Trends in pre-hospital volume resuscitation of blunt trauma patients: a 15-year analysis of the British (TARN) and German (TraumaRegister DGU®) National Registries.

INTRODUCTION: Fluid resuscitation has long been a cornerstone of pre-hospital trauma care, yet its optimal approach remains undetermined. Although a liberal approach to fluid resuscitation has been linked with increased complications, the potential survival benefits of a restrictive approach in blunt trauma patients have not been definitively established. Consequently, equipoise persists regarding the optimal fluid resuscitation strategy in this population. METHODS: We analysed data from the two largest European trauma registries, the UK Trauma Audit and Research Network (TARN) and the German TraumaRegister DGU® (TR-DGU), between 2004 and 2018. All adult blunt trauma patients with an Injury Severity Score > 15 were included. We examined annual trends in pre-hospital fluid resuscitation, admission coagulation function, and mortality rates. RESULTS: Over the 15-year study period, data from 68,510 patients in the TARN cohort and 82,551 patients in the TR-DGU cohort were analysed. In the TARN cohort, 3.4% patients received pre-hospital crystalloid fluids, with a median volume of 25 ml (20-36 ml) administered. Conversely, in the TR-DGU cohort, 91.1% patients received pre-hospital crystalloid fluids, with a median volume of 756 ml (750-912 ml) administered. Notably, both cohorts demonstrated a consistent year-on-year decrease in the volume of pre-hospital fluid administered, accompanied by improvements in admission coagulation function and reduced mortality rates. CONCLUSION: Considerable variability exists in pre-hospital fluid resuscitation strategies for blunt trauma patients. Our data suggest a trend towards reduced pre-hospital fluid administration over time. This trend appears to be associated with improved coagulation function and decreased mortality rates. However, we acknowledge that these outcomes are influenced by multiple factors, including other improvements in pre-hospital care over time. Future research should aim to identify which trauma populations may benefit, be harmed, or remain unaffected by different pre-hospital fluid resuscitation strategies.

Ulcerative colitis after statin treatment.

Statin treatment is widely used in both primary and secondary prevention of diseases in which hyperlipidaemia is a major risk factor, for example, ischaemic heart disease. The development of ulcerative colitis as an adverse reaction to simvastatin is reported, which, despite withdrawal of the drug, proved fatal. The adverse reaction profile of the statins is reviewed, which suggests that this is a class effect and not one limited to simvastatin.

Organochlorine pesticides and chlorinated hydrocarbon solvents in the blood of chemically sensitive patients [corrected]. A statistical comparison with therapeutic medication and natural hormones.

The blood levels of organochlorine pesticides and chlorinated hydrocarbon solvents were measured in 200 and 114 chemically sensitive patients respectively, and compared with blood concentrations of standard medication (non- chlorinated substances. Clonidine, Haloperidol) of comparable toxicity after therapeutically effective dosage, and with reference levels of highly potent chemicals in the blood such as hormones. It was shown that the average blood levels of the most toxic environmental pollutants are comparable with the therapeutic steady state average blood levels of medications which have similar toxicities in the animal model. In addition the toxicity levels of xenoestrogens are at least an order of magnitude higher than normal plasma estrogen or progesterone levels. These findings suggest the possibility of additive or synergistic effects of these chlorinated compounds and the aforementioned medications. Also, these findings suggest the possibility of hormone deregulation from exposure to the aforementioned toxic chlorinated compounds.

Kappa-opioid receptor activation prevents alterations in mesocortical dopamine neurotransmission that occur during abstinence from cocaine.

In vivo microdialysis was used to characterize basal dopamine dynamics and cocaine-evoked dopamine levels in the medial prefrontal cortex of male Sprague-Dawley rats that had previously received once daily injections of cocaine (days 1-5; 20mg/kg, i.p.) in combination with the selective kappa-opioid receptor agonist U-69593 (days 3-5; 0.32mg/kg, s.c.) or its vehicle. The influence of these treatments on [3H]dopamine uptake in medial prefrontal cortex synaptosomes was also determined. Three days following the cessation of drug treatment, animals with prior history of cocaine administration exhibited enhanced psychomotor stimulation in response to a subsequent cocaine challenge. This effect was not apparent in animals that had previously received the cocaine treatment regimen in combination with the kappa-opioid receptor agonist U-69593. Cocaine challenge increased prefrontal dopamine levels in all pretreatment groups, but cocaine-pre-exposed animals had lower cocaine-evoked dopamine levels and higher basal in vivo extraction fraction, indicative of an increase in basal dopamine uptake relative to controls. Pretreatment with U-69593 prevented these effects of cocaine. Measurement of [3H]dopamine uptake in synaptosomes revealed a significant increase in uptake three days after the cessation of cocaine treatment. No increase in uptake was observed in animals that had received the cocaine treatment regimen in combination with U-69593. These results demonstrate that the early phase of abstinence from cocaine is associated with marked alterations in medial prefrontal cortex dopamine neurotransmission and that these neuroadaptations are prevented by the activation of kappa-opioid receptors. Furthermore, they raise the possibility that mesocortical dopamine neurons may be an important neural substrate upon which kappa-opioid agonists act to prevent the development of cocaine-induced behavioral sensitization.

