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Congenital heart disease in adult patients
Challenges and management issues in adults with cyanotic congenital heart disease
  1. Craig S Broberg
  1. Correspondence to Dr Craig S Broberg, Knight Cardiovascular Institute, Oregon Health & Sciences University, UHN 62, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239, USA; brobergc{at}ohsu.edu

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Learning objectives

  • Understand the expected physiological adaptations to cyanotic heart disease.

  • Recognise long-term complications of cyanotic heart disease and their clinical manifestations.

  • Be able to make individualised recommendations in the care of patients with chronic cyanosis.

Introduction

A 22-year-old woman with a large unrepaired ventricular septal defect presented with significant haemoptysis. She was 22 weeks pregnant at the time. Her resting oxygen saturation was 78%, and her haematocrit was 66%. How should this complicated patient be managed? Should one recommend acute endotracheal intubation, phlebotomy or termination of her pregnancy? How should providers navigate the complicated decision-making needed in her critical situation?

Adults with cyanotic congenital heart disease represent a wide variety of defects and histories. Some are those for whom corrective surgery either was not or could not be offered who, in spite of this, beat the odds and survived. Despite anecdotes of being told they would not live to reach the age of 4, 12 or 21, some have survived to their 60th decade or beyond. Others are those who had various palliative surgeries but did not achieve complete separation of pulmonary and systemic blood flow. For most, exertional tolerance is below normal, but they otherwise carry on with life, careers and family. Many are relatively stable, with often fewer hospital encounters, for example, than some of their palliated counterparts. They participate in activities that defy many providers’ expectations, such as maintaining full-time employment, air travel,1 living at high altitude2 or neurosurgery. They have developed important physiological adaptations that allow them to carry on, although with an ongoing risk that their fragile balance could be unfavourably tipped at any time.

These patients rely on life-sustaining haematological adaptations to their chronic cyanosis, and are at risk of adverse consequences if such adaptations are out of balance. Clinical events may reflect either inadequate tissue oxygen delivery or embolism of thrombus or air. Complications include pulmonary thrombosis, haemoptysis, iron deficiency and cerebral vascular events. Patient's presenting circumstances are highly variable and each patient deserves individualised care decisions. While all such patients should have regular contact with specialty congenital heart expertise, any provider who encounters these special patients should be aware of their particular nuances in order to be able to direct care in a prudent manner. This review will discuss the expected physiological adaptations and considerations for patient management. It is important to realise that each patient’s situation is unique and a highly individualised approach is necessary.

Many cyanotic adults have coexisting pulmonary vascular disease (Eisenmenger syndrome). Such patients can often be distinguished from those without by the absence of a harsh systolic murmur. Such a murmur usually indicates stenotic pulmonary flow, preventing overcirculation. While many of the issues discussed herein apply to both groups, there are some fundamental differences that apply differently to the Eisenmenger population including the risk of haemoptysis, pulmonary artery enlargement and thrombosis, the role of pulmonary vasodilators and contraindication to pregnancy. Patients with cyanosis without Eisenmenger physiology may benefit from exploration of ways to improve pulmonary blood flow, if possible.

General assessment

Without exception all patients with cyanosis should have yearly visits with an experienced congenital heart specialist to coordinate care with primary care providers or other consultants as needed. The physical examination should record a resting oxygen saturation on room air measured in the fingers, and toes if a patent ductus is present, to check for differential cyanosis. Earlobe oxygen saturation tends to be a few percentage points higher than the fingers, a reminder of distinctions between central cyanosis and peripheral cyanosis.3 The physical examination should also note nail bed clubbing, surgical scars and any systolic murmur. Annual assessment should include baseline complete blood count for haemoglobin/haematocrit, platelet count, routine blood chemistries and iron stores. Serum uric acid may be beneficial since patients are at risk for gout. Brain natriuretic peptide is prognostic4 and may be considered for baseline assessment. Coronary artery disease is rare as lipids are usually low and there is little value in regular lipid screening.5 All patients deserve a baseline ECG and chest radiograph. Imaging should be done on occasion to assess for biventricular function.

Secondary erythropoiesis

The expected physiological response to chronic hypoxaemia is secondary erythropoiesis. This is an appropriate and necessary rise in both haemoglobin and red cell mass. Erythropoiesis differs significantly from polycythaemia since not all cell lines are increased. Leucocytes and platelets, either of which may contribute substantially to hyperviscosity in other conditions, are not overly expressed. Indeed, there is typically a lower than expected platelet count.

