European Journal of Cardiovascular Medicine

Pulmonary arterial hypertension (PAH) is commonly seen in children with congenital left to right intracardiac shunt and affects the outcome of cardiac surgical correction. ⁽¹⁾ Surgical closure of intracardiac left to right shunts in children with pre-existing PAH using cardiopulmonary bypass (CPB) can exacerbate pulmonary hypertension and predispose to acute right ventricular dysfunction and episodes of pulmonary hypertensive crisis. ⁽²⁾

In other words, PAH is an important cause of morbidity and mortality in patients with cardiac diseases as PAH increases right ventricular (RV) afterload, which can lead to RV dysfunction, more so after surgical closure under cardiopulmonary bypass. ^(3,4,5) The presence of RV failure carries a poor prognosis, with a high risk of perioperative mortality ranging from 37% to 90%. ^(6,7,8)

For management of these patients, factors that can precipitate pulmonary hypertensive crisis should be avoided and drugs to lower pulmonary vascular resistance should be used. Parenteral prostacyclin and phosphodiesterase inhibitors, such as milrinone, calcium channel sensitizer like Levosimendan have been used successfully for that purpose. However, intravenous administration is limited by systemic hypotension because of systemic vasodilation and by hypoxemia through worsening of intrapulmonary shunt caused by inhibition of hypoxic pulmonary vasoconstriction. ^(9,10)

These side effects warrant the use of selective pulmonary vasodilators by inhalational route, without systemic effects, in patients with PAH. Nitric oxide has been used widely via the inhalational route to selectively dilate the pulmonary vasculature. However, it is expensive, requires specialized equipment, and there is a concern regarding its toxicity. ^(11,12) Therefore, the use of other inhaled NO alternatives like prostacyclin, and prostacyclin analogues which are likely to act directly on pulmonary vasculature, thus having least effect on systemic vasculature has been proposed. Also, drugs like Milrinone and Levosimendan, when used in systemic route cause pulmonary vasodilatation and their feasibility as selective pulmonary vasodilators when administered in inhaled route are being investigated in various studies. ⁽¹³⁾

PAH usually treated with pulmonary vasodilators, such as nitroglycerin or sodium nitroprusside, phosphodiesterase inhibitors, prostacyclin, and prostacyclin analogues as intravenous (IV) or inhaled. These are the modalities that can be used during the perioperative period ⁽¹⁴⁾.

Milrinone, a phosphodiesterase inhibitor and inodilator is frequently used in open-heart surgery for PAH management and reducing afterload to the right ventricle. It is usually administered intravenously, principally during weaning off from Cardio Pulmonary Bypass (CPB) ^{(15, 16)}. This inhibitory effect is associated with increased intracellular ionized calcium and contractile strength of heart muscle ⁽¹⁷⁾. A significant disadvantage of the IV administration of milrinone is systemic hypotension ⁽¹⁸⁾ which entails the further addition of vasopressor. Another alternative to minimize systemic effect is to use the inhalational route ⁽¹⁹⁾. The inhaled route of administration achieves a high local concentration in the pulmonary vasculature, resulting in a selective action, which also causes rapid absorption and high bioavailability ⁽²⁰⁾.

Levosimendan is a calcium‑channel sensitizer with positive inotropic, lusitropic, and vasodilatory effects, that have beneficial effects on myocardial performance. ⁽²¹⁾ Therefore, in many occasion Levosimendan is used in place of Milrinone. But these patients are more prone for hypotension when given through intravenous route.

In a study conducted by Kundra et al in 2018, on patients undergoing mitral valve surgery it was demonstrated that inhaled levosimendan being a selective pulmonary vasodilator, causes a decrease in PASP and mPAP without causing a decrease in SVR and MAP and has a longer duration of action than Milrinone. ⁽¹³⁾

Abdelbaser et al (2021) ⁽²⁵⁾ also conducted a study on the direct comparison of inhaled versus intravenous levosimendan in reducing elevated pulmonary artery pressure on 50 children with intracardiac left to right shunt complicated by pulmonary hypertension undergoing surgical repair under cardiopulmonary bypass. Inhaled levosimendan was non-inferior to intravenous levosimendan in reducing high PAP in children who underwent on-pump cardiac surgery but was associated with less tachycardia, hypotension and reduced need for vasoactive drugs.

However, till date, there has been no study comparing effect of inhaled Levosimendan and inhaled Milrinone on Pulmonary Hypertension in children with congenital left to right intracardiac shunt undergoing surgical correction under CPB.

