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Three Part Question

In [Tricyclic antidepressant overdose with refractory hypotension] does the use of [intravenous catecholamines] improve [hypotension and survival]?

Clinical Scenario

A 30 year old female librarian is brought into the emergency department after being found collapsed next to an empty bottle of Amitriptyline. She has a glasgow coma scale of 7/15 and a systolic blood pressure of 65 mmHg. She has been treated with gastric lavage and is on a sodium bicarbonate infusion. However there has been no change in her blood pressure. You wonder whether the use of catecholamines would improve her condition.

Search Strategy

Ovid Medline 1950 - 2008 June Week 1
Ovid Embase 1980 - 2008 Week 23
(exp Antidepressive Agents, Tricyclic/ OR tricyclic.mp. OR amitriptyline.mp. OR exp Amitriptyline/ OR desipramine.mp. OR exp Desipramine/ OR clomipramine.mp. OR exp Clomipramine/ OR doxepin.mp. OR exp Doxepin/ OR dothiepin.mp. OR exp Dothiepin/ OR imipramine.mp. OR exp Imipramine/ OR lofepramine.mp. OR exp Lofepramine/ OR nortriptyline.mp. OR exp Nortriptyline/ OR trimipramine.mp. OR exp Trimipramine/) AND (exp Overdose/ OR exp Poisoning/ OR overdose.mp. OR exp Drug Overdose/) AND (exp Catecholamines/ OR exp Epinephrine/ OR exp Norepinephrine/ OR exp Dopamine/ OR exp Adrenalin/ OR exp Noradrenalin/ OR (catecholamine OR epinephrine OR norepinephrine OR dopamine OR adrenaline OR noradrenaline).mp. limit to English language

Search Outcome

810 papers were identified (699 in Embase and 111 in Medline). Five were relevant to the three-part question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Teba L et al 1988 Nov USA	Case 1: 47 year old Female BP 66 mmHg Case 2: 56 year old Female BP 52 mmHg Both treated with Sodium bicarbonate and Dopmaine without significant improvement in hypotension	Case report	Systemic Systolic BP (SBP)	Case 1: Continuous infusion of norepinephrine increased SBP from 68 mmHg to >100 mmHg.Case 2: Following Norepinephrine infusion SBP increased from 52 mmHg to 130 mmHg	Only 2 case reports These may be exceptional cases
Knudsen K, Abrahamsson J 1997 April Sweden	91 Male Sprague-Dawley rats. All given Amitriptyline HCl infusion at@ 2mg/kg/min for 60 mins. After 5 mins given either: (a)Epinephrine infusion + 5 min bolus of sodium bicarbonate (b)Norepinephrine infusion +5 min bolus sodium bicarbonate (c)Epinephrine infusion + 5 min bolus placebo (d)Norepinephrine infusion + 5 min bolus placebo (e)Placebo infusion + 5 min bolus sodium bicarbonate (f)Placebo infusuion + 5 min bolus placebo Placebo infusion= Glucose 5% Placebo bolus= sodium chloride (9 mg/mL) 1mL/Kg/min	Non-randomised, Animal controlled intervention trial	Survival	Epinephrine+Sodium bicarbonate > survival rate than other groups (p<0.01). Epinephrine treatment groups > survival rates than Norepinephrine treatment groups (p<0.01). Treatment groups > survival rate than control groups (p<0.01). Epinephrine + Sodium bicarbonate treatment > survival rate than Epinephrine alone (p < .01). Norepinephrine + Sodium bicarbonate treatment > survival rate than Norepinephrine alone (p < .01).	Animal study hence extrapolation to humans may be difficult Not blinded Raw data unavailable in some measurments
			Arrhytmias	Epinephrine treated rats had a longer time to onset of arrythmias than Norepinephrine treated rats (21.5 Vs 11.6 mins) (p<0.05). Epinephrine+sodium bicarbonate treated rats had the longest time in sinus rhytm
			QRS duration	Epinephrine treatment associated with shorter QRS interval than Norepinephrine treatment (p<0.05)
Knudsen K, Abrahamsson J Sept 1993	101 Male wistar rats poisoned with Amitriptyline Given either 0.1, 0.5 or 5.0 mg/Kg/min of Epinephrine or Norepinephrine. Control group recieved Glucose infusion	Non-Randomised, Animal controlled intervention trial	Mean arterial Blood Pressure	All doses of Norepinephrine and 2 higher doses of Epinephrine increased MAP. Norepinpehrine>Epinephrine at low+intermediate doses	Animal study-difficult to apply data to humans Experiment not Blinded Raw data absent from study No significant Difference between treatmeant according to Fischer's exact test
			Mortality at 75 min(%)	Control group=75%; Norepinephrine=45%; Epinephrine=27%. At intermediate dose Epinephrine group has lowest death risk (p=0.012)
			Arryhthmia	Intermediate dose: Norepinephrine>arrhythmia than Epinephrine (p<0.05)
Knudsen K, Abrahamsson J 1994 Sweden	86 Male Wistar Rats infused with Amitriptyline HCl Treated with: Epinephrine Norepinephrine Epinephrine+Magnesium Norepinephrine+magnesium Milrinone	Nonrandomised, controlled intervention trial	Survival	Epinephrine+Norepinephrine > survival than control (P<0.001). Epinephrine>Norepinephrine survival rate	Animal study-can it be useful in humans? Not blinded Small number Raw data absent in some measurements
			Increase in QRS duration	Epinephrine significantly lower increase in QRS comapred to control + norepinephrine groups
			Onset Arrhythmia	Epinephrine delayed onset of arrytmias compared to control (p<0.01)
			Duration Sinus rhythm	Epinephrine>control (p<0.01). Epinephrine> Norepinephrine (p<0.05)
Vernon D et al 1991 USA	15 Dogs infused with Amitriptyline HCL Recieved Dopamine 5,15 and 30 micrograms sequentially or Norepinephrine 0.25,0.5 and 1.0 micrograms sequentially Hemodynamic measurements after each dose.	Experimental Randomised Controlled Trial	Mean Arterial Pressure (mmHg)	All doses of norepinephrine > MAP compared to Control (p<0.05). 2 higher Dopmaine doses > MAP compared to Control (p<0.05). At highest does no significant difference between Norepinephrine and Dopamine	Animal Study Not blinded Randomisation questionable Small number Eacg catecholamine infusion given sequentially
			Cardiac Output (CO) L/min	All doses of norepinephrine > CO than Control (p<0.05). 2 higher Dopmaine doses > CO than Control (p<0.05). At highest does no significant difference between Norepinephrine and Dopamine
			Peak Left Ventricular dP/dt (rate of change of LV pressure)	All doses of norepinephrine > LV dP/dt than Control (p<0.05). 2 higher Dopmaine doses > LV dP/dt than Control (p<0.05). At highest does no significant difference between Norepinephrine and Dopamine
			Mixed Venous Oxygen Saturation (SVO2)	All doses of norepinephrine > SVO2 than Control (p<0.05). 2 higher Dopmaine doses > LV SVO2 than Control (p<0.05). At highest does no significant difference between Norepinephrine and Dopamine
			Systemic Vascular Resistance (SVR)	All doses of norepinephrine > SVP than Control (p<0.05). At highest does no significant difference between Norepinephrine and Dopamine

