Programme Day 109.00 Course introduction

M. Ranucci (Milan)

Opening LectureOpening Lecture

09.15 Towards new concepts in outcome measurement

S. Nashef (Cambridge)

Session Ia A focus on clot firmnessSession Ia A focus on clot firmness

Chair: M. Ranucci and N. Rahe-Meyer

10.00 Clot firmness: what happens after thrombin generation

C. Solomon (Salzburg)

10.30 Fibrinogen and cardiac operations

N. Rahe-Meyer (Hannover)

11.30 Measuring fibrinogen: thromboelastography, thromboelastometry, Clauss method

C. Solomon (Salzburg)

12.00 INTERACT with the INTERCEPT:

Clot firmness and point-of-care tests Clinical cases, Qs & As

Discussant: M. Ranucci (Milan)

Session Ib Contributors of clot firmnessSession Ib Contributors of clot firmness

Chair: M. Ranucci and A. Nimmo

14.30 Factor XIII - lights and shadows

A. Jeppsson (Gothenburgh)

15.00 When the clot is in the wrong place

M. Ranucci (Milan)

15.30 Fibrinogen and platelets: building the wall

E. Baryshnikova (Milan)

16.00 Fibrinogen in major vascular surgery

A. Nimmo (Edinburgh)

Session II Bleeding and bleeding definitionsSession II Bleeding and bleeding definitions

Chair: M. Ranucci

17.00 Towards a universal definition of postoperative bleeding in cardiac surgery

M. Ranucci (Milan)

17.20 Bleeding associated with anti-platelet agents: the correct timing for stopping thienopyridines

U. Di Dedda (Milan)

Programme Day 208.30 INTERACT with the INTERCEPT:

The Coagulation Clinic Clinical cases presentations with Interactive Questions & Answers

M. Ranucci, C. Solomon, A. Jeppsson and the Audience

Session III ECMO in clinical contextSession III ECMO in clinical context

Chair: M. Ranucci and M. Massetti

09.30 Post-cardiotomy ECMO in adults: limits, indications, outcomes

M. Massetti (Rome)

09.50 Post-cardiotomy ECMO in infants: limits, indications, outcomes

C. Carlucci (Milan)

10.10 Anticoagulation protocols in ECMO: changing the paradigm?

A. Ballotta (Milan)

11.00 INTERACT with the INTERCEPT: What should I do with this ECMO problem? Clinical cases presentations with Interactive Questions & Answers

M. Ranucci and M. Massetti and the Audience

Session IV Acute kidney injury in cardiac surgerySession IV Acute kidney injury in cardiac surgery

Chair: M. Ranucci and F. De Somer

12.00 Modifiable and non-modifiable risk factors

M. Ranucci (Milan)

12.20 The goal-directed perfusion concept

F. de Somer (Gent)

Late breakings in Clinical TrialsLate breakings in Clinical Trials

12.40 Preoperative AT supplementation in cardiac surgery: a randomized, controlled trial

E. Baryshnikova (Milan)

Session V Assessing treatment effects:RCTs, pragmatic trials, propensity adjusted studies

Session V Assessing treatment effects:RCTs, pragmatic trials, propensity adjusted studies

Chair: M. Ranucci and S. Patterson

14.30 Randomized controlled trials: still the gold standard for evidence-based medicine?

N. Cartwright (London)

14.50 Pragmatic trials: the real guide for clinical decision-making?

S. Patterson (London)

15.00 Non-randomized studies with propensityscore analysis: just hypothesis generators?

G. Heinze (Vienna)

Guest LectureGuest Lecture

15.20 Frailty, age, and hemostatic/inflammatory response

D. Royston (Harefield)

15.50 The AKI pattern in newborns: novel treatment strategies

C. Ronco (Vicenza)

17.00-18.00 The INTERCEPT Seminars17.00-18.00 The INTERCEPT Seminars

HALL 1 Thromboelastography in clinical context

Tutor: B. Martinez Lopez de Arroyabe

HALL 2 Monitoring pro-hemostatic drugs

Tutor: M. Ranucci

HALL 3 NIRS: an outcome predictor?

Tutor: M. Heringlake

Programme Day 3Session VI CPB and monitoringSession VI CPB and monitoring

Chair: M. Ranucci and M. Heringlake

08.40 Hemodilution: all the evil

M. Ranucci (Milan)

09.00 Near-infrared spectroscopy and other cerebral monitoring techniques

M. Heringlake (Lubeck)

09.20 A Clinical and Practical Perspective of Hb, Pump Flow and DO2

J. Mulholland (London)

Guest LectureGuest Lecture

09.40 Risk stratification: from statistics towards physiology

S. Castelvecchio (Milan) and M. Ranucci (Milan)

Session VII Philosophy, religion, and outcomeSession VII Philosophy, religion, and outcome

Chair: M. Ranucci and P. Sleight

10.30 MAGISTRAL LECTURE

Prayer, mantras, music and the autonomic nervous system

P. Sleight (Oxford)

11.00 Approaching Jehova Witnesses in cardiac surgery

M. Ranucci (Milan)

11.20 Religiosity and survival after organ transplantation

F. Bonaguidi (Pisa)

11.40 INTERACT with the INTERCEPT:The 20 MCQs game: check your knowledge and get rewarded

12.30 Final remarks

Faculty

A. Ballotta (Milan) M. Massetti (Rome)

E. Baryshnikova (Milan) J. Mulholland (London)

F. Bonaguidi (Pisa) S. Nashef (Cambridge)

C. Carlucci (Milan) A. Nimmo (Edinburgh)

N. Cartwright (London) S. Patterson (London)

S. Castelvecchio (Milan) N. Rahe-Meyer (Hannover)

F. De Somer (Gent) M. Ranucci (Milan)

U. Di Dedda (Milan) C. Ronco (Vicenza)

G. Heinze (Vienna) D. Royston (Harefield)

M. Heringlake (Lubeck) P. Sleight (Oxford)

A. Jeppsson (Gothenburgh) C. Solomon (Salzburg)

B. Martinez Lopez de Arroyabe (Udine)B. Martinez Lopez de Arroyabe (Udine)

AgendaApril 12 April 13 April 14

A. Ballotta E. Baryshnikova F. BonaguidiC. CarlucciN. Cartwright S. CastelvecchioF. De SomerU. Di Dedda G. Heinze M. HeringlakeA. JeppssonB. Martinez Lopez de ArroyabeM. Massetti

J. MulhollandS. Nashef A. Nimmo S. Patterson N. Rahe-Meyer M. Ranucci

C. Ronco D. Royston P. Sleight C. Solomon

10:1015:30 12:40

11:2009:5014:30

09:4012:2017:20

15:0017:00 09:00

14:30 08:3017:00

09:3011:00

9:2009:1516:00

14:5010:3009:00 08:30 08:4012:00 11:00 09:4015:00 12:00 11:0017:00 17:00 11:40

15:5015:20

10:3010:00 08:3011:30

Towards new concepts in outcome measurement

S A M NashefConsultant Cardiac SurgeonEuroSCORE Project LeadPapworth Hospital, Cambridge

Clinical outcomes can and should be measured. The development of risk profiling and stratification means that clinical outcomes can be related to casemix. The clinical performance of any health care provider can therefore be monitored on a continuous basis. This allows for continuous quality management and the early detection of underperformance.

In cardiac surgery, we are fortunate in having a clear, unambiguous clinical outcome that is survival. This can be related to the risk profile of the patient population so that comparisons can be made between actual and expected outcomes, and an assessment of performance made, as well as a measure of improvement of performance and the detection of any underperformance so that it can be rectified (the Shipman scenario).

There is evidence in cardiac surgery in Europe of the Hawthorne effect at work. If this is true, then the numbers of lives saved by outcome measurement alone is probably in the tens of thousands., and this may have partially contributed to well-established risk models such as EuroSCORE falling out of calibration. This was the impetus for the development of a new model, EuroSCORE II.

With most hospitals in Europe and many in the world having robust survival outcome measures, attention is being diverted to other measures relating to outcomes which directly matter to the patient, such as long-term survival, symptomatic status, quality of life and freedom from adverse events. The Amaze randomised control trial is an example of such a shift in focus from the traditional outcome measure for the doctor (restoration of sinus rhythm) to the outcome measure for the patient (long-term survival, freedom from stroke and anticoagulant-related haemorrhage and quality of life). Additional risk models are being developed for specific non-survival outcomes after cardiac surgery, such as stroke, renal failure and length of stay. The importance of health economic assessment is also increasingly recognised at a time when the cost of treatment must be justified by any improvement in clinical outcome.

Papworth was the first hospital in the United Kingdom to incorporate a clinical outcome measure as a management performance indicator in 1995. Since then, Papworth has embarked on an ambitious and pioneering programme of performance monitoring. Clinical indicators deemed to be objective, evidence-based, measurable and of importance to patient outcomes are chosen by directorates and professionals. Outcomes are monitored by the directorates with the assistance of the Department of Audit and Clinical Effectiveness. Where audit indicates underperformance, the issue is investigated, an action plan is set up and reassessment carried out after a set period. Clinical performance is currently monitored using 23 indicators. Some are hospital-wide (cardiopulmonary resuscitation outcomes) and others based within single specialties or are multidisciplinary. The indicators themselves are in evolution as the tools for assessing performance are refined.

Further work must be done in relation to the communication of the measurement of survival outcomes to the patient when interventions are offered on prognostic grounds. The novel concept of TUTE (time until treatment equipoise) offers the ability to explain with a simple statement of a time period the complexity of the difference between the risk of surgical intervention and medical treatment. TUTE can be calculated on fairly robust evidence for many prognostic interventions in several medical specialties, and such evidence-base informed consent is beneficial in good medical practice.

Faxtor XIII, lights and shadowsAnders Jeppsson, MD, PhDDepartment of Cardiothoracic SurgerySahlgrenska University Hospital, Gothenburg, Sweden

Blood coagulation factor XIII (FXIII) is a protransglutaminase that becomes activated in the final stages of the clotting cascade1. The activation is caused by thrombin and calcium in combination. When activated, FXIII crosslinks fibrin monomers to produce a stable clot. FXIII is present in plasma but also in macrophages and monocytes. Besides its coagulation properties FXIII is involved in angiogenesis and wound healing, and may also have anti-inflammatory properties1, 2. Normal plasma concentration of FXIII is 0.7-1.4 kIE/ml. Inherited FXIII deficiency is extremely rare with a prevalence of 1 in a million to 1 in 5 million people3.

Effects of FXIII’s supplementation on clot formation ex vivo have been tested in a few studies with diverging results4-8. Diluted whole blood samples or samples from trauma patients or cardiac surgery patients have been spiked with varying doses of FXIII and the effects have been evaluated with thromboelastography/metry. Haas et al spiked samples diluted with crystalloids from healthy volunteers and found no effect of FXIII alone on clotting time or clot firmness5 and Fenger-Eriksen et al and Schramko et al have reported similar results4, 9. However, in Haas et al’s study FXIII potentiated the effect of fibrinogen on FIBTEM-MCF analysis5. Nielsen et al showed that FXIII improves clot formation but that study was performed on plasma samples, not on whole blood6. Theusiger et al tested supraphysiological doses of FXIII in samples from trauma patients and found that FXIII increased the speed of clot formation and increased maximum clot firmness7 and Chandler et al reported that addition of FXIII to postoperative samples from cardiac surgery patients improved clot strength8. So far, no study has demonstrated a dose-response relationship between FXIII levels and clot firmness ex vivo in whole blood samples, neither with physiological nor with supraphysiological doses.

In cardiac surgery patients studies have shown an inverse correlation between pre- and postoperative plasma concentration or activity of FXIII, and postoperative bleeding 8, 10, 11. However, even if statistically significant, the correlations are not very high and not accurate enough to estimate bleeding risk in individual patients. During cardiac surgery plasma activity of FXIII is reduced with approximately 30-40% and thus, the reduction rarely reaches critical levels. Two German studies have investigated whether plasma derived FXIII concentrate reduces bleeding after cardiac surgery 12, 13. The studies reported a tendency towards reduced postoperative blood loss but the studies were small and the results not conclusive. Current American guidelines for treatment of bleeding complications in cardiac surgery suggest that FXIII may be used in bleeding patients for clot stabilization when other methods prove unsatisfactory14. Strong evidence lacks, it is a Class IIb recommendation (level of evidence C). Recombinant FXIII has been developed and has been tested in cardiac surgery patients15. A phase II study in cardiac surgery patients has recently been completed and the results are awaited later this year16.

In summary, the exact role and importance of FXIII in prediction and treatment of bleeding complications in cardiac surgery are yet to be defined. Further studies investigating the effect of FXIII supplementation on clot formation alone, or in combination with other prohemostatics, are warranted.

REFERENCES

1. Muszbek L, Bereczky Z, Bagoly Z, Komaromi I, Katona E. Factor XIII: A coagulation factor with multiple plasmatic and cellular functions. Physiol Rev. 2011;91:931-972

2. Wozniak G, Noll T, Akinturk H, Thul J, Muller M. Factor XIII prevents development of myocardial edema in children undergoing surgery for congenital heart disease. Ann N Y Acad Sci. 2001;936:617-620

3. Muszbek L, Bagoly Z, Cairo A, Peyvandi F. Novel aspects of factor XIII deficiency. Curr Opin Hematol. 2011;18:366-372

4. Fenger-Eriksen C, Tonnesen E, Ingerslev J, Sorensen B. Mechanisms of hydroxyethyl starch-induced dilutional coagulopathy. J Thromb Haemost 2009;7:1099-1105

5. Haas T, Korte W, Spielmann N, Mauch J, Madjdpour C, Schmugge M, Weiss M. Perioperative course of fxiii in children undergoing major surgery. Paediatr Anaesth. 2011

6. Nielsen VG, Gurley WQ, Jr., Burch TM. The impact of factor XIII on coagulation kinetics and clot strength determined by thrombelastography. Anesth Analg. 2004;99:120-123

7. Theusinger OM, Baulig W, Asmis LM, Seifert B, Spahn DR. In vitro factor XIII supplementation increases clot firmness in rotation thromboelastometry (rotem). Thromb Haemost. 2010;104:385-391

8. Chandler WL, Patel MA, Gravelle L, Soltow LO, Lewis K, Bishop PD, Spiess BD. Factor XIIIa and clot strength after cardiopulmonary bypass. Blood Coag Fibrinolys. 2001;12:101-108

9. Schramko AA, Kuitunen AH, Suojaranta-Ylinen RT, Niemi TT. Role of fibrinogen-, factor VIII- and XIII-mediated clot propagation in gelatin haemodilution. Acta Anaesthesiol Scand. 2009;53:731-735

10. Shainoff JR, Estafanous FG, Yared JP, DiBello PM, Kottke-Marchant K, Loop FD. Low factor XIIIa levels are associated with increased blood loss after coronary ar tery bypass graf t ing. J Thorac Cardiovasc Surg . 1994;108:437-445

11. Ternstrom L, Radulovic V, Karlsson M, Baghaei F, Hyllner M, Bylock A, Hansson KM, Jeppsson A. Plasma activity of individual coagulation factors, hemodilution and blood loss after cardiac surgery: A prospective observational study. Thromb Res. 2010;126:e128-133

12. Godje O, Gallmeier U, Schelian M, Grunewald M, Mair H. Coagulation factor XIII reduces postoperative bleeding after coronary surgery with extracorporeal circulation. Thorac Cardiovasc Surg. 2006;54:26-33

13. Godje O, Haushofer M, Lamm P, Reichart B. The effect of factor XIII on bleeding in coronary surgery. Thorac Cardiovasc Surg. 1998;46:263-267

14. Ferraris VA, Brown JR, Despotis GJ, et al. 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg. 2011;91:944-982

15. Levy JH, Gill R, Nussmeier NA, Olsen PS, Andersen HF, Booth FV, Jespersen CM. Repletion of factor XIII following cardiopulmonary bypass using a recombinant a-subunit homodimer. A preliminary report. Thromb Haemost. 2009;102:765-771

16. clinicaltrials.gov number NCT00914589

WHEN THE CLOT IS IN THE WRONG PLACEMarco Ranucci, MD, FESCIRCCS Policlinico San Donato

Clot formation is the result of a complex interaction starting with the activation of soluble coagulation factors, leading to thrombin formation. At this stage, there is no visible clot, but the coagulation system is activated. Thrombin triggers the conversion of fibrinogen to fibrin monomers, and the final clot is the result of platelet and fibrinogen interaction.

