Introduction
Surgery in general is associated with some
complications and one of them is bleeding which ranges from mild to severe form
and accordingly increases the mortality, morbidity and hospital stay.(1,2)
Bleeding is a serious complication after cardiac
surgery where 3-5% of patients require reexploration and up to 7% lose more
than 2 liters of blood in the first 24 hours.(3-5)
After exclusion of the surgical causes bleeding due to
impaired hemostasis may be attributed to many factors where hemodilution,
excessive fibrinolysis, platelets dysfunction, residual heparin and effect of
hypothermia could be some causes that increase bleeding on microvascular level.(3,4,6)
Identification of patients at high
risk of bleeding and testing new modalities for blood loss management will
reduce the burden of coagulopathy and excessive blood loss.(7)
Optimization of the transfusion of the blood and its
products should be considered to decrease the risks.(8)
Procoagulant therapy including desmopressin acetate,
aminocaproic acid, tranexamic acid, aprotinin (withdrawn from the market in
2007) and activated prothrombin complex concentrates have not been so widely
adopted into practice in the perioperative surgical management except for the
emerging of rfVIIa with ever increasing use by wide range of surgeons.(9)
Recombinant Factor VIIa exerts its action through two
mechanisms both of them act on the site of local injury (tissue damage) to
restrict the coagulation activation. First one by adherence to the tissue
factor forming a complex that activates the remaining coagulation cascade. The
second mechanism through binding to activated platelets which additionally
direct the activation of factor Χ to the site of tissue injury. The thrombus
formation generated by the activated factor Χ from the above two mechanisms
will finally lead to the formation of fibrin network that is very essential to
clot stabilization and secondary coagulation.(10)
The food and drug administration (FDA) approved its
use in treating bleeding in patients with congenital hemophilia A (deficiency
of factor VIII) or B (deficiency of factor IΧ) with inhibitors and congenital
factor VII deficiency. Recently, it expands its use on prophylactic purposes
for the above conditions as well as the acquired forms of hemophilia with
inhibitors for factors VIII and IΧ.(11)
The off label indications of Factor VIIa
use gained a lot of interest in the last period as it became more
available where it expands to be involved in the management of uncontrolled
hemorrhage, prophylaxis and treatment response to massive intra and
postoperative bleeding.(12)
It was clear that it can induce excellent hemostasis
for intractable bleeding in vascular surgery as well as its known previous role
in trauma and major surgery.(9)
Several reports have described the efficacy and safety
of using recombinant activated factor VII for the management of intraoperative
and post operative bleeding in cardiac surgery.(3,5,6,10-18)
The aim of this study is to describe our experience in
the use of recombinant activated factor VII (Novoseven) in the management of
post operative bleeding in cardiac surgery at Queen Alia Heart Institute / King Hussein
Medical Center.
Methods
A simple
descriptive study at Queen Alia Heart Institute between January2008 till
December 2011 for a total of 160 patients who underwent open heart surgery and
received recombinant activated factor VII (rf VIIa) was conducted. A specially designed medical record abstract
form was used to collect demographic,
surgical and hematological data. Simple descriptive statistics (mean,
percentage, interquartile range) was used to describe the relevant data. T-test
was used also for determining bleeding, transfusion and coagulation profile
before and after rfVIIa treatment. P value was considered statistically
significant if <0.005.
The demographical, procedural, hematological data were
abstracted from the patient’s medical records; operating rooms and ICU database
to asses the efficacy and safety of recombinant factor VIIa treatment.
Hematological database included activated partial
thromboplastin time (APTT), International normalized ratio (INR), Prothrombin
time (PT) and platelets count. Coagulation profiles were measured before and
within 3-6 hours of recombinant factor VIIa administration.
The amounts of packed red blood cells, platelets,
fresh frozen plasma and cryoprecipitate as well as the volume of total blood
loss before and after the administration were all monitored. The comorbidities, clinical outcome and associated
complications were all registered. All of our
patients in the study underwent cardiac surgery operations using
cardiopulmonary bypass where standard institutional guidelines were always
followed.
Cardiopulmonary bypass (CPB) was performed using a
noncoated circuit and a membrane oxygenator. Heparin (5000 IU) was added to the
CPB priming solution and initial intravenous dose of 300 IU/kg of heparin was
administered.
Heparinization was monitored with a kaolin activated
clotting time (ACT) measured every 30 minutes and ACT was maintained above 480
seconds with additional dose of 500IU
Heparin intravenously if needed. Heparin was reversed using 1mg protamine sulphate
for each 1mg of heparin. Reversal was assessed using
heparinase treated ACT (normal <150 seconds), protamine was given based on
the ACT where a ratio of 1.3mg protamine to 1mg heparin is always not exceeded.
