1University of Liverpool, Liverpool, 2Royal Liverpool Childrens NHS Trust, Alder Hey, Eaton Road, Liverpool L12 2AP, UK. 3Present address: Queens Medical Centre, Derby Road, Nottingham NG7 2UH, UK
Accepted for publication: March 5, 2000
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Abstract |
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Br J Anaesth 2000; 85: 20510
Keywords: pharmacokinetics; enoximone; infants; cardiac surgery
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Introduction |
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Enoximone is primarily metabolized in the liver by oxidation to enoximone sulphoxide. In a study of six adult patients with severe congestive heart failure, 74% of a single intravenous dose of enoximone was excreted in urine over the following 24 h as the sulphoxide metabolite, together with 0.5% of the parent drug.5 The median terminal elimination half-life for the sulphoxide metabolite in these patients was 7.6 (range 611) h. Accurate in vivo determination of metabolite potency in humans is made somewhat problematic by the reversibility of enoximone metabolism, as reduction of enoximone sulphoxide to enoximone can occur both in kidney and liver. An experimental study in dogs suggests that the potency of the metabolite is about one-seventh that of the parent drug.7
For over 10 years, enoximone has been used as one of our first line inotropic drugs in infants and children recovering from cardiac surgery, though our dosage regimen has until now been based solely on paediatric clinical studies and published adult pharmacokinetic data. However, as no pharmacokinetic studies have been carried out in children, there remains some uncertainty as to the optimal loading dose and subsequent infusion rates of the drug. It is a tribute to the drugs wide therapeutic ratio that we continue to use it, despite knowing so little about its distribution and clearance in sick children. Nevertheless, there are potential dangers in giving too much enoximone: reported adverse effects include hyperosmolality8 and hypotension.9 One study of healthy adults demonstrated a significant correlation between the plasma concentration of both enoximone and its sulphoxide metabolite and effects on contractility.10 Subsequent clinical studies have been unable to confirm this relationship in adults with cardiac failure6 or in patients recovering from cardiac surgery,11 12 though plasma concentrations between 1000 and 2000 ng ml1 appear to be related with maximal clinical effects. One aim of our study was to discern whether we were achieving similar therapeutic plasma concentrations when using our standard dosage regimen. We also wished to determine whether enoximone pharmacokinetic values in infants were significantly different from those previously described in adults.
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Methods |
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A 1-ml arterial blood sample was taken during rewarming on CPB (zero control). Approximately 10 min before the anticipated discontinuation of CPB, a loading dose of enoximone 1 mg kg1 was given over 2 min into a central vein. An infusion of enoximone 10 µg kg1 min1 was then started. A 1-ml blood sample was taken 30 min after successful weaning from CPB. Further samples were taken 12 and 24 h after CPB, and then every 24 h until the infusion was stopped. Clinical criteria determined when the enoximone infusion was discontinued. Another blood sample was taken immediately before stopping the infusion, and then at 2, 4, 8, 12 and 24 h. All blood samples were obtained from the arterial cannula, centrifuged, the serum separated and stored at 22°C until assay.
In addition to routine haemodynamic, haematological and biochemical monitoring, serum osmolality was measured each day in patients receiving infusions lasting > 48 h. This was compared to calculated values and the osmolal gap recorded. From the second postoperative day and thereafter, all patients had liver function tests measured daily for the duration of their enoximone infusion. Patients who had alanine aminotransferase and unconjugated bilirubin concentrations more than twice the normal values for >24 h were deemed to have significant hepatic dysfunction. Patients were deemed to have significant renal dysfunction if their serum creatinine concentration increased to more than twice the normal values for >24 h, and their urine output was <0.5 ml kg1 h1 for >6 h despite diuretic therapy and a normal blood pressure for their age.
