Effects of Landiolol Hydrochloride on Intractable ... · Effects of Landiolol Hydrochloride on Intractable Tachyarrhythmia After ... Wolff - Parkinson White ... 1 Intractable tachyarrhythmia

Effects of Landiolol Hydrochloride onIntractable Tachyarrhythmia After PediatricCardiac Surgery

著者 Tokunaga Chiho, Hiramatsu Yuji, KanemotoShinya, Takahashi-Igari Miho, Abe Masakazu,Horigome Hitoshi, Sakakibara Yuzuru

journal orpublication title

The annals of thoracic surgery

volume 95number 5page range 1685-1688year 2013-05権利 (C) 2013 The Society of Thoracic Surgeons

Published by Elsevier Inc. NOTICE: this is theauthor’s version of a work that was acceptedfor publication in The Annals of ThoracicSurgery. Changes resulting from the publishingprocess, such as peer review, editing,corrections, structural formatting, and otherquality control mechanisms may not bereflected in this document. Changes may havebeen made to this work since it was submittedfor publication. A definitive version wassubsequently published in The Annals ofThoracic Surgery, [VOL95, ISSUE5, May 2013.DOI:10.1016/j.athoracsur.2013.01.057

URL http://hdl.handle.net/2241/119455doi: 10.1016/j.athoracsur.2013.01.057

1 TOKUNAGA ET AL

LANDIOLOL FOR PEDIATRIC TACHYARRHYTHMIA

Effects of Landiolol Hydrochloride on Intractable Tachyarrhythmia 1

After Pediatric Cardiac Surgery 2

3

4

Chiho Tokunaga, MD, PhD, 5

Yuj i Hiramatsu, MD, PhD, Shinya Kanemoto, MD, PhD, 6

Miho Takahashi-Igar i , MD, Masakazu Abe, MD, PhD, 7

Hitoshi Horigome, MD, PhD, Yuzuru Sakakibara , MD, PhD 8

9

Depar tments of Cardiovascular Surgery and Pediat r ic Cardiology, 10

Universi ty of Tsukuba, Ibaraki , Japan 11

12

13

Running head: Landiolol for pediat ric tachyarrhythmia 14

Keywords: arrhythmia, pediat ric , congeni tal hear t disease 15

Word Count; 2562 words 16

17

Address for correspondence: 18

Chiho Tokunaga, MD, PhD 19

Department of Cardiovascular Surgery, 20

Ibaraki Cl inical Educat ion and Training Center, 21

Faculty of Medicine, Universi ty of Tsukuba 22

1-1-1 Tennodai , Tsukuba 305-8577, Japan 23

Tel; +81 29 853 3210 24

Fax; +81 29 853 3097 25

e-mai l : [email protected]

2 TOKUNAGA ET AL


Abstract 1

Background. While β -blockers can be effective in controll ing 2

tachyarrhythmias after pediatr ic cardiac surgery, a negat ive inotropic 3

inf luence somet imes complicates their use. Landiolol hydrochlor ide is a novel , 4

ul t ra-shor t -act ing β -blocker recent ly developed in Japan. The drug has higher 5

β1/β2 selectivi ty rat io and a less negative inotropic effect . This s tudy 6

retrospectively evaluates the eff icacy and safety of landiolol in the 7

management of tachyarrhythmias af ter pediat r ic cardiac surgery. 8

Methods. A retrospective analysis was performed on 312 consecut ive 9

pat ients undergoing surgery for congeni tal hear t disease. Twelve pat ients were 10

t reated with landiolol for cr i t ical tachyarrhythmia. The mean age of patients 11

was 28.7 ± 10.6 months. Five junct ional ectopic tachycardia , 2 at ria l f lut ters , 12

1 paroxysmal supraventr icular tachycardia , 1 at ria l f ibr i l la t ion, 1 13

at rioventricular reciprocating tachycardia wi th Wolff - Parkinson White 14

Syndrome and 2 excessive s inus tachycardia were treated. 15

Results . The mean loading and maintenance doses were 11.3 ± 4.0 and 6.8 ± 16

0.9 μg / kg / min, respect ively. Rate control was achieved in all pat ients . 17

