Biomedical subjects
Publications and source records attributed to M Thoresen.
Posthaemorrhagic ventricular dilatation is the most serious direct complication of intraventricular haemorrhage after preterm birth. It results initially from multiple small blood clots throughout the cerebrospinal fluid channels impeding circulation and reabsorption. Management is difficult and new treatment approaches are needed.
BACKGROUND: The results from clinical studies with statins have directed attention to the benefits of risk factor intervention in atherosclerotic disease, and achievement of treatment goals for blood lipids. MATERIAL AND METHODS: In 1999, a total of 3,935 patients treated with a statin were screened in 412 general practices in Norway for their blood lipids, in order to evaluate the achievement of the new European treatment guidelines (total cholesterol < 5 mmol/l and LDL cholesterol < 3 mmol/l). Inclusion criterion was ongoing medication with a statin, independent of indication. Consecutive patients were interviewed and examined when they attended their regular check-ups. The mean age of the patients was 63 years; 42% of them were women. Two-thirds of the patients were in secondary prevention. RESULTS: Before treatment, the mean level of total cholesterol was in primary prevention 8.8 mmol/l, in secondary prevention and in diabetes 7.5 mmol/l. In the total material, 36% of the patients achieved the treatment goal of total cholesterol and LDL cholesterol. Significantly more patients in secondary prevention than in primary prevention achieved the treatment goal (44% versus 17%), more patients with than without diabetes achieved it (45% versus 34%), and more men than women (42% versus 27%). These differences were mainly due to differences in base levels of total cholesterol and LDL cholesterol. To assess the statin doses, the average dose of each type of statin was converted to a simvastatin dose. The average dose in this manner was found to be 23.8 mg, with small differences between the subgroups. INTERPRETATION: The doctors did not uptitrate the statin doses according to the lipid levels and in line with the evidence from the clinical trials. General practitioners in Norway should intensify their use of lipid lowering therapy.
UNLABELLED: Upcoming trials of neuroprotective strategies in severely asphyxiated newborn infants emphasize the need for early and objective markers of both good and bad long-term prognosis. Traditional markers such as neurological depression and seizures are not specific. AIM: To study whether measurement in the cerebrospinal fluid of some proteins known to be specific to the central nervous system was in covariance with the clinical course and long-term prognosis. METHODS: Twenty-two asphyxiated infants were included in the study and compared with a control group of 8 infants without signs of perinatal asphyxia. Cerebrospinal fluid (CSF) was collected during the first 4 d of life and analysed for neurofilament protein (NFp), glial fibrillary acidic protein (GFAp), protein S-100 and neuron-specific enolase (NSE). RESULTS: The concentrations of all four proteins were significantly increased in the CSF of asphyxiated infants. The concentrations correlated significantly with other indicators of long-term prognosis and to neurological impairment at I y of age, or death before that time. Specifically, concentrations were excessively high in the five infants who died. CONCLUSIONS: High concentrations of brain-specific proteins are released into the CSF of asphyxiated infants. It might therefore be useful to measure these concentrations when excluding patients with the gravest prognosis from neuroprotective trials.
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Selective head cooling has been proposed as a neuroprotective intervention after hypoxia-ischemia in which the brain is cooled without subjecting the rest of the body to significant hypothermia, thus minimizing adverse systemic effects. There are little data showing it is possible to cool the brain more than the body. We have therefore applied selective head cooling to our hypoxia-ischemia piglet model to establish whether it is possible. Nine piglets were anesthetized, and brain temperature was measured at the surface and in the superficial (0.2 cm) and deep (1.7-2.0 cm) gray matter. Rectal (6-cm depth), skin, and scalp temperatures (T) were recorded continuously. Lowering T-rectal from normothermia (39 degrees C) to hypothermia (33.5-33.8 degrees C) using a head cap perfused with cold (6-24 degrees C) water was undertaken for up to 6 h. To assess the impact of the 45-min hypoxia-ischemia insult on the effectiveness of selective head cooling, four piglets were cooled both before and after the insult, and four, only afterward. During selective head cooling, it was possible to achieve a lower T-deep brain than T-rectal in all animals both before and after hypoxia. However, this was only possible when overhead body heating was used. The T-rectal to T-deep brain gradient was significantly smaller after the insult (median, 5.3 degrees C; range, 4.2-8.5 degrees C versus 3.0 degrees C; 1.7-7.4 degrees C; p = 0.008). During rewarming to normothermia, the gradient was maintained at 4.5 degrees C. We report for the first time a study, which by direct measurement of deep intracerebral temperatures, validates the cooling cap as an effective method of selective brain cooling in a newborn animal hypoxia-ischemia model.
