C2005 Evidence Evaluation Template - Oct.14, 2003circ.ahajournals.org/content/suppl/2005/11/16/... · Web viewOnly low levels of evidence exists to guide recommendations (4, 5, 6)

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WORKSHEET for PROPOSED Evidence-Based GUIDELINE RECOMMENDATIONSNOTE: Save worksheet using the following filename format: Taskforce.Topic.Author.Date.Doc where Taskforce is a=ACLS, b=BLS, p=Pediatric, n=neonatal and i=Interdisciplinary. Use 2 or 3 letter abbreviation for author’s name and 30Jul03 as sample date format.Worksheet Author: Jim Tibballs

Taskforce/Subcommittee: __BLS __ACLS _X_PEDS __ID __PROAD__Other:

Author’s Home Resuscitation Council: __AHA _X_ANZCOR __CLAR __ERC __HSFC__HSFC __RCSA ___IAHF ___Other:

Date Submitted to Subcommittee: December 17, 2004

STEP 1: STATE THE PROPOSAL. State if this is a proposed new guideline; revision to current guideline; or deletion of current guideline.Existing guideline, practice or training activity, or new guideline: Review of existing guideline: (Circulation 2000; 102: I-310);

“Sodium bicarbonate is recommended in the treatment of symptomatic patients with hyperkalemia (Class 11a; LOE 6,7), hypermagnesemia, tricyclic antidepressant overdose, or overdose from other sodium channel blocking agents (Class 11b; LOE 6,7)”

Step 1A: Refine the question; state the question as a positive (or negative) hypothesis. State proposed guideline recommendation as a specific, positive hypothesis. Use single sentence if possible. Include type of patients; setting (in- /out-of-hospital); specific interventions (dose, route); specific outcomes (ROSC vs. hospital discharge).Sodium bicarbonate or other alkalinisation of blood reduces toxics effects of tricyclic antidepressantsStep 1B: Gather the Evidence; define your search strategy. Describe search results; describe best sources for evidence.Medline: Oct 04:’sodium bicarbonate’ and ‘tricyclic antidepressant’: 56 hitsEmbase; Nov 04:’bicarbonate drug therapy’ or ‘bicarbonate drug toxicity’ and ‘sodium bicarbonate’ and ‘tricyclic antidepressant agent’: 149 hitsAHA Endnote database Oct 04:’sodium bicarbonate’ and ‘tricyclic antidepressant’: 36 hitsCochrane: Oct 04: ‘sodium bicarbonate and tricyclic antidepressant’: nil

List electronic databases searched (at least AHA EndNote 7 Master library [http://ecc.heart.org/], Cochrane database for systematic reviews and Central Register of Controlled Trials [http://www.cochrane.org/], MEDLINE [http://www.ncbi.nlm.nih.gov/PubMed/ ], and Embase), and hand searches of journals, review articles, and books.

• State major criteria you used to limit your search; state inclusion or exclusion criteria (e.g., only human studies with control group? no animal studies? N subjects > minimal number? type of methodology? peer-reviewed manuscripts only? no abstract-only studies?)

Exclude journal lettersExclude single animal reportsExclude only abstract human reports

• Number of articles/sources meeting criteria for further review: Create a citation marker for each study (use the author initials and date or Arabic numeral, e.g., “Cummins-1”). . If possible, please supply file of best references; EndNote 6+ required as reference manager using the ECC reference library.

36 journal articles

STEP 2: ASSESS THE QUALITY OF EACH STUDYStep 2A: Determine the Level of Evidence. For each article/source from step 1, assign a level of evidence—based on study design and methodology.

Level of Evidence

Definitions(See manuscript for full details)

Level 1 Randomized clinical trials or meta-analyses of multiple clinical trials with substantial treatment effectsLevel 2 Randomized clinical trials with smaller or less significant treatment effectsLevel 3 Prospective, controlled, non-randomized, cohort studiesLevel 4 Historic, non-randomized, cohort or case-control studiesLevel 5 Case series: patients compiled in serial fashion, lacking a control groupLevel 6 Animal studies or mechanical model studiesLevel 7 Extrapolations from existing data collected for other purposes, theoretical analysesLevel 8 Rational conjecture (common sense); common practices accepted before evidence-based guidelines

http://www.ncbi.nlm.nih.gov/PubMed/

http://www.cochrane.org/

http://ecc.heart.org/



Step 2B: Critically assess each article/source in terms of research design and methods. Was the study well executed? Suggested criteria appear in the table below. Assess design and methods and provide an overall rating. Ratings apply within each Level; a Level 1 study can be excellent or poor as a clinical trial, just as a Level 6 study could be excellent or poor as an animal study. Where applicable, please use a superscripted code (shown below) to categorize the primary endpoint of each study. For more detailed explanations please see attached assessment form.

Component of Study and Rating Excellent Good Fair Poor UnsatisfactoryDesign &

Methods

Highly appropriate sample or model, randomized, proper controls ANDOutstanding accuracy, precision, and data collection in its class

Highly appropriate sample or model, randomized, proper controlsOROutstanding accuracy, precision, and data collection in its class

Adequate, design, but possibly biased

ORAdequate under the circumstances

Small or clearly biased population or model

ORWeakly defensible in its class, limited data or measures

Anecdotal, no controls, off target end-points

ORNot defensible in its class, insufficient data or measures

A = Return of spontaneous circulation C = Survival to hospital discharge E = Other endpointB = Survival of event D = Intact neurological survival

Step 2C: Determine the direction of the results and the statistics: supportive? neutral? opposed?

DIRECTION of study by results & statistics: SUPPORT the proposal NEUTRAL OPPOSE the proposal

ResultsOutcome of proposed guideline superior, to a clinically important degree, to current approaches

Outcome of proposed guideline no different from current approach

Outcome of proposed guideline inferior to current approach

Step 2D: Cross-tabulate assessed studies by a) level, b) quality and c) direction (ie, supporting or neutral/ opposing); combine and summarize. Exclude the Poor and Unsatisfactory studies. Sort the Excellent, Good, and Fair quality studies by both Level and Quality of evidence, and Direction of support in the summary grids below. Use citation marker (e.g. author/ date/source). In the Neutral or Opposing grid use bold font for Opposing studies to distinguish them from merely neutral studies. Where applicable, please use a superscripted code (shown below) to categorize the primary endpoint of each study.

Supporting EvidenceHypothesis: Sodium bicarbonate or other alkalinisation of blood reduces toxics effects of tricyclic antidepressants

Excellent

Good

Knudsen 1997 BMcCabe 1998E1,3Nattel 1984b E 1,3Pentel 1984 E1,3


REMEMBER TO SAVE THE BLANK WORKSHEET TEMPLATE USING THE FILENAME FORMATQ

ualit

y of

E

vide

nce Fair

Hoffman 1993 C Brown 1973 C,E3

Auclair 1983 E1, 3, 6Bou-Abboud 1996E5Bou-Abboud 1998 E 6Brown 1976 E 4Brown 1973 E3Brunn 1992 E1Hedges 1985 E1,3,4Nattel 1984a E 1,3Sasyniuk 1984 E 4Sasyniuk 1986 E1,4Wananukul 1996E1,3

Poor#Dequin 1994 B, E1,2#Hodes 1984 D#Hoffman 1981 B, E 1,2Kingston 1979 E1Koppel 1992 E1Lomholt 1975 E1#McKinney 2003 B#Molloy 1984 B, E2,3#Newton 1994 B, E 1,2#Sandeman 1997 B

Levitt 1986 E5Stone 1995 B, E1

Unsatisfactory#Bessen 1983 B, E3

1 2 3 4 5 6 7 8Level of Evidence

A = Return of spontaneous circulation C = Survival to hospital discharge E = Other endpoint (1 reduction QRS prolongation, 2 restoration of BP, 3 suppression of dysrhythmia, 4 in vitro improvement of Vmax, 5 change in free plasma drug concentration, 6 restoration of membrane conductive properties)B = Survival of event D = Intact neurological survival # single case report

*Neutral or Opposing EvidenceHypothesis: Sodium bicarbonate or other alkalinisation of blood reduces toxics effects of tricyclic antidepressants

Qua

lity

of E

vide

nce

Excellent

Good McCabe 1994 E1,2,3

Fair Larkin 1994 B

Poor *Shannon 1992 E2Wrenn 1992 B1

*Dumovic 1976 E4Pentel 1995 E 1,3,4

1 2 3 4 5 6 7 8Level of Evidence

A = Return of spontaneous circulation C = Survival to hospital discharge E = Other endpoint (1 reduction QRS prolongation; 2 reduction of duration of QRS widening; 3 restoration of BP; 4 suppression of



dysrhythmia; 5 in vitro improvement of Vmax) B = Survival of event (1 did not survive) D = Intact neurological survival

STEP 3. DETERMINE THE CLASS OF RECOMMENDATION. Select from these summary definitions.CLASS CLINICAL DEFINITION REQUIRED LEVEL OF EVIDENCE

Class IDefinitely recommended. Definitive, excellent evidence provides support.

• Always acceptable, safe• Definitely useful • Proven in both efficacy & effectiveness• Must be used in the intended manner for proper clinical indications.

• One or more Level 1 studies are present (with rare exceptions) • Study results consistently positive and compelling

Class II:Acceptable and useful

• Safe, acceptable• Clinically useful• Not yet confirmed definitively

• Most evidence is positive• Level 1 studies are absent, or inconsistent, or lack power • No evidence of harm

• Class IIa: Acceptable and usefulGood evidence provides support

• Safe, acceptable• Clinically useful • Considered treatments of choice

• Generally higher levels of evidence• Results are consistently positive

• Class IIb: Acceptable and usefulFair evidence provides support

• Safe, acceptable • Clinically useful• Considered optional or alternative treatments

• Generally lower or intermediate levels of evidence• Generally, but not consistently, positive results

Class III: Not acceptable, not useful, may be harmful

• Unacceptable• Not useful clinically• May be harmful.

• No positive high level data• Some studies suggest or confirm harm.

Indeterminate• Research just getting started.• Continuing area of research• No recommendations until further research

• Minimal evidence is available• Higher studies in progress • Results inconsistent, contradictory• Results not compelling

STEP 3: DETERMINE THE CLASS OF RECOMMENDATION. State a Class of Recommendation for the Guideline Proposal. State either a) the intervention, and then the conditions under which the intervention is either Class I, Class IIA, IIB, etc.; or b) the condition, and then whether the intervention is Class I, Class IIA, IIB, etc.Indicate if this is a __Condition or X InterventionFinal Class of recommendation: __Class I-Definitely Recommended __Class IIa-Acceptable & Useful; good evidence _X_Class IIb-Acceptable & Useful; fair evidence __Class III – Not Useful; may be harmful __Indeterminate-minimal evidence or inconsistent

REVIEWER’S PERSPECTIVE AND POTENTIAL CONFLICTS OF INTEREST: Briefly summarize your professional background, clinical specialty, research training, AHA experience, or other relevant personal background that define your perspective on the guideline proposal. List any potential conflicts of interest involving consulting, compensation, or equity positions related to drugs, devices, or entities impacted by the guideline proposal. Disclose any research funding from involved companies or interest groups. State any relevant philosophical, religious, or cultural beliefs or longstanding disagreements with an individual.

The reviewer is a Pediatric Intensive Care Physician and a Member of Australian Resuscitation Council. The reviewer has no conflicts of interest.

REVIEWER’S FINAL COMMENTS AND ASSESSMENT OF BENEFIT / RISK: Summarize your final evidence integration and the rationale for the class of recommendation. Describe any mismatches between the evidence and your final Class of Recommendation. “Mismatches” refer to selection of a class of recommendation that is heavily influenced by other factors than just the evidence. For example, the evidence is strong, but implementation is difficult or expensive; evidence weak, but future definitive evidence is unlikely to be obtained. Comment on contribution of animal or mechanical model studies to your final recommendation. Are results within animal studies homogeneous? Are animal results consistent with results from human studies? What is the frequency of adverse events? What is the possibility of harm? Describe any value or utility judgments you may have made, separate from the evidence. For example, you believe evidence-supported interventions should be limited to in-hospital use because you think proper use is too difficult for pre-hospital providers. Please include relevant key figures or tables to support your assessment.Intravenous sodium bicarbonate suppresses induced arrhythmias, shortens QRS prolongation and corrects hypotension in some animal models of tricyclic antidepressant intoxication (Pentel et al., 1984; McCabe et al., 1998; Brunn et al., 1992; Brown 1976), but not in some others (Larkin et al., 1994; Pentel et al., 1995). In an uncontrolled case series of human intoxications hypotension and arrhythmias were corrected (Hoffmann et al., 1993; Brown 1976) but not in another series (Shannon 1992).. The effect of



sodium bicarbonate is likely to be brief and require re-treatment. There is very little evidence that alkalinisation per se adds to the severity of illness caused by tricyclic poisoning (Wrenn et al., 1992).

