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`British Journal of Anaesthesia 97 (2): 208–14 (2006)
`doi:10.1093/bja/ael112 Advance Access publication May 17, 2006
`
`Efficacy of nitroglycerin inhalation in reducing pulmonary
`arterial hypertension in children with congenital heart disease
`
`P. Goyal1*, U. Kiran1, S. Chauhan1, R. Juneja2 and M. Choudhary1
`
`1Department of Cardiac Anaesthesiology and 2Department 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@yahoo.co.uk
`
`Background. There has been a renewed interest in nitric oxide donor drugs, such as nitrogly-
`cerin, delivered by the inhalational route for treatment of pulmonary arterial hypertension (PAH).
`We investigated the acute effects of inhaled nitroglycerin on pulmonary and systemic haemo-
`dynamics 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.
`
`Br J Anaesth 2006; 97: 208–14
`
`Keywords: complications, congenital defects; complications, pulmonary arterial hypertension;
`drug delivery, inhalational; heart, catheterization; nitroglycerin
`
`Accepted for publication: April 2, 2006
`
`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 admin-
`istered 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 toxi-
`city5 remains a concern, which stresses the importance of
`avoiding its indiscriminate use.6
`Alternative modes of treatment for PAH include prosta-
`glandin E1, prostaglandin I2 (prostacyclin), phosphodies-
`terase 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, admin-
`istered 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 nitro-
`glycerin on pulmonary and systemic haemodynamics in
`children with PAH associated with acyanotic congenital
`heart disease with left to right shunt. The study was con-
`ducted 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.
`
`Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
`
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`Inhaled nitroglycerin for reducing PAH
`
`Methods
`After approval from the Ethics Committee of the institute
`and written informed consent from the parents, 19 consecu-
`tive children below the age of 12 yr, suffering from acyan-
`otic congenital heart disease and left to right shunt with
`severe PAH [defined by mean pulmonary arterial (PA) pres-
`sure >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 capil-
`lary wedge pressure (PCWP) were recorded for all the
`patients, while breathing room air. Haemodynamic data
`were obtained using MAC-LAB 6H, cath lab haemody-
`namic monitoring system (1996 Marquette Medical Systems
`Inc., now a part of GE Healthcare worldwide), which pro-
`vided the electronic mean of all haemodynamic variables.
`Blood samples were collected from superior vena cava,
`pulmonary artery (PA) and from femoral artery in hep-
`arinized 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
`the patients.10 Oxygen consumption
`shunt
`in any of
`(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 haemody-
`namic variables to return to baseline), with children breath-
`ing room air, nebulized nitroglycerin was given in the dose
`1
`1 min
`1 for a period of 10 min (i.e. 25 mg kg
`of 2.5 mg kg
`of nitroglycerin was needed during the 10 min period).
`1) was dissolved
`Original nitroglycerin drug (5 mg ml
`in normal saline (up to 20 ml) to make a solution of
`1 of drug. The required amount of nitroglycerin
`250 mg ml
`
`was taken with the help of 1 ml syringe bearing marks for
`each 0.1 ml, so that 25 mg 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,
`1 of medical air, delivering
`Berkshire, UK) using 8 litre min
`the particles from aqueous solution at a rate of 0.25–
`1. After completion of nebulization, a complete
`0.3 ml min
`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 mea-
`sures using statistical package SAS 8.0 was used. Pairwise
`comparisons were made between baseline, post 100% oxy-
`gen and post nitroglycerin values of the haemodynamic
`variables that showed significant difference with ANOVA.
`P-value of <0.05 was considered as statistically significant.
`
`Results
`Nineteen consecutive children with unrestricted ventricular
`septal defect and left to right shunt with severe PAH, under-
`going routine diagnostic cardiac catheterization study in a
`catheterization lab were included in the study. Clinical char-
`acteristics of the patients are shown in Table 1. Haemody-
`namic variables, both measured and calculated, expressed as
`mean (SD) are shown in Table 2. Heart rate, systolic, dias-
`tolic 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 vent-
`ricular 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.
`Systolic pulmonary artery pressure significantly decrea-
`sed from 94.6 (13.8) mm Hg to 85.0 (14.4) mm Hg
`
`Table 1 Patient characteristics. Data are expressed as median (range) or abso-
`lute numbers. BSA, body surface area; Hb, haemoglobin; VSD, ventricular
`septal defect
`
`Age (months)
`M:F
`Weight (kg)
`Height (cm)
`BSA (m2)
`1)
`Hb (gm dl
`Type of VSD
`Perimembranous
`Muscular
`Multiple muscular
`Perimembranous with muscular
`
`33 (8–54)
`12:7
`11 (5–17)
`89(64–115)
`0.52 (0.29–0.75)
`11.2 (10–14)
`
`15
`2
`1
`1
`
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`Goyal et al.