Modulation of behavioral sensitization to cocaine by NAALADase inhibition.

Sensitization to cocaine has been attributed to alterations in excitatory amino acid and dopamine neurotransmission in the mesolimbic system. The present study sought to determine whether inhibition of NAALADase, an enzyme that cleaves glutamate from the endogenous neuropeptide, N-acetyl-aspartyl-glutamate (NAAG), attenuates sensitization to the psychomotor stimulant effects of cocaine. Rats received daily injections of cocaine (20.0 mg/kg/day; i.p.) or saline for 5 days. Fifteen minutes prior to these injections they received an i.p. injection of the NAALADase inhibitor, 2-PMPA (50.0-100 mg/kg), or vehicle. Locomotor activity and stereotypy produced by a challenge dose of cocaine (15.0 mg/kg) were assessed 3 days later. Acute cocaine administration increased locomotor activity in control animals. In animals with a prior history of cocaine administration, the behavioral response to cocaine was significantly enhanced. In animals that had received 2-PMPA in combination with cocaine, the enhancement of cocaine-induced locomotor activity was attenuated. No alteration in cocaine-evoked activity was observed in animals that had received once daily injections of 2-PMPA, alone. Acute administration of 2-PMPA also did not modify saline-induced locomotor activity or activity produced by an acute cocaine challenge. These data demonstrate that NAALADase inhibition attenuates the development of sensitization to the locomotor-activating effects of cocaine. Furthermore, this action cannot be attributed to an antagonism of the acute effects of cocaine.

Neurotoxicity in single photon emission computed tomography brain scans of patients reporting chemical sensitivities.

The subset of patients reporting chemical sensitivity with neurocognitive complaints usually exhibits specific abnormalities of brain metabolism consistent with neurotoxicity, on imaging with single photon emission computed tomography (SPECT). These recurrent neurotoxic patterns are characterized by a mismatch in tracer uptake between early- and late-phase imaging, multiple hot and cold foci throughout the cortex, temporal asymmetry and increased tracer uptake into the soft tissues and, sometimes, the basal ganglia. Previous studies confirm these neurotoxic findings in patients with neurotoxic chemical exposures and breast implants. Affective processes such as depression do not, alone, show this pattern. These abnormalities in SPECT images correlate with documented neurocognitive impairment. Controlled challenges to ambient chemicals can induce profound neurotoxic changes seen on SPECT imaging in chemically sensitive patients. Detoxification treatment techniques frequently produce significant improvement on brain SPECT brain imaging in these patients. Neurotoxicity appears to be characteristic in many cases of chemical sensitivity.

Evaluation of the conditioned reinforcing effects of phentermine and fenfluramine in the rat: concordance with clinical studies.

An unbiased place-preference conditioning procedure was used to characterize the conditioned reinforcing effects of phentermine (PHEN), fenfluramine (FEN), and their combination (PHEN/FEN) in previously drug-naive rats. Animals exhibited marked preferences for an environment previously associated with the administration of phentermine. The minimum dose producing a significant effect was 3.0 mg/kg. In contrast, FEN produced dose-related place aversions. In animals which received a subthreshold dose of FEN in combination with a dose of PHEN that produced a conditioned place preference, no preference or aversion for the drug-paired place was seen. Similarly, no significant conditioning in response to administration of PHEN (3.0 mg/kg) and FEN (3.0 mg/kg) was seen. The failure of PHEN/FEN to produce conditioned reinforcing effects is in line with recent clinical studies, and suggests that PHEN/FEN and drug combinations sharing the same neurochemical mechanisms of action will have low potential for abuse.

The role of the T lymphocytic cell cycle and an autogenous lymphocytic factor in clinical medicine.

