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* From the Département d'Anesthésie-Réanimation, Faculté de Médecine, Centre hospitalier de l'Université de Montréal, Hôpital Notre-Dame,
Montréal and Centre hospitalier Régional, Rimouski, Québec, Canada.
Address correspondence to: Gilbert Blaise MD, Département d'Anesthésie-Réanimation, CHUM-Hôpital Notre- Dame, 1560, rue Sherbrooke est, Montréal, Qc H2L 4M1, Canada. Phone: 514-281-6000, Ext 5397; Fax: 514-896-4615; E-mail: blaisegil{at}videotron.ca
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Clinical features: We report the case of a female patient with chronic secondary pulmonary hypertension and cardiac failure who underwent right hemicolectomy under general anesthesia. Insertion of a pulmonary artery catheter before the operation revealed pulmonary artery pressure (PAP) of 55/24 mmHg which was lowered moderately by 40 parts per million (ppm) inhNO. During surgery, the patient presented an episode of atrial fibrillation with a slow, irregular heart rate of 45-50 min–1 and variable systemic pressure. A dipyridamole DPD (0.2 mg•kg–1) bolus stabilized systemic pressure and increased heart rate and cardiac output. However, PAP did not change. Nitroglycerine infusion was started at 10 mg•hr–1 shortly after the initiation of DPD. The patient responded favourably to combined inhNO, intravenous DPD and NTG therapy with a marked and sustained reduction of PAP and a systemic hemodynamic stability.
Conclusion: We conclude that: 1) in combination with inhNO, DPD does not augment the inhNO-induced decrease in PAP; 2) DPD improves the hemodynamic profile and elevates cardiac output; 3) therapeutic combination (inhaled NO, NTG, DPD) has a potent effect on pulmonary pressure in cardiac failure patients.
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On arrival, she was anticoagulated with heparin until the day of surgery. Electrocardiography revealed atrial fibrillation with a ventricular rate of 60-65 min–1, complete right bundle-branch block and right ventricular hypertrophy. Chest X-ray showed moderate enlargement of the right heart with signs of pulmonary hypertension. Transesophageal echocardiography presented a 6 mm patent foramen ovale associated with considerable bidirectional shunt. The left ventricular ejection fraction was estimated to be 40% with severe biventricular diastolic dysfunction. The left atrium was dilated with moderate mitral regurgitation. The right heart was markedly dilated and hypokinetic. No arteriostenosis was observed by coronary angiography.
Surgical procedure
After receiving 2 mg ativan as premedication, anesthesia was induced with 68 µg sufentanil, 100 mg propofol and 80 mg rocuronium, and maintained by continuous infusion of 130 µg•kg–1•min–1 propofol, 0.5 µg•kg–1•min–1 sufentanil and intermittent vecuronium for muscle relaxation. The trachea was intubated and the lungs ventilated with oxygen 100%, adjusted to keep partial pressures of arterial carbon dioxide (PaCO2) in the low range (35 mmHg). Inhaled nitric oxide (40 parts per million ppm) was injected cyclically into an inspiratory line by NO injector, with NO and nitrogen dioxide (NO2) concentration being monitored via an electrochemical NO and NO2 analyser. An arterial cannula and pulmonary artery flotation catheter were inserted for continuous monitoring of systemic and pulmonary pressures.
In the perioperative period, pulmonary artery pressure (PAP) decreased from 55/24 to 41/18 mmHg following inhNO. During the surgical procedure, the patient presented rapid atrial fibrillation with a slow, irregular heart rate of 45-50•min–1 and fluctuation of systemic pressure from 80/30 to 145/70 mmHg. A DPD bolus (0.2 mg•kg–1) was injected to augment inhNO-induced pulmonary vasodilatation. Heart rate increased to its preoperative level, systemic pressure stabilised at 135/70 mmHg and cardiac output increased from 5.1 to 5.8 L•min–1. However, pulmonary pressure did not change. A NTG infusion was then started at a rate of 10 mg•hr–1; this combined treatment effectively reduced PAP from 41/18 to 26/7 mmHg and systemic pressure from 135/70 to 115/60 mmHg (Table
).
