- Email: [email protected]
COMPARISON OF THE HAEMODYNAMIC EFFECTS OF ENOXIMONE AND PIROXIMONE IN PATIENTS AFTER CARDIAC SURGERY
British Journal of Anaesthesia 1993; 71: 869-872
COMPARISON OF THE HAEMODYNAMIC EFFECTS OF ENOXIMONE AND PIROXIMONE IN PATIENTS AFTER CARDIAC SURGERY A. PATEL, L. D. CALDICOTT, J. R. SKOYLES, P. DAS AND K. M. SHERRY
SUMMARY
PATIENTS AND METHODS
After obtaining local Ethics Committee approval and written informed consent, we studied patients aged 18 yr or more with a stable decreased cardiac output state (defined as baseline cardiac index (CI) of less than 2.5 litre min"1 m~2 with a minimum pulmonary capillary wedge pressure (PCWP) of 8 mm Hg) after cardiac surgery. The baseline CI was the mean of two measurements obtained at least 10 min apart and reproducibility was confirmed if the measurements were within 15%. Patients were excluded if they had evidence of uncontrolled arrhythmias, inotropic therapy within 1 h of study or long acting vasodilator therapy within 12 h of the baseline measurements, PDE inhibitor therapy within 48 h of surgery and any preoperative evidence of hepatic or renal impairment. Patients were not entered or withdrawn TABLE I. Patient data {number or mean {range or SD))
KEY WORDS Phosphodiesterase inhibitors: enoximone, piroximone. Surgery: cardiac.
Enoximone and piroximone are imidazole derivatives with inotropic and vasodilator activity. They promote these effects by specific inhibition of a cyclic AMP (cAMP) phosphodiesterase (PDE III) in cardiac myocytes and vascular smooth muscle. This results in an increase in sarcoplasmic cAMP and cAMP-dependent phosphorylation of the proteins which control cellular calcium flux. This mechanism is independent of beta adrenergic receptors and so offers an alternative to catecholamine therapy in patients with endogenous or exogenous beta receptor tolerance [1] or beta receptor block [2]. The beneficial haemodynamic effects of enoximone and piroximone have been validated in patients with chronic heart failure. Recently there has been increased interest in the haemodynamic effects of PDE inhibitors in patients with decreased cardiac output after heart surgery—patients who require both inotropic and vasodilator therapy. The
Enoximone No. of patients Sex (M/F) Age (yr) Weight (kg) Surface area (m~2) Operation Coronary artery surgery (CAS) Valve surgery (VS)
CAS+VS
Cardiopulmonary bypass time (min) Myocardial ischaemia time (min)
10 6/5
58.7(51-68) 77.0(17.1) 1.83(0.21)
Piroximone 10 7/3
61.2(49-78) 83.6(10.9) 1.93(0.13)
6
9
3 1
1 0
95.6 (32)
80.5 (21)
56.8 (25)
44.6(10)
A. PATEL, M.B., B.S., F.R.C.A.; P. DAS, M.B., B.S., F.R.C.A.; K. M . SHERRY, M.B., B.S., F.R.C.A. ; Department of Anaesthetics, North-
ern General Hospital, Herries Road, Sheffield S5 7AU. L. D. CALDICOTT, M.B., B.S., F.R.C.A., Department of Anaesthetics,
Leeds General Infirmary, Leeds. J. R. SKOYLES, M.B., B.S., F.R.C.A., Department of Anaesthetics, Leicester Royal Infirmary, Leicester LEI 5WW. Accepted for Publication: July 13, 1993. Correspondence to K.M. S.
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on May 31, 2015
We have compared the haemodynamic effects of the imidazole derivative phosphodiesterase inhibitors enoximone and piroximone in patients with low cardiac output after cardiac surgery. Ten patients (group E) received enoximone and 10 patients (group P) received piroximone, both at a loading dose of 0.5 mg kg-1 followed by an infusion of 5 fig kg~1 min'1. In both groups the main changes with time were increases in cardiac index (maximum 24.5% in group E, 25.8% in group P) and decreases in systemic vascular resistance (maximum 26.8% in group E and 24.8% in group P). There were moderate increases in heart rate (maximum 11.3% in group E and 13% in group P) but a greater percentage decrease in mean arterial pressure in group E (maximum 11.9% vs 7.9%) with time. One patient in group E developed hypertension during the loading dose. Two patients in group E and two in group P developed hypotension during the loading dose. One patient in group E developed ventricular extrasystoles which may have been related to the drug being studied. (Br. J. Anaesth. 1993; 7 1 : 869-872)
primary aim of this study was to compare the haemodynamic effects of i.v. enoximone and piroximone in patients with decreased cardiac output after cardiac surgery.
