Plasma Concentrations after Intravenous Administration of Phylloquinone (vitamin K1) in Preterm and Sick Neonates

doi:10.1016/S0049-3848(00)00280-2

Thrombosis Research

Volume 99, Issue 5, 1 September 2000, Pages 467-472

https://doi.org/10.1016/S0049-3848(00)00280-2 Get rights and content

Abstract

Vitamin K prophylaxis usually is administered orally or intramuscularly, but in neonatal intensive care oral administration might not be feasible and intramuscular administration is not general practice in very small infants. No data are available about plasma levels after intravenous administration of vitamin K to neonates. Therefore, we investigated plasma levels in 18 infants: 14 preterms with a birthweight of 1785±648 g and 4 sick newborns with a birth-weight of 3167±510 g after administration of a single dose of 0.3±0.1 mg/kg phylloquinone (vitamin K₁) (Konakion MM^®, Roche) intravenously after birth. Blood was collected 22.9±18.4 hours after intravenous administration of vitamin K₁. In 10 neonates a second sample was obtained 111.8±49.1 hours after the first vitamin K₁ administration. Gas chromatography-mass spectrometry (GC-MS) was used as the method for determination of vitamin K₁. The measured plasma concentration after intravenous administration of vitamin K₁ was 191.3±102.6 ng vitamin K in the first sample /mL in the first sample and 98.7±75.2 ng vitamin K₁/mL in the second samples. These results are similar to those described in newborns after oral administration of 3 mg vitamin K₁ and after intramuscular administration of 1.5 mg vitamin K₁. In conclusion, the recommendation of the producer to give 0.4 mg/kg of vitamin K intravenously to neonates, in whom oral or intramuscular administration is not feasible, seems to be rational.

Section snippets

Patients

At our department all neonates admitted to the neonatal intensive care unit receive 0.2–0.4 mg vitamin K₁/kg/week (Konakion MM^®, Roche) intravenously, as long as oral administration is not feasible. Vitamin K₁ was administered by continuos infusion over several minutes. No intramuscular vitamin K administration is given in our neonatal intensive care unit. Blood samples were collected from 18 infants, 14 preterms with a birthweight of 1785±648 g and 4 sick newborns with a birthweight of

Results

The exact amount of vitamin K₁ administered to each specific child, diagnosis, gestational age, nutrition, the time of blood sampling, and the measured plasma concentrations of vitamin K₁ are summarized in Table 1. Figure 1 shows the measured plasma vitamin K₁ concentrations.

Blood was collected 22.9±18.4 hours after the first intravenous administration of vitamin K₁; the measured plasma concentrations were 191.3±102.6 ng vitamin K₁/mL. In 10 neonates a second sample was obtained 111.8±49.1

Discussion

There are only a few reports about direct measurements of plasma concentrations of vitamin K after oral and intramuscular vitamin K administration. And there are no reports about plasma concentrations after intravenous administration of vitamin K in neonates.

Blood sampling in small neonates presents several problems: in our neonatology unit it is general practice to reduce irritation of the neonates to a minimum. Due to the small blood volume, sample volumes have to be very small. The same

