Pulmonary hypertension is characterized by a gradual, progressive increase  in  pulmonary artery pressure leading to enlargement and hypertrophy of the right ventricle. The mean pressure exceeding 25 mm Hg at rest and 30 mm Hg on effort is diagnosed as pulmonary hypertension. In 1998, a new more clinically useful classification was introduced, which divided pulmonary hypertension into 5 categories. The first category denotes familial, rare (sporadic) pulmonary hypertension associated with collagenoses, congenital systemic-pulmonary shunt, HIV infection, drugs or toxic substances. The second category includes diseases, which due to mitral valve pathology or left ventricular failure, lead to venous hypertension in pulmonary circulation (venous pulmonary hypertension). The third category hypertension results from respiratory diseases and hypoxemia whereas the forth category hypertension – from embolism and thrombosis of pulmonary vessels. The fifth category of pulmonary hypertension includes diseases causing lesions in the pulmonary vascular walls (e.g. sarcoidosis) [1].

Another classification identifies primary and secondary hypertension. Primary hypertension is a progressing process involving vascular walls characterized by poor prognosis due to increasing right ventricular failure. Its aetiology is unknown. A strict relation between environmental and genetic factors is implicated.  The confirmed risk factors include female sex, anorectic drugs and AIDS. The likely risk factors are connective tissue diseases, portal hypertension, congenital heart defects with shunts, pregnancy, and amphetamine addiction [2].

Elevated pressure in the pulmonary artery may be passive or result from increased pulmonary capillary wedge pressure (PCWP) (left ventricular failure); it may be hyperkinetic as a consequence of increased cardiac output and pulmonary blood flow or increased pulmonary vascular resistances due to changes in the pulmonary vessels [3]. Based on this mechanism, pulmonary hypertension is divided into post- and pre-capillary. Post-capillary pulmonary hypertension, i.e. venous hypertension is passive and caused by elevated PCWP (≥15 mm Hg). It is accompanied by normal transpulmonary pressure. The pre-capillary type called arterial hypertension is characterized by normal PCWP values (≤ 15 mm Hg). The transpulmonary gradient is high and depends on increased cardiac output or high pulmonary vascular resistances.

 The pulmonary vascular resistance depends on the geometry of cross-sections of distal capillaries. According to the Poiseuille`s law, resistances are inversely proportional to the vascular radius to the power of 4, meaning that the endothelium and smooth muscular layer of vessels significantly affect their values. Moreover, resistances are directly proportional to blood viscosity. In overweight and obese patients, the indexed values of pulmonary vascular resistances should be used as the nonindexed ones are underestimated by existing pulmonary hypertension. In patients with high body weight, the index of cardiac output is lower, thus their pulmonary vascular resistances higher. When the nonindexed values are used, the existing pulmonary hypertension is underestimated in candidates for heart transplants and the unanticipated post-transplantation right ventricular failure is likely to develop [3].

Various management strategies have been implemented for patients with pulmonary hypertension scheduled for heart transplants. One of them is the transplant of a bigger heart, usually coupled with perioperative pharmacotherapy - intraoperative administration of  nitric oxide (NO) (after the induction of anaesthesia excluding the period of extracorporeal circulation), a phosphodiesterase inhibitor and prostacyclin. Another option is the so-called “domino heart” transplant: a recipient is transplanted the heart from a donor who undergoes the heart-lung transplantation due to e.g. primary pulmonary hypertension. The enlarged right ventricle adjusted to high pressures has a good chance to manage the conditions in the recipient’s pulmonary circulation [4]. The benefits of this strategy are associated with a larger pool of donors, short time of ischemia as the heart is retrieved and transplanted in the same hospital; most importantly, the right ventricle is prepared for working under increased afterload conditions.