Ideally, the patient's own physiology will determine the level of haemoglobin. Oxygen saturation is an imperfect metric of right to left shunt since it reflects other issues such as ventilation/perfusion mismatch and tissue oxygen extraction in response to metabolic need. Over a 24 h period there will be an expected rise and fall in oxygen saturation, usually reflecting the patient's regular activity. O2 saturation change is very often a mirror image of the heart rate response to similar activity (figure 1), with expected fluctuation. Hence, recorded levels should always be obtained at rest. Oftentimes, simply asking the patient what his or her resting oxygen saturation tends to be may help a provider gauge whether the severity of cyanosis for a presenting situation represents an acute deterioration. The degree of nail bed clubbing may also serve as a general indicator.

Figure 1

Scatterplot of heart rate (blue) and oxygen saturation (red) over a day in a patient with Eisenmenger syndrome. There is variation in oxygen saturation with activity, and an inverse relationship with heart rate. Y axis is heart rate (beats per minute) and oxygen saturation (%).

Erythropoiesis to allow achievement of an optimal haemoglobin level ought to be set by the patient's own need over time.6 Therefore, the degree of cyanosis should be reflected in the patient's haemoglobin level, not saturation, akin to the haemoglobin A1c level indicating overall trends in blood glucose levels. The greater the degree of right to left shunt, the higher the haemoglobin ought to be in order to maintain a normal systemic oxygen transport (the product of oxygen content and cardiac output).

There is an expected relationship between O2 saturation and haemoglobin,6 although there can be many factors that disrupt this expected relationship. The regulatory mechanisms of erythropoiesis are more sophisticated than our current understanding or ability to regulate them. While there are recognised adverse consequences to excessive erythropoiesis, a general principle for providers is that the patient's optimal haemoglobin should be set by the intrinsic demands of tissue hypoxia rather than titrated through any therapy we offer, including phlebotomy. Patients should be given the proper building blocks necessary for erythropoiesis and then left alone as much as possible.

Iron deficiency

Iron deficiency is frequently encountered in cyanotic individuals.w7 Aetiology includes frequent phlebotomy, or bleeding such as from haemoptysis, epistaxis or menorrhagia. In addition to contributing to symptoms independent of anaemia, iron deficiency leads to production of a higher number of smaller cells with less haemoglobin per cell, translating to an overall lower haemoglobin without change in haematocrit. Since haemoglobin is the main determinant of oxygen delivery and haematocrit is the main determinant of blood viscosity, iron deficiency compromises systemic oxygen transport without lowering viscosity.w7 Cyanosis tends to induce a relative macrocytosis, therefore mean corpuscular volume (MCV) is not a reliable screening test for iron deficiency and should not be relied upon to exclude this.w8 Instead, transferrin saturation should be measured regularly to check for iron deficiency. Patients with transferrin saturation <20% should be offered iron supplementation until iron stores are replete.w9 There have been published concerns about ‘decompensated erythropoiesis’10 from iron supplementation, which argues for regular follow-up when treating with iron, though the majority of patients do not demonstrate detrimental overproduction of red cells.w9

Hyperviscosity

A potential downside to excessive red cell production is hyperviscosity, which may occur to a degree that compromises blood flow. While there is an exponential relationship between whole blood viscosity and haematocrit, there is not a clear correlation between viscosity and the patient's clinical condition (either symptoms or exertional capacity).w7 Indeed, the nature and aetiology of hyperviscosity symptoms are not well understood. Measured viscosity differs significantly between arterial and venous conduits, and across ranges of shear from vessel wall to the centre of flow. While experience shows that symptoms of hyperviscosity are not uncommon, and more problematic in certain patients, the severity and frequency of symptoms do not necessarily correlate with measured haematocrit. Therefore, available data do not justify a cut point for a ‘safe’ haematocrit. Therapeutic phlebotomy is rarely necessary, and almost never on a routine, recurring basis. Patients may present with chest pain, headaches, joint aches and so on and in some cases even specifically request phlebotomy. In response, as a first line of therapy, patients with suspected hyperviscosity should be adequately hydrated including with intravenous saline (with appropriate air filters on any intravenous line) if oral hydration is not sufficient. After adequate hydration, if symptoms persist or there is evidence of end-organ damage and the remeasured haematocrit remains higher than the patient’s expected baseline, phlebotomy (with equal volume intravenous fluid replacement) could be considered. In practice this is a rare occurrence, and often driven by patient’s perceptions of their condition (sometimes misled by previous providers). Alternative causes for the patient's symptoms should always be sought (such as a cerebral abscess, bronchitis or gout) rather than simply assuming hyperviscosity is the culprit and removing cells inappropriately. Similarly, there is not an established role for preoperative phlebotomy to improve coagulative properties, though this has been recommended and practiced in the past.11 Overall, although there are potential negative haematological consequences of an increased haematocrit,w12 a guiding principle for providers should be that erythropoiesis is a necessary adaptation, not maladaptation, and left alone as much as possible.

