Expert opinion: fomepizole may ameliorate the need for hemodialysis in methanol poisoning

Fomepizole is now the antidote of choice in methanol poisoning. The use of fomepizole may also change the indications for hemodialysis in these patients. We have addressed this change in a review of articles on methanol poisonings. Review of the literature (through PubMed) combined with our own experiences from two recent methanol outbreaks in Estonia and Norway. The efficiency of dialysis during fomepizole treatment was reported in only a few reports. One recent study challenged the old indications, suggesting a new approach with delayed or even no hemodialysis. Methanol-poisoned patients on fomepizole treatment may be separated into two categories: 1) The critically ill patient, with severe metabolic acidosis (base deficit >15 mM) and/or visual disturbances should be given buffer, fomepizole and immediate hemodialysis: dialysis removes the toxic anion formate, and assists in correcting the metabolic acidosis, thereby also reducing formate toxicity. The removal of methanol per se is not important in this setting because fomepizole prevents further production of formic acid. 2) The stable patient, with less metabolic acidosis and no visual disturbances, should be given buffer and fomepizole. This treatment allows for the possibility to delay, or even drop, dialysis in this setting, because patients will not develop more clinical features from methanol poisoning when fomepizole and bicarbonate is given in adequate doses. Indications and triage for hemodialysis in methanol poisonings should be modified. Delayed hemodialysis or even no hemodialysis may be an option in selected cases.     

Clinical presentation and management in acute toluene intoxication: a case series

Context: Toluene inhalation is a common form of drug abuse throughout the world. Acute toluene toxicity causes neurological changes as well as various metabolic alterations. Hypokalemic paralysis and renal failure are life-threatening complications.

Objective: To identify the clinical and metabolic alterations associated with toluene intoxication.

Materials and methods: We retrospectively analyzed the records of 22 patients that were admitted to a single center’s emergency department from 2006 to 2012 with clinical and metabolic alterations due to toluene inhalation.

Results: Of the 22 patients, 77% were male and mean age was 23.5 years (range: 17–30). The main clinical presentation was weakness associated to severe hypokalemia. Severe metabolic acidosis was found in 20 patients. Renal tubular acidosis was diagnosed in five patients. The patients responded to supportive measures and aggressive potassium repletion. Prognosis was generally good.

Conclusion: Toluene inhalation is associated with various severe metabolic alterations. Treatment guidelines are needed considering the frequency of toluene inhalation in the population.     

Treatment of severe pediatric ethylene glycol intoxication without hemodialysis

BACKGROUND: There is limited experience treating severe ethylene glycol poisoning in children without hemodialysis. The objective of this study was to describe the clinical course and outcome of severe pediatric ethylene glycol poisoning treated without hemodialysis. METHODS: Patient records were identified retrospectively by hospital discharge diagnosis (ICD-9 code) of ethylene glycol poisoning from 1999 through 2002 at a pediatric medial center. Patients with initial serum ethylene glycol concentrations less than 50 mg/dL or those who received hemodialysis were excluded. RESULTS: Six patients with an age range of 22 months to 14 years were admitted for treatment of ethylene glycol poisoning over a four-year period. Initial serum ethylene glycol concentrations ranged from 62 to 304 mg/dL (mean 174.0 mg/dL). The lowest-measured individual serum bicarbonates ranged from 4 to 17 mEq/L. All patients were initially admitted to intensive care. One patient received ethanol only, two patients received fomepizole only, and three patients received a loading dose of ethanol and then were converted to fomepizole therapy. None of the patients received hemodialysis. Treatment was continued until the serum ethylene glycol was less than 10 mg/dL. Metabolic acidosis resolved with intravenous fluid and supplemental bicarbonate within 24h. All patients had a normal creatinine upon presentation and at discharge. The mean length of stay in intensive care was 21h and on the ward was 33.7h. One episode of hypoglycemia occurred in a 22-month-old. All patients recovered without evidence of renal insufficiency or other major complications at discharge. CONCLUSION: Six pediatric patients with severe ethylene glycol intoxication and normal renal function were successfully treated without hemodialysis.     

What are the adverse effects of ethanol used as an antidote in the treatment of suspected methanol poisoning in children?

