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Approach to cyanosis in children

Approach to cyanosis in children
Literature review current through: Jan 2024.
This topic last updated: Mar 17, 2023.

INTRODUCTION — This topic will discuss the differential diagnosis and approach to cyanosis in children. The approach to cyanosis in the newborn is discussed separately. (See "Approach to cyanosis in the newborn" and "Cardiac causes of cyanosis in the newborn".)

BACKGROUND — Cyanosis, a bluish purple discoloration of the tissues due to an increased concentration of deoxygenated hemoglobin in the capillary bed, results from a variety of conditions, many of which are life-threatening [1]. It is most easily appreciated in the lips, nail beds, earlobes, mucous membranes, and locations where the skin is thin. It may be enhanced or obscured by lighting conditions and skin pigmentation. In children, life-threatening cyanosis most often results from respiratory disorders.

DEFINITIONS — Two mechanisms result in cyanosis: systemic arterial oxygen desaturation and increased oxygen extraction by the tissues. Based upon these mechanisms, two types of cyanosis are described: central and peripheral. In addition, dermatologic conditions may result in blue skin color that mimics cyanosis in the absence of increased levels of deoxygenated blood in the capillary beds. (See 'Mimics of cyanosis' below.)

Central cyanosis — Central cyanosis is evident when systemic arterial concentration of deoxygenated hemoglobin (Hb) in the blood exceeds 5 g/dL (3.1 mmol/L) (oxygen saturation ≤85 percent) [2]. Of note, cyanosis may not be readily detectable in patients with severe anemia (eg, Hb <5 g/dL [3.1 mmol/L]).

Peripheral cyanosis — Patients with peripheral cyanosis have a normal systemic arterial oxygen saturation. However, increased oxygen extraction results in a wide systemic arteriovenous oxygen difference and increased deoxygenated blood on the venous side of the capillary beds. The increased extraction of oxygen results from sluggish movement of blood through the capillary circulation. Causes include vasomotor instability, vasoconstriction caused by exposure to cold, venous obstruction, elevated venous pressure, polycythemia, and low cardiac output.

LIFE-THREATENING CAUSES — Cyanosis may be caused by a wide range of disorders, but it usually stems from one of several common disorders of childhood and adolescence (table 1). Respiratory causes are most often to blame in previously healthy children with the new onset of central cyanosis [1]. Vascular causes, including cardiac and pulmonary vascular etiologies, are also important etiologies of both central and peripheral cyanosis, particularly in young infants. (See 'Definitions' above.)

Other serious conditions produce central cyanosis through disordered breathing caused by neurologic disease or decreased ability for hemoglobin to carry oxygen (eg, methemoglobinemia) [1,3].

Respiratory causes — Any condition that inhibits oxygen from reaching the alveoli or disrupts its movement across the alveolar interface can cause life-threatening cyanosis.

Decreased inspired oxygen — Exposure to an environment where the concentration of inspired oxygen (FiO2) is decreased can lead to cyanosis [4]. In children, the most common scenario is smoke inhalation from house fires. With this exposure, hypoxia from the diminished ambient FiO2 is frequently compounded by toxicity from carbon monoxide exposure (which primarily affects O2 delivery and to a lesser extent O2 utilization), and cyanide poisoning (which primarily affects O2 utilization). In addition, lower airway obstruction from smoke particles and upper airway obstruction from direct thermal injury are common. (See "Carbon monoxide poisoning" and "Cyanide poisoning" and "Inhalation injury from heat, smoke, or chemical irritants".)

Occasionally, children experience environments with diminished FiO2 through unintentional exposure to asphyxiating gases (eg, hydrogen sulfide ["sewer gas"], methane [common in peat bogs]) or intentional inhalation of hydrocarbons (eg, propane, butane, trichloroethane). Initial treatment consists of removal from the asphyxiating environment and immediate administration of 100 percent oxygen. (See "Inhalant misuse in children and adolescents".)

Upper airway obstruction — Severe upper airway obstruction, as with a foreign body, croup, thermal injury, epiglottitis, bacterial tracheitis, tracheal/bronchial disruption, or congenital airway abnormalities, quickly leads to decreased alveolar ventilation and hypoxemia [3]. Physical findings include stridor, voice changes or aphonia, drooling, suprasternal retractions, and prolonged inspiratory time.

The initial approach to the child with severe symptoms includes a rapid assessment of respiratory function and identification of key clinical features (such as history of injury, fever, and onset of symptoms) that suggest the diagnosis and guide therapeutic interventions (algorithm 1). (See "Emergency evaluation of acute upper airway obstruction in children", section on 'Emergency airway assessment and management'.)

Central cyanosis indicates severe airway obstruction and is an ominous finding. The child's condition will rapidly deteriorate if the airway obstruction is not relieved. Treatment must be initiated immediately by the most expert clinician available (algorithm 2). (See "Emergency evaluation of acute upper airway obstruction in children", section on 'Severe or complete obstruction'.)

Nasal secretions may cause obstruction and, in infants younger than six months of age who are obligate nasal breathers, can cause cyanosis. Suction of secretions may rapidly restore normal oxygenation.

