Full HSR proceedings Vol. 1

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Full HSR proceedings Vol. 1
ISSN: 2037-0504
IN THE NEXT ISSUES
• Do we need an italian thoracic anesthesia network?
• The Edge-to-Edge Technique for mitral valve repair.
• Echocardiography in pulmonary embolism
• Cardiac protection by volatile anesthetics in non-cardiac surgery?
A meta-analysis of randomized controlled studies
on clinically relevant endpoints.
• Transoesophageal echocardiography during coronary artery
bypass procedures: impact on surgical planning.
• Activities of a Medical Emergency Team twenty years after its introduction.
• A new method for managing emergency calls
• Treatment of extubation failure by partial extracorporeal CO2 removal.
• Prevention of Intensive Care Unit infections. The nursing point of view.
• Perioperative evaluation of primary hemostasis in patients
undergoing mitral valve repair.
• Glucose metabolism in patients submitted to cardiac and vascular surgery:
proceedings
Intensive Care
Cardiovascular Anesthesia
in
Editors
Alberto Zangrillo
Roland Hetzer
from preoperative to post surgical assessments.
• The contemporary effect of antifibrinolytics in lung and heart-lung
transplantation rejection and blood transfusion.
• Papers, Posters, Presentations: communicating the biomedical sciences.
Endorsed by
Vol. 1
· N° 3 · 2009
ASSociAtE EditorS
Luciano Gattinoni
Università degli Studi di Milano,
Policlinico di Milano, Italia
Massimo Antonelli
Università Cattolica Sacro Cuore,
Policlinico Gemelli, Roma, Italia
Antonio Pesenti
Vol. 1 • n° 3 • 2009
Università degli Studi di Milano Bicocca,
Ospedale San Gerardo, Italia
SEction EditorS
EditorS in chiEf
Alberto Zangrillo
Università Vita-Salute San Raffaele
Milano, Italia
roland hetzer
Deutsches Herzzentrum Berlin, Germany
n intEnSiVE cArE
Luciano Gattinoni
Università degli Studi di Milano. Policlinico di Milano, Italia
n AnESthESiA
Fabio Guarracino
Azienda Ospedaliera Universitaria Pisana, Pisa, Italia
n VASculAr SurgEry
Roberto Chiesa
Università Vita-Salute San Raffaele, Milano, Italia
Official Journal of
School of Anesthesiology
and Intensive Care
n cArdiAc SurgEry
Ottavio Alfieri
Cattedra di Anestesia e Rianimazione
Università Vita-Salute San Raffaele
Milano, Italia
n cArdiology
Giuseppe Biondi-Zoccai
Endorsed by
ITACTA
(Italian Association
of Cardiothoracic Anaesthesiologists)
www.itacta.org
Deutsches Herzzentrum Berlin, Germany
WEb Site
www.itacta.org
Editore
Università Vita-Salute San Raffaele, Milano, Italia
Università degli Studi di Torino, Italia
n clinicAl cArdiology
Alberto Margonato
Università Vita-Salute San Raffaele, Milano, Italia
n inVASiVE cArdiology
Stephan Dreysse
Deutsches Herzzentrum Berlin, Germany
n intErVEntionAl pEdiAtric cArdiology
Peter Ewert
Deutsches Herzzentrum Berlin, Germany
n EchocArdiogrAphy
Michele Oppizzi
Università Vita-Salute San Raffaele, Milano, Italia
n mEtAboliSm
Dionisio Colella
Università degli Studi di Tor Vergata, Roma, Italia
n nEw tEchnologiES
Federico Pappalardo
Università Vita-Salute San Raffaele, Milano, Italia
n in hoSpitAl EmErgEnciES
Luca Cabrini
Edizioni Internazionali srl
Divisione EDIMES
EDIzIonI MEDICo SCIEnTIfICHE - PAVIA
Via Riviera 39 - 27100 Pavia
Tel. 0382526253 r.a. - fax 0382423120
E-mail: [email protected]
Università Vita-Salute San Raffaele, Milano, Italia
n nurSing
Mariano Fichera
Università Vita-Salute San Raffaele, Milano, Italia
n hEmAtology
Andreas Koster
Deutsches Herzzentrum Berlin, Germany
EXEcutiVE Editor
Massimiliano Nuzzi
Università Vita-Salute San Raffaele, Milano, Italia
EditorS
John T. Apostolakis
Segreteria di redazione
Lara Sussani
Cattedra di Anestesia e Rianimazione
Università Vita-Salute San Raffaele, Milano
Via olgettina, 60 - 20132 Milano
Tel. +39 02 26437164
fax +39 02 26437178
[email protected]
Cleveland Clinic, OH, US
Elena Bignami
Università Vita-Salute San Raffaele, Milano, Italia
Tiziana Bove
Università Vita-Salute San Raffaele, Milano, Italia
Maria Grazia Calabrò
Università Vita-Salute San Raffaele, Milano, Italia
Michele De Bonis
wEb Site
www.itacta.org
direttore responsabile
Paolo E. zoncada
Registrazione Tribunale di Milano
in corso
The Journal is indexed in
EBSCo, InDEX CoPERnICUS, HInARI
ISSn (onLInE): 2037-0512
ISSn (PRInTED): 2037-0504
Stampa
Jona Srl
Paderno Dugnano (MI)
Editore
Università Vita-Salute San Raffaele, Milano, Italia
Francesco De Simone
Università Vita-Salute San Raffaele, Milano, Italia
Nicola Colangelo
Università Vita-Salute San Raffaele, Milano, Italia
Giuseppe Giardina
Università Vita-Salute San Raffaele, Milano, Italia
James L. Januzzi
Harvard University - Massachusetts General Hospital, US
Giovanni Landoni
Università Vita-Salute San Raffaele, Milano, Italia
Kevin Lobdell
Carolinas Heart and Vascular Institute, Charlotte, NC, US
Giovanni Marino
Università Vita-Salute San Raffaele, Milano, Italia
Andrea Morelli
Università degli Studi “La Sapienza”, Roma, Italia
Massimiliano Nuzzi
Università Vita-Salute San Raffaele, Milano, Italia
Edizioni Internazionali srl
Divisione EDIMES
EDIzIonI MEDICo SCIEnTIfICHE - PAVIA
Via Riviera 39 - 27100 Pavia
Tel. 0382526253 r.a. - fax 0382423120
E-mail: [email protected]
Antonio Emilio Scala
Dean, Università Vita-Salute San Raffaele, Milano, Italia
Anna Mara Scandroglio
Università Vita-Salute San Raffaele, Milano, Italia
Luigi Tritapepe
Università degli Studi “La Sapienza”, Roma, Italia
proceedings
in Intensive Care
Cardiovascular Anesthesia
ConTEnTS
n EditoriAl...........................................................................................................................................................................................................................................................................5
n rEViEw ArticlE
the role of recombinant activated factor Vii in cardiac surgery ..................................................................................9
A. Richardson, M. Herbertson, R. Gill
Acute renal failure and cardiac surgery..................................................................................................................................................................... 13
T. Bove, F. Monaco, R.D. Covello, A. Zangrillo
n originAl ArticlE
troponin testing After cardiac Surgery ................................................................................................................................................................. 22
J.L. Januzzi Jr
carotid Endarterectomy: experience in 8743 cases ............................................................................................................................ 33
R. Chiesa, G. Melissano, R. Castellano, Y. Tshomba, E.M. Marone, E. Civilini, D. Astore, F. Calliari,
B. Catenaccio, G. Coppi, A. Carozzo, R. Mennella
Solving the challenges of large multicenter trials in Anesthesia....................................................................... 46
S. Wallace, P.S. Myles
infusione tramite via venosa periferica di fenoldopam
mediante pompa elastomerica ........................................................................................................................................................................................................ 54
T. Quaranta, G. Cornaggia, S. Turi, A. Mizzi, A. Zangrillo
n pApErS, poStErS, prESEntAtionS:
communicAting thE biomEdicAl SciEncES
the target journal: choosing the right place to submit your paper ...................................................................... 60
M. John
3
EditoriAlE
6
I punti fondamentali del nostro lavoro sono stati:
- definire i criteri utili ad indicare la necessità di una consulenza
rianimatoria nel quadro clinico evolutivo di Insufficienza Respiratoria;
- definire i criteri minimi indispensabili per poter identificare
un’Unità di Terapia Intensiva in un Referral Centre per il trattamento dei casi più gravi.
Un dato infatti emerge prepotentemente dallo studio dei livelli organizzativi di coloro che hanno già affrontato le conseguenze dell’infezione da AH1n1: i casi più difficili ed i quadri più gravi di insufficienza respiratoria acuta devono essere centralizzati in Unità di Terapia
Intensiva predisposte per la cura con le tecniche più avanzate.
Di seguito riporto i primi dati parziali del nostro lavoro.
Indicazioni di massima per consulenza rianimatoria.
Una consulenza rianimatoria è indicata, di massima, in pazienti
con sintomatologia respiratoria, storia clinica ed obiettività compatibile con influenza AH1n1 (da accertare tempestivamente qualora
non si sia proceduto) ove si verifichi almeno una delle seguenti condizioni:
a) Sat cap<90% con maschera o2 10 l/min
oppure
b) Acidosi respiratoria (pH <7.25)
oppure
c) Evidenza clinica di imminente distress respiratorio o
frequenza respiratoria >35 atti/min
oppure
d) incapacità di proteggere le vie aeree (Glasgow Coma score <8)
oppure
e) Ipotensione: Pressione sistolica arteriosa <90 mmHg + alterati
livelli di coscienza+ contrazione della diuresi+ mancata risposta al carico volemico.
nota Bene: non si tratta di criteri che indichino il ricovero in Rianimazione nè l’intubazione. L’indicazione per il ricovero è decisa
dall’anestesista rianimatore dopo valutazione collegiale del quadro
clinico specifico.
Concludiamo ritornando allo studio col quale ho aperto l’editoriale.
nello studio CESAR, tra il 2001 ed il 2006, sono stati reclutati 180
pazienti (18-65aa) con insufficienza respiratoria acuta severa ma
reversibile. novanta sono stati destinati a ricevere un trattamento
convenzionale, 90 a ricevere ECMo.
I pazienti destinati a ricevere trattamento convenzionale sono stati
lasciati negli ospedali in cui erano ricoverati e curati senza un protocollo definito, ma con la raccomandazione di utilizzare strategie di
ventilazione protettiva.
I pazienti destinati a ricevere trattamento con ECMo sono stati
EditoriAlE
trasferiti in un unico centro nazionale di riferimento. Il 63% dei
pazienti destinati a ricevere ECMo sono sopravvissuti a 6 mesi senza disabilità severe contro il 47% del gruppo di controllo. Dei 90
pazienti destinati a ricevere ECMo, 68 (75%) sono stati effettivamente trattati con questa metodica mentre 17 (migliorati dopo la
randomizzazione) sono stati trattati con metodiche convenzionali,
14 di questi pazienti sono sopravvissuti. Questi soggetti non sono
stati esclusi dalla casistica ma lasciati nel gruppo ECMo considerando come preponderante l’“intent-to-treat”.
Il trattamento con ECMo si traduce in un aumento dei costi di circa 45.000 Euro/paziente che sembrano essere compensati, anche da
un punto di vista economico, dalla maggior sopravvivenza e qualità
della vita.
Editor in Chief
Professor Alberto zangrillo
bibliogrAfiA
1. Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of
conventional ventilatory support versus extracorporeal membrane oxygenation
for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. The Lancet 2009. In Press DoI:10.1016/S0140-6736(09)61069-2.
2. Brun-Buisson C, Minelli C, Bertolini G, et al. Epidemiology and outcome of acute
lung injury in European intensive care units. Results from the ALIVE study.
Intensive Care Med 2004; 30: 51-61.
3. Mancebo J, fernandez R, Blanch, L, et al. A multicenter trial of prolonged prone
ventilation in severe acute respiratory distress syndrome. Am J Respir Crit Care
Med 2006; 173: 1233-39.
4. Kolobow T, Gattinoni L, Tomlinson TA, Pierce JE. Control of breathing using an
extracorporeal membrane lung. Anesthesiology 1977; 46: 138-41.
5. Gattinoni L, Pesenti A, Mascheroni D, et al. Low-frequency positive-pressure
ventilation with extracorporeal Co2 removal in severe acute respiratory failure.
JAMA 1986; 256: 881-6.
6. Chowell G, Bertozzi SM, Colchero MA, et al. Severe respiratory disease concurrent with the circulation of H1n1 influenza. n Engl J Med 2009; 361: 674-9.
7. Perez-Padilla R, de la Rosa-zamboni D, Ponce de Leon S, et al. Pneumonia and
respiratory failure from swine-origin influenza A (H1n1) in Mexico. n Engl J
Med. 2009; 361: 680-9.
7
proceedings
in Intensive Care
Cardiovascular Anesthesia
rEViEw ArticlE
the role of recombinant activated
factor Vii in cardiac surgery
A. Richardson, M. Herbertson, R. Gill
Shackleton Department of Anaesthesia, Southampton University Hospitals NHS Trust
AbStrAct
Recombinant factor VIIa may reduce surgical blood loss and transfusion of blood products in cardiac surgery.
However, the true risks of its use in this setting remains to be elucidated, especially when it is administered
with other potent pro-haemostatic agents. We reviewed the recent literature on this topic and suggest that the
off label use of recombinant factor VIIa is likely to continue. It is our institutional practice to use it in the operating room at a dose of 90mcg/Kg to ensure there is no obvious correctable surgical source of blood loss, and
to be certain that bleeding has stopped before the chest is closed.
Keywords: recombinant factor VII, cardiac surgery, bleeding, transfusion.
introduction
Bleeding is a common complication following cardiac surgery, leading to transfusion
and/or surgical re-exploration. Both interventions are associated with significant
cost, in terms of both risk to the patient
and financial outlay to the healthcare system (1).
Perioperative allogeneic red cell and haemostatic component transfusion has been
shown to be associated with increased
length of intensive care unit and hospital
stay (2), increased infection rates (3), increased rates of every postoperative morbid
event (4), and decreased short- and longterm survival rates (5, 6).
Re-exploration is associated with significant increases in mortality, the need for
intra-aortic balloon counter-pulsation, haeCorresponding author:
Ravi Gill, BM, fRCA
Shackleton Department of Anaesthesia
Southampton University Hospitals nHS Trust
Tremona Road, Southampton So16 6YD, UK
e.mail: [email protected]
mofiltration, prolonged ventilation and intensive care unit stay (7). novel haemostatic agents may have role in reducing surgical
blood loss and the associated transfusion of
blood products.
rEcombinAnt fActor ViiA
Recombinant factor VIIa (rfVIIa) is licensed for the prevention and treatment of
bleeding in patients with haemophilia with
auto-antibodies to coagulation factors VIII
or IX, fVII deficiency, and acquired haemophilia. The binding of VIIa to perivascular
tissue factor (Tf) initiates coagulation, although the process can only progress beyond the generation of small amounts of
thrombin when the injury allows platelets
and larger proteins to leave the vascular
space and adhere to Tf-bearing cells in the
perivascular area. However, Tf may also be
expressed on activated neutrophils, monocytes and microparticles.
The exact role of this circulating Tf remains
9
A. Richardson, et al.
10
controversial, as under normal conditions
it is thought to be inactive or encrypted (8).
Thus, although the effects of VIIa are believed to be localized predominantly to the
site of vessel injury, concerns remain about
the potential for thrombotic complications
arising from its use. The complex nature of
haemostasis and the role rfVIIa plays have
been previously described (9).
uSE
The medical literature increasingly describes “off-label” rfVIIa use to treat severe
bleeding after major surgery in patients
without haemophilia. Whilst some studies
have used it to prevent bleeding and transfusion (prophylaxis), the majority have
used it as rescue therapy when conventional surgical exploration and blood product
and anti-fibrinolytic agent administration
has failed to arrest bleeding.
It has therefore rarely been studied in isolation from other pro-haemostatic agents.
The majority of trials have reported on
rfVIIa use in adults; some have examined
the paediatric population. The range of surgical procedures in which it has been used
has been comprehensive, with a significant
rate of redo cardiac surgery in the adult setting (10).
doSE
The optimal dosing regime for rfVIIa in
the post-cardiac surgical setting remains
unclear. The reported dose range for single
bolus administration has been broad (11.1
– 180 mcg/kg), although many have used
single doses of 90 mcg/kg or less. Some
studies have limited treatment to a single
bolus dose, whilst others have used repeated doses at varying intervals. Recommendations made by various expert panels have
suggested doses in the order of 40-100 mcg/
kg in the setting of uncontrolled post-cardiac surgical haemorrhage, with second doses
considered if no response is seen after 30 to
60 minutes (10).
EfficAcy
The consensus is that rfVIIa reduces bleeding after cardiac surgery, as evidenced by a
reduction in chest tube drainage and red
cell and component therapy transfusion
rates. Some authors have found that these
effects are more sustained with increasing
rfVIIa doses. There is also evidence that
rates of surgical re-exploration for bleeding
are reduced (11, 12). However the majority
of trials have been underpowered, whilst
case reports and series are subject to positive reporting and publication bias.
AdVErSE EVEntS
Since cardiopulmonary bypass may upregulate the expression of systemic tissue factor, the main focus of concern has
been inappropriate thrombosis associated
with rfVIIa use in the cardiac surgical
setting. Interestingly, the incidence of adverse thrombotic events is almost zero in
the paediatric population. This may have
something to do with their naive vascular
endothelium. observational uncontrolled
data from the US food and Drug Administration adverse event reporting system
reveals an alarming 1 in 50 thromboembolic complication rate (associated with a
0.5% mortality) when “off label” rfVIIa
is used in a diverse range of patients (13).
