Download Full Article - College of Intensive Care Medicine

Case reports
Diltiazem Overdose Haemodynamic Response to
Hyperinsulinaemia-Euglycaemia Therapy: A
Case Report
L. MIN, K. DESHPANDE
Department of Critical Care Medicine, Flinders Medical Centre, Bedford Park, SOUTH AUSTRALIA
ABSTRACT
A 59-year-old woman was admitted to the intensive care unit after ingesting 5.76 g of an extended
release preparation of diltiazem. The patient was hypotensive and bradycardic and was treated initially
with intravenous fluids, adrenaline, noradrenaline, vasopressin and standard insulin doses to maintain the
blood glucose levels between 6 - 10 mmol/L. As the patient remained inotrope dependent the insulin dose
was increased to 25 U/hr with an infusion of 50% dextrose to maintain the blood glucose levels between 6 8 mmol/L. Within 30 minutes, the mean arterial pressure increased from 65 mmHg to 80 mmHg and within
60 minutes all vasoactive agents were discontinued. A right heart catheter inserted before the increased
dose of insulin revealed that the predominant haemodynamic effect of the hyperinsulinaemia-euglycaemia
therapy appeared to be an increase in the peripheral vascular resistance. (Critical Care and
Resuscitation 2004; 6: 28-30)
Key words: Diltiazem poisoning, calcium-channel blocker, severe hypotension, bradycardia, insulin
Calcium-channel blockers act predominantly at the
plasma membrane to block the slow current influx of
Ca2+ during the plateau phase of the action potential.1
They are used for one or more of their cardiovascular
effects of inhibition of conduction, chronotropism and
refractoriness (particularly at the SA and AV nodes, to
treat supraventricular tachycardias), negative inotropism
(to treat hypertrophic subaortic stenosis) and vasodilation (to treat hypertension, angina and cerebral
vasospasm).1,2
Diltiazem is a benzothiazepine calcium channel
blocker which has a similar action to verapamil,
although its ability to directly reduce the rate of SA
node discharge appears to be greater. It has a lower
vascular/cardiac effect ratio compared with other
calcium channel blockers (e.g. amlodipine and
nifedipine), although its peripheral vasodilator effect is
not insignificant.3 Overdosage of diltiazem is
characterised by hypotension due to a combination of a
negative inotropic and chronotropic effects, arrhythmias
(e.g. heart block) and peripheral vasodilation.4
We report a case of diltiazem overdosage managed
initially by intravenous calcium, glucagon, adrenaline,
noradrenaline, vasopressin and insulin therapy which
rapidly responded to hyperinsulinaemia-euglycaemia
therapy by increasing the patient’s peripheral vascular
resistance.
CASE REPORT
A 59 year-old female was admitted to the intensive
care unit following the ingestion of 24 x 240 mg
diltiazem extended release capsules (5.76 g), 12 x 10
mg zolpidem tablets and 4 x 1 mg lorazepam tablets.
She had a past history of hypertension, depression and
Correspondence to: Dr. L. Min, Department of Critical Care Medicine, Flinders Medical Centre, Bedford Park, South Australia
5042
28
Critical Care and Resuscitation 2004; 6: 28-30
L. MIN, ET AL
Figure 2. The 12-lead ECG on admission to the intensive care unit showing sinus bradycardia.
five previous suicide attempts.
On examination she was drowsy but oriented. Her
blood pressure was 60/35 mmHg and pulse rate was 40
beats per minute. During the next 30 minutes 2 g
calcium chloride (13.6 mmol), 2 mg glucagon and 1.5
litre of 0.9% saline, were administered, resulting in her
mean blood pressure increasing to 60 mmHg although
her pulse remained at 40 beats per minute (Figure 1).
Plasma biochemistry revealed a sodium of 140
mmol/L, potassium 4.3 mmol/L, bicarbonate 18
mmol/L, glucose 9.0 mmol/L and a total calcium of
3.43 mmol/L. The arterial gas analysis revealed a PO2
of 92 mmHg, PCO2 30 mmHg, pH 7.4, lactate 4
mmol/L and ionised calcium of 1.79 mmol/L.
