Fatal diquat intoxication Fatalno trovanje dikvatom

Background. Since the introduction of diquat in agriculture practice in 1960`s, about 40 cases of poisoning have been described in detail in medical literature. Case report. We presented two cases. A case one, a 35-year-old, previously healthy, woman ingested 14% diquat solution. The poisoning had fulminant course, consisted of severe stomachache, vomiting, cardiocirculatory shock, respiratory failure and cardiac arrest 20 hours post-ingestion. Autopsy revealed myocardial infarction, bronchopneumonia and incipient renal damage. A case two, a 64-year-old man developed severe gastroenteritis, corrosive lesions of mucosal surfaces, acute renal injury, arrhythmias, brain stem infarction and bronchopneumonia. The diagnosis of diquat poisoning was made retrospectively upon the clinical picture and identification of pesticides he had been exposed to. The patient died 18 days post-exposure. The most prominent findings on autopsy were pontine hemorrhage and infarction, bronchopneumonia, left ventricle papillary muscle infarction and renal tubular damage. Conclusion. Cardiocirculatory disturbances led to fatal complications, the heart and brain infarction. We pointed out the heart as one of the most severely affected organs in diquat poisoning.


Introduction
Diquat (1,1'-ethylene-2,2'-bipyridilium) is a nonselective bipyridyl herbicide.It acts as a potent redox cycler, generating superoxide anion and other redox products, which induce lipid peroxidation in cell membranes leading to cell death.Ingestion of bypyridil herbicides, diquat and paraquat may cause severe and fatal poisoning.These herbicides produce corrosive lesions as a local effect, but their systemic effects are much more dangerous.Paraquat is used more widely, and its multiorgan toxicity is well recognized.Diquat is not so commonly used, and less than 40 cases of poisoning are reported in detail in medical literature.Acute lethal doses (LD 50 ) for both compounds are of the same order of magnitude, but diquat does not produce progressive pulmonary fibrosis as paraquat, so it is considered less toxic 1 .Clinical manifestations of diquat poisoning include primarily gastroenteritis and acute renal failure, but in severe cases respiratory failure, cardiovascular collapse, dysrhythmias, seizures and coma with brain haemorrhage and infarction may develop 2,3 .
We reported two cases of fatal diquat intoxication, both with severe complications including myocardial infarction.

Case report
Case 1, a 35-year-old woman, was brought to the Emergency Department (ED) by ambulance.The patient was able to provide a history and it was positive only for depressive disorder.In a suicide attempt she ingested approximately 30 ml of a pesticide.Shortly after the ingestion, she developed a severe stomachache and felt extremely nauseated, vomited once.Gastric lavage was performed at the local medical centre, two hours post-ingestion.Her relatives brought along a bottle of ingested herbicide Reglone ® , containing 14% water solution of diquat.
The patient was admitted to intensive care unit.Peripheral intravenous line was instituted and initially she was given 2 000 ml of normal saline and 250 mL of 8.4% sodium bicarbonate.The patient had been on a cardiac monitoring since admission.Sinus tachycardia at 130-150 beats/minute with diffuse ST segment depression was present.She was restless with severe stomach pain, so tramadol and diazepam were given intravenously.Despite the fluids replacement, blood pressure fell to 80/55 mmHg, and dopamine infusion was started.Eight hours post admission, repeated laboratory analyses showed BUN 9.2 mmol/L, creatinine 557 μmol/L, sodium 142 mEq/L, potassium 3.6 mEq/L, glucose 10.5 mmol/L, AST 1213 U/L, ALT 675 U/L, CK 1257 U/L.ABG revealed worsening of acidosis to pH 6.99 and ABE to -24.1.At that point the urine output was noted to be only 20 mL.Therefore, the rate of fluids was increased and 80 mg of furosemid was administrated.Haemoperfusion was planed, but it could not be performed because over next few hours the patient's condition deteriorated rapidly.Respiratory failure developed, and she was intubated and placed on mechanical ventilation.Normal oxygen saturation was maintained, but cardiocirculatory disturbances consisted of hypotension, tachycardia followed by bradycardia, and finally asystolia were refractory to the treatment.Despite the cardiopulmonary resuscitation (CPR) treatment the patient died 20 hours after ingestion of diquat solution.Autopsy revealed the area of about 3 cm × 2 cm of myocardial infarction on the posterior left ventricular wall.Hyperaemia of brain, lungs, liver, pancreas and kidneys with incipient renal tubular damage were present.Acute purulent bronchopneumonia was also noted.Toxicological analysis for diquat was not available.