Coagulation issues: pulmonary thrombosis and haemoptysis

Patients with cyanosis, particularly those with Eisenmenger physiology, may face challenges of both excessive bleeding and thrombosis. Pulmonary artery thrombosis is found in roughly 20% of Eisenmenger individuals.13 ,w14 Pulmonary vascular arteriosclerotic changes and pulmonary artery enlargement may lead to mural thrombosis in larger vessels. Bleeding (notably epistaxis or haemoptysis among others) has been described and may be life-threatening.14–17 These features pose a therapeutic paradox for providers.16 A proposed mechanism for thrombosis and haemoptysis,15 both present in Eisenmenger's first index case,18 is that small thrombotic fragments may break from a large vessel mural thrombus and flow peripherally to lodge in the microcirculation.w14 Pulmonary vascular calcifications have been described, consistent with an arteriosclerotic process.w19 ,w20 An alternative cause is thrombosis in the venous circulation which then embolises to the pulmonary circulation, as evidenced by peripheral perfusion abnormalities in patients without demonstrable mural thrombi.w20 Observational studies have shown evidence of altered synthesis and function of clotting factors that may contribute to both hypocoagulability and hypercoagulability.1 ,21 ,22

Given the above, the potential role of anticoagulation for primary prevention is often raised, as is recommended in patients with pulmonary arterial hypertension. Ascribing to the hypothesis that haemoptysis occurs secondary to microthrombi in the distal pulmonary vasculature, anticoagulation has been previously recommended in prior eras.15 In light of the common prevalence, it is tempting to believe such a strategy could be beneficial. However, in limited studies to date there is no difference in thrombosis in those with or without anticoagulation,2 ,w20 although only in retrospective studies. Anticoagulation is not benign in these patients for a number of reasons, haemoptysis among them. Measurement of International Normalized Ratio (INR) in a patient with an elevated haematocrit should be done with proper adjustment of citrate in the blood collection vials to account for lower plasma volume. Therefore, most providers do not routinely offer anticoagulation to patients with cyanosis and Eisenmenger syndrome, although do so for idiopathic pulmonary arterial hypertension.23

These competing factors preclude forming conclusive recommendations for long-term antiplatelet or anticoagulant therapy. Generally, anticoagulation is reserved for those with appropriate secondary indications such as atrial arrhythmia. In response to identified pulmonary artery thrombosis, most patients will be offered anticoagulation, with fastidious control of INR. There is no published experience on new oral anticoagulant agents in cyanotic individuals.

In response to haemoptysis, the recommended approach is to keep the patient rested and quiet, offer cough suppressants and avoid bronchoscopy until the episode subsides. Some have argued in favour of bronchial artery embolisation in severe or recurrent cases,25 though often such endeavours are not successful outside of anecdotal experience, and bronchial artery size does not correlate with thrombosis or haemoptysis. An observational study found a favourable role of phlebotomy in the setting of haemoptysis,2 in deference to previous data.17 However, there are several rational and concerning arguments against such a practice, including the fact that there may be an expected fall in haematocrit from haemoptysis itself, and that gas exchange may be compromised due to alveolar blood. Therefore, the practice is best left experimental until more data are obtained.

Cerebral vascular considerations

The cerebral is vulnerable to injury in two ways: inadequate cerebral circulation oxygen transport and emboli of either clot or air. Out of 72 individuals studied with brain MRI, nearly half had evidence of a prior cerebral vascular injury, and most of these had evidence of more than one.w20 Many of these findings were in patients with no prior clinical neurological event. Affected patients did not differ by haematocrit, platelet count, iron levels or thromboelastography. Presumably each lesion represents a prior episode of low oxygen tension long enough to induce tissue changes, which could be from multiple causes. These include periods of suboptimal haemoglobin (iron deficiency, or following phlebotomy, significant epistaxis or haemoptysis), supra-optimal haemoglobin (causing flow-limiting hyperviscosity), hypermetabolic states (such as infection) or poor systemic blood flow (such as transient arrhythmia or due to ventricular dysfunction).

Cerebral abscesses are also common anecdotally. Patients presenting with a new headache or neurological symptoms should undergo appropriate head imaging to exclude abscess.

Gas exchange considerations

For most patients supplemental O2 is not needed despite their low O2 saturation, which is driven by the intracardiac right to left shunt for which a higher FiO2 will not necessarily add available oxygen to the circulation. However, most patients will exhibit some degree of pulmonary vasodilatation in response to oxygen supplementation and saturations will increase slightly. Continuous supplemental O2 or high flow O2 to fully correct the saturation is usually ineffective and unwarranted. Patients should not be obligated to use supplemental O2 especially if it restricts their activity or contributes to epistaxis.

Another component of right to left shunt is compromised CO2 clearance. Altered CO2 clearance likely affects exercise capacity significantly, as evidenced by the very high ventillatory efficiency slope demonstrated in patients with Eisenmenger syndrome.26 Yet at rest, younger patients demonstrate more than adequate CO2 clearance. Hypoxia drives hyperventilation which means many patients have a resting respiratory alkalosis with a compensatory metabolic acidosis.w27 Therefore, a fall in respiratory drive may upset this balance and compromise CO2 clearance, and it seems prudent to avoid conditions that may compromise ventilation (such as excess supplemental O2, narcotics, etc).

Pulmonary vasodilator therapy

In the Eisenmenger population there is an established benefit of pulmonary vasodilator therapy, particularly endothelin antagonists.w28–w30 In addition to improvements in submaximal exertional capacity and physiology31 ,32 including maintained long-term benefits,33 ,34 observational studies suggest a survival advantage from such therapy.w35 Discussion of options is beyond the scope of this chapter, but all patients with cyanosis and pulmonary hypertension deserve referral for consideration of appropriate therapy.

Additional considerations

Finally, cyanosis affects multiple organ systems. Abnormalities may be found in myocardial blood flow,5 ,36 retinal blood flow,37 uric acid handling and kidney function.4 ,38 Therefore, it is important for providers to recognise multiorgan susceptibility and avoid therapies that may have adverse non-cardiac effects avoided if possible. Additional considerations for cyanotic management are provided (box 1).

Box 1

Summary of management recommendations for cyanotic heart disease

  • Recording clinical oxygen saturation at rest rather than after exertion.

  • Supplemental oxygen as needed for symptom relief only, not for a target oxygen saturation level.

  • Use of air filters on all intravenous access lines.

  • Cerebral imaging for any new headache or neurological sign to exclude the presence of a cerebral abscess.

  • Measurement of serum uric acid and treatment with allopurinol with any prior episode of gout.

  • Avoidance of or cautious use of therapies that may reduce drive towards hyperventilation such as narcotics or excess oxygen.w27

  • Cardiac anaesthesia by experienced providers for any non-cardiac surgery.39

  • Stable patients have been shown to fly safely on commercial airlines without supplemental oxygen,w12 ,40 and preflight simulation testing is not justifiable.

  • Appropriate measurement of INR using citrate-adjusted phlebotomy tubes.

  • Non-oestrogen containing birth control to women of child-bearing potential (intrauterine device may be preferred option).

  • Avoidance of pregnancy for women with coexisting pulmonary hypertension (Eisenmenger syndrome).

  • Referral for consideration of pulmonary vasodilator therapy.

Summary

The case scenario presented above occurred 60 years ago. At the time the patient presented to Professor Paul Wood, whose seminal observation largely defined the Eisenmenger physiology.15 She was treated mostly with careful observation and given little more than cough suppressants and gentle oxygen supplementation in the short term. She received neither phlebotomy nor blood products. Her haemoptysis stabilised. Despite the risks of pregnancy, she fortunately carried the baby to term under careful observation and delivered vaginally. She was thereafter anticoagulated, and experienced no further haemoptysis. She died 50 years later at the age of 73 with her son at her side.

Though her story is remarkable, it reminds us that cyanosis is not incompatible with meaningful life, and that physiological adaptations to cyanosis are more complicated than our current understanding of them. Although survivors of cyanotic heart disease are susceptible to multiorgan system complications, many can do well if important physiological compensations are left in balance.

Key messages

  • Patients with cyanosis should all be seen in conjunction with congenital heart disease providers.

  • Iron deficiency should be sought and treated if present.

  • Phlebotomy is rarely indicated in the management of cyanotic heart disease, since secondary erythrocytosis is a necessary compensatory mechanism.

  • Pulmonary vasodilator therapy should be considered in patients with Eisenmenger syndrome.

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Footnotes

  • Competing interests None declared.

  • Provenance and peer review Commissioned; externally peer reviewed.

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