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A concise review of quantification methods for determination of vitamin K in various biological matrices
2019, Journal of Pharmaceutical and Biomedical Analysis
Citation Excerpt :
Raith group has provided the GCMS method used to quantify VK1 levels in neonatal plasma with smaller sample volume (200 μg). They developed a direct measurement method of VK1 plasma concentrations after intravenous administration in neonates [41]. A highly sensitive and selective HPLC-ECD trace analysis method has been established to quantify multiple vitamin K analogs (VK1, MK 4–10) in human serum.
Vitamin K is an essential nutrient in the body and involved in numerous physiological and pathophysiological functions. Both the lack and surplus of vitamin K can put human health at risk. Therefore, it becomes necessary to monitor vitamin K concentrations in different biomatrices through establishing sensitive and specific analytical methods. This review collectively describes an updated overview of the sample pretreatment methodologies and methods for quantitative determination of vitamin K that have been used in last two decades. High Performance Liquid Chromatography (HPLC) is commonly utilized as a standard for separation of vitamin K in combination with different detection including spectroscopic, spectrometric, fluorometric and mass spectroscopy. Recent progress in sample pretreatment technologies and quantitation methodologies have enhanced the ability to identify and quantitate vitamin K in biomatrices to further advance our understanding of the role of this vitamin in human health and disease.
Vitamin K prophylaxis for preterm infants
2010, Early Human Development
Vitamin K is the most common ‘drug’ administered to babies born in the western world. For many decades vitamin K prophylaxis has been a routine treatment at birth for preterm infants. Despite universal use in preterm infants, very little work has been done to date to refine vitamin K dosage in this population or to assess vitamin K status after prophylaxis. Current regimens of prophylaxis used for preterm infants vary widely in terms of dose, route of administration, and formulation used.
Vitamin K the basics-What's new?
2010, Early Human Development
Relatively little is known about the vitamin K status and requirements in term and preterm infants, though hemorrhagic disease of the newborn infant continues to be a worldwide problem. This brief review of vitamin K metabolism, vitamin K dependent proteins, and the vitamin K cycle covers some new thoughts about the importance of vitamin K to human health including the preterm infant. A review of perinatal vitamin K metabolism concludes that little vitamin K actually crosses the placenta from mother to infant. The neonatal sources of vitamin K are generally limited to the vitamin K prophylaxis given at the time of birth, dietary sources, and questionable amounts from vitamin K present in the intestinal tract synthesized from bacteria. Preterm infants receive large quantities of vitamin K from prophylaxis, TPN solutions, infant formula and breast milk fortifiers. Thus, vitamin serum concentration in preterm infants is up to one hundred times higher than those found in adults and 10–20 times those found in term formula-fed infants. Though no toxicity has been reported, the elevation of epoxide reductase (VKOR) from the vitamin K cycle found in the serum of preterm infants is worthy of additional study. PIVKA-II (abnormal prothrombin) is not a reliable indicator of vitamin K deficiency in preterm or term infants.
Vitamin K<inf>1</inf> (phylloquinone) induces vascular endothelial dysfunction: Role of oxidative stress
2006, Toxicology and Applied Pharmacology
We aimed to investigate the mechanisms underlying the vascular effects induced by phylloquinone (Vitamin K₁; VK₁). Vascular reactivity experiments, using standard muscle bath procedures, showed that VK₁ (5 and 50 μM) enhances the contractile response of endothelium-intact, but not denuded, rat carotid rings to phenylephrine. Similarly, maximal contraction induced by phenylephrine was enhanced in the presence of the nitric oxide (NO) synthase inhibitor N^G-nitro-l-arginine methyl ester (l-NAME). The combination of l-NAME and VK₁ did not produce any further additional effect. Pre-incubation of intact-rings with VK₁ reduced both acetylcholine- and bradykinin-induced relaxation. VK₁ induced an increment in tension on carotid rings submaximally pre-contracted with phenylephrine. VK₁-induced increment in tension was completely abolished by endothelial removal or incubation of intact rings with l-NAME and l-NNA. Conversely, 7-nitroindazole, 1400 W, or indomethacin did not affect VK₁-induced contraction. Moreover, VK₁ reduced l-arginine-induced relaxation in endothelium-intact rings. Lucigenin-amplified chemiluminescence assays showed that VK₁ induced an increase in the level of superoxide anions in endothelium-intact but not denuded rings. Measurement of nitrite and nitrate generation showed that VK₁ did not alter nitrate formation but strongly inhibited the generation of nitrite. Finally, the superoxide anions scavenger tiron prevented the endothelial vasomotor dysfunction caused by VK₁ on phenyleprine-induced contraction and acetylcholine or bradykinin-induced relaxation. In conclusion, our data show that VK₁ disrupts the vasomotor function of rat carotid. Our results suggest that VK₁-induced oxidative stress through production of superoxide anion is interfering with the NO pathway, which in turn is responsible for the altered vascular reactivity induced by VK₁.
Hemostatic Disorders of the Newborn
2005, Avery's Diseases of the Newborn
Vitamin K<inf>1</inf> attenuates hypoxia-induced relaxation of rat carotid artery
2002, Pharmacological Research
Vascular responses to hypoxia are heterogeneous and involve the release of vasodilators substances such as nitric oxide (NO) and prostacyclin (PGI₂). In vitro studies have shown that Vitamin K₁ modulates the release of arachidonic acid (AA) in vascular cells, and thus inhibits the capacity of blood vessels to synthesise vasodilator AA metabolites. The aim of our work was to investigate the effects of Vitamin K₁ on the hypoxia-induced vasorelaxation. Hypoxia was induced by changing the gas from 95% O₂/5% CO₂ to a mixture containing 95% N₂/5% CO₂. Rat carotid arteries were pre-contracted with phenylephrine (Phe, 10⁻⁸ mol/l) and when the contraction reached a plateau, the bath was bubbled with 95% N₂/5% CO₂ for 15 min. In intact rings, there was a total relaxation after 15 min of exposure to hypoxia. Removal of the endothelium strongly reduced hypoxia-induced relaxation. In intact rings, indomethacin and l-NAME reduced the hypoxic relaxation after 5 min of exposure but not after 10 or 15 min. Exposure of endothelium-intact rings to Vitamin K₁ (5×10⁻⁶ and 5×10⁻⁵ mol/l), l-NAME+indomethacin as well as the combination of l-NAME+indomethacin+Vitamin K₁ reduced the hypoxic relaxation after 5 and 10 min of exposure but not after 15 min. At 5×10⁻⁷ mol/l Vitamin K₁ did not attenuate hypoxia-induced relaxation. It was also found that Vitamin K₁ (5×10⁻⁶ and 5×10⁻⁵ mol/l) inhibited ACh-induced relaxation in normoxic conditions. These results show that the effect of Vitamin K₁ on attenuating hypoxia-induced vasorelaxation is concentration-dependent and probably related to its action on endothelial cells.

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Original articlePlasma Concentrations after Intravenous Administration of Phylloquinone (vitamin K1) in Preterm and Sick Neonates

Abstract

Section snippets

Patients

Results

Discussion

Int J Pharm

Vitamin K in infancy

Europ J Pediatr

Haemorrhagic disease of the newborn in the British Islestwo year prospective study

BMJ

Vitamin K deficiency bleeding (VKDB) in infancy

Thromb Haemost

Factors associated with childhood cancer in a national cohort study

Br J Cancer

Childhood cancer, intramuscular vitamin K, and pethidine given during labour

BMJ

Vitamin K and childhood cancera population based case-control study in Lower Saxony, Germany

BMJ

Childhood leukaemia and intramuscular vitamin Kfindings from a case-control study

BMJ

Administration of vitamin K to newborn infants and childhood cancer

BMJ

Case-control studies of relation between childhood cancer and neonatal vitamin K administration

BMJ

Original article
Plasma Concentrations after Intravenous Administration of Phylloquinone (vitamin K₁) in Preterm and Sick Neonates