BACKGROUND: Ethanol used as an antidote is said to have various adverse effects, particularly in children. The rate of these adverse effects is not known. METHODS: Twenty-one-year retrospective chart review (1980-2000) from suspected methanol poisoning patients treated with ethanol in two large pediatric tertiary care centers. RESULTS: A total of 60 children (median age of 24 months) received ethanol for suspected methanol poisoning: 39 orally and 21 intravenously. Median initial methanol level was 4.16 mmol/L (13.3 mg/dL) (range 0 to 87.5 mmol/L or 0 to 280 mg/dL). Median duration of ethanol treatment was 16 hours (range 1.5 to 72 hours). None [0% (95% CI 0-5%)] of the 60 patients developed symptomatic hypoglycemia. Of the 50 patients that had a glucose level measured, none [(0% [95% CI 0-6%)] had a serum glucose concentration < 2.78 mmol/L (< 50 mg/dL). Eight patients [16% (95% CI 8-30%)] had at least one serum glucose concentration between 2.78-3.61 mmol/L (50-65 mg/dL), but none of those had symptoms compatible with hypoglycemia. A total of 42 patients [84% (95% CI 70-92%)] had all their serum glucose concentrations > 3.61mmol/L (> 65 mg/dL). There was no identifiable difference in the glucose intake between the serum glucose concentration groups. Six out of the 60 patients [10% (95% CI 4-21%)] were described as more drowsy after ethanol but none was comatose or needed intubation. No child showed signs of hypothermia [0/40 (95% CI 0-8%)] (rectal temperature < 35 degrees C), hepatotoxicity (0/12) (AST or ALT > 100 U/L) or even thrombophlebitis (0/21). None of the 22 patients with toxic levels of methanol (> or = 26.2 mmol/L- > or = 20 mg/dL) died or had ethanol-induced morbidity despite wide variation in ethanol levels. CONCLUSION: The rate of clinically important adverse effects related to ethanol used as an antidote to treat methanol poisoning in children was either absent or low in a tertiary care pediatric hospital setting. There was no morbidity or mortality associated with ethanol when it was used despite wide variation in ethanol levels. These results suggest that with appropriate monitoring and intravenous glucose intake in a controlled environment such as a pediatric intensive care unit, ethanol therapy does not carry as many risks as currently believed.     

American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning

EPIDEMIOLOGY: Almost all cases of acute methanol toxicity result from ingestion, though rarely cases of poisoning have followed inhalation or dermal absorption. The absorption of methanol following oral administration is rapid and peak methanol concentrations occur within 30-60minutes. MECHANISMS OF TOXICITY: Methanol has a relatively low toxicity and metabolism is responsible for the transformation of methanol to its toxic metabolites. Methanol is oxidized by alcohol dehydrogenase to formaldehyde. The oxidation of formaldehyde to formic acid is facilitated by formaldehyde dehydrogenase. Formic acid is converted by 10-formyl tetrahydrofolate synthetase to carbon dioxide and water. In cases of methanol poisoning, formic acid accumulates and there is a direct correlation between the formic acid concentration and increased morbidity and mortality. The acidosis observed in methanol poisoning appears to be caused directly or indirectly by formic acid production. Formic acid has also been shown to inhibit cytochrome oxidase and is the prime cause of ocular toxicity, though acidosis can increase toxicity further by enabling greater diffusion of formic acid into cells. FEATURES: Methanol poisoning typically induces nausea, vomiting, abdominal pain, and mild central nervous system depression. There is then a latent period lasting approximately 12-24 hours, depending, in part, on the methanol dose ingested, following which an uncompensated metabolic acidosis develops and visualfunction becomes impaired, ranging from blurred vision and altered visual fields to complete blindness. MANAGEMENT: For the patient presenting with ophthalmologic abnormalities or significant acidosis, the acidosis should be corrected with intravenous sodium bicarbonate, the further generation of toxic metabolite should be blocked by the administration of fomepizole or ethanol and formic acid metabolism should be enhanced by the administration of intravenous folinic acid. Hemodialysis may also be required to correct severe metabolic abnormalities and to enhance methanol and formate elimination. For the methanol poisoned patient without evidence of clinical toxicity, the first priority is to inhibit methanol metabolism with intravenous ethanol orfomepizole. Although there are no clinical outcome data confirming the superiority of either of these antidotes over the other, there are significant disadvantages associated with ethanol. These include complex dosing, difficulties with maintaining therapeutic concentrations, the need for more comprehensive clinical and laboratory monitoring, and more adverse effects. Thus fomepizole is very attractive, however, it has a relatively high acquisition cost. CONCLUSION: The management of methanol poisoning includes standard supportive care, the correction of metabolic acidosis, the administration of folinic acid, the provision of an antidote to inhibit the metabolism of methanol to formate, and selective hemodialysis to correct severe metabolic abnormalities and to enhance methanol and formate elimination. Although both ethanol and fomepizole are effective, fomepizole is the preferred antidote for methanol poisoning.     