`
`Table 2 Systemic and pulmonary haemodynamic variables expressed as mean (SD). HR, heart rate; NS, not significant; PCWP, pulmonary capillary wedge pressure;
`PVRI, pulmonary vascular resistance index; Qp/Qs, ratio of pulmonary to systemic blood flow; SaO2
`, systemic arterial oxygen saturation; SAP, DAP and MAP,
`systolic, diastolic and mean systemic arterial pressure, respectively; S_PAP, D_PAP and M_PAP, systolic, diastolic and mean pulmonary artery pressure, respec-
`tively; SVRI, systemic vascular resistance index. *Paired comparison between baseline and values after 100% oxygen; **between values after 100% oxygen and after
`nitroglycerin; †between baseline and values after nitroglycerine
`
`Baseline (a)
`
`Post 100% oxygen (b)
`
`Post nitroglycerin (c)
`
`ANOVA
`
`Paired comparisons (ab)* (bc)**(ac)†
`
`1)
`
`HR (beats min
`SAP (mm Hg)
`DAP (mm Hg)
`MAP (mm Hg)
`S_PAP (mm Hg)
`D_PAP (mm Hg)
`M_PAP (mm Hg)
`PCWP (mm Hg)
`SVRI (units m2)
`PVRI (units m2)
`Qp/Qs
`SaO2
`
`140.9 (15.9)
`97.6 (17.2)
`65.4 (10.7)
`76.3 (12.2)
`94.6 (13.8)
`59.3 (9.4)
`71.9 (9.5)
`9.1 (3.2)
`10.3 (2.8)
`5.4 (2.0)
`1.79 (0.55)
`92.8 (5.2)
`
`136.3 (17.2)
`97.3 (17.6)
`65.2 (10.3)
`75.8 (12.8)
`85.0 (14.4)
`50.5 (7.9)
`63.2 (8.1)
`8.8 (2.9)
`10.2 (3.0)
`2.1 (0.9)
`3.44 (1.09)
`97.6 (4.5)
`
`137.7 (16.2)
`97.1 (17.1)
`63.8 (11.8)
`75.8 (12.3)
`75.5 (13.6)
`44.3 (10.0)
`55.1 (8.9)
`8.6 (3.2)
`10.1 (3.3)
`1.2 (0.6)
`4.53 (1.64)
`97.4 (4.1)
`
`NS
`NS
`NS
`NS
`<0.001
`<0.001
`<0.001
`NS
`NS
`<0.001
`<0.001
`<0.001
`
`–
`–
`–
`–
`(<0.001) (<0.001) (<0.001)
`(<0.001) (<0.001) (<0.001)
`(<0.001) (<0.001) (<0.001)
`–
`–
`(<0.001) (<0.001) (<0.001)
`(<0.001) (<0.001) (<0.001)
`(<0.001) (NS) (<0.001)
`
`Table 3 Pulmonary haemodynamic variables in individual patients. (a) Baseline, (b) following 100% oxygen and (c) after nitroglycerin inhalation. PAP, pulmonary
`artery pressure (mm Hg); PCWP, pulmonary capillary wedge pressure (mm Hg); PVRI, pulmonary vascular resistance index (units m2); Qp/Qs, ratio of pulmonary to
`systemic blood flow
`
`No.
