])
(p=0.71). Adrenaline levels post-intubation were 54.3 ng·l-1 (41.5) [29.3 to 79.4] in the Airtraq® group and
30.5 ng·l-1 (25.6) [15.1 to 46.0] in the MacIntosh group (p=0.016). The duration of intubation with the
Airtraq® laryngoscope was 88 s (31 [72-104]) while, with the MacIntosh laryngoscope, the duration was 75 s
(35 [59-92]) (p=0.26).
Conclusions: The use of the Double-lumen Airtraq® laryngoscope provides no benefit regarding stress response compared to the MacIntosh laryngoscope.
Keywords: stress response, intubation, double-lumen-tube, haemodynamics.
INTRODUCTION
Intubation can produce a major haemodynamic response that may be harmful in patients with cardiac, pulmonary or cerebral
diseases. Some intubation devices (e.g. fibre
Corresponding author:
Thomas Hamp, M.D.
Department of Cardiothoracic and Vascular Anaesthesia
and Intensive Care Medicine
Medical University of Vienna
Waehringer Guertel, 18-20. 1090 Vienna, Austria
e-mail: thomas.hamp@meduniwien.ac.at
optic devices, GlidescopeZS) have already
been investigated to determine if they are
able to attenuate the haemodynamic response to tracheal intubation, but the results remain controversial. The Airtraq®
laryngoscope was originally designed to
facilitate tracheal intubation in difficultto-intubate situations. The Airtraq® laryngoscope provides an indirect view of
the laryngeal structures similar to other
alternative laryngoscopes such as the Gli-
Heart, Lung and Vessels. 2015, Vol. 7
DLT placement - Airtraq vs. MacIntosh
descopeZS. The image is transmitted by a
combination of mirrors and prisms and an
included heater prevents the lens from fogging. Steering of the tube is provided via a
channel attached to the blade. The feasibility of double lumen-bronchial-tube (DLT)
insertion with an Airtraq® laryngoscope
was first described by Hirabayashi and an
Airtraq® laryngoscope specially designed
for DLT placement is now available (1).
Tracheal intubation with the Airtraq® laryngoscope designed for single lumen tracheal tubes seems to produce a less accentuated haemodynamic response than tracheal
intubation with the MacIntosh laryngoscope, at least in obese patients (2). Therefore, intubation with the Airtraq® laryngoscope could be beneficial for patients at risk
for cardiovascular events (e.g.patients undergoing cardiothoracic surgery). This possible benefit has been so far shown for tracheal intubation with a single lumen tube.
In cardiothoracic surgery, single lung ventilation is frequently necessary to perform
the operation and this usually requires the
placement of a DLT. Placement of a DLT
differs from the placement of a single lumen tube in several respects. For instance,
most double lumen tubes are more rigid
and much thicker than single lumen tubes
and we feel that this makes the insertion of
a DLT more difficult than the insertion of
single lumen tubes. We also speculate that
the pushing of the DLT down the trachea
into one main bronchus creates more stimulus than a single-lumen tube intubation,
where the tube ends in the middle of the
trachea.
However, there are no data regarding the
haemodynamic response to DLT intubation
with conventional laryngoscopy or with an
alternative device.
A recently published study focusing on
the duration of intubation with the DLT
Airtraq® laryngoscope found no superiority of the DLT Airtraq® laryngoscope over
the conventional MacIntosh laryngoscope
(3).
Our hypothesis was that intubation with
the DLT-Airtraq® could provide similar
haemodynamic advantages to those shown
by Ndoko et al. (1) for single lumen tube intubation, although we were aware that DLT
placement significantly differs from single
lumen tube intubation. Thus, the aim of
our study was to investigate the haemodynamic and catecholamine response at DLT
placement with the DLT-Airtraq® laryngoscope compared to DLT placement with the
conventional MacIntosh laryngoscope.
METHODS
Before we enrolled patients in our study,
we obtained institutional ethics committee approval, registration at EudraCT (Ethics Committee of the Medical University
Vienna, Ref.Nr. 549/2008, EudraCT Ref.
Nr. 2008-006233-27) and written informed
consent.
In previous studies with comparable protocols for induction of anaesthesia, systolic
arterial blood pressure (SAP) at tracheal
intubation was approximately 110 mmHg
(20 mmHg SD) (1, 4). Assuming a type-1
error of 5% and a 90% chance to detect a
difference in SAP at intubation of 20% (22
mmHg) between the groups, 18 patients in
each group were required. To keep the statistical power high, we enrolled 20 patients
per group to account for a possible drop-out
rate of 10%. We included adult patients of
ASA class 1-3 undergoing elective surgery
with the need for DLT tube placement. Patients taking medication with anti-hypertensive or beta-blocking agents on the day
of surgery were excluded because this may
affect haemodynamic and catecholamine
responses. Further exclusion criteria were
cardiac arrhythmias and history of previous difficult intubation procedures, as these
Heart, Lung and Vessels. 2015, Vol. 7
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T. Hamp, et al.
56
may inappropriately prolong intubation attempts or require awake fibre-optic intubation.
Patients were randomised either to the
MacIntosh group or the Airtraq® group.
Therefore, group labels were written on a
total of 40 cards (20 per group). The cards
were put into opaque envelopes, effectively
mixed, and put into a box. This was done
by a person who was not involved in the
study. After entering the operation room,
an envelope was picked from the box,
opened and the patient was assigned to the
indicated group.
Patient´s demographic data (ASA-status,
age, height, weight, gender) and the Mallampati Score were recorded after informed
consent was received.
Patients received midazolam 7.5 mg p.o. 1
hour before induction of anaesthesia for
premedication. All patients received 500
mL lactated ringer’s solution prior to induction of anaesthesia.
According to our standard of care, invasive
blood pressure monitoring (IBP), pulse
oximetry (SpO2), electrocardiogram and
bispectral index (BIS) were initiated in the
operation theatre. After the initial measurements were recorded, patients were
preoxygenated for several minutes with
pure oxygen.
Anaesthesia was induced in all patients
with a single bolus of midazolam 0.04
mg=kg-1, fentanyl 2 µg=kg-1, propofol 1.5
mg=kg-1 and rocuronium 0.6 mg=kg-1 over
60 seconds. After patient’s loss of consciousness, bag mask ventilation with FiO2
1.0 was started to maintain normocapnia
and avoid hypoxia during the subsequent
intubation procedure. The intubation procedure was started 2 min after the application of the induction agents. No further
medication was given during the intubation attempt.
In the MacIntosh group, a MacIntosh laryngoscope with a curved blade of size 3
or 4 was used for laryngoscopy; the decision regarding what size was used was left
to the personal experience of the performing anaesthetist. In the Airtraq® group, the
yellow DLT-Airtraq® laryngoscope was
used (Prodol Ltd, Vizcaya, Spain, product
code Nr. A-071). For male patients a Ch
39 DLT was used and for female patients
a Ch 37 left-sided DLT (Ruesch Austria,
Vienna, Austria) was used. Intubation
was performed by an anaesthetist with experience in DLT placement using the MacIntosh laryngoscope as well as using the
DLT-Airtraq® laryngoscope. After placement of the DLT, it was immediately connected to the respirator and intra-tracheal/
bronchial placement was confirmed via the
respirator`s capnography (Draeger Primus,
Draeger Medical Austria GmbH, Vienna,
Austria). The placement of the DLT in the
left main bronchus was checked and, if
necessary, corrected after the study period
was completed, in order to ensure that haemodynamic response was not affected by
bronchoscopy or manipulation of the tube.
If intubation was not possible at the first
attempt (within 180 s or if SpO2 dropped
below 92%), patients were excluded from
calculation.
Systolic- (SAP), diastolic- (DAP) and mean
arterial blood pressure (MAP), heart rate
(HR) and BIS were measured at predefined
time points: baseline (prior induction of
anaesthesia), post induction (immediately
prior to laryngoscopy), at laryngoscopy
(immediately prior to DLT insertion), at
tube insertion (immediately after intubation was completed) and 1 and 2 min after
intubation was completed. The measured
values were recorded by screenshots of the
monitor in the operation room at the specific time points. Time was measured to
determine the duration of the laryngoscopy (from mouth opening for laryngoscopy
until the anaesthetist started to insert the
DLT) and the whole intubation procedure
Heart, Lung and Vessels. 2015, Vol. 7
DLT placement - Airtraq vs. MacIntosh
(from mouth opening for laryngoscopy
until the tube position was confirmed by
capnography). Times and measured values were recorded by a study nurse. Blood
samples for measurement of noradrenaline,
adrenaline and dopamine in the plasma
were taken at baseline (prior anaesthesia
induction in the operation room) and postintubation (2 min after intubation was
completed). The blood samples were placed
on ice and transported to the laboratory for
further processing.
After the intubation, anaesthetists were interviewed about the view on the glottis according to the Cormack and Lehane Score,
the difficulty of inserting the tube as a separate part of the whole intubation procedure
and the difficulty of the whole procedure
(very simple, simple, difficult, or very difficult).
Lastly, the position of the DLT was recorded via bronchoscopy and - if not in the left
main bronchus - corrected afterwards.
Data were analysed with SPSS 19.0. (IBM
SPSS Statistics, IBM Corp. NY, United
States). The male/female distribution and
comparisons of other nominal and ordinal data between the groups (ASA classification, Mallampati Score, Cormack and
Lehane Score, difficulty of tube insertion
and intubation procedure, position of the
DLT) were tested with Fisher’s exact test.
Comparisons of further demographic data
(age, weight, height), haemodynamic measurements (blood pressure, heart rate),
BIS, time for laryngoscopy/intubation and
catecholamine levels were tested with an
ANOVA.
Where necessary, p-values were corrected
for multiple testing with Bonferroni´s correction. P-values less than 0.05 were considered to be statistically significant.
RESULTS
A total of 40 patients were randomly assigned to the MacIntosh and Airtraq®
groups. In the MacIntosh group, data from
all allocated patients were analysed. In the
Airtraq® group, data from 17 patients were
analysed as shown in the CONSORT flow
diagram.
Both groups were comparable with respect
to ASA status, age, height, weight, gender
distribution, Mallampati score and haemodynamic baseline values (Table 1).
After induction of anaesthesia, blood pressure dropped in both groups, then started to
increase with laryngoscopy to its maximum
immediately after intubation and declined
at 1 to 2 min after intubation (Figure 1).
There were no statistically significant differences in absolute blood pressure or in
the relative increase/decrease of blood pressure between the groups, at any time dur-
Table 1 - Characteristics of patients who received double-lumen-bronchial tube insertion with either the MacIntosh
or the Airtraq® laryngoscope. Values are the mean (SD) [95% CI] or number (proportion).
MacIntosh (n=20)
Airtraq (n=17)
ASA status 1/2/3
8 (40%) / 10 (50%) / 2 (10%)
9 (53%) / 7 (41%) / 1 (6%)
Age, y
63.4 (9.3) [59.0 to 67.7]
56.8 (10.6) [51.3 to 62.2]
Height,cm
169.2 (10.0) [164.5 to 173.9]
171.4 (8.8) [166.9 to 175.9]
Weight,kg
71.3 (13.3) [65.1 to 77.5]
73.0 (18.9) [63.3 to 82.7]
Male/female
11 (55%) / 9 (45%)
9 (53%) / 8 (47%)
Mallampati Score 1/2/3/4
7 (35%) / 10 (50%) / 2 (10%) / 1 (5%) 4 (24.5%) / 9 (53%) / 4 (24.5%) / 0
ASA = American Society of Anesthesiologists; SD = standard deviation; CI = confidence interval.
Heart, Lung and Vessels. 2015, Vol. 7
57
T. Hamp, et al.
58
Figure 1 - Course of systolic arterial blood pressure (mean, 95% CI) in patients using the MacIntosh
(grey) or the Airtraq® (black) laryngoscope.
CI = confidence interval.
ing the study period, with respect to systolic, diastolic or mean arterial blood pressure
(Table 2).
Baseline heart rate, before anaesthesia was
induced, was similar in both groups. Postinduction heart rate dropped in both groups
without significant differences between
the groups. With laryngoscopy heart rate
increased and was higher in the Airtraq®
group than in the MacIntosh group, but
this difference was not statistically significant (p=0.71). Immediately after the DLT
was inserted, as well as 1 and 2 min afterwards, heart rate in the Airtraq® group was
still higher than in the MacIntosh group,
but again without statistical significance
(p=0.35, p=0.90 and p=0.36).
Figure 2 illustrates the course of heart rate
through the study period; detailed data are
provided in Table 3.
The bispectral index was comparable in
both groups throughout the study period
(Table 4).
