Since the observation that continuous intravenous furosemide might be superior to intermittent administrations in infants after CPB surgery, the use of continuous furosemide infusion has increasingly be documented in patients following CPB surgery [3–6, 15]. Based upon the observations in infants after CPB surgery, the use of continuous intravenous furosemide in neonates treated with ECMO is increasing.
We recently evaluated furosemide regimens used in neonates treated with ECMO in our unit and concluded that continuous intravenous furosemide was frequently used in neonates (78%) treated with ECMO [7]. The furosemide regimens used varied widely, in continuous doses and in additional intermittent doses. Although all used regimens achieved adequate urine output within 24 hours, the use of additional furosemide bolus injections suggests that the regimens might not be the optimal for neonates treated with ECMO, and therefore dosing regimens should be developed [7].
Since ECMO and CPB are 'comparable' procedures, the developed PK/PD model for infants after CPB surgery might also be applicable for neonates treated with ECMO [9]. There are, however, obvious differences between ECMO and CPB: in the time of exposure to the procedure, and thereby the presence of the 'circuit' with an ongoing inflammatory reaction, in the underlying illness and in the age of the patients. We therefore conducted a prospective exploratory study in neonates treated with ECMO to evaluate a suggested furosemide regimen developed for infants after CPB surgery. The results suggest that the used regimen was effective and well tolerated in neonates treated with ECMO.
Continuous intravenous furosemide was started in all patients at a rate of 0.2 mg/kg per hour and was preceded by a loading bolus of 1 mg/kg. The furosemide dose was adapted according to urine output. The dose was decreased from the first day to the second day of the study, from 0.17 ± 0.06 mg/kg per hour to 0.08 ± 0.04 mg/kg per hour. The furosemide doses used in neonates treated with ECMO (0.17 ± 0.06, 0.08 ± 0.04, and 0.12 ± 0.07 mg/kg per hour) were lower than the doses used in infants after CPB surgery (0.22 ± 0.06, 0.25 ± 0.10, and 0.22 ± 0.11 mg/kg per hour) over the first day, second day, and third day of furosemide therapy, respectively [16].
The PK/PD model for diuretic therapy with furosemide in infants after CPB suggested that doses between 0.2 and 0.3 mg/kg per hour, preceded by a loading bolus, would result in a urine production of 6 ml/kg per hour [9]. Based upon our observational study, which indicated that relatively low doses of continuous furosemide were used, we decided to use the lowest dose suggested by the model. The rational for the loading bolus was based on the simulated urine production profiles generated with the use of different furosemide regimens and on the observed effects of the loading bolus in the retrospective study [7, 9].
In the retrospective study, positive effects of the 'loading' bolus were observed, although not statistically significant, in the urine output in the first 24 hours and in the time to reach the desired urine output of 6 ml/kg per hour [7]. Also, no additional furosemide bolus injections were administered during the continuous infusion to the patients who received a bolus prior to the continuous infusion. These observed effects might suggest that one loading bolus might be sufficient to overwhelm the effects of the ECMO circuit.
The data from the present study suggest that the starting dose was too high, as indicated by the urine output exceeding the target urine output in the first 24 hours. Although a full understanding of this phenomenon is hard to reach, it seems logical to assume that contributing factors might be the ECMO circuit, the renal function of the patients, and the age of the patients [17–23]. The patients treated with ECMO were younger (median 3 days) than the patients after CPB surgery (median 12 weeks), and therefore by definition had a less mature renal function, which leads to a decreased renal clearance of furosemide.
The renal function (median creatinine 30 μmol/l) was normal for age in the ECMO patients, whereas (transient) renal failure (median creatinine 95 μmol/l) was observed in the majority of the patients after CPB surgery [12, 16]. Therefore it can be hypothesized that the acute renal failure observed in the patients after CPB surgery had a major impact on renal clearance, which is most closely related with drug response, since furosemide is excreted renally and only acts after reaching the tubular lumen [24–27]. This hypothesis might explain why higher doses were needed in the patients after CPB surgery. In addition, phase II reactions are better developed in infants and, as a result, the percentage of furosemide glucuronide will be higher [23]. Less unchanged furosemide can therefore be assumed available to interact with the furosemide receptor in the infants included in the cardiac surgery study, and higher doses are consequently needed to reach the same furosemide excretion rate [25, 26]. This assumption might clarify why higher doses were required in the patients after CPB surgery.