Pulmonary hypertension may be persistent or reversible. The constriction of the lumen and remodelling of vascular walls are responsible for persistent hypertension. The active increase in vascular wall tension is reversible and may account for even 50% of their total resistance [3]. It is believed that the positive response of pulmonary vessels during the vasodilator test is a decrease in PVRI by 20% or even 30% or a decrease in MPAP by 10 mm Hg or an increase in CI by 30% [3]. The test for reversibility of pulmonary hypertension is obligatory in candidates for heart transplants whose pulmonary vascular resistance exceeds 3 Wood units (norm 1.1-1.4 units). In such patients, the administration of sodium nitroprusside decreases resistances to the values below 3 Wood units maintaining MAP at 70 mm Hg [5]. The long-term supportive therapy (inotropic drugs, intra-aortal balloon) combined with pulmonary hypertension management is likely to convert the persistent type of pulmonary hypertension into the reversible one (vasodilator conditioning).

The pulmonary vessels generate lower resistances compared to systemic vessels, which is associated with higher compliance of pre-capillary arterioles. The vascular walls of the pulmonary circulation are characterized by a thin middle layer and lower number of smooth muscle cells. Increased CO dilates the pulmonary vessels filled with blood and induces recruitment of collapsed arteries; thus, the transverse cross-section of pulmonary circulation increases and resistances decrease [6].

Pulmonary vasoconstriction due to hypoxia is the adaptation mechanism enabling redistribution of blood to properly ventilated lung segments; the flow is optimized and intrapulmonary shunt reduced [7]. This reflex is weakened under lung hyperinflation and alkalosis conditions. The hypoxia-related vasoconstriction may increase pulmonary vascular resistances by 50-300%. This reflex is only characteristic of pulmonary circulation vessels. In systemic vessels, hypoxia leads to reverse effects, i.e. dilation of their lumen. The experimental studies are being carried out in which oxygen in the aqueous solution is administered directly to pulmonary circulation vessels. The administration of hyperbaric oxygen solutions reverses the haemodynamic effects of severe hypoxia [8].

Early histological changes characteristic of pulmonary hypertension, irrespective of its aetiology, involve the hypertrophied muscular membrane of distal pulmonary vessels resulting from hyperplasia of smooth muscle cells. In the developed form of hypertension, fibrosis of the internal membrane, hypertrophy of the muscular layer, hypertrophied changes in vascular adventitia and obliteration of small arterioles are observed (remodelling of pulmonary vessels). The lesions in pulmonary vessels lead to progressive pressure overload of the right ventricle, resulting in its hypertrophy, ectasia and eventually failure. The thin-walled, compliant right ventricle manages well a high extra volume (e.g. effort) yet is markedly dependent on afterload. Increased afterload induces hypertrophy and dilatation of the right ventricle. Persistent high vascular resistances and dilatation of the right ventricle widen the ring and cause tricuspid valvular incompetence, which significantly impairs the ventricle function. The hypertrophy of the muscle and increasingly hard work of the ventricle to induce higher pressures contribute to increased oxygen requirements. High pulmonary vascular resistances limit the stroke volume of the right ventricle, hence the volume of blood filling the left ventricle. The left ventricular capacity is additionally decreased due to systolic bulging of the ventricular septum paradoxically to the left. Such abnormalities result in reduced minute output of the left ventricle and systemic blood pressure. Moreover, tachycardia and lack of sinus rhythm lead to elevated pressure in the left atrium and pulmonary circulation [3].

Patients with pulmonary hypertension manifest higher activities of platelets, high levels of serotonin, tissue plasminogen activator inhibitor and fibrinopeptide A with low levels of thrombomoduline. Serotonin favours proliferation of the smooth muscle cells, vasoconstriction and local microthrombosis. Platelet granules are the biggest systemic stores of serotonin (5HT). The disturbances in serotonin storage and excessive breakdown of platelets in the lungs are likely to increase the pulmonary bed pressure. Pulmonary hypertensive patients develop imbalance between the levels of substances maintaining the tension of vascular walls. Excessive amounts of vasoconstricting mediators (endothelin, thromboxan) and deficiencies in vasodilators (prostacyclin, NO) are observed.