The time anaesthetists needed to provide
laryngoscopy, before they started to in-
sert the DLT (22.3s vs. 31.8s; p=0.06), as
well as for the whole intubation procedure
(75.4s vs. 88.1; p=0.256s), tended to be
longer in the Airtraq® group than in the
MacIntosh group, but without statistical
significance. The time needed to insert the
DLT was comparable in both groups (Table
5).
Adrenaline increased through the study period in the Airtraq® group (+11.1 (71.2)
[-31.9 to +67.9] ng =l-1) and decreased in
the MacIntosh group (-76.6 (93.8) [-139.6
to -13.5] ng =l-1) (Figure 3). This difference
in the course of the study period was statistically significant (p=0.02).
Noradrenaline also increased in the
Airtraq® group (+24.6 (147.6) [-54.0 to
+103.3] ng =l-1) and decreased in the MacIntosh group (-87.5 (212.4) [-186.9 to
+11.9] ng =l-1), but without statistical significance (p=0.08). Dopamine decreased
in both groups (Airtraq® group -22 (39.0)
[-62.9 to +18.9] ng =l-1; MacIntosh group
-8.9 (9.9) [-18.1 to +0.4] ng =l-1) without
statistical significance (p=0.41).
Heart, Lung and Vessels. 2015, Vol. 7
DLT placement - Airtraq vs. MacIntosh
Table 2 - Blood pressure at different time points in patients who received double-lumen-bronchial tube insertion
with either the MacIntosh or the Airtraq® laryngoscope. Values are the mean (SD) [95% CI].
MacIntosh (n = 20)
Airtraq (n = 17)
p-value
SAP baseline
150 (26) [138 to 162]
145 (22) [134 to 157]
1.0
MAP baseline
101 (17) [93 to 110]
101 (16) [92 to 109]
1.0
DAP baseline
75 (13) [69 to 81]
77 (14) [69 to 81]
1.0
SAP post induction
100 (20) [91 to 109]
107 (35) [89 to 124]
1.0
MAP post induction
73 (12) [67 to 78]
74 (11) [69 to 124]
1.0
DAP post induction
56 (11) [50 to 61]
57 (10) [52 to 63]
1.0
SAP laryngoscopy
110 (25) [99 to 122]
124 (34) [106 to 141]
1.0
MAP laryngoscopy
80 (18) [73 to 89]
89 (23) [77 to 101]
1.0
DAP laryngoscopy
61 (16) [53 to 68]
70 (20) [60 to 81]
0.6
SAP tube insertion
140 (31) [125 to 154]
151 (37) [131 to 170]
1.0
MAP tube insertion
100 (22) [89 to 110]
109 (29) [94 to 124]
1.0
DAP tube insertion
76 (17) [68 to 84]
84 (20) [74 to 95]
1.0
SAP 1 min
132 (27) [120 to 145]
132 (29) [117-147]
1.0
MAP 1 min
94 (20) [85 to 103]
96 (21) [86 to 107]
1.0
DAP 1 min
73 (15) [65 to 80]
75 (14) [67 to 82]
1.0
SAP 2 min
118 (27) [105 to 130]
127 (31) [111 to 143]
1.0
MAP 2 min
83 (18) [75 to 92]
95 (25) [83 to 108]
0.6
DAP 2 min
65 (13) [59 to 71]
73 (15) [66 to 81]
0.42
SAP = systolic arterial blood pressure; MAP = mean arterial blood pressure; DAP = diastolic arterial blood pressure. SD =
standard deviation; CI = confidence interval.
Figure 2 - Course of heart rate (mean, 95% CI) in patients using the MacIntosh (grey) or the Airtraq®
(black) laryngoscope. CI = confidence interval.
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T. Hamp, et al.
60
Table 3 - Heart rate and catecholamine levels at different time points in patients who received double-lumen-bronchial tube insertion with either the MacIntosh or the Airtraq® laryngoscope. Values are the mean (SD) [95% CI].
The concentrations of noradrenaline, adrenaline and dopamine are given in ng=l-1.
MacIntosh (n = 20)
Airtraq (n = 17)
p-value
HR baseline
74 (15) [67 to 80]
77 (9) [72 to 82]
1.0
HRpost induction
61 (12) [56 to 67]
68 (9) [63 to 73]
0.39
HR laryngoscopy
64 (14) [58 to 71]
75 (16) [67 to 83]
0.71
HRtube insertion
77 (16) [69 to 84]
85 (16) [77 to 94]
0.35
HR 1 min
75 (16) [67 to 82]
82 (12) [76 to 88]
0.9
HR 2 min
71 (13) [65 to 77]
82 (13) [75 to 89]
0.36
Noradrenaline baseline
307.7 (290.0) [172.0 to 443.4]
233.4 (162.3) [150.0 to 316.9]
0.71
Noradrenaline post intubation
220.2 (133.8) [157.6 to 282.8]
258.0 (152.7) [180.6 to 343.4]
0.78
Adrenaline baseline
107.1 (84.9) [36.1 to 120.5]
43.2 (36.5) [25.5 to 63.0]
0.27
Adrenaline post intubation
30.5 (25.6) [15.1 to 46.0]
54.3 (41.5) [29.3 to 79.4]
0.18
Dopamine baseline
24.7 (17.2) [14.3 to 35.1]
34.1 (33.4) [3.2 to 65.1]
0.82
Dopamine post intubation
15.8 (8.7) [11.1 to 24.4]
12.1 (15.0) [6.3 to 31.3]
1
HR= heart rate min-1; SD = standard deviation; CI = confidence interval.
Table 4 - Bispectral index at different time points in patients who received double-lumen-bronchial tube insertion,
measured with either the MacIntosh or the Airtraq® laryngoscope. Values are the mean (SD) [95% CI].
MacIntosh (n = 20)
Airtraq (n = 17)
p-value
BIS post induction
23.3 (9.0) [18.8-27.8]
25.2 (5.6) [22.4-28.1]
1.0
BIS laryngoscopy
23.0 (8.3) [18.9-27.1]
27.4 (6.8) [23.9-30.9]
0.56
BIS tube insertion
27.2 (10.2) [22.1-32.2]
28.5 (6.3) [25.3-37.8]
1.0
BIS 1 min
25.0 (12.8) [19.0-31.0]
29.5 (12.8) [22.9-36.0]
1.0
BIS 2 min
25.2 (12.8) [19.2-31.1]
30.5 (10.5) [25.1-35.9]
1.0
BIS = Bispectral index; SD = standard deviation; CI = confidence interval.
Baseline catecholamine levels in the
Airtraq® and the MacIntosh group were
comparable, as were catecholamine levels
post-intubation (2 min after intubation was
completed) (Table 3).
In the Airtraq® group, a Cormack-LehaneScore of 1 or 2 was present in 100% of patients. In the MacIntosh group, a CormackLehane Score of 1 or 2 was present only in
80% of patients, but this difference did not
reach statistical significance (Table 5). The
difficulty of inserting the DLT, as part of
the whole intubation procedure, was comparable in both groups (Table 5). The whole
intubation procedure was determined “difficult” or “very difficult” in 6% of patients
within the Airtraq® group and in 20% within the MacIntosh group, without reaching
a statistically significant difference. Correct
DLT positioning in the left main bronchus
was achieved only in 71% of patients in the
Airtraq® group and in 95% of patients in
the MacIntosh group, again without reaching statistical significance.
Heart, Lung and Vessels. 2015, Vol. 7
DLT placement - Airtraq vs. MacIntosh
Table 5 - Characteristics of the intubation procedure in patients who received double-lumen-bronchial tube insertion
with either the MacIntosh or the Airtraq® laryngoscope. Values are the mean (SD) [95% CI] or number (proportion).
MacIntosh (n = 20)
Airtraq (n = 17)
p-value
Time for laryngoscopy, s
22 (13) [16-28]
32 (17) [23-41]
0.06
Time for tube insertion, s
59 (52) [35-83]
56 (30) [41-72]
0.84
Time for intubation, s
75 (35) [59-92]
88 (31) [72-104]
0.26
15 (75%)/1 (5%)/3 (15%)/1 (5%)
16 (94%)/1 (6%)/0/0
0.28
16 (80%)/4 (20%)
13 (76%)/4 (24%)
1.0
Intubation was: easy/difficult*
16 (80%)/4 (20%)
16 (94%)/1 (6%)
0.35
Tube position correct/ incorrect†
19 (95%)/1 (5%)
12 (71%)/5 (29%)
0.08
Cormack-Lehane Score 1/2/3/4
Tube insertion was: easy/difficult
*
†”
*“easy” includes: “very simple” and “simple”; “difficult” includes: “difficult” and “very difficult”; correct” in the left main bronchus, “incorrect” any position other than in the left main bronchus. SD = standard deviation; CI = confidence interval.
Figure 3 - Changes
in catecholamine concentrations
through
the study period (post
intubation minus baseline levels) in patients
receiving DLT intubation with either the MacIntosh- (grey) or the
Airtraq® (black) laryngoscope. Values are the
mean (SD) [95% CI].
DLT = double lumenbronchial-tube; SD =
standard deviation; CI
= confidence interval.
DISCUSSION
The most important finding in our study
is that there was no clear benefit of the
DLT-Airtraq® laryngoscope in blunting the
haemodynamic response due to DLT intubation compared to the MacIntosh laryngoscope.
Theoretically, less force to the tongue and
the supraglottic tissue by indirect laryngoscopy (e.g., fibre optic bronchoscopy, intubation laryngeal mask, glidescope, etc.)
should result in attenuated haemodynamic
response to intubation. However, data supporting this theory are limited and controversial (4-8). Our hypothesis was that
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T. Hamp, et al.
62
the use of the Airtraq® laryngoscope for
DLT placement instead of the MacIntosh
laryngoscope would attenuate the haemodynamic response by reducing the force
needed for laryngoscopy. This hypothesis
could not be confirmed by our study. In
fact, there even was a tendency towards a
higher heart rate and higher catecholamine
concentration in the Airtraq® group, suggesting an enhanced stress response in patients of the Airtraq® group compared with
the MacIntosh group.
An explanation for this tendency may be
that the duration of the laryngoscopy was a
little bit longer in the Airtraq® group than
in the MacIntosh group (without reaching
statistical significance). Equal or higher
time needed for DLT intubation with the
Airtraq® laryngoscope was also recently
found by Wasem et al. (3). In contrast,
Di Marco found that intubation with the
Airtraq® laryngoscope, designed for single
lumen tubes, was easier and faster than
with the conventional MacIntosh laryngoscope (9).
However in our study, as well as in Wasem´s
study, DLTs were used and time for intubation was similar in both groups. We believe
that the benefit of having a good view of
the glottis with the Airtraq® laryngoscope
is outweighed by the difficulty of inserting
the large and stiff DLT, which results in a
comparable duration of the intubation procedure.
In contrast with our results, Ndoko et al.
reported significantly lower blood pressure and heart rate values at laryngoscopy
with the Airtraq® laryngoscope than with
conventional laryngoscopy (1) in obese patients. This result is in contrast with the
findings of our study and may be explained
by the fact that morbidly obese patients are
prone to difficulties with conventional intubation. The Airtraq® laryngoscope was
primarily designed to facilitate DLT intubation under difficult conditions, leading
to shorter duration of the intubation procedure and, consequently, a reduced haemodynamic response. In our study, patients
with a history of difficult intubation were
excluded and most of the patients had a
Mallampati score of 1 or 2.
Although the view of the glottis tended to
be better with the Airtraq® laryngoscope
than with the MacIntosh laryngoscope, no
significant differences were observed.
Therefore, the main advantage of the
Airtraq® laryngoscope, which is a better
view of the glottis in patients who are difficult to intubate, played no role in our study.
A limitation of our study is that complications related to intubation (such as tongue
or lip oedema, evidence of blood, and sore
throat) were not recorded.
Therefore, we cannot draw any conclusion
regarding whether the Airtraq® laryngoscope provides fewer such complications
than the MacIntosh laryngoscope. Only a
small number of ASA class 3 patients were
included in our study and it is unclear if in
this higher risk group haemodynamic and
stress response differ from the responses
noted in American Society of Anesthesiologists (ASA) class 1 and 2 patients. So,
there is the possibility that, in this higher
risk group, one laryngoscope might actually be superior to the other.
Also the measured catecholamine levels provide a limitation, because of their
wide variability and somewhat confusing
courses. For instance, in some patients of
the same group, catecholamine levels increased from baseline to post-intubation,
whereas in others, they decreased. Additionally, noradrenaline and adrenaline levels increased in the Airtraq®-group while
dopamine levels decreased in both groups.
One explanation for these findings might
be that the half-lives of catecholamines are
very short and even minor differences in
timing of drawing blood probes could affect these results.
