Patient is a 65 year old previously healthy Caucasianmale, who came to the ED today because he feels“weak all over”.Symptoms began 2 days ago. Vital Signs: Heart rate 49, Blood Pressure 90/60, Respiratory Rate 12, Pulse Oximetry 95% on room air, Temperature 96.9 degrees FahrenheitPast Medical History: Provided only if requested. He hashad two previous myocardial infarctions (with a stentplaced in his right coronary artery 2 yearsago), congestive heart failure with an ejection fractionof 40%, hypertension, hyperlipidemia, diabetes mellitustype II, osteoarthritis, depression.
Medications include aspirin, glipizide, furosemide, metoprolol, clopid ogrel, simvastatin, sertraline. Allergy to penicillin (rash.) Familyand Social History: 40 pack-year history of smoking, occasional alcohol use, denies illicit drug use. His mother died of a stroke at 82; his father died in a motor vehicle accident at age 40.
During assessment the patient’s condition deteriorated. His blood pressure got lower, as well as his heart rate. Initially: IV fluids was administered in response to his worsening hypotension, but IV fluid alone didn’t correct his low blood pressure. Atropine: was given according to ACLS protocol, atropine didn’t improve the patient’s bradycardia Laboratory results came normal. Delayed interventions he had PEA arrest and appropriate ACLS protocols was followed. the patient did not respond to external cardiac pacing despite maximal efforts
The cardiovascular system. The central nervous system. Bronchospasm may be seen usually in patients with pre-existing bronchospastic diseases such as asthma.There are no clear guidelines for estimatingtoxicity but beta-blocker doses in excess of2-3 times the therapeutic dose should beconsidered potentially life-threatening.
The most common manifestations of ß-blocker toxicity are bradycardia and hypotension. hypotension :1. peripheral vasodilatation (renin blockade),2. decrease in cardiac output (b1 receptor blockade). the ß-blockers overdose can exert a membrane- stabilizing (quinidine-like) effect that inhibits fast sodium channels, prolongs atrioventricular (AV) conduction (causing heart block), and can impair myocardial contractility (causing refractory hypotension) Membrane-stabilizing activity is greatest for propranolol, less for metoprolol and labetalol
Agents with high lipid solubility, such as propranolol, may display greater CNS toxicity due to better penetration of the blood-brain-barrier. Those beta-blockers which have a Vd greater than 1.0 L/kg, are highly protein bound, and have high lipid solubility are not ideal agents for removal by hemodialysis. As a result, ß-blocker overdose is often accompanied by lethargy, depressed consciousness, and generalized seizures. The latter manifestation is more prevalent than suspected, and has been reported in 60% of overdoses with propranolol. the neurological manifestations are not the result of ß-receptor blockade and are likely related to membrane stabilizing activity.
A. Airway support, adequate ventilation and oxygenation, IV access, foley catheter. B. Hypotension 1. Intravenous Fluid Boluses (10 ml/kg) 2. Glucagon. 3. Catecholamines: a. Isoproterenol (direct Beta-1 and Beta-2 agonist) O.1 mcg/kg/min and titrate rapidly to effect800 mcg/min. Beta- 2 peripheral vasodilation may potentially exacerbate hypotension. b. Dobutamine (direct Beta-1 agonist; theoretically useful but clinical experience is limited) 2.5 mcg/kg/min and titrate rapidly to effect c. Epinephrine (direct Beta-1 Agonist, Beta-2 Agonist, Alpha-1 agonist) 1 mcg/kg/min and titrate rapidly to effect. 6 mg has been administered over one hour Amrinone or Milrinone Inotropes which increases intracellular cAMP activity by inhibiting the enzyme phosphodiesterase III Amrinone: 1 mg/kg IV bolus over 2 minutes followed by 5 to 20 mcg/kg per minute. Milrinone: 50 mcg/kg IV bolus over 2 minutes, then 0.25-1.0 mcg/kg/min.
Other Treatment Modalities to Consider for Refractory Hypotension1. Calcium: case reports have demonstrated that calcium chloride may be effective in treating hypotension from isolated beta-blocker poisoning as well as combined calcium channel blocker and beta- blocker poisoning. DOSE: Calcium Chloride 1-2 grams (10-20 ml 10% CaCl2) IV bolus over 5 minutes, repeat every 10-20 minutes.2. Hyperinsulinemic Euglycemia (Experimental but promising) Insulin has demonstrated positive inotropic effects when administered in conjunction with dextrose in This inotropic effect is believed to be due to better carbohydrate delivery and utilization by cardiac cells, as well as increases in intracellular calcium.3. Non-pharmacologic Interventions • Intra-aortic balloon counterpulsation • Cardiopulmonary bypass
C. Arrhythmias. atropine therapy: beta-blocker induced bradyarrhythmias to be refractory to atropine therapy. cardiac pacing will generally follow atropine for the treatment of refractory bradyarrhythmia. hypertonic sodium bicarbonate 1-2 meq/kg IV bolus. sodium bicarbonate in membrane stabilizing drug intoxications (propanolol, metoprolol, acebutolol and labetalol) may be helpful in increasing intracellular sodium content, antagonizing thereby cardiac toxicityD. Bronchospasms• Aerosolized or nebulized Beta-2 agonist such asalbuterolE. Seizures• Diazepam and, if necessary, phenobarbital.
