Download Comparison of Hemodynamic Effects of Inhaled Milrinone and Inhaled Prostacyclin

Journal of Applied Sciences Research, 6(1): 38-44, 2010
© 2010, INSInet Publication
Comparison of Hemodynamic Effects of Inhaled Milrinone and Inhaled Prostacyclin
after Adult Cardiac Surgery
1
Nasr Hegazy, MD; 2 Abdelsalam Elhenawy, MD.
1
2
Assistant professor of Anesthesia,Ain Shams University,Egypt
Assistant professor of Cardiothoracic surgery, Al Azhar University,Egypt
Abstract: Several preoperative conditions increase the risk of developing perioperative pulmonary
hypertension in cardiac surgery. The use of inhaled milrinone has recently been described to induce a
dose-dependent selective pulmonary vasodilatation in cardiac surgical patients with pulmonary hypertension.
Also, aerosolized form of PGI 2 causes a selective dilatation of the pulmonary vessels without systemic
hypotension encountered with the intravenous administration. The aim of the present study was to compare
the effects of inhaled milrinone and aerosolized prostacyclin on pulmonary and systemic hemodynamic
responses in cardiac surgery patients with pulmonary hypertension. 95 patients with pulmonary
hypertension electively scheduled for cardiac operations required cardiopulmonary bypass were enrolled
in this prospective, randomized non-blind study. The patients were randomly allocated to one of 2 groups,
GroupI: Received inhaled milrinone which was administered through endotracheal tube by inhalation
preceding the initiation of CPB.5milligrams (1mg/ml) was administered, resulting in a dose ranging from
50-80 ug/kg, over 5 minutes. Group II: Received Epoprostenol which was given through the endotracheal
tube by inhalation, preceding the CPB, as Epoprostenol salt dissolved in a sterile glycine buffer, for a
concentration of 15 ug/ml.Each patient received 5 ml of solution containing PGI 2. Hemodynamic
parameters were measured after induction of anaesthesia (T1) ,15 minutes after nebulization of the study
drug(T2) , 15 (T3) and 30 minutes(T4) after weaning from CPB and on arrival to ICU(T5).The
hemodynamic variables were: heart rate(HR),mean arterial pressure(MAP), mean pulmonary artery pressure
(MPAP),cardiac index(CI),systemic vascular resistance (SVR)and pulmonary vascular resistance
(PVR).There were no differences in M AP, M PAP, SVR or PVR among the two groups at any data point.
Also, there were no significant differences among the two groups for CI or right ventricular ejection
fraction (RVEF) .Patients in prostacyclin group had longer intubation time, ICU LOS, hospital LOS than
that in milrinone group.However,none of these differences reach statistical significance. W e concluded
that inhaled milrinone is as effective as inhaled prostacyclin in reducing the pulmonary artery pressure and
pulmonary vascular resistance without systemic hemodynamic side effects.
Key words: Milrinone,prostacyclin,pulmonary hypertension,cardiopulmonary bypass,cardiac surgery
dysfunction after CPB carries a poor prognosis with a
perioperative mortality ranging from 44% to 86% [7].
The pulmonary vascular endothelium has an
important role in regulating the vascular tone by
releasing several vasorelaxing and vasoconstrictor
substances [5,8]. Several pharmacologic agents have been
used to limit the increase in pulmonary vascular
resistance after cardiac surgery including nitroglycerin
[9,10]
milrinone [6,11] prostacyclin (PGI 2) [12,13] and nitric
oxide [1,10,14]. In fact, it is a relatively common practice
to employ inodilators empirically during separation
from CPB in patients with a history of valve disease
complicated by pulmonary hypertension with or without
right ventricular systolic dysfunction. However
,intravenous administration of many of these agents is
INTRODUCTION
Pulmonary hypertension is a frequent and morbid
condition at the time of cardiac surgery. Several
preoperative conditions increase the risk of developing
perioperative pulmonary hypertension, including preexisting pulmonary hypertension, mitral stenosis or
regurgitation and left ventricular dysfunction [1,2].
