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SECTION 4 Pre- , intra- , and postoperative management ofthe coronary artery bypass graft patient178
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surgery suggests that the shorter- acting opioid (remifentanil) may
reduce time to extubation (−139 minutes; 95% CI −244 to −32
minutes) and hospital length of stay (−1.1days; 95% CI −1.6 to
−0.6days); though caution is warranted regarding this conclusion
as there was signicant heterogeneity across the trials in morphine
delivered postoperatively and adequacy of follow- up with respect
to analgesia and need for reintubation. e challenge with ultrashort- acting opioids such as remifentanil is that additional analgesia
is required postoperatively to cover for the rapid oset of eect of
remifentanil.
Inhaled versus intravenousanaesthetics
Meta- analysis of head- to- head comparisons of inhaled versus intravenous anaesthesia as a component of balanced anaesthesia during
for tracheal extubation post cardiac surgery. Table 21.4 outlines
the initial parameters for stabilization of cardiac surgical patients
aer entry to the cardiac recovery unit, and suggested criteria for
extubation. Patients should achieve normothermia, haemodynamic
stability, and normal blood gases before extubation is considered.
A number of patient characteristics predict higher risk of failure
to achieve early extubation postoperatively. Predictors have included
increased age, female sex, postoperative use of intra- aortic balloon
pump, inotropic support, bleeding, atrial arrhythmia, renal failure,
hypertension, prolonged cardiopulmonary bypass time, base decit
aer surgery, prolonged clamp time, and advanced age.,
Fast- track versus ultra- fast- track extubation
cardiac surgery has suggested that use of inhaled anaesthesia reduces ICU stay (−16 hours, 95% CI −24 to −7 hours), and overall risk
of mortality in cardiac surgical patients. However, caution is warranted regarding this conclusion, as the number of studies reporting
on ICU length of stay was small, even aer combination through
systematic review and meta- analysis.
Head- to- head comparisons of dierent inhaled agents (isourane,
desurane, and sevourane) have not denitively shown important
dierences for cardiac surgery, and the choice should be determined
by local availability and costs.
Neuromuscular blockers/ muscle relaxants for
fast- track cardiacrecovery
Since the use of long- acting neuromuscular blocking agents may in-
A number of studies have evaluated ‘ultra- fast- track’ extubation
(within the operating room) to further reduce the extubation time
to less than 1 hour. While some centres have adopted such an approach as a uniform goal, the practice has not achieved widespread
acceptance since ultra- fast- track extubation has not been shown
to further reduce resource utilization and safety beyond that provided by fast- track extubation in the recovery unit (within 1– 6 hours
postoperatively). In fact, ultra- fast- track extubation may increase
the risk of prolonging operating room time, which is the scarcest
resource within the chain of resources required for cardiac surgery.
Furthermore, ultra- fast- track extubation pre- empts the ability to
stabilize patient haemodynamics and initial recovery parameters in
the ‘golden hour’ postoperatively.
crease the risk of residual muscle weakness and can delay extubation
in the recovery period, the choice of muscle relaxant (and reversal
agent) remains a key consideration in fast- track recovery patients.
Cardiac surgical recoveryunits
Rocuronium (0.5– 1 mg/ kg, as a single dose) has been shown to reduce time to extubation when compared with pancuronium (0.1
mg/ kg, as a single dose) in randomized trials., For this reason,
shorter- acting neuromuscular blockers (rocuronium, vecuronium)
have generally replaced pancuronium for fast- track cardiac surgery.
Regional anaesthesia added togeneralanaesthesia
oracic epidural analgesia has been proposed for improvement of
intraoperative and postoperative pain control in cardiac surgical patients. Recent meta- analyses of RCTs suggest that epidural analgesia
A number of centres have developed a devoted recovery unit for
surgical patients so that the eciencies of fast- track recovery can
be ensured and the overall length of stay in the recovery unit can
be minimized. As opposed to specialized cardiac surgical recovery
units, when cardiac patients are managed within conventional ICUs,
it may be particularly challenging to ensure fast- track recovery
protocols are sequenced with sucient eciency to ensure that the
benets of fast- track cardiac care on resource utilization and stream-
lining can be realized.