`
`Age in months
`
`Systolic/diastolic (mean) PAP
`
`PVRI
`
`PCWP
`
`Qp/Qs
`
`(a)
`
`(b)
`
`(c)
`
`(a)
`
`(b)
`
`(c)
`
`(a)
`
`(b)
`
`(c)
`
`(a)
`
`(b)
`
`(c)
`
`Group I—patients responding to both 100% oxygen and nitroglycerin (n=8)
`1
`48
`96/56 (78)
`81/43 (65)
`67/55 (56)
`2
`24
`88/60 (69)
`75/52 (60)
`65/40 (48)
`3
`8
`70/52 (58)
`61/44 (50)
`55/34 (41)
`4
`48
`96/62 (73)
`84/50 (61)
`74/42 (53)
`5
`30
`89/63 (72)
`78/52 (61)
`68/54 (59)
`6
`9
`71/54 (60)
`61/44 (50)
`50/38 (42)
`7
`54
`96/62 (73)
`84/50 (61)
`74/42 (53)
`8
`30
`91/67 (75)
`87/54 (65)
`68/50 (56)
`Group II—patients responding to nitroglycerin but not to 100% oxygen (n=8)
`9
`24
`97/60 (75)
`92/48 (65)
`90/47 (64)
`10
`9
`91/51 (63)
`77/46 (59)
`74/30 (45)
`11
`36
`98/64 (75)
`82/57 (65)
`70/44 (53)
`12
`42
`100/68 (79)
`94/62 (73)
`85/50 (62)
`13
`42
`120/70 (87)
`108/60 (76)
`98/58 (71)
`14
`12
`96/51 (66)
`85/46 (59)
`74/35 (48)
`15
`36
`100/64 (76)
`86/57 (67)
`72/54 (60)
`16
`33
`100/72 (81)
`92/61 (71)
`82/49 (60)
`Group III—patients not responding to either 100% oxygen or nitroglycerin (n=3)
`17
`8
`70/40 (50)
`67/32 (48)
`71/21 (44)
`18
`51
`110/40 (70)
`113/41 (68)
`100/40 (60)
`19
`54
`118/71 (87)
`108/60 (76)
`97/58 (71)
`
`7.62
`5.54
`2.14
`2.8
`5.62
`2.7
`5.92
`5.9
`
`5.71
`2.72
`4.66
`7.23
`5.67
`3.03
`6.25
`8.07
`
`8.75
`4.46
`7.13
`
`2.1
`1.39
`1.1
`1.43
`1.84
`1.12
`1.99
`1.49
`
`1.51
`1.5
`1.69
`3.59
`1.65
`1.57
`1.78
`3.54
`
`3.59
`3.56
`3.49
`
`0.43
`0.84
`1.01
`0.78
`1.3
`0.69
`1.27
`0.86
`
`1.12
`0.77
`1.05
`1.52
`1.09
`0.89
`1.06
`2.05
`
`3.22
`1.81
`1.63
`
`11
`10
`8
`9
`6
`8
`9
`6
`
`7
`13
`4
`9
`10
`13
`4
`8
`
`17
`11
`10
`
`11
`9
`7
`8
`7
`7
`8
`7
`
`11
`11
`5
`8
`9
`11
`5
`7
`
`18
`10
`8
`
`11
`9
`7
`9
`6
`7
`7
`6
`
`11
`12
`5
`8
`6
`12
`5
`7
`
`18
`10
`7
`
`1.79
`1.60
`2.57
`2.60
`1.30
`2.25
`1.80
`1.40
`
`1.33
`1.86
`2.14
`1.18
`1.67
`1.86
`1.67
`1.33
`
`1.06
`3.17
`1.36
`
`4.19
`2.33
`2.50
`4.33
`3.25
`4.0
`3.50
`4.66
`
`3.33
`1.83
`5.0
`2.0
`4.33
`2.75
`4.66
`2.66
`
`2.43
`5.25
`2.33
`
`5.0
`2.80
`3.0
`5.99
`3.25
`4.0
`4.99
`6.98
`
`3.20
`2.50
`5.0
`3.99
`6.94
`3.32
`6.99
`4.24
`
`2.34
`7.30
`4.33
`
`following 100% oxygen administration (P<0.001) and
`decreased significantly to 75.5 (13.6) mm Hg after nitro-
`glycerin 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
`after nitroglycerin inhalation (P<0.001). SaO2
`(1.64)
`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 adminis-
`tration 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
`
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`Inhaled nitroglycerin for reducing PAH
`
`Table 4 Systemic haemodynamic variables in individual patients in the three groups. (a) Baseline, (b) following 100% oxygen administration and (c) after
`1); SVRI, systemic vascular resistance index (units m2)
`nitroglycerin inhalation. AP, systemic arterial pressure (in mm Hg); HR, heart rate (beats min
`
`No.