During cardiac surgery, pulmonary hypertension and its
deleterious effects on the right side of the heart may be
aggravated by the release of vasoactive substances
d u r in g c a r d io p u lm o n ary b y p a s s ( C P B ) [ 3-5] a nd
unfavourable changes in loading conditions which
sometimes are imposed on left ventricle as a
consequence of valve replacement[6]. Right ventricular
Corresponding Author: Nasr Hegazy, Anaesthesia Dept., Faculty of Medicine, Ain Shams University, Egypt.
E-mail: [email protected]
38
J. Appl. Sci. Res., 6(1): 38-44, 2010
limited by systemic hypotension because of nonselective vasodilatation [15]. Inhaled vasodilators may
circumvent potentially systemic side effects because
large concentrations can be selectively presented to
pulmonary circulation [16].
Milrinone is a nonglycosidic, nonsympathomimetic,
phosphodiesterase III inhibitor that increases
intracellular levels of cyclic adenosine monophosphate
(cAMP), induces positive cardiac inotropy and systemic
vasorelaxation. Doolan et al., [17], in a placebocontrolled study, demonstrated the benefit of
intravenous milrinone in facilitating weaning of high
risk patients with pulmonary artery mean pressures>20
mmHg from CPB .W hen administered intravenously,
milrinone decreases systemic vascular resistance
,causing hypotension [18]. The use of inhaled milrinone
has recently been described by Haraldson and
colleagues [19] to induce a dose-dependent selective
pulmonary vasodilatation in cardiac surgical patients
with pulmonary hypertension.
Prostacyclin (PGI 2) is an endogenous prostaglandin
derived from arachidonic acid metabolism through
cyclooxygenase pathway in the vascular endothelium.
The physiological effects are the vascular dilatation,
inhibition of endothelin secretion, inhibition of platelet
aggregation and inhibition of leukocyte adhesion to the
endothelium [20]. Due to these systemic side effects,
researchers have favoured the bronchial tree as a route
of administration, because the aerosolized form of PGI 2
causes a selective dilatation of the pulmonary vessels
without systemic hypotension encountered with the
intravenous administration [21]. Fattouch and colleagues
[22]
have shown similar effectiveness for iNO and
inhaled prostacyclin for treatment of pulmonary
hypertension after mitral valve replacement in a
randomized, double-blinded clinical trial. It is stabilized
as pharmaceutical preparation by freeze drying and can
be reconstituted for use in man in an alkaline glycine
buffer [23].
The aim of the present study was to compare the
relative effects of inhaled milrinone and aerosolized
prostacyclin on pulmonary and systemic hemodynamic
responses in cardiac surgery patients with pulmonary
hypertension.
>30mmHg or mean pulmonary artery pressure >25
mmHg [24] as estimated preoperatively by Doppler
echocardiography [25]. Exclusion criteria included
emergency surgery, pregnancy, history of recurrent
ventricular arrhythmia, left ventricular ejection fraction
< 30%, obstructive cardiomyopathy, bleeding diatheses,
bronchial asthma or had biochemical evidence of
hepatic disease or renal impairment defined as a serum
creatinine >2.0 mg/dl. Patients who were preoperatively
dependent on inotropes, vasopressors, or vasodilators
were excluded from the study.
