Cyanosis or blue jaundice (jaune = 'yellow' in French (contrary to the usage of Latin or Greek of the early times in medicine & related subjects) is a pathological condition with bluish discolouration of the individual's skin. Closer observation may reveal the bluish discolouration affecting mainly the peripheral parts, as it commonly happens in freezing situations and just before frostbite, or an article of tight clothing cutting off the circulation to a part, discolouration due to certain drugs, etc. When the visible organs and the mucosa are affected, there is inadequate perfusion of blood. Thus, cyanosis in c be peripheral or central. In peripheral cyanosis, the central parts may be pink. Central cyanosis, where the mucous surfaces are blue and the rest of the body may be warm, worsens with exercise.
A deficiency of oxygenation in the blood is usually the cause of central cyanosis and this is more generalized. However, we must remember that a threshold of 5 grams of haemoglobin is a must for cyanosis to be appreciated. In severe anaemic subjects where the haemoglobin level is below this level, cyanosis is not visible.
Characteristically cyanosis brings about certain structural changes as well as curving and deformity of fingertips with nail and nail-beds – clubbing. Angiomatous skin lesions may also accompany some diseases associated with generalized cyanosis. Altered haemoglobin adsorption leading to methemoglobinemia has been known since antiquity to cause the generalized blue jaundice of the skin or cyanosis. In improper dosage or even prolonged use, some drugs may cause cyanosis. Amiodarone is one such example, of greyish discoloration of the skin, resembling cyanosis.
Cyanosis and clubbing are considered inseparable, though clubbing without cyanosis happens, and is the oldest possible observational clinical finding. References have been there since Hippocratic times. These may be associated with several causes. For ease of remembering, the causes of clubbing without cyanosis are –
1. Heart or lung disease with shunting of blood meant for oxygenation.
2. Cystic fibrosis.
3. Lung causes like empyema of long duration, lung abscess, extensive bronchiectasis, malignancy, interstitial lung diseases (ILDs), idiopathic lung fibrosis, pleural mesotheliomas, etc.
4. Infective endocarditis.
5. Ulcerative colitis.
6. Other chronic gastrointestinal diseases.
There are a thousand proposed causes of clubbing. To summarize they are sequelae of chronic hypoxia. There is increased production of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) by the peripheral megakaryocytes. The result is increased vascularity and permeability of nutrients leading to uncharacteristic and unsightly soft-tissue growth. Other signalling proteins thought to be associated with digital clubbing include prostaglandins, bradykinin, ferritin, adenosine nucleotides, interleukin-6, von Willebrand factor, serum transforming growth factor-beta1 (TGF-beta1), tumour necrosis factor-a, growth hormone, epidermal growth factor, etc. Shunting of blood past the capillary bed of either the lung or the liver, suggests that a lack of metabolism of angiogenic factors that bypass a critical organ may be involved.
The constant finding in all cases happens to be an increased capillary vessel system growth. There may be wide variations and almost constantly seen in divers who are accustomed to holding their breath for long periods. ‘Parrot beak’ appearance of the fingertip and the nails is a common term for clubbing, and this may even be found in otherwise normal individuals.
Clubbing is graded for understanding the progression of the disease and the recognized grades are –
Grade – I --- increase in fluctuation between the nail and the nail bed.
Grade – II --- Obliteration of the onychodermal
space and angulations.
Grade III --- Increase in the curvature of the nail with the fingertip. 'Parrot beak' appearance.
Grade IV --- Increase both in the transverse and vertical diameter of the fingertip, also known as the ‘drumstick' appearance indicating hypertrophic osteoarthropathy. The change is localized and strongly suspected of pulmonary origin.
Cyanosis with grade IV clubbing and hypertrophic osteoarthropathy was investigated by Magdi Yacoub for extrathoracic malignancies and showed that autonomic interruption leads to a pain-free better quality of life for the remaining life. Sarcomas and extrathoracic malignancies with pulmonary metastases are more likely to precipitate this as a paraneoplastic syndrome.
Nowadays cyanosis and clubbing can only be seen in congenital heart conditions and heart lesions with shunts. Lung lesions are mostly treatable, and cyanosis is seen only with extensive and gradually developing pulmonary destruction.
Clubbing without cyanosis can be found in normal individuals as well and when they do, the recessive genes hiding within two individuals come together to display a trait in the offspring.
The newborn human individual is completely dependent and spends most of the time with the mother. The newborn cannot communicate, and the mother is the one who notices the problems first and reports them. If the newborn is unduly irritable, not feeding satisfactorily, is showing an increased rate of breathing, tiring easily, and is not as playful as it should be the mother consults a physician. An obvious change or altered appearance of skin and nail colour alerts the mother of a problem.
Cyanosis can be due to multiple problems, but in newborns, we are mostly concerned about inherent lung and heart problems. The newborn quite suddenly gets exposed to the colder temperatures of the environment once delivered. The peripheral fingertips of the limbs may for a short period appear bluish. This is known as acrocyanosis. This is a normal phenomenon, and the usual explanation is blood from the peripheries is diverted for better perfusion of the brain, heart itself, the liver, and the kidneys which are vital for the sustenance of the baby.
