Animal models for the study of perinatal hypoxic-ischemic encephalopathy: a critical analysis.

We critically evaluated various design features from 292 animal studies related to perinatal hypoxic-ischemic encephalopathy (HIE). Rodents were the most frequently used animals in HIE research (26%), followed by piglets (23%) and sheep (22%). Asphyxia with or without ischemia was the most predominant method of producing experimental brain damage, but there were significant variations in specific details, particularly regarding the method and duration of brain insult. In 71% (207/292) of studies the CNS outcomes were tested within 24 h of experimental insult and in 29% (85/292) they were tested 24 h or more after the insult. Acute CNS metabolic end-points were assessed in 82-100% of all studies. In 90% of studies the chronological age of the animal was equivalent to that of human term newborn infant. However, in only 23% (67/292) were clinical neurological, developmental or behavioral outcomes evaluated, and in only 26% (76/292) was neuropathology assessed. While no single animal model was found to be ideal for all HIE research, some models were distinctly superior to others, depending upon the specific research question. The fetal sheep, newborn lamb and piglet models are well suited for the study of acute and subacute metabolic and physiologic endpoints, whereas the rodent and primate models could be used for long-term neurological and behavioral outcome experiments as well. We also feel that standardizing the study design features, including an HI insult method that produces consistent and predictable brain damage is urgently needed. Studies in neuro-ethology should explore how well brains of various animals compare with that of the newborn human infant. There is also a need for developing animal models that mimic clinical entities in which long-term neuro-developmental and behavioral outcomes can be assessed.

Intravenous morphine attenuates pain induced changes in skin blood flow in newborn infants.

In a previous study we found that pain and discomfort caused a marked increase in skin blood flow in newborn infants, and that skin blood flow decreased after morphine. In this study we tested morphine effect on the skin blood flow response to pain more systematically. Skin blood flow was measured using a laser Doppler technique during 19 percutaneous central venous catheter placements in 18 infants, 10 of whom received intravenous morphine premedication. The mean +/- SD baseline skin blood flow was similar between the two groups: 22.5 +/- 9.5 ml 100 g-1 min-1 in the morphine group, and 23.7 +/- 8.0 ml 100 g-1 min-1 in the no-morphine group, respectively (p = n.s.). During PCVC placement in the morphine treated group, skin blood flow remained low with minimal variability. The mean value was 22.6 +/- 7.7 ml 100 g-1 min-1 (p = n.s. compared to baseline). In 7/9 infants not treated with morphine skin blood flow increased dramatically during PCVC placement, while in two it did not. But the mean skin blood flow in this group of 9 infants during PCVC placement was 45.3 +/- 34 ml 100 g-1 min-1, an overall change of 97% increase from the baseline. This was statistically significant compared with the baseline and the morphine group value during PCVC insertion (p < 0.04). During the 45 min time period after PCVC placement, skin blood flow values between groups again were similar. We conclude that morphine pretreatment for PCVC placement minimizes pain-associated increases in skin blood flow. The issue of whether skin blood flow changes could serve as measures of adequate analgesia needs to be evaluated with further studies.