Eisenmenger reaction

The Eisenmenger reaction was first described pathologically and anatomically by Victor Eisenmenger in 1897 in a 32-year-old patient with a large ventricular septal defect and a riding aorta, who suffered from severe cyanosis and cardiac insufficiency and ultimately died of haemoptysis. The first pathophysiological and clinical description is by Paul Wood et al., who published it in the 1950s (Pinger 2019 / Siegenthaler 2005).

Eisenmenger's reaction is a pulmonary arterial hypertension with shunt inversion or bidirectional shunt (Siegenthaler 2005). It is a secondary disease of a non-operated shunt vitium in which the pulmo-arterial perfusion resistance increases to values above those of the systemic resistance. The resistance of the pulmonary vessels reaches values > 800 dyn.s.cm-5. The initial shunt direction from system arterial to pulmonary arterial (so-called left-right shunt) is reversed by pulmonary hypertension into a right-left shunt on atrial, ventricular and arterial level (Erdmann 2009 / Rath 2005).

The term Eisenmenger's syndrome is reserved exclusively for patients who have a large connection at an atrial, ventricular or aortopulmonary level between the two circuits and who have a bi-directional shunt or a right-left shunt due to the great resistance of the vessels and obstructive pulmonary hypertension (Kasper 2015).

These patients always have a complex multi-organ involvement due to cyanosis (Mebus 2015) (Herold 2019). Primarily only the heart and the lungs are affected, but secondarily also the liver, the intestine and the kidneys (Biro 2011).

In the classification of pulmonary hypertension in congenital heart defects, Eisenmenger's syndrome is classified as type 1 of a total of 4 types (Mebus 2015).

Depending on the location of the shunt, a distinction is made between:

• pre-tricuspid (proximal to the tricuspid valve, e.g. in atrial septal defect)
• post-tricuspid (distal to the tricuspid valve, e.g. in ventricular septal defect) (Herold 2019)

The classification according to morphological changes comprises 6 degrees.

• Grade 1 (histologically a media hypertrophy is found here).

• Grade 2 (In addition to media hypertrophy, there is intimate proliferation).

• Grade 3 (In grade 3 there are also first vascular occlusions).

• Grade 4 (Here, angiomatous changes and dilatation also occur).

• Grade 5 (in addition to the above-mentioned changes, there is also atrophy of the vessel wall).

• Grade 6 (Necrotizing arteritis also occurs here).

Herold (2019) differentiates between Eisenmenger's reaction and Eisenmenger's syndrome: Eisenmenger's reaction describes the pathological process leading to Eisenmenger's syndrome.

Pathophysiology: The pathophysiological mechanism is not fully understood (Herold 2019). The increased blood volumes cause a pressure load on the pulmonary vessels, which in turn causes an irreversible pulmonary arterial vasculopathy. This results in an obstruction, which leads to dilatation of the pulmonary arteries, concentric right ventricular or right atrial hypertrophy and fibrosing right-sided dilatation of the valves, which can even lead to calcification of the pulmonary arteries (Erdmann 2009). Platelet activation and endothelial dysfunction also play an important role pathophysiologically. Overall, however, further investigations are necessary to fully clarify the pathophysiological mechanism (Herold 2019).

Pulmonary hypertension affects about 5 % to 10 % of patients with congenital vitae (Pingler 2019).

The incidence of pulmonary hypertension in newborns with congenital left-right shunt is approximately 1.6 to 12.5 cases per million adults. Of these, approx. 25% to 50% develop Eisenmenger's syndrome (Biro 2011), although the tendency is continuing to decrease, since in western countries both the diagnosis by means of child screening examinations efficiently identifies heart defects and the surgical options for newborns and children are also constantly improving (Erdmann 2009).

Congenital defects with primary left-right shunt can lead to an Eisenmenger reaction. In particular, this occurs with the following anomalies:

• Large defects of the atrial septum.
• large defects of the ventricular septum
• open ductus botalli
• surgically applied aortopulmonary anastomoses (Rath 2005)
• Ductus arteriosus persistens
• truncus arteriosus
• complex forms of complete transposition of the large vessels (Herold 2019)

First, the Eisenmenger reaction is based on heart failure caused by ventricular volume stress. In newborns the pulmonary vascular resistance decreases in the first months of life and a left-right shunt exists under stress.