The regulatory hormone glucagon is the agent of choice for reversing the cardiovascular depression in ß-receptor blockade. Glucagon is indicated for the treatment of hypotension and symptomatic bradycardia. Glucagon is not indicated for reversing the prolonged AV conduction or neurological abnormalities in ß-blocker overdose because these effects are not mediated by ß-receptor blockade.
The initial dose is 3 mg (or 0.05 mg/kg), and this can be followed by a second dose of 5 mg (or 0.07 mg/kg) if necessary. The response to glucagon is most pronounced when the plasma ionized calcium is normal. The effects of glucagon can be short-lived (5 minutes), and so a favorable response should be followed by a continuous infusion (5 mg/hr).
Adverse Effects Nausea and vomiting are common at glucagon doses above 5 mg/hr. Mild hyperglycemia is common, and is due to glucagon-induced glycogenolysis and gluconeogenesis. hypokalemia : The insulin response to the hyperglycemia can drive potassium into cells hypertensive response : glucagon stimulates catecholamine release from the adrenal medulla, and this can raise the blood pressure in hypertensive patients. This hypertensive response is exaggerated in pheochromocytoma, so glucagon is contraindicated in patients with pheochromocytoma.
A 65-year-old male was admitted to our ICU. He was a known case ofhypertension for 15 years, on regular medications. He was diagnosed tohave mild renal insufficiency 6 years prior to present admission, with astable serum creatinine level .. On examination he was conscious, orientedwith normal sinus rate of 62/ min, blood pressure of 112/76 mmHg andbilateral pedal edema. Respiratory, cardiovascular and neurologicalexaminations were normal. Electrocardiograph showed normal sinusrhythm. Initial hemogram, random blood sugar, serum electrolytes, arterialblood gas and electrocardiogram were unremarkable. Blood urea and serumcreatinine values were 79 mg/dl and 4.3 mg/dl respectively.Echocardiography revealed left ventricular hypertrophy with normal LVsystolic and diastolic function he presented with a history of restlessness following accidental ingestionof 50 mg of Amlodipine along with his usual dose of 50 mg Atenolol, sixhours earlier.The patient was given 30 ml of 10 % calcium gluconate - over 5mins, followed by an infusion of calcium gluconate at a rate of 10 ml/hrand after a bolus dose of Glucagon of 10 mgm, an infusion of Glucagon at arate of 3 mg/hr was commenced.
Over the next six hours the patient became hypotensive not responding tovolume resuscitation and requiring inotropic support with adrenaline anddopamine infusion. His sensorium gradually deteriorated. Twelve hours following the overdosehe was unresponsive to painful stimuli. Arterial blood gas analysis revealedmixed respiratory and metabolic acidosis with a pH of 6.8, pCO 2 of 115mmHg, pO 2 of 76 mmHg and a HCO3 of 16 mmol/L. He was on high dose inotropic support with normal central venous pressureand there was a drop in the hourly urine output. Gastric aspirate was coffeeground. He was electively intubated and ventilated.Ultrasonography of the abdomen showed normal kidney size with increasedechogenicity. UGI endoscopy revealed erythematous gastric mucosa withoutany ulcer crater.The next day the patient started showing signs of improvement. Hissensorium improved but he remained oliguric. Arterial blood gas analysisshowed pH of 7.2 pCO 2 of 34. mm Hg, pO 2 of 115 mmHg and a bicarbonateof 13.7 mmol/L. Repeat potassium was 7.8 mEq/L. In view ofoliguria, persistent acidosis and hyperkalemia hemodialysis was started. Over the next 24h, his condition stabilised and inotropicsupport, glucagon, calcium infusions were tapered off. He was successfullyweaned off from the ventilator on the following day. On day 10 of admissionhe was discharged from the hospital.
Noncardiovascular manifestations of calcium blocker toxicity include lethargy and depressed consciousness (most common), generalized seizures, and hyperglycemia (caused by inhibition of insulin release, which is calcium-dependent)
There are two approaches to calcium channel blockade. The first involves the administration of calcium to antagonize the blockade on the outer surface of the cell membrane. The second involves the use of drugs that activate the cyclic AMP pathway, which antagonizes the blockade from the inner surface of the cell membrane.
includes vital parameters monitoring, airways management, ventilatory and circulatory support, if needed . Even apparently stable 14 patients can rapidly develop fatal arrhythmias and cardiac arrest during treatment. A 12 leads ECG, blood drawings for renal and liver function, determination of glycaemia, electrolytes and blood gases shouldbe performed. An intravenous access for fluid resuscitation and drug administration should be immediately placed
Sinus bradycardia, AV block and cardiac arrest should be treated according to the advanced life support algorithms . In l4 particular boluses of atropine 0.5 mg, repeated if needed up to 3 mg, associated with adrenalin ev 2- 10 microg/min are commonly used for bradyarrhythmias. in most serious cases transthoracic or transvenous temporary cardiac pacing is necessary. Cristalloids and vasopressors (isoproterenol,dopamine, dobutamine, epine phrine and norepinephrine) are first line treatment for hypotension and shock
Gut decontamination procedures with gastric lavage should be performed within 1-2 hours after drug ingestion. Repeated activated charcoal administrations (0.5-1 g/kg every 2-4 h for 48-72 h) are useful because CCB and BB have a prevalent liver metabolism with recycling in the bowel. Hemodialysis and hemoperfusion techniques cannot be used for CCB because of their high volume distribution and their lipophilic properties. These techniques are beneficial for some BB (atenolol, sotalol, nadolol, acebutolol)
Treatment of choice in CCB poisoning is calcium administration1. Repeated boluses of 10 mEq every 10-15 minutes may be given, but total acute calcium administration should not exceed 45 mEq to avoid superimposed hypercalcemia induced arrhythmias. The response to calcium may last only 10 to 15 minutes, so the initial response to calcium should be followed by a continuous infusion at 0.3 to 0.7 mEq/ kg/hr.