In cardiac surgery, mortality and complication rates of patients who have failed to
respond to standard transfusion therapy
and then received rfVIIa are within range
of 19% to 40%. The lack of control pa-
the role of recombinant activated factor Vii in cardiac surgery
tients in most of these case series makes
it difficult to determine whether the reported adverse events are related to the
administration of rfVIIa or the critical
unstable condition of patients when they
received rfVIIa (14-17). When rfVIIa has
been used on a compassionate basis to reduce uncontrolled bleeding in 51 patients
after cardiac surgery, propensity matching techniques to adjust for baseline risks
demonstrated that the rates of serious
adverse events were equivalent (18). In a
group of patients with very high risk of
stroke, a matched analysis of patients receiving rfVIIa after major ascending and
aortic arch reconstructive surgery suggested stroke rates were equal (19). A recent multicentre randomized clinical trial
of rfVIIa in patients actively bleeding after cardiac surgery showed a non-significant trend to an increase in the rates of
thromboembolic complications. This trial
demonstrated a 50 % reduction in reoperation rates for bleeding and as expected a
marked dose-dependant decrease in transfusion rates in those patients randomized
to rfVIIa (11).
in this context. Thus, it remains to be seen
whether rfVIIa use may reduce the mid- to
late-term complications of red cell transfusion, such as pulmonary dysfunction and
sepsis. There is currently no consensus on
the appropriate “off-label” dose of rfVIIa.
Since the thrombin-generation response to
VIIa depends on the availability of other
coagulation factors and platelets, it would
seem that the ‘optimal’ rfVIIa dose will
vary according to the degree of transfusion
of other blood products. This will need to
be accounted for when planning future
studies. Given the uncontested efficacy of
rfVIIa in preventing and reducing bleeding and transfusion, it’s “off label” use is
likely to continue.
Clinicians must be aware of both the potential risk and benefits when using this potent thrombin-generating agent. It is our institutional practice to use it in the operating
room at a dose of 90mcg/Kg to ensure there
is no obvious correctable surgical source of
blood loss, and to be certain that bleeding
has stopped before the chest is closed.
Dr Herbertson and Dr Gill worked on advisory boards for Novo Nordisk; Dr Gill received
speaker fees from Novo Nordisk.
diScuSSion
There appears to be general agreement that
rfVIIa has the potential to reduce bleeding,
blood product administration and re-operation rates post-cardiac surgery. However,
these are not outcomes in themselves, and
the true risks of its use in this setting remain to be elucidated, especially when it is
administered with other potent pro-haemostatic agents. The under-powering of trials
performed to date mean that differentiation
between adverse events arising specifically
from rfVIIa use, and arising generally from
the critical condition of those receiving is
currently impossible. There has also been
a lack of longer-term follow-up in studies
rEfErEncES
1. freedman J, Luke K, Monga n, et al. A provincial program of blood conservation: The
ontario Transfusion Coordinators (onTraC).
Transfus Apher Sci 2005; 33: 343-349.
2. Hein oV, Birnbaum J, Wernecke KD, et al.
Three-year survival after four major post-cardiac operative complications. Crit Care Med.
2006; 34: 2729–2737.
3. Murphy PJ, Connery C, Hicks GL Jr, Blumberg
n. Homologous blood transfusion as a risk factor for postoperative infection after coronary
artery bypass graft operations. J Thorac Cardiovasc Surg 1992; 104: 1092-1099.
4. Koch CG, Li L, Duncan A, et al. Morbidity and
mortality risk associated with red blood cell
and blood-component transfusion in isolated
11
A. Richardson, et al.
12
coronary artery bypass grafting. Crit Care Med
2006; 34: 1608-1616.
5. Koch CG, Li L, Duncan AI, et al. Transfusion
in coronary artery bypass grafting is associated
with reduced long-term survival. Ann Thorac
Surg 2006; 81: 1650-1657.
6. Surgenor SD, Kramer RS, olmstead EM, et al.
The association of perioperative red blood cell
transfusions and decreased long-term survival
after cardiac surgery. Anesth Analg 2009; 108:
1741-1746.
7. Choong CK, Gerrard C, Goldsmith KA, et al.
Delayed re-exploration for bleeding after coronary artery bypass surgery results in adverse
outcomes. Eur J Cardiothorac Surg 2007; 31:
834-838.
8. Smith SA. The cell-based model of coagulation.
J Vet Emerg Crit Care 2009; 19: 3-10.
9. Monroe DM, Hoffman M. What does it take
to make the perfect clot? Arterioscler Thromb
Vasc Biol. 2006; 26: 41-48.
10. Warren o, Mandal K, Hadjianastassiou V, et
al. Recombinant activated factor VII in cardiac
surgery: a systematic review. Ann Thorac Surg
2007; 83: 707-714.
11. Gill R, Herbertson M, Vuylsteke A, et al. Safety and efficacy of recombinant activated factor
VII. A randomized placebo-controlled trial in
the setting of bleeding after cardiac surgery.
Circulation 2009; 120: 21-27.
12. zangrillo A, Mizzi A, Biondi-zoccai G, et al.
Recombinant activated factor VII in cardiac
surgery: a meta-analysis. J Cardiothorac Vasc
Anesth 2009; 23: 34-40.
13. o’Connell KA, Wood JJ, Wise RP, et al. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA
2006; 295: 293-298.
14. McCall P, Story DA, Karapillai D. Audit of factor VIIa for bleeding resistant to conventional
therapy following complex cardiac surgery.
Can J Anaesth 2006; 53: 926-933.
15. von Heymann C, Redlich U, Jain U, et al. Recombinant activated factor VII for refractory
bleeding after cardiac surgery: a retrospective
analysis of safety and efficacy. Crit Care Med
2005; 33: 2241-2246.
16. Herbertson M. Recombinant activated factor
VII in cardiac surgery. Blood Coagul fibrinolysis 2004; 15: S31-S32.
17. Isbister J, Phillips L, Dunkley S, et al. Recombinant activated factor VII in critical bleeding:
experience from the Australian and new zealand Haemostasis Register. Intern Med J. 2008;
38: 156-165.
18. Karkouti K, Yau TM, Riazi S, et al. Determinants of complications with recombinant factor VIIa for refractory blood loss in cardiac
surgery. Can J Anaesth 2006; 53: 802-809.
19. Tritapepe L, De Santis V, Vitale D, et al. Recombinant activated factor VII for refractory
bleeding after acute aortic dissection surgery: a
propensity score analysis. Crit Care Med 2007;
35: 1685-1690.
proceedings
in Intensive Care
Cardiovascular Anesthesia
rEViEw ArticlE
Acute renal failure and cardiac
surgery
T. Bove, F. Monaco, R.D. Covello, A. Zangrillo
Department of Anesthesia and Intensive Care, Università Vita-Salute San Raffaele, Milano, Italy
AbStrAct
Acute renal failure (ARf) is s a major complication after cardiac surgery and its prevalence still remains high.
Even minor changes in serum creatinine are related to an increase morbidity and mortality.
Recently two consensus conferences have suggested new diagnostic criteria to define acute kidney injury and
risk scores to better identify patients who will probably develop ARf after cardiac surgery. In fact a prompt
recognition of high risk patients could allow a more aggressive therapy at a reversible stage of an incoming
ARf. To date prophylactic strategies of renal function preservation during surgery include the avoidance of
nephrotoxic insult and the prevention or correction of renal hypoperfusion. Although there are still no pharmacological agents able to prevent the perioperative ARf, several trials are investigating new pharmacological
approaches.
When prophylactic strategies fail and severe ARf occurs, renal replacement therapy becomes mandatory. The
timing and the kind of renal replacement therapy remain an open issue.
further randomized case-control studies with adequate statistical power are needed to have more conclusive
data. Aim of this paper is to start from the acute renal injury physiopathology to analyze the most common
prophylactic and pharmacological strategies.
Keywords: acute renal failure, acute kidney injury, renal replacement therapy, cardiac surgery.
Acute renal failure (ARf) still remains a
major complication after cardiac surgery.
Even minor changes in serum creatinine
are related to an increase morbidity and
mortality. As recently shown by Chertow et
al. (1), ARf “per se” is an independent determinant of mortality as much as cardiac
arrest.
The true incidence of acute renal failure in
patients undergoing cardiac surgery is still
unknown because different authors have
used different nomenclature to define ARf.
To sort out this lack of uniformity in 2004
the Acute Dialysis Quality Initiative Group
(ADQI) published the Rifle criteria (2).
Corresponding author:
Tiziana Bove
Department of Cardiothoracic Anesthesia and Intensive Care
Istituto Scientifico San Raffaele, Milano, Italia
Via olgettina, 60 - 20132 Milano, Italy
E-mail: [email protected]
RIfLE is the acronym of 3 severity grades
(Risk, Injury and failure) identified on the
basis of the creatinine serum variation or
urine output (the worst between them is
considered), and 2 outcomes (Loss and EndStage Kidney Disease) related to the length
of loss of kidney function (Table 1).
The 3 classes of severity have a higher sensitivity than specificity, on the other hand
the 2 categories related to the lengh of the
kidney function loss have a low rate of false
negative.
In September 2004 the ADQI group, the
representatives of three nephrology societies, and the European Society of Intensive Care Medicine in Vicenza, Italy have
introduced the concept of acute kidney injury (AKI) including the entire spectrum
of ARf. In the same meeting they created
the Acute Kidney Injury network (AKIn)
13
T. Bove, et al.
14
table 1 - The RIFLE scale, modified by Bellomo et al. (2).
grf criteria
urine output criteria
Risk
Serum creatinine increased 1.5 times or GfR
decrease >25%
<0.5 ml/kg/h for 6 h
Injury
Serum creatinine increased 2.0 times or GfR
decrease >50%
<0.5 ml/kg/h for 12h
failure
Serum creatinine increased 3.0 times orGfR
decrease >75% or creatinine >4 mg/dl (Acute rise
>0.5 mg/dl)
<0.3 ml/kg/h for 24 h or anuria
for 12 h
Loss
Persistent acute renal failure; complete loss of kidney
function for longer then 4 weeks
End-stage renal
disease
End stage renal disease for longer than 3 months
as independent multidisciplinary collaborative network formed by experts selected by
the participating societies (3) (Table 2).
As in the Rifle score, in the AKI system the
main criteria to classify the renal failure
stage are the creatinine serum variation
and/or the urine output. Major advantages
of the new staging system classification for
acute kidney injury are:
1) a more flexible interim classification of
the renal failure (a patient on RRT is
classified as stage 3 regardless of the severity class at the time of the start of the
RRT) and
2) a more accurate detection of the AKI.
Using the RIfLE criteria the incidence of
AKI after cardiac surgery is considerably
higher than previously reported incidence
of ARf (15-20%) in 2 large studies (4, 5).
AcutE rEnAl inJury
phySiopAthology
Acute renal injury can result from:
1) decreased renal perfusion without cellular injury;
2) ischemic, toxic, or obstructive insult of
the renal tubule;
3) a tubule-interstitial process with inflammation and edema;
4) primary reduction of the glomerulus filtering capacity.
In terms of etiology the acute renal failure
is pre-renal, renal, or post-renal, unfortunately, the critically ill patients recognize a
combination of multiple factors and generally a worst outcome. Anyway we have to
keep in mind that the AKI is not a “yes or
no” phenomenon, but a continuum process
table 2 - Classification/staging system for acute kidney injury (AKI). Modified from Metha et al. (3).
Stage
Serum creatinine criteria
urine output criteria
1
Increase in serum creatinine of more than or
equal to 0.3 mg/dl or increase to more than or
equal to 150% to 200% (1.5-to 2-fold) from
baseline
Less than 0.5 ml/kg per hour for more than 6
hours
2
Increase in serum creatinine to more than 200% less than 0.5 ml/kg per hour for more than 12
to 300% (>2-to3-fold) from baseline
hours
3
Increase in serum creatinine to more than 300% Less than 0.3 ml/kg per hours for 24 hours or
(>3-fold) from baseline (or serum creatinine of anuria for 12 hours
more than or equal to 4.0 mg/dl with an acute
increase of at least 0.5 mg/dl)
Acute renal failure and cardiac surgery
which ranges from mild changes in markers
of renal function, (i.e. creatinine and urea),
until the complete renal failure.
In particular elderly patients are vulnerable
to prerenal azotemia because of their predisposition to hypovolemia and high prevalence of renal-artery atherosclerotic disease. In this kind of patients, who are often
affected by large-vessel or small-vessel renal
vascular disease, the therapy itself plays an
important role, in fact, a combination of
angiotensin-converting-enzyme inhibitors
and diuretics can worse the renal failure
increasing the hypovolemia.
The low cardiac output syndrome can lead
to kidney ischemia after cardiac surgery either decreasing the renal flow or changing
the renal physiology.
During the CBP the non pulse blood flow,
the macroembolic and microembolic insults to the kidney (organic and inorganic
debris), the release of catecholamines and
inflammatory mediators such as the free
hemoglobin from traumatized red blood
cells increase the renal vascular resistances
and decrease the glomerular filtration rate
of the 25-75% compare to the perioperative
period.
often the ischemic renal injury is reversible after the correction of the underlying
causes, but if the ischemia is severe the cortical necrosis is irreversible.
However the kidney can restore its structure and function also after severe ischemia
by the spreading and dedifferentiation of
viable cells.
from the clinical point of view the early
post cardiac surgery AKI is strongly associated with two major factors: reduced functional reserve and renal ischemia. Chertow
has defined the renal ischemia occult, because asymptomatic, silent, unlike myocardial and cerebral ischemia. for these
reasons the development of scores able to
predict the ischemic AKI becomes mandatory (6).
prEdictiVE ScorES
15
The Continuous Improvement in Cardiac
Surgery Program (CICSP) score is a good
predictor of AKI in a cardiac surgery population (6). The CICSP risk-stratification algorithms has been developed and validated
in 43 Department of Veterans Affairs medical centers between the 1987 and the 1994.
It includes the following risk factors: low
ejection fraction ≤35% (2 points); valvular surgery (3 points); chronic obstructive
pulmonary disease (2 points); nYHA functional class IV (2 points); peripheral vascular disease (2 points); preoperative use of
an intra-aortic balloon pump (5 points);
prior heart surgery (3 points); pulmonary
rale (2 points); systolic blood pressure ≥160
mmHg and CABG surgery (3 points); systolic blood pressure ≤120 mmHg and valvular surgery (2 points); and creatinine
clearance 80 to 100 mL/min (2 points), 60
to 80 mL/min (3 points), 40 to 60 mL/min
(5 points), ≤40 mL/min (9 points).
table 3 - The Thakar score (Minimum score 0;
maximum score 17). Modified from Thakar et al. (7).
risk factor
points
female gender
1
Congestive heart failure
1
Left ventricular ejection fraction <35%
1
Preoperative use of IABP
2
CoPD
1
Insulin-requiring diabetes
1
Previous cardiac surgery
1
Emergency surgery
2
Valve surgery only (reference to CABG)
1
CABG+ valve (reference to CABG)
2
other cardiac surgery
2
Preoperative creatinine 1.2 to
2.1 mg/dl
2
Preoperative creatinine
>2.1
5
T. Bove, et al.
16
More recently Thakar et al have developed
another clinical score to predict postoperative ARf “weighing” the effect of ARf’s
major risk factors (7).
A total of 33,217 patients who underwent
open-heart surgery at the Cleveland Clinic
foundation (1993 to 2002) have been studied.
The primary outcome was ARf requiring
dialysis. The score was a a good predictor of
ARf across all risk categories (Table 3).
These results allowed to identify high-risk
subgroups who could be involved in future
randomized trials with the aim to identify
strategies able to reduce the incidence of
AKI after cardiac surgery.
prophylActic StrAtEgiES
The prophylactic strategies of the renal
function preservation during the surgery
traditionally emphasized two goals:
1) avoidance of nephrotoxic insult;
2) prevention or reversibility of the renal
hypoperfusion supporting the renal perfusion pressure by the cardiac outcome,
the arterial pressure and an adequate
intra-vascular volume state (8). Renal
injury in critically ill patients is worsened by contrast agents and antibiotics
among others (Table 4).
Minimizing and avoiding the use of contrast agents perioperatively, especially in
patients at high-risk for contrast nephropathy, helps to reduce renal injury. When postable 4 - Nephrotoxins
Contrast agents
ACE-inhibitors
non-steroidal anti-inflammatory drugs
Pigments (hemoglobin, mioglobin )
Antibiotics (aminoglycosides, cephalosporins,
anphotericin B)
Chemiotherapeutic/immunosuppressive agents
sible, plasmatic nephrotoxic drugs concentrations must be measured daily.
The kidney performance is strictly bridged
to the cardiac performance in fact the kidneys, although their combined weight is
less than 1% of total body weigh, normally
receive the 20-25% of the cardiac output
(Co).
A low Co, during the surgery, decrease dramatically the renal perfusion pressure and
activates a number of renal vasoconstrictor systems (sympathetic nervous system,
renin angiotensyn system, and vasopressin secretion) which damage indirectly the
kidneys. Marathias et al. have shown that
preoperative intravenous hydration has decreased the risk of irreversible renal damage in patients with moderate-to-severe
renal insufficiency undergoing cardiac surgery regardless of the kind of fluid adopted
(crystalloids or colloids) (9). obviously, an
excessive perioperative fluid load should
not be administrated in order to avoid several complications such as pulmonary oedema.
Beyond an adequate Co and an intravascular volume status an optimal arterial pressure is mandatory to ensuring an adequate
renal perfusion pressure. In the normal
mammalian kidney, loss of autoregulation
of RBf generally occurs at a mean arterial
pressure (MAP) of 75-80 mmHg. There
are no absolute MAP values to sustain the
renal perfusion pressure in fact, a MAP of
65 mmHg could be inadequate for renal resuscitation in elderly or diabetics patients,
while it could be high enough for patients
without co-morbidities. A blood pressure of
60 mmHg is likely to be inadequate in every
patient (10).
When the volume expansion is not sufficient to achieve these goals in ICU patients,
the vasoactive drugs (many of which have
inotropic and vasopressor properties) could
be used. Anyway, to our knowledge no
randomized controlled studies have inves-
Acute renal failure and cardiac surgery
tigated if the perfusion pressure affects the
renal outcome.