Impairment of chest wall or lung expansion — Cyanosis ensues rapidly when chest wall movement or lung inflation is impeded (algorithm 2). This condition is often a result of major trauma (eg, motor vehicle collisions) and includes external chest compression (eg, victims of building collapse or mudslides), flail chest, open pneumothorax, tension pneumothorax, or hemothorax (table 2). (See "Thoracic trauma in children: Initial stabilization and evaluation" and "Chest wall injuries after blunt trauma in children".)

Clinical features include abnormal chest wall movement (as may occur with splinting from pain or with a flail segment), chest wall ecchymosis or abrasions, deformity of the chest wall, subcutaneous air with crepitus, open sucking chest wound, tracheal deviation, abnormal breath sounds, or focal tenderness to palpation over ribs, sternum, or scapula.

Immediately life-threatening injuries must be identified and treated during the initial rapid assessment. Interventions may include assisted ventilation (flail chest), needle or tube thoracostomy (tension pneumothorax, hemothorax), application of an occlusive dressing secured on three of four sides (open pneumothorax), or (rarely) emergency thoracotomy (hemothorax unresponsive to tube thoracostomy). (See "Thoracic trauma in children: Initial stabilization and evaluation".)

Cyanosis also accompanies chest wall muscle fatigue in infants and children with worsening respiratory distress and is an indication for advanced respiratory support such as noninvasive or mechanical ventilation. (See "Noninvasive ventilation for acute and impending respiratory failure in children" and "Initiating mechanical ventilation in children".)

Intrinsic lung disease — Primary pulmonary conditions such as severe asthma, bronchiolitis, pertussis, pneumonia, empyema, cystic fibrosis, noncardiogenic pulmonary edema, and, in the premature infant, hyaline membrane disease, comprise the most common life-threatening conditions that cause cyanosis [1]. These etiologies can be broadly described as causing small airway obstruction (eg, asthma, bronchiolitis), parenchymal disease (eg, pneumonia), or disruption of oxygen exchange in the alveoli (eg, pulmonary edema, hyaline membrane disease).

The work of breathing is often increased in such patients and may be associated with retractions, nasal flaring, and/or grunting. The auscultatory abnormalities vary by etiology:

Expiratory wheezing typically occurs in diseases that cause small airway obstruction (eg, asthma, bronchiolitis). Children with bronchiolitis also frequently have coarse or fine rales. (See "Bronchiolitis in infants and children: Clinical features and diagnosis", section on 'Examination' and "Acute asthma exacerbations in children younger than 12 years: Overview of home/office management and severity assessment", section on 'Assessment of exacerbation severity'.)

Inspiratory rales are prominent in patients with parenchymal lung disease or alveolar disruption. In addition, patients with pneumonia may have lung findings of consolidation, such as decreased breath sounds, bronchial breath sounds, or dullness to percussion. (See "Respiratory distress syndrome (RDS) in the newborn: Clinical features and diagnosis", section on 'Clinical manifestations' and "Community-acquired pneumonia in children: Clinical features and diagnosis", section on 'History and examination'.)

In infants and young children with pertussis at the paroxysmal stage, coughing persists and severity increases, occurring in paroxysmal attacks. The classic cough of pertussis is distinctive. The paroxysm is a long series of coughs during which the child may develop gagging and cyanosis and appear to be struggling for breath (movie 1). Whooping, which is characterized by the noise of the forced inspiratory effort, may be observed following a coughing attack during the paroxysmal phase (movie 2) but is not always present (movie 3). Post-tussive emesis occurs frequently. (See "Pertussis infection in infants and children: Clinical features and diagnosis", section on 'Classic presentation'.)

Patients with severe lung disease and poor air entry may not have lung findings that easily distinguish among the possible causes.

Circulatory causes — Circulatory conditions may cause cyanosis by mixing oxygenated and deoxygenated blood (eg, intracardiac or vascular shunts), structural or vascular alteration in pulmonary blood flow, cardiac decompensation with pulmonary edema, or shock.

Congenital heart disease — Cyanotic congenital heart disease (CHD) is a common cause of central cyanosis in newborns (table 3) [1,3]. Although most newborns with cyanotic congenital heart disease are discovered either in utero or while still in the newborn nursery, occasionally infants with cyanosis from undiagnosed CHD will present to an emergency department or a primary care office. Specifically, those infants with lesions dependent upon a patent ductus arteriosus for pulmonary blood flow (eg, coarctation of the aorta, hypoplastic left heart syndrome, pulmonary atresia) can have profound cyanosis when the ductus closes, usually one to two weeks after birth (table 4) [1].

The hyperoxia test can help distinguish cardiac from pulmonary causes of cyanosis in some infants, but ultimately echocardiography is necessary to diagnose structural heart disease. (See "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Hyperoxia test' and "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis", section on 'Arterial blood gas'.)

Infants with suspected cyanotic congenital heart disease warrant emergency pediatric cardiology consultation. (See "Suspected heart disease in infants and children: Criteria for referral".)

Once CHD has been identified as the cause of cyanosis, findings on physical examination, chest radiograph, and electrocardiogram (ECG) vary depending upon the cardiac lesion (table 5).

Pulmonary edema — Pulmonary edema may result from cardiac and noncardiac causes and diminishes arterial oxygenation by limiting diffusion of O2 across the alveoli into the pulmonary capillaries [5].

