BJA Advance Access originally published online on May 17, 2006
British Journal of Anaesthesia 2006 97(2):208-214; doi:10.1093/bja/ael112
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Efficacy of nitroglycerin inhalation in reducing pulmonary arterial hypertension in children with congenital heart disease
1 Department of Cardiac Anaesthesiology, Cardio Thoracic Centre, All India Institute of Medical Sciences New Delhi 110029, India
2 Department of Cardiology, Cardio Thoracic Centre, All India Institute of Medical Sciences New Delhi 110029, India
*Corresponding author: Department of Cardiac Anaesthesiology, 7th Floor, Cardio Thoracic Centre, All India Institute of Medical Sciences, New Delhi 110029, India. E-mail: princeofcoma{at}yahoo.co.uk
Accepted for publication April 2, 2006.
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Abstract |
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Background. There has been a renewed interest in nitric oxide donor drugs, such as nitroglycerin, delivered by the inhalational route for treatment of pulmonary arterial hypertension (PAH). We investigated the acute effects of inhaled nitroglycerin on pulmonary and systemic haemodynamics in children with PAH associated with congenital heart disease.
Methods. Nineteen children with acyanotic congenital heart disease and a left to right shunt with severe PAH, undergoing routine diagnostic cardiac catheterization were included in this study. Systolic, diastolic and mean systemic as well as pulmonary artery pressures, right atrial pressure and pulmonary capillary wedge pressure (PCWP) were recorded and systemic vascular resistance index (SVRI) and pulmonary vascular resistance index (PVRI) were calculated at room air, following 100% oxygen as well as after nitroglycerin inhalation in all patients.
Results. Systolic, diastolic and mean pulmonary artery pressure and PVRI decreased significantly, whereas heart rate, systolic, diastolic and mean systemic arterial pressure, PCWP and SVRI did not change significantly following 100% oxygen or inhalation of nitroglycerin.
Conclusion. Inhaled nitroglycerin significantly decreases systolic, diastolic and mean pulmonary artery pressure as well as PVRI without affecting systemic haemodynamics, and thus can be used as a therapeutic modality for acute reduction of PAH in children with congenital heart disease.
Keywords: complications, congenital defects; complications, pulmonary arterial hypertension; drug delivery, inhalational; heart, catheterization; nitroglycerin
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Introduction |
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Traditional therapeutic interventions for pulmonary arterial hypertension (PAH) include use of i.v. vasodilators1 such as nitroglycerin or prostaglandins; however, lack of selectivity for pulmonary vasculature leads to systemic side-effects limiting their role in treatment of PAH.2 Administering drugs by the inhalational route seems advantageous because large concentration of the drugs can be selectively administered to the pulmonary circulation, thus reducing their systemic side-effects. Commonly used therapy by the inhalational route is nitric oxide (iNO).3 4 Administration of iNO requires special and expensive equipment which is not widely available. Apart from this, potential iNO toxicity5 remains a concern, which stresses the importance of avoiding its indiscriminate use.6
Alternative modes of treatment for PAH include prostaglandin E1, prostaglandin I2 (prostacyclin), phosphodiesterase inhibitors such as milrinone, sildenafil and zaprinast, and nitric oxide donor drugs such as nitroglycerin and sodium nitroprusside.7 There has been a renewed interest in the nitric oxide donor drugs such as nitroglycerin, administered via the inhalational route for the treatment of PAH. A previous study has demonstrated the efficacy of inhaled nitroglycerin in reducing PAH in adult patients undergoing mitral valve replacement surgery,8 but data in children with PAH secondary to congenital heart disease and a left to right shunt are limited.9
We decided to study the acute effects of inhaled nitroglycerin on pulmonary and systemic haemodynamics in children with PAH associated with acyanotic congenital heart disease with left to right shunt. The study was conducted during routine diagnostic cardiac catheterization in these children so that the effects of anaesthetic drugs, high inspired oxygen concentration, controlled ventilation and surgical repair could be avoided.
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Methods |
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After approval from the Ethics Committee of the institute and written informed consent from the parents, 19 consecutive children below the age of 12 yr, suffering from acyanotic congenital heart disease and left to right shunt with severe PAH [defined by mean pulmonary arterial (PA) pressure >50 mm Hg] undergoing routine diagnostic cardiac catheterization were included in the study. Patients with associated mitral valve disease, left heart obstructive lesion, severe left ventricular (LV) dysfunction, mild to moderate PAH, severe pulmonary or tricuspid valvular regurgitation, trisomy 21, Eisenmenger syndrome and those already receiving vasodilator treatment were excluded.
