The first multicentre study on coronary anomalies in the Netherlands: MuSCAT.

BACKGROUND: Current guidelines on coronary anomalies are primarily based on expert consensus and a limited number of trials. A gold standard for diagnosis and a consensus on the treatment strategy in this patient group are lacking, especially for patients with an anomalous origin of a coronary artery from the opposite sinus of Valsalva (ACAOS) with an interarterial course. AIM: To provide evidence-substantiated recommendations for diagnostic work-up, treatment and follow-up of patients with anomalous coronary arteries. METHODS: A clinical care pathway for patients with ACAOS was established by six Dutch centres. Prospectively included patients undergo work-up according to protocol using computed tomography (CT) angiography, ischaemia detection, echocardiography and coronary angiography with intracoronary measurements to assess anatomical and physiological characteristics of the ACAOS. Surgical and functional follow-up results are evaluated by CT angiography, ischaemia detection and a quality-of-life questionnaire. Patient inclusion for the first multicentre study on coronary anomalies in the Netherlands started in 2020 and will continue for at least 3 years with a minimum of 2 years of follow-up. For patients with a right or left coronary artery originating from the pulmonary artery and coronary arteriovenous fistulas a registry is maintained. RESULTS: Primary outcomes are: (cardiac) death, myocardial ischaemia attributable to the ACAOS, re-intervention after surgery and intervention after initially conservative treatment. The influence of work-up examinations on treatment choice is also evaluated. CONCLUSIONS: Structural evidence for the appropriate management of patients with coronary anomalies, especially (interarterial) ACAOS, is lacking. By means of a structured care pathway in a multicentre setting, we aim to provide an evidence-based strategy for the diagnostic evaluation and treatment of this patient group.

Shift of aberrant antigen expression at relapse or at treatment failure in acute leukemia.

The flow cytometric detection of aberrant antigen expression is one method proposed for the quantification of minimal residual disease (MRD) in acute leukemias. The present study was designed to investigate the stability of the aberrant antigen expression at relapse or at treatment failure of initial chemotherapy. For this purpose, multiparameter immunophenotyping with a panel of 15 monoclonal antibodies was used at diagnosis as well as at relapse (43 patients with overall 65 aberrations) and at treatment failure (35 patients with overall 66 aberrations). There was a significant decrease in the percentage of the initially described aberrant antigen expression on leukemia blasts at relapse (P = 0.001; n = 65) as well as at treatment failure (P = 0.0001; n = 66) considering all aberrations in the whole leukemia population. Concerning only patients with acute myelogenous leukemia (AML), significant decreases in the aberrant expression could be detected at relapse (P = 0.031; n = 42) and at treatment failure (P = 0.0001; n = 52). The changes in patients with acute lymphoblastic leukemia (ALL) were significant only at relapse (P = 0.006; n = 23). Initially, the most informative aberration was not detectable in four patients at relapse and in seven patients at treatment failure. A decrease of under 50% of the initial value was observed in another 8 patients at relapse and in 10 patients at treatment failure. In further studies assessing the detection of aberrant antigen expression for MRD, quantification of the relapses should be explicitly analyzed regarding the persistence of the initially described aberrant antigen expression.

Performance of the SE-9000 automated haematology analyser in a laboratory serving a haematological oncology unit.

The performance of the SE-9000 automated haematology analyser in a laboratory receiving a high number of abnormal specimens from haematological oncology patients was assessed according to formal protocols for the evaluation of blood cell counters. Linearity over a useful working range, precision in clinically important ranges and negligible carry-over were demonstrated in this group of patient samples confirming the results of previous investigators. The comparability of instrument derived differential leucocyte counts from both normal and distributionally abnormal samples with those obtained by visual microscopy using the NCCLS H-20 A protocol was very good. The sensitivity of flags for the detection of immature granulocytes and myeloid blast cells was high and this can be attributed to the incorporation of a new measuring channel (Immature Myeloid Information or IMI channel). The number of unrecognized abnormalities was low and when compared with the poor sensitivity of the routine 100-cell visual differential leucocyte count, the analyser was judged suitable for monitoring patients with haematological malignancies. The performance of flags such as 'left shift' and 'atypical lymphocytes' can be improved by taking into consideration distributional abnormalities such as neutrophilia and lymphocytosis. The trigger level for these flags should be adapted to the clinical need particularly in cases of neutropenia following chemotherapy, and in lymphoproliferative disorders and infection.