Three to 12 h of mild hypothermia (HT) starting after hypoxia-ischemia is neuroprotective in piglets that are anesthetized during HT. Newborn infants suffering from neonatal encephalopathy often ventilate spontaneously and are not necessarily sedated. We aimed to test whether mild posthypoxic HT lasting 24 h was neuroprotective if the animals were not sedated. Thirty-nine piglets (median weight 1.6 kg, range 0.8-2.2 kg; median age 24 h, range 7-48 h) were anesthetized and ventilated and subjected to a 45-min hypoxic (FiO(2) approximately 6%) global insult (n = 36) or sham hypoxia (n = 3). On reoxygenation, 18 were maintained normothermic (NT, 39.0 degrees C) for 72 h, and 21 were cooled from 39 (NT) to 35 degrees C (HT) for the first 24 h before NT was resumed (18 experimental, three sham hypoxia). Cardiovascular parameters and intermittent EEG were documented throughout. The brain was perfusion fixed for neuropathology and five main areas examined using light microscopy. The insult severity (duration in minutes of EEG amplitude < 7 microV) was similar in the NT and HT groups, mean +/- SD (28 +/- 7.2 versus 27 +/- 8.6 min), as was the mean FiO(2) (5.9 +/- 0.7 versus 5.8 +/- 0.8%) during the insult. Six NT and seven HT piglets developed posthypoxic seizures that lasted 29 and 30% of the time, respectively. The distribution and degree of injury (0.0-4.0, normal-maximal damage) within the brain (hippocampus, cortex/white matter, cerebellum, basal ganglia, thalamus) were similar in the NT and HT groups (overall score, mean +/- SD, 2.3 +/- 1.5 versus 2.4 +/- 1.3) as was the EEG background amplitude at 3 h (13 +/- 3.5 versus 10 +/- 3.3 microV). The HT animals shivered and were more active. The sham control group (n = 3) shivered but had normal physiology and neuropathology. Plasma cortisol was significantly higher in the HT group during the HT period, 766 +/- 277 versus 244 +/- 144 microM at 24 h. Mild postinsult HT for 24 h was not neuroprotective in unsedated piglets and did not reduce the number of animals that developed posthypoxic seizures. Cortisol reached 3 times the NT value at the end of HT. We speculate that the stress of shivering and feeling cold interfered with the previously shown neuroprotective effect of HT. Research on the appropriateness of sedation during clinical HT is urgent.
Statin drug treatment has still not achieved complete acceptance, and titration to recommended target goals is still not used by physicians in Norway.
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Many years of experimental work on hypoxic-ischaemic injury have supported the hypothesis that cooling the body and brain after the primary injury offers permanent neuroprotection. Clinically, the question of how late cooling can start after the insult and still have a protective effect is important and not fully investigated. Pilot studies in human adults initiated cooling after 10-18 h (trauma, stroke), however animal data suggest cooling is not effective if started later than 6 h. There might be a threshold for 'cooling dose' - by depth or duration - to achieve permanent protection. Hypothermia must be administered with understanding of the extensive physiological effects. Different enzymes have different sensitivity to changes in temperature, hence some effects may be beneficial and some deleterious. Hypothermia and cardiovascular responses and coagulation needs careful monitoring.
OBJECTIVE: To examine changing trends in the field of secondary prevention of atherosclerotic disease in Norwegian general practice. DESIGN: A multipractice survey of consecutive patients with atherosclerotic disease consulting general practitioners in 1994/95 compared with a similar survey in 1996/97. SETTING: Primary health care. SUBJECTS: 707 patients attending 31 general practitioners in 1994/95 and 1353 patients attending 63 general practitioners in 1996/97. MAIN OUTCOME MEASURES: The patients were examined and interviewed for risk factors and pharmacological treatment. RESULTS: In 1994/95, 18% of the patients had been prescribed a lipid-lowering agent as opposed to 55% in the later survey. Consequently, the average level of LDL cholesterol in the 1996/97 population was 19% lower than in the 1994/95 population (3.8 mmol/l vs 4.7 mmol/l), which may imply a marked risk reduction. Aspirin and beta-blockers were prescribed to approximately 50% of the patients in both surveys. Diabetic patients had the same drug prescription rate and lipid profile as non-diabetics. In both surveys, about 25% of the patients were smokers. CONCLUSION: Secondary prevention in the majority of patients with atherosclerotic disease though ameliorating is still unsatisfactory. More attention is needed to achieve and sustain treatment goals.
