Metformin accumulation: lactic acidosis and high plasmatic metformin levels in a retrospective case series of 66 patients on chronic therapy.

OBJECTIVE. The relationship between metformin accumulation and lactate increase is still debated. This observational case series aims to evaluate the correlation of metformin plasma levels with the pH, lactate and creatinine levels, and with the mortality rate in selected patients with metformin accumulation confirmed through metformin plasma concentration detection at hospital admission. MATERIAL AND METHODS. All cases of lactic acidosis (pH, ≤ 7.35; arterial lactate, ≥ 5 mmol/L) related to metformin accumulation (plasma level ≥ 4 mcg/mL) from 2007 to 2011 were retrospectively reviewed. Erroneous ingestion and voluntary overdoses were excluded. Epidemiological, medical history, clinical and laboratory data were evaluated in all cases. RESULTS. Sixty-six patients were included. Thirty-one patients (47%) had contraindication to therapy with metformin. All patients showed severe lactic acidosis (pH, 6.91 ± 0.18; lactate, 14.36 ± 4.90 mmol/L) and acute renal failure (creatinine, 7.24 ± 3.29 mg/dL). The mean metformin plasma concentration was 40.68 ± 27.70 mcg/mL. Metformin plasma concentrations showed a correlation, statistically significant even if not strong, with creatinine (p = 0.002, R = 0.37), pH (p < 0.0001, R = - 0.43) and plasma lactate levels (p = 0.001, R = 0.41). Sixty-two (94%) underwent dialysis. Early mortality (before discharge from ICU) was 26% (17 cases). Lactate and metformin concentrations had mean levels not statistically different in surviving and deceased patients. CONCLUSIONS. Patients on chronic therapy with metformin may develop a mitochondrial-related toxicity that should be considered when patients present with lactic acidosis, renal failure, and frequently, a medical history of gastrointestinal manifestations during the days preceding the hospital admission. The correlation between metformin plasma concentrations and creatinine, pH, and lactate levels seems to be related to the mechanism of action (inhibition of complex I of the mitochondrial respiratory chain) and to the kinetic properties (high distribution volume and low protein binding) of the drug. The relevant early mortality seems not correlated with the levels of metformin or lactates: this could be due to the possible role of concurrent illness even if, such as for the relationships with lactate and creatinine, a more proper toxicological evaluation could be obtained by assessing metformin erythrocyte concentrations instead of the plasmatic ones.

Recurrent tonic-clonic seizures and coma due to ingestion of Type I pyrethroids in a 19-month-old patient.

CONTEXT: Pyrethroids are synthetic pyrethrin analogues that induce sodium-channel depolarization and hyperexcitation. Severe pyrethroid poisoning is manifested by a "Tremor Syndrome" (Type I cyano-agents) or a "Choreoathetosis/Salivation Syndrome" (Type II non cyano-agents). Very few reports of neurotoxic effects caused by Type I pyrethroids ingestion are available, and no human data concerning Type I pyrethroid blood levels in pediatric poisoning are reported in the medical literature. CASE DETAILS: A 19-month-old female patient presented with irritability and inconsolable crying that rapidly worsened to tonic-clonic seizures and coma (GCS 6). On admission vital signs including BP 110/70 mmHg, HR 110 beats/min, and SpO2 98% on room air were normal. Orotracheal intubation, oxygen administration, and midazolam infusion (4 µg/kg/min) were performed. Intravenous thiopental sodium, up to 18 mg/kg/hour, was administered to control convulsions. An inquiry revealed that 9 h before presentation the patient had ingested an unknown amount of an insecticide containing 7% piperonyl-butoxide and a mixture of the Type I pyrethroids bifenthrin (5%) and esbiothrin (3%). Consequently, gastric lavage was performed, followed by administration of activated charcoal and cathartics. On the subsequent 48 h, the patient returned progressively alert; she was extubated on day 4 and discharged asymptomatically 12 days after hospitalization. After 9, 48, and 72 h of ingestion, the plasma levels were 500, 95, and 40 ng/mL for bifenthrin and 1,640, 640, and 165 ng/mL for piperonyl-butoxide respectively. DISCUSSION: This pediatric case showed severe pyrethroid neurotoxicity associated with measurable plasma levels of bifenthrin and piperonyl-butoxide. In pediatric pyrethroid poisoning, coma and seizures may represent the main life-threatening features. First-aid therapy including airway maintenance and control of muscle fasciculation and seizures is of major importance. Benzodiazepines and high-dose thiopental sodium were effective treatments for convulsion.

[Evaluation of a protocol of health surveillance for the personnel exposed to inhalation anesthetics in a sample of 3 operating rooms]. / Valutazione di un protocollo di sorveglianza sanitaria per il personale esposto ad anestetici inalatori in tre sale operatorie campione.