Rethinking the toxic methanol level

INTRODUCTION: Treatment thresholds for methanol poisoning are based on case reports and published opinion. Most guidelines recommend treatment for a methanol level > or = 20 mg/dL in a nonacidotic patient. No supportive data have been offered nor has the time of the exposure been addressed. For instance, no distinction has been drawn between a methanol level drawn 1 hr vs. 24 hr from ingestion. We analyzed all published cases of methanol poisoning to determine the applicability of the 20 mg/dL threshold in a nonacidotic patient, specifically those arriving early for care (within 6 hr) with a peak or near-peak blood methanol concentration. METHODS: Using predefined search criteria, a systematic review of the world literature was performed using MEDLINE and EMBASE. In addition, each article's references were hand searched for pre-1966 articles, as were fatality abstracts from all U.S. poison centers. Human cases were included if they reported a known time of a single methanol exposure, acid-base data, blood methanol, and blood ethanol (if not acidotic). RESULTS: Dating to 1879, 372 articles in 18 languages were abstracted using a standard format; 329 articles (2433 patients) involved methanol poisoning, and 70 articles (173 patients) met inclusion criteria. Only 22 of these patients presented for care within 6hr of ingestion with an early methanol level. All but 1 patient was treated with an inhibitor of alcohol dehydrogenase (ADH). A clear acidosis developed only with a methanol level > or = 126 mg/dL. The patient that did not receive an ADH inhibitor was an infant with an elevated early methanol level (46 mg/dL) that was given folate alone and never became acidotic. Intra and inter-rater reliability were 0.95. CONCLUSIONS: Nearly all reports of methanol poisoning involve acidotic patients far removed from ingestion. The small amount of data regarding patients arriving early show that 126 mg/dL is the lowest early blood methanol level ever clearly associated with acidosis. Contrary to conventional teaching, there are case reports of acidosis after only a few hours of ingestion. The data are insufficient to apply 20 mg/dL as a treatment threshold in a nonacidotic patient arriving early for care. Prospective studies are necessary to determine if such patients may be managed without antidotal therapy or dialysis.     

Formate kinetics in methanol poisoning

OBJECTIVE: The objective is to describe the kinetics of formate, the main toxic metabolite of methanol, in a series of consecutive patients treated in the same intensive care unit for severe methanol poisoning. METHODS: The charts of the patients admitted between 1987 and 2001 were reviewed. Inclusion criteria were: a history of deliberate methanol ingestion, with a blood methanol concentration greater than 20 mg/dL (6.2 mmol/L) or a high anion gap metabolic acidosis. Indications for hemodialysis were: blood methanol concentration >50 mg/dL (15.8 mmol/L), metabolic acidosis (bicarbonate <15 mmol/L, arterial pH <7.30), visual toxicity. Antidotal therapy included ethanol administration in 22 cases, and fomepizole in three cases. Serial blood measurements were obtained for pH, bicarbonate, methanol and formate. Endogenous and hemodialysis elimination half-lives were calculated as t1/2 =0.693/Ke. Fick principle was applied for hemodialysis clearance calculation. RESULTS: The records of 25 methanol poisoned patients were analysed. Among them, 18 patients had sufficient data to allow accurate determinations of formate kinetics. Formate half-life elimination during hemodialysis was 1.80+/-0.78 h, which was statistically different from the values observed before or in the absence of dialysis (6.04+/-3.26 h, P =0.004). The mean hemodialysis formate clearance rate calculated in eight cases was 176+/-43 mL/min. A rebound in plasma formate concentration was observed in three patients after the discontinuation of hemodialysis. CONCLUSIONS: In accordance with previous isolated case reports and in contrast with a recent case series, our data document that hemodiaysis is effective in reducing formate elimination half-life. The impact on clinical outcome is still debatable.     