In this study 315 individuals (25 controls, 290 chemically sensitive immunocompromised patients) were investigated. Each patient had been on a standard therapy of avoidance of pollutants, nutritional supplementation, and injections of antigens for foods, and biological inhalants, but did not attain their immunological competence. Peripheral lymphocytes were collected and DNA histograms were constructed. The flow cytometer was used to evaluate the cell cycle, haematological, and other immunological profiles. From the other portion of the blood specimen, lymphocytes were propagated in vitro, harvested, and a lysate, termed the autogenous lymphocytic factor (ALF), was prepared. When treated with ALF, 88% of these individuals showed a significant (p < 0.001) clinical improvement which correlated with laboratory findings, involving regulation of abnormal cell cycles, increase in total lymphocytes and subsets T4, T8, (p < 0.05) and cell mediated immunity (CMI) response (p < 0.001). The ALF presumably acts as a biological response modifier. The cell cycle and ALF provide clinical tools for diagnosis and regulation of immunological incompetence.

Phentermine and fenfluramine. Preclinical studies in animal models of cocaine addiction.

Combined dopamine (DA) and 5-hydroxytryptamine (5-HT) releases such as phentermine (PHEN) and fenfluramine (FEN) are reported, in open label studies, to reduce craving for alcohol and cocaine and to prevent relapse. The objective of the studies reported here was to assess the actions of these agents alone and in combination in various animal models of drug addiction. Study 1. In vivo microdialysis experiments demonstrate that these agents preferentially release mesolimbic DA (PHEN) and 5-HT (FEN). Patients who relapse and use cocaine while taking these medications report diminished cocaine-like subjective effects. Microdialysis experiments were performed in awake rats, and dialysate samples were analyzed for DA and 5-HT. PHEN (1 mg/kg, intravenously (i.v.)) elevated DA (2-3-fold) for over 1.5 hr. Administration of cocaine (3 mg/kg, i.v.) increased DA 6-fold in saline-treated rats, but only 3-fold in PHEN-treated rats. PHEN did not reduce cocaine-induced increases in 5-HT. Study 2. These agents were assessed in a mouse model of cocaine-conditioned motoric activity (CCMA). Pretreatment with non-activating doses of PHEN (4.6 mg/kg, intraperitoneally (i.p.)) enhanced CCMA, whereas non-depressing doses of FEN (0.1 mg/kg, i.p.) did not alter CCMA or the PHEN-induced increase in CCMA. In contrast, sub-effective doses of FEN reduced CCMA stereotypy-like locomotion, whereas sub-effective doses of PHEN were without effect. PHEN reversed the FEN-induced increase in CCMA stereotypy-like locomotion. Study 3. PHEN and FEN were assessed in the conditional place preference model. FEN produced marked aversions for an environment previously associated with its administration and the minimum dose producing this effect was 3.0 mg/kg. In contrast, administration of PHEN, amphetamine (1.0-3.0 mg/kg) or morphine (3.0-5.0 mg/kg) produced dose-related preferences for the drug-paired place. However, the magnitude of the response to PHEN was less than that produced by the other prototypic drugs of abuse. In rats that received FEN (0.3 or 3.0 mg/kg) in combination with PHEN (3.0 mg/kg), the conditioned rewarding effects of PHEN were abolished. These data demonstrate that the rewarding effects of PHEN can be conditioned to stimuli previously associated with its administration. However, the conditioned response to this agent is less than that produced by prototypic drugs of abuse. The finding that PHEN-induced place preferences were attenuated by doses of FEN demonstrates that the combination of FEN/PHEN is devoid of motivational effects. The preclinical data obtained with PHEN/FEN in various models of drug provide a strong rationale for pursuing controlled clinical trials in humans with agents that act via a similar mechanism of action.

Sensitization to the behavioral effects of cocaine: modulation by dynorphin and kappa-opioid receptor agonists.

Several lines of evidence suggest an involvement of the mesolimbic dopamine (DA) system in the mediation of psychostimulant-induced sensitization. It is also apparent that endogenous opioid peptide systems can modulate the activity of this same DA system. Psychostimulant-induced alterations in opioid peptide gene expression have also been reported. In this review, evidence will be presented that demonstrates that the administration of kappa-opioid agonists can prevent the initiation of behavioral sensitization to cocaine and that such treatment is also effective in preventing alterations in mesolimbic DA neurotransmission that occur as a consequence of repeated cocaine administration. The putative role of opioid-DA interactions in the modulation of psychostimulant-induced sensitization will also be discussed.

Neurogenic inflammation: with additional discussion of central and perceptual integration of nonneurogenic inflammation.