for cardiac surgery reduces time to extubation (−2.1 hours; 95% CI
−2.7 to −1.5 hours), ICU stay (−2.4days; 95% CI −4.2 to −0.52days),
and visual analogue scale (VAS) pain scores (0.8– 1.1 points on a 10-
Current progress and futuredirections
point VAS), as well as risk of supraventricular arrhythmias and pulmonary complications, though without measurable dierences on
ICU and hospital length of stay.,
Meta- analyses of RCTs of intrathecal analgesia added to general
anaesthesia versus general anaesthesia alone in cardiac surgery suggested that there was an increased risk of respiratory depression and
were no important dierences in time to extubation, ICU length of
stay, or any other clinically relevant outcomes; although VAS scores
were reduced.,
Criteria forextubation and predictors offailure
One of the most important drivers of success for fast- track anaesthesia is the presence of a protocol with clearly dened criteria
It is clear that while no single denition of fast- track care exists, the
strong and consistent evidence base for clinical and economic advantages of fast- track management has ushered a new standard of care
whereby fast- track management with the goal of early extubation
and discharge is now routine standard of care. All patients should be
considered eligible for fast- track cardiac care and extubation, until
proven otherwise (contraindications are very rare).
It is important to note that fast- track care refers to a full programme across the continuum of care, involving ‘fast- track’ anaesthesia with balanced anaesthesia using reduced doses of opioids
(sufentanil, fentanyl) or short- acting opioids (remifentanil) along
with short- acting anaesthetics and hypnotics (inhaled or intravenous
21 Fast-track cardiac anaesthesia and earlyextubation 179
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anaesthetics, benzodiazepines), usually with the goal of extubation
within 1– 6 hours postoperatively.
Fast- track cardiac anaesthesia is just one component of care which
itself does not guarantee reduced length of stay and reduced complications without other supporting components of care, starting
with appropriate preoperative planning and patient optimization,
through to fast- track cardiac anaesthesia, mildly hypothermic or
normothermic surgical technique, and subsequent postoperative
protocols for monitoring, extubation, and discharge based on patient milestones. Amultimodal approach to managing sedation and
analgesia postoperatively is also an integral component of fast- track
cardiac care. Devoted postoperative cardiac recovery units allow
protocols and patient ow to be optimized in order to achieve efciencies that are more dicult to coordinate in a generalized ICU.
While 1– 6 hours has oen been quoted as the goal, there is no
particular physiological reason for this goal. Some centres have attempted immediate postoperative extubation while the patient is
still on the operating table. However, since operating room time is
usually the most severely restricted resource, deferring extubation
to recovery or critical care units remains most common, and is
unlikely to be replaced by on- the- table extubation until otherwise
proven safer and more cost- eective than outside- of- operating
room extubation.
Conclusion
Fast- track cardiac care requires an interdisciplinary approach to anaesthesia during surgery, as well as a coordinated approach aer surgery, in order to achieve early extubation and an overall streamlined
approach to recovery and hospital discharge. An interdisciplinary
approach to the use of protocols to dene specic goals and criteria
for extubation is an even more important determinant of success
than the specic anaesthetic agents chosen. Acoordinated fast- track
approach optimizes resource utilization in the perioperative setting
while also improving patient outcomes, which ultimately translates
to an overall improvement in value not only for patients, but also for
healthcare professionals, hospitals, and health systems.
REFERENCES
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K, etal. Does modern cardiac surgery require conventional intensive
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J, etal. Early tracheal extubation aer coronary artery bypass gra
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MH. Does fast- track treatment lead to a decrease of intensive
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anesthesia. Can J Anesth. 2005;52(1):12– 7.
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Pasculli N, etal. Remifentanil in cardiac surgery:a meta- analysis
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Testa V, etal. Additive eect on survival of anaesthetic cardiac
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16. Murphy GS, Szokol JW, Marymont JH, Avram MJ, Vender JS,
Rosengart TK. Impact of shorter- acting neuromuscular blocking
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Anesthesiology. 2002;96(3):600– 6.
17. Murphy GS, Szokol JW, Marymont JH, Vender JS, Avram MJ,
Rosengart TK, etal. Recovery of neuromuscular function aer
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22
Management ofcoagulopathy
Zev Noah Kornfield and George Despotis
Introduction
Patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) are at increased risk for excessive perioperative blood
loss and coagulopathy requiring transfusion. In a recent review of transfusion practices in cardiac surgical patients, it was
noted that cardiac surgery patients utilize as much as 10– 15%
of the almost 15million units of red blood cells transfused in
surgical patients in the United States annually and more than
half of cardiac surgical patients receive blood products during
their hospitalization. Despite publication of blood conservation
guidelines, blood product utilization continues to increase for all
cardiac operations. Coagulopathy and microvascular bleeding
when excessive after cardiac surgery can result in re- exploration,
which has been shown to be associated with a three- to fourfold
increase in mortality, renal failure, sepsis, atrial arrhythmias,
prolonged mechanical ventilation, and longer length of stay.