Anesthetic M anagement: All patients received
premedication with sublingual lorazepam 2mg ,1-2
hours before surgery.Anesthetic technique was
standardized to include fentanyl 10-20ug/kg, midazolam
0.1mg/kg, pancuronium 0.15 to 0.20mg/kg, and
isoflurane 0.5% to 1.5% .All patients received
tranexamic acid 50 mg/kg intravenously after induction
of anesthesia. Each patient was monitored with intraarterial catheter for continuous blood pressure
monitoring. A right ventricular ejection fraction(RVEF)cap ab le pulm onary a rte ry c a the ter(Sw an-G anz
thermodilution Ejection Fraction/volumetric catheter,
Baxter International, Santa Ana,CA)coupled to a
RVEF/thermodilution cardiac output computer (RVEF1,Baxter International) was used. It provided continuous
pulmonary artery pressure and central venous pressure
monitoring, intermittent pulmonary capillary wedge
pressure monitoring, thermodilution cardiac output
determination, and RVEF determinations. Urinary
catheter for monitoring urine output and serial blood
gas analysis up to the discretion of attending
anaesthesiologist. After surgery, patients were
transferred to the intensive care unit for postoperative
ventilation .Sedation was achieved with propofol
infusion 0.5 to 4 mg/kg / hour and morphine boluses.
Patients were extubated according to the standard
criteria.
Operative Technique and M anagement of CPB:”
After median sternotomy, Heparin was given to
maintain activated clotting time >400 seconds.
M anagement of CPB included systemic temperature
drift to 33 oc to 34 oc(nasopharyngeal), alpha-stat pH
management, mean perfusion pressure between 60 and
80 mmHg, pump flow rates of 2.0 to 2.4 L/min per
square meter, and hematocrit >20%. A single aortic
cross clamp technique was used in all patients.
Myocardial protection was achieved with intermittent
antegrade and occasionally retrograde cold blood
cardioplegia. Before separation from CPB, patients
were rewarmed to 36 oc - 37 oc.During rewarming, the
maximum inflow temperature was limited to 37 oc.
M ATERIALS AND M ETHODS
After approval by research and ethics committee
and obtaining informed consent, 95 patients with
pulmonary hypertension electively scheduled for cardiac
operations required cardiopulmonary bypass were
enrolled in this prospective, randomized non-blind
study. Patients were considered to have pulmonary
hypertension if systolic pulmonary artery pressure was
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J. Appl. Sci. Res., 6(1): 38-44, 2010
After separation from CPB, heparin was neutralized
with protamine sulphate.
The study drugs were administered with jet
nebulizers (Micro Mist Nebulizer model 1880; Hudson
RCI, Temecula, CA) attached to the inspiratory limb of
the ventilator circuit, just before Y-piece, approximately
15 cm proximal to the endotracheal tube. The mean
mass diameter of the particles delivered by this
nebulizer from aqueous solution is 2.1um at a rate of
0.25-0.3 ml/min.Nebulization was synchronized to the
inspiratory phase with a timing device (Servo Nebulizer
945; Seimens Elema). Humidification of ventilatory
circuit was stopped before and during the period of
inhalation. Accessory inspiratory gas flow from the
nebulizer was compensated for by adjustment of minute
ventilation settings on the ventilator, keeping minute
ventilation constant. Inspiratory oxygen fraction (FiO 2)
was kept constant throughout the procedure. If MAP
decreased below 60 mmHg, inhalation of the study
drug was stopped and the patient excluded from the
study.
pulmonary artery diastolic pressure > 15 mmHg, the
use of inotropic support for at least 1 hour, intra-aortic
balloon pump or CPB reinitiating.
Statistical A nalysis: Statistical analyses were
performed using SAS version 9.1 (SAS institute, Cary,
NC). Categorical variables were summarized as
frequencies and percentages; continuous variables as
means with standard deviation. A logarithmic
transformation was used when a continuous variable
was not normally distributed. For continuous variables,
comparison of groups was performed using parametric
(student’s t test) or non parametric (W ilcoxon) test
depending on the distribution. For categorical variables,
comparison of groups was performed using Pearson
Chi-square test. To test variation between groups and
over time, repeated measures with ANOVA with group,
time and group x time were performed. A p value of
less than 0.05 was considered to indicate statistical
significance.
