- Email: [email protected]
Clinical update: cyanotic adult congenital heart disease
Comment
Clinical update: cyanotic adult congenital heart disease Worldwide, the annual incidence of adult congenital heart disease (CHD) is 1·5 million,1,2 and advances in medical and surgical techniques now enable 85% of patients with CHD to survive well into adulthood.3 In the UK, about 250 000 adults have CHD and this number is growing.3,4 Cyanosis is common in these patients and is accompanied by adaptive mechanisms and pathological changes to compensate for the associated hypoxia. Patients with cyanotic CHD have a complex multisystem disorder with unique pathophysiology, and need tertiary care. However, many are managed by physicians from a range of disciplines.1,5,6 Longstanding management dogmas and misconceptions about pathophysiology are now being challenged in the light of new data. Secondary erythrocytosis—and not polycythaemia— associated with cyanotic CHD is a physiological and desirable response to chronic hypoxia. In iron-replete patients, the severity of secondary erythrocytosis is inversely related to resting oxygen saturation. Red blood cells increase in number, an adaptive mechanism driven by the chronic cyanosis to increase oxygen-carrying capacity.7 This mechanism has important implications for current practice, especially the use of phlebotomy to decrease haemoglobin concentrations. Phlebotomy has harmful rather than beneficial effects in adults with cyanotic CHD.8 However, routine phlebotomies are still done inappropriately around the world because of the perceived benefits against stroke and on myocardial function.9 Patients might report short-lived relief of hyperviscosity symptoms with phlebotomy. But these symptoms resemble those of iron deficiency, and we have to question whether routine phlebotomy has a real non-placebo clinical effect in these patients. Stable adults with cyanotic CHD have, by definition, abnormal oxygen saturations. In these patients, the extent of cyanosis is usually a manifestation of admixture of oxygenated and deoxygenated blood (as occurs with right-to-left shunting or with univentricular physiology) or inadequate pulmonary blood flow. Cyanosis is also dynamic and varies with factors such as exercise. The resultant hypoxia initiates major compensatory mechanisms.9 First, the low concentrations of oxygen delivered to tissues stimulates renal production of erythropoietin, which enhances stimulation of the 1530
production of red blood cells, with a consequential increase in red-blood-cell mass, packed cell volume, and whole-blood viscosity.7,10,11 This process occurs in patients with cyanotic CHD,12 and contrasts with polycythaemia vera, in which polycythaemia indicates proliferative activity along all cell lines (red and white blood cells and platelets). High haemoglobin concentration (often above 20 g/dL) is therefore a common finding in adults with cyanotic CHD.12 Second, a rightwards shift in the oxygen dissociation curve encourages off-loading of oxygen to tissues. Third, cardiac output increases, to achieve optimum oxygen delivery and prevent endorgan damage. Compensatory dilation of the coronary circulation by a combination of endothelial vasodilators and mural attenuation is thought to prevent adverse effects on myocardial perfusion.13 In the past, there were concerns that this compensatory secondary erythrocytosis could increase plasma viscosity and lead to impairment of the microcirculation, thereby compromising tissue oxygen delivery.7 Symptoms attributable to hyperviscosity include headache, dizziness, visual disturbance, paraesthesia, altered mental function, tinnitus, fatigue, muscle weakness, and genitourinary and gastrointestinal bleeding.11 In our experience, only rare patients with chronic compensated secondary erythrocytosis and no previous history of phlebotomy show such hyperviscosity symptoms. To add to the complexity, iron deficiency itself might also cause symptoms similar to hyperviscosity.14 Furthermore, symptoms previously attributed to hyperviscosity might actually arise from decreased tissue oxygen delivery. There is also conflicting evidence about whether iron deficiency itself increases blood viscosity.15 Iron deficiency and microcytosis did not actually increase whole-blood viscosity in adults with cyanotic CHD, and hyperviscosity symptoms were relatively common but not related to packed cell volume, haemoglobin, iron indices, or cell size.16 Although symptoms correlated with measured viscosity (after correcting for packed cell volume), exercise capacity was greater in patients with a higher packed cell volume and higher blood viscosity. Furthermore, a normal or increased erythrocyte size (as indicated by mean corpuscular volume) was common in patients with iron deficiency. Blood rheology in patients www.thelancet.com Vol 370 November 3, 2007