BRITISH JOURNAL OF ANAESTHESIA
870
MAP (mm Hg) PCWP (mm Hg) PAP (mm Hg) CI (litre mirr 1 m"2) HR (beat min"1) SV (ml) RVEF RVESV (ml) RVEDV (ml) SVR (dyn s cm"5) PVR (dyn s cm"5) LVSWI (g m m"2)
Enoximone
Piroximone
82.1 (15) 10.3 (2.7) 18.8 (3.5) 1.93(0.3) 82 (13.8) 44.2 (9.5) 0.36 (0.07) 79.3(19.2) 123(20.5) 1734(450) 216(56) 23.7 (7.2)
71.5(11.8) 10.1(1.3) 17.5 (3.8) 2.08 (0.3) 73(12.1) 56.1 (7.3) 0.40 (0.09) 87.1(27.1) 144 (25.7) 1252(119) 157(86) 24.1 (5.6)
0.05 ns ns ns ns 0.01 ns ns 0.05 0.01 0.05 ns
from the study if they required additional short acting inotropic or vasodilator therapy. Twenty-one patients were allocated randomly to receive either enoximone (E) (11 patients) or piroximone (P) (10 patients) and drug administration was open. One patient in group E was withdrawn from the study and the statistical analysis was made on the remainder (table I). Anaesthesia was not standardized, but was based on an opioid premedication and a fentanyl and sedation technique without volatile agents. The lungs were ventilated by intermittent positive pressure throughout the study and sedation was by intermittent opioids (i.v.
TABLE I I I . Cardiovascular variables: percentage change from baseline (mean (SD)). E= Enoximone; P = piroximone. * P < 0.05 compared with baseline
Time (min) 60
120
180
MANOVA
-11.9(15)* 2.2 (9)
-10.0(13)* -0.7(9)
-11.2(12)* -2.7(10)
0.01 0.05
-13.9(37) -11.7(17)
-3.2(41) -16.4(25)
-12.6 (37) -13.6(24)
-17.7(23) -9.2(21)
ns ns
-4.3(20) 0.4(11)
-1.4(23) 6.8 (20)
-1.6(22) 9.0(15)
2.9 (23) 8.4(15)
ns
15
MAP (mm Hg) E P
-9.1 (14)* -7.9(14)*
PCWP (mm Hg) E P
PAP (mm Hg) E P
1
2
ns
CI (litre min- m" ) E P
14.2(13) 25.8(16)*
23.8 (18)* 15.3(19)*
20.1 (14)* 18.9(17)*
24.5 (19)* 19.8 (14)*
0.001 0.001
5.6(11) 13.0(11)*
11.3(11)* 8.4(11)*
9.1(10)* 8.2 (14)
8.8(11)* 11.1 (13)*
0.01 0.001
8.2(11) 11.7(11)*
13.2 (25) 6.5(14)
10.9(17) 10.0(15)
16.4(27) 9.3 (15)
ns 0.05
-0.7(22) 9.8(12)
8.4 (25) 7.7(19)
10.0 (20) 14.9 (22)
15.7 (25) 7.5(17)
ns ns
18.1 (47) -3.3(14)
7.7 (49) -2.2(19)
0.7 (41) -8.5(20)
-1.5(43) -5.3(21)
ns ns
E P
14.9(31) 2.0 (9)
10.2 (35) 1.0(15)
5.0 (27) -2.3(11)
1.4(22) -0.6(14)
ns ns
E P
-18.4(20)* -24.8(14)*
-25.9(19)* -7.4(13)
-24.0(19)* -13.4(14)*
-26.8(19)* -17.1 (17)*
0.001 0.001
-7.9(31) -3.8(20)
-14.2 (30) 32.4 (54)
-11.2(29) 30.3 (49)
-5.8(28) 25.3 (52)
ns ns
2.0(13) 5.2(16)
-1.5(25) 13.5 (20)
-2.4(16) 12.9(19)
3 7 (29) 7.7 (21)
ns ns
1
HR (beat min" ) E P
SV (ml) E P
RVEF E P
RVESV (ml) E P
RVEDV (ml) SVR (dyn s cm"5) PVR (dyn s cm"5) E P
2
LVSWI (g m m" ) E P
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on May 31, 2015
papaveretum or morphine 2.5-5 mg) and a continuous infusion of propofol 1-2 mg kg"1 h"1 as required. Fluid therapy comprised continuous infusion of 5 % glucose 0.5 ml kg"1 h"1 with blood, plasma or Haemaccel as indicated clinically from the PCWP and arterial pressure measurements. Pressures were measured via a right ventricular function thermodilution pulmonary artery (Baxter-Edwards) and radial artery cannula, using the mid axilla as the zero reference point. ECG was monitored continuously. Cardiac output and right ventricular function were measured in triplicate using the Baxter REF-1 cardiac output computer. The study period was from the baseline measurement until 3 h after the start of infusing the study drug. Patients in group E received a loading dose of enoximone 0.5 mg kg"1 over 20 min followed by an infusion of 5 ug kg"1 h"1. Patients in group P received a loading dose of piroximone 0.5 mg kg"1 over 20 min followed by an infusion of 5 ug kg"1 h"1. Mean arterial pressure (MAP), PCWP, mean pulmonary artery pressure (PAP), right atrial pressure, cardiac output (CO), heart rate (HR), stroke volume (SV), right ventricular ejection fraction (RVEF), right ventricular end-systolic volume (RVESV) and right ventricular end-diastolic volume (RVEDV) were recorded at baseline. These were repeated at 15, 30, 45, 60, 90, 120 and 180 min after the start of the
TABLE II. Baseline haemodynamic state {mean (SD))
HAEMODYNAMIC EFFECTS OF PDE INHIBITORS
Statistical methods Patient characteristics were assessed by t test and Fisher's exact probability test as appropriate. The changes with time were assessed by multiple analysis Of variance (MANO VA) for repeated measures using the SPSS statistical package. As appropriate for small groups, significance was also tested using Wilcoxon signed rank. P < 0.05 was considered statistically significant. RESULTS
DISCUSSION
Previous studies have investigated enoximone given before [2], during [3-7] and after [8-10] cardiopulmonary bypass. At present there is limited experience of piroximone in cardiac surgical patients [11-13].