Butoxyethanol ingestion with prolonged hyperchloremic metabolic acidosis treated with ethanol therapy

BACKGROUND: Severe toxic ingestions of butoxyethanol (CAS No. 111-76-2) are rare despite the prevalence of this glycol ether in products such as glass and surface cleaners. Manifestations of acute butoxyethanol toxicity include metabolic acidosis, hemolysis, hepatorenal dysfunction, and coma, but vary widely in reported cases. Furthermore, the optimal therapeutic approach is not yet established. Much of the toxicity of butoxyethanol has been ascribed to its aldehyde and acid metabolites which are similar to those produced by oxidative metabolism of methanol and ethylene glycol. Although the roles of alcohol dehydrogenase inhibition with ethanol or fomepizole and hemodialysis are clear in the case of toxic ingestions of methanol and ethylene glycol, they remain poorly defined for butoxyethanol poisoning. CASE REPORT: We report the case of a 51-year-old female who ingested up to 8 ounces of Sanford Expo White Board Cleaner (butoxyethanol and isopropanol). She developed prolonged hyperchloremic metabolic acidosis and mental status depression and was treated with ethanol therapy but not hemodialysis. This patient recovered without apparent sequelae. The kinetics of butoxyethanol metabolism in this case are described and the potential therapeutic options are discussed.     

Acute methanol poisonings reported to the Drug and Poison Information Center in Izmir, Turkey

The demographics, sources and outcomes of methanol poisoning have not been described in Turkey. Our study identified the profile of acute methanol exposures reported to Drug and Poison Information Center (DPIC) in Izmir, Turkey, from 1993 to 2002. Data analysis included patient demographics, sources of methanol, reason for the exposure, clinical effects and outcomes of methanol poisoning. The DPIC recorded 30,485 calls concerning poisoning; 996 (3.3%) alcohol poisonings were recorded and 113 (11.3%) of them were methanol poisonings. There were 91 (80.5%) males and 22 (19.5%) females with a mean age of 34.7+/-1.3 y (range 19-65) and 4.8+/-0.9 y (range 1-18) in adults and children, respectively. The sources of methanol were eu de cologne (72.6%), spirits (10.6%) and antifreeze (2.7%). Accidental poisoning occurred in all children between 0 and 12 y old, abuse (55.7%) and intentional poisoning (27.3%) were predominant in adults. Clinical signs in all cases were central nervous system symptoms (45.1%), metabolic acidosis (23.0%), visual symptoms (21.2%) and gastrointestinal symptoms (10.6%). Sixteen patients (14.1%) died, 63 (55.8%) had complete recovery and 1 (0.9%) had irreversible visual problems. Most patients with methanol poisoning may die or present serious morbidity without appropriate treatment in a health care facility. Methanol for producing cheap "eu de colognes" in Turkey is the principal reason for severe poisoning and deaths. Public education about colognes and legislative control of cologne production are important in preventing methanol poisoning.     

Ethylene glycol poisoning: experiences from an epidemic in Sweden.

In 1987 two lethal adult cases of accidental ethylene glycol poisoning were given spectacular attention in the Swedish mass media. This resulted in an epidemic of intentional ethylene glycol poisonings. In addition to six cases related to alcohol abuse, another 30 severe suicidal poisonings were reported to the Swedish Poison Information Centre in five months. The clinical course and outcome in these 36 severe cases are reviewed. The primary clinical manifestations were metabolic acidosis, CNS disturbances and kidney damage with circulatory failure in the most severe cases. Mortality was 17%. Fragmentation of the normal striation in heart cells was found in two of the fatal cases and severe brain damage in all fatal poisonings. The degree of acidosis but not the serum ethylene glycol level correlated with both kidney damage and outcome. Treatment included ethanol, correction of the metabolic acidosis and dialysis. Four patients with serum ethylene glycol concentrations of 10-20 mmol/L (620-1240 mg/L) but with no or minimal metabolic acidosis were treated with ethanol alone; none of these patients developed renal damage.     

Intracranial hemorrhage associated with methanol intoxication

Methanol is a common component of gasoline, antifreeze, washer fluid, perfume, household cleaners and various other industrial products. Acute methanol poisoning produces severe metabolic acidosis, serious neurologic sequelae and rarely imaging findings. In this paper, we describe a 35-year-old man with methanol intoxication who was in a comatose stage. Computed tomography (CT) showed widespread brain edema and hemorrhages localized in the supratentorial region of the temporal lobe, nearly 3 x 1 cm in a crescent shape, in the white matter surrounding the capsula externa and extending to the periventricular white matter and occipital lobes. Temporal lobe hemorrhage in our patient might also have been due to the effect of heparinization during hemodialysis, metabolic and lactic acidosis, or formate.     