Case 2, a 64-year-old farmer, presented to ED with nausea, abdominal pain and vomiting.The patient claimed that the symptoms had started two hours ago, during his work on plants spraying with malathion and some other pesticides of the names he was not able to remember.He denied any intentional ingestion of pesticide.There was no significant prior medical history.
On admission, he vomited profusely and continued to do so for the next few hours.He also had diarrhea.He was diaphoretic, but there were no excessive lacrimation and salivation.The pupils were slightly miotic, equal and reactive.The lungs were clear, the heart sounds were normal.The abdominal examination showed diffuse tenderness and hyperactive bowel sounds, liver and spleen were not palpable.Arterial blood pressure was 130/80 mmHg, heart rate 90 beats/min, temperature 36.8º C. Initial blood chemistry analyses showed normal values of BUN 3.2 mmol/L, sodium 141mEq/l, potassium 4.3 mEq/L, and mild elevation of creatinine 147 μmol/L and glucose 11.0 mmol/L.WBC was 19.4 × 103/mm 3 , RBC 5.03 × 106/mm 3 , hemoglobin 15.3 g/dL, hematocrit 44.0%, and platelets 317 × 103/mm 3 .Laboratory estimation of organophosphate exposure by measuring the activity of erythrocyte acetylcholinesterase (AChE) and plasma pseudocholinesterase (ChE) revealed normal values of 5 560 U/L, and 9 370 u/L, respectively.AST was 16 U/L, ALT 13 U/L and CK 94 U/L.Arterial blood gases analysis showed pH 7.29, pCO 2 25.5 mmHg, pO 2 90.75 mmHg, sO 2 95.4%, ABE -13.5, SB 13.8.
The patient was admitted to the hospital and because of severe gastroenteritis, infusions of isotonic saline and glucose were given.Subsequent laboratory data, 8 hours post admission, showed increased values of urea 25.5 mmol/L, creatinine 711 μmol/L and CK 1 916 U/L.AST was 76 U/L, ALT 89 U/L.Values of cholinesterase decereased: AChE was 2 150 U/L and ChE was 3 188 U/L.Though the clinical course did not indicate severe poisoning by organophosphorous pesticides, the treatment with atropine was started.After a few mg of atropine signs and symptoms of hyperatropinization occurred, so it was stopped.
On the 2nd day after exposure the patient became febrile, the temperature was 38.2º C and clinical and chest radiographic findings of bronchopneumonia developed.A small zone of dysepitalisation of tongue mucosa appeared.Similar erosion was noted sublingually, also.Despite fluid replacement and normal values of arterial blood pressure and central venous pressure, the patient remained oliguric with diuresis of 400 mL during the first day, and 100 mL during the second day of hospitalization.
Severe gastroenteritis, corrosive lesions of mucosal surfaces, the development of acute renal injury and bronchopneumonia observed in our patient, strongly suggested a possibility of poisoning by bipyridylium herbicides.By this Jović-Stošić J, et al.Vojnosanit Pregl 2009; 66(6): 477-481.time, we contacted the patient's family and asked them to bring the pesticides he had used.The members of his family indicated a possibility of deliberate ingestion and brought along two marked bottles of pesticides containing organophosphorus compounds malathion and dimethoate, and an unmarked bottle containing a dark liquid.The patient recognized all of them as the pesticides he used.Toxicological analysis of the unmarked bottle content revealed a 26% solution of diquat dibromide.Blood and urine samples were taken at the same time, but no traces of diquat or organophosphorous compounds were proven.
