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Cardiotoxic Drugs

QT PROLONGATION

Some drugs in therapeutic use, combination or overdose can cause QT interval prolongation. Patients with QT prolongation are at increased risk of arrhythmias, particularly Torsades de Pointes, which in turn can disintegrate into life-threatening VF or asystole. Measurement of the QT interval to determine if it is prolonged is necessary to help determine patients at risk, and who therefore require closer observation and possible further management. Determining at what point the QT interval is long, and therefore a danger is controversial and poorly understood.

What is QT prolongation?

The ECG is a visual manifestation of what is occurring at an electrical level in the cardiac cells. The cardiac action potential has 4 phases:

  • Phase 4: the resting membrane potential
  • Phase 0: the rapid depolarization phase; rapid sodium influx
  • Phase 1: Intial repolarisation; potassium and chloride efflux
  • Phase 2: the plateau phase; balance between calcium influx and potassium efflux
  • Phase 3: the rapid repolarisation phase; potassium efflux

The QT interval is a representation of the repolarisation phase of the cardiac action potential.

Some drugs can interfere with phase 3 of the action potential by blocking cardiac potassium channels, namely the rapid component of the delayed rectifier potassium channel (IKR), coded by the human ether-a-go-go related gene (HERG). If this channel is blocked then phase 3 of the action potential takes longer and is visualised on the ECG as a longer T wave (figure 1).

Figure 1: QT prolongation at action potential level

Measuring the QT interval

The most sensitive and specific assessment tool/cutoff for the QT interval is the QT nomogram (see figure below) (1). The QT nomogram assesses the QT interval in relation to the heart rate without the use of correction formulas, such as Bazett's formula (often reported as the QTc on ECGs). These correction formulas have been shown to be inaccurate at measuring the QT interval and have also been shown to be less specific than the QT nomogram when determining a QT interval at risk (1,2).

The QT nomogram relies on correctly measuring the QT interval manually in 6 leads of the ECG as outlined below in table 1.The QT interval should be measured from the beginning of the Q wave till the end of the T wave (figure2). The median measurement is then plotted against the heart rate on the QT nomogram and any measurement above the line is considered a prolonged QT interval and therefore an at risk patient.

Figure 2: Measuring the QT interval

jt_interval_addition.jpg

Table 1: Step by step guide on how to use the QT nomogram to determine if there is a prolonged QT interval (modified from Isbister BJCP 2013)

Steps Approach
The absolute QT intervalThe QT interval is manually measured from the start of the Q wave until the T wave returns to baseline.
On a standard ECG at 25 mm/s this is best done by counting the number of small squares
E.g.: (See Figure 3)
5 small squares = 200ms
8 small squares = 320ms
Do not use the ECG automated readout or QTc
Obtain ECGThe QT interval length is manually measured in six leads on the ECG, usually:
Three limb leads: I, II and aVF
Three chest leads: V2, V4 and V6
Calculate the median QTThe median is the middle number of all 6 measured QT intervals when arranged in numerical order.
If there are two middle numbers, eg position 3 and 4, then the average of these two measurements is the median.
Determine heart rateThe heart rate is the average measurement from the RR interval on the 12 lead ECG and is most accurate when read from the automated ECG calculation.
Plot on QT nomogramThe median QT length is then plotted against the heart rate on the QT nomogram. If the QT-HR pair is above the line on the nomogram it is a prolonged QT and there is an increased risk of Torsades de Pointes.

A spread sheet with the nomogram can be downloaded here: QT Nomogram File_public.xls

This spreadsheet copyright in commons to Dr Geoff Isbister, it is not for sale
Press Click to Edit on the menu bar of the spreadsheet
Enter the pulse rate and QT interval in the spreadsheet and it will plot on the graph


QT prolongation and Torsades de Pointes

QT prolongation is of concern because of the risk of Torsades de Pointes (TdP). TdP is a rare occurrence, some estimate at low as 1 in 100,000 cases, but can be life threatening. The proposed mechanism is and early after-depolarisation beat occuring before the previous action potential cycle has completed. If this early-afterdepolarisation is of enough magnitude, it can break threshold and create an ectopic beat. TdP occurs when this beat (the R wave) occurs on top of the end of the previous beat (the T wave), called the R-on-T phenomenon (Figure 3).

Figure 3: The R-on-T Phenomenom resulting in an episode of TdP

tdponset_1_300dpi.jpg

Figure 4: Examples of plots of QT versus heart rate (HR) for non-cardiotoxic drugs (paracetamol, temazepam, oxazepam, diazepam) [A], quetiapine [B], citalopram [C] and amisulpride [D]. Data re-plotted from Chan et al. 2007, Isbister and Duffull 2009, Isbister et al 2007, Isbister et al 2010.

qt_nomogram_examples.jpg

Figure 5: ECG showing QT interval with ziprasidone

ecg_qt_ziprasidone.jpg

Figure 6: QT action potentials

ecg_qt_action_potentials_berling.jpg

REFERENCES

1. Chan A, Isbister GK, Kirkpatrick CM, Dufful SB. Drug-induced QT prolongation and torsades de pointes: evaluation of a QT nomogram. QJM 2007;100(10):609-15 PMID 17881416

2. Isbister GK, Duffull SB. Quetiapine overdose: predicting intubation, duration of ventilation, cardiac monitoring and the effect of activated charcoal. Int Clin Psychopharmacol 2009;24(4):174-80 PMID 19494786

3. Isbister GK, Bali, CR, MacLeod D, Duffull SB. Amisulpride overdose is frequently associated with QT prolongation and torsades de pointes. J Clin Psychopharmacol 2010;30(4):391-5 PMID 20531221

4. Isbister GK, et al. Activated charcoal decreases the risk of QT prolongation after citalopram overdose. Ann Emerg Med 2007;50(5):593-600 PMID 17719135

5. Berling I, Isbister GK, Calver L, Clunas, S. Digital Holter measurement of QT prolongation in ziprasidone overdose. Clin Toxicol 2011;49(7):694-6 PMID 21819290

6. Isbister GK, Page CB. 2013. Drug induced QT prolongation: the measurement and assessment of the QT interval in clinical practice. Br J Clin Pharmacol 2013;76(1):48-57 PMID 23167578

wikitox/cardiotoxic_drugs.txt · Last modified: 2018/09/01 09:01 by 127.0.0.1

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