+30-
+20 •
E E
+ 10 •
0 •
-10in
—20 '
1 k rrr
i
in.
li !/
{
Xy
•i.
•
on .
j Q-X
1 -20
120
60
180
'min) FIG. 1. Mean (SEM) percentage changes in cardiac index (CI), systemic vascular resistance (SVR) and mean arterial pressure (MAP) in the enoximone (O) and piroximone ( # ) groups. * Significant difference between groups (P < 0.05).
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on May 31, 2015
There were no significant differences between the groups in sex, weight, surface area, type of surgery or bypass times (table I). The comparative baseline haemodynamic measurements of the two groups are presented in table II. MAP, SVR and PVR were greater and SV and RVEDV less in group E compared with group P. The only difference between the groups with time was a significantly greater percentage decrease in MAP in group E from 45 to 120 min inclusive. Table III presents the percentage changes from baseline in each group. Although the analysis included the measurements at all times, only those at 15, 60, 120 and 180 min are tabulated. In both groups, the main changes were significant increases in CI, and decreases in SVR. There were moderate increases in HR and decreases in MAP, and an increase in SV in group P. The remainder of the measured and derived variables were unchanged. Hypertension which developed during the loading dose was reported in one patient in group E. SAP increased from 112 mm Hg to 139 mm Hg and was treated with specific hypotensive therapy outside the study design. This patient was withdrawn from the study. Hypotension which developed during the loading dose occurred in four patients, who were not withdrawn from the study. In two patients from group E, SAP decreased by 30-50 % and was treated by rapid infusions of fluid. In one patient from group P, SAP decreased by 30% and was treated by i.v. fluids and calcium chloride 5 mmol. One other patient in group P developed mild hypotension which required no specific treatment. No patient was hypotensive during the subsequent infusion. Only one patient, who was in group E, developed a rhythm disorder which might have been related to the study drug. This was unifocal ventricular ectopic activity which was not serious and the infusion was continued unchanged.
The choice of drug doses used in this study was based on previous studies in patients undergoing cardiac surgery. Beneficial haemodynamic effects of enoximone and piroximone have been demonstrated after recommended loading doses of 0.5 mg kg"1 [7, 9, 12-14] and maintenance infusions of enoximone 5 ug kg"1 min"1 [8] or piroximone 3-6 ug kg"1 h"1 [13]. It was important to have a stable baseline for comparisons because the numbers in each group were small. By conducting this study in the intensive care unit on patients with stable decreased cardiac output and using the mean of two baseline measurements with good reproducibility, we established that any significant changes in haemodynamics were likely to be caused by the study drug. Baseline haemodynamic state showed that group E had a greater degree of vasoconstriction (SVR and PVR) which led to the baseline differences in MAP and SV. The presence of baseline differences in small groups is not surprising, but it does validate the use of percentage changes from baseline to detect differences between groups. The greater decrease in MAP in group E may represent true differences in actions of the drugs. However, it may also be caused by greater baseline vasoconstriction in group E or non-equipotent dose regimens. We found the patterns of haemodynamic response in the two groups interesting (fig. 1). In group E, the haemodynamic changes were early and sustained,
(lit
study drug. Systemic (SVR) and pulmonary (PVR) vascular resistances and left ventricular stroke work index (LVSWI) were derived using standard formulae.
