Pediatric Respiratory Acidosis

Respiratory acidosis occurs when the arterial partial pressure of carbon dioxide (P_a CO₂) is elevated above the normal range (>44 mmHg) leading to a blood pH lower than 7.35. ^[1] By definition, the diagnosis of respiratory acidosis requires measurement of P_a CO₂ and pH. When the diagnosis is made, the underlying cause should be thoroughly investigated.

Respiratory acidosis is not a specific disease. Instead, it is an abnormality that results from an imbalance between production of carbon dioxide by the body and its excretion by the lungs, owing to inadequate minute ventilation. Low minute ventilation can occur anywhere along the continuum of the respiratory system, from central initiation of ventilation to appropriate gas exchange at the capillary-alveolar interface.

Respiratory acidosis may result from an acute or chronic process and may occur at any age. Acute respiratory acidosis can be life-threatening when a sudden and sharp increase in P_a CO₂ is associated with severe hypoxemia and acidemia. In contrast, chronic respiratory acidosis (>24 h) is characterized by a gradual and sustained increase in P_a CO₂.

P_a CO₂ is directly proportional to carbon dioxide production and inversely proportional to alveolar ventilation. Alveolar ventilation is responsible for carbon dioxide elimination and is calculated when the respiratory rate is multiplied by the difference between the tidal volume and the physiologic dead space. Respiratory acidosis results primarily when alveolar ventilation is decreased or when carbon dioxide production is increased.

Many clinical scenarios contribute to inadequate removal of carbon dioxide from the blood. A few examples include depressed central respiratory drive, acute paralysis of the respiratory muscles, acute parenchymal lung and airway diseases, and increased dead space or wasted ventilation. If breathing ceases, arterial carbon dioxide increases further at a rate of 3-6 mmHg/min.

In other cases, hypercarbia gradually develops as it does in a progressive neuromuscular disease, in worsening scoliosis leading to restrictive lung disease, or in chronic pulmonary diseases. In this scenario, persistently elevated P_a CO₂ leads to effective compensatory mechanisms.

In rare instances, increased carbon dioxide production can exceed the patient’s ability to compensate, leading to respiratory acidosis. This situation occurs during hypermetabolic states, such as extensive burn injury, malignant hyperthermia, or fever when the patient is unable to increase minute ventilation. When P_a CO₂ rises acutely, other organ systems are affected.

General physiologic and metabolic effects

Carbon dioxide is carried in the blood in 3 forms: dissolved gas, bicarbonate, and protein bound. It diffuses freely across cell membranes, and this diffusion allows it to be efficiently transported from peripheral tissues to the lungs for excretion. When hypercapnia is present, this same property causes excess carbon dioxide to shift intracellularly and decrease intracellular pH.

Carbon dioxide (CO₂) normally combines with water (H₂ O) to form carbonic acid (H₂ CO₃), which then dissociates to release hydrogen ion (H⁺) and bicarbonate (HCO₃^–), as in the following equation:

CO₂ + H₂ O ↔ H₂ CO₃ ↔ H⁺ + HCO₃^–

When respiratory acidosis is present, excess carbon dioxide increases H₂ CO₃ formation, shifting the equilibrium of the equation toward the accumulation of hydrogen ions.

The body has several compensatory systems to minimize the decrease in pH. Intracellular proteins and inorganic phosphates are initially the most effective buffers. The most important blood buffer is hemoglobin. Deoxygenated hemoglobin readily accepts hydrogen ions to prevent substantial changes in pH, and approximately 10% of carbon dioxide is bound to hemoglobin to form carbaminohemoglobin.

Cellular buffering elevates plasma bicarbonate (HCO₃^–) only slightly and causes plasma HCO₃^– to increase by 1 mEq/L for every 10-mmHg increase in P_a CO₂.

Renal compensation for sustained hypercapnia begins in 6-12 hours, but 3-5 days pass before maximal compensation occurs. The kidneys increase excretion of hydrogen ions (predominantly in the form of ammonium [NH₄⁺]) and chloride while retaining HCO₃^– and sodium (Na⁺). This process increases the plasma HCO₃^– concentration by approximately 3.5-4 mEq/L for every 10-mmHg increase in P_a CO₂. As a result, additional NaHCO₃^– is available to buffer free hydrogen ions.

Because neonates and infants have a relatively large amount of hemoglobin and interstitial fluid for their body weight, their increase in plasma HCO₃^– concentrations and decrease in plasma hydrogen ion concentrations are greater than those of older children.

Chemoreceptors in the brainstem and in the carotid body rapidly detect changes in P_a CO₂. Carbon dioxide is a potent respiratory stimulant, and elevated levels lead to an increase in minute ventilation to excrete increased quantities of carbon dioxide and normalize the pH. However, this effect is attenuated if the carbon dioxide level remains elevated for more than several hours. In general, acute respiratory acidemia causes no change or only a slight increase in extracellular potassium and phosphate levels.