resulting in improved inotropy, conduction disorders, and hypotension.
In the CCB and BB intoxication insulin has been proposed at high dosages (0.5-1 IU/kg/h) with a continuous glucose infusion to maintain euglycaemia. Insulin administration in fact switches cell metabolism from fatty acid to carbohydrates and restores calcium fluxes, improving thereby cardiac contractility.
Glucagonis usually accepted as first line treatment in the management of BB and verapamil overdose
Phosphodiesterase III inhibitors represent possible alternatives to glucagon in CCB and BB poisoning, as their inotropic effect is not mediated by beta adrenoceptors
1. 4 aminopyridine, a potassium channel inhibitor,2. Bay K 8644, a calcium channel activator studied in animal models.
A 56 year-old woman with history of severe rheumatic mitral stenosis and atrial fibrillation, was being treated with digoxin 0.25mg and warfarin 3mg daily for the past five years. Patients target international normalized ratio (INR) was being maintained between 2.0 and 3.0. She presented to our institution with fever and cough for 5 days. Two days prior to presentation, she was started empirically on clarithromycin 500 mg twice daily by her primary care physician for presumed community acquired pneumonia. Her chest X-ray on admission was abnormal for left lower lobe pneumonia. Patient was started on intravenous ampicillin/clavulanic acid 1.2 gm every eight hours and clarithromycin was also continued
Initial electrocardiogram (EKG) showed atrial fibrillation with ventricular rate of 70/minute with minor lateral T wave abnormalities . Two days later patient developed profound weakness associated with nausea, vomiting, dizziness and dyspnea. On examination pulse rate was 40/minute. Another 12 lead EKG done showed underlying atrial fibrillation with complete heart block, junctional escape rhythm and multifocal PVCs with fixed coupling interval ). Laboratory results revealed digoxin level of 8.7 ng/ml (therapeautic range=1.0-2.6) and an international normalized ratio (INR) of 3.97 (2.0-3.0). Patient was shifted to coronary care unit and all medications were discontinued except ampicillin/clavulanic acid. Due to nonavailability of digoxin binding fragments only a temporary pacemaker was inserted to increase the heart rate. Her heart rhythm returned to baseline (atrial fibrillation) after 48 hours with decrease in digoxin level to 3.0 ng/ml. The patient was finally discharged on day 7 with a digoxin level 1.6 ng/ml
ECG signs of glycoside intoxication are extrasystole, junctional arrhythmias,bradycardia, various degrees of AV block, ventricular tachycardia (VT) and ventricular fibrillation (VF). Hypokalemia increases the cardiac tissue automaticity during digoxin poisoning while hyperkalemia seems to interfere particularly with the cardiac conductivity abnormalities. Hypercalcemia may worsen the risk of fatal arrhythmias. Systemic glycoside poisoning symptoms and signs include nausea, vomiting, diarrhoea,visual disturbances, disorientation, mental confusion and hallucinations.
Elderly Heart failure Dehydration Hypokalemia Hypomagnesemia Kidney disease Medications that interact with digoxin, such as:
Liver and renal function test, determination of electrolytes, blood gases and plasma level of glycosides and a 12 leads ECG must be performed at the arrival in the Emergency Department. Monitoring of vital parameters, ventilatory and hemodynamic support and fluid resuscitation should immediately be undertaken, if necessary.
bradycardia and AV block (atropine and transthoracic Pacing) Ventricular arrhythmias with signs of cardiac failure should be treated with DC shock. First line pharmacological approach in these cases is lidocaine (50 mg iv in 2 min, every 5 min for VT, 100 mg or 1-1.5 mg/kg in VF or pulselessness VT). Alternative to lidocaine is phenytoin 100 mg by slow intravenous infusion every 5 min 37. Electrolyte disturbances should be promptly treated as necessary
gastric lavage should be performed within 1 hour after drug ingestion; these procedures may worsen the bradycardia because of additional vagal stimulation. Activated charcoal (0.5-1 g/kg every 2-4 h for 48-72h. Hemodialysis and hemofiltration are not useful because of the high plasma protein link of the glycosides.
Digoxin specific antibodies fragments (Fab): Equimolar doses of anti digoxin Fab fragments completely bind digoxin in vivo. Fab administration is associated with rapid improvement of cardiac symptoms, in particular of AV block, symptomatic bradycardia, and digoxin levels over 10 ng/ml or digitoxin levels over 25 ng/ml Dose: plasmatic concentration (ng/ml) × 0.0056 for digoxin, 0.00056 for digitoxin (conversion factor for distribution volume in mg) × weight in kg = total digoxin or digitoxin amount in the body × 60 plasmatic levels of 20, in a patient weighting 70 kg: 20 × 0.0056 × 70 = 7.84 mg × 60 = 480 mg).