Landiolol reduced the heart rate from 169.7 ± 11.4 to 127.7 ± 7.5 bpm 18

(p<0.05) whi le blood pressure did not s ignif icant ly change. Tachyarrhythmias 19

were conver ted to s inus rhythm in 70.0% of the cases and the average t ime 20

3 TOKUNAGA ET AL


needed to achieve hear t ra te reduct ion was 2.3 ± 0.5 hours . 1

Conclusions. Landiolol was eff icacious in treating tachyarrhythmia in 2

pediat ric cardiac surgery. The desi red negative chronotropic effect was 3

achieved without s ignif icant hemodynamic compromise. The ul tra-shor t 4

half -l i fe of landiolol provided rapid dose manipulation. This s tudy suggests 5

that landiolol is a promising opt ion for the management of postoperative 6

tachyarrhythmias in pediat r ic pat ients . 7

(255words) 8

9

10

11

12

4 TOKUNAGA ET AL


Intractable tachyarrhythmia af ter pediat r ic cardiac surgery can quickly 1

lead to hemodynamic instabil i ty and requires prompt management 1 2 3 . While 2

β -blockers can be effect ive in controll ing these tachyarrhythmias , a negat ive 3

inotropic inf luence somet imes complicates their use 4 . 4

Landiolol hydrochlor ide (Ono Pharmaceutical Co, Ltd, Osaka, Japan) is a 5

novel ul tra-shor t -act ing β -blocker developed in Japan. Plasma half -l i fe of the 6

drug is 4 minutes . It has a higher β1/β2 select ivi ty rat io and as a result a less 7

pronounced negat ive inotropic effect compared with other intravenous 8

β -blockers 5 . Landiolol has become a common therapeut ic option for the 9

management of postoperative tachyarrhythmia in adult pat ients in Japan 6 7 . 10

However, l i t t le has been reported regarding i ts use in pediatr ic patients . 11

We report our exper ience with landiolol in postoperat ive pediatr ic 12

cardiac surgical pat ients suffering f rom intractable tachyarrhythmia. 13

14

Patients and Methods 15

Between 2006 and 2012, 312 patients underwent open heart surgery for 16

congeni tal hear t disease at the Tsukuba Universi ty hospital . Twelve of these 17

pat ients developed intractable tachyarrhythmia af ter surgery and were treated 18

with landiolol . The study was approved by the Universi ty of Tsukuba 19

Inst i tut ional Review Board and patient records were analyzed ret rospectively. 20

5 TOKUNAGA ET AL


In al l pat ients tachyarrhythmia resulted in hemodynamic instabil i ty, and 1

was t reated with a s tandard protocol which included cooling for hyper thermia, 2

sedation, elect rolyte imbalance management and minimizat ion of int ravenous 3

catecholamine infusion i f possible . 4

In the ear l ier cases , the adminis t rat ion of landiolol was ini t ia ted at 40 μg 5

/ kg / min for loading and gradually decreased into the recommended 6

maintenance dose of 10 to 40μg / kg / min according to the pharmaceutical 7

reference. In la ter cases , the adminis tration of landiolol was s tar ted with a 8

relat ively low dose at 3-5 μg / kg / min with special concern for excessive 9

negat ive chronotropic effect wi th a loading of 40 μg / kg / min s ince we 10

experienced one case that developed excessive bradycardia wi th the init ia l 11

protocol . The maintenance dose of landiolol was set t led at the lowest effect ive 12

dose needed to sustain s inus rhythm or adequate heart rate with stabi l ized 13

hemodynamics. 14

15

Statist ical analysis 16

All values are expressed as the mean ± standard error of the mean. 17

Stat is t ical analysis was performed using the Wilcoxon signed-rank test to 18

compare pre- and post-adminis t rat ion heart ra te and systol ic blood pressure . 19

SPSS 19.0 for windows (SPSS Inc, Chicago, IL) was used for analyses . 20

6 TOKUNAGA ET AL


1

Results 2

The characteris t ics of the 12 pat ients t reated with landiolol are l is ted in 3