Comment
with cyanotic CHD showed slower blood-passage time in cyanotic patients than in controls, which correlated with red-blood-cell count, haemoglobin concentration, and packed cell volume.17 Consistent with other recent reports, mean corpuscular volume was not different between patients with cyanotic CHD and controls.16,17 Higher mean corpuscular-haemoglobin concentration was associated with faster blood-passage time.17 Although speculative, these studies suggest a larger red-cell volume might enable these patients to maximise haemoglobin capacity per red cell, while keeping blood viscosity low and optimising tissue oxygen delivery. More than a third of adults with cyanotic CHD are iron-deficient,12,18 and can be overlooked easily because the common laboratory measures, such as microcytosis and hypochromia, are rarely found.10,18 The cause of iron deficiency in this group of patients is multifactorial, with the consumption of iron stores from excessive erythropoiesis being a universal and predominant factor. Other causes include recurrent phlebotomies, gastrointestinal blood loss, decreased dietary intake, and menorrhagia. Iron status should be routinely and periodically assessed by measuring serum ferritin and transferrin saturation concentrations, and not by haemoglobin, packed cell volume, and erythrocyte indices alone.7,9,10,18 When ferritin concentrations are increased, assay of soluble transferrin receptor is useful to identify concomitant iron deficiency.18 Low-dose oral iron or pulses of parenteral iron in patients who are intolerant of or have failed oral iron therapy should be administered until the packed cell volume begins to rise.9,10 Gradual replacement of iron stores is advised to avoid an excessive rebound of iron and resultant erythropoietic response.7 The objective is to provide sufficient iron to attain steady-state erythropoiesis as appropriate for the patient’s underlying physiology11,16 Correction of iron deficiency alleviates hyperviscosity symptoms in patients with cyanotic CHD. Inappropriate phlebotomies in adults with cyanotic CHD are still done widely, to decrease symptoms attributed to hyperviscosity and the risk of cerebrovascular events. Cerebrovascular events have been extrapolated inappropriately from studies in polycythaemia vera, in which phlebotomy to maintain a packed cell volume of 40–45% remains current practice.19 However, studies in adults with cyanotic CHD have failed www.thelancet.com Vol 370 November 3, 2007
to find an association between red-cell mass and the incidence of stroke.8,9,12,20 The best available evidence derived from a retrospective case-series of 162 patients (3135 patient-years) is to the contrary, which suggests that phlebotomy and iron deficiency are independent risk factors for cerebrovascular events.8 The decreased oxygen-carrying capacity of iron-deficient erythrocytes compared with their iron-replete counterparts might contribute to this increased risk. Co-existing abnor-
Assess annually Anaemia history* Symptoms of hyperviscosity† Measure oxygen saturation‡ Laboratory measures:§ haemoglobin, packed cell volume, red-cell indices, serum ferritin, transferrin saturation
Serum ferritin ≤15 μg/L Transferrin saturation ≤15%
Serum ferritin ≥15 μg/L Transferrin saturation ≥15%
Patient iron-deficient
Patient iron-replete
Patient iron-replete
Iron supplementation Address other causes of iron deficiency as identified from history
No symptoms of hyperviscosity
Symptoms of hyperviscosity
Assess for other causes of symptoms and treat accordingly: eg, Hypovolaemia Gout Brain abscess Hypothyroidism Depression
Reassess symptoms Repeat laboratory tests Consider cessation of iron supplementation when iron replete (serum ferritin ≥15 μg/L and transferrin saturation ≥15%) Some patients will require chronic iron supplementation for steady-state erythrocytosis Regularly reassess symptoms and laboratory tests
Resolution of symptoms Patient remains iron-replete
Reassess every 6–12 months
Persistent moderate– severe hyperviscosity symptoms Packed cell volume >65%
Trial of phlebotomy with fluid replacement
Figure: Assessment and management of secondary erythrocytosis and iron deficiency in cyanotic CHD *Including details of haemoptysis, gastrointestinal or other bleeding, phlebotomy, menses, diet, medication, and use of iron supplements. †Headache, faintness or dizziness, visual disturbance, fatigue, muscle aches, joint aches, paraesthesia, easy bruising, epistaxis, gingival bleeding, gout, and poor mental function.16 ‡In seated position, breathing air, after 2 min of complete rest with standard transcutaneous finger-pulse oximeter; if differential peripheral cyanosis is suspected, saturation should be measured in toe. §If discrepancy between serum ferritin and transferrin saturation, transferrin saturation is more important.