The Working Group on Neurogenic Inflammation proposed 11 testable hypotheses in the three domains of neurogenic inflammation, perceptual and central integration, and nonneurogenic inflammation. The working group selected the term people reporting chemical sensitivity (PRCS) to identify the primary subject group. In the domain of neurogenic inflammation, testable hypotheses included: PRCS have an increased density of c-fiber neurons in symptomatic tissues; PRCS produce greater quantities of neuropeptides and prostanoids than nonsensitive subjects in response to exposure to low-level capsaicin or irritant chemicals; PRCS have an increased and prolonged response to exogenously administered c-fiber activators such as capsaicin; PRCS demonstrate augmentation of central autonomic reflexes following exposure to agents that produce c-fiber stimulation; PRCS have decreased quantities of neutral endopeptidase in their mucosa; exogenous neuropeptide challenge reproduces symptoms of PRCS. In the domain of perceptual and central integration, testable hypotheses included: PRCS have alterations in adaptation, habituation, cortical representation, perception, cognition, and hedonics compared to controls; the qualitative and quantitative interactions between trigeminal and olfactory systems are altered in PRCS; higher integration of sensory inputs is altered in PRCS. In the domain of nonneurogenic inflammation, testable hypotheses included: increased inflammation is present in PRCS in symptomatic tissues and is associated with a heightened neurosensory response; PRCS show an augmented inflammatory response to chemical exposure. The working group recommended that studies be initiated in these areas.

Comparison of single photon emission computed tomography findings in cases of healthy adults and solvent-exposed adults.

Single photon emission computed tomography (SPECT) is a useful tool in measuring dynamic brain functioning. Its potential to reveal the physiological mechanisms of neurotoxicity has not been fully explored. In the present study, the SPECT findings for 25 healthy control subjects were compared to the findings for 25 mixed organic solvent exposure subjects. Specific physiological abnormalities related to regional cerebral blood flow activity (rCBF) were revealed. In the early phase of uptake, significantly decreased uptake was found in the mixed organic solvent group; in the late phase of uptake, a significant increase in uptake was found in specific regions of interest. The discovery of this abnormality in brain functioning may be a significant step toward the creation of a biological marker of neurotoxicity. Early detection of neurotoxicity is important in occupational medicine to prevent neurotoxic illnesses in working populations.

Mitogenic effects of mycotoxins on T4 lymphocytes.

Mycotoxins have compromising effects on varied biological systems, even when ingested at levels which do not evoke manifestations of clinical mycotoxicoses. No data have been previously found as to the therapeutic and mitogenic effects of mycotoxins. This was the objective of the present work. Human peripheral T4 lymphocytes were obtained by venipuncture, propagated in RPMI 1640 medium and challenged with varied concentrations of aflatoxins, B1, B2, G1, and G2. The cells were stained with propidium iodide and fluorescent isothiocyanate (FITC) and examined microfluorometrically. All the mycotoxins were significantly mitogenic on the basis of dose response. No adverse effects were observed when doses of 10, 50 and 100 micrograms were administered on a modest clinical basis to volunteers.

Relationship of hematological variables to learning performance in aged Fischer-344 rats.

The relationship between hematological variables and the ability to perform behaviorally in two learning tests was evaluated in male F344 rats aged 22-24 months. Rats were screened for ability to meet criterion for learning one-way active avoidance in a straight runway task. Rats failing to meet criterion were given no further testing and were assigned to Group 1 (G1). Rats meeting criterion were tested in a 14-unit T-maze (2 days, 10 trials/day). Failure to negotiate the T-maze within 600 s on any three trials resulted in assignment to Group 2 (G2) with no further testing. Rats successfully completing both tasks constituted Group 3 (G3). Trunk blood was collected following behavioral testing and was assayed to determine red blood cell count (RBC), hematocrit (HCT), hemoglobin (HGB), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), white blood cell count (WBC), bands (BND), polymorphs (POLY), lymphocytes (LYM), monocytes (MON), and eosinophils (EOS). The combined G1/G2 group had significantly lower RBC, HCT, HGB, and EOS but significantly higher MCV and MCH than G3 rats. Correlation analysis revealed a positive relationship of group membership (i.e., learning test completion) to RBC, HCT, HGB, and EOS, but a negative correlation of group membership to MCH. No significant correlation emerged between any hematological characteristic and performance in either behavioral task. These results suggest that a simple blood test to determine HCT may be a useful screen for removal of moribund rats from aging studies attempting to control for effects of health on behavioral performance in rodent models.

Single photon emission computed tomography of the brain in patients with chemical sensitivities.