On the basis of limited human data (LOE 4,5) and from animal experimentation (LOE 6) treatment of tricyclic antidepressant intoxication with sodium bicarbonate and/or hyperventilation is recommended (Class IIb). It is not certain however, whether the mechanism of benefit with the use of sodium bicarbonate is solely by alkalosis or with the additional benefit of its sodium content.

Preliminary draft/outline/bullet points of Guidelines revision: Include points you think are important for inclusion by the person assigned to write this section. Use extra pages if necessary.

Publication: Chapter: Pages:

Topic and subheading: Treatment of tricyclic antidepressant intoxication. Only low levels of evidence exists to guide recommendations (4, 5, 6). Although a handful of human and animal studies argue that alkalinisation is not beneficial, the majority support the

practice. In view of the seriousness of this type of poisoning, alkalinisation appears justified particularly since the therapy has little

(if any) adverse effects provided pH and plasma sodium concentrations are monitored and maintained within reasonable limits (pH <7.55, Na+ < 155).

Repeated doses of sodium bicarbonate may be needed since its effects may be short-term. The efficacy of NaHCO3 has been attributed to alkalinisation but a separate additional benefit may be due to its sodium

content.

Citation List

Citation Marker Full Citation*

Bessen 1983

Bessen 1985

HUMAN CASE REPORTS, CASE SERIES and EXPERIMENTATION

Bessen, H. A., J. T. Niemann, et al. (1983). "Effect of respiratory alkalosis in tricyclic antidepressant overdose." Western Journal of Medicine 139(3): 373-6.

Worksheet author Comments:

1. LOE 5, QOE poor, supporting hypothesis2. No abstract or summary by article author3. Single adult case report of poisoning by amitryptaline, flurazepam, acetaminophen

and codeine associated with hypotension and VT. Unsuccessful therapy consisted of normal saline (1 L), dopamine infusion, physostigmine and precordial blows. Restoration of normal blood pressure and sinus tachycardia was associated with hyperventilation and eventual full recovery.

Bessen, H. A. and J. T. Niemann (1985). "Improvement of cardiac conduction after hyperventilation in tricyclic antidepressant overdose." Journal of Toxicology Clinical Toxicology 23(7-8): 537-46.

Three patients with severe cardiotoxicity secondary to tricyclic antidepressant (TCA) overdosage were treated with induced mechanical hyperventilation. All three demonstrated marked QRS narrowing, reflecting improved intracardiac conduction, after hyperventilation therapy. Such therapy may help to prevent or abolish ventricular dysrhythmias, often a feature of life-threatening TCA overdoses.

1. LOE 5, QOE poor, supporting hypothesis2. Three case reports of amitryptaline poisoned adults whose QRS prolongation



Brown 1973

Brown 1973

Dequin 1994

shortened with hyperventilation. One also received IV NaHCO3 (88 mmol). In the 3, indicative EKGs obtained at different intervals (90, 25, 270 min respectively) after initial EKG.

Brown, T. C. (1976). "Sodium bicarbonate treatment for tricyclic antidepressant arrhythmias in children." Med J Aust 2(10): 380-382.

Sodium bicarbonate has modified or reversed arrhythmias due to tricyclic antidepressants in 11 children. It has proved to be the most clinically effective method of treatment of these arrhythmias in children, and reference is made to experimental studies which support this view.

Worksheet Author Comments:

1. LOE 5, QOE fair, supporting hypothesis2. 12 children with arrhythmias (multifocal VEs, runs of VT and varying degrees of

heart block) who had been poisoned with tricyclics (8 imipramine, 2 amitryptaline and 2 nortryptaline) were treated with NaHCO3 (doses 0.5 – 2 mmol/kg). Nine of these were treated with NaHCO3 only and 3 also received other drugs. Eleven responded to treatment with reversion to sinus rhythm.

Brown, T. C., G. A. Barker, et al. (1973). "The use of sodium bicarbonate in the treatment of tricyclic antidepressant-induced arrhythmias." Anaesth Intensive Care 1(3): 203-210.

Summary: sodium bicarbonate has been successfully used clinically to treat arrhythmias induced by tricyclic antidepressant drugs (imipramine, amitryptaline, nortryptaline, dibenzepin). Experiments conducted in puppies showed that arrhythmias caused by amitryptaline disappear when acidosis is adequately treated. Plasma protein binding of amitryptaline increases as pH rises, reducing the unbound fraction of drug. This mechanism is an important factor in the antiarrhythmic action of sodium bicarbonate in tricyclic antidepressant overdosage.

Worksheet author comments:

1. LOE 5 & 6, QOE fair, supporting hypothesis2. This is a combined publication of a series of case reports of 5 children poisoned

with tricyclics and who were treated with NaHCO3 and of 4 dogs poisoned with amitryptaline.

3. In 4 of 5 children an arrhythmia immediately reverted to normal rhythm after administration of NaHCO3.

4. In the 4 dogs, administration of 2-3 mmol/kg NaCO3 abolished arrhythmias.

Dequin, P. F., R. Lanotte, et al. (1994). "[Molar sodium bicarbonate and adrenaline combination during severe tricyclic intoxication in a gastrectomized woman]." Presse Medicale 23(11): 540-1.


1. LOE 5, QOE poor, supporting hypothesis2. No article author abstract or summary3. Single adult case report (French) of amitryptaline poisoning with severe

hypotension and prolongation of QRS. Treatment consisted of mechanical ventilation, administration of 250 mmol NaHCO3 and an infusion of adrenaline. This was associated with improvement in BP and reduction in QRS duration with eventual recovery.



Hodes 1984

Hoffman 1981

Hoffman 1993

Hodes, D. (1984). "Sodium bicarbonate and hyperventilation in treating an infant with severe overdose of tricyclic antidepressant." British Medical Journal Clinical Research Ed 288(6433): 1800-1.


1. LOE 5, QOE poor, supporting hypothesis2. Single case report of a child who had a cardiac arrest after overdose of dothiepin

and was successfully resuscitated (neurologically normal) with hyperventilation and NaHCO3 administration

Hoffman, J. R. and C. R. McElroy (1981). "Bicarbonate therapy for dysrhythmia and hypotension in tricyclic antidepressant overdose." Western Journal of Medicine 134(1): 60-4.


1. LOE 5, QOE poor, supporting hypothesis2. Single case report of adult after overdose of imipramine and probable small

quantities of salicylate, barbiturate and diazepam who exhibited mild hypotension, widened QRS and probable VT or SVT. Treatment consisted of several doses of NaHCO3 (each 44 mmol) which was associated with restoration of BP and reduction of QRS widening.

Hoffman, J. R., S. R. Votey, et al. (1993). "Effect of hypertonic sodium bicarbonate in the treatment of moderate-to-severe cyclic antidepressant overdose." American Journal of Emergency Medicine 11(4): 336-41.

The objective of this study was to characterize the effect of intravenous hypertonic sodium bicarbonate (NaHCO3) administration in patients with moderate-to-severe cyclic antidepressant (CA) overdose. We reviewed charts of all 91 patients given the diagnosis of CA overdose in the University of California Los Angeles (UCLA) Emergency Medicine Center (EMC), who either died in the EMC or were admitted to the medical intensive care unit (MICU), and who received NaHCO3 in the EMC between 1980 and 1988. Twenty-four other patients with the same EMC diagnosis were admitted to the MICU during this period but did not receive NaHCO3. The response of blood pressure, electrocardiographic parameters, and mental status to serum alkalinization with NaHCO3 were evaluated. Major morbidity and mortality were recorded for all patients. Hypotension was corrected within 1 hour in 20 of 21 (96%) patients, QRS prolongation corrected in 39 of 49 (80%), and mental status improved in 40 of 85 (47%). There was one death, in a patient who was moribund on arrival to the EMC. No complications were attributable to the administration of NaHCO3. NaHCO3 seems to improve hypotension and normalize QRS duration rapidly in most patients treated, and improve mental status changes in almost one half. Serum alkalinization with NaHCO3, in conjunction with appropriate supportive care, seems to limit major morbidity and mortality effectively in patients with serious CA overdose.


1. LOE 4, QOE fair-poor, supporting hypothesis2. Retrospective chart review of 91 patients presenting with tricyclic poisoning alone (36 patients of whom 24 ingested a combination of tricyclics) or in combination with other types of medication (55 patients) and who were treated with NaHCO3, compared with 43 other patients poisoned with tricyclics but who were not treated with NaHCO3. The number of patients in the ‘control group who might have had combined poisoning was not declared nor was any other treatment in both groups.3. In the tricyclic-NaHCO3 treated group, 21 patients had hypotension of whom 20 ‘responded’ (SBP increased above 90 mmHg or by more than 15 mmHg within 60 minutes) to NaHCO3 while 49 had QRS prolongation of whom 39 (80%) ‘responded’ (decrease of more than 0.03 secs or to a duration equal to or less than 0.11 secs). This QRS improvement included 12 of 15 patients with concomitant hypotension.



Kingston 1979

Koppel 1992

4. Median time to discharge from ICU was 2 days and then (?) 2 days from hospital in NaHCO3-treated group whereas the comparative times were 4 and 5 days for the non-NaHCO3 treated group.5. The incidence of QRS prolongation in NaHCO3-treated group was 54% but 29% in the non-NaHCO3 treated group.6. NaHCO3 treatment was not associated with worsening of vital signs, ECG parameters or mental status.

Kingston, M. E. (1979). "Hyperventilation in tricyclic antidepressant poisoning." Critical Care Medicine 7(12): 550-1.

A patient with severe tricyclic antidepressant poisoning who showed recurrent ventricular fibrillation and wide QRS complexes on the ECG, failed to respond to intravenous physostigmine and lidocaine. Deliberate artificial hyperventilation was immediately effective in preventing further arrhythmia and in decreasing the width of the QRS complexes. Hyperventilation, a neglected treatment, may be immediately effective in the treatment of severe tricyclic antidepressant poisoning.


1. LOE 5, QOE poor, supporting hypothesis2. Single case report observing that hyperventilation seemed effective decreasing

width of QRS.

Koppel, C., A. Wiegreffe, et al. (1992). "Clinical course, therapy, outcome and analytical data in amitriptyline and combined amitriptyline/chlordiazepoxide overdose." Human & Experimental Toxicology 11(6): 458-65.

A total of 103 cases of amitriptyline (AT) overdose (group 1) and 81 cases of overdose with a fixed combination of AT and chlordiazepoxide (CDE) (group 2), treated at our Intensive Care Unit or reported to our Poison Information Center between 1985-1990, were evaluated with respect to clinical course, symptoms and outcome, as well as efficacy of therapy. The mean amount of AT was considerably higher in group 1 compared to group 2 (13 mg kg-1 vs 7.7 mg kg-1). The most frequent symptoms in both groups were impaired consciousness, anticholinergic symptoms, seizures, arrhythmia and hypotension. Respiratory insufficiency necessitated respirator therapy in 63 of the patients. Two patients in group 1 and one patient in group 2 did not survive. Therapy included primary detoxification by gastric lavage and repeated administration of activated charcoal. In four of eight patients with cardiac conduction disturbances, hypertonic sodium bicarbonate led to a significant reduction in QRS duration and AV interval. Physostigmine was effective in eight of 14 patients with pronounced anticholinergic symptoms. No effect was observed in the other six patients. Haemoperfusion, which was performed in five patients, led to rapid improvement of coma after initiation of therapy in four patients. The clinical efficacy of haemoperfusion in AT overdose despite the high volume of distribution of AT deserves further investigation. The rather high average overdose of AT implies that large package sizes of AT were available to the patients. A major step towards prevention of serious AT overdose would be the prescription of package sizes containing a total of less than 500 mg AT.(ABSTRACT TRUNCATED AT 250 WORDS) Worksheet author continuation of abstract: Different analytical methods (enzyme immunoassay, fluorescence polarization immunoassay, and gas chromatography/mass spectrometry) for rapid detection of AT and its metabolites in plasma and urine were evaluated. Commercially available immunoassays like EMIT and ADX were highly reliable and sensitive in the detection of AT overdose. Five previously unknown metabolites or derivatives of AT could be detected in cases of AT overdose with the aid of a gas chromatography/mass spectrometry screening procedure.


1. LOE 5, QOE poor, supporting hypothesis



Lomholt 1975

McKinney 2003

2. Eight patients poisoned with amitryptaline or amitryptaline plus chlordiazepoxide overdose were treated with 100 mmol NaHCO3. These 8 had A-V conduction disturbances.