Measurement error models in logistic regression have received considerable theoretical interest over the past 10-15 years. In this paper, we present the results of a simulation study that compares four estimation methods: the so-called regression calibration method, probit maximum likelihood as an approximation to the logistic maximum likelihood, the exact maximum likelihood method based on a logistic model, and the naive estimator, which is the result of simply ignoring the fact that some of the explanatory variables are measured with error. We have compared the behavior of these methods in a simple, additive measurement error model. We show that, in this situation, the regression calibration method is a very good alternative to more mathematically sophisticated methods.
Randomised clinical trials show that two injections of corticosteroid into the mother before preterm delivery reduce respiratory distress syndrome, neonatal mortality, and intraventricular haemorrhage. However, repeated courses of antenatal steroid are not backed by such evidence of safety and efficacy. Animal studies have shown that maternal corticosteroid delays myelination and reduces the growth of all fetal brain areas particularly the hippocampus. Corticosteroids may reduce or enhance hypoxic-ischaemic injury to the developing brain depending on timing and dosage. Clinical trials of maternally administered corticosteroid show no evidence of increased disability on follow up but numbers are small. Postnatal trials of dexamethasone when brain maturity is still preterm show a significant increase in later disability in the dexamethasone treated groups. There is evidence from randomised trials, retrospective data, experiments on pregnant mice, and the chemical make up of the preparations that betamethasone may be safer and more protective of the immature brain than dexamethasone. Single course corticosteroid treatment before preterm delivery must still be recommended as a life saving and cost effective intervention, but clinicians may wish to change from using dexamethasone to betamethasone. In view of the animal and postnatal data, clinicians should be cautious with repeated courses of antenatal corticosteroids and repetition may be unnecessary for lung maturity.
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 degrees C) for 72 h (n = 8) or mild hypothermia (35 degrees C) for 24 h followed by normothermia (39 degrees 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 degrees 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.
BACKGROUND: Clinical trials of mild cooling to 35 degrees C or below in infants with early hypoxic-ischemic encephalopathy are under way. The objective of this study was to systematically document cardiovascular changes associated with mild therapeutic hypothermia and rewarming in such infants. PATIENTS AND METHODS: Nine infants with gestational ages of 36 to 42 weeks, with 10-minute Apgar scores of 5 or less, clinical encephalopathy, and an abnormal electroencephalogram before 6 hours were cooled by surface cooling the trunk (n = 3) or by applying a cap perfused with cooled water (n = 6) for a median of 72 hours. The target core temperature was 34.0 degrees C to 35.0 degrees C for head-cooled infants and 33.0 degrees C to 34.0 degrees C for surface-cooled infants. Maintenance heating and rewarming were provided by an overhead heater. RESULTS: Mean arterial blood pressure increased by a median of 10 mm Hg during cooling and fell by a median of 8 mm Hg on rewarming. Heart rate decreased by a median of 34 beats/minute on cooling and increased by a median of 32 beats/minute on rewarming. A large increase in the output of the overhead heater decreased mean arterial blood pressure in 5 infants. Anticonvulsant drugs, sedatives, or intercurrent hypoxemia also produced falls in temperature. The inspired oxygen fraction had to be increased by a median of.14 to maintain oxygenation during cooling with 2 infants requiring 100% oxygen, an effect probably attributable to pulmonary hypertension, which was reversible with rewarming. CONCLUSIONS: Therapeutic cooling produces changes in heart rate and blood pressure that are not hazardous, but the combination of inadvertent overcooling and inappropriately rapid rewarming, together with sedative drugs that can impair normal thermoregulatory vasoconstriction, can cause hypotension in posthypoxic newborn infants. Infants who already require 50% oxygen should be cooled cautiously because pulmonary hypertension may develop. Knowledge of these cardiovascular changes, careful monitoring, anticipation, and correction should help to avoid potential adverse effects in the upcoming clinical trials.