Cardiogenic – Cardiogenic pulmonary edema may occur as a result of volume overload associated with congenital heart lesions that shunt blood from the systemic to the pulmonic circulation (eg, atrial or ventricular septal defect, patent ductus arteriosus, or total or partial anomalous pulmonary venous return); pressure overload associated with lesions that create severe ventricular outflow obstruction (eg, aortic or pulmonic valve stenosis); or ventricular dysfunction. Myocarditis is one of the most important causes of acquired heart failure in children (table 6). (See "Heart failure in children: Etiology, clinical manifestations, and diagnosis", section on 'Etiology and pathophysiology' and "Clinical manifestations and diagnosis of myocarditis in children".)

Children with cardiogenic pulmonary edema usually have inspiratory rales on lung auscultation and a gallop rhythm with or without a murmur on cardiac examination. Patients with congenital heart lesions often have abnormal ECGs (table 5) and the heart is often enlarged on chest radiograph (image 1). (See "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Electrocardiogram'.)

In children with myocarditis, the ECG may show decreased voltage (waveform 1) and the heart size may either be normal or increased on chest radiograph (image 2 and image 3). Echocardiography by a pediatric cardiologist helps identify the degree of failure and the underlying cause. (See "Heart failure in children: Etiology, clinical manifestations, and diagnosis", section on 'Clinical manifestations' and "Heart failure in children: Etiology, clinical manifestations, and diagnosis", section on 'Diagnostic evaluation'.)

Noncardiogenic – Permeability pulmonary edema due to acute respiratory distress syndrome (ARDS) is the most common form of noncardiogenic pulmonary edema. It presents with severe respiratory distress (dyspnea) in association with the acute appearance of diffuse chest radiographic infiltrates and hypoxemia. The onset of ARDS is often within the first two hours after an inciting event, although this can be delayed as long as one to three days. Chest radiographs usually progress to a bilateral alveolar filling pattern.

The diagnosis of permeability pulmonary edema requires distinction from cardiogenic pulmonary edema and from other causes of lung disease and is usually associated with a normal cardiac examination and normal cardiac function on echocardiography. (See "Noncardiogenic pulmonary edema", section on 'Permeability pulmonary edema due to ARDS'.)

Noncardiogenic pulmonary edema may also occur in association with rapid high-altitude exposure, neurologic insults (eg, head trauma, intracranial surgery, intracranial bleeding), reexpansion of a pneumothorax, after relief of marked airway obstruction (post-obstructive pulmonary edema), selected overdoses (eg, heroin, methadone, and salicylates), and viral infections (eg, hantavirus, enterovirus). (See "Noncardiogenic pulmonary edema", section on 'Other noncardiogenic forms of pulmonary edema' and "High-altitude disease: Unique pediatric considerations", section on 'High-altitude pulmonary edema'.)

Pulmonary hypertension — Pulmonary hypertension may arise from any condition that raises pulmonary artery pressure and may ultimately cause right ventricular failure. In children, pulmonary hypertension may be idiopathic or may occur secondary to unrepaired congenital heart disease, left-sided heart failure from acquired heart disease (eg, myocarditis, rheumatic heart disease), or obesity with obstructive sleep apnea. On cardiac examination, the clinician may note a single or narrowly split S2 with a systolic ejection murmur or, in severely affected patients, a holosystolic murmur of tricuspid regurgitation. Prominent jugular venous pulse and a gallop may also be present. (See "Pulmonary hypertension in children: Classification, evaluation, and diagnosis" and "Pulmonary hypertension in children: Management and prognosis".)

Persistent pulmonary hypertension of the newborn (PPHN) occurs when pulmonary vascular resistance remains abnormally elevated after birth, resulting in right-to-left shunting of blood through fetal circulatory pathways. PPHN is discussed in detail separately. (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis".)

Pulmonary embolism — Pulmonary embolism (PE) is rarely diagnosed in children but occurs not uncommonly in adolescents, particularly females. Risk factors in the pediatric patient include hypercoagulable states (eg, protein C deficiency, protein S deficiency, sickle cell disease, nephrotic syndrome, SARS CoV-2 infection) [6], indwelling central venous catheters, solid tumors, heart disease, use of oral contraceptives, and pregnancy termination. As in adults, PE can manifest with pleuritic chest pain, tachypnea, cough, tachycardia, acute dyspnea, and sudden collapse. Most commonly, however, the clinical manifestations of PE in children, especially younger ones, are not specific and often mimic the clinical symptoms of the underlying disease. For this reason and because younger children cannot verbalize their symptoms, the diagnosis of PE should be remembered in critically ill children with sudden, unexplained cardiorespiratory deterioration. (See "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis", section on 'Pulmonary embolism'.)

Pulmonary hemorrhage — Pulmonary hemorrhage sufficient to cause cyanosis is very rare in children. Potential causes include acute histoplasmosis, exposure to Stachybotrys chartarum, Goodpasture syndrome, granulomatosis with polyangiitis (GPA), idiopathic pulmonary hemosiderosis, bronchiectasis (especially children with cystic fibrosis), lupus pneumonitis, and pulmonary arteriovenous malformations (Osler-Weber-Rendu syndrome). (See "Hemoptysis in children", section on 'Causes of hemoptysis'.)