Table 1. The mean age of pat ients was 28 ± 10 months ( range, 10 days to 108 4

months) . There were 5 junctional ectopic tachycardia (JET), 2 at ria l f lutter, 1 5

paroxysmal supraventr icular tachycardia (PSVT), 1 at rial f ibri l la t ion, 1 6

at rioventricular reciprocating tachycardia (AVRT) by Wolff-Parkinson-White 7

(WPW) syndrome and 2 excessive s inus tachycardia . Digoxin and l idocaine 8

were used in 2 cases before the adminis tra t ion of landiolol . 9

The mean loading dose was 11.3 ± 4.0 μg / kg / min and the maintenance 10

dose was 6.8 ± 0.9 μg / kg / min. Landiolol reduced the heart rate signif icantly 11

from 169.7 ± 11.4 to 127.7 ± 7.5 beats / minute (Figure 1) , whi le pre- and 12

post-adminis trat ion systolic blood pressure did not s ignificant ly change. The 13

average t ime needed to achieve a 20% hear t ra te reduct ion was 2.3 ± 0.4 hours 14

(Table 2) . 15

Tachyarrhythmias 16

were conver ted to regular sinus rhythms in 70 % of cases and the f inal average 17

percent reduct ion in hear t rate was 23.7 ± 4.2 %. One neonate among the 18

ear l ier cases rapidly developed an excessive bradycardia wi th heart ra te below 19

100 beats / min at 48 hours after the onset of landiolol infusion with 10.0 μg / 20

7 TOKUNAGA ET AL


kg / min. Hemodynamic stabil i ty was reestabl ished by immediate cessat ion of 1

landiolol and introduct ion of a tr ia l pacing. Hear t ra te was maintained under 2

at ria l pacing without res tar t of landiolol . 3

Comment 4

The efficacy of β -blockade in t reating tachyarrhythmia af ter cardiac 5

surgery is widely recognized. Despi te this the myocardial depressant effects 6

of these drugs complicates their use. 7

Landiolol i s a novel ul t ra-shor t -act ing β -blockade which has a plasma 8

half -l i fe of 4 minutes 5 . Landiolol was developed in Japan and released in 9

2002. In a recent randomized control s tudy, Sezai e t a l . reported that landiolol 10

adminis t rat ion s ignif icantly reduced the occurrence of a tr ial f ibri l la t ion and 11

heart rate in patients af ter adul t cardiac surgery without s ignificant change in 12

blood pressure 7 . Another prospect ive mult icenter randomized s tudy in adul t 13

pat ients (JL-KNIGHT) was also recent ly under taken in Japan. In this study, 14

landiolol was effective for the conversion of a t rial f ibri l la t ion to s inus rhythm 15

af ter open heart surgery with a lower incidence of hypotension 8 . The drug has 16

been widely used in Japan and recognized as one of the useful options for the 17

management of postoperative tachyarrhythmias in adul t pat ients . However, 18

unt i l now the efficacy of landiolol in pediat ric cardiac surgery patients has not 19

been publ ished. The present study reports our earl ies t exper ience. 20

8 TOKUNAGA ET AL


β -adrenergic receptors are subdivided into two basic types . β1-receptors 1

exist in the myocardium and their st imulation has both inotropic and 2

chronotropic effects . β2-receptors exis t in smooth muscle cel ls and their 3

s t imulation results in bronchodi lat ion and vasodilation. β -blockades are 4

character ized by the select ivi ty for β1 and β2 s t imulation. There are 3 5

β -blockades avai lable for int ravenous inject ion at present . One is propranolol 6

which has a low β1 / β2 selectivi ty rat io of 0.6 and a long plasma half -l i fe of 7

120 min. Because of i t s st rong negat ive inotropic effect and long half-l i fe , 8

propranolol is not the drug of choice for cri t ical care after pediatr ic cardiac 9

surgery. Esmolol hydrochloride is another β-blockade which has a higher β1 / 10

β2 selectivi ty rat io of 20 and a plasma half -l i fe of 9 minutes 9 . Esmolol has 11

been also commercial ly avai lable in Japan s ince 2002. Compared with these 12

int ravenous β -blockades, landiolol has the shor test plasma half -l i fe of 4 13

minutes and the highest β1 / β2 selectivi ty rat io of 277. 14

Ikeshi ta e t a l . reported that landiolol and esmolol had equipotent 15

negat ive chronotropic effects . However , landiolol showed less of a negat ive 16

