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

Highlighted lines and questions below provide links to the pertinent description of criteria in The EBM User's Guide, now available at the Canadian Centres for Health Evidence

Article Reviewed:

Please visit the new Evidence Based Journal Club Reviews

Comparison of hyperventilation and inhaled nitric oxide for pulmonary hypertension after repair of congenital heart disease

Morris K, Beghetti M, Petros A, Adatia I, Bohn D

Crit Care Med. 2000;28(8):2974-8. [abstract]

Reviewed by Rohit Rao MD, Matthew Scanlon MD, Children's Hospital of Wisconsin

Review posted November 11, 2001

I. What is being studied?:

The study objective:

To compare the efficacy of hyperventilation-induced alkalosis with iNO (iNO) in reducing pulmonary vascular resistance (PVR) in the immediate postoperative management of pulmonary hypertension after cardiac surgery

The study design:

This study is a prospective, unblinded study with measurement of immediate, physiologic (surrogate) endpoints using a randomized, crossover treatment design.

The patients included:

12 children with pulmonary hypertension (pulmonary arterial pressure (PAP) >25) following cardiac surgery. The range of PAP is wide and ranges from means of 27 mmHg to 55 mmHg. The patients included a diverse group of heart lesions with varying physiology.

The lesions included hemitruncus, total anomalous pulmonary venous return, AV canal, mitral stenosis with subaortic stenosis, mitral valve replacement, VSD and obstructed baffle of a Mustard procedure. The age range of the patients varied widely from 1month to 17 years.

The patients excluded:

None

The interventions compared:

Hyperventilation with an aim of reaching an arterial pH of 7.50 for 30 minutes and iNO at concentrations of 5ppm for 15 minutes followed by 40 ppm for an additional 15 minutes. A period of at least 30 minutes was permitted between the end of the first treatment and the start of the second treatment to allow hemodynamic variables to return to baseline. At the end of the second treatment, both treatments were given in combination for a further 30 minutes so that they could look for possible additive effects of hyperventilation and iNO.

The outcomes evaluated:

Change in pulmonary vascular index (PVRI), heart rate, systemic arterial pressure, PAP, left atrial pressure (LAP), central venous pressure (CVP), cardiac output, cardiac index, systemic vascular resistance (SVRI), arterial pH, PaO2, PaCO2, mixed venous oxygen saturation.

II. Are the results of the study valid?

1. Is there a strong, independent, consistent association between the surrogate end point and the clinical end point?

There is an association between the surrogate endpoint of PVR and the clinical endpoint of cardiac output. It is clear that pulmonary hypertensive crises in postoperative cardiac patients are associated with higher mortality.. There are no trials to show that keeping PA pressures lower throughout the postoperative period results in improved outcome. It is also not known if keeping PA pressures lower through this period can prevent pulmonary hypertensive crises.

2. Is there evidence from randomized trials in other drug classes that improvement in the surrogate end point has consistently led to improvement in the target outcome?

Yes. There have been reports using other drug classes (e.g., tolazoline) to reduce pulmonary hypertension in postoperative cardiac surgery patients with apparent reduction in immediate mortality (1). As mentioned in the previous point, it is self-evident that high PA pressures can be fatal if untreated.

3. Is there evidence from randomized trials in the same drug class that improvement in the surrogate end point has consistently led to improvement in the target outcome?

No. Nitric oxide has been conclusively shown to reduce PVR. But as mentioned, there is no evidence that PVR reduction throughout the postoperative period conclusively results in an increased survival. It seems to be the right conclusion though.

IIa. Validity Questions for Therapy Articles:

Primary questions:

1. Was the assignment of patients to treatments randomized?

The order of how patients were given the individual interventions was randomized, although the method of randomization was not stated. All patients were given the combination of iNO and hyperventilation as a final intervention after exposure to each therapy individually.

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

Was followup complete? and were patients analyzed in the groups to which they were randomized?

Yes. Every patient entered into the trial completed the study. There was also a complete evaluation of all the patients after each intervention.

Patients were studied a median of 8.5 hours (range 4-40 hours) after arrival to the intensive care unit. I think the range is wide and I an unsure as to what an acceptable endpoint in time would be acceptable for postoperative pulmonary hypertension. It would also be better if the study period was fixed at the outset and same for all the subjects.

All patients crossed over by design.

Secondary questions:

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

No.

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

There was only one group; each patient served as his/her own control. All patients were postoperative from cardiac surgery. However they varied with respect to age, diagnosis and procedure performed.

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

For any given patient there was no other change in interventions during the trial. However, there was quite a bit of variation between patients in terms of what medications each patient was receiving.

III. What were the results?

1. How large, precise, and lasting was the treatment effect? (Effect should be large, precise, and lasting to consider a surrogate trial as possible basis for offering patients the intervention.)

	Mean PAP Pre/Post	Mean SVRI Pre/Post	Mean CI Pre/Post
HV	36.8± 9.8/28.4± 5.3	19.5± 12.7/22.7± 12.	3.08± 1.11/2.76±.96
NO	34.5± 2.8/29.4± 2.7	19.2± 8.9/19.5± 8.8	2.99±.91/3.01± 1.08

(data are mean ± s.d.)

Both iNO and HV were effective in reducing the mean PAP (14.7% and 22.8% respectively). Hyperventilation however, clearly caused increase in SVRI by 16.4% and a decrease in CI by 10.3%. iNO had no significant effect on SVRI (increased by 1.5%) and consequently did not influence CI much (increased by 0.6%)

With combined HV and iNO, the mean PAP fell further, to 26.8 ± 3.5, but the SVRI increased significantly to 29.2 ± 15.9 and the CI fell significantly to 2.62 ± 0.89.

This is a short term physiological study and was not meant to assess lasting changes. As for precision, we cannot comment as there are no confidence intervals provided to us.

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

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

Perhaps. If the study was repeated in patients with only clinically significant increased PVR and the findings were the same, then the results may apply to a similar population of patients.

2. Were all clinically important outcomes considered?

The full range of hemodynamic measurements was made. The study does not stop at just PVR implications but also covers the different impacts on cardiac output and systemic hemodynamics.

However, all the clinically important outcomes such as survival, days on ventilator, quality of life indicators, and cost were not addressed at all, since this was a short-term, physiologic study. Another short-term outcome they did not measure - presumably due to the brief experimental period - was prevention of potentially life-threatening pulmonary hypertensive "events."

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

Potential side effects of nitric oxide include methhemoglobinemia, which is measurable and usually both preventable and reversible. Rebound pulmonary hypertension is a definite serious side effect ; this was not seen in this short-term study and the benefits of treating acute life threatening pulmonary hypertension far outweigh the risks.

However, the amount of PVR in several if not the majority of the patients were such that the clinical significance of this could be questioned. In other words, many of the patients enrolled did not have PVR increased to the degree that they would merit treatment in the first place.

From a cost standpoint, there is no comparison as hyperventilation has no added cost but knowing that it can be detrimental by increasing SVRI and reducing CI might preclude its use.

References

1. Jones ODH, Shore DF, Rigby ML, et al: The use of tolazoline hydrochloride as a pulmonary vasodilator in potentially fatal episodes of pulmonary vasoconstriction after cardiac surgery in children. Circulation 1981; 64 (Suppl2): 134Ð139 [abstract]

    

Comments

Back to the EB Journal Club Index