The concentrations of enoximone and enoximone sulphoxide in the serum samples were determined using a high-performance liquid chromatographic (HPLC) technique, as described previously by Chan and co-workers.13 The method involves addition of internal standard and organic solvent extraction, followed by separation with HPLC and detection by ultraviolet absorption. The assay range for both enoximone and enoximone sulphoxide was 503000 ng ml1. The coefficients of variation for enoximone at the level of the lowest and highest standards were 2.4% and 2.8%, respectively. The coefficients of variation for enoximone sulphoxide at the level of the lowest and highest standards were 0.4% and 2.4%, respectively. The lower limit of quantification (LLQ) for both enoximone and enoximone sulphoxide was 50 ng ml1.
Pharmacokinetic parameters for enoximone and enoximone sulphoxide were determined by non-compartmental analysis using TOPFIT computer software (Gustav Fischer Verlag, Stuttgart, Germany). The elimination rate constant (z) was calculated by log linear regression of the terminal portion of the plasma drug concentrationtime curve using the method of least squares. The terminal elimination half-life (t
z) for enoximone and enoximone sulphoxide was calculated from ln 2/
z. The area under the drugtime curve (from time=0 to infinity; AUC) was determined by the log-linear trapezoidal rule. Clearance (Cl) of enoximone was calculated from dose/AUC, where dose is the product of infusion rate, infusion duration and weight of individual. Calculation of the volume of distribution at steady-state required an accurate calculation of mean residence time. However, our data set was too complex to be analysed by normal non-compartmental analysis, and our calculations of mean residence time produced many obviously anomalous results. Hence, we have simply reported the volume of distribution during the elimination phase, calculated as the product of Cl and 1/
z.
The MannWhitney test (SPSS for Windows, version 10.0) was used to compare pharmacokinetic parameters in patients with severe hepatic or renal dysfunction with those in patients with no evidence of organ dysfunction. Kendalls tau-b rank-order correlation coefficient was used to assess associations between age and calculated pharmacokinetic parameters. Partial correlations, controlling for hepatic dysfunction, were used to assess associations between duration of infusion or age and calculated pharmacokinetic parameters, and between age and peak concentration.
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Results |
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Discussion |
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This is the first study to examine enoximone pharmacokinetics in infants, and also the first to examine drug concentrations during and after prolonged infusions in any age group. Previous adult pharmacokinetic studies have been performed only after single intravenous injections or short infusions (<48 h).6 10 11 15 16 In our study, the enoximone infusion was stopped when the patients general condition, and ventricular function in particular, had improved sufficiently such that inotropic support was no longer required. If a patient required more than one inotropic drug, enoximone was always the last one to be discontinued. Inevitably, therefore, the patients receiving the most prolonged infusions of enoximone were, by definition, the patients who were sickest for the longest time period. However, there was no significant correlation between duration of infusion and calculated pharmacokinetic parameters. Nevertheless, we observed very high plasma drug and metabolite concentrations in some sick patients at various times during their infusion. However, by the time the infusion was stopped, drug concentration had usually returned to near target levels. We observed no significant increase in plasma concentration during infusions of 72144 h duration in those infants retaining normal hepatic and renal function. This suggests that an enoximone infusion rate of 10 µg kg1 min1 does not usually result in drug accumulation in neonates or infants who have normal hepatic function.
All patients who exhibited peak enoximone concentrations >3000 ng ml1 demonstrated marked biochemical evidence of hepatic derangement. Clearance values of enoximone suggest that enoximone metabolism will be affected both by hepatic blood flow and by microsomal activity. A transient increase in drug plasma concentration during a constant rate infusion must reflect either a decrease in hepatic microsomal enzyme metabolic activity and/or a decrease in hepatic blood flow. The latter explanation seems more likely, as these perturbations usually occurred in the first 2448 h after surgery, when cardiac output was particularly labile and vasoconstrictor inotropic drugs were also being used. Our criteria for a patient to be deemed as having hepatic dysfunction were relatively strict, though somewhat arbitrary: our measures of liver function had to rise to more than twice normal values for >24 h.17 One clinical study in adults has demonstrated that low sulphoxidation activity does not correlate with the degree of hyperbilirubinaemia or histological severity of liver disease, and may even occur in otherwise normal individuals.18 Nevertheless, the six patients who fulfilled our criteria for hepatic dysfunction had a reduced clearance rate and a significantly longer elimination half-life than the other 14 patients. As the neonate has reduced microsomal enzyme function compared to the older infant,17 we were not surprised to find a significant correlation between age and peak concentration, after controlling for hepatic dysfunction (P=0.03). However, we were unable to demonstrate any significant correlation between age and any calculated pharmacokinetic parameter, after controlling for hepatic dysfunction.