Acute chest syndrome — Acute chest syndrome (ACS) is a common condition in children with sickle cell disease that frequently complicates vaso-occlusive crisis with resulting hypoxia and cyanosis. The diagnosis of ACS in a patient with SCD is made clinically and requires both of the following criteria (see "Acute chest syndrome (ACS) in sickle cell disease (adults and children)", section on 'Diagnostic criteria'):

A new pulmonary infiltrate detected by chest radiograph involving at least one complete lung segment that is not consistent with the appearance of atelectasis

and one or more of the following signs or symptoms:

Chest pain

Temperature >38.5ºC

Tachypnea, wheezing, cough, or the appearance of increased work of breathing (eg, retractions)

Hypoxemia relative to baseline measurements

The management of ACS in children is discussed separately. (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)", section on 'Management'.)

Shock — Patients in septic or cardiogenic shock have a low perfusion state. When transit time for red cells across capillary beds is lengthened, there is greater time for unloading of oxygen to the tissues, and perfusion related peripheral cyanosis occurs [3]. The type and cause of shock can generally be determined from a focused history, thorough physical examination, and selected diagnostic studies (algorithm 3). (See "Initial evaluation of shock in children".)

Methemoglobinemia — Methemoglobin is an altered state of hemoglobin in which the ferrous (Fe2+) irons of heme are oxidized to the ferric (Fe3+) state. The ferric hemes of methemoglobin are UNABLE to bind oxygen. In addition, the oxygen affinity of any remaining ferrous hemes in the hemoglobin tetramer is increased. The net effect is an impaired delivery of oxygen to the tissues and central cyanosis. (See "Methemoglobinemia", section on 'Pathophysiology'.)

Methemoglobinemia can be either congenital or acquired. Congenital methemoglobinemia results from a genetically determined deficiency in hemoglobin structure (eg, hemoglobin M) or in key enzyme systems that normally participate in reducing naturally occurring methemoglobin (figure 1). Acquired methemoglobinemia results from oxidative stress either from endogenous (eg, severe dehydration) or exogenous causes (eg, drugs, environmental exposures) (table 7). Infants are particularly susceptible to this stress because of immature enzyme systems required to reduce hemoglobin. Symptoms in patients with acquired methemoglobinemia tend to be more severe than in patients with congenital methemoglobinemia because they result from an acute impairment in oxygen delivery to tissues that does not allow sufficient time for compensatory mechanisms to take place. Early symptoms include headache, fatigue, dyspnea, and lethargy. At higher methemoglobin levels, respiratory depression, altered consciousness, shock, seizures, and death may occur. Acquired methemoglobinemia is life-threatening when methemoglobin comprises more than 40 percent of total hemoglobin. (See "Methemoglobinemia", section on 'Mechanisms of cyanosis'.)

Clinical clues to the diagnosis of acute toxic methemoglobinemia include the following (see "Methemoglobinemia", section on 'Clinical presentation (acquired/toxic)'):

Sudden onset of cyanosis with symptoms of hypoxia and/or clinical symptoms of reduced oxygen availability after administration or ingestion of an agent with oxidative potential (table 7). (See "Methemoglobinemia", section on 'Clinical presentation (acquired/toxic)'.)

Cyanosis that does not improve with an increased administration of oxygen.

Abnormal coloration of the blood observed during phlebotomy. The blood in methemoglobinemia has been variously described as dark red, chocolate, or brownish to blue in color, and unlike deoxyhemoglobin, the color does not change when the blood is exposed to oxygen (picture 1 and picture 2). (See "Methemoglobinemia", section on 'Evaluation and diagnosis (congenital)'.)

Methemoglobinemia is strongly suggested when there is clinical cyanosis in the presence of a calculated normal arterial pO2 (PaO2) as obtained by arterial blood gases. Arterial blood gas analysis is deceptive because the partial pressure of oxygen is normal in subjects with excessive levels of methemoglobin. Because methemoglobin absorbs light at both 660 and 940 nm, the wavelength for deoxy- and oxy-hemoglobin, respectively, it interferes with pulse oximetry. To a methemoglobin level of 20 percent, oxygen saturation (SaO2) by pulse oximetry drops by about one-half of the methemoglobin percentage. At higher methemoglobin levels, SaO2 trends toward 85 percent regardless of the true percentage of oxyhemoglobin, thus leading to over- or under-estimation of the true SaO2. (See "Pulse oximetry", section on 'Methemoglobin'.)

Diagnostic testing for methemoglobinemia is discussed in detail separately. (See "Methemoglobinemia", section on 'Mechanisms of cyanosis'.)

Other — Neurologic conditions that result in disordered breathing comprise an important cause of central cyanosis in children. Common etiologies include major head trauma, poisoning particularly related to opioid exposure, brief resolved unexplained events (BRUE), and seizures. However, any neurologic disease that results in altered mental status or weakness can lead to hypoventilation and cyanosis [3]. (See "Evaluation of stupor and coma in children" and "Etiology and evaluation of the child with weakness".)