`
`Systolic/diastolic (mean) AP
`
`(a)
`
`(b)
`
`(c)
`
`SVRI
`
`(a)
`
`(b)
`
`(c)
`
`14.76
`10.45
`7.91
`8.18
`8.6
`8.0
`13.97
`9.1
`
`Group I—patients responding to both 100% oxygen and nitroglycerin (n=8)
`1
`89/73 (77)
`89/61 (76)
`105/65 (80)
`2
`92/65 (74)
`95/66 (76)
`95/65 (75)
`3
`69/50 (56)
`70/52 (58)
`68/50 (56)
`4
`98/64 (75)
`96/65 (74)
`94/65 (75)
`5
`98/73 (81)
`102/74 (83)
`100/72 (81)
`6
`72/48 (56)
`69/50 (56)
`71/50 (57)
`7
`115/75 (88)
`114/75 (88)
`112/75 (87)
`8
`99/72 (81)
`103/74 (84)
`101/73 (82)
`Group II—patients responding to nitroglycerin but not to 100% oxygen (n=8)
`7.84
`9
`92/60 (73)
`93/60 (70)
`108/67 (87)
`6.27
`10
`92/57 (68)
`86/57 (63)
`89/52 (68)
`10.86
`11
`108/70 (83)
`105/68 (80)
`102/65 (77)
`9.74
`12
`110/70 (83)
`112/72 (85)
`106/70 (82)
`10.72
`13
`120/78 (92)
`118/80 (93)
`116/77 (90)
`6.86
`14
`98/57 (71)
`94/55 (68)
`92/54 (67)
`11.52
`15
`110/72 (85)
`108/70 (83)
`107/70 (82)
`11.64
`16
`104/73 (83)
`106/72 (83)
`102/69 (80)
`Group III—patients not responding to either 100% oxygen or nitroglycerin (n=3)
`17
`57/40 (48)
`55/42 (46)
`51/30 (44)
`10.44
`18
`110/68 (82)
`113/70 (84)
`110/67 (81)
`17.53
`19
`122/78 (93)
`120/76 (91)
`116/76 (89)
`11.12
`
`13.7
`9.5
`9.24
`8.23
`8.83
`8.29
`11.09
`10.42
`
`11.51
`5.05
`10.68
`9.22
`9.26
`5.75
`10.62
`11.65
`
`10.76
`19.71
`10.15
`
`14.62
`9.28
`9.34
`7.62
`8.49
`7.39
`11.58
`9.39
`
`12.54
`4.98
`10.13
`8.84
`9.79
`5.12
`10.57
`11.86
`
`11.01
`19.89
`9.28
`
`HR
`
`(a)
`
`137
`136
`165
`135
`138
`161
`130
`138
`
`133
`158
`130
`129
`141
`154
`128
`143
`
`180
`114
`128
`
`(b)
`
`(c)
`
`120
`132
`162
`121
`132
`159
`121
`136
`
`134
`146
`132
`130
`138
`146
`130
`138
`
`182
`107
`124
`
`137
`138
`163
`124
`131
`158
`124
`132
`
`135
`142
`135
`126
`142
`147
`132
`137
`
`180
`106
`128
`
`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 respec-
`tively of all the patients in these three groups.
`
`Discussion
`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 vasodila-
`tor 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, pre-
`medication with i.m. meperidine in combination with pro-
`methazine is widely used for sedation of children during
`cardiac catheterization.14 Studies demonstrating the effects
`of meperidine and promethazine on pulmonary and sys-
`temic 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 com-
`bination with promethazine and chlorpromazine.15 There
`are no data regarding the effects of meperidine on pul-
`monary haemodynamics in children after i.m. administra-
`tion. Moreover, the administration of alternate drugs for
`sedation of children during cardiac catheterization is also
`not without any confounding effects on various haemody-
`namic 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
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`Goyal et al.
`
`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 accompa-
`nied by a similar decrease in mean PA pressure (Table 3).
`This is because passive distension and recruitment of pul-
`monary arteries or an increase in cardiac index can affect the
`calculation of pulmonary vascular resistance without nec-
`essarily indicating a decrease in vascular tone.12 Similarly
`assumed VO2 values can also produce inaccurate calcula-
`tions of PVRI and SVRI.10 Reduction in systemic blood
`pressure can be associated with a decrease in pulmonary
`artery pressure without necessarily influencing the pul-
`monary vascular bed directly. We therefore defined a
`positive response to 100% oxygen administration or nitro-
`glycerin inhalation as >15% decrease in mean pulmonary
`artery pressure to mean systemic arterial pressure ratio12
`and without a significant change in systemic arterial pres-
`sure. 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, indi-
`cating that nitroglycerin inhalation is superior to 100% oxy-
`gen 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 admin-
`istration requires a special and expensive equipment which
`is not widely available. Secondly, it has a number of poten-
`tial 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 inade-
`quate methaemoglobin reductase
`activity, pulmonary
`oedema by increasing left ventricular filling pressure in
`patients with preexisting LV dysfunction,19 rebound pul-
`monary hypertension and arterial desaturation after with-
`drawal 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 car-
`diopulmonary 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 selec-
`tively 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 inhala-
`tion. Nitroglycerin is metabolized to nitric oxide, which
`produces smooth muscle relaxation in the vascular endothe-
`lial 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
`1 day
`1 to prevent methaemoglobinaemia26 and to
`5 mg kg
`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.
`1,
`it produces
`At a driving gas flow of 8 litre min
`particles with a mass mean diameter of 2.75 mm, 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 pres-
`sure as well as in PVRI following 100% oxygen, we admin-
`istered 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 cor-
`rected, and the haemodynamic parameters were not affected
`by surgical repair of congenital heart defect, anaesthetic
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`Inhaled nitroglycerin for reducing PAH
`
`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 ther-
`apy 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 pul-
`monary 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 cath-
`eterization, 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 pul-
`monary 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 dem-
`onstrating 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 mul-
`tiple 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 pul-
`monary 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 car-
`diac 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 pul-
`monary 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 resis-
`tance 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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