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.

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.

Acute trichloroethylene poisoning with additional ingestion of ethanol--concentrations of trichloroethylene and its metabolites during hyperventilation therapy.

One hour after suicidal ingestion of about 150 g of trichloroethylene, a 32-year-old male was admitted to hospital. On admission, the patient's state of consciousness deteriorated from somnolence to coma. Based on blood level data, an absorbed trichloroethylene dose of at least 35 g was estimated. Additionally, ethanol, which is a strong inhibitor of trichloroethylene metabolism, had been ingested. With respect to the high dose of trichloroethylene, hyperventilation therapy was performed for 28 h. Concentrations of trichloroethylene and its metabolites in blood and urine were determined by gas chromatography. Due to hyperventilation and inhibition of trichloroethylene metabolism, not more than 30% of the absorbed dose was metabolized and excreted via kidneys. Under normal respiratory conditions and in the absence of ethanol, this fraction amounts to about 75%. Obviously, hyperventilation and ethanol-induced inhibition of metabolism led to considerably enforced pulmonary elimination of the absorbed trichloroethylene.

Hemoperfusion in acute camphor poisoning.

After ingestion of an unknown dose of a 10% camphor spirit (maximum dose 200 ml), a 54-year-old female was found in coma, having developed grand-mal-like seizures and respiratory failure. For detoxification, gastric lavage and hemoperfusion with amberlite XAD4 were performed. During hemoperfusion, seizures ceased, but no marked influence on the clinical course of the intoxication--especially on grade of coma--was observed. For further evaluation of the efficacy of treatment, camphor plasma elimination kinetics during hemoperfusion were compared to plasma elimination kinetics determined in a volunteer after an oral dose of 200 mg of camphor. Although the plasma compartment was almost completely (89%-95%) cleared of camphor by hemoperfusion, only a total of 35 mg of camphor was removed due to its high apparent volume of distribution (estimated 2-4 l/kg). The plasma elimination half-life was not affected by hemoperfusion, which may be explained by the saturation of metabolizing enzymes, still incomplete absorption, or metabolic interference of isopropanol. In the case presented here, neither the clinical course of the intoxication nor plasma level data gave evidence for a pronounced beneficial effect of hemoperfusion.

Suicidal ingestion of formalin with fatal complications.

After ingestion of an unknown amount of formalin with suicidal intent, a 55-year-old female and a 34-year-old male were admitted to the hospital with extensive gastrointestinal corrosive damage, circulatory shock, metabolic acidosis, respiratory insufficiency and impairment of renal function, which rapidly progressed to acute renal failure. Metabolic acidosis was in part due to high plasma levels of formic acid, the main metabolite of formaldehyde, and hyperlactatemia. Both patients underwent hemodialysis and hemofiltration treatment. In the male patient, a gastrectomy had to be performed. The further clinical course in the patients was characterized by sepsis and protracted pulmonary complications. Both patients died after developing adult respiratory distress syndrome and global cardiac insufficiency. In vitro experiments on formaldehyde reactivity to proteins yielded evidence for almost complete but reversible binding to plasma and blood. Formaldehyde probably exerts systemic toxicity in the form of its labile Schiff's base with proteins, but not as free formaldehyde.

Hemoperfusion in severe chlorprothixene overdose.

Two to twelve hours after suicidal ingestion of an estimated dose of 10 g chlorprothixene, a 31-year-old female was admitted to the emergency ward of the clinic with cardiorespiratory arrest. After successful resuscitation, the further clinical course was complicated by persistent ventricular extrasystoles and ventricular fibrillation which necessitated repeated defibrillation. Since the patient did not respond satisfactorily to supportive treatment, a combined hemoperfusion/hemodialysis was performed. Under extracorporeal detoxication, elimination of chlorprothixene from plasma was accompanied by substantial improvement of the patient's clinical condition, although only about 1.6% of the estimated dose had been removed. This case seems to indicate that evaluation of the therapeutic efficacy of hemoperfusion should not be based exclusively on the relation of the amount of the eliminated drug to total absorbed dose.

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.

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.

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)

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.

Effects of enzyme induction, renal and cardiac function on ketamine plasma kinetics in patients with ketamine long-term analgosedation.