Under normal circumstances, the heart and the vessels are free from visible clots. As a matter of fact, there are many natural inhibitors of coagulation that maintain a normal balance of the hemostatic system. Antithrombin is a natural antagonist of thrombin; The protein C-S complex prevents and limits thrombin formation by inhibition of Factor V. Tissue factor pathway inhibitor (TFPI) is released by the endothelium and inhibits the reaction between TF and Factor Xa again blunting thrombin generation.

Even after clot formation, natural factors may reduce clot firmness finally leading to fibrinolysis. Plasminogen is converted to plasmin which destroys fibrin. Plasminogen is released by liver into the circulation. It adopts a closed, activation resistant conformation. Upon binding to clots, or to the cell surface, plasminogen adopts an open form that can be converted into active plasmin by a variety of enzymes, including tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), kallikrein, and factor XII (Hageman factor). Fibrin is a cofactor for plasminogen activation by tissue plasminogen activator. Urokinase plasminogen activator receptor (uPAR) is a cofactor for plasminogen activation by urokinase plasminogen activator. The conversion of plasminogen to plasmin involves the cleavage of the peptide bond between Arg-561 and Val-562.

Under a number of pathologic conditions, this balance between thrombin and fibrin generation is disturbed, and clots may be found inside venous and arterial vessels, and inside the cardiac chambers. This of course is a dangerous situation that may lead to pulmonary and systemic embolism.

A prothrombotic pattern is present in many different (but sometimes associated) genetic or acquired defects. This includes conditions where thrombin generation is enhanced, or natural anticoagulants are ineffective, or fibrinolysis is impaired:

1. Antithrombin deficiency Decrease thrombin inhibition

2. Factor V Leiden Decreased thrombin inhibition

3. Protein C deficiency Decreased thrombin inhibition

4. Protein S deficiency Decreased thrombin inhibition

5. Hyperhomocysteinemia Increased thrombin generation

6. Factor VIII hyperactivity Increased thrombin generation

7. Prothrombin gene (G20210A) Increased thrombin generation

8. HIT Increased thrombin generation

9. Hyperfibrinogenemia Increased clot firmness

10. Plasminogen deficiency Decreased fibrinolysis

11. tPA deficiency Decreased fibrinolysis

Aside of these conditions, the fluidodynamics of blood plays a very important role in intravascular and intracardiac clot formation. Various conditions leading to blood stagnation can be found in the cardiac surgery patients:

1. Venous blood stasis in the lower limbs

2. Atrial fibrillation

3. Fontan circulation

4. ECMO

Once the clot is formed inside the cardiac chambers, and especially in ECMO procedures, lysis of the clot is a challenging issue. The use of recombinant tissue-type plasminogen activator (tPA) for thrombolysis has been previously described in cases where thrombi have developed despite adequate anticoagulation. Thrombolytics (uorokinase – streptokinase) is a possible approach, however both tPA and urokinase have been associated with bleeding and cerebral hemorrhagia in newborns.

Heparin treatment is a safer option, but probably less effective due to the limited activity of heparin on clot-bound thrombin.

Fibrinogen and platelets: building the wallEkaterina Baryshnikova PhD Dept of Cardiothoracic – Vascular Anesthesia and ICUIRCCS Policlinico San Donato, Milan, Italy

Invasive surgery is frequently associated with significant impairment of individual hemostatic capacity due to loss, consumption, endogenous inhibition, dilution of coagulation factors and increased fibrinolysis. Coagulation is a very complex, multistage process that leads to the formation of an impermeable plug at the site of injury. An established hemostatic clot is a network-like structure composed of, but not limited to, fibrin and platelets, complex both in terms of structure and stability, so both quality and quantity of the single components need to be considered.

When talking about clot stability we intend the resistance of the clot to mechanical stress and fibrinolytic dissolution. Stability could be tested either directly or indirectly in a variety of clinical assays for measuring clotting times, clot properties (thromboelastography and analogues) or rate of fibrinolysis. Mechanical and viscoelastic properties of the clot are determined mainly by the fibrin structure and both are important for thrombus behavior. The clot must be strong enough to withstand blood pressure but thrombi that are too rigid or fragile cannot deform reversibly and have a greater risk to embolize, whereas more plastic clots might deform to a new shape. The fibrinolytic properties of fibrin are also important because the clot is a temporary plug for hemostasis and wound healing. There must be a finely regulated balance between clotting and lysis, so that hemostasis is efficient but the plug is promptly removed to avoid thrombosis. In general, coarse networks have a lower elastic modulus and increased susceptibility to fibrinolysis, whereas dense networks have a higher elastic modulus and are relatively resistant to fibrinolysis.

Coagulation is initiated by the exposure of the tissue factor (TF) localized on stromal fibroblasts to blood, formation of the factor VIIa/TF complex and conversion of factor X to Xa. These extrinsic activities lead to prothrombinase activity on the TF-bearing cell surface and subsequent thrombin generation, which converts fibrinogen to fibrin near the cell surface. In the meantime, exposure of collagen and von Willebrand factor from the damaged endothelium provides an array of binding sites for the fast moving platelets from the bloodstream that attach through a dedicated receptor, slow down and stop by the injury site. Small amounts of thrombin generated so far induce higher levels of platelet activation than adhesive interactions alone and the expression of the specific glycoprotein IIb/IIIa (GPIIb/IIIa) through which platelets aggregate to each other via fibrinogen bridging. At present, it is generally accepted that fibrinogen bound to GP IIb/IIIa at activated platelets is the predominant adhesive bridge between aggregating platelets, at least at lower shear rates. Recruitment of the activated platelets to the injury site provides a highly procoagulant surface to additional thrombin generation via intrinsic (factor IXa/VIIIa) tenase and platelet prothrombinase activity and propagating fibrin formation. The burst of thrombin produced so far is of sufficient magnitude to clot generation, catalyzing large-scale fibrinogen to fibrin conversion with a stable clot establishment. Finally, Factor XIII forms covalent bonds that crosslink the fibrin polymers that form from activated monomers making the clot insoluble.

Fibrinogen is a soluble glycoprotein synthesized by the hepatocytes in the liver. Fibrinogen protein is a hexamer and contains pairs of three different polypeptide

chains - Aα, Bβ and γ linked to each other by disulfide bonds. The N-terminal domain of these chains contain cysteine residuals that participates in cross-linking of the chains. During clotting thrombin converts fibrinogen to fibrin by cleaving fibrinopeptides from the central domain, exposing key residuals that interact with specific domains always exposed at the ends of the molecule and giving rise to a half-staggered structure called the protofibril. When protofibrils grow sufficiently long, they aggregate laterally to form fibers. Fiber branching is what produces a three-dimensional network. Emerging fibrin fibers are subsequently cross-linked to each other and an array of proteins and cells are incorporated to the growing clot to further improve the strength of the clot and its resistance to dissolution.

The conditions present during the conversion of fibrinogen to fibrin influence the structure (fiber thickness, branching and network density) of the resulting fibrin network. These conditions include the local pH, ionic strength and concentrations of calcium, polyphosphate, fibrinogen itself, fibrinogen and fibrin binding proteins and thrombin present during fibrin formation. The pH of the fibrin matrix determines the fiber thickness and growth of tubular structures, experimental models showed that acidosis also increased fibrinogen breakdown compared with control values. Chloride ions have been identified as modulators of fibrin polymerization because these ions control fiber size by inhibiting the growth of thicker, stiffer and straighter fibers. High fibrinogen concentration elevate clot stiffness through the establishment of greater fiber and branch point densities. The increased incidence of myocardial infarction in patients with elevated levels of plasma fibrinogen has been partly attributed to the resulting stiffer clots. The introduction of cross-links by FXIIIa increases substantially the stiffness of the clot and the creep or irreversible deformation is nearly eliminated. The rare patients lacking FXIII have serious bleeding problems. Moreover, the polymerization rate is influenced both by FXIII concentration and activation rate.

As already seen, platelets and fibrinogen are linked at various levels. Thrombin is needed to convert fibrinogen to fibrin and major amounts of thrombin are generated by the prothrombinase complex localized to the activated platelet surface. Fibrinogen is needed to bridge platelet aggregation through GPIIb/IIIa receptor. Platelets present up to 40,000 – 50,000 copies of GPIIb/IIIa on its surface and is able to recruit large amounts of fibrinogen. In case of a severe thrombocytopenia, thrombin-activated platelets could bind larger amounts of fibrinogen strengthening the overall clot. The importance of the interactions between fibrinogen, fibrin and platelet GPIIb/IIIa receptors is clinically confirmed by bleeding diathesis in the congenital GPIIb/IIIa deficiency Glanzmann thromboasthenia, pharmacological GPIIb/IIIa blockade (abciximab) and congenital afibrinogenemia and dysfibrinogenemias.

Platelet concentration could affect hemostasis in multiple ways, including thrombin generation rate. Observations of TF-initiated blood coagulation models (synthetic plasma or whole blood where intrinsic pathway has been specifically blocked) showed that low platelet levels (> 25 000/ul) does not affect clotting time but influence significantly the maximum thrombin generation rate and the maximum thrombin concentration that steadily increase modifying platelet concentration to normal physiological levels. Other studies reported that a significant prolongation of the clotting time is observed at platelet concentration as low as 10 000/ul. Clotting time depends on the small amount of thrombin produced during initiation phase. Most thrombin generation occurs later during propagation and depends on the concentration of the activated platelet membrane binding sites available for intrinsic tenase activity and factor Xa generation. The influence of thrombin concentration is the most well-studied mechanism modulating fibrin quality. Low thrombin

concentrations produce coarse, unbranched networks of thick fibrin fibers, whereas high thrombin concentrations produce dense, highly branched networks of thin fibers.

Platelets themselves have greatly affect clot structure and fibrinolysis. Observations of platelet-rich plasma clots show that fibrin fibers originate from regions with dense platelet aggregates. The fibers adjacent to the platelets aggregates are both thinner and denser that those without the presence of platelets. Platelet-rich plasma clots also show a marked resistance to fibrinolysis mainly due to a large reduction of tissue-type plasminogen activator (tPA) binding velocity and the lysis speed of platelet-rich as compared to platelet-poor areas, in addition to the presence of plasminogen activator inhibitors. In these areas fibrinolysis appears heterogeneous, proceeding through meandering channels and leaving platelet-rich areas unlyzed. Addition of a pharmacological concentration of an antibody blocking platelet aggregation, abciximab, before the initiation of clotting, results in a large reduction of the average surface of platelet-rich areas. As a consequence, the tPA binding front velocity and the lysis front velocity of platelet-rich areas recover to values similar of platelet-poor zones leading to a significant acceleration of the overall fibrinolysis process. Abciximab facilitates the rate and the extent of fibrinolysis by promoting the accessibility of fibrin in platelet-rich areas to tPA, leading to similar fibrinolysis rates of both platelet-poor and platelet-rich areas.

In case of major blood loss or important consumption, for example during cardiopulmonary bypass, fibrinogen is the first coagulation factor to reach critical values even if a threshold level is still debated (now established at circa 100 mg/dl but even higher levels have been associated with increased risk of bleeding). It has been observed that in presence of reduced platelet count and thrombin generation (e.g. after a cardiopulmonary bypass) fibrinogen supplementation could strengthen the clot. A certain amount of data on fibrinogen replacement is available from studies in trauma-induced coagulopathy where haemodilution, hyperfibrinolysis, acidosis and hypothermia all depleted fibrinogen availability and consequently impair coagulation process. Nevertheless, there is a lack of high-quality randomized controlled trials assessing the efficacy and the safety of fibrinogen concentrate supplementation in perioperative setting of major surgery or trauma. Scientific evidence produced so far could suggest an indication of benefit of the fibrinogen concentrate usage in many clinical settings but in the meantime raises a number of issues on the quality of the studies that bring to such a conclusion.

In conclusion, both fibrinogen and platelets are needed to establish an efficient hemostasis. But clinical and experimental evidences collected so far show that relatively low levels of platelets are required to initiate coagulation and fibrin polymerization to achieve an acceptable clot strength whereas fibrinogen concentration seems to become critical early during hemorrhage. A wall with a lot of cement and a few bricks could resist to the environmental adversities but a wall with low cement even if bricks are present in right number will fall down very quickly.

Bibliography

1. Wolberg AS. Plasma and cellular contributions to fibrin network formation, structure and stability. Haemophilia 2010; 16: 7-12.

2. Fries D and Martini WZ. Role of fibrinogen in trauma-induced coagulopathy. Brit J Anesth 2010; 105: 116-21.

3. Standeven KF, Ariens RAS, Grant PJ. The molecular physiology and pathology of fibrin structure/function. Blood Rev 2005; 19: 275-88.

4. Mosesson MW. Fibrinogen and fibrin structure and functions. J Thromb Haemost 2005; 3: 1894-1904.

5. Weisel JW. Structure of fibrin: impact on clot stability. J Thromb Haemost 2007; 5: 116-124.

6. Kozek-Langenecker S, Sorensen B, Hess JR, Spahn DR. Clinical effectiveness of fresh frozen plasma compared with fibrinogen concentrate: a systematic review. Crit Care 2011; 15: R239.

