CASE SERIES

Arundathi Y.A. Jayasena, MBBS^*, Herath H.M.D.R, BSc,^** Tilak W. A. Jayalath, MD,^*** Chulananda D.A. Goonasekera, MD, PhD.^****

* Lecturer, Department of Anesthesiology

** Department of Pharmacy, Faculty of Allied Health Sciences

*** Senior Lecturer, Department of Medicine,

**** Professor of Anesthesiology,

Faculty of Medicine, University of Peradeniya, Peradeniya (Sri Lanka).

Correspondence: C.D.A. Goonasekera, Department of Anaesthesiology, Faculty of Medicine,University of Peradeniya, Peradeniya, Sri Lanka. E-mail; cgoonase@slt.lk; Fax 94 81 2389106

ABSTRACT

Clarithromycin, a macrolide antibiotic is known to have an arrhythmogenic potential in the presence of comparable QT prolongation. Indeed, the extent of QT prolongation hasbeen used as a surrogate marker for cardiotoxicity and sudden cardiac death. We report a case series of three adult patients who were transferred to our intensive care unit (ICU) at Peradeniya Teaching Hospital, Peradeniya (Sri Lanka), and needed inotropic support and mechanical ventilation. All the three of them were treated with a standard dose regimen of intravenous clarithromycin for suspected atypical pneumonia, after which they dramatically deteriorated and unexpectedly died within 72 hours. In the absence of other known precipitating factors, cardiotoxicity of clarithromycin was suspected as the main causative factor for these deaths.

Key words: Clarithromycin; Cardiotoxicity; Naranjo Causality Scale; QT prolongation

Citation: Jayasena AYA, Herath HMDR, Jayalath TWA, Goonasekera CDA. Suspected cardiotoxicity of clarithromycin in critically ill patients. Anaesth Pain & Intensive Care 2009;13(1):28-30

INTRODUCTION

QT interval prolongation is a risk factor in a number of cardiovascular as well as non-cardiovascular diseases (e.g. microbial infections). Among non-cardiovascular drugs that prolong repolarization, macrolide antibiotics are widely prescribed and have been incriminated in prolonging action potential of the heart apart from their antibioticeffects. Clarithromycin is a relatively new macrolide broad spectrum antibiotic. It binds to 50 S ribosomal subunit of the susceptible microorganisms resulting in inhibition of protein synthesis. It is rapidly absorbed, widely distributed and metabolized to 14-hydroxyclarithromycin, a metabolite with considerable pharmacological activity.

The macrolides have been associated with the prolongation of cardiac repolarization and blockage of the HERG channel dependent potassium in myocyte membranes resulting in prolongation of the QTc interval which may give rise to potentially life-threatening polymorphic ventricular tachycardia of the torsadede pointes type or ventricular fibrillation. Thus, clarithromycin, which has a potential to cause cardiac toxicity, is best avoided in critically ill patients especially receiving ionotropic support. The aim of this case series is to highlight the possibly aggravated cardiotoxicity of clarithromycin in the critically ill patient and establish link through Naranjo Causality Scale.

We report three patients, who rapidly deteriorated clinically following the administration of clarithromycin in the ICU on a standard dose regimen of clarithromycin 500mg IV bid for atypical pneumonia. The brand ‘Klarid^®’ which contained clarithromycin lactobionate (50mg/ml), batch No. 220624XVO3 marketed by Messers Abbott Laboratories Ltd., Landhi, Karachi (Pakistan), with license No. 000001 and registration No. 018142 was used.

CASE REPORT 1

A 55 year old male patient was admitted to ICU of our hospital with suspected dengue shock syndrome. On admission his pulse rate was 110/min and blood pressure was maintained at 80/56 mmHg on dopamine 10µg/kg/min and dobutamine 10µg/kg/min support and central venous pressure 13 cmH₂O. 2D echo revealed an ejection fraction of 60% with mild left ventricular hypertrophy. He was mechanically ventilated with FiO₂ of 100%, maintaining a peripheral saturation (SpO₂) of 98-100%. Blood gas analysis revealed a pH of 7.29, PCO₂of 30.7 mmHg and PO₂of 95mmHg. On the second day of his admission to ICU, intravenous clarithromycin was prescribed for signs of atypical pneumonia in the chest X-ray.

