Predictors of massive blood transfusion: a Delphi Study to examine the views of experts.

BACKGROUND: Trauma patients requiring massive blood transfusion (MBT) have high morbidity and mortality: early and aggressive use of blood products during immediate resuscitation may improve survival. There is currently a lack of evidence to guide initial identification of these patients which is especially important in areas where plasma may need to be thawed. In the absence of this evidence, this study aimed to robustly evaluate expert opinion by using a Delphi process to identify predictors of massive transfusion. This process can be used to ensure that decision rules include variables that have clinical validity, which may improve translation of rules into clinical practice. METHODS: An international panel of 35 experts was identified through expert advice against specific criteria. Military and civilian experts from the fields of emergency medicine, critical care, anaesthesia, prehospital care, haematology and general/trauma surgery were included. The Delphi Study was carried out over three rounds. Consensus level was predefined at 80%. RESULTS: 195 statements were generated by the panel of which 97 (49.7%) achieved consensus at the 80% level by the end of round 3. Strikingly no clinical observations reached consensus individually. Metabolic acidosis of a base excess of -5.0 or worse, lactate >5 mmol/L and a low haematocrit on arrival were all considered predictive. Some patterns of injury, but few mechanisms of injury, were considered highly predictive of the need of MBT. CONCLUSIONS: This Delphi process has produced a list of parameters that expert clinicians felt were predictive for MBT. This list can be used to inform the generation of decision rules. It is of note that many factors used in current decision rules were not valued by clinical experts-this may be a cause for poor uptake of those rules.

On the philosophy of diagnosis: is doing more good than harm better than "primum non nocere"?

Diagnosis is arguably the cornerstone of medicine. Without at least some form of diagnosis the practice of medicine would not be possible. This narrative review explores common philosophical assumptions and challenges the notion that a certain diagnosis can ever be made. The idealistic concept of "primum non nocere" is discussed, and whether the utilitarian goal of achieving "the greatest happiness for the greatest number" is a feasible or preferable alternative is considered. It is concluded that utilitarianism is inescapably intertwined with modern medical practice. Suggestions are presented to further the understanding of diagnostic medicine by embracing its principles.

Can a modified thrombolysis in myocardial infarction risk score outperform the original for risk stratifying emergency department patients with chest pain?

BACKGROUND: The thrombolysis in myocardial infarction (TIMI) risk score has been shown to risk stratify patients with suspected acute coronary syndromes (ACS) effectively in the emergency department (ED) but cannot be used to guide patient disposition. We aimed to evaluate whether modifying the TIMI risk score to give greater weighting to ischaemic ECG changes and troponin elevations would enhance its risk stratification and thus potentially facilitate safe patient discharge after 12-h troponin testing. METHODS: A prospective diagnostic cohort study was performed within the ED at Manchester Royal Infirmary, a university-affiliated teaching hospital with an annual ED census of approximately 145,000 patients. 804 patients who had presented to the ED with suspected cardiac chest pain were recruited. All patients underwent 12-h troponin T testing and were followed up by telephone and chart review after 30 days for the composite primary outcome of death, acute myocardial infarction (AMI) or urgent coronary revascularisation. RESULTS: The modified TIMI risk score outperformed the original (area under the receiver operator characteristic curve 0.87 versus 0.77, p<0.001). Using a cut-off of more than 2 points the score had a sensitivity of 96.4% for the prediction of 30-day events. The specificity of the score was only 51.0%, suggesting that in practice over 40% of patients would be ineligible for discharge even after troponin testing. CONCLUSIONS: Modifications to the TIMI risk score can improve its performance in the risk stratification of patients presenting to the ED with chest pain. However, a lack of specificity may still limit its use for guiding patient disposition after troponin testing.

Morphological properties of respiratory intercostal motoneurons in cats as revealed by intracellular injection of horseradish peroxidase.

This study was undertaken to describe details of the location and cellular morphology of functionally identified (inspiratory or expiratory) external and internal intercostal motoneurons on the basis of intracellular injection of horseradish peroxidase (HRP). Sixty HRP-labeled motoneurons were examined; 44 in transverse, 16 in sagittal sections. In the upper thoracic segments (T3-T4), there was only a small overlap in the location of inspiratory external and internal intercostal motoneurons; the inspiratory external motoneurons were generally found more ventromedially within the ventral horn than either inspiratory or expiratory internal intercostal motoneurons. No major morphological differences were observed between the types of motoneurons studied. The number of primary dendrites ranged from 6 to 10. The dendrites projected mainly along the medial or the lateral border of the ventral horn, and rostrocaudally up to 1,760 micron from the cell body. The paths taken by dendrites to fill the territory occupied by the dendritic trees appeared to depend upon location of the cell body. Few dendrites penetrated the white matter. Axon diameters varied from 1.1 to 6.7 micron (mean 3.6 +/- 1.3 micron, n = 55). Collateral branches were identified in 78% of axons. The number of branches arising from a given axon varied from 1 to 4. It is concluded that the respiratory intercostal motoneurons form a morphologically homogeneous population, in spite of their functional differences.