During cardiopulmunary bypass hematocrit is kept above 25mg/dl. Cardiopulmunary
bypass was conducted at 33°C for
coronary artery bypass grafting or valvular surgery. Antegrade crystalloid
cardioplegia was mainly used for myocardial protection while some surgeons
prefer to use both antigrade and retrograde blood cardioplegia during their
surgeries. For patients who underwent Aortic surgery for arch reconstruction,
they were cooled to 18°C for a period of circulatory arrest of < 30 minutes.
We considered the patient to have significant post operative bleeding if he
postoperatively bleed >500cc in any hour or > 400 cc during
each of any 2 successive hours or >
300cc in each of any 3 successive hours or by the end of the 4th
or 5th post operative hour the patient has bleed 1000cc or
1200cc respectively. A protocol for
management of significant bleeding at our hospital which depends on the
hemodynamic status of the patients is shown in Fig. 1.
Trigers for transfusion was hemoglobin <10mg/dl for
red cell concentrate, INR>1.5, plasma activated partial thromboplastin time
>50 seconds or platelets < 100.000.
If after surgical exploration and substitution therapy
patient is still having bleeding we give Novoseven (45,90µg/kg). For
intraoperative severe uncontrolled nonsurgical bleeding some cases of redo
surgery or in case of severe pericardial adhesions regardless proper packing
and replacement therapy we also gave Novoseven. We used to correct the
temperature and metabolic status before commencement of management.
The approval of
the local ethical committee and a written consent was obtained from each
patient. T-test was used also for determining bleeding, transfusion and
coagulation profile before and after rfVIIa treatment. P value was
considered as statistically significant if <0.005.
Results
Between January 2008-December 2011, 8786 cardiac
surgery operations were performed out including 392 operations as reopening for
bleeding. The reopening rate was around 4.5%. The mean age of the reopened
patients was 59 years (range between 19-81years). The mean preoperative
hemogobin was 13.4mg/dl (range between 9-19mg/dl), average euroscore 3.66
(range between 2-8), average total pump time 118 minutes (range 54-242
minutes). The ICU stay, postoperative complications, total hospital stay was
prolonged in comparison to the non-reopened patients.
Through the last 4 years, 160 patients were given
Novoseven (134 male (84%), 26 females (16%)). The frequency of the patients who
were given Novoseven to the total number of operations carried out was around
0.02%.
The demographic and surgical data of the 160 patients
are shown in Table I. The decision to use recombinant factor VIIa was made by
the surgical team after following the protocol in our institution. The yearly
usage of factor VIIa is described in Fig. 2 where it showed ongoing increase
from 2008 through 2010 even though the rate decreased once again in 2011 due to the drop off the
total number of operations because of the ICU maintenance.
To ensure adequate media for the hemostasis, the blood
products were always transfused before Novoseven administration. The mean dose
of rfVIIa used was 65µg/kg and it was repeated if bleeding persists. A total 152
patients of the study group received single dose (95%), 7 patients received 2
doses (4.4%) and for only one patient we had to repeat the dose 3 times (0.6%).
One hundred and thirty-five patients (84%) received
their dose in the ICU while 25 patients (16%) received their dose in the
operating theater. The median time between the end of cardiopulmonary bypass
and the first dose of Novoseven was 280 minutes, range (20-880minutes). After
the administration of recombinant factor VIIa it was clear that the amount of
blood loss significantly decreased. The range of the loss before Novoseven was
given (1250cc-3050cc) with a median of 2100cc while after infusion the range
declined to (500cc-1150cc) with a median of 750cc.
There was dramatic reduction in the requirements of
the blood (packed red blood cells)and blood products (fresh frozen plasma (FFP),
platelets, cryoprecipitate) as demonstrated in Table II; where average of 4
units of blood, 10 units of FFP, 10 units of platelets and 4 units of
cryoprecipitate were transfused between the end of the bypass and before
Novoseven administration.
The usage of the blood and its products was
significantly lower with Novoseven therapy (packed red blood cells 1unit, range
(0-3), FFP 1.3(0-6), Platelets 1.1(0-3), cryoprecipitate 0.5 (0-2)) than before
it (packed red blood cells 4(2-8), FFP10 (8-16), platelets10 (6-16),
cryoprecipitate4 (1-6)). P-value was <0.001. On the other hand there was no
significant difference in the laboratory value except for the obvious reduction
in the INR rates as shown in Table III.
Clinical outcome revealed 4 deaths (2.5%), one patient
died in the operating room after intractable bleeding for complex arch
reconstruction surgery. Two other patients died early from multisystem failure.
The 4th patient died after massive stroke where he was known to have
peripheral vascular disease and carotid stenosis but he was operated on emergency basis.
One patient had sternal wound dehiscence after he was
opened 2 times (hemodynamically unstable) before Novoseven was given.