There is evidence that patients with excessive bleeding who require transfusion are predisposed to end- organ injury, stroke,
and potentially increased short- term or long- term mortality.
Given the aforementioned facts, it is imperative to understand
the pathophysiology of haemostatic system abnormalities after
cardiac surgery to facilitate optimal and efficient management of
excessive bleeding.
Coagulationsystem
e coagulation system consists of a complex interplay of platelets,
von Willebrand factor, coagulation factors, and brinolytic factors that are in balance, providing local haemostasis where needed
while limiting excessive thrombosis during injury or surgery, as
summarized in Fig. 22.1 and Fig. 22.2. When intact, the vascular
endothelium serves as a protective layer against haemostatic activation with bound heparin molecules and secretion of various
antiplatelet and antithrombotic mediators (e.g. nitric oxide, prostacyclin (PGI), adenosine, etc.). When the endothelium is damaged,
platelets adhere to exposed subendothelium via critical ligands (i.e.
either collagen and/ or von Willebrand factor) and then aggregate
to provide initial haemostasis. is initial activated platelet plug
provides an active phospholipid surface for interaction with coagulation factors that leads to further activation and formation of
a stable brin clot. e coagulation system can be subdivided into
the intrinsic, extrinsic, common, and brinolytic pathways. Tissue
factor derived from cells or subendothelium activates the extrinsic
pathway to form thrombin which converts brinogen to brin;
thrombin also leads to platelet activation and expression of IIb/
IIIa receptors which facilitate crosslinking of platelets by brin and
stabilizes the platelet– brin plug. PGI and nitric oxide counter
platelet clot formation via platelet inhibition while proteins C
and S, antithrombin III, heparin cofactor II, tissue plasminogen
activator/ plasmin, and tissue factor pathway inhibitor counter
thrombus formation in the coagulation cascade by inhibiting or
degrading key activation products/ mediators such as factors V/
VIII, factors IIa and Xa, brin, and tissue factor, respectively. e
brinolytic system is modulated by plasminogen activators such as
tissue plasminogen activator and urokinase that produce plasmin.
Plasmin lyses brin and potentially prevents vaso- occlusion at the
site of vessel injury by limiting extensive brin formation. e brinolytic system is regulated by other factors such as plasminogen
activator inhibitor (PAI- 1) and thrombin- activatable brinolytic
inhibitor (TAF1), which neutralize alpha- 2- antiplasmin which
neutralizes plasmin (Fig. 22.2).
Predictors and mechanisms ofbleeding
e Society of oracic Surgeons and the Society of Cardiovascular
Anesthesiologists (STS/ SCA) blood conservation clinical practice
guidelines have identied several potential risk factors for excessive bleeding and increased transfusion requirement in cardiac
surgery. ese include advanced age, low red blood cell volume
due to preoperative anaemia or from low body mass, preoperative anticoagulation or antiplatelet therapy, urgent or emergent
operation, anticipated prolonged duration of CPB, and other
comorbidities including congestive heart failure, renal dysfunction, and chronic obstructive pulmonary disease. Although
excessive bleeding during and aer surgery may be related to isolated hereditary defects within a patient’s haemostatic system (see
top section of Table 22.1), it is more likely to be multifactorial
SECTION 4 Pre- , intra- , and postoperative management ofthe coronary artery bypass graft patient182
Haemostatic system physiology
Site of endothelial damage
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IIIa
IIb
IIb
Platelet aggregation
Thrombin (IIa)
ADP
VIIa (1%)
IIb
IIb
Fibrin
Fibrinogen
IIIa
IIIa
BTG, PF4
Fibrin/Fibrinogen
13-HODE, NO,
PGI2,
adenosine
Heparan
IIb
IIb
Ia
Collagen
IIIa
IIIa
IIa
VWF
Ib
VWF
IIIa
IIb
IIb
IIIa
Fibronectin
IIb
IIIa
IIb
IIIa
VIIIa
Tissue factor
Prothrombin (II)
Va
Xa
IXa
Fig.22.1 The haemostatic system involves three major components that interact to attenuate spontaneous thrombosis and promote haemostasis
with vasculature breach:vascular wall (endothelium/ subendothelium), coagulation proteins, and platelets. Under normal conditions, the endothelium
releases several different substances 12- (Z,E)- hydroxyoctadecadienoic acid (12- HODE), nitric oxide (NO), prostaglandin I2 (PGI2), and adenosine to
inhibit platelets. The first step involved with breach of the integrity of the vessel wall involves platelet adhesion mediated by the interaction of collagen
and platelet Ia/ IIa receptors and high- molecular- weight von Willebrand factor (vWF) multimers and the Ib platelet glycoprotein receptor (Gp Ib).