3. In 4 of these 8, a ‘beneficial effect’ (reduction of QRS duration and A-V interval) was observed. No other details were provided.

Lomholt, B. S. (1975). "[Hyperventilation therapy in acute tricyclic antidepressive poisoning. Controlled clinical research]." Ugeskrift for Laeger 138(1): 4-9.

Summary: ECG disturbances in acute poisoning with tricyclic antidepressives were treated with prolonged hyperventilation with pCO2 = 20-25 mmHg (0.60-0.76 mmol/L). The investigation comprised ten patients to whom CO2 was administered in the inspired air by means of hyperventilation for two periods of one hour so that the pCO2 became normal (41-46 mmHg). The heart rate and the width of the QRS complex were measured in the ECG during hypo- and normocapnia and the results were analysed statistically. During hypocapnia, the rate was found to be reduced and the QRS complex narrowed. Both of these parameters vary significantly from the conditions present during normocapnia.


1. LOE 5, QOE poor, supporting hypothesis2. Experimental variation of PCO2 in 10 patients (Norwegian) poisoned with

imipramine (1), amitryptaline (6), nortryptaline (1), clomipramine (1) and doxepin (1).

3. Infrequent ECG analysis, eg, after 10 hours of hypocapnia and then after 1 hour of normocapnia

4. Although QRS prolongation and heart rate was reduced, outcome effects of hyperventilation were not reported systematically – at least one patient died

McKinney, P. E. and R. Rasmussen (2003). "Reversal of severe tricyclic antidepressant-induced cardiotoxicity with intravenous hypertonic saline solution." Annals of Emergency Medicine 42(1): 20-24.

A 29-year-old woman ingested 8 g of nortriptyline and presented to the emergency department with coma, hypotension, and widened QRS interval. After intubation, gastric lavage, hyperventilation, and therapy with intravenous normal saline solution, sodium bicarbonate boluses (rapid intravenous push), and high doses of norepinephrine and dopamine, she transiently improved, only to deteriorate on arrival to the ICU. Because her arterial pH was alkalemic at 7.5 at this point, she was given additional sodium in the form of 200 mL of 7.5% NaCl by means of rapid intravenous infusion (intravenous push) to treat hypotension and widening QRS interval with ventricular ectopy. A continuous 12-lead ECG documented narrowing of her QRS interval with concomitant improvement of hypotension within 3 minutes of hypertonic saline solution infusion. Hypertonic saline solution should be considered for wide complex QRS and hypotension caused by tricyclic antidepressant-induced cardiotoxicity that is unresponsive to standard therapies.

Worksheet Author comments;

1. LOE 5, QOE poor, supporting hypothesis2. Single adult case report of nortryptaline poisoning in which hypotension and QRS

widening responded initially and transiently to NaHCO3, hyperventilation, normal saline, dopamine and noradrenaline. Despite alkalosis, re-occurrence of QRS widening and ventricular ectopy occurred but which responded to hypertonic saline.

Molloy, D. W., S. B. Penner, et al. (1984). "Use of sodium bicarbonate to treat tricyclic antidepressant-induced arrhythmias in a patient with alkalosis." Canadian Medical Association Journal. 130(11): 1457-9.



Molloy 1984

Newton 1994

Sandeman 1997

Sodium bicarbonate has been recommended for the treatment of arrhythmias induced by tricyclic antidepressants. It is unclear, however, whether this therapy is effective only in the presence of acidosis. A case is presented in which there was an immediate response to sodium bicarbonate in three episodes of ventricular tachycardia despite the presence of alkalosis on two of the three occasions. Given the poor response to conventional therapy of arrhythmias induced by tricyclic antidepressants the use of sodium bicarbonate may be reasonable even in the presence of alkalosis. However, in the presence of pre-existing respiratory or metabolic alkalosis, such therapy is not without risk, and it is suggested that it be reserved for life-threatening situations when the arrhythmia has failed to respond to hyperventilation or antiarrhythmics or both.


1. LOE 5, QOE poor, supporting hypothesis2. Single case report of adult poisoned with imipramine causing hypotension and

ventricular tachycardia. Treatment consisted of hyperventilation and of NaHCO3 administration which on 3 occasions converted VT to sinus rhythm. Complete recovery occurred.

Newton, E. H., R. D. Shih, et al. (1994). "Cyclic antidepressant overdose: a review of current management strategies." American Journal of Emergency Medicine 12(3): 376-9.

Cyclic antidepressant (CA) overdose can produce life-threatening seizures, hypotension, and dysrhythmias. It accounts for up to half of all overdose-related adult intensive care unit admissions and is the leading cause of death from drug overdose in patients arriving at the emergency department alive. Several factors contribute to the significant morbidity and mortality associated with CA overdose. First, CAs are widely prescribed and are dispensed to patients at increased risk for attempting suicide. Second, drugs of this class generally have a low therapeutic toxic ratio. Third, in the majority of fatal cases, the patient dies before reaching a hospital. Finally, and of greatest significance for the clinician, the presenting signs and symptoms of CA overdose may be missed by the physician, even in cases of severe toxicity. Therefore, CAs must be considered early in any case of suspected overdose, and all such cases should be managed as potentially fatal ones. The following case demonstrates the current approach to the patient with significant CA toxicity.


1. LOE 5, QOE poor, supporting hypothesis2. Single case report of adult poisoned with an unspecified cyclic antidepressant

which caused mild hypotension, QRS prolongation and sinus tachycardia. Treatment with NaHCO3 and hyperventilation was associated with restiration of normal BP, reduction of QRS prolongation and reduction of snus tachycardia with eventual full recovery.

Sandeman, D. J., T. I. Alahakoon, et al. (1997). "Tricyclic poisoning--successful management of ventricular fibrillation following massive overdose of imipramine." Anaesthesia & Intensive Care. 25(5): 542-5.

Serious complications from tricyclic antidepressant (TCA) overdose are uncommon. We present a case of massive imipramine overdose complicated by ventricular fibrillation and a prolonged period of cardiovascular collapse. A total of 400 mmol of sodium bicarbonate, 5 mg of adrenaline and 80 mg of sotalol were given during 50 minutes of cardiac arrest. The patient made a full recovery with no apparent neurological sequelae. The highest TCA plasma level we could find in the published literature was 4873 ng/ml4; our patient's peak TCA level was 6000 ng/ml. Tricyclic antidepressant overdose is a common cause of intensive care unit admission. It has a low mortality rate.




Shannon 1992

Wrenn 1992

1. LOE 5, QOE poor, supporting hypothesis2. Single case report of adult with imipramine overdose who arrested in VT-VF.

Treatment consisted of 100 mmol NaHCO3 which was followed by appearance of VT which progressed to VF. Additional treatment included more NaHCO3, adrenaline, sotalol and hyperventilation for arrhythmia and diazepam and phenytoin for convulsions. Full neurological recovery.

Shannon, M. W. (1992). "Duration of QRS disturbances after severe tricyclic antidepressant intoxication." J Toxicol Clin Toxicol 30(3): 377-386.

While the clinical toxicity of tricyclic antidepressants, particularly the development of seizures and arrhythmias, has been strongly correlated with a QRS interval of greater than or equal to 100 msec on electrocardiography, the resolution pattern of QRS abnormalities remains poorly defined. We prospectively monitored 22 consecutive patients who were referred to a regional poison center after a tricyclic antidepressant ingestion associated with a QRS interval of greater than 100 msec. An ECG was obtained every 6-8 h in all patients until the QRS interval was less than 100 msec. Among enrolled patients the mean maximal QRS interval was 145 msec. Ten patients (45.5%) developed seizures while 6 (27%) developed cardiac arrhythmias. The time from ingestion to the last ECG demonstrating a widened QRS interval was a median 12.3 h (range 1-70 h); the time from ingestion to the first ECG with a QRS less than 100 msec was a median 19.3 h (range 3-78 h). No patients developed seizures or life-threatening cardiac arrhythmias after the QRS interval was less than 100 msec. Ten patients received sodium bicarbonate while 12 did not. There were no significant differences in the duration of QRS widening between the two groups. These data suggest that the typical period of QRS prolongation after severe tricyclic antidepressant ingestion is 12-18 h but may be as long 3 d. The factors which determine the duration of QRS widening are unclear. Sodium bicarbonate may not reduce the total duration of QRS disturbances.


1. LOE 5, QOE poor, neutral to hypothesis2. Prospective observational study of duration of QRS prolongation of 22 poisoned

patients, 10 of whom received NaHCO3 while 12 did not. The duration of the QRS prolongation was not different in the two groups.

3. Study has multiple methodological flaws including small numbers, irregular and infrequent analysis of ECGs (some by non-investigators), and administration of several antidotes to recipients who may or may not have received NaHCO3: Nine patients received phenytoin and 2 received physostigmine but it is not revealed which of these did /did not receive NaHCO3, i.e many received more than one antidote which renders difficult an analysis of the effect of NaHCO3 alone.

4. The bicarbonate group had more seizures (50% v 33%) and also had more arrhythmias (40% v 16%)

Wrenn, K., B. A. Smith, et al. (1992). "Profound alkalemia during treatment of tricyclic antidepressant overdose: a potential hazard of combined hyperventilation and intravenous bicarbonate." American Journal of Emergency Medicine 10(6): 553-5.

Two patients with cardiovascular and neurologic toxicity from intentional tricyclic antidepressant overdose received bicarbonate infusions in association with hyperventilation for alkalinization. Both patients developed profound alkalemia. One patient died, and the other patient's alkalemia resolved prior to her death. Bicarbonate infusions have become the standard of care for symptomatic tricyclic antidepressant toxicity. Severe alkalemia (pH greater than 7.60) in other settings has been reported to correlate with higher rates of mortality. Careful monitoring of the pH is imperative when bicarbonate therapy is used. It is probably prudent to keep the pH level in the range 7.45 to 7.60. Capnography may also be useful in monitoring patients during alkalinization.




Auclair 1983

Bou-Abboud 1996

1. LOE 5, QOE poor, opposing hypothesis

------------------------------------------------------------------------------------------------------------------------

ANIMAL and/or IN VITRO EXPERIMEMTATION

Auclair, M. C., H. Daoud El-Assaf, et al. (1983). "[Cardiac disorders induced by mianserin in guinea pigs. Comparison with imipramine]." Journal de Pharmacologie 14(3): 311-24.

Infusion of mianserin to anesthetized guinea-pigs induced electrocardiographic changes (auriculo-ventricular and intraventricular conduction lenghthening, bradycardia, QRS axis and T axis rotations) quite identical to those induced by imipramine. However they appeared later and mianserin produced cardiac arrest at higher dose (133 mg/kg) than did imipramine (73 mg/kg). In vitro, increasing concentrations of mianserin suppressed the electrical response of stimulated, isolated ventricular heart strips, but this suppression was obtained by a higher concentration (172 micrograms/ml) than with imipramine (80 micrograms/ml). Transmembrane potentials were not affected by a 5 or 10 micrograms/ml mianserin or a 5 micrograms/ml imipramine perfusion. With 20 micrograms/ml mianserin or 10 micrograms/ml imipramine, only a reduced duration of the action potential was obtained. With 50 micrograms/ml mianserin or 20 micrograms/ml imipramine, the resting potential was reduced. However, with imipramine only it was preceded by a decrease in the maximal velocity of depolarisation. These results show that mianserin induces transmembrane permeability changes which appear to differ from and to be less marked than those induced by imipramine. Molar sodium bicarbonate reversed in vivo and in vitro the electrophysiologic changes elicited either by mianserin or by imipramine, but with mianserin the transient improvement was followed by an aggravation of the cardiac troubles.


1. LOE 6, QOE fair, supporting hypothesis2. In vivo experiments: anaesthetised guinea pigs (250-300g) with ECG abnormalities

(QRS and PR prolongation, axis deviation) after being poisoned with imipramine or mianserine were treated with 0.5 mmol NaHCO3 (0.5-0.6 mmol/kg). NaHCO3 caused amelioration of ECG abnormailites such as narrowing of QRS duration which in the case of imipramine poisoning lasted 5 +/- 2 minutes and in the case of mianserine poisoning 2 +/- 1 minute. Then in mianserine poisoning, an aggravation of ECG abnormaity ensued with first degree block, arryhtmia (unspecified) and bradycardia.

3. In vitro experiments: both drugs suppressed electrical response of ventricular muscle strips, reduced the duration of action potentials and decreased the maximum velocity of depolarisation. These effects were reversed by NaHCO3.

Bou-Abboud, E. and S. Nattel (1996). "Relative role of alkalosis and sodium ions in reversal of class I antiarrhythmic drug-induced sodium channel blockade by sodium bicarbonate." Circulation 94(8): 1954-61.

