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Department of Cardiovascular and Thoracic Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine (Formerly Shanghai Second Medical University), Shanghai, China
Accepted for publication May 5, 2008.
* Address correspondence to Dr Yang, Cardiac Studies, Institute for Biodiagnostics, National Research Council of Canada, 435 Ellice Ave, Winnipeg, Manitoba, R3B 1Y6, Canada (Email: victor.yang{at}nrc-cnrc.gc.ca).
Presented at the Forty-fourth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28–30, 2008.
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Abstract |
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Methods: Forty-six patients with high pulmonary vascular resistance (transpulmonary pressure gradient >10 mm Hg or central venous pressure >15 mm Hg) and impaired oxygenation after Fontan operation were prospectively randomized into three groups: group Mil (n = 15, milrinone at 0.5 µg · kg–1 · min–1), group iNO (n = 15, iNO at <20 ppm), and group iNO + Mil (n = 16, iNO plus Mil). Pulmonary hemodynamic and oxygenation changes were compared among the three groups.
Results: Inhalation of nitric oxide with milrinone led to (1) the most significant reduction of pulmonary vascular resistance (transpulmonary pressure gradient from 11.26 ± 1.40 mm Hg [baseline] to 7.93 ± 0.90 mm Hg [24-hour use] in group iNO + Mil versus from 11.10 ± 1.38 to 8.69 ± 0.86 mm Hg; p = 0.048 in group iNO and from 11.17 ± 1.41 mm Hg to 9.72 ± 1.32 mm Hg; p < 0.001 in group Mil); (2) the most significant improvement of arterial blood oxygenation (ratio of arterial oxygen partial pressure to inspired fraction of oxygen from 68.88 ± 14.09 to 131.25 ± 15.92 in group iNO + Mil versus from 70.07 ±14.24 to 120.20 ± 15.92; p = 0.047 in group iNO and from 72.60 ± 12.92 to 95.20 ± 13.49; p < 0.001 in group Mil). Time on mechanical ventilation was shortest in group iNO + Mil (p = 0.043).
Conclusions: Combined use of iNO and milrinone optimally stabilized pulmonary hemodynamics after Fontan operation.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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To meet this objective, inhalation of nitric oxide (iNO) has become the most preferred option [6], if available, as it can selectively reduce PVR by relaxing the smooth muscle without major negative impact on the systemic circulation because of its high affinity for hemoglobin after diffusion into the blood. However, clinical practices have also implied that its efficiency might not be sustainable during or after its withdrawal, which sometimes could lead to severe PVR rebound requiring its prolonged use [7–9].
Milrinone has long been proven to be an efficient medication for patients with preexisting pulmonary hypertension or depressed postoperative cardiac function as it can (1) relax vascular smooth muscle and (2) improve both systolic and diastolic cardiac function. Its usage has become a first-line choice for patients with various extents of pulmonary hypertension. Its efficiency as an adjunct to iNO for treatment of high PVR after a Fontan operation, however, has not been reported before.
The purpose of this study was to determine the early hemodynamic and oxygenation responses to iNO, milrinone (intravenous use), or both in patients with marked elevation of PVR after a Fontan operation.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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Patient Selection
Pediatric patients, who underwent modified fenestrated Fontan operation and suffered marked elevation of PVR (1) with no explainable causes (eg, low cardiac output, arrhythmia, and atrial-ventricular valve regurgitation) and (2) without response to conventional managements (ie, sedation, analgesia, and respiration adjustment so as to establish normal arterial carbon dioxide tension of about 40 mm Hg and an arterial pH of about 7.40) were enrolled in this study. The inclusion criteria for elevated PVR included patients whose transpulmonary pressure gradient (TPG, ie, the difference between central venous pressure [CVP] and left atrial pressure) was higher than 10 mm Hg or CVP was higher than 15 mm Hg with concomitant deterioration of arterial blood oxygen saturation (SaO
2 <85%) despite increased inspiratory oxygen fraction. Patients were assigned with random number allocation to iNO group (inhalation of NO), milrinone group (intravenous administration of milrinone), or iNO in conjunction with milrinone group (inhalation of NO and intravenous milrinone), immediately after they were determined to be a suitable candidate. The exclusion criteria of enrolled patients during the study were complications of major organ dysfunction, pulmonary infection, and conduit thrombosis.