Comment(s)

There is no published evidence of the effectiveness of catecholamines to treat refractory hypotension following tricyclic antidepressant overdose. Perhaps importantly, however, there were no reports of harmful or potential pro-arrhythmic effects of catecholamines in this situation. Experimental studies in animals suggest that epinephrine may be more effective than norepinephrine in this situation with epinephrine potentially reducing some of the cardiotoxic effects of tricyclic antidepressants.

Clinical Bottom Line

There is no published evidence of benefit or harm with intravenous catecholamines following tricyclic antidepressant overdose. They may be a useful adjunct in the treatment of refractory hypotension in this situation. Animal evidence suggests that epinephrine may be preferable to norepinephrine.

Level of Evidence

Level 3 - Small numbers of small studies or great heterogeneity or very different population.

References

1. Teba L, Scheibel F, Dedhia H, Lazzell V Beneficial effect of Norepinephrine in the Treatment of Circulatory Shock Caused by Tricyclic Antidepressant overdose American Journal of Emergency Medicine 6(6):566-8, 1988 Nov
2. Knudsen K, Abrahamsson Epinephrine and sodium bicarbonate independently and additively increase survival in experimental amitriptyline poisoning Critical Care medicine April 1997 Volume 25 Page 669-674
3. Knudsen K, Abrahamsson J Effects of epinephrine and norepinephrine on hemodynamic parameters and arrhythmias during a continuous infusion of amitriptyline in rats Journal of Toxicology - Clinical Toxicology Vol. 31(3)(pp 461-471), 1993
4. Knudsen K, Abrahamsson J Effects of epinephrine, norepinephrine, magnesium sulfate, and milrinone on survival and the occurrence of arrhythmias in amitriptyline poisoning in the rat Critical Care Medicine 22(11):1851-5, 1994 Nov
5. Vernon DD, Banner W, Garrett J, Dean J Efficacy of dopamine and norepinephrine for the treatment of hemodynamic compromise in amitriptyline intoxication Critical care medicine 1991 19:544