Recently Di Giantomasso et al. (11) in a
study on animals showed that 0.4 mcg/
kg/minute of norepinephrine (nE) in the
normal mammalian circulation increased
renal blood flow, urine output and creatinine clearance. notably the effect of nE on
the renal function was safe in patients with
post-bypass hypotensive vasodilatation
(12). Although further studies are needed
to evaluate the effect of nE, in subject with
normal cardiac function or septic shock
there are no reasons to avoid nE administration in patient with poor renal function.
To date, nE remains the vasopressor of
choice in hypotensive states with preserved
or increased cardiac output for its efficacy
in restoring the MAP.
phArmAcologicAl StrAtEgiES
Diuretics
The administration of loop diuretics in
ARf patients is common practice in ICUs.
Loop diuretics:
1) improve the tubular flow and the hydraulic pressure;
2) increase the production of vasodilating
prostaglandins increasing the cyclo-oxygenases’s activity;
3) reduce the efficacy of the na–K–2Cl
co-transporter (nKCC2) decreasing the
sodium transport and the o2 consumption;
4) preserve the vulnerable medullary tubulus segments from the ischaemic damage.
Mehta et al. showed that the use of diuretics in critically ill patients with ARf is associated with an increased risk of death and
non recovery of renal function (13). The
following consideration should be done:
1) the use of diuretics by converting an
oliguric in a nonoliguric form could de-
lay the recognition of ARf, the severity
of the ARf and the institution of dialysis;
2) the successful conversion of oliguria to
diuresis does not mean a milder form of
ARf;
3) the diuretics have no impact on the patient outcome.
In a double-blind randomized controlled
trial continuous infusion of furosemide has
been associated with the highest rate of renal impairment in cardiac surgery patients
(14). The same authors have suggested the
use of mannitol to protect the renal function. In fact the mannitol;
1) induces an osmotic diuresis which prevents the tubular obstruction;
2) decrease the epithelial and endothelial
cell swelling limiting the vascular congestion and tubular obstruction;
3) is a free radicals scavenger;
4) increases the synthesis of intra-renal
prostaglandin generating an efficacious
renal vasodilation. Sides effects are volume depletion, and an increased medullary consumption of o2. Despite of
these features, a small prospective randomized clinical trial in cardiac surgery
patients without previous renal impairment failed to show any significant differences in renal outcome when mannitol was administrated with prophylaxis
purpose (15).
Steroids
In a randomized clinical trial, anti-inflammatory agents such as dexamethasone, administrated before CPB, showed no protective effect on perioperative renal dysfunction in low-risk cardiac surgical patients
(16).
Dopamine receptors agonists
When infused in so-called “renal doses,”
between 0.5 to 2 μg/kg body weight/minute, dopamine increases renal plasma flow,
17
T. Bove, et al.
18
GfR, and sodium excretion. In a doubleblind, randomized, controlled trial, 126
patients with preoperatively normal renal
function undergoing elective cardiac surgery received a continuous infusion “renal
dose” dopamine (2 μg/kg/minute), furosemide (0.5 mg/kg/minute), or isotonic sodium chloride as placebo, at the beginning of
surgery for 48 hours or until the discharge
from the intensive care unit (14). The continuous infusion of dopamine was ineffective for renal protection and not superior to
isotonic saline in preventing postoperative
dysfunction. Also a larger randomized trial
in early ARf has failed to show any benefit
of the dopamine in preventing renal injury,
renal replacement therapy, or death (17).
fenoldopam stimulates dopamine 1 (and
not dopamine 2) receptors, thus inducing,
theoretically, a greater vasodilation in the
renal medulla than in the cortex. furthermore, fenoldopam has no alpha or beta
adrenergic activity and as evidenced by
Aravidan et al., in a rat model, fenoldopam
is able to reduce the ischemic-reperfusion
injury-induced inflammation involving nfkB pathway (18). In patients at high risk of
postoperative acute renal failure undergoing cardiac surgery with cardiopulmonary
bypass, fenoldopam prophylaxis was an
independent protective factor for postoperative renal failure within the subgroup of
patients who suffered a postoperative low
output syndrome (19).
on the other hand Bove et al. in a prospective single-center, randomized, double-blind trial in a cardiac surgery setting
evidenced no significant difference in peak
postoperative serum creatinine level, need
of renal replacement therapy and intensive
care unit, hospital stay, and mortality between fenoldopam and placebo group (20).
Recently two interesting meta-analysis
showed fenoldopam efficacy in preventing renal damage (21, 22) in critically ill
patients or in those undergoing major sur-
gery. Anyway further large multicentric
randomized clinical trials are needed to
justify a widespread use of fenoldopam to
avoid renal impairment.
Radical scavengers
Because cardiopulmonary bypass and cardioplegic arrest are associated with formation of free radicals, which damage various
organs particullary the kidneys, radical
scavengers were hypothesized to protect
the renal function.
oxidative stress could be attenuated by nacetylcysteine (nAC), which directly scavenges reactive oxygen species, regenerates
the glutathione pool, and reduces oxidative
stress during CPB. nevertheless in a phase
II, randomized, controlled trial, Haase et al.
have shown that n-acetylcysteine has been
no more effective than placebo in attenuating cardiopulmonary bypass-related acute
renal failure in high-risk cardiac surgery
patients (23).
Arteriolar vasodilator
natriuretic peptides showed to cause afferent arteriolar vasodilation and efferent
arteriolar vasoconstriction, thereby increasing GfR. They also block tubular reabsorption of sodium chloride, re-distribute
renal medullary blood flow, disrupt TGf
and reverse endothelin-induced vasoconstriction. In the nAPA trial, a prospective
double-blind clinical trial, the administration of nesiritide, a recombinant human
B-type natriuretic peptide, in patients undergoing CABG with CPB was associated
with a better renal function and survival
outcome (24). Sackner-Berneistein et al. in
a recent metanalysis on the use of the nesiritide in acutely decompensated heart failure (ADHf) showed that nesiritide significantly increases the risk of renal function
impairment although the worsening renal
function could reflect only hemodynamic
effects and no a true renal injury (25).
Acute renal failure and cardiac surgery
Calcium channel blockers cause afferent
arteriole vasodilation and natriuresis. They
also reduce intracellular calcium influx and
act as a free radical scavenger. In a placebocontrolled study led in patients undergoing
CABG, diltiazem has increased urine output and creatinine clearances (26). However two more recent placebo controlled
clinical trials showed no effect on renal
function (27, 28).
Prostaglandins are involved in the afferent
arteriole vasodilatation such as the inhibition of pro-inflammatory cytockines during
cardiac surgery. A pilot study indicated that
low-dose of prostacyclin could preserve the
renal function in high-risk patients after
coronary bypass surgery (29).
on the hypothesis that the adenosine receptors are involved in modulating intrarenal haemodynamics during ischaemia
theophylline was studied with a doubleblind, placebo-controlled trial in patients
with normal preoperative renal function
who underwent elective CABG (30). no
difference in the incidence of acute renal
failure has been found between cases and
controls.
Clonidine has been associated with a higher creatinine clearance in two randomized
double blind trial conducted by Myles et al.
and Kulka et al. (31, 32).
optimization of renal function prior to the
surgery could reduce the risk of perioperative ARf.
Durmaz et al. have performed an interesting study to assess whether correcting fluid
and electrolyte abnormalities with dialysis
in patients with chronic renal insufficiency
prior to surgery would have reduced the incidence of post-operative ARf and mortality (33).
The study showed a significant low incidence of acute renal damage, death and a
shorter length of ICU and hospital stay between the patients who received hemodialysis twice within 72 hours before the sur-
gery and who not. However the results can
not be conclusive because of a small size of
patients involved into the study.
rEnAl rEplAcEmEnt
thErApy
There is no agreement on the timing and
the kind of RRT in AKI. Bellomo et al. have
suggested these criteria to start the RRT
(34):
1) anuria or oliguria (urine output <200
ml/12 h);
2) hyperkalemia (k>6.5 mmol/l);
3) severe acidemia (pH<7.1);
4) azotemia (urea >30 mmol/l);
5) clinically significant organ edema (particularly lung);
6) uremic encephalopathy, pericarditis, or
neuropathy/myopathy;
7) severe dysnatremia (na>160 or<115
mmol/l);
8) hyperthermia;
9) drug overdose with a dialyzable product.
About the kind of RRT to use in ARf there
are no conclusive studies. In fact, although
the intermittent hemodialysis (IHD) remains the most common treatment, continuous renal replacement therapies (CRRT)
and slow, low-efficiency daily dialysis
(SLEDD) are becoming widely used. Each
technique carries its own set of advantages
and disadvantages.
concluSionS
In conclusion AKI is one of the most serious complications of cardiac surgery associated with increased morbidity and mortality. Ischemic injury of the kidney, exotoxins (antibiotics, anesthetic agent, contrast
media, diuretics), endotoxins (myoglobin),
and preexisting renal impairment are risk
19
T. Bove, et al.
20
factors associated to acute postoperative renal failure.
Maintenance of adequate intravascular volume perioperatively, optimization of preoperative renal function, and the avoidance
of nephrotoxic medications are currently
the keys to prevent perioperative AKI. Several studies on the use of pharmacological
agents have failed to show any effect to prevent the perioperative AKI. further randomized case-control studies with adequate
statistical power are needed to have more
conclusive data.
No conflict of interest acknowledged by the authors.
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21
proceedings
in Intensive Care
Cardiovascular Anesthesia
originAl ArticlE
22
troponin testing After cardiac Surgery
J.L. Januzzi Jr
Cardiology Division and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
AbStrAct
Single biomarker measurements can predict outcome after cardiac surgery. and may assist in decision making
about diagnostic and therapeutic steps following surgery. Although comparative data are relatively lacking
some data exist to suggest that among markers of myocardial necrosis, results from cardiac troponin (cTn)
measurement may be superior for risk prediction after cardiac surgery to those from the MB isoenzyme of
CK (CK-MB). Loss of cardiac troponins from necrotic myocardium is not replenished through re-expression
of genes that might increase protein synthesis, and release of cTn appears to represent irreversibly damaged
myocardium.
not every cardiac surgical procedure is associated with the same degree of cTn elevation and forms of cardioprotection may importantly affect concentrations of cTn after coronary artery bypass grafting. Similarly,
less cardiac injury may occur depending on the form of anesthesia used during surgery. Great caution must
be exercised when utilizing cTnT or cTnI for diagnosis of post-cardiac surgery regional acute myocardial
infarction: in this context clinical factors must be applied at the risk of a false diagnosis. on the other hand,
concentrations of both cTnT and cTnI have repeatedly and unequivocally been shown to be prognostic for
delayed recovery, intensive care unit utilization, as well as short- and longer-term mortality following cardiac surgery.
Keywords: coronary artery bypass grafting surgery, troponin, myocardial infarction.
Multiple methods exist for stratifying patient risk for complications after cardiac
surgical procedures.
Including complex risk scoring systems
such as the EURoSCoRE (1), as well as
more simple approaches such as single biomarker measurements, the ability to judge
risk following potentially life-threatening
open-heart procedures is of considerable
importance.
The ability to accurately judge prognosis
for adverse outcome not only provides important information regarding risk for the
clinician to discuss with the patient both
pre- and post-operatively, but also may asCorresponding author:
James L. Januzzi, Jr, MD
32 fruit Street
Yawkey 5984
Boston, MA, 02114
e.mail: [email protected]
sist in decision making about diagnostic
and therapeutic steps following surgery
in the context of a post-operative complication (such as detection of acute loss of
bypass grafts in the setting of a coronary
artery bypass graft (CABG) procedure);
furthermore, knowledge of impending
complications allows for decision making
regarding intensive care unit (ICU) bed
availability, as those patients predicted to
have complications are more likely to have
prolonged ICU lengths of stay (LoS).
As noted, options for risk assessment include accurate, albeit complicated risk scoring systems.
on the other hand, more discrete, singlemeasure risk tools have been examined
for post-cardiac surgery risk assessment,
including biomarker testing. The attractiveness of biomarker-based risk asses-
troponin testing After cardiac Surgery
sment of patients either pre-operatively or
post-operatively is intuitively attractive,
as measurement of biomarkers such as natriuretic peptides, creatine kinase (CK),
or the cardiac troponins (cTn) allows for
an objective assessment of the underlying
biology of the patient, rather than focusing
on more subjective measures. Although
each of these biomarkers have been shown
to be predictive of risk following cardiac
surgical procedures, their use is limited by
a relatively poor understanding of the factors that lead to their release during and
after cardiac surgery, as well as the optimal mode for their measurement and interpretation.
Although comparative data are relatively
lacking with respect to the value of biomarkers for risk prediction after cardiac
surgical procedures, some data exist to
suggest that among markers of myocardial
necrosis, results from cTn measurement
may be superior for risk prediction after cardiac surgery to those from the MB
isoenzyme of CK (CK-MB) (2-5). This is
consistent with the superiority of cTn for
diagnosis and risk stratification across the
wide spectrum of cardiac syndromes. With
this in mind, recent consensus guidelines
table 1 - Consensus guidelines for application of cTn
testing following cardiac surgery (6).
• for patients with normal baseline cTn values,
elevations above the 99th percentile upper
reference limit (essentially any measurable
cTn) are indicative of peri-procedural
myocardial necrosis.
• A type 5 MI is defined as:
– Increases of cTn greater than five times
the 99th percentile upper reference limit,
plus
– new pathological Q waves/new left bundle
branch block or
– Angiographically documented new graft
or native coronary artery occlusion or
imaging evidence of new loss of viable
myocardium
have adopted measurement of serum cTn
as the “gold standard” for diagnosis of
myocardial injury and risk stratification
in the setting of cardiovascular diseases
(6). Among the situations considered in
consensus guidelines for cTn use is excessive myocardial necrosis following cardiac
surgery, including CABG; referred to as a
“Type 5” myocardial infarction (MI), the
use of cTn is endorsed in manner depicted
in Table 1.
cArdiAc troponin biology
The distribution of Tn in muscle tissue is
best considered as a “two compartment”
model. The contractile proteins of the
myofibril contain the majority of the protein, which is a complex of three protein
subunits: Tn C (the calcium-binding component; molecular mass 18 kDa), TnI (the
inhibitory component; molecular mass
22.5 kDa), and TnT (the tropomyosin-binding component; molecular mass 37 kDa);
the myofibril is thought to contain about
95% of the Tn present in muscle, while a
smaller cytosolic component is also known
to exist (7).
Although multiple Tn isoforms exist in
muscle, cardiac-specific isoforms of TnT
(cTnT) and TnI (cTnI) have been identified, and assays for their measurement are
now widely available.
Mechanistically, the release of cTn is thought to occur whenever myocardial injury
occurs, irrespectively of the mechanism.
The best studied situation, of course, is
acute MI from an ischemic cause; in this
setting a 40-80% decrease of tissue cTnT
and cTnI may be documented, which is directly reflective of release of either peptide
in the peripheral blood. furthermore, in
pig hearts with severe left ventricular remodeling two months postinfarction, both
cTnI and cTnT were decreased 80% and
23
J.L. Januzzi
24
40%, respectively, compared with nondiseased normal myocardium (8). These data
demonstrate that loss of cardiac troponins
from necrotic myocardium is not replenished through re-expression of genes that
might increase protein synthesis, and release of cTn appears to represent irreversibly damaged myocardium.
Some debate exists about whether transient ischemia without cell death may lead
to release of cTn from efflux of the cytosolic component, however this has not been
proven, and only speculative at present.
In the setting of acute ischemic injury,
detectable concentrations of cTn may be
found in peripheral blood within 4 hours;
with the advent of higher sensitivity cTn
(hsTn) methods, a change in the concentration of cTn may be found even earlier,
perhaps within an hour of injury.
following acute MI, depending on the size
of the infarct as well as whether revascularization occurred, peak concentrations of
cTnT or cTnI tend to be seen within 24-48
hours, and fall over a period of days.
It is not well known if other mechanisms
of myocardial cell death lead to a different
set of release kinetics.
for example, unusual patterns of cTn release may be seen after endurance exercise.
on the other hand, following cardiac surgery - where a multiplicity of mechanisms
for cTn elevation may exist (see below) - it
has been established that cTn kinetics are
largely similar to that of acute MI.
ctn ElEVAtion AftEr
cArdiAc SurgEry:
why doES it occur?
It is very well-established that cTn elevation is nearly universal after cardiac surgical procedures (3, 9-12); there are multiple mechanisms proposed to explain the
finding of myocardial injury after cardiac
table 2 - Selected variables predictive of cTn
concentrations after cardiac surgery.
Effect on
post-operative
ctn
Age
↑
Estimated glomerular filtration
rate
↑
Acute MI within a week
of surgery
↑
Pre-operative need for IABP
Total number of distal
anastomoses
↑
Bypass time
↑
number of intra-operative
defibrillations
↑
need for placement of intra/
post-operative IABP
↑
Higher core temperature
during surgery
↓
Warm cardioplegia
↓
↓
Desflurane, sevoflurane
anesthesia
↓
Beating heart surgeries
IABP denotes: intra-aortic balloon pump
surgery: pre-operative elevation of cTn
may persist into the post-operative setting,
intra-operative injury may occur related
to cardiac manipulation, inadequate myocardial protection, intra-operative defibrillation or acute post-bypass hemodynamic
instability, while post-operative injury
may be associated with acute loss of bypass
grafts. In one recent study, each of these
mechanisms were supported as a cause of
cTnT elevation in the post-operative setting (11) (Table 2).
not every cardiac surgical procedure is associated with the same degree of cTn elevation, an important fact to be kept in mind.
