Valeria Petrolini

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

Abstract 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.

Neurotoxicity of European viperids in Italy: Pavia Poison Control Centre case series 2001-2011

Abstract Context. Some clinical aspects about neurotoxicity after snakebites by European viper species remain to be elucidated. Objective. This observational case series aims to analyze neurological manifestations due to viper envenomation in Italy in order to describe the characteristic of neurotoxicity and to evaluate the clinical response to the antidotic treatment, the outcome, and the influence of individual variability in determining the appearance of neurotoxic effects. Materials and methods. All cases of snakebite referred to Pavia Poison Centre (PPC) presenting peripheral neurotoxic effects from 2001 to 2011 were included. Cases were assessed for time from bite to PPC evaluation, Grade Severity Score (GSS), onset/duration of clinical manifestations, severity/time course of local, non-neurological and neurological effects, and antidotic treatment. Results. Twenty-four were included (age, 3–75 years) and represented on average of 2.2 cases/year (about 5% of total envenomed patients). The mean interval time of PPC evaluation from snakebite was 10.80 ± 19.93 hours. GSS at ED-admission was 0 (1 case), 1 (10 cases), and 2 (13 cases). All patients showed local signs: 41.6%, minor; 58.4%, extensive swelling and necrosis. The main systemic non-neurological effects were as follows: vomiting (86.7%), diarrhea (66.7%), abdominal discomfort (53.3%), and hypotension (20%). Neurotoxic effects were accommodation troubles and diplopia (100%), ptosis (91.7%), ophtalmoplegia (58.3%), dysphagia (20.8%), drowsiness (16.6%), cranial muscle weakness (12.5%), and dyspnea (4.2%). Neurotoxicity was the unique systemic manifestation in 9 cases; in 4 cases, they were associated with only mild local swelling. In 10 patients the onset of neurotoxic effects followed the resolution of systemic non-neurological effects. Antidote was intravenously administered in 19 (79.2%) patients. The mean duration of manifestations in untreated versus treated groups was 53.5 ± 62.91 versus 41.75 ± 21.18 hours (p = 0.68, local effects) and 9.77 ± 3.29 versus 8.25 ± 12.23 hours (p = 0.1, systemic non-neurological effects) and 43.4 ± 14.69 versus 26.58 ± 20.62 hours (p = 0.03, neurotoxic effects). Conclusions. Neurotoxicity may appear late (11 hours after the bite in 58.3% of cases), in contrast with the data reported in medical literature. Neurotoxic effects have been reversible in all cases and may be the unique systemic manifestation of envenomation. Neurotoxic effects are shorter in treated group. The antidotic treatment of patients considered as GSS 2 only for neurotoxic effects (with mild local effects) may not be necessary. Variable factors such as different amount of venom injected, concentration of PLA2 component, and individual susceptibility may explain the less percentage of patients presenting neurotoxic effects.

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

Abstract 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.

Fatal course of foodborne botulism in an eight-month old infant

An 8-month old girl, weighing 9 kg, was brought by her parents at 8.15 am to the Emergency Department (ED) for a progressive worsening of weakness and acute respiratory failure. On admission, the baby presented with poor oral intake, a weak cry and extremely weak muscular body control. Poor gag and suck, unreactive mydriasis, hypotonia, lethargy and absence of peristalsis were noted. Laboratory data showed severe respiratory acidosis. Chest X-ray, electroencephalography, encephalic CT scan and MRI were all normal, as were cerebrospinal fluid analysis and viral tests. Orotracheal intubation and continuous mechanical ventilation were applied. The patient received fluids, corticosteroids, aerosol therapy, large-spectrum antibiotics and enteral-nutrition. Further investigation revealed ingestion of an improperly prepared home-canned homogenized turkey meal. Type A botulinum neurotoxin was identified. Trivalent botulinum antitoxin, prostigmine and oral activated charcoal were administered. Generalized flaccid paralysis, areflexic bilateral mydriasis, gastric stasis and deep coma persisted for the duration of the hospital stay, and the patient died of severe respiratory failure and cardiac arrest 12 days after ED admission. Botulism poisoning should be suspected in any infant presenting with feeding difficulties, constipation, descendent paralysis or acute respiratory failure. Supportive treatment and antidotal therapy should be performed as soon as a clinical diagnosis is made. We describe a case of foodborne botulism in an 8-month old infant caused by ingestion of an improperly prepared home-canned homogenized turkey meal, representing the youngest fatal case reported in medical literature.