In the first two years of life, the pulmonary vascular resistance increases due to increased pulmonary blood flow. Due to the increase, the signs of previously existing heart failure decrease and clinical signs of shunt inversion appear (Siegenthaler 2005).

In post-tricuspid defects, pulmonary vascular disease begins in infancy, while patients with pre-tricuspid defects are less likely to develop Eisenmenger's syndrome (Michel Behnke 1997).

• general inefficiency
• Tiredness
• Headaches
• Visual disorders
• Swindle
• Arrhythmias
• Dyspnea
• Cyanosis (see also "Inspection and Palpation")
• Haemoptyses (these are caused by lung infarctions or ruptures of lung tissue)
• Syncopes (these occur due to the low cardiac output)
• cerebrovascular events such as hyperviscosity, brain abscess, paradoxical embolisms (Herold 2019)
• Nocturia (Lasserre 2002)

X-ray thorax

An X-ray of the thorax is part of the basic diagnostics. It may show:

• dilated central pulmonary arteries
• partial calcifications in the pulmonary arteries
• broken vessels in the periphery
• caliber fluctuations (also in the periphery)
• Plethora (increased vascular markings in the lungs) as long as a left-right shunt is dominant (Siegenthaler 2005)

Echocardiography

Color Doppler echocardiography is the method of choice for diagnosing Eisenmenger syndrome (Siegenthaler 2005). Characteristic morphological and functional signs of Eisenmenger's syndrome can be detected. Semiquantitative information on intracardiac and pulmonary pressures can be obtained. This non-invasive examination method also plays a major role in follow-up (Mebus 2015).

Cardio- MRI

MRI can provide complementary findings to echocardiography. It can be used to assess in more detail:

• Size of the ventricles
• Function of the ventricles
• Myocardial mass
• Vitality of the myocardium
• Stroke volumes
• Flow volumes
• Lung perfusion

MRI is also used in the assessment of progression (Mebus 2015).

Cardiac catheterization

Cardiac catheterization can be used to accurately quantify as well as verify the responsiveness of the pulmonary vascular bed (Dittrich 2010). Cardiac catheterization is mandatory for quantification of pulmonary vascular resistance. However, angiographic imaging of the pulmonary vessels carries a high risk with possible fatality during the examination (Erdmann 2009).

Laboratory chemistry shows reactive erythrocytosis. This is a typical picture in an Eisenmenger syndrome. Total iron status should be determined, as iron deficiency is common. (Herold 2019). In addition to the blood count, the coagulation status, kidney values, iron, bilirubin and uric acid should be checked (Erdmann 2009).

Inspection and palpation:

• Central cyanosis (as a result of the right-to-left shunt via ductus arteriosus, the lower extremities are more perfused with venous blood, causing the toes and legs to be more affected by cyanosis than the fingers and arms [Pinger 2019]).
• Signs of right heart failure (Biro 2011) with.
• Neck venous congestion
• Edema in the dependent parts of the body
• Liver enlargement
• Pleural effusions
• enlargement of the vena cava

(Lasserre 2002)

• watch glass nails (Pinger 2019)
• drumstick finger (Mebus 2015)
• Palpable 2nd heart sound may possibly be present (Siegenthaler 2005)

Auscultation

• loud 2nd heart sound
• in the 2nd ICR left parasternal a diastolic may be auscultable (in case of existing pulmonary insufficiency)
• at the left distal edge of the sternum, a pansystolic may be auscultated (in case of tricuspid regurgitation; the murmur increases during inspiration and decreases during expiration: so-called Carvallo's sign)

(Pinger 2019)

ECG

In the ECG are present:

• Signs of right hypertrophy such as:
  • P- dextrocardiac (Cook- Sup So 2013).
  • Sokolow- Lyon index: RV1 + SV 5 / 6 > 1,05 mV
  • (in-) complete right bundle branch block

(Herold 2018)

• Atrial fibrillation and atrial flutter (occur in about 35%).
• Ventricular fibrillation (found in up to 10% of patients)

(Pinger 2019)

Long-term ECG

A long-term ECG is indicated if there is a history of arrhythmias. The presence of arrhythmias is always associated with a poor prognosis (Mebus 2015).

Pulmonary function test and exercise testing (6-minute walk test).

To objectify physical exercise capacity, exercise testing should be performed in children from about school age.

(Mebus 2015)

Pulse oximetry

Pulse oximetry can be used to draw conclusions about the extent of the right-to-left shunt (Dittrich 2010).