Further activation of the haemostatic system occurs via activation of platelet surface- bound prothrombinase complex involving coagulation factors
Va and Xa via either platelet- bound coagulation factors VIIIa and IXa or via coagulation factor VIIa via activation by subendothelial tissue factor. These
activation mechanisms ultimately lead to conversion of prothrombin (II) to thrombin (IIa) which further activates coagulation factors as well as platelet
activation to release the contents of alpha and dense granules that enhances further platelet/ haemostatic activation via generation of thrombin, release
of adenosine diphosphate (ADP) from platelets that further stimulates platelet activation, and release of both betathromboglobulin (BTG) and platelet
factor 4 (PF4) that bind to endothelial- bound heparan to facilitate platelet recruitment to the area of vascular injury. With these activities, thrombin
concentrations rise substantially which ultimately lead to conversion of fibrinogen to fibrin expression of platelet glycoprotein IIb/ IIIa receptors (Gp IIb/
IIIa) which facilitates platelet aggregation via linkage by either fibrinogen/ fibrin or vWF, with ultimate formation of a platelet- rich haemostatic plug that
is stabilized by cross- linking of fibrin.
including pre- existing hereditary, and more commonly, defects
acquired either preoperatively (e.g. pharmacological) (Table 22.2)
or intraoperatively (i.e. during CPB as related to hemodilution
or hemostatic system consumption—see bottom section of Tab l e
22.1) (Table 22.3).
e use of CPB increases the risk for microvascular bleeding, related to acquired quantitative and qualitative abnormalities in platelets
and coagulation factors (Table 22.3) secondary to acquired haemo-
static system abnormalities, and is due to several factors. ese factors
include (1)haemodilution related to CPB and cardioplegia crystalloid solutions, (2)hypothermia and haemostatic system activation/
consumption due to a disseminated intravascular coagulation- like
process secondary to either contact activation (i.e. non- endothelial
surface of CPB circuit) and/ or autotransfusion of cardiotomy-derived
shed pericardial blood (i.e. that contains high levels of tissue plasminogen activator and tissue factor- mediated activation) (Table 22.3),
(3)excessive brinolysis, (4) intravenous residual heparin or heparin
rebound, and (5) excessive protamine dosing. See Table 22.3. e lit-
erature demonstrates that o- pump coronary artery bypass graing is
associated with less blood utilization and postoperative bleeding compared with conventional coronary artery bypass graing using CPB
but is associated with other technical challenges.
e use of preoperative aspirin and non- steroidal antiinammatory agents can lead to bleeding in a subset of patients who
are hyper- responders but the majority of patients do not bleed excessively since most manifest only mild platelet inhibition to aspirin.
Although patients on preoperative warfarin may bleed aer cardiac
surgery, especially if patients have high international normalized
ratio values and have other bleeding- related risk factors, some
studies have demonstrated an inverse relationship between postoperative international normalized ratio and blood loss, which may be
secondary to warfarin- mediated haemostatic system preservation
during CPB. Residual eects of low- molecular- weight heparin compounds, direct thrombin inhibitors, platelet inhibitors, and brinolytic agents can increase bleeding and complicate management. e
risk of bleeding related to these agents depends on their relative potency, pharmacodynamic half- life, time interval from most recent
dose before surgery, and availability of a reversal agent (Table 22.2).
e long- acting platelet adenosine diphosphate (ADP) receptor antagonists are associated with excessive bleeding and transfusion especially when they are more potent (e.g. prasugrel) or are administered
within 5days of surgery. New testing paradigms have been investigated to identify the optimal timing for surgery based on the quantication of the degree of residual ADP antagonism using either
22 Management ofcoagulopathy 183
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Fig.22.2 Mechanisms and effects of excessive haemostatic activation with cardiac surgery. Dashed line designates release of protein cleavage by-
products. The following coagulation factors, haemostatic mediators, and by- products are abbreviated as follows (activated factors are designated by
a lowercase a):XII, factor XII; VII, factor VII; X, factor X; VIII, factor VIII; IX, factor IX; V, factor V; XIII, factor XIII; PT, prothrombin; FPA, fibrinopeptide A;
Fibrin (m), fibrin monomer; Fibrin (p), fibrin polymer; PAI1, plasminogen activator inhibitor; tPA, tissue plasminogen activator; FSP, fibrinogen/ fibrin
degradation products; D- dimers, polymerized fibrin degradation products.