Steady-state plasma levels of ketamine and its metabolites norketamine and dehydronorketamine were determined in 4 different groups of a total of 27 patients with ketamine long-term analgosedation (1.1 - 1.3 mg/kg/h). In 9 of the patients who had normal liver and kidney function (group 1), steady-state levels after 3 days of continuous infusion were 1.2 +/- 0.3 micrograms/ml ketamine, 1.0 +/- 0.6 micrograms/ml norketamine, and 2.6 +/- 1.0 micrograms/ml dehydronorketamine. The measured ketamine levels in group 1 were in agreement with the expected value, which may be calculated from published pharmacokinetic data after bolus injection. In 8 patients with acute renal failure (group 2), a tendency to about 20% higher ketamine steady-state plasma levels compared to group 1 was observed, but this difference was not significant. However, dehydronorketamine plasma levels were significantly higher in this group. Only a minor fraction of the ketamine dose (10% and 4%) was eliminated during hemodialysis or hemofiltration treatment, respectively. Steady-state plasma levels in 5 patients with cardiogenic shock (group 3) did not differ significantly from those of group 1. In 5 patients with long-term use of barbiturates (group 4), steady-state plasma levels of ketamine were significantly lower compared to groups 1 and 3, most likely due to barbiturate-induced enzyme induction. Hyperdynamic circulatory reactions were not observed in any of the patients. Psychomimetic effects could be excluded in 16 of the patients and were unlikely in 6 patients. In 5 further patients, psychomimetic effects could not definitely be excluded due to difficulties in non-verbal communication.

Metabolic disposition of ajmaline.

Urine was collected from six patients receiving a continuous infusion of 20 mg/h ajmaline. Pooled urine was extracted with and without enzymatic conjugate cleavage or hydrolysis with concentrated hydrochloric acid. The extracts were analyzed by gas chromatography/mass spectrometry. Ajmaline and its metabolites in urine were identified in the form of their acetylated derivatives. Twenty two different acetylated derivatives of ajmaline and its metabolites could be detected. Three of these derivatives were artifacts generated by acetylation and/or thermal decomposition. The major metabolic pathways were mono- and di-hydroxylation of the benzene ring with subsequent O-methylation, reduction of the C-21, oxidation of the C-17 and C-21-hydroxyl function, N-oxidation, and a combination of these metabolic steps. Ajmaline and its metabolites were mainly excreted in the form of their conjugates. Furthermore, the interference of sparteine, debrisoquine, quinidine, and nifedipine with ajmaline metabolism was studied with semiquantitative thin-layer chromatography. Ajmaline metabolism was inhibited by co-administration of sparteine or quinidine, but not by debrisoquine or nifedipine. Sparteine most likely competed with ajmaline metabolism. Quinidine probably bound competitively to ajmaline-metabolizing enzymes without being metabolized itself. Additionally, the metabolic ratio of hydroxyajmaline/ajmaline in urine was determined in 9 extensive metabolizers and one poor metabolizer of dextromethorphan. The poor metabolizer had a significantly reduced metabolic ratio of hydroxyajmaline/ajmaline, which indicates that ajmaline metabolism probably co-segregates with polymorphic sparteine/debrisoquine/dextromethorphan metabolism.

Pharmacokinetics and antiarrhythmic efficacy of intravenous ajmaline in ventricular arrhythmia of acute onset.

21 patients with acute myocardial infarction and ventricular arrhythmia of Lown class II-IIIB of acute onset received a short infusion of (50 mg/5 min) ajmaline (Gilurytmal). 6 of the patients had normal kidney and liver function (Group 1), 4 patients had acute renal failure and hemodialysis treatment (Group 2), 4 patients had impaired hepatic function (Group 3), 3 patients had cardiogenic shock (Group 4), and 4 patients had been pretreated with phenobarbital for seizures for at least 5 days (Group 5). A distribution half-life of 6 +/- 1 min and an elimination half-life of 95 +/- 6 min was determined in Group 1. The total plasma clearance was significantly lower in patients with impaired liver or cardiac function and significantly higher in Group 5, whereas impaired renal function did not affect total plasma clearance. After short infusion, ventricular arrhythmia of Lown II-IIIB completely disappeared for at least 16 to 36 min (mean: 19 min), which was associated with an ajmaline plasma level of 0.1-0.45 micrograms/ml. Additionally, steady-state plasma levels of ajmaline were determined after continuous infusion of 10-50 mg/h to 16 patients (Group 6) with ventricular arrhythmia of acute onset (Lown class IVA-V). Ventricular arrhythmia completely disappeared or at least changed to lower Lown classes at ajmaline plasma levels of 0.4-2.0 micrograms/ml. The ajmaline plasma protein binding was 76 +/- 9%. Ajmaline had a special affinity to alpha 1-acid glycoprotein.

