Single Dose Inamrinone in Terminal Warm Cardioplegia in On-Pump Coronary Artery Bypass Patients

doi:10.4236/ojts.2012.21002

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Open Journal of Thoracic Surgery, 2012, 2, 5-9

http://dx.doi.org/10.4236/ojts.2012.21002 Published Online March 2012 (http://www.SciRP.org/journal/ojts) 5

Single Dose Inamrinone in Terminal Warm Cardioplegia

in On-Pump Coronary Artery Bypass Patients

Aarne Jyrala1*, Nicole M. Gatto2, Gregory L. Kay1

1Department of Cardiothoracic Surgery, The Heart Institute at Good Samaritan Hospital, Los Angeles, USA; 2School of Public

Health, Department of Biostatistics, University of California, Los Angeles, USA.

Email: *[email protected]

Received December 11th, 2011; revised January 28th, 2012; accepted February 4th, 2012

ABSTRACT

Background: Phosphodiesterase inhibitors (PDI) are used in cardiac surgery to improve and stabilize cardiac function

after surgery. The aim of this study is to evaluate changes in hemodynamics and early outcomes when PDI (Inocor/

inamrinone) is given in terminal warm blood cardioplegia to on-pump CABG only patients and compare results with

patients who did not receive the drug. Material and Methods: From April 2003 through September 2004 241 pts under-

went elective on-pump CABG only surgery. 141 pts received Inocor in the terminal warm blood cardioplegia (Group 1)

and 100 pts did no t (Group 2). Result s: Demographic data, preoperative EuroSCORE risk scores and operative details

were similar. Of pts preoperatively in sinus rhythm (SR) 80.15% in Group 1 and 69.79% in Group 2 regained spontaneous

SR (p = 0.07) after release of crossclamp. Ino tropic support was need ed in 5 pts in Group 1 and in 12 pts in Group 2, p

= 0.02. Post cardiopu lmona ry b y-p ass ( CPB) IABP suppor t was ne eded for 4 p ts in Gr oup 2 and non e for Group 1 pts, p

= 0.01. There was no operative mortality in either Group and hospital/30 day mortality was similar (3/2.13% vs

3/3.00%, p = 0.69). There w ere no statistical difference in stay in postoperative inten sive care unit (p = 0 .15), total hos-

pital stay (p = 0.07), appearance of postoperative atrial fibrillation (p = 0.23) or appearance of postoperative kidney

injury (p = 0.27). Post CPB cardiac index improved 16.90% in Group1but decreased 1.49% in Group 2, p < 0.0001.

Mean arterial pressure decreased 7.46% in Group 1 pts and 5.08% in Group 2 pts, p = 0.002, but no pts in either Group

needed medication for too low blood pr essure. Systemic vascular resistance decr eased 28.40% in Group 1 and 9.02% in

Group 2, p < 0.0001. Conclusions: Inamrinone in terminal warm blood cardioplegia (hot shot) is safe and effective way

to improve and stabilize cardiac function after on-pump CABG surgery but does not affect short-term outcomes.

Keywords: Phosphodiesterase Inhibitors; Postop erative Cardiac Function

1. Introduction

Phosphodiesterase (PDE) III inhibitors (PDI) are widely

used in cardiac surgery [1] to facilitate weaning from

cardiopulmonary bypass (CPB) and to stabilize the pa-

tient after surgery. Mostly used is Primacor® (milrinone,

Sanofi-Aventis, Bridgewater, NJ, USA), which is a de-

rivative of Inocor® (inamrinone, Bedford Laboratories,

Bedford, OH, USA) and has several times greater ino-

tropic and vasodilatory properties on weight basis than

Inocor but is short-lived (half life approx 30 min) and

needs initial bolus dose and continued intravenous admini-

stration which often leads to low systemic blood pressure

and subsequent ne ed for drugs to increase blood pressur e

[2,3] Inocor has a half-life of 3.6 hours and is able to

sustain its effect for the critical early postoperative hours

when given in a single dose before or after release of cross-

clamp [4-7]. The hemodynamic effects of both drugs are

similar [8].

We hypothesized that giving a PDI directly into the

coronaries rather than intravenously or into CPB would

result in better cardiac recovery and performance after

CPB and possibly have less vasodilatory effects than

systemic delivery. Intracoronary administration has been

studied with CHF patients and shown to be effective in

increasing cardiac performance acutely [9]. There are no

earlier reports available about intracoronary use of PDI’s

in combination with cardiac surgery. The PDI was given

preemptively to all pts operated with cardiopulmonary

by-pass by two surgeons. One surgeon did not give PDI to

any patient, so we were able to compare two groups of

elective on-pump CABG surgery patients for differences

which may be achieved by giving preemptive Inocor

intracoronary with the hot shot.