She was admitted to the intensive care unit where a
central venous catheter was inserted. She was given 50
g activated charcoal orally and adrenaline by
intravenous infusion. Within 6 hours the adrenaline
infusion rate had increased to 32 µg/min. A
noradrenaline infusion was added and increased to 25
µg/min over the next 4 hours. Finally a vasopressin
infusion at 2 U/hour was introduced. An intravenous
infusion of actrapid varying between 5 - 8 U/hr was
used to keep the plasma glucose level between 6 - 10
mmol/L.
After 12 hours, despite the substantial vasoactive
therapy, the blood pressure remained at 93/49 mmHg
(MAP 64 mmHg) although the pulse rate had increased
to 84 beats per minute. A right heart catheter was
inserted and revealed a cardiac index (CI) of 4.17
L/min/m2, pulmonary artery occlusion pressure (PAOP)
of 20 mmHg, left ventricular stroke work index
(LVSWI) of 30.4 g.m/m2/beat and systemic vascular
resistance index (SVRI) 1016 dyne.sec/cm5/m2.
After 15 hours the actrapid was increased from 5
U/hr to 0.5 U/kg/hr (25 U/hr) and 50% dextrose was
infused to keep the hourly plasma glucose levels
varying between 6 - 8 mmol/L. Within 30 minutes the
mean arterial blood pressure had increased to 80 mmHg
and after a further 30 minutes the adrenaline,
noradrenaline and vasopressin infusions were
discontinued. The haemodynamic parameters at this
stage revealed a blood pressure of 107/58 mmHg (MAP
74 mmHg), pulse rate of 77 beats per minute, CI of 2.79
L/min/m2, PAOP of 14 mmHg, LVSWI of 29.1
g.m/m2/beat and SVRI 1750 dyne.sec/cm5/m2.
The insulin infusion was continued at 25 U/hr for a
further 6 hours then reduced to 10 U/hr for 2 hours and
thereafter the 50% dextrose was discontinued and the
insulin varied between 0 - 4 U/hr to keep the plasma
glucose level varying between 6 - 8 mmol/L.
DISCUSSION
Overdosage of a calcium channel blocker (e.g.
verapamil, diltiazem, nifedipine or amlodipine) may be
associated with hypotension, bradycardia, hyperglycaemia and lactic acidosis.5 Treatment includes gastric
lavage and oral charcoal as well as haemodynamic
29
L. MIN, ET AL
support.5 Hypotension and bradycardia may respond to
intravenous fluids and calcium chloride,6,7 although
adrenaline, noradrenaline, dopamine, isoprenaline,
glucagon, cardiac pacing, intra-aortic balloon pump and
even extracorporeal membrane oxygenation may be
required.5,8-12
Normally, myocyte and vascular smooth muscle
cells oxidise free fatty acids for energy, but during a
state of shock the cells primarily metabolise glucose for
energy.13 However, during calcium channel blockade,
secretion of insulin by pancreatic beta cells is
inhibited,14 causing hypoinsulinaemia and a reduction in
cellular entry of glucose. Glucose, insulin and
potassium infusions have been used to treat
experimental myocardial depression associated with
verapamil poisoning,14 and in clinical reports of severe
calcium channel blocker poisoning (e.g. verapamil,
amlodipine
and
diltiazem),
hyperinsulinaemiaeuglycaemia therapy (e.g. a continuous infusion of
insulin 0.5 U/kg/hr or 35 U/70kg/hr and glucose) has
been used successfully to manage patients.13,15-17
While a negative inotropic effect and bradycardia
are often believed to be the major cause of the haemodynamic compromise in calcium channel blocker
toxicity, the haemodynamic features that have been
reported in diltiazem overdose are low systemic
vascular resistance in the presence of a good cardiac
output.18-20
Diltiazem poisoning in our patient was associated
with severe hypotension and sinus bradycardia, which
required large doses of vasoactive agents to maintain a
mean arterial pressure greater than 60 mmHg. The
insulin dose required to manage the plasma glucose
level between 6 - 10 mmol/L did not negate the
requirement for inotropic agents. However, within 30
minutes of increasing the insulin infusion to 25 U/hr
and infusing 50% dextrose to maintain the plasma
glucose level between 6 - 8 mmol/L the mean arterial
blood pressure increased to 80 mmHg. The vasoactive
agents were discontinued 30 minutes later. A right heart
catheter revealed that the major haemodynamic effect of
the hyperinsulinaemia-euglycaemia therapy was an
increase in the peripheral resistance as the LVSWI and
CI did not change significantly.