7. Stanworth SJ, Hunt BJ. The desperate need for good-quality clinical trials to evaluate the optimal source and dose of fibrinogen in managing bleeding. Crit Care 2011; 15: 1006.

8. Laurens N, Koolwijk P, de Maat MP. Fibrin structure and wound healing. J Thromb Haemost 2006; 4: 932-9.

9. Lang T, Johanning K, Metzler H, Piepenbrock, Solomon C, Rahe-Meyer N, Tanaka KA. The effects of fibrinogen levels on thromboelastometric variables in the presence of thrombocytopenia. Anesth Analg 2009; 108: 751-8.

TOWARDS A UNIVERSAL DEFINITION OF PERIOPERATIVE BLEEDING

IN CARDIAC SURGERYMarco Ranucci, MD, FESCIRCCS Policlinico San Donato

Perioperative bleeding in cardiac surgery is an important issue. For a number of reasons, perioperative bleeding may be considered as a real outcome measurement. Patients who experience an important bleeding are of course more prone to receive packed red cells, fresh frozen plasma, and platelets. Massive transfusions have been widely recognized as determinants of a number of bad outcomes in cardiac surgery, including mortality.

Moreover, many prohemostatic treatments have been investigated for efficacy in the cardiac surgery setting. This includes aprotinin, tranexamic acid, EACA, desmopressin, fibrinogen, prothrombin complexes, rFVIIa, FXIII, and others. On the other side, the effects of preoperative use of anticoagulants and anti-platelet agents have been analyzed in terms of postoperative bleeding in many RCTs.

The great majority of the outcome endpoints in cardiac surgery have been standardized for definition: this includes mortality (30-days); major morbidity (one of the following: prolonged mechanical ventilation, stroke, acute renal failure, deep wound infection, reoperation); acute renal failure (RIFLE or AKIN criteria)…

Major or minor bleeding have been defined in the setting of patients receiving anti-platelet agents or anticoagulants, according to the TIMI criteria. This, however, does not apply to cardiac surgery patients.

As a result of this situation, it is presently difficult to assess bleeding as an outcome measurement in cardiac surgery, and the many existing RCTs addressing this did use different definitions, making impossible a comparison of the results.

Perioperative bleeding has been defined based on

1. Intraoperative blood loss (time to sterna closure; surgical swabs weight, autologous blood processed in cell-saver)

2. Postoperative chest drain blood volume (at different times, ranging from 6 to 24 hours)

3. Hemoglobin changes

4. Need for blood products

5. Need for surgical re-exploration

6. Need for “extreme” treatments (rFVIIa)

The International Initiative on Haemostasis Management in Cardiac Surgery (IIHMCS) has undertaken a process aimed to develop the concept of Universal Definition of Perioperative Bleeding (UDPB) in cardiac surgery. This process is presently endorsed by theEuropean Association of Cardiothoracic Anaesthesiologists (EACTAthe American Association for Thoracic Surgery (AATS), the European

Association of Cardiothoracic Surgeons (EACTS) the Society of Thoracic Surgeons (STS), the Society for the Advancement of Blood Management (SABM) and the International International Society on Thrombosis & Haemostasis Scientific and Standardization Committee (ISTH-SSC).

Bleeding associated with anti-platelet agents: the correct timing for stopping thienopyridines

Umberto Di Dedda, MDIRCCS Policlinico San DonatoMilan (Italy)

Acquired platelet dysfunction is a common report in the cardiac patient. Anti-platelet agents are a large-use therapy in cardiologic procedures with a good efficacy but, in terms of safety, they represent a big challenge for clinicians in the cardiac surgery setting.

The patient taking anti-platelet agents and undergoing a cardiac operation has an increased post operative bleeding risk and a higher platelet transfusion rate.

Therefore, investigation of platelet function preoperatively can be useful for predicting post-operative bleeding risk, and to design proper therapeutic strategies.

The therapy with thienopyridines may achieve a very wide range of responses, from the complete platelet pool disaggregation to a poor response to the agent, depending on the individual genetic patterns of drug metabolism. Even the discontinuation effect is not completely predictable.

Although we have recommendations on the safe timing for stopping the therapy before cardiac surgery, there is no consensus on the system to be used for the platelet function assessment, on the definition of poor response to the drug, and on the course of action.

In the clinical practice, the correct time for stopping thienopyridines safely before cardiac surgery is still an issue under investigation.

Multiple electrode platelet aggregation (MEA) is a simple and fast point of care test to assess platelet function in patients in which a residual drug activity is suspected.

We present preliminary results of a series of 340 consecutive patients receiving thienopyridines in which we tested platelet function preoperatively with the Multiplate analyzer (Verum Diagnostica GmbH, Munich, Germany), trying to establish

1. The different levels of platelet dysfunction between patients under therapy with the three thienopyridines (ticlopidine, clopidogrel, and prasugrel), measured as area under the curve (AUC) on the adenosine diphosphate (ADP) test

2. How long does it take to restore a functional platelet pool, and whether this depends on the type of anti-platelet agent

3. What are the individual factors playing a role on the recovery time.

Post-cardiotomy ECMO in infants: limits, indications, outcomes

C. Carlucci (Milan)

Extracorporeal membranous oxygenation (ECMO) is an established treatment of pediatric patients with severe yet amenable lung or heart failure. It’s a prolonged more complex extracorporeal cardiopulmonary bypass.

Although initially designed for respiratory failure, venoarterial extracorporeal membrane oxygenation has become a mainstay of therapy in the treatment of patients with congenital heart disease, providing preoperative and postoperative support for infants with temporary impairment of myocardial function.

This kind of support is now essential for critical pediatric patients in a number of clinical situations, including end-stage cardiac failure, acute heart failure, acute respiratory failure, and cardiopulmonary resuscitation.

Infact cardiac extra-corporeal life support is used more frequently and more successful in the current era of complex and high-risk pediatric heart surgery.

Furthermore neonatal cardiac extra-corporeal support is a technically challenging therapy that is applied in a range of contexts including: post-operative low cardiac output syndrome, cardiac arrest, high-risk interventional catheterisation or as a bridge to recovery from dysrhythmia and myocarditis.

The outcome for neonates with complex heart disease has improved in the last decade, thanks to advances in surgery and intensive care; even survival in the subset that require extra-corporeal support is equally increased.

From the technical point of view it follows the same principle as the extracorporeal circulation during the by-pass surgery, but it is adapted to the long-term use.

In the year 1976, Bartlett presented the first group of neonates treated by the ECMO. The ECMO machine continuously pumps blood from the patient through a membrane oxygenator that imitates the gas exchange process of the lungs. (1)

There are several forms of ECMO, the two most common of which are veno-arterial (VA) and veno-venous (VV). In both modalities, blood drained from the venous system is oxygenated outside of the body. In VA ECMO, this blood is returned to the arterial system and in VV ECMO the blood is returned to the venous system.

In VV ECMO, no cardiac support is provided.VV ECMO can provide sufficient oxygenation for several weeks, allowing diseased lungs to heal while the potential additional injury of aggressive mechanical ventilation is avoided.

Indications for ECMO support: low cardiac output resulting from right, left, and biventricular failure following repair of congenital heart defect; pulmonary vasoreactive crisis following repair of congenital heart defect; as a bridge to cardiac surgery in patients with serious end-organ damage resulting from profound low cardiac output related to congenital heart disease; as a bridge to cardiac transplant ; as a bridge to recovery in temporary cardiomyopathy secondary to renal failure, myocarditis, and burns. (2-3)

These techniques of VA ECMO have evolved and improved over the last two decades, allowing expanded application of this life saving support.

Evaluation of a pediatric patient for ECMO support is largely based on an assessment of the patient's condition and the institutional experience with pediatric ECMO. Therefore, there are no clear indications for ECMO use after pediatric cardiac surgery. (4)

However, due to the high technical demands, cost, and risk of complications, ECMO is usually only considered as a last resort therapy.

In the classic use of neonatal ECMO, the typical ventilator settings are FiO2 of 0.30, PIP of 15-25 cm H2O, a positive end-expiratory pressure (PEEP) of 3-5 cm H2O, and intermittent mechanical ventilation (IMV) of 10-20 breaths per minute. Systemic perfusion and intravascular volume should be maintained. Volume status can be assessed clinically by urine output and physical signs of perfusion and by measuring the central venous pressure and the mean arterial blood pressure. Native cardiac output can be enhanced with inotropic agents. An echocardiogram should be performed to check congenital heart function or defects that may require immediate intervention other than ECMO. (5)

Central nervous system complications are the most serious and are primarily related to the degree of hypoxia and acidosis. About the kidney point of view, oliguria and acute tubular necrosis are associated with capillary leak and intravascular volume depletio, because frequently ECMO triggers an acute inflammatorylike reaction. The diuretic phase, which usually begins within 48 hours, often is one of the earliest signs of recovery. When renal failure does not improve, hemofiltration or hemodialysis filters may be added to the circuit.(6)

To optimize oxygen delivery, the patient's hemoglobin should be support using packed red blood cells (pRBCs). As a result of platelet consumption during ECMO, platelet transfusions are requie. Many different coagulation tests need to be done to avoid bleeding complications.

Strict aseptic precautions are required. The presence of infection is monitored by obtaining cultures from the circuit at least once per day..

Patients on ECMO require close monitoring of fluids and electrolytes. The high-energy requirements should be met using hyperalimentation techniques. The patient's weight increases in the first 1-3 days on ECMO because of fluid retention.(7)

Clots in the circuit are the most common mechanical complication. Major clots can cause oxygenator failure, consumption coagulopathy, and pulmonary or systemic embolic events. Air in the circuit can range from a few bubbles to a complete venous air lock. This air can originate in the dislodgement of the venous cannula, a small tear in the membrane, or high partial pressure of oxygen in the blood.(8)

Even hemolysis and consumption coagulopathy may occur. Haemorrhage at the surgical site, cannula site, or into the site of a previous invasive procedure is a frequent complication. Decreases in platelet count occur because of decreased production, increased consumption, sequestration, or dilution.

Conclusion

Further research is required in order to determine the optimal methods for pediatric patient selection and to establish important predictors of outcome including the long term neurological development of survivors.

However, ECLS plays a valuable role in children with low cardiac output state following cardiac surgery.

Today ECMO support can be offered intraoperatively to any children after palliative or corrective surgery for congenital heart disease with potentially reversible pulmonary, cardiac or cardiopulmonary failure.

In the majority of patients who cannot survive late after weaning from ECMO support, significant myocardial dysfunction can persist or pulmonary hypertensive events can develop.

Nevertheless, today exists an acceptable proportion of patients who successfully are weaned from ECMO and ultimately survives to leave the hospital.

References

1. Bartlett RH, Gazzaniga AB, Jefferies MR, Haiduc NJ, Fong SW. Extracorporeal membrane oxygenaction (ECMO) cardiopulmonary support in infancy. Trans Am Soc Artif Intern Organs 1976;22:80-93.

2. Van Litsenburg R, de Moos N, Edgell D, Gruenwald C, Bohn DJ, Parshuram CS. Resource use and health outcomes pf paediatric extracorporeal membrane oxygenation. Arch Dis Child Fetal Neonatal Ed 2005;90: F176-7.

3. Primožič J, Kalan G, Grosek Š , Vidmar I, Lazar I, Kosin M, et al, editors. Zunajtelesna membranska oksigenacija (ZTMO) pri otrocih 12. letne izkušnje. Zdrav Vest 2006;75:61-70.

4. Ivan Vidmar, Janez Primožić, Gorazd Kalan, Š tefan Grosek. Extracorporeal membranous oxygenation (ECMO) in neonates and children experiences of a multidisciplinary paediatric intensive care unit. SIGNA VITAE 2008; 3 Suppl 1: S 17-21.

5. Brown KL, Goldman AP. Early Hum. Neonatal extra-corporeal life support: indications and limitations. Dev 2008, Mar; 84(3):143-8.

6. Itoh H, Ichiba S, Ujike Y, Kasahara S, Arai S, Sano S. Extracorporeal membrane oxygenation following pediatric cardiac surgery: development and outcomes from a single center experience. Perfusion 2012 Jan 16.

7. Aharon AS, Drinkwater DC Jr, Churchwell KB, Quisling SV, Reddy VS, Taylor M, Hix S, Christian KG, Pietsch JB, Deshpande JK, Kambam J, Graham TP, Chang PA. Extracorporeal membrane oxygenation in children after repair of congenital cardiac lesions.. Ann Thorac Surg 2001 Dec :72(6):2095:101; Discussion 2101-2.

8. Ranucci M, Ballotta A, Kandil H, Isgrò G, Carlucci C, Baryshnikova E, Pistuddi V; the Surgical and Clinical Outcome Research Group. Bivalirudin-based versus conventional heparin anticoagulation for postcardiotomy extracorporeal membrane oxygenation. Crit Care 2001 Nov 20;15 (6):R 275.

Anticoagulation protocols in ECMO: changing the paradigm?

A. Ballotta (Milan)Extracorporeal membrane oxygenation (ECMO) offers temporary heamodynamic support for those with refractory cardiogenic shock after cardiac surgery. Anticoagulation for extracorporeal life support (ECLS) including ECMO is routinely achieved using heparin which can be harmful in patients suspected of having heparin-induced thrombocytopenia. Unfractioned heparin remains the gold standard anticoagulant used in ECMO but its use is not without problems. Heparin requires the presence of antithrombin III and certain patients may be relatively ATIII deficient resulting in heparin resistance. Some patients develop antibodies to platelet factor four that can lead to heparin-induced thrombocytopenia (HIT) and subsequent thrombosis and/or bleeding. The pharmacokinetics of unfractioned heparin are unpredictable and even at apparently moderate levels of anticoagulation, some patients will have bleeding complications.

Heparin-induced thrombocytopenia in ECMO patients is quite common with reported rate of 10 to 15 % and is, of course, a dramatic complication of this procedure.

In this setting some groups experienced argatroban as alternative to heparin for systemic anticoagulation while on extracorporeal life support (ECLS).

Cornell and co. described a case series in which argatroban, a direct thrombin inhibitor was used to achieve systemic anticoagulation as an alternative to heparin during ECLS patients suspected to have HIT. They concluded that heparin remains the so called “gold standard” for anticoagulation in the setting of extracorporeal life support although argatroban could be a reasonable alternative when heparin is contraindicated.

Bivalirudin si a recombinant variant of hirudin, a natural direct thrombin inhibitor; bivalirudin inhibits both bound and unbound thrombin, is excreted by kidneys while argatroban is metabolized by the liver into inactive non toxic metabolites and is excreted through the feces.