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Recently, pulmonary endothelial damage was demonstrated to be an early histological finding in children with congenital heart disease and pulmonary hypertension.7 It appears that longterm left-to-right shunt through a VSD results in a persistent increase of pulmonary flow, leading to pulmonary endothelial injury. In addition, the endothelial injury coupled with excessive release of locally active mediators produces vascular structural changes such as smooth muscle hypertrophy, intimal fibrosis, irregularity of elastic fibres, vessel wall infiltration with erythrocytes and inflammatory cells. This process is characterized by an inexorable cycle of endothelial dysfunction with decreased production of endothelium-derived vasodilators or an increase of vasoconstrictors.8
Inhaled nitric oxide is now regarded as a very potent pulmonary vasodilator that effectively reduces PAP and pulmonary vascular resistance by stimulating guanylate cyclase in pulmonary vascular smooth muscle to produce cGMP and cause vascular smooth muscle relaxation.9 Cyclic guanosine 3',5' monophosphate production in vascular smooth muscle cells is countered by its degradation by cGMP-specific phosphodiesterases.10 Recently, inhNO was confirmed to induce pulmonary vasodilatation in primary pulmonary hypertension,11 in pulmonary hypertension resulting from congenital heart disease,12 in the adult respiratory distress syndrome13 and in patients after cardiac surgery.14 However, some patients may show partial2 or no clinical responses to inhNO therapy. The vasodilator effect of DPD is mediated by: 1) inhibiting cGMP degradation in vascular smooth muscle9 via suppression of phosphodiesterase V to cause pulmonary vasodilation; 2) blockade of adenosine cellular reuptake, leading to adenosine accumulation in interstitial spaces around the arterioles, which results in dilation of the coronary, systemic and pulmonary vasculature.15 Ovine models of pulmonary hypertension have shown that the effect of DPD on pulmonary vasodilation is not influenced by adenosine receptor blockade.16 This observation has established that cGMP-specific phosphodiesterase inhibition is the main mechanism by which DPDs reduce pulmonary vasodilation.
Fullerton et al.9 reported DPD-induced augmentation of pulmonary vasodilatation in 10 postoperative cardiac patients treated with inhNO. On the opposite, except for two subjects with pulmonary hypertension resulting from longstanding left atrial hypertension, Ziegler et al.3 found no increase of pulmonary vasodilatation with DPD in eight patients given inhNO.
In the present case, DPD did not alter PAP during inhNO treatment but improved the hemodynamic profile by stabilizing systemic pressure, increasing heart rate and cardiac output. It is not surprising that the vasodilating effect of DPD is not specific to the pulmonary circulation, since cGMP modulation of vascular tone is located in both pulmonary and systemic vessels.3 It is unclear whether the action of DPD on the pulmonary circulation could be augmented through an increase of initial doses in patients with chronic heart failure. Kinsella et al.4 have described their successful experience with combined treatment of a neonate after extracorporeal membrane oxygenation; their DPD dose was 0.6 mg•kg–1. Ivy et al.1 who reported the hemodynamic effects of DPD (0.6 mg•kg–1) and inhNO (20 ppm) in 13 pediatric patients with pulmonary hypertension, found that DPD augmented the NO-induced fall in the pulmonary vascular resistance index in 50% of these subjects. Thus, a positive clinical response to DPD in terms of the potentiated effect of inhNO may depend on its dose and on underlying cardiac function.
Nitroglycerine is a NO donor that has the same mechanism of action as inhNO via the cGMP pathway, but its effect is produced only after intracellular NO release.17 Intravenous NTG alone has been shown to reduce pulmonary pressure and pulmonary vascular resistance effectively while increasing cardiac indices in patients with severe pulmonary hypertension.6 The addition of NTG (10 mg•kg–1) to our patient's ongoing inhNO and intravenous DPD regimen effectively decreased PAP from 41/18 to 26/7 mmHg with recovery of preoperative systemic pressure. This result suggested that NTG not only potentiated the inhNO-induced pulmonary vasodilation, but also modulated left ventricular afterload since it releases NO and activates guanylyl cyclase in both the pulmonary and systemic circulations.18 Why was the addition of a small NTG dose more effective in reducing pulmonary hypertension than the combination of inhNO and DPD? Several explanations can be offered: (1) The inhNO dose was not high enough to stimulate cGMP production maximally, (2) NTG dilated some peripheral pulmonary vessels where inhNO was not present. Furthermore, NTG had more pronounced beneficial effects on the heart than inhNO. It decreased left ventricular afterload and improved ventricular relaxation as well as diastolic distensibility19 by increasing cGMP in the systemic circulation and myocardium.