Hemodialysis treatment was started on the 3rd hospital day because of a progressive renal failure.The patient became increasingly somnolent after the first hemodialysis.On the 4th day, during the second hemodialysis, supraventricular tachycardia of 150 beats/min with signs of myocardial ischemia (depression of ST segment and inverted T waves in leads D 1 , aVL and V 2 -V 5 by ECG) occurred.The patient experienced respiratory arrest, so he was placed on mechanical ventilation.The treatment with propaphenon and verapamil resulted in slowing down the heart rate, but the signs of myocardial ischemia persisted.Deterioration of consciousness was progressive leading to deep coma.Computed tomographic brain scan performed on the next day revealed extensive hypodense lesions of brain stem, suggesting infarction in the pons and mesencephalon on the left side with marked oedema around hypodense area.In deep coma, on mechanical ventilation, treated with antibiotics, fluid infusions, hemodialysis and other symptomatic and supportive therapy, the patient remained stabile in the following period.A total of eight hemodialiysis treatments were necessary for the period of 10 days, and after that renal function started to improve.The highest values of BUN (55.6 mmol/L) and creatinine (1 075 μmol/L) were noticed on the 8th day postexposure.The other laboratory disturbances indicating multiorgan toxicity were transient increase of blood total bilirubin reaching maximum value of 179 μmol/L on the 4th postexposure day, and constantly increased values of serum amylase activity with peak value of 712 U/L on the 2nd hospital day.The activities of amino transferases and creatine phosphokinase were increasing with peak values reaching on the 4th day post-exposure (AST 129 U/L, ALT 93 U/L, CK 3753 U/L).On the 14th hospital day cardiac arrest happened.Sinus rhythm was established, but on the 18th day postexposure cardiac arrest happened again and was refractory to the treatment.
Postmortem examination revealed abnormalities in the pons and region of the left capsula interna, which were purpuric by cut surface of brain.Microscopic examination revealed areas of hemorrhage in association with multiple confluent areas of infarction.A small erosion of tongue, and a couple of similar erosions of laryngeal, upper tracheal, esophageal and gastric mucosa surfaces were noted.Edema, congestion and patchy areas of consolidation, containing purulent material, were observed in the lungs.Microscopic examination revealed thickening of alveolar walls.Cut surface of heart showed recent infarction of left ventricle papillary muscle.Perivascular myocardial fibrosis was observed by histology examination, also.Liver histology was normal.Incipient fatty infiltration of pancreas and reactive hyperemia of spleen were noted.Histological examination of kidneys revealed partial acute tubular necrosis.Fat loss of the suprarenal glands tissue was also observed.

Discussion
The case 1 represents an acute fulminant poisoning by diquate.It is reported that the ingestion of large amount of bipyridyil herbicides may cause death within a day or two, and clinical picture is essentially the same for diquat as for paraquat 2 .
The case 2 despite the anamnesis of organophosphorous pesticides exposure and the slight decrease of cholinesterase activity, in view of characteristic clinical course was diagnosed with severe bipyridyl poisoning.The route of exposure to diquat was dubious.Inhalation usually causes mild signs and symptoms of poisoning, and fatal outcome is unlikely in such cases 2,3 .Corrosive lesions of tongue, sublingual mucosa, esophagus, stomach, larynx and trachea indicated these tissues contact with the poison.The patient allowed possibility of accidental ingestion of small quantity during spraying.Similar way of exposure with corrosive lesions of upper gastrointestinal tract and systemic intoxication has been reported 4 .Anyway, in view of severity of poisoning and the information of possible depressive disorder provided from patient's family, it was more likely the case of intentional ingestion.
Initial clinical manifestations of diquat intoxication include severe gastroenteritis, followed by acute renal failure, as was noticed in both our patients.In the case 2 renal failure developed despite the adequate fluids replacement and normal arterial and central venous pressure, so we believe it was the consequence of diquat nephrotoxicity, rather than hemodynamic disturbances.In the case 1 it could be partially caused by inadequate perfusion, and because of fulminant course, full clinical image of renal damage did not developed.Discrepancy between normal BUN and high creatinine levels in this case probably was the artifact due to interference of diquat in the laboratory assay for serum creatinine 5 .Toxicology analysis for diquat in patient's serum was not available, but this finding may indicate its presence in blood.
