There are wide range of causes for junctional rhythm. Toxicological causes like Cardiac glycosides are one among them, because of their widespread use and their presence in natural sources. Poisoning can manifest as varying degrees of toxicity. Most common clinical features include gastrointestinal signs, bradycardia and heart block. Digoxin has certain peripheral effects apart from cardiac manifestations like peripheral vasoconstriction and mesenteric ischemia. Death occurs from ventricular fibrillation or tachycardia. Its presentation and severity also depend on comorbidities and their interaction with other medications. A wide range of treatments have been used, like activated charcoal, atropine, β-adrenoceptor agonists, temporary pacing, anti-digoxin Fab and magnesium, and more novel agents include fructose-1,6-diphosphate (clinical trial in progress) and anticalin.

CASE REPORT

A 30 years old female patient with no comorbidities presented to our ER with consumption of crushed bark mixed with water as a treatment for some allergy. She was presented with 3-4 episodes of vomiting and 4 episodes of loose stools. On arrival to our ER, Her HR is around 55/min with mild fluctuations. Her Blood pressure was 80/50 mmhg. Her ECG showed JUNCTIONAL RHYTHM with some ST changes. Resuscitation has been started with crystalloids. Even after adequate fluid resuscitation, her BP was not improved, so we have started on injection dopamine. In view of presentation and ECG changes, we have suspected it could be cardiac glycoside poisoning as it is most common cause of poisoning. Emergency cardiology opinion was sought, for ECG changes and probable need of TPI if her HR drops. She was started on supportive management and shifted to ICU.There it was switched over to noradrenaline for hypotension, later her BP improved and HR is maintained.

On day 2 of admission, she complained of left lower limb pain. She was evaluated clinically and found to have non palpable pulses in left lower limb. Her extremities are cold and cyanosis present, no motor deficit. Emergency vascular surgeon opinion was taken, they evaluated clinically and she was found to have bilateral critical limb ischemia with acute changes in left lower limb. CT peripheral angiogram has been done which showed chronic thrombosis in common femoral artery, narrowing of distal vessels with atherosclerotic changes and severe edema suggesting rhabdomyolysis. Her digoxin levels are 0.95ng/ml and CPK levels are 22353U/L and other parameters are within normal limits (Table 1). But in view of delayed decision, it went into acute limb ischemia and compartment syndrome with rhabdomyolysis. Retrospectively we have enquired the patient, she had a history of claudication type of pain for which she was not evaluated previously.

On day 5, she underwent embolectomy and multiple debriments of left lower limb. In due course in hospital i.e. from day 8 to day 10 she developed anemia with reactive thrombocytosis. She was under observation and progressively has ECG changes has been resolved, her blood parameters improved and her limb showed improvement and she got discharged in stable condition on day 15.

TABLE 1 Showing blood parameters with normal range

Junctional rhythm is caused by sick sinus syndrome, Sinus arrest, AV blocks, hyperkalemia, drug induced like beta blockers, calcium channel blocker and digoxin poisoning. Our patient is young female without any previous comorbidities typically presented with GI symptoms and specific ECG changes which is giving you a clue that it is digoxin poisoning and she took a tree bark above as Ayurvedic treatment for some allergy. We have treated this case as glycoside consumption as there is no other cause in this patient.

Plant poisoning is common and among this cardiac glycoside consumption is common because of easy availability and long-standing therapeutic use in tropics. Here we will be discussing about its manifestations and management. They are found in a diverse group of plants as in fig:

Yellow oleander and common oleander toxicity is major public health problem in Sri Lanka and India and it causes even death. Treatment is complicated due to variability in toxic threshold, diagnostic tests, delayed onset of toxicity [1]. The pharmacokinetics of digoxin is important as it may give clue to onset and peak levels and manifestation and duration of symptoms. Its duration of distribution (2–6h) and t1/2 is 40 h, range 20–50 h, and elimination is mostly by renal.  In acute poisoning, the initial serum digoxin levels may not reflect the total body burden because full distribution has not occurred. Our patient levels were in therapeutic range may be due to delayed presentation. Its mechanism of action is to inhibit the Na+ -K+ -ATPase on cardiac tissue causing increase in intracellular Ca2+ levels and promotes inotropy and bradycardia, which in turn increases automaticity and ventricular ectopy. It also increases vagal tone, which causes bradycardia and impaired conduction through the AV node. 