Brain stem projections of the glossopharyngeal nerve and its carotid sinus branch in the rat.

Transganglionic transport of horseradish peroxidase or lectin-conjugated horseradish peroxidase from an application site in the cervical trunk of the glossopharyngeal (IXth cranial) nerve of the rat produced extraperikaryal reaction product characteristic of axon terminal processes in three regions of the brain stem: (1) the nucleus of the tractus solitarius, from approximately 2.5 mm rostral to the obex to approximately 3 mm caudal to the obex; (2) the spinal trigeminal nucleus at the level of obex; (3) the cuneate fasciculus, approximately 3 mm caudal to the obex. In contrast, labelling of the carotid sinus nerve, a branch of the glossopharyngeal nerve which conveys chemoreceptor and baroreceptor afferent fibers from the carotid bifurcation, revealed a restricted central projection to within 1 mm of the obex and corresponding to the intermediate region of the glossopharyngeal nerve projection to the nucleus of the tractus solitarius. Two distinct aggregations of label were observed: (1) rostral to the obex, within the lateral and dorsomedial subnuclei of the nucleus of the tractus solitarius; (2) caudal to the obex, within the commissural and ventrolateral subnuclei of the nucleus of the tractus solitarius. Between these two sites the density of labelling was reduced. Retrogradely labelled neurons were demonstrated in the inferior salivatory nucleus and in the nucleus ambiguus after application of lectin-conjugated horseradish peroxidase to the glossopharyngeal nerve. Of the labelled neurons in the nucleus ambiguus (approximately 100), 25% contributed fibers to the carotid sinus nerve. The concentration of extraperikaryal reaction product located rostral to the obex after labelling of the carotid sinus nerve closely matches descriptions of the region of afferent terminations from carotid and aortic baroreceptors in the cat. The concentration of label caudal to the obex may therefore correspond to the region of afferent terminations from carotid chemoreceptors. This study may therefore provide some basis for a separation of the central synapses of primary afferent fibers from the carotid baroreceptors and chemoreceptors in the rat. The labelled neurons of the nucleus ambiguus provide the anatomical substrate for centrifugal control of carotid chemoreceptor activity.

Changes in the number of astrocytes and microglia in the thalamus of the monkey Macaca fascicularis following long-term subclinical methylmercury exposure.

The effects of long-term subclinical exposure to methylmercury on the number of neurons, oligodendrocytes, astrocytes, microglia, endothelial cells and pericytes within the thalamus from the left side of the brain of the monkey Macaca fascicularis has been determined by use of the Optical Volume Fractionator stereological method. The accumulated burden of inorganic mercury (IHg) within these same cell types has been determined by autometallographic methods. Four groups of monkeys were exposed to methylmercury (MeHg; 50 micrograms Hg/kg body weight/day) by mouth for 6 months, 12 months, 18 months, or 12 months followed by 6 months without exposure (clearance group). Neurons, oligodendrocytes, endothelia, and pericytes did not show a significant change in cell number for any exposure group. Astrocyte cell number exhibited a significant decline for both the 6 month and clearance exposure groups. The microglia, in contrast, showed a significant increase in the 18 month and clearance exposure groups. Results from mercury speciation and quantification analysis of contralateral matched samples from the thalamus of the right side of the brain from these same monkeys indicated that MeHg concentrations plateaued at around 12 months exposure, whereas the inorganic levels, presumably derived from demethylation of MeHg, continued to increase throughout all exposure durations. Autometallographic determination of the distribution of IHg by cell type indicates that both the astrocytes and microglia contain substantially elevated IHg deposits relative to all other cell types. The data suggest that the inorganic mercury present in the brains, accumulating after long-term subclinical methyl mercury exposure, may be a proximate toxic form of mercury responsible for the changes within the astrocyte and microglial populations.

Effect of methylmercury body burden on kidney following unilateral nephrectomy.

The model of renal enlargement after unilateral nephrectomy is chosen to study the effect of methylmercury (MeHg) burden on organ growth. The results show that MeHg burden only impedes DNA synthesis, but not other macromolecular synthesis (RNA and protein). Despite the gradual increase of kidney weight and increase of total RNA and protein content in the remaining kidney, DNA remained unchanged. There is no difference between the control and the MeHg-treated group. 3H-thymidine incorporation study shows that unilateral nephrectomy elicited minimal DNA synthesis in the remaining kidney. Again there is no statistically significant difference of 3H-thymidine incorporation between the control and the MeHg-treated group. On a separate experiment, the folic-acid-induced renal DNA synthesis is also suppressed by MeHg burden. From these data it is concluded that chronic exposure to MeHg does not affect one of the cellular repair mechanisms: hypertrophy.