In a cohort of 224 subjects undergoing a
wide range of cardiac surgeries, including
CABG but also valve repair or replacement, heart transplantation, ventricular
troponin testing After cardiac Surgery
4
3.5
TnT (ng/ml)
3
25
Arrival
6-12 H
18-24 H
2.5
2
1.5
1
0.5
0
Pericardiectomy OPCAB
Asc Ao
Valve only
CABG/Asc Ao
CABG
CABG/VR
All
figure 1
Concentrations of cTnT at various time points (arrival to ICU, 6-12 hours and 18-24 hours) for different
forms of cardiac surgery. Of note, pericardiectomy, off-pump CABG (OPCAB), and non-CABG procedures were generally associated with lower post-operative cTnT values (3).
assist device implantation, or more minor
procedures such as pericardial stripping, a
wide range of cTnT values were observed
(3) (Figure 1), with the higher concentrations of the marker seen in those patients
that underwent coronary revascularization; this implies - supported by the data
in Table 2 - that a significant percentage of
circulating cTn following cardiac surgery
is related to an ischemic mechanism. This
is further borne out in studies of patients
with excessive cTnI elevation after CABG,
where a higher prevalence of acute graft
loss was detected (4), as well as longerterm follow up of patients after CABG,
where excessive post-operative cTnT release was associated with a higher likelihood
for death and need of revascularization at
one year (13), implying more complex coronary anatomy and higher risk for intraoperative ischemic necrosis. nonetheless,
the association between coronary disease
and cTn after surgery is not absolute: notably, cTnT and cTnI have both been shown
to be useful after pediatric cardiac surgical procedures in the absence of coronary atherosclerosis. While the association
between cTn and the presence/severity of
coronary artery disease (CAD) in patients
undergoing CABG is necessary to keep in
mind, other caveats are important to consider when measuring cTn in this setting.
firstly, while less well understood, there
are certain forms of cardiac surgery associated with surprisingly high levels of cTn
in the absence of CAD or obvious complications, in particular surgical maze procedures for atrial fibrillation management.
In addition and perhaps more importantly,
it is also well-known that forms of cardioprotection may importantly affect concentrations of cTn after CABG, such that
a wide range of release might be expected
to occur depending on the form of cardio-
J.L. Januzzi
26
plegia utilized. for example, those patients
undergoing revascularization with cardiopulmonary bypass are expected-even
in the absence of obvious complication-to
have considerably higher concentrations
of cTn (5, 9, 14-19).
This difference in “expected” cTn might be
problematic if the marker is used for postoperative risk stratification, but it turns
out that in the context of complications,
use of the same cTn cut-point is associated
with similar prognostic value whether a
patient was revascularized using on-pump
(onCAB) or off-pump (oPCAB) methods
(11, 20) (see below for more details). Similarly, less cardiac injury may occur depending on the form of anesthesia used during
surgery (21-28).
In recognition of the multiple reasons for
cTnT or I elevation after cardiac surgery,
it should not be surprising that values for
these biomarkers are elevated very soon
after surgery, often upon arrival to the
ICU; prognostic associations will be discussed later, yet both the value of cTn on
arrival to the ICU as well as later values
may be prognostically meaningful. Thus,
sampling at ICU arrival, as well as 18-24
hours may provide unique prognostic information (3, 11).
ctn concEntrAtionS
AftEr cArdiAc SurgEry:
whAt iS truly AbnormAl?
Keeping in mind the multiple reasons for
elevation of cTnT or I after cardiac surgery, it should become obvious to the reader
that use of these markers for diagnosis of
“acute MI” after CABG is incrementally
challenging. one can appreciate the efforts of consensus recommendations to incorporate other variables into the equation
for definition of post-cardiac surgery MI,
such as electrocardiogram (ECG) findings,
documentation of bypass graft loss or imaging findings suggesting loss of myocardial
function. However, associations between
the presence of Q-waves or LBBB and acute graft loss following CABG are weak at
best, and cTn concentrations do not clearly
elevate more excessively when such ECG
changes are found (11). furthermore, coronary and graft angiography after CABG is
rarely performed, and imaging studies for
myocardial dysfunction are variably specific for MI.
Thus, an inevitable reliance on biomarker
results for post-operative risk assessment
could theoretically occur, and if misinterpreted, could lead to an excessive percentage of patients diagnosed with an “acute
MI”; this becomes a particularly thorny
issue when considering the cut-points endorsed by consensus guidelines, which are
rather low. for example, in a recent study
of patients undergoing CABG, the median
cTnT was 1.08 ng/mL.
Among these subjects, 99.4% had a cTnT
≥.01 ng/mL (the 99th percentile concentration for a normal healthy population), and
96.6% had a cTnT ≥.15 ng/mL (the consensus recommended cut-point), most often in
the absence of obvious complication. Using
consensus cut-points for cTn, a 100% sensitivity for post-CABG MI was observed,
but this was associated with a specificity
of 4.2% and a dreadfully high misclassification rate (11).
Although the utility of cTn testing for secure diagnosis of regional acute MI after
cardiac surgery is in question (particularly
given the robust data suggesting that significant elevation of cTnT and cTnI is very
common after these procedures in the absence of such a syndrome), the results of
numerous analyses would argue that troponin testing after cardiac surgical procedures may add important prognostic value
nonetheless. Indeed, it is now well-established that cTn concentrations following
troponin testing After cardiac Surgery
cardiac surgery are strongly predictive of
impending adverse cardiovascular events
including post-cardiac surgery instability
(4, 5, 12, 14, 17, 29-46), ICU length of stay
(LoS) (30, 40), ICU utilization (such as duration of ventilator use and need for and
number of vasopressors) (3, 11), shock,
post-operative quality of life (2), and both
short and longer term mortality (4, 5, 12,
14, 17, 29-46).
Interestingly, although current guidelines
accept a very low upper reference limit
for cTn testing after cardiac surgery, the
results of numerous studies would suggest
the true inflection point in cTn values for
risk prediction is considerably higher (Table 3).
for example, in a prospectively gathered cohort of patients undergoing a wide range of
surgical procedures, the optimal cut-point
for cTnT to predict adverse outcomes was
1.58 ng/mL (3); this cut-point, more than
10 times above the currently endorsed upper reference limit for cardiac surgery, was
recently validated among a larger group of
more than 800 subjects undergoing CABG
(11) (Table 4).
table 3 - Examples of recently reported optimal
cTn cut-points for prediction of risk following cardiac
surgery.
marker
cut-point
reference
cTnT
0.46 ng/mL
0.80 ng/mL
1.0 ng/mL
1.58 ng/mL
1.60 ng/mL
Lehrke, et al. (36)
nesher, et al. (12)
Brown, et al. (20)
Januzzi, et al. (3)
Mohammed, et al. (11)
cTnI*
8.49 ng/mL
13.0 ng/mL
13.0 ng/mL
14.0 ng/mL
19.0 ng/mL
23.8 ng/mL
25.0 ng/mL
Croal, et al. (34)
Lasocki, et al. (48)
Papparella, et al. (18)
Hashemzadeh et al. (49)
Benoit, et al. (31)
fellahi, et al. (35)
Immer, et al. (50)
*Various assays for cTnI were used in these various studies,
so reference ranges may not entirely correlate.
table 4a - Percentage of cTn elevation as a function
of upper reference limit among patients undergoing
CABG, including off-pump CABG (OPCAB) (11).
ctnt
cut-point
Elevated, Elevated,
all
opcAb
Value
99th
percentile
0.01 ng/mL
for a healthy
population
10%
coefficient
0.03 ng/mL
of variation
Consensus
0.15 ng/mL
cut-point
Januzzi et al. 1.60 ng/mL
99.4%
96.4%
98.9%
84.0%
96.6%
72.6%
36.7%
13.1%
table 4b - Performance of different potential cut-points
for predicting risk following CABG.
ctnt
cut-point
Value
npV misclassification
Consensus
0.15 ng/mL 100%
cut-point
96%
Januzzi
et al.
28%
1.60 ng/mL 99%
Importantly, in a multivariable logistic regression model adjusted for the Society for
Thoracic Surgery risk score, cTnT values
significantly predicted early post-operative
complications of death (oR=3.20; 95%
CI=1.5-6.9; P=.003), death/heart failure (oR=2.04; 95% CI=1.2-3.5; P=.008),
death/vasopressor need (oR=2.70; 95%
CI=2.0-3.6; P=<.001), and the triple composite of death/heart failure/vasopressor
need (oR=2.57; 95% CI=1.9-3.4; P<.001)
(11), results similar to those from Simon
et al (41).
This suggests that excessive cTn release
after surgery adds to the prognostic merit
of an already complex risk stratification
model and should be considered an independent predictor of bad outcomes independent of other variables considered in
this setting.
27
J.L. Januzzi
28
figure 2
Off-pump CABG (OPCAB) is typically associated with lower median
concentrations of cTn than in patients
operated on the pump (ONCAB).
Nonetheless, the prognostic value of
cTn is preserved in OPCAB patients,
using the same cut-points as ONCAB
patients (11).
4.00
Peak cTnT (ng/mL)
3.00
P<.001
2.00
1.00
0.00
OPCAB
(N=84)
ONCAB
(N=764)
SpEciAl circumStAncES:
cArdiAc opErAtionS
whErE ctn VAluES ArE low
As noted, cTn values are nearly universally elevated among those patients who undergo cardiac surgical procedures, but this
is not entirely the case. In a very small percentage of patients, normal or even unmeasurable cTn values may be observed. As
already demonstrated in figure 1, a wide
range of cTn values are observed after cardiac surgical procedures, largely dependent
on the use of cardiopulmonary bypass as
well as the presence and extent of CAD.
Accordingly, those patients who are expected to have the lowest concentrations
of cTn after cardiac surgery include those
patients who undergo non-bypass, beating
heart surgeries, such as pericardiectomy.
Interestingly, even in the presence of
CAD, when beating heart, off-pump CABG
(oPCAB) is utilized for revascularization,
cTn concentrations are considerably lower
than in on-pump CABG (CABG) patients
(Figure 2) (11, 15-20). This naturally has
raised concerns about whether the same
cTn cut-points could be used for both on-
CAB and oPCAB patients. fortunately, it
would appear that despite concentrations
of cTn are lower in oPCAB patients in general, in the context of a complication, values for cTn are similar to onCAB patients
with complications (11, 20), and when cut
at similar levels as for onCAB patients
(e.g. 10-15 times the upper reference limit),
the marker has comparable negative predictive value (91-97%) for excluding complications, irrespective of cardioprotection
strategy (11).
ctn tESting: potEntiAl
futurE ApplicAtionS
In addition to being adopted in a more widespread fashion simply for post-cardiac
surgical risk stratification, cTn testing in
this setting may have other logical applications in the future. for example, with
more widely available non-invasive imaging options such as computed tomography
angiography, an elevated cTn might trigger
early graft angiography to ensure patency
(4, 46); such an approach has been suggested to be of value to “save” potentially th-
troponin testing After cardiac Surgery
reatened grafts in the early post-operative
period (47). furthermore, given the clear
association between cTn concentrations
and cardioprotection, it is quite clear that
these markers may be considered as a surrogate endpoint for the value of novel cardioplegia agents, as well as other forms of
intra-operative myocardial protection strategies (21-28).
ctn tESting AftEr
cArdiAc SurgEry: SummAry
And logicAl ApplicAtion
Based on the available data in the literature, cTnT and cTnI are superior to CKMB as a biomarker for post-cardiac surgery patient evaluation. Elevation in both
cTnT and cTnI is expected nearly universally after cardiac surgery, particularly in
onCAB patients, and those undergoing
CABG with associated valve replacement
surgery. These elevations are due to multiple causes, including presenting syndromes, intra-operative management and
post-operative events.
Given the multiplicity of causes for cTn
elevation after cardiac surgery, and the
particular rarity of a regional MI, in this
context, the use of cTnT or cTnI for the
diagnosis of regional MI after cardiac surgery is problematic. furthermore, consensus recommended cut-points for diagnosis
of the so-called “Type 5” MI are so low
as to render the application of cTnT and
cTnI quite problematic, given the expected
over-reliance on objective measures - such
as biomarkers - for the diagnostic evaluation of the post-operative patient, in whom
other means for evaluation (such as ECG
or echocardiography) are either non-specific or not easily delivered/interpreted in
the ICU setting. Thus, great caution must
be exercised when utilizing cTnT or cTnI
for diagnosis of post-cardiac surgery regio-
nal acute MI: in this context clinical factors must be applied at the risk of a false
diagnosis.
on the other hand, concentrations of both
cTnT and cTnI have repeatedly and unequivocally been shown to be prognostic for
delayed recovery, ICU utilization, as well
as short- and longer-term mortality following cardiac surgery.
The optimal cut-points for this application
are considerably higher than consensus
guideline cut-points for “Type 5 MI”, typically in the range of 10-15 times the upper
reference limit.
Data would suggest that a cTn below this
threshold on ICU arrival and/or at 18-24
hours provides sufficient prognostic information for identifying those patients with
a low likelihood for a complicated course.
for those patients with excessive cTnT
or cTnI elevation, an adverse outcome is
more likely and more assiduous evaluation
and management for such patients is suggested.
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graft-related and non-graft-related perioperative myocardial infarction with cardiac troponin I after coronary artery bypass surgery.
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proceedings
in Intensive Care
Cardiovascular Anesthesia
originAl ArticlE
carotid Endarterectomy:
experience in 8743 cases
R. Chiesa¹, G. Melissano¹, R. Castellano¹, Y. Tshomba¹, E.M. Marone¹, E. Civilini¹,
D. Astore¹, F. Calliari¹, B. Catenaccio¹, G. Coppi¹, A. Carozzo², R. Mennella²
¹Department of Vascular Surgery; ²Anesthesia and Intensive Care, San Raffaele Scientific Institute,
Università Vita-Salute, Milan, Italy
AbStrAct
introduction: Recently published case series of patients undergoing carotid endarterectomy suggested a reduction in the rate of perioperative neurologic events when compared to those reported in the large randomized
trials performed in the 1990s, without great differences between high and low risk patients.
methods: As a major center of Vascular Surgery we prospectively collected data on 8743 carotid endarterectomy procedures (eversion technique 75%, patch closure 17.5%) performed in the period 1992-2009.
results: Perioperative mortality was 0.32% (27/8743) with myocardial infarction being the most frequent
cause (9 patients). Perioperative neurological morbidity was 1.04% (91/8743) with 51 major and 40 minor
strokes. In 201 cases (2.3%) a cervical hematoma (suture-line bleeding in 41 cases and or diffuse oozing in 160
cases) in the early postoperative period necessitated urgent wound revision. In 262 (3.0%) cases we observed
permanent or transient lesions of cranial nerves in the postoperative period. There was no significant difference in the combined ipsilateral stroke and perioperative death rate in octogenarian patients (2.1% in octogenarians and 1.2% in younger patients, p>0.05), even though an increasing trend was evident.
conclusions: Carotid endarterectomy has a reduced rate of perioperative complications when compared to
those previously reported in literature. The low complication rate is related to improved preoperative patients
evaluation, surgeons’ increasing experience and to surgical and anesthesiological techniques. Carotid angioplasty and stenting should have their results compared to these real world results of carotid endarterectomy in
order to asses their reliability when treating extracranial cerebrovascular disease.
Keywords: vascular surgery, carotid endarterectomy, stroke survival anesthesia.
introduction
In the early 1990’s several well designed
randomized studies clearly demonstrated
the effectiveness of carotid endarterectomy
(CE) over best medical therapy alone for
symptomatic and asymptomatic patients
with a significant stenosis of the internal
carotid artery (ICA) (1-6).
Corresponding author:
Roberto Chiesa, M.D.
Professor of Vascular Surgery,
San Raffaele Scientific Institute, Università Vita-Salute
Via olgettina 60 - 20132 Milan, Italy
e.mail: [email protected]
More recently, published case series of
patients undergoing CE (7-10) assessed a
more conclusive reduction in rate of perioperative complications (neurologic events)
compared to risk/benefit ratio reported in
the former trials (1-6), without great differences between high- and low- risk selected
patients.
In this article we report our experience as a
major center of Vascular Surgery, performing 8743 CE procedures in the period 19922009, and we show our results analysis
with evaluation of perioperative complication rates.
33
R. Chiesa, et al.
34
table 1 - Clinical characteristics of 6468 patients who
underwent 8743 carotid endarterectomy procedures in
the period 1992-2009 in our centre.
clinical features
n
Male sex, n (%)
Stroke
Asymptomatic
14%
TIA
5764 (69%)
Age, mean (years)
32%
69
Symptoms
Stroke
TIA
Asymptomatic
1176 (14%)
2689 (32%)
4538 (54%)
Risk factors
Hypertension
Dislipidemia
Diabetes
Smoke
5579 (66%)
3966 (47%)
1664 (20%)
3975 (47%)
Positive TC
5151 (61%)
mEthodS
from 1992 to 2009, we performed a total
of 8743 CE, on 6468 patients, with a mean
age of 69.3 years (range 32-92).
Clinical characteristics and age distribution
are presented in table 1 and Graph 1.
neurological history was positive for stroke
in 1224 (14%) and for transient ischemic
attack (TIA) in 2798 patients (32%).
In 4721 cases (54%) patients were neuro-
54%
graph 2
Neurologic medical history of 6468 patients who
underwent 8743 carotid endarterectomy procedures in the period 1992-2009 in our centre.
logically asymptomatic or presented non
specific symptoms (Graph 2).
our current clinical protocol and the percentage of adherence to it in this case series
are described below.
Indications
According to well-defined guidelines, established in 1998 during the Consensus Conference of the American Heart Association
(11, 12) and endorsed by the Italian Society
graph 1
Age distribution of 6468 patients who underwent 8743
carotid endarterectomy procedures in the period 1992-2009
in our centre.
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
30-40
40-50
50-60
60-70
70-80
>80
carotid Endarterectomy: experience in 8743 cases
of Vascular Surgery (13), symptomatic and
asymptomatic patients with carotid stenosis >60% are judged eligible for CE, depending on life expectancy, comorbidities,
general condition and surgical risk (which
must be less than 3% for asymptomatic patients and less than 6% for symptomatic
patients).