Fab are given intravenously over 15-30 min after dilution to at least 250 ml with plasma protein solution or 0.9 sodium chloride solution. Effects of Fab administration are observed 30-60 minutes after drug administration, with a peak effect reached in 4 hours. Side effects include hypokalemia and skin rash.
An 81-year-old man demented presented to hospital with increasing auditory hallucinations, persecutory delusions and depressive symptoms, Pt is prescribed Haloperidol, prozac Twelve hours later the patient had diaphoresis, tremulousness, urinary incontinence and some cognitive impairment. His temperature was elevated (38.3°C), and although normotensive (blood pressure 124/84 mm Hg) he had tachycardia (heart rate 128 beats/min) exhibited Parkinsonian features, including tremor, rigidity and unsteady gait. An electrocardiogram revealed no acute
Laboratory investigation revealed mild leukocytosis (leukocyte count 11.7 × 109/L), with a shift to the left (neutrophil count 9.9 × 109/L). His aspartate aminotransferase level was elevated (82 U/L), and his creatine kinase (CK) level was markedly elevated (1145 U/L), with normal CK MB fraction and cardiac troponin levels. Other laboratory results, including electrolyte levels, were normal. The next morning his Parkinsonian features and elevated temperature persisted, and he was found to have bilateral hyporeflexia. That afternoon the CK level climbed to 2574 U/L. The next day, the patient had increased rigidity and his temperature rose to 39.3°C. A septic workup yielded normal results, but the urine myoglobin test result was positive.
A firm diagnosis of NMS was made, and therapy with dantrolene (70 mg intravenously) was started and about 24 hours later was changed to bromocriptine (2.5 mg 3 times daily). Within a few days, the patient’s NMS symptoms improved and his CK level returned to normal. As his symptoms resolved, the bromocriptine dose was tapered off. In order to control his ongoing psychotic symptoms, the patient was prescribed olanzapine (2.5 mg once daily) because of its lower reported rate of NMS. He was also given sertraline (25 mg once daily) to control his depressive symptoms. After 5 weeks, his depressive and psychotic symptoms improved considerably, and he was discharged from hospital without further complications.
The frequency of the syndrome ranges from 0.07% to 2.2% among patients receiving neuroleptic medications. The mortality is 10%–30% NMS most often occurs after the initiation or increase in dose of neuroleptics, but rarely it can occur after the sudden discontinuation of the drug therapy. Dehydration with the concomitant use of neuroleptics is a risk factor for the syndrome, because the decreased blood volume induces peripheral vasoconstriction and impairs heat dissipation. Other risk factors for NMS include stress, humidity and concomitant use of lithium, anticholinergic agents or some antidepressants
The symptoms usually develop over 24 to 72 hours and can last from 1 to 44 days (about 10 days on average). extrapyramidal symptoms usually occur before autonomic ones. Hyperthermia, rigidity and recent initiationof drug therapy with one or more neuroleptics arecommon features of NMS
stop the neuroleptic therapy immediately. Supportive therapy, such as fever reduction, hydration and nutrition. intravenous dantrolene sodium therapy, to reduce body temperature and to relax peripheral muscles by inhibiting the release of calcium from the sarcoplasmic reticulum of muscle. The recommended dose is 2 mg/kg intravenously, repeated every 10 minutes if necessary, to a maximum of 10 mg/kg daily. Hepatotoxic
Bromocriptine, a dopamine agonist improves muscle rigidity within a few hours, followed by a reduction in temperature and an improvement in blood pressure. Doses of 2.5–10 mg up to 4 times daily. Hypotension Starting with an atypical neuroleptic such as olanzapine at a low dose and slowly increasing the dose while monitoring for signs of NMS and for control of psychotic symptoms is the safest option
an 80-year-old man with a history of depression, was admitted to hospital with pneumonia. His condition deteriorated and he was sent to the intensive care unit (ICU) and placed on mechanical ventilation for several days. He used of fluoxetine almost 10 years, was discontinued Approximately 1 week after discontinuation of the fluoxetine, he started using 20 mg of paroxetine daily. Within 24 hours of starting paroxetine, Mr J.W. was found to be confused and agitated with periods of unresponsiveness. Vital signs revealed a temperature of 38.5°C and a pulse of 115 beats per minute. A neurological examination revealed myoclonus in all limbs with any stimulation.
The paroxetine was discontinued and the patient was given intravenous fluids to decrease the risk of renal failure. Mr J.W. initially received 2 mg of lorazepam intravenously, then received, 1-mg doses of lorazepam every 4 hours, resulting in decreased tachycardia, hypertonicity, and clonus. He was discharged from hospital without antidepressants, and he planned to follow up with his family doctor several weeks after hospitalization in order to have his mood reviewed
symptoms of serotonin syndrome usually present within 6 to 8 hours of initiating or increasing serotonergic medications.