Chlormezanone plasma and blood levels in patients after single and repeated oral doses and after suicidal drug overdose.

Chlormezanone plasma concentrations were determined in 5 volunteers (group 1) after a single oral dose of 200 mg of chlormezanone with high performance liquid chromatography. A plasma elimination half-life of 23 +/- 2.3 h was calculated. The mean peak chlormezanone plasma level was 1.86 +/- 0.2 micrograms/ml, 1 h after ingestion. Additionally, chlormezanone plasma levels were determined after repeated oral doses of chlormezanone recommended for treatment of muscular spasms due to degenerative skeletal disease. After 5 days of repeated daily doses of 3 x 200 mg (group 2; 12 patients) or 3 x 400 mg (group 3; 10 patients) of chlormezanone, mean predose chlormezanone plasma levels were 12.0 +/- 2.0 micrograms/ml (group 2) and 22.7 +/- 4.0 micrograms/ml (group 3), respectively. Comparable plasma concentrations were determined after 10 days of repeated doses of 3 x 200 mg or 3 x 400 mg of chlormezanone in 3 patients from each of these 2 groups. In 7 patients of group 3, chlormezanone had to be discontinued on the 5th day due to increasing muscular weakness, ataxia and exercise-inducible tachycardia. After a loading dose of 800 mg and repeated doses of 3 x 200 mg chlormezanone to 5 patients (group 4), plasma levels of 6.5 +/- 2.1 micrograms/ml, 8.9 +/- 2.2 micrograms/ml, 12.7 +/- 2.0 micrograms/ml, and 10.4 +/- 2.4 micrograms/ml were determined after 2, 8, 16, and 36 h, respectively. Trace amounts of a degradation product of the acid-labile chlormezanone could be detected in plasma besides the unchanged drug after administration of repeated oral doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical features, pathogenesis and management of drug-induced rhabdomyolysis.

Striated musculature is considered unusually tolerant to all kinds of injuries, and rhabdomyolysis associated with drug overdose or chronic drug intake is a rare event. This may be because striated musculature, in contrast to other tissues such as liver and kidney, shows little affinity for most drugs. Several different types of drug-induced rhabdomyolysis may be distinguished, and the clinical features of the condition may vary widely, from moderate myalgia to involvement of groups of muscles to involvement of the total skeletal musculature. In clinically asymptomatic rhabdomyolysis, early diagnosis is only made if routine laboratory tests include determination of serum creatine kinase. Determination of myoglobin in serum and urine is more sensitive and allows earlier diagnosis of muscle necrosis. Myoglobinaemia may lead to toxin-induced tubular necrosis, and impairment of renal function or even acute renal failure. About 10% of all cases of acute renal failure are due to rhabdomyolysis. Fulminant rhabdomyolysis may be associated with excessive hyperkalaemia and hypocalcaemia which may induce further life-threatening complications. Therefore, early diagnosis of rhabdomyolysis is most important for prevention of its potentially life-threatening sequelae. Therapy of rhabdomyolysis consists of supportive and specific measures. Early diagnosis may help to prevent life-threatening sequelae like acute renal failure, electrolyte imbalance and shock. Withdrawal of the incriminated drug or detoxification in drug overdose should be followed by supportive measures including infusion therapy and correction of dehydration and electrolyte imbalances. Forced diuresis with sodium bicarbonate may protect the kidney function from acidosis and precipitation of myoglobin in tubules. Elimination of myoglobin from plasma may be enhanced by plasmapheresis. In patients with acute renal failure, haemodialysis is necessary. In malignant hyperthermia, immediate infusion of dantrolene sodium is required. This drug also seems to have a beneficial effect in neuroleptic malignant syndrome. The repair mechanisms of striated musculature function extremely well. The prognosis of muscular atrophy after the acute stage of rhabdomyolysis is excellent. The same is true for the prognosis of acute renal failure. However, the extent of complications or survival of the acute stage of rhabdomyolysis strongly depend on early diagnosis and start of adequate therapy.

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.