Elderly patients are not excluded from surgical treatment on the basis of age alone
(10.1% of octogenarians in our series), as,
even in this subgroup of patients, CE may
be a safe mean of stroke prevention, provided that patients receive adequate selection (14-16).
Indication and timing of urgent carotid
revascularization in presence of acute neurological symptoms still represent a much
debated issue, even though some investigators advocate good results with emergent
surgery in highly selected patient (17-19).
In our series we had 157/8743 cases (1.8%)
of urgent carotid revascularization, performed for two specific conditions: patients
with crescendo TIAs and a single TIA with
ulcerated plaque (136 cases); patients developing post-operative cerebral ischemia
(21 cases), respectively.
Preoperative hospital stay
and diagnostic work-up
Although patients could be ideally admitted to hospital the same day of surgery (20),
we usually prefer to admit the patient 1 day
before surgery.
Duplex Scanning: duplex scanning (i.e. an
ultrasonography study characterized by the
combination of B-scan imaging and Doppler
imaging) performed at a validated laboratory has almost completely replaced angiography (21-24). When the results of a duplex
scan are uncertain, magnetic resonance angiography (MRA)/computed tomography
angiography (CTA) represent our second
choice while contrast angiography with arterial catheterization (stroke rate of 1.2%
in ACAS trial) (6) is our last choice.
Cerebral Parenchymal Study/Neurological Auditing: as far as cerebral parenchymal imaging is concerned, preoperative
computed tomography (CT) scan is useful to show previous ischemic cerebral lesions with prognostic significance for new
strokes after CE (25). CT may also reveal
the presence of aneurysms, vascular malformations, and brain tumors.
In the last 2 years, preoperative cerebral
CT was performed in 87% of our patients,
especially those showing high risk features
(neurologic symptoms, bilateral stenosis,
high risk plaque). Magnetic resonance imaging (MRI) is performed only in selected
cases (5.8%).
Cardiac Status: the most important nonneurologic area to explore preoperatively
is cardiac status. As a matter of fact, most
of perioperative complications and deaths
are cardiac in origin (26). There is no consensus on optimal cardiovascular preoperative evaluation before CE. Some studies
suggest that routine scintigraphic or ultrasonographic tests are useful in detecting
patients at high risk (27, 28), but there is
no evidence of cost-effectiveness of this approach.
According to our current protocol, echocardiography with dobutamine test is performed in patients with a history of cardiac
disease or with a pathologic electrocardiogram (EKG) (16%).
Preoperative Medication: given the benefit
of antiplatelet therapy in patient undergoing CE without a substantial higher risk of
bleeding (29) we discontinue acetylsalicylic
acid/ticlopidine only the day of operation,
while low molecular weight heparin at low
doses is administered overnight.
Surgical procedure
Anesthesia: the choice of the anesthetic
management for carotid surgery is still controversial. A recent large randomized trial
35
R. Chiesa, et al.
graph 3
The increase in the use of Loco
Regional Anesthesia in our
centre in the study period to
perform 8743 carotid endarterectomy procedures.
36
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0
93
94
95
Locoregional a.
96
97
98
99
00
04
06
08 y
General a.
showed no differences between general and
locoregional anesthesia (30) in clinically
relevant endpoints.
nevertheless, minor advantages of locoregional anesthesia (LRA) are well recognized. It can be performed outside the operating room with adequate patient monitoring, and allows a less cumbersome neurological monitoring during clamping. Some
authors also described better hemodynamic
stability during surgery and improved postoperative pain control with the use of LRA
(31).
Performing LRA in recovery room before
entering the operating room helped us to
save at least 30 min on the use of the operating room, compared togeneral anesthesia.
Currently LRA is used in most cases of our
series (96.3%) (Graph 3).
The choice between superficial or deep
cervical plexus block is performed by the
attending anesthesiologist, taking into account his/her experience in the technique
and patients’ characteristics (e.g. double antiplatelet therapy). Superficial cervical plexus blocks is performed by a 20 G needle, introduced into the skin at the midpoint of the
posterior border of the sternocleidomastoid
muscle in a slightly caudal direction, and
0.75% ropivacaine (≈5 ml) is injected along
the posterior border in cranial and caudal
directions subcutaneously, superficial and
deep to the fascia of the muscle. An injection in a fan-like fashion is also performed
subcutaneously from the posterior border
of sternocleidomastoid toward the midline
of the neck. Deep cervical plexus block is
performed at C2-C3-C4 level. A 20 G needle
is inserted in the skin until it reaches the
transverse process of the corresponding vertebra and then anesthetic is injected after
an accurate suction-test. We generally administer 5 ml of 0.75% ropivacaine for each
injection. The total amount of ropivacaine
used is 1.5 mg/kg (considering both the superficial and the deep cervical block). The
last step of the procedure is the infiltration
of the incision line with 10 to 15 ml of lidocaine 1%. Subsequent sensory loss to a pinprick in the C2-4 dermatome distribution is
recorded. Additional lidocaine (1%) is administered intraoperatively by surgeons in
1 ml aliquots (either superficially into skin
and subcutaneous tissues or deep into and
around the carotid sheath), as required when
the patient reported discomfort. It should be
useful to add a mild intravenous injection of
opiates (fentanyl 1ug/kg or Remifentanyl
0.025-0.05 ug/kg/min), to reduce discomfort associated to the forced posture during
carotid Endarterectomy: experience in 8743 cases
surgery. We feel very comfortable with use
of lidocaine and ropivacaine, as the former
ensues a rapid onset of pain control while
the latter, with its long lasting nerve block
(5-8 hours), guarantees good analgesia in
the early postoperative period.
Heparinization: systemic heparinization
is routinely used (a dose of 70 IU/kg was
used until ’04 when we reduced the dose to
50 IU/kg in order to minimize the risk of
cerebral haemorrhage). Activated Clotting
Time (ACT) is measured before and after
heparin administration, with a target ACT
greater than 200”. Protamine is administered in half the dose required to antagonize all heparin.
Surgery
Exposure of the carotid bifurcation: exposure
starts with incision of the skin right on the
anterior border of the sternocleidomastoideus muscle. Depending on the characteristic of the neck, our standard incision usually was 10-15 cm long. Recently we have
started to reduce the length of the skin incision by mapping the location of the carotid
bifurcation at the time duplex is performed
(32) (Figure 1). once the bifurcation is
freed from the sorrounding structures, we
progress to mobilization of the arteries.
Special care is mandatory to avoid damage
to the vagus nerve. The internal carotid artery (ICA) is then mobilized to a point distal to the visible atheromatous lesion. The
ICA is dissected along its edge, starting at
the upper end of the bulb. During dissection
is important to avoid the X and XII cranial
nerves. As we use eversion as our routine
technique, we routinely dissect the ICA distally in order to have a secure end-point.
The surgical technique used in each single
case is chosen according to carotid anatomy
and cerebral tolerance to cross-clamping.
Standard endarterectomy: once the component of the carotid bifurcation are dissected
and heparin administered, the arteries are
37
figure 1
Our currently used shorter incision (5-7 cm long).
figure 2
Complete clamping of the carotid bifurcation.
figure 3
Arteriotomy of the bifurcation (two suture lines are
placed to help maintaining the bifurcation open)..
R. Chiesa, et al.
38
figure 4
Polyurethane carotid patch.
figure 5
Transverse arteriotomy during eversion andarterectomy.
figure 6
Eversion: the plaque is firmly hold with forceps
while the outer wall is everted. Pulling the
plaque should be avoided by any means.
clamped with microsurgical clamps. We
usually clamp the ICA first, then the CCA
and finally the ECA. If the superior thyroid
artery has to be clamped, we usually deal
with it using a mini-bulldog clamp (Figure
2). We always perform a tolerance test of 1
minute before starting with the CE. Arteriotomy extends over the last 2 centimeters
of CCA and into the ICA to a point beyond
the termination of the plaque (Figure 3).
The plane for endarterectomy is sought at
the level of the bulb, where the plaque is
usually most developed. The proximal endpoint of the plaque, at the level of the CCA,
is usually obtained by direct cutting. The
ICA endarterectomy is the most important
part. The plaque is therefore pulled along
its axis, paying attention not to stay close
to the artery wall, while the ICA is pushed
the opposite way. The remaining surface
is then accurately debrided using forceps.
finally we proceed to closure of the arteriotomy with a synthetic patch (Figure 4).
We have currently abandoned direct closure, as a recent metanalysis has shown a
higher rate of restenosis, compared to patch
closure or eversion (33).
Eversion technique: eversion allows optimal correction of elongated ICAs either by
shortening the ICA after endarterectomy
or by reimplanting the ICA a little further
down into the CCA (34). The suture line
is basically an end to side anastomosis that
does not produce diameter reduction. This
technique is expeditous and straightforward and it is the most used in our series
(75% of cases). one drawback is that occasionally it does not allow a clear-cut view of
the distal end-point of the endarterectomy,
thus requiring systematic intraoperative arteriograpy as a quality check. once clamping of the ICA, CCA and ECA is established
and the patient responds well to neurologic
evaluation (of at least 1 minute), the ICA is
transected at its origin (Figure 5). ICA endarterectomy is carried out by eversion in
carotid Endarterectomy: experience in 8743 cases
39
figure 7
Final reconstruction of carotid bifurcation after
eversion.
cranial direction (Figure 6). Careful flushing of the ICA and the CCA is performed
before reimplanting of the ICA (Figure 7).
At the end of the reimplantation an intraoperative arteriography is performed in order
to exclude a distal intimal flap in the ICA
which could lead to dissection or thrombosis (Figure 8).
Shunting: we are used to perform selective
shunting with a Javid shunt (10.7%). on
declamping we perform the Imparato ma-
figure 8
Intraoperative arteriography showing optimal final result of the endarterectomy.
figure 9
Imparato maneuver.
neuver in order to minimize the ischemic
time (Figure 9).
Intraoperative quality check: to reduce the
incidence of complications related to technical defects after CE, several types of quality
control tests have been employed by different authors (35,36). Angiography through
direct puncture of the CCA is probably the
simplest and most direct way to show technical defects in the endarterectomized ICA.
In our series, intraoperative completion arteriography is used routinely for eversion
endarterectomy and only in dubious cases
for other techniques. Selective carotid arteriography is performed through direct
puncture of the CCA. If angiography shows
a substantial defect of the distal end-point,
the surgical options include resection and
bypass grafting or a longitudinal incision
on the internal carotid artery, with fixation
of the intimal flap with tacking sutures and
patch closure. Intraoperative carotid artery
stenting (CAS) has emerged as a valuable
R. Chiesa, et al.
40
figure 10
Intraoperative view of the transcervical approach
for ICA stenting.
figure 11
Stentig of the ICA for a distal end point defect.
alternative in the management of perioperative technical complications following CE
(Figure 10). Currently stenting of the distal
flap through direct cannulation of the CCA
is often performed in case of a technical defect detected intraoperatively (Figure 11).
Post-operative management
In our experience selective postoperative
ICU stay was necessary only in 1.5% of
cases. This result is related to the highquality nursing in the surgical ward, to the
presence of a surgeon on call 24 hr/day, and
to the availability of accurate, noninvasive
monitoring at the patient’s bedside.
Bleeding: in spite of meticulous hemostasis and cautious administration of heparin,
postoperative bleeding is relatively frequent,
particularly for patients on double antiplatelet therapy (37-39). The amount of tolerable
bleeding in the neck is reduced by anatomic
limitations related to the fasciae and the
risk of airways’ compression makes cervical hematoma a surgical emergency. When
orotracheal intubation is required, it is important to remember that this may be extremely difficult to carry out because of the
hematoma and swelling of the soft tissues
that may limit the view of the larynx and
the passage of the tube. Therefore intubation should be performed with a fibroscope.
If the patient is breathing well, we perform
hemostasis under local anesthesia. If the patient is intubated and there is large swelling of the soft tissues, we prefer to leave the
tube in for at least 24 hr, along with steroid
administration and head elevation.
Discharge: because the surgical procedure
has a rather low local invasivity, safe discharge from the hospital may be as early
as the first postoperative day (40). on the
first postoperative morning, the surgeon inspects the wound and remove the drain. An
independent neurologist rechecks the neurological status. If the patient is stable from
a cardiovascular and neurologic standpoint,
the EKG is unchanged, and the patient has
no fever, has a dry wound without any neck
swelling, and can eat, void, and ambulate
spontaneously, discharge from the hospital
can be scheduled for the same day. In our
series patients are discharged at a mean of
2.5±0.8 postoperative days.
Follow-up/Restenosis
The patient is seen at the outpatient clinic
on postoperative day 10 to remove the skin
staples. If the patient is living far from the
Hospital, he/she spends 1 more day in hospital and is asked to stay in town for a few
days after the procedure. follow-up duplex
carotid Endarterectomy: experience in 8743 cases
scan is scheduled after 3,6 and 12 months
and then on a yearly basis. Patients living
in Lombardia have a 93% clinical and duplex scan follow-up. for patients not living
in Lombardia follow-up rate is lower but
still acceptable (62%).
rESultS
The eversion technique was used in 6558
cases (75%). CE with patch closure (we
used Dacron patches until 2001 then we
turned to polyurethane patches) was used in
1530 cases (17.5%) and direct suture, now
abandoned, in 655 cases (7.5%) (Graph
4). A Javid shunt was selectively used in
935 cases (10.7%) because of the presence
of clinical and instrumental (modification
of the EEG pattern) signs of cerebral ischemia. Shunting was twice as common in
case of contralateral occlusion. Mean use of
the operating room was 74 min. Through
systematic use of locoregional anesthesia
(LRA), our use of the operating room is
at least 30 min less than that that we have
during general anesthesia. Mean clamping
time accounted for 14 minutes in case of
patch closure and for 10 minutes in case
of eversion endarterectomy. Perioperative mortality was 0.32% (27/8743), with
myocardial infarction being the most frequent cause (9 patients). other causes of
death were: ischemic stroke (7 patients),
hemorrhagic stroke (7 patients), respiratory failure caused by cervical hematoma
(1 patient), wound infection (1 patient)
and suture failure with massive bleeding
(2 patients). Perioperative neurological
morbidity was 1.04% (91/8743). of these
91 cases 51 (56%) were major strokes and
40 (44%) minor strokes, with complete or
near complete resolution of all symptoms.
A total of 201 cases (2.3%) developed cervical hematoma in the early postoperative
period, which necessitated urgent wound
revision. of these, 8 patients had the wound
emergently reopened in the surgical ward
because of progressive airway compression,
which was fatal in one case. The cause of
hematoma was either suture-line bleeding
(41 cases) or diffuse oozing (160 cases).
In 262 (3.0%) cases we observed permanent or transient lesions of cranial nerves
in the postoperative period, with the recurrent laryngeal nerve involved in 135 cases
(51.7%), the hypoglossal in 67 (25.8%), the
facial in 27 (10.3%), the glossopharyngeal
in 21 (7.5%) and the accessory in 12 cases
(4.7%). We registered 25 cases of wound
infection. All were readmitted to hospital
and treated with surgical drainage. In case
of patch closure (13 patients), the patch
was removed and replaced with a saphenous vein one. In all cases except one, who
suffered fatal stroke, recovery was unevent-
100%
Eversion %
Patch %
Direct %
80%
60%
40%
20%
0
92
93
94
95
96
97
98
99
02
05
08
graph 4
Trends in use of different endarterectomy techniques in our
serie.
41
R. Chiesa, et al.
42
figure 12
Reoperation for restenosis after a previous patch
closure (Dacron).
ful. Elderly patients (i.e., octogenarians)
face an increased operative risk (41). Since
1995 we performed 883 CE in octogenarians. The 1-year mortality was significantly
higher among the octogenarians (1.37% vs.
0.32%, chi-square test, p<0.05), however,
there was no significant difference in the
combined ipsilateral stroke and perioperative death rate (2.1% in the octogenarians
and 1.2% in younger patients, p>0.05),
even though an increasing trend was evident. At the time of first admission 21.3%
of patients presented with bilateral carotid
stenosis greater than 70% and underwent
staged bilateral CE. After the first intervention we experienced a rate of combined ipsilateral stroke and perioperative death rate
of 1.4%, comparable to those experienced
in normal patients. Similarly, the rate of
combined ipsilateral stroke and perioperative death after the second operation was
1.3%. It is noteworthy that there was a sig-
nificantly greater need for shunting if the
second operation was performed early, especially within 30 days from the first one
(42). Contralateral occlusion was present
in 18.2% of the patients. The rate of combined ipsilateral stroke and perioperative
death rate was 1.37% in this subgroup.
Complication rate did not differ from that
of other patients, the only difference being
a double rate of shunt insertion in patients
with contralateral occlusion (43). In 431
cases (5%) we observed a >50% restenosis that was treated only if symptomatic or
critical ≥80% (44), either with PTA-Stenting (71 cases; 0.8%) or surgically (32 cases; 0.3%). In 32 cases we performed redo
open procedures (Figure 12) with 6 cases
(18.7%) of cranial nerve injuries, and a
combined ipsilateral stroke and perioperative death rate of 6%.
diScuSSion
Carotid endarterectomy is safe and effective
for stroke prevention in significant symptomatic and asymptomatic carotid stenosis.
Writing the word “carotid endarterectomy”
on the browser of any service that include
English citations from MEDLInE and other
life science journals for biomedical articles,
each one of us can easily notice than over
9000 papers on CE have been published
in peer-reviewed journals from 1953, and,
incredibly, until nowadays, the surgical indications, the choice of neurological monitoring, the anesthetic management, and the
surgical technique are still controversial.
