378
The Use of Dopexamine after Cardiac Surgery: Acute and Long-Term Effects in Patients with Impaired Cardiac Function N. Friedel. R. Wenzel. G. Math eis. and R. Hetz er Dept. of Cardiothoracic Surgery, German Hea rt Insti tute Berlin . Berlin . Germany
The haem od ynamic efficacy of dopexa mine, a Bz-adrenergic agonist with dopaminer gic activity. was eva luated during dosetitr ation a nd longterm infus ion in 20 cardiosurgical patients with low ca rdiac output following coronary a rtery bypass grafting a nd/o r valve replacemen t or repa ir. After infusion of
four doses It . 2. 4, and 6 ug/kg/min). the dose producing the optima l response was administer ed for up to 36 h. Dopexam ine infusion resulted in a dose-depe ndent s ~ i fica n t incre ase in cardi ac ind ex (CI: 2.2 3.3 U minl m ) asso ciated --t
with a mark ed reduction of syst emic vas cula r res istance (SVR: 1820 -. 1144 dyn . sec cm- 5 ) . Hea rt rate incr ea sed sign ifica ntly (HR: 89 -. 117 beats/min) , wh ile mea n ar terial blood pr essur e remai ne d unch anged (MAP: 94 -. 89 mmH g). Unwa nte d effects (tachycardia a nd h ypoten sion) were ch iefly see n at hig her dose s ( --f 4 pg/k g/ min). The beneficial haemodynamic effects were well mai ntained d uring the exte nde d infusion perio d up to 36 hours at a mea n dop exam ine dose of 2.8 ug/k g/min . At these low dos es. the positi ve ch ronotro pic respo nse to th e dr ug remai ned within th e limit s of clin ica l a ccepta bility. During long-ter m infu sion up to 36 hours th er e was no in dica tion of tole rance or a n effect attenuation . It can be con clude d that dopexamine actin g as "inodilator " with do pa min er gic pro pe r ties is an usefu l adjunct to the pharmocologica l s pec trum in the mana gement of low -ou tput states followin g ca rdiac s urgery. Key words Dopexamine - Low ou tput syn drom - Cardiac surgery
Anwe nd ung von Dope xami n in d er Herzchi rur gte: Akute un d Langz eit-\\l r k u ngen be i Pa tien te n mit el ngeschra nkter kardlal er Fu n ktio n Die hamodynamische Wirksamk eit von Dopexamin. einem neu en Katech olamin mit vorwiegend beta-2 -a dre nerger u nd do pa minerger Wirku ng. wur de be i 20 kardioch iru rgisch en Pa tien ten mit eingeschra n kter Auswurfleist un g nach Bypa ssode r Klap pen chirurgie doslsa bh an glg und wa hre n d la nger frtstiger Anwe ndun g unters uch t. Dope xa min w ur de zun ac hst in ste igende r Dos ierung von 1, 2, 4 u nd 6 ug/k g/min infund iert . Anschli eBend wurde d ie Dosis. bei der ein opti ma ler ham od ynami sch er EITekt erreicht wurde , tiber ein en Zeitra um bis zu 36 h applt ziert. Dopexamin fuhr te dostsabh an gig zu einer signifikante n Stelger ung d es lIer zind ex (Cl: 2,2 -. 3,3 Umin /m 2) bel gleichzeitige r Hed u ktlon des systemvaskularen Widerstandes (SVR: 1820 --f 1144 dyn - sec cm- 5 ) . Die Herzfrequen z stieg deslsabha ngig sign ifika n t a n (HF: 89 --f 11 7 min- I), w ah rend der arter ielle Mitteldruck weitgeh end konsta nt blieb (MAP: 9 4 --f 89 mmH g). Unerwunschte EITekte w ie Tachyka rd ie und Hypoten sion wurd en led iglich bei hcheren Dosieru ngen beobach tet ( --f 4 llg/k glmin ). Die Verbesser ung der Hamodyn am tk wa r au ch nach 36s ttind iger Infusionsdauer unter eine r mittler en Dopexam in-Dosierung von 2,8 pg/kg/mln unverandert na ch weis ba r; Die positiv chronotro pe n EITekte wa re n in dieser niedrigen Dosierung gering ausgepragt. Auch bei Ian ger dau ernder Infusion bis zu 36 h wu rde ke ine Tolera nzentwicklung beo bac htet. Dopexamin s tellt als . Jnodtlata tor" mit gleichze itig do pamine rge n Eigensc haften cine Erweiterung des ph a rm ak ologischen Spektrums in de r Behandlung des Low-outpu t-Syndroms nach herzchirurgischen Eingriffen da r.