BACKGROUND: Hypertonic sodium salts are used to treat sodium channel-blocking drug cardiotoxicity. The relative roles of alkalinization and increased sodium concentration ([Na+]o) for various drugs are incompletely known. METHODS AND RESULTS: The effects of four class I drugs on action potential characteristics of canine Purkinje fibers at equieffective concentrations (disopyramide 30 mumol/L, mexiletine 80 mumol/L, flecainide 7 mumol/L, imipramine 5 mumol/L) were studied in the presence of normal Tyrode solution and one altered solution (increased [Na+]o, increased bicarbonate concentration, or both) in each experiment. Combined increases in sodium and bicarbonate concentration significantly reduced the depressant effects of flecainide, imipramine, and mexiletine on phase 0 upstroke (Vmax) but did not alter the effects of disopyramide. The effects of sodium bicarbonate were entirely due to alkalinization in the case of imipramine, but both alkalinization and increased [Na+]o contributed to the interaction with flecainide and mexiletine. The reversal of Vmax depression by increased [Na+]o and pH was due in



Bou-Abboud 1998

Brown 1976

part to hyperpolarization. In addition, alkalosis directly reversed the hyperpolarizing shift in Vmax inactivation caused by flecainide and imipramine without altering the shift caused by disopyramide and mexiletine. CONCLUSIONS: Increases in sodium bicarbonate concentration reverse the effects of class I antiarrhythmic drugs to a varying extent, with drug-specific contributions of the sodium and bicarbonate moiety. The molecular basis for this drug specificity remains to be elucidated, but it has important potential implications for the use of hypertonic sodium salts to treat cardiotoxicity caused by sodium channel-blocking drugs.

Bou-Abboud, E. and S. Nattel (1998). "Molecular mechanisms of the reversal of imipramine-induced sodium channel blockade by alkalinization in human cardiac myocytes." Cardiovascular Research 38(2): 395-404.

BACKGROUND: Alkalinizing agents reverse cardiotoxicity of a variety of sodium channel blockers, including tricyclic antidepressants, but their mechanisms of action are poorly understood. PURPOSE: To establish the mechanisms by which alkalinization diminishes the sodium channel blocking action of imipramine. METHODS: The whole-cell voltage-clamp technique was used to measure INa during a variety of depolarizing pulse protocols in isolated human atrial myocytes, in the presence and absence of imipramine. A three-state model was used to analyze state-dependent INa block. RESULTS: Imipramine (1 and 5 microM) strongly inhibited INa. Experimental data and piecewise exponential analysis suggested significant binding to both activated and inactivated states. Alkalosis antagonized imipramine-induced INa blockade by increasing the unbinding rate, with intracellular alkalosis being more effective than extracellular alkalosis. The dissociation constant (Kd) for the inactivated state was increased from 0.55 to 1.40 microM by extracellular alkalosis and to 2.51 microM by intracellular alkalosis. Along with the reversal of drug-induced shifts in the inactivation curve, these data indicate that alkalosis on either side of the membrane antagonized drug interactions with the inactivated state. On the other hand, only intracellular alkalosis antagonized activated state block, increasing the Kd from 0.67 microM to 2.18 microM, while extracellular alkalosis left the activated state Kd unaltered at 0.67 microM. CONCLUSIONS: Alkalinization antagonizes the INa-blocking action of imipramine by promoting unbinding from the receptor. Intracellular alkalosis has a particularly important effect related to the activated-state interaction. The lipid-soluble, uncharged moiety appears to be a critical determinant of imipramine's ability to dissociate from the Na+ channel receptor.


1. LOE 6, QOE fair, supporting hypothesis2. Elegant in vitro study with human myocytes in which it was demonstrated that

alkalinisation restored towards normal the conductive properties altered by desipramine.

Brown, T. C. (1976). "Tricyclic antidepressant overdosage: experimental studies on the management of circulatory complications." Clin Toxicol 9(2): 255-272.

Tricyclic antidepressant overdosage may be complicated by cardiac arrhythmias, which were sometimes difficult to treat prior to the use of sodium bicarbonate. Experiments have been done with several antiarrhythmics in an attempt to define the optimum treatment. Sodium bicarbonate proved the most effective experimentally and this supports our clinical experience. Physostigmine is a useful second drug, having beneficial effects against arrhythmias and central nervous system manifestations of toxicity. Practolol, although reversing the arrhythmias, tends to cause hypotension. Other drugs tried were less effective.


1. LOE 6, QOE fair, supporting hypothesis2. NaHCO3 (1-5 mmol/kg) was administered to 4 anaesthetised dogs poisoned with

amitryptaline. Seven other dogs were also treated with NaHCO3 but had been



Brunn 1992

Dumovic 1976

previously given other potential antidotes including practolol, physostigmine, dilantin, potassium chloride, magnesium chloride or calcium gluconate.

3. NaHCO3 restored normal rhythm – in 2 dogs the abnormal rhythm had been ventricular tachycardia and ventricular fibrillation but was not declared in the remaining 2 dogs.

Brunn, G. J., D. E. Keyler, et al. (1992). "Reversal of desipramine toxicity in rats using drug-specific antibody Fab' fragment: effects on hypotension and interaction with sodium bicarbonate." J Pharmacol Exp Ther 260(3): 1392-1399.

The effect of drug-specific antibody Fab' fragment on desipramine (DMI) toxicity was studied in anesthetized rats to determine 1) whether DMI- induced hypotension can be reversed, and 2) whether the effect of this Fab' fragment can be enhanced by the concurrent administration of hypertonic NaHCO3. DMI (60 mg/kg) was administered i.p. to produce marked hypotension. Antitricyclic antidepressant (TCA) Fab' (molar Fab'/DMI ratio = 0.11) or control Fab' was administered 15 min later as a 10 min i.v. infusion. The mean arterial pressure was higher at the end of anti-TCA Fab' infusion than after control Fab' (58 +/- 8 vs. 17 +/- 7 mm Hg, P less than .001). In a second protocol, DMI (30 mg/kg) was administered to prolong QRS duration. Anti-TCA Fab' alone (molar Fab'/DMI ratio = 0.09) and NaHCO3 alone both reduced QRS prolongation compared to control treatment, and combined therapy was more effective than either one alone. In both protocols, anti-TCA Fab' markedly increased the total DMI concentration and the bound fraction of DMI in serum, but did not alter the unbound DMI concentration. In the low DMI dose protocol, anti-TCA Fab' also reduced the cardiac DMI concentration. Concurrent treatment with anti-TCA Fab' and NaHCO3 substantially increased urinary DMI and anti-TCA Fab' excretion compared to treatment with anti-TCA Fab' alone.(ABSTRACT TRUNCATED AT 250 WORDS). Added by worksheet author: These data suggest that 1) anti-Fab’ rapidly reduces the cardiovascular toxicity associated with DMI overdose in the rat, 2) NaHCO3 enghances the efficacy of anti-TCA Fab’, 3) reduction of toxicity is due to DMI redistribution, 4) DMI toxicity can be substantially reduced by the binding of only a small fraction of the DMI dose and 5) NaHCO3 enhances urinary DMI excretion by increasing anti-TCA Fab’ excretion. These observations support the potential clinical use of drug-specific antibody fragments to treat DMI toxicity.


1. LOE 6, QOE poor, supporting hypothesis2. Study in desipramine poisoned anaesthetised rats primarily evaluating efficacy of

antibody therapy. 3. NaHCO3 not tested alone but tested in conjunction with a control antibody (not

desipramine specific) – QRS prolongation duration reduced when combination administered 15 minutes after poisoning, and effect lasted until 60 minutes after poisoning when monitoring stopped. No outcome data. Number of animals in this sub-group not declared but presumably 7 (28 were randomnly assigned to each of 4 groups).

Dumovic, P., G. D. Burrows, et al. (1976). "The effect of tricyclic antidepressant drugs on the heart." Archives of Toxicology. 35(4): 255-62.

The effects on the heart rate and ECG of anaesthetised guines-pigs of amitriptyline, doxepin, imipramine and nortiptyline infused at 1.0 mg/kg/min until death were observed. In addition an in vitro study on guinea-pig atria was performed on the chronotropic and inotropic effects of these drugs and of desmethylimipramine and protriptyline at a concentration of 10(-5) M. The effect of sodium bicarbonate (3 mEq/kg i.v.) and propranolol (0.01--0.2 mg/kg i.v.) on amitriptyline and doxepin induced ECG changes was also assessed. A difference in the cardiac effects of the in vivo and in vitro model was observed. Guinea-pigs infused with doxepin survived significantly longer than those infused with amitriptyline, imipramine or nortriptyline. No statistically significant difference was found between the tricyclic drugs with respect to onset of widening of the QRS complex, increased PR and QT intervals. In the spontaneously beating atrial preparation doxepin was the most potent cardio-depressant. Sodium bicarbonate had no effect on arrhythmias



Hedges 1985

Knudsen 1997

induced by tricyclics, while propranolol, apart from the bradycardia induced, was without beneficial effect on the ECG. The guinea-pig provides a good model for studying the arrhythmogenic actions of tricyclic antidepressants.

Worksheet author comments;

1. LOE 6, QOE poor, opposing hypothesis.2. 3 mmol/Kg given to groups of anaesthetised ventilated guinea pigs poisoned with

IV amitryptaline (n = 8), IV doxepin (N = 8) and to intraperitoneal amitryptaline (N = 4) or doxepin (N = 4).

3. NaHCO3 had no effect on heart rate or ECG. No outcome data.

Hedges, J. R., P. B. Baker, et al. (1985). "Bicarbonate therapy for the cardiovascular toxicity of amitriptyline in an animal model." J Emerg Med 3(4): 253-260.

The beneficial hemodynamic effects of sodium bicarbonate as treatment for tricyclic antidepressant poisoning were investigated in an animal model. Seven adult dogs (17.5 to 20 kg) were poisoned by an intravenous infusion of amitriptyline. Toxicity was defined as a doubling of the initial QRS width. A continuous infusion was used to maintain toxicity for 30 minutes after which 44.5 mEq of sodium bicarbonate was administered intravenously. Five of the animals survived to completion of the experiment. Three of the surviving animals developed dysrhythmias. All dysrhythmias ceased within one minute of administration of sodium bicarbonate. An increase in mean blood pressure (P less than .05) and serum pH (P less than .05) and a decrease in mean QRS width (P less than .05) occurred following administration of sodium bicarbonate. The maintenance of toxicity for 30 minutes suggests that this model can be used for future studies of tricyclic antidepressant poisoning.

Worksheet authors comments

1. LOE 6, QOE fair-poor, Supporting hypothesis2. Small number of animals (7) – 2 died before NaHCO3 given 3. NaHCO3 decreased QRS duration (5 animals), increased amitryptaline induced

hypotension (5 animals) and stopped dysrhythmia (3 animals)4. Did not address question of whether bicarbonate or Na+ was responsible

Knudsen, K. and J. Abrahamsson (1997). "Epinephrine and sodium bicarbonate independently and additively increase survival in experimental amitriptyline poisoning." Critical Care Medicine 25(4): 669-74.

OBJECTIVES: Cardiac depression is the main adverse effect of severe tricyclic antidepressant poisoning. The aim of this study was to investigate whether treatment with epinephrine or norepinephrine increases survival as compared with standard treatment with sodium bicarbonate in experimental amitriptyline poisoning. DESIGN: Nonrandomized, controlled intervention trial. SETTING: University laboratory. SUBJECTS: Male, anesthetized, paralyzed, and mechanically ventilated Sprague-Dawley rats (n = 91). INTERVENTIONS: Rats subjected to a 60-min infusion of amitriptyline (2 mg/kg/min) were treated with a continuous infusion of either epinephrine, norepinephrine, sodium bicarbonate, epinephrine plus sodium bicarbonate, norepinephrine plus sodium bicarbonate, or placebo. MEASUREMENTS AND MAIN RESULTS: Inotropic drug treatment was associated with an increased survival rate as compared with treatment with sodium bicarbonate and treatment with placebo. Epinephrine treatment was superior to norepinephrine. Additional treatment with sodium bicarbonate increased survival rate for each inotropic drug. Sodium bicarbonate and inotropic drug treatment independently increased the survival rate (p < .001 for both effects). No interaction between these two treatment effects was observed. CONCLUSIONS: Both epinephrine and norepinephrine increased the survival rate in tricyclic antidepressant poisoning in rats. Sodium bicarbonate increased the survival rate independent of inotropic drug treatment. Furthermore, epinephrine was superior to norepinephrine when used both with and without sodium bicarbonate, and the most effective treatment was epinephrine plus sodium bicarbonate.