The hypothesis in this prospective study, was that, there would be a significant difference in Pulmonary systemic arterial pressure changes between the two study drugs namely inhaled Levosimendan and inhaled Milrinone when given to children with intra cardiac left to right shunt and preexisting pulmonary hypertension undergoing surgical correction under CPB. Hence this study was conducted

• To compare the effects of both inhaled drugs on Transthoracic echocardiographic Variables [Right ventricular fractional area change (RV FAC), Tricuspid annular plane systolic excursion (TAPSE), lateral tricuspid annulus peak systolic velocity(S’)] and other hemodynamic parameters like Heart rate (HR), Mean Arterial Pressure (MAP), central venous pressure (CVP) at various postoperative study points.
• To compare Inotropic Score and maximum dose of nor-epinephrine during study period (if required) at various study points in patients receiving either inhaled Levosimendan or inhaled Milrinone.
• To compare time to extubation after shifting to ICU, ICU stay, hospital stay, in hospital mortality, incidence of post-operative complication (hypotension, acute renal failure, CNS dysfunction etc.) in patient receiving either inhaled Levosimendan or inhaled Milrinone.

This Parallel group, Single Blind, Randomized Controlled Trial study was conducted at Paediatric Cath Lab, Cardiothoracic OT and Cardiac surgery recovery unit, I.P.G.M.E&R. (university affiliated tertiary care hospital and teaching institute).

TIMELINES- Two years (24 months)

STUDY POPULATION- Children up to 6 years of age with congenital left to right intracardiac shunt with Pulmonary Hypertension (mean PAP more than 20mm Hg as found during right heart catheterization measured in paediatric cath lab preoperatively) scheduled for surgical correction under cardiopulmonary bypass.

STUDY VARIABLES-

• Echo Variables- PASP, RV FAC, TAPSE, S’, Left ventricular ejection fraction (LVEF).
• Hemodynamic Variables- HR, MAP, CVP, Oxygen saturation (SPO₂), End tidal carbon dioxide (ETCO₂).
• Ionotropic Score (IS) and maximum dose of nor-epinephrine in study period if given.
• Other variables- CPB duration, Cross clamp duration, duration of surgery, episodes of Pulmonary Hypertensive Crisis, Time to extubation (after shift to ICU), ICU length of stay, and in-hospital Mortality.

STUDY TIME POINTS-

After Shifting to ICU,

T0- Before inhalation of study drug,

T1- After completion of inhalation of study drug.

T2, T3, T4, T5, T6 study points are half an hour, 1 hr, 2 hr, 4hr, 6 hr after completion of inhalation of study drug respectively.

SAMPLE SIZE- Sample size for the study was calculated based on pulmonary artery systolic pressure (PASP) as the primary outcome measure. It is calculated that 37 subjects should be required per group to detect difference of 4 mm Hg in PASP between groups at selected time points with 80% power and 5% probability of type 1 error. This calculation assumes SD of 6 mm Hg for PASP based on an earlier study and two-sided testing. Keeping a margin of 10% for dropouts, the recruitment target is being kept at 41 subjects per group. Sample size calculation was done by MedCalc version 19.6 (MedCalc Software Ltd.,Ostend, Belgium,2020) Software.

INCLUSION CRITERIA-

Children, aged upto 6 years, with congenital intracardiac left to right shunt complicated by PAH (mean PAP more than 20mm Hg as found during right heart catheterization) scheduled for surgical correction under CPB will be recruited for the study.

EXCLUSION CRITERIA-

• refusal by guardians to give consent for participation of their wards in the study
• association with right to left shunts
• history of previous cardiac surgery
• heart failure (defined as failure of pumping function and manifested by dyspnea, tachypnea, chest wheezes, pulmonary edema, hepatomegaly, lower limb edema and congested neck veins)
• preoperative inotropic support
• hypersensitivity to Levosimendan and/or Milrinone
• associated with Atrial Fibrillation
• Re exploration in ICU due to bleeding

METHODOLOGY-

After obtaining institutional ethical committee approval, children aged upto 6 years of age with congenital left to right intracardiac shunt with Pulmonary Hypertension scheduled for surgical correction under CPB with mean PAP more than 20 mm hg as found in right heart catheterization were selected for the study. Parents were explained in detail about the study and an informed consent was obtained from each parent. A thorough preoperative checkup was done in each patient including history taking, physical examination, airway assessment and preoperative routine examinations.