On the other hand, the lower continuous furosemide doses after the loading bolus used in the ECMO patients might be explained by the effects of the ECMO circuit [17, 18]. The observed increased volume of distribution in our patients was in accordance with the values reported in the literature [17]. Wells and colleagues reported that the steady-state volume of distribution and the elimination half-life of the loop diuretic, bumetanide, in term neonates treated with ECMO were increased compared with values in premature and term neonates without ECMO, while the plasma clearance was similar for both groups [17].
The increased volume of distribution is not only due to the addition of a large exogenous blood volume for priming of the circuit, but is also caused by the possible absorption of furosemide onto the ECMO circuit components [18, 28]. Scala and coworkers performed an in vitro analysis to identify loss of furosemide in the ECMO circuit and observed a reduction of 63–87% in the serum furosemide concentration over a 4-hour period. The loss of drug was most pronounced in the first 30 minutes [29]. Since the continuous infusion was started at the time of the bolus injection, and as only furosemide samples were taken during the continuous infusion, we could not estimate the furosemide clearance in our patients.
Mehta and colleagues recently published research on the potential sequestration of drugs to the ECMO circuit. In vivo experiments showed that there was a significant drug loss in crystalloid-primed circuits as well as in blood-primed circuits. For instance, the loss of analgetics ranged from 17% for morphine to 87–100% for fentanyl depending on the type of circuit [30]. In addition, our own group described a decreased clearance of morphine during the first 10 days of ECMO in neonates and infants treated with venoarterial ECMO compared with patients after noncardiac major surgery [31, 32].
The furosemide loading bolus especially seems to compensate for the increased volume of distribution. Since the effects of furosemide are dependent on renal function, the apparent need for lower continuous furosemide dose might be explained by the absence of impaired renal function, and consequently the increased renal clearance, in the patients on ECMO compared with the patients post CPB surgery [24].
We previously noticed that additional loop diuretics were needed in approximately 40% of the patients on ECMO therapy during the continuous furosemide infusion [7]. In the present study no additional loop diuretics were needed, demonstrating that furosemide monotherapy is highly effective, which is a considerable advantage.
The total administered furosemide dose in the current study was substantial higher on the first day (4.97 mg/kg per 24 hours) than the dose used in our retrospective study (1.92 mg/kg per 24 hours). The respective doses were slightly lower on the second day and third day (1.63 mg/kg per 24 hours and 1.50 mg/kg per 24 hours in the present study compared with 1.92 mg/kg per 24 hours and 2.0 mg/kg per 24 hours in the retrospective study). The cumulative furosemide doses over the three study days, however, were comparable between the two studies. The cumulative furosemide dose in the current study showed less variation in dose [7]. Importantly serum furosemide levels remained far below the commonly accepted safety level for ototoxicity (50 μg/ml) [33].
To obtain an acceptable fluid balance with a maintenance fluid of 120–140 ml/kg per 24 hours, the target urine production is set at 6 ml/kg per hour in our unit. In all patients studied, the target urine production of 6 ml/kg per hour was obtained a median 7 hours after the start of the continuous infusion. This is considerable faster than in our retrospective study in which the target urine production was reached in median 24 hours. The rapid attainment of the target urine may be explained by the initial higher infusion rate and the loading bolus.
The observed variability in urine output was small (4.1–8.8 ml/kg per hour) throughout the entire observation period – although it was striking that in one patient, despite administration of a high dose of furosemide, the urine output remained low, if not negligible, for a period of approximately 33 hours. We could not identify an obvious cause for this. In our retrospective study in which the patients received additional intermittent furosemide bolus injections, the variability in urine output was 0.7–16.1 ml/kg per hour during the study period. This is in accordance with studies in infants after CPB surgery, where less variance in urine output was observed with continuous administration compared with intermittent furosemide administration [3–5]. This suggests that strict protocols for diuretic therapies reduce variability in patients' response. It is probable that a tailored PK/PD model for furosemide therapy in neonates treated with ECMO may further optimize diuretic therapy for these critically ill neonates.
The obtained fluid balances were approximately zero for all three study days, although with substantial variability. The forced diuresis was well tolerated, as shown by the stable haemodynamic parameters and by the reduction of the vasopressor score.
Hypochloraemic metabolic alkalosis is a well-known side effect of furosemide therapy. A tendency for metabolic alkalosis was observed in two patients after approximately 48 hours of furosemide therapy. Since hypochloraemia was present in one patient, furosemide therapy was most probably the cause of the metabolic alkalosis. We have no explanation, however, for the metabolic alkalosis in the other patient, after contraction alkalosis and prerenal failure were excluded, and no increased use of inotropic drugs was present. This aspect should be recognized in the ongoing development and testing of a PK/PD model including more patients.