bungarus caeruleus ( common krait ) bites are a continuing medical problem in sri lanka ( kularatne , 2002 ; ariaratnam et al , 2008 ) . these bites rapidly lead to a classical occulo - facio - bulbar and respiratory muscle paralysis that requires mechanical ventilation in about half of all victims ( kularatne , 2002 ) . physicians managing bungarus caeruleus bites frequently encounter patients in states of deep coma mimicking brain death . a prospective study of 210 cases of bungarus caeruleus bites in the north central province of sri lanka reported a high incidence of deep coma ( kularatne , 2002 ) . this series reported a state of  total unresponsiveness to deep pain or loud voices associated with fixed dilated pupils and absent brain stem and spinal reflexes ' in 35 ( 17% ) patients . all of the survivors in this group ( 22 patients ) made a complete neurological recovery after varying periods of mechanical ventilation . personal communication with many practicing physicians in the island revealed similar transient and completely reversible deep coma in a significant number of victims of common bungarus caeruleus in sri lanka . this phenomenon may be due to hypoxia secondary to respiratory failure or a direct effect of venom on the cortical and/or brainstem neurons . we assumed that eeg and brainstem auditory and visual evoked potentials will be abnormal if the venom acted on the cortical and brainstem neurones . another intriguing phenomenon reported following bungarus caeruleus bite in sri lanka is hypokalaemia ( sellahewa , 1997 ; kularatne , 2002 ) . kularatne reported a high incidence ( 71% ) of hypokalaemia ( < 3.5mmol / l ) in their series ( kularatne , 2002 ) . author postulated beta adrenergic stimulation and intra - cellular shift of potassium as the potential cause of this phenomenon . we postulated that measurement of urinary potassium excretion would be a reliable surrogate marker of renal conservation of potassium . if there is intracellular shifting of potassium , the renal tubules would attempt to conserve potassium and thus , potassium excretion of would be minimal . there are no published reports on human studies conducted to describe the pathophysiology of these phenomena . the objective of the current report is to postulate two putative mechanisms of deep coma and hypokalaemia following bungarus caeruleus bites in sri lanka . two patients who were transferred in november 2008 to the study hospital following proven bites by bungarus caeruleus were prospectively followed up until death or discharge . daily blood samples were analysed for serum potassium and sodium while the daily urine was collected for the analysis of potassium excretion . digital electroencephalograms ( eeg ) and electrocardiograms ( ecg ) were performed on a daily basis . in patient 1 , we performed peripheral nerve conduction studies ( ncs ) , repetitive nerve stimulation studies ( rns ) , visual ( vep ) and brain stem auditory evoked potentials ( baep ) to assess the peripheral and central nerve pathways . clinical management included replacement of potassium at a rate of 1 - 1.5mmol / kg / day , replacement of fluids and nutrients . both patients were presented to the local hospital with the killed specimen of bungarus caeruleus . both patients were treated with polyvalent antivenom ( 20 vials of lyophilised , enzyme refined , equine snake venom antiserum ; ( vins bioproducts limited ) raised against indian cobra , common krait , russell 's viper and saw scaled viper ) at the local hospital , before being transferred to the study hospital for further care . a 43-year - old man was bitten by a bungarus caeruleus while he was sleeping on the ground and was admitted to the local hospital within one hour of the bite . he arrived with a normal glasgow coma scale ( gcs ) , peripheral oxygen saturation of 100% and normal blood pressure . within an hour after admission , he developed respiratory failure and was intubated . on arrival at the study hospital , his gcs was 3/15 , blood pressure 90/70 mmhg and pulse rate of 80/min . his pupils were dilated ( 6 mm ) and were not reacting to light . all brain stem and spinal reflexes were absent . admission blood gases revealed : ph 7.332 , pco2 26.7,po2 233,hco3 13.8 and be 9.5 . blood pressure and metabolic acidosis responded promptly to administration of intravenous fluids . over the next 4 days , his cortical functions improved from a flicker of