Patients who ingest oxidizing drugs (eg, dapsone, sulfonamides, metoclopramide, or nitrates) may develop sulfhemoglobinemia, which similar to methemoglobinemia, causes cyanosis. However, patients with sulfhemoglobin typically do not have clinically significant clinical findings of tissue hypoxia. (See "Pulse oximetry", section on 'Sulfhemoglobin'.)

Several hemoglobin mutations (eg, Hb Kansas) have low oxygen affinity and present with cyanosis. These hemoglobinopathies are discussed in greater detail separately. (See "Hemoglobin variants that alter hemoglobin-oxygen affinity", section on 'Low oxygen affinity hemoglobin variants: Cyanosis'.)

OTHER CAUSES — Other etiologies of cyanosis include acrocyanosis, cold exposure, or polycythemia.

Acrocyanosis — Acrocyanosis refers to bluish color in the hands and feet and around the mouth (circumoral cyanosis) (picture 3). The mucus membranes generally remain pink. Acrocyanosis is a form of peripheral cyanosis that usually reflects benign vasomotor changes in the affected extremities. It does not indicate pathology unless cardiac output is extremely low, resulting in cutaneous vasoconstriction (eg, myocarditis).

Acrocyanosis of the newborn is an impressive example of cyanosis arising from intense peripheral vasoconstriction and variable perfusion in the extremities compared with the central circulation [7]. It is seen in well babies and resolves within the first few days of life.

Acrocyanosis may also occur in infants when they cry, regurgitate, vomit, cough, or hold their breath. This finding is often very alarming to the caregiver who witnesses the event and requires careful questioning and observation to differentiate from serious underlying pathology (eg, seizure, apneic episode, cardiac arrhythmia). The child with acrocyanosis typically does not have major changes in mental status during the event and appears well on physical examination.

Occasionally, children with significant gastroesophageal reflux will have paroxysmal acrocyanosis (especially perioral cyanosis) in association with brief episodes of limpness, stereotypical positioning or tonic clonic motions suggestive of a seizure, or apnea. This constellation of features is called Sandifer syndrome and typically responds to treatment of the gastroesophageal reflux. (See "Nonepileptic paroxysmal disorders in infancy", section on 'Sandifer syndrome'.)

Raynaud phenomenon — Raynaud phenomenon (RP) is a specific type of acrocyanosis that causes white, blue, and red discoloration of the fingers and/or the toes after exposure to changes in temperature (cold or hot) or emotional events. Skin discoloration occurs because an abnormal spasm of the blood vessels causes diminished blood flow to the local tissues. Initially, the fingers/toes turn white because of the diminished blood supply. As oxygen is removed from the blood in this low circulation state, the fingers and/or toes turn blue [8]. RP is considered primary if these symptoms occur alone without evidence of any associated disorder. By comparison, secondary RP refers to the presence of the disorder in association with a related illness, such as systemic lupus erythematosus and scleroderma. (See "Clinical manifestations and diagnosis of Raynaud phenomenon".)

Cold exposure — Moderate cold exposure slows the transit times through capillary beds and allows for increased unloading of oxygen from the blood to the tissues in infants and young children, leading to cyanosis, especially in the lips and perioral region [7]. This form of peripheral cyanosis rapidly resolves with patient warming.

Polycythemia — Polycythemia can cause cyanosis due to the increased red blood cell mass and relatively increased amount of deoxygenated hemoglobin [1,3,7]. Causes of polycythemia in children vary by age. Chronic hypoxia due to lung or heart disease is the most common cause of polycythemia in children outside of the neonatal period. Sleep apnea secondary to obesity and high-altitude exposure are other important etiologies. Genetic causes or erythropoietin secreting tumors rarely occur in children. (See "Diagnostic approach to the patient with erythrocytosis/polycythemia".)

Cyanotic breath-holding spells — The child with cyanotic breath-holding spells manifests with a history of crying, typically followed by sudden breath-holding in forced expiration with apnea and cyanosis. These features may progress to limpness and loss of consciousness. Cyanosis can appear faster than anticipated with simple breath-holding, and the loss of tone is often striking. As the child resumes normal breathing, the cyanosis resolves. Cyanotic breath-holding spells most commonly occur around one year of age with a range of six months to four years. Up to 15 percent of cases may have an initial episode below the age of six months. (See "Nonepileptic paroxysmal disorders in infancy", section on 'Breath-holding spells'.)

Mimics of cyanosis — Certain conditions may uncommonly cause blue skin in children that may rarely be mistaken for cyanosis [9-11]:

Pigmentary lesions (eg, Mongolian spots (picture 4) or large birthmarks) [9]

Drug therapy (eg, gray-blue skin discoloration from amiodarone administration, use of products containing silver) [10,12]

Large and extensive tattoos [11]

Blue clothing dye

Consumption of blue- or purple-dyed food (eg, popsicles or flavored ice) mimicking perioral cyanosis

RAPID ASSESSMENT AND STABILIZATION — Patients who appear cyanotic with respiratory distress or poor perfusion warrant prompt administration of supplemental oxygen, measurement of pulse oximetry, and further support of airway, breathing, and circulation while targeting specific etiologies based upon further evaluation. (See "Pediatric advanced life support (PALS)", section on 'Respiratory distress and failure' and "Shock in children in resource-abundant settings: Initial management".)