Early development of bronchopneumonia was noticed in both presented cases, and contributed to respiratory failure.Impaired respiratory function has been reported in the most cases of severe diquat poisoning [6][7][8] .It may be the manifestation of an acute lung injury, like in other kinds of severe illness and trauma.Consequently, thickening of alveolary walls, as revealed by histology in the case 2, may develop.Though pulmonary fibrosis after intratracheal administration of diquat is reported, and paraquat and diquat share similar mechanisms of toxicity, experimental studies showed that diquat is not accumulated in the lung and does not produce progressive pulmonary fibrosis like paraquat [9][10][11][12] .
Toxic effects of bipyridyl herbicides also include damage of liver, pancreas, heart and muscle.Signs of hepatotox- icity, such as jaundice, elevations in serum aminotransferases and liver centrilobular necrosis, as well as the development of pancreatitis, have been reported in paraquat poisonings 13- 15 .In the case 2, transient elevation of serum bilirubin and increased activity of amylase were noted, but histological examination of liver and pancreas did not revealed significant damage.Activities of transaminases were increased concomitantly with CK activity elevation, indicating muscle damage rather than liver necrosis.
We point out heart damage, noted in both presented patients.Besides gastrointestinal, cardiocirculatory disturbances including hypotension, tachycardia, and myocardial ischaemia were the leading signs of poisoning in the case 1. Cardiovascular hypotension unresponsive to fluids and vasoactive drugs is described in similar cases, but myocardial infarction, what we proved by postmortem examination, was not described in these reports 5,16,17 .The patient was previously healthy young woman, so we believe that the development of myocardial infarction shortly after diquat ingestion was the consequence of its toxicity.In the case 2, four days post-exposure, the patient developed cardiac arrhythmias, which were transient, but electrocardiographic signs of ischemia persisted.Concomitant elevation of enzyme activity also indicated myocardial infarction, and finally it was confirmed by autopsy.
At the time the patient became hemodynamically unstable, progressive deterioration of consciousness was noted.Computerized tomography revealed infarctions in regions of pons and left capsula interna.There have been reports on pontine infarction or hemorrhage after diquat ingestion 9,10,18,19 .In discussion, the brain stem damage was attributed to the possible effects of diquat itself or hemodynamic disturbances (hypoperfusion and extracorporal procedures).In our case myocardial ischemia and cardiocirculatory disturbances preceded significant central nervous system damage consistent with infarctions and hemorrhage.
Systemic toxicity with parenchymatous organs damage in bipyridylium herbicides poisoning is attributed to their oxidation and reduction in a cycling manner.This process leads to the production of superoxide anion and other free radicals, resulting in the chain reactions that damage cellular structures.Cells are additionally damaged due to depletion of NADPH that is consumed during redox cycling and detoxification of free radicals 3 .Being the site of intensive energetic metabolism, the heart may be among the most sensitive target organs.The results of recent clinical study on patients with paraquat and/or diquat poisoning indicate that marked imbalance between increased oxygen demand and decreased oxygen supply because of myocardial depression, was a possible cause of death in circulatory failure 20 .We believe that in the presented cases of diquat poisoning, primary cardiocirculatory disturbances led to fatal complications, heart and brain infarction.
Since the immediate measures to reduce the further diquat absorption and to enhance elimination by hemoperfusion, as well as administration of antioxidants, were not beneficial for survival in most cases of severe diquat poisoning, supportive care and symptomatic treatment in intensive care unit remains the mainstream therapy 10,16,21,22 .

Conclusion
Clinical picture of diquat poisoning has been described in detail in a small number of cases.Local corrosive lesions, and systemic manifestations including severe gastroenteritis, acute renal failure, early development of bronchopneumonia, and signs of liver damage have been recognized.In all available reports, marked cardiocirculatory disturbances have been noticed, but there have been no reports on myocardial infarction, which we proved in the presented patients.We pointed out the heart as one of the most severely affected organs in diquat poisoning.