871
872
ACKNOWLEDGEMENT We thank Marion Merrell Dow, R&D, Berkshire for their financial support and for supply of the drugs. REFERENCES 1. Feldman AM, Bristow MR. The |3-adrenergic pathway in the failing heart: Implications for inotropic therapy. Cardiology 1990; 77 (Suppl. 1): 1-32. 2. Boldt J, Kling D, Zickmann B, Dapper F, Hempelmann G. Haemodynamic effects of the phosphodiesterase inhibitor enoximone in comparison with dobutamine in esmolol-treated cardiac surgery patients. British Journal of Anaesthesia 1990; 64: 611-616. 3. Raftery S, Wright I, Monk C, Bolsin S, Pry-Roberts C. Enoximone during coronary bypass surgery. British Journal of Anaesthesia 1991; 67: 651P-625P. 4. Boldt J, Kling D, Zickmann B, Dapper F, Hempelmann G. Efficacy of the phosphodiesterase inhibitor enoximone in complicated cardiac surgery. Chest 1990; 98: 53-58. 5. Birnbaum DE, Preuner JG, Gieseke R, Trenk D, Jaehnchen E. Enoximone versus dopamine in patients being weaned from cardiopulmonary bypass. Cardiology 1990; 77 (Suppl. 3): 34-^1. 6. Tarr TJ, Jeffrey RR, Kent AP, Cowen ME. Use of enoximone in weaning from cardiopulmonary bypass following mitral valve surgery. Cardiology 1990; 77 (Suppl. 3): 51-57. 7. Boldt J, Dieterich HA, Hempelmann G. Comparison of haemodynamic efficacy of enoximone and dobutamine in coronary surgery patients. British Journal of Clinical Practice 1988; 42 (Suppl. 64): 41-45. 8. Gonzalez M, Desager J-P, Jacquemart J-L, Chenu P, Muller T. Efficacy of enoximone in the management of refractory low output states following cardiac surgery. British Journal of Clinical Practice 1988; 42 (Suppl. 64): 53-64. 9. Hausen B, von der Leyen H, Vogelpohl J, Dresler Ch, Heublein B, Haverich A. Enoximone, a post-operative inodilator in patients following mitral valve operation: a prospective and controlled study. European Heart Journal 1992; 13: 679-686. 10. Keogh B, Priddy R, Morgan C, Gilbe C. Comparative study on the effects of enoximone and dobutamine in patients with impaired left ventricular function undergoing cardiac surgery. Cardiology 1990; 77 (Suppl. 3): 58-61. 11. Zeplin HE, Dressier HT, Fell JJ, Dieterich HA, Stegmann T. Efficacy and safety of the PDE-III-inhibitor piroximone iv in patients with low-output states (LOS) refractory to conventional therapy after cardiac surgery. Journal of Cardiothoracic and Vascular Anaesthesia 1992; 6 (Suppl. 1): 33. 12. Tarr TJ, Frazer RS, Moore NA, Desmond MJ. The hemodynamic effects of the PDE inhibitor piroximone to assist in weaning from CPB. Anesthesiology 1990; 73 (Suppl. 3A): A120. 13. Hausen B, Heublein B, Vogelpohl J, von der Leyen H, Haverich A. Comparison of enoximone and piroximone in patients after mitral valve operation: A prospective and controlled clinical study. Journal of Cardiovascular Pharmacology 1992; 19: 299-307. 14. Bolt J, Kling D, Dietrich HA, Marck P, Hempelmann G. The new phosphodiesterase inhibitor enoximone in patients following cardiac surgery: Pharmacokinetics and influence on parameters of coagulation. Intensive Care Medicine 1990; 16: 54-59. 15. Haegele KD, Belz GG, Meinicke TT, Schechter PJ. Pharmacokinetics of piroximone (MDL 19.205) in healthy volunteers. European Journal of Clinical Pharmacology 1986; 31: 239-242. 16. Dage RC, Okerholm RA. Pharmacology and pharmacokinetics of enoximone. Cardiology 1990; 77 (Suppl. 3): 2-13.
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on May 31, 2015
and this is predictable from the pharmacokinetic profiling of Gonzalez and co-workers using similar dosing schedules [8]. In group P, for MAP, CI and SVR there was maximal change at 15 min with a return towards baseline values at 60 min and progressive changes thereafter. The difference may be related to the serum concentrations of the drugs. Theoretically, the larger volume of distribution of piroximone (2.5 litre kg"1) [15] compared with enoximone (1.6 litre kg"1) [16] may result in a greater decrease after the loading dose, perhaps to less than therapeutic values, until a greater concentration is restored by the infusion. Further investigation is required to determine ideal loading and infusion doses of piroximone, possibly using step-down infusion regimens. The haemodynamic changes observed in this study are in broad agreement with those found by others. There was a significant increase in CI, closely associated with a decrease in SVR. As changes in loading affect myocardial contractility, it was impossible to separate the contribution of inotropic and vasodilator effects. However, after cardiac surgery both properties are desirable and we found both drugs appropriate and beneficial. In contrast with others, we could not comment on the effect of the drug on PCWP as our practice was to compensate for large decreases by infusing fluids. However, some patients had profound decreases in PCWP as reflected in the large SD and these individuals may have benefited from greater fluid therapy. As PDE inhibitors have pulmonary vasodilating properties and are beneficial in patients with mitral valve disease [13], we were interested to detect effects on right ventricular function using the RVEF catheter. Our patient population was not entirely appropriate. In general, these patients did not have pulmonary hypertension or compromised right heart function, therefore it was not surprising that we did not detect significant changes in right ventricular function. We did note a consistent, non-significant increase in mean RVEF in both groups and so feel that the effect of these drugs in right heart failure requires closer investigation. Transient severe hypotension was a complication during the loading dose in three patients who had PCWP in the range 9-11 mm Hg. The hypotension was corrected rapidly and not associated with ECG evidence of ischaemia. It could be argued that our initial filling pressures should have been greater. However, we are cautious with fluid preloading in patients with decreased cardiac output after cardiac surgery. It may be that giving the loading dose over 20 min was too rapid. With careful monitoring, slower loading dose infusions and an awareness of the potent vasodilator effects of these drugs, hypotension should not present a serious clinical problem.