Neuroleptic malignant syndrome (NMS):similar symptoms of fever, mental status changes, and alteredmuscle tone. However, patients with NMS are usually akinetic withrigidity, have decreased levels of consciousness, and are morelikely to have mutism rather than rambling speech, which isassociated with serotonin toxicity.More important, the onset of NMS is slow, developing over daysrather than hours Anticholinergic toxicity is differentiated by presence of skin colour changes (red as a beet), dry mouth (dry as a bone), and constipation or absence of bowel sounds
Management Prompt recognition of toxicity and discontinuation of offending medications are most important. Supportive care, including intravenous fluids, is indicated in patients with vital sign abnormalities. Neurological symptoms, including serious myoclonus and hyperreflexia, are sometimes treated with benzodiazepines. Hyperthermia should be aggressively managed with external cooling, hydration, and benzodiazepines (eg, diazepam, lorazepam). Patients with a temperature higher than 41°C should be intubated with induced neuromuscular paralysis. The antihistamine cyproheptadine, which is also a 5- HT2A inhibitor initial dose is 12 mg; the dosage is then adjusted to 2 mg every 2 hours until symptoms improve.
A 77-year-old Caucasian female was admitted to the emergency department after two weeks of increasing abdominal pain associated with vomiting. Two days before admission, she developed psychomotor agitation. She had a past medical history of type 2 diabetes, arterial hypertension and cerebrovascular disease. She had had a stroke one month before with full recovery; at that time her creatinine was normal and she had been discharged from hospital with the following medications: perindopril 8 mg daily, and simvastatin 20 mg daily, metformin 3 g daily. On admission examination revealed :a Glasgow Coma Scale score of 12/15 (E4V3M5),blood pressure 136/87 mmHg, pulse 100 beats per minute,respiratory rate 20 breaths per minute and core bodytemperature 36.6°C. eupnoeic with oxygen saturationmeasured by pulse oximetry was 97% on room air.
Initial investigations : Cr :6 mg/dL, Na 142 mEq/L K 4.7 mEq/L, ch 103 mEq/L, RBS 216 mg/dL CRP 3.14 mg/dl. CBC WBC 22.4 × 109/L , HB 13.8 g/dL, platelet 365 × 109/L. ABG (pH 6.87, PaCO2 8.2 mmHg, PaO2 146 mmHg, HCO3- 1.4 mEq/L, blood lactate 16 mmol/L). Chest X-rays and ECG were normal at the time of her admission. Serum toxicological results, namely benzodiazepines, tricyclic antidepressants, opiates and barbiturates, were negative.
The patient was admitted to (ICU) with the diagnosis of metformin related lactic acidosis. Continuous venovenous haemodialysis (CVVHD) was initiated, with 2 L/h Elective endotracheal intubation and mechanical ventilation was performed. Four hours after the initiation of CVVHD significant improvement of acid-base status was observed and blood lactate level had halved On the third day the patient was successfully weaned from the ventilator. On the 5th day a primary methicillin resistant Staphylococcus aureus bloodstream infection was diagnosed and the patient was started on vancomycin. The patient was discharged to the nephrology department ward on the seventh day. Full recovery of renal function was observed after 30 days and the patient was discharged from hospital on the 60th day medicated with insulin and glycazide.
Metformin is a small molecule. (165 kDa), 50% oral bioavailability; it does not undergo hepatic metabolism and the main route of elimination is renal tubular secretion. Metformin is not bound to proteins and its apparent volume of distribution is usually reported to be higher than 3 L/kg. the predominance of the intracellular location. metformin can theoretically be extracted from blood by haemodialysis if dialysis is conducted for long enough to mobilise the intracellular form
Metformin-associated lactic acidosis (MALA) is a rare but classic side effect of metformin. the incidence of MALA of two to nine cases per 100,000 patients treated with metformin each year. The associated mortality rate as high as 50%. Pathogenesis: unknown 1. related to the anti-hyperglycaemic effect of metformin 2. impairs lactate clearance of the liver(the inhibition of complex I of the mitochondrial respiratory chain) 3. increased lactic acid production by haemodynamic instability and/or tissue hypoxia associated with severe metformin overdose or any underlying unstable cardiovascular or respiratory condition, lactic acidosis is predominantely due to a lack of lactates clearance than to an increased production
Anyfactors that decrease metformin excretion or increase blood lactate levels are important risk factors for lactic acidosis. Renal insufficiency is a major consideration. factors that depress the ability to metabolize lactate: liver dysfunction or alcohol abuse, increase lactate production by increasing anaerobic metabolism: cardiac failure, cardiac or peripheral muscle ischemia, or severe infection) Intravascular (IV) administration of iodinated contrast media to a patient taking metformin is a potential clinical concern
Lactic acidosis is defined as a metabolic acidosis with a blood pH less than 7.35 and a serum lactate more than 2 mmol /L. It is subdivided into : type A, which is associated with tissue hypoxia, as occurs in sepsis type B, which occurs in the absence of hypoxia, and is the type associated with metformin overdose
Sodium bicarbonate alone frequently fails to correct the acidosis. Survival appears to be better in patients treated with early high volume CVVHF or haemodialysis. This treats the metabolic acidosis and removes the metformin from the circulation, preventing further acidosis. The patients may be too haemodynamically unstable to tolerate haemodialysis.9 Thus, haemofiltration seems to be the better option.