INITIAL EVALUATION — A targeted history and physical examination provides a working diagnosis for the underlying cause of cyanosis and guides further management and diagnostic testing.

History – Several historical features help determine the cause of cyanosis in children (table 1):

Age – Although respiratory disorders predominate as the cause of central cyanosis in all children, cyanotic congenital heart disease and polycythemia are much more common etiologies for life-threatening central cyanosis in neonates.

Because of the decreased function of enzymatic systems required to reduce methemoglobin, methemoglobinemia is more likely in young infants, especially those with gastroenteritis due to enteric bacterial production of nitrites or other oxidant toxin exposure (table 7). Acrocyanosis and cold exposure are common causes of peripheral cyanosis in otherwise healthy neonates and young infants.

Fever – Fever may be present in children with infectious causes of cyanosis secondary to upper airway obstruction (eg, croup), lower airway disease (eg, pneumonia), or shock (eg, septic shock).

Trauma – Chest wall or upper airway trauma may cause central cyanosis due to lung injury or upper airway obstruction.

Exposures – Smoke inhalation or exposure to other low oxygen environments suggests central cyanosis from decreased inspired oxygen.

Oxidant toxin exposure may lead to methemoglobinemia [13]. Domestic and environmental substances implicated in methemoglobinemia include foods or well water contaminated with nitrates or nitrites, aniline dyes, naphthalene, and certain industrial compounds (nitrobenzenes, nitrous gases, and organic amines) (table 7) [14].

Medications – Blue skin color may occur in patients undergoing treatment with amiodarone. Colloidal silver use can cause argyria, an irreversible blue-gray tinting of the skin [12].

Prior lung disease – Exacerbation of pre-existing lung disease (eg, asthma, bronchopulmonary dysplasia) is a common cause of respiratory distress and central cyanosis in children.

Congenital heart disease – Cyanotic congenital heart disease may explain profound central cyanosis in an otherwise well-appearing child or underlie pulmonary edema or shock in the ill-appearing child.

Neurologic disease – Any neurologic condition that results in decreased respiratory effort can lead to cyanosis. A history of drug or toxin-related respiratory depression, central nervous system lesions, seizures, breath-holding spells, and neuromuscular disease should be pursued.

Physical examination — Cyanosis is always a concerning finding and is often less apparent in the skin of patients with darker pigmentation. For this reason, examination should include the nail beds, tongue, and mucous membranes, which are less affected by pigmentation. Patients with peripheral cyanosis typically have cyanotic nail beds, decreased peripheral perfusion, and cold extremities in conjunction with a pink tongue and oral mucous membranes. Pulse oximetry can assist in identifying cyanosis. Supplemental oxygen is usually indicated when pulse oximetry is <90 percent. Pulse oximetry provides inaccurate readings for patients with certain conditions (eg, sickle cell anemia, methemoglobinemia, or severe anemia). When these conditions are present or suspected, an arterial blood gas is needed to detect hypoxemia. (See "Pulse oximetry", section on 'Falsely low readings'.)

Fever – Fever is often present in cyanotic children with intrinsic pulmonary conditions (eg, pneumonia, bronchiolitis), infectious upper airway obstruction (eg, croup), and septic shock.

Lung examination – Tachypnea is seen in patients with either respiratory or circulatory causes of cyanosis. Similarly, flaring, grunting, and retractions are nonspecific indicators of respiratory distress in the child with cyanosis.

Stridor and suprasternal retractions identify upper airway obstruction. (See 'Upper airway obstruction' above.)

Rales (crackles), asymmetric breath sounds, and/or wheezing suggest lower airway disease, pneumonia, or pulmonary edema. (See 'Intrinsic lung disease' above.)

Clear lung sounds may be present in patients with cyanotic congenital heart disease, early myocarditis, pulmonary embolus, methemoglobinemia, or neurologic conditions associated with hypoventilation (eg, coma, seizures, or muscle weakness).

Traumatic lung injury may have multiple findings including (see 'Impairment of chest wall or lung expansion' above):

Abnormal chest wall movement (eg, a flail segment)

Open, sucking chest wound

Chest wall ecchymosis or abrasions

Subcutaneous air with crepitus

Tracheal deviation

Abnormal breath sounds

Focal tenderness to palpation over ribs, sternum, or scapula

Cardiac examination – Tachycardia frequently accompanies cyanosis in children. Bradycardia is an ominous sign of impending cardiorespiratory collapse.

A cardiac murmur and a second heart sound that is loud or single is heard in many patients with cyanotic structural heart disease (table 5) and/or pulmonary hypertension. (See "Cardiac causes of cyanosis in the newborn".)

Myocardial dysfunction with pulmonary edema is suggested by the presence of a gallop rhythm, palpable cardiac thrill, and/or laterally displaced point of maximal impulse.

Skin examination – Peripheral vasoconstriction with cool extremities is found in children with peripheral cyanosis caused by cold exposure.

Central cyanosis with a slate gray appearance to the skin is characteristic of methemoglobinemia [13].

Dermatologic conditions that may mimic cyanosis are often well demarcated (eg, Mongolian spot, tattoo) or are present at sites of external exposures (eg, blue clothing dye, finger paints).