An anesthesiologist who was not be involved in the study and blinded to study group allocation, prepared the study drugs. The patients were randomly allocated by a computer-generated randomization table, and group assignments were concealed in sealed opaque envelopes into 2 groups:

• Group A: Inhaled milrinone (in a single dose of 50 mcg/kg) was administered by nebulizer when the patient arrived in the post-operative cardiac ICU room post-surgical correction.
• Group B: Inhaled levosimendan. (in a single dose of 24 mcg/kg) was administered by nebulizer when the patient arrived in the post-operative cardiac ICU room post-surgical correction.

Patients were premedicated with oral midazolam 0.75 mg/kg 30 min before separation from their parents in surgical waiting area. Pulse oximetry, non-invasive blood pressure monitoring was applied to the patient and observed for desaturation and if occurred oxygen mask was applied. After the children were calm and sedated with no separation anxiety, they were taken to OT and all standard monitors were applied and pre-operative baseline values were taken. Peripheral line was placed after sevoflurane inhalation. Antibiotic was given before incision as per institutional protocol. The induction of anaesthesia was done using intravenous fentanyl 5 μg/kg, midazolam 0.05 mg/kg, Thiopentone (sleep dose if necessary) and rocuronium 0.9 mg/kg and then patient was intubated with appropriate size endotracheal tube and was attached to ventilator with proper ventilator settings. Under complete aseptic precautions, appropriate size Femoral arterial cannula was inserted into one of the femoral arteries and a central venous catheter of appropriate size was inserted guided by ultrasonography into the right internal jugular vein. Temperature monitoring was done by nasopharyngeal temperature probe. Anaesthesia was maintained with isoflurane (0.5 MAC) inspired in a mixture of oxygen and nitrous oxide (1:1), with intermittent Inj Vecuronium 0.02 mg/kg and Inj Fentanyl 0.5-1 mcg/kg as and when required, and BIS maintained around 40-60. All lines were kept air free. Anaesthesia ventilator was used and pressure-controlled ventilation was selected and adjusted to maintain end-tidal carbon dioxide between 30 and 35 mmHg.

Transthoracic Echocardiography (TTE) was performed for echocardiographic examinations after intubation and before surgical dressing and draping, by a Cardiac Anaesthesiologist with 8 years’ experience in perioperative TTE and Transesophageal Echocardiography &/or board certified in perioperative echocardiography. The systolic PAP was measured from TR Jet peak velocity using the formula, PASP=4v²+CVP (v= TR peak Jet velocity). RV FAC, TAPSE, S’, LVEF were noted. All the echo parameters were measured in transthoracic apical 4 chamber view except LVEF which was measured by Teich method in Parasternal long Axis view. 

The heart was explored via standard median sternotomy incision. CPB was initiated after heparin administration in a dose of 3–4 mg/kg to raise the activated clotting time more than 480s. The pump flow was calculated as per body surface area and the mean perfusion pressure will be maintained between 40 and 60 mmHg while on CPB. The patient was cooled to (32–35) ◦C. The patient’s hematocrit value was maintained between 25% and 30%. The patient received cardioplegia anterogradely in the aortic root after clamping the ascending aorta. Anaesthesia was maintained during CPB by intermittent IV anaesthetics on CPB. After surgical correction and cross clamp release, the patient was re-warmed, heart was de-aired and weaned off from CPB after giving progressive load to heart. Ionotropes were started and heart was paced if required while weaning from CPB. After surgery and chest closure, the patients were shifted to the post- operative cardiac ICU room with IPPV. After shifting the patient to ICU, monitors were attached, patient was stabilized, and ventilator was set in pressure control mode to maintain optimal blood gases. All study parameters (echocardiographic and hemodynamic) were noted just before inhalation of study drug at study time point T0. Administration of study drugs by nebulization was done and the person administering the study drug was blinded to the study drug and group allocation. The drugs will be administered through an ultrasonic mesh nebulizer (droplet diameter less than 3.3 micrometer) attached to the inspiratory limb of the ventilator near the endotracheal tube.

Pre-inhalation T0 and post-inhalation T1 hemodynamic parameters were noted along with the TTE Parameters like PASP, RV FAC, TAPSE, S’, Left Ventricular Ejection Fraction (LVEF), as well as, at other study time points as mentioned below:

T2, T3, T4, T5, T6 study points are half an hour, 1 hr, 2 hr, 4hr, 6 hr after completion of inhalation of study drug respectively.

The inotropic score (IS) is also noted at these study points. In case of persistent hypotension with mean arterial blood pressure falling below 20% of pre-inhalation base line, Norepinephrine was added and maximum dose used in study period was noted.