Moreover, in the last decade, carotid artery
angioplasty and stenting (CAS) gained popularity as an alternative to carotid endarterectomy (CE), particularly in high risk
patients, being less invasive and potentially
minimizing the risks of wound complications and cranial nerve injury, which may
translate into shorter length of hospitaliza-
carotid Endarterectomy: experience in 8743 cases
tion and less resource utilization. Waiting
for future developments, CAS is at present
an effective treatment, particularly appealing in high-risk patients with significant
carotid artery stenosis, however, there is no
real evidence that CAS provides better results in the prevention of stroke compared
to CE. We currently limit its use in cases
of restenosis, in patients unfit for surgery,
and for the periopertive correction of distal
flaps after CE that may be difficult to treat
surgically.
our results of 8743 CEs demonstrate a progressive reduction in the incidence of complications, which can be compared to that
reported by the major international studies
of the last few years. This reduction is related to improved preoperative patients evaluation, surgeons’ increasing experience, and
to surgical and anesthesiological technique
developments.
In terms of surgical technique, good results
have been reported for all commonly used
surgical techniques. We prefer to adopt a
flexible approach choosing surgical technique on the basis of intraoperative findings
and the need for shunt insertion. Shunt use
has become less frequent, reflecting better
neurologic monitoring and shorter clamping times.
Limitations
our study entails some limits. first of all
the intrinsic limit of being a retrospective
study, with all the bias due to its design.
Moreover, in the first years, only major
adverse cerebrovascular events were recorderd, whereas TIA or non fatal myocardial
infarction were not labeled as complications. This has led without any doubt to an
under-extimation of the total rate of complication of CEA, even if it is still a topic of
discussion what the real importance of this
minor complications might be.
one second major limit is the fact that the
short in-hospital stay of these patients (2.5
days) might make a discrete amount of postoperative complications, in particular those
cardiac in origin, to go unnoticed. It is in
fact well documented in literature that, on
average, cardiac complications happen 2 to
4 days after the surgical stress has occurred.
This might then lead to underestimate the
total incidence of MI in the postoperative
period, as many of our patients come from
areas outside of our district.
The authors certify that there is no conflict of
interest with any financial organization regarding the material discussed in the manuscript.
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45
proceedings
in Intensive Care
Cardiovascular Anesthesia
originAl ArticlE
46
Solving the challenges of large
multicenter trials in Anesthesia
S. Wallace¹, P.S. Myles²
¹Department of Anaesthesia and Perioperative Medicine, Alfred Hospital; Melbourne, Australia;
² Department of Anaesthesia and Perioperative Medicine, Alfred Hospital;
Professor, Academic Board of Anaesthesia and Perioperative Medicine, Monash University; NHMRC Practitioner Fellow;
Melbourne, Australia.
AbStrAct
This paper describes many of the challenges encountered when establishing a large multicentre trial in cardiac
anesthesia. We address funding, authorship, multisite ethics review, patient recruitment, data quality management, communication with individual sites, and strategies to enhance cooperation and patient recruitment.
Keywords: cardiac anesthesia, anesthesia, multicenter trials, methodology.
introduction
Large randomized controlled trials, testing new treatments in routine clinical
practice, can optimize generalizability and
so are clinically relevant and reliable (1).
They thus provide the best evidence of
effectiveness (2, 3). Most large trials are
multicenter studies, and often conducted
in many countries. Despite being labelled
as “simple” or “pragmatic” trials (1, 3, 4),
reflecting their focus on easy-to-administer
treatments in routine settings, they create
a number of difficult challenges for those
involved. However the rewards are great
and include the opportunity to answer important clinical questions reliably, to publish in top-ranked journals, and to be recognized by your peers. We would like to
share our experience of establishing a large
multicenter trial testing two interventions
Corresponding author:
Sophie Wallace
BHlthSc, MPH , Research Manager
Department of Anaesthesia & Perioperative Medicine
Alfred Hospital, Commercial Road, Melbourne, Vic, 3004, Australia
e.mail: [email protected]
in coronary artery surgery (5). The aspirin
and tranexamic acid for coronary artery surgery (ATACAS) trial is a factorial designed
trial in 4600 patients, designed to detect
thrombotic (principally myocardial infarction (MI), stroke, and death) and bleeding
complications – see www.atacas.org.au.
We reasoned that although aspirin may increase bleeding, there is some evidence that
it could reduce thrombotic complications
after coronary artery surgery. The opposite
can be said for antifibrinolytic therapy. In
both cases there are insufficient randomized
trials to address these questions unequivocally. A large multicenter trial is required
(5). Pharmaceutical companies are unlikely
to fund such reaearch, and so specialty or
government research bodies must provide
financial support.
protocol dEVElopmEnt
And plAnnEd Sub-StudiES
The effort and commitment to undertake
or contribute to a large multicenter trial
Solving the challenges of large multicenter trials in Anesthesia
is substantial. Before embarking on such
a project, the aims and study hypothesis
should be clearly outlined, hopefully addressing a clinically important question. A
supportive literature review will provide a
background and justification for conducting
such a trial. There are often opportunities
to design small sub-studies at selected centres, requiring additional data collection,
increasing opportunities for authorship
and additional publications. The explanatory data can be used to link the effects of
an intervention to selected intermediate
outcomes that may correlate with the main
study aims. for the ATACAS trial we are
conducting substudies to investigate aspirin non-responsiveness in a subset of our
study population, perioperative genomics
with the iPEGASUS group, and the effects
of tranexamic acid on seizure risk.
The study protocol describes the science of
the research project, and the study procedures manual the structure and processes
that allow it to be properly conducted.
Study mAnAgEmEnt
Experienced trial management and leadership are vital for successful large scale clinical trials. numerous individual centers,
sometimes with their own research interests and studies, must arrive at a consensus
regarding study procedures and data collection, inclusion of other clinicians (not just
anaesthesiologists) and language and cultural differences, all of which test goodwill and
cooperation on a multinational scale. Trials
should have a core group of co-investigators
responsible for the overall management and
running of the trial, headed by a Principal
Investigator (PI). The PI, co-investigators,
and perhaps other experts, constitute the
trial steering group. Some bodies recommend that the chairman of the trial steering
committee should not otherwise be involved
in the trial (6). The trial steering committee
should meet at regular intervals throughout
the life of the trial to discuss overall management, progress and policy decisions.
Trial management includes data management, data security and back-up, quality
checks, review of patient safety and including consideration of reports from the trials’ data and safety monitoring board. Each
individual site reports via the study chief
investigators to the steering committee. Ideally each site should have a lead investigator
who takes responsibility for overseeing the
study at their site, for which they should be
acknowledged in the final publication. financial management should be continually
assessed throughout the trial (7).
funding
Large trials require substantial funding.
The ATACAS trial is primarily funded by
the Australian national Health and Medical Research Council (nHMRC). Being government provided, such funding is usually
limited, and when considering the costs
and demands on clinicians and research
staff, it is usually insufficient to properly
fund all aspects of the trial. Most centers
have other cardiothoracic research projects
which may compete for patients, research
staff availability, and interest from local
clinicians. There may be competition with
pharmaceutical company-funded projects
which typically provide much higher rates
of remuneration (8, 9). The ATACAS trial
is an investigator-initiated trial, funding
individual sites Australian Dollars (AUD)
700 (about Euro 390) per patient enrolled;
we have been involved in some pharmaceutical company-funded studies providing
funds at 5-10 times that rate.
Large clinical trials aim to address clinically
important questions, often testing simple inexpensive interventions. There is a compelling
47
S. Wallace, P.S. Myles
48
argument that such trials ought to be funded
by the health (not medical research) budget
because of the opportunities to immediately
improve outcomes of healthcare (1, 10).
procurEmEnt of Study drug
Initial management hurdles can include
sourcing of study drug and matched placebo, and these issues can vary across countries because of differences in the status of
the study drug licensing. for ATACAS, we
approached the pharmaceutical companies
that produce aspirin and tranexamic acid
to assist with free supply of study drug and
matched placebo.
for aspirin, this proved to be relatively
straight-forward and positive, but for
tranexamic acid it resulted in a two year
delay and eventual disappointment. We
subsequently arranged our own purchase
of tranexamic acid from the UK, leaving us
with the cost-burden for supply of this drug
to most ATACAS sites around the world.
This of course also delayed the commencement of the trial.
following public announcement of the results of the BART trial (11), and the market
withdrawal of aprotinin around the world
(12), the initial purchase price of tranexamic acid went from AUD30 (about € 17) per
box to AUD100 overnight.
This added a new and unexpected cost burden to the study.
fortunately this did not interrupt recruitment although it highlights how trial budgets can suddenly be tested.
goVErnAncE
Before enrolling participants in a clinical
trial individual sites must gain approval by
their hospital’s institutional review board
or ethics committee (13).
Another mandatory step is informed consent (14), for which local expectations and
requirements can vary, as well as sometimes introducing a need for translation of
such documents.
The time line for this process from beginning (initial contact with site) to end (management receiving the approval letter) averages six months. This is a major barrier
for many sites who may otherwise be interested in collaboration (15).
AuthorShip AgrEEmEnt
Researchers are rated according to the quality and quantity of their publication record.
Large trials involve many individuals, but
only some deserve authorship on the main
publication(s). others may share in authorship of subsidiary publications. In any
case, all of those involved in the conduct of
a large trial should be acknowledged, and
this is typically published as an appendix to
the main publications.
for this reason acknowledged site leaders
ought to be given credit for their leading
role within their own institutions.
Authorship is a vexed topic, and it cannot
be overstated: who and under what circumstances each collaborator is included in the
authorship or acknowledgement lists must
be outlined at the beginning of the trial,
and ideally a signed authorship agreement
be completed in order to avoid disappointment and conflict.
indEmnity
Multicenter trials should have a clinical trial
agreement (CTA) signed with each individual site. This pertains to both pharmaceutical-sponsored and investigator-initiated
trials.
The CTA document requires legal review
Solving the challenges of large multicenter trials in Anesthesia
and comment from each site. This adds cost
and poses another potential for delaying
start up of the trial.
Pharmaceutical-sponsored trials have the
resources to provide their own indemnity
insurance, but investigator-initiated trials rarely can because such funding is not
included in most research funding bodies’
budgets.
In such cases it is usual to ask that individual sites cover their own indemnity costs,
because the study procedures usually only
involve currently established therapies.
As we, and others (10), argue, investigatorinitiated large pragmatic trials ought to be
considered “public good” research and so
individual institutions should support such
trials.
SitE SElEction
Site selection is vital to a successful trial. It
relies on some research infrastructure and
staffing, to identify eligible patients for recruitment, study interventions and followup (16).
Initial site investigators invited to join the
ATACAS trial were those previously involved in other multicenter trials (17-20),
and have proven track records. All sites
were asked to discuss the feasibility of undertaking the trial with their respective
cardiothoracic surgical colleagues. Support
from the surgeons at each institution was
an essential component for the trial. new
sites were also sought.
Publicity for the trial occurred via presentation at scientific meetings, establishment
of a trial website (www.atacas.org.au), and
journal publication (5).
Rahbari et al (21) challenge the surgical
community to optimize study power using properly conducted, pragmatic (multicenter) trials with large sample sizes. Variation in surgical practice, surgical skill and
surgeon preference have proven to be obstacles to large multicenter trials in surgery
(8), but Devereaux et al. (22) have suggested solutions.
rESEArch
nurSES/coordinAtorS
And pAtiEnt rEcruitmEnt
It is very important that the infrastructure
and staff to conduct research at each site
are actively sought, available and most importantly supported (23-26). Sites that have
limited infrastructure in place to conduct
research must commence with recruitment
of a research nurse or coordinator, and this
takes time (recruitment, training). The coordinating center for the trial can assist in
this regard.
Constant communication and availability
of assistance has proved to be important in
facilitating this role. The research nurse is
responsible for the screening, recruitment,
consent, data collection, data storage, subject logs, data entry, and protection of human subjects in clinical trials (Figure 1)
(27).
It is vital that the research nurse be supported by the site investigator, and participating units (28), as this will be the main
contributing factor to the success or failure
of patient recruitment (25). It has been
previously reported that the individual undertaking the recruitment can influence recruiting patients to the trial (29). no difference was found when doctors or research
nurses were examined, but there was a
statistically significant difference when recruitment was undertaken by the operating
surgeon (29).
This therefore highlights the importance of
having the support from all disciplines involved in the research.
A recent survey of trials published in the
Lancet or BMJ found that nearly 60% of
49
S. Wallace, P.S. Myles
50
Figure 1
Day-to-day role
of the research nurse.
trials had either failed their recruitment
target or required an extension of their
planned recruitment period (29). Recruitment of participants to trials is one of the
most important aspects to a successful trial
(23, 24, 30).
It has long been recognized that recruitment is a much greater problem than is perceived by the investigator when instigating
and designing of the trial (8, 24). During
the course of the trial it is important to implement and identify strategies to overcome
barriers to recruitment (31).
Delays in recruitment lead to important
scientific answers being left unanswered,
increased unidentified costs, early closure of trial (8, 23-25, 30, 31), statistical
power may be reduced (29, 31), poor morale (16), and delayed uptake into clinical
practice.
Studies have shown that individual site
training and regular feedback and communication to staff improve recruitment rates
(15, 32). Start-up meetings, personalised
education and training visits assist in im-
proving recruitment (29). The management
team provide the following process to assist
with site recruitment (Figure 2).
Newsletters are used to disseminate information to all sites and focus on recruitment
techniques, addressing frequently asked
questions, current and new sites, future
meetings, changes to the database and recently published literature relevant to the
study.
Data ManageMent
anD Monitoring
Data collection from multiple sites, in various time zones, needs to be streamlined
and secure.
For the ATACAS trial we use paper-based
case report forms (CRF) at each centre, and
the data are later transferred onto a webbased form. The online data entry is accessed through a password-protected link
on the trial website.
The site also offers a trial summary, recruit-
Solving the challenges of large multicenter trials in Anesthesia
51
figure 2
Personalising the trial.
ing centres, current randomisation and also
a trial register interest section for any sites
wishing to participate or contact the management team.
The web-based database therefore allows
for the original study CRf to be retained
at each site for audit and privacy purposes,
as well as reducing the time spent in identifying and resolving data queries, and minimising data entry errors.
This has been identified as one factor that
may assist in increasing efficiency (29). We
believe simple study procedures encourage
participation in multicentre trials.
Careful monitoring of the recruitment process throughout studies is vital, and enables
the management center to identify problem
areas at individual sites (25).
These logs can be sent to the data management center on a monthly basis and
tabulated for review by the steering committee. If a site has a lag in recruitment, the
research manager or project officer can initiate communication with the site to assist
in identifying areas requiring assistance.
Correct and complete study procedures can
be checked, including consent, secure data
storage, and verification of trial events.
concluSionS
Large multicenter clinical trials are demanding but ultimately rewarding in that
they provide reliable answers to everyday
clinical problems.
Clear guidelines on all aspects of the trial
procedures assist in a teamwork approach
to overcoming the many barriers to successful completion of such trial.
S. Wallace, P.S. Myles
52
No conflict of interest acknowledged by the
authors
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53
proceedings
in Intensive Care
Cardiovascular Anesthesia
originAl ArticlE
54
infusione tramite via venosa
periferica di fenoldopam mediante
pompa elastomerica
T. Quaranta, G. Cornaggia, S. Turi, A. Mizzi, A. Zangrillo
Department of Anaesthesia and Intensive Care, San Raffaele Scientific Institute, Università Vita-Salute, Milan, Italy
AbStrAct
introduction - fenoldopam has been used to protect renal function in critically ill patients and in those undergoing major surgery, where a possible damage of kidney is expected. numerous randomized studies and metaanalysis demonstrated the efficacy of fenoldopam in this setting. We performed this study to demonstrate the
feasibility of administering fenoldopam, trough an elastomeric pump connected to a peripheral vein, to patients
undergoing nephron sparing surgery.
materials and methods - Twenty consecutive patients, ASA physical status class I-III, undergoing laparoscopic or laparotomic renal tumorectomy were enrolled. fenoldopam was infused trough an elastomeric pump
at a fixed dosage of 0.1 mcg/kg/min, obtained after diluting the drug with saline solution according to the
weight of the patient. We injected the drug trough a peripheral vein from the induction of anaesthesia for 48
hours after the end of surgery.
results - The infusion of fenoldopam did not modify the haemodynamic parameters. We did not find episodes
of hypotension and only in three patients we registered episodes of tachycardia, not requiring the suspension
of the infusion. no other side-effect was noted.
conclusion - The administration of fenoldopam, trough an elastomeric pump, in patients undergoing renal
tumorectomy is feasible through a peripheral vein access
Keywords: fenoldopam, acute renal failure, elastomeric ump, peripheral vein, kidney.
introduZionE
L’insufficienza renale perioperatoria costituisce un importante fattore determinante
il prolungamento della degenza ospedaliera e un incremento della mortalità e della
morbilità.
Il ruolo del fenoldopam come agente nefroprotettore è già stato suggerito in diverse situazioni nelle quali è possibile il realizzarsi
di un deterioramento della funzione renale, come ad esempio, la chiurgia vascolare
Corresponding author:
Tamara Quaranta
Dipartimento di Anestesia
Ville Turro - ospedale San Raffale
Via Stamira d’Ancona, 20 - 20157 Milano, Italy
E-mail: [email protected]
e cardiaca (1-4). Due recenti meta-analisi
hanno mostrato come il fenoldopam riduca
la necessità di trattamento dialitico renale e
incida positivamente sulla mortalità sia in
pazienti “critically ill” (5) che in quelli sottoposti a chirurgia cardiovascolare (6).