The maturity of the alveolar units and the production of surfactants also matter. The fetal circulation is different, and the first breath is the first time when oxygenation of blood starts. Another thing is the right and left ventricular pressures. Initially, these are equal after delivery, and adaptation to a lower pressure system of the lung circulation gradually lowers the pressure on the right side. The pulmonary vascular pressures are also high to start with and this also comes down in time as an adaptive response.
An important consideration to be remembered is that the lung on each side is bathed in a fluid medium in utero and the moment a baby is delivered the medium changes. Aerial oxygen becomes the sole source and the lung on either side has to function with alternate inflation and deflation for maintaining the oxygenation of blood after delivery. Surfactants help to keep the lungs inflated. Development adequacy of the alveolar units may be compromised, and this can affect the oxygenation of blood.
The causes of neonatal cyanosis may be summarized as follows:
1. Primary pulmonary disease.
2. Upper airway obstruction.
3. Cystic fibrosis
4. Persistent pulmonary hypertension of the newborn (PPHN).
5. Congenital cardiac malformations with the mixing of blood and right-to-left
shunting.
There are several congenital heart conditions where cyanosis is one of the presenting features. The degree of the tinge and the time of appearance depends upon the nature of the defect, the amount of mixing of oxygenated and non-oxygenated blood, and also the degree of obstruction to the pulmonary circuit. Thus, a baby may be born with a normal APGAR score, gradually become lethargic, develop a bluish-grey hue, and soon fail to thrive in hypoplastic left heart syndrome (HLHS). In the tetralogy of Fallout (TOF), on the other hand, cyanosis usually takes time to develop as the obstructive structures to the pulmonary circuit have to grow to optimum levels. The usual causes are:
1. Truncus arteriosus.
2. Transposition of great arteries.
3. Tricuspid atresia.
4. Tetralogy of Fallout (TOF).
5. Total anomalous venous connection (TAPVC).
6. Double outlet right ventricle.
7. Taussig-Bing syndrome
8. Hypoplastic left heart syndrome (HLHS).
9. Severe pulmonary stenosis.
10. Sinus venosus large atrial septal defects with directional IVC flow through the ASD.
Reversal of the shunt in cases where the pulmonary vascular resistance exceeds a limit and becomes irreversible happens in cases with a large pulmonary vascular flow. In neonates, the right to left shunt has to be of such large magnitude so no or little time is there for the right ventricle or the pulmonary circuit to adapt to a new situation. Rapid Eisenmengeristion is the result of the development of cyanosis. A-P window, large PDA, or truncus are examples of similar conditions. In these situations, it is clinically very difficult to distinguish from persistent pulmonary hypertension in the newborn (PPHN).
In transposition physiology, the problem is different. Training the right ventricle to withstand left-sided pressures has to be done early before there is an effect on lung circulation.
Low pulmonary flow situations have different problems. Though more time for palliative or corrective measures is available, ancillary adaptive changes occur in related organs that are deleterious.
Polycythemia occurs in varying levels in proportionate cyanotic conditions and is a compensatory measure for delivering more oxygen to the tissues. But we have to remember that the usual small capillary vessels are not designed to handle the thick blood, and consequences happen after a time.
Differential cyanosis is another intriguing condition. As the name suggests there is a difference in the degree of the bluish discoloration of the upper and lower limbs. There may be the following conditions:
1. PDA with Eisenmengeristion where the upper limb bluish discolouration is less than that of the lower limbs due to the flow of more desaturated blood through the patent PDA to the descending aorta and lower limbs. The upper limbs, before Eisenmengeristion, will have a paler hue suggesting the flow of more oxygenated blood. The brain and the upper limbs get preferential more oxygenated blood. The role of greater deoxygenation of blood in the IVC owing to a larger organ load cannot be ruled out.
2. The same situation is as above but a coarctation makes a difference. If the coarctation is pre-ductal then only the right upper limb will show a lighter bluish tinge, and in the post-ductal type, both the upper limbs will differ in the discoloration than the darker lower limbs.
3. Differential cyanosis may also be seen in some supracadiac total anomalous venous connection (TAPVC) implying the flow of more oxygenated blood through SVC to the right side of the heart. Only the bluish discolouration will be less.
4. There is reversed differential cyanosis in the transposition of great arteries (TGA) with PDA with Eisenmengeristion. The already mixed and desaturated blood enters an irreversible pulmonary hypertensive lung circulation and is circulated. If the ASD or the foramen ovale is severely restricted, then the upper limb saturation will be lower than that of the lower limb. Aortic stenosis, supravalvular aortic stenosis, and interrupted aortic arch with a similar association cause a similar reversal of cyanosis. Though clinically evident, a comparative blood gas analysis between the limbs corroborates the diagnosis. The recent use of fingertip plethysmography makes detection easier.
Nowadays we see mostly grown-up children with congenital heart conditions (GUCH) who escape the myriads of invasive and non-invasive diagnostic procedures apart from the thorough clinical examination by a Neonatologist just after birth. Thus, cyanosis will be appreciated mainly by a Neonatologist and a Neonatal Cardiac surgeon. Cyanosis, differential cyanosis, and reverse differential cyanosis are signs and symptoms of a bygone era.
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