A 30-year-old lady was transferred to the emergency department (ED) by ambulance. She was found in a collapse state at home by her husband. The ambulance men reported that the patient had repeated generalized seizures. Her husband recalled he had a quarrel with the patient that night and suspected that she took a large amount of imipramine about two hours ago. This patient had a past history of depression and attended the psychiatric clinic 4 days ago. She was given 2 months supply of antidepressant. On arrival: She was comatosed and had a poor respiratory effort. Her pulse was weak and her blood pressure was not recordable. She developed grand mal seizure immediately after arrival. It lasted 30-60 seconds and stopped spontaneously.
Her proximal pulse was not palpable afterwards. Cardiac monitor revealed an irregular wide complex bradycardia (30-40 beats/ min). She was intubated and ventilated. External cardiac message was commenced. Adrenaline and 60 ml 8.4% sodium bicarbonate (NaHCO3) were given intravenously. The patient was found to extremely acidotic with a pH of 6.751. Another bolus of 60 ml 8.4% NaHCO3 was given. She regained her central pulse and the arterial pH increased to 7.028.The ECG after 120 mmols of NaHCO3 showed atrial fibrillation with slow ventricular response rate of between 30 to 40 per minute, prolonged QRS (0.20s), right axis deviation with a prominent R in lead aVR (R=5 mm, R/S ratio=2.8)
She developed repeated grand mal seizures of brief duration. That was controlled by intravenous diazepam. Episodes of pulseless ventricular tachycardia also developed which required repeated defibrillation. Another 60 ml NaHCO3 was given and raised the pH to 7.231.
A second ECG after 180 mmols of NaHCO3 : wide- complex rhythm of rate between 50 to 60 per minute, indeterminate axis and the QRS duration of 0.16s.
Bolus dose of lignocaine was administered and this was followed by infusion. That appeared to stabilise the myocardium but the patient remained in severe hypotension. She was in and out of pulseless electrical activity and required intermittent boluses of adrenaline. Her hypotension was unresponsive to fluid challenge (1 litre normal saline). She was started on dopamine infusion that produced little improvement in the haemodynamic status. Further bolus of 100 ml NaHCO3 was given which raised the pH to 7.49. Blood pressure also improved to 70- 80/40 mmHg. The third ECG after a cumulative total of 280 mmols of NaHCO3 : sinus rhythm at a rate of 94 per minute, right axis deviation, narrower QRS complex (duration of 0.12s) and a less prominent R in lead aVR (R=3.5 mm, R/S ratio=1.75).
Gastric lavage was performed and retrieved a moderate amount of medication. Fifty grams of activated charcoal was also given. The patient was resuscitated in the ED for over 2 hours and received 280 ml of 8.4% sodium bicarbonate, 15 mg diazepam, 7 ml 1:10000 adrenaline and 60 mg lignocaine. She was on lignocaine infusion at a rate of 2 mg/min and 15 mcg/kg/min of dopamine infusion on her transfer to the medical unit. Her condition remained critical after admission. She was given repeated doses of activated charcoal, lignocaine infusion was tailed off and the dopamine infusion was gradually reduced to 5 mcg/kg/min.She subsequently became more stable haemodynamically. blood pressure of 110-120/70- 80 mmHg. However, her GCS remained at 3/15 and she required mechanical ventilation. On the following day after admission, she developed a high fever and a falling blood pressure. She was started on intravenous antibiotics and dobutamine infusion. There was no response to treatment. She died 30 hours after admission
TCA exerts its therapeutic effects by inhibiting the neuronal re-uptake of noradrenaline and serotonin after the release at pre-synaptic sympathetic nerves It also has anticholinergic, anti-alpha-adrenergic and a quinidine-like (type Ia antiarrhythmic) action on the heart; i.e., blockade of fast sodium channel. Early features of toxicity are mainly anticholinergic: dry mucous membrane, dry skin, mydriasis, tachycardia, urinary retention, decreased bowel sounds, excitation and confusion Life threatening complications like hypotension, arrhythmia, seizure and coma may develop suddenly and require immediate attention.
1.Cardiac toxicity –Prolonged QRS, QT (Inhibits myocytefast Na+ channels leading to ↑repolarizationtime) –↑R-wave amplitude inaVR) –Hypotension (secondary to α-adrenergic blockade)2.CNS toxicity Initial excitation and confusion will progress to seizures, alteration in mental status and even coma in severe overdose. Seizures are typically generalised, brief and easily controlled by benzodiazepines3. Anticholinergiceffects –Early features of toxicity are mainly anticholinergic: dry mucous membrane, dry skin, mydriasis, tachycardia, urinary retention, decreased bowel sounds, excitation and confusion.
