Helen Porter

Head cooling with mild systemic hypothermia in anesthetized piglets is neuroprotective

Hypothermia is potentially therapeutic in the management of neonatal hypoxic‐ischemic brain injury. However, not all studies have shown a neuroprotective effect. It is suggested that the stress of unsedated hypothermia may interfere with neuroprotection. We propose that selective head cooling (SHC) combined with mild total‐body hypothermia during anesthesia enhances local neuroprotection while minimizing the occurrence of systemic side effects and stress associated with unsedated whole‐body cooling. Our objective was to determine whether SHC combined with mild total‐body hypothermia while anesthetized for a period of 24 hours reduces cerebral damage in our piglet survival model of global hypoxia‐ischemia. Eighteen anesthetized piglets received a 45‐minute global hypoxic‐ischemic insult. The pigs were randomized either to remain normothermic or to receive SHC. We found that the severity of the hypoxic‐ischemic insult was similar in the SHC versus the normothermic group, and that the mean neurology scores at 30 and 48 hours and neuropathology scores were significantly better in the SHC group versus the normothermic group. We conclude that selective head cooling combined with mild systemic hypothermia and anesthesia is neuroprotective when started immediately after the insult in our piglet model of hypoxic‐ischemic encephalopathy. Ann Neurol 2003;53:000–000

Prediction of chorionicity in twin pregnancies at 10–14 weeks of gestation

Objective To examine the accuracy of sonographic determination of chorionicity in twin pregnancies at 10–14 weeks of gestation.

Delayed Hypothermia as Selective Head Cooling or Whole Body Cooling Does Not Protect Brain or Body in Newborn Pig Subjected to Hypoxia-Ischemia

The neuroprotective efficacy of hypothermia (HT) after hypoxia-ischemia (HI) falls dramatically the longer the delay in initiating HT. Knowledge is scarce regarding protective or adverse effects of HT in organs beyond the brain. In addition, the relative effectiveness of selective head cooling (SHC) and whole body cooling (WBC) has not been studied. We aimed to examine whether 24 h HT, initiated 3 h after global HI is brain- and/or organ-protective using pathology, neurology, and biochemical markers. Fifty, ≤1-d-old pigs were subjected to global HI causing permanent brain injury. Animals were randomized to normothermia (NT), (Trectal) 39.0°C, SHCTrectal 34.5°C, or WBCTrectal 34.5°C for 24 h, all followed by 48 h NT. There was no difference in injury to the brain or organs between groups. There was no gender difference in brain injury but females had significantly more organs injured [2.3 (± 1.3) [mean ± SD] vs. 1.4 ± (1.0)]. The postinsult decline in lactate was temperature independent. However, HT animals normalized their plasma-calcium, magnesium, and potassium significantly faster than NT. Delayed SHC or WBC, initiated 3 h after HI, does not reduce pathology in the brain nor in organs. Delayed HT improves postinsult recovery of plasma-calcium, magnesium, and potassium. There were no differences in adverse effects across groups.

Effect of Global Hypoxia-Ischaemia followed by 24 h of Mild Hypothermia on Organ Pathology and Biochemistry in a Newborn Pig Survival Model