Oral trichlofos and i.m. meperidine with promethazine was given for sedation and right heart catheterization was carried out under local anaesthesia using pulmonary artery catheter. During cardiac catheterization study, baseline heart rate, systolic, diastolic and mean systemic as well as PA pressures, right atrial pressure and pulmonary capillary wedge pressure (PCWP) were recorded for all the patients, while breathing room air. Haemodynamic data were obtained using MAC-LAB 6H, cath lab haemodynamic monitoring system (1996 Marquette Medical Systems Inc., now a part of GE Healthcare worldwide), which provided the electronic mean of all haemodynamic variables. Blood samples were collected from superior vena cava, pulmonary artery (PA) and from femoral artery in heparinized syringes to measure saturation and partial pressure of oxygen representing systemic venous, pulmonary arterial and systemic arterial blood, respectively. As pulmonary veins were not entered during cardiac catheterization study, pulmonary venous saturation was substituted with systemic arterial saturation as there was no right to left shunt in any of the patients.10 Oxygen consumption (VO2) was obtained from a standard nomogram routinely used in the cardiac catheterization lab of our institute, based on age, sex and heart rate of the child.11 Pulmonary vascular resistance index (PVRI), systemic vascular resistance index (SVRI) and pulmonary to systemic blood flow ratio (Qp/Qs) was calculated using standard formulas based on Fick's principle. All patients received 100% oxygen for 10 min, as a part of routine cardiac catheterization study protocol; 100% oxygen was administered using a face mask and Jackson Rees system attached to Datex Ohmeda Excel 210 anaesthesia machine (Datex-Ohmeda Inc., MA, USA). Haemodynamic and oximetric data were recorded again in a similar manner as described above. Fifteen minutes after discontinuing the oxygen (time allowed for haemodynamic variables to return to baseline), with children breathing room air, nebulized nitroglycerin was given in the dose of 2.5 µg kg–1 min–1 for a period of 10 min (i.e. 25 µg kg–1 of nitroglycerin was needed during the 10 min period). Original nitroglycerin drug (5 mg ml–1) was dissolved in normal saline (up to 20 ml) to make a solution of 250 µg ml–1 of drug. The required amount of nitroglycerin was taken with the help of 1 ml syringe bearing marks for each 0.1 ml, so that 25 µg of drug could be taken precisely, then 0.1 ml of drug solution was taken for every 1 kg body weight of patient (i.e. 0.5 ml for a 5 kg child) and made up to 3 ml with normal saline and nebulized with the help of CIRRUS Jet Nebulizer (Inter Surgical Respiratory systems, Berkshire, UK) using 8 litre min–1 of medical air, delivering the particles from aqueous solution at a rate of 0.25–0.3 ml min–1. After completion of nebulization, a complete set of haemodynamic and oximetric data were recorded again, as described for the baseline data.
Statistical analysis
Patient characteristics were expressed as median (range), while haemodynamic variables were expressed as mean (SD). For the statistical analysis ANOVA with repeated measures using statistical package SAS 8.0 was used. Pairwise comparisons were made between baseline, post 100% oxygen and post nitroglycerin values of the haemodynamic variables that showed significant difference with ANOVA. P-value of <0.05 was considered as statistically significant.
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Results |
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Nineteen consecutive children with unrestricted ventricular septal defect and left to right shunt with severe PAH, undergoing routine diagnostic cardiac catheterization study in a catheterization lab were included in the study. Clinical characteristics of the patients are shown in Table 1. Haemodynamic variables, both measured and calculated, expressed as mean (SD) are shown in Table 2. Heart rate, systolic, diastolic and mean systemic arterial pressure, PCWP and SVRI did not show any significant change following 100% oxygen administration as well as after nitroglycerin inhalation. One patient (No. 17 in Tables 3 and 4) had moderate left ventricular dysfunction pre-procedure, while left ventricular contractility was normal in all other patients. No adverse effects such as an increase in heart rate, hypotension or a decrease in systemic arterial oxygen saturation (SaO2) were seen in any of the patients after nitroglycerin inhalation.