Heart, Lung and Vessels. 2015, Vol. 7
DLT placement - Airtraq vs. MacIntosh
Processing of the probe might also influence catecholamine levels measured: for
instance, transportation into the laboratory
was out of our control in this study.
However, because we cannot adequately
explain these findings these results should
be interpreted with caution.
CONCLUSION
As found in previous studies, we believe
that the insertion of the endotracheal tube
is usually the major cause of the haemodynamic response and outweighs the stimulus
of laryngoscopy, at least in unchallenging
laryngoscopies (10, 11).
We speculate that the insertion of a thick
and rigid bronchial tube would therefore
usually be able to diminish any differences
in the haemodynamic response caused by
laryngoscopy, regardless of which technique for laryngoscopy is used.
The routine use of the DLT-Airtraq® laryngoscope for DLT placement provides
no benefit regarding haemodynamic response compared with the MacIntosh laryngoscope. In patients with predicted difficult airway, laryngoscopy may contribute
more to the haemodynamic response and
the usefulness of the DLT-Airtraq® laryngoscope in these patients has yet to be determined.
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Housseini L, et al. Tracheal intubation of morbidly obese
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7. Siddiqui N, Katznelson R, Friedman Z. Heart rate/blood
pressure response and airway morbidity following tracheal
intubation with direct laryngoscopy, GlideScope and Trachlight: a randomized control trial. Eur J siol 2009; 26: 740-5.
8. Xue FS, Zhang GH, Sun HT, Li CW, Li P, Liu KP, et al.
A comparative study of hemodynamic responses to orotracheal intubation with fiberoptic bronchoscope and laryngoscope in children. Paediatr Anaesth 2006; 16: 743-7.
9. Di Marco P, Scattoni L, Spinoglio A, Luzi M, Canneti A,
Pietropaoli P, et al. Learning Curves of the Airtraq and the
Macintosh Laryngoscopes for Tracheal Intubation by Novice Laryngoscopists: A Clinical Study. Anaesth Analg 2011;
112: 122-5.
10. Adachi YU, Takamatsu I, Watanabe K, Uchihashi Y, Higuchi H, Satoh T. Evaluation of the cardiovascular responses
to fibreoptic orotracheal intubation with television monitoring: comparison with conventional direct laryngoscopy.
J Clin Anaesth 2000; 12: 503-8.
11. Takahashi S, Mizutani T, Miyabe M, Toyooka H. Hemodynamic responses to tracheal intubation with laryngoscope
versus lightwandintubating device (Trachlight) in adults
with normal airway.Anaesth Analg 2002; 95: 480-4.
Cite this article as: Hamp T, Stumpner T, Grubhofer G, Ruetzler K, Thell R, Hager H. Haemodynamic response at double
lumen bronchial tube placement - Airtraq® vs. MacIntosh laryngoscope, a randomised controlled trial. Heart, Lung and Vessels.
2015; 7(1): 54-63.
Source of Support: This study was solely financed by the Medical University of Vienna, Waehringer Guertel 18-20, 1090
Vienna, Austria. Disclosures: None declared.
Heart, Lung and Vessels. 2015, Vol. 7
63
REVIEW ARTICLE
Heart, Lung and Vessels. 2015; 7(1): 64-73
64
Biomarkers, diagnosis and
management of sepsis-induced acute
kidney injury: a narrative review
Zhongheng Zhang
Department of Critical Care Medicine, Jinhua Municipal Central Hospital, Jinhua Hospital of Zhejiang University, Zhejiang, P.R.
China
Heart, Lung and Vessels. 2015; 7(1): 64-73
ABSTRACT
Sepsis is a leading cause of acute kidney injury in clinical practice. The diagnosis of sepsis-induced acute
kidney injury requires the diagnosis of sepsis and subsequent occurrence of acute kidney injury. The current
definition for acute kidney injury is based on Scr and urine output, which is limited by the delayed identification of such patients. Numerous novel biomarkers have been found to be up-regulated in kidney injury, among
which cystatin C and neutrophil gelatinase-associated lipocalin are the most studied. In the management of
sepsis-induced acute kidney injury, early goal directed therapy may be potentially useful, but requires further
validation in large clinical trials. It is well known that fluid overload is harmful in septic patients with established acute kidney injury and should be avoided. Renal replacement therapy is the mainstay treatment for
the severe form of sepsis-induced acute kidney injury. However, there is still no consensus on the definition of
timing and dosing in clinical practice, and the optimal timing and dosing are still unknown.
Keywords: sepsis, acute kidney injury, review, diagnosis, management.
INTRODUCTION
Sepsis is a primary cause of mortality and
morbidity worldwide, affecting more than
160,000 people in the United States alone in
1979, and the number increased to 659,000
in the year 2000 (1). The trend is expected
to continue due to the aging population and
increases in comorbidities (2). Kumar G et
al. found that the incidence of severe sepsis keeps on risingfrom 143 in 2000 up to
343 per 100,000 persons in 2007 (3). Not
only the quantity, but the severity of sepsis also accentuated as represented by the
number of organ failure. In the same study,
Corresponding author:
Zhongheng Zhang
351, Mingyue Road, Jinhua
Zhejiang province, China, 321000
e.mail: zh_zhang1984@hotmail.com
Kumar G et al. reported that the mean
number of organ failure increased from 1.6
to 1.9 (p<0.001) during study period (3).
Sepsis is a systemic inflammatory disorder
that will affect other organs, and the number of organ failure had additive effect on
patients’ outcome. Following lung (18%),
the kidney is the second most frequently
involved organ in sepsis (15%). If a kidney
is involved, the mortality rate will increase
exponentially.
Acute kidney injury (AKI) is commonly
seen in septic patients. It is estimated that
more than 20% septic patients may show
some degree of AKI, and mortality rate
of this subgroup will increase up to 35%
(4). Other causes of AKI include major
surgery, heart failure, respiratory failure
and hypovolemia, all of which associated
with shock and hypoperfusion. Tissue
Heart, Lung and Vessels. 2015, Vol. 7
Sepsis-induced acute kidney injury
hypoperfusion is the main reason for the
development of sepsis-induced AKI. Some
authors believe that resuscitation aiming
to restore tissue perfusion will minimize or
even reverse the kidney injury (5). However, this paradigm has been challenged by
evidences from clinical and experimental
studies. AKI can develop in the setting of
increased renal blood flow (6). In clinical
setting, it is reported that only a very small
proportion of patients after cardiac arrest
showed signs of AKI (7). Only patients
with cardiogenic shock after cardiac arrest
are prone to the development of AKI (5).
While there is an active research area on
the mechanisms underlying AKI development in sepsis, but this is not the primary
focus of current review. Readers who are
interested in this topic are referred to another review (8).
The primary goal of the review is to summarize the diagnosis and the management
of sepsis-induced AKI (SIAKI). The current guidelines for the diagnosis will be reviewed and incorporated together to reach
the diagnosis of SIAKI. I will not limit my
attention to the diagnosis of SIAKI, but I
will extend the review to the prediction of
SIAKI, because I believe that early identification of patients at increased risk of SIAKI will alert clinicians to adopt strategies to
avoid this potentially deadly condition.
Identification of patients with sepsis
The earliest consensus achieved to define
sepsis is done by American College of Chest
Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) in 1991 (9). In
this meeting, “systemic inflammatory response syndrome (SIRS)” was developed
and the definition required at least two of
the four clinical criteria: hyperthermia or
hypothermia, tachypnea, tachycardia, and
leukocytosis or leukopenia with immature
neutrophils. However, this definition is
criticized for its non-specificity that SIRS
is not only specific to infection but can be
caused by many other critical conditions including trauma, burn, pancreatitis and ischemia injury (10). In the conference held in
2001, sepsis was further stratified into four
aspects: predisposing factors, infection,
host response and organ failure (Figure 1)
(11). This was deemed as the PIRO (predisposing, infection, response, organ dysfunction) system (10). The diagnosis of sepsis
becomes more complex than the original
one. In the new definition, some other important aspects of sepsis are incorporated
such as the hemodynamics and organ dysfunction (Figure 2).
AKI definition and diagnosis
AKI is defined with respect to the increase
in serum creatinine (Scr) and decrease in
urine output: these parameters are widely
available and intensively investigated. The
two most widely used definition system for
AKI is the RIFLE (risk, injury, failure, loss,
end stage) and AKIN (acute kidney injury
network) criteria (12). The RIFLE criteria uses the following categories: “Risk” is
the least severe form, followed by “Injury”,
“Failure”, ”Loss” and ”End-stage renal
disease” (Figure 3) (13). AKIN criteria is
slightly modified from the RIFLE to incorporate the finding that even small increase
in Scr is associated with significantly elevated mortality rate (14). Historically, plasma
urea nitrogen has been used as a marker of
renal dysfunction before discovery of Scr.
The value of plasma urea nitrogen, however, is discounted because there are numerous factors other than renal function that
influences its concentration. These include
diet, muscle mass, age, gender and medications (15).
The definition of AKI based on Scr has long
been debated, mostly due to its shortcomings such as assay interference, dilution
during fluid resuscitation, altered metabolism during critical illness and altered clear-
Heart, Lung and Vessels. 2015, Vol. 7
65
Zhongheng Zhang
Figure 1 - Four aspects of sepsis: predisposing factors, infection, host response and organ
failure.
SIRS = systemic inflammatory response syndrome;
WBC = white blood cell count;
DIC = disseminated intravascular coagulation;
GI = gastrointestinal.
66
ance with drugs (16). Furthermore, Scr is
a late and indirect reflect of renal damage.
As a result, scientists are trying to discover
and develop novel biomarkers to represent
kidney injury, aiming to identify the injury timely. An ideal biomarker should be
the one that is able to predict AKI and its
outcomes, locate the site of injury (glomerulus vs tubule), determine the type of
injury, and enable the initiation of therapeutic interventions (16). Several potential
biomarkers have been identified and merit
extensive researches to establish their role
in the diagnosis of AKI.
Figure 2 - Definition of sepsis
from several aspects.
WBC = white blood cell count;
CRP = c-reactive protein;
GCS = Glasgow coma scale.
Heart, Lung and Vessels. 2015, Vol. 7
Sepsis-induced acute kidney injury
Figure 3 - Definition of
acute kidney injury with
RIFLE criteria.
RIFLE = risk, injury,
failure, loss, end stage; A
KI = Acute kidney injury;
GFR = glomerular filtration rate;
Scr = serum creatinine;
UO = urine output.
Cystatin C is a 13-kDa protein that is secreted from all nucleated cells and does not
bind to plasma proteins. It is freely filtered
by the glomerulus and it is subsequently reabsorbed and degraded in proximal tubule
by the endocytic receptor. Since Cystatin C
is not secreted into urine by the tubule in
normal condition, its appearance in urine
can reflect the impairment of tubule (15).
Serum concentration of Cystatin C is dependent on the glomerular filtration rate
(GFR) and it is more sensitive than Scr in
detecting minor impairment in GFR (such
as a GFR of 60-90 ml/min) (17). In clinical studies, more evidence is demonstrating
the good diagnostic performance of Cystatin C in early diagnosis of AKI. In children undergoing cardiac surgery, Hassinger
et al. (18) found that Cystatin C is a good
predictor of “risk” of AKI with an area under receiver operating characteristic curve
of 0.834-0.875. In another study conducted
also in pediatric cardiopulmonary bypass
surgery, the authors showed that the 12hour Cystatin C strongly correlated with severity and duration of AKI (19). A systematic review and meta-analysis by our group
demonstrated that the combined diagnostic
odds ratio for cystatin C to predict AKI was
27.7 (95% confidence interval [12.8-59.8]),
with the sensitivity and specificity of 0.86
and 0.82, respectively (20). The diagnostic
performance of urine cystatin C, unfortunately, is less than satisfactory, with sensitivity and specificity of 0.52 and 0.70 respectively. Beyond its diagnostic value for
AKI, our group has also demonstrated that
cystatin C measured on initiation of continuous renal replacement therapy (CRRT)
could predict the renal function recovery
(21, 22). However, the value of cystatin C is
criticized for some limitations. Royakkers
AA et al. showed that in mixed intensive
care unit (ICU) patients the diagnostic performance of serum cystatin C was fair on
day-2 (area under the curve (AUC) 0.72)
and was poor on day-1 (AUC 0.62) to predict AKI (23). These inconsistent results
may be partly explained by different definitions for AKI.
Neutrophil gelatinase-associated lipocalin
(NGAL) is another potential candidate for
early detection of kidney injury. NGAL is
a 25 kDa molecule composed of a single
disulphide-bridged polypeptide. It is secreted by injured renal tubular epithelial cells
(24). Experimental studies have shown
that NGAL is one of the most increased
Heart, Lung and Vessels. 2015, Vol. 7
67
Zhongheng Zhang
68
genes and proteins in early stage after renal insult, suggesting its potential role in
predicting AKI (25). Later clinical observations confirmed its diagnostic performance.