Larkin 1994

Levitt 1986

Worksheet author comments

1. LOE 6, QOE fair, Supporting hypothesis2. NaHCO3 alone (3 mmol/kg) or with epinephrine significantly increased survival of

rats poisoned with amitryptaline3. Non-randomised study

Larkin, G. L., G. M. Graeber, et al. (1994). "Experimental amitriptyline poisoning: treatment of severe cardiovascular toxicity with cardiopulmonary bypass." Annals of Emergency Medicine 23(3): 480-6.

STUDY OBJECTIVE: To compare cardiopulmonary bypass (CPB) with more conventional therapy in the treatment of severe amitriptyline poisoning. DESIGN: Prospective, randomized, controlled, laboratory investigation. INTERVENTIONS: Profound cardiovascular toxicity was induced in 20 anesthetized Yorkshire swine (72 +/- 8.3 kg) by amitriptyline infusion at 0.5 mg/kg/min. Ventilation was adjusted to keep arterial pH at 7.50 +/- 0.05 and the PCO2 at 35 mm Hg. The swine were randomized in a 1:1 ratio to one of two groups, CPB or control. Both groups received amitriptyline infusion until they experienced near-lethal toxicity, defined as a systolic blood pressure below 30 mm Hg for one minute. The control group was then given supportive treatment, including IV fluids, sodium bicarbonate, vasopressors, and standard pharmacologic (advanced cardiac life support) interventions. Control animals failing to respond to supportive measures after five minutes were given open-chest cardiac massage for 30 minutes or until the return of spontaneous circulation. The CPB group received only mechanical support by CPB for 90 to 120 minutes. No sodium bicarbonate, antiarrhythmics, or cardiotonic agents were provided to the CPB group during this resuscitation. RESULTS: All 20 animals experienced cardiac conduction delays, dysrhythmias, and progressive hypotension within 30 minutes of receiving IV amitriptyline at 0.5 mg/kg/min. The ten swine receiving CPB as treatment for cardiovascular toxicity were able to completely correct the dysrhythmias, cardiac conduction abnormalities, and hypotension produced by the amitriptyline; however, only one of ten control animals could be resuscitated (P = .0001). Nine of ten swine treated with CPB were easily weaned off bypass without any pharmacologic intervention; however, one required norepinephrine to be weaned. All 11 resuscitated swine were able to be salvaged. CONCLUSION: CPB improved survival in our swine model of severe amitriptyline poisoning.


1. LOE 6, QOE fair, opposing hypothesis2. Outcome in 2 groups of anaesthetised ventilated amitryptaline-poisoned

hypotensive animals. The control group was treated with boluses of saline, NaHCO3 (1-2 mmol/kg), adequate ventilation and oxygen, norepinephrine infusions (0.1 – 10 mcg/kg/min), epinephrine (0.05mg/kg) and ‘standard ACLS interventions’ including internal cardiac massage and additional doses of NaHCO3 and catecholamines and antiarrhythmics, whereas the experimental group received only up to 120 veno-arterial CPB and low dose norepinephrine infusion (1 mcg/kg/min) during weaning. All bypass animals survived but only one control animal.

3. Experimental design precludes easy distinction of benefits or harm from NaHCO3 alone in the control group.

Levitt, M. A., J. B. Sullivan, Jr., et al. (1986). "Amitriptyline plasma protein binding: effect of plasma pH and relevance to clinical overdose." American Journal of Emergency Medicine 4(2): 121-5.

Reversing ventricular ectopy with plasma alkalinization following acute tricyclic antidepressant overdose is a recognized mode of therapy. The mechanism responsible for this effect is unclear. Changes in plasma protein binding of free drug, effects of the sodium



McCabe 1998

McCabe 1994

ion on the myocardium, and alterations of plasma concentrations of alpha-1-acid glycoprotein may all interact to alter toxicity of tricyclics in overdose. An in vitro investigation using equilibrium dialysis was designed to examine the effect of altering plasma pH on percentage of free amitriptyline at clinical overdose plasma concentrations. A 1973 report on this effect lacked adequate controls and was faulty in experimental protocol. The current investigation used plasma concentrations typically present in amitriptyline overdose, a sensitive gas liquid chromatographic assay to detect total and free drug, and adequate control of plasma pH. The results of two separate experiments demonstrated a significant decrease in percentage of free amitriptyline of 20% over a pH range of 7.0-7.4 (P less than 0.05) and 42% over a pH range of 7.4-7.8 (P less than 0.05). The rate of change in slope in both experiments was not significantly different (P less than 0.01) indicating similar effects of pH change on plasma protein binding of amitriptyline within the two groups.

Worksheet Author Comments;

1. LOE 6, QOE poor, supporting hypothesis2. In vitro study of percentage of amitryptaline binding in human plasma with

alteration of pH by phosphate buffers.3. The percentage change in the free drug is notable (20% change over pH range 7.0

– 7.4; 42% change over pH 7.4 – 7.8 but the absolute actual percent binding (MEAN +/-SD) is less so: at pH 7.1, 9.7+/-0.5%; pH 7.22, 9.4+/-0.6%; pH 7.24, 8.7+/-0.23; pH, 7.33 8.0+/-1.3; pH 7.45, 7.4+/-not stated.

McCabe, J. L., D. J. Cobaugh, et al. (1998). "Experimental tricyclic antidepressant toxicity: a randomized, controlled comparison of hypertonic saline solution, sodium bicarbonate, and hyperventilation." Ann Emerg Med 32(pt 1)(3): 329-333.

STUDY OBJECTIVE: We sought to compare the effects of hypertonic sodium chloride solution (HTS), sodium bicarbonate solution, and hyperventilation (HV) on severe tricyclic antidepressant (TCA) toxicity in a swine model. METHODS: Twenty-four mixed-breed, domestic swine of either sex were given an intravenous infusion of nortriptyline (NT) until development of both a QRS duration longer than 120 ms and a systolic blood pressure (SBP) less than or equal to 50 mm Hg. Animals were randomly assigned to 1 of 4 groups. On reaching toxicity, the control group received 10 mL/kg of 5% dextrose in water (D5W); the HTS group received 10 mL/kg of 7.5% NaCl solution (15 mEq Na+/kg); the NaHCO3 group received 3 mEq/kg of 8.4% sodium bicarbonate solution followed by enough D5W solution to equal 10 mL/kg of total volume; and the HV group was mechanically hyperventilated to maintain arterial pH between 7.50 and 7.60 and given 10 mL/kg of D5W. RESULTS: The mean SBP 10 minutes after treatment was 54+/-18 mm Hg in the control group, 134+/-21 mm Hg in the HTS group, 85+/-19 mm Hg in the NaHCO3 group, and 60+/-12 mm Hg in the HV group (P<.05). Mean QRS duration 10 minutes after treatment was 144+/-38 ms in the control group, 80+/-14 ms in the HTS group, 105+/-38 ms in the NaHCO3 group, and 125+/-46 ms in the HV group (P<.05). CONCLUSION: In this model of TCA, toxicity HTS was more effective than sodium bicarbonate. Hyperventilation had little effect. Sodium loading may be the most important factor in reversing TCA toxicity.

Worksheet author comments

1. LOE 6, QOE fair, supporting hypothesis2. Twenty four anaesthetised mechanically ventilated nortryptaline poisoned animals

were randomnly assigned to receive D5W, hypertonic saline, NaHCO3 or hyperventilation

3. Hypertonic saline (15 mmol/kg) was superior to NaHCO3 (3 mmol/kg) but both were superior to hyperventiulation compared with D5W.

McCabe, J. L., J. J. Menegazzi, et al. (1994). "Recovery from severe cyclic antidepressant overdose with hypertonic saline/dextran in a swine model." Academic Emergency Medicine 1(2): 111-5.



Nattel 1984a

OBJECTIVE: To determine the effect of a hypertonic saline and dextran (HSD) solution on blood pressure and QS duration during severe cyclic antidepressant (CA) toxicity in swine. METHODS: Ten domestic swine weighing 20-24 kg were anesthetized and placed on mechanical ventilation. Nortriptyline solution was infused intravenously to achieve hypotension (systolic blood pressure equal to 50% of baseline) and a QRS duration of 120 msec. After reaching toxicity, the animals received in a randomized fashion either 10 mL/kg of a 7.5% saline/6% dextran solution or an equal volume of 0.9% saline as a rapid intravenous bolus. The animals were observed for one hour or until they died. Blood pressure and ECG were recorded continuously. Arterial pH was maintained in the physiologic range by controlled ventilation. RESULTS: Mean systolic blood pressure 10 minutes after treatment was 45 +/- 8 torr in the normal- saline group compared with 115 +/- 12 torr in the HSD group (p < 0.05). Mean QRS duration 10 minutes after treatment was 180 +/- 8 msec in the normal-saline group; it was 88 +/- 13 msec in the HSD group (p < 0.05). All normal-saline--group animals died within 20 minutes, and four of the five animals in the HSD group survived to 60 minutes (p < 0.05). The mean peak sodium concentration was 157 mmol/dL (mEq/dL) in the HSD group, and this was transient. CONCLUSION: In this swine model of severe CA toxicity, a solution of 7.5% saline/6% dextran significantly reversed hypotension and QRS prolongation. HSD also improved survival to 60 minutes.


1. LOE 6, QOE good, opposing hypothesis2. Randomised single blinded trial of normal saline vs hypertonic saline in

mechanically ventilated anesthetised nortryptaline poisoned swine.3. Hypertonic saline significantly shortened QRS prolongation, restored blood

pressure and enabled better short term survival compared with normal saline leading the investigators to suggest that sodium in NaHCO3 may have an independent effect in reversing tricyclic toxicity (although was not the subject iof this study).

Nattel, S., H. Keable, et al. (1984). "Experimental amitriptyline intoxication: electrophysiologic manifestations and management." Journal of Cardiovascular Pharmacology 6(1): 83-9.

Amitriptyline intoxication can result in severe ventricular arrhythmias that may be refractory to medical management. The mechanisms of these arrhythmias are unclear, and their optimal management is problematic. We studied the cardiac effects of amitriptyline infusion in anesthetized and awake dogs. Amitriptyline significantly increased heart rate, QRS duration, and AH and HV intervals. The concentration-response curves for these effects were, however, quite different, with significant changes beginning at a concentration of 1.5 +/- 0.4 mg/L for heart rate, compared with 2.4 +/- 0.4 mg/L for QRS and HV intervals and 3.7 +/- 0.5 mg/L for the AH interval. Ventricular tachyarrhythmias developed after marked QRS widening had occurred, and appeared in all six awake dogs and five of the six anesthetized dogs studied. Sodium bicarbonate was given to seven animals with ventricular tachyarrhythmias, and it rapidly reversed the arrhythmia in all instances. The benefit from sodium bicarbonate could not be attributed to changes in serum potassium or amitriptyline concentrations. It may have been due to alkalinization or changes in serum sodium concentration. These experiments suggest that: (a) amitriptyline intoxication frequently produces ventricular tachyarrhythmias, if high enough drug concentrations are achieved; (b) these arrhythmias are associated with marked slowing of intraventricular conduction; and (c) sodium bicarbonate is effective therapy for amitriptyline-induced ventricular arrhythmia.


1. LOE 6, QOE fair, supporting hypothesis2. Experimental study of efficacy of NaHCO3 in amitryptaline poisoned awake and

anesthetised dogs.3. NaHCO3 reversed arrhythmias in 7 dogs and reduced QRS duration



Nattel 1984b

Pentel 1984

Nattel, S. and M. Mittleman (1984). "Treatment of ventricular tachyarrhythmias resulting from amitriptyline toxicity in dogs." Journal of Pharmacology & Experimental Therapeutics 231(2): 430-5.

This study was designed to analyze the effects of lidocaine and sodium bicarbonate on ventricular arrhythmias resulting from amitriptyline infusion in dogs. Amitriptyline was infused i.v. at 0.5 mg/kg/min for 30 min, followed by 1 mg/kg/min to dogs anesthetized with morphine and alpha-chloralose. When arrhythmia occurred, the infusion rate was reduced by one-third and the effect of various interventions studied. In the initial 18 dogs, lidocaine, sodium bicarbonate or isotonic saline was administered i.v. to six dogs each in a randomized, blinded fashion. The prevalence of ventricular ectopic complexes was not changed after isotonic saline, but was reduced by lidocaine at concentrations greater than or equal to 5 mg/l and by sodium bicarbonate. The effects of lidocaine were transient and associated with significant blood pressure reduction. Sodium bicarbonate produced more dramatic and sustained arrhythmia reversal along with a reduction in amitriptyline-induced conduction slowing. Administration of hypertonic sodium chloride in equimolar quantities to sodium bicarbonate failed to affect amitriptyline-induced ventricular arrhythmias significantly, but hyperventilation to a pH similar to that produced by sodium bicarbonate (7.48) significantly reduced the frequency of amitriptyline-induced ventricular ectopy. When amitriptyline was infused into dogs ventilated with various respiratory rates, ventricular arrhythmia resulted in 18 of 18 (100%) dogs with pH less than 7.42, 2 of 4 (50%) dogs with pH between 7.48 and 7.51 and 0 of 8 (0%) dogs with a pH between 7.59 and 7.65 (P less than or equal to .001). These results suggest that sodium bicarbonate is effective treatment for amitriptyline-induced cardiac arrhythmias with beneficial effects largely due to alkalinization.(ABSTRACT TRUNCATED AT 250 WORDS) Continued by worksheet author: Alkalinization has both therapeutic and prophylactic value and appears to be superior to lidocaine therapy.