card@) is a recently developed peripherally acting dopamine-receptor agonist with properties reducing afterload Low-cardiac-outp ut states cha racterized by a depr ession of (1). It is one-third as potent as dopamine in stimulating myocardial function as a result of decreas ed contrac tility DA,- receptors but 60 times as potent as a ~2- adren o c eptor and increas ed afterload remain one of the major causes of agonist and does n ot stimul at e vasc ular a lpha-receptors. morb idity and mortali ty following cardiac surgery. The stimulation of vascular DA,-rece ptors and ~ 2-adreno The pharmacological management of postoperative . ceptors results in improvement of renal blood flow an d carmyocardial failure is primaril y bas ed on the use of inotropi c diac output secondary to afterload reduction. In addition. and vasodilating agen ts to increase contr actility an d to re- the agent exerts indirect eITects at ~ J -adren o ceptor s by inhidu ce after load (12). Dopexamine hydrochlorid e (Dopabiting neuron al reuptake (uptake-1 blockade) of endogenous norep inephrine (8). Other features of dopexamine hydrochloride that should enha nce its clinical use ar e lack of Present ed in part at the 21st Annual Meeting of the arrhyth mogenicity and rap id res ponsiveness to alteration Germa n Society for Thoracic and Cardiovascular Surgery in infusion rate. February 19 - 22, 1992, Bonn Introdu cti on
Thor ac. cardiovasc. Surgeon 40 (1992) 378 - 38 1 © Georg Thieme Verla g Stuttgart New York
Received for Publi cation : July 22. 1992
Downloaded by: University of British Columbia. Copyrighted material.
Sum mary
The Use of Dopexamine afte r Cardiac Surgery
Thome. eardiovase. Surgeon 40 (1992)
We report on the haem odynamic efficacy during dose titration and tolerability of long-term infusion up to 36 h in patients with impaired pump function following cardiac s urger y.
379
least signifi cant difTerence (LSD) method. All statistica l te sts we re two -ta iled and ca rrie d out at th e 5 % level of significance. Results
Patients and m ethods Eleven patients (I after CABG and ail a fter MVR) re quired a tria l or ventricula r pa cing be cause of bradycardi c dysrh ythmias immed iat ely after ca rdiopulm onary bypass . Th ose pati ents who had pa ced hea rt rates during both th e contro l period and th e 1 ug/k g/ min step of th e dos e titration period were excluded from all an a lyses of heart rate an d th e deri ved stroke-volum e index a nd rate-pressure product.
Dose Titration All patients who ente re d the study received all four dopex a mine doses du ring the dose titration ph ase. Significant changes from control values at all doses were see n for the increase in cardiac index (Cl) and the decrease in systemic vascular resistan ce (SVR) . Mean arterial pressure (MAP) , howev er, remained constant. heart rate (HRl and rate-p ressure produ ct in crea sed sign ifica ntly at dose levels ab ove 1 ug/kg/rnin and pea ked at 6 ug/kg/min. Stroke volume ind ex was slightly incr eas ed; however. these changes were not significant. Left and right atrial pressures wer e un changed exce pt for th e 4 -s g/kg/ min do se level wher e the right a tr ial pressure wa s signifi cantly reduced . There were no significant changes in pulmonary vascular resistance or in mean and diastolic pulmonary artery pressures, although systolic artery pressures tended to increase at all dose levels. The maximum changes from baseline for most of the haemodynamic parameters were observe d at 6 ug/k g/rnin and th e dose -r esp onse re la tionship was less thereafter (Tab le 11.