Other forms of pulmonary arterial hypertension must be excluded by differential diagnosis (Biro 2011)

The treatment options include both conservative and surgical therapies. Conservative treatment should always be carried out in conjunction with an appropriately experienced centre, as should monitoring of the clinical picture (Herold 2019).

Conservative treatment options include:

1. general recommendations

• Limitation of stress (symptom oriented)
• Avoidance of:
  • Alcohol
  • hot baths
  • Sauna visits
  • disco visits
• Special caution should be exercised with:
  • fever
  • Dehydration
  • Vasodilatation (see also below "Drug treatment")
  • Blood loss

2. drug treatment

In recent years, the start of drug treatment has shifted to earlier NYHA stages. Therapy should begin no later than NYHA- class III, but earlier if necessary (Mebus 2015).

Medications that can be used for Eisenmenger's syndrome include the following:

• Pulmonary hypertension should be treated according to the guidelines.

Dosage recommendations:

• Endothelin- receptor antagonists: e.g., bosentan
  • Approval only from 2 years of age
  • Children: 4 mg/kg/d in 2 single doses p. o. (target dose).
  • Adults: 2 x / d 62.5 mg p. o. (4-week starting dose)
  • 2 x / d 125 mg p. o. (target dose)
• phosphodiesterase-5 inhibitors: e.g. sildenafil
  • Approval from 1 year
  • Dosage according to the technical information for children:
  • Children with 8 - 20 kg and age > 1year: 3 x /d 10 mg p. o.
  • Children with >20 kg: 3 x /d 20 mg p. o.
  • Expert recommendation: 1 - 4 mg/kg/d in 3 -4 single doses p. o.
  • Dosage according to the professional information for adults:
  • Adults: 3 x /d 20 mg p. o.
  • Recommendation of the Cologne Consensus Conference: dose increase to max. 3 x /d 80 mg p.o., then off-label use.
• Caution is advised with the following medications:
  • Drugs that lower resistance in the large circulation, e.g. ACE inhibitors, angiotensin blockers, etc.
  • Drugs that increase the risk of bleeding such as anticoagulants (increase the risk of pulmonary embolism up to 30% [Pinger 2019]), aggregation inhibitors, etc.
  • Drugs that increase the risk of thrombosis such as diuretics, estrogens, etc. (Mebus 2011)
• Anticoagulants
  • The administration of anticoagulants is controversial. There are no studies in this regard (Pinger 2019). Anticoagulants may possibly be required in Eisenmenger's syndrome at:
    • Atrial arrhythmias
    • Z. n. mechanical valve replacement
    • Thromboembolism
• Vasodilators
  • Bosentan, a vasodilator, was given a class I recommendation by the ESC in 2015 for WHO FC III patients. Studies have shown that patients receiving bosentan improve both walking distance (plus 53 m) and functional class. Likewise, the risk of mortality has been reduced in observational studies.(Pinger 2019)
• If iron deficiency is present, it is essential to substitute iron, as iron deficiency increases the risk of apoplexy and decreases exercise capacity (Pinger 2019). (Cave: Under iron therapy, a disproportionate increase in Hb and HKT is found [Herold 2019]).

3. phlebotomy

• Bloodletting should be performed in adults exclusively in case of symptomatic hyperviscosity (with the following symptoms: clouding, headache, dizziness, visual disturbances).
• An elevated hematocrit (even with very high values) is not an indication for phlebotomy in asymptomatic patients (Herold 2019).

Technique of phlebotomy: During phlebotomy, a maximum of 500 ml of blood (Pinger: 250 - 500 ml) should be collected with i. v. substitution of an isovolemic fluid. Bloodletting should not be performed more frequently than 4 times per year in patients with Eisenmenger's syndrome, if possible. The hazards are:

• Shock if volume loss is too rapid or too rapid.
• Danger of iron deficiency
• danger of increased viscosity due to aging erythrocytes
• the risk of apoplexy is increased
• the stress tolerance can decrease (Pinger 2019)

4. oxygen therapy

• Oxygen administration is among the IIa- indications according to ESC 2015 (Pinger 2019).
• It may lead to subjective improvement in some adult patients. However, the data on this is still insufficient (Herold 2019). Prolongation of life with oxygen administration has not yet been demonstrated (Pinger 2019).

Due to the risk of cardiac decompensation, a shunt that may be present must not be surgically closed (Pinger 2019). The only possibility of surgical treatment is transplantation. The single lung TX, the bilateral lung TX plus intracardiac correction or the heart-lung TX are available as options.