Increased serum formate in the diagnosis of methanol poisoning

Early diagnosis is essential for successful treatment in methanol poisoning. Methanol detection by gas chromatography is not available in most hospitals. Methanol increases the osmolal gap in serum and its metabolite formate increases the anion gap. The sensitivity of these indirect diagnostic methods is not good at low concentrations of methanol or formate. We therefore studied the usefulness of formate measurement in diagnosing methanol poisoning. In 15 patients poisoned with methanol, serum formate was measured enzymatically on a Cobas Mira analyzer using formate dehydrogenase and nicotinamid adenine dinucleotid. Day-to-day coefficient of variation was 5%, and the upper reference limit was 2 mg/dL (0.4 mmol/L). Methanol was detected in all 15 patients of whom 14 had elevated serum formate concentrations. Anion gap was increased in 11 of 11, and osmolal gap in 11 patients of 15 examined. Metabolic acidosis was present in 12 of 15 patients, but pH was below 7.30 in only 9 of them. Four patients with no symptoms had formate concentrations in the range 2-38 mg/dL (0.5-8.3 mmol/L), indicating that increased serum formate was a sensitive indicator of methanol poisoning. Our results proved formate analyzes to be a simple, sensitive, and specific way of diagnosing methanol poisoning. Confounders are patients admitted early, or concomitant ethanol ingestion, and therefore no acidosis. This problem may, however, be omitted by repeated formate analysis in patients developing metabolic acidosis.     

Formate kinetics in methanol poisoning

OBJECTIVE: We sought to describe the kinetics, dialysis clearance, and laboratory markers of formate (FA), the toxic metabolite of methanol (meOH). METHODS: Data were obtained from a prospective, multicenter study of fomepizole +/- dialysis for methanol poisoning. Inclusion criteria confirmed methanol exposure or suspicion of exposure plus either acidemia or abnormal osmolar gap. Dialysis indications were [meOH] > 50 mg/dL, pH < 7.1, refractory acidosis, or visual toxicity. Serial plasma formate, methanol, pH, and electrolyte measurements were made. Formate was determined by gas chromatography. Endogenous and dialysis elimination half-lives were calculated as t(1/2) = 0.693/Ke, with Ke (elimination constant) derived from the slope of log (FA) vs. time. Half-lives were compared with an unpaired Student's t-test. Dialysis clearance was calculated using the Fick Principle. Pearson correlation analysis compared initial formate with initial pH, serum bicarbonate, and anion gap. RESULTS: Eleven patients were treated in the study. Eight had detectable formate with mean [FA] of 15.1 mmol/L (range 0.5-34.8). Endogenous elimination half-life was 205 +/- 90 minutes. Elimination half-life during dialysis (n = 5) was 150 +/- 37 minutes, which was not different (t = 0.22; NS). The overall dialysis formate clearance rate was 223 +/- 25 mL/min. Correlation coefficients were: pH vs. formate r2 = 0.93; bicarbonate vs. formate r2 = 0.81; and anion gap vs. formate r2 = 0.76 (all p < 0.05). CONCLUSIONS: Although dialysis clears formate, it did not significantly enhance endogenous elimination in our series of patients. Low pH, low bicarbonate, and elevated anion gap correlate independently with formate presence.     