BRITISH JOURNAL OF ANAESTHESIA
COMPARISON OF THE HAEMODYNAMIC EFFECTS OF ENOXIMONE AND PIROXIMONE IN PATIENTS AFTER CARDIAC SURGERY A. PATEL, L. D. CALDICOTT, J. R. SKOYLES, P. DAS AND K. M. SHERRY
SUMMARY
PATIENTS AND METHODS
After obtaining local Ethics Committee approval and written informed consent, we studied patients aged 18 yr or more with a stable decreased cardiac output state (defined as baseline cardiac index (CI) of less than 2.5 litre min"1 m~2 with a minimum pulmonary capillary wedge pressure (PCWP) of 8 mm Hg) after cardiac surgery. The baseline CI was the mean of two measurements obtained at least 10 min apart and reproducibility was confirmed if the measurements were within 15%. Patients were excluded if they had evidence of uncontrolled arrhythmias, inotropic therapy within 1 h of study or long acting vasodilator therapy within 12 h of the baseline measurements, PDE inhibitor therapy within 48 h of surgery and any preoperative evidence of hepatic or renal impairment. Patients were not entered or withdrawn TABLE I. Patient data {number or mean {range or SD))
KEY WORDS Phosphodiesterase inhibitors: enoximone, piroximone. Surgery: cardiac.
Enoximone and piroximone are imidazole derivatives with inotropic and vasodilator activity. They promote these effects by specific inhibition of a cyclic AMP (cAMP) phosphodiesterase (PDE III) in cardiac myocytes and vascular smooth muscle. This results in an increase in sarcoplasmic cAMP and cAMP-dependent phosphorylation of the proteins which control cellular calcium flux. This mechanism is independent of beta adrenergic receptors and so offers an alternative to catecholamine therapy in patients with endogenous or exogenous beta receptor tolerance [1] or beta receptor block [2]. The beneficial haemodynamic effects of enoximone and piroximone have been validated in patients with chronic heart failure. Recently there has been increased interest in the haemodynamic effects of PDE inhibitors in patients with decreased cardiac output after heart surgery—patients who require both inotropic and vasodilator therapy. The
Enoximone No. of patients Sex (M/F) Age (yr) Weight (kg) Surface area (m~2) Operation Coronary artery surgery (CAS) Valve surgery (VS)
CAS+VS
Cardiopulmonary bypass time (min) Myocardial ischaemia time (min)
10 6/5
58.7(51-68) 77.0(17.1) 1.83(0.21)
Piroximone 10 7/3
61.2(49-78) 83.6(10.9) 1.93(0.13)
6
9
3 1
1 0
95.6 (32)
80.5 (21)
56.8 (25)
44.6(10)
A. PATEL, M.B., B.S., F.R.C.A.; P. DAS, M.B., B.S., F.R.C.A.; K. M . SHERRY, M.B., B.S., F.R.C.A. ; Department of Anaesthetics, North-
ern General Hospital, Herries Road, Sheffield S5 7AU. L. D. CALDICOTT, M.B., B.S., F.R.C.A., Department of Anaesthetics,
Leeds General Infirmary, Leeds. J. R. SKOYLES, M.B., B.S., F.R.C.A., Department of Anaesthetics, Leicester Royal Infirmary, Leicester LEI 5WW. Accepted for Publication: July 13, 1993. Correspondence to K.M. S.
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on May 31, 2015
We have compared the haemodynamic effects of the imidazole derivative phosphodiesterase inhibitors enoximone and piroximone in patients with low cardiac output after cardiac surgery. Ten patients (group E) received enoximone and 10 patients (group P) received piroximone, both at a loading dose of 0.5 mg kg-1 followed by an infusion of 5 fig kg~1 min'1. In both groups the main changes with time were increases in cardiac index (maximum 24.5% in group E, 25.8% in group P) and decreases in systemic vascular resistance (maximum 26.8% in group E and 24.8% in group P). There were moderate increases in heart rate (maximum 11.3% in group E and 13% in group P) but a greater percentage decrease in mean arterial pressure in group E (maximum 11.9% vs 7.9%) with time. One patient in group E developed hypertension during the loading dose. Two patients in group E and two in group P developed hypotension during the loading dose. One patient in group E developed ventricular extrasystoles which may have been related to the drug being studied. (Br. J. Anaesth. 1993; 7 1 : 869-872)
primary aim of this study was to compare the haemodynamic effects of i.v. enoximone and piroximone in patients with decreased cardiac output after cardiac surgery.
