Indika Gawarammana

Medical management of paraquat ingestion

Poisoning by paraquat herbicide is a major medical problem in parts of Asia while sporadic cases occur elsewhere. The very high case fatality of paraquat is due to inherent toxicity and lack of effective treatments. We conducted a systematic search for human studies that report toxicokinetics, mechanisms, clinical features, prognosis and treatment. Paraquat is rapidly but incompletely absorbed and then largely eliminated unchanged in urine within 12-24 h. Clinical features are largely due to intracellular effects. Paraquat generates reactive oxygen species which cause cellular damage via lipid peroxidation, activation of NF-κB, mitochondrial damage and apoptosis in many organs. Kinetics of distribution into these target tissues can be described by a two-compartment model. Paraquat is actively taken up against a concentration gradient into lung tissue leading to pneumonitis and lung fibrosis. Paraquat also causes renal and liver injury. Plasma paraquat concentrations, urine and plasma dithionite tests and clinical features provide a good guide to prognosis. Activated charcoal and Fullers earth are routinely given to minimize further absorption. Gastric lavage should not be performed. Elimination methods such as haemodialysis and haemoperfusion are unlikely to change the clinical course. Immunosuppression with dexamethasone, cyclophosphamide and methylprednisolone is widely practised, but evidence for efficacy is very weak. Antioxidants such as acetylcysteine and salicylate might be beneficial through free radical scavenging, anti-inflammatory and NF-κB inhibitory actions. However, there are no published human trials. The case fatality is very high in all centres despite large variations in treatment.

Acute Human Lethal Toxicity of Agricultural Pesticides: A Prospective Cohort Study.

In a prospective cohort study of patients presenting with pesticide self-poisoning, Andrew Dawson and colleagues investigate the relative human toxicity of agricultural pesticides and contrast it with WHO toxicity classifications, which are based on toxicity in rats.

Acute Human Self-Poisoning with Imidacloprid Compound: A Neonicotinoid Insecticide

Background Deliberate self-poisoning with older pesticides such as organophosphorus compounds are commonly fatal and a serious public health problem in the developing world. The clinical consequences of self-poisoning with newer pesticides are not well described. Such information may help to improve clinical management and inform pesticide regulators of their relative toxicity. This study reports the clinical outcomes and toxicokinetics of the neonicotinoid insecticide imidacloprid following acute self-poisoning in humans. Methodology/Principal Findings Demographic and clinical data were prospectively recorded in patients with imidacloprid exposure in three hospitals in Sri Lanka. Blood samples were collected when possible for quantification of imidacloprid concentration. There were 68 patients (61 self-ingestions and 7 dermal exposures) with exposure to imidacloprid. Of the self-poisoning patients, the median time to presentation was 4 hours (IQR 2.3–6.0) and median amount ingested was 15 mL (IQR 10–50 mL). Most patients only developed mild symptoms such as nausea, vomiting, headache and diarrhoea. One patient developed respiratory failure needing mechanical ventilation while another was admitted to intensive care due to prolonged sedation. There were no deaths. Median admission imidacloprid concentration was 10.58 ng/L; IQR: 3.84–15.58 ng/L, Range: 0.02–51.25 ng/L. Changes in the concentration of imidacloprid in serial blood samples were consistent with prolonged absorption and/or saturable elimination. Conclusions Imidacloprid generally demonstrates low human lethality even in large ingestions. Respiratory failure and reduced level of consciousness were the most serious complications, but these were uncommon. Substitution of imidacloprid for organophosphorus compounds in areas where the incidence of self-poisoning is high may help reduce deaths from self-poisoning.

Survival Pattern in Patients with Acute Organophosphate Poisoning Receiving Intensive Care

Background. Approximately 35% of patients acutely poisoned with organophosphates (OP) in developing countries like Sri Lanka require intensive care and mechanical ventilation. However, death rates remain high. Objective. To study the outcomes and predictors of mortality in patients with acute OP poisoning requiring intensive therapy at a regional center in Sri Lanka over a period of 40 months. Methods. Retrospective analysis of all intensive care records of patients with acute OP poisoning admitted to the Intensive Care Unit (ICU) between March 1998 and July 2001. Results. During the study period, 126 subjects were admitted to the ICU with acute OP poisoning. Records of 10 patients were lost and those of 37 were incomplete and hence were excluded. All the remaining 71 patients (59 male) had required endotracheal intubation and mechanical ventilation for a period of four (median) days (range 1–27) in addition to gastric lavage and standard therapy with atropine and oximes and adequate hydration. Of these 71 patients, 36 (28 male) had died. Life table analysis demonstrated a steep decline in the cumulative survival to 67% during the first three days. Systolic blood pressure of < 100 mmHg and FiO2 of > 40% to maintain a SpO2 of > 92% within the first 24 h were recognized as poor prognostic indicators among mechanically ventilated patients. Conclusion. Mortality following OP poisoning remains high despite adequate respiratory support, intensive care, and specific therapy with atropine and oximes. One‐third of the subjects needing mechanical ventilation and reaching intensive care units die within the first 72 h of poisoning. Systolic blood pressure of less than 100 mmHg and the necessity of a FiO2 > 40% to maintain adequate oxygenation are predictors of poor outcome in patients mechanically ventilated in the ICU.