In patients undergoing cardiac surgery, the
most important study is the multicenter
TRIBE (Translational Research Involving
Biomarkers and Endpoints). A total of 1219
adults and 311 children were included in the
analysis. NGAL was measured in both serum and urine peaked within 6 hours after
surgery. The diagnostic performance is only
moderate with an area under curve (AUC)
of 0.75 (26). A similar result was replicated
in mixed critically ill patients (27, 28). Due
to the large number of investigations in this
area a systematic review and meta-analysis
was conducted by the NGAL Meta-analysis
Investigator Group. The diagnostic accuracy of serum and urinary NGAL was similar, with diagnostic odds ratio (DOR)/AUC
of 17.9 (95% CI [6.0-53.7])/0.775 (95% CI
[0.679-0.869]) for serum NGAL, and 18.6
(95% CI [7.2-48.4])/0.837 (95% CI [0.7620.906]) for urinary NGAL (29). However,
this study was done five years ago and numerous new studies have been published
since then. Thus, an updated systematic
review and meta-analysis is needed. With
sufficient number of component studies,
some statistical techniques such as cumulative meta-analysis and meta-regression can
be incorporated into the analysis.
There are nearly 30 novel biomarkers being
developed and are now under investigation
for their role in diagnosing AKI. For instance, urinary interleukin-18 (IL-18) and
kidney injury molecule-1 (KIM-1) have
both been demonstrated to be satisfactory
biomarkers of AKI (15). In a recent observational cohort study, we focused specifically
on septic patients and found that increases
in microalbuminuria is able to predict subsequent development of AKI, with an AUC
of 0.86 (95% CI: [0.77-0.94]) (30). This is
a single center study and it bears inherent
limitations of such design, and the result
requires further validation. Other candidate biomarkers include `2-microglobulin,
Gamma glutamyl transpeptidase, Livertype fatty acid-binding protein, N-Acetyl
beta glucosaminidase, and plasminogen activator inhibitor 1. Comprehensive reviews
of these biomarkers are out of scope of the
current article.
A well written review of these biomarkers
and their clinical usefulness has been published, and interested readers are referred
to this article (15).
Sepsis induced acute kidney injury
Although sepsis is a leading cause of AKI
(31), the framework for the definition and
management of SIAKI has not been well
established. For instance, the time interval
required between the onset of sepsis and
subsequent elevation of AKI biomarkers
to define SIAKI has not been developed.
Probably, the time interval between onset
of sepsis and elevation of AKI biomarkers
is important in that it helps to determine
the underlying causes of SIAKI as well as
to guide therapeutic decision. As for the
definition of nosocomial pneumonia, it
is required for the pneumonia onset to be
lagged for over 48 hours after hospitalization. If the identification of pneumonia is
within 48 hours after hospitalization, it is
regarded as community acquired pneumonia and the pathogen as well as the choice
of antibiotics can be quite different (32,
33). It is currently unknown whether the
same situation exists in the field of AKI.
Due to the lack of strong clinical evidence,
I propose that the management of AKI
caused by sepsis and hypovolaemia should
be different. Antibiotics and inflammatory
modulators can be beneficial in the former
condition, whereas the latter may benefit
from volume resuscitation to restore tissue
perfusion.
Identification of SIAKI in clinical setting
Heart, Lung and Vessels. 2015, Vol. 7
Sepsis-induced acute kidney injury
is merely to identify patients meeting the
diagnosis of both sepsis and AKI. The relationship between AKI and sepsis are bidirectional. While sepsis is a leading cause of
AKI, patients with renal failure are also at
an increased risk of developing sepsis during hospitalization.
Management of SIAKI
Fluid. AKI caused by sepsis is thought to
be associated with inadequate intra-vascular volume (so called pre-renal failure),
and thus fluid resuscitation is the indication for its initial treatment. The aim of the
fluid resuscitation is to restore adequate
renal blood flow. However, fluid resuscitation does not follow the rule “the more, the
better”: administration of excessive fluid
has been frequently proven to be harmful
in the literature (34). The observation between fluid overload and adverse renal out-
come was first described in children (35). In
adults with AKI, Payen et al. showed that
mean fluid balance was an independent risk
factor for 60-days mortality (hazards ratio
1.21 for each 1 unit increase in L/24 hours),
after adjusting for age, Simplified Acute
Physiology Score II (SAPS II), heart failure,
medical admission, mechanical ventilation
and liver cirrhosis (36). Similar findings
supporting the association between fluid
overload and adverse outcome in patients
with AKI have been reported (37).
The type of fluid is also important for the
management of AKI. Hydroxyethyl starches (HES) have been frequently proven to
be harmful. A systematic review and metaanalysis performed by Serpa Neto A et al.
showed that patients receiving HES for resuscitation were at significantly increased
risk of AKI development (relative risk (RR)
1.24; 95% CI [1.13-1.36]) and need of RRT
Table 1 - Commercially available solution formulas for renal replacement therapy.
Calcium formula
Calcium-free formula
Dextrose free
PrismSol
PrismSol PrismSol
BGK4/0/1.2 BGK2/0 B22GK/4/0
PrismSol
BK0/0/1.2
Plasma
PrismSol
BGK/2.5
PrismSol
BGK/3.5
PrismSol
BGK0/2.5
Potassium
(mEq/l)
3.5-5.0
4
2
0
4
2
4
0
Calcium
(mEq/l)
2.3-2.6
2.5
3.5
2.5
0
0
0
0
Magnesium
(mEq/l)
1.4-2.0
1.5
1
1.5
1.2
1
1.5
1.2
Sodium
(mEq/l)
135-145
140
140
140
140
140
140
140
Chloride
(mEq/l)
100-108
113
111.5
109
110.5
108
120.5
106.2
Bicarbonate
(mEq/l)
22-26
32
32
32
32
32
22
32
Lactate
(mEq/l)
0.5-2.2
3
3
3
3
3
3
3
Dextrose
(mg/dl)
70-110
100
100
100
100
100
100
100
Osmolarity
(mOsm/l)
280-296
300
296
292
295
291
296
282
BGK = Bicarbonate glucose potassium.
Heart, Lung and Vessels. 2015, Vol. 7
69
Zhongheng Zhang
70
(RR, 1.36; 95% CI [1.17-1.57]), as compared to those receiving crystalloids (38).
The same result was replicated by another
group (39). In the systematic review, a total of 31 trials are eligible for analysis and
8725 patients were eligible for endpoint of
AKI. The results showed an increased rate
of renal failure with the use of Hydroxyethyl starches (RR, 1.27; 95% CI [1.09 to
1.47]; I2, 26%; AR, 5.45%; 95% CI, 0.44%
to 10.47%).
The adverse effect of HES is associated
with its localization to circulatory system
and deposition to the muscle, skin, liver, endothelial cells and kidneys. The toxic effect
on renal function has been demonstrated in
animal and clinical studies, which may be
attributable to the volume and molecular
weight of HES.
Systematic resuscitation protocol
Sepsis is a multifaceted disorder that requires management within a multidisciplinary framework. Resuscitation bundle
is defined as quantitative administration
of serial strategies aiming to achieve prespecified goals. The 2012 Surviving Sepsis
Campaign guideline recommendsstandard,
quantitative resuscitation of patients with
sepsis-induced tissue hypoperfusion to
achieve goals during the first 6 h of resuscitation:
1) Central venous pressure 8–12 mmHg;
2) Mean arterial pressure (MAP) ≥65
mmHg;
3) Urine output ≥0.5 mL kg−1 h;
4) Central venous (superior vena cava) or
mixed venous oxygen saturation 70 or
65 %, respectively. These recommendations, however, are not well validated by
clinical trials and the best recommendation grade is 1C (40).
The idea of systematic resuscitation comes
from a landmark study by Rivers et al. (41).
In the study, patients with sepsis and septic
shock were randomly assigned to the 6-hour
early goal directed therapy (EGDT) group
or control group. Patients in EGDT group
received a central venous catheter that was
capable of measuring central venous oxygenation. Serial strategies including fluid
bolus, use of vasopressors and red blood
cell transfusion were initiated with the target to achieve a central venous oxygenation
of more than 70%. The results showed
that the mortality rate was significantly reduced as compared with standard therapy,
but the renal function was not assessed
(42). A recent large clinical trial called ProCESS (Protocol-Based Care for Early Septic
Shock) showed that EGDT-based protocol
was associated with marginally significant
reduction in the risk of new-onset AKI as
compared to the standard protocol care
group (3.1% vs 6%, p=0.04). However,
the EGDT-based protocol was harmful in
terms of new-onset AKI as compared to the
usual care group (43).
Renal replacement therapy (RRT)
Substantial proportion of SIAKI requires
RRT to avert deadly complications such as
severe hyperkalcemia, acidosis and volume
overload. Depending on different criteria
to initiate RRT, however, the reported rate
of RRT in AKI varies greatly across institutions. In general, about 5% of AKI patients require initiation of RRT (44). Hsu
RK et al. reported that RRT-requiring AKI
increased from 222 to 533 cases/million
person-years from 2000 to the year 2009,
with an average 10% increase per year
(incidence rate ratio=1.10, 95% CI [1.101.11] per year) (45).
RRT comprised two important aspects
when given to SIAKI patients. One refers
to the dose or intensity of RRT. In the literature, the intensity of RRT may be referred to as high-flow and slow-flow. There
is no consensus on the definition of dose
for RRT. Currently, the most widely used
definition is the normalized effluent rate,
Heart, Lung and Vessels. 2015, Vol. 7
Sepsis-induced acute kidney injury
which has been incorporated into many
clinical trials (46). This definition has the
advantage of simplicity, but our subsequent
work has demonstrated that it underestimates the real dialysis dosage and the gap
between actually delivered dose and estimated dose become progressively larger
with prolonged use of the filter (47). A
meta-analysis by our group showed that intensive dose RRT had no additional benefit
for the overall AKI patients (RR 0.91, 95%
CI [0.77-1.08]), as well as for the subgroups
with SIAKI (RR 0.99, 95% CI [0.90-1.09])
(48). We proposed that the turning point
for CRRT dose to be beneficial is below 25
ml/kg/hr (46). There are varieties of solutions available for RRT as the replacement
fluid. Seven formulas, varying in calcium,
potassium, bicarbonate and dextrose levels,
are commercially available (Table 1).
Since the mortality rate of sepsis increases
dramatically when the sepsis is complicated by AKI, it is intuitive to postulate that
early initiation of RRT may confer beneficial effects on SIAKI. The clinical question
is the timing of CRRT, which has received
much interest in the scientific community.
A retrospective study conducted by Oh HJ
et al.showed that the early use of CRRT
could significantly reduce the risk of death
within 28 days (p=0.034) (49). A recent
study, unfortunately, failed to identify any
benefit from early initiation of RRT in patients with SIAKI (50). The inconsistent
results may be due to the fact that there is
no consensus on the timing of RRT. The criteria used to classify “early” and “late” are
generally arbitrary. For instance, in Oh HJ’s
study timing of CRRT application is based
on the interval between the start time of
vasopressors use and CRRT initiation, and
“early” was defined as a time interval between vasopressor use and CRRT of more
than two days. In contrast, in Shum HP’s
study timing is based on the magnitude of
Scr rise according to RIFLE criteria (50),
and “early” was defined as the initiation of
CRRT at the risk stage of RIFLE list.
CONCLUSION
Sepsis is a leading cause of AKI, and thus
SIAKI requires special attention as its diagnosis and treatment may have some distinctive features. The diagnosis of SIAKI
requires the determination of sepsis and
subsequent occurrence of AKI. The current
definition for AKI is based on Scr and urine
output, and is limited by their delayed identification of patients with AKI. Numerous
novel biomarkers have been found to be
upregulated early after renal insult, and
these include cystatin C, IL-18, KIM-1 and
NGAL. In the management of SIAKI, the
early goal directed therapy may be useful,
but requires further validation in large clinical trials. It is well known that fluid overload is harmful in septic patients with established AKI and should be avoided. RRT
is the mainstay treatment for the severe
form of SIAKI. However, the best timing
and dosing of RRT is still under debate, and
there is still no consensus on the definition
of timing and dosing in clinical practice.
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Cite this article as: Zhang Z. Biomarkers, diagnosis and management of sepsis-induced acute kidney injury: a narrative review. Heart, Lung and Vessels. 2015; 7(1): 64-73.
Source of Support: The study was partly supported by the science and technology foundation of Jinhua city (approval No.
2013-3-008). Disclosures: None declared.