RESULTS AND DISCUSSION
The patients were randomly allocated to one of 2
groups:
A total of 95 patients were enrolled in the study.2
patients were not randomized as they failed to meet the
inclusion criteria of pulmonary hypertension on arrival
to the operating room. Another patient was withdrawn
from the study after randomization, before completion
of their study period because of failure of
hemodynamic monitoring caused by early dysfunction
of the pulmonary artery catheter. Twenty seven patients
had CABG, 51 had valve procedures and 14 had
combined valvular and CABG.As shown in Table 1,
patients were randomized to receive milrinone or
prostacyclin were well matched. Specifically, there were
no significant difference between the two groups
regarding age, gender, weight, height, associated
comorbidities and preoperative medications. Also, the
two study groups were statistically comparable as
regard the type of surgery, CPB time, cross clamp
time (table 2) or baseline hemodynamic parameters
(table 3).
After administration of the study drug (milrinone
or prostacyclin), there was no statistically significant
difference in MAP, M PAP, SVR or PVR among the
two groups at any data point. Also, there was no
statistically significant difference among the two study
groups for CI or RVEF at any time. At all data points
after initiation of the study regimen, the milrinone
group tended to have a higher heart rate, although did
not reach statistical significance (Table 3).
As shown in table (4), 12 patients in milrinone
group and 15 patients in prostacyclin group had a
difficulty in weaning from CPB as defined in patients
Group I: Received inhaled milrinone (Primacor,
Sanofi-Synthelabo Canada Inc., M arkham, ON, Canada)
which was administered through endotracheal tube by
inhalation preceding the initiation of CPB.5milligrams
(1mg/ml) was administered, resulting in a dose ranging
from 50-80 ug/kg, over 5 minutes.
Group II:
Received Epoprostenol (Folan, Glaxo
W ellcome Inc, Mississauga, ON, Canada) which was
given through the endotracheal tube by inhalation,
preceding the CPB, as Epoprostenol salt dissolved in
a sterile glycine buffer, for a concentration of 15
ug/ml. Each patient received 5 ml of solution
containing PGI 2.
M easurements: Hemodynamic parameters were
measured after induction of anesthesia(T1), 15 minutes
after nebulization of the study drug(T2), 15 (T3) and
30 minutes(T4) after weaning from CPB and on arrival
to ICU(T5).The hemodynamic variables were: heart
rate(HR),mean arterial pressure(MAP), mean pulmonary
artery pressure (MPAP),cardiac index(CI),systemic
vascular resistance (SVR) right ventricular ejection
fraction and pulmonary vascular resistance (PVR).
Also, we monitored the vasopressor need in the 1 st 24
hours postoperatively, postoperative intubation time,
ICU length of stay(ICU LOS) and hospital length of
stay (Hospital LOS). Difficult separation from CPB
was defined as systolic blood pressure <80 mmHg,
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J. Appl. Sci. Res., 6(1): 38-44, 2010
and methods. Also, 7 patients in milrinone group and
5 patients in prostacyclin group needed vasopressor
infusion in ICU for >24 hours postoperatively. Also,
the noreadrenaline dose needed in milrinone group was
higher than that in prostacyclin group. On the other
hand, patients in prostacyclin group had longer
intubation time, ICU LOS, hospital LOS than that in
milrinone group. However, none of these differences
shown in Table 4 reached a statistical significance i.e.
p$ 0.05.
Discussion: Although cardiac index is thought to be a
good hemodynamic surrogate endpoint in cardiac
surgery, most of large scale studies have confirmed that
pulmonary arterial pressure represents the most
predictive hemodynamic variable in regard to
postoperative outcome [26-28]. The present study sought
to determine the differential effect that two recent
therapies for pulmonary hypertension in cardiac
surgery, inhaled milrinone and inhaled prostacyclin,
have on hemodynamic parameters.