IS = dopamine dose (mcg/kg/min) + dobutamine dose (mcg/kg/min) +100 × epinephrine dose (mcg/kg/min).

Ionotropic requirement order was dobutamine, dopamine and then epinephrine.

Statistical Analysis:

Categorical variables are expressed as Number of patients and percentage of patients and compared across the groups using Pearson’s Chi Square test for Independence of Attributes/ Fisher's Exact Test as appropriate. Continuous variables are expressed as Mean, Median and Standard Deviation and compared across the groups using Mann-Whitney U test since the data does not follow normal distribution. The statistical software SPSS version 25 has been used for the analysis. An alpha level of 5% has been taken, i.e. if any p value is less than 0.05 it has been considered as significant.

The findings and results of our study are tabulated and described in the following tables and text.

Table 1: Comparison of Patient Demographics between the two study Groups

Group A: Inhaled milrinone (in a single dose of 50 mcg/kg) was administered by nebulizer when the patient arrived in the post-operative cardiac ICU room post-surgical correction.

Group B: Inhaled levosimendan. (in a single dose of 24 mcg/kg) was administered by nebulizer when the patient arrived in the post-operative cardiac ICU room post-surgical correction.

Table 1 shows distribution of Age, Height, Weight & BSA (Body Surface Area) in the two groups. No significant difference was found using Mann-Whitney U(P>0.05).

There was no statistically significant difference between the groups when compared using Pearson’s Chi Square test with respect to patient’s sex (p> 0.05).

Table 2: Comparison of Transthoracic Echocardiographic variables between the two study Groups

T0 After shifting to  ICU pre inhalation of study drug, T1 Post inhalation of study drug, T2, T3, T4, T5, T6 study points are half an hour, 1 hr, 2 hr, 4hr, 6 hr after completion of inhalation of study drug respectively.

PASP- Pulmonary Artery Systolic Pressure, RV FAC- Right Ventricular Fractional Area Change, TAPSE- Tricuspid annular plane systolic excursion, RV S’- lateral tricuspid annulus peak systolic velocity, LVEF- Left Ventricular Ejection Fraction

Figure 1: Comparison of Transthoracic Echocardiographic variables between the two study Groups at different time points

Group A: Inhaled milrinone , Group B: Inhaled levosimendan

Table 2 & Fig 1 show that there was a reduction in PASP with both inhaled milrinone and inhaled levosimendan at time points T1(Post Inhalation of study drugs) and T2 (0.5 hr of ICU stay) compared to baseline T0 (Pre inhalation of study drugs in postoperative ICU), however these reduction in PASP was found to be comparable in both study groups (p>0.05). The reduction in PASP (mm of Hg) at time points T3 (1 hr of ICU stay)  [Group A- 39.48 ± 3.43 vs Group B- 32.27 ± 4.87], T4 (2 hr of ICU Stay) [Group A- 41.00 ± 5.38 vs Group B- 33.86 ± 6.17] and T5 (4 hr of ICU stay) [Group A- 39.46 ± 4.74 vs Group B- 35.62 ± 5.64] were more in the inhaled levosimendan group as compared to the inhaled milrinone group, and the difference was found to be statistically significant (p<0.05). The reduction in PASP at time point T6 (6hr of ICU stay) was more in the inhaled levosimendan group as compared to the inhaled milrinone group, however, the difference was not statistically significant.

Other Transthoracic Echocardiographic right ventricular systolic parameters which were observed in our study like TAPSE, RV S’, RV FAC and left ventricular ejection fraction improved slightly at time points T1, T2, T3, T4, T5 and T6 compared to baseline T0 in both the groups and were found to be comparable in both the study groups (p>0.05). (Table 2 & Fig 1)

Table 3: Comparison of Perioperative Hemodynamic variables between the two study Groups

T0 After shifting to  ICU pre inhalation of study drug, T1 Post inhalation of study drug, T2, T3, T4, T5, T6 study points are half an hour, 1 hr, 2 hr, 4hr, 6 hr after completion of inhalation of study drug respectively.

SPO2- O2 Saturation, ETCO2- End Tidal CO2, MAP- Mean arterial Pressure, HR- Heart Rate, CVP- Central venous pressure

Figure 2: Comparison of SpO2, ETCO2, MAP, HR, CVP between the two study Groups at different time intervals

Group A: Inhaled milrinone , Group B: Inhaled levosimendan

Table 3 & Fig 2 shows mean arterial pressure (MAP) was comparable in both the groups (p>0.05). Change in heart rate (HR) from the baseline was observed at different time points, however, the difference was not statistically significant (p>0.05). Central venous pressure (CVP) and oxygen saturation (SPO2) were also comparable in both the study groups (p>0.05).