Heart, Lung and Vessels. 2015, Vol. 7
73
CASE REPORT
Heart, Lung and Vessels. 2015; 7(1): 74-80
74
Ventilator strategies for VV ECMO
management with concomitant
tracheal injury and H1N1 influenza
Adam P. Johnson, Nicholas C. Cavarocchi, Hitoshi Hirose
Department of Surgery, Thomas Jefferson University, Philadelphia, PA
Heart, Lung and Vessels. 2015; 7(1): 74-80
ABSTRACT
Tracheal injury is a rare but highly morbid complication of endotracheal intubation. Recent reviews have advocated conservative management of these injuries without operative intervention. Extracorporeal membrane
oxygenation may be a useful tool in non-operative management of tracheal injury in the setting of severe
respiratory failure and need for prolonged intubation. We present a morbidly obese 33 year-old-female with
H1N1 influenza pneumonia complicated by acute respiratory distress syndrome and bacterial super-infection
who sustained a post-intubation tracheal injury. Concomitant tracheal injury and acute lung injury pose a difficult ventilation dilemma. This patient was successfully managed by venovenous extracorporeal membrane
oxygenation, high frequency oscillator ventilation, proning position and tube thoracostomy. The venovenous
extracorporeal membrane oxygenation and ventilator management were essential for this patient’s recovery.
Keywords: ECMO, tracheal injury, H1N1 influenza, traumatic intubation.
INTRODUCTION
Venovenous extracorporeal membrane oxygenation (VV ECMO) has been well described to manage acute respiratory distress
syndrome (ARDS) (1). The onset of ARDS
in the setting of H1N1 influenza is often
hyper-acute, requiring emergent ventilatory support and, in severe cases, ECMO cannulation.
In the setting of emergent intubation, tracheal injury is a rare but catastrophic complication, occurring in 1 in 20,000 endotracheal intubations (2). Historically, urgent
Corresponding author:
Hitoshi Hirose, MD.
Division of Cardiothoracic Surgery
Department of Surgery, Thomas Jefferson University
1025 Walnut Street Room 605
Philadelphia, PA 19107, USA.
e-mail: Hitoshi.Hirose@jefferson.edu
surgical intervention has been the mainstay
of management of post-intubation tracheal
injury. However, more recent reviews advocate a conservative approach, especially in
patients who will require prolonged ventilation due to underlying pulmonary pathology (3, 4).
Our case demonstrates successful management of concomitant tracheal injury and
H1N1 influenza complicated by bacterial
super-infection with VV ECMO supplemented by high-frequency oscillator ventilation (HFOV), prone positioning, and tube
thoracostomy in an adult patient.
CASE REPORT
A 33 year-old previously healthy, morbidly obese (body mass index 40, body weight
98 kg, height 157 cm) female presented
Heart, Lung and Vessels. 2015, Vol. 7
ECMO on H1N1 and tracheal injury
Figure 1 - Series of the chest
x-rays of the patient. Initial
radiograph upon presentation showed bilateral infiltrates (1A). Post intubation
x-ray shows endotracheal
tube in the right main stem
bronchus (1B). After repositioning the endotracheal
tube, there is the progression
of the bilateral infiltrations
(1C). Post ECMO cannulation at arrival to our facility, there is a large loculated
pneumothorax in the left
thorax (1D).
ECMO = extracorporeal
membrane oxygenation.
to an outside emergency department with
progressive dyspnea and malaise. In the
emergency department, she rapidly developed acute hypoxic respiratory failure with
bilateral infiltrates on chest x-ray (Figure
1A). She deteriorated and was emergently intubated. Post-intubation chest x-ray
showed the endotracheal tube in the right
main stem bronchus (Figure 1B), requiring adjustment (Figure 1C). She remained
hypoxic and was transferred to a tertiary
center for ARDS management. At arrival,
she was hypoxic (arterial blood gas was pH
7.18, PaCO2 58, PaO2 52, saturation 78%),
despite fractional inspiratory oxygen
(FiO2) of 100%, tidal volume (TV) 600 ml,
respiratory rate of 20 positive end expiratory pressure (PEEP) of 20 mm H2O with
paralysis and Epoprostenol (50 ng/kg/
min) support. Failed medical management
necessitated urgent VV ECMO using a
bi-caval dual lumen cannula (Maquet, Rastatt, Germany) via the right internal jugular vein, after we obtained consent from
her family. Her oxygenation improved (pH
7.35, PaCO2 31, PaO2 176 and saturation
>99%) with VV ECMO flow of 4 LPM,
sweep of 6 LPM and FiO2 100%. The patient was found to be positive for H1N1
influenza with super imposed methicillin-sensitive Staphylococcus aureus (MSSA)
pneumonia; Tamiflu (75 mg q12 hours)
and broad-spectrum antibiotic coverage
with vancomycin (1.5 gram q12 hours, titrate by the rough level 15-20 mg/L) and
piperacillin/tazobactam (3.375 gram q8
hours) were initiated.
Ventilator settings were changed from conventional mode (TV 600 ml, rate 20, FiO2
100%, PEEP 20) to ARDSNet protocol,
with 300cc TV (TV=4-6 ml/kg, based on
an ideal body weight of 55 kg), respiratory
rate 10, and FiO2 of 100% with PEEP 10
for lung protection. Peak airway pressure
and mean airway pressure remained elevated (58 cm H2O and 15 cm H2O respectively). Post-ECMO chest x-ray showed a
loculated lower left pneumothorax, treated
immediately with bedside thoracostomy
tube placement (Figure 1D). On the follow-
Heart, Lung and Vessels. 2015, Vol. 7
75
A.P. Johnson, et al.
76
Figure 2 - Bronchoscopy confirms membranous
defect 1 cm above the carina.
ing day, bronchoscopy (Figure 2) showed a
3-4 cm injury of the posterior membranous
trachea approximately 1 cm above the carina, confirmed by computed tomography
(Figure 3). Thoracic surgery was consulted
for evaluation of the trachea injury, but the
patient was deemed a poor surgical candidate due to severe ARDS requiring ECMO
with high positive pressure ventilation. The
patient began to show failure of ARDSnet
conventional ventilation (TV = 220-330 cc
PEEP 10) with worsening air leak around
the endotracheal tube despite of inflation of
the cuff, air leak from the chest tube, pneumothorax, pneumomediastinum, and CO2
retention (ABG: pH 7.29, PaCO2 59, PaO2
147 and saturation 99%); high frequency oscillatory ventilation (HFOV, setting
mean airway pressure 18 cm H2O, amplitude (∆P) 75 cm H2O. frequency 5 Hz, FiO2
50%.) was initiated. Pneumothorax, pneumomediastinum and chest tube air leak improved, as well as the ABG was improved
with the HFOV (pH 7.37, PaCO2 39, PaO2
116, saturation 99%).
The tracheal tear was evaluated daily by
bronchoscopy with airway lavage to prevent mucous accumulation. With pneumothorax, pneumomediastinum, and air leak
from the chest tube stabilized, on ECMO
day 14 and 11 total days of HFOV support,
the patient was successfully weaned back
to ARDSNet protocol ventilation from
HFOV. With ongoing poor lung recruitment and progression of pulmonary infil-
Figure 3 - Axial (A) and sagittal (B) computed tomography images demonstrating 3-4 cm defect in
posterior membranous trachea (arrow).
Heart, Lung and Vessels. 2015, Vol. 7
ECMO on H1N1 and tracheal injury
trate, the patient was transitioned to prone
position ventilation, using the automated
RotoProne system (KCI, San Antonio, TX).
In prone position, ABG improved to pH
7.46, PaCO2 34, PaO2 105, saturation 98%
from pH 7.41, PaCO2 43, PaO2 67, saturation 93% while in supine. Per protocol, the
patient was continually rotated to at least
40 degrees for a minimum of 18 hours per
day with a maximum prone interval of 3
hours and 15 minutes, interrupted with 45
minutes periods of supine positioning for
general nursing care and to minimize facial
edema.
The patient’s sedation was maintained
with ketamine, fentanyl, and midazolam
and she was paralyzed with rocuronium.
Enteral nutrition was continued while the
patient was paralyzed through a post-pyloric nasal-duodenal tube to minimize risk for
aspiration.
The patient’s pulmonary status improved
with prone positioning after 6 days and she
was successfully weaned and decannulated
from VV ECMO on day 20.
At the time of decannulation, bronchoscopy showed improvement of the tracheal
injury and esophagogastroscopy confirmed
no communication with the esophagus. On
day 5 post-decannulation, the patient had a
tracheostomy and gastrostomy tube placed
for long-term ventilation weaning. On day
20 post decannulation, she was tolerating
tracheostomy collar and transferred out of
the intensive care unit to the ward. On day
28 post-decannulation, the patient underwent swallow evaluation and was cleared
for a diet, tolerating a Passy-Muir valve
(Passy-Muir, Irvine, CA).
The patient worked well with physical
therapy, ambulating with assistance and
was transferred to a rehabilitation facility
on post decannulation day 48.
The data presented in this paper was collected under approval from Thomas Jefferson University Internal Review Board.
DISCUSSION
Concurrent acute hypoxic respiratory failure secondary to infection with H1N1 influenza and post-intubation tracheal injury
pose a difficult management dilemma due
to the requirement for long term positive
pressure ventilation. During endotracheal
intubation, superficial mucosal tears occur
in 18% of patients; however, full thickness
post-intubation tracheal injury like this
case is rare. Patient risk factors for post-intubation tracheal injury include female gender, short stature (≤160 cm tall), difficult
airway anatomy, underlying connective
tissue disorder and mechanical risk factors
include use of rigid stylet, inadequate intubation tube size, cuff over-inflation, emergent intubation, and intubation by non-anesthesiologists. Our patient filled many of
these criteria. Emergency intubation and
delayed diagnosis have been identified as
independent risk factors for mortality after
post-intubation tracheal injury (2). Initial
presentation is most often characterized
by subcutaneous emphysema, pneumothorax, persistent air leak and hemoptysis-less
commonly pneumomediastinum, angina,
hypotension and shock (2, 4). Pneumothorax and pneumomediastinum first aroused
suspicion for tracheal injury in our patient.
ECMO management for isolated tracheal
injury has been previously described, in 10
published reports - 4 pediatric patients and
6 adults (Table 1) (5-14). Early reports utilized veno-arterial cannulation, but the majority of patients had isolated pulmonary
failure secondary to tracheal tear, requiring
only VV ECMO. The majority of iatrogenic
injuries resulted in a distinct longitudinal
injury to the membranous portion of the
trachea, as opposed to blunt chest trauma
that resulted in transverse injury with irregular borders (3). Blunt chest trauma
usually required surgical repair, likely due
to the nature of tracheal injury especially if
Heart, Lung and Vessels. 2015, Vol. 7
77
A.P. Johnson, et al.
78
Table 1 - Summary of case reports of tracheal injuries managed by extracorporeal membrane oxygenation.
Authors
(year)
Age
(gender)
Mechanism
of injury
Characterization of
injury (size)
Type of
ECMO
Duration of Adjunct
ECMO
therapy
Surgical
repair
Niwa
(1995)
39 years
(Male)
Tracheal stenting
with rigid
bronchoscopy
for polychondritis
stricture
Longitudinal tear (5cm)
in membranous trachea
extending to left main
stem bronchus
VA
6 days
None
Yes
Goldman
(1996)
13 months Aspirated porcelain
(NA)
foreign body
Longitudinal tear (NA)
in membranous trachea
from cricoid cartilage to
right lower lobe bronchus
VA
17 days
HFOV
Yes
Voelckel
(1998)
12 years
(Male)
Blunt chest trauma
by falling tree
Tear (NA) in lateral wall
of distal trachea to the
right main stem bronchus
VV
6 days
None
Yes
Campione
(2007)
14 years
(Male)
Blunt chest trauma
during go-cart race
Transverse (NA)
disruption in the right
intermediate bronchus
VV
3 days
None
Yes
Madershahian 19 years
(2007)
(Female)
Blunt chest trauma
from motor vehicle
accident
Rupture (NA) of right
main stem bronchus
VA
6 days
None
Yes
Korvenoja
(2008)
56 years
(Female)
Elective dual lumen
intubation for
pneumonectomy
Longitudinal tear (3cm)
in membranous left main
stem bronchus extending
from carina to left upper
lobe bronchus
VV
48 minutes
None
Yes
Fitzgerald
(2011)
7 years
(Male)
Emergent intubation
for aspiration
pneumonia
Diverticulum
(2.2x0.7x1cm) in distal
membranous trachea
with distal discontinuity
(0.6x0.8cm)
VV
16 days
HFOV
No
Walker
(2012)
20 years
(Male)
Blunt chest trauma
from motor vehicle
accident
Transection right main
stem bronchus
VV
2 days
None
Yes
Mitilian
(2013)
41 years
(Male)
Tracheal stenting
for polychondritis
stricture
Tear (NA) of
VV
membranous trachea from
carina to bilateral main
bronchi
14 days
None
No
Sian
(2014)
34 years
(Female)
Emergent intubation
for drug overdose
Tear of membranous
trachea extending to right
main stem bronchus
VV
NA
None
Yes
Current
33 years
(Female)
Emergent intubation
for ARDS due
to H1N1and
overlapping bacterial
pneumonia
Longitudinal tear (3-4cm)
in distal membranous
trachea
VV
20 days
HFOV,
prone
position
No
ARDS = acute respiratory distress syndrome; ECMO = extracorporeal membrane oxygenation; NA = not available; VA =
venoarterial; VV = Venovenous; HFOV = high frequency oscillatory ventilation.