Carbohydrate-deficient transferrin for identification of drug overdose patients at risk of an alcohol withdrawal syndrome.

BACKGROUND: Chronic alcohol abuse is frequent in patients admitted to the intensive care unit with acute drug overdose. During detoxification, an alcohol withdrawal syndrome may develop in patients with a history of chronic alcohol abuse. Withdrawal or delirium is associated with serious risks, necessitating early identification of patients at risk. Since the information obtained from the patients or their relatives on alcohol consumption is often unreliable, biochemical markers may be helpful. Carbohydrate deficient transferrin is considered a highly specific marker (reported maximum specificity 97%, sensitivity 40-85%) for identifying alcohol abuse. METHODS: In 20 patients with acute drug overdose and suspected alcohol abuse, carbohydrate deficient transferrin was determined by an immunoturbidimetric assay on admission to the intensive care unit. Eight of the patients had carbohydrate deficient transferrin levels above the "positive" threshold and nine in a suspicious range. A "false" negative carbohydrate deficient transferrin was found in three patients who were thought to have changed their drinking habits prior to hospitalization. A "positive" carbohydrate deficient transferrin test is assumed to be associated with ingestion of more than 60-80 g ethanol/d for a period of more than seven days. RESULTS: In all patients, clonidine (30-210 micrograms/h i.v.) was started. None developed delirium. Since alcohol addiction is frequently denied, determination of carbohydrate deficient transferrin may be useful for its early diagnosis but the sensitivity of this parameter requires further evaluation.

Toxicological and neuropsychological findings in patients presenting to an environmental toxicology service.

Patients presenting to an environmental toxicology service are frequently convinced that their multiple symptoms are caused by exposure to environmental toxicants. In order to evaluate the patients' hypotheses, 120 consecutive patients referred by health care providers to the environmental toxicology service for various symptoms were included in an open prospective study. The basic diagnostic procedure included an environmental toxicology questionnaire, psychological tests, a 45 minute interview, a physical examination and standard biomonitoring for cadmium, mercury, lead, lindane, hexachlorobenzene, DDT, DDE, DDD, and pentachlorophenol and a salivary test for mercury released from amalgam. Allergic disease was found in 42 patients. Nineteen of the 42 patients also had psychosomatic disorders. An unusually high release of mercury from amalgam fillings in the saliva test was found in six patients. An environmental toxic exposure was demonstrated in 19 patients (4 lead, 8 DDE, 6 mercury--most likely from broken thermometers, 1 neurotoxic alkyl naphtol derivatives). Ten of the 19 patients had psychosomatic disorders and six had medical/neurological disorders. Only two patients had symptoms attributable to environmental exposure alone. Rather classical psychosomatic disorders were diagnosed in 83 patients. Of the 37 patients without identifiable neuropsychological dysfunction, 18 had allergic disorders and 12 had other medical diagnoses. The diagnosis of a toxic environmental exposure should be performed in an integrated diagnostic approach covering environmental toxicology and medicine as well as psychosomatic medicine.

Scope and limitations of a general unknown screening by gas chromatography-mass spectrometry in acute poisoning.

The gold standard for the diagnosis of acute poisoning is toxicological analysis. Because information on the incorporated toxic substance provided by the patient or his relatives is known from experience to be unreliable in about 40% of all intoxications, a screening procedure that covers most relevant drugs and toxicants is required rather than an analytical procedure optimized for the identification of a single class of substances. The special task for a general unknown screening procedure is to identify a toxic substance among endogenous or food-derived substances as well as environmental toxicants in a biological matrix on an emergency basis. Because the unknown toxic substance may vary considerably in its physicochemical properties and its concentration range, a universally applicable screening procedure is required. Although gas chromatography-mass spectrometry has been used for three decades, it still offers many unique advantages in terms of sensitivity, specificity, reliability, and coverage of a large number of toxic substances. Because the procedure has to be kept as simple and as short as possible, compromises have to be made with respect to extraction, derivatization, and mass-spectral techniques. The specimen of choice for a general unknown screening is-if available-urine. The standard mode of ionization is electron impact. The identification of unknown substances is highly challenging because, in our experience, previously unknown metabolites may be detected rather frequently in acute poisoning. Although an automated mass spectra library search considerably facilitates the identification process, expert knowledge on the identification of substances not included in the library as well as knowledge in clinical toxicology and metabolism is indispensable.