A retrospective study recently published in Critical Care 2011 by Ranucci and co. compared the conventional heparin based anticoagulation protocol with a bivalirudin based , heparin free protocol in the setting of postcardiotomy ECMO.

Endpoints of the study have been blood loss, blood product use and costs during ECMO procedure. Patients in the bivalirudin group had significant longer activated clotting times, activated partial thromboplastin times and reaction times at thromboelastography. The platelet count and antithrombin activity were not significantly different, but in the heparin group a significantly higher amount of platelet concentrates, fresh frozen plasma, and purified antithrombin were administered. Blood loss was significantly lower in the bivalirudin group and the cost of ECMO was significantly lower in the subgroup of pediatric patients treated with bivalirudin: no difference have been shown in terms of thromboembolic complications.

So the experience by Ranucci and co. suggests that bivalirudin can be safely used in a heparin-free protocol for anticoagulation in postoperative ECMO patients. The limited size of study population, the differences in the ECMO systems utilized in this study do not allow to claim a superiority of one treatment versus the other but can certaintly support bivalirudin as a reliable alternative to heparin in the setting of ECMO in terms of safety and efficacy.

Bibliography

1. Po-Shun H, Jia-Lin C, Guo-Jieng H and co.: Extracorporeal oxygenation for refractory cardiogenic shock after cardiac surgery: predictors of early mortality and outcome from 51 adult patients. Eur J of Cardiothorac Surg 37(2010):328-33.

2. Cornell T, Wyrick P, Fleming G and co.: A case series describing the use of argatroban in patients on extracorporeal circulation. ASAIO Journal 2007;53:460-63.

3. Ranucci M, Ballotta A, Kandl H and co.: Bivalirudin based versus conventional heparin anticoagulation for postcardiotomy extracorporeal membrane oxygenation. Critical Care 2011, 15:R275.

MODIFIABLE AND NON-MODIFIABLE RISK FACTORS FOR ACUTE RENAL FAILURE IN

CARDIAC SURGERYMarco Ranucci, MD, FESCIRCCS Policlinico San Donato

Morbidity and mortality after cardiac surgery are continuously explored for definition of their risk factors. In many cases, this approach produced mortality risk scores (EuroSCORE, STS-Prom, ACEF, Parsonnet, and others) and specific morbidity risk scores stroke; acute renal failure ARF).

After cardiac surgery, renal function impairment is common, and acute kidney injury (AKI) has an incidence that may reach 50% according to some definitions [1]. Early mortality rate in patients with AKI ranges around 5% but climbs up to 50% when a renal replacement therapy is required [2-4]. Various factors related to the conduction of cardiopulmonary bypass (CPB) have been advocated as possible determinants of AKI. They include CPB duration [2,5,6] a low perfusion pressure [7], low pump flow [7,8], severe hemodilution [8-11], and low oxygen delivery [8].

In 2005, the Cleveland Clinic produced a risk score for ARF in cardiac surgery. It includes the following risk factors:

Female gender 1 point

Congestive heart failure 1 point

LVEF < 0.35 1 point

COPD 1 point

Diabetes 1 point

Redo surgery 1 point

Valve surgery 1 point

Preoperative IABP 2 points

Emergency 2 points

CABG+valve 2 points

Serum creatinine 1.2 – 2 mg/dL 2 points

Serum creatinine ≥ 2.1 mg/dL 5 points

This score was validated with good accuracy in a subsequent series of 15,000 patients:

0

7,5

15,0

22,5

30,0

0 to 2 3 to 5 6 to 8 9 to 13Development cohortValidation cohort

However, the most important value of a risk score is certainly, more than predicting the rate of events, reducing the risk of the events, by acting on the identified predictors. Unfortunately, the risk factors included in the Cleveland Clinic model belong to the category of the non-modifiable risk factors, leaving little or no space for intervention.

It is probably better, on a clinical ground, to concentrate more on the modifiable risk factors, which will be treated in this presentation. They include:

1. Timing of preoperative angiography2. Perfusion pressure3. Perfusion flow4. Hematocrit on CPB5. Oxygen delivery on CPB6. Low cardiac output7. Use of inotropic drugs

References

1. Dasta JF, Kane-Gill SL, Durtschi AJ, Pathak DS, Kellum JA: Costs and outcomes of acute kidney injury (AKI) following cardiac surgery. Nephrol Dial Transplant 2008; 23: 1970-1974.

2. Mangano CM, Diamondstone LS, Ramsay JG, Aggarwal A, Herskowitz A, Mangano DT: Renal dysfunction after myocardial revascularization: risk factors, adverse outcomes, and hospital resources utilization. Ann Intern Med 1998; 128: 194-203.

3. Provenchere S, Plantefeve G, Hufnagel G, Vicaut E, De Vaumas C, Lecharny JB, Depoix JP, Vrtovsnik F, Desmonts JM, Philip I: Renal dysfunction after cardiac surgery with normothermic cardiopulmonary bypass: incidence, risk factors, and effect on clinical outcome. Anesth Analg 2003; 96: 1258-1264.

4. Chertow GM, Lazarus JM, Christiansen CL, Cook EF, Hammermeister KE, Grover F, Daley J: Preoperative renal risk stratification. Circulation 1997; 95: 878-884.

5. Llopart T, Lombardi R, Forselledo M, Andrade R: Acute renal failure in open heart surgery. Ren Fail 1997; 19: 319-323.

6. Wijeysundera DN, Karkouti K, Dupuis J-Y, Rao V, Chan CT, Granton JT, Scott Beattie W: Derivation and validation of a simplified predictive index for renal replacement therapy after cardiac surgery. JAMA 2007; 297: 1801-1809.

7. Fischer UM, Weissenberger WK, Warters RD, Geissler HJ, Allen SJ, Mehlhorn U: Impact of cardiopulmonary bypass management on postcardiac surgery renal function. Perfusion 2002; 7: 401-406.

8. Ranucci M, Romitti F, Isgrò G, Cotza M, Brozzi S, Boncilli A, Ditta A: Oxygen delivery during cardiopulmonary bypass and acute renal failure after coronary operations. Ann Thorac Surg 2005; 80: 2213-2220.

The goal-directed perfusion conceptFilip De Somer, Ph.D.University Hospital GentBelgium

Cardiac surgery with cardiopulmonary bypass will induce some degree of systemic inflammatory response (SIRS) post operatively. This inflammatory reaction can finally lead to organ dysfunction and failure. As such it is important to recognize signs of SIRS early and to correlate them with morbidity and mortality.

As in SIRS post cardiac surgery, host defense response plays a pivotal role in the development of sepsis and for this reason major efforts were undertaken to define uniform criteria. The first definitions were published in 1992 and formed the basis of many clinical sepsis trials. These definitions were mainly based on the concept of the systemic inflammatory response syndrome (SIRS) but turned out to miss specificity and clinical utility. In order to overcome these shortcomings a new concept, build on the definitions of the 1992 conference, was published in 2001 by the International Sepsis Definitions Conference. In this publication the authors propose a new concept based on predisposition (P), infection/or insult type (I), response (R) and organ dysfunction (O) (PIRO). Although PIRO is a theoretical concept, it makes a lot of sense as it can help to explain why patients with a similar risk for mortality might have a completely different response to therapy caused by a difference in phenotype. Recently, the PIRO concept was validated as an accurate predictor of mortality in a patient population who admitted the hospital from the emergency department with suspected infection.

PIRO thus seems a very attractive instrument for studying host defense post cardiac surgery as it can be used in any clinical discipline.

Predisposition (P): means of profile more prone to develop morbidity post operatively. Higher morbidity and mortality is associated to some genetic polymorphisms. But also pre-existing infection, such as endocarditis or pneumonia are associated with increased morbidity post-operatively. Finally, pre-existing organ dysfunction, such as an increased creatinine concentration or a metabolic syndrome, correlate with a higher incidence of complications post CPB.

Insult (I): the insult will be influenced by the type of surgery. More complex surgery will lead in a prolonged CPB duration and ischemia time. Severe haemodilution below a haematocrit of 23% is another important insult which has been associated with an important increase in the occurrence of almost any complication not only short term but also long term.

Response (R): The response of the body to this insult can be quite divers and will be reflected by some measures of organ function such as creatinine, cytokine release, lactate accumulation

Organ (O) dysfunction: finally this primary body response can further progress into real organ dysfunction and failure. In order to make a good appreciation of the seriousness of the dysfunction good function scales should be used such as the RIFLE score for acute kidney failure.

Once more and more data are obtained using this approach, a better understanding of the pathophysiology of SIRS will be obtained. However the technique allows only

for post hoc analysis of large cohorts of patients. The more important variables should then be used in an online statistical analysis unit as proposed by Ranucci in the past. A combination of both PIRO and online analysis of perfusion quality will make it, for the first time in perfusion history, possible to develop goal directed perfusion techniques.

References

1. Ranucci M, Pavesi M, Mazza E, Bertucci C, Frigiola A, Menicanti L, et al. Risk factors for renal dysfunction after coronary surgery: the role of cardiopulmonary bypass technique. Perfusion. 1994;9(5):319-26.

2. Swaminathan M, Phillips-Bute BG, Conlon PJ, Smith PK, Newman MF, Stafford-Smith M. The association of lowest hematocrit during cardiopulmonary bypass with acute renal injury after coronary artery bypass surgery. The Annals of thoracic surgery. 2003 Sep;76(3):784-91; discussion

3. Landis RC, Arrowsmith JE, Baker RA, de Somer F, Dobkowski WB, Fisher G, et al. Consensus statement: Defining minimal criteria for reporting the systemic inflammatory response to cardiopulmonary bypass. The heart surgery forum. 2008;11(5):E316-22.

4. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med. 2003 Apr;29(4):530-8.

5. Vincent JL. Dear SIRS, I'm sorry to say that I don't like you. Crit Care Med. 1997 Feb;25(2):372-4.

6. Weiss M, Huber-Lang M, Taenzer M, Traeger K, Altherr J, Kron M, et al. Different patient case mix by applying the 2003 SCCM/ESICM/ACCP/ATS/SIS sepsis definitions instead of the 1992 ACCP/SCCM sepsis definitions in surgical patients: a retrospective observational study. BMC Med Inform Decis Mak. 2009;9:25.

7. Howell MD, Talmor D, Schuetz P, Hunziker S, Jones AE, Shapiro NI. Proof of principle: the predisposition, infection, response, organ failure sepsis staging system. Crit Care Med. Feb;39(2):322-7.

8. Onorati F, Rubino AS, Cuda A, Foti D, Sica V, Santini F, et al. Impact of endothelial activation on infective and inflammatory complications after cardiac surgery in type II diabetes mellitus. Int J Artif Organs. Jun;34(6):469-80.

9. Parolari A, Pesce LL, Pacini D, Mazzanti V, Salis S, Sciacovelli C, et al. Risk factors for perioperative acute kidney injury after adult cardiac surgery: role of perioperative management. The Annals of thoracic surgery. Feb;93(2):584-91.

10.Dinarello CA. Proinflammatory cytokines. Chest. 2000 Aug;118(2):503-8.

11.Dinarello CA, Pomerantz BJ. Proinflammatory cytokines in heart disease. Blood Purif. 2001;19(3):314-21.

12.Drabe N, Zund G, Grunenfelder J, Sprenger M, Hoerstrup SP, Bestmann L, et al. Genetic predisposition in patients undergoing cardiopulmonary bypass surgery is associated with an increase of inflammatory cytokines. Eur J Cardiothorac Surg. 2001 Sep;20(3):609-13.

13.Sanders J, Hawe E, Brull DJ, Hubbart C, Lowe GD, Rumley A, et al. Higher IL-6 levels but not IL6 -174G>C or -572G>C genotype are associated with

post-operative complication following coronary artery bypass graft (CABG) surgery. Atherosclerosis. 2009 May;204(1):196-201.

14.Grocott HP, White WD, Morris RW, Podgoreanu MV, Mathew JP, Nielsen DM, et al. Genetic polymorphisms and the risk of stroke after cardiac surgery. Stroke; a journal of cerebral circulation. 2005 Sep;36(9):1854-8.

15.Esmon CT. The interactions between inflammation and coagulation. Br J Haematol. 2005 Nov;131(4):417-30.

16.Mathew JP, Rinder CS, Howe JG, Fontes M, Crouch J, Newman MF, et al. Platelet PlA2 polymorphism enhances risk of neurocognitive decline after cardiopulmonary bypass. Multicenter Study of Perioperative Ischemia (McSPI) Research Group. The Annals of thoracic surgery. 2001 Feb;71(2):663-6.

Preoperative AT supplementation in cardiac surgery: a randomized, controlled trial

Ekaterina Baryshnikova PhD Dept of Cardiothoracic – Vascular Anesthesia and ICUIRCCS Policlinico San Donato, Milan, Italy

Antithrombin (AT) supplementation in cardiac operations with cardiopulmonary bypass (CPB) is still an open issue. It is widely recognized that low levels of AT before and during CPB are associated with a poor response to heparin, commonly defined as “heparin resistance” (HR), and the use of purified AT has been suggested as an alternative to fresh frozen plasma administration. Moreover, the AT consumption during CPB may trigger postoperative thromboembolic complications, in presence of a high thrombin generation. It has been observed that a postoperative AT activity value of less than 58% immediately at the admission in the ICU was found as an accurate cut-off value for prolonged ICU stay after cardiac operations.

The present study is a phase II randomized controlled trial on pre-CPB purified AT supplementation aimed to investigate the effects of this treatment on postoperative AT values, HR avoidance, and postoperative complications rate.

The study was approved at the local ethics committee and written informed consent was obtained from all patients. From June 2009 to April 2011 we enrolled patients undergoing heart operations with CPB at our single institution. Inclusion criteria were: male or female subject of at least 18 years of age, needing an elective heart surgery operation with CPB with baseline AT between 60% and 100%. Exclusion criteria included heart transplant operation, congenital heart operation, non-elective surgery, participation in another investigational study in the past 3 months, documented AT deficiency, history of anaphylactic reaction(s) to blood or blood components, allergies to excipients, pregnancy.

1990 patients were evaluated for screening. One thousand four hundred and seven patients did not meet the eligibility criteria, 377 patients declined to participate in the study or were not able to give consent because of their clinical condition. Two hundred and six eligible patients consented to participate in the study, 5 then resulted in screening failure and 1 patient died before intervention. Two hundred patients were randomly allocated to either treatment or control group immediately before anesthesia induction. The randomization scheme was electronically generated by an independent biostatistician and delivered to the center in sealed numbered envelops. No stratification factors were considered for the randomization process.