Moreover, pulmonary hypertension is favoured by pathological processes at the cellular level. The potassium channels are built of proteins containing the pores selectively permeating potassium ions. One of them – Kv (voltage-dependent) affects the membranous potential of the smooth muscle cells. Inhibited ion migration in the smooth muscle cells leads to their accumulation and increased potential of the cellular membrane (depolarization), which enhances the activity of certain (L-type) calcium channels. Calcium ions penetrating the cells activate their contracting capacity [1]. The changes described result in increased tension of the vascular wall. Dilated cavities of the right heart, slower blood flow through the pulmonary circulation and sedentary lifestyle trigger the development of embolism. The smooth muscle constriction, remodelling of vascular walls and embolism in situ create favourable conditions for the development of pulmonary hypertension [9].
The clinical manifestations of pulmonary hypertension are not characteristic. The most typical symptom is progressive dyspnoea. The common symptoms also include chest pain due to right ventricular failure, easy fatigue, peripheral oedemas and fainting. Advanced pulmonary hypertension manifests itself as fully symptomatic failure of the right ventricle. ECG shows deviation of the heart axis to the right, hypertrophy of the right ventricle and the right bundle branch block. The ECG criteria of right ventricular failure may be useful for choosing the appropriate therapy and setting the optimal time of lung transplantation in patients with primary pulmonary hypertension [10]. Once the clinical symptoms of hypertension have occurred, its stage is highly advanced.

The golden standard for the diagnosis of pulmonary hypertension is the right heart catheterization. The results of the thermodilution method are comparable with those obtained using the Fick`s method in the wide spectrum of CO values (1.7–7.8 L min-1). Even severe tricuspid valvular incompetence does not affect the reliability of results of both methods [3]. The thermodilution method is not used in cases of coexisting cardiac shunt. MPAP > 25 mm Hg confirms the diagnosis of hypertension. PCWP < 15 mm Hg excludes the venous hypertension component. Monitoring of central venous pressue is relevant to assess the severity of right ventricular failure.

The standard therapy for pulmonary hypertension is limited to anticoagulants, oxygen therapy, high doses of calcium channel blockers combined with diuretics and digoxin. Anticoagulants should be administered to lengthen INR to the values 2-3 times exceeding the normal values. Hypoxia substantially constricts pulmonary vessels. The goal of oxygen therapy is to maintain SpO2 within the range of 90–92 % [9]. The calcium channel blockers most commonly used are nifedipine (120–240 mg day-1) and diltiazem (120–900 mg day-1). In patients diagnosed with peritoneal fluid, loop diuretics should be combined with spironolactone. Digitalis is recommended for left ventricular failure. The risk of its toxicity in this group of patients increases due to hypoxemia, diuretic-induced hypocalaemia and kidney failure.

The modern therapy of pulmonary hypertension uses additional preparations, e.g. NO- selectively dilating pulmonary vessels and stimulating guanyl cyclase thus generating increased concentrations of cyclic guanosinemonophosphate (cGMP). Cyclic GMP activates protein kinase, which enables dephosphorylation of myosin light chains leading to reduced tension of the smooth muscular layer [11]. Moreover, nitric oxide has antiaggregative effects. The activity of NO administered by inhalation is confined to the pulmonary circulation; therefore, therapy is not accompanied by decreases in systemic pressure. The optimal effect is observed already after 5-10 min of NO breathing in the dose of 10 ppm. The maximal safe dose is 40 ppm [11].