Il fenoldopam è un dopamino agonista che
esplica la sua azione selettivamente a livello
dei recettori adrenergici DA1, la sua azione è quasi nulla o trascurabile a livello dei
recettori DA2. Il recettore DA1 è localizzato a livello postsinaptico sul muscolo liscio
renale, cardiaco, mesenterico e cerebrale,
a livello renale il recettore è situato nel
tubulo prossimale, nella midollare e nella
corticale. Pertanto il fenoldopam è in grado
di aumentare il flusso ematico renale e la
infusione tramite via venosa periferica di fenoldopam
filtrazione glomerulare senza che si verifichino aumento della frequenza cardiaca o
comparsa di tachiaritmie come può accadere con la dopamina. Il fenoldopam esplica
il suo effetto ipotensivo attraverso un decremento delle resistenze vascolari periferiche ed è approssimativamente sei volte più
potente della dopamina nel produrre vasodilatazione renale. La natriuresi e la diuresi
possono avvenire senza vasodilatazione, ciò
sta ad indicare un sito d’azione a livello del
tubulo renale prossimale. Gli effetti benefici
del fenoldopam possono essere correlati ad
un’altra proprietà del farmaco (ancora in
studio), quale un effetto anti-infiammatorio
descritto da Aravindan et al. (7).
In chirurgia urologica, oggi, sempre più
spesso rispetto al passato, si preferisce in
caso di neoplasie renali effettuare, quando
possibile, un approccio conservativo effettuando interventi di tumorectomia o crioterapia renale in alternativa alla nefrectomia
radicale. numerosi studi hanno infatti dimostrato che vi è un rischio significativamente aumentato di nuova insorgenza di
IRC in pazienti sottoposti a nefrectomia
radicale rispetto a quelli sottoposti a nefrectomia parziale (8). Gli interventi di tumorectomia renale, siano essi laparotomici
o laparoscopici, comportano un periodo di
clampaggio dell’arteria renale e impongono all’anestesista la messa in atto di tutte
le strategie nefroprotettive disponibili. La
nefroprotezione è ancora più importante
in pazienti monorene (su base congenita o
chirurgica) o in pazienti con insufficienza
renale cronica (IRC). Al fine di prevenire il
danno ischemico renale è necessario mantenere anzitutto un’ottimale volemia, inoltre
si è soliti far ricorso a farmaci quali mannitolo, furosemide o dopamina a dosaggio
renale sebbene non vi sia alcuna evidenza
scientifica sulla loro efficacia.
Dal momento che i migliori benefici del
fenoldopam sono stati ottenuti per somministrazioni prolungate, ci siamo proposti di
validare la sicurezza e l’efficacia di un sistema di infusione continua del fenoldopam
che a differenza delle comuni pompe infusionali di uso intensivistico, fosse gestibile
con maggiore facilità e sicurezza anche in
un reparto chirurgico. Abbiamo scelto di
utilizzare elastomeri a velocità fissa per infondere fenoldopam al dosaggio fisso di 0.1
gamma/kg/min in via venosa periferica, avviando l’infusione del farmaco subito dopo
l’induzione dell’anestesia e proseguendola
per le 48 h successive.
mEtodi
nel nostro servizio di urologia presso la
struttura ospedale San Raffaele - Ville
Turro vengono eseguiti circa 300 interventi annui di tumorectomia renale; quando
possibile è privilegiata la tecnica laparoscopica o robotica.
L’intervento di tumorectomia renale prevede il clampaggio dell’arteria renale con una
fase di ischemia calda il cui tempo massimo
di sicurezza per evitare il danno renale dovrebbe essere di 30 minuti.
nel caso in cui si preveda un tempo di clampaggio più lungo, il chirurgo provvede ad
effettuare un’ischemia fredda portando la
temperatura renale al di sotto di 20°.
Sono stati inclusi nello studio 20 pazienti
consecutivi classe ASA 1-3 candidati ad
interventi di tumorectomia renale mono o
bilaterale condotti per via laparoscopica o
laparotomica. Sono stati considerati criteri
di esclusione gravi patologie cardiache (gravi deficit valvolari e coronarici), polmonari
ed epatiche.
Dopo essere giunti nel blocco operatorio
sono stati posizionati ai pazienti due accessi venosi di grosso calibro su cui si è avviata
un infusione di cristalloidi. Il monitoraggio
in sala operatoria prevedeva la valutazione dell’ECG, della pressione arteriosa non
cruenta, della pulsiossimetria periferica e
55
T. Quaranta, et al.
56
tabella 1 - Schema di diluizione in soluzione fisiologica di una fiala di fenoldopam in funzione del peso
corporeo del paziente.
tabella 2 - Effetti collaterali prevedibili in seguito a
somministrazione di fenoldopam con rispettiva incidenza nel gruppo di pazienti analizzati.
peso kg
diluizione ml fisiologica
40
166,5
1
Ipotensione
0
45
148
2
Tachicardia
3
50
133
3
Cefalea
0
55
121
4
necessità dialisi
0
60
111,0
5
Arrossamento cutaneo
0
65
102,5
6
Ipokaliemia
0
70
95,0
7
Aritmie
0
75
88,5
8
Vomito
0
80
83
9
Vertigine
0
85
78
90
74
95
70
100
67
formula
gamma/ml=0,1 gamma/kg/min x Peso x60
velocità infusione 2 ml/h
della diuresi. L’induzione dell’anestesia è
avvenuta tramite somministrazione di tiopentone sodico 5-7 ml/kg, atracurium 0.5
mg/kg, fenatnyl 2 mcg/kg.
Il mantenimento dell’anestesia è stato conseguito con l’erogazione di gas anestetico
alogenato (sevoflurane o desflurane).
L’infusione di fenoldopam è avvenuta tramite pompa elastomerica ad un dosaggio
fisso di 0.1 mcg/kg/min ottenuta attraverso
una diluizione in soluzione fisiologica calcolata sulla base del peso del paziente (Tabella 1).
La somministrazione del farmaco è avvenuta tramite cannula venosa periferica subito
dopo l’induzione dell’anestesia e il posizionamento del paziente ed è proseguita per 48
dopo il termine dell’intervento.
Si è mantenuta una perfusione di cristalloidi (6-8 ml/kg) e colloidi (3-4 ml/kg) mantenendo una PAM >60 mmHg (se PAM <60
Effetti collaterali
pazienti
10 Crampi arti inferiori
0
11 Congestione nasale
0
12 Sindrome vaso-vagale
0
13 fatica
0
14 Calo visivo
0
15 Dolori toracici aspecifici
0
16 Palpitazioni
0
mmHg per più di 10 min era prevista la sospensione del farmaco).
Durante l’intervento è avvenuto un monitoraggio ogni 15 minuti dei valori di frequenza cardiaca, pressione arteriosa non
cruenta (sistolica, diastolica e media), saturimetria e diuresi.
Gli stessi parametri sono stati valutati
nell’immediato post-operatorio ed in prima
e seconda giornata con un intervallo di 2
ore. Sono state inoltre eseguite valutazioni
dei valori di creatininemia sierica, creatinina clearance, potassiemia, sodiemia e calcemia nel giorno dell’intervento ed in prima e
seconda giornata post-operatoria. Abbiamo
anche ricercato la presenza di eventuali effetti collaterali connessi al possibile utilizzo
del farmaco (Tabella 2).
Per ogni pazienti si è poi proceduto alla valutazione del danno renale sulla base della
classificazione RIfLE (Tabella 3).
infusione tramite via venosa periferica di fenoldopam
tabella 3 - Schema di classificazione del danno renale RIFLE. Otto pazienti sono rientrati nella prima classe di
danno renale (RISK). Soltanto due in quella FAILURE (con un paziente in questo caso monorene ed un altro con
clampaggio e tumorectomia bilaterale).
glomerular filtration
rate criteria
urinary output criteria
pazienti
rISK
se crea 1.5x o GfR <25%
Uo <0.5 ml/kh/hr per 6 h
8
inJURY
se crea 2x o GfR <50%
Uo <0.5 ml/kh/hr per 12 h
0
fAILURE
se crea 3x o GfR<75%
Uo <0,3 ml/kg/h in 24 o anuria 12h
2
loSS of fUnCTIon perdita di funzione >4 settimane perdita di funzione >4 settimane
0
EnD STAGE
0
perdita di funzione>3 mesi
riSultAti
In nessuno dei 20 pazienti è stato necessario sospendere l’infusione di fenoldopam
per insorgenza di ipotensione o di effetti
collaterali. I 20 pazienti partecipanti allo
studio (14 maschi, 6 femmine) sono stati
sottoposti ad interventi di tumorectomia
renale laparotomica (13) o laparoscopica (7). In tre casi la tumorectomia è stata
bilaterale. otto pazienti erano affetti da
ipertensione arteriosa, quattro da diabete
mellito, due da insufficienza renale cronica
e tre risultavano essere monoreni ad inizio
procedura.
I pazienti presentavano un’età media di
62±9 anni, un peso di 80±15,3 kg, un’altezza media 172±6,4 cm. Il tempo di calmapaggio e di ischemia renale è stato in
media di 33±18,6 minuti.
I parametri emodinamici sono rimasti stabili durante tutta l’infusione di fenoldopam.
non sono stati registrati episodi di ipotensione e soltanto in tre pazienti si sono verificati episodi di tachicardia non grave e non
richiedente la sospensione del farmaco.
non sono stati registrati altri effetti collaterali (Tabella 2).
La diuresi è rimasta valida in tutti i pazienti
durante la giornata dell’intervento e nelle
prime due giornate post-operatorie. Soltanto in tre pazienti (o monorene o sottoposti
a tumorectomia e a clampaggio bilaterale) è
stato necessario stimolarla con furosemide.
perdita di funzione>3 mesi
In giornata 0 la diuresi media nelle 24
h è stata di 1,6±0,7 ml/kg/h, in giornata 1=1,5±0,7 ml/kg/h ed in giornata
2=1,5±0,6 ml/kg/h. Si è assistito ad un
incremento dei valori di creatininemia che
si sono poi normalizzati entro la quinta
giornata post-operatoria.
Abbiamo poi valutato la classificazione RIfLE per i diversi pazienti (Tabella 3). È importante sottolineare come i due pazienti in
classe f (failure) siano rispettivamente un
paziente monorene ed uno sottoposto a tumorectomia bilaterale.
diScuSSionE
Questo studio ha dimostrato, per la prima
volta, la fattibilità della somministrazione per lunghi periodi del fenoldopam per
via periferica e senza necessità di utilizzare una pompa siringa connessa ad una
presa di corrente. Dal momento che il farmaco ha mostrato le sue migliori proprietà
quando somministrato per lungo tempo,
questa tecnica di somministrazione è particolarmente appetibile per i malati con o
a rischio di insufficienza renale perioperatoria o periprocedurale che non hanno un
accesso venoso centrale. nella nostra casistica di 20 malati non sono stati osservati
effetti collaterali (ipotensione) o problemi
tecnici tali da indurre l’interruzione della
somministrazione di fenoldopam postope-
57
T. Quaranta, et al.
58
ratoriamente a malati, sottoposti ad intervento urologico e a rischio di insufficienza
renale operatoria.
Il peggioramento della funzione renale
nell’immediato periodo post-operatorio è
associato ad un aumento della mortalità e
della morbilità.
Agenti farmacologici quali il mannitolo, la
furosemide o la dopamina a dosaggio renale
incrementano il flusso ematico renale ma
non sono efficaci nel prevenire o trattare
l’insufficienza renale acuta.
Il fenoldopam è un agonista selettivo dei recettori dopaminergici DA1; in questo modo
attraverso la sua azione riesce a determinare una vasodilatazione renale senza provocare tachicardie o aritmie come può accadere con la dopamina.
Recenti meta-analisi hanno dimostrato la
sua efficacia nel ridurre morbilità e mortalità in pazienti candidati ad interventi di
chirurgia cardiovascolare o “critically ill”.
La review sistematica della letteratura ha
mostrato come l’utilizzo del fenoldopam
sia associato ad una minore permanenza in
terapia intensiva oltre che ad una minore
mortalità intraospedaliera in pazienti sottoposti ad intervento cardiovascolare (6).
Appare intuitivo come alcune forme di chirurgia urologica possano essere associate ad
un peggioramento della funzione renale, fra
queste in particolare le tumorectomie renali per il periodo di clampaggio dell’arteria
renale e la conseguente ischemia. Questo è
maggiormente valido per pazienti con insufficienza renale cronica o monoreni.
Inoltre alcuni studi hanno dimostrato come
la stessa chirurgia laparoscopica possa essere associata ad un breve e reversibile peggioramento della funzione renale (per un
compressione pneumatica sulle strutture
dell’ilo renale o forse per una tendenza da
parte dell’anestesista a garantire un minor
riempimento volemico) (9-11).
Il fenoldopam è stato sempre adoperato
tramite infusioni attraverso vie venose cen-
trali e con un costante monitoraggio in un
ambiente protetto quale la terapia intensiva. nei pazienti da noi studiati tale farmaco è stato somministrato attraverso un via
periferica e mediante pompa elastomerica.
Come indicato nella tabella 1 il farmaco è
stato diluito in modo tale che si potesse avere una concentrazione identica ed una stessa quantità di farmaco infusa nell’unità di
tempo (0,1 mcg/kg/min) a prescindere dal
peso del soggetto in studio.
Allo stesso modo tutti i pazienti sono stati
ricoverati al proprio piano di degenza con
un monitoraggio non invasivo (PA, ECG,
Spo2) effettuato ogni due ore per le prime
due giornate post-operatorie.
Scopo principale è stato perciò quello di validare una diversa via di somministrazione
rapida, efficace, facilmente standardizzabile ma allo stesso modo altrettanto sicura e
precisa di quelle tradizionali.
Il nostro primo end-point è stato perciò
quello di verificare l’insorgenza di possibili
effetti collaterali. In nessun paziente è stato
necessario sospendere l’infusione del farmaco. L’unico effetto collaterale descritto in
tre pazienti è risultato essere la tachicardia;
in tutti i casi non così grave da compromettere l’equilibrio emodinamico del paziente.
In tutti i pazienti si è avuto un mantenimento di una diuresi valida e soltanto in
due casi è stato necessario stimolarla con
furosemide. Gli aumenti di creatininemia e
il calo della creatinina clearance osservabili nelle prime due giornate post-operatorie
(Tabella 2) sono poi andati incontro ad una
normalizzazione entro la quinta giornata in
tutti i pazienti.
concluSioni
La somministrazione di fenoldopam tramite pompa elastomerica in pazienti candidati
ad interventi di tumorectomia renale risulta sicura e di facile esecuzione.
infusione tramite via venosa periferica di fenoldopam
rEfErEncES
1. Bove T, Calabrò MG, Landoni G, et al. The incidence and risk of acute renal failure after cardiac surgery. J Cardiothorac Vasc Anesth 2004;
18: 442-445.
2. Landoni G, Bove T, Crivellari M, et al. Acute
renal failure after isolated CABG surgery: six
years of experience. Minerva Anestesiol 2007;
73: 559-565.
3. zangrillo A, Romano A, Landoni G, et al. Postoperative complications after coronary artery
bypass grafting surgery. A comparison between the off pump and the on pump techniques.
Eur J Anaesthesiol 2004; 21: 1-3.
4. Landoni G, Roberti A, Boroli f, et al. Mitral
valve surgery and acute renal failure. Eur J
Anaesthesiol 2007; 24: 100-101.
5. Landoni G, Biondi-zoccai GGL, Tumlin JA,
et al. Beneficial impact of fenoldopam in critically ill patients with or at risk for acute renal
failure: a meta-analysis of randomized clinical
trials. Am J Kidney Dis 2007; 49: 56-68.
6. Landoni G, Biondi-zoccai GGL, Marino G,
et al. fenoldopam reduces the need for renal
replacement therapy and in-hospital death in
cardiovascular surgery: a meta-analysis. J Cardiothorac Vasc Anesth 2008; 22: 27-33.
7. Aravindan n, natarajan M, Shaw AD. fenoldopam inhibits nuclear translocation of nuclear factor kappa B in a rat model of surgical
ischemic acute renal failure. J Cardiothorac
Vasc Anesth 2006; 20: 179-186.
8. Huang WC, Levey AS, Serio AM et al. Chronic kidney disease after nefrectomy in patients
with renal cortical tumours: a retrospective cohort study. Lancet oncol 2006; 7: 735-740.
9. Chiu AW, Chang LS, Birkett DH, et al. Changes
in urinary output and electrolytes during gaseous and gasless laparoscopy. Urological Research 1996; 24: 361-366.
10. Holte K, Klarskov B, Christensen DS, et al.
Liberal versus restrictive fluid administration
to improve recovery after laparoscopic cholecystectomy: a randomized, double-blind study.
Annals of Surgery 2004; 240: 892-899.
11. Gudmundsson ff, Viste A, Myking oL, et al.
Effects of the aldosterone receptor antagonist
potassium canrenoate on renal blood flow and
urinary output during prolonged increased intraabdominal pressure (IAP) in pigs. Surgical
Endoscopy 2004; 18: 1528-1534.
59
proceedings
in Intensive Care
Cardiovascular Anesthesia
pApErS, poStErS, prESEntAtionS:
communicAting thE biomEdicAl SciEncES
60
the target journal: choosing
the right place to submit your paper
M. John
Professor of Applied English, Faculty of Medicine, Vita-Salute San Raffaele University, Milan, Italy
After having written a wonderful paper, full
of interesting ideas, fascinating data and
exhaustive statistics you make a terrible
mistake: you send it to the wrong journal.
What does ‘the wrong journal’ mean? for
many it would be a journal with an unsatisfactory impact factor.
In my opinion, it is a journal where you
will not have any interested readers.
Impact factor is, of course, crucial as it looks good on your CV and can earn you research funds, but citation will only occur, at
least in most cases, when you are read with
interest by fellow professionals from your
own specific field of biomedicine.
Choosing the right place to submit your paper is therefore the first thing you have to
do, even before you actually start bashing
it out on your computer keyboard.
You might feel that your paper is of fundamental importance to the biomedical community, but it is always a good idea to be
realistic and aim for a journal that is within your reach.
What I mean is, if you are convinced of the
quality and importance of your paper, and
Corresponding author:
Prof. Michael John
Vita-Salute San Raffaele University
Via olgettina, 60
20132 Milano, Italy
E-mail: [email protected]
also feel that it could be of interest to a particular group of readers, then by all means
submit it to a high-impact-factor journal.
for example, who wouldn’t like to be published in the new England Journal of Medicine? What you have to remember is that
the nEJM receives around 4,000 papers
a year yet only has the chance to publish
around 450 of them.