Study Design
The following protocol was used for all patients: (1) baseline measurements of all variables (detailed in the following section), (2) administration of iNO (group iNO), milrinone (group Mil), or both (group iNO + Mil), (3) repeated measurements of variables at 4, 12, and 24 hours after initiation of respective medication strategies. To prevent confounding results, normal ventilation, stable oxygen inspiration fraction (60%), and one intravenous positive inotropic agent, ie, dopamine (5 µg · kg–1 · min–1), were continued throughout the study.
Drug Administration
Patients assigned to groups iNO and iNO + Mil would inhale NO, which was stored as a mixture with nitrogen at 800 ppm NO (Shanghai Jiliang Gas Reference Co Ltd, Shanghai, China) in a cylinder. The gas was added into the part of the inspiratory circuit of the prototype Servo ventilator 300 NO-A (Siemens, Germany). Inhalation of NO began from 10 ppm with subsequent adjustment aimed at achieving greater than 20% improvement in TPG or greater than 10% SaO
2 with the lowest possible dose of iNO (1 to 20 ppm) within 2 hours after initiation. Peak nitrite and nitrate concentrations were continuously monitored during NO administration. Methemoglobin concentration in the blood was measured with a radiometer ABL 700 blood gas analyzer (Copenhagen, Denmark) at baseline and every 4 hours after the first exposure to iNO. Gradual weaning from iNO was attempted 24 hours after its use. If the patient's hemodynamics or SaO
2 deteriorated during iNO withdrawal, the weaning attempt was postponed until their recovery. Milrinone (Lunan Pharmaceutical Inc, Shandong, China), which would be used for patients in group Mil and iNO + Mil, was prepared from a vial of 5 mg/5 mL and infused continuously into the circulation at 0.5 µg · kg–1 · min–1 with an infusion pump. If there was no significant improvement in TPG (>10%) and SaO
2 (>5%) within 6 hours after its use, iNO was added to the therapeutic regimen and the patient was excluded from final statistical analysis. Milrinone would be gradually weaned from patients after uneventful extubation with consistently stable hemodynamic condition. The total intake and output volume was strictly balanced every day to exclude any other factors influencing results.
Measurements
Primary outcome
Primary outcomes to be measured included both pulmonary (TPG and CVP) and systemic hemodynamics as well as arterial blood oxygenation (oxygenation index, ie, ratio of arterial oxygen partial pressure to inspiratory oxygen fraction, and SaO
2). To achieve these measurements, catheters were placed inside the superior vena cava through the right internal jugular vein, the left atrium through the right superior pulmonary vein, and a peripheral systemic artery to allow their simultaneous measurements. Intravascular pressures were measured with fluid-filled transducers. Blood gas was sampled from the systemic arterial blood. Inspiratory oxygen fraction was acquired from the ventilator.
Secondary outcome
To further evaluate the short-term effect of iNO or milrinone use, total time on mechanical ventilation and amount of chest drainage, as well as time in the intensive care unit and hospital, were evaluated.
Statistical Analysis
The data are expressed as the mean ± standard deviation for continuous variables. Statistical analysis was performed using statistical software (Statistica 6.0, Statsoft Inc, Tulsa, OK). Two-way analysis of variance for repeated measurements was used to test null hypotheses regarding the effects of between-subject factor (medication group), the within-subjects factor (time), and the interaction between them. If a statistically significant interaction between group and time was found, subsequent comparison among the groups at respective time points was performed by one-way analysis of variance followed by Duncan's multiple range test. Nominal variables were analyzed by nonparametric test. A difference was considered significant if the probability value was less than 0.05.