Heart, Lung and Vessels. 2015, Vol. 7
ECMO on H1N1 and tracheal injury
anticoagulation and ECMO is required for
support (7, 9-12). In these papers ECMO
support varied from 48min to 20days (Table 1). Although there is likely publication
bias, the results from these isolated reports
show ECMO to be a promising strategy for
tracheal injury with potential for positive
outcomes.
Retrospective review has shown a two-fold
increase in mortality for surgical management of tracheal injuries detected outside
the operating room (2). Conservative management strategies include low tidal volume
ventilation, permissive hypercapnia, endotracheal tube fixation in the distal trachea,
double lumen intubation, daily bronchoscopy, HFOV, and even ECMO, as in our case
(4). Early reports utilized these strategies
only as a bridge to definitive surgical management. However, current strategies have
shifted to reserve surgery only for cases
that have failed conservative management
- signified by worsening mechanical ventilation requirements, uncontrolled air leak,
and active endobronchial bleeding (3, 4).
Surgery for patients requiring ECMO poses
added risk due to anticoagulation requirements. Conservative therapy is particularly
successful in small injuries, less than 2 cm,
with minimal non-progressive symptoms,
and no air leakage on spontaneous breathing (2).
VV ECMO provides oxygenation and ventilation allowing for minimal ventilatory
support and reduced associated baro- and
volu-trauma to the injured bronchial tree.
However, VV ECMO requires the lungs
to participate in the oxygenation process.
Failed oxygenation on VV ECMO may
require transition to VA ECMO in order
to fully rest the lungs and bronchial tree.
In our case, VA ECMO was not ideal due
concern to increased infectious risk with
femoral cannulation in an morbidly obese
patient. In combination with VV ECMO,
rescue ventilation therapies may further
minimize barotrauma to the injured trachea (6, 11). Important adjunct therapies to
aid in the healing of the tracheal injury in
our patient were prone position ventilation
and high frequency oscillatory ventilation.
A recent randomized control trial showed
the benefit of prone positioning on survival
in ARDS, but evidence for use with HFOV
and concomitant tracheal injury is limited
(15).
Tracheal injury, especially in the setting of
underlying severe lung injury, is rare and
has a high mortality rate. The management
has evolved over time, with a movement
toward conservative management due to
the high morbidity and mortality associated with surgical repair. Here we present
a conservative management strategy that
incorporates the newest advances in pulmonary critical care, and the first report of
successful management of an adult patient
with concomitant ARDS, MSSA super-infection and post-intubation tracheal injury
with VV ECMO, HFOV and prone position
ventilation.
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Cite this article as: Johnson AP, Cavarocchi NC, Hirose H. Ventilator strategies for VV ECMO management with concomitant
tracheal injury and H1N1 influenza. Heart, Lung and Vessels. 2015; 7(1): 74-80.
Source of Support: Nil. Disclosures: None declared.
Heart, Lung and Vessels. 2015, Vol. 7
IMAGE IN MEDICINE
Heart, Lung and Vessels. 2015; 7(1): 81-82
Idiopathic ascending aortitis
as a rare cause of supravalvular
aortic stenosis
Amedeo Pergolini1, Giordano Zampi2, Maria Denitza Tinti3, Andrea Vallone1,
Paolo Giuseppe Pino1, Francesco Musumeci1, Giampaolo Luzi1
1
Department of Cardiovascular Science, “S. Camillo-Forlanini” Hospital, Rome, Italy; 2Department of Cardiology, Belcolle Hospital,
Viterbo, Italy; 3Department Heart and Great Vessels “A. Reale”, Policlinico Umberto I, “La Sapienza”, Rome, Italy
Keywords: aortitis, supravalvular aortic stenosis,
aortic stenosis, idiopathic aortitis.
A 65-year-old Caucasian man was admitted
to the Cardiothoracic Department for elective coronary artery bypass graft (CABG).
At pre-operative bidimensional transthoracic echocardiography (TTE), a narrowing of the ascending aorta was observed:
the inner lumen was reduced by a circumferential, bulky ridge of tissue projecting
from the aortic wall and causing a mild supravalvular stenosis (mean PG 20 mmHg)
(Figure 1, A-B). An electrocardiogram-gated cardiac computed-tomography (CT) an-
giography was performed in order to characterize the aortic root and the anatomic
aortic valvular abnormalities.
CT images demonstrated normal aortic
diameters with a low attenuation of the
thickened aortic wall in the non-contrast
phase and an enhancement after contrast
administration. This image was clearly
identified from the aortic root to the arch
and a short segment of the descending thoracic aorta (Figure 2, A-D). Moreover, CT
imaging characterized a mural thickening
of about 2 mm. It is noted that no sings of
dissection such as, periaortic fibrosis, retroperitoneal fibrosis and intimal flap were
Figure 1 - Transthoracic Echocardiography showing a) supravalvular aliasing
and acceleration of
the flow at the ColorDoppler and b) a mild
supravalvular aortic
stenosis at the Continous-wave Doppler.
Corresponding author:
Giordano Zampi
Strada Sammartinese s.n.c. Viterbo, Italy
e-mail: giordano.zampi@alice.it
Heart, Lung and Vessels. 2015, Vol. 7
81
A. Pergolini, et al.
82
detected. Therefore, based on this data, an
ascending aortitis was suspected, as there
were no symptoms or previous history suggestive of aortic syndrome.
Figure 2 - Computed Tomography Angiography, a) coronal view of the ascending aorta and
axial slices of the b) supravalvular and c-d) ascending aorta showing an enhancement of the
thickened aortic wall.
Intraoperative TEE demonstrated a diffuse
aortic mural thickening with an echolucent periaortic mass, a “halo”, which may
be due to mural edema (Figure 3, A-B). No
complications such as aortic root dilation
nor valve regurgitation were identified.
Surgical examination confirmed the diagnosis of isolated thoracic aortitis; considering there were no complications or aortic
aneurism, a conservative approach was
preferred by the surgeons and the patient
underwent only CABG.
In order to avoid complications, cannulation for cardio-pulmonary bypass was
made through the arch and both the mammary arteries were used instead of the safena. Infective and immunological workup
were all negative, so the patient was diagnosed as having an idiopathic ascending
aortitis and was enrolled in a 6-months
follow-up (1).
REFERENCES
1. Burke AP, Tavora F, Narula N, Tomaszewski JE, Virmani
R. Aortitis and ascending aortic aneurysm: description
of 52 cases and proposal of a histologic classification. Human Pathology 2008; 39: 514-26.
Figure 3 - Transesophageal echocardiography, mid-esophageal view of the aortic root (a) without and (b)
with color Doppler. There was increased wall thickness (white arrows) without significant dilation of the
aortic root and showing a post valvular acceleration of the flow.
Cite this article as: Pergolini A, Zampi G, Tinti MD, Vallone A, Pino PG, Musumeci F, Luzi G. Idiopathic ascending aortitis
as a rare cause of supravalvular aortic stenosis. Heart, Lung and Vessels. 2015; 7(1): 81-82.
Source of Support: Nil. Disclosures: None declared.
Heart, Lung and Vessels. 2015, Vol. 7
IMAGES IN MEDICINE
Heart, Lung and Vessels. 2015; 7(1): 83-85
Hybrid endovascular repair of
Kommerell diverticulum and aberrant
right subclavian artery in a patient
with repaired coarctation of the aorta
Marc Najjar, Monir Mohar, Allan Stewart, Isaac George
Division of Cardiothoracic Surgery, New York Presbyterian Hospital - College of Physicians and Surgeons of Columbia University,
New York, NY
Keywords: aberrant right subclavian artery, Kommerell diverticulum, hybrid endovascular repair, coarctation of aorta repair.
Aberrant right subclavian (Lusoria) artery
(ARSA) has a prevalence of 0.5-1.5% in
the general population (1). Kommerell diverticulum (KD) is by definition a dilatation at the base of the ARSA. Although it
is usually asymptomatic, ARSA can cause
symptoms such as dysphagia, coughing or
even Horner syndrome.
The traditional therapy has been open surgical repair with carotid-subclavian bypass
(CSB) and resection of the ARSA aneurysm with replacement of the abnormal
portion of descending aorta with a graft (2).
Recently, the use of hybrid endovascular
therapy in complex congenital anatomy has
been increasing. Hybrid repair of ARSA
with KD was first described by Lacroix et
al. (1) and has since been performed by others with satisfying outcomes (3), however,
no reports of concurrent aortic coarctation
Corresponding author:
Isaac George, M.D.
Assistant Professor of Surgery
Division of Cardiothoracic Surgery
College of Physicians and Surgeons of Columbia University
New York Presbyterian Hospital
MHB 7GN-435, 177 Fort Washington Ave
New York, NY, 10032
e-mail: ig2006@cumc.columbia.edu
complicating this repair has been documented. Total endovascular approaches
have been reserved for specific cases where
the anatomy and the tortuousness of the
aortic arch allow such interventions without posing a risk (4).
We describe for the first time a case of
successful hybrid endovascular repair of
ARSA associated with a KD at the site of a
previously repaired pre and post-ductal coarctation of the aorta.
The patient is a 55-year old female with an
ARSA coming off a KD. Her past medical
history is notable for a coarctation of the
aorta repaired at the age of 15 and a Ross
procedure at the age of 41 for severe calcific
aortic stenosis. It was noted on imaging
that an ARSA arose 2 cm distal to the left
subclavian artery (LSA) at the previously
repaired coarctation of the aorta, with a 5
cm KD aneurysm (Figure 1).
Since the proximal landing zone of the thoracic endograft has to be proximal to the
LSA, we chose a two-stage approach consisting of right CSB followed by left CSB
and endovascular ARSA aneurysm exclusion. First a right CSB (PTFE, Gore-Tex, 6
mm in diameter) was performed through
a supraclavicular approach, with surgical ligation of the right subclavian artery
(proximal to anastomosis to prevent a Type
Heart, Lung and Vessels. 2015, Vol. 7
83
M. Najjar, et al.
84
Figure 1 - Preoperative three-dimensional CT
reconstructions showing Kommerell diverticulum with aberrant right subclavian artery coming off of it and relationship with other vessels.
KD = Kommerell diverticulum; LSA = Left
subclavian artery; ARSA = Aberrant right
subclavian artery; LCA = Left common carotid
artery; RCA = Right common carotid artery.
II endoleak). Twelve days later, a left CSB
(PTFE, Gore-Tex, 6mm in diameter) was
done, immediately followed by thoracic
endografting in the same setting. A Cook
TX2 endograft (28 mm x 120 mm) was
advanced through the right common femoral artery over a Lunderquist wire into the
aortic arch, distal to the head vessels and
proximal to the aneurysm and LSA. This
placement was confirmed with multiple
aortograms.
The device was deployed with a 3 cm landing zone proximally. Excellent apposition
was noted proximally and distally; a small,
clinically insignificant Type II endoleak
was seen, due to the contribution of the
LSA retrograde.
The proximal and mid portions of the graft
were ballooned with a 36 CODA balloon.
Repeat angiography revealed almost no
Type II leak and the complete exclusion of
the aneurysm of KD (Figure 2).
The patient was extubated in the operating
room and was taken to the intensive care
unit without vasopressor support. She had
no postoperative complications and was
discharged home on postop day 3. The patient was still asymptomatic at 12 months
postoperatively.
Due to its low prevalence and the heterogeneity of the patients, there are still no wellestablished guidelines for the treatment of
KD with an ARSA. Our report reinforces
the ease and safety of the 2-stage hybrid approach, as well as highlights the advantage
the technique carries over both the traditional open repair and the total endovascular approach.
On one hand, being less invasive than open
repairs, the hybrid endovascular technique
spares the need for cardiopulmonary by-
Figure 2 - Postoperative three-dimensional CT
reconstructions showing good positioning of endograft with exclusion of the diverticulum and no
sign of endoleak, patent bilateral carotid-subclavian bypass grafts. LCA = Left common carotid
artery; RCA = Right common carotid artery.