Table 4: Comparison of other intraoperative & postoperative variables between two study Groups

Group A: Inhaled milrinone (in a single dose of 50 mcg/kg) was administered by nebulizer when the patient arrived in the post-operative cardiac ICU room post-surgical correction.

Group B: Inhaled levosimendan. (in a single dose of 24 mcg/kg) was administered by nebulizer when the patient arrived in the post-operative cardiac ICU room post-surgical correction.

NE Dose- Maximum dose of Norepinephrin used

The inotropic score (IS):

IS = dopamine dose (mcg/kg/min) + dobutamine dose (mcg/kg/min) +100 × epinephrine dose (mcg/kg/min).

Ionotropic requirement order will be dobutamine, dopamine and then epinephrine.

In case of persistent hypotension with mean arterial blood pressure falling below 20% of pre-inhalation base line, Nor epinephrine was added and dose was noted.

Table 4 shows the inotropic score and the maximum dose rate of nor-epinephrine infusion used and were found to be comparable between both the groups (p>0.05).

The duration of CPB, aortic cross clamp and duration of surgery were comparable between both the groups and statistically insignificant (p>0.05).

There was no statistically significant difference in time to extubation and length of ICU stay between both the groups.

Table 4: Comparison of Complications between the two study Groups

PHC- Pulmonary Hypertensive Crisis

Table 4 shows that that there was no statistically significant difference in occurrence of episodes of pulmonary hypertensive crisis, or incidence of complications in both the groups.

There was no in-hospital mortality in both the study groups.

Surgical closure of intracardiac left to right shunts in children with pre-existing PAH using cardiopulmonary bypass (CPB) can exacerbate pulmonary hypertension and predispose to acute right ventricular dysfunction and episodes of pulmonary hypertensive crisis. ⁽²⁾ In other words PAH is an important cause of morbidity and mortality in patients with cardiac diseases as PAH increases right ventricular (RV) afterload, which can lead to RV dysfunction, more so after surgical closure under cardiopulmonary bypass. ^(3,4,5) The presence of RV failure carries a poor prognosis, with a high risk of perioperative mortality ranging from 37% to 90%.^(6,7,8)

For management of these patients, factors that can precipitate pulmonary hypertensive crisis should be avoided and drugs to lower pulmonary vascular resistance should be used. Parenteral prostacyclin and phosphodiesterase inhibitors, such as milrinone, calcium channel sensitizer like Levosimendan have been used successfully for that purpose. However, intravenous administration is limited by systemic hypotension because of systemic vasodilation and by hypoxemia through worsening of intrapulmonary shunt caused by inhibition of hypoxic pulmonary vasoconstriction. ^(9,10) Therefore, administration of the above drugs by inhaled route for selective pulmonary vasodilation was tested in several studies and were found to be effective.

In a study by Kundra et al in 2008 it has been seen that inhaled levosimendan being a selective pulmonary vasodilator, causes a decrease in pulmonary artery systolic pressure and mean pulmonary artery pressure without causing a decrease in Systemic vascular resistance and mean arterial pressure than Milrinone in adult population undergoing mitral valve repair under CPB. ⁽¹³⁾

In the study, the effect of inhaled Levosimendan and inhaled Milrinone on Pulmonary Hypertension in children with congenital left to right intracardiac shunt undergoing surgical correction under CPB has been compared.

From demographic point of view, both groups were comparable including age, sex, height, weight and body surface area. Mean age in inhaled milrinone group was 40 months and inhaled levosimendan was 45 months in our study. In the study by Abdelbaser et al (2021) ⁽²⁵⁾ comparing effect of inhaled versus intravenous levosimendan in reducing elevated pulmonary artery pressure in children with intracardiac left to right shunt complicated by pulmonary hypertension undergoing surgical repair under cardiopulmonary bypass, the mean age in inhaled vs IV group were 32.5 months and 32.5 months respectively.