Fatal poisoning with detajmium: identification of detajmium and its metabolites and artifacts by gas chromatography-mass spectrometry and quantification by high-performance liquid chromatography.

After ingestion of an unknown dose of detajmium, a 14-year-old female collapsed with asystolia. Resuscitation efforts were not successful. A medicolegal autopsy was carried out, and blood, liver and gastric content were extracted and analyzed by gas chromatography-mass spectrometry (GC-MS). After derivatization with acetic anhydride, detajmium and twelve of its derivatives and metabolites were identified. The main metabolic pathways include hydroxylation and subsequent O-methylation of the indol ring, and oxidation as well as reduction of the C-21 hydroxyl function. Cleavage of the N-alkyl side-chain is a further, possibly non-enzymatic degradation pathway. Artifact formation induced by acetylation included dehydratation of the hydroxyl function of C-21 and the N-alkyl side-chain. The detajmium concentration in blood of the decreased was determined by high-performance liquid chromatography with fluorimetric detection (12 micrograms/ml).

Inhaled nitric oxide in advanced paraquat intoxication.

No effective treatment is available for adult respiratory distress syndrome, pulmonary hypertension and progressive lung fibrosis in severe paraquat poisoning. A potentially beneficial effect of nitric oxide inhalation on the mean pulmonary artery pressure and gas exchange in a subject with advanced paraquat intoxication is reported. Eight days after the suicidal ingestion of an unknown dose of paraquat, a 52-year-old female had a PaO2 < or = 50 mm Hg despite ventilation with an FiO2 of 1 and a positive end-expiratory pressure of 14 to 18 cm H2O. After administration of 25 ppm nitric oxide, PaO2 increased and the mean pulmonary artery pressure and the right-to-left shunt decreased. Discontinuation of nitric oxide resulted in rapid reversal. Ventilatory function was stabilized for three days during nitric oxide inhalation but the patient developed massive pleural effusions and died on d 11 during an interruption of nitric oxide therapy. The response of serious paraquat intoxications to nitric oxide therapy may merit further study. A remarkable post-mortem finding was extensive myonecrosis supporting prolonged muscular retention of paraquat with toxic myopathy or neuromyopathy as a late manifestation of paraquat toxicity.

Clinical symptomatology and management of mushroom poisoning.

Among poisonous mushrooms, a small number may cause serious intoxication and even fatalities in man. Humans may become symptomatic after a mushroom meal for rather different reasons: (1) ingestion of mushrooms containing toxins, (2) large amounts of mushrooms may be hard to digest, (3) immunological reactions to mushroom-derived antigens, (4) ingestion of mushrooms causing ethanol intolerance, and (5) vegetative symptoms may occur whenever a patient realizes that there might be a possibility of ingestion of a toxic mushroom after a mushroom meal. Based on the classes of toxins and their clinical symptoms, seven different types of mushroom poisoning can be distinguished: (1) phalloides, (2) orellanus, (3) gyromitra, (4) muscarine, (5) pantherina, (6) psilocybin, and (7) gastrointestinal mushroom syndrome. Two other entities of adverse reactions to mushrooms are (8) coprinus and (9) paxillus syndrome. Phalloides, orellanus, gyromitra and paxillus syndrome may lead to serious poisoning, which generally requires treatment of the patient in an intensive care unit. Diagnosis of mushroom poisoning is primarily based on anamnestic data, identification of mushrooms from leftovers of the mushroom meal, spore analysis, and/or chemical analysis. Therapeutic strategies include primary detoxification by induced emesis, gastric lavage and activated charcoal, secondary detoxification, symptomatic treatment and rarely specific antidotes. Owing to progressing fulminant hepatic failure, lethality associated with phalloides syndrome is still high (5-20%). Basic treatment includes administration of silibinin and penicillin G, although controlled studies on its therapeutic efficacy are still lacking. In serious phalloides syndrome, orthotopic liver transplantation has to be considered. Fortunately, the prognosis in most other mushroom poisonings is excellent.