They may have extra cardiac effects. In both normal human subjects and in other species, digitalis increases smooth muscle tone of resistance and capacitance vessels. The vasoconstriction is mediated by a direct action of on smooth muscle and by an increase in alpha-adrenergic tone. The probable cause of gangrene in our patient may be due to extracardiac effects of digoxin i.e. vasoconstriction of peripheral vasculature and underlying atherosclerotic changes with chronic thrombosis. Constriction of coronary and splanchnic vessels may lead to myocardial or mesenteric ischemia. In contrast to normal subjects, patients with congestive heart failure demonstrate arteriolar and venodilation in response to these glycosides, possibly because the myocardial effect, to increase cardiac output and peripheral blood flow, overcomes the vasoconstrictor properties of these drugs [2]. There is a case report in which cardiac glycosides caused the rhabdomyolysis [3]. Regarding extra cardiac effects it may require further studies.

CLINICAL PRESENTATION:

Acute poisoning manifests as nausea, vomiting, abdominal pain, diarrhea, hyperkalemia, generalized weakness, drowsiness and, cardio toxicity. The therapeutic range of digoxin is 0.5–2.0ng/mL) and this patient levels are 0.95ng/ml which is in therapeutic range.

Increased automaticity and conduction blockade causes tachydysrhythmia, like atrial tachycardia with block, Junctional tachycardia, VT, VF, PAT with block, Bidirectional ventricular tachycardia. Death occurs due to refractory VF or asystolic arrest Nonspecific ST segment and T wave abnormalities, consistent with "dig effect," (e.g., ST "scooping" or "strain"-like pattern) may be noted. It indicates the presence of cardiac glycosides.

Vision changes, include photophobia, scotomas, blurring vision, green/yellow discoloration, have been reported but these manifestations are very rare, may be seen in chronic digoxin poisoning. There was a case report showing certain types of glycosides may manifest with vision abnormalities [4] Neurological manifestations include Confusion, Drowsiness, Disorientation, delirium, Headache, Hallucinations, Seizures. However, other electrolyte abnormalities may be noted in patients with chronic poisoning due to concomitant conditions and medications [1]. In the above-mentioned patient, we have seen all the mentioned symptoms which is significant indicating important extra cardiac effects of glycosides and it was understudied.

MANAGEMENT:

Management of glycoside poisoning is mainly symptomatic and supportive i.e. treating abnormal heart rhythm and enhancing elimination. Up to 40% of patients with severe cardio toxicity may revert to sinus rhythm after a number of hours without specific treatment, but it is not possible to determine and it is a common practice to wait and watch until it gets eliminated. The use of antidotes in chronic poisoning is less clear. Continuous monitoring of ECG changes and electrolytes especially potassium is important. This patient is also managed symptomatically and supportive care is provided but unfortunately because of underlying chronic thrombosis and atherosclerotic changes, she developed acute limb ischemia which is in supportive of peripheral effects of cardiac glycosides. Initial management is decontamination. MDAC are recommended for toxic exposures to digoxin because of pharmacokinetic data. MDAC regimen is 50-100g stat, followed by 25 gm 2-4 hourly for 24hrs.It increases the clearance and decreases the elimination half-life. [5,6] A RCT (n = 401) noted that MDAC reduced mortality compared with SDAC (yellow oleander) [7] and while some advocate the use of gastric lavage but no significant role [8,9]

Electrolyte disturbances are seen in glycoside poisoning. This patient never had any electrolyte disturbances but may be patients may manifest them and it is more common with renal abnormalities. Treatment of hyperkalemia is controversial. Insulin may interact directly with receptor, altering its effect as well as correcting hyperkalemia by pushing potassium into cells and the effect of insulin on receptor may depend on the type of cardiac glycoside due to differences in the sub units. Hypokalemia could be due to GI symptoms or medications such as diuretics. Hypokalemia should be corrected as it increases cardio toxicity with therapeutic dose and even death.

Calcium for hyperkalemia may increase toxicity and animal data have reported increased toxicity including death, which may relate to sustained cardiac contraction (stone heart). However, case reports and resources show controversial data regarding calcium use [9,10,11,12]. Therefore, according to theory, calcium can be used after administration of Fab fragments and reversal of cardiac glycoside toxicity. Forced diuresis, hemoperfusion, and hemodialysis is ineffective because of its large volume of distribution. Hemodialysis will efficiently remove potassium from ECF.