inotropic effect including the maximal rate of lef t ventr icular force 17

development (LVdP / dtmax ) while esmolol demonstrated a st rong inhibi tory 18

effect 1 0 , 1 1 . 19

In our cases , more than 20 % heart rate reduct ion was achieved in al l 20

9 TOKUNAGA ET AL


pat ients wi thout decrease in blood pressure by landiolol . Also rhythm 1

conversion was obtained in 70 % of patients. These results are consis tent with 2

previous studies which demonstrate the s trong negat ive chronotropic effect 3

without negat ive inotropic effect of landiolol in adult patients af ter cardiac 4

surgery 7 8 . Addi t ionally, Shibata et al . reported that landiolol had no 5

apparent effects on the action potent ial or ionic currents of ventricular 6

myocytes , whi le esmolol shor tened action potential durat ion and demonstrated 7

a negat ive inotropic effect in a dose related fashion. 1 2 . This could explain 8

why landiolol has less negat ive inotropic effect . However, the detai led 9

mechanism is s t i l l unknown and fur ther invest igation is needed. 10

The efficacy of other ant iarrhythmic drugs is widely recognized, though 11

there are possible adverse side effects such as bradycardia , hypotension or 12

proarrythmia 1 4 1 3 1 4 . Amiodarone is recognized as one of the most potent 13

drugs for the management of arrhythmias and i ts efficacy in the management 14

of cri t ical tachyarrhythmia in pediat ric pat ients has been reported 1 5 1 6 . 15

However, in Japan, intravenous administ rat ion of amiodarone was approved in 16

2007, and landiolol was released a l i t t le earl ier than amiodarone. We started 17

using landiolol as a f irs t l ine drug for tachyarrhythmia to preserve 18

hemodynamics before the commercial release of amiodarone and we have seen 19

the effectiveness of this novel drug. Therefore we have no cl inical exper ience 20

10 TOKUNAGA ET AL


to contrast landiolol wi th amiodarone in pediatr ic tachyarrhythmia. 1

Amiodarone should be used with caut ion when t reating chi ldren because of the 2

adverse s ide effects including a 36% rate of hypotension and a 20% rate of 3

bradycardia 1 3 . Moreover s ince the plasma half -l i fe of amiodarone is 14 days, 4

adverse s ide effects could be prolonged when they appear in cr i t ical si tuat ion. 5

In contrast , the ult ra-shor t half -l i fe of landiolol provides the advantage of 6

rapid dose manipulation to maintain s table hemodynamics and this may make 7

landiolol more sui table for emergency medical care . 8

The recommended loading dose of landiolol based on the company’s 9

instruct ion is 40 μg / kg / min and the maintenance dose is 10 μg / kg / min. 10

However, we exper ience one case of bradycardia which required atr ial pacing. 11

In addi t ion, based on our exper ience of using landiolol in adult pat ients in 12

JL-KNIGHT study 8 , we speculated that the loading dose of 40 μg / kg / min 13

could be too much for pediat ric pat ients . Therefore, we recommend a low 14

start ing dose of 3 to 5 μg / kg / min instead of a high loading dose, and the 15

dose should be increased gradually under careful hemodynamic observat ion 16

with backup pacing. 17

18

19

Limitations 20

11 TOKUNAGA ET AL


The numbers of cases we have examined are relat ively smal l to have any 1

s t rong conclusions. Never theless this is s t i l l the country’s largest experience 2

of this newly developed drug in pediatr ic populat ion as far as we know. Also 3

our s tudy did not make comparisons of landiolol hydrochlor ide with other 4

ant i -arrhythmia drugs including amiodarone. Fur ther comparative studies wi th 5

other anti -arrhythmia drugs and more informat ion in a larger ser ies of patients 6

would be necessari ly to assess the effectiveness of landiolol for rate and 7

rhythm control in pediat ric pat ients . 8

9

Conclusion 10

Landiolol was efficacious in t reat ing int ractable tachyarrhythmia in 11

pediat ric pat ients after cardiac surgery. This s tudy suggests that landiolol may 12