The selection process is extremely severe,
therefore, and your paper really does have
to be out-of-the-ordinary and of extreme
relevance to the journal’s reading population to even begin going through the peerreview process.
Submitting a paper that is even slightly
below this level would mean immediate
rejection (nEJM normally rejects within
one week when they are not interested), so
think carefully about where you decide to
send your manuscript.
In any case, the destination of your paper is
known as the target journal.
As I said at the beginning, your target
journal does not necessarily need to have a
high impact factor, but must guarantee you
a reading population.
The next thing to remember is that you can
only send your paper to one journal at a
time.
Stick to your specialty and even try contacting the Editor via e-mail before submit-
the target journal: choosing the right place to submit your paper
ting your paper to find out whether or not
he will consider publishing it, based on its
subject matter.
This can save you time, sometimes a lot of
time.
When you have chosen the journal be sure
to follow its Instructions to Authors.
Although more than 500 journals use the
uniform requirements for manuscripts
Submitted to biomedical Journals
(http://www.icmje.org/), also known as the
Vancouver Document, each journal will also
have its own set of rules and regulations.
Uniform requirements include:
• the use of double spacing throughout the text
• the necessity to use the standard IMRAD
(Introduction, Methods, Results And Discussion) format
• the sequence to be used: title page - abstract
- key words and abbreviations - text - acknowledgements - references - tables and figures - legends
Specific requirements might include:
• the use of abbreviations
• the type of spelling to use (American or
British English)
• the maximum length of the paper
So, remember:
• choose a journal that is relevant to your
specialty to guarantee you an audience
• choose the target journal realistically as you
can only submit your work to one journal at
a time: inevitable rejection means delayed
publication
• get in touch with the editor of your target
journal beforehand to see whether your
work might be of interest or not
finally, if you are convinced that your paper
deserves to be published in the NEJM then
don’t worry about the 90% rejection rate
and send it to them as your target journal.
He who dares sometimes wins. There’s no
harm in trying.
“Questo è il terzo di una serie di articoli sull’argomento.
Potete indirizzare domande (in italiano o in inglese) a [email protected] e vedrete le
risposte pubblicate su questa rubrica”.
‘This is the third of a series of articles on this topic.
Send any questions to [email protected] who will answer them as part of this
column.’
61
M. John
62
Questions from the readers
1
Should numbers be written
as words or numbers at the
beginning of sentences?
The rule is that in a biomedical manuscript
single-digit numbers (1-9) have to be written as words, except when indicating units
of measurement, but all other two or more
digit numbers should be written as numbers. However, when the sentence begins
with a number, whatever the number of
digits involved, you should always write it
in words.
2
what is the correct spelling
for compound numbers in English:
with or without a hyphen?
In the literature all compound numbers are
hyphenated (e.g. twenty-five patients were
enrolled)
3
is it possible to use the present
perfect form (have been) in a
biomedical manuscript?
no. At times, the present perfect tense is
unavoidable: e.g. when you are speaking
of past events where time is not defined.
However, a biomedical manuscript reports
a procedure, therefore you should ALWAYS
use the simple past (and simple tenses in
general) throughout even when time is not
specified.
4
is it better to use the active or
passive voice in medical English?
Active. Many people mistakenly feel that
the passive voice is ‘more scientific’ than the
active voice. Indeed, some journals might
specify their preference for the passive and,
at times, use of the passive is unavoidable
and even necessary. However, the active
voice is clearer, simpler and improves the
flow of the written text. Avoid the passive.
Be active!
proceedings
in Intensive Care
Cardiovascular Anesthesia
rEcEnSionE
Ecocardiografia transesofagea in area critica
di Fabio Guarracino
Elsevier Masson, 2009, pagine 240
L’ecocardiografia transesofagea (TEE) ormai
fa parte del monitoraggio standard del paziente sottoposto a chirurgia cardiaca, e fornisce
molte informazioni anche riguardo al paziente ricoverato in Terapia Intensiva.
nonostante la scelta di testi sull’argomento
sia vasta, abbiamo accolto con molto piacere (e con un pò di orgoglio italiano - vedi fig.
12.1 di Ecocardiografia transesofagea in area
critica) il libro del Dr fabio Guarracino, Primario di Anestesia e Rianimazione CardioToracica dell’Azienda ospedaliera Universitaria
Pisana e Presidente di ITACTA (Italian Association of CardioThoracic Anesthesia), che
mette a disposizione di tutti la sua esperienza
nel campo dell’ecocardiografia transesofagea.
La lettura del capitolo 1 “fisica degli ultrasuoni e formazione dell’immagine” (argomento
tabù della maggior parte dei medici che si interessano di ecocardiografia), illude chi spera
di acquisire quelle nozioni che, a detta di molti, sono fondamentali per un buon esame ecocardiografico: la fisica dei suoni, pur essendo
trattata in maniera chiara, avrebbe meritato
più spazio.
Il 2° capitolo elenca le principali indicazioni
e le (poche) controindicazioni all’ecocardiografia transesofagea, le precauzioni per l’uso
e la cura della sonda transesofagea.
Quindi nel 3° capitolo, il Dr Guarracino ci
spiega passo passo i movimenti possibili della
sonda e, secondo le indicazioni dell’American
Society of Echocardiography e della Society
of Cardiovascular Anesthesiologists le proiezioni fondamentali per un corretto esame
TEE.
finalmente nel 4° capitolo, si entra nel vivo
dell’argomento, con lo studio del ventricolo
sinistro e della sua funzione, le varie metodiche di studio ed i limiti di quest’ultime.
Il 5° capitolo è dedicato allo studio del ventricolo destro, che troppo spesso viene dimenticato, e invece in Ecocardiografia transesofagea
in area critica trova il suo giusto spazio.
Il 6° capitolo esplora in modo approfondito la
funzione diastolica, partendo da richiami di
fisiologia, fino all’impatto clinico delle valutazioni, trattando tutte le metodiche ecocardiografiche, dallo studio del flusso transmitralico
alla velocità di propagazione, al doppler tissutale.
Si arriva quindi ai capitoli dedicati allo studio
delle valvole, aortica (cap. 7) e mitrale (cap.
8). Soprattutto per quanto riguarda la mitrale, la trattazione è approfondita e spende
molte pagine sulla classificazione anatomica
e funzionale, permettendo quindi al lettore di
comprendere con facilità i vari meccanismi
dell’insufficienza.
Da segnalare che, come da linee guida American College of Cardiology/American Heart
Association del 2006, viene raccomandata la
necessità della valutazione intraoperatoria
della valvola mitrale dopo chirurgia riparativa, da parte di un medico formato in TEE,
a prescindere dalla sua specialità. In virtù di
questa precisazione, ci saremmo aspettati di
trovare qualche pagina sulla valutazione delle
valvole cardiache dopo chirurgia.
Il capitolo 9° riveste una grande importanza,
in quanto esplora la patologia dell’aorta, nella quale il TEE è l’esame di scelta per porre
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diagnosi di molte gravi lesione aortiche. nel
capitolo 10° e 11° vengono studiate in dettaglio le patologie del pericardio e le masse
cardiache.
Inizia quindi una serie di 4 capitoli dedicati
al rianimatore. Capitoli dedicati al trauma toracico, alla sepsi, al cuore polmonare acuto e
allo shock e alla rianimazione cardio-polmonare. Sono argomenti che, spesso tralasciati
da altri libri, possono invece rivelarsi molto utili. Chiude il libro un capitolo dedicato
alle equazioni fondamentali che si utilizzano
(spesso inconsapevolmente) durante un esame ecocardiografico.
La trattazione dei vari argomenti non si limita alla teoria pura, ma in ogni capitolo il Dottor Guarracino integra le varie metodiche con
delle considerazioni cliniche e decisionali.
Molto utili le indicazioni pratiche per ogni
misurazione (“come si misura”): sembra di
avere accanto qualcuno che, passo passo, ti
spiega come eseguire le varie misure. È un
peccato che le tavole fuori testo, così utili,
siano così piccole; si fa fatica a interpretarle
bene. Di fronte ad una scelta molto ampia di
testi, manuali e atlanti, finalmente possiamo
contare su di un libro scritto da un anestesista-rianimatore e dedicato a chi lavora in area
critica, dalla sala operatoria alla terapia intensiva al pronto soccorso, completo e al tempo
stesso chiaro.
Dr. Paolo Prati
Dr. Michele Oppizzi
How to prepare a manuscript for submission to
hSr proceedings in intensive care and cardiovascular Anesthesia
Articles in English or in Italian will be considered.
The abstract should always be in English.
Manuscripts must be double-spaced on A4 pages.
A margin of at least 3 cm should be provided on all
sides. All type should be 12 points in size. Pages
must be numbered. Word limits are not imposed
on any manuscript types, but all papers should be
as concise as possible.
Please send your manuscript to [email protected]
The Editorial office will send by e-mail to the corresponding author all communications related to
the status of a submission, including the final decision and the scheduled date of publication.
Different manuscripts could be submitted to “HSR
proceedings” including: original articles; Teaching articles; Brief reports; Review; Editorial; Case
series; Letters to the editor; Case reports; Images
in clinical medicine. The peer-review process is applied to all submissions, including appraisal by at
least 2 peer-reviewers.
coVEr lEttEr
Please also send us a cover letter addressed to the
Editor in Chief. The letter must include at the end
a list of all authors as if for signature. The cover
letter must state that the authors agree with and
are responsible for the data presented. The letter
should also acknowledge or deny any potential
conflicts of interest.
mAnuScript
our preferred file type for new manuscript submissions is a single Microsoft Word Doc with all
figures embedded in the same document. In the
manuscript, provide the title of the paper on the
first page (TITLE PAGE); the title should be concise. Also list the name of each author, including
the first name, and the highest graduate degree; the
department and institutional affiliation of each author; and the name, address, telephone number, fax
number, and e-mail address of the author to whom
correspondence should be addressed. ABSTRACT.
Provide an abstract of not more than 250 words.
If possible, it should consist of four paragraphs,
labelled Background, Methods, Results, and Dis-
cussion. They should briefly describe, respectively,
the problem being addressed in the study, how
the study was performed, the salient results, and
what the authors conclude from the results. The
manuscript itself should be possibly divided into 4
sections: Introduction, Methods, Results, and Discussion. REfEREnCES. Please refrain from using
automatic reference list software because its features are often lost during the publication process.
Simply insert the reference number in parentheses
in the text and type the reference list. References
must be numbered with Arabic numerals, and cited in the text in numerical order. The reference list
at the end of the article must also be in numerical
order. The list headed “REfEREnCES” should begin on a new page of the main text document and
be double-spaced.
Abbreviations for titles of medical periodicals
must conform to those used in Index Medicus
(http://www.nlm.nih.gov/tsd/serials/lji.html).
References to abstracts, supplements, and letters
to editors must be identified as such. Inclusive
page numbers of references are required.
dEtAilS
“HSR proceedings in Intensive Care and Cardiovascular Anesthesia” will consider for publication
suitable articles on all topics related to intensive
care and to anesthesia for cardiac, thoracic and
vascular surgery. The aim of “HSR proceedings”
is to contribute to the spread of knowledge in the
field of intensive care, emergencies, and major surgical operations.
Manuscripts are examined by members of the editorial staff, and then sent to outside reviewers. We
encourage authors to suggest the names of possible
reviewers, but we reserve the right of final selection. Communications about manuscripts will be
sent after the review and editorial decision-making
process is complete.
All articles represent the opinion of the authors
and do not necessarily reflect the opinion of the
Editor, Editorial Board, or Publisher. The Editors and Publisher deny any responsibility or liability for statements and opinions expressed by
the authors. neither the Editor nor the Publisher
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guarantees, warrants, or endorses any product or
service advertised in this publication, nor do they
guarantee any claim made by the manufacturer of
such product or service.
Manuscripts containing original material are accepted for consideration if neither the article nor
any part of its essential substance, tables, or figures has been or will be published or submitted
elsewhere before appearing in “HSR proceedings”.
This restriction does not apply to abstracts or
press reports published in connection with scientific meetings.
Authors of all types of articles should follow the
general instructions. These guidelines are in accordance with the “Uniform Requirements for
Manuscripts Submitted to Biomedical Journals,”
published by the International Committee of
Medical Journal Editors at http://www.icmje.org.
Papers reporting human experimentation will be
reviewed in accordance with the precepts established by the Helsinki Declaration (available at
http://www.wma.net/e/policy/b3.htm). Copies of
this declaration may also be obtained by writing
to the American Medical Association, 515 n State
St, Chicago, IL 60610.
As stated in the Uniform Requirements, credit
for authorship requires substantial contributions
to (a) the conception and design or analysis and
interpretation of the data, and (b) the drafting of
the article or critical revision for important intellectual content.
Each author must sign a statement attesting that
he or she fulfills the authorship criteria of the Uniform Requirements. Any change in authorship
after submission must be approved in writing by
all authors.
In appropriate places in the manuscript, please
provide, if applicable, a statement that the research protocol was approved by the relevant institutional review boards or ethics committees and
that all human participants gave written informed
consent. If photographs of patients are used, either
they should not be identifiable or the photographs
should be accompanied by written permission to
use them.
All text, references, figure legends, and tables
should be in one double-spaced electronic document (Word Doc). You may either insert figures
in the text file or upload your figures separately.
We prefer the former, but this may not work well
for complicated graphics, which should be sent
separately. It is permissible to send low-resolution
images for peer review, although we may ask for
high-resolution files at a later stage. Legends for all
figures should be included in the file with the text
and should not appear on the figures. Acceptable
formats for pictures, photos, and figures are PDf,
DoC, PPT, JPG, TIf. Please send TIf not inferior
to 300 DPI when your paper is accepted for publication.
References. References must be double-spaced and
numbered consecutively as they are cited. Possibly
list all authors when there are four or fewer; when
there are five or more, list the first three, followed
by “et al.”
Abbreviations. Except for units of measurement,
abbreviations are strongly discouraged. Except for
units of measurement, the first time an abbreviation appears, it should be preceded by the words
for which it stands.
Drug names. Generic names should be used.
When proprietary brands are used in research, include the brand name and the name of the manufacturer in parentheses after the first mention of
the generic name in the Methods section.
Instructions for Submitting a Revised Manuscript.
We require two versions of the revised manuscript,
one with “tracked” or highlighted changes, and
one without. Please double-space. Include your response to the reviewers as a separate file.
If a submitted article is accepted for publication,
editorial revisions may be made to aid clarity and
understanding without altering the meaning.
conflict of intErESt
Conflicts of Interest: “HSR proceedings” expects
that all authors acknowledge financial associations
with a company (or its competitor) that makes a
product discussed in the article. Information published in medical journals helps shape diagnostic
and therapeutic decisions. for a journal to be of
value, it must publish authoritative, up-to-date
information that is free of commercial influence.
Because relationships between authors and biomedical companies are growing we want to ensure
that the articles we publish are not influenced by
financial interests.
Authors should disclose any financial arrangement they may have had in the last 3 years or
in the foreseeable future with a company whose
product is pertinent to the submitted manuscript
or with a company making a competing product.
Such information will be held in confidence while
the paper is under review and will not influence
the editorial decision, but if the article is accepted
for publication, a disclosure statement will appear
with the article. Here are some examples: Dr. “A”
reports having served as a consultant to “A1”. Dr.
“B” reports having been paid lecture fees by “B1”,
“B2” and “B3” Drs. “C, D, E” report having received grant support from “C1” neither Dr. “f”A
nor Dr. “G” has any financial interest in the patent. Dr. “H” and Dr. “I” are consultants to “H1”
Dr. “L” reports having received consulting fees
from “I1” Dr. “M” reports having been a member
of speakers’ bureaus sponsored by “M1”.
copyright
“HSR proceedings” is the owner of all copyright to
any published work. “HSR proceedings” and its licensees have the right to use, reproduce, transmit,
derive works from, publish, and distribute the contribution, in the “HSR proceedings” or otherwise,
in any form or medium. Authors may not use or
authorize the use of the contribution without the
“HSR proceedings” written consent,
Please direct any questions to [email protected]
or visit www.itacta.org
“HSR proceedings in Intensive Care and Cardiovascular Anesthesia” editorial offices are located in
the Department of Anesthesia and Intensive Care
at 60 Via olgettina, Milano, Italy 20132. telephone
(+39) 02.26437164 fax (+39) 02.26437178 email
[email protected]
normE rEdAZionAli
I manoscritti possono essere in italiano o in
inglese, mentre l’abstract deve sempre essere
in inglese.
I manoscritti devono avere testo doppiospaziato, carattere 12, margini di 3 cm, pagine numerate ed essere il più concisi possibile.
Inviare i manoscritti a [email protected], accompagnati da una lettera indirizzata all’Editor
in Chief con l’elenco degli autori e l’elenco dei
possibili conflitti d’interesse.
Il formato preferito è un documento unico di
Microsoft Word, con incluse le eventuali figure.
nella “title page” indicare il titolo del manoscritto, gli autori, l’istituzione di appartenenza
ed i dati completi del correspondent author.
L’abstract non deve superare le 250 parole e
deve essere possibilmente strutturato in Introduzione, Metodi, Risultati e Discussione
così come il manoscritto. Le referenze devono
essere riportate alla fine del manoscritto in
ordine di apparizione. nel testo le referenze
devono semplicemente essere inserite tra parentesi.
Verranno presi in considerazione per essere
pubblicati articoli di terapia intensiva, di emergenze e di chirurgia maggiore.
Tutti gli autori devono esplicitare tutti i possibili conflitti di interesse nei confronti dei prodotti o delle tecniche discusse nel paper (e dei
concorrenti).
Ulteriori istruzioni possono essere trovate su
www.itacta.org
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