Indication: Since patients with Eisenmenger's syndrome have a significantly better prognosis than, for example, patients with idiopathic pulmonary arterial hypertension, patient selection is difficult (Pinger 2019). Indications that may require transplantation include:

• unfavourable prognostic factors (recurrent syncope ?)
• poor exercise tolerance
• refractory right heart failure
• severe hypoxemia

With regard to the prognosis, the extent of the preoperative resistance of the pulmonary vessels plays a decisive role. A good prognosis and the probability that pulmonary vascular disease will not progress postoperatively are given to patients with a pulmonary vascular resistance of at most one third of the systemic resistance or less. Patients in whom the pulmonary vascular resistance preoperatively is more than one third of the systemic resistance are not expected to have improved symptoms postoperatively, and the disease will continue to progress (Kasper 2015). The survival rates of patients with pulmonary TX or cardiopulmonary TX are > 80 % after 1 year, 70 % after 5 years and 50 % after 10 years (Herold 2019).

Spontaneous course: The majority of patients with Eisenmenger's syndrome live longer than 20 - 30 years without therapeutic measures. There are also known cases in which the patients experience the 4th or 5th decade.

The survival rates are according to:

• 10 years at 80%.
• 15 years at 75
• 25 years at 40
• (Erdmann 2009)
• Associated non-cardiac diseases:

Eisenmenger's syndrome can lead to diseases in several organs:

• Dysfunctions of the liver
• Intestine (necrotizing enterocolitis)
• Functional disorders of the kidneys up to kidney failure (Biro 2011)
• Tendency to form gallstones
• Scoliosis Arthralgias (at about 5 %)

Aftercare

Regular follow-ups should be carried out in close cooperation with physicians who have experience in the field of Eisenmenger's syndrome (Herold 2019).

The following findings should be recorded:

• clinical status (including weight history)
• 6- minute walking test
• Spirometry
• Measurement of the transcutaneous oxygen saturation
• Echocardiography with special consideration
  • of right ventricular dysfunction
  • the possible presence of pericardial effusion
  • any enlargement of the atria or ventricles
• Laboratory chemical analysis should be carried out, among other things:
  • Blood gas analysis
  • Liver and kidney retention parameters (Mebus 2015)

Contraception and pregnancy

Patients with Eisenmenger's syndrome should be advised in detail by experienced gynaecologists as well as cardiologists familiar with congenital vitae about adequate contraception immediately after sexual maturity (hormonal oral contraceptives increase the risk of thrombosis). Contraception is controversially discussed in these cases, guidelines do not exist (Mebus 2015).

Pregnancy and childbirth pose a considerable risk for both mother and child. The maternal Eisenmenger syndrome is a common indication for abortion.

Maternal mortality is high during delivery and also in the first weeks post partum.

There are deaths due to pre-eclampsia, thromboembolism and hypovolaemia.

The infant risks are spontaneous abortions (approx. 30 %), intrauterine growth retardation (approx. 30 %), preterm birth (approx. 50 %) and perinatal mortality ( > 20 %) (Herold 2019).

Air travel

Patients with right heart strain usually tolerate stays at altitudes of 1200 - 1400 m without any problems. In aircraft cabins the air pressure corresponds to an altitude of 1800 - 2400 m above sea level. Mebus (2015) recommends that the individual risk be decided on a case-by-case basis. Pinger (2019) says that air travel is generally well tolerated. However, one should avoid stress and dehydration. There is currently insufficient data available for a possible O2 supplementation. In the course book on travel medicine, Jelinek (2012) refers to a 10-year extensive medical study. Patients with Eisenmenger's syndrome, who had an SO2 between 63% - 92%, showed no relevant complications during a commercial flight.

Endocarditis risk

Endocarditis prophylaxis is necessary in any case. The following therapy recommendation is given:

• to administer antibiotic prophylaxis 30 - 60 min before the procedure as a single dose
• if oral administration is possible, amoxicillin or ampicillin 2 g p. o. may be administered
• if oral administration is not possible, ampicillin or cefalexin 2 g i.v. is recommended
• for ampicillin or penicillin allergy, clindamycin 600 mg should be given orally
• if an i.v. administration of clindamycin is necessary 600 mg i.v. (Herold 2018).

Vaccinations

Patients should be vaccinated against influenza and pneumococcus (Pinger 2019).

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