Reproduced from Despotis, G.J., Joist, J.H., Goodnough, L.T., 1997. Monitoring of hemostasis in cardiac surgical patients:impact of point- of- care testing on blood loss and
transfusion outcomes. Clin. Chem. 43, 1684– 1696 with permission from Oxford University Press.
laboratory-based ADP aggregometry or point of care methods (e.g.
Verify Now Plavix Test).
In addition to correction of acidosis and hypothermia, the management of severe bleeding and coagulopathy oen requires replenishment of haemostatic factors with FFP, platelets, cryoprecipitate,
Transfusion therapy, testing, andalgorithms
and various factor concentrates. Coagulation factor deciency is a
less common cause of bleeding aer cardiac surgery, and use of FFP
has been shown to be required less frequently; however, transfu-
A review of transfusion algorithms in cardiac surgery noted several
studies that suggest adhering to transfusion algorithms, especially
in conjunction with concomitant point- of- care haemostasis monitoring, may decrease the number of transfusions administered, decrease volume of blood loss, and decrease the rate of re- exploration
for bleeding. ese studies have used standard tests of haemostatic
function such as prothrombin time, activated partial thromboplastin
time, and platelet count as well as tests that evaluate the viscoelastic
properties of whole blood such as thromboelastography (TEG) or
thromboelastometry (ROTEM). ere is growing evidence, primarily extracted from elective cardiac surgery trials, that application of
TEG- or ROTEM- guided transfusion strategies may reduce the need
for blood products especially fresh frozen plasma (FFP) and reduce
bleeding, and improve morbidity in patients with bleeding. In general, the STS/ SCA guidelines recommend institution- specic transfusion algorithms, point- of- care testing, and a multimodal approach to
coagulopathy treatment. e ecacy of point- of- care testing coupled
with a standardized algorithm to reduce transfusion and bleeding may
be related to several factors such as optimal management of bleeding,
resetting of the transfusion trigger, and/ or early identication of a surgical source of bleeding by ruling out microvascular bleeding.
sion of FFP is reasonable in patients with excessive bleeding in the
context of multiple or single coagulation factor deciencies when
safer fractionated products are not available. e American Society
of Anesthesiologists practice guidelines suggest that FFP be used
when bleeding is related to reductions in coagulation factor levels
with prothrombin time and activated partial thromboplastin time
results, greater than 1.5 times normal values, and that the dose of
FFP achieve at least 30% factor levels. Approximately 15 mL of FFP
per kilogram of body weight will result in a rise in factor values by
30% in the average adult.
According to the American Society of Anesthesiologists guidelines, platelets should be administered in the setting of active
bleeding based on platelet counts. If counts are less than 50 × 10/
L, they are generally needed. With platelet counts of more than 100
× 10/ L, transfusion is rarely indicated unless there are substantial
qualitative platelet abnormalities. When platelet counts are between 50 × 10/ L and 100 × 10/ L, clinical circumstances should
be evaluated. One apheresis- derived platelet unit is equivalent to
six random- donor platelet units (i.e. containing at least 3 × 10
platelets) and should result in a 1- hour post- transfusion increase of
30 × 10/ L to 60 × 10/ L in platelet count. Hypobrinogenaemia
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Table22.1 Hereditary versus acquired defects aftercardiac surgery
Source of haemostatic defect(s) Prevalence/ incidence
Hereditary
Platelet disorders (e.g. abnormal adhesion or aggregation; receptors,
storage pool defects)
Severe bleeding (i.e. as related to adhesion or aggregation defects) 1:1,000,000
Mild bleeding (storage pool defects, signal transduction defects) Incidence unknown, less common than von Willebrand disease
Coagulation factor deficiency
FVIII 1:5,000– 10,000
FIX 1:30,000
FXI 1:1,000,000 or 1:50 (Ashkenazi Jewish births)
FVII 1:500,000
FV, FX 1:1,000,000
Afibrinogenemia, dysfibrinogenaemia 1:1,000,000
FXIII 1:2,000,000
FII (prothrombin deficiency) 1:2,000,000
von Willebrand disease (75% type 1) 1.5%– 1:10,000
Acquired with extracorporeal circulation
Thrombocytopenia
<50 × 103/ L 6%
<100 × 103/ L 60%
Qualitative platelet abnormalities
Reduced TRAP- mediated activation in PRP 10%
Reduced PAF- mediated activation in whole blood 33%
Coagulation factor deficiency (<20% activity) 30%
Hypofibrinogenaemia (fibrinogen <100 mg/ dL) 9%
130 cases described in the literature; 0.4% of general population and 8% of patients
with history of bleeding/ abnormal screening tests
PAF, platelet- activating factor; PRP, platelet- rich plasma; TRAP, thrombin receptor agonist peptide.