movement of the eye lids to deep pain to movement of hands to verbal commands ( gcs 10/15 ) . on day 7 , he developed features of disseminated intravascular coagulation ( dic ) with bleeding from mucous membranes , thrombocytopenia and the chest x ray revealed evidence of adult respiratory distress syndrome ( ards ) . maintenance of oxygenation became increasingly difficult and he died of an asystolic cardiac arrest 13 days after the bite . serum potassium was found to be persistently low ( 2.2 , 2.1 , 3.1 , 3 and 3mmol / l on admission , days 2,3,4 and 5 respectively ) despite replacement of potassium at a rate of 1 - 1.5mmol / kg / day . twenty four hour urinary potassium excretion was persistently lower than the normal 1 - 1.5mmol / kg / day ( figure 2 ) . daily serum potassium and urinary potassium excretion . in patient 1 , serum potassium remained below normal ( 3.5mmol / l ) throughout while urinary potassium excretion remained below normal daily excretion ( 1 - 1.5mmol / kg / day ) . in patient 2 , serum potassium normalized on day 3 while the urinary excretion remained low . eeg ( figure 3 ) revealed absent alpha and delta activity and dominant theta activity ( 4 - 5hz ) on the day of the bite . serial daily eegs revealed that alpha activity and delta did not appear while theta activity dominated for 7 days after the bite . eeg of patient 1 done on the day of the bite demonstrating absent alpha and delta activity with dominant theta activity . a 32-year - old male was admitted to the same local hospital as in case 1 following a bungarus caeruleus bite . he was transferred to the study hospital with a gcs of 3/15 with no brain stem and spinal reflexes . on the 3 day after the bite , he regained consciousness and was extubated on the 4 day and discharged with no residual neurological complications . he had no memory of events that occurred after the bite until the third day . ( 2.9mmol / l ) on the day of the admission and improved ( 3.8mmol / l)on day 3 . his urinary potassium excretion was normal ( i.e. , 1 - 1.5mmol / kg / day ) on day 1 but reduced on days 2 and 3 ( 1.16 , 0.2 and 0.22 mmol / kg / day on admission , day 2 and day 3 , respectively ) ( figure 1 ) . eeg on day 1 ( figure 5 ) revealed theta activity with absent alpha and delta activity for 2 days . eeg of patient 2 done on the day of the bite demonstrating theta activity with absent alpha and delta activity . a 43-year - old man was bitten by a bungarus caeruleus while he was sleeping on the ground and was admitted to the local hospital within one hour of the bite . he arrived with a normal glasgow coma scale ( gcs ) , peripheral oxygen saturation of 100% and normal blood pressure . within an hour after admission , he developed respiratory failure and was intubated . on arrival at the study hospital , his gcs was 3/15 , blood pressure 90/70 mmhg and pulse rate of 80/min . his pupils were dilated ( 6 mm ) and were not reacting to light . all brain stem and spinal reflexes were absent . admission blood gases revealed : ph 7.332 , pco2 26.7,po2 233,hco3 13.8 and be 9.5 . blood pressure and metabolic acidosis responded promptly to administration of intravenous fluids . over the next 4 days , his cortical functions improved from a flicker of movement of the eye lids to deep pain to movement of hands to verbal commands ( gcs 10/15 ) . on day 7 , he developed features of disseminated intravascular coagulation ( dic ) with bleeding from mucous membranes , thrombocytopenia and the chest x ray revealed evidence of adult respiratory distress syndrome ( ards ) . maintenance of oxygenation became increasingly difficult and he died of an asystolic cardiac arrest 13 days after the bite . serum potassium was found to be persistently low ( 2.2 , 2.1 , 3.1 , 3 and 3mmol / l on admission , days 2,3,4 and 5 respectively ) despite replacement of potassium at a rate of 1 - 1.5mmol / kg / day . twenty four hour urinary potassium excretion was persistently lower than the normal 1 - 1.5mmol / kg / day ( figure 2 ) . daily serum potassium and urinary potassium excretion . in patient 1 , serum potassium remained below normal ( 3.5mmol / l ) throughout while urinary potassium excretion remained below normal daily excretion ( 1 - 1.5mmol / kg / day ) . in patient 2 , serum potassium normalized on day 3 while the urinary excretion remained low . eeg ( figure 3 ) revealed absent alpha and delta activity and dominant theta activity ( 4 - 5hz ) on the day of the bite . serial daily eegs revealed that alpha activity and delta did not appear while theta activity dominated for 7 days after the bite . eeg of patient 1 done on the day of the bite demonstrating absent alpha and delta activity with dominant theta activity . a 32-year - old male was admitted to the same local hospital as in case 1 following a bungarus caeruleus bite . he was transferred to the study hospital with a gcs of 3/15 with no brain stem and spinal reflexes . on the 3 day after the bite , he regained consciousness and was extubated on the 4 day and discharged with no residual neurological complications . he had no memory of events that occurred after the bite until the third day . ( 2.9mmol / l ) on the day of the admission and improved ( 3.8mmol / l)on day 3 . his urinary potassium excretion was normal ( i.e. , 1 - 1.5mmol / kg / day ) on day 1 but reduced on days 2 and 3 ( 1.16 , 0.2 and 0.22 mmol / kg / day on admission , day 2 and day 3 , respectively ) ( figure 1 ) . eeg on day 1 ( figure 5 ) revealed theta activity with absent alpha and delta activity for 2 days . eeg of patient 2 done on the day of the bite demonstrating theta activity with absent alpha and delta activity . these two cases demonstrate clearly that severely envenomed patients with bungarus caeruleus have depressed cortical activity and brain stem functions . in addition to deep coma , both patients had identical eeg activity of absent alpha and delta waves and dominant theta waves after the bite . the survivor had restored alpha activity on the third day while in the other , alpha activity did not return . the cause of death in the patient 1 was a combination of disseminated intravascular coagulopathy and adult respiratory distress syndrome ( ards ) . the latter complication has been reported previously by kularatne ( kularatne , 2002 ) in 5 patients who died while being in a deep coma . necrosis of diaphragmatic muscles following bungarus caeruleus has not been reported previously and may have contributed to the respiratory failure . venom of bungarus caeruleus contains a mixture of alpha- and beta - bungarotoxin and a caerulotoxin . beta - bungarotoxin acts on the presynaptic terminal while alpha - bungarotoxin and caerulotoxin act on the post synaptic membrane ( abe et al , 1977 ; bon and changeux , 1977 ) . beta - bungarotoxin of bungarus multicinctus causes rapid release of acetyl choline ( ach ) from the pre - synaptic membrane , but rapidly causes inhibition of choline re - uptake into the pre - synaptic membrane thus depleting choline available for recycling of ach . therefore , ach levels are decreased leading to an inhibition of neurotransmission ( sen et al , 1976 ) , which causes peripheral neuromuscular paralysis . in addition to its effects on the peripheral nervous system , beta bungarotoxin has been shown to possess the ability to act on the central cholinergic systems of the cortex , cerebellum and hippocampus in rats ( gulya et al , 1984 ) . inhibition of central cholinergic neurotransmission may theoretically cause deep coma with representative eeg abnormalities . in the rat , the alpha waves are generated from the thalamocortical pathways , predominantly in the sensory motor cortex ( semba and komisaruk , 1984 ) . in the rhesus , monkey , both patients presented in this report had absent alpha activity , which gives indirect evidence of inhibition of cortical neurotransmission . alpha - bungarotoxin binds extensively throughout the hippocampi of both the rat and the rhesus monkey ( freedman et al , 1993 ; han et al , 2003 ) . in the rat , binding is particularly heavy with gabaergic interneurones in the dentate gyrus and the ammon of the hippocampus ( freedman et al , 1993 ) . theta activity is believed to be generated in the hippocampus in both animals and man ( miura et al , 1985 ) . this is further strengthened by the fact that addition of scopolamine , a acetylcholine inhibitor , inhibits the generation of theta activity in the rat hippocampus ( brazhnik et al , 1993 ) . excess theta activity observed in both patients perhaps indicates that bungarotoxin does not bind , or does so less avidly , in the humans . in patients with other forms of coma , such as cerebral malaria , delta activity , a waveform believed to be generated from the thalamus in association of the reticular activating system ( ras ) , is the predominant wave form observed in the eeg ( thumasupapong et al , 1995 ) . neither of the patients showed delta activity indicating that a mechanism different to that observed in metabolic coma is in operation in patients with bungarus caeruleus bite - induced coma . further , beta - bungarotoxin from bungarus multicinctus has been shown to cause release of the inhibitory neurotransmitter , gaba , in experimental models ( wernicke et al , 1975 ) , which may also contribute to deep coma . patient 2 and all the severely envenomed patients reported by kularatne ( kularatne , 2002 ) had anterograde memory loss , a phenomenon that further supports reversible inhibition of these structures . there may be dose - dependent structural damage to the synapse membranes , which may explain the lack of recovery in one of the patients presented ( ueno and rosenberg , 1996 ; herkert et al , 2001 ) . preferential binding of bungarotoxin to the brain stem structures is the most likely explanation of absent brain stem reflexes and vep and grossly delayed baep . involvement of brain stem should be a key contributory factor in the rapid the development of respiratory failure . ramachandran reported eeg abnormalities of a heterogeneous group of patients with snake bites in sri lanka ( ramachandran et al , 1995 ) . none of the 26 cases in this report included a bungarus caeruleus bite and therefore a comparison can not be made . daily renal potassium excretion is proportional to the dietary intake and an average adult looses about 80 - 120mmol of potassium each day ( 1 - 1.5mmol / kg / day ) ( giebisch and wang , 1996 ; rabinowitz , 1996 ) . urinary potassium excretion was extremely low in both patients , and neither patient excreted the 1 - 1.5mmol / kg / day ( 70 to 90mmol ) of potassium given to them each day . further , daily replacement of 1 - 1.5mmol / kg of potassium did not normalize serum potassium in the deceased patient while it took three days in the survivor . this suggests that , extracellular potassium was either being lost to the gastrointestinal tract or being shifted intracellularly . furthermore , the contribution of gastrointestinal loss in normal potassium homeostasis is minimal ( giebisch and wang , 1996 ) . it could be argued that there was a significant intracellular shift of potassium in both patients similar to that seen in patients with barium poisoning ( bradberry and vale , 1995 ) . as only 2% of total body potassium is extracellular and contributes to maintenance of resting membrane potential , shifting of potassium into the intracellular compartment should contribute significantly to neuromuscular weakness of these patients . the clinical features , eeg , vep and baep , suggest that bungarotoxin induced deep and reversible coma is due to its effects on the cortical and brain stem structures . knowledge of the potential underlying mechanisms of these phenomena could be used in the clinical management and would stimulate further research .
bungarotoxin present in bungarus caeruleus ( bc ) causes life threatening respiratory muscle paralysis . 
 deep coma and hypokalaemia have been observed in a significant proportion of patients , but the cause is unknown . 
 we postulate the likely mechanism behind these two phenomena . 
 we studied clinical details of two patients admitted with deep coma and performed electroencephalograms ( eeg ) and brain stem auditory and visual evoked potentials ( baep and vep ) . 
 daily serum potassium was measured along with urinary potassium excretion as a marker of total extracellular body potassium . 
 both patients had no brain stem reflexes on admission and the eeg revealed absent alpha and delta activity and presence of dominant theta activity . 
 alpha rhythm returned on the 3rd day in one patient , while in the other it did not , and the latter patient died on the 13th day due to disseminated intravascular coagulation . 
 baep were delayed and vep were absent in the deceased patient . both had low serum potassium and low urinary potassium excretion . 
 replacement of potassium ( up to 1.5mmol / kg / day ) did not improve serum potassium and urinary potassium excretion . 
 absent alpha and delta activity in eeg and delayed baep and absent vep are suggestive of a central action of the venom on both the cortical and brain stem neurones . 
 persistently low serum potassium and reduced urinary potassium excretion are suggestive of intracellular shift as the causative mechanism of hypokalaemia .