Ancillary studies — Additional testing in the cyanotic child is frequently necessary to identify the presence and degree of systemic arterial oxygen desaturation and to determine the underlying etiology.

Arterial blood gas – Cyanotic patients with abnormalities in respiration, control of breathing, or circulation have a decreased partial pressure of oxygen (PaO2) in arterial blood. In many patients, pulse oximetry can be used instead of an arterial blood gas to identify and treat cyanosis. However, severely ill children and those whose cyanosis does not readily respond to oxygen warrant measurement of an arterial blood gas.

If the patient has a normal PaO2 and is well-appearing despite central cyanosis, possible etiologies include mild methemoglobinemia, acrocyanosis, polycythemia, cold exposure, or dermatologic etiologies. If the patient is ill-appearing with a normal PaO2, one must evaluate for septic or cardiogenic shock, polycythemia, or severe methemoglobinemia.

In many cases of peripheral cyanosis, central oxygenation is obvious on physical examination, and arterial blood gas determination is unnecessary.

Hematocrit – The hematocrit should be measured in children who appear plethoric or who have signs or symptoms that may be due to polycythemia.

Echocardiography – Infants and children with suspected congenital heart disease warrant emergency echocardiography by a pediatric cardiologist.

Chest radiograph – An abnormal chest radiograph can lead directly to the diagnosis of traumatic lung inflation conditions, intrinsic pulmonary conditions, pulmonary edema, or congenital heart disease (table 5) and/or pulmonary hypertension.

Electrocardiogram – In cyanotic patients with abnormal findings on cardiac examination, an electrocardiogram (ECG) can be very helpful in solidifying a diagnosis of heart disease (table 5) and/or pulmonary hypertension. However, echocardiography is necessary to more specifically identify the cardiac lesion and function.

Methemoglobin level – Direct measurement of methemoglobin should be performed in cyanotic patients with a normal PaO2 in whom cardiac disease has been excluded. Methemoglobinemia is also indirectly suggested by a difference between the calculated oxygen saturation on an arterial blood gas and direct measurement by cooximetry. (See "Methemoglobinemia", section on 'Evaluation and diagnosis (acquired/toxic)'.)

DIAGNOSTIC APPROACH — The approach to the cyanotic child focuses on physical examination, the presence of decreased oxygen saturation, and the results of ancillary studies [15]. Patients with cyanosis should have urgent assessment of pulse oximetry, initial stabilization as needed, and further evaluation as described below. Patients with signs of severe anemia (eg, no color in the palmar crease associated with a hemoglobin <7 g/dL or marked conjunctival or mucosal pallor) may not appear cyanotic despite significant oxygen desaturation.

Respiratory distress – Patients with significant respiratory distress warrant immediate administration of supplemental oxygen along with rapid assessment and emergency management of the airway and breathing (table 8). (See "Acute respiratory distress in children: Emergency evaluation and initial stabilization", section on 'Rapid assessment' and "Acute respiratory distress in children: Emergency evaluation and initial stabilization", section on 'Initial stabilization'.)

If there is no murmur present and the patient is cyanotic, evaluation is focused on a respiratory etiology (table 9), although metabolic, cardiac, and pulmonary vascular problems cannot be entirely dismissed. (See "Causes of acute respiratory distress in children".)

The clinical evaluation may be all that is required to diagnose the etiology of respiratory distress. Diagnostic tests should be used selectively based upon clinical findings and the likelihood that study results will change management (table 10).

Previously healthy patients whose clinical cyanosis and ill appearance does not resolve with supplemental oxygen therapy and respiratory support warrant assessment for methemoglobinemia. (See "Methemoglobinemia", section on 'Clinical presentation (congenital)' and "Methemoglobinemia", section on 'Management (acquired/toxic)'.)

Signs of shock – Ill-appearing children with central or peripheral cyanosis and signs of shock (eg, tachycardia, abnormal perfusion, weak pulses, or hypotension) warrant rapid treatment of compromised circulation (algorithm 4), including management of airway and breathing as needed, and additional evaluation for hypovolemic, septic or cardiogenic shock (algorithm 3) with further targeting of therapy based upon the underlying etiology for shock. (See "Shock in children in resource-abundant settings: Initial management" and "Initial evaluation of shock in children".)

Altered mental status – Cyanotic patients with altered mental status often have decreased oxygen saturation due to disordered control of breathing (eg, traumatic brain injury or acute toxic-metabolic coma) or neuromuscular weakness causing respiratory depression. Such patients typically cannot maintain their airway and warrant rapid sequence intubation (table 11) and mechanical ventilation unless the underlying cause of coma can be rapidly treated medically (eg, dextrose infusion for hypoglycemia, naloxone for opioid overdose, or benzodiazepine administration for seizures). (See "Initiating mechanical ventilation in children", section on 'Ineffective respiration'.)

In addition, transient central cyanosis is a common feature of breath-holding spells and seizures.