The investigational drug was administered as a single dose targeted to achieve a level of 120% according to the formula ATIII (IU) = (120 – actual ATIII activity) x (weight in kg) x 0.8 after anesthesia induction. Patients randomized to the control group did not received any study drug injection. AT was not to be administered postoperatively unless the investigator would decide otherwise for clinical reasons. Heparin sensitivity index (HSI, sec/IU/mL) was performed before administering the study drug, and repeated in patients of the AT group after receiving the study drug.

The primary efficacy endpoints of this study were (i) AT activity levels at the ICU admission (ii) percentage of patients with AT activity < 58% at ICU admission. AT levels were measured at the screening visit and postoperatively immediately after the ICU admission, on postoperative days 1 and 2, at the discharge from the ICU, and

after 1 month of follow-up. Secondary efficacy endpoints were: heparin resistance rate, blood loss in the first postoperative 12 hours, number of units of plasma and packed red cells needed during the ICU stay, surgical re-exploration rate due to bleeding, low cardiac output syndrome, postoperative myocardial infarction rate, adverse neurologic outcome, acute kidney injury rate, thromboembolic events rate, mechanical ventilation duration (hours), ICU stay duration (days), ICU stay longer than 7 days rate, postoperative hospital stay (days), in-hospital mortality.

All the patients who received the study drug were included in the analysis. The results of this study will be delivered in the oral presentation

References

1. Ranucci M, Isgrò G, Cazzaniga A, Soro G, Menicanti L, Frigiola A. Predictors for heparin resistance in patients undergoing coronary artery bypass grafting. Perfusion 1999; 14: 437-442.

2. Ranucci M, Isgrò G, Cazzaniga A, Ditta A, Boncilli A, Cotza M, Carboni G, Brozzi S. Different patterns of heparin resistance: therapeutic implications. Perfusion 2002; 17: 199-204.

3. Rodríguez-López JM, del Barrio E, Lozano FS, Muriel C. Does preoperative level of antithrombin III predict heparin resistance during extracorporeal circulation? Anesth Analg 2008; 107: 1444-1445.

4. Muedra V, Bonanad S, Gomez M, Villalonga V, Sanchez F, LLopis JE. Relationships between antithrombin activity, anticoagulant efficacy of heparin therapy and perioperative variables in patients undergoing cardiac surgery requiring cardiopulmonary bypass. Perfusion 2011; 26: 487-495.

5. Spiess B. treating heparin resistance with antithrombin or fresh frozen plasma. Ann Thorac Surg 2008; 85: 2153-2160.

6. Williams MR, D’Ambra AB, Beck JR, A, Spanier TB, Morales DL, Helman DN, Oz MC. randomized trial of antithrombin concentrate for treatment of heparin resistance. Ann Thorac Surg 2000; 70: 873–877.

7. Avidan MS, Levy JH, Scholz J, Delphin E, Rosseel PM, Howie MB, Gratz I, Bush CR, Skubas N, Aldea GS, Licina M, Bonfiglio LJ, Kajdasz DK, Ott E, Despotis GJ . A phase III, double-blind, placebo-controlled, multicenter study on the efficacy of recombinant human antithrombin in heparin-resistant patients scheduled to undergo cardiac surgery necessitating cardiopulmonary bypass. Anesthesiology 2005; 102: 276–284.

8. Avidan MS, Levy JH, van Aken H, Feneck RO, Latimer RD, Ott E, Martin E, Birnbaum DE, Bonfiglio LJ, Kajdasz DK, Despotis GJ. Recombinant human antithrombin III restores heparin responsiveness and decreases activation of coagulation in heparin-resistant patients during cardiopulmonary bypass. J Thorac Cardiovasc Surg 2005; 130:107–113.

9. Lemmer JH Jr, Despotis GJ. Antithrombin III concentrate to treat heparin resistance in patients undergoing cardiac surgery. J Thorac Cardiovasc Surg 2002; 123: 213–217.

10. Society of Thoracic Surgeons Blood Conservation Guideline Task Force, Ferraris VA, Brown JR, Despotis GJ, Hammon JW, Reece TB, Saha SP, Song HK, Clough ER; Society of Cardiovascular Anesthesiologists Special Task Force on Blood Transfusion, Shore-Lesserson LJ, Goodnough LT, Mazer CD, Shander A, Stafford-Smith M, Waters J; International Consortium for Evidence Based Perfusion, Baker RA, Dickinson TA, FitzGerald DJ, Likosky DS, Shann KG. 2011 Update to The Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists

Blood Conservation Clinical Practice Guidelines. Ann Thorac Surg 2011; 91: 944- 982.

11. Ranucci M, Frigiola A, Menicanti L, Ditta A, Boncilli A, Brozzi S. Postoperative antithrombin levels and outcome in cardiac operations. Crit Care Med 2005; 33: 355-360.

12. Rossi M, Ranucci M, Soro G, Schiavello R, Guarneri S. Purified antithrombin supplementation in coronary revascularization operations. Eur J Anaesth 2007; 24 (suppl 40): 71-76.

13. Garvin S, Muehlschlegel JD, Perry TE, Chen J, Liu KY, Fox AA, Collard CD, Aranki SF, Shernan SK, Body SC. Postoperative activity, but not preoperative activity, of antithrombin is associated with major adverse cardiac events after coronary artery bypass graft surgery. Anesth Analg 2010;111:862–869.

14. Koster A, Fischer T, Gruendel M, Management of patients with heparin resistance during cardiopulmonary bypass: the effect of five different anticoagulation strategies on hemostatic activation. J Cardiothorac Vasc Anesth 2003;17:171–175.

Randomized controlled trials: Still the gold standard for evidence-based medicine?

Nancy CartwrightLondon School of Economics and University of California at San Diego

There are two general reasons RCTs may not be the gold standard in particular cases. First, there may be good reason to think other methods are likely to be more reliable in answering the questions RCTs answer. Second, our questions may not in fact be the ones that RCTs answer best. This talk will catalogue a number of cases under both headings, many of which are familiar but whose full weight, taken together, is often under appreciated. Then it will focus on well-conducted large scale observational studies as an alternative and look at one example of each type.

The first problem is due to interaction. Because of interactions of the treatment with other causally relevant factors, RCTs deliver reliable results about causal effects only if these confounders are balanced in the treatment and control group. If the treatment interacts not with each confounder separately, but interacts differently with each combination of confounders, a very large number of cells needs to be distributed evenly by the randomization process. This pushes up the required size for the experimental population dramatically. Second, RCTs do not tell us about distributions, including rough shapes and variance. There are many distributions – ones that are not all that unlikely, at least in public health and public policy issues I have studied – in which the vast majority of the population would benefit from a treatment whose effect size is negative.

Non-randomized studies with propensity-score analysis: just hypothesis generators?

Georg Heinze, PhDAssoc. Prof., BiostatisticianSection for Clinical BiometricsCenter for Medical Statistics, Informatics and Intelligent SystemsMedical University of ViennaSpitalgasse 23, A-1090 Vienna, Austriae-mail: georg.heinze@meduniwien.ac.at

Randomized clinical trials are useful to estimate causal effects of treatments on an outcome of interest. In these trials, patients are randomly allocated to an experimental or a control group. In observational studies, patients are not randomly allocated to experimental or control group, and then the assessment of treatment effects may be biased by confounding. This type of bias arises as the characteristics of a patient may have influenced the decision which treatment the patient was given. As a consequence, the characteristics of patients allocated to the experimental treatment group differ from those allocated to the control group. One way to overcome this conceptual shortcoming of observational studies is the use of propensity scores to adjust for differences of the characteristics between patients with experimental and control interventions (1). The propensity score is defined as the probability that a patient received the experimental intervention conditional on pre-treatment characteristics at baseline (2). Here we review how propensity scores are estimated and how they can help in adjusting the treatment effect for baseline imbalances. We further discuss how to evaluate adequate overlap of baseline characteristics between patient groups and provide guidelines for variable selection and model building in modeling the propensity score. Methods of propensity adjustments commonly used are: matching by propensity score, covariate adjustment, stratification by quintiles of propensity scores and inverse probability-of-treatment weighting.

In the light of these recent advances in propensity methodology, one may be seduced to conclude that observational studies analysed by propensity methods can replace randomized clinical trials. However, there remain some concerns with this type of analyses.

First, propensity score analysis assumes that all confounders are known, since bias due to unmeasured confounding cannot be corrected for. The assumption of no unmeasured confounding is rarely met in practice, but may be approximately fulfilled if the investigators have access to a rich set of potential confounding variables. By contrast, conclusions from randomized clinical trials do not suffer from confounding bias, as the patients are randomly allocated to experimental or control treatment. Here, the treatment allocation is by design expected to be independent from any characteristics of the patients.

Second, observational studies often provide information only at the level of the treatment actually received, while randomized studies are usually analysed by the ‚intention-to-treat‘ principle. Therefore, the type of conclusion is fundamentally different. While effect estimators based on the received treatment information (‚as-treated‘ estimators), even if appropriately adjusted for confounders, provide a summary of the biological effect of an intervention under optimal conditions, an

‚intention-to-treat‘ analysis estimates the causal effect of the intention to apply the experimental treatment. The biological effect usually overestimates the causal effect of the intention to treat. Some empirical meta-analysis-type investigations comparing randomized trials and observational studies on the same topic have revealed overestimation of effects by observational studies analysed using propensity score techniques compared to randomized trials (3, 4).

Many publications have dealt with methodological aspects of propensity score modeling. While the type of modeling may have some impact on the results, issues of proper study design, and the availability of all relevant confounders could be of greater importance. Some investigations using simulated data revealed that propensity score analyses provide only little or no improvement over conventional multivariable regression adjustment of confounders (5).

In contrast to randomized clinical trials, observational studies often suffer from many other shortcomings, such as selection bias or information bias. On top of it, publication bias may contribute to the overestimation of treatment effects from observational studieds. To minimize these problems and to improve the reporting of observational studies, experts have suggested to follow the STROBE recommendations when designing, analysing or reporting observational studies (6).

Randomized trials have been criticized for being restricted to a highly selected patient population. Thus, their generalizability to a more general target population may be questionable. In such cases, results found in randomized trials could be validated by observational studies.

In summary, properly conducted observational studies analysed by propensity score approaches may enhance knowledge about treatment effects in the following cases:

- if results from randomized trials are not (yet) available

- if ethical issues make randomized trials impossible

- to validate results from randomized trials in clinical routine

References

1. Heinze, G. and Jüni, P. (2011). An overview of the objectives of and the approaches to propensity score analyses. European Heart Journal 32, 1704-1708.

2. Rosenbaum, P. R. and Rubin, D. B. (1983). The central role of the propensity score in observational studies for causal effects. Biometrika 70, 41–55.

3. MacLehose, R. R., Reeves, B. C., Harvey, I. M., Sheldon, T. A., Russell, I.T. and Black, A. M. (2000). A systematic review of comparisons of effect sizes derived from randomised and nonrandomised studies. Health Technol Assess 4(34), 1-154.

4. Ioannidis, J.P., Haidich, A. B., Pappa, M., Pantazis, N., Kokori, S. I., Tektonidou, M. G., Contopoulos-Ioannidis, D. G and Lau, J. (2001). Comparison of evidence of treatment effects in randomized and nonrandomized studies. JAMA 286, 821-30.

5. Glynn, R. J., Schneeweiss, S. and Stürmer, T. (2006). Indications for propensity scores and review of their use in pharmacoepidemiology. Basic Clin Pharmacol Toxicol 98, 253–259.

6. von Elm, E., Altman, D. G., Egger, M., Pocock, S. J., Gotzsche, P. C., Vandenbroucke, J. P. for the STROBE initiative (2008). The Strenghtening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Journal of Clinical Epidemiology 61, 344-349.

Pragmatic trials: the real guide for clinical decision making?

Sue Patterson, Rohan Borschmann, James Scott and Tim Weaver.

In the swampy lowland, messy confusing problems defy technical solution (Schon, 1987:28).

That high quality evidence is the appropriate foundation for health care is recognized internationally. The World Health Organization considers research as an essential component of robust health systems and has called for high quality evidence to be accessible by policy makers, commissioners and practitioners who should apply it to health care decision making (WHO, 2004). Whilst the nexus of research, policy and practice is anything but linear, “What is the evidence?” has become a catch cry; Archie Cochrane’s view that evidence from trials was ”key to a rational health service” (Cochrane, 1972), accepted prima facie as ‘good’, has become normative. The traditional tightly controlled model, criticised by some because findings were insufficiently generalisable to routine clinical practice (ref), has been adapted pragmatically to enable evaluation of the effectiveness of diverse interventions. It has been authoritatively argued that, if the finding of a pragmatic trial “is positive, it [the intervention] really works and you can implement the treatment just about everywhere” (Sackett et al, undated, emphasis in original).

However this position does not receive universal support – some commentators argue that the pragmatic trial is no panacea, offering only conditional support and others question the relevance and appropriateness of applying the method to health care decision making. In this paper, we address the question ‘pragmatic trials: the real guide for clinical decision making?’ We proceed by outlining the trial method and presenting cases for and against before weighing the evidence. For the purpose of the argument, we assume ‘real guide’ to mean the default position or overriding influence on decision making.

Introduced to medicine to test streptomycin in the treatment of tuberculosis in the 1940’s, the RCT is an experiment designed to test a hypothesized causal relationship. In prototypical form, the method involves division of an experimental population, believed to represent a target population, by some random process into two exhaustive and mutually-exclusive subsets: the experimental and control groups. The experimental group receives a standardized intervention and the control group nothing or a placebo within neutral and equivalent environments. Random allocation is assumed to preclude systematic difference between groups (except in receipt of intervention) and the control group separates out treatment effects from any other extraneous influences, evidencing, it is argued, cause (intervention) and effect (measure of change) for trial participants.

The trial of 2012, however, is multifarious, applied in diverse circumstances to test a range of health care interventions. Whilst arguments for dimensional rather than categorical description are compelling, a fundamental distinction is drawn between trials designed to test efficacy – whether an intervention can work – and those concerned with effectiveness – whether an intervention “does more good than harm in the circumstances of usual care” (Cochrane, 1972). Following Schwarz and Lellouch (1967), who distinguished attitudes toward the purpose of trials of which governed design, the former are commonly referred to as ‘explanatory’ and the latter as ‘pragmatic’. Explanatory trials are characterized by high internal validity, a function

of tight control on sample, intervention and environment and highly specified outcome. In contrast, in pragmatic trials, employed where investigators are concerned with practical outcomes, sample, intervention and environment are standardized to approximate the conditions within which findings are likely to be applied are replicated as closely as possible (Wells, 1999). Whether explanatory or pragmatic, as set out by Bradford Hill, a precisely framed question is crucial to the integrity of the study.

