signs and managing common drug toxicity in clinical scenario

2.  Patient is a 65 year old previously healthy Caucasian
male, 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 Fahrenheit
Past Medical History: Provided only if requested. He has
had two previous myocardial infarctions (with a stent
placed in his right coronary artery 2 years
ago), congestive heart failure with an ejection fraction
of 40%, hypertension, hyperlipidemia, diabetes mellitus
type II, osteoarthritis, depression.

3.  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.

4.  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

9.  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 estimating
toxicity but beta-blocker doses in excess of
2-3 times the therapeutic dose should be
considered potentially life-threatening.

11.  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

12.  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.

14.  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.

15.  Other Treatment Modalities to Consider for
Refractory Hypotension
1. 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

16. 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 toxicity
D. Bronchospasms
• Aerosolized or nebulized Beta-2 agonist such as
albuterol
E. Seizures
• Diazepam and, if necessary, phenobarbital.

18.  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.

19.  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).

20. 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.

22. A 65-year-old male was admitted to our ICU. He was a known case of
hypertension for 15 years, on regular medications. He was diagnosed to
have mild renal insufficiency 6 years prior to present admission, with a
stable serum creatinine level .. On examination he was conscious, oriented
with normal sinus rate of 62/ min, blood pressure of 112/76 mmHg and
bilateral pedal edema. Respiratory, cardiovascular and neurological
examinations were normal. Electrocardiograph showed normal sinus
rhythm. Initial hemogram, random blood sugar, serum electrolytes, arterial
blood gas and electrocardiogram were unremarkable. Blood urea and serum
creatinine values were 79 mg/dl and 4.3 mg/dl respectively.
Echocardiography revealed left ventricular hypertrophy with normal LV
systolic and diastolic function
he presented with a history of restlessness following accidental ingestion
of 50 mg of Amlodipine along with his usual dose of 50 mg Atenolol, six
hours earlier.
The patient was given 30 ml of 10 % calcium gluconate - over 5
mins, followed by an infusion of calcium gluconate at a rate of 10 ml/hr
and after a bolus dose of Glucagon of 10 mgm, an infusion of Glucagon at a
rate of 3 mg/hr was commenced.

23. Over the next six hours the patient became hypotensive not responding to
volume resuscitation and requiring inotropic support with adrenaline and
dopamine infusion.
His sensorium gradually deteriorated. Twelve hours following the overdose
he was unresponsive to painful stimuli. Arterial blood gas analysis revealed
mixed respiratory and metabolic acidosis with a pH of 6.8, pCO 2 of 115
mmHg, pO 2 of 76 mmHg and a HCO3 of 16 mmol/L.
He was on high dose inotropic support with normal central venous pressure
and there was a drop in the hourly urine output. Gastric aspirate was coffee
ground. He was electively intubated and ventilated.
Ultrasonography of the abdomen showed normal kidney size with increased
echogenicity. UGI endoscopy revealed erythematous gastric mucosa without
any ulcer crater.
The next day the patient started showing signs of improvement. His
sensorium improved but he remained oliguric. Arterial blood gas analysis
showed pH of 7.2 pCO 2 of 34. mm Hg, pO 2 of 115 mmHg and a bicarbonate
of 13.7 mmol/L. Repeat potassium was 7.8 mEq/L. In view of
oliguria, persistent acidosis and hyperkalemia hemodialysis was started.
Over the next 24h, his condition stabilised and inotropic
support, glucagon, calcium infusions were tapered off. He was successfully
weaned off from the ventilator on the following day. On day 10 of admission
he was discharged from the hospital.

24. CCB poisoning

25.  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)

26.  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.

27.  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

28.  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

29.  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)

30.  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.

31.  resulting
in improved inotropy, conduction
disorders, and hypotension.

32.  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.

33.  Glucagonis usually accepted as first line
treatment in the management of BB and
verapamil overdose

34.  Phosphodiesterase III inhibitors represent
possible alternatives to glucagon in CCB and
BB poisoning, as their inotropic effect is not
mediated by beta adrenoceptors

35. 1. 4 aminopyridine, a potassium channel
inhibitor,
2. Bay K 8644, a calcium channel activator
studied in animal models.

37. 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. Patient's 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

38.  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

39.  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.

40.  Elderly
 Heart failure
 Dehydration
 Hypokalemia
 Hypomagnesemia
 Kidney disease
 Medications that interact with digoxin, such as:

41.  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.

42.  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

43.  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.

44. 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).

45.  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.

47.  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

48.  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.

49.  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.

50.  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

52.  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 initiation
of drug therapy with one or more neuroleptics are
common features of NMS

53.  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

54.  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

57.  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.

58.  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

59. Serotonin syndrome

60.  symptoms of serotonin syndrome usually present
within 6 to 8 hours of initiating or increasing
serotonergic medications.

62.  Neuroleptic malignant syndrome (NMS):
similar symptoms of fever, mental status changes, and altered
muscle tone. However, patients with NMS are usually akinetic with
rigidity, have decreased levels of consciousness, and are more
likely to have mutism rather than rambling speech, which is
associated with serotonin toxicity.
More important, the onset of NMS is slow, developing over days
rather 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

63. 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.

65.  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 body
temperature 36.6°C. eupnoeic with oxygen saturation
measured by pulse oximetry was 97% on room air.

66.  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.

67.  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.

69.  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

70.  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 lactate's
clearance than to an increased production

71.  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

72.  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

73.  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.

75.  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.

76.  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)

77.  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.

78. 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.


79.  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).

80. TCA toxicity

81.  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

82.  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.

83. 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 benzodiazepines
3. Anticholinergiceffects
–Early features of toxicity are mainly anticholinergic: dry mucous
membrane, dry skin, mydriasis, tachycardia, urinary
retention, decreased bowel sounds, excitation and confusion.

84.  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

85. 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

86.  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.

87.  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

88. Management of seizures
 Phenytoin should be avoided in patients with TCA
overdose .
 Benzodiazepines should be used to control
seizures following TCA overdose.

90.  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

92. 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 °F
Management:
 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

94.  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.

95.  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

97.  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 patient's 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 patient's 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

98.  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 patient's 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

99.  Chest radiographs showed basilar effusions and right-sided basilar
infiltrates. The patient's 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 patient's 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

100.  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

101.  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 patient's pulmonary status was
stable, and 12 days after discontinuation of the flumazenil
infusion, he was discharged.

102.  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 patient's serum were unsuccessful due to
laboratory constraints

105.  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