Table 1: Demographic and preoperative data of the study population
Milrinone Group (n=46)
Prostacyclin Group ( n=46)
P value
Demographic Data:
Age (years)
63 ±11
59 ±13
>0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Male/Female(No,)
32/14
30/16
>0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Weight (Kg)
78 ±10
72 ±17
>0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Height(cm)
164 ± 10
162 ± 19
>0.05
Preoperative Comorbidities:
Hypertension
15
13
>0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Diabetes Mellitus
9
12
>0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Peripheral vascular disease
7
8
>0.05
Preoperative Medications:
ACE Inhibitors
8
8
>0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Beta Blockers
11
13
>0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Diuretics
6
5
>0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Angiotensin receptor blocker
2
1
>0.05
ËData are presented as mean ±SD or number
ËP value #0.05 =statistically significant
ËACE=angiotensin converting enzyme
Table 2: Operative characteristics
Milrinone (n=46)
Prostacyclin (n=46)
P value
CABG
n (%)
13(27)
14(30)
>0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------MVR
n (%)
15(32)
15(32)
>0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------MV Repair
n (%)
6(12)
7(15)
>0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------AVR
n (%)
5(9)
4(8)
>0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Complex procedure
n (%)
8(17)
6((13)
>0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------CPB time
(min+SD)
156.7 ±93
127.9 ±53
>0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Cross clamp time (min+SD)
99 ±67
77.8 ±31.7
>0.05
ËData are presented as mean ± SD, or number (n) and percentage
Ë P value #0.05 =Statistical significance
ËCABG= coronary artery bypass graft; MVR= mitral valve replacement; MV repair =mitral valve repair; AVR=aortic valve replacement;
CPB=cardiopulmonary bypass; complex procedure= CABG + valvular surgery
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J. Appl. Sci. Res., 6(1): 38-44, 2010
Table 3: Hemodynamic Data
T1
T2
T3
T4
T5
HR(bpm)
80±23
87±17
103±14
105±17
103±17*
-------------------------------------------------------------------------------------------------------------------------------------------------------MAP(mmHg)
89±15
79±12
75±11
78±10
80±10
-------------------------------------------------------------------------------------------------------------------------------------------------------MPAP(mmHg)
43±13
35±8
26±7*
28±7*
26±6*
-------------------------------------------------------------------------------------------------------------------------------------------------------CI (L/min/m2 )
2.2±0.8
2.2±0.7
2.8±0.6*
2.7±0.7*
2.8±0.8*
-------------------------------------------------------------------------------------------------------------------------------------------------------SVR(dyne.sec.cm-5 )
2014±679
1838±1217
1537±646
1537±633
1504±690
-------------------------------------------------------------------------------------------------------------------------------------------------------PVR(dyne.sec.cm-5 )
344±229
189±197
175±87*
158±69*
145±82*
-------------------------------------------------------------------------------------------------------------------------------------------------------RVEF(%)
26±12
31±12
37±7*
35±10*
35±9*
Prostacyclin Group HR(bpm)
75±18
83±19
92±9
99±21*
100±22*
-------------------------------------------------------------------------------------------------------------------------------------------------------MAP(mmHg)
87±18
84±12
77±11
78±8
81±15
-------------------------------------------------------------------------------------------------------------------------------------------------------MPAP(mmHg)
39±9
34±9
27±7*
26±9*
27±7*
-------------------------------------------------------------------------------------------------------------------------------------------------------CI(L/min/m2 )
2.3±1.0
2.2±0.7
2.6±0.4
2.7±0.7*
2.6±0.8
-------------------------------------------------------------------------------------------------------------------------------------------------------SVR(dyne.sec.cm-5 )
1987±592
1804±703
1680±303
1625±287
1589±447
-------------------------------------------------------------------------------------------------------------------------------------------------------PVR(dyne.sec.cm-5 )
435±321
360±316
159±124*
147±94*
165±99*
-------------------------------------------------------------------------------------------------------------------------------------------------------RVEF (%)
27±14
30±9
30±11
35±11*
36±10*
ËData are presented as mean±SD
Ë* = P value#0.05 =statistically significant compared to the baseline measurement
ËT1=after induction of anesthesia; T2=15 minutes after nebulization of the study drug; T3=15minutes after weaning from CPB; T4=30 minutes
after weaning from CPB; T5= on arrival to ICU.HR=heart rate; MAP=mean arterial pressure; MPAP= mean pulmonary artery pressure; CI=
cardiac index; SVR=systemic vascular resistance; PVR= pulmonary vascular resistance; RVEF= right ventricular ejection fraction ;bpm=beat
per minute.