The case for pragmatic trials as the real guide for clinical decision making is grounded in the widespread endorsement of tenets of evidence based medicine (EBM). This is underwritten by the view that epidemiological principles, particularly the use of statistically based inference, provides a basic science for clinical medicine and that application of robust ‘scientific’ evidence to the care of individuals will optimize care (Sackett et al., 1985). Any of multiple research methods could be used to generate scientific ‘evidence’ but EBM qualifies this further, requiring use of ‘best’ evidence.

Reflecting the “modern, positivist, empiricist tradition within which western medicine evolved” (Little, 1995:31), ‘best’ evidence is that generated by methods which optimize capacity to ‘objectively’ and accurately estimate the effects of the intervention being evaluated. Minimisation of potential bias, and/or confounding which potentially systematically distort the ‘truth’ regarding an intervention’s effect are key to this. Thus, although the method does not “underwrite” claims of ‘truth’ beyond trial participants (Cartwright, 2007), the RCT is accorded “special scientific weight” (Worrall, 2007) and is widely endorsed as the ’gold standard’ for enabling conclusions regarding the potential for an intervention to achieve improved health outcomes. Because the findings pragmatic trials are assumed to be generalisable to the complex clinical world, they are regarded as the real guide for clinical decision making and clinicians are urged to frame their clinical questions in terms pertinent to trial evidence.

The case against the pragmatic trial as the real guide for clinical decision making is multi-layered, reflecting the perspectives of diverse commentators. Interlinked challenges are philosophical, political, scientific, and practical. Some are generic in that they are made in respect of the evidence based approach broadly. EBM is described as dogmatic in that it cannot be judged by its own standards and persuades on faith alone. What Wilson (2000) describes as the “myth of objectivity”, which accompanies the notion of findings as fact, obscures the multiple social, political and professional influences on production and dissemination of ‘evidence’ and the subjectivity that “inescapably enters all forms of human inquiry” (Goldenberg, 2006). Questions are also asked about how pragmatic trials can be the real guide to decision making when conflicting or equivocal evidence is generated by trials. Moreover, it may be unethical or not practical to implement trials to answer some clinical questions circumstances. For example, it may be unethical to withhold or alter treatment for one group of patients. In these circumstances observational evidence has to be used and accepted as ‘good enough’.

The key argument in relation to the question at hand, however, seems to be that the findings of randomized controlled trials, however pragmatic, inadequately represent the real complex world in which clinicians care for individual patients. In attempting to iron out variation, vital individual difference is denied. In artificially isolating health problems, intervention and outcome independent of human, social context, the method is reductionist. The integrity of the method is reliant on the notion that the

whole is no more than the sum of its parts and predictability of action and reaction. The summative findings belie the complex processes through which outcomes are generated in the interaction between trial, intervention participant and circumstance (Patterson et al., 2010; Kent & Kitsiosis; 2009) and obscure within group differences. Whilst the RCT provides “a sense of sense of order, logic and neatness” (Miles et al., 2007) that sense can be illusory and at best, the method offers an impoverished secessionist account of the association between two variables measured in arbitrary ways. When trials are so pragmatic that questions, whilst framed in the appropriate format are imprecise they risk being meaningless; when the samples are heterogeneous, determination of the characteristics of those likely to benefit is problematic; when interventions are flexibly applied and complex, active ingredients cannot be determined and when contexts are more ‘real world’, circumstances necessary to support effectiveness of the intervention, and the contribution of context to outcome, remain uncertain. In sum, the test of causality is compromised, conditional causal conditions are not clear and findings must be interpreted and applied cautiously. If the finding of a trial is positive, rather than be applicable ‘just about everywhere’ lack of clarity about active ingredients, mechanism(s) of action and contextual influences beyond the control of investigators hinders clinical application. If findings are unexpected, marginal or no effect is found, differentiating between intervention and evaluation failure (type III error) may be difficult, especially where efficacy has not previously been established and interpretation bias may be introduced. Moreover, because the RCT is limited to testing one of a “range of possible outcomes” (MRC, 2008:7), clinically important or personally valued change arising from the intervention may be missed.

Weighing the evidence:

Clinical decision making is in the real world of pragmatic practice is a complex cognitive process, necessarily informed by various forms of knowledge – experiential and propositional and practical – and the values, motivation and capacities of practitioner and patient. Pragmatic practitioners are embedded within multiple cultures shaped by myriad influences and imbued with tensions related to efficiency and performance management. Contexts constrain options and decisions must take account of the potentially competing priorities of various stakeholders. Various factors will be weighted differently dependent on circumstances. We propose that findings of pragmatic randomized controlled trial are appropriately regarded as a piece of the puzzle, informing or influencing but not governing clinical decision making. The relevance and direct transferability of trial findings are, in our view, inversely proportional to the complexity of the question to be answered, which in turn is a function of the nature of the health problem, the intervention and outcome of interest and the circumstances of health care. Where a health problem has a definable course, the outcome of interest is binary and the intervention easily replicable and adherence is non-problematic and context independent, then the pragmatic trial can be the real guide to clinical decision making, applied with due respect and regard for patient choice. However, as each component of the equation becomes less simple and causal pathways become more complicated or complex the balance shifts. The technical solutions afforded by pragmatic trials prove inadequate and clinicians generate their own evidence perhaps conducting uncontrolled experiments with an n of 1; in the real world of pragmatic practice, the skilled clinician’s wise judgment is the real guide to decision making.

References Cartwright, N. (2007). Are RCTs the gold standard? BioSocieties; 2: 11-20. London School of Economics and Political Science. DOI:10.1017/S1745855207005029.

Cochrane, A. L. (1972). Effectiveness and efficiency: Random reflections on health services. London, UK: The Nuffield Provincial Hospitals Trust.

Kent, D. & Kitsios, G. (2009) Against pragmatism: on efficacy, effectiveness and the real world. Trials 10:48 doi:10.1186/1745-6215-10-48

Godwin, M., Ruhland, L., Casson, I., MacDonald, S., Delva, D., Birtwhistle, R., Lam, M., Sequin, R. (2003) Pragmatic controlled clinical trials in primary care: the stuffle between external and internal validity BMC Medical Research Methodology, 3: 20 doi 10.1186/1471-2288-3-28.

Little, J.M. (1995). Humane Medicine. Cambridge: Cambridge University Press.

Medical Research Council (2008). Developing and evaluating complex interventions: New Guidance www.mrc.ac.uk/Utilities/Documentrecord/index.htm?d=MRC004871

Miles, A., Loughlin, M. & Polychronis, A. (2007). Medicine and evidence: knowledge and action in clinical practice. Journal of Evaluation in Clinical Practice; 13: 481-503.

Patterson, S., Kramo, K., Soteriou, T. & Crawford, M. J. (2010). The great divide: a qualitative investigation of factors influencing researcher access to potential randomised controlled trial participants in mental health settings. Journal of Mental Health. 19:532-541.

Sackett, D.L., Haynes, R.B. & Tugwell, P. (1985). Clinical Epidemiology, a basic science for clinical medicine. Boston: Little, Brown & Co.

Sackett et al, undated www.support-collaboration.org/precis.pdf -

Schön, D.A. (1987). Educating the Reflective Practitioner: Toward a new design for teaching and learning in the professions. San Francisco: Jossey-Bass.

Schwartz D, Lellouch J.(1967/2009) Explanatory and pragmatic attitudes in therapeutical trials. Journal of Clinical Epidemiology; 62(5): 499-505.

Wells, K. (1999). Treatment research at the crossroads: The scientific interface of clinical trials and effectiveness research. American Journal of Psychiatry; 156: 5-10.

World Health Organization. (2004). The Mexico statement on health research. Knowledge for better health: strengthening health systems. From the Ministerial Summit on Health Research, Mexico City, 16-20 November 2004.

Wilson, H.J. (2000). The myth of objectivity: is medicine moving towards a social constructivist medical paradigm? Family Practice; 17 (2);203-209.

Worrall, J (2007b). 'Evidence in Medicine and Evidence-Based Medicine', Philosophy Compass; 2 (6): 981-1022. doi: 10.1111/j.1747-9991.2007.00106.x.

Frailty, age and hemostatic/inflammatory responses

Dave RoystonConsultant in Cardiothoracic AnesthesiaRoyal Brompton and Harefield NHS TrustHarefield Hospital, UK

The haemostatic system is an integral part of the homeostatic processes in humans. This presentation will focus on describing the known changes in the haemostatic and inflammatory systems occurring with advancing years and discuss their possible relevance to longevity. There will also be discussion of their relevance to adverse outcomes after major cardiac surgery.

A vast amount of effort has been put forwards to reduce the incidence of occlusive vascular disease leading to myocardial infarction and stroke. This occlusive disease is arterial and mainly due to platelet activation in high shear stress environments. A common mantra is that patients should have an active life-style , try to lower or normalise there cholesterol concentrations and take aspirin. However this is questioned when recent studies and those in the oldest old (typically centenarians) are considered. A recent study in over 100,000 patients showed that the incidence of myocardial infarction and stroke could ber reduced by aspirintherapy but at the expense of an increased likelyhood of a major life threatening, usually gastrointestinal haemorrhage. A study in 724 patients followed for 10 years from a median age of 89 years showed no effect of total holesterol on cardiovascular outcome but a paradoxical protective effect of high cholesterol due to a reduced incidence of cancer and severe infections (Weverling-Rijnsburger et al Lancet 350:1119–23,1997).

These apparent paradoxes are also reflected for other aspects of the immune and haemostatic systems.

Platelet function is a critical determinant of the initial phase of haemostasis and also the propensity to thrombosis in the coronary and cerebral circulation. The skin bleeding time is a simple test of global platelet-endothelial reaction. This has been shown to shorten with advancing years. This observation is explained by an increase in platelet activation withan increased aggregation response to agonists such as ADP and serotonin Gleerup et al Eur J Clin Invest;18(5):504-6:1988 & Angiology;46(8):715-8:1995 A unifying hypothesis for this increased activation has been suggested to involve chronic oxidative injury to the phospholipid membranes of the platelet leading to reduced fluidity in the cell membrane Cesari et al Antioxid Redox Signal;8(3-4):609-19:2006 . However subjects aged >100 years show a different profile with a reduced susceptibility to peroxidation of cell membranes and a higher fluidity of the membrane compared with other age groups (Rabini et al Exp Gerontol;37(5):657-63:2002 )implying this mechanism was not present in subjects of extreme age.

There is incraesing data to show that deep venous thrombosis and venous thromboembolism ( DVT/VTE) are a significant cause of morbidity and mortality in North America and Europe. This low shear stress thrombus comprising fibrin thrombus and red cells is thought to account for 300,000 deaths per year on each continent. There is also striking evidence to show a significant increase in the incidence of thrombosis with age andespectially embolic thrombus or VTE

(Silverstein et al Arch Intern Med.158:585-593 1988).

Multiple studies have shown that the plasma concentrations of fibrinogen, factor V, factor VII, factor VIII, factor IX, factor XIII, high molecular-weight kininogen and prekallikrein increase in healthy humans in parallel with the physiological processes of aging (Mari et alExp Gerontol;43(2):66-73:2008). The intreguing question is if the increase in acute phase proteins such as fibrinogen or factor VIII is in response to a low-grade inflammatry process. There is convincing evidence that the aging process is associated with increased markers of inflammations such as IL-6 . Moreover, It has also been demonstrated in 1723 subjects aged over 71 years that activation of coagulation and inflammation, reflected by D-dimer and interleukin-6 levels respectively, is accompanied by mortality and functional decline/frailty Cohen et al Am J Med;114(3):180-7:2003 .

There is convincing evidence for not only an increase in plasma concentration of various coagulation protiens but also their activation peptides such as activated factor VII, factor X activation peptide, factor IX activation peptide, prothrombin fragments 1 + 2, thrombin–antithrombin (TAT) complex and fibrinopeptides A (FPA). Concentrations were not only higher in centenarians than in two younger control groups in the age range 18 to 50 years and 51 to 69 years respectively but also exceeded the laboratory normal range for most measures Mari et al Exp Gerontol;43(2):66-73:2008.

The fibrinolytic system provides the most complex and paradoxical but possibly the most important factors in successful ageing. Plasminogen concentrations tend to show a modest fall with ageing. and there is strong evidence for an age associated increase in plasminogen activator inhibitor 1(PAI-1). As with other proteins PAI-1 is an acute phase reactant and this association may be as a result of the low-grade inflammatory state associated with ageing. Nonetheless the interest in PAI-1 is due to not only the well documented association between a raised concentration and coronary artery disease but also because this can be lowered by environment factors such as diet (specifically Omega-3 fatty acids) and moderate exercise. An increased PAI-1 may be thought to translate to fibrinolytic shutdown It is therefore surprising that studies in centenarians show that plasma concentrations of plasmin-antiplasmin complexes and fibrin degradation products (D-dimers) are elevated to well above the laboratory normal range. This implies that the hypercoagulable state found in the elderly is balanced by a secondary hyperfibrinolysis. This somehow converts into a survival advantage. One suggestion is that the fibrinolytic process is diverted from its other activity to provide remodeling thereby preventing both invasion by neoplastic cells and increased angiogenesis.

HEMODILUTION: ALL THE EVILMarco Ranucci, MD, FESCIRCCS Policlinico San Donato

Hemodilution on CPB determines important effects on different physiologic systems. Basically, these effects include:

1. Hemodynamic changes

2. Coagulation changes

3. Oxygen availability changes

From the hemodynamic point of view, hemodilution impacts on blood viscosity, by decreasing it.

Flow: some basic definitions and relationshipsFlow: volume that crosses a plane per unit of time (ml/min)Perfusion: Flow per unit of tissue mass (ml/min*100g))Flow_velocity (cm/sec): v = velocity, Q = flow rate A = cross sectional area Ohm’s Law for fluids: Flow is driven by a pressure gradient DP = pressure gradient , R = resistance cardiac output: Q = ( MAP - MVP ) (total peripheral Resistance).(note about pressure units: 1 mm Hg = 1.36 cm H2O = 1330 dynes/cm2 ,1 Newton = 105 dynes = 0.22 lb)

The hematocrit refers to percentage of the blood volume that is made up of red blood cells.

RBC’s increase blood viscosity and thus vascular resistance

Red cells carry most of blood’s oxygen

Studies on resuscitation of patients with severe acute anemia, have demonstrated that a preserved blood viscosity is mandatory for maintain the functional capillary density, which in turn is associated with a better microcirculation and improved survival.Coagulation factors activity is reduced in conditions of hemodilution. Fibrinogen is probably the most affected coagulation factor.

Hemodilution during CPB is one of the main determinants of perioperative anemia, leading to an increased need for transfusions:

Finally, low values of HCT on CPB have been associated with a number of bad outcomes, including ARF and mortality.