1. LOE 6, QOE good, supporting hypothesis2. Controlled single blinded study of efficacy of two doses each of lidocaine (2 mg/kg),

sodium bicarbonate (1 mmol/kg) and isotonic saline (30 mL) in anaesthetised mechanically ventilated amitryptaline poisoned dogs, and in unblinded fashion the efficacy of hyperventilation and of two doses of hypertonic saline (Na+ 1 mmol/kg).

3. Whereas isotonic saline was ineffective, both lidocaine and NaHCO3 reduced prevalence of VEs but lidocaine caused hypotension, and NaHCO3 curtailed arrhythmias and reduced prolongation of QRS. Whereas hyperventilation reduced frequency of ventricular ectopy, hypertonic saline did not – leading investigators to conclude that NaHCO3 reduces amitryptaline-induced arrhythmia by alkalinization.

Pentel, P. and N. Benowitz (1984). "Efficacy and mechanism of action of sodium bicarbonate in the treatment of desipramine toxicity in rats." Journal of Pharmacology & Experimental Therapeutics 230(1): 12-9.

Alkalinization of the blood by administration of sodium bicarbonate or hyperventilation is widely recommended for treatment of cardiac toxicity due to tricyclic antidepressant overdose, yet its efficacy and mechanism of action are poorly defined. We studied the effects and possible mechanism of action of 1 M NaHCO3 on desipramine (DMI) toxicity in anesthetized, paralyzed rats. Administration of DMI (45 mg/kg i.p.) produced a mean increase in QRS duration of 142% and a mean decrease in mean arterial pressure of 46%. Treatments were administered i.v. 35 min after DMI and their effects were assessed 10 min later. NaHCO3 (1 M) at doses of 3 and 6 mEq/kg decreased mean QRS duration 15 +/- 5 and 24 +/- 6%, respectively (mean +/- S.D.) and was superior to no treatment (P less than .01). NaCl (1 M) was as effective as NaHCO3 in decreasing QRS duration, as was 1 M NaHCO3 supplemented with 48 mM KCl. Respiratory alkalosis and 10% mannitol did not decrease QRS duration. NaHCO3, NaCl and NaHCO3/KCl all produced comparable increases in mean arterial blood pressure. Respiratory alkalosis and mannitol did not increase mean arterial pressure, but did prevent the decline seen in control animals. Acidosis produced by ventilation with 10% CO2 exacerbated QRS



Pentel 1995

prolongation due to DMI. In acidotic animals, NaHCO3 and NaCl were equally effective in reversing QRS prolongation and hypotension. Correction of respiratory acidosis by discontinuation of inhaled CO2 did not improve QRS duration or mean arterial pressure.(ABSTRACT TRUNCATED AT 250 WORDS) Added by worksheet author: The beneficial effects of treatments on QRS prolongation correlated with increases in plasma sodium concentration but not with changes in plasma potassium or DMI concentrations, arterial pH or the degree of intravascular volume expansion. We conclude that 1) 1 M NaHCO3 can partially reverse the cardiovascular toxicity of DMI in both normal pH and acidotic animals, 2) the beneficial effects of NaHCO3 on QRS prolongation may be due to increasing the plasma sodium concentration, 3) acidosis exacerbates DMI toxicity but correction of acidosis or increasing blood pH above normal were not effective therapies and 4) the beneficial effect of NaHCO3 on blood pressure may be due to factors in addition to increasing plasma sodium concentration, such as intravascular volume expansion.


1. LOE 6, QOE good, supporting hypothesis2. Well conducted study in anaesthetised ventilated rats poisoned with desipramine

which increased QRS duration and caused hypotension..3. NaHCO3 at 3 or 6 mmol/kg significantly decreased QRS duration but this effect

was also observed with NaCl and with NaHCO3/KCl whereas respiratory alkalosis (and mannitol) had no effect.

4. NaHCO3 significantly increased blood pressure but this was also observed with NaCl, NaHCO3/KCl, Mannitol and respiratory alkalosis.

5. No outcome data.

Pentel, P. R., W. Scarlett, et al. (1995). "Reduction of desipramine cardiotoxicity and prolongation of survival in rats with the use of polyclonal drug-specific antibody Fab fragments." Annals of Emergency Medicine 26(3): 334-41.

STUDY OBJECTIVE: Tricyclic antidepressants (TCAs) are a leading cause of death from intentional drug overdose. Available therapies are often unsatisfactory. In this study we evaluated the use of a high-affinity drug-specific polyclonal Fab fragment (TFab) as an antidote to desipramine toxicity. DESIGN: We gave anaesthetized rats under mechanical ventilation IV desipramine so that we might study the effect of TFab on survival or IP desipramine to facilitate study of the interaction of TFab and hypertonic sodium bicarbonate (NaHCO3), the standard clinical treatment for TCA overdose. INTERVENTIONS: For the study of the effects of TFab and NaHCO3 on survival, each rat was given a constant IV infusion of desipramine until it died, together with TFab 2 g/kg, bovine serum albumin, or .9% NaCl starting 5 minutes after the desipramine infusion. In the study of the interaction of TFab and NaHCO3, each rat received 30 mg/kg IP desipramine followed by TFab (molar TFab:desipramine ratio, .11), NaHCO3, TFab+NaHCO3, or NaCl at the time of maximal toxicity (15 minutes). RESULTS: In the survival protocol, QRS-interval duration, systolic blood pressure, and heart rate were significantly improved by TFab, and survival was prolonged by 58% compared with that in the albumin and NaCl groups (P < .001). The molar ratio of TFab to administered desipramine was .21. The unbound fraction of desipramine in serum at the time of death was reduced by TFab, but the unbound desipramine concentration was not, suggesting that TFab prolonged survival by delaying the increase in the unbound serum desipramine concentration. In the interaction protocol, neither TFab nor NaHCO3 was effective alone, but the combination significantly reduced QRS-interval prolongation (P = .001). CONCLUSION: These data demonstrate the efficacy of TFab in reducing desipramine-induced cardiovascular toxicity and prolonging survival. The pharmacokinetic effects of TFab in rats with severe desipramine toxicity were similar to those observed in sublethal desipramine toxicity. Therapeutic benefit is enhanced by the concurrent use of NaHCO3 and may be achieved despite binding only a fraction of the desipramine dose.

Worksheet author comments;

1. LOE 6, QOE poor, neutral to hypothesis.



Sasyniuk 1984

Sasyniuk 1986

2. Study of reduction of QRS prolongation, amelioration of hypotension, or reduction in increased heart rate by 4 treatments in anaesthetised ventilated desipramine poisoned rats: drug-specific Fab antibody plus NaHCO3, Fab antibody plus NaCL, NaHCO3 plus NaCl, NaCl plus NaCl. Combined treatments were administered at separate times allowing seoarate analysis of components of each treatment.

3. Neither Fab antibody nor NaHCO3 alone reduced QRS prolongation but their combination was effective. Neither Fab antibody nor NaHCO3 alone had any effect on hypotension or heart rate in comparison to the other treatments.

4. Unfortunately, the control treatment NaCl is also a putative antidote which limits the scope of permissible conclusions which can be drawn from this study.

Sasyniuk, B. I. and V. Jhamandas (1984). "Mechanism of reversal of toxic effects of amitriptyline on cardiac Purkinje fibers by sodium bicarbonate." Journal of Pharmacology & Experimental Therapeutics 231(2): 387-94.

Alkalinization with NaHCO3 can effectively reverse ventricular arrhythmias caused by amitriptyline intoxication, but the mechanism is unclear. To test whether alkalinization per se is important or whether increases in extracellular Na concentration also contribute, we exposed Purkinje fibers to 500 ng/ml (1.8 microM) of amitriptyline and then superfused them with three different test solutions, viz. 1) high Na-Tyrode's, 2) high NaHCO3-Tyrode's and 3) high pH-low pCO2-Tyrode's. Amitriptyline significantly depressed action potential amplitude and Vmax without altering resting membrane potential and abbreviated action potential duration at all phases of repolarization. Effects on phase 0 were accompanied by a depression of conduction velocity. All three test solutions produced significant hyperpolarization and improvement in action potential amplitude and Vmax. However, the magnitude of improvement of phase 0 characteristics was significantly greater after high NaHCO3 and resulted in significant improvement of conduction velocity in fibers depressed by amitriptyline. The effects of amitriptyline on phase 0 were rate-dependent. Reversal of this effect by NaHCO3 was equally effective at all rates. Improvement of Vmax was partly related to a shift of the Vmax-membrane potential relationship in the depolarizing direction. NaHCO3 had minimal and variable effects on action potential duration. The results suggest that the beneficial effects of NaHCO3 are related to a reversal of drug effects on phase 0 characteristics and that this effect is due both to alkalinization and to increases in extracellular Na concentration.


1. LOE 6, QOE fair, supporting hypothesis2. In vitro study on canine Purkinje fibers to determine if alkalinisation per se or Na

neutralises amitryptaline toxicity.3. Both Na+ and alkalinisation improved action potential magnitude and Vmax

Sasyniuk, B. I., V. Jhamandas, et al. (1986). "Experimental amitriptyline intoxication: treatment of cardiac toxicity with sodium bicarbonate." Ann Emerg Med 15(9): 1052-1059.

Overdose with amitriptyline and other tricyclic antidepressants can result in ventricular conduction abnormalities as well as severe ventricular arrhythmias. The arrhythmogenic effects of these compounds may be attributed to their direct local anesthetic actions in blocking sodium channels in cardiac membranes. Thus tricyclic-induced ventricular arrhythmias usually do not respond well to therapy with standard Class I antiarrhythmic drugs that also have the same direct local anesthetic action and may potentiate the adverse effects of tricyclic antidepressants. Cardiac toxicity was produced in dogs by the administration of amitriptyline, both orally and IV. At serum concentrations less than 2,000 ng/mL, sinus tachycardia occurred with widened QRS complexes. At higher concentrations, QRS duration became more markedly prolonged and was followed by ventricular tachyarrhythmias. Occurrence of ventricular tachyarrhythmias was associated with QRS durations of more than 0.11 second. Sodium bicarbonate (18 to 36 mEq) administered IV over either 30 seconds or two minutes rapidly converted ventricular tachycardia to normal sinus rhythm. Conversion was associated with abbreviation of the QRS complex and was accompanied by a rise in both systolic and diastolic pressures. The



Stone 1995

duration of sodium bicarbonate effect paralleled the duration of the changes in arterial pH and plasma bicarbonate concentrations. In vitro studies in cardiac Purkinje fibers suggested that reversal of amitriptyline-induced cardiac membrane effects by sodium bicarbonate may be attributed not only to alkalinization but also to increased in extracellular sodium concentration, diminishing the local anesthetic action of amitriptyline and resulting in less sodium channel block.(ABSTRACT TRUNCATED AT 250 WORDS) Added by worksheet author: The direct depressant effect of amitryptaline on conduction is frequency dependent, and thus would be expected to be potentiated by the anti-cholinergic -mediated sinus tachycardia that accompanies toxicity. Counteracting the sinus tachycardia with either propranolol or physostigmine may reduce the direct cardiotoxic effect of the drug, but may exacerbate the hypotensive effects. Our results suggest that alkalinization with sodium bicarbonate provides an effective therapeutic modality for the treatment of tricyclic-induced cardiac toxicity.


1. LOE 6, QOE fair-good, supporting hypothesis2. Eight dogs, poisoned experimentally with amitryptaline, exhibited either ventricular

arrhythmias or supraventricular tachycardia. In these, administration of 18 to 36 mmol Na HCO3 (average 1.96 mmol/Kg) was associated with reversion of ventricular arrhythmia to ‘a regular rhythm’ and in every case reversion was accompanied by an abbreviation of QRS complex and an improvement in blood pressure. Supraventricular tachycardia ‘usually responded with a slowing of the heart rate and an abbreviation of the QRS complex’. After 15 minutes, the QRS duration resumed pre-sodium bicarbonate status. In thgis respect, only the results from 5 animals were presented while those from the remaining 3 were not explained.