S tatistical analysi s
Long-term inf usion
Data were analysed by parametric statistical methods. Tw o-way analysis was used , with dose and patients (for the dos e titrat ion ph ase) or time a nd pa tien ts (for the long-term infusion) as factors. Where a significant treatment effect wa s see n, mean values we re co mpaired pairwise using the
Eight patien ts received dopexamine for at lea st 36 h . The infu sion wa s sto ppe d prematurely in 11 patien ts w ho had no need for further catecholamine medication . One patient (exclud ed from thi s a na lysis) was withdrawn becau se of postoperative bleeding necessitating rethoracotomy.
Table 1 Haemodynamic effect of dopexamine hydrochloride during dose-titration
2
Control Cardiac index (L;min/m2)
Heart rate (beats/mini
Systemicvascular resistance (dyn. sec . cm- s) Mean blood pressure (mmHg) Stroke-volume index (mVm 2)
PACWpressure (mmHg ) Right atrial pressure (mmHg) Pulmonary vascular resistance (dyn . sec . cm- 5) Pulmonary artery pressure (mmHg):
systolic diastolic mean Rate-pressure product (mm Hg/min)
2.20 88.7 1820.4 94.1 24.1 13.6 10.0 180.7 32.8 15.8 22.0 12397.6
2.63" 95.9 1600.7' 98.2 25.4 13.4 9.8 193.8 37.4' 16.6 24.2 14527.1
Dose (~g;Kg/m inl
4
3.12' 105.0' 1374.5" 98.7 27.4 13.3 9.5 173.8 39.3" 17.2 24.7 16210.6'
36.3' 15.4 22.8 17434.9'
aMeans whichdiffer by more than theLSD are significantly different (p < 0.05). b No significant treatment effect.
. Signilicently different from control (p
The Use of Dopexamine after Cardiac Surgery: Acute and Long-Term Effects in Patients with Impaired Cardiac Function N. Friedel. R. Wenzel. G. Math eis. and R. Hetz er Dept. of Cardiothoracic Surgery, German Hea rt Insti tute Berlin . Berlin . Germany
The haem od ynamic efficacy of dopexa mine, a Bz-adrenergic agonist with dopaminer gic activity. was eva luated during dosetitr ation a nd longterm infus ion in 20 cardiosurgical patients with low ca rdiac output following coronary a rtery bypass grafting a nd/o r valve replacemen t or repa ir. After infusion of
four doses It . 2. 4, and 6 ug/kg/min). the dose producing the optima l response was administer ed for up to 36 h. Dopexam ine infusion resulted in a dose-depe ndent s ~ i fica n t incre ase in cardi ac ind ex (CI: 2.2 3.3 U minl m ) asso ciated --t
with a mark ed reduction of syst emic vas cula r res istance (SVR: 1820 -. 1144 dyn . sec cm- 5 ) . Hea rt rate incr ea sed sign ifica ntly (HR: 89 -. 117 beats/min) , wh ile mea n ar terial blood pr essur e remai ne d unch anged (MAP: 94 -. 89 mmH g). Unwa nte d effects (tachycardia a nd h ypoten sion) were ch iefly see n at hig her dose s ( --f 4 pg/k g/ min). The beneficial haemodynamic effects were well mai ntained d uring the exte nde d infusion perio d up to 36 hours at a mea n dop exam ine dose of 2.8 ug/k g/min . At these low dos es. the positi ve ch ronotro pic respo nse to th e dr ug remai ned within th e limit s of clin ica l a ccepta bility. During long-ter m infu sion up to 36 hours th er e was no in dica tion of tole rance or a n effect attenuation . It can be con clude d that dopexamine actin g as "inodilator " with do pa min er gic pro pe r ties is an usefu l adjunct to the pharmocologica l s pec trum in the mana gement of low -ou tput states followin g ca rdiac s urgery. Key words Dopexamine - Low ou tput syn drom - Cardiac surgery