OBJECTIVES: To verify the results of a health surveillance protocol for personnel exposed to inhalation anaesthetics. DESIGN: Yearly follow-up of operating room personnel. SETTING: Operating theatres of a university hospital; one "clean" room with waste anaesthetic scavengers, a second older room an thus "dirty", a third room with appropriate technical requirements, but with a considerable environmental emission of anaesthetics. PATIENTS OR PARTICIPANTS: Twenty-four technical surgical assistants and anaesthesiologists. INTERVENTION OR METHODS: Determination of the number of changes of air by means of concentration decay; determination of the baseline and final value of the environmental anaesthetics by infrared photoacoustic spectroscopy; analysis of the microclimate and inspection of the equipment. Determination of anaesthetics in the urine of personnel at the end of the work shift, using a gas-chromatograph with head space. Yearly medical check-up and blood tests. RESULTS: In the first year of observation we found values of nitrous oxide in one room and of isoflurane in all three rooms which exceeded the upper limit value. Acceptable values in all the rooms were detected during the second year. The values of anaesthetics found in urine samples reflected those measured in the rooms. Personnel reported subjective symptoms, but no blood alterations related to exposure were found. CONCLUSIONS: The application of the protocol has allow us to estimate the level of pollution and to suggest behavioral rules and technical precautions that have decreased the emission of anaesthetics in the environment. Blood tests are not a valid index of possible damage caused by exposure.

[Qualitative characteristics of human exposure to air chemical pollutants in operating rooms]. / Caratteristiche qualitative dell'esposizione umana a contaminanti chimici aerodispersi in sale operatorie.

UNLABELLED: For more than two decades many studies have been published searching for a link between exposure to volatile anaesthetic agents and health damage even if it is noteworthy that many other chemical substances can be found in the Operating Room. Purpose of this study was to demonstrate that the Operating Room is not a totally confined environment and that it is possible to perform an, at least qualitative, evaluation of many different polluting contaminants, even unexpected, to whom the working staff is exposed. MATERIAL AND METHODS: The study has been performed in the Operating Rooms of the Departments of Urology and Orthopaedics. Two methods have been employed: a long-casting sampling of volumes of air (with a sampling device composed of an enrichment system and a low flow aspirating pump) and an anaesthetic vapours and gas continuous analyzer. Results. We never recorded environmental levels of anesthetic higher than the currently accepted ones. Many other organic compounds of different kind have been found (irritants, cancer-organs). Their presence, not desirable in a place where a demanding work is performed, deserve further investigation and a quantitative evaluation of these compounds.

Phagocyte activation in coronary artery disease.

Recent studies suggest that granulocytes (PMNs) play a role in the pathogenesis of acute and chronic myocardial ischemia and extension of myocardial injury. Granulocytes can release a variety of molecules mediating tissue injury which act synergistically with other molecules and cells. The aim of our investigation was to evaluate the granulocyte function in patients affected by coronary artery disease (CAD) and during coronary angioplasty (PTCA). We studied 20 patients suffering from CAD. The PMN's aggregating activity was greater in the coronary sinus than in the aorta (P < 0.01). The increase in aggregating activity was evident in patients who were smokers: their cells release significantly lower quantities of leukotriene C4 (P < 0.025). In the 20 patients who underwent coronary angioplasty we analyzed superoxide release after stimulation with phorbol-myristate-acetate (PMA). The results showed a greater decrease of PMN's superoxide production in the coronary sinus than in the aorta (P < 0.05). In all patients affected by CAD we evaluated the PMN's expression of CD11b/CD18 membrane integrins. In these patients the increase in expression of CD11b/CD18 was statistically significant in comparison with the controls (P < 0.01). This increase in expression correlates with a higher aggregation (r = 0.87, P < 0.001). The potential role of leukocytes, oxygen radicals, leukotrienes and granulocyte enzymes in the pathophysiology of myocardial injury due to regional ischemia and reperfusion is an area of intense investigation. This paper presents studies carried out in vivo which have been instrumental in demonstrating the role of granulocytes as mediators of myocardial ischemia.

[Etiopathogenetic and clinical notes on the syndrome of the micropolycystic hyperandrogenic ovary and matrimonial sterility]. / Considerazioni eziopatogenetiche e cliniche in tema di sindrome da ovaio micropolicistico iperandrogenico e sterilità matrimoniale

The nosological, clinical, aetiopathogenetic and therapeutic aspects of hyperandrogenic micropolycystic ovary are examined with particular reference to matrimonial sterility. There is not doubt about the existence of a syndrome substantially characterized, clinically, by menstrual trouble, inability to procreate, more or less evident signs of hyperandrogenism and a tendency to obesity and, morphologically, by ovarian micropolycystic alterations of typical pathognomonic aspect: the marked production of androgens on the part of the female gonad possibly accompanied by peripheral alterations interfering with their metabolism. The syndrome is not too frequent and, in personal experience, occurs in less than 1% of the series. The main therapeutic approach remains cuneiform resection of the ovary. Still in personal experience, 21.2% of cases treated led to pregnancy but not more than eight-ten months after operation. The effect would therefore appear to be transitory and the operation is decisively rejected where unmarried women are involved.