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between baseline and values after nitroglycerine
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Systolic pulmonary artery pressure significantly decreased from 94.6 (13.8) mm Hg to 85.0 (14.4) mm Hg following 100% oxygen administration (P<0.001) and decreased significantly to 75.5 (13.6) mm Hg after nitroglycerin inhalation (P<0.001). Similarly diastolic and mean PA pressures significantly decreased from baseline of 59.3 (9.4) and 71.9 (9.5) mm Hg to 50.5 (7.9) and 63.2 (8.1) mm Hg, respectively following 100% oxygen administration (P<0.001) and decreased significantly further to 44.3 (10.0) and 55.1 (8.9) mm Hg after nitroglycerin inhalation (P<0.001). PVRI decreased significantly from a baseline of 5.4 (2.0) Wood units m2 to 2.1 (0.9) Wood units m2 (P< 0.001) following 100% oxygen administration and significantly decreased still further to 1.2 (0.6) Wood units m2 after nitroglycerin inhalation (P<0.001).
Pulmonary to systemic blood flow ratio (Qp/Qs) increased significantly from baseline of 1.79 (0.55) to 3.44 (1.09) following 100% oxygen administration (P<0.001) and significantly increased further to 4.53 (1.64) after nitroglycerin inhalation (P<0.001). SaO2 increased significantly from a baseline of 92.8 (5.2) to 97.6 (4.5)% following 100% oxygen administration (P<0.001), increase was also significant from the baseline to 97.4 (4.1) after nitroglycerin inhalation (P<0.001).
Based on a positive response to 100% oxygen administration or to nitroglycerin inhalation (defined by a greater than 15% decrease in mean pulmonary artery pressure to mean systemic arterial pressure ratio),12 patients were divided into three groups; those responding both to 100% oxygen and nitroglycerin inhalation (8 patients, Group I), those not responding to 100% oxygen but responding to nitroglycerin inhalation (8 patients, Group II), and those neither responding to 100% oxygen nor to nitroglycerin inhalation (3 patients, Group III). There was no patient who responded to 100% oxygen administration and did not respond to nitroglycerin inhalation. Tables 3 and 4 show pulmonary and systemic haemodynamic data respectively of all the patients in these three groups.
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Discussion |
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The acute effects of nitroglycerin inhalation on pulmonary circulation, in 19 children with congenital heart disease and severe PAH in our study, demonstrate a significant decrease in systolic, diastolic and mean PA pressure as well as PVRI, without any significant change in heart rate or systemic arterial pressure. Our findings are similar to those by Yurtseven and colleagues8 in adult patients with PAH undergoing mitral valve replacement surgery. A significant increase in Qp/Qs following 100% oxygen and nitroglycerin inhalation, in our study, was a result of the decrease in PVRI with no significant effect on SVRI. SaO2 after nitroglycerin inhalation in our study was significantly higher than baseline values and was comparable with values obtained following 100% oxygen administration, indicating the advantage of the inhalational route of administration, in which vasodilator drug is preferentially distributed to well-ventilated lung areas, effecting a redistribution of blood flow from non-ventilated regions to these areas,13 thereby reducing the ventilation–perfusion mismatch and intrapulmonary shunt fraction.
We have excluded patients with mild and moderate PAH and included only the patients with severe PAH (mean PA pressure >50 mm Hg) secondary to unrestricted ventricular septal defect and a left to right shunt, which might have contributed to relatively high baseline PA pressures in our study. Administration of meperidine may theoretically increase PA pressure if given as i.v. bolus, however, premedication with i.m. meperidine in combination with promethazine is widely used for sedation of children during cardiac catheterization.14 Studies demonstrating the effects of meperidine and promethazine on pulmonary and systemic circulation have mainly used animal data and have shown reduction in mean PA pressure along with an increase in PVR following i.v. meperidine alone or in combination with promethazine and chlorpromazine.15 There are no data regarding the effects of meperidine on pulmonary haemodynamics in children after i.m. administration. Moreover, the administration of alternate drugs for sedation of children during cardiac catheterization is also not without any confounding effects on various haemodynamic variables. Propofol can result in clinically important changes in cardiac shunt direction and flow.16 Ketamine has been shown to increase VO2, heart rate, cardiac output and PA pressure and can confuse interpretation of cardiac catheterization data especially if VO2 is assumed (derived from standard nomogram) and not actually measured,17 as was the case in our study. Considering all of the above issues, the sedation protocol formulated for children at our institute's cardiac catheterization lab is oral trichlofos with i.m. meperidine and promethazine, and the same was used in our study.