be a promising option for the management of postoperative tachyarrhythmias 13

in pediatr ic patients . 14

15

Acknowledgment 16

The authors wish to thank Joseph H. Gorman, III , MD, Universi ty of 17

Pennsylvania for the language review.18

12 TOKUNAGA ET AL


References 1

1. Dodge-Khatami A, Miller OI, Anderson RH, et al . Surgical 2

substrates of postoperative junctional ectopic tachycardia in 3

congenital heart defects. J Thorac Cardiovasc Surg 4

2002;123:624-630. 5

2. Valsangiacomo E, Schmid ER, Schupbach RW, et al . Early 6

postoperative arrhythmias after cardiac operation in children. Ann 7

Thorac Surg 2002;74:792-796. 8

3. Delaney JW, Moltedo JM, Dziura JD, Kopf GS, Snyder CS. Early 9

postoperative arrhythmias after pediatric cardiac surgery. J Thorac 10

Cardiovasc Surg 2006;131:1296-1300. 11

4. Dodge-Khatami A, Miller OI, Anderson RH, Gil-Jaurena JM, 12

Goldman AP, de Leval MR. Impact of junctional ectopic 13

tachycardia on postoperative morbidity following repair of 14

congenital heart defects. Eur J Cardiothorac Surg 15

2002;21:255-259. 16

5. Atarashi H, Kuruma A, Yashima M, et al . Pharmacokinetics of 17

landiolol hydrochloride, a new ultra-short-acting beta-blocker, in 18

patients with cardiac arrhythmias. Clin Pharmacol Ther 19

2000;68:143-150. 20

13 TOKUNAGA ET AL


6. Ito H, Sobue K, So M, et al . Use of landiolol in the perioperative 1

management of supraventricular tachycardia. J Anesth 2

2006;20:253-254. 3

7. Sezai A, Minami K, Nakai T, et al . Landiolol hydrochloride for 4

prevention of atrial fibri l lat ion after coronary artery bypass 5

graft ing: new evidence from the PASCAL trial . J Thorac 6

Cardiovasc Surg 2011;141:1478-1487. 7

8. Sakamoto A, Kitakaze M, Takamoto S, Namiki A, Kasanuki H, 8

Hosoda S. Landiolol , an Ultra-Short-Acting beta(1)-Blocker, More 9

Effectively Terminates Atrial Fibri l lat ion Than Dilt iazem After 10

Open Heart Surgery. Circ J 2012;76:1097-1101 . 11

9. Adamson PC, Rhodes LA, Saul JP, et al . The pharmacokinetics of 12

esmolol in pediatric subjects with supraventricular arrhythmias. 13

Pediatr Cardiol 2006;27:420-427. 14

10. Ikeshita K, Nishikawa K, Toriyama S, et al . Landiolol has a less 15

potent negative inotropic effect than esmolol in isolated rabbit 16

hearts. J Anesth 2008;22:361-366. 17

11. Sasao J , Tarver SD, Kindscher JD, Taneyama C, Benson KT, Goto 18

H. In rabbits, landiolol , a new ultra-short-acting beta-blocker, 19

exerts a more potent negative chronotropic effect and less effect 20

14 TOKUNAGA ET AL


on blood pressure than esmolol. Can J Anaesth 2001;48:985-989. 1

12. Shibata S, Okamoto Y, Endo S, Ono K. Direct effects of esmolol 2

and landiolol on cardiac function, coronary vasoactivity, and 3

ventricular electrophysiology in guinea-pig hearts. J Pharmacol 4

Sci 2012; 118:255-265. 5

13. Saul JP, Scott WA, Brown S, et al . Intravenous amiodarone for 6

incessant tachyarrhythmias in children: a randomized, 7

double-blind, antiarrhythmic drug trial . Circulation 8

2005;112:3470-3477. 9

14. Wong KK, Potts JE, Etheridge SP, Sanatani S. Medications used to 10

manage supraventricular tachycardia in the infant a North 11

American survey. Pediatr Cardiol . 2006;27:199-203. 12

15. Figa FH, Gow RM, Hamilton RM, Freedom RM. Clinical efficacy 13

and safety of intravenous Amiodarone in infants and children. Am 14

J Cardiol 1994;74:573-577. 15

16. Perry JC, Fenrich AL, Hulse JE, Triedman JK, Friedman RA, 16

Lamberti JJ . Pediatric use of intravenous amiodarone: efficacy and 17

safety in cri t ically i l l patients from a multicenter protocol. J Am 18

Coll Cardiol 1996;27:1246-1250. 19

20

21

15 TOKUNAGA ET AL


Table 1. Patient characteristic

Case DiagnosisOperativeprocedure

Bodyweight

(kg)Sex Age

Bypasstime(min)