BRITISH JOURNAL OF ANAESTHESIA
870
MAP (mm Hg) PCWP (mm Hg) PAP (mm Hg) CI (litre mirr 1 m"2) HR (beat min"1) SV (ml) RVEF RVESV (ml) RVEDV (ml) SVR (dyn s cm"5) PVR (dyn s cm"5) LVSWI (g m m"2)
Enoximone
Piroximone
82.1 (15) 10.3 (2.7) 18.8 (3.5) 1.93(0.3) 82 (13.8) 44.2 (9.5) 0.36 (0.07) 79.3(19.2) 123(20.5) 1734(450) 216(56) 23.7 (7.2)
71.5(11.8) 10.1(1.3) 17.5 (3.8) 2.08 (0.3) 73(12.1) 56.1 (7.3) 0.40 (0.09) 87.1(27.1) 144 (25.7) 1252(119) 157(86) 24.1 (5.6)
0.05 ns ns ns ns 0.01 ns ns 0.05 0.01 0.05 ns
from the study if they required additional short acting inotropic or vasodilator therapy. Twenty-one patients were allocated randomly to receive either enoximone (E) (11 patients) or piroximone (P) (10 patients) and drug administration was open. One patient in group E was withdrawn from the study and the statistical analysis was made on the remainder (table I). Anaesthesia was not standardized, but was based on an opioid premedication and a fentanyl and sedation technique without volatile agents. The lungs were ventilated by intermittent positive pressure throughout the study and sedation was by intermittent opioids (i.v.
TABLE I I I . Cardiovascular variables: percentage change from baseline (mean (SD)). E= Enoximone; P = piroximone. * P < 0.05 compared with baseline
Time (min) 60
120
180
MANOVA
-11.9(15)* 2.2 (9)
-10.0(13)* -0.7(9)
-11.2(12)* -2.7(10)
0.01 0.05
-13.9(37) -11.7(17)
-3.2(41) -16.4(25)
-12.6 (37) -13.6(24)
-17.7(23) -9.2(21)
ns ns
-4.3(20) 0.4(11)
-1.4(23) 6.8 (20)
-1.6(22) 9.0(15)
2.9 (23) 8.4(15)
ns
15
MAP (mm Hg) E P
-9.1 (14)* -7.9(14)*
PCWP (mm Hg) E P
PAP (mm Hg) E P
1
2
ns
CI (litre min- m" ) E P
14.2(13) 25.8(16)*
23.8 (18)* 15.3(19)*
20.1 (14)* 18.9(17)*
24.5 (19)* 19.8 (14)*
0.001 0.001
5.6(11) 13.0(11)*
11.3(11)* 8.4(11)*
9.1(10)* 8.2 (14)
8.8(11)* 11.1 (13)*
0.01 0.001
8.2(11) 11.7(11)*
13.2 (25) 6.5(14)
10.9(17) 10.0(15)
16.4(27) 9.3 (15)
ns 0.05
-0.7(22) 9.8(12)
8.4 (25) 7.7(19)
10.0 (20) 14.9 (22)
15.7 (25) 7.5(17)
ns ns
18.1 (47) -3.3(14)
7.7 (49) -2.2(19)
0.7 (41) -8.5(20)
-1.5(43) -5.3(21)
ns ns
E P
14.9(31) 2.0 (9)
10.2 (35) 1.0(15)
5.0 (27) -2.3(11)
1.4(22) -0.6(14)
ns ns
E P
-18.4(20)* -24.8(14)*
-25.9(19)* -7.4(13)
-24.0(19)* -13.4(14)*
-26.8(19)* -17.1 (17)*
0.001 0.001
-7.9(31) -3.8(20)
-14.2 (30) 32.4 (54)
-11.2(29) 30.3 (49)
-5.8(28) 25.3 (52)
ns ns
2.0(13) 5.2(16)
-1.5(25) 13.5 (20)
-2.4(16) 12.9(19)
3 7 (29) 7.7 (21)
ns ns
1
HR (beat min" ) E P
SV (ml) E P
RVEF E P
RVESV (ml) E P
RVEDV (ml) SVR (dyn s cm"5) PVR (dyn s cm"5) E P
2
LVSWI (g m m" ) E P
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on May 31, 2015
papaveretum or morphine 2.5-5 mg) and a continuous infusion of propofol 1-2 mg kg"1 h"1 as required. Fluid therapy comprised continuous infusion of 5 % glucose 0.5 ml kg"1 h"1 with blood, plasma or Haemaccel as indicated clinically from the PCWP and arterial pressure measurements. Pressures were measured via a right ventricular function thermodilution pulmonary artery (Baxter-Edwards) and radial artery cannula, using the mid axilla as the zero reference point. ECG was monitored continuously. Cardiac output and right ventricular function were measured in triplicate using the Baxter REF-1 cardiac output computer. The study period was from the baseline measurement until 3 h after the start of infusing the study drug. Patients in group E received a loading dose of enoximone 0.5 mg kg"1 over 20 min followed by an infusion of 5 ug kg"1 h"1. Patients in group P received a loading dose of piroximone 0.5 mg kg"1 over 20 min followed by an infusion of 5 ug kg"1 h"1. Mean arterial pressure (MAP), PCWP, mean pulmonary artery pressure (PAP), right atrial pressure, cardiac output (CO), heart rate (HR), stroke volume (SV), right ventricular ejection fraction (RVEF), right ventricular end-systolic volume (RVESV) and right ventricular end-diastolic volume (RVEDV) were recorded at baseline. These were repeated at 15, 30, 45, 60, 90, 120 and 180 min after the start of the
TABLE II. Baseline haemodynamic state {mean (SD))
HAEMODYNAMIC EFFECTS OF PDE INHIBITORS
Statistical methods Patient characteristics were assessed by t test and Fisher's exact probability test as appropriate. The changes with time were assessed by multiple analysis Of variance (MANO VA) for repeated measures using the SPSS statistical package. As appropriate for small groups, significance was also tested using Wilcoxon signed rank. P < 0.05 was considered statistically significant. RESULTS
DISCUSSION
Previous studies have investigated enoximone given before [2], during [3-7] and after [8-10] cardiopulmonary bypass. At present there is limited experience of piroximone in cardiac surgical patients [11-13].