From these findings, we speculate that DPD may enhance the response to inhNO therapy in some patients with chronic pulmonary hypertension and cardiac failure, and this effect is dependent on a suitable dose. We conclude that to control chronic pulmonary hypertension effectively in patients with cardiac failure, an improvement of hemodynamic profile is required. This appears to be achieved more readily by the use of combined therapy with inhNO, intravenous DPD and NTG during surgery.
Accepted for publication February 4, 2000.
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2
Fullerton DA, McIntyre RC Jr. Inhaled nitric oxide: therapeutic applications in cardiothoracic surgery. Ann Thorac Surg 1996; 61: 1856–64.
3
Ziegler JW, Ivy DD, Wiggins JW, Kinsella JP, Clarke WR, Abman SH. Effects of dipyridamole and inhaled nitric oxide in pediatric patients with pulmonary hypertension. Am J Respir Crit Care Med 1998; 158: 1388–95.
4 Kinsella JP, Torielli F, Ziegler JW, Ivy DD, Abman SH. Dipyridamole augmentation of response to nitric oxide (Letter). Lancet 1995; 346: 647–8.[Medline]
5
Van Obbergh LJ, Charbonneau M, Blaise G. Combination of inhaled nitric oxide with i.v nitroglycerin or with a prostacyclin analogue in the treatment of experimental pulmonary hypertension. Br J Anaesth 1996; 77: 227–31.
6
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7
Haworth SG. Pulmonary vascular remodelling in neonatal pulmonary hypertension. Chest 1988; 93: 133S–8S.
8 Gaine SP, Rubin LJ. Primary pulmonary hypertension. Lancet 1998; 352: 719–25.[Medline]
9
Fullerton DA, Jaggers J, Piedalue F, Grover FL, McIntyre RC Jr. Effective control of refractory pulmonary hypertension after cardiac operations. J Thorac Cardiovasc Surg 1997; 113: 363–8.
10
Thomas MK, Francis SH, Corbin JD. Characterization of a purified bovine lung cGMP-binding cGMP phosphodiesterase. J Biol Chem 1990; 265: 14964–70.
11
Hoehn T, Krause M, Hentschel R. High-frequency ventilation augments the effect of inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Eur Respir J 1998; 11: 234–8.
12 Berner M, Beghetti M, Ricou B, Rouge JC, Prêtre R, Friedli B. Relief of severe pulmonary hypertension after closure of a large ventricular septal defect using low dose inhaled nitric oxide. Intensive Care Med 1993; 19: 75–7.[Medline]
13
Troncy E, Collet J-P, Shapiro S, et al. Inhaled nitric oxide in acute respiratory distress syndrome. A pilot randomized controlled study. Am J Respir Crit Care Med 1998; 157: 1483–8.
14
Fullerton DA, Jones SD, Jaggers J, Piedalue F, Grover FL, McIntyre RC Jr. Effective control of pulmonary vascular resistance with inhaled nitric oxide after cardiac operation. J Thorac Cardiovasc Surg 1996; 111: 753–63.
15 Cortigiani L, Baroni M, Picano E, et al. Acute hemodynamic effects of endogenous adenosine in patients with chronic heart failure. Am Heart J 1998; 136: 37–42.[Medline]
16
Ziegler JW, Ivy DD, Fox JJ, Kinsella JP, Clarke WR, Abman SH. Dipyridamole, a cGMP phosphodiesterase inhibitor, causes pulmonary vasodilation in the ovine fetus. Am J Physiol 1995; 269: H473–9.
17 Salvemini D, Pistelli A, Vane J. Conversion of glyceryl trinitrate to nitric oxide in tolerant and non-tolerant smooth muscle and endothelial cells. Br J Pharmacol 1993; 108: 162–9.[Medline]
18 Troncy E, Jacob E, Peres da Silva E, et al. Comparison of the effect of inhaled nitric oxide and intravenous nitroglycerine on hypoxia-induced pulmonary hypertension in pig. Eur J Anaesthesiol 1996; 13: 521–9.[Medline]
19 Paulus WJ, Vantrimpont PJ, Shan AM. Acute effects of nitric oxide on left ventricular relaxation and diastolic distensibility in humans. Assessment by bicoronary sodium nitroprusside infusion. Circulation 1994; 89: 2070–8.[Medline]
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