Cardiopulmonary bypass and monitoring: Near-infrared spectroscopy and other cerebral monitoring

techniquesMatthias Heringlake, Hauke Paarmann, Julika SchönDepartment of Anesthesiology, University of Lübeck

Background:

Neurological complications are among the most feared unwarranted effects of cardiac surgery. And they are observed rather frequently: According to the data of the German Cardiac Surgery Quality Register (AQUA) about 1 % of patients undergoing elective or urgent first time cardiac surgery (coronary artery bypass surgery, aortic valve surgery, or both combined) suffered from a persistent neurological deficit graded Rankin II or greater in 2010. This, however, is only the tip of the iceberg; the incidence of severe neurological complications in patients undergoing more complex surgery and Re-do cases is much higher [(1)]. Beyond stroke and coma, typically referred to as type I neurological complications after cardiac surgery, type II complications like postoperative cognitive dysfunction (POCD) and delirium are increasingly recognized as frequent and also often devastating complications after cardiac surgery [(2)] .

Type I neurological complications. Embolic events are the most frequent causes of strokes in patients undergoing cardiac surgery, followed by hypoperfusion and unclassified events [(3)]. While it is obvious that the monitoring of an embolic event may sometimes be useful to initialize measures to ameliorate the consequences (to reduce the penumbra), but cannot not prevent a stroke, monitoring the adequacy of perfusion is an important aspect in the care of patients undergoing major thoracic surgery with circulatory arrest and selective cerebral perfusion [(4) ].

Type II neurological dysfunction. While the pathophysiological mechanisms leading to type II neurological complications like POCD and delirium are clearly multifactorial, evidence is ermerging that cerebral hypoperfusion plays an important role in this situation [(5) ].

Available monitoring technologies:

The available technologies for monitoring the brain during cardiac surgery and CPB may be divided into perfusion- and functional monitoring. While techniques to monitor cerebral perfusion directly during cardiac surgery (i.e. by tracers (Xenon133) or thermodilution) are not availabe for routine use, several indirect technologies to assess cerebral perfusion are commercially available: transcranial doppler, measurement of the jugular venous oxygen saturation and regional cerebral oxygen saturation (ScO2) by Near-Infrared Spectroscopy (NIRS). Monitoring of brain function can be accomplished by raw electroenecephalography (EEG), processed EEG, and sensory evoked potentials (SEP). The analysis of the raw EEG to detect subtle changes in electrical brain activity is difficult to accomplish during routine clinical care. Consequently, few data on formal associations between changes in the raw EEG and neurological outcome in patients undergoing cardiac surgery have been published.

In contrast, the use of a processed EEG (i.e. bispectral index (BIS)) for titrating anesthesia depth and the association of BIS levels with outcome has been the focus of several recent studies [(6)]. In line with data gathered in non-cardiac surgery, the most recent work analyzing BIS in the context of cardiac surgery revealed a dose dependent association between the duration of intraoperative periods with a low BIS (< 45) and long-term prognosis [(7)]. However, patients with different duration of low BIS values also differed regarding variables reflective of the severity of the surgical insult, but not regarding the anesthetic doses; supporting the concept, that low BIS values are more reflective of systemic perfusion disturbances than of “too deep” anesthesia. Various types of SEPs (visually, acoustically induced, etc.) serve as a basis to assess the neurological response to a sensory stimulus and thereby to determine not only cortical, but also subcortical functional integrity. And despite monitoring of SEPs is rather complex in clinical practice, some centers use this technology routinely during carotid surgery i.e. to assess the need of a shunt. However, when comparing different monitoring technologies to determine the accuracy of the individual systems to detect a loss of consciousness in patients undergoing awake carotid surgery, Moritz and coworkers showed that SEP were significantly less accurate in achieving this goal than cerebral oximetry or TCD [(8) ].

Monitoring the brain during CPB:

No formal recommendations (i.e guidelines) on the use and individual choice of cerebral monitoring technologies for patients undergoing cardiac surgery have been published, primarily related to the fact that – with the notable exception of the use of BIS monitoring - only few high-quality studies on the use of cerebral monitoring during cardiac surgery are available. However, a relevant number of these studies clearly support the concept that monitoring ScO2, and maintaining this variable in a normal range, reduces type II and – at least during the conditions of thoracic aortic surgery – also type I complications.

Figure 1.: A proposed algorithm for the intraoperative use of cerebral oximetry. Denault A et al. Seminars Cardiothorac Vasc Anesth 2007; 274-281

Yao and coworkers were among the first to show that low ScO2 levels in patients undergoing cardiac surgery were associated with an increased rate of POCD and neurological dysfunction [(9)]. Meanwhile these findings have been confirmed by various groups [(10),(11)], and also in patients undergoing non-cardiac surgery [(12) ] . Additionally, prospective, randomized trials in cardiac and non-cardiac surgical patients have shown that maintaining cerebral oxygen saturation in the normal range (preventing a decrease below 75% to 80% of the preoperative baseline) not only improved postoperative cognitive performance but also reduced general postoperative complications [(13)]and hospital length of stay [(12)]. A useful algorithm to maintain ScO2 is given in figure 1.

However, neurological complications in patients undergoing cardiac surgery are multifactorial, and beyond hypoperfusion and reperfusion, embolic events play an important role in mediating an adverse neurological outcomes. Consequently, despite it is not a “direct” monitor of cerebral perfusion, epiaortic ultrasound is crucial in detecting aortic atheroma and determining the need for adapting the surgical and CPB approach (i.e. by switching from On- to Off-pump surgery, or by using alternative canulation sites) to reduce the risk of embolic complications [(14)].

Additionally, with respect to the complexity of the setting, it is rather plausible, that the monitoring of only one parameter may sometimes be misleading. In contrast one may speculate that a multimodal monitoring may lead to a better understanding of the complex interplay between rapidly changing hemodynamics and body temperature, cerebral oxygen delivery and consumption, neurological function, and integrity ([(15)]). However, if such an approach does ultimately lead to improved outcomes needs to be verified in randomized controlled trials.

References:

1. Hedberg M, Boivie P, Engstrom KG: Early and delayed stroke after coronary surgery -- an analysis of risk factors and the impact on short- and long-term survival. European Journal of Cardio-thoracic Surgery 2011; 40:379–387

2. Roach G, Kanchuger M: Adverse cerebral outcomes after coronary bypass surgery. … England Journal of … 1996;

3. Likosky DS, Marrin CAS, Caplan LR, et al.: Determination of etiologic mechanisms of strokes secondary to coronary artery bypass graft surgery. Stroke 2003; 34:2830–2834

4. OLSSON C, THELIN S: Regional cerebral saturation monitoring with near-infrared spectroscopy during selective antegrade cerebral perfusion: Diagnostic performance and relationship to postoperative stroke. J. Thorac. Cardiovasc. Surg. 2006; 131:371–371

5. Murkin J: Near-infrared spectroscopy as an index of brain and tissue oxygenation. Br J Anaesth 2009;

6. Avidan M, Jacobsohn E, Glick D: Prevention of Intraoperative Awareness in a High-Risk Surgical Population — NEJM. … England Journal of … 2011;

7. Kertai MD, Pal N, Palanca BJA, et al.: Association of perioperative risk factors and cumulative duration of low bispectral index with intermediate-term mortality after cardiac surgery in the B-Unaware Trial. Anesthesiology 2010; 112:1116–1127

8. Moritz S, Kasprzak P, Arlt M, et al.: Accuracy of cerebral monitoring in detecting cerebral ischemia during carotid endarterectomy: a comparison of transcranial Doppler sonography, near-infrared spectroscopy, stump pressure, and somatosensory evoked potentials. Anesthesiology 2007; 107:563–569

9. Yao F-SF, Tseng C-CA, Ho C-YA, et al.: Cerebral oxygen desaturation is associated with early postoperative neuropsychological dysfunction in patients undergoing cardiac surgery. YJCAN 2004; 18:552–558

10. Slater JP, Guarino T, Stack J, et al.: Cerebral oxygen desaturation predicts cognitive decline and longer hospital stay after cardiac surgery. The Annals of Thoracic Surgery 2009; 87:36–44; discussion 44–5

11. Schoen J, Husemann L, Tiemeyer C, et al.: Cognitive function after sevoflurane- vs propofol-based anaesthesia for on-pump cardiac surgery: a randomized controlled trial. Br J Anaesth 2011; 106:840–850

12. Casati A, Fanelli G, Pietropaoli P, et al.: Continuous monitoring of cerebral oxygen saturation in elderly patients undergoing major abdominal surgery minimizes brain exposure to potential hypoxia. Anesth. Analg. 2005; 101:740–7, table of contents

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14. Yamaguchi A, Adachi H, Tanaka M, et al.: Efficacy of Intraoperative Epiaortic Ultrasound Scanning for Preventing Stroke after Coronary Artery Bypass Surgery. Ann Thorac Cardiovas 2009; 15:98–104

15. Fedorow C, Grocott HP: Cerebral monitoring to optimize outcomes after cardiac surgery. Curr Opin Anesthesiol 2010; 23:89–94

A Clinical and Practical Perspective of Hemoglobin, Pump Flow and Oxygen Delivery

J. Mulholland (London)

Without doubt the future of Cardiopulmonary Bypass (CPB) management will involve Goal-Directed Perfusion (GDP). The GDP concept and the importance of oxygen delivery (DO2) will have been described earlier in the Course Programme. This presentation will focus on the clinical and practical aspects of delivering of GDP with regards to the relationship between Hemoglobin, arterial pump flow and DO2.

The DO2 index is a derived variable influenced by four of the individual parameters we control during CPB. Whilst it is a modifiable parameter that can affect outcome, in order to effectively tailor DO2 throughout the course of a CPB run it is important that we understanding the impact of the individual valuables involved. To do this we need to explore the underlying oxygen delivery equation from a more clinically applicable viewpoint.

Figure 1 identifies the parameters in red that can be modified to influence DO2. The structure of the equation dictates the extent to which each parameter influences DO2. Understanding their individual impact is very important. Depending on the clinical scenario this understanding gives the Perfusionist the ability to significantly modify DO2 or merely make minor adjustments.

From a practical standpoint DO2 should be considered in terms of the ‘oxygen bound to hemoglobin’, the ‘oxygen dissolved in blood’ and the patient specific flow rate that this total oxygen is delivered.

By theoretically varying each component in isolation it is possible to quantify the impact of that parameter on oxygen delivery. This theoretical exercise is summarised below:

The Impact of Varying Hemoglobin (Hb)By keeping all other parameters constant and modifying Hemoglobin by 1g/dl the impact on the DO2 Index will be 31ml/min/m2.

The Impact of Varying Arterial Oxygen Saturations (SaO2)Modifying Arterial O2 Saturations by 1% has a 2ml/min/m2 impact on the DO2 Index. You would have to modify the SaO2 by 12% to compete with the impact of a 1g/dl increase in Hemoglobin. This is clinically impractical during artificial heart and lung support given the SaO2 routinely runs at 98% and above.

The Impact of Varying Arterial Partial Pressure of Oxygen (PaO2)The PaO2 is directly proportional to the O2 dissolved in the blood and is reflected by a constant of 0.003ml/dl/mmHg. As the value of the constant suggests this dissolved O2 does not significantly contribute to the total oxygen content of the blood (CaO2). For a typical CPB run the dissolved oxygen will only contribute between 4-6% of the overall CaO2 (given a PaO2 range between 150-225mmHg (20-30kPa)). These findings are put in perspective by the fact that you would have to modify the PaO2 by 450mmHg (60kPa) to compete with the impact of a 1g/dl increase in Hemoglobin. This is also clinically impractical during CPB.

The Impact of Varying Arterial Pump FlowIf all other parameters are stable you would have to increase the arterial pump flow by 0.5L/min to compete with the impact of a 1g/dl increase in Hemoglobin. An 0.1L/min change is arterial pump flow has a 6ml/min/m2 impact on the DO2 Index.

  Parameter Variation

Impact on DO2 Index (ml/min/

m2 )Hemoglobin (Hb) 1g/dl 31

Arterial Pump Flow 0.1L/min 6Arterial O2 Saturations (SaO2) 1% 2

Arterial Partial Pressure of O2 (PaO2) 10mmHg 1

Whilst this theoretical impact on the DO2 Index is not an ‘exact science’ it does clearly provide a league table (table 1) that demonstrates and quantifies the importance of Hb and arterial pump flow on this outcome predictive parameter. Depending on the patient either of these parameters could be seated at the top of this league table.

We must consider this information alongside the fact that modern Perfusion for our current patient population has to focus on influencing outcomes as early in the patient pathway as possible. As a cardiac team we should be focusing on strategies for optimising these parameters pre-CPB in the first instance, then modifying them during CPB if required.

The remainder of the presentation will focus on multidisciplinary pre and peri-CPB strategies for maintaining or optimising Hemoglobin. The presentation will also consider the role that maintaining adequate circulating volume and appropriate Systemic Vascular Resistance (SVR) plays in Arterial Pump Flow delivery. It may be

beneficial to re-visit strategies that have not had a significant impact on their own and incorporate them into an interrelated multifaceted approach. Numerous small contributions may become relevant and worthwhile especially given the growing evidence supporting Goal Directed Perfusion and the clinical influence of DO2.

Prayer, Mantras, & Music Can Entrain Cardiovascular Rhythms in Humans

Peter Sleight MD, University of Oxford, UK

1) Effect of rosary prayer and yoga mantras on autonomic cardiovascular rhythms: comparative study

Luciano Bernardi, Peter Sleight, Gabriele Bandinelli, Simone Cencetti, Lamberto Fattorini, Johanna Wdowczyc-Szulc, Alfonso LagiBMJ 2001;323:1446

AbstractObjective: To test whether rhythmic formulas such as the rosary and yoga mantras can synchronise and reinforce inherent cardiovascular rhythms and modify baroreflex sensitivity.Design: Comparison of effects of recitation of the Ave Maria (in Latin) or of a mantra, during spontaneous and metronome controlled breathing, on breathing rate and on spontaneous oscillations in RR interval, and on blood pressure and cerebral circulation.Setting: Florence and Pavia, Italy.Participants: 23 healthy adults.