急性乙二醇中毒3例报告及文献回顾

乙二醇为防冻剂的主要成分。乙二醇主要在肝脏内先后代谢为羟乙醛、乙醇醛、乙醇酸及草酸。这些代谢特可导致代谢性酸中毒。典型临床表现通常为3个阶段：第1阶段在摄入后12h内，乙二醇致中枢神经系统抑制；第2阶段在摄入12～24h后，出现代谢性酸中毒和心肺疾病；第3阶段在摄入后24～72h。出现肾小管坏死和肾衰竭。乙二醇致死量为1．4-1．6ml／kg[成人（70kg）约为100m1]。一旦怀疑乙二醇中毒，应尽快测定乙二醇和乙醇酸血浓度明确诊断。中毒治疗原则包括早期及时洗胃，给予乙醇或甲吡唑解毒剂，血液透析，碳酸氢钠vitB6等。大多数乙二醇中毒患者经早期诊断治疗后可恢复正常。本文报告3例急性乙醇中毒，3例患者均为男性（48岁），每人服用防冻液约为150ml。2倒出现头痛有，1例出现上腹不适、兴奋、躁动。3倒患者在摄入乙醇后12～18h出现代谢性酸中毒，24h出现血尿。经洗胃和血液透析，给予法莫替丁40mg，10％葡萄糖酸钙20ml。4％碳酸氢钠静脉注射，38％白酒200ml口服。2倒治愈，1例于摄入乙二醇后29h死亡。     

Unusual neurological symptoms in a case of severe crotalid envenomation

In Sweden bites by non-European venomous snakes are reported to the Poison Information Centre 5-10 times annually. These incidents generally take place in private homes and may result in severe poisoning. We report a recent case of envenomation from a bite by Crotalus durissus terrificus with a prolonged, atypical course. The patient, a 24-year old man, was admitted to hospital approximately eight hours after the snakebite. On admission we noted coma, circulatory failure, hypofibrinogenaemia with bleeding from fang marks on his right arm, melaena and haematemesis. Antishock therapy including intravenous fluids, steroids and epinephrine was instituted immediately and within six hours infusion of polyvalent antivenom was started. Next day, when the initial disturbances were corrected, peripheral neurological features were noted and the patient gradually became comatose. Antivenin therapy was reinstituted. The coma lasted for one week and recovery extended over several months with persisting neurological symptoms. Six months after the bite there were still pathological findings in the electromyogram.     

Pharmacokinetics of the oral direct renin inhibitor aliskiren alone and in combination with irbesartan in renal impairment

BACKGROUND: Aliskiren is an orally active direct renin inhibitor approved for the treatment of hypertension. This study assessed the effects of renal impairment on the pharmacokinetics and safety of aliskiren alone and in combination with the angiotensin receptor antagonist irbesartan. METHODS: This open-label study enrolled 17 males with mild, moderate or severe renal impairment (creatinine clearance [CL(CR)] 50-80, 30-49 and <30 mL/minute, respectively) and 17 healthy males matched for age and bodyweight. Subjects received oral aliskiren 300 mg once daily on days 1-7 and aliskiren coadministered with irbesartan 300 mg on days 8-14. Plasma aliskiren concentrations were determined by high-performance liquid chromatography/tandem mass spectrometry at frequent intervals up to 24 hours after dosing on days 1, 7 and 14. RESULTS: Renal clearance of aliskiren averaged 1280 +/- 500 mL/hour (mean +/- SD) in healthy subjects and 559 +/- 220, 312 +/- 75 and 243 +/- 186 mL/hour in patients with mild, moderate and severe renal impairment, respectively. At steady state (day 7), the geometric mean ratios (renal impairment : matched healthy volunteers) ranged from 1.21 to 2.05 for the area under the plasma concentration-time curve (AUC) over the dosage interval tau (24h) [AUC(tau)]) and from 0.83 to 2.25 for the maximum observed plasma concentration of aliskiren at steady state. Changes in exposure did not correlate with CL(CR), consistent with an effect of renal impairment on non-renal drug disposition. The observed large intersubject variability in aliskiren pharmacokinetic parameters was unrelated to the degree of renal impairment. Accumulation of aliskiren at steady state (indicated by the AUC from 0 and 24 hours [AUC(24)] on day 7 vs day 1) was similar in healthy subjects (1.79 [95% CI 1.24, 2.60]) and those with renal impairment (range 1.39-1.99). Coadministration with irbesartan did not alter the pharmacokinetics of aliskiren. Aliskiren was well tolerated when administered alone or with irbesartan. CONCLUSIONS: Exposure to aliskiren is increased by renal impairment but does not correlate with the severity of renal impairment (CL(CR)). This is consistent with previous data indicating that renal clearance of aliskiren represents only a small fraction of total clearance. Initial dose adjustment of aliskiren is unlikely to be required in patients with renal impairment.     