Heavy metal poisoning from Ayurvedic traditional medicines: an emerging problem?

The use of Ayurvedic medicines is common in both adults and children and is increasing in many areas of the world. This paper will discuss the risks of heavy metal poisoning associated with the use of Ayurvedic medicines and illustrate this with some cases managed by the authors. Many Ayurvedic medicines contain heavy metals, including lead, mercury and arsenic, and there have been numerous reports of clinically significant heavy metal poisoning related to their use. However, there have been few studies that allow quantification of the incidence of this problem. There is limited regulation of these products in most areas of the world. Recent European legislation may help to improve safety of products bought in shops, but it is likely to have a relatively limited overall impact as it will not cover personal imports or products prescribed by traditional medicine practitioners. There is an urgent need for studies to quantify the frequency and potential risk of heavy metal poisoning from Ayurvedic medicines and for culturally appropriate education to inform the public of the potential for toxicity associated with these products.

Acute ischemic strokes due to bites by Daboia russelii in Sri Lanka - first authenticated case series.

UNLABELLED Bites due to Russells Viper (Daboia russelii) are common in Sri Lanka. Commonest haematological manifestation is consumptive coagulopathy and bleeding. Commonest neurological manifestations are ptosis, ophthalmoplegia and rarely respiratory failure which are due to presynaptic inhibition of neuromuscular transmission. There are no authenticated reports of acute ischemic strokes following bites by D. russelii. We report the first authenticated case series of ischemic strokes following bites by D. russelii in Sri Lanka. METHODS This was a prospective observational study of all atypical neurological manifestations following bites by D. russelii admitted to a hospital in Sri Lanka. We documented clinical features of all atypical neurological manifestations of D. russelii bites and recorded the findings of brain imaging. RESULTS During a period of 18 months, at one centre, 9 patients out of an estimated 500 victims of D. russelii bites were found to have Computerized Tomographic evidence of single or multiple ischemic (non-haemorrhagic) strokes of medium to large vessel territories of the brain. These patients had either low Glasgow coma scale or hemiparesis within minutes to 4 days following bites. One patient died and another had gross neurological deficit, while others had mild or no neurological deficit at three months. DISCUSSION This report confirms that ischemic strokes can occur following envenoming by D. russelii. Involvement of multiple medium to large vessel territories and absence of watershed infarctions points to prothrombotic properties of the venom as the putative mechanism.

Epidemiology and clinical effects of Hump-nosed pit viper (Genus: Hypnale) envenoming in Sri Lanka

Hump-nosed pit vipers of Genus Hypnale are the commonest cause of snake bite in Sri Lanka. Although there are many reports of local effects, coagulopathy and acute kidney injury, it remains unclear how frequent these clinical effects are and therefore the medical importance of this snake genus. The genus has been recently revised to include Hypnale hypnale from Sri Lanka and Western Ghats of Southern India, and the two endemic species to Sri Lanka, Hypnale zara and Hypnale nepa. This was a prospective hospital-based clinical study of definite Hypnale spp. bites from July 2008 to July 2010 in six Sri Lankan hospitals. There were 114 patients included and all snakes were correctly identified by hospital staff as Hypnale spp. Of these, 93 snakes were identified as H. hypnale by an expert, 16 as H. zara and five as H. nepa. Most bites occurred on the lower limbs in the daytime. There was no difference in the clinical effects between the three species. Pain and fang marks were present in all patients, 101 had local swelling and only 16 (14%) developed extensive local swelling that spread proximally and involved more than half of the bitten limb. Systemic symptoms occurred in 18 patients; four patients had an abnormal 20 min whole blood clotting test and one patient developed an acute kidney injury that required haemodialysis. All patients were discharged alive with a median length of stay of 2 days. This study confirms that hump-nosed viper bites cause only minor effects in most cases. Future studies need to undertake formal coagulation studies and identify important early indicators of renal impairment.