The primary value in measuring TCA level is to confirm the diagnosis rather than to predict morbidity ECG has emerged as a useful tool and the changes with prognostic significance are prolonged QRS (>0.1s), rightward shift of the ter minal 40 millisecond of the frontal QRS axis, R>3 mm and/ or a R/S ratio >0.7 in lead aVR. stable patient with a normal ECG apart from sinus tachycardia can be discharged for psychiatric evaluation after 6 hours of observation
Treatment Like all medical emergencies, initial management of TCA poisoning should focus on the support of airway, breathing and circulation Within 1 hr of ingestion -consider gastric lavage Activated charcoal ( 1gm/kg) Fluids for hypotension. Refractory hypoTtnsion give α-agonist(Norepi, Neosynephrine) Benzodiazepines for seizure NaHCO3 1-3meg/kg rapid push, then consider continuous infusion Goal serum pH 7.45-7.55. Give when QRS ≥100 msec or R-wave amplitude ≥3 mm in lead AVR, ventricular arrhythmia and hypotension unresponsive to fluid challenge (0.5-1.0 L) normal saline –Systemic alkalinisation to increase the protein binding and to decrease the availability of free drug is the mainstay of treatment sodium loading effect to overcome the competitive blockade of sodium channel by TCA. hypertonic saline to be more effective than sodium bicarbonate in TCA toxicity
TCA induced hypotension should be treated by fluid challenge and sodium bicarbonate as stated above. Those refractory to treatment need inotropic support. The drug of choice is noradrenaline because of its prominent alpha agonistic effect. Dopamine is the second choice and theoretically can be deleterious due to its vasodilatation effect at lower dose. Therefore dosage for alpha- adrenergic receptor stimulation is usually chosen. High dose 10 mg glucagon has been reported to produce a dramatic improvement in cases refractory to the above measures.
Ventricular arrhythmia due to TCA overdose needs some modification of the standard ACLS protocol. Lignocaine is second to sodium bicarbonate as the drug of choice. If chosen, lignocaine needs to be given cautiously to avoid precipitating seizures and causing further hypotension. Magnesium sulphate may be considered for the treatment of TCA-induced dysrhythmias when other treatments have been unsuccessful
Management of seizures Phenytoin should be avoided in patients with TCA overdose . Benzodiazepines should be used to control seizures following TCA overdose.
Mrs. T, a 70-year-old widowed Caucasian woman, came to the psychiatric outpatient clinic for evaluation of chronic memory problems, hearing accusatory voices, paranoia, word-finding difficulties, sedation, and poor concentration that had been present for the past year but had worsened during the last 2 months. Mrs. T was accompanied by her daughter. Mrs. T also complained of urinary retention and urgency, dry mouth, constipation, blurred vision, and unsteady gait, and reported falling three times during the past 6 months. She had a 40- year history of schizophrenia, which was being treated with trifluoperazine and benztropine. Six months before her clinic visit, Mrs. T was diagnosed with a neurogenic bladder with urine retention for which frequent catheterizations of the bladder were recommended. Because she was often non-compliant with these catheterizations, she had been placed on oxybutynin and hyoscyamine
Examination : the presence of paranoia and auditory hallucinations. a Mini-Mental State Examination (MMSE) score of 25 with impairments in short-term recall and concentration. she exhibited unsteady gait and marked dryness of the mouth. Her vital signs were: blood pressure 158/76 mm Hg, pulse rate 91 beats/min, respiratory rate 18 breaths/ min, and temperature 97.7 °FManagement: Mrs. T’s trifluoperazine was discontinued, and she was started on risperidone, 2 mg at bedtime. Mrs. T’s buspirone, hyoscyamine, desloratadine, benztropine, and meclizine were also discontinued. She tolerated the above medication changes well and did not experience side effects to risperidone. Several days later, at the time of discharge, she exhibited less dry mouth, a steadier gait, improved cognition, less paranoia, and fewer auditory hallucinations. During the succeeding 2 months, her cognitive functioning returned to normal with an MMSE score of 30. Expressing some animation
a single anticholinergic medication may not cause significant side effects, taking two or more of these medications often results in cognitive and physical impairments. Anticholinergic side effects are divided into two types: peripheral and central. Peripheral effects include blurred vision, dry mouth, decreasedGI motility, decreased secretions, tachycardia, and urinary bladder retention. Clinically, these side effects are manifested by poor vision and falls, dental and speech problems, constipation, and a lack of bladder control. Central effects include sedation, decreased concentration, forgetfulness, confusion, and psychotic symptoms. These side effects can result in inaccurate psychiatric diagnoses such as depression, dementia, mania, and schizophrenic exacerbation. Left undetected, severe anticholinergic toxicity can ultimately lead to coma, circulatory collapse, and death.