In our study, we found that both Inhaled Milrinone & Inhaled Levosimendan caused a comparable reduction in pulmonary artery systolic pressure, both immediately after completion of inhalation of study drugs (T1), 0.5 hr post inhalation (T2) as well as 6hr post inhalation (T6) of study drugs in consecutive groups compared to baseline, that is before inhalation (T0) of study drugs. The reduction in PASP (mm of Hg) was significantly greater in the inhaled levosimendan group as compared to the inhaled milrinone group at 1 hr after completion of inhalation of study drugs (T3) [Group A- 39.48 ± 3.43 vs Group B- 32.27 ± 4.87], at 2 hr after completion of inhalation of study drugs (T4) [Group A- 41.00 ± 5.38 vs Group B- 33.86 ± 6.17] and at 4 hr after completion of inhalation of study drugs (T5) [Group A- 39.46 ± 4.74 vs Group B- 35.62 ± 5.64]. Abdelbaser et al (2021) ⁽²⁵⁾, in their study on children who underwent on-pump cardiac surgery, found that inhaled levosimendan was non-inferior to intravenous levosimendan in reducing high pulmonary artery pressure at different time points, that is before institution of CPB, after separation from CPB, at the end of surgery, during the first postoperative hour in ICU and at 12^th postoperative hour in ICU. This indicates that both inhaled milrinone and inhaled levosimendan were equally effective in reducing pulmonary arterial pressure.

Kundra et al (2018) ⁽¹³⁾, in their study on patients undergoing mitral valve surgery associated with PAH, demonstrated that MAP, pulse rate & SVR were comparable in the 3 groups (Control Group, Inhaled Levosimendan & Inhaled Milrinone group) at various time points and PASP & MPAP decreased comparably after inhalation of levosimendan and milrinone, however, they reached levels near the control group after 2.5-3 hours in the levosimendan group and 0.5 hr in the milrinone group, thus concluding that inhaled levosimendan was as effective as milrinone in reducing PASP and MPAP with an advantage of longer duration of action. In our study effect of reduction of PASP lasted longer in inhaled Levosimendan group (4 hr after completion of inhalation) as compared to inhaled Milrinone group, suggesting that Inhaled levosimendan probably has longer duration of action.

In our study, hemodynamic parameters including MAP, HR were comparable in both the groups, while in the study conducted by  Ibrahim et al ⁽²⁶⁾ inhaled levosimendan was associated with less tachycardia and hypotension with reduced need for vasoactive drugs as compared to intravenous levosimendan .

In our study the inotropic score and the peak nor-epinephrine dose rate were comparable between both the groups. In the study conducted by Ibrahim et al ⁽²⁶⁾ vasoactive drug requirements were significantly higher in the intravenous Levosimendan group than in inhaled Levosimendan group.

The duration of CPB, aortic cross clamp and duration of surgery were comparable between both the groups in our study. There was no statistically significant difference in time to extubation and length of ICU stay between both the groups corroborative with the study conducted by Ibrahim et al⁽²⁶⁾  and Kundra et al⁽¹³⁾.

In the Kundra et al (2018) ⁽³²⁾ study, on the effect of inhaled vs intravenous Levosimendan on PASP and RV FAC in patients undergoing mitral valve replacement surgery under CPB, there was a significant and comparable reduction in PASP and improvement in RV-FAC with both inhaled and intravenous levosimendan, while SVR significantly decreased with intravenous levosimendan. In our study, improvement in RV FAC, TAPSE and RV S’ was comparable between both inhaled milrinone and inhaled levosimendan groups, suggesting similar effect of inhaled milrinone and inhaled levosimendan on the RV systolic function echo parameters.

Although in the study conducted by Ibrahim et al. there was no episode of pulmonary hypertensive crisis in either of the group, in our study we also didn’t have observed any episode of pulmonary hypertensive crisis. Also as in the  study by Ibrahim et al. there were no in hospital mortality in our study.

Inhaled Milrinone has been found to be equally effective as Inhaled Levosimendan in reducing elevated PASP post operatively in children with congenital heart disease with left to right intra cardiac shunt with pulmonary hypertension undergoing surgical correction under CPB. However we found that effect of Inhaled levosimendan in reducing PASP lasted longer than Inhaled Milrinone.

Both Inhaled Milrinone and Inhaled Levosimendan do not cause significant systemic hemodynamic effects or  do not result in increased requirement of vasopressors.

Both Inhaled Milrinone and Inhaled Levosimendan do not cause significant increase in post operative complication including ICU length of stay and in hospital mortality.

Therefore, although both Inhaled Milrinone and Inhaled Levosimendan are effective in reducing elevated pulmonary artery systolic pressure without causing systemic hypotension in children with congenital heart disease with left to right intra cardiac shunt with pulmonary hypertension undergoing surgical correction under CPB, inhaled levosimendan probably has longer duration of action.

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