N-Acetyl-Cysteine as Effective and Safe Chelating Agent in Metal-on-Metal Hip-Implanted Patients: Two Cases

Systemic toxicity associated with cobalt (Co) and chromium (Cr) containing metal hip alloy may result in neuropathy, cardiomyopathy, and hypothyroidism. However clinical management concerning chelating therapy is still debated in literature. Here are described two metal-on-metal hip-implanted patients in which N-acetyl-cysteine decreased elevated blood metal levels. A 67-year-old male who underwent Co/Cr hip implant in September 2009 referred to our Poison Control Centre for persisting elevated Co/Cr blood levels (from March 2012 to November 2014). After receiving oral high-dose N-acetyl-cysteine, Co/Cr blood concentrations dropped by 86% and 87% of the prechelation levels, respectively, and persisted at these latter concentrations during the following 6 months of follow-up. An 81-year-old female who underwent Co/Cr hip implant in January 2007 referred to our Centre for detection of high Co and Cr blood levels in June 2012. No hip revision was indicated. After a therapy with oral high-dose N-acetyl-cysteine Co/Cr blood concentrations decreased of 45% and 24% of the prechelation levels. Chelating agents reported in hip-implanted patients (EDTA, DMPS, and BAL) are described in few cases. N-acetyl-cysteine may provide chelating sites for metals and in our cases reduced Co and Cr blood levels and resulted well tolerable.

Treatment of foodborne botulism in current clinical toxicology: authors’ reply

Dr. Zamani pointed out the role of the whole bowel irrigation (WBI) with polyethylene glycol as an appropriate adjunctive option of gastrointestinal decontamination in severe botulism poisoning. Secondly, the author underline the early administration of trivalent antitoxin as soon as clinical suspicion of botulism poisoning is made.1 However in the case described there are some considerations that need to be evaluated.2 First of all, regarding the gastrointestinal decontamination in severe botulism poisoned patient, all procedures aimed to remove spores and toxin from the gut should be applied. In details when post-pyloric decontamination with cathartic agents must be performed, sorbitol should be preferable than magnesium salts because the latter may exacerbate neuromuscular blockade.3 WBI may have a theoretical role in decontamination and it could be evaluated in severe poisoning.3 However, these procedures may be difficult and their efficacy may be reduced in the presence of drug- or toxin-induced ileus.4 In some cases prostigmine, which inhibits the enzymatic degradation of acetylcholine, appears to be useful in reversing ileus.5 In our case, the prolonged absence of peristalsis and the gastric stasis made cathartic agents administration difficult; in fact gastrointestinal decontamination with nasogastric tube, activated charcoal oral administration and intravenous prostigmine were performed to reduce the toxin absorption and to promote the gut peristalsis. About the timing of antidote administration, it should keep in mind that the aim of the antitoxin therapy consists in neutralizing the circulating toxin molecules still unbound to the nerve endings: this mechanism of action limits the involvement of new nerve endings, but cannot reverse the paralysis nor neutralize the toxins already bound to the nerve receptors.4 The clinical picture of our baby was severe still at admission (severe respiratory failure with hypoxemia and metabolic acidosis) and rapidly worsening consistent with the ingestion of a large dose of type A toxin, the most potent type of botulinum neurotoxins. In our case, trivalent antitoxin was administered about 10 hours after laboratory confirmation. Little age of the infant, the insidious onset of clinical manifestation, the rapid worsening of respiratory and neurological features and initial lack of specific history for a food source at hospital admission made the diagnostic suspicion difficult and delayed by differential diagnosis procedures (e.g. chest X-ray, electroencephalogram, cranial-computed tomography and magnetic resonance imaging scan, cerebrospinal analysis). Moreover when foodborne botulism was suspected, the antidote was immediately requested and obtained from the Health Ministry Stockpile after the laboratory confirmation was obtained. As Dr. Zamani correctly observed, an immediate antitoxin administration should be evaluated both in symptomatic patients and asymptomatic individuals recently exposed to a presumptive food source.1 In fact, the antitoxin should be administered also before the laboratory results, immediately as soon as clinical suspicion of botulism poisoning is suspected.4 In our case: i) a positive history for food consumption was not promptly reported on hospital admission, ii) the clinical suspicion for botulism poisoning was difficult and unfortunately hypothesized late and iii) antitoxin research was performed only after laboratory confirmation: these aspects made the diagnosis and the treatment of this case of severe foodborne botulism complicated and not as timely and prompt as theoretically desired.