Rarely used; indicated only when life- threatening symptoms related to anticholinergic toxicity. Initial: 0.5-2 mg slow IV (not to exceed 1 mg/min); keep atropine nearby for immediate use If no response, repeat q20min If initial dose effective, may give additional 1-4 mg q30-60min
A 67-year-old Caucasian man with a long history of alcohol consumption was admitted to the hospital voluntarily for treatment of alcohol abuse. He had been drinking heavily for the past 16 months despite three previous detoxification episodes. On admission he was tremulous, but his sensorium was clear. His medical history was significant for malaria, atrial fibrillation, and lung cancer. The patients laboratory values on admission revealed elevated liver function tests: total bilirubin 1.0 mg/dl (normal range 0.2-1.3 mg/dl), aspartate aminotransferase 377 IU/L (15-46 IU/L), alanine aminotransferase 201 IU/L (21-72 IU/L), g-glutamyl transferase 1722 IU/L (13-59 IU/L), and alkaline phosphatase 215 IU/L (38-126 IU/L). The patients renal function was normal, with an accompanying serum creatinine level of 0.8 mg/dl. His serum sodium level was slightly decreased at 130 mEq/L (137-145 mEq/L). The patient was treated with folic acid 1 mg/day, thiamine 100 mg/day, chlordiazepoxide 50 mg every 2 hours as needed for alcohol withdrawal symptoms, ramipril 1.25 mg/day, and digoxin 0.25 mg/day. On hospital day 1, the patient received a total dose of 250 mg of chlordiazepoxide but remained distraught and slightly agitated. The next day, chlordiazepoxide was increased to 100 mg every 2 hours as needed due to severe withdrawal symptoms
On day 3, the patient became oversedated after receiving a total of 400 mg of chlordiazepoxide the previous day. The drug was therefore discontinued. In addition, the patient complained of shortness of breath, chest pain, and "heart fluttering." Oral diltiazem 30 mg every 6 hours was begun for atrial fibrillation. Because of the severity of the patients mental status changes, a lumbar puncture was performed; results were negative. A computed tomography head scan revealed generalized cerebral and cerebellar atrophy consistent with alcoholism, but was otherwise unremarkable. On day 5, the patient was transferred to the intensive care unit for better management of his worsening arrhythmia and respiratory depression. He was obtunded and unresponsive; his serum chlordiazepoxide levels were toxic
Chest radiographs showed basilar effusions and right-sided basilar infiltrates. The patients mental status changes were thought to be due to possible hepatic encephalopathy rather than infection. Intravenous piperacillin 3 g-tazobactam 0.375 g every 6 hours was begun to treat possible aspiration pneumonia. The diltiazem was increased to 60 mg every 6 hours; other drugs were continued as ordered on admission. Oxygen therapy by nasal cannula was begun, and an oxygen saturation of 96% was achieved. The patients serum ammonia level was within normal limits (9 µmol/L). His liver function tests improved: g-glutamyl transferase 934 IU/L, aspartate aminotransferase 60 IU/L, and alanine aminotransferase 64 IU/L. A neurologist was consulted. The encephalopathy was thought to be multifactorial, with sepsis, hypoxia, and chlordiazepoxide as possible etiologies. A trial of flumazenil at a total dose of 1 mg aroused the patient; the encephalopathy was therefore attributed to chlordiazepoxide toxicity. The patient was able to answer questions and move his extremities on command. Increased difficulty in breathing with mild hypercapnia was noted
On day 7, the patient required intubation and was unresponsive. Another trial of flumazenil (total dose 1 mg) resulted in no improvement. His atrial fibrillation was stable with administration of diltiazem and digoxin. On day 8, the patient grimaced with pain but was otherwise unresponsive. An electroencephalograph showed no seizure activity, only low-voltage slowing with intermittent a-wave activity. On day 9, he regained some alertness, opening his eyes in response to loud stimuli and orienting himself visually to sound. A magnetic resonance image of the head revealed no anatomic basis for his diminished mental status. The patient was still obtunded on day 10. His chest radiograph was clear. A third trial of flumazenil (total dose 1 mg) resulted in alertness, with the patient opening and closing his eyes. Mechanical ventilation was still required. To reverse his continued chlordiazepoxide toxicity, flumazenil 5 mg was mixed with 250 ml of normal saline and, after a literature review of previous reports of flumazenil infusions, the infusion was started at 0.5 mg/hour. Due to inadequate response after the first hour, the rate was increased to 1 mg/hour. The patient became more alert while receiving the infusion, and responded to questions and followed commands
Two days after the flumazenil infusion was begun, the patient was extubated and the infusion was discontinued. His atrial fibrillation converted to normal sinus rhythm. On day 14, however, 1 day after the flumazenil was discontinued, the patient became less reactive, and mucous secretions were accumulating. He again was given a bolus of flumazenil 1 mg, and the continuous infusion was restarted at 1 mg/hour. He became more alert, followed commands, and breathed comfortably. A urine toxicology screen was still positive for benzodiazepines. On day 15, after the flumazenil infusion was discontinued again, the patient became lethargic; the infusion was restarted. At 0.5 mg/hour the patient was sleepy, whereas at 1 mg/hour he was alert and cooperative. By day 17, the infusion was tapered to 0.5 mg/hour and was maintained at this rate for 2 more days. Nine days after the flumazenil infusion was started, it was discontinued; it no longer required reinitiation secondary to decreased mentation. The patients pulmonary status was stable, and 12 days after discontinuation of the flumazenil infusion, he was discharged.
Theprolonged course of the chlordiazepoxide intoxication in this patient was due to the presence of active metabolites in his system long after the parent drug was detected in the serum at levels well below the toxic level. Attempts to determine the levels of these metabolites in the patients serum were unsuccessful due to laboratory constraints
Flumazenil is given as an intravenous bolus. The initial dose is 0.2 mg, and this can be repeated at 1 to 6 minute intervals if necessary to a cumulative dose of 1.0 mg. The response is rapid, with onset in 1–2 minutes, peak effect at 6–10 minutes, and duration of approximately one hour . Since flumazenil has a shorter duration of action than the benzodiazepines, resedation is common after 30–60 minutes. Because of the risk for resedation, the initial bolus dose of flumazenil is often followed by a continuous infusion at 0.3–0.4 mg/hr