Anwe nd ung von Dope xami n in d er Herzchi rur gte: Akute un d Langz eit-\\l r k u ngen be i Pa tien te n mit el ngeschra nkter kardlal er Fu n ktio n Die hamodynamische Wirksamk eit von Dopexamin. einem neu en Katech olamin mit vorwiegend beta-2 -a dre nerger u nd do pa minerger Wirku ng. wur de be i 20 kardioch iru rgisch en Pa tien ten mit eingeschra n kter Auswurfleist un g nach Bypa ssode r Klap pen chirurgie doslsa bh an glg und wa hre n d la nger frtstiger Anwe ndun g unters uch t. Dope xa min w ur de zun ac hst in ste igende r Dos ierung von 1, 2, 4 u nd 6 ug/k g/min infund iert . Anschli eBend wurde d ie Dosis. bei der ein opti ma ler ham od ynami sch er EITekt erreicht wurde , tiber ein en Zeitra um bis zu 36 h applt ziert. Dopexamin fuhr te dostsabh an gig zu einer signifikante n Stelger ung d es lIer zind ex (Cl: 2,2 -. 3,3 Umin /m 2) bel gleichzeitige r Hed u ktlon des systemvaskularen Widerstandes (SVR: 1820 --f 1144 dyn - sec cm- 5 ) . Die Herzfrequen z stieg deslsabha ngig sign ifika n t a n (HF: 89 --f 11 7 min- I), w ah rend der arter ielle Mitteldruck weitgeh end konsta nt blieb (MAP: 9 4 --f 89 mmH g). Unerwunschte EITekte w ie Tachyka rd ie und Hypoten sion wurd en led iglich bei hcheren Dosieru ngen beobach tet ( --f 4 llg/k glmin ). Die Verbesser ung der Hamodyn am tk wa r au ch nach 36s ttind iger Infusionsdauer unter eine r mittler en Dopexam in-Dosierung von 2,8 pg/kg/mln unverandert na ch weis ba r; Die positiv chronotro pe n EITekte wa re n in dieser niedrigen Dosierung gering ausgepragt. Auch bei Ian ger dau ernder Infusion bis zu 36 h wu rde ke ine Tolera nzentwicklung beo bac htet. Dopexamin s tellt als . Jnodtlata tor" mit gleichze itig do pamine rge n Eigensc haften cine Erweiterung des ph a rm ak ologischen Spektrums in de r Behandlung des Low-outpu t-Syndroms nach herzchirurgischen Eingriffen da r.
card@) is a recently developed peripherally acting dopamine-receptor agonist with properties reducing afterload Low-cardiac-outp ut states cha racterized by a depr ession of (1). It is one-third as potent as dopamine in stimulating myocardial function as a result of decreas ed contrac tility DA,- receptors but 60 times as potent as a ~2- adren o c eptor and increas ed afterload remain one of the major causes of agonist and does n ot stimul at e vasc ular a lpha-receptors. morb idity and mortali ty following cardiac surgery. The stimulation of vascular DA,-rece ptors and ~ 2-adreno The pharmacological management of postoperative . ceptors results in improvement of renal blood flow an d carmyocardial failure is primaril y bas ed on the use of inotropi c diac output secondary to afterload reduction. In addition. and vasodilating agen ts to increase contr actility an d to re- the agent exerts indirect eITects at ~ J -adren o ceptor s by inhidu ce after load (12). Dopexamine hydrochlorid e (Dopabiting neuron al reuptake (uptake-1 blockade) of endogenous norep inephrine (8). Other features of dopexamine hydrochloride that should enha nce its clinical use ar e lack of Present ed in part at the 21st Annual Meeting of the arrhyth mogenicity and rap id res ponsiveness to alteration Germa n Society for Thoracic and Cardiovascular Surgery in infusion rate. February 19 - 22, 1992, Bonn Introdu cti on
Thor ac. cardiovasc. Surgeon 40 (1992) 378 - 38 1 © Georg Thieme Verla g Stuttgart New York
Received for Publi cation : July 22. 1992
Downloaded by: University of British Columbia. Copyrighted material.