3. To determine whether it was alkalinization or sodium which was effective, canine cardiac Purkinje fibres in vitro with amitryptaline were exposed to solutions which mimicked respiratory alkalosis and/or hypernatraemia. Changes in fibre Vmax

suggested that both alkalinization and high sodium concentration had beneficial effects.

Stone, C. K., C. M. Kraemer, et al. (1995). "Does a sodium-free buffer affect QRS width in experimental amitriptyline overdose?" Annals of Emergency Medicine 26(1): 58-64.

STUDY OBJECTIVES: We carried out this study to determine the effects of pH alteration on QRS width with administration of tromethamine, a non-sodium-containing buffering agent, in experimental amitriptyline overdose. DESIGN: Prospective, nonblinded trial. PARTICIPANTS: Adult mongrel dogs. INTERVENTIONS: Pentobarbital-anesthetized dogs were overdosed with amitriptyline 5 mg/kg followed by infusion at 1.0 mg/kg/minute until the QRS width doubled, then decreased to .5 mg/kg/minute until the end of the experiment. At two defined points of toxicity, the dose of tromethamine required to raise the pH to 7.50 +/- 4 was given. pH and QRS width at a speed of 100 mm/second were measured over a 30-minute period after each tromethamine dose. Data were analyzed with non-linear-regression analysis. RESULTS: At toxicity 1 the mean pH was 7.32, with a QRS width of 11.6 mm. Two minutes after the tromethamine dose the pH rose to 7.51, with narrowing of the QRS width to 8.4 mm. At toxicity 2 the pH was 7.40, with QRS width of 10.6 mm. Two minutes after tromethamine, the pH rose to 7.49 and the QRS width decreased to 9.7 mm. Regression analysis showed a correlation between pH and QRS width; as pH increased, QRS width decreased (P = .0001). CONCLUSION: Cardiac toxicity of amitriptyline overdose, as manifested by QRS widening, is reversible by pH changes alone.


1. LOE 6, QOE poor, supporting hypothesis2. Administration of buffer tromethamine (THAM) to anaesthetised amitryptaline

poisoned dogs to determine effect on QRS duration.3. A significant correlation was demonstrated between blood pH as altered by THAM,

and QRS width (As pH increased QRS reduced).



Tobis 1981

Wananukul 1996

4. However, 4 of the 8 animals died irrespective of the buffer.

Tobis, J. M. and W. S. Aronow (1981). "Cardiotoxicity of amitriptyline and doxepin." Clin Pharmacol Ther 29(3): 359-364.

The cardiotoxicity of the tricyclic antidepressants amitriptyline and doxepin were compared in an animal with acute overdose. The mean repetitive extrasystole threshold (RET) decreased 71.5% with amitriptyline and 27.5% with doxepin (mean blood levels 933 ng/ml and 1889 ng/ml). Physostigmine reversed these effects. Sodium bicarbonate had a variable effect on the lowered RET. The toxic arrhythmogenic effects of the tricyclic antidepressants can be measured by RET and are partly autonomic tone manipulation. In the same blood level range, doxepin is less toxic than amitriptyline.

Wananukul, W., D. E. Keyler, et al. (1996). "Effect of calcium chloride and 4-aminopyridine therapy on desipramine toxicity in rats." J Toxicol Clin Toxicol 34(5): 499-506.

BACKGROUND: Hypotension is a major contributor to mortality in tricyclic antidepressant overdose. Recent data suggest that tricyclic antidepressants inhibit calcium influx in some tissues. This study addressed the potential role of calcium channel blockade in tricyclic antidepressant-induced hypotension. METHODS: Two interventions were studied that have been shown previously to improve blood pressure with calcium channel blocker overdose. CaCl2 and 4-aminopyridine. Anesthetized rats received the tricyclic antidepressant desipramine IP to produce hypotension, QRS prolongation, and bradycardia. Fifteen min later, animals received CaCl2, NaHCO3, or saline. In a second experiment, rats received tricyclic antidepressant desipramine IP followed in 15 min by 4-aminopyridine or saline. RESULTS: NaHCO3 briefly (5 min) reversed hypotension and QRS prolongation. CaCl2 and 4- aminopyridine failed to improve blood pressure. The incidence of ventricular arrhythmias (p = 0.004) and seizures (p = 0.03) in the CaCl2 group was higher than the other groups. CONCLUSION: The administration of CaCl2 or 4-aminopyridine did not reverse tricyclic antidepressant-induced hypotension in rats. CaCl2 therapy may possibly worsen both cardiovascular and central nervous system toxicity. These findings do not support a role for calcium channel inhibition in the pathogenesis of tricyclic antidepressant-induced hypotension.


1. LOE 6, QOE poor, supporting hypothesis2. This study not designed primarily to test NaHCO3 (was for CaCl2, 4-aminopyridine)3. NaHCO3 was better than saline at increasing BP and reducing QRS duration, but

these effects were not different from controls after 30 minutes

SOME REVIEWS and COMMENTARY ARTICLES (NOT INCLUDED IN EVIDENCE GRIDS)

Blackman, K., S. G. Brown, et al. (2001). "Plasma alkalinization for tricyclic antidepressant toxicity: a systematic review. [Review] [48 refs]." Emergency Medicine 13(2): 204-10.

OBJECTIVE: To review the evidence that plasma alkalinization improves the outcome in tricyclic antidepressant toxicity. METHODS: Medline search from 1966 to October 2000 (articles in all languages were included) and examination of bibliographies. Published papers including animal studies, in vitro studies, human case reports, case series and retrospective studies were reviewed. RESULTS: Our search identified 115 publications, all of which were retrieved. Human studies included eight case reports, four case series, one controlled study and two retrospective chart reviews. No randomized controlled human trials were found. Twelve animal studies were identified that investigated pH manipulation or saline load and their effects on physiological parameters in tricyclic antidepressant toxicity. CONCLUSIONS: The practice of alkalinization for tricyclic



antidepressant toxicity is based on animal studies, case reports and opinion. The mechanism of action appears to be multifaceted and may vary between different tricyclic antidepressants. Significant interspecies variation makes extrapolation from animal studies to humans difficult. Alkalinization therapy appears reasonable in patients with compromising dysrhythmias and shock when supportive interventions have been ineffective; however, the available evidence does not support prophylactic alkalinization in the absence of life-threatening cardiovascular toxicity. [References: 48]

Braden, N. J., J. E. Jackson, et al. (1986). "Tricyclic antidepressant overdose. [Review] [48 refs]." Pediatric Clinics of North America 33(2): 287-97.

Overdose of a tricyclic antidepressant is a serious and all-too-frequent occurrence. The diagnosis must be considered in known or suspected overdoses, and signs such as a dry axilla, tachycardia, and wide QRS must be specifically sought. Management depends upon support of vital functions and a thorough understanding of the pharmacology of the drug. Emptying the gastrointestinal tract with ipecac or lavage and hastening elimination with activated charcoal and a cathartic are extremely important measures. Cardiac arrhythmias generally respond to sodium bicarbonate, and seizures respond to intravenous diazepam. Neither physostigmine nor dialysis are considered to be treatments of choice. As in other overdoses, counseling to prevent ingestions is more than worth "a pound of the cure." [References: 48]

Crome, P. (1986). "Poisoning due to tricyclic antidepressant overdosage. Clinical presentation and treatment." Medical Toxicology. 1(4): 261-85.

Tricyclic antidepressants are among the commonest causes of both non-fatal and fatal drug poisoning in the world. Their toxicity is due to effects on the brain, the heart, the respiratory system and the parasympathetic nervous system. Symptoms usually appear within 4 hours of an overdose and all but the most seriously poisoned patients recover within 24 hours. The most common clinical features are dry mouth, blurred vision, dilated pupils, sinus tachycardia, pyramidal neurological signs, and drowsiness. In severe poisoning, there may be coma, convulsions, respiratory depression, hypotension and a wide range of electrocardiographic (ECG) abnormalities. The most frequent findings on the ECG are prolongation of the PR and QT intervals; the tracing may resemble bundle branch block or supraventricular or ventricular tachycardias. Treatment of poisoning due to the tricyclic antidepressants is essentially supportive, there being insufficient evidence at present to recommend the use of methods to increase elimination of the drug from the body. Gastric aspiration and lavage should be performed if more than 750 mg of drug have been taken. There must be regular monitoring for hypoxia, acidosis and hypokalaemia and these complications should be corrected enthusiastically. Convulsions should be treated with diazepam or chlormethiazole. Muscular paralysis and artificial ventilation should be employed if anticonvulsants are ineffective. Hypotension should be treated firstly by fluid replacement and then with sympathomimetic agents (dopamine or dobutamine). Antiarrhythmic drugs should only be employed if there is evidence of circulatory failure which fails to respond to correction of hypotension. Sodium bicarbonate infusions should be given to cardiotoxic patients who are acidotic and are worth trying even if the patient is not acidotic. Although physostigmine salicylate will reverse most of the features of tricyclic antidepressant poisoning, its effects are short-lived in serious toxicity and it can produce dangerous side effects; physostigmine should therefore be reserved for those patients who have complications of coma or who have resistant cardiotoxicity or convulsions. Drug screening and quantitative determination of tricyclic antidepressant serum concentrations are useful in a minority of patients who have severe, unusual or prolonged symptoms. [References: 213]

Dziukas, L. J. and J. Vohra (1991). "Tricyclic antidepressant poisoning. [Review] [98 refs]." Medical Journal of Australia 154(5): 344-50.

OBJECTIVE: To review poisoning with tricyclic antidepressants. DATA SOURCE: English language literature search using Australian Medlars Service (1977-1989), manual search of journals and review of bibliographies in identified articles. STUDY SELECTION:



Approximately 250 articles, abstracts and book chapters were selected for analysis. DATA EXTRACTION: The literature was reviewed and 93 articles were selected as representative of important advances. DATA SYNTHESIS: The major features of overdose are neurological, cardiac, respiratory and anticholinergic. Life-threatening complications develop within six hours of overdose or not at all. All patients seen within six hours of overdose should have their stomachs emptied. All patients should receive activated charcoal. Coma, convulsions, respiratory depression and hypotension are treated with standard resuscitation techniques and drugs. Treat patients with significant cardiotoxicity or cardiac arrest with alkalinisation by sodium bicarbonate or hyperventilation, aiming for an arterial pH of 7.45-7.55. Lignocaine is used for ventricular arrhythmias. Other antiarrhythmic drugs are contraindicated (Class 1A, Class 1C), potentially lethal (Class II), of no benefit (phenytoin) or of unproven efficacy (Class III and Class IV). Physostigmine has no role at all. Haemodialysis and haemoperfusion are of no benefit. CONCLUSION: The death rate of those who reach hospital is 2%-3%. Most of these deaths are cardiac in origin, and are caused by direct depression of myocardial function rather than cardiac arrhythmias. [References: 98]

Glauser, J. (2000). "Tricyclic antidepressant poisoning. [Review] [38 refs]." Cleveland Clinic Journal of Medicine 67(10): 704-6.

Tricyclic antidepressant poisoning causes predictable electrocardiographic abnormalities and can be lethal. Cardiac arrhythmias, hypotension, seizures, and coma are common. Sodium bicarbonate is still considered the treatment of choice for severe toxicity, although a variety of supportive measures may be taken. Hypertonic saline appears to be a promising alternative. A QRS interval longer than 100 ms appears to be a better predictor of serious complications than is an elevated serum tricyclic antidepressant level. Cardiovascular toxicity is classically manifested as ventricular dysrhythmias, hypotension, heart block, bradyarrhythmias, or asystole. Activated charcoal binds tricyclic antidepressants. Give 30 to 50 g orally or by nasogastric tube with or without a cathartic (sorbitol 0.5 g/kg or 30 g of magnesium sulfate). Sodium bicarbonate is indicated if the QRS duration is more than 100 ms or the terminal right-axis deviation is more than 120 degrees. The suggested dosage is 1 to 2 mEq/kg, repeated as needed. Tricyclic antidepressants are used not only for depression but also for chronic pain syndromes, obsessive-compulsive disorder, panic and phobic disorders, eating disorders, migraine prophylaxis, and peripheral neuropathies. [References: 38]

Grillo, J. A. and E. R. Gonzalez (1993). "Changes in the pharmacotherapy of CPR. [Review] [42 refs]." Heart & Lung: Journal of Acute & Critical Care 22(6): 548-53.