Respiratory effects

When a patient develops respiratory acidosis while breathing air, the alveolar gas equation predicts that hypoxemia will develop. The alveolar gas equation (Equation 2) states that the alveolar partial pressure of oxygen (P_A O₂) is equal to the partial pressure of inspired oxygen (P_I O₂) minus the quantity of alveolar partial pressure of carbon dioxide (P_A CO₂) divided by the respiratory quotient (RQ), as follows:

P_A O₂ = P_I O₂ – (P_A CO₂/RQ)

The RQ is the ratio of the volume of carbon dioxide expired to the volume of oxygen consumed by an organism. In steady-state conditions, the human body produces carbon dioxide at a rate of approximately 200 mL/min and consumes oxygen at a rate of 250 mL/min; therefore, the RQ is about 0.8. If the RQ is rounded to 1, the alveolar gas equation is reduced as follows:

P_A O₂ = P_I O₂ – P_A CO₂

The P_I O₂ is equivalent to the difference between the barometric pressure (PB) and the partial pressure of water vapor (PH₂ O) multiplied by the fraction of inspired oxygen (F_I O₂), as follows:

P_I O₂ = F_I O₂ (PB – PH₂ O)

In view of this equivalence, the alveolar gas equation may be expressed as follows:

P_A O₂ = F_I O₂ (PB – PH₂ O) – P_A CO₂

If this equation is rearranged, P_A CO₂ is seen to be ultimately dependent on the level of inspired oxygen, as follows:

P_A CO₂ = F_I O₂ (PB – PH₂ O) – P_A O₂

Because PB at sea level is 760 mmHg and PH₂ O in the atmosphere is 47 mmHg, when a person is breathing air (F_I O₂ = 0.21), the sum of P_A CO₂ and P_A O₂ adds up to approximately 150 mmHg, as follows:

P_A O₂ = 0.21 (760 mmHg – 47 mmHg) – P_A CO₂

P_A O₂ = 149.7 mmHg – P_A CO₂

P_A O₂ + P_A CO₂ = 149.7 mmHg

In the acute setting, P_a CO₂ values higher than 80-90 mmHg while the patient is breathing air are life-threatening because of the associated hypoxemia. When P_a CO₂ exceeds 100 mmHg, an iatrogenic or an acute-on-chronic condition is present. Hypoventilation can lead to clinically significant hypercarbia without hypoxemia only if a patient is breathing supplemental oxygen.

Consider the case of a child in the pediatric ICU who is breathing supplemental oxygen given by a mask (F_I O₂ = 0.80). The child has partial airway obstruction or central hypoventilation secondary to narcotic administration. Supplemental oxygen allows an increased P_a CO₂ given the principle of the alveolar gas equation without arterial desaturation. The profound acidemia associated with the hypercapnia can lead to bradycardia, the first sign of the problem.

Some have used the term supercarbia to describe scenarios in which P_a CO₂ is greater than 150 mmHg. In the example just given, the alveolar gas equation yields the following results:

P_A O₂ = 0.80 (760 mmHg – 47 mmHg) – 150 mmHg = 420 mmHg

Hypercapnia is associated with increased pulmonary vascular resistance. However, the absolute carbon dioxide level does not have the greatest effect on pulmonary vascular tone; rather, decreased serum pH most likely mediates the effect. When hypercapnia is combined with acidemia and hypoxemia, the resultant pulmonary vasoconstriction can be severe and life-threatening.

Cardiovascular effects

Acute respiratory acidosis increases epinephrine and norepinephrine release. Several studies have shown that acute moderate hypercapnia produces a hyperdynamic state defined by tachycardia, high cardiac output, and reduced systemic vascular resistance. In experimental models, cardiac contractility decreases with acute respiratory acidosis.

Some have proposed that the rapid development of intracellular acidosis interferes with the interaction between calcium and myofilaments. This adverse effect of acute moderate hypercapnia on myocardial contractility has not been seen in adult human studies. With severe acidemia at a serum pH of less than 7.20, the catecholamine response is blunted, and this change may contribute to a state of decreased cardiac output.

Supraventricular arrhythmias are increased in the presence of a severe respiratory acidosis, but these problems are most likely caused by concomitant hypoxemia, electrolyte shifts, and increased catecholamines rather than by a direct hypercapnia-induced cardiac irritability. Cardiovascular symptoms of respiratory acidosis are often difficult to discern, because of the concomitant effects of hypoxemia and metabolic acidosis.

Inhaled carbon dioxide gas can be administered to preoperative neonates with hypoplastic left heart syndrome and low systemic cardiac output associated with high arterial saturations (> 85%). P_a CO₂ is maintained above 40 mmHg, and the patient is mechanically ventilated, sedated, and paralyzed to prevent a compensatory tachypnea.