Crossclamp time

(min)

1 TGA ASO 3.3 M 10 days 269 1062 IAA,VSD Ao repair + ICR 3.4 M 17 days 144 713 TOF ICR 8.4 M 1 year 151 914 Asplenia, SV Extra TCPC 13.7 M 5 years 157 695 DILV, CoA DKS+BDG 7.7 F 1 year 160 1076 TAPVC TAPVCrepair 2.8 M 4 days 166 717 DORV DKS 7.0 M 1 year 257 688 Asplenia, PA BCPS 15.2 F 9 years 90 -9 TGA Senning 5.2 M 30 days 179 10710 HLHS NW 3.3 F 6 days 209 10811 HOCM Myectomy 19.2 M 6 years 103 5612 DILV, PS Extra TCPC 11.5 M 5 years 145 -

Mean 8.4 169.2 85.4SE 1.6 15.5 6.5

ASO: Aortic switch operation, BDG: Bidirectional Glenn,

BCPS: Bidirectional cavopulmonary shunt, DILV: Double inlet left ventricle,

DKS: Damus-Kaye-Stansel, DORV: Double outlet right ventricle,

HLHS: Hypoplastic left heart syndrome, HOCM: Hypertrophic obstructive cardiomyopathy,

IAA: Interrupted aortic arch, NW: Norwood operation,

PA: Pulmonary atresia, PS: Pulmonary stenosis,

SV: Single ventricle, TAPVC: Total anomalous pulmonary vein connection,

TCPC: Total cavopulmonary connection, TOF: Tetralogy of Fallot,

TGA: Transposition of great arteries, VSD: Ventricular septal defect,

16 TOKUNAGA ET AL


Table 2. Hemodynamic data of pre and post landiolol hydrochloride administration.

CaseType of

arrythmiaSinus

conversionPre sBP(mmHg)

Post sBP(mmHg)

Pre HR(bpm)

Post HR(bpm)

Time to20% HR

reduction(hr)

Time to SRconversion

(hr)

Loadidngdose oflandiolol

(μg/kg/min)

Maintenancedose oflandiolol

(μg/kg/min)

dosage ofdopamin

(γ）

dosage ofPDEⅢinhibitor

(γ）

1 JET yes 48 56 195 163 6 10 40 10 7.5 0.252 JET no 75 72 219 175 1 - 3 8 3 0.53 JET yes 59 70 170 130 2 5 4 8 10 0.54 JET yes 73 72 130 100 1 5 5 10 5 0.55 JET yes 110 120 200 140 2 4 4 8 10 0.756 AF no 74 75 180 120 3 - 3 1 0 07 AF no 112 99 149 120 4 - 5 5 10 0.758 af yes 104 99 120 100 2 5 40 10 9 0.259 PSVT yes 75 85 233 129 2 24 5 7 1 010 WPW AVRT yes 80 75 130 115 2 2 3 3 0 0.2511 sinus tachy - 117 101 120 90 1 - 8 8 0 012 sinus tachy - 60 80 190 150 2 - 16 4 10 0.5

Mean 82.3 83.7 169.7 127.7 2.3 7.9 11.3 6.8 5.5 0.4SE 6.6 5.1 11.4 7.5 1.5 2.8 4.0 0.9 1.3 0.1

af: Atrial fibrillation, AF: Atrial flutter, BP: blood pressure, HR: heart rate, JET: Junctional ectopic tachycardia,

PDEⅢinhibitor: phosphodiesteraseⅢinhibitor、PSVT: Paroxysmal supraventricular tachycardia, SR: sinus rhythm,

WPW AVRT: Wolff-Parkinson White Syndrome and Atrioventricular reciprocating tachycardia

17 TOKUNAGA ET AL


Figure 1. Heart rate, pre and post landiolol hydrochloride administration in each case. * p < 0.05

Documents

Effects of Landiolol Hydrochloride on Intractable ... · Effects of Landiolol Hydrochloride on Intractable Tachyarrhythmia After ... Wolff - Parkinson White ... 1 Intractable tachyarrhythmia