Milrinone Group
Table4: Postoperative outcome:
Milrinone
Prostacyclin
P value
Difficult weaning from CPB
(n)
12
15
>0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Vasopressors > 24hrs
7
5
>0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Noreadrenaline dose(Mcg/min)(mean+SD)
9.9±8.5
8.1±8.7
>0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Intubation time(h) (mean±SD)
38±66
48±78
>0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ICU LOS (days) (mean±SD)
5.6±5.8
5.3±7.5
>0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Hospital LOS(days) (mean±SD)
12.5±10.6
12.5±14.1
>0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Mortality(n)
1
2
>0.05
ËData are presented as mean ±SD or number (n).
ËP value#0.05 =statistically significant
ËICU LOS= intensive care unit length of stay; Hospital LOS =hospital length of stay.
During the study design, we chose the inhaled
milrinone to be 1mg/ml as this dose was demonstrated
by Haraldsson and his colleagues [19] to cause the
maximum pulmonary vasodilatation without associated
side effects. Also, the administration of the study drug
in our study was before the cardiopulmonary bypass as
it was found in a previous study that inhaled milrinone
is more effective if administered before CPB than the
post-CPB administration [24].
Both of study drugs induced a statistically
significant decrease in PVR and MPAP without
statistically significant decrease in MAP and SVR .This
indicates that both of treatment strategies have a
selective pulmonary vasodilator effect without
“spillover” of the drug in the systemic circulation.
There was no significant disparity in the cardiac
indices of patients treated with inhaled milrinone versus
inhaled prostacyclin. It might have been anticipated that
42
J. Appl. Sci. Res., 6(1): 38-44, 2010
the patients in the milrinone group would have a a
statistically significant higher cardiac index and RVEF
on the basis of milrinone being a positive inotrope.
However, this can be explained on the basis of
unloading the right ventricle by prostacyclin, similar to
that produced by milrinone, allowed the right ventricle
to work as effective as that in the milrinone group.
The milrinone treated patients tended to have a
higher heart rate when compared with prostacyclin
group. However, this difference did not reach statistical
significance. It is unclear if the lower MAP in the
milrinone group induced a reflex tachycardia or the
higher heart rate was a result of chronotropic effect of
milrinone.
Although patients treated with inhaled milrinone
had a shorter intubation time, ICU LOS, hospital LOS,
these differences were statistically insignificant.
These findings of our study were comparable to
that demonstrated in previous studies about milrinone
[16,18,19,24,29]
or prostacyclin [13,19,21,22] which studied
therapeutic modalities of pulmonary hypertension in
experimental animals and humans.
5.
6.
7.
8.
9.
10.
Conclusion: CPB causes an increase in pulmonary
vascular resistance, which may induce right ventricular
dysfunction. This study comparing the effects of
inhaled milrinone and inhaled prostacyclin on the
pulmonary vasculature in cardiac surgery demonstrated
that inhaled milrinone is as effective as inhaled
prostacyclin in reducing the pulmonary artery pressure
and pulmonary vascular resistance without systemic
hemodynamic side effects. On the other hand, inhaled
milrinone is less expensive, is readily available in any
operating room and needs no special preparation,as
opposed to inhaled prostacyclin, since it only requires
a simple nebulizer for administration.
11.
12.
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