Accidental dermal and inhalation exposure with fipronil--a case report

BACKGROUND: Fipronil which has initiated the new generation of insecticides and possesses greater affinity at GABA receptors in insects than humans is supposed to be safer than the old generation of insecticides. Dermal and inhalation exposure to fipronil has not been reported in the literature. CASE REPORT: A 50-year-old male was admitted to the Clinic after 5h of spraying his field with the solution of fipronil. The patient was fully conscious with the BP and HR within normal range. There were no seizures, other neurological deficits, signs of conjunctivitis or skin irritation. Physical examinations and biochemical results were normal. The patient complained of a headache, nausea, vertigo and weakness. All symptoms resolved spontaneously after about 5h. During hospitalization and the follow up after three weeks he was asymptomatic. CONCLUSIONS: Further investigations should be carried on to evaluate the risk of fipronil in humans. The benzodiazepines are drugs of choice during seizures, B1 agonists and steroids may be useful during severe inhalation exposure.     

Ethylene Glycol Toxicity Presenting with Non‐Anion Gap Metabolic Acidosis

Abstract: Ethylene glycol classically produces an elevated anion gap metabolic acidosis. We report a series of patients with ethylene glycol toxicity with a component of non‐anion gap metabolic acidosis without known associated confounding factors. A retrospective review of Poison Control Center records were searched more than 8 years (2000–2007) for ethylene glycol and antifreeze. Cases were reviewed and excluded for miscoding, information calls, animal exposures, or non‐ingestion exposures. The bicarbonate gap, or delta ratio (DR), was calculated using the formula: DR = (AG ? 12)/[24 – measured serum where anion gap (AG) = [Na⁺] ? [Cl^?] ? , all in mEq/l. Non‐anion gap metabolic acidosis was considered present when the DR < 1. Of 254 cases, 175 were excluded. Of the remaining 79 cases, 14 had a component of non‐anion gap metabolic acidosis at presentation. Their calculated anion gap was 14–28, and measured serum ranged from 2–20 mEq/l. A normal anion gap was present in two patients who presented with non‐anion gap metabolic acidosis. The DR ranged from 0.28–0.95. Seven out of 14 patients with non‐anion gap metabolic acidosis had elevated serum [Cl^?]. In the other cases, no explanation for the non‐anion gap metabolic acidosis could be determined. The absence of a significant anion gap elevation in the setting of metabolic acidosis after ethylene glycol ingestion without other confounding factors (such as ethanol, lithium carbonate or bromide) has not previously been recognized. Clinicians should be aware of the potential for non‐anion gap metabolic acidosis in patients with ethylene glycol toxicity, and should not exclude the diagnosis in patients who present with a non‐anion gap metabolic acidosis. Further study is needed to determine the mechanisms by which this occurs.     

Chronic maternal methanol inhalation in nonhuman primates (Macaca fascicularis): exposure and toxicokinetics prior to and during pregnancy

Toxicokinetic studies were conducted following daily inhalation exposure to methanol vapor prior to and throughout pregnancy in adult female Macaca fascicularis monkeys. They were part of a larger study to investigate the effects of chronic methanol exposure on maternal reproductive performance and early offspring effects. In a two-cohort study design, 48 females (24/cohort) were assigned to parallel exposure groups at 0 (control), 200, 600, or 1800 ppm methanol vapor for approximately 2.5 h/day, 7 days/week throughout breeding and pregnancy. Blood methanol at 30 min postexposure was monitored biweekly. The time course for the clearance of blood MeOH concentrations following exposure was characterized on four occasions: twice during the prebreeding period and during mid- and late pregnancy. Average blood methanol concentrations at 30 min postexposure were 5, 11, and 35 microg/ml across all four toxicokinetic studies in the 200, 600 and 1800 ppm groups, respectively. Blood concentrations in the 200 ppm group were barely above basal (preexposure) blood methanol concentrations or those observed in the control group (approximately 3 microg/ml). Nonlinear elimination kinetics were observed in most of the 1800 ppm group females. There was a decrease in elimination half-life (7-20%) and an increase in clearance (30%) after 3-months of daily MeOH exposure compared to the initial exposure. There were no statistically significant changes in the first-order blood methanol half-life or clearance during pregnancy, but the mean distribution volume per kilogram body weight decreased by 22% and 17% in the 600 and 1800 ppm groups. Plasma formate levels did not differ between the methanol and control exposure groups. Plasma formate and serum folate concentrations increased slightly over the course of this study in both the exposed and control groups but these increases were not related to methanol exposure.