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Results |
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Arterial Blood Oxygenation
The change of oxygen index (ratio of arterial oxygen partial pressure to fraction of inspired oxygen) and SaO
2 is detailed in Figure 2. There was no significant difference among the three groups in baseline values of either variable. Use of iNO alone (group iNO) or in conjunction with milrinone (group iNO + Mil) quickly increased both variables within 4 hours after their use, which was in contrast to much slower improvement in patients receiving milrinone exclusively. Beginning from 4 hours until 24 hours after administration of respective medication, the difference in both variables between group Mil and the other two groups was statistically significant. Additionally, the difference in the ratio of arterial oxygen partial pressure to fraction of inspired oxygen between group iNO and group iNO + Mil at the 24th-hour measuring point also achieved statistical difference.
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Other Secondary Outcomes
Other outcomes are detailed in Table 2. The total amount of chest drainage was not different among the three groups. Although the time in the intensive care unit and hospital tended to be shorter in group iNO + Mil, the difference was not statistically significant.
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Comment |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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Inhaled NO could induce selective pulmonary vasodilation in ventilated lung regions by increasing the levels of the vasodilator cyclic-guanosine 5'-monophosphate (cGMP) within the pulmonary vascular smooth muscle. As a result, iNO has been proposed as a therapeutic choice for patients with acutely elevated TPG and impaired arterial blood oxygenation after Fontan-type operation [14, 15]. However, clinical practices indicate that the response to iNO remains inconsistent in respective patients and may require higher dosage or prolonged exposure. The reasons for various individual responses to iNO exposure may involve (1) varied extent of preoperative pulmonary arteriole abnormalities that are not detectable based on current hemodynamic measurements [5]; (2) impaired preoperative ventricular mechanical property, especially, relaxation in patients with single-ventricular pathophysiology [2, 16]; and (3) varied extent of body response to cardiopulmonary bypass–induced inflammation and endothelial sensitivity to reperfusion after temporary ischemia. However, prolonged use or high dosage of iNO may easily incur various toxic side effects in human beings [17] and withdrawal rebound [7] owing to various mechanisms [8, 18]. As a result, every effort is made to minimize the length and dosage of iNO exposure for individual patients.
In most reported studies, the strategy aimed at minimizing iNO exposure and achieving early uneventful withdrawal focused on maintaining cGMP level inside the pulmonary vascular smooth muscle as several studies have found that exogenous NO exposure would inhibit the endogenous NO-cGMP cascades. For example, Black and colleagues [19] found that iNO use for 6 hours at 40 ppm in neonatal lambs could reduce endogenous NO synthase activity by approximately 40%, although twice the increment in plasma cGMP level was observed during the period of NO inhalation owing to stimulation of guanylate cyclase by exogenous NO. As a result, after acute withdrawal of NO, PVR bounced back with simultaneous significant decrement of plasma cGMP concentration, both of which did not return to normal levels until 60 minutes later with concomitant partial recovery of endogenous NO synthase [19]. Furthermore, Thelitz and associates [20] found that iNO use also reduced soluble guanylate cyclase level in pulmonary vascular smooth muscle and thus, decreased intracellular cGMP concentration immediately after its withdrawal. As a result, phosphodiesterase-5 inhibitors such as dipyridamole [21] and sildenafil [22] have been proposed as a method of choice to facilitate earlier withdrawal from iNO by inhibiting cGMP degradation.