However, the use of NO has certain limitations. The development of methemoglobinaemia depends on the concentration of haemoglobin, saturation, methemoglobin reductase activity and NO dose. Nitrogen dioxide, an active metabolite of oxide may increase the reactivity of airways in patients with concomitant bronchial asthma. The gas price is increasing high, the treatment requires the closed respiratory system, thus becomes useless in patients who breathe spontaneously. Its effectiveness in some patients is limited due to tachyphilaxia. The action of NO is enhanced and prolonged by phosphodiesterase-5 inhibitors, which inhibit the breakdown of cGMP.  Dipiridamol and sildefanil belong to such inhibitors. The latter may induce hypotension; in such cases, its doses should be reduced [12]. When administered orally, sildefanil enables the continuation of pulmonary hypertension therapy after the completion of mechanical lung ventilation. The discontinuation of NO insufflation is likely to cause withdrawal syndrome with a sudden, drastic increase in pulmonary artery pressure (rebound syndrome), which may be prevented with sildefanil. Once NO and sildefanil are used simultaneously, hypotension is likely to develop, particularly when combined with nitroglycerine.

Moreover, the derivatives of prostaglandins are used for treatment of pulmonary hypertension. Epoprostenol increases the concentration of adenomonophosphate (cAMP)  by stimulating adenil cyclase, which results in increased volume of the vascular bed. Its chronic administration has additional antiplatelet and antiproliferative effects. Treprostinil is a more stable analogue of prostacyclin characterized by longer half-life, which enables its subcutaneous administration. Iloprost, another analogue, may be administered by inhalation. Other drugs successfully used for pulmonary hypertension include endothelin inhibitors, bosental and sitaxentan, a selective endothelin A receptor inhibitor [1, 9]. Losartan, an angiotensin receptor inhibitor, decreases pulmonary pressure and resistances in patients with secondary pulmonary hypertension already 4 h after its administration [6].  

The treatment of choice in pulmonary hypertension is the combined use of many drugs affecting various receptors points. In patients with pulmonary hypertension, all respiratory infections should be treated early and aggressively. Moreover, regular anti-influenza vaccination is recommended.  

Pulmonary hypertension developing due to chronic obstructive pulmonary disease (secondary form) results from hypoxia, is characterized by moderate values of pulmonary artery pressure and responds well to oxygen supply. Remodelling of pulmonary vascular walls affects all coats, yet the most severe changes occur in the internal membrane. Such a specific histological picture results from hypoxia, mechanical, repeated stretching of excessively aired lungs during respiration, inflammatory lesions and toxic effects of tobacco smoke [13]. In such patients, pulmonary artery pressure substantially increases on effort, which results from increasing hypoxia, increased tension of sympathetic system and decreased pH due to hypercapnia and lactate acidosis. Peripheral oedemas are caused by excessive aldosterone stimulation with water and salt retention as well as increased adrenergic stimulation. Hypercapnia and acidosis additionally enhance water-electrolyte imbalance.

In patients with pulmonary hypertension qualified for various surgeries the incidence of complications and postoperative mortality rates are higher compared to patients with normal pulmonary artery pressure. The commonest complications include right ventricular failure, hypoxia and ECG ischemic changes. Intraoperative vasoconstrictors are the risk factor of complications and mortality in the early postoperative period. Pulmonary hypertension is also an important risk factor of complications and deaths in patients undergoing cardiac surgeries.

Pulmonary hypertension is considered moderate when the ratio of systolic right ventricular-to-systolic systemic pressure is below 0.66 or severe if the ratio exceeds 0.66 [14]. The assessment of pulmonary artery-to-systemic pressure ratio enables us to follow a  relation between both circulatory systems, systemic and pulmonary as well as effects of pulmonary hypertension on systemic circulation [15]. Such an approach facilitates the interpretation of pressures during anaesthesia. Hypoxia, hypercapnia, acidosis, pain and anxiety induce elevated pulmonary vascular resistances. Haemodynamic destabilization in this group of patients occurs suddenly and progresses rapidly. Therefore, hypotension and cardiac arrhythmias should be treated promptly and explicitly [16].  

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REFERENCES

1.    Blaise G, Langleben D, Huber K: Pulmonary arterial hypertension. Pathophysiology and anesthetic approach. Anesthesiology 2003; 99: 1415-32.