Rapid determination of functional liver plasma flow in ICU patients by a modified hepatic D-sorbitol plasma clearance method.

Changes in liver perfusion may have a substantial influence on the pharmacokinetics of drugs with flow-controlled metabolism. This may have important implications for drug dosage in patients in an intensive care unit (ICU). The hepatic D-sorbitol plasma clearance has been suggested as a non-invasive test for evaluating functional liver plasma flow, which is in reasonable agreement with the direct blood measurement. However, its determination requires D-sorbitol infusion for 3 h or administration of a D-sorbitol bolus and withdrawal of blood specimens every 3-5 min. Since both variants are impractical in the ICU setting, a bolus/infusion technique was tested. A combined technique applying a bolus (0.85 mg/kg) and steady-state infusion (0.0014 mg/kg/min) of D-sorbitol was tested in 10 ICU patients without hepatic disease (group 1) and in 10 ICU patients with liver disease (group 2). Steady-state plasma levels (+/- 9%, P < 0.05) could be achieved within 60 min in all patients. The modified D-sorbitol clearance method requires a bolus and an infusion of D-sorbitol and withdrawal of a single blood specimen after 60 min. The lowest values of functional liver plasma flow were determined in patients with decompensated liver cirrhosis, acute fatty degeneration of the liver or Budd-Chiari syndrome. The method for routine determination of functional hepatic plasma perfusion proved to be rapid, safe and non-invasive in ICU patients. Hepatic D-sorbitol clearance may be especially useful for assessing the functional aspect of liver perfusion.

Clinical course, therapy, outcome and analytical data in amitriptyline and combined amitriptyline/chlordiazepoxide overdose.

A total of 103 cases of amitriptyline (AT) overdose (group 1) and 81 cases of overdose with a fixed combination of AT and chlordiazepoxide (CDE) (group 2), treated at our Intensive Care Unit or reported to our Poison Information Center between 1985-1990, were evaluated with respect to clinical course, symptoms and outcome, as well as efficacy of therapy. The mean amount of AT was considerably higher in group 1 compared to group 2 (13 mg kg-1 vs 7.7 mg kg-1). The most frequent symptoms in both groups were impaired consciousness, anticholinergic symptoms, seizures, arrhythmia and hypotension. Respiratory insufficiency necessitated respirator therapy in 63 of the patients. Two patients in group 1 and one patient in group 2 did not survive. Therapy included primary detoxification by gastric lavage and repeated administration of activated charcoal. In four of eight patients with cardiac conduction disturbances, hypertonic sodium bicarbonate led to a significant reduction in QRS duration and AV interval. Physostigmine was effective in eight of 14 patients with pronounced anticholinergic symptoms. No effect was observed in the other six patients. Haemoperfusion, which was performed in five patients, led to rapid improvement of coma after initiation of therapy in four patients. The clinical efficacy of haemoperfusion in AT overdose despite the high volume of distribution of AT deserves further investigation. The rather high average overdose of AT implies that large package sizes of AT were available to the patients. A major step towards prevention of serious AT overdose would be the prescription of package sizes containing a total of less than 500 mg AT.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical experience in the therapy of bites from exotic snakes in Berlin.

Since there are nearly no indigenous poisonous snakes in Germany, snake bites by poisonous snakes are rare. Most serious snake bites reported to poison information centres or treated at hospitals are caused by exotic snakes that are kept in private households. Only few types of antivenom are stored in emergency depots in Germany including polyvalent antivenoms from commercial sources. Since experience with the treatment of poisonous snake bites is limited, the records of the Intensive Care Unit and the Poison Information Centre of the Universitätsklinikum Rudolf Virchow from 1980-1991 were evaluated. During this period, 51 snake bites were reported. Eleven patients who had been bitten by exotic poisonous snakes were treated in intensive care. In eight of the cases, ethanol (blood levels on admission 1.2-4.2 g-1) had played an important role in the cause of the bite. A moderate to severe local inflammation at the site of the bite followed by oedema and necrosis was typical. One patient developed respiratory failure, probably because of the neurotoxic effects of the snake venom and a compartment syndrome necessitating fasciotomy. Haemolysis was observed in four patients and coagulopathy in six patients. All patients received polyvalent antivenom within 2-12 h of the snake bite. Despite serious coagulopathy in two of the patients and respiratory arrest in one, all survived without sequelae.