Chemical sensitivities display a recurrent pattern on scintigraphic examinations of the brain. The pattern can include mismatching between early and late imaging, multiple hot and cold foci distributed throughout the cortex without regard to lobar distribution (salt and pepper pattern), temporal asymmetries, and sometimes increased activity in the basal ganglia. This study used Desert Shield/Desert Storm veterans who present with abnormal neurological and psychological symptoms as a model to exhibit abnormalities by brain scintigraphy. These are typical of those seen in patients with documented exposure to neurotoxic compounds who develop a clinical syndrome that has been termed "chemical sensitivity." Exposure to cocaine, alcohol, and other substances of abuse can result in abnormal scintigrams of the brain using tracers such as [technetium-99m]hexamethylpropyleneoxime. This study used techniques combining regional cerebral blood flow data with delayed distributional data after the intracellular conversion of the tracer into a hydrophilic molecule. In addition to delayed image abnormalities, a mismatch occurs in the regional activity between the two image sets of the veterans. This degree of mismatch was not seen in control subjects who were screened for avoidance of neurotoxic agents. Patterns identified from examinations performed on patients with known exposure to petroleum distillates, pesticides and other materials linked with neurotoxicity were identified in some veterans of the Desert Shield/Desert Storm operation. A single case of repeated examinations on a veteran showed a reversion of these patterns toward normal after therapy. This reversion followed independent assessments of clinical improvement.

Chemical sensitivity in physicians.

By the nature of their work environment, physicians may be exposed to potentially toxic substances that can trigger chemical sensitivity. Nineteen physicians with chemical sensitivity were evaluated at the Environmental Health Center - Dallas regarding: type of specialty, history of chemical exposure, symptoms produced, food and water tolerance, immune parameters and double-blind chemical inhalation challenge. Food and chemical sensitivities were demonstrated in these physicians by oral, intradermal and inhalation challenges. After treatment, fifteen of the nineteen physicians were able to resume medical practice. Potential sources of chemical exposure in medical environments are evaluated.

Confirmation of chemical sensitivity by means of double-blind inhalant challenge of toxic volatile chemicals.

Fifty chemically sensitive patients with vascular, asthmatic and arthritic signs, ranging in age from 21 to 61, were exposed to double-blind challenges of ambient doses of inhaled toxic chemicals in a specially designed booth in an Environmental Control Unit (ECU). Primary signs and symptoms were recorded before and after challenge with five chemicals and three placebos. Inhaled challenges included phenol (less than .0025 ppm), petroleum-derived ethyl alcohol (less than .5 ppm), formaldehyde (less than .2 ppm), chlorine (less than .3 ppm), and pesticide (2, 3,-D at less than .0034 ppm). Placebos were water or saline. A set on testing criteria were evaluated for maximizing the likelihood of well-defined, reproducible information from these ambient-dose double-blind challenges. For best results, these testing criteria include: Before testing, the patient must be housed in a chemically less polluted environment. The individual must have been de-adapted to food, air, and water pollutants by means of a water fat for three to four days. At the time of the challenge, the patient must be on food and water previously determined to be safe. An enclosed non-pulluted challenge booth must be used for these chemical exposures. Sign and symptom scores appropriate for that patient must be recorded, before and after challenge. Appropriate doses of the chemical in question (determined by air concentration and length of exposure) are necessary to investigate a particular problem. The conclusion of the study is that in these patients, chemical sensitivity clearly does exist (pulse rate differences between positive responses and placebo - p .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Aliphatic hydrocarbon solvents in chemically sensitive patients.

The purpose of the present study was to see if chemically sensitive individuals had aliphatic hydrocarbon solvents as part of their total body load. This was done by measuring blood levels from 85 chemically sensitive patients. These were measured by a purging trap method with gas chromatography/mass spectrometry (GCC/MS) by the methods of Laseter. Thirteen patients had blood levels below the detection limit of less than 1 ppb and 72 were above the detection limit. An average of three solvents, out of seven measured, including n-pentane, 2,2-dimethylbutane, cyclopentane, 2-methylpentane, 3-methylpentane, n-hexane, n-heptane, was found in 85% of the patients' blood on the 1 to 299 ppb range. The means were as follows: n-pentane 14.7 ppb, 2,2-dimethylbutane 2.5 ppb, cyclopentane 9.0 ppb, 2-methylpentane 16.7 ppb, 3-methylpentane 28.0 ppb, n-heptane 5.5 ppb. The most frequently found of the above solvents was 2-methylpentane (found in 68.1% of the patients), 3-methylpentane (62.5%), n-hexane (61.1%), and pentane (40.3%).