The aim of this study is to evaluate the safety and ef-

fects of intracoronary administration of Inocor after elec-

*Corresponding a uthor.

Single Dose Inamrinone in Terminal Warm Cardioplegia in On-Pump Coronary Artery Bypass Patients

tive on-pump CABG surgery. The effects are compared

with a matching population of patients who did not re-

ceive Inocor.

The study was approved by the hospital’s research

committee.

2. Material and Methods

From April 2003 through September 2004 510 pts under-

went on-pump cardiac surgery at our institute. Only elec-

tive on-pump CABG patients were included into the study.

Patients with concomitant cardiac procedures, valve or

aortic procedures, emergency operations, patients with

ongoing inotrope infusions and pts with preoperative

IABP support were excluded leaving 241 pts for the

study.

At the time of the study two surgeons gave preemptive

Inocor to every pt and one surgeon did not give it to any

pt and did not contribute in the preparation of manuscript.

This created two groups of pts: Inocor group ( Group 1) n =

141 pts and no In ocor group (Gr ou p 2) n = 100 pts.

25 - 50 mg Inocor was given into the terminal warm

cardioplegia (hot shot) by perfusionist. The dose was de-

pendent on the size of the patient. Pts with a BSA > 2 m2

were given 50 mg and smaller pts 25 mg. The dose is about

two thirds of the manufacturer recommended starting

dose.

Cardiac output, cardiac index (CI), arterial pressure

were measured and systemic vascular resistance (SVR)

calculated when pts were anesth etized but before open ing

the chest and again 30 - 45 minutes after cross-clamp had

been released and the patient weaned from CPB. The

results were documented on the anesthesia sheet. Mean

arterial pressures (MAP) were calculated using formula

MAP = (Syst BP + 2 × Diast BP)/3. Operative and perfu-

sion reports were analyzed for nu mber of graf ts, len g th of

CPB, length of aortic cross-clamp, need for cathechola-

mines at the time of separation from CPB and need for

IABP support. Spontaneous return of sinus rhythm (SR)

of pts preoperatively in SR were documented.

Early outcomes [stay in the postoperative intensive

care unit (ICU)], length of hospitalization (LOS), occur-

rence of postoperative atrial fibrillation (AF) and acute

kidney injury (AKI), operative and hospital/30 day mor-

tality) were obtained from hospital charts of all pts.

3. Statistical Analysis

Variables were examined in their continuous form and

categorized as follows: baseline serum creatinine (>2.2

mg/dl, <2.25 mg/dl) and left ventricular ejection fraction

(<0.3, >0.3). Demographic characteristics, EuroSCORE

variables, operative factors and short-term follow-up

measures were summarized by administration of PDI in

the hot shot (Group 1-Inocor n = 141, Group 2-no Inocor,

n = 100). Variables were compared between Groups us-

ing simple parametric t-test or chi = square test and a

p-value < 0.05 was regarded as statistically significant.

All analyses used SAS version 9.2 (SAS Institute Inc.

Cary, NC, USA).

4. Surgical Technique

All pts were operated through standard median sternotomy.

Ascending aorta was cannulated when feasible and single

venous cannulation with vacuum assistance was used for

venous return. Moderate hypothermia to 34˚C was used

during CPB.

Cold whole blood cardioplegia was used given ante-

gradely and retrogradely. Retrograde cardioplegia was given

continuously during cross-clamp time stopping only when

it interfered with visualization and for maximum of 10

minutes at a time. Pts were rewarmed in the later stages

of the procedure and when the pts temperature was

>36˚C, 500 ml of warm blood was given retrogradely

(hot shot). Inocor 25 - 50 mg was added to this by the

perfusionist to Group 1 pts. Cross-clamp was removed

when the hot shot was completed.

Anesthesia was conducted according to hospital ap-

proved protocol in all cases.

5. Results

The demographic variables and ES risk scores were equal

between the groups and no single variable had a statistic-

cally significant difference. The data is summarized in

Tables 1 an d 2.

Comparing operative details the number of grafts, CPB

and cross-clamp times were equal. Appearance of spon-

taneous sinus rhythm in pts in preoperative SR after re-

lease of cross-clamp was quite similar between the Groups:

Group 1 pts (109/80.15% vs 67/69.79%, p = 0.07). Need

for cathecholamines for weaning and stabilization the pa-

tient was lower in Group 1 pts (5/3.55% vs 12/12.00%,

P = 0.01). No pt needed IABP support after CPB in

Group 1 but 4 pt s in Group 2, p = 0.01.

Postoperative outcomes did not differ statistically al-

though there was a tendency for longer ICU and LOS

and higher incid ence of postoperativ e AF in Group 2 pts.