Main outcome measures: Breathing rate, regularity of breathing, baroreflex sensitivity, frequency of cardiovascular oscillations.Results: Both prayer and mantra caused striking, powerful, and synchronous increases in existing cardiovascular rhythms when recited six times a minute. Baroreflex sensitivity also increased significantly, from 9.5 (SD 4.6) to 11.5 (4.9) ms/mm Hg, P<0.05.Conclusion: Rhythm formulas that involve breathing at six breaths per minute induce favourable psychological and possibly physiological effects

2) Cardiovascular, cerebrovascular, and respiratory changes induced by different types of music in musicians and non-musicians: the importance of silence

L Bernardi, C Porta, & P Sleight Heart 2006;92:445-452

Introduction

Music now plays an increasing role in several disparate areas. Music can reduce stress, improve athletic performance, motor function in neurologically impaired patients with stroke or parkinsonism, or milk production in cattle. Listening to music is a complex phenomenon, involving psychological, emotional, neurologic, and cardiovascular changes, with behavioural modifications of breathing. Non musicians listen using the non dominant hemisphere, while musicians (probably more attentive) use the dominant hemisphere. These responses, might be influenced by musical style (eg classical vs rock), melody, harmonic structure, rhythm and tempo, but also verbal content: for example, the brain asymmetry shown for language and melody perception has not been found in rhythm perception. Heart rate, blood pressure, or respiration have been studied, but so far, no comprehensive comparisons of autonomic, cardiovascular and respiratory changes to such a large range of music,

order of presentation or the effect of a short interpolated pause, and also the reponses related to musical training. Cardiorespiratory variables can be modified by rhythmic repetition of a prayer or a yoga mantra, or poetry recitation. We therefore investigated listening to music for similar effects.

Abstract

Objective: To assess the potential clinical use, particularly in modulating stress, of changes in the cardiovascular and respiratory systems induced by music, specifically tempo, rhythm, melodic structure, pause, individual preference, habituation, order effect of presentation, and previous musical training.

Design: Measurement of cardiovascular and respiratory variables while patients listened to music.

Setting: University research laboratory for the study of cardiorespiratory autonomic function.

Patients: 12 practising musicians and 12 age matched controls.

Interventions: After a five minute baseline, presentation in random order of six different music styles (first for a two minute, then for a four minute track), with a randomly inserted two minute pause, in either sequence.

Main outcome measures: Breathing rate, ventilation, carbon dioxide, RR interval, blood pressure, mid-cerebral artery flow velocity, and baroreflex.

Results: Ventilation, blood pressure, and heart rate increased and mid-cerebral artery flow velocity and baroreflex decreased with faster tempi and simpler rhythmic structures compared with baseline. No habituation effect was seen. The pause reduced heart rate, blood pressure, and minute ventilation, even below baseline. An order effect independent of style was evident for mid-cerebral artery flow velocity, indicating a progressive reduction with exposure to music, independent of style. Musicians had greater respiratory sensitivity to the music tempo than did non-musicians.

Previous studies suggested that meditative music decreased heart rate, blood pressure, and plasma cathecolamines. Our study confirmed these findings only partially. Slow meditative music increased RR interval but had no significant effect on respiration and blood pressure. Instead, our data showed a consistent increase in all these variables (from baseline, or from the pause) with increasing speed of music. In order to maintain a stable style of music we (and most previous researchers) selected periods of music with a relatively constant speed and rhythm (see methods). However, composers (even of techno music) always include pauses, even in the fastest rhythms, and in general alternate fast and slow tempi. Interestingly, it was precisely during this short intermission, rather than during music, that we observed the greatest evidence of relaxation, as compared to baseline or music tracks.

Conclusions: Music induces an arousal effect, predominantly related to the tempo. Slow or meditative music can induce a relaxing effect; relaxation is particularly evident during a pause. Music, especially in trained subjects, may first concentrate attention during faster rhythms, then induce relaxation during pauses or slower rhythms.

3) Dynamic Interactions Between Musical, Cardiovascular, and Cerebral Rhythms in Humans

Luciano Bernardi, MD; Cesare Porta, MD; Gaia Casucci, MD; Rossella Balsamo, MD; Nicolò F. Bernardi, MSc; Roberto Fogari, MD; Peter Sleight, MD (Circulation. 2009;119:3171-3180.)

Background: Reactions to music are considered subjective, but previous studies suggested that cardiorespiratory variables increase with faster tempo independent of individual preference. We tested whether compositions characterized by variable emphasis could produce parallel instantaneous cardiovascular/respiratory responses and whether these changes mirrored music profiles.

Methods and Results: Twenty-four young healthy subjects, 12 musicians (choristers) and 12 nonmusician control subjects, listened (in random order) to music with vocal (Puccini’s “Turandot”) or orchestral (Beethoven’s 9th Symphony adagio) progressive crescendos, more uniform emphasis (Bach cantata), 10-second period (ie, similar to Mayer waves) rhythmic phrases (Giuseppe Verdi’s arias “Va pensiero” and “Libiam nei lieti calici”), or silence while heart rate, respiration, blood pressures, middle cerebral artery flow velocity, and skin vasomotion were recorded. Common responses were recognized by averaging instantaneous cardiorespiratory responses regressed against changes in music profiles and by coherence analysis during rhythmic phrases. Vocal and orchestral crescendos produced significant (P_0.05 or better) correlations between cardiovascular or respiratory signals and music profile, particularly skin vasoconstriction and blood pressures, proportional to crescendo, in contrast to uniform emphasis, which induced skin vasodilation and reduction in blood pressures. Correlations were significant both in individual and group-averaged signals. Phrases at 10-second periods by Verdi entrained the cardiovascular autonomic variables. No qualitative differences in recorded measurements were seen between musicians and nonmusicians.

Discussion

This study reveals several novel findings, which are potentially important for the therapeutic use of music and for understanding the underlying physiological mechanisms: (1) The cardiovascular (particularly skin vasomotion) and respiratory fluctuations mirrored the music profile, particularly if it contained a crescendo. (2) Specific music phrases (frequently at a rhythm of 6 cycles/min in famous arias by Verdi) can synchronize inherent cardiovascular rhythms, thus modulating cardiovascular control. This occurs regardless of respiratory modulation, which suggests the possibility of direct entrainment of such rhythms and allows us to speculate that some of the psychological and somatic effects of music could also be mediated by modulation or entrainment of these rhythms. (3) Musicians and nonmusicians showed similar qualitative responses, but musicians showed closer and faster cardiovascular and particularly respiratory modulation induced by the music. (4) Music induces predictable physiological cardiovascular changes even in the absence of conscious reactions, which suggests that these changes may “precede” the psychological appreciation. This finding may explain the apparent discrepancy between individual appreciation (subjective) and physiological reactions (common to all subjects despite different music culture and practice) and provide a rational basis for the use of music in cardiovascular medicine.

Conclusions: Music emphasis and rhythmic phrases are tracked consistently by physiological variables. Autonomic responses are synchronized with music, which

might therefore convey emotions through autonomic arousal during crescendos or rhythmic phrases. These responses are at subconscious level and all subjects respond similarly.

This means that Music Therapy does not need to be tailored to an individual taste – rendering its’ use much more practical & standardised

APPROACHING JEHOVAH WITNESSES IN CARDIAC SURGERY

Marco Ranucci, MD, FESCIRCCS Policlinico San Donato

Due to their religious faith, Jehovah Witnesses refuse to receive allogeneic blood products. This, of course, represents a challenge for cardiac surgery operations.

In literature, Jehovah Witnesses represented an exceptionally sound model of extreme hemodilution, allowing to demonstrate that very severe anemia can be tolerated with an acceptable level of safety.

In 2002, Carson and coworkers published a series of Jehovah Witnesses receiving different kind of operations. Patients without associated cardiac problems demonstrated no increase in mortality rate for Hb values as low as 3 g/dL, whereas those with cardiac pathologies demonstrated an increase in mortality rate for Hb value < 6 g/dL. Only below 2 g/dL the mortality rate was 100%.

Excluding case reports, there is not a big deal of literature for Jehovah Witnesses and cardiac surgery. In a recent study, Jassar and coworkers explored 91 JW patients operated in 10 years. In-hospital mortality was 5.5% (n=5). Mortality for isolated coronary artery bypass graft surgery and isolated aortic valve replacement was 2.2% (observed to expected ratio=1.05, 95% confidence interval: 0 to 3.02) and 5.6% (observed to expected=1.46, 95% confidence interval: 0 to 3.76), respectively. Other complications included reoperation (all=8.8%, cardiac=2.2%), sepsis (2.2%), sternal wound infection (1.1%), transient ischemic attack (1.1%), renal failure requiring dialysis (1.1%), and prolonged ventilation (18.7%). Major complication rates were not significantly different between the elective group and the urgent group.

In 2011, Moraca and coworkers presented a series of 40 JW. The mean age was 70 (± 9.5) years with 21 men and 19 women. Patients were classified as high risk (45%, n = 18) and low risk (55%, n = 22) with demographics and comorbidities listed in Table 2. Operative procedures included: isolated coronary artery bypass grafting (CABG) (n = 19), isolated valve replacement/repair (n = 7), valve/CABG (n = 7), reoperative valve replacement (n = 4), reoperative CABG (n = 2), valve/ascending aorta replacement (n = 1), and CABG/ascending aorta replacement (n = 1). All JW were evaluated by The Department of Bloodless Medicine to individually define acceptable blood management strategies. The mean preoperative hemoglobin was 14.1 g/dL (±1.6). Overall mortality was 5% (n = 2) all of which were in the high-risk group.

In our Institution, 61 JW patients were operated in the last 5 years. Operative mortality was 1.6% (1 case). Outcome data of these patients are presented in this lecture, together with the possible procedures applied to reduce the risk of allogeneic blood transfusions.

Religiosity and survival after organ transplantationFranco BonaguidiInstitute of Clinical Physiology, National Research Council, Pisa, Italy

Literature shows that in the general population, religious practice appears to prolong lifespan. The risk of death is actually lower in those who frequently attend religious services vs. those who do not attend them at all.1,2 However this association seems to be mediated by unhealthy habits (smoking, alcohol consumption, and a sedentary lifestyle) and by social isolation, which all influence the prognosis negatively and which are less frequent in people who attend religious services.

In patients who face a serious disease such as cancer, terminal renal insufficiency or HIV infection, there is often a return to religiosity allowing patients to face the disease better and improve their quality of life. Surprisingly this increased spirituality positively affects the progression of the disease. In patients affected by HIV, a better immune response and a lower viral load has been documented in those who reported an increased religiosity after diagnosis3. At present there is some debate regarding whether this religiosity also affects lifespan and scientific literature reports discordant data.

In a group of patients who had survived to myocardial infarction, and presented depression and low social support, religiosity did not influence mortality and re-infarction4. Conversely, in a group of elderly patients undergoing heart surgery, a lack of social support and religious strength and comfort were correlated with the risk of dying at 6 months5. In patients on hemodialysis, spirituality appears to be associated with longer survival6. On the contrary, a negative attitude toward God may increase the risk of death, as shown in elderly patients who have experienced a religious struggle with their illness7.

Recently Bonaguidi et al.8 evaluated the impact of religiosity on survival of patients with end-stage liver disease who had undergone liver transplantation. These patients were psychologically evaluated before the transplant. Waiting for liver transplantation is a very stressful condition for the patient, and as the disease proceeds there are alternating moments of fear and hope. Patients feel their frailty and impermanence, they live suspended between life and death. Many of them return to God which infuses in them a feeling of revival and of beauty, towards the world and the mystery of life. Patients emerge from the dark and recover new energy and wish to truly live. Before these manifestations, we tried to understand whether this attitude to religiosity might be related to psychological frailty and therefore be a risk factor, or on the contrary might be a psychological resource and hence a protective factor for liver transplant outcome.

On this occasion a group of 179 patients was given a questionnaire on religiosity describing the way to face their difficulties by applying to God. For each item, the patients were asked how much he/she had been practicing such behaviour when faced with the challenges of the disease. After the transplantation, patients entered a program of clinical follow-up of an average duration of 21 months, during which 18 patients died. To identify which variables contributed significantly to the prediction of survival we used Cox analysis. The following variables: age, sex, marital status, educational level, occupation, type of liver disease, Child-Pugh score, serum creatinine level, donor age, time of ischemia of the graft, and several variables

related to surgery, such as perioperative bleeding and post-transplant length of stay in the intensive care unit, were tested. Finally, a factorial analysis on the questionnaire answers on religiosity identified three main components of religiosity defined as “searching for God” (active), “waiting for God” (passive) and “ fatalism”.

The results of the multivariate Cox analysis showed that the patients who presented an “active search for God” had a risk of death three times lower than patients who did not refer this experience. A passive behaviour of waiting or an attitude characterized by generic trust in destiny were not associated with a prognostic advantage.

Expressing the results in terms of survival using the Kaplan-Meier method during the follow-up period, patients with a high score on the factor “search for God” showed a significantly higher survival (93.4 %) in comparison with the others (79.5%).

A peculiarity of this study was directly studying the relationship between the individual and God, regardless of religious creed (Christian, Muslim, or other) and church attendance. This religiosity is a personal encounter with God at a time when the patient, unable to bear painful reality, confronts his own existence. One patient reported the following: “I recovered my life by the will of someone up there who loves me. I knew I was in God’s hands, I had great faith in Him. I was with Him. This closeness made me feel strong and calm”.

The possible mechanisms linking religiosity to the survival of the patients are not known, but they seem linked to an improvement in immune defences and to a more favorable neuroendocrine activation.

References

1. Hummer RA, Rogers RG, Nam CB, Ellison CG. Religious involvement and U.S. adult mortality. Demography. 1999;36:273-85.

2. Gillum RF, King DE, Obisesan TO, Koenig HG. Frequency of attendance at religious services and mortality in a U.S. national cohort. Ann Epidemiol. 2008;18:124-9.

3. Ironson G, Stuetzle R, Fletcher MA. An increase in religiousness/spirituality occurs after HIV diagnosis and predicts slower disease progression over 4 years in people with HIV. J Gen Intern Med. 2006;21 Suppl 5:S62-8.

4. Blumenthal JA, Babyak MA, Ironson G, Thoresen C, Powell L, Czajkowski S, et al; for the ENRICHD Investigators. Spirituality, religion, and clinical outcomes in patients recovering from an acute myocardial infarction. Psychosom Med. 2007;69:501-8.

5. Oxman TE, Freeman DH Jr, Manheimer ED. Lack of social participation or religious strength and comfort as risk factors for death after cardiac surgery in the elderly. Psychosom Med. 1995;57:5-15.

6. Spinale J, Cohen SD, Khetpal P, Peterson RA, Clougherty B, Puchalski CM, et al. Spirituality, social support, and survival in hemodialysis patients. Clin J Am Soc Nephrol. 2008;3:1620-7.

7. Pargament KI, Koenig HG, Tarakeshwar N, Hahn J. Religious struggle as a predictor of mortality among medically ill elderly patients: a 2-year longitudinal study. Arch Intern Med. 2001;161:1881-5.

8. Bonaguidi F., Michelassi C., Filipponi F., Rovai D. Religiosity associated with prolonged survival in liver transplant recipients. Liver Transplantation 2010; 16:1158-1163.