Abnormal cardiac examination – A centrally cyanotic patient with an abnormal cardiac examination warrants an electrocardiogram (ECG) and a chest radiograph. An abnormal ECG and/or chest radiograph suggests congenital heart disease (table 5) or heart failure. However, a normal ECG does not exclude certain lesions such as tetralogy of Fallot, truncus arteriosus, and transposition of the great arteries. In addition, patients with marked pulmonary hypertension may also have an abnormal cardiac examination with severe cyanosis. In infants with or who have a clinical suspicion for a ductal-dependent congenital heart defect, prostaglandin E1 (alprostadil) should be administered until a definitive diagnosis or treatment is established by echocardiography. (See "Diagnosis and initial management of cyanotic heart disease in the newborn" and "Pulmonary hypertension in children: Classification, evaluation, and diagnosis".)

Central cyanosis, well-appearing – Infants with polycythemia and mild methemoglobinemia (<20 percent methemoglobin) have central cyanosis and normal or near normal oxygen saturation. (See "Methemoglobinemia", section on 'Clinical presentation (congenital)'.)

Children with cutaneous mimics of cyanosis (eg, blue-colored clothing dyes on the skin) will also be well-appearing with a normal oxygen saturation. (See 'Mimics of cyanosis' above.)

Peripheral cyanosis, well-appearing – Peripheral cyanosis in the well-appearing neonate is typically due to acrocyanosis and mild to moderate cold exposure. In the older child, Raynaud phenomenon (RP) is a specific type of acrocyanosis that causes white, blue, and red discoloration of the fingers and/or the toes after exposure to changes in temperature (cold or hot) or emotional events. (See "Clinical manifestations and diagnosis of Raynaud phenomenon", section on 'Clinical features' and "Approach to cyanosis in the newborn", section on 'Peripheral versus central cyanosis'.)

SUMMARY AND RECOMMENDATIONS

Definitions – Central cyanosis is evident when systemic arterial concentration of deoxygenated hemoglobin (Hb) in the blood exceeds 5 g/dL (3.1 mmol/L) (oxygen saturation ≤85 percent). Of note, cyanosis may not be readily detectable in patients with severe anemia (eg, Hb <5 g/dL [3.1 mmol/L]) despite significant oxygen desaturation. Patients with peripheral cyanosis have a normal systemic arterial oxygen saturation but increased deoxygenated blood on the venous side of the capillary beds due to impaired capillary perfusion. (See 'Definitions' above.)

Causes – Cyanosis may be caused by a wide range of disorders, but it usually stems from one of several common disorders of childhood and adolescence (table 1). Respiratory causes are most often to blame in previously healthy children with the new onset of central cyanosis. (See 'Life-threatening causes' above and 'Other causes' above.)

Rapid assessment and stabilization – Patients who appear cyanotic with respiratory distress or poor perfusion warrant prompt administration of supplemental oxygen, measurement of pulse oximetry, and further support of airway, breathing, and circulation. (See 'Rapid assessment and stabilization' above.)

Initial evaluation – A targeted history (table 1) and physical examination that focuses on the lungs, heart, and skin provide a working diagnosis for the underlying cause of cyanosis and guides further management and diagnostic testing. Distinguishing peripheral from central cyanosis is of great importance. Patients with central cyanosis require further diagnostic testing based upon clinical findings and the likelihood that study results will change management (table 10). (See 'Initial evaluation' above.):

Diagnostic approach – Patients with cyanosis should have further treatment and evaluation as follows (see 'Diagnostic approach' above):

Respiratory distress – In addition to supplemental oxygen, patients with significant respiratory distress and abnormal lung findings warrant emergency management of the airway and breathing (table 8). Previously healthy patients with a normal cardiac examination whose clinical cyanosis and ill appearance do not resolve with supplemental oxygen therapy and respiratory support warrant assessment for methemoglobinemia. (See "Acute respiratory distress in children: Emergency evaluation and initial stabilization" and "Methemoglobinemia".)

Signs of shock – Ill-appearing children with central or peripheral cyanosis and signs of shock (eg, tachycardia, abnormal perfusion, weak pulses, or hypotension) warrant rapid treatment of compromised circulation (algorithm 4), including management of airway and breathing as needed, and additional evaluation for hypovolemic, septic or cardiogenic shock (algorithm 3) with further targeting of therapy based upon the underlying etiology for shock. (See "Shock in children in resource-abundant settings: Initial management" and "Initial evaluation of shock in children".)

Altered mental status – Cyanotic patients with altered mental status often have decreased oxygen saturation due to disordered control of breathing (eg, traumatic brain injury or acute toxic-metabolic coma) or neuromuscular weakness causing respiratory depression. Such patients typically cannot maintain their airway and warrant rapid sequence intubation (table 11) and mechanical ventilation unless the underlying cause of coma can be rapidly treated medically (eg, dextrose infusion for hypoglycemia, naloxone for opioid overdose, or benzodiazepine administration for seizures). (See "Acute toxic-metabolic encephalopathy in children", section on 'Management approach' and "Opioid intoxication in children and adolescents", section on 'Naloxone'.)

Abnormal cardiac examination – A centrally cyanotic patient with an abnormal cardiac examination warrants an electrocardiogram (ECG) and a chest radiograph. An abnormal ECG and/or chest radiograph suggests congenital heart disease (table 5) or heart failure. In infants with or who have a clinical suspicion for a ductal-dependent congenital heart defect, prostaglandin E1 (alprostadil) should be administered until a definitive diagnosis or treatment is established. (See "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Specific congenital heart disease measures'.)

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