Sum mary
The Use of Dopexamine afte r Cardiac Surgery
Thome. eardiovase. Surgeon 40 (1992)
We report on the haem odynamic efficacy during dose titration and tolerability of long-term infusion up to 36 h in patients with impaired pump function following cardiac s urger y.
379
least signifi cant difTerence (LSD) method. All statistica l te sts we re two -ta iled and ca rrie d out at th e 5 % level of significance. Results
Patients and m ethods Eleven patients (I after CABG and ail a fter MVR) re quired a tria l or ventricula r pa cing be cause of bradycardi c dysrh ythmias immed iat ely after ca rdiopulm onary bypass . Th ose pati ents who had pa ced hea rt rates during both th e contro l period and th e 1 ug/k g/ min step of th e dos e titration period were excluded from all an a lyses of heart rate an d th e deri ved stroke-volum e index a nd rate-pressure product.
Dose Titration All patients who ente re d the study received all four dopex a mine doses du ring the dose titration ph ase. Significant changes from control values at all doses were see n for the increase in cardiac index (Cl) and the decrease in systemic vascular resistan ce (SVR) . Mean arterial pressure (MAP) , howev er, remained constant. heart rate (HRl and rate-p ressure produ ct in crea sed sign ifica ntly at dose levels ab ove 1 ug/kg/rnin and pea ked at 6 ug/kg/min. Stroke volume ind ex was slightly incr eas ed; however. these changes were not significant. Left and right atrial pressures wer e un changed exce pt for th e 4 -s g/kg/ min do se level wher e the right a tr ial pressure wa s signifi cantly reduced . There were no significant changes in pulmonary vascular resistance or in mean and diastolic pulmonary artery pressures, although systolic artery pressures tended to increase at all dose levels. The maximum changes from baseline for most of the haemodynamic parameters were observe d at 6 ug/k g/rnin and th e dose -r esp onse re la tionship was less thereafter (Tab le 11.
S tatistical analysi s
Long-term inf usion
Data were analysed by parametric statistical methods. Tw o-way analysis was used , with dose and patients (for the dos e titrat ion ph ase) or time a nd pa tien ts (for the long-term infusion) as factors. Where a significant treatment effect wa s see n, mean values we re co mpaired pairwise using the
Eight patien ts received dopexamine for at lea st 36 h . The infu sion wa s sto ppe d prematurely in 11 patien ts w ho had no need for further catecholamine medication . One patient (exclud ed from thi s a na lysis) was withdrawn becau se of postoperative bleeding necessitating rethoracotomy.
Table 1 Haemodynamic effect of dopexamine hydrochloride during dose-titration
2
Control Cardiac index (L;min/m2)
Heart rate (beats/mini
Systemicvascular resistance (dyn. sec . cm- s) Mean blood pressure (mmHg) Stroke-volume index (mVm 2)
PACWpressure (mmHg ) Right atrial pressure (mmHg) Pulmonary vascular resistance (dyn . sec . cm- 5) Pulmonary artery pressure (mmHg):
systolic diastolic mean Rate-pressure product (mm Hg/min)
2.20 88.7 1820.4 94.1 24.1 13.6 10.0 180.7 32.8 15.8 22.0 12397.6
2.63" 95.9 1600.7' 98.2 25.4 13.4 9.8 193.8 37.4' 16.6 24.2 14527.1
Dose (~g;Kg/m inl
4
3.12' 105.0' 1374.5" 98.7 27.4 13.3 9.5 173.8 39.3" 17.2 24.7 16210.6'
36.3' 15.4 22.8 17434.9'
aMeans whichdiffer by more than theLSD are significantly different (p < 0.05). b No significant treatment effect.
. Signilicently different from control (p