UNLABELLED: Recent research using newborn animal models of hypoxia-ischaemia has shown that cooling the subject from 3 to 6 degrees C starting after the insult and lasting up to 72 h offers long-lasting neuroprotection. One concern is that additional stress during hypothermia seems to reduce the beneficial effect. Phase 1 studies on cooling severely asphyxiated infants have not yet revealed any systemic adverse effects. CONCLUSION: The evidence is strongly in favor of hypothermia reducing brain damage after asphyxia and the time has come for undertaking randomized trials.
The newborn pig is currently the most used species in animal neonatal research. Valid non-invasive monitoring is important in particular for long-term survival of unsedated animals. In the unsedated newborn pig (n = 35, median age 24 h, range 7-48 h) we standardized two-dimensional Doppler echocardiography and determined the normal ranges for cardiac function. Probe positioning had to be adjusted to the V-shaped thorax and the mid-line position of the heart. Six out of the sixteen animals < 20 h had a patent ductus arteriosus compared with one of the twenty animals > 20 h old. One atrial septal defect (5 mm) and one small ventricular septal defect were diagnosed. The average heart size was 0.7-0.9% of body weight which is similar to human infants of the same size. The mean aortic diameter was 6.0 +/- 0.5 mm (mean +/- S.D.) and cardiac output was 0.38 +/- 0.08 l min-1; both correlate with body weight (r = 0.80 and 0.73, respectively). Tricuspid regurgitation velocity was 3.0 +/- 0.4 m s-1 (mean +/- S.D.), giving an estimated pressure gradient across the tricuspid valve of 37 +/- 9.7 mmHg. The aortic diameter and the heart weight per kg body weight are comparable to those reported for preterm neonates. The cardiac output and velocities across the four valves are more comparable with term neonates.
In 1996 and 97, a total of 1,353 patients with coronary heart disease and peripheral arterial disease were screened in 63 general practices for their specific risk factors and treatment. 63% of the patients were males and 25% were smokers. 55% of the patients had been prescribed a lipid lowering agent, in most cases by their general practitioner, as opposed to 18% in a similar screening in 1994 and 95. This corresponds with a general increase in the number of prescriptions for this kind of drug. The majority of patients treated were 75 years of age and under. The recommended level of LDL-cholesterol in secondary prevention is 2.6 mmol/l or less. 83% of the patients had values above this level. Neither the treatment with antithrombotic agents and beta-blockers, nor the reduction in the systolic blood pressure in hypertensive patients was found to be satisfactory. The same lipid profile and frequency with which drugs were prescribed was seen in both diabetic and non-diabetic patients. We found that lipid lowering agents were prescribed more frequently and aspirin less frequently than in comparable European surveys. It is essential to develop effective intervention strategies and for general practitioners and specialists to collaborate closely to implement these strategies for patients with atherosclerotic disease.
The study has a parallel group design with two intervention groups (T and S) and one control group (C) of VDU operators. Three serial interventions were carried out in the T and S groups, first a new lighting system, then new workplaces and last an optometric examination and corrections if needed. The new lighting gave significantly increased illuminance levels, increased luminances of the room surfaces and better luminance distribution. The two intervention groups reported significant improvement of the lighting conditions, as well as of the visual conditions and significantly reduced visual discomfort and glare. Significant reduction of headache was found in one of the intervention groups. Optometric corrections reduced the visual discomfort in both the intervention groups. When looking at those given new corrections, a significant reduction was found in the T group and a clear tendency was also found in the S group. The C group reported no improvements for any of these health outcomes. The workplace intervention gave the operator the possibility to support the whole forearm and hand on the table top. Before the intervention there were no significant differences between the three groups regarding shoulder pain and static trapezius electromyographic (EMG) load. Two years after the intervention, a significant reduction of shoulder pain was reported in the T and S groups in parallel with a significant reduction in static trapezius load, while no such reduction was found in the C group. At the same time, both static trapezius load and shoulder pain were significantly lower in the T and S groups compared with the C group. Pain in the forearm and hand showed no significant changes in any of the groups during the study period. However, there seem to be a relationship between pain in the forearm and hand and the time the operator used the mouse. The C group reported significantly higher intensity of pain and used the mouse significantly more than the S group.