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Re: Additives in medication for preterm infants: documentation of exposure is only the first step…

Dear editor, We thank Whittaker et al. to refocus on the use of additives in medications by illustrating the incidence and magnitude of exposure in a cohort of preterm neonates.1 We hereby would like to suggest to further extent the adagio of Paracelsus, that ‘all is toxic, it only depends on the dose’, by adding that the ‘recipient’ should also be considered. In addition to their paper, we felt it appropriated to mention two additional aspects. Firstly, additives are also used in parenteral formulations. The neonatal gasping syndrome, due to the presence of benzyl alcohol as additive in parenteral formulations is a historical well known example of the potential side effects associated with the use of additives. Currently used additives like mannitol may result in increased urine output and propylene glycol (PEG) may lead to hyperosmolarity. However, we have to be aware that – and this is the second aspect to be stressed – all these (side-) effects have been claimed or suggested, but never were prospectively evaluated in (pre)term neonates. In a reflection paper of EMEA with specific focus on formulation in children, it has been claimed that PEG should not be administered to children below the age of 4 years.2 In contrast with this suggestion, neonatologists routinely already administer phenobarbital, phenytoin or diazepam. All these active compounds (not limitative list) can only be administered by parenteral route in a stable solution with PEG. Similarly to the established use of off-label drugs, we have to be aware that we are in a setting of established administration of additives. The only way to further improve the clinical use of drugs in children is by evaluation of its efficacy and side effects. In addition to the collection of data on active compounds, this necessitates the collection of information on safety and tolerance of the additives co-administered. We therefore hope that the paper of Whittaker et al. may serve as a catalyst to all stakeholders involved, that we have to collect more information on additives: documentation of exposure is only the first step.

References: 1.Whittaker A, Currie AE, Turner MA, Field DJ, Mulla H, Pandya HC. Toxic additives in medication for preterm infants. Arch Dis Child Fetal Neonatal Ed 2009;94:F236-40.

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Re: Alcohol Intake in Infants Treated with Oral Furosemide Solution

It was with interest that I read the article by Whittaker et al regarding toxic additives in medication for preterm infants, particularly the assessment of alcohol intake in the infant population treated with furosemide oral solution. I was surprised by the statement “ethanol exposure in the preterm infants … ranged from 0.2mL to 1.8mL/ week uncorrected for weight, the equivalent of a 70kg man consuming between 1 and 7 units”. I agree that the alcohol content of oral medications should be of concern and that infants should not be exposed to alcohol if at all possible. However I found the analogy with the weekly alcohol intake of a 70kg man alarming and challenge this calculation.

Whittaker et al put forth two “safe limits”. The first is the recommended safe weekly limit of ethanol consumption of 3mL/kg/week, the other 0.14mL/kg/week. Which limit is to be used? The highest ethanol exposure in neonates depicted in Figure 1 is approximately 0.6mL/kg/week. Although this is equivalent to approximately 4 units of alcohol/week, it does not exceed the stated safe weekly limit.

In Canada, furosemide 10mg/mL oral solution (Lasix) contains 0.2mL of ethanol 95% in each milliliter (verbal communication with Sanofi-Aventis). The usual dose used for chronic lung disease is 2mg/kg/day or 0.2mL/kg/day, equivalent to 1.4mL/kg/week. The amount of ethanol in this volume of furosemide oral solution is 0.28mL/kg/week, equivalent to approximately 2 units of alcohol/week, but not exceeding the stated safe weekly limit.