Two patients had postoperative strokes where this
outcome was relatively expected as the first case was known to have previous
recurrent events of Transient Ischemic Attack (TIA) and the second one
underwent prolonged deep hypothermic circulatory arrest resulting in multiple
ischemic brain injuries.
Three patients developed acute renal impairment where
they were managed conservatively and had complete recovery.
The use of Novoseven showed no thromboembolic
complications in our study group. The median ICU stay for patients received
Novoseven comparing to nonbleeding group was 4 days (range 2-8 days) vs 1 day
(range 1-3 days) and median hospital length of stay was 9 days (range 7-19
days) vs 6 days (range 5-8 days) respectively.
Discussion
Bleeding due to a non surgical cause is usually due to
failure of the hemostatic pathways.The surgical trauma and use of
cardiopulmonary bypass where the contact between the circuits of the pump and
blood may result in hemodilution, activation of the fibrinolysis, hypothermia,
and consumption coagulopathy.(19, 20)
Massive blood transfusion is a common topic in cardiac
surgery where serious post operative complications such as adult respiratory
distress syndrome, renal failure, sepsis, transfusion reaction and even death
may occur.(21-23)
It was suggested that when thromboelastography is
performed during cardiopulmonary bypass and added to the current on hand model,
excessive blood loss risk stratification is significantly improved.(24)
In our study, it is clear that the use of rf VIIa was
of great benefit in the management of life threatening bleeding after cardiac
surgery. The cessation of blood loss, decline in the amount of the transfused
blood and its products, normalization of the hematological parameters, fewer
reoperation and absence of the common side effects proved its efficacy in
practice.
The mean dose of the received Novoseven was 65µg/kg
where 95 % of our study group received a single dose that was effective. It is
still unclear what is the optimum dose used in cardiac surgery as doses ranging
from 13-192 µg/kg yielded a satisfactory coagulation.(6)
While some studies showed the efficacy of using small
dose of rf VIIa in the management of intractable bleeding,(16,25-27)
others raise the issue if there is any benefit ever over the conventional
hemostatic therapy.(28,29)
Around 84% of the patients received their dose in the
intensive care unit where we so much support the idea that recombinant factor
VIIa administration in the ICU (after exclusion of the surgical causes) appears
sometimes comparable with the reopening for refractory bleeding after complex
cardiovascular surgical procedures which might be in some patients another
option substituting reoperation.(30)
As Novoseven appears to be a safe and effective agent
in controlling bleeding still there are some critics about the cost, time of
administration, optimal dose and thromboembolic complications.(3)
It was suggested that the action of rfVIIa is so much suppressed by the
hypothermia and acidosis;(11,31,32) that’s why we used to
correct the temperature and metabolic status before commencement of management Some groups support the idea of giving rFVIIa early in
the course of refractory blood loss where the presence of adequate amount of
circulating coagulation factors is much enough to ensure adequate hemostasis.(33,34,35)
None of our patients developed thrombosis during
Novoseven administration. The cause of the phenomena is theoretically
attributed to the binding of the exogenous Factor VIIa to the tissue factor at
the sites of vascular injury and the new couple allows conversion of Factor VII
to VIIa which activate factor IΧ and Χ and enhance thrombin formation.
While some centers found no difference in the
thromboembolic phenomena for patients received the Novoseven,(3,36)
others reported rates of 5.3%(37) and even
in a very recent study it may reach up to 30% which might result in high
mortality and morbidity.(38,39)
Despite the fact that it is still not clear how much
the influence of Factor VIIa on graft patency after coronary artery bypass
grafting,(16,40) a new study published recently by Levi et al
suggested 2.5 times increase in the rate of coronary occlusion in comparison to
placebo.(41) A dose dependent effect was suggested for the
thrombosis process in fresh vascular grafts occlusion in a rabbit model.(42)
Although the incidence of reopening for bleeding in
our center was about 4.5% which is very much comparable to what mentioned in
the literature,(43-45) still we agree with others opinion(46-48)
that more than 90% of the
inhospital use of rfVIIa were off-label. It was the expensive cost beside the high rate of the
off-lable use that forced many institutions including our unit to develop their
own guidelines to minimize the wasting of such a valued drug.
In order to give out a final comprehensive assessment
regarding the cost-effectiveness, safety and proper use of recombinant factor
VIIa, further analytical studies on a larger number of patients are needed.(49)
Conclusion
It was clear from our experience that the use of
recombinant factor VIIa was of great benefit in the management of life
threatening bleeding conditions after cardiac surgery. It has the ability to
control blood loss, restore hemostasis and decrease the amount of blood
transfusion. In order to achieve the maximum benefit of Novoseven therapy and
certainly after roling out the surgical cause it should be administered early
in the course of refractory bleeding after the correction of hypothermia and
metabolic acidosis to ensure adequate environment for hemostasis.
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