Reproduced from Despotis, G., Eby, C., Lublin, D.M., 2008. Areview of transfusion risks and optimal management of perioperative bleeding with cardiac surgery. Transfusion (Paris) 48,
2S– 30S.doi:10.1111/ j.1537- 2995.2007.01573 with permission from John Wiley and Sons.
(<80– 100 mg/ dL) and dysbrinogenaemia can be treated with either
cryoprecipitate or FFP. Administration of either 10 units of cryoprecipitate, 15 mL/ kg of FFP, or 3000 mg of brinogen concentrate will
haemorrhage, transfusion of xed ratios of red blood cells, FFP, and
platelets should be considered when situations analogous to trauma
situations are encountered.
increase brinogen by approximately100 mg/ dL. Recent published
data indicate that brinogen concentrates can substantially decrease
bleeding and blood component utilization when guided by tests of
Other treatments ofcoagulopathy
viscoelastic function.
Fixed red blood cell:FFP ratio transfusion schemes and massive
transfusion protocols have been shown to improve survival in the
setting of trauma- related massive transfusion, where several blood
volumes may be lost and replaced by the time laboratory values are
resulted. In the Pragmatic, Randomized Optimal Platelet and Plasma
Ratios (PROPPR) trial, early administration of plasma, platelets, and
red blood cells in a 1:1:1 ratio was compared with a 1:1:2 ratio in a
randomized controlled trial involving trauma patients. ere were
no dierences in mortality at 24 hours or 30days or safety assessments despite increased use of plasma and platelets in in the 1:1:1
group. However, the 1:1:1 group manifested improved haemostasis
and fewer died from exsanguination by 24 hours. In at least one
observational study, use of MTP was associated with lower organ
dysfunction rates and lower 7 day mortality aer cardiac surgery.
us, based on current evidence available, with life-threatening
Prothrombin complex concentrates (PCCs) are pooled concentrates
of coagulation factors that include factors II, VII, IX, and X in variable
concentrations and when compared to FFP provide quicker international normalized ratio correction, can completely normalize factor
levels without causing uid overload, have a small infusion volume,
and do not require cross- matching but are derived from multiple
donors (i.e. 10,000– 20,000 donors). While a historical concern about
potential thrombotic risk with PCCs exists, present- day PCCs are
much improved based on the use of non- activated factors and reasonable concentrations of anticoagulant proteins such as antithrombin III
and proteins C and S with thrombosis rates at 1– 2%. Currently, PCCs
are approved for prophylactic administration before emergency surgery in patients with reduced levels of vitamin K- dependent clotting
factors (warfarin treatment, haemophilia B). While there are few published studies comparing FFP and PCCs in the perioperative period,
Table22.2 Selected pharmacological agents that affect coagulation
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22 Management ofcoagulopathy 185
Target Half- life (hours) Metabolism and
Dabigatran Direct FII inhibitor 12– 17 Renal, hepatic Idarucizumab
Rivaroxaban Direct FXa inhibition 7– 13 Renal, hepatic Andexanetalfaa
Apixaban Direct FXa inhibition 8– 15 Renal, faecal Andexanetalfaa
Unfractionated heparin ATIII- mediated FII and
LMWH (enoxaparin, dalteparin,
tinzaparin, nadroparin)
Fondaparinux ATIII- mediated FXa
Warfarin Vitamin K antagonist 20– 60 Hepatic, renal Vitamin K 3– 4days
Aspirin IPLT COX 1 inhibitor Irreversible— await new
Ticlopidine (thienopyridine) ADP P2Y12 receptor
Clopidogrel (thienopyridine) ADP P2Y12 receptor Irreversible— await new
Prasugrel (thienopyridine) ADP P2Y12 receptor Irreversible— await new
Ticagrelor ADP P2Y12 receptor 7 Hepatic, renal, faeces NA 12– 24 hours
Abciximab Monoclonal antibody
Eptifibatide GP IIb/ IIIa 2.5 Renal NA 4– 8 hours following
FXa inhibition
ATIII- mediated FXa
inhibition
inhibition
antagonist
to GP IIb/ IIIa
1– 2 Reticuloendothelial
Variable Renal, hepatic Protamine
17– 21 Renal, hepatic Ciraparantag
PLT production
Irreversible— await new
PLT production
PLT production
PLT production
0.5 Proteolytic cleavage NA 24 hours
excretion
system, renal, hepatic
Hepatic, GI mucosa, red
blood cell, renal
Hepatic, renal, faeces NA 7– 10days
Hepatic, renal, faeces NA 5– 7days
Renal, faeces NA 5– 7days
Pharmacological
reversal agent
Ciraparantaga
Haemodialysis
Ciraparantag
Ciraparantag
Protamine
Ciraparantag
Ciraparantag
NA 5– 7days
a
a
a
a
a
Minimum time after
last dose to normal
function