There were no difference in appearance of AKI (defined

as postoperative rise in s-crea > 2.2 mg/dl). Outcomes are

summarized in Table 3.

Mean pre CPB CI, MAP and SVR did not differ be-

tween the groups. CI improved after CPB in Group 1

with 16.90%, p < 0.0001, while in Group 2 CI decreased

by 1.49%, p = 0.64.

MAP decreased sign ificantly in bo th groups, 7.46% v s

4.82%, p < 0.0001 for Group 1 pts and p = 0.002 for

Group 2 pts. There was no pt in either Group who needed

drugs for too low blood pressure.

Single Dose Inamrinone in Terminal Warm Cardioplegia in On-Pump Coronary Artery Bypass Patients

Table 1. Demographics of Groups 1 and 2 patients.

Variable Group 1, n = 141

m ± SD/n (%) Group 2, n = 100

m ± SD/n (%) p

Age, years 66.76 ± 9.56 66.31 ± 11.36 0.71

Females 50 (35.50) 32 (32.00) 0.58

NYHA 2.71 ± 0.62 2.78 ± 0.76 0.48

LVEF 0.48 ± 0.14 0.48 ± 0.14 0.93

LVEF < 0.3 11 (7.81) 13 (13.00) 0.19

CHF 34 (24.11) 22 (22.00) 0.76

DIABETES 53 (37.58) 49 (49.00) 0.08

PTS IN PREOP SR 136 (96.45) 96 (96.00) 0.86

S-CREA 1.27 ± 1.03 1.28 ± 1.04 0.96

S-CREA > 2.2 mg/dl 7 (4.96) 6 (6.00) 0.73

RE-DO 14 (9.93) 10 (10.00 %) 0.99

3VD 78 (67.38) 68 (68.00) 1.00

2VD 36 (25,53) 18 (18.00) 0.21

1VD 10 (7.09) 14 (14.00) 0.09

LM > 70% 31 (21.99) 13 (13.00) 0.09

AES 5.48 ± 3.31 5.23 ± 3.26 0.57

LES 7.80 ± 10.02 7.44 ± 9.08 0.77

NYHA: New York Heart Association functional classification; LVEF: left ventricular ejection fraction; CHF:

congestive heart failure; SR: sinus rhythm; S-CREA: serum creatinine concentration in mg/dl; RE-DO: reopera-

tion on the heart; 3VD: triple vessel coronary artery disease; 2VD: double vessel disease; 1VD: single vessel dis-

ease; LM: l eft main coronary artery stenosis; AES: additi v e EuroSCORE points; LES: logistic EuroSCORE %.

Table 2. Operative details.

Variable Group 1

m ± SD/n (%) Group 2

m ± SD/n (%) p

Grafts/patient 3.51 ± 0.99 3.52 ± 1.11 0.92

CPB 1 21 .72 ± 34.71 115.90 ± 34.78 0.20

X-clamp 102.50 ± 28.72 95.27 ± 27.20 0.05

Spont SR 109 (80.15) 67 (69.79) 0.07

Inotropes1 5 (3.55) 12 (12.00) 0.01

IABP support 0 4 (4.00) 0.01

Oper. mortality 0 0

CPB: cardiopulmonary bypass time, minutes; X-clamp: aortic cross clamp time, minutes; SR: sinus rhythm;

IABP: intra-aortic balloon pulsation device; ¹Cathecolamines, dopamine, adrenaline or noradrenaline for weaning

off CPB and continued to intensive care unit.

Table 3. Postoperative outcomes.

Variable Group 1

m ± SD/n (%) Group 2

m ± SD/n (%) p

Hospital/30 day mortality 3 (2.13) 3 (3.00) 0.67

ICU days 1.53 ± 1.66 2.12 ± 4.38 0.15

LOS days 7.79 ± 5.43 9.16 ± 6.24 0.08

Postop AF1 13 (10.74) 16 (16.67) 0.11

Postop AKI2 11 (8.21) 12 (12.77) 0.28

ICU: stay in postoperative intensive care unit; LOS: total hospital stay; AF: atrial fibrillation; AKI: acute kidney

injury, postoperative rise in s-crea > 2.2 mg/dl. 1Of pts with preoperative SR, Group 1 n =136, Group 2 n = 94;

2Of pts with preopera tive s-crea < 2.25 mg/dl, Group 1 n = 13 3 Group 2, n = 94.

Single Dose Inamrinone in Terminal Warm Cardioplegia in On-Pump Coronary Artery Bypass Patients

SVR decreased in both Groups after CPB, significantly

in Group, 28.40% 1, p < 0.0001 but not significantly in

Group 2 9.02%, p = 0.05. See Table 4.