Critical Care and Resuscitation 2004; 6: 28-30
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
Received 5 February 04
Accepted 20 February 04
19.
REFERENCES
20.
1.
2.
30
Opie LH. Calcium antagonists. mechanisms, therapeutic
indications and reservations: a review. Q J Med
1984;53:1-16.
Kanneganti M, Halpern NA. Acute hypertension and
calcium-channel blockers. New Horiz 1996;4:19-25.
Lip GY, Ferner RE. Poisoning with anti-hypertensive
drugs: calcium antagonists. J Hum Hypertens
1995;9:155-161.
Ramoska EA, Spiller HA, Winter M, Borys D. A oneyear evaluation of calcium channel blocker overdoses:
toxicity and treatment. Ann Emerg Med 1993;22:196200.
Salhanick SD, Shannon MW. Management of calcium
channel antagonist overdose. Drug Saf 2003;26:65-79.
Lüscher TF, Noll G, Stürmer T, Huser B, Wenk M.
Calcium gluconate in severe verapamil intoxication. N
Engl J Med 1994;330:718-720.
Lam Y-M, Tse H-F, Lau C-P. Continuous calcium
chloride infusion for massive nifedipine overdose. Chest
2001;119:1280-1281.
Morris DL, Goldschlager N. Calcium infusion for
reversal of adverse effects of intravenous verapamil.
JAMA 1983;249:3212-3213.
Worthley LIG. Treating adverse effects of verapamil.
JAMA 1984;252:1129.
Coaldrake LA. Verapamil overdose. Anaesth Intens
Care 1984;12:174-175.
Zaritsky AL, Horowitz M, Chernow B. Glucagon
antagonism of calcium channel blocker-induced
myocardial dysfunction. Crit Care Med 1988;16:246251.
Durward A, Guerguerian AM, Lefebvre M, Shemie SD.
Massive diltiazem overdose treated with extracorporeal
membrane oxygenation. Pediatr Crit Care Med
2003;4:372-376.
Yuan TH, Herns WP, Tomaszewski CA, Ford MD,
Kline JA. Insulin-glucose as adjunctive therapy for
severe calcium channel antagonist poisoning. J Toxicol
Clin Toxicol 1999;37:463-474.
Kline JA, Leonova E, Raymond RM. Beneficial
myocardial metabolic effects of insulin during
verapamil toxicity in the anesthetized canine. Crit Care
Med 1995;23:1251-1263.
Boyer EW, Shannon M. Treatment of calcium-channelblocker intoxication with insulin infusion. N Engl J Med
2001;344:1721-1722.
Rasmussen L, Husted SE, Johnsen. Severe intoxication
after an intentional overdose of amlodipine. Acta
Anaesthesiol Scand 2003;47:1038-1040.
Boyer
EW,
Duic
PA,
Evans
A.
Hyperinsulinemia/euglycemia therapy for calcium
channel blocker poisoning. Pediatr Emerg Care
2002;18:36-37.
Williamson KM, Dunham GD. Plasma concentrations of
diltiazem and desacetyldiltiazem in an overdose
situation.Ann Pharmacother 1996;30:608-611.
Proano L, Chiang WK, Wang RY.Calcium channel
blocker overdose. Am J Emerg Med 1995;13:444-450.
Satchithananda DK, Stone DL, Chauhan A, Ritchie AJ.
Unrecognised accidental overdose with diltiazem. BMJ
2000;321:160-161.