Systematic review of controlled clinical trials of gastric lavage in acute organophosphorus pesticide poisoning

Background. Organophosphorus pesticide (OP) self-poisoning is a major problem in the developing rural world. There is little clinical trial data to guide therapy, hindering the identification of best therapy. Despite the recognition of adverse effects, gastric lavage is commonly done in Asia. We aimed to identify studies assessing its effectiveness. Method. We systematically searched the literature for controlled clinical studies that assessed the effect of gastric lavage in OP pesticide self-poisoning. Results. All 56 studies identified were Chinese and reported benefit from the intervention studied, including multiple gastric lavages, use of norepinephrine or pralidoxime in the lavage fluid, concurrent treatment with naloxone or scopolamine, insertion of the gastric tube via a laparotomy incision, and lavage later than 12 h post-ingestion. However, only 23 were RCTs and none presented adequate methodology for their quality to be assessed. The patient population and study treatment protocol were not defined – large variation in case fatality in the control arm of the studies (from 4.5 to 93%) suggests marked variation between studies and likely between study arms. No study compared an intervention against a control group receiving no gastric lavage or provided any data to indicate whether a significant quantity of poison was removed. Conclusion. Despite widespread use of multiple gastric lavages for OP pesticide poisoning across Asia, there is currently no high-quality evidence to support its clinical effectiveness. There is a need for studies to identify in which patients and for what duration gastric lavage is able to remove significant quantities of poison. Following these studies, large clinical trials will be required to address the effectiveness and safety of gastric lavage (either single or multiple) in acute OP pesticide poisoning.

Simple and sensitive liquid chromatography-tandem mass spectrometry methods for quantification of paraquat in plasma and urine: application to experimental and clinical toxicological studies.

Simple, sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods have been developed and validated for quantification of paraquat (PQ) in plasma and urine. Plasma and urine sample preparation were carried out by one-step protein precipitation using cold acetonitrile (-20 to -10 °C). After centrifugation, an aliquot of 10 μL of supernatant was injected into a Kinetex™ hydrophilic interaction chromatography (HILIC) column with a KrudKatcher™ Ultra in-line filter. The chromatographic separation was achieved using the mobile phase mixture of 250 mM ammonium formate (with 0.8% aqueous formic acid) in water and acetonitrile at a flow rate of 0.3 mL/min. Detection was performed using an API2000 triple quadrupole tandem mass spectrometer in multiple reaction monitoring (MRM) mode via an electrospray ionization (ESI) source. The calibration curve was linear over the concentration range of 10-5000 ng/mL, with an LLOQ of 10 ng/mL. The inter- and intra-day precision (% R.S.D.) were <8.5% and 6.4% for plasma and urine, respectively with the accuracies (%) within the range of 95.1-102.8%. PQ in plasma and urine samples was stable when stored at -70 °C for three freeze-thaw cycles. The methods were successfully applied to determine PQ concentration in rat and human samples.

Peripheral burning sensation: a novel clinical marker of poor prognosis and higher plasma-paraquat concentrations in paraquat poisoning.

Introduction. Self-poisoning with paraquat has a case fatality ratio (CFR) over 65% in Sri Lanka. Plasma-paraquat concentration is the best prognostic indicator for patient outcome but is not readily available. Alternative surrogate clinical markers could be useful in management and determining prognosis. Anecdotal reports by medical and research staff suggested that patients who complained of burning sensation of the body had a poor prognosis and a prospective study was initiated. Methods. This was a prospective observational study in three hospitals in Sri Lanka. We collected demographic data, presence or absence of burning sensation, and major outcome, and determined the plasma-paraquat concentration within 24 h post-ingestion. Results. There were 179 patients with deliberate self-ingestion of paraquat over 30 months. Burning sensation was reported in 84 patients (48%), which was initiated at a median of 1 day (range 1–3 days) post-ingestion. Of the patients who had burning, 61 died [CFR = 72.62%; 95% confidence interval (CI) = 62–81]. Of the 91 patients who had no peripheral burning, 23 died (CFR = 25.27%, 95% CI = 18.15–35.9). Presence of peripheral burning sensation was associated with a significantly higher risk of death (odds ratio = 7.8, 95% CI = 3.9–15, p < 0.0001). Patients who complained of peripheral burning died at a median of 36 h (interquartile range = 30.5–88) following ingestion whereas those who had no peripheral burning died at a median of 50.5 h (interquartile range = 16.75–80). The difference was not significant (p > 0.05). Median admission plasma-paraquat concentration in patients with peripheral burning (2.67 μg/mL, 95% CI = 0.84–14.2) was significantly higher than in the patients with no peripheral burning (0.022 μg/mL, 95% CI = 0.005–0.78; p < 0.001). Peripheral burning has a sensitivity of 0.72 (95% CI = 0.6–8) and specificity of 0.74 (95% CI = 0.64–0.08) and a positive predictive value of 0.73 (95% CI = 0.6–0.8). Discussion. It is possible that this symptom may help discriminate between patients who have poor chance of survival and those who may potentially benefit from interventions. The mechanism is not clear but could either include a direct concentration-related effect or be a marker of oxidative stress. Conclusion. Presence of burning sensation is associated with high plasma-paraquat concentrations and is strongly predictive of death.