Monitoring of ajmaline in plasma with high-performance liquid chromatography.

A rapid, reliable and sensitive assay for routine determination of ajmaline in plasma by high-performance liquid chromatography with fluorimetric detection is presented. A low limit of detection in plasma (less than 1 ng/ml ajmaline) could be achieved by the extraction of plasma samples and the use of fluorimetric detection. Deproteinization of the plasma sample instead of extraction, or the use of an ultraviolet detector, yielded a higher limit of detection (less than 50 ng/ml). Two different eluents were studied. Eluent 1 allowed clear separation of ajmaline from isoajmaline and sandwicine, but did not separate isoajamaline from sandwicine. With eluent 2, separation of isoajmaline and sandwicine was achieved, but separation of ajmaline from sandwicine was less optimal than with eluent 1. Therefore, eluent 1 was used for further clinical studies. No interference was observed from therapeutic doses of other commonly co-administered drugs, such as acetylsalicylic acid, digoxin, digitoxin, ranitidine, dopamine, dobutamine, furosemide, captopril or glycerol trinitrate. In addition, the chemical stability of ajmaline and a possible rearrangement of ajmaline to its stereoisomers isoajmaline and sandwicine was studied in vivo and in vitro. Ajmaline proved to be unusually stable under both in vivo and in vitro conditions.

Plasma level monitoring of D,L-verapamil and three of its metabolites by reversed-phase high-performance liquid chromatography.

A high-performance liquid chromatographic assay was developed for determination of verapamil, norverapamil (M1) and its N-dealkylated metabolites (M2 and M3) in plasma. Plasma samples were vortex-mixed, deproteinized and centrifuged. The analysis was performed on a C18 reversed-phase column with fluorimetric detection. Since the polarity of verapamil and norverapamil differs considerably from that of M2 and M3, two different eluents were used for rapid high-performance liquid chromatographic separation. The eluent for the separation of verapamil and norverapamil was acetonitrile-0.07% orthophosphoric acid (33:67, v/v), and for M2 and M3 acetonitrile-0.07% orthophosphoric acid (25:75, v/v). The high-performance liquid chromatographic assay allowed rapid, sensitive and reliable quantitation of verapamil and three of its metabolites in plasma without an extraction procedure. The limit of detection was less than 5 ng/ml (plasma) for all compounds. No interferences with other commonly co-administered drugs was observed. Plasma concentrations of verapamil and its metabolites were determined in 21 patients receiving a continuous infusion of verapamil for tachyarrhythmia of acute onset. The steady-state plasma concentration data of verapamil and its three main metabolites in these patients gave evidence that the plasma concentration of verapamil and its active metabolite norverapamil was primarily determined by the extent of the formation of M2.

Acute poisoning with bromofosmethyl (bromophos).

One hour after suicidal ingestion of about 20 mL of a 38% solution of bromofosmethyl, CAS: 2104-96-3 (bromophos), a 52 year-old female was admitted to the hospital with extreme miosis, hypersalivation, hyperperistalsis and muscular fibrillation. Gastric lavage was performed and activated charcoal administered. Cholinergic symptoms were antagonized by repeated doses of 0.5 mg atropine. Because of the high dose of bromophos, hemoperfusion was performed with amberlite XAD4. The bromophos clearance during hemoperfusion was 95 mL/min (flow 200 mL/min). The patient received two doses of 500 mg obidoxime for recurrent muscular fibrillation. The further clinical course was uneventful. On day 4, the patient was transferred to a psychiatric ward because of persistent suicidality. In contrast to poisoning by most organophosphates, red blood cell acetyl cholinesterase was only minimally depressed but the plasma butyryl cholinesterase was initially decreased and normalized within a few days. The records of 25 patients reported to our Poison Control Center with ingestion of more than 1 g bromophos were also evaluated. The most frequent symptoms were miosis, hyperperistalsis, hypersalivation, agitation, nausea/vomiting and convulsions. Nine of the patients had no symptoms. Bromophos is relatively less toxic than its phosphate derivative, parathion.