6. Comments

PDE III inhibitors were discovered in the 70’s and their

hemodynamic effects soon evaluated [10] which led to

widespread use in cardiac surgery and used instead or

together with cathecholamines for pts who developed

low output after CPB [11-13]. Several different dosing

regimens have been used usually with a loading dose and

iv-infusion for several hours post surgery. Single dosage

use has been tried sp ecifically with Inocor [4,6 ,7 ] with its

longer half life. The drugs ar e usually given into the CPB

or intravenously with no obvious hemodynamic differ-

ences but both leaves the heart for second or third p ass of

the drug. Also the timing of introducing the drug has

many modifications, they have been given prior to CPB,

at the end of CPB or after CPB but all regimens seem to

have good hemodynamic effects.

The heart is the primary target for PDI but there are no

clinical reports available where the drug have been given

into coronary circulation (i.e. via cardioplegia) at the end

or CPB. There is one recent experimental study from Ko

and coworkers from 2009 [5] where high dose of Inocor

was given in the terminal warm blood cardioplegia before

releasing the crossclamp. They observed much improved

cardiac function with Inocor vs no Inocor specifically

increased myocardial cAMP. Coronary perfusion was

also higher with Inocor as reported for humans also [14].

They concluded that (one dose) Inocor promote a rapid

and sustained cardiac functional recovery with various

cellular protective effects [15,16] after open heart surgery

Our idea was to deliver Inocor directly into the heart in

order to have the first pass of the drug in the heart/myo-

cardium and possibly have less effect of the vasodilatory

properties with less use of medications to boost low blood

pressure commonly seen with intravenous infusions.

Our results parallel the results of Ko [5] although we

do not have any biochemical data. Comparing the groups

there is a definite improvement in cardiac performance in

Group 1 specially comparing pre- and post CPB CI and

less use of cathecolamine suppor t.

SVR and MAP also decreased statistically more in Group

1 but there were no instances where the blood pressure

needed to be medically improved. This is in contrast to

giving PDI as a loading dose and continue with intrave-

nous infusion and it has been recommended to give si-

multaneous norepinephrine with this dosing. Intracardiac

route decreases or eliminates the inappropriate fall of blood

pressure but is highly effective in promoting better hemo-

dynamics and stability in the early postoperative hours.

There are no statistical differences in early outcomes

as reported by others [17,18] although there is a tendency

of longer IC U and LOS in Grou p 2 pts.

The reason for postoperative AF is multifactorial but

theoretically good myocardial recovery together with good

myocardial protection should result in lesser amount of

postoperative AF but it was not evid ent in this stud y. In a

recent report Fleming and coworkers [19] found increased

amount of postoperative AF when PDI was used after

separation from CPB but the pts who had AF had lower

EF, were older, had longer CPB times and already had

cathecholamine support which all resu lt in an increase in

postope ra t ive AF.

No adverse effects of Inocor were observed.

7. Drawbacks

There are several shortcomings in this study. It is an ob-

servational retrospective single unit study with rather low

numbers of patient s .

The goal of this study was to analyze hemodynamic

effects and safety of a not earlier reported way of deliv-

ering preemptive PDI during on-pump CABG surgery.

8. Conclusions

Preemptive intracardiac/intracoronary PDI at the end of

CPB is safe and reliable way to improve hemodynamics

and myocardial recovery after cardiac surgery.

Table 4. Changes in cardiac index, mean arterial pressure and systemic vascular re sistanc e post CPB.

Variable Group 1

m ± SD/n (%) Group 2

m ± SD/n (%) p

Pre CPB CI 2.61 ± 0.66 2.68 ± 0.56 0.35

Post CPB CI 3.03 ± 0.74 2.64 ± 0.58 <0.0001

Pre CPB MAP 83.60 ± 8.17 83.64 ± 8.17 0.97

Post CPB MAP 77.36 ± 5.12 79.61 ± 5.87 0.002

Pre CPB SVR 1277.16 ± 421.5 4 1277.50 ± 390.55 0.99

POST CPB SVR 914.48 ± 278.50 1162.214 ± 413. 64 <0.0001

CPB: cardiopulmonary bypass; CI: cardiac index, l/min/m2; MAP: mean arterial pressure, mmHg; SVR: systemic

vascular resistance, dyne*sec/cm5.

Single Dose Inamrinone in Terminal Warm Cardioplegia in On-Pump Coronary Artery Bypass Patients 9

When given directly into the heart with terminal warm

cardioplegia the expected improvements in hemodynamics

are prominent but the strong vasodilatation seen with

intravenous use is decreased.

The study was funded by Elma Larsson Foundation

and Los Angeles Thoracic and Cardiovascular Foundation.

Los Angeles, USA.

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