The next day, hemodialysis had to be started utilizing continuous venovenous haemodiafiltration (CVVHDF) due to acute renal failure. His CVP was maintained at 13 cmH₂O and the SpO₂ was 95% with 100% inspired oxygen. Despite optimization of metabolic environment and fluid balance by CVVHDF, his blood pressure continued to deteriorate. The arterial blood gas analysis revealed a pH of 7.15, PCO₂31.3 mmHg and a PO₂of 56.9 mmHg. He also developed a bleeding tendency and a low platelet count (33 x 10⁹/mm³). His hemoglobin was 8.8g/dl. On 4th day in ICU his blood pressure remained persistently low (68/35, 76/41, 69/27mmHg) and CVP rose to 20mmHg. An ECG trace taken before 24 hours of his death demonstrated a QTc of 0.55 sec (normal upper limit: males 0.44sec, females 0.46sec).The acidosis gradually worsened (pH: 7.06) despite sodium bicarbonate therapy, CVVHDF and hyperventilation. He developed severe bradycardia and ultimately irreversible asystole.

CASE REPORT 2

A 25 year old female university student was transferred to the ICU for mechanical ventilation following treatment for a febrile illness with features suggestive of myocarditis. Her platelet count was 91 x 10⁹/mm³,whilst hemoglobin was 9.2g/dl. She had had a demand temporary pacemaker inserted as a prophylactic measure following an episode of severe bradycardia in the ward. On admission to ICU, she was in a state of shock with cold and clammy peripheries and a blood pressure of 60/40mmHg. She was maintaining a sinus rhythm of 80 to110 beats/min. She was resuscitated with ionotropes, oxygen therapy and mechanical ventilation. Her cardiorespiratory parameters were then recorded as pulse rate 105/min, blood pressure 110/65mmHg with dopamine and dobutamine support at 10µg/kg/min each and SpO₂ at 99% with FiO₂of 35%. Features of atypical pneumonia seen on her chest X- ray prompted the inclusion of intravenous clarithromycin in the management regimen. A single dose of clarithromycin was administered. Six hours later she developed a severe sinus tachycardia with pulse rates reaching 150/min to 190/ min despite carotid sinus massaging, β-blockers, adequate sedation with morphine and hyperventilation. Her SpO₂ rapidly deteriorated and the FiO₂ had to be increased to 80% to maintain her SpO₂ above 95%. Her CVP was 17 cmH₂O. Later on, FiO₂ was raised to100%, but the tachycardia continued. Her blood pressure progressively reduced. The next day she expired following a cardiac arrest.

CASE REPORT 3

A 44 year old female was transferred to the ICU due to falling blood pressure and a low SpO₂. She had a low platelet count (40×10⁹) and her hemoglobin was 10.9g/dl. On admission to ICU, she received the first dose of clarithromycin intravenously for a chest infection, which was revealed by the chest radiograph. Before the commencement of clarithromycin, her blood pressure was 110/70mmHg, but had a tachycardia (120-150/min) and was breathing spontaneously. In the ICU, she went into respiratory failure, so was intubated and ventilated and a peripheral saturation of 92% was maintained with 80% oxygen. The arterial blood gas analysis revealed a pH: 7.24, PCO₂ 21.9 mmHg and PO₂ 75.1 mmHg. Her blood pressure fell to 95/65 mmHg and hence an infusion of dobutamine was started at 5µg/kg/min, increasing successively to 10.5µg/kg/min. Her tachycardia continued between 150-170/min and she expired following a cardiac arrest within 8 hours of admission to the ICU.