Inspired 3% carbon dioxide improved cerebral oxygenation measured by near-infrared spectroscopy and mean arterial pressure in preoperative neonates with single ventricles. ^[2] Experimental evidence also suggests that hypercarbia may have some beneficial effects at assisting the mechanical recovery of hypoxic injured myocytes; however, further human clinical correlation is still needed.

Neurologic effects

The clinical manifestations of acute hypercapnia are primarily neurologic. Acute elevations of P_a CO₂ above 60 mmHg cause confusion and headache. A P_a CO₂ higher than 70 mmHg produces a hypercapnic encephalopathy or carbon dioxide narcosis manifesting as drowsiness, depressed consciousness, or coma.

However, the neurologic changes associated with hypercarbia are reversible. In one report, children without hypoxemia but with severe respiratory acidosis (lowest pH was 6.76, and highest P_a CO₂ was 269 mmHg) did not have long-term adverse neurologic or developmental effects. ^[3]

Acute elevations in P_a CO₂ increase intracranial pressure by increasing cerebral blood flow (CBF) and cerebral blood volume secondary to vasodilatation. With a P_a CO₂ of 40-80 mmHg, CBF increases by 1-2 mL per 100 g of brain per minute for each 1-mmHg increase in P_a CO₂. A P_a CO₂ of 80 mmHg or more produced a maximal increase in CBF in anesthetized animals. During sustained hypercapnia, CBF returns to baseline after about 36 hours as brain extracellular pH is corrected.

In acute hypercapnia, carbon dioxide rapidly diffuses across the blood-brain barrier, which leads to accumulation of hydrogen ions in the cerebrospinal fluid (CSF). This change in pH is rapidly detected by the brainstem, causing rapid compensation (ie, increased elimination of carbon dioxide by the lungs). If the CSF acidosis persists for several hours, HCO₃^– levels in the CSF gradually increase to normalize the pH. In general, the response of the cerebral circulation to P_a CO₂ increases during development from the neonatal period to adulthood.

Causes of respiratory acidosis related to central nervous system (CNS) respiratory drive suppression include the following:

• Trauma

• Infection (eg, encephalitis, meningitis, or respiratory syncytial virus infection)

• Neoplasm

• Stroke

• Hypoxia

• Toxins, overdose (eg, of narcotics or alcohol) (Tramadol overdose appears to raise the risk of apnea in children with respiratory acidosis. ^[4]  There also appears to be an increased risk of respiratory acidosis in newborns in association with premedication use of atropine in general anesthesia for ductal ligation, particularly when used in conjunction with ketamine. ^[5] )

• Seizures - Postictal state

• Spinal causes (eg, trauma to C3-C5 or impairment of phrenic nerve function)

Nerve-related causes include the following:

• Spinal muscular atrophy

• Guillain-Barré syndrome

• Poliomyelitis

• Phrenic nerve trauma

Neuromuscular junction–related causes include the following:

• Myasthenia gravis

• Botulism

• Neuromuscular blockade

• Muscle causes (eg, muscular dystrophy)

Airway-related causes include the following:

• Loss of CNS control (eg, from brain injury, toxin or overdose, trauma, angioedema, tonsillar adenoid hypertrophy, thermal or chemical burn, foreign body, pharyngeal abscess, epiglottitis, or paralyzed vocal cords)

• Congenital lesions (eg, subglottic stenosis, laryngomalacia, craniofacial abnormalities, tracheal rings, or vascular slings)

• Laryngotracheobronchitis (croup)

• Neoplasm, mediastinal mass

• Bronchiolitis

• Asthma

Acute lung injury–related causes include the following:

• Pneumonia

• Pulmonary edema

• Lung contusion

• Bronchiolitis

Chronic lung disease–related causes include the following:

• Bronchopulmonary dysplasia

• Cystic fibrosis

• Chronic bronchitis

• Chronic obstructive pulmonary disease

Causes related to chest wall restriction and reduced respiratory compliance include the following:

• Flail chest

• Pneumothorax

• Pleural effusions

• Kyphoscoliosis

• Abdominal distention

Causes related to increased carbon dioxide production include the following:

• Malignant hyperthermia

• Extensive burns

• Overfeeding

The effects of respiratory acidosis vary according to the severity, the duration, the underlying disease, and the associated arterial saturation. Hypercapnic neurologic changes are reversible with no residual effect. The most important consideration may be the degree to which hypercarbia or the underlying disease adversely affects arterial oxygenation.

The prognosis depends on the underlying etiology. Respiratory acidosis can be an acute and transient event with no long-term sequelae if it is not associated with hypoxemia (eg, seizure and treatment-associated hypoventilation). Respiratory acidosis may be associated with a chronic disease that has associated morbidity (eg, asthma or Duchenne muscular dystrophy). It may also be the sign of an irreversible progressive disease that leads to death (eg, idiopathic pulmonary hypertension). Neuroapoptosis and brain damage are significant risks in newborns with respiratory acidosis at birth. ^[6]