Heart, Lung and Vessels. 2015, Vol. 7
Hybrid repair of Kommerell diverticulum with coarctation of aorta
pass and deep hypothermic arrest, and thus
is suitable for high-risk patients.
On the other hand, when compared to total
endovascular repairs, a hybrid technique is
more versatile and allows for a larger margin of maneuver.
Although at first appealing, a total endovascular approach should be considered with
caution since its success is highly dependent on the individual anatomy of the aneurysm.
REFERENCES
1. Lacroix V, Astarci P, Philippe D, Goffette P, Hammer F,
Verhelst R, et al. Endovascular treatment of an aneurysmal
aberrant right subclavian artery. J Endovasc Ther 2003; 10:
190-4.
2. Kouchoukos NT, Masetti P. Aberrant subclavian artery and
Kommerell aneurysm: Surgical treatment with a standard
approach. J Thorac Cardiovasc Surg 2007; 133: 888-92.
3. Idrees J, Keshavamurthy S, Subramanian S, Clair DG,
Svensson LG, Roselli EE, et al. Hybrid repair of Kommerell
diverticulum. J Thorac Cardiovasc Surg 2014; 147: 973-6.
4. Attmann T, Brandt M, Müller-Hülsbeck S, Cremer J. Twostage surgical and endovascular treatment of an aneurysmal aberrant right subclavian (Lusoria) artery. Eur J Cardiothorac Surg 2005; 27: 1125-7.
Cite this article as: Najjar M, Mohar M, Stewart A, George I. Hybrid endovascular repair of Kommerell diverticulum and
aberrant right subclavian artery in a patient with repaired coarctation of the aorta. Heart, Lung and Vessels. 2015; 7(1): 83-85.
Source of Support: Nil. Disclosures: None declared.
Heart, Lung and Vessels. 2015, Vol. 7
85
IMAGES IN MEDICINE
Heart, Lung and Vessels. 2015; 7(1): 86-88
86
McConnell’s echocardiographic
sign in acute pulmonary embolism:
still a useful pearl
Jorge A. Brenes-Salazar
Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN
Keywords: McConnell’s sign, echocardiography, acute
pulmonary embolism.
A 69 year old female with a history of gastric bypass surgery with a recent revision
(12 weeks prior to presentation) was admitted from a skilled nursing facility with
subacute progressive dyspnea, cough and
pleuritic chest pain.
On initial assessment her blood pressure
was 150/80 mmHg, pulse of 130 beats per
minute, with a respiratory rate of 30 per
minute and oxygen saturation of 85%.
She had evidence of hypoxemic respiratory failure on arterial blood gases, with a
PaO2 of 46 mmHg and thus was intubated
and sedated before further workup was obtained.
A bedside echocardiogram showed preserved left ventricular performance, with
an ejection fraction of 65%, but exhibited
severe right ventricular enlargement and
systolic dysfunction (Figures 1 and 2), with
akinesis of the mid-ventricular segments
but preserved contractility of the apex (McConnell sign, Figure 3).
Right ventricular systolic pressure was estimated to be 50 mmHg by peak tricuspid
regurgitant velocity.
Corresponding author:
Jorge A Brenes-Salazar, MD
Mayo Clinic
200 First St. SW,
Rochester, MN 55905
e-mail: brenessalazar.jorge@mayo.edu
Figure 1 - Tissue Doppler signal of the systolic
velocity at the lateral annulus of the right ventricle, measured at 0.07 m/s (normal 0.12-0.14 m/s).
Figure 2 - M-mode of the tricuspid annular
plane systolic excursion (TAPSE), measured at
11.5 mm (normal 20-22 mm).
Heart, Lung and Vessels. 2015, Vol. 7
McConnell’s echocardiographic sign in acute pulmonary embolism
Figure 3 - Apical four chamber 2-D image of
the left (LV) and right (RV) ventricles, displaying preserved contraction of the RV apex with
akinesis of the free wall, consistent with McConnell’s sign. Compare the relative sizes of the RV
and LV.
Figure 4 - Computed tomography (CT) scan of
the chest, maximum intensity projection (MPI)
that shows the presence of multiple abrupt filling
defects of the sub-segmental right pulmonary arteries (arrow). Notice the remarkable oligemia of
the right lung as compared to the left.
No thrombus in transit was identified.
Given these findings, the patient was empirically started on intravenous un-fractioned heparin while she was transported
to the computed tomography (CT) scanner.
Chest CT angiography displayed multiple
pulmonary emboli in lobar and segmental
branches of the right pulmonary arteries,
with associated right ventricular enlargement consistent with right ventricular
strain (Figure 4).
Given the patient’s respiratory and hemodynamic compromise, intravenous tissue
plasminogen activator (tPA) was administered, with marked improvement of her
cardiorespiratory status in a matter of
hours. She was successfully extubated on
day 2 and transitioned to oral warfarin
therapy.
The role of echocardiography in the workup of acute pulmonary embolism has not
been well established formally (1), but it
can provide a series of indirect clues that
can guide clinicians to reach a definitive
diagnosis.
In cases of pulmonary embolism with cardiorespiratory compromise, such non-invasive data can crucially aid in therapeutic
decisions such as thrombolysis.
McConnell’s sign is a distinct echocardiographic pattern of regional wall motion abnormalities of the right ventricle, with akinesis of the mid-ventricular free wall with
normal or hyperdynamic contractility of
the apex (2).
Potential mechanisms that may account
for this phenomenon include tethering of
the right apex to a compensating and hyperdynamic left apex, attempts of the right
ventricle to provide acute spherical remodeling that may be hemodynamically more
efficient and localized ischemia of the free
wall due to increased wall stress (3).
Although not pathognomonic of acute pulmonary embolism, since it can also be present in cases of right ventricular infarction
Heart, Lung and Vessels. 2015, Vol. 7
87
J.A. Brenes-Salazar
88
(4), the diagnostic value of McConnell’s
sign should not be underestimated in patients presenting with hypoxemia and additional signs of right ventricular pressure
overload, such as increased tricuspid jet
velocity and RV outflow tract acceleration
times.
REFERENCES
1. Torbicki A. Echocardiographic diagnosis of pulmonary
embolism: a rise and a fall of McConnell sign? Eur J Echocardiogr 2005; 6: 2-3.
2. Sosland RP, Gupta K. Images in cardiovascular medicine:
McConnell’s Sign. Circulation 2008; 118: e517-8.
3. Calvin JE. Pressure segment length analysis of right ventricular function: influence of loading conditions. Am J
Physiol 1991; 260: 1087-97.
4. Casazza F, Bongarzoni A, Capozi A, Agostoni O. Regional
right ventricular dysfunction in acute pulmonary embolism and right ventricular infarction. Eur J Echocardiogr
2005; 6: 11-4.
Cite this article as: Jorge A. Brenes-Salazar. McConnell’s echocardiographic sign in acute pulmonary embolism: still a useful
pearl. Heart, Lung and Vessels. 2015; 7(1): 86-88.
Source of Support: Nil. Disclosures: None declared.
Heart, Lung and Vessels. 2015, Vol. 7
LETTER TO THE EDITOR
LETTER TO THE EDITOR
89
REFERENCES
Isoproterenol infusion in septic shock
Dear Editor,
the recent report on “Isoproterenol infusion in
septic shock” is very interesting (1). Wiramus
et al. concluded that “use of isoproterenol was
associated with an increase of tissue oxygen
saturation (1).” In fact, there are some issues
of isoproterenol use to be discussed. First, the
increased heart rate due to infusion is common
(2).
On the other hand, the occurrence of paradoxical bradycardia can also be observed (3). In addition, the possibility of occurrence of isoproterenol-induced myocardial infarction should
be kept in mind (4).
The fatal case due to the infusion is reported
in the literature (5). To prevent cardiac toxicity
due to isoproterenol infusion, careful evaluation before usage is required.
1. Wiramus S, Textoris J, Bardin R, Vigne C, Kelway C,
Martin C, et al. Isoproterenol infusion and microcirculation in septic shock. Heart Lung Vessel. 2014; 64: 274-9.
2. Garg M, Khanna D. Exploration of pharmacological interventions to prevent isoproterenol-induced myocardial
infarction in experimental models. Ther Adv Cardiovasc
Dis. 2014; 8: 155-69.
3. Leone M, Boyadjiev I, Boulos E, Antonini F, Visintini P,
Albanèse J, et al. A reappraisal of isoproterenol in goaldirected therapy of septic shock. Shock. 2006; 26: 353-7.
4. Brembilla-Perrot B, Muhanna I, Nippert M, Popovic B,
Beurrier D, Houriez P, et al. Paradoxical effect of isoprenaline infusion. Europace. 2005; 7: 621-7.
5. Kurland G, Williams J, Lewiston NJ. Fatal myocardial
toxicity during continuous infusion intravenous isoproa63: 407-11.
Viroj Wiwanitkit
Surin Rajabhat University, Surin Thailand
Corresponding author:
Professor Viroj Wiwanitkit
Wiwanitkit House, Bangkhae, Bangkok Thailand 10160
e-mail: wviroj@yahoo.com
Cite this article as: Wiwanitkit V. Isoproterenol infusion in septic shock. Heart, Lung and Vessels. 2015; 7(1): 89.
Source of Support: Nil. Conflict of interest: None declared.
RESPONSE
No coronary artery occlusion in septic
shock: Isoproterenol
infusion should not be discouraged
Dear Editor,
in their relevant letter, Dr Wiwanitkit pointed
out important limitations about the use of isoproterenol: these authors should be commended for their input to our research. Indeed, in
animal models of coronary occlusion, isoproterenol administration augmented infarct size
(1), suggesting that the use of isoproterenol in
patients with coronary artery occlusion should
be discouraged, probably in favor of the use of
dobutamine in the same patients (2). However,
in those models, isoproterenol was used as repeated boli of 0.15 mg/kg (i.e. 9 mg for 60 kg)
in non-resuscitated animals, whereas in our
patients we infused continuously a maximal
dosage of 0.5 mg/h after well-conducted resuscitation.
Patients with septic shock do not suffer from
coronary occlusion. Several experimental models suggest that septic shock induces an even
increased coronary flow (3). In addition, betaadrenoreceptors are desensitized in patients
with sepsis (4), supporting the need to introduce the most powerful beta-adrenergic inotrope in selected patients developing a septic
acute heart failure (4, 5). Finally, to date, both
experimental models and cohorts of patients
did not reveal harm associated with the use of
isoproterenol in this indication (6, 7).
In conclusion, inotropes should be carefully
used in few, selected patients. The harmful effect of isoproterenol in animals with coronary
occlusion, however, should not discard its potential role in septic shock.
REFERENCES
1. Shell WE, Lavelle JF, Covell JW, Sobel BE. Early estimation of myocardial damage in conscious dogs and patients
with evolving acute myocardial infarction. J Clin Invest.
1973; 52: 2579-90.
Heart, Lung and Vessels. 2015, Vol. 7
90
2. Pollock GD, Bowling N, Tuttle RR, Hayes JS. Effects of Sdobutamine on ischemic myocardium caused by coronary
artery narrowing. J Cardiovasc Pharmacol. 1994; 24: 6473.
3. Papadakis EJ, Abel FL. Left ventricular performance in
canine endotoxin shock. Circ Shock. 1988; 24: 123-31.
4. Bernardin G, Strosberg AD, Bernard A, Mattei M, Marullo S. Beta-adrenergic receptor-dependent and -independent stimulation of adenylate cyclase is impaired during
severe sepsis in humans. Intensive Care Med. 1998; 24:
1315-22.
5. Yoneyama M, Sugiyama A, Satoh Y, Takahara A, Nakamura Y, Hashimoto K. Cardiovascular and adenylate
cyclase stimulating effects of colforsin daropate, a watersoluble forskolin derivative, compared with those of isoproterenol, dopamine and dobutamine. Circ J. 2002; 66:
1150-4.
6. Boillot A, Massol J, Maupoil V, Grelier R, Capellier G,
Berthelot A, et al. Alterations of myocardial and vascular
adrenergic receptor-mediated responses in Escherichia
coli-induced septic shock in the rat. Crit Care Med. 1996;
24: 1373-80.
7. Leone M, Boyadjiev I, Boulos E, Antonini F, Visintini P,
Albanèse J, et al. A reappraisal of isoproterenol in goaldirected therapy of septic shock. Shock. 2006; 26: 353-7.
