Results

The effect of a slow intravenous infusion of caffeine citrate on peak systolic velocity (PSV) is shown in fig 1. It is important to note that changes in peak systolic velocity reflect changes in mean velocity. There was a significant (p<0.05) and rapid reduction in PSV in both the coeliac axis and superior mesenteric artery which began during the infusion of caffeine and was maximal at (mean (SEM) 176 (24) minutes and 133 (22) minutes, respectively. Blood flow velocity remained depressed for 2 to 3 hours after caffeine infusion, after which there was a slow recovery with a return to baseline after about 6 hours. The maximum percentage decline in coeliac axis and superior mesenteric arterial PSV was not significantly different (29 (3) and 31 (4) %; p>0.05 using Student’s t test). No ill effects were noted in the subjects.

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Figure 1

Effect of caffeine (slow intravenous infusion of caffeine citrate, 50 mg/kg over 30 min) on peak systolic velocity in the coeliac axis (CA) and superior mesenteric artery (SMA) in preterm infants. Data are presented as mean (SEM).

Discussion

The pharmacological actions of caffeine and theophylline are diverse, and in neonates they are used primarily for their stimulatory effect on the respiratory centre. The methylxanthines have been implicated in the pathogenesis of necrotising enterocolitis.3 Robinson et al 3 reported five anecdotal cases in neonates who had received oral xanthines. These babies were all very low birthweight and preterm and as such were at risk. But Jones5 presented data from her own unit over a three year period which demonstrated no link between either oral or intravenous theophylline and necrotising enterocolitis in a large cohort of 269 babies. Although not significant, those infants who had received xanthines had a slightly higher incidence (9%) than those who had received no xanthines (5%).

We can only speculate as to the mechanism of this probable vasoconstriction following the first dose of intravenous caffeine. In adults who do not normally take caffeine it induces a decrease in regional blood flow not seen in regular users.6 Caffeine affects both the optic and cerebral circulation and inhibits adenosine induced vasodilatation.7-9 In vitro there seems to be both endothelium dependent and endothelium independent vasoconstriction with caffeine.10 Caffeine seems to have an important role in the regulation of intracellular calcium. At a cellular level there are caffeine and noradrenaline sensitive calcium stores as well as caffeine sensitive but noradrenaline insensitive stores.11

Our data show that the first slow intravenous caffeine infusion to preterm neonates causes a prolonged and significant reduction in splanchnic perfusion. We have already shown that a similar slow infusion of indomethacin had no effect on the splanchnic vasculature,4 while bolus administration caused a significant reduction in splanchnic blood flow velocities. However, the response to indomethacin was much more short lived than that after caffeine and had returned to baseline after about one hour.

Whether this observation is of clinical importance is unclear, but it is a finding of which clinicians should be aware and one which deserves further study, as does the nature of the response to the second and subsequent doses.