Nevertheless, recent studies also indicated that iNO could also induce other important biochemical changes inside the pulmonary tissue related to its later withdrawal rebound. For example, Thelitz and coworkers [23] found that although iNO could lead to a decrement of lung tissue cyclic adenosine monophosphate concentrations by 25.3%, PVR remained stable after acute iNO withdrawal and lung tissue cyclic adenosine monophosphate concentrations were preserved during NO therapy in milrinone-treated lambs [23]. The first reported clinical study comparing the effects of iNO or milrinone for postoperative patients with congenital heart diseases causing pulmonary hypertension also appeared recently. In that report, Khazin and colleagues [24] found that combined use of both drugs could maximally lower PVR. In our study, we also observed that their combination could provide fastest and maximal effects in reducing PVR and, thus, ameliorate arterial blood oxygenation. Of course, use of milrinone did not only benefit the pulmonary circulation as it also provided important lusitropic effects on the heart, which has extreme importance for the heart with single-ventricle pathophysiology. Penny and associates [25] used Doppler echocardiography and micromanometer pressure during steady states before bypass and after bypass to assess the effects of Fontan surgery. The perioperative increase in mass to volume ratio of the single ventricle was described as an "acute hypertrophic cardiomyopathy" with inherent diastolic dysfunction, quantified as prolongation of the time constant of isovolumic pressure decay. Garofalo and colleagues [2] further reported the ventricle had significantly higher stiffness immediately after Fontan operation as a result of cardiopulmonary bypass use. As such, milrinone could further improve the pulmonary circulation by increasing myocardial relaxation. Simultaneously, milrinone also helped improve myocardial contractility without further exhaustion of oxygen. Of course, the influence of milrinone on the systemic circulation was still a major concern in carrying out this study. As a result, we carefully initiated its intravenous administration using a maintenance dosage. The results indicated that this strategy provided a satisfactory outcome as indicated by a minor increment in systemic arterial blood pressure.
However, use of milrinone alone may not be enough to address severely elevated PVR as its effect appeared slower and weaker than iNO use. Three potential explanations are proposed here. Firstly, a limited amount of milrinone could enter the pulmonary circulation at the initial stage as a result of a significant shunt to the systemic circulation through the fenestration secondary to high PVR. As a result, its concentration in the pulmonary vascular wall would be low and fail to provide an immediate influence. Second, the pharmacodynamic potency within its therapeutic window in reducing PVR was less than NO. Third, the effective concentration in the blood was gradually increased as the maintenance dosage was directly used in our study.
Our study had several limitations. Perioperative histologic and immunohistochemical analyses of lung and cardiac tissue were not performed. Also, we did not measure both cGMP and cyclic adenosine monophosphate levels in both tissue and blood. Finally, we did not continuously monitor cardiac systolic and diastolic function, which may have revealed the cardiac influence of both drugs.
In summary, this study demonstrated the benefits of the association of iNO and milrinone for patients exhibiting high PVR after the Fontan procedure. This association produced better and longer-lasting hemodynamic effects than iNO alone. By reducing iNO administration time, the association strategy might help minimize the risk of iNO-induced side effects in clinical practice. The hemodynamic improvement related to this pharmacologic approach might be of particular value in the management of patients with associated cardiac insufficiency.
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Discussion |
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DR YANG: As we did not see significant difference regarding the venous oxygen saturation among the three groups, we didn't put the data into the report.
DR PIGULA: Because I'm just wondering if that is one way to look at cardiac output as a contributor with improved mixed venous saturations versus the pulmonary effect of the milrinone and nitric oxide?
DR YANG: We didn't find significant difference in this variable among the three groups.
DR CHRISTOPHER A. CALDARONE (Toronto, Canada): The dosage of milrinone is given as an infusion, but there wasn't any loading dose. I'm sure that you considered that. What were your considerations and why did you make the choice you did?
DR YANG: During our initial study, we found that a loading dose of milrinone before its subsequent continuous infusion led to severe hypotension in some patients. As a result, a maintenance dose was applied in this study. We suspected that milrinone (administered via a loading dose) was immediately shunted, to some extent, to the systemic circulation from the fenestration, a reason leading to severe hypotension. Inhalation of milrinone, instead of intravenous loading dose, might be helpful to prevent hypotension.
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Acknowledgments |
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p < 0.05; 