+30-
+20 •
E E
+ 10 •
0 •
-10in
—20 '
1 k rrr
i
in.
li !/
{
Xy
•i.
•
on .
j Q-X
1 -20
120
60
180
'min) FIG. 1. Mean (SEM) percentage changes in cardiac index (CI), systemic vascular resistance (SVR) and mean arterial pressure (MAP) in the enoximone (O) and piroximone ( # ) groups. * Significant difference between groups (P < 0.05).
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on May 31, 2015
There were no significant differences between the groups in sex, weight, surface area, type of surgery or bypass times (table I). The comparative baseline haemodynamic measurements of the two groups are presented in table II. MAP, SVR and PVR were greater and SV and RVEDV less in group E compared with group P. The only difference between the groups with time was a significantly greater percentage decrease in MAP in group E from 45 to 120 min inclusive. Table III presents the percentage changes from baseline in each group. Although the analysis included the measurements at all times, only those at 15, 60, 120 and 180 min are tabulated. In both groups, the main changes were significant increases in CI, and decreases in SVR. There were moderate increases in HR and decreases in MAP, and an increase in SV in group P. The remainder of the measured and derived variables were unchanged. Hypertension which developed during the loading dose was reported in one patient in group E. SAP increased from 112 mm Hg to 139 mm Hg and was treated with specific hypotensive therapy outside the study design. This patient was withdrawn from the study. Hypotension which developed during the loading dose occurred in four patients, who were not withdrawn from the study. In two patients from group E, SAP decreased by 30-50 % and was treated by rapid infusions of fluid. In one patient from group P, SAP decreased by 30% and was treated by i.v. fluids and calcium chloride 5 mmol. One other patient in group P developed mild hypotension which required no specific treatment. No patient was hypotensive during the subsequent infusion. Only one patient, who was in group E, developed a rhythm disorder which might have been related to the study drug. This was unifocal ventricular ectopic activity which was not serious and the infusion was continued unchanged.
The choice of drug doses used in this study was based on previous studies in patients undergoing cardiac surgery. Beneficial haemodynamic effects of enoximone and piroximone have been demonstrated after recommended loading doses of 0.5 mg kg"1 [7, 9, 12-14] and maintenance infusions of enoximone 5 ug kg"1 min"1 [8] or piroximone 3-6 ug kg"1 h"1 [13]. It was important to have a stable baseline for comparisons because the numbers in each group were small. By conducting this study in the intensive care unit on patients with stable decreased cardiac output and using the mean of two baseline measurements with good reproducibility, we established that any significant changes in haemodynamics were likely to be caused by the study drug. Baseline haemodynamic state showed that group E had a greater degree of vasoconstriction (SVR and PVR) which led to the baseline differences in MAP and SV. The presence of baseline differences in small groups is not surprising, but it does validate the use of percentage changes from baseline to detect differences between groups. The greater decrease in MAP in group E may represent true differences in actions of the drugs. However, it may also be caused by greater baseline vasoconstriction in group E or non-equipotent dose regimens. We found the patterns of haemodynamic response in the two groups interesting (fig. 1). In group E, the haemodynamic changes were early and sustained,
(lit
study drug. Systemic (SVR) and pulmonary (PVR) vascular resistances and left ventricular stroke work index (LVSWI) were derived using standard formulae.