2.    Kasimir MT, Seebacher G, Jaksch P, Winkler G, Schmid K, Marta GM, Simon P, Klepetko W: Reverse cardiac remodeling in patients with primary pulmonary hypertension after isolated lung transplantation. Eur J Cardiothorac Surg 2004; 26: 776-781.

3.    Chemia D, Castelain V, Herve P, Lecarpentier Y, Brimioulle S: Haemodynamic evaluation of pulmonary hypertension. Eur Respir J 2002; 20: 1314-1331.

4.    Birks EJ, Yacoub MH, Anyanwu A, Smith RR, Banner NR, Khaghani A: Transplantation using hearts from primary pulmonary hypertensive donors for recipients with a high pulmonary vascular resistance. J Heart Lung Transplant 2004; 23: 1339-1344.

5.    Lindelow B, Andersson B, Waagstein F, Bergh CH: High and low pulmonary vascular resistance in heart transplant candidates: a 5-year follow-up after heart transplantation shows continuous reduction in resistance and no difference in complication rate. Eur Heart J 1999; 20: 148-156.

6.    Fischer LG, Van Aken H, Burkle H: Management of pulmonary hypertension: physiological and pharmacological considerations for anesthesiologist. Anesth Analg 2003; 96: 1603-1616.

7.    Moundgil R, Michelakis ED, Archer SL: Hypoxic pulmonary vasoconstriction. J Appl Phisiol 2005; 98: 390-403.

8.    Corno AF, Boone Y, Mallabiabarrena I, Augsburger M, von Segesser LK: Aqueous oxygen: the solution to relief hypoxic pulmonary hypertension. Eur J Cardiothorac Surg 2004; 26: 301-305.

9.    Schleyer Berkowitz D, Grimes Coyne N: Understanding primary pulmonary hypertension. Crit Care Nurs Q 2003; 26: 28-34.

10.    Bossone E, Pacioccio G, Iarussi D, Agretto A, Iacono A, Gillespie BW, Rubenfire M: The prognostic role of ECG in primary pulmonary hypertension. Chest 2002; 121: 513-518.

11.    Szold O, Khoury W, Biderman Ph, Klausner JM, Halpern P, Weinbroum AA: Inhaled nitric oxide improves pulmonary functions following massive pulmonary embolism: a report of four patients and review of the literature. Lung 2006; 184: 1-5.

12.    Ng J, Finney SJ, Shulman R, Bellingan GJ, Singer M, Glynne PA: Treatment of pulmonary hypertension in the general adult intensive care unit: a role for oral sildenafil? Br J Anaesth 2005; 94: 774-777.

13.    Naeije R, Barbera JA: Pulmonary hypertension associated with COPD. Crit Care 2001; 5: 286-289.

14.    Ramakrishna G, Sprung J, Ravi BS, Chandrasekaren K, McGoon MD: Impact of pulmonary hypertension on the outcomes of noncardiac surgery. JACC 2005; 45: 1691-1699.

15.    Robitaille A, Denault AY, Couture P, Belisie S, Fortier A, Guertin MC, Carrier M, Martineau R: Importance of relative pulmonary hypertension in cardiac surgery: the mean systemic-to-pulmonary artery pressure ratio. J Cardiothorac Vasc Anesth 2006; 20: 331-339.

16.    Manecker GR, Wilson WC, Auger WR, Jamieson SW: Chronic thromboembolic pulmonary hypertension and pulmonary thromboendarterectomy. Sem Cardiothorac Vasc Anesth 2005; 9: 189-204.

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Address:

*Ewa Kucewicz
Oddział Kliniczny Kardioanestezji i Intensywnej Terapii
Śląskiego Centrum Chorób Serca
ul. Szpitalna 2, 41-800 Zabrze
tel.: 0-322 373 37 24
e-mail:kardanest@sum.edu.pl

Received: 02.03.2008.
Accepted: 10.01.2009.