3– 5days
3– 5days
3– 5days
4– 8 hours
24 hours
24 hours
discontinuation of
infusion
Herbal supplements which may increase bleeding risk or bleeding:garlic, ginkgo, ginseng, saw palmetto, black cohosh, chamomile, feverfew, fish oil.
a
In trials. ADP, adenosine diphosphate; ATIII, antithrombin 3; COX, cyclooxygenase; GI, gastrointestinal, GP, glycoprotein; FII, factor II; FX, factor X; LMWH, low- molecular- weight
heparin; PDE, phosphodiesterase;
there is some evidence that PCCs may be a viable alternative to FFP in
coagulopathic bleeding post CPB. In some European countries, PCCs
have replaced FFP as the treatment for perioperative bleeding but further trials are needed to support this practice.
Recently, non- vitamin K oral anticoagulants, such as direct
thrombin inhibitors and direct factor Xa inhibiters, have emerged
as alternatives to warfarin for the prevention and treatment of
thromboembolic disease. One of the primary concerns with nonvitamin K oral anticoagulants is the early lack of specic agents to
reverse their anticoagulant eect in cases of emergency surgery.
Previous methods for managing bleeding in patients on these agents
include activated charcoal if it had been less than 2 hours since ingestion and dialysis for direct thrombin inhibiters. From in vitro data,
PCCs may be helpful to normalize thrombin generation when used
o label to counteract the eects of irreversible factor Xa inhibitors
but have not been shown to counteract the eects of direct thrombin
inhibitors (dabigatran) which impact brin production downstream of where PCCs have the most impact. While activated PCC
(FEIBA®) and recombinant activated factor VIIa (discussed in the
next section) show some promise in reversing both direct thrombin
inhibitors and direct factor Xa inhibiters, the current data on reversing major haemorrhage and balancing the risk of thrombosis
is equivocal. Specic reversal agents have been recently developed
and are in various stages of approval. Idarucizumab, a humanized
monoclonal antibody fragment, has recently been approved by the
United States Food and Drug Administration to reverse dabigatran
activity in emergency situations. Other specic reversal agents
(andexanetalfa and ciraparantag) for both factor Xa inhibitors and
direct thrombin inhibitors are currently in clinical trials.,
Recombinant activated factor VIIa (rFVIIa) currently has Food
and Drug Administration approval for the management of bleeding
in haemophilia patients with inhibitors to factors and in patients
with congenital factor VII deciency. While the o- label use of this
agent has been reported to be successful in reversing life- threatening
haemorrhage in a number of clinical scenarios, the decision whether
to use activated factor concentrates such as rFVIIa for cardiac surgery patients with uncontrolled bleeding continues to be one that
has inevitably to be made by individual physicians, assisted by their
hospital pharmacotherapeutics and transfusion committees. Alarge
review of rFVIIa used in an o- label basis demonstrated a signicantly increased the risk of arterial but not venous thromboembolic
events, especially among the elderly and the risks of thrombus versus
the benets of haemostasis must be carefully considered. In a review article, Sniecinski and Levi oer guidelines for o- label use
SECTION 4 Pre- , intra- , and postoperative management ofthe coronary artery bypass graft patient186
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Table22.3 Asummary ofhaemostatic abnormalities that may
precipitate or aggravate excessive bleeding associated withcardiac
surgery involving extracorporeal circulation
DIC
Excessive fibrinolysis due to either primary or secondary fibrinolysis (i.e. as
related to CPB- mediated DIC and/ or reduced fibrinolysis inhibitors such as
PAI1, alpha- 2- antiplasmin)
Decreased or degraded coagulation factors
PLT related:
Thrombocytopenia
PLT activation and/ or desensitization
Prolonged bleeding time
Decreased PLT reactivity to one or more PLT agonists
Loss of PLT glycoprotein receptors
Fibrinogen (GP IIb/ IIIa)
VWF receptor (GP Ib)
PLT degranulation (i.e. as demonstrated by release of BTG, PF4, ADP)
Changes in PLT signalling/ adhesion molecule expression
Hypothermia- related effects
Heparin- related inhibition
Heparin- related activation
Protamine- related PLT dysfunction
ADP, adenosine diphosphate; BTG, beta- thromboglobulin; DIC, disseminated
intravascular coagulation; GP, glycoprotein; PAI1, plasminogen activator inhibitor 1; PF4,
PLT factor 4; VWF, von Willebrand factor.