871
872
ACKNOWLEDGEMENT We thank Marion Merrell Dow, R&D, Berkshire for their financial support and for supply of the drugs. REFERENCES 1. Feldman AM, Bristow MR. The |3-adrenergic pathway in the failing heart: Implications for inotropic therapy. Cardiology 1990; 77 (Suppl. 1): 1-32. 2. Boldt J, Kling D, Zickmann B, Dapper F, Hempelmann G. Haemodynamic effects of the phosphodiesterase inhibitor enoximone in comparison with dobutamine in esmolol-treated cardiac surgery patients. British Journal of Anaesthesia 1990; 64: 611-616. 3. Raftery S, Wright I, Monk C, Bolsin S, Pry-Roberts C. Enoximone during coronary bypass surgery. British Journal of Anaesthesia 1991; 67: 651P-625P. 4. Boldt J, Kling D, Zickmann B, Dapper F, Hempelmann G. Efficacy of the phosphodiesterase inhibitor enoximone in complicated cardiac surgery. Chest 1990; 98: 53-58. 5. Birnbaum DE, Preuner JG, Gieseke R, Trenk D, Jaehnchen E. Enoximone versus dopamine in patients being weaned from cardiopulmonary bypass. Cardiology 1990; 77 (Suppl. 3): 34-^1. 6. Tarr TJ, Jeffrey RR, Kent AP, Cowen ME. Use of enoximone in weaning from cardiopulmonary bypass following mitral valve surgery. Cardiology 1990; 77 (Suppl. 3): 51-57. 7. Boldt J, Dieterich HA, Hempelmann G. Comparison of haemodynamic efficacy of enoximone and dobutamine in coronary surgery patients. British Journal of Clinical Practice 1988; 42 (Suppl. 64): 41-45. 8. Gonzalez M, Desager J-P, Jacquemart J-L, Chenu P, Muller T. Efficacy of enoximone in the management of refractory low output states following cardiac surgery. British Journal of Clinical Practice 1988; 42 (Suppl. 64): 53-64. 9. Hausen B, von der Leyen H, Vogelpohl J, Dresler Ch, Heublein B, Haverich A. Enoximone, a post-operative inodilator in patients following mitral valve operation: a prospective and controlled study. European Heart Journal 1992; 13: 679-686. 10. Keogh B, Priddy R, Morgan C, Gilbe C. Comparative study on the effects of enoximone and dobutamine in patients with impaired left ventricular function undergoing cardiac surgery. Cardiology 1990; 77 (Suppl. 3): 58-61. 11. Zeplin HE, Dressier HT, Fell JJ, Dieterich HA, Stegmann T. Efficacy and safety of the PDE-III-inhibitor piroximone iv in patients with low-output states (LOS) refractory to conventional therapy after cardiac surgery. Journal of Cardiothoracic and Vascular Anaesthesia 1992; 6 (Suppl. 1): 33. 12. Tarr TJ, Frazer RS, Moore NA, Desmond MJ. The hemodynamic effects of the PDE inhibitor piroximone to assist in weaning from CPB. Anesthesiology 1990; 73 (Suppl. 3A): A120. 13. Hausen B, Heublein B, Vogelpohl J, von der Leyen H, Haverich A. Comparison of enoximone and piroximone in patients after mitral valve operation: A prospective and controlled clinical study. Journal of Cardiovascular Pharmacology 1992; 19: 299-307. 14. Bolt J, Kling D, Dietrich HA, Marck P, Hempelmann G. The new phosphodiesterase inhibitor enoximone in patients following cardiac surgery: Pharmacokinetics and influence on parameters of coagulation. Intensive Care Medicine 1990; 16: 54-59. 15. Haegele KD, Belz GG, Meinicke TT, Schechter PJ. Pharmacokinetics of piroximone (MDL 19.205) in healthy volunteers. European Journal of Clinical Pharmacology 1986; 31: 239-242. 16. Dage RC, Okerholm RA. Pharmacology and pharmacokinetics of enoximone. Cardiology 1990; 77 (Suppl. 3): 2-13.
Downloaded from http://bja.oxfordjournals.org/ at Simon Fraser University on May 31, 2015
and this is predictable from the pharmacokinetic profiling of Gonzalez and co-workers using similar dosing schedules [8]. In group P, for MAP, CI and SVR there was maximal change at 15 min with a return towards baseline values at 60 min and progressive changes thereafter. The difference may be related to the serum concentrations of the drugs. Theoretically, the larger volume of distribution of piroximone (2.5 litre kg"1) [15] compared with enoximone (1.6 litre kg"1) [16] may result in a greater decrease after the loading dose, perhaps to less than therapeutic values, until a greater concentration is restored by the infusion. Further investigation is required to determine ideal loading and infusion doses of piroximone, possibly using step-down infusion regimens. The haemodynamic changes observed in this study are in broad agreement with those found by others. There was a significant increase in CI, closely associated with a decrease in SVR. As changes in loading affect myocardial contractility, it was impossible to separate the contribution of inotropic and vasodilator effects. However, after cardiac surgery both properties are desirable and we found both drugs appropriate and beneficial. In contrast with others, we could not comment on the effect of the drug on PCWP as our practice was to compensate for large decreases by infusing fluids. However, some patients had profound decreases in PCWP as reflected in the large SD and these individuals may have benefited from greater fluid therapy. As PDE inhibitors have pulmonary vasodilating properties and are beneficial in patients with mitral valve disease [13], we were interested to detect effects on right ventricular function using the RVEF catheter. Our patient population was not entirely appropriate. In general, these patients did not have pulmonary hypertension or compromised right heart function, therefore it was not surprising that we did not detect significant changes in right ventricular function. We did note a consistent, non-significant increase in mean RVEF in both groups and so feel that the effect of these drugs in right heart failure requires closer investigation. Transient severe hypotension was a complication during the loading dose in three patients who had PCWP in the range 9-11 mm Hg. The hypotension was corrected rapidly and not associated with ECG evidence of ischaemia. It could be argued that our initial filling pressures should have been greater. However, we are cautious with fluid preloading in patients with decreased cardiac output after cardiac surgery. It may be that giving the loading dose over 20 min was too rapid. With careful monitoring, slower loading dose infusions and an awareness of the potent vasodilator effects of these drugs, hypotension should not present a serious clinical problem.
BRITISH JOURNAL OF ANAESTHESIA