Background: Perinatal asphyxia may lead to multiorgan damage as well as brain injury. Posthypoxic hypothermia (HT) may protect other organs in addition to the brain. The aim of this study was to assess the systemic effects of our global hypoxic-ischaemic (HI) insult and compare the effect of mild 24-hour HT with normothermia (NT) during unsedated recovery. Method: Thirty-eight newborn pigs were subjected to 45 min of global HI by ventilating them with ∼6% O2. On reoxygenation, pigs were randomised to NT or HT. The 18 NT piglets were maintained at rectal temperature 39.0°C for 72 h. Twenty-three HT pigs (20 experimental HT and 3 sham controls) were cooled to rectal temperature 35°C for 24 h before NT was resumed and the animals then survived a further 48 h. Results: All lesions were small with no apparent clinical effect. The incidence of any damage to the heart (6 HT vs. 9 NT), liver (9 HT vs. 7 NT), kidney (6 HT vs. 9 NT) or intestinal injury (8 HT vs. 2 NT, p = 0.07) was not different in the two groups. More HT piglets developed lung injury, 10 HT and 3 NT. Plasma [Na], [K], [Ca] and [Mg] increased significantly after the HI insult as compared to baseline values. For the 24-hour period plasma [K] and [Ca] were significantly higher in the HT group, the mean area under the curve (AUC) being for [K] AUCHT 4.4 mmol/l vs. AUCNT 3.9 mmol/l, p = 0.04 and for [Ca] AUCHT 2.7 mmol/l vs. AUCNT 2.5 mmol/l, p = 0.01, respectively. Aspartate aminotransferase peaked at 48 h in the HT group and at 24 h in the NT group. Creatinine peaked at >72 h in the HT pigs and at 48 h in the NT pigs. White blood cells (WBC) peaked at 12 h for the HT pigs and at 6 h for the NT animals. AUC of the WBC during the cooling was significantly lower in the HT pig (AUCHT 11.1 vs. AUCNT 15.3 103/mm3, p = 0.04). The HT pigs needed more glucose to maintain normal glucose during the last 12 h of HT. Also HT animals needed more oxygen during cooling to maintain PaO2. Conclusion: Twenty-four hours of mild HT did not reduce damage in any organ. There was a slight increase in lung damage in the HT group. None of the biochemical or pathological changes were of clinical significance. We conclude that mild HT for 24 h does not affect the organ systems adversely when compared to NT. Additional glucose and oxygen is needed during cooling to maintain normal values.

A neonatal piglet model of intraventricular hemorrhage and posthemorrhagic ventricular dilation

OBJECT The combination of intraventricular hemorrhage (IVH) and posthemorrhagic ventricular dilation (PHVD) remains an important cause of disability in children surviving prematurity. Currently, there is no clear agreement on the management of neonatal IVH, apart from the eventual insertion of a shunt to control PHVD. Cerebrospinal fluid (CSF) shunts are associated with a relatively high complication rate in this population. The development of new treatment options requires greater understanding of the pathophysiological mechanisms of IVH and PHVD, as well as an opportunity to monitor closely their effects on the immature brain. The authors have developed a neonatal large animal model of IVH with long-term survival, allowing the full development of PHVD. METHODS Fourteen piglets that were 3 to 24 hours old were randomized to receive slow injections of autologous blood, autologous blood with elevated hematocrit, or artificial CSF after induction of general anesthesia. A fourth group served as controls. All animals underwent surgery to form an artificial fontanelle at the bregma. Physiological parameters, including intracranial pressure and electroencephalography, were monitored during injection. RESULTS Serial cranial ultrasonography studies performed during the 23- to 44-day survival period demonstrated progressive ventricular dilation in the animals injected with blood. Ventricular volumes, measured with image analysis software, confirmed the highest dilation after injection of blood with an elevated hematocrit. Histological evaluation showed fibrosis in the basal subarachnoid space of hydrocephalic piglets. CONCLUSIONS This piglet model closely replicates human neonatal IVH and PHVD. It allows detailed physiological and ultrasonographic monitoring over a prolonged survival period. It is suitable for evaluation of noninvasive as well as surgical options in the management of IVH and PHVD.

Influence of Mild Hypothermia after Hypoxia-Ischemia on the Pharmacokinetics of Gentamicin in Newborn Pigs

The renal function is often affected in asphyxiated newborn infants. The pharmacokinetics of drugs like aminoglycosides eliminated through the kidneys may be impaired and require a different than usual dosage regimen. A decrease in body temperature is associated with a decrease in glomerular filtration rate and may, therefore, impair the elimination of aminoglycosides. When hypothermia is applied as neuronal rescue therapy after birth asphyxia, the pharmacokinetics of kidney-eliminated drugs may be impaired even more. We used our well-established global hypoxia-asphyxia newborn pig model to evaluate the effect of mild hypothermia after hypoxia-ischemia on gentamicin pharmacokinetics. Newborn pigs underwent global hypoxia-ischemia followed by normothermia (39°C) for 72 h (n = 8) or mild hypothermia (35°C) for 24 h followed by normothermia (39°C) for 48 h (n = 8). Gentamicin pharmacokinetics was studied after three gentamicin doses: before hypoxia-ischemia, after hypoxia-ischemia during mild hypothermia or normothermia, and during normothermia 48 h after the first dose. The gentamicin pharmacokinetics variables were calculated using a SAAM II program. Hypoxia-ischemia altered renal function and gentamicin pharmacokinetics. The gentamicin clearance correlated with the creatinine plasma concentration (r = 0.89) and with the kidney pathology score (r = 0.55). There was no significant difference in gentamicin pharmacokinetics at 35 and 39°C in newborn pigs after hypoxia-ischemia. The gentamicin pharmacokinetics variables were not different in the hypothermic or normothermic pigs after all three studied doses. Mild hypothermia for 24 h after hypoxia-ischemia does not affect gentamicin pharmacokinetics.