Development of a method to measure plasma and whole blood choline by liquid chromatography tandem mass spectrometry.

BACKGROUND: Current gold standard markers for myocardial damage are troponins I and T, which are both sensitive and specific for the detection of myocardial infarction, but require up to 6 h to become reliably elevated in serum. Investigation into markers with potential to identify patients with early ischaemic changes is therefore intense. Choline is reported to be prognostic in patients presenting with acute coronary syndromes via its release from ischaemic cell membranes. METHODS: Liquid chromatography tandem mass spectrometry was used to develop a method to quantitate choline in plasma and blood. The method involves addition of a deuterated internal standard to an aliquot of plasma or blood followed by organic solvent addition, which precipitates the proteins in the sample. Preparation was carried out directly into a 96-deep-well plate. Chromatography of choline used a strong cation exchange column and separation used a Waters Atlantis dC18 analytical column positioned directly before the mass spectrometer source, allowing on-line preanalytical clean up of the sample. RESULTS: The lower limit of quantitation was 0.38 micromol/L, linearity was observed up to 754 micromol/L, with a working concentration range of 0.38-224 micromol/L, inter- and intra-assay coefficients of variation were <6% and <4%, respectively. Samples were stable throughout five freeze-thaw cycles and recovery was between 94% and 114%. CONCLUSIONS: The assay was successfully validated in accordance with FDA guidelines and is suitable for quantitation of choline in research and clinical settings.

Ecological validity in assessment of discourse in traumatic brain injury: ratings by clinicians and non-clinicians.

Researchers studying discourse after traumatic brain injury (TBI) increasingly recognize the need to take account of variation within the non-brain-damaged (NBD) population in order to validate their findings. This study investigated the use of ratings by professional clinicians trained in speech pathology (P raters) and by peers of TBI individuals (NP raters) as a method of placing TBI individuals' communication in context. Twenty TBI adults and 20 NBD controls matched for age, sex, education and social background retold a 1400 word story presented on audiotape, following which the narratives were transcribed and segmented. Raters used two 5-point scales, representing independent parameters of Content and Clarity, to rate the transcripts. Statistical analysis demonstrated that P raters tended to give higher ratings across the board than NP raters but that P and NP ratings were also highly correlated. In general, the ratings assigned to the two subject groups overlapped and exhibited an even spread across the range of mean ratings. On the evidence of this study clinicians appear to share perceptions regarding discourse performance with peers of the TBI subjects. In addition, many TBI subjects perform as well or better than NBD controls on high-level tasks.

Primate paneth cell degeneration following methylmercury hydroxide ingestion.

The effects of methylmercury on the intestinal epithelium were studied in 14 adolescent male Macaca mulatta monkeys weighing 3 to 5 kg. They were divided into three groups: two controls received daily applesauce vehicle without methylmercury. Nine chronic low-dose animals received 0.2 to 1.0 mg of methylmercury per day for 80 to 491 days. Three acute high-dose animals received 2.0 mg methylmercury for 17 to 18 days, when they became terminally ill. Light and electron microscopic observations were made on samples of duodenum and ileum following perfusion and immersion fixation in a glutaraldehyde-paraformaldehyde fixative. Numerous uniquely structured inclusions were prominent in the Paneth cells of the chronic low-dose animals and some necrotic Paneth cells were seen, especially in the most chronic and higher dosed animals of the group. Acute high-dose treatment produced some inclusions in the Paneth cells similar to those of the chronic low-dose group, but degenerative and necrotic cells were more frequently seen. These alterations were not seen in other intestinal epithelial cells. Paneth cells are selectively altered. These findings suggest that a function of Paneth cells may be to eliminate metals from the body.

Biochemical and morphological studies of monkeys chronically exposed to methylmercury.

This study was designed to correlated autopsy findings with the effects on cage behavior, laboratory values, and mercury clearance of long-term, low-dose exposure of primates to methylmercury. Six rhesus monkeys were given daily methylmercury hydroxide (MeHg) orally in apple juice on a preplanned dosage schedule. Three were sacrificed while receiving MeHg (group I) and the other 3 were sacrificed 2-5 mo after cessation of MeHg administration (group II). Whole-blood Hg levels (organic and inorganic) were assayed weekly, and major organ levels were assayed at autopsy. Whole-blood Hg levels were maintained between 1 and 2 micrograms/ml when the monkeys were given a MeHg dose of 80-125 micrograms/kg . d for up to 1 yr. The Hg burden of the major organs appeared to be dose- and duration-related. After periods of clearance (2.5-5 mo), intestinal wall Hg burden decreased to less than 1 microgram/g, and the hepatic Hg burden was still between 1.12 and 2.37 micrograms/g. However, the kidneys had a higher concentration of Hg, ranging from 10.34 to 29.54 micrograms/g. Whenever there was a high concentration of Hg, significant ultrastructural changes were observed. In the kidneys there were intracytoplasmic vacuoles and electron-dense inclusion bodies. In the small intestine of the animals cleared of mercury (group II), there were normal Paneth cells, as well as some degenerative cells characterized by dilation of endoplasmic reticulum and the presence of intracellular inclusion bodies. These findings suggest the long turnover time of Hg in these cell populations. During the period of study, weekly routine laboratory data including hematology, blood chemistry, and liver and kidney function tests did not reveal any significant changes.