In bradycardia, atropine antagonizes vagal activation. Initial dose is 0.6–1 mg, but up to 2–3 mg can be used for persistent bradycardia. Atropine acts as a bridging therapy until TPI is inserted. TPI is associated with more complications and deaths than anti-digoxin Fab, and it will not reverse hyperkalemia. Insertion of the pacing wire may also trigger VF. Other limitations are non-availability, interhospital transfer leads to death [7,13,14]

In tachyarrhythmias, phenytoin and lidocaine reduce automaticity. Magnesium has been reported to reverse digoxin-induced dysrhythmias [13] Cardioversion is last resort, as it causes VF and increases the mortality. If we want to cardiovert, 1st we have to administer Fab fragments. If time permits, cardioversion should be attempted after a loading dose of phenytoin and at a significantly reduced initial power setting of 5-10 J.

Anti-digoxin Fab binds to digoxin and remove it from receptor, thereby reducing toxicity. Case series have reported benefits from anti-digoxin Fab, but data regarding the response in acute or chronic poisoning are conflicting.[15]. The dose of anti-digoxin Fab is not established. There was a case report where 2 patients presented with acute glycoside poisoning are treated with anti-digoxin antibody and showed improvement within 1-2 h [16] Dose proposed are 40 mg (1 vial) for chronic poisoning and 80 mg (2 vials) for acute poisoning. It can be repeated after 60 mins if inadequate response or recurrence or clinical deterioration [6]. Larger doses can be used if the patient had cardiac arrest. Give 10-20 vials of Fab and continue to treat with standard ACLS protocols. Prolonged efforts at resuscitation may be warranted until Fab fragments begin to work [17]. A dose–response study associated with the above-mentioned RCT recommended dosage of yellow oleander poisoning is 1200 mg, but subsequent data suggest that 800 mg iv may also be effective [15,14,18,19].

Primary treatment of glycoside poisoning is to know the compound consumed and emergency treatment is maintaining ABCD. Activated charcoal is recommended. MDAC is more useful than SDAC because of delayed distribution. Gastric lavage can be given but there is no proven benefit. Symptomatic treatment with atropine or antiarrhythmics. Supportive management with inotropic support for shock. Avoiding drugs that cause electrolyte abnormalities and careful monitoring of electrolyte disturbances will the risk of toxicity. Anti Digoxin Fab are not in practice as of now. Still further studies are needed for its efficacy in digoxin poisoning. Patients with potential risk factors may have complication like acute limb ischemia due to vasoconstriction effects. Although there are a range of options available for the treatment of cardiac glycoside poisoning, their efficacy is poorly defined and this appears to influence their use in practice. More data are required to clarify the optimal treatment of cardiac glycoside poisoning.

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2. LONGHURST ANDROSS EXTRACARDIAC EFFECTS OF DIGITALIS. ] lACC Vol. 5, No.5 May 1985:99A-105A
3. An unusual case of "catecholamine necrosis" caused by accidental digitalis poisoning Piccone U1, Saviotti M, Pala M, Caprari M 1995 Sep;43(9):383-8.
4. An unusual case of oleandrin poisoning suggesting its possible antiarrhythmic activity Pietro Palmisano 1*, Yusef Hadad 2,and Fernando Antonio DeNuccio 1
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7. de Silva HA, Fonseka MMD, Pathmeswaran A, Alahakone DGS, Ratnatilake GA, Gunatilake SB, Ranasinha CD, Lalloo DG, Aronson JK, De Silva HJ. Multiple-dose activated charcoal for treatment of yellow oleander poisoning: a single-blind, randomised, placebo-controlled trial. Lancet 2003; 361: 1935–8.
8. Fonseka MMD, Seneviratne SL, de Silva CE, Gunatilake SB, De Silva HJ. Yellow oleander poisoning in Sri Lanka: outcome in a secondary care hospital. Hum Exp Toxicol 2002; 21: 293–5.
9. Hoffman RS, Howland M, A LN, Nelson LS, Goldfrank LR. Goldfrank’s Toxicologic Emergencies, 10th edn. New York: McGraw-Hill Education, 2015

• Levine M, Nikkanen H, Pallin DJ. The effects of intravenous calcium in patients with digoxin toxicity. J Emerg Med 2011; 40: 41–6.