Reproduced from Despotis, G., Eby, C., Lublin, D.M., 2008. Areview of transfusion risks
and optimal management of perioperative bleeding with cardiac surgery. Transfusion
(Paris) 48, 2S– 30S.doi:10.1111/ j.1537- 2995.2007.01573 with permission from John
Wiley and Sons.
of rFVIIa including severe (1 L/ hour) or life- threatening bleeding
without surgical source of bleeding, marginal response to routine
haemostatic therapy, patients with antibodies to either platelets or
to non- ABO red cell antigens (cross- match incompatibility issues),
or when factors or platelets are not available, and potentially for
Jehovah’s witnesses. For o- label uses, low doses (10– 15 micrograms/ kg) should be considered and titrated to clinical response to
minimize the risk of thrombotic complications. In order to optimize
haemostasis with the use of rFVIIa, platelets, brinogen, and factor
II, VIII, IX, or X deciencies may require correction to fully restore
thrombin generation and brin clot formation.
e STS/ SCA guidelines have assigned the prophylactic use of
the lysine analogue antibrinolytics tranexamic acid (TXA) and
epsilon- aminocaproic acid (EACA) a class I recommendation.
Areview of the literature reveals fewer transfusions, and decreased
average blood loss in CPB and o- pump coronary artery bypass
graing cases when antibrinolytics are used in high- and mediumrisk cardiac surgery although benets may be less clear in low- risk
cardiac surgery. While there was similar ecacy between TXA and
EACA with regard to blood loss and transfusion rates, there has
been an association between high- dose TXA and an increased incidence of postoperative seizures, postoperative atrial brillation, and
renal failure when compared to other antibrinolytics., Although
prophylactic use of antibrinolytic agents may be generally well tolerated and safe, the risk:benet ratio in individual patients needs to
be considered with judicious use of these agents in patients who may
be at higher risk for thrombotic complications (e.g. sepsis, disseminated intravascular coagulation, or hypercoagulability). ere may
also be a role for the use of tests of viscoelastic function to identify
patients with hyperbrinolysis and hypercoagulability to enable judicious use of these agents. It should be noted that when compared
to TXA and EACA, aprotinin was superior in reducing blood loss,
transfusion rates, and surgical re- exploration in cardiac surgery but
was withdrawn from the market in 2008 when a large randomized
trial was stopped early due to an increased risk of death in highrisk cardiac surgery. Aer further review of the data, beginning
in 2010, the European Medicines Agency Committee for Medicinal
Products for Human Use (CHMP) of the European Medicines
Agency approved reinstatement of aprotinin marketing authorizations in the European Union as of 2013. e CHMP concluded that
the benets of aprotinin outweigh its risk in appropriately managed
patients undergoing isolated heart bypass surgery not combined
with other heart surgery.
An understanding of coagulopathy in cardiac surgery and coronary artery bypass graing is essential to the successful management of bleeding in this patient population. Transfusion protocols,
point- of- care testing, and new blood product concentrates or reversal agents can facilitate eective management of life- threatening
bleeding. While much progress has been made in management of
coagulopathy, emerging challenges continue in the setting of use of
new and more potent anti-platelet or anti-thrombotic agents that
either have long half lives or lack a specic reversal agent which requires innovative solutions and more research.
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