Marc Leone, Claude Martin
Service d’Anesthésie et de Réanimation, Hôpital Nord,
Assistance Publique Hôpitaux de Marseille,
Aix Marseille Université, Marseille, France
Corresponding author:
Marc Leone
Service d’Anesthésie et de Réanimation, Hôpital Nord,
Chemin des Bourrely, 13015 Marseille, France
e-mail : marc.leone@ap-hm.fr
Cite this article as: Leone M, Martin C. No coronary artery occlusion in septic shock: Isoproterenol infusion should not be
discouraged. Heart, Lung and Vessels. 2015; 7(1): 90.
Source of Support: Nil. Conflict of interest: None declared.
Heart, Lung and Vessels. 2015, Vol. 7
LETTER TO THE EDITOR
LETTER TO THE EDITOR
Paravertebral analgesia in transapical
transcatheter aortic valve replacement
Dear Editor,
Patients who qualify for transapical transcather
aortic valve replacement (TA-TAVR) are considered to be high-risk or inappropriate candidates
for traditional aortic valve replacement surgery,
frequently possessing poor peripheral arterial
access excluding them from transfemoral TAVR
(1). Poor respiratory function has been shown to
be a predictor of mortality in TA-TAVR patients
(2). The rate of chronic obstructive pulmonary
disease in TA-TAVR patients ranges between 2040% (1, 3, 4). A recent single institution review
found that epidural analgesia was associated with
a decrease in respiratory complications, new onset atrial fibrillation and in hospital death (5).
However, epidural anesthesia in patients with severe aortic stenosis can result in problematic vasodilation and is not recommended in patients on
clopidogrel therapy (6, 7). Accordingly, single injection paravertebral analgesia with 0.2% ropivicaine with clonidine has been used safely since the
initiation of the TA-TAVR program at the Maine
Medical Center. Anaesthetic procedures adopted
at Maine Medical Center for patients receiving
transapical transcatheter aortic valve replacement
have shown encouraging results suggesting clinical benefits of single injection paravertebral blockade (left sided paravertebral blocks between one
and three levels at the discretion of the anesthesiologist), such as: decreased opiate administration,
more frequent on table extubation, a lower rate
of post-operative delirium, decreased rate of new
onset atrial fibrillation, and a shorter ICU stay. In
early observations there were no complications
related to paravertebral blockades which are usually performed in a time efficient manner (15-30
minutes per patient). Addressing peri-operative
sympathetic stimulation with neuraxial anesthesia may have a measurable salubrious benefit
garnered beyond what is achieved with an opioidbased approach alone. The lack of complications
at a minimum demonstrates the technique can be
done safely in this high-risk patient cohort. Currently there is an on-going trial investigating the
impact of paravertebral catheters in TA-TAVR pa-
tients on delirium and length of hospital stay (8).
This clinical trial highlights the growing interest
in regional techniques for this very frail and highrisk patient cohort. However, clopidogrel therapy
in the immediate post-operative period precludes
the use of catheters at many centers. For this reason, a similar prospective trial is imperative to
investigate the use of single injection paravertebral blockades, which may be applicable to more
TAVR centers.
REFERENCES
1. Cobey FC, Ferreira RG, Naseem TM, Lessin J, England M,
D’Ambra MN, et al. Anesthetic and perioperative considerations for transapical transcatheter aortic valve replacement. J Cardiothorac Vasc Anesth 2014; 28: 1087-99.
2. Kempfert J, Rastan A, Holzhey D, Linke A, Schuler G, van
Linden A, et al. Transapical aortic valve implantation: analysis of risk factors and learning experience in 299 patients.
Circulation 2011; 124: 124-9.
3. Beller CJ, Schmack B, Seppelt P, Arif R, Bekeredjian R,
Krumsdorf U, et al. The groin first approach for transcatheter aortic valve implantation: are we pushing the limits for
transapical implantation? Clin Res Cardiol 2013; 102: 111-7.
4. Chopard R, Meneveau N, Chocron S, Gilard M, Laskar M,
Eltchaninoff H, et al. Impact of chronic obstructive pulmonary disease on Valve Academic Research Consortium-defined outcomes after transcatheter aortic valve implantation
(from the FRANCE 2 Registry). Am J Cardiol 2014; 113:
1543-9.
5. Amat-Santos IJ, Dumont E, Villeneuve J, Doyle D, Rheault
M, Lavigne D, et al. Effect of thoracic epidural analgesia on
clinical outcomes following transapical transcatheter aortic
valve implantation. Heart 2012; 98: 1583-90.
6. Horlocker TT, Wedel DJ, Rowlingson JC, Enneking FK,
Kopp SL, Benzon HT, et al. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy:
American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (Third Edition). Reg Anest
Pain Med 2010; 35: 64-101.
7. Hodgson RE, Miller SM, Fortuna A. Epidural analgesia in
vascular surgery patients actively taking clopidogrel. Br J
Anaesth. 2010;105:233.
8. Reducing Delirium After Trans-Apical Aortic Valve Replacement (TAVI): A Multifaceted Approach of Perioperative
Care. https://clinicaltrials.gov/ct2/show/NCT01404975.
Justin M. Poltak1, *Frederick C. Cobey2,
John G. Augoustides3, Christopher W. Connors1
1
Maine Medical Center, Portland, ME;
Tufts Medical Center, Boston, MA; 3Perelman School of Medicine
at the University of Pennsylvania, Philadelphia, PA
*Co-First Author
2
Corresponding author:
Justin Poltak MD
Spectrum Medical Group Portland, ME, USA
e-mail: poltak5@gmail.com
Cite this article as: Poltak JM, Cobey FC, John G. Augoustides JG, Christopher W. Connors CW. Paravertebral analgesia in
transapical transcatheter aortic valve replacement. Heart, Lung and Vessels. 2015; 7(1): 91.
Source of Support: Nil. Conflict of interest: None declared.
Heart, Lung and Vessels. 2015, Vol. 7
91
ACKNOWLEDGEMENTS
LIST OF GUEST REVIEWERS
92
We would like to thank the following referees who kindly gave of their time
with two or more papers during 2014.
J. Ali
G. Alvaro
J. Appoo
M.L. Azzolini
D. Baccellieri
A.M.A. Badreldin
R. Baldassarri
P.F. Beccaria
A. Belletti
S. Benussi
F. Biancari
L. Brazzi
C. Cariello
M. Caruselli
S. Colombo
M. Comis
M. Cottini
A. Crescenti
M. Crivellari
A. David
C. Davila
R.A. De Blasi
J. Deng
F. Monaco
N.M. Disma
H. El Ashmawi
N. Elsharnouby
P. Feltracco
O. Fochi
E. Fominskiy
M.F. Gemma
P. Grassi
T. Greco
M. Gürsoy
L. Hajjar
D. Haxhiademi
S. Hobbs
J. Huang
A. Kilic
G. Koksal
C.P. Koutsogiannidis
L. Krzych
L. Kuilman
H. Kulkarni
C. Leggieri
R. Lembo
W.M. Liu
R. Lobreglio
M. Loebe
M. Lombardi
R. Maj
N. Makhija
D. Mamo
A. Manzato
B. Martinez
L. Mascia
T. Mauri
P. Mazzone
Y. Mehta
P. Mura
M. Musu
N.D. Nader
C. Nigro Neto
G. Ntoumenopoulos
L. Olper
G. Pala
Heart, Lung and Vessels. 2015; 7(1): 92.
Heart, Lung and Vessels. 2013, Vol. 5
T. Papadimos
V. Paruchuri
S. Periasamy
A. Peris
C. Picariello
F. Piccioni
M. Pieri
D. Piras
A. Pisano
M. Pocar
A. Putzu
A. Quarti
K.R Ramanathan
H. Riha
A. Roasio
F. Ruberto
C. Sandroni
F. Santini
C. SenDasgupta
S.I. Sersar
P. Silvani
S. Silvetti
F. Simeone
R. Sreedhar
I. Tosetti
Y. Tshomba
S. Upadhyay
M. Winkler
D. Winterton
E. Yalcinkaya
G. Zagli
M. Zagurovskaya
M. Zambon
FUTURE EVENTS
Calendar for future meetings
Heart, Lung and Vessels
2015
January 17-21. 44th Congress Critical Care Medicine. Phoenix, Arizona.
Info: www.sccm.org
January 18-24. 33rd Annual Symposium: Clinical Update in Anesthesiology, Surgery and Perioperative Medicine. Four free workshops. St.
Kitts, West Indies. Info: george.silvay@mountsinai.org
February 11-15. 35th Annual Cardiothoracic Surgery Symposium CREF.
Info: www.crefmeeting.co
March 1-6. 30th International Symposium Interventional Cardiology.
Snowmass, CO. Info: rlaw@promedicacme.com
March 1-4. 34th Annual Meeting Association of Physician Assistants in
Cardiovascular Surgery. Las Vegas, NE, Info: http://apacvs.org
March 8-14. 33rd Cardiovascular Surgical Symposium. Zurs, Austria.
Info: congress@surgery-zurs.at
March 17-20. 35th International Symposium on Intensive Care and
Emergency Medicine. Brussels, Belgium. Info: www.intensive.org
March 21-24. International Anesthesia Research Society (IARS), Honolulu, Hawaii. Info: www.iars.org/2015meeting
April 15-18. 8th International Symposium: Diabetes, Hypertension, Metabolic Syndrome. Berlin, Germany. Info: www.comtecmed.com/DIP
April 25-29. 95th Annual Meeting AATS. Seattle, Washington.
Info: www.aats.org
April 30-May 2. 62nd Annual Meeting Association of University Anesthesiologists. Nashville, TN. Info: www.AUAhq.org
May 20-22. 22nd Annual Congress Slovak Society of Anesthesiology and
Intensive Medicine. Piestany, Slovak Republic. Info: www.ssaim.sk
My 28-30. 62nd Annual Meeting of the Japanese Society of Anesthesiologists. Kobe, Japan. Info: jsa-62@anesth.or.jp
May 28-June 2. ESA Annual Meeting, Berlin, Germany.
Info: www.info@esahq.org.
June 4-6. 3rd International Symposium: Perioperative Care for Seniors.
Prague, Czech Republic. Info: www.anesthesiaforseniors2015.cz
June 24-26. EACTA Annual Meeting. Gothenburg, Sweden.
Info: anne.westerlind@medfak.se
August 26-29. 42nd Annual Argentina Anesthesia Congress. Rosario,
Argentina. Info: edcontinua@anestesia.or.ae
August 29-September 1. World Federation of Societies of Critical Care
Medicine, Seoul, Korea. Info: www.wfsiccm2015.com
September 12-15. EACTA ECHO. The Hague, The Netherlands.
Info: www.eacta.org
September 17-20. Canadian Association of Thoracic Surgeons. Montreal, Canada. Info: cats@canadianthoracicsurgeons.ca
September 24-26. XXII Congress of the Czech Society of Anesthesiology
and Intensive Care Medicine. Pilsen, Czech Republic.
Info: www.csarim2015.cz
October 16. AATS Aortic Symposium, Kobe, Japan.
Info: www.aats.org/kobe
October 24-28. ASA Annual Meeting. San Diego, CA.
Info: www.asahq.org
November 9-10. Surgery of the Aorta. Bologna, Italy.
Info: www.noemacongressi.it
December (DTA), 7th International Congress: Aortic Surgery and Anesthesia “How to do it”. Milan, Italy. Info: www.aorticsurgery.it
December 11-15. Sixty-Ninth Postgraduate Assembly. New York Stat of
Anesthesiologists. New York, NY. Info: www.nyssa-pga.org
2016
January 17-23. 34th Annual Symposium: Clinical Update in Anesthesiology, Surgery and Perioperative Medicine. San Juan. Puerto Rico.
Info: George.silvay@mountsinai.org
March 22-25. 36th International Symposium on Intensive Care and
Emergency Medicine, Brussels, Belgium, Info: www.intensive.org
August 28-September 2. 16th World Congress of Anesthesiologists Hong
Kong. Info: www.WCA2016.com
December 16-20. 70th Postgraduate Assembly. New York State of Anesthesiologists. New York, NY. Info: www.nyssa-pga.org
2020
September 29-25. 17th World Congress of Anesthesiologists. Prague,
Czech Republic. Info: www.csarim202.cz
“Heart, Lung and Vessels” welcomes announcements of interest to physicians, researchers and others concerned with cardiothoracic and vascular surgery, anesthesiology, medicine, pharmacology and related areas. All copies are reviewed and
edited for style, clarity and length. Information is due at least 90 days before the date of publication, and should be addressed
to: George Silvay, M.D., Ph.D., Editor, Professor of Anesthesiology, Department of Anesthesiology, Icahn School of Medicine
at Mount Sinai, One Gustave L. Levy Place, Box 1010, New York, NY 10029-6574. E-mail: george.silvay@mountsinai.org
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