Some effects of continuous low-dose congenital exposure to methylmercury on organ growth in the rat fetus.

Congenital low-dose exposure of rat fetuses to methylmercury produced smaller offspring without anatomical abnormalities. The present study explored the mechanisms of the smallness of fetuses. The pregnant rats were given methylmercury water (25 ppm) from day 1 of pregnancy continuously until day 20 of gestation. There was a negative correlation of fetal weight and maternal and fetal mercury burden. The whole organ DNA and protein content of the livers and kidneys in the experiments were significantly lower than the control (P less than 0.05) indicating that there were fewer cells per organ in the mercury exposed fetuses. When the data were compared on a per gram of tissue basis, there was no significanct difference, indicating that the number and size of the cells of each were not diminished. The incorporation of 3H-thymidine into fetal tissue DNA was also substantially lower in the experimental group indicating decreased proliferative activity. We conclude from this study that, at least for some major organs, the decreased size in the mercury exposed fetuses is due to fewer cells in the organs due to decreased proliferative activity.

Brain transections demonstrate the central origin of hypoxic ventilatory depression in carotid body-denervated rats.

1. The characteristics of hypoxic ventilation were studied in awake adult rats after brain transections about the intercollicular level. The results were compared with studies made before transection, 17-24 h after bilateral carotid body denervation effected by carotid sinus nerve section. 2. Transection at or below the intercollicular level converted the depressive hypoxic frequency response of control studies to a stimulatory response, increased the stimulation of tidal volume by hypoxia, and so converted the dominant pattern of ventilation in hypoxia from a depression to a progressive stimulation. 3. Transection above the intercollicular level failed to reverse the hypoxic frequency response but increased the stimulation of tidal volume by hypoxia. Consequently minute ventilation progressively increased as the severity of hypoxia increased. 4. The experiments demonstrate that in the adult rat depression of respiratory frequency by hypoxia after carotid body denervation requires the integrity of a region at or immediately above the intercollicular level. In contrast, the stimulation of tidal volume by hypoxia is markedly dependent upon precollicular structures. 5. The results are discussed in relation to the hypoxic depression of fetal breathing and the biphasic hypoxic ventilatory response of the newborn.

Biologic variables in the hair uptake of methylmercury from blood in the macaque monkey.

The total mercury (Hg) in hair and blood of 45 young healthy adult female Macaque fascicularis given 0, 50, 70, or 90 micrograms MeHg/kg body wt orally in apple juice daily revealed a close and constant ratio between blood Hg and hair. The amount of hair Hg does not increase with time (maximum period of observation 490 days) at a given dose level. Also the ratio was unchanged between background and subtoxic dose levels. Individuals at a given dose level with a higher-than-average blood level had a proportionately higher hair level. The Macaque blood/hair ratio is markedly lower than that reported for humans. Pregnancy did not have an appreciable effect on the hair mercury level. Review of the known variables in human and Macaque hair growth and structure does not provide an explanation for the difference. We suggest that an as yet unidentified biological variable(s), possibly circumfollicular blood flow, could account for the difference. This ratio difference notwithstanding, controlled studies on Macaque hair such as this add support for the validity of terminal hair as a trace metal exposure indicator.

Variability of neuropathologic lesions in experimental methylmercurial encephalopathy in primates.

Acute and chronic intoxications of rhesus monkeys with methylmercury produced lesions in the central nervous system (CNS) with different distributions. Neuronal degeneration and astroglial proliferation predominated in the dentate nucleus, lateral geniculate nucleus, thalamus and pontine nuclei in 2 monkeys that received 2 mg/kg/day for 17 and 18 days, whereas pseudolaminar necrosis and astroglial proliferation were observed in the cerebral crotex, maximally in the calcarine and insular regions, in 4 monkeys that received 0.5 to 0.8 mg/kg/day for 3 to 8.5 months. Mercury concentrations in the CNS were much higher in the acutely intoxicated animals than in the chronically intoxicated animals, but the correlation between concentrations of mercury and the histologic destruction was not precise.