A decrease in PVRI after 100% oxygen administration was very marked in Groups I and II but was not accompanied by a similar decrease in mean PA pressure (Table 3). This is because passive distension and recruitment of pulmonary arteries or an increase in cardiac index can affect the calculation of pulmonary vascular resistance without necessarily indicating a decrease in vascular tone.12 Similarly assumed VO2 values can also produce inaccurate calculations of PVRI and SVRI.10 Reduction in systemic blood pressure can be associated with a decrease in pulmonary artery pressure without necessarily influencing the pulmonary vascular bed directly. We therefore defined a positive response to 100% oxygen administration or nitroglycerin inhalation as >15% decrease in mean pulmonary artery pressure to mean systemic arterial pressure ratio12 and without a significant change in systemic arterial pressure. According to this definition we found positive response to nitroglycerin inhalation in 16 (Groups I and II) of a total of 19 patients. Of these 16 patients who had positive response to nitroglycerin inhalation, 8 patients had negative response to a prior 100% oxygen administration (Group II), whereas all the patients with positive response to 100% oxygen responded to nitroglycerin inhalation, indicating that nitroglycerin inhalation is superior to 100% oxygen as pulmonary vasodilator. The negative response was not an all or none phenomenon, other patients also responded but did not cross the limit of 15% reduction in mean pulmonary artery pressure to mean systemic arterial pressure ratio.
Because of selective pulmonary vasodilatory effect, iNO is considered a standard therapy for treatment of PAH in various adult and paediatric cardiac patients3 4 but its administration requires a special and expensive equipment which is not widely available. Secondly, it has a number of potential toxic effects on various organ systems of the body5 including the formation of NO2 and free radicals,18 direct pulmonary cytotoxicity in the form of immune pulmonary fibrosis reaction (bronchiolitis fibrosa obliterans), the risk of methaemoglobinaemia especially in patients with inadequate methaemoglobin reductase activity, pulmonary oedema by increasing left ventricular filling pressure in patients with preexisting LV dysfunction,19 rebound pulmonary hypertension and arterial desaturation after withdrawal of iNO, and modification of platelet aggregation and agglutination in a non-dose-dependent manner. The unresolved issue of possible side-effects of iNO therapy necessitate the search for alternative inhaled drug therapies for the treatment of PAH, some of which are prostaglandin I2,20–22 iloprost, prostaglandin E1, phosphodiesterase inhibitors such as milrinone,21 sildenafil23 and zaprinast, and nitric oxide donor drugs such as nitroglycerin and sodium nitroprusside.24 25
Inhaled prostacyclin has been found to reduce pulmonary artery pressure and PVR as well as improve the systemic haemodynamics in patients with mitral stenosis and PAH undergoing mitral valve replacement surgery,20 and in new born with unobstructed total anomalous pulmonary venous connection with PAH after surgical correction under cardiopulmonary bypass.22 Inhaled prostacyclin combined with inhaled milrinone produces prolonged reduction of PVR and increases stroke volume without affecting mean systemic pressure and SVR.21 The disadvantages of administering prostacyclin and prostaglandin E1 are their high cost, local toxicity of commercial preparations of PGI2 (glycine buffer, pH 10.5) and PGE1 (ethanol–saline), limited period of stability of the solution once dissolved and the need for protection from light to avoid photodegradation.
Efficiency of various aerosolized nitric oxide donor drugs (including nitroglycerin and sodium nitroprusside) in selectively reducing PA pressure and PVR has been demonstrated in various animal studies,24 25 but human studies on the role of inhaled nitric oxide donor drugs in the treatment of PAH are limited.8 9
Nitroglycerin inhalation is less expansive and easy to administer as compared with iNO and prostacyclin inhalation. Nitroglycerin is metabolized to nitric oxide, which produces smooth muscle relaxation in the vascular endothelial cells, thereby causing vasodilatation. Nitroglycerin is a safe drug and does not produce any toxicity in contrast with iNO. The suggested precautions are to keep the dose below 5 mg kg–1 day–1 to prevent methaemoglobinaemia26 and to remember the possibility of increased peripheral air flow resistance, with inhaled nitroglycerin therapy.27
In our study, inhalation of nitroglycerin in normal saline was done with the help of CIRRUS jet nebulizer. At a driving gas flow of 8 litre min–1, it produces particles with a mass mean diameter of 2.75 µm, which are suitable for alveolar deposition.28 29 Targeting efficiency to alveolar region can be increased up to 96% with breath-holding manoeuvre during drug inhalation.30 Although breath holding could not be applied in small children in our study, it can be used to improve the drug delivery in older children and adults with PAH, who can follow the instructions.