The objective of this study was to review current changes in the pharmacologic management of cardiac arrest (ventricular fibrillation, pulseless ventricular tachycardia, asystole, and electromechanical dissociation) as put fourth by the American Heart Association's 1992 Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiac Care. We concluded that the 1992 Guidelines provide a reference base for all clinicians involved in emergency cardiac care. The newly revised recommendations are classified on the basis of the true clinical merit of the intervention, for example, an intervention that has been proved effective (i.e., high-dose epinephrine) versus one that is possibly effective (i.e., high-dose epinephrine). The preferred intravenous fluid to be used in resuscitation is saline solution or lactated ringers solution because of possible adverse neurologic outcomes seen with dextrose-containing fluids. The dose of all drugs administered via the endotracheal route should be 2 to 2.5 times the intravenous dose. Modifications in the dose or dosing interval have been recommended for epinephrine, atropine, lidocaine, bretylium, and procainamide during cardiopulmonary resuscitation. Options for high-dose epinephrine therapy are offered, but neither recommended or discouraged. Magnesium sulfate has been added for the management of torsades de points, severe hypomagnesemia, or refractory ventricular fibrillation. The maximum total dose of atropine in the treatment of asystole and electromechanical dissociation has been increased from 2 mg to 0.04 mg/kg. The use of sodium bicarbonate should be limited to the treatment of hyperkalemia, tricyclic antidepressant overdose, overdoses requiring urinary alkalinization, or preexisting bicarbonate sensitive acidosis. [References: 42]



Groleau, G., R. Jotte, et al. (1990). "The electrocardiographic manifestations of cyclic antidepressant therapy and overdose: a review. [Review] [53 refs]." Journal of Emergency Medicine 8(5): 597-605.

Cyclic antidepressants may cause changes in the electrocardiogram at therapeutic or toxic serum levels. The most serious complications of cyclic antidepressant toxicity are dysrhythmias, hypotension, and seizures. It is predominantly the cardiotoxic effects that cause mortality. Once cardiotoxicity is evident, the treatment of choice is serum alkalinization, preferably by sodium bicarbonate therapy. In order to predict which overdose patients are at high risk for complications, electrocardiographic criteria have been identified as reliable screens. For "first generation" tricyclic antidepressants, QRS prolongation (particularly greater than 100 msec) and a terminal 40-ms frontal plane axis greater than 120 degrees are the most sensitive. This article reviews antidepressant pharmacology, electrocardiographic manifestations of antidepressant cardiotoxicity, and approaches to treatment of antidepressant-induced conduction disturbances and dysrhythmias. [References: 53]

Haddad, L. M. (1992). "Managing tricyclic antidepressant overdose. [Review] [35 refs]." American Family Physician 46(1): 153-9.

Tricyclic antidepressant overdose is the most common cause of death from prescription drugs. Clinical presentation of overdose from the tricyclic agents includes cardiac arrhythmias, hypotension, seizures, coma and anticholinergic signs such as hyperthermia, flushing and intestinal ileus. The highly toxic/lethal level (greater than 1,000 ng per mL) is manifested on electrocardiograms as prolongation of the QRS interval to 100 milliseconds or more. Treatment includes establishment of an airway, proper oxygenation and ventilation, fluid replacement at maintenance levels, cardiac monitoring, gastric lavage and charcoal administration, alkalinization to a blood pH of 7.5 with intravenous sodium bicarbonate, supportive therapy and continued cardiac monitoring after clinical recovery. [References: 35]

Harrigan, R. A. and W. J. Brady (1999). "ECG abnormalities in tricyclic antidepressant ingestion." Am J Emerg Med 17(4): 387-393.

The tricyclic antidepressant (TCA) agents are recognized for their potentially lethal cardiovascular and neurological effects in poisoned patients. The 12-lead electrocardiogram (ECG) has emerged as a popular bedside tool in the evaluation of TCA toxicity. Although the history and physical examination play a key role in the assessment of the patient with potential TCA poisoning, the presence or absence of features of the TCA toxidrome are not sufficient to detect or exclude toxicity from this class of drugs. A variety of ECG findings occur with TCA toxicity. Aside from the sinus tachycardia due principally to anticholinergic effects, TCA-toxic changes seen on the ECG are attributable primarily to the sodium channel blockade caused by these agents. The majority of patients at significant risk for developing cardiac or neurological toxicity will have a QRS complex greater than 0.10 seconds or a rightward shift of the terminal 40 ms of the frontal plane QRS complex vector. The majority of these patients will also display these changes early in their emergency department stay. However, the appearance of these findings, either alone or in combination, does not mean the patient will develop significant cardiac or neurological toxicity. The ECG can neither unequivocally rule in nor rule out impending toxicity; recognizing these limitations, the emergency physician can use this bedside tool in combination with other clinical data during the assessment of the poisoned patient.

Kerr, G. W., A. C. McGuffie, et al. (2001). "Tricyclic antidepressant overdose: a review.[see comment]. [Review] [99 refs]." Emergency Medicine Journal 18(4): 236-41.

Overdoses of tricyclic antidepressants are among the commonest causes of drug poisoning seen in accident and emergency departments. This review discusses the pharmacokinetics, clinical presentation and treatment of tricyclic overdose. [References: 99]



Krishel, S. and K. Jackimczyk (1991). "Cyclic antidepressants, lithium, and neuroleptic agents. Pharmacology and toxicology. [Review] [143 refs]." Emergency Medicine Clinics of North America 9(1): 53-86.

Cyclic antidepressants, lithium, and phenothiazines are frequently prescribed to psychiatric patients. Emergency department physicians must be familiar with these medications, and the pharmacologic and toxicologic characteristics of them are discussed. Cyclic antidepressants are the primary cause of drug-related death in the United States, with sodium bicarbonate recognized as the treatment of choice. Lithium toxicity may be subtle, and treatment is generally supportive in addition to volume replacement with normal saline and hemodialysis for significant intoxications. A neuroleptic overdose is managed primarily with supportive care. Neuroleptic malignant syndrome must be considered in any psychiatric patient presenting to the Emergency Department. [References: 143]

Lewis-Abney, K. (2000). "Overdoses of tricyclic antidepressants: grandchildren and grandparents." Critical care nurse 20(5): 69-77.

TCAs are an extremely toxic source of poisoning in young children. Overdoses of TCAs can cause coma, seizures, hypotension, cardiac arrhythmias, and cardiac arrest. Treatment is directed at rapid assessment, monitoring, support of vital functions, halting drug absorption, and treating CNS and cardiac toxic effects. All children should be monitored for a minimum of 6 hours, and many require admission to a critical care unit. The mainstay of therapy is alkalinization. Intravenous administration of sodium bicarbonate is the preferred treatment for hypotension, shock, and arrhythmias. Blood pH should be monitored and should be maintained between 7.45 and 7.55. More specific drug therapy, cardioversion, or artificial pacing may be required for refractory arrhythmias. Before the child is discharged from the hospital, strategies to reduce the risk of future poisonings should be discussed with the child's family.

Mackway-Jones, K. (1999). "Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Alkalinisation in the management of tricyclic antidepressant overdose. [Review] [4 refs]." Journal of Accident & Emergency Medicine 16(2): 139-40.

Pentel, P. R. and N. L. Benowitz (1986). "Tricyclic antidepressant poisoning. Management of arrhythmias." Medical Toxicology 1(2): 101-21.

Deaths from tricyclic antidepressant (TCA) overdose are usually due to arrhythmias and/or hypotension. Tricyclic antidepressant toxicity is due mainly to the quinidine-like actions of these drugs on cardiac tissues. Slowing of phase 0 depolarisation of the action potential results in slowing of conduction through the His-Purkinje system and myocardium. Slowed impulse conduction is responsible for QRS prolongation and atrioventricular block, and contributes to ventricular arrhythmias and hypotension. Therapies that improve conduction, e.g. hypertonic sodium bicarbonate, are useful in treating these toxic effects. Other mechanisms contributing to arrhythmias include abnormal repolarisation, impaired automaticity, cholinergic blockade and inhibition of neuronal catecholamine uptake. Toxicity may be worsened by acidaemia, hypotension or hyperthermia. Sinus tachycardia is due to the anticholinergic effects of the tricyclic antidepressants as well as blockade of neuronal catecholamine reuptake. Sinus tachycardia is generally well-tolerated and requires no therapy. Sinus tachycardia with QRS prolongation may be difficult to distinguish from ventricular tachycardia. Electrocardiograms obtained using oesophageal or atrial electrodes may be useful in determining the relationship of atrial and ventricular activity. Although QRS prolongation alone is not compromising, it is a marker for patients at highest risk of developing seizures, arrhythmias or hypotension. Ventricular tachycardia (monomorphic) is a consequence of impaired myocardial depolarisation and impulse conduction. Hypertonic sodium bicarbonate may partially correct impaired conduction and be of benefit in treating ventricular tachycardia. Since hypertonic sodium bicarbonate appears to act by increasing the extracellular sodium concentration as well as by increasing extracellular pH, hyperventilation may be less effective. Hypertonic sodium bicarbonate is of particular benefit in patients who are acidotic, since acidosis aggravates cardiac toxicity. However, administration of hypertonic sodium bicarbonate is beneficial



even when blood pH is normal. Lignocaine (lidocaine) may be useful in treating ventricular tachycardia but should be administered cautiously to avoid precipitating seizures. Ventricular bradyarrhythmias are due to impaired automaticity or depressed atrioventricular conduction and can be treated by placement of a temporary pacemaker, or with a chronotropic agent, e.g. isoprenaline (isoproterenol), with or without concomitant vasoconstrictors.(ABSTRACT TRUNCATED AT 400 WORDS)

Shanon, M. (1998). "Toxicology reviews: targeted management strategies for cardiovascular toxicity from tricyclic antidepressant overdose: the pivotal role for alkalinization and sodium loading." Ped Emerg Care 14(4): 293-297.

Smith, R. K. and K. O'Mara (1982). "Tricyclic antidepressant overdose." Journal of Family Practice 15(2): 247-53.

Overdose from tricyclic antidepressants (TCAs) is increasing. TCAs are well absorbed orally, highly protein bound, and highly lipid soluble. Clinical features of poisoning with TCAs occur within 12 hours of ingestion, usually after a dose of 20 mg/kg or more. Clinical symptomatology involves various anticholinergic, central nervous system, and cardiovascular effects. Cardiovascular toxicity accounts for the majority of the fatalities and may include a hyperdynamic response, various arrhythmias and heart blocks, or severe hypotension. Prolongation of the QRS interval of 10 msec or more implies severe toxicity. Many factors limit the usefulness of drug levels in the overdosed patient. Treatment revolves around good supportive care and general poisoning management. The physician should no longer use physostigmine precipitously. Sodium bicarbonate is effective in treating many of the cardiovascular complications. Other cardiac drugs are used but with varying efficacy. Patients with significant signs or symptoms of toxicity require monitored hospitalization until clinically free of manifestations for 24 to 48 hours.

Vrijlandt, P. J. W. S., T. M. Bosch, et al. (2001). "Sodium bicarbonate infusion for intoxication with tricyclic anti-depressives: Recommended despite a lack of scientific evidence." Nederlands Tijdschrift voor Geneeskunde 145(35): 1686-1689.

Sodium bicarbonate infusion is widely recommended in textbooks for patients who present with self-poisoning from tricyclic antidepressives. Cardiac conduction disorders could also be treated or prevented by means of such an infusion. The scientific basis for these recommendations was investigated by using Medline to search for publications about clinical studies that supported the use of sodium carbonate; 111 articles were scrutinized. Observational studies and case reports mention a rapid improvement in hypotension and cardiac arrhythmias following the administration of sodium bicarbonate. Results from animal experiments are contentious; it is not clear whether alkalinisation or the administration of extra sodium causes the effect. Randomized studies in patients have not been carried out. As the toxicity of sodium bicarbonate is low, and its potential benefit appears to be high, we recommend its use, despite the lack of scientific evidence. No recommendations concerning dosing, concentration and the length of the therapy can be provided on the basis of the literature.

Walsh, D. M. (1986). "Cyclic antidepressant overdose in children: a proposed treatment protocol." Pediatric Emergency Care 2(1): 28-35.

Cyclic antidepressant overdose is a major cause of drug overdose deaths and morbidity in the United States. The cyclic antidepressants are prescribed widely by primary care physicians and psychiatrists, and accidental overdose in children is not uncommon. Children have exhibited toxic effects with relatively small amounts of cyclic antidepressants. The management of cyclic antidepressant overdose is difficult because of the complex effects on the cardiovascular and nervous systems. The pertinent pharmacology of cyclic antidepressants in therapeutic amounts and in overdose is reviewed in this article. The clinical manifestations of cyclic antidepressant overdose are described. A protocol for effective management of cyclic antidepressant overdose in children is proposed.



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C2005 Evidence Evaluation Template - Oct.14, 2003circ.ahajournals.org/content/suppl/2005/11/16/... · Web viewOnly low levels of evidence exists to guide recommendations (4, 5, 6)