Andrea Giampreti

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.

Acute neurotoxicity after yohimbine ingestion by a body builder

Yohimbine is an alkaloid obtained from the Corynanthe yohimbe tree and other biological sources. Yohimbine is currently approved in the United States for erectile dysfunction and has undergone resurgence in street use as an aphrodisiac and mild hallucinogen. In recent years yohimbine use has become common in body-building communities for its presumed lipolytic and sympathomimetic effects. We describe a 37-year-old bodybuilder in which severe acute neurotoxic effects occurred in 2 h after yohimbine ingestion. The patient presented with malaise, vomiting, loss of consciousness, and repeated seizures after ingestion of 5 g of yohimbine during a body-building competition in a gymnasium. His Glasgow Coma Score was 3, requiring orotracheal intubation. Two hours after admission, vital signs were blood pressure 259/107 mmHg and heart rate 140 beats/min. Treatment with furosemide, labetalol, clonidine, and urapidil and gastrointestinal decontamination were performed. Twelve hours later the patient was extubated with normal hemodynamic parameters and neurological examination. The yohimbine blood levels at 3, 6, 14, and 22 h after ingestion were 5,240; 2,250; 1,530; and 865 ng/mL, respectively, with a mean half-life of 2 h. Few data are available about yohimbine toxicity and the related blood levels. This is a case of a large ingestion of yohimbine in which severe hemodynamic and neurological manifestations occurred and elevated blood levels of yohimbine were detected.

Chelation in Suspected Prosthetic Hip-Associated Cobalt Toxicity

To the Editor: We read with interest the letter from Dr Devlin et al. concerning cobalt (Co) chelation in prosthetic hip-associated Co toxicity. Currently, chelation in prosthetic hip-associated Co toxicity has been described in only a few cases with chelating agents such as edetate calcium disodium, sodium 2,3-dimercaptopropane sulfonate, and dimercaprol. Currently, the role of different chelating agents, timing of administration, and chelating efficacy represent debated aspects in Co chelation. As reported by Dr Devlin, in the medical literature N-acetyl-cysteine (NAC) has been described as an effective chelator only in animal models of Co poisoning. We observed a case of cardiac toxicity resulting from Co and chromium (Cr) release from a metal on metal (MoM) hip replacement in which NAC had been used to treat high CoCr blood levels. In October 2012, a 75-year-old male patient was referred to our Poison Control Centre for persisting high Co-Cr blood levels from MoM hip prosthesis. In 2006, the patient underwent revision of left hip arthroplasty with insertion of a MoM Co-Cr alloy hip. In July 2011, a ceramic hip revision was performed because of the appearance of local hip pain, asthenia, and abrasion of the left metal head with local metallosis. Echocardiography revealed a dilatated left ventricle, with global hypokinesis (ejection fraction, 32%; normal value > 55%), pericardial effusion and increased pulmonary pressures (43 mm Hg; normal value 15-28). Renal function was normal. Co-Cr serum levels before MoM explantation were 352.6 mg/L (normal value < 0.9) and 67.85 mg/L (normal value < 0.5) respectively. Fourteen months after MOM explantation, high Co-Cr blood levels (46.5 and 77.1 mg/L) persisted and chelation with intravenous high-dose NAC (150 mg/kg/90 min bolus followed by 300 mg/kg/ d for 10 days) was performed. Co-Cr serum concentrations dropped by about 51% and 40% of the prechelation levels,

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.

Carbon Monoxide Poisoning in Children

We read with great interest the retrospective study by Cho and colleagues 1 describing the clinical features of 30 pediatric patients with carbon monoxide (CO) poisoning in Taiwan. The acute clinical manifestations and delayed neurologic sequelae, severity of poisoning (initial Glasgow Coma Scale and HbCO, presence of severe metabolic acidosis,andseizure),therapeuticmanagement(mechanical ventilation, inotropic therapy, and normobaric/hyperbaric antidotical treatment) and patient outcome [consciousness recovery time, hospital, and intensive care unit (ICU) stay] has been accurately and extensively described. Moreover, we have observed that patients were interestingly divided in two different groups related to different CO type of exposure: house fire versus other causes, including accidental exposure to improperly vented hot water heaters and intentional poisoning due to charcoal burning. After analyzing the house-fire exposed group (n Z 8), we noticed that five of eight patients (62.5%) presented severe metabolic acidosis and needed mechanical ventilation, two of eight (25%) presented seizures and required inotropic agent use; the non fire-related group (n Z 22) included only one patient (4.5%) with severe metabolic acidosis, one (4.5%) patient that required mechanical ventilation, and none needed vasoactive agents. The clinical outcome of the patients exposed to a house fire seems to be more severe in terms of consciousness recovery time, hospital, and ICU stay. The authors underline that patients exposed to house fire presented higher risk of associated burns, severe metabolic acidosis, endotracheal intubation, hemodynamic disorders, long hospital stay, inhalation pneumonitis, and other not specified toxic substances at the fire scene. In our opinion, considering the high percentages and type of severe clinical manifestations reported by the authors for the fire exposed group, it should be of interest to keep in mind the potential role played by hydrogen cyanide (HCN) in CO-HCN poisoning related to fire smoke inhalation; in fact, the signs and symptoms described, such as severe metabolic acidosis, hypotension, and seizures, are highly suggestive of CO-HCN poisoning. 2 In this case series, it should be very interesting to know the lactate plasma levels and, if available, blood cyanide concentrations. Treatment in suspected CO-HCNepoisoned patients may require not only oxygen administration but may need early administration of safe and effective antidotes such as hydroxocobalamin.

A young Indian male with abdominal pain

A young man with abdominal pain who had radiopaque tablets in his gut is described. Investigations showed the diagnosis of lead poisoning from ayurvedic medicines.

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.

An insidious skin rash without itch

Abstract A 74-year-old female with a 5-year medical history of breast infiltrating lobular carcinoma was admitted to our Rehabilitation Unit ward for left hemiparesis secondary to neurosurgical removal of frontal and right parietal metastatic lesions. After the intervention, prophylactic treatment with the antiepileptic diphenylhydantoin 100 mg/tid was started. On 38th day of drug administration an erythema without itch appeared in jugular and parasternal region and absent in the clothing covered areas, suggesting a contact dermatitis. Next day, the erythema extended to the neck with poorly delineated red plaques. During the following 4 days the patient presented oral stomatitis with fetid breath, atypical targetoid and erythematous confluenced macules. The clinical picture rapidly worsened with vesiculate, bullate lesions and frank skin erosions. The patient was sent to a Dermatology Burn Unit where a therapy with corticosteroids, antibiotics, fluids, albumin and immunoglobulins was administrated. Complete clinical resolution was observed after 1 month without long-term sequelae. Toxic epidermal necrolysis (TEN) is a rare (incidence about 0.01%) adverse drug reaction related to idiosyncratic mechanism, burdened by a mortality rate ranging from 3.2 to 90%. In our patient, TEN covered 63% of body surface, a condition associated with a death risk of 58.3% according to the specific severity illness scale SCORTEN. The disease onset may be insidious, and it could appear as a skin rash without itch; the cutaneous manifestations appear quite lately, then the disease quickly progresses. Early recognition of the disease, especially in oncologic patients, is critical for effective management of this condition in terms of mortality reduction.