PA pressure and PVR is reduced by 100% oxygen, which is routinely used during diagnostic cardiac catheterization, after baseline study to determine the decrease in PA pressure and PVR, and to establish operability/non-operability of a particular congenital heart defect. After determining the extent of decrease in systolic, diastolic and mean PA pressure as well as in PVRI following 100% oxygen, we administered nitroglycerin by the inhalational route, which further decreased systolic, diastolic and mean PA pressure and PVRI significantly over the post 100% oxygen values, but without any significant effect on systolic, diastolic and mean systemic arterial pressure or on SVRI.
Our study was carried out in a cardiac catheterization lab, where the underlying congenital heart defect was not corrected, and the haemodynamic parameters were not affected by surgical repair of congenital heart defect, anaesthetic drugs, high inspired oxygen concentration or by controlled ventilation. Hence the findings of this study are more valid, as compared with the studies done in postoperative patients, where the extent of reduction of PAH attributable to the surgical correction of the lesion cannot be ascertained. Therefore this study conclusively demonstrates the efficacy of nitroglycerin inhalation in reducing the PAH in children with congenital heart defects. Because of its short duration of action and development of tachyphylaxis, nitroglycerin inhalation may not be considered useful for long-term therapy of PAH, where drugs with longer half-life (such as inhaled prostanoids) will be more acceptable because of reduced frequency of administration. But nitroglycerin inhalation can be effectively utilized for acute reduction of PA pressure during the perioperative period of surgical correction of congenital heart defect, for example pulmonary hypertensive crisis where reduction of PA pressure is needed urgently, also it can be very useful in places where facilities for iNO administration are not available.
As of now, nitroglycerin inhalation cannot be used to test pulmonary vasoreactivity during diagnostic cardiac catheterization, because it is not yet clear that the patients exhibiting reduction in PVR with vasodilators similar to that of 100% oxygen, will have similarly reversible pulmonary vascular changes. Also, it is not certain that the response after surgical therapy of congenital heart defect would be the same as that might be anticipated with demonstrating reversibility of PAH with 100% oxygen. Thus nitroglycerin inhalation can be a useful adjunct to (but not at present a substitute for) the use of 100% oxygen during diagnostic cardiac catheterization.
The limitation of our study is that we did not study the duration of the effect of inhaled nitroglycerin to avoid multiple blood sampling and to avoid undue prolongation of cardiac catheterization time in these small children, which could have raised ethical concerns. Also the exact amount of drug actually reaching the pulmonary circulation could not be calculated. But these drawbacks can be minimized by titrating drug doses and frequency to the desired response. The effects of repeated nitroglycerin inhalation on pulmonary haemodynamics and the issue of nitrate tolerance need to be carefully addressed in further studies. We have taken values of VO2 from standard nomogram used in cardiac catheterization labs (instead of measuring VO2 in each patient) because of practical reasons, which can produce inaccuracies in calculations of PVRI and SVRI, but this disadvantage was largely circumvented by demonstrating the effects of inhaled nitroglycerin on systemic and pulmonary artery pressures also, along with its effect on SVRI and PVRI.
In conclusion, nitroglycerin inhalation significantly decreased systolic, diastolic and mean pulmonary artery pressure as well as pulmonary vascular resistance without affecting systemic arterial pressure, systemic vascular resistance and PCWP in children with severe PAH secondary to congenital heart disease. Efficacy of inhaled nitroglycerin in decreasing the pulmonary artery pressure is more than that of 100% oxygen. Thus it can be used as an alternative mode of therapy in reducing PAH in children with congenital heart disease, mainly in clinical situations where acute reduction of PA pressure is needed, and at places where facilities for iNO administration are not available.
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