Rational use of dopamine in hypotensive newborns: Improving our understanding of the effect on cerebral autoregulation.

Hypotension in critically ill newborn infants is associated with higher mortality and higher risk of cerebral injuries. Yet treating hypotension has never been shown to improve outcomes. In fact, some studies have found that hypotensive newborn infants who were treated with dopamine fared worse than a comparable group of newborn infants who were not. Therefore, a concern has been raised that dopamine might cause the observed adverse outcomes. Cerebral autoregulation is a protective mechanism that maintains a fairly constant cerebral blood flow despite fluctuations in blood pressure. We hypothesized that dopamine might impair the cerebral autoregulation by inducing a rightward shift of the cerebral autoregulation curve. An increased cerebrovascular resistance due to a dopaminergic stimulation of α-adrenoceptors might cause this effect. The main focus of this thesis is to clarify whether dopamine induces a rightward shift of the cerebral autoregulatory pressure curve. The thesis is based on four papers: (I) A methodological study comparing the two most commonly used methods of estimating cerebral autoregulation: time-domain analysis and frequency-domain analysis. We found that the consistency between the two methods was poor, and that time-domain analysis appeared a more robust - and simpler - method for describing cerebral autoregulation when estimates of cerebral autoregulation are based on spontaneous changes in blood pressure. (II) A retrospective study estimating cerebral autoregulation in very preterm infants by time domain analysis. This study found an association between dopamine therapy and impaired cerebral autoregulation. (III) An experimental animal study examining whether dopamine affected cerebral autoregulation in newborn piglets with low blood pressure. We found that dopamine did not negatively affect cerebral venous saturation, cerebral blood flow, or cerebral autoregulation capacity in hypotensive newborn piglets. (IV) An in vitro experiment where middle cerebral arteries from newborn piglets were examined by wire myography and pressure myography. In the wire myograph, increasing concentrations of dopamine caused a biphasic response: starting with vasodilation at low concentrations followed by vasoconstrictions at higher concentrations. In the pressure myograph, dopamine mainly induced vasodilation and the internal arterial diameter only tended to decrease at the highest concentrations. In summary, dopamine has been associated with impaired cerebral autoregulation and our conclusions in study II accorded with this. However, other work has found that initiation of dopamine infusion does not affect cerebral autoregulation. This may indicate that dopamine itself does not lead to impaired cerebral autoregulation. In support of these counter-observations, we did not find any causal relationship between dopamine therapy and impaired cerebral autoregulation in newborn piglets in study III. Also, dopamine in therapeutic concentrations did not induce vasoconstriction in pial arteries in study IV. Based on a review of the current literature, and on the studies included in this thesis, the answer to the central question in this thesis is: "No, dopamine did not induce a rightward shift of the cerebral autoregulation curve".