DISCUSSION

In this article we review the risk of clarithromycin cardiotoxicity in critically ill patients. The extent of QT prolongation has been used as a marker for cardiotoxicity.³ The QT interval on the electrocardiogram (ECG) is an indirect measure of the duration of the ventricular action potential and ventricular repolarisation. Prolongation of ventricular repolarisation can cause arrhythmias; the most characteristic of which is torsades de pointes (twisting of the points) – a specific form of ventricular tachycardia.⁴Erythromycin and clarithromycin are known to cause early afterdepolarizations and torsades de pointes.³ This effect may be related to triangular monophasic action potential prolongation of these drugs.³ These agents produce a blockage of HERG (Human Ether-a-go-go Related Gene) channel dependant potassium current in myocyte membrane, resulting in a prolonged QTc interval which may give rise to potentially life-threatening polymorphic ventricular tachycardia of the torsadede pointes type or ventricular fibrillation.

Cardiotoxicity was obviously not present in our patients before the commencement of the drug, although they had had cardiac dysfunction. They were on ionotropic support, and showed a rapid deterioration of their cardiac function after administration of clarithromycin at the standard dosage regimen, which suggests an enhanced susceptibility to the drug’s adverse cardiac action hitherto not described. All three critically ill patients were commenced on intravenous clarithromycin for suspected atypical pneumonia on the chest X-ray. The first patient with DSS was started on CVVHDF for optimization of lung function. The first two patients were resuscitated with ionotropic support, oxygen therapy and mechanical ventilation before commencement of claroithromycin; and the second patient’s oxygen demand went up from FiO₂of 35% to 80% and tachycardia worsened within eight hours of a single dose of clarithromycin. They showed some signs of recovery before the commencement of clarithromycin. The third case had already received the first dose of clarithromycin on admission and had a persistent tachycardia. She developed respiratory failure and soon required ionotropic support.

A marked deterioration of the vital parameters was seen in all the three patients following the administration of clarithromycin IV. In contrast to what has been reported in literature, our patients showed development of a sinus tachycardia and a significant and rapid deterioration of cardiac function. Sinus tachycardia in the presence of a weak heart would have contributed to the lowering of cardiac output further, aggravating the problem due to the development of acidosis. The acidosis did not respond to corrective therapy. Our assessment utilizing Naranjo Causality Scale indicates that this clinical scenario can be a possible adverse drug reaction (Table 1). This score relates the clinical scenario to an adverse drug reaction (ADR); 0 = doubtful, 1-4 = possible, 5-8 = probable , > 9 = definite.

Table 1 : Naranjo Causality Scale and its application to the 3 cases

Drug reactions	Case 1	Case 2	Case 3
1. Are there previous conclusive reports on this reaction?	+1	+1	+1
2. Did the ADR appear after the suspected drug was given?	+2	+2	+2
3. Did the ADR improve when the drug was discontinued or a specific antagonist was given?	0	0	0
4. Did the ADR appear when drug was re-administered?	0	0	0
5. Are there alternative causes that could have caused the reaction?	0	0	0
6. Did the reaction appear when placebo was given?	0	0	0
7. Was the drug detected in any body fluid in toxic concentration?	0	0	0
8. Was reaction more severe when the dose was increased or less severe when the dose was decreased?	0	0	0
9. Did the patients have a similar drug in any previous exposure?	0	0	0
Total Score	+3	+3	+3

The ADR is considered severe ( FDA definition) if the consequences resulted in (a) death (b) a life threatening situation ( c) hospitalization (d) disability – significant, persistent, or permanent change, impairment, damage or disruptions in the patient’s body function/structure, physical activities or quality of life (e) congenital anomaly or (f) required intervention to prevent permanent impairment or damage. In our cases, all the three patients deteriorated rapidly and succumbed to the disease condition before any positive change could be noticed with withdrawal of the suspected drug.

CONCLUSION

It appears one should be prudent and clarithromycin is best avoided in critically ill patients who already have a compromised cardiac status with associated cardiac instability and are on ionotropic support.

REFERENCES

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Milberg P, Eckrdt L, Bruns HJ, Biertz J, Ramtin S, Reinsch N, et al. Divergent proarrhythmic potential of macrolide antibioptics despite similar QT prolongation: Fast phase 3 repolarization prevents early afterdepolarization and torsade de pointes. J Pharmacol Exp Ther 2002;303(1):218-225. [Medline]