The criteria we used to determine whether a patient should be deemed as having renal dysfunction were similar to those we normally use as indications for peritoneal dialysis, that is a rising creatinine >100 µmol litre1 and a urine output <0.5 ml kg1 h1 for >6 h despite diuretic therapy and a normal arterial pressure. Only patients who had very poor renal function and required peritoneal dialysis demonstrated serum concentrations of enoximone sulphoxide >10 000 ng ml1 at any time during their infusion. Prolonged elimination of the metabolite was demonstrated in all three patients with severe renal dysfunction.
There is one case report of an infant becoming hyperosmolar secondary to an enoximone infusion given at 20 µg kg1 min1 for several days.8 This was thought to be due to propylene glycol accumulation, though the diluent also contains alcohol, which could have added to the problem. We both measured and calculated osmolality in all our patients who required prolonged infusions of enoximone, and found high transient osmolal gaps of 2040 in six of our sickest patients, all of whom had hepatic dysfunction. No other patient exhibited an abnormal osmolal gap. Although this hyperosmolality may have been at least partially due to alcohol and propylene glycol, there were probably other contributing factors in these very sick infants. As vital organ function returned to normal, osmolal gaps similarly reduced to within normal limits, despite continuation of the same enoximone infusion rate.
In accordance with a previous adult study,15 we could not demonstrate that enoximone produced clinically significant thrombocytopaenia. We believe that the post-CPB decrease in platelet count that we observed was similar to that often seen in sick patients not given enoximone, though a formal matched-pair comparison was not performed. Furthermore, although platelet counts decreased initially after CPB, they all returned spontaneously to normal values during the time course of the infusion.
We have confirmed that a loading dose of enoximone is necessary to achieve therapeutic concentrations in the early post-CPB period. The administration of the loading dose to the patient while still on CPB avoided any drug-induced hypotension. This study has demonstrated that enoximone 1 mg kg1 given to the patient in the final few minutes of CPB will produce near therapeutic plasma concentrations in most patients by 30 min post-CPB, if an infusion at 10 µg kg1 min1 is started at the same time. Adult data suggest that the optimum dosage regimen is one that achieves plasma concentrations ranging between 1000 and 2000 ng ml1, though this has not been confirmed for the paediatric age group. Although worthwhile therapeutic effects can be achieved at lower plasma concentrations than these, we aim for the maximum possible inotropic effect. This is because enoximone has a wide therapeutic ratio and substantially reduces the likelihood of having to use other potentially more noxious agents at high dose. Nevertheless, there is no therapeutic benefit in producing very high plasma concentrations, although enoximone appears devoid of obvious adverse effects during short-term infusions.
We conclude, therefore, that our current dosage regimen for enoximone, a 1 mg kg1 loading dose followed by an infusion at 10 µg kg1 min1, appears suitable for most patients. However, hepatic dysfunction may induce transient, very high concentrations in some individuals. Hence, we recommend that any clinical or biochemical indication of hepatic dysfunction should trigger a substantial reduction in the infusion rate. Similarly, isolated renal dysfunction resulting in oliguria should trigger a moderate reduction in the infusion rate.
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Acknowledgements |
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Footnotes |
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References |
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