Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

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Article Reviewed:

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Tri-iodothyronine treatment in children after cardiac surgery: a double-blind, randomised, placebo-controlled study .

Bettendorf M, Schmidt KG, Grulich-Henn J, Ulmer HE, Heinrich UE.

Lancet. 2000; 356(9229):529-34. [abstract]

Reviewed by Logi Rajagopalan, Pediatric Critical Care, Children's Hospital of New York-Presbyterian

Review posted March 2, 2003

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I. What is being studied?:

The study objective:

The objective of this study was to assess prospectively the safety and efficacy the of tri-idothyronine treatment after cardiac bypass surgery in children with congenital heart defects.

The study design:

It was a placebo controlled double blind study in which patients were randomized blockwise in groups of four.

The patients included:

Patients (n = 40) aged between 2 days and 10.4 years scheduled for cardiac surgery for congenital heart defects.

The patients excluded:

Premature neonates, preexisting thyroid or metabolic disease, preexisting uncontrolled cardiac arrhythmias or participation in another trial.

The interventions compared:

The study group received intravenous tri-idothyronine 2 mcg/kg dissolved in 10 ml normal saline over 30 minutes on day 1 after surgery and 1 mcg/kg on subsequent days.

The placebo group received normal saline infusion at the same time points and at the same infusion rates.

Treatment was stopped when post operative dopamine was discontinued at the discretion of the attending cardiologist or after maximum of 12 days.

The outcomes evaluated:

Primary outcomes:

1. Plasma thyrotropin, thyroxine, free thyroxine, tri-idothyronine and reverse tri-idothyronine concentrations were measured before the first infusion and at 2 hours, 24 hours and 72 hours after.
2. At the same time points cardiac performance was measured by echocardiography and doppler scan. Left ventricular systolic function was assesed by measuring left ventricular shortening fraction, corrected mean velocity of circumferential shortening of the left ventricle and left ventricular systolic ratio. Cardiac index was measured from doppler velocity traces at the aortic valve level.

Secondary outcomes:

1. The degree of intensive care required was assessed by by using a therapeutic intervention scoring system, which reflected the invasiveness, the intensity and the complexity of the clinical measures. Total score was applied to compare quantitatively the course of intensive care in different patient groups.
2. The postoperative inotropes support with catecholamines (dopamine, dobutamine and epinephrine) and diuretics (furosemide) was calculated as the mean cumulative dose in mg/kg bodyweight.
3. The postoperative need for mechanical ventilation, oxygen supplementation and the duration of both intensive and regular care were assessed in days.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. A computer generated randomization schedule was used to assign patients to tri-idothyronine or placebo group.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete?

Yes. All patients in the study group and control group completed the study and were managed according to the study protocol.

Were patients analyzed in the groups to which they were randomized?

Yes. There was no crossover between the groups.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

Yes. All physicians and nurses involved in the patients care were unaware of treatment assignments. The therapeutic intervention score was assessed daily, for 12 days after surgery from the patients charts by a research assistant who was unaware of the treatment assignments.

4. Were the groups similar at the start of the trial?

The two groups did not differ significantly in age, cardiac presentation, complexity of repair and duration of cardiac surgery or cardiopulmonary bypass time.

5. Aside from the experimental intervention, were the groups treated equally?

Although the authors present some evidence that there was no difference in operative course (e.g., complexity of repair, duration of surgery or cardiopulmonary bypass etc.) there is no information about anesthesia or a real breakdown of procedures performed (other than hypoxemia or cardiac failure noted) based upon group assignment. It would be helpful to have more information to confirm for us that other aspects of care did not differ between the two groups.

III. What were the results?

1. How large was the treatment effect?

Primary outcomes:

1. The authors do not present the results clearly in the paper. Figure 2 shows tri-idothyronine levels less than 2 nmol/L after surgery in both groups. In the tri-idothyronine treated group plasma concentrations were higher (5-7 nmol/L) after the first dose and remained high throughout the observation period. This correlated with improved cardiac function variables in this group. In the placebo group plasma concentrations remained low (less than 2 nmol/L) at 2 hours, 24 hours and 72 hours after the first infusion.
2. The three indicators of LV function were supposedly measured at 4 time points postoperatively (same time as the thyroid hormone levels). Yet only one value for each of the three echo indicators is shown in Table 3. There are no units to the values and it is not clear what the values represent. Since there are no units the values might mean percentage from baseline. If so, the mean change of cardiac index was significantly higher in children given tri-idothyronine 20.4% (s.d. 19.6) vs. 10.0% (s.d. 15.2) with a p value of 0.004. Measured echocardiographic variables of systolic left ventricular function were also improved in this group but were not statistically significant.
3. The authors state that when the functions were assessed separately for shorter or longer operations (> or < 3.9hours) and shorter or longer bypass duration (> or < 1.8 hours), the tri-idothyronine treated group with longer cardiopulmonary bypass operation showed a very significant increase in all the left ventricular systolic function variables assessed compared to the placebo group with longer cardiopulmonary bypass operation.
4. If you look at Figure 4, the percentage of overall change of echocardiographic variables seems to be higher in the treated group (20-40% vs 0-10%). But the clinical significance and magnitude of this observation is difficult to interpret since the results are not presented clearly.

Secondary outcomes:

1. The decline in mean therapeutic intervention score, which assessed the degree of intensive care received, was more pronounced after tri-idothyronine treatment. Greater decline or lower score indicates less and shorter lasting intensive care measures. But this was not statistically significant
2. Tri-idothyronine group had shorter stays in intensive care unit (7 vs. 8 days), smaller postoperative cumulative catecholamine doses (69 mg/kg vs. 90 mg/kg), shorter periods of mechanical ventilation (3.2 vs. 4.5 days) and oxygen supplementation (7 vs. 9.4 days) than the placebo group, but the results were not significant statistically.

2. How precise was the estimate of the treatment effect?

There were no binary outcome measures provided to calculate a relative risk or odds ratio since all the results are provided as continuous variables. We really do not have any good measure of 'precision' in this study except to look at the box and whiskers plots and comment that although there were 'statistically significant' differences between groups there seemed to be a lot of overlap of the plots between the groups. This is a real drawback of this study.

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

The study group is comparable to my patient population. Even though the results show a positive trend, the study consisted of a small number of patients. The type and complexity of cardiac malformation and the type of surgery in each group was not mentioned.

Before I apply the results to my patient care I would like to see a multicenter trial conducted on a larger patient population strictly matched in all aspects. Such trial must have clinically relevant and durable outcome measures.

2. Were all clinically important outcomes considered?

No. The cardiac output and the left ventricular systolic function have been considered as primary outcome measures and analyzed in detail. The significance of these measures is uncertain.

Other important outcomes based on the requirement of vasopressors and diuretics and the need mechanical ventilation also have been considered, but were only secondary outcomes and the study was not designed primarily to asses these variables. In order to potentially affect care management decisions, a future study must have such clinically durable outcome measures as primary variables.

3. Are the likely treatment benefits worth the potential harms and costs?

Even though no adverse effects were noted in cardiac rhythm or rate, the study fails to convince me strongly about the treatment benefits. The study group did not have a significantly better outcome compared to the control group. Cost benefits have not been analyzed. Furthermore the numbers of patients were too small to detect meaningful differences in benefit and potential harms.

References

1. Bettendorf M, Schmidt KG, Tiefenbacher U, Grulich-Henn J, Heinrich UE, Schonberg DK. Transient secondary hypothyroidism in children after cardiac surgery. Pediatr Res. 1997 Mar;41(3):375-9. [abstract]

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