Twin-to-twin blood transfusion in a dichorionic pregnancy without the oligohydramnious-polyhydramnious sequence

That eradication of associated with a foreign body using topical 3% acetic acid is possible is an interesting comment from Cook but it is unlikely that such an intervention would be useful in cases such as ours, because not only was there no cervical suture, but also because the interval between detection of asymptomatic colonisation and overwhelming sepsis was so short. Furthermore, in cases of suspected SROM, vaginal ‘douches’ could promote ascending fetal infection. We again emphasise that the management dilemmas faced with SROM, potential chorioamnionitis and preterm labour at the limits of viability are difficult and this case exhibits one complication associated with prolonged antibiotic therapy. At present none of the trials of prophylactic antibiotic treatment for preterm rupture of membranes, and their meta-analyses, show an improvement in perinatal survival and therefore further large randomised clinical trials are required.

In vitro heating of human fetal vertebra by pulsed diagnostic ultrasound

The temperature rise generated at the surface of unperfused human fetal vertebrae in vitro by an ultrasound beam with characteristics typical of those used in pulsed Doppler examinations has been measured. The bone samples were from fetuses that ranged in age from 14 to 39 weeks, dating from the last menstrual period. The samples were embedded in agar gel and the temperature rise at their surface was measured using a 50-microm diameter K-type thermocouple. The power in the ultrasound beam was 50 +/- 2 mW and the -6 dB diameter was 2.9 mm. The temperature rise at 295 s ranged from 0.6 degrees C in the youngest sample to 1.8 degrees C in the oldest. Approximately 70% of the temperature rise occurred in the first min.

Placental Lesions: Is Growth a Predictor of Bad Outcome?

Placental lesions are difficult to assess because there is often a discrepancy between the ultrasound findings, clinical diagnosis and pathology. Large placental lesions especially when solid and echogenic on ultrasound may be associated with a high maternal serum alpha-fetoprotein, intrauterine growth retardation or uteroplacental insufficiency. We report three cases in which mainly solid placental lesions were noted to increase in size during the second trimester and the placental weights at birth were relatively heavy when compared to the fetal weight. In all cases there were serious pregnancy complications. Pathological examination showed infarction, haematoma or both. We suggest that the growth of placental lesions during pregnancy may be an important sign related to the severity of the disease and therefore poor outcome.

Liver enzymes cannot be used to predict liver damage after global hypoxia-ischemia in a neonatal pig model.

Background: The term newborn pig is an established model for studying both brain and organ pathology after hypoxia-ischemia (HI). Serial liver enzyme activity is often used to predict liver injury but little is known about the relation between consecutive values of different liver enzymes and histologically verified liver injury. Objective: To determine whether plasma values of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) differed between newborn pigs with liver injures and pigs with normal livers after a severe global HI insult. Methods: Nineteen ≤36-hour-old pigs underwent a 45-min global HI insult followed by 72-hour survival. Four histological sections from standardized areas within each liver were examined. Areas under the curve (AUC) for the enzymes were calculated and compared between pigs with pathological changes in the liver (n = 12) and pigs with normal liver histology (n = 7). Results: No differences in AUC for the enzyme values were seen between the groups. However, in pigs with liver injuries a transient significant increase in LDH at the end of the HI insult (928 U/l (567–1,031)) was seen compared to the baseline value (679 U/l (548–866), p = 0.010). Significantly more liver injury was seen in animals with the umbilical vein catheter (UVC) tip inserted into the liver (p = 0.040) compared to animals with the UVC tip located outside the liver. Conclusions: In newborn pigs subjected to global HI, only LDH increases alongside pathological changes in the liver. Normal values of ALT and AST do not exclude hepatic injury.