1531
Comment
malities in clotting factors and platelets are also believed to have a role.16 Furthermore, phlebotomy-associated hypovolaemia without volume replacement might lead to an acute fall in systemic blood flow, compromising oxygen transport and delivery and resulting in cerebral hypoxia.9 Thus the existing evidence (from case series and translational research) is that prophylactic phlebotomy exacerbates iron deficiency,10 decreases exercise tolerance,16 and increases cerebrovascular events.8 Prophylactic phlebotomy for secondary erythrocytosis in adults with cyanotic CHD should therefore be abandoned. Instead, phlebotomy should be restricted to two indications: temporary relief of moderate-to-severe hyperviscosity symptoms in the presence of a high packed cell volume (>65%), and preoperatively to improve haemostasis.8,9,11 These indications are based on current expert opinion, although the supportive evidence is scarce and any benefit might be exaggerated by a placebo effect in those treated by phlebotomy. Hypovolaemia and iron deficiency must have been excluded. Careful clinical and laboratory assessment is vital and might identify other causes for the symptoms. A management algorithm might assist decisionmaking for phlebotomy (figure).16 No more than one unit of blood should be removed at any one time, and removal should be combined with equivalent volume replacement with normal saline or Hartmann’s solution.8,9 Air filters need to be used for intravenous lines to lower the risk of paradoxical air embolism. Blood pressure should be monitored regularly during the procedure, and further fluid replacement might be needed until it stabilises. The patient’s clinical status, rather than haematological laboratory tests, should be closely assessed after removal of each unit of blood to assess whether further phlebotomy is necessary.10,11 Phlebotomy under these circumstances might be done in an outpatient setting.11 Secondary erythrocytosis in patients with cyanotic CHD is a physiologically appropriate response to hypoxia. Iron deficiency is common, produces significant morbidity, and is often exacerbated by inappropriate phlebotomy. Importantly, iron deficiency produces symptoms that resemble, and are often confused with, those of hyperviscosity. Therefore timely identification
1532
of iron deficiency, appropriate iron supplementation, and avoidance of inappropriate phlebotomy for patients with cyanotic CHD are all warranted. *Mark S Spence, Michelle S Balaratnam, Michael A Gatzoulis Adult Congenital Heart Centre and Centre for Pulmonary Hypertension, Royal Brompton Hospital, and the National Heart & Lung Institute, Imperial College, London SW3 6NP, UK (MSS, MSB, MAG); and Royal Jubilee Hospital, Victoria Heart Institute Foundation, Victoria, BC, Canada (MSS) [email protected] We thank Henryk Kafka for his comments. MAG has received support from the Clinical Research Committee, the Waring Trust, and the British Heart Foundation. MSS and MSB declare that they have no conflict of interest. 1 2 3 4 5 6 7
8 9 10 11
12
13 14
15
16
17
18
19
20
Brickner ME, Hillis LD, Lange RA. Congenital heart disease in adults. N Engl J Med 2000; 342: 256–63. Moller JH, Taubert KA, Allen HD, et al. Cardiovascular health and disease in children: current status. Circulation 1994; 89: 923–30. Warnes CA, Liberthson R, Danielson GK, et al. The changing profile of congenital heart disease in adult life. J Am Coll Cardiol 2001; 37: 1170–75. Wren C, O’Sullivan JJ. Survival with congenital heart disease and need for follow up in adult life. Heart 2001; 85: 438–43. Perloff JK, Warnes C. Challenges posed by adults with repaired CHD. Circulation 2001; 103: 2637–43. Niwa K, Perloff JK, Webb GD. Survey of specialized tertiary care facilities for adults with congenital heart disease. Int J Cardiol 2004; 96: 211–16. Rosove MH, Hocking WG, Child JS, et al. Chronic hypoxaemia and decompensated erythrocytosis in cyanotic congenital heart disease. Lancet 1986; 2: 313–15. Ammash N, Warnes CA. Cerebrovascular events in adult patients with cyanotic congenital heart disease. J Am Coll Cardiol 1996; 28: 768–72. Thorne SA. Management of polycythemia in adults with cyanotic congenital heart disease. Heart 1998; 79: 315–16. Diller GP, Gatzoulis M. Pulmonary vascular disease in adults with congenital heart disease. Circulation 2007; 115: 1051–58. Oechslin E. Eisenmenger’s syndrome. In: Gatzoulis MA, Webb GD, Daubeney PEF, eds. Diagnosis and management of adult congenital heart disease. Philadelphia, PA, USA: Churchill Livingstone, 2003: 363–78. Diller GP, Dimopoulos K, Broberg CS, et al. Presentation, survival prospects, and predictors of death in Eisenmenger syndrome: a combined retrospective and case-control study. Eur Heart J 2006; 27: 1737–42. Dedkov EI, Perloff JK, Tomanek RJ, et al. The coronary microcirculation in cyanotic congenital heart disease. Circulation 2006; 114: 196–200. Fairbanks VF, Beutler E. Iron deficiency. Beutler E, Lichtman MA, Coller BS, Kipps TJ, Seligsohn U, eds. Williams haematology, 5th edn. New York, USA: McGraw Hill, 1995: 490–511. Milligan DW, MacNamee R, Roberts BE, et al. The influence of iron-deficient indices on whole blood viscosity in polycythaemia. Br J Haematol 1982; 50: 467–71. Broberg CS, Bax BE, Okonko DO, et al. Blood viscosity and its relationship to iron deficiency, symptoms, and exercise capacity in adults with cyanotic congenital heart disease. J Am Coll Cardiol 2006; 48: 356–65. Katayama Y, Horigome H, Murakami T, et al. Evaluation of blood rheology in patients with cyanotic congenital heart disease using a microchannel array flow analyzer. Clin Hemorheol Microcirc 2006; 35: 499–508. Kaemmerer H, Fratz S, Braun SL, et al. Erythrocyte indexes, iron metabolism, and hyperhomocysteinemia in adults with cyanotic congenital cardiac disease. Am J Cardiol 2004; 94: 825–28. Berk PD, Goldberg JD, Donovan PB, et al. Therapeutic recommendations in polycythemia vera based on Polycythemia Vera Study Group protocols. Semin Hematol 1986; 23: 132–43. Perloff JK, Marelli AJ, Miner PD. Risk of stroke in adults with cyanotic congenital heart disease. Circulation 1993; 87: 1954–59.
www.thelancet.com Vol 370 November 3, 2007
Clinical update: cyanotic adult congenital heart disease Worldwide, the annual incidence of adult congenital heart disease (CHD) is 1·5 million,1,2 and advances in medical and surgical techniques now enable 85% of patients with CHD to survive well into adulthood.3 In the UK, about 250 000 adults have CHD and this number is growing.3,4 Cyanosis is common in these patients and is accompanied by adaptive mechanisms and pathological changes to compensate for the associated hypoxia. Patients with cyanotic CHD have a complex multisystem disorder with unique pathophysiology, and need tertiary care. However, many are managed by physicians from a range of disciplines.1,5,6 Longstanding management dogmas and misconceptions about pathophysiology are now being challenged in the light of new data. Secondary erythrocytosis—and not polycythaemia— associated with cyanotic CHD is a physiological and desirable response to chronic hypoxia. In iron-replete patients, the severity of secondary erythrocytosis is inversely related to resting oxygen saturation. Red blood cells increase in number, an adaptive mechanism driven by the chronic cyanosis to increase oxygen-carrying capacity.7 This mechanism has important implications for current practice, especially the use of phlebotomy to decrease haemoglobin concentrations. Phlebotomy has harmful rather than beneficial effects in adults with cyanotic CHD.8 However, routine phlebotomies are still done inappropriately around the world because of the perceived benefits against stroke and on myocardial function.9 Patients might report short-lived relief of hyperviscosity symptoms with phlebotomy. But these symptoms resemble those of iron deficiency, and we have to question whether routine phlebotomy has a real non-placebo clinical effect in these patients. Stable adults with cyanotic CHD have, by definition, abnormal oxygen saturations. In these patients, the extent of cyanosis is usually a manifestation of admixture of oxygenated and deoxygenated blood (as occurs with right-to-left shunting or with univentricular physiology) or inadequate pulmonary blood flow. Cyanosis is also dynamic and varies with factors such as exercise. The resultant hypoxia initiates major compensatory mechanisms.9 First, the low concentrations of oxygen delivered to tissues stimulates renal production of erythropoietin, which enhances stimulation of the 1530
production of red blood cells, with a consequential increase in red-blood-cell mass, packed cell volume, and whole-blood viscosity.7,10,11 This process occurs in patients with cyanotic CHD,12 and contrasts with polycythaemia vera, in which polycythaemia indicates proliferative activity along all cell lines (red and white blood cells and platelets). High haemoglobin concentration (often above 20 g/dL) is therefore a common finding in adults with cyanotic CHD.12 Second, a rightwards shift in the oxygen dissociation curve encourages off-loading of oxygen to tissues. Third, cardiac output increases, to achieve optimum oxygen delivery and prevent endorgan damage. Compensatory dilation of the coronary circulation by a combination of endothelial vasodilators and mural attenuation is thought to prevent adverse effects on myocardial perfusion.13 In the past, there were concerns that this compensatory secondary erythrocytosis could increase plasma viscosity and lead to impairment of the microcirculation, thereby compromising tissue oxygen delivery.7 Symptoms attributable to hyperviscosity include headache, dizziness, visual disturbance, paraesthesia, altered mental function, tinnitus, fatigue, muscle weakness, and genitourinary and gastrointestinal bleeding.11 In our experience, only rare patients with chronic compensated secondary erythrocytosis and no previous history of phlebotomy show such hyperviscosity symptoms. To add to the complexity, iron deficiency itself might also cause symptoms similar to hyperviscosity.14 Furthermore, symptoms previously attributed to hyperviscosity might actually arise from decreased tissue oxygen delivery. There is also conflicting evidence about whether iron deficiency itself increases blood viscosity.15 Iron deficiency and microcytosis did not actually increase whole-blood viscosity in adults with cyanotic CHD, and hyperviscosity symptoms were relatively common but not related to packed cell volume, haemoglobin, iron indices, or cell size.16 Although symptoms correlated with measured viscosity (after correcting for packed cell volume), exercise capacity was greater in patients with a higher packed cell volume and higher blood viscosity. Furthermore, a normal or increased erythrocyte size (as indicated by mean corpuscular volume) was common in patients with iron deficiency. Blood rheology in patients www.thelancet.com Vol 370 November 3, 2007
Comment
with cyanotic CHD showed slower blood-passage time in cyanotic patients than in controls, which correlated with red-blood-cell count, haemoglobin concentration, and packed cell volume.17 Consistent with other recent reports, mean corpuscular volume was not different between patients with cyanotic CHD and controls.16,17 Higher mean corpuscular-haemoglobin concentration was associated with faster blood-passage time.17 Although speculative, these studies suggest a larger red-cell volume might enable these patients to maximise haemoglobin capacity per red cell, while keeping blood viscosity low and optimising tissue oxygen delivery. More than a third of adults with cyanotic CHD are iron-deficient,12,18 and can be overlooked easily because the common laboratory measures, such as microcytosis and hypochromia, are rarely found.10,18 The cause of iron deficiency in this group of patients is multifactorial, with the consumption of iron stores from excessive erythropoiesis being a universal and predominant factor. Other causes include recurrent phlebotomies, gastrointestinal blood loss, decreased dietary intake, and menorrhagia. Iron status should be routinely and periodically assessed by measuring serum ferritin and transferrin saturation concentrations, and not by haemoglobin, packed cell volume, and erythrocyte indices alone.7,9,10,18 When ferritin concentrations are increased, assay of soluble transferrin receptor is useful to identify concomitant iron deficiency.18 Low-dose oral iron or pulses of parenteral iron in patients who are intolerant of or have failed oral iron therapy should be administered until the packed cell volume begins to rise.9,10 Gradual replacement of iron stores is advised to avoid an excessive rebound of iron and resultant erythropoietic response.7 The objective is to provide sufficient iron to attain steady-state erythropoiesis as appropriate for the patient’s underlying physiology11,16 Correction of iron deficiency alleviates hyperviscosity symptoms in patients with cyanotic CHD. Inappropriate phlebotomies in adults with cyanotic CHD are still done widely, to decrease symptoms attributed to hyperviscosity and the risk of cerebrovascular events. Cerebrovascular events have been extrapolated inappropriately from studies in polycythaemia vera, in which phlebotomy to maintain a packed cell volume of 40–45% remains current practice.19 However, studies in adults with cyanotic CHD have failed www.thelancet.com Vol 370 November 3, 2007
to find an association between red-cell mass and the incidence of stroke.8,9,12,20 The best available evidence derived from a retrospective case-series of 162 patients (3135 patient-years) is to the contrary, which suggests that phlebotomy and iron deficiency are independent risk factors for cerebrovascular events.8 The decreased oxygen-carrying capacity of iron-deficient erythrocytes compared with their iron-replete counterparts might contribute to this increased risk. Co-existing abnor-
Assess annually Anaemia history* Symptoms of hyperviscosity† Measure oxygen saturation‡ Laboratory measures:§ haemoglobin, packed cell volume, red-cell indices, serum ferritin, transferrin saturation
Serum ferritin ≤15 μg/L Transferrin saturation ≤15%
Serum ferritin ≥15 μg/L Transferrin saturation ≥15%
Patient iron-deficient
Patient iron-replete
Patient iron-replete
Iron supplementation Address other causes of iron deficiency as identified from history
No symptoms of hyperviscosity
Symptoms of hyperviscosity
Assess for other causes of symptoms and treat accordingly: eg, Hypovolaemia Gout Brain abscess Hypothyroidism Depression
Reassess symptoms Repeat laboratory tests Consider cessation of iron supplementation when iron replete (serum ferritin ≥15 μg/L and transferrin saturation ≥15%) Some patients will require chronic iron supplementation for steady-state erythrocytosis Regularly reassess symptoms and laboratory tests
Resolution of symptoms Patient remains iron-replete
Reassess every 6–12 months
Persistent moderate– severe hyperviscosity symptoms Packed cell volume >65%
Trial of phlebotomy with fluid replacement
Figure: Assessment and management of secondary erythrocytosis and iron deficiency in cyanotic CHD *Including details of haemoptysis, gastrointestinal or other bleeding, phlebotomy, menses, diet, medication, and use of iron supplements. †Headache, faintness or dizziness, visual disturbance, fatigue, muscle aches, joint aches, paraesthesia, easy bruising, epistaxis, gingival bleeding, gout, and poor mental function.16 ‡In seated position, breathing air, after 2 min of complete rest with standard transcutaneous finger-pulse oximeter; if differential peripheral cyanosis is suspected, saturation should be measured in toe. §If discrepancy between serum ferritin and transferrin saturation, transferrin saturation is more important.
1531
Comment
malities in clotting factors and platelets are also believed to have a role.16 Furthermore, phlebotomy-associated hypovolaemia without volume replacement might lead to an acute fall in systemic blood flow, compromising oxygen transport and delivery and resulting in cerebral hypoxia.9 Thus the existing evidence (from case series and translational research) is that prophylactic phlebotomy exacerbates iron deficiency,10 decreases exercise tolerance,16 and increases cerebrovascular events.8 Prophylactic phlebotomy for secondary erythrocytosis in adults with cyanotic CHD should therefore be abandoned. Instead, phlebotomy should be restricted to two indications: temporary relief of moderate-to-severe hyperviscosity symptoms in the presence of a high packed cell volume (>65%), and preoperatively to improve haemostasis.8,9,11 These indications are based on current expert opinion, although the supportive evidence is scarce and any benefit might be exaggerated by a placebo effect in those treated by phlebotomy. Hypovolaemia and iron deficiency must have been excluded. Careful clinical and laboratory assessment is vital and might identify other causes for the symptoms. A management algorithm might assist decisionmaking for phlebotomy (figure).16 No more than one unit of blood should be removed at any one time, and removal should be combined with equivalent volume replacement with normal saline or Hartmann’s solution.8,9 Air filters need to be used for intravenous lines to lower the risk of paradoxical air embolism. Blood pressure should be monitored regularly during the procedure, and further fluid replacement might be needed until it stabilises. The patient’s clinical status, rather than haematological laboratory tests, should be closely assessed after removal of each unit of blood to assess whether further phlebotomy is necessary.10,11 Phlebotomy under these circumstances might be done in an outpatient setting.11 Secondary erythrocytosis in patients with cyanotic CHD is a physiologically appropriate response to hypoxia. Iron deficiency is common, produces significant morbidity, and is often exacerbated by inappropriate phlebotomy. Importantly, iron deficiency produces symptoms that resemble, and are often confused with, those of hyperviscosity. Therefore timely identification
1532
of iron deficiency, appropriate iron supplementation, and avoidance of inappropriate phlebotomy for patients with cyanotic CHD are all warranted. *Mark S Spence, Michelle S Balaratnam, Michael A Gatzoulis Adult Congenital Heart Centre and Centre for Pulmonary Hypertension, Royal Brompton Hospital, and the National Heart & Lung Institute, Imperial College, London SW3 6NP, UK (MSS, MSB, MAG); and Royal Jubilee Hospital, Victoria Heart Institute Foundation, Victoria, BC, Canada (MSS) [email protected] We thank Henryk Kafka for his comments. MAG has received support from the Clinical Research Committee, the Waring Trust, and the British Heart Foundation. MSS and MSB declare that they have no conflict of interest. 1 2 3 4 5 6 7
8 9 10 11
12
13 14
15
16
17
18
19
20
Brickner ME, Hillis LD, Lange RA. Congenital heart disease in adults. N Engl J Med 2000; 342: 256–63. Moller JH, Taubert KA, Allen HD, et al. Cardiovascular health and disease in children: current status. Circulation 1994; 89: 923–30. Warnes CA, Liberthson R, Danielson GK, et al. The changing profile of congenital heart disease in adult life. J Am Coll Cardiol 2001; 37: 1170–75. Wren C, O’Sullivan JJ. Survival with congenital heart disease and need for follow up in adult life. Heart 2001; 85: 438–43. Perloff JK, Warnes C. Challenges posed by adults with repaired CHD. Circulation 2001; 103: 2637–43. Niwa K, Perloff JK, Webb GD. Survey of specialized tertiary care facilities for adults with congenital heart disease. Int J Cardiol 2004; 96: 211–16. Rosove MH, Hocking WG, Child JS, et al. Chronic hypoxaemia and decompensated erythrocytosis in cyanotic congenital heart disease. Lancet 1986; 2: 313–15. Ammash N, Warnes CA. Cerebrovascular events in adult patients with cyanotic congenital heart disease. J Am Coll Cardiol 1996; 28: 768–72. Thorne SA. Management of polycythemia in adults with cyanotic congenital heart disease. Heart 1998; 79: 315–16. Diller GP, Gatzoulis M. Pulmonary vascular disease in adults with congenital heart disease. Circulation 2007; 115: 1051–58. Oechslin E. Eisenmenger’s syndrome. In: Gatzoulis MA, Webb GD, Daubeney PEF, eds. Diagnosis and management of adult congenital heart disease. Philadelphia, PA, USA: Churchill Livingstone, 2003: 363–78. Diller GP, Dimopoulos K, Broberg CS, et al. Presentation, survival prospects, and predictors of death in Eisenmenger syndrome: a combined retrospective and case-control study. Eur Heart J 2006; 27: 1737–42. Dedkov EI, Perloff JK, Tomanek RJ, et al. The coronary microcirculation in cyanotic congenital heart disease. Circulation 2006; 114: 196–200. Fairbanks VF, Beutler E. Iron deficiency. Beutler E, Lichtman MA, Coller BS, Kipps TJ, Seligsohn U, eds. Williams haematology, 5th edn. New York, USA: McGraw Hill, 1995: 490–511. Milligan DW, MacNamee R, Roberts BE, et al. The influence of iron-deficient indices on whole blood viscosity in polycythaemia. Br J Haematol 1982; 50: 467–71. Broberg CS, Bax BE, Okonko DO, et al. Blood viscosity and its relationship to iron deficiency, symptoms, and exercise capacity in adults with cyanotic congenital heart disease. J Am Coll Cardiol 2006; 48: 356–65. Katayama Y, Horigome H, Murakami T, et al. Evaluation of blood rheology in patients with cyanotic congenital heart disease using a microchannel array flow analyzer. Clin Hemorheol Microcirc 2006; 35: 499–508. Kaemmerer H, Fratz S, Braun SL, et al. Erythrocyte indexes, iron metabolism, and hyperhomocysteinemia in adults with cyanotic congenital cardiac disease. Am J Cardiol 2004; 94: 825–28. Berk PD, Goldberg JD, Donovan PB, et al. Therapeutic recommendations in polycythemia vera based on Polycythemia Vera Study Group protocols. Semin Hematol 1986; 23: 132–43. Perloff JK, Marelli AJ, Miner PD. Risk of stroke in adults with cyanotic congenital